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REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY ISBN- 13: 978–0–323–04054–9

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Notice
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge,
changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most
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recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the
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The Publisher
Library of Congress Cataloging-in-Publication Data
Alvero, Ruben.
Reproductive endocrinology and infertility : the requisites in obstetrics and gynecology/Ruben Alvero, William D. Schlaff.—1st ed.
p. cm.
ISBN 0–323–04054–3
1. Endocrine gynecology. 2. Obstetrical endocrinology. 3. Infertility. I. Schlaff, William D. II. Title
RG159.A48 2007
618.1—dc22 2006048137
Acquisitions Editor: Rebecca Gaertner

Publishing Services Manager: Frank Polizzano
Senior Project Manager: Peter Faber
Design Direction: Steven Stave
Printed in the United States of America.
Last digit is the print number: 9 8 7 6 5 4 3 2 1

Dr. Alvero dedicates this book to
Karen, Erika, Alicia, and William.
Dr. Schlaff dedicates this book to
Lorraine, Daniel, Maura, and Julia.
CONTRIBUTORS
Ruben Alvero, MD
Associate Professor, Advanced Reproductive Medicine, Department
of Obstetrics and Gynecology, University of Colorado Health Sciences
Center, Aurora, Colorado
Alicia Armstrong, MD
Combined Federal Fellowship in Reproductive Endocrinology, Walter
Reed Army Medical Center; National Naval Medical Center; Uniformed
Services University of the Health Sciences F. Edward Hébert School of
Medicine; and National Institutes of Health, Bethesda, Maryland
vii
Linda A. Barbour, MD, MSPH, FACP
Associate Professor, Division of Endocrinology, Metabolism, and Diabetes,
Departments of Medicine and Obstetrics and Gynecology, University of
Colorado Health Sciences Center, Aurora, Colorado
Bruce R. Carr, MD
Paul C. MacDonald, MD Distinguished Chair and Director, Division of
Reproductive Endocrinology and Infertility, Department of Obstetrics
and Gynecology, UT Southwestern Medical School, Dallas, Texas
William H. Catherino, MD, PhD
Assistant Professor, Department of Obstetrics and Gynecology, Uniformed
Medicine; Combined Federal Fellowship in Reproductive Endocrinology
and Infertility, National Institutes of Health, Bethesda, Maryland
Seth G. Derman, MD
Clinical Assistant Professor of Obstetrics, Gynecology, and Reproductive
Sciences, University of Medicine and Dentistry of New Jersey–Robert
Wood Johnson Medical School, New Brunswick; Director, Reproductive
Endocrinology and IVF Program, Princeton IVF, Delaware Valley OB/GYN
and Infertility Group, Lawrenceville, New Jersey
Sheri M. Dey, MD
Division of Urology, Department of Surgery, University of Colorado
Health Sciences Center, Denver, Colorado
Jani R. Jensen, MD, MS
Fellow in Reproductive Endocrinology and Infertility, UT Health Sciences
Center at San Antonio, San Antonio, Texas
Shahryar K. Kavoussi, MD, MPH
Division of Reproductive Endocrinology and Infertility, Department of
Obstetrics and Gynecology, University of Michigan Medical School,
Ann Arbor, Michigan
Contributors
Andrew J. Levi, MD
Attending, Division of Reproductive Endocrinology and Infertility,
Bridgeport Hospital, Bridgeport, Connecticut
Richard Scott Lucidi, MD
Chief, Reproductive Endocrinology Infertility, Department of
Obstetrics and Gynecology, Tripler Army Medical Center, Honolulu,
Hawaii
Kirsten J. Lund, MD
Associate Professor, Department of Obstetrics and Gynecology,
University of Colorado Health Sciences Center, Aurora; Staff Physician,
University of Colorado Hospital, Denver, Colorado
Deborah L. Manzi-Smith, MD
viii Director, Assisted Reproduction, Advanced Reproductive Medicine,
Department of Obstetrics and Gynecology, University of Colorado Health
Sciences Center, Aurora, Colorado
Randall B. Meacham, MD
Associate Professor , Division of Urology, Department of Surgery,
University of Colorado Health Sciences Center, Denver, Colorado
Jesse N. Mills, MD
Chief Resident, Division of Urology, Department of Surgery, University of
Colorado Health Sciences Center, Denver, Colorado
Randall Odem, MD
Professor and Chief, Division of Reproductive Endocrinology and
Infertility, Department of Obstetrics and Gynecology, Washington
University in St. Louis School of Medicine, St. Louis, Missouri
Mark Payson, MD
Combined Federal Fellowship in Reproductive Endocrinology, Walter
Reed Army Medical Center; National Naval Medical Center; Uniformed
Medicine; and National Institutes of Health, Bethesda, Maryland
Rocio I. Pereira, MD
Instructor in Medicine, Division of Endocrinology, Diabetes, and
Metabolism, Department of Medicine, University of Colorado School
of Medicine at Denver and Health Sciences Center, Aurora; Associate
Investigator, Denver VA Medical Center, Denver, Colorado
William D. Petok, PhD
Clinical Assistant Professor, University of Colorado Health Sciences
Center, Denver, Colorado
John M. Randolph, Jr., MD
Professor and Director, Division of Reproductive Endocrinology and
Infertility, Department of Obstetrics and Gynecology; Associate Research
Scientist, Reproductive Sciences Program, University of Michigan
Medical School, Ann Arbor, Michigan
Contributors
Randal D. Robinson, MD
Associate Professor of Obstetrics and Gynecology, Uniformed Services
University of Health Sciences, Bethesda, Maryland; Chairman and
Residency Program Director, Department of Obstetrics and Gynecology,
San Antonio Uniformed Services Health Education Consortium, Wilford
Hall Medical Center, Lackland AFB, and Brooke Army Medical Center,
San Antonio, Texas
Stacey Leigh Rubin, MD
Division of Reproductive Endocrinology and Infertility, Department of
Obstetrics and Gynecology, Washington University in St. Louis School of
Medicine, St. Louis, Missouri
William D. Schlaff, MD
Professor and Chief, Section of Reproductive Endocrinology and ixix
Infertility, University of Colorado Health Sciences Center, Aurora,
Colorado
Stephen M. Scott, MD
Associate Professor, Department of Obstetrics and Gynecology, University
of Colorado Health Sciences Center; Chairman, Department of Pediatrics
and Adolescents, The Children’s Hospital, Denver, Colorado
David B. Seifer, MD
Professor of Obstetrics, Gynecology and Reproductive Sciences, Mount
Sinai School of Medicine, New York, New York; Co-Director, Genesis
Fertility And Reproductive Medicine, Maimonides Medical Center,
Brookyln, New York
Michael D. Wittenberger, MD
Assistant Professor, Department of Obstetrics and Gynecology, Uniformed
Medicine; Combined Federal Fellowship in Reproductive Endocrinology
and Infertility, National Institutes of Health, Walter Reed Medical Center,
Bethesda, Maryland
Craig A. Witz, MD
Associate Professor and Chief, Reproductive Endocrinology and Infertility,
Department of Obstetrics and Gynecology, University of Texas Health
Science Center at San Antonio, San Antonio, Texas
Lynda J. Wolf, MD
Assistant Professor and Director, Reproductive Endocrinology and
Infertility, Department of Obstetrics and Gynecology, Medical University
of Ohio at Toledo; Director, Fertility Center, Department of Obstetrics
and Gynecology, Richard D. Ruppert Health Center, Toledo, Ohio
The Requisites in Obstetrics
and Gynecology
FOREWORD
We are living in an era of rapidly changing technologies, in which techni-
cal and now many medical services can be performed remotely and often
impersonally. At the same time, the cultures of medical practice and train-
ing have been radically transformed, as resident work rules, the use of new xi
procedures and equipment, and changing perspectives on the practice of
medicine have evolved quite significantly over the past two decades. As a
consequence, the overall approach to medical education, the slower rate
of increasing responsibilities given to residents during their training, and
the tolerance for non-standardized approaches to patient care have likewise
changed, with both positive and negative consequences. Thus, the basics,
the “requisites,” needed to operate in the current environment likewise have
evolved. In this series, the editors and chapter authors crystallize the founda-
tions needed for independent practitioners to survive and, in fact, thrive in
the current medical climate. We hope readers will view the materials as the
basis for evolving sophistication in the practice of obstetrics and gynecology.
Mark I. Evans, MD
PREFACE
It has been a wonderful experience for us to complete the first edition of
Reproductive Endocrinology and Infertility for the Requisites in Obstetrics and
Gynecology series. We have brought together an outstanding set of practi-
tioners and academicians to cover the various topics in this rapidly growing
field, and we feel fortunate to have worked with them.
The first half of the book broadly covers normal physiology and patho-
physiology not related to infertility. Some basic science is necessary to under-
stand this area, and the first chapter addresses steroids and prostaglandins,
which play an important role in the normal menstrual cycle. The normal xiii
menstrual cycle, as well as normal pubertal development, is then reviewed,
along with some of the aberrations that occur during adolescence. Special
focus is given to amenorrhea, which may be a primary disorder or can
occur after normal female cyclicity has been established. Polycystic ovarian
syndrome is the most common endocrinopathy in women of reproductive
age, so, along with other hyperandrogenic disorders, it gets its own chapter.
Abnormal uterine bleeding is one of the most common causes for visits to
the gynecologist’s office, and this is ably addressed in its own chapter. As
the population ages, the issues faced by menopausal women have moved
to the forefront of society, and the climacteric and osteoporosis each are
considered in their own chapters. Human sexuality is an important yet sur-
prisingly little-recognized aspect of reproductive life, and it too gets ample
treatment in this book.
Infertility is a critical area for most reproductive endocrinologists. With
one in eight couples suffering from this disorder, this probably is the most
common reason to visit a reproductive endocrinologist. An entire chapter is
devoted to evaluating the infertile female, and then another to male factor
infertility. Ovulatory dysfunction is related to polycystic ovarian syndrome
but is reemphasized in its own chapter. Anatomic infertility and endome-
triosis are similarly related, but each receives separate treatment, to ensure
that the nuances are amply considered.
With more women delaying childbearing to pursue careers, diminished
ovarian reserve is an increasingly important infertility diagnosis, and it is
incumbent on the practitioner to adequately counsel patients in this com-
plicated and emotional area. Equally trying for the affected couple is recur-
rent pregnancy loss, and this topic also receives its own chapter. Finally,
assisted reproductive technologies constitute a mainstay of treatment for
the infertile couple regardless of their diagnosis. Indeed, greater than 1% of
all babies born in the United States now come from in vitro fertilization, so
this critical treatment modality gets its own chapter as well.
We hope that all of these chapters will provide the reader with a com-
prehensive view of the field of reproductive endocrinology and infertility.
Although a subspecialty of obstetrics and gynecology, this field surfaces
Preface
very commonly in many clinical practices, including family medicine, inter-

nal medicine, and of course obstetrics and gynecology.
This book is the result of an impressive effort by the contributing chap-
ter authors, and our jobs were greatly simplified by the high quality of the
product that they submitted. We would like to thank them for their efforts.
Finally, we would like to thank our families for their support throughout this
process.
xiv
1
STEROIDS AND
PROSTAGLANDINS
Shahryar K. Kavoussi and John M. Randolph, Jr.
DEFINITIONS
Steroids A family of chemical compounds with a structure consisting of three 3
6-carbon rings and an adjoined 5-carbon ring
Pregnanes A group of steroids, including progestins, glucocorticoids, and
mineralocorticoids, with a 21-carbon structure
Androstanes A group of steroids, consisting primarily of androgens, with a 19-carbon
structure
Estranes A group of steroids, consisting primarily of androgens, with an
18-carbon structure
Prostaglandins Fatty acid–derived compounds, containing 20 carbons in the basic
structure, that have a multitude of tissue effects
STEROIDS
The main classes of steroid hormones are progestins, androgens, estrogens,

glucocorticoids, and mineralocorticoids. They are pervasive in nature, pres-
ent in animal and plant systems, and integral to homeostasis and physiology
in humans. Based on structure and receptor activity, steroid hormones are
lipophilic compounds that affect various functions in different organ sys-
tems in an endocrine, autocrine, paracrine, or intracrine fashion. The basic
structural unit of a steroid is termed perhydrocyclopentaphenanthrene. This
steroid “nucleus” is composed of three 6-carbon rings (phenanthrene) and
an adjoining 5-carbon ring (cyclopentane).
The various natural steroid hormones are produced via a series of inter-
related pathways. Acetate (2 carbons) molecules undergo a complex series
of reactions to produce cholesterol (27 carbons), the essential structural
foundation that is modified to yield steroid hormones. The synthesis of cho-
lesterol from acetate is performed by all of the organs that produce steroids,
with the exception of the placenta. Sex steroids, mineralocorticoids, and glu-
cocorticoids are end products that are characterized by a specified number
of carbons with side chain carbons added to the steroid nucleus. Pregnanes
(progestins, glucocorticoids, and mineralocorticoids) have 21 carbons,
androstanes (androgens) have 19 carbons, and estranes (estrogens) have
Reproductive Endocrinology and Infertility
18 carbons (Fig. 1-1). The enzymes that facilitate the reactions in the steroid
pathways are members of the cytochrome P-450 family.
Physiology The ovaries, adrenals, and placenta function as the major organs that produce
and Clinical steroids in women. The ovaries produce estrogens, progestins, and androgens.
Presentation Because of a lack of the enzymes 21α-hydroxylase, 11β-hydroxylase, and 18-
hydroxylase, ovaries do not produce glucocorticoids or mineralocorticoids.
The adrenal glands have limited amounts of the enzyme aromatase to convert
androgens to estrogens and produce lesser amounts of estrogen.
The main androgens synthesized by the ovaries are testosterone and andro-
stenedione, a portion of which is secreted as androgen and most of which is
converted to estradiol and estrone. The theca-granulosa “two-cell system”
4 accounts for the production of these steroids. The production of androgen
occurs in the theca cell, where luteinizing hormone (LH) acts on its recep-
tor at the cell surface, activating cyclic adenosine monophosphate (cAMP).
cAMP acts on cholesterol to produce androstenedione, some of which is
converted to testosterone. These two androgens diffuse out of the theca cell
and cross the adjacent basement membrane into the granulosa cell, where
aromatase catalyzes the conversion of androstenedione to estrone and tes-
tosterone to estradiol.
The transport of lipophilic steroids through the bloodstream is predomi-
nantly through binding to hydrophilic proteins, such as steroid-binding
globulins and albumin. Sex hormone–binding globulin (SHBG) is a β-globu-
lin that binds most estradiol and testosterone molecules in the bloodstream.
Figure 1-1
Basic steroid C27

structures. Cholesterol
C21
Progesterone
C19
Testosterone
Androstenedione
C18
Estrone
Estradiol
Estriol
Steroids and Prostaglandins
Table 1-1
Fractions of Bound SHBG Albumin Free Hormone
and Unbound
Estrogen and Estrogen 69% 30% 1%
Testosterone Testosterone 69% 30% 1%
SHBG, sex hormone–binding globulin.
Albumin binds with less affinity to most of the remaining circulating hor-
mone. Corticosteroid-binding globulin (CBG) binds to progesterone and corti-
costeroids. Free, unbound hormone, which is the biologically active fraction,
is present in the bloodstream in relatively small quantities (Table 1-1).
Although the percentage of free, active hormone seems low, changes in
the concentration of SHBG can produce a dramatic effect in the relative lev- 5
els of unbound hormone, exerting a profound physiologic effect. As listed in
Table 1-2, various physiologic and disease processes can affect the concen-
tration of SHBG. Weight gain may modestly decrease SHBG levels, result-
ing in an increase in free androgen from 1% to 2%. This seemingly subtle
increase may manifest as hirsutism as a result of a twofold increase in free
androgen levels. In such a scenario, it may be important to measure the free
androgen concentrations because total androgen levels may not reflect a
clinically significant increase if hirsutism is due to decreased SHBG levels.
Hormones that are transported in the bloodstream produce their biologic
effects at target cells in various organ systems. Each class of steroid hormone
has a corresponding steroid receptor (or receptors). In contrast to glycopro-
tein hormones, which bind to cell-surface receptors, steroid hormones tra-
verse cell membranes via simple diffusion and interact with receptors located
within the cell. It is believed that estrogens, androgens, and progesterone
bind to steroid receptors within the nucleus. Glucocorticoids and mineralo-
corticoids bind to steroid receptors in the cytoplasm and subsequently are
transported to the nucleus.
When a steroid is transported to the cell nucleus as part of a hormone-
receptor complex, it binds to DNA hormone response elements, and tran-
scription of mRNA is initiated. This interaction leads to changes in the DNA
that result in effects at many levels, including an increased affinity to bind
the remaining available estrogen and an amplification of the responsive-
ness of the progesterone receptor gene. Antiestrogens, such as the triphen-
ylethylene clomiphene citrate, have the opposite effect on estrogen activity.
They bind to estrogen receptors and result in the interaction with hormone
response elements, but minimal transcription occurs, and the affinity of
Table 1-2
Physiologic and Increase SHBG Decrease SHBG
Disease Processes
and Effects on Sex Estrogen use/hypersecretion Testosterone use/hypersecretion
Hormone–Binding Thyroid hormone use/hypersecretion Hypothyroidism
Globulin (SHBG) Pregnancy Obesity/polycystic ovary syndrome
Anorexia nervosa Corticosteroid use/hypersecretion
DNA to available estrogen is decreased. Conformational changes may acti-

vate other hormone response elements or corepressors at the level of the
hormone-receptor complex and DNA.
Estrogens and Estrone (E1) is produced in the ovary by the aromatization of androstene-
Estrogen dione, after which estrone can be secreted or converted to estradiol in the
Receptors granulosa layer. Estrone possesses one-tenth the potency of estradiol but is
produced in much greater quantities. Estrone also is produced in skin, mus-
cle, and adipose tissue by the peripheral conversion of circulating andro-
stenedione.
Estradiol (E2) is the most potent estrogen but is produced in much smaller
amounts than estrone. Estradiol is secreted by the ovary and can be syn-
6 thesized by the conversion of androstenedione to testosterone, which is
quickly aromatized. In addition, androstenedione can be aromatized to
estrone, which is secreted from the ovary and can be converted to estradiol
peripherally.
Estriol (E3) is one-one hundredth as potent as estradiol and is a metabolic
by-product of estrone and estradiol inactivation. Estriol also is a product of
the placenta during pregnancy, the only time when estriol is secreted and
known to be clinically significant. Its synthesis and measured levels provide
indirect evidence of an intact fetoplacental unit. Estriol also is measured in
conjunction with other markers prenatally to assess risk for chromosomal
abnormalities. Levels are decreased in conditions such as Down syndrome.
Estrogens have various clinical effects on multiple organ systems. Some of
these physiologic and pathologic processes depend on the stage of a woman’s
life; the major processes are listed in Table 1-3.
There are at least two estrogen receptors, ER-α and ER-β. Proportions of
each receptor vary by tissue, and effects vary as a result. ER-α is predomi-
nant in the uterus, breast, liver, bone, and cardiovascular system, whereas
ER-β is predominant in the brain, cardiovascular system, and ovarian gran-
ulosa cells. Both receptors are found in the breast. It has been shown that
one estrogen receptor type may potentiate and the other may inhibit the
effects of estrogen within the same site. The estrogen agonist or antagonist
response depends on the estrogen (E1, E2, E3), the estrogen receptor type (ER-
α, ER-β), and the site at which the hormone/receptor interaction occurs and
effects at the DNA level. The estrogen/receptor system has multiple layers of
variability, providing significant plasticity.
Progestins Progesterone is primarily synthesized by the ovary. A small amount is made

and Progestin by the adrenal gland as an intermediate in the pathway of mineralocorticoid
Receptors and glucocorticoid production. Progesterone has primary effects on the endo-
metrium, which undergoes secretory changes after ovulation. Progesterone
also facilitates the growth of the alveoli in breast lobules during develop-
ment. An increased risk of breast cancer with exogenous progesterone use is
postulated. Progesterone produces smooth muscle relaxation. During preg-
Table 1-3
Physiologic Organ System Effect
Effects of
Estrogen Central nervous system Suggested positive effects on mood, memory, sense
of well-being, cognitive function, and adult sexual
behavior
Temperature regulation/preventing vasomotor
symptoms
Breasts Breast ductal development
Reported increased risk in estrogen-positive breast
cancer
Cardiovascular Increased risk for thrombosis/stroke
Lipid profile effects: increased HDL, decreased LDL,
increased triglycerides
Possible effects on plaque formation in vascular
endothelium
Urogenital tract Promotes urogenital development and maturation 7
Prevention of vaginal atrophy
Promotes müllerian growth
Endometrial proliferation
Increased risk of endometrial hyperplasia/cancer if
unopposed
Bone Promotes bone growth and closure of epiphyses by
inhibiting osteoclasts
Minimizes bone mineral density loss
HDL, high-density lipoprotein; LDL, low-density lipoprotein.
nancy, the effects of high levels of progesterone include relaxation of the

smooth muscle of the ureters and the lower esophageal sphincter. Prolonged
relaxation of the ureters and the lower esophageal sphincter is presumably
responsible for the increased incidence of pyelonephritis and gastroesopha-
geal reflux disease. The two receptors for progesterone are known as PR-A
and PR-B. It has been shown that the transcription of progesterone recep-
tors is increased by estrogens and decreased by progestins. These receptors
are predominantly found in the breast and genital tract.
Androgens Androgens are produced by the ovaries and the adrenal glands. The ovaries
and Androgen synthesize and secrete androstenedione and, to a much lesser extent, testos-
Receptors terone. The adrenals synthesize dehydroepiandrosterone (DHEA), dehydro-
epiandrosterone sulfate (DHEAS), androstenedione, and testosterone.
Androgens are integral to development of male sexual organs and are
active in skin. Testosterone acts directly on structures derived from the
wolffian ducts. In the skin, testosterone is reduced to dihydrotestosterone,
which acts primarily on hair follicles. Dihydrotestosterone also acts on struc-
tures derived from the urogenital sinus. The effects of androgens on mood
and behavior are reported, but are not well characterized. The potential for
androgen supplementation to increase libido in postmenopausal women is
under investigation.
Diagnostic Methods for assaying steroidal hormones in the blood include enzyme-linked
Testing immunosorbent assay and radioimmunoassay. Normal ranges for assays
vary depending on the assay and the laboratory (Box 1-1). Estrogen assays
have been shown to allow for reliable comparisons for cycling, reproductive-
age women within a given time frame in the menstrual cycle. Similarly, pro-
gesterone measurements are reliable for midfollicular and midluteal phases,
with a lesser degree of reliability for women who are perimenopausal.
Clinically available testosterone assays were designed for measuring male
hormone levels. The lower limits of the assay values are less reliable for meas-
uring low testosterone levels in women.
Therapeutic Hormonal Contraception

Interventions Hormonal contraception may consist of an estrogen and a progestin (E+P)
8 or a progestin alone (P). It may be administered via different routes: oral
(E+P, P), transdermal (E+P), intramuscular (P), vaginal ring (E+P), and
intrauterine device (P). Contraceptives with E+P are the most effective in
suppressing ovulation because the P component inhibits the LH surge and
the E component inhibits follicle-stimulating hormone (FSH), suppressing
follicular selection and growth. The mechanism of action of progestins is
multipronged in that they induce an endometrium that is not conducive to
implantation, alter tubal motility, and thicken cervical mucus, creating a
barrier to sperm transport.
Side effects are mostly due to estrogen. Headache, nausea, breast tender-
ness, weight gain, and hair loss have been reported. If a patient has side
effects with oral contraceptive pills that contain E+P, it is reasonable to have
the patient try a different pill, such as one with a lower dose of estrogen, or
to use a different delivery system.
Absolute contraindications include breast cancer, liver disease, clotting
disorders, undiagnosed vaginal bleeding, and smoking after age 35. Relative
contraindications include migraines, hypertension, diabetes, and seizure
disorders. In addition, postpartum women who breastfeed their newborns
may have decreased milk production as a result of systemic absorption of
hormonal contraception with an estrogen component.
Hormone Therapy
During the perimenopausal and postmenopausal years, patients may elect
hormone therapy for short-term or long-term benefit. Short-term (<5
years) benefits include prevention of hot flashes and urogenital atrophy and
theorized mood and cognitive improvements. Long-term benefits include
prevention of osteoporotic fractures and colon cancer. Cardioprotection pre-
viously was believed to be a long-term benefit of hormone therapy and was
supported by observational studies. The Women’s Health Initiative (WHI),
Box 1-1 Units of Measurement for Sex Steroid Hormones

● Estradiol—pg/mL
● Testosterone—ng/dL
● Progesterone—ng/dL
a large randomized primary prevention trial, did not support that observa-
tion, however, and suggested an increased risk of cardiovascular events and
stroke with E+P therapy. Although the subjects were patients with a history
of cardiovascular events, the Heart and Estrogen/Progestin Replacement
Study (HERS) did not show a decrease in the risk of coronary events with
hormone therapy.
Women with a history of hysterectomy may take estrogen alone for hor-
mone therapy, whereas women with an intact uterus are advised to add a
progestin to the regimen to minimize the risk of endometrial hyperplasia
and cancer. In light of the WHI and the HERS trials, patient selection for
hormone therapy should be considered by assessing potential risks and ben-
efits, based on individual history and risk factors. Hormone therapy may be
administered via the oral, transdermal, subcutaneous, or vaginal route.
9
SUMMARY OF KEY POINTS—STEROIDS

1. Estrogen, progesterone, and testosterone share a common basic struc-
ture and are derived from cholesterol.
2. The ovaries produce androstenedione and testosterone in theca cells,
and these two androgens are aromatized to estrone and estradiol in
granulosa cells.
3. Changes in SHBG/CBG levels can have dramatic, inversely proportional
effects on free hormone levels, which can have great clinical significance.
4. Estrogens, produced by the ovaries and converted peripherally, have
various effects on different tissues based on the type of estrogen (E1, E2,
E3), the estrogen receptor, the tissue involved, and factors at the DNA
level.
5. Progesterone, produced almost exclusively by the ovaries, exerts most of
its action on the female breast, urogenital tract, and smooth muscle.
6. Androgens are produced by the ovaries and adrenal glands. They affect
hair follicles, body composition, and possibly mood and cognition.
7. Examples of steroids in clinical practice include hormonal contraception
and menopausal hormone therapy, both of which have risks and ben-
efits. Patients should be selected for such therapies based on history and
risk factor profiles.
PROSTAGLANDINS
Naturally occurring prostaglandins (PGs), 20-carbon fatty acid derivatives,

are the products of arachidonic acid (AA), which is provided through the
diet and synthesized from linoleic acid. AA is a compound that is found in
vast quantities and is predominantly present as an esterified form in phos-
pholipid membranes and esterified cholesterol. Sex steroids and other stimuli
promote the action of phospholipase enzymes A2 and C, which release AA
from membranes. AA can be catalyzed by the lipoxygenase pathway or by
the cyclooxygenase pathway. The lipoxygenase pathway leads to the forma-

tion of leukotrienes and eicosanoids. The cyclooxygenase pathway leads to
the formation of prostanoids via the enzymes cyclooxygenase-1 (COX-1) and
cyclooxygenase-2 (COX-2) (Fig. 1-2).
Physiology PGs, produced via the cyclooxygenase pathway, are clinically relevant in
and Clinical reproductive medicine in terms of pathophysiology and therapy. Clinically
Presentation significant PGs include PGG2 and PGH2, both of which are short-lived inter-
mediates. PGG2 and PGH2 are converted to PGs with longer half-lives, such
as prostacyclin (PGI2), thromboxane (TX), PGE2, and PGF2α.
After PG synthesis is completed, they are secreted from the cell. PGs pri-
marily exert their actions locally (Box 1-2). PG receptors are cell surface, G
10 protein–coupled members of a superfamily of rhodopsin-like proteins with
seven domains that traverse the cell membrane. PGs can elicit responses in
multiple organ systems simultaneously, such as the bronchoconstriction
Figure 1-2 O O
Basic prostaglandin
structures. OH
OH
Arachidonic acid
Leukotrienes PGI2
Lipooxygenase Cyclooxygenase
pathway pathway
O OH
O PGE2
OH
OH OH
TXA2
OH
O
O
O
OH
PGF2α
HO
OH
HO
O
O
Prostaglandins
Box 1-2 Effects of Prostaglandins

PGI2
Vasodilation
Inhibition of platelet aggregation
TX
Vasoconstriction
Promotion of platelet aggregation
PGF2α
Vasoconstriction
Bronchoconstriction
Smooth muscle contraction in cervix and myometrium
PGE2
Vasodilation
Promotion of platelet aggregation 11
Smooth muscle relaxation in cervix
that occurs in an obstetric patient who is undergoing cervical ripening with

PGs. PGs are transported to distant sites via free fatty acids.
PGI2 and TXs have several effects that counterbalance each other. TXs are
predominantly produced by platelets, but also are made by the spleen and
the placenta. They are vasoconstrictors and increase platelet aggregation to
repair sites of damage (e.g., on vascular endothelium). PGI2 is synthesized
mostly by blood vessel endothelium, but also is made by the heart, stomach,
and lungs. It is a vasodilator and inhibits platelet aggregation to prevent clot
formation on vascular endothelium. In pregnancy, disruption of the homeo-
stasis between TX and PGI2 occurs, leading to an increased TX-to-PGI2 ratio,
and suggesting an underlying mechanism of preeclampsia.
During labor, measurements of PG levels in the blood and amniotic fluid have
shown increased levels from baseline. The AA in fetal membranes is metabo-
lized via the COX-2 pathway, which results in an increased level of PGE2. For
the purposes of ripening the cervix and for inducing labor, the use of synthetic
PGs, such as PGE1 (misoprostol) and PGE2 (dinoprostone), has become com-
monplace. Preterm labor is treated with PG inhibitors, such as indomethacin
and sulindac. Because of concern for increased risk of intrauterine closure of
the fetal ductus arteriosus and pulmonary hypertension after 32 weeks, how-
ever, these agents are not recommended for use after this gestational age. PGs
such as PGE1 also have been effective when used as abortifacients.
PGs have been found to play a role in ovarian physiology, specifically that
of folliculogenesis and the corpus luteum. An increase in blood supply to
selected follicles has been attributed to PGs. In addition, PGF2α, present in
follicular fluid, may inhibit collagen production and facilitate the rupture of
an ovulatory follicle.
Therapeutic Primary Dysmenorrhea

Interventions The diagnosis of primary dysmenorrhea, painful cramps with menstrua-
tion, is made when no anatomic or functional abnormality is identified.
High levels of PGF2α have been detected in the secretory endometrium of
patients with primary dysmenorrhea. These levels peak during the time of
menstruation, resulting in myometrial exposure to PG and increased myo-
metrial contractility with consequent cramping and pain. In addition, some
patients experience gastrointestinal symptoms in association with high PG
levels during menses. The pharmacologic inhibition of PG is an effective
treatment, achieved by the administration of pharmacologic agents such
as nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors.
Ibuprofen, naproxen, and mefenamic acid are examples of NSAIDs. Celecoxib
is an example of a COX-2 inhibitor. Rofecoxib, another COX-2 inhibitor, was
removed from the market because of an increased risk of cardiovascular
events, such as heart attack and stroke, and now there are concerns about
all agents in this class of medications.
NSAIDs have been shown to decrease the levels of PG produced by the
12 endometrium, shorten the duration of menses, and decrease the amount of
menstrual flow. PG-mediated gastrointestinal symptoms also may be allevi-
ated. The major side effect of NSAIDs is gastrointestinal with potential ulcer-
ation; excessive use may lead to renal toxicity.
COX inhibitors have been synthesized to inhibit COX-1 and COX-2 selec-
tively. The COX-1 enzyme, present in virtually all tissues, is instrumental in
producing PG. As a result of the presence of COX-1 in gastric mucosa, inhi-
bition of this enzyme leads to decreased levels of PGE2, increasing the risk
of gastrointestinal side effects and ulcers. The COX-2 enzyme is considered
the inducible form of COX and is produced in response to inflammation. The
selective inhibition of COX-2 seems to reduce the incidence of gastrointesti-
nal sequelae.
Postpartum Hemorrhage
Synthetic PGs, such as PGF2α (carboprost tromethamine [Hemabate]) and
PGE1 (misoprostol), are useful in treating postpartum hemorrhage that is
secondary to uterine atony. PGs typically are administered if ergot alkaloids
(e.g., methylergonovine maleate [Methergine]) do not diminish the bleeding
or if the patient has a contraindication to ergots, such as hypertensive dis-
ease. Asthma is a contraindication to the use of PGF2α because of its bron-
choconstrictive properties. The smooth muscle contraction elicited by these
particular PGs is instrumental in achieving increased uterine tone postpar-
tum. These agents have been found to be useful in the treatment of uterine
atony.
SUMMARY OF KEY POINTS—PROSTAGLANDINS

1. PGs are derived from AA by the COX pathway via the enzymes COX-1
and COX-2.
2. PGI2 and TX have counterbalancing effects on vessel caliber and platelet
aggregation.
3. PGE1 and PGE2 are useful for cervical ripening and induction of labor.
4. PGE1 and PGF2α are useful in treating postpartum hemorrhage, but
PGF2α is contraindicated in asthmatics.
SUGGESTED READINGS
Chu MC, Lobo RA: Formulations and use of androgens haemorrhage. Cochrane Database Syst Rev 2002;3:
in women. Mayo Clin Proc 2004;79(suppl):S3-S7. CD000494.
Fears TR, Ziegler RG, Donaldson JL, et al: Marjoribanks J, Proctor ML, Farquhar C: Nonsteroidal
Reproducibility studies and interlaboratory anti-inflammatory drugs for primary dysmenorrhea.
concordance for androgen assays in female plasma. Cochrane Database Syst Rev 2003;4:CD001751.
Cancer Epidemiol Biomarkers Prev 2000;9:403-412. Mendel CM: The free hormone hypothesis: a physi-
Gail MH, Fears TR, Chandler DW, et al: ologically based mathematical model. Endocr Rev
Reproducibility studies and interlaboratory concor- 1989;10:232-274.
dance for assays of serum hormone levels: estrone, Narumiya S, Sugimoto Y, Ushikubi F: Prostanoid
estradiol, estone sulfate, and progesterone. Cancer structures, properties, and functions. Physiol Rev
Epidemiol Biomarkers Prev 1996;5:835-844. 1999;79:1193-1226.
Gallo MF, Grimes DA, Schulz KF: Skin patch and Nelson HD: Assessing benefits and harms of hormone
vaginal ring versus combined oral contraceptives for replacement therapy: clinical applications. JAMA
contraception. Cochrane Database Syst Rev 2003;1: 2002;288:882-884.
CD003552. Nelson HD, Humphrey LL, Nygren P, et al: 1313
Gulmezoglu AM, Forna F, Villar J, Hofmeyr GJ: Postmenopausal hormone replacement therapy:
Prostaglandins for prevention of postpartum scientific review. JAMA 2002;288:872-881.
2
THE NORMAL
MENSTRUAL CYCLE
Randal D. Robinson*
The normal menstrual cycle is simultaneously one of the simplest and most
complex and elegant physiologic processes. To manage obstetrics and gyne-
cology patients competently, one must understand the normal menstrual 15
cycle. One cannot deal with physiologic or anatomic abnormalities or patho-
logic processes without an adequate understanding of what constitutes nor-
mal. Disturbances in normal menstrual function are usually concerning to
patients and frequently lead them to seek medical evaluation. This evalua-
tion could reveal a temporary deviation from normal or might uncover one
of numerous pathologic processes.
Normal menstruation is defined as the periodic efflux of the sloughed
endometrium and blood out of the uterine cavity into the vagina and ulti-
mately outside of a woman’s body. There are many different cultural beliefs,
myths, and taboos, even within educated countries, about the purpose and
function of the menstrual cycle. For adolescent girls, it is an obvious sign
of pubertal development and signifies the passage into womanhood and the
capability and responsibility of reproducing. Monthly menses become for
many women a reassuring sign that they are not pregnant, if conception
was not desired, or a cause of frustration and disappointment if pregnancy
was desired. Teleologically and functionally, the ultimate aim of the human
menstrual cycle is the development of a mature oocyte that is ovulated and
fertilized. Ultimately, if fertilization is successful, implantation of a dividing
pre-embryo into the receptive endometrium of the uterus occurs.
Primates are the only mammals known to menstruate. Menarche, the age
at onset of menstruation, averages 12.8 years in the United States. There is
significant ethnic variability in the age of menstrual onset, with African-
American adolescent girls experiencing menarche earlier than white girls.
The normal age range for menarche is 10 to 16 years. The average age for
menarche has steadily declined over the past 200 years. The decline in age
at first menses is attributed to the improvement in nutrition and subsequent
increased weight of adolescent girls today compared with their ancestors.
*The opinions and assertions contained herein are the expressed views
of the author and are not to be construed as official or reflecting the
opinions of the Department of the Army, Department of the Air Force, or
Department of Defense.
Figure 2-1
Length of 16
menstrual cycles.
(Modified from
Munster K, Schmidt 14
L, Hahm P: Length
and variation in the
menstrual cycle: 12
a cross-sectional
study from a
10
Percentage of incidence
Danish country. Br
J Obstet Gynaecol
1992;99:422.) 8
6
16
4
0
21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 40
Days
The idealized length of the normal human menstrual cycle is 28 days

from the onset of bleeding until the next episode of bleeding (Fig. 2-1). The
average length of the menstrual cycle found in large population studies is
28.1 days; 28 days is merely the most common or modal distribution, how-
ever. Only 14% of women experience a menstrual cycle of 28 days in length.
There is great variability in menstrual cycle length; an interval of 24 to 35
days is considered normal. The amount of bleeding also varies widely in the
number of days of bleeding and the amount of blood lost. The number of
days of bleeding ranges from 2 to 8 days, but the usual length is 4 to 6 days.
The average amount of blood lost with each menstrual cycle is 30 mL, and
the normal range is 25 to 60 mL. Even this relatively small amount of blood
loss can lead to iron deficiency anemia if adequate iron is not ingested or
absorbed. Blood loss of greater than 80 mL is excessive and commonly leads
to iron deficiency anemia.
Ovulatory women individually have consistent menstrual cycle lengths
and number of days of bleeding (Box 2-1). There is some cycle length vari-
ability for most women, however. Even in a woman with regular menstrual
Box 2-1 Normal Menstrual Cycle

● Modal interval—28 days
● Normal range—24-35 days
● Mean blood loss—30 mL (range 25-60 mL)
● Usual length of menstrual bleeding—4-6 days (normal range 2-8 days)
The Normal Menstrual Cycle
cycles, variation by 2 days in length can be seen in one third of their cycles.
This variation in cycle length is attributed to the variability in the length of
the follicular phase of the cycle. The luteal phase consistently is 13 to 15 days
in length after menarche and remains consistent until the perimenopausal
period. Great variability is seen at the extremes of reproductive life, with
adolescents and perimenopausal women experiencing wide fluctuations in
menstrual cycle length and the number of days of bleeding because of their
tendency to experience anovulatory cycles (Fig. 2-2). Adolescent girls aver-
age menstrual cycle lengths of 34 days. There is a gradual decrease in cycle
length until women reach their late 30s or early 40s, when cycle length aver-
ages 27 days. Anovulatory cycles frequently begin when a woman reaches
her late 40s. Cycles lengthen again and average 33 days beginning 3 years
before menopause. Significant variation in the menstrual cycle length or
number of days of menses commonly leads reproductive-age women to seek 17
medical advice. Pregnancy-related reasons for alterations in menstrual cycle
length are the most common reasons for disruption in normal menstrual
cycles in reproductive-age women. Lactation and abnormal pregnancies
always must be ruled out as reasons for a change in menstrual pattern in
every woman who seeks evaluation.
The normal menstrual cycle is best conceptualized by focusing on the
physiologic effect on the two main organ systems involved in menstrual func-
tion—the uterus and the ovary. The menstrual cycle classically is divided
into phases. These phases are a convenient way to examine what is happen-
ing at different times at the level of the two main organ systems. The first
Figure 2-2
Distribution of 75
menstrual intervals
throughout menstrual
life. (Modified from 70
Mean interval in days between menstrual onset
Treloar AE, Boynton

RE, Borghild BG,
Brown BW: Variation 60
of the human
menstrual cycle
through reproductive 50
life. Int J Fertil 95%
1967;12:77.)
40 75%
Mean
30
20 25%
5%
10
15 20 25 30 35 40 45 50 55 60
Chronological age
phase of the menstrual cycle is called the follicular phase at the level of the
ovary and the proliferative phase at the level of the uterus. The follicular phase
ends with the onset of the luteinizing hormone (LH) surge. Ovulation occurs
in response to the LH surge. The next phase of the menstrual cycle, which
begins after the onset of the LH surge, is called the luteal phase at the level of
the ovary and the secretory phase at the level of the uterus.
FOLLICULAR/PROLIFERATIVE PHASE
Early Follicular/ Endometrium

Menstrual Phase It is convenient to divide the follicular/proliferative phase into early, mid-, and
late phases. By convention, day 1 of the menstrual cycle is the start of vagi-
18 nal bleeding and is characterized as menstrual bleeding at the level of the
uterus/endometrium. The endometrium is often indistinct on ultrasound
during menses and is seen as a thin echogenic line on completion of menses.
The endometrium is composed of two main layers: the stratum basale adjacent
to the myometrium and the stratum functionale above the basale and closer
to the lumen of the uterus (Box 2-2). The basale layer does not slough with
menses and changes minimally throughout the menstrual cycle. The func-
tionale layer is subdivided further: A superficial layer closer to the lumen, the
stratum compactum, is composed of gland necks and dense stromal cells. The
deeper functionale layer is called the stratum spongiosum and is adjacent to
the underlying basale layer. The spongiosum contains predominantly endo-
metrial glands, increased interstitial tissue, and less dense stroma. The entire
stratum compactum and a portion of the stratum spongiosum are sloughed
with menses. After menses, the endometrium consists of the stratum basale
and a portion of the stratum spongiosum. The stratum functionale begins rapid
proliferation and growth in response to the increase in estrogen seen in the
early follicular phase.
Ovary
The onset of menses also signals the beginning of the follicular phase in the
ovary. The early follicular phase (days 1-5) is hormonally quiescent, from a
sex steroid standpoint, because estradiol and progesterone serum levels are
very low (Fig. 2-3). This physiologic quiescence also is observed on ultra-
sound evaluation of the female pelvis. The ovaries exhibit small preantral
follicles that measure 3 to 8 mm in diameter, and an occasional residual or
resolving corpus luteum sometimes can be visualized.
Box 2-2 Endometrial Layers

● Stratum basale: adjacent to myometrium
● Stratum functionale
● Stratum compactum: superficial layer adjacent to lumen; contains gland
necks and dense stroma
● Stratum spongiosum: adjacent to basale; contains glands, interstitial tissue,
and less dense stroma
Figure 2-3 Follicular Ovulation Mature corpus Corpus

Changes throughout growth luteum luteum
the normal menstrual involution
cycle in the ovary and
the endometrium.
(Modified from
Shaw ST Jr, Roche Inhibin Progesterone
PC: Menstruation. FSH Estradiol 17-OHP
In Finn CA [ed]: IU/L pg/mL Ng/mL
Oxford Reviews of 20 500 Progesterone 10
Reproduction and
18 LH 9
Endocrinology, vol
2. London: Oxford 16 400 8
University Press; 14 7
1980; and Regulation
12 300 6
of the menstrual
cycle. In Speroff 10 5 19
L, Fritz MA [eds]: 200 FSH 4
8
Clinical Gynecologic
Endocrinology 6 Inhibin-B 3
and Infertility, 4 100 2
7th ed. Philadelphia: Estradiol
2 1
Lippincott Williams &
Wilkins; 2005: 0 0 Inhibin-A 0
195–198.)
Ovulation
1 7 14 21 28
Period of Period First growth Second growth Period of

regression of rest period period regression
Menstrual Premenstural
phase phase
Menstrual
Postmenstrual
phase
phase
1 5 14 24 28 1 5
Pre-menstrual
Bleeding Proliferative, follicular, Secretory, luteal or Bleeding

involution
or estrogenic phase progestational phase

Ischemia
The low serum levels of sex steroids found in the early follicular phase,
combined with declining luteal phase inhibin A levels, effectively release the
hypothalamus from the negative feedback exerted by these substances in the
previous luteal phase. Inhibin A, estrogen, and progesterone levels begin to
decline with the demise of the corpus luteum. The low levels of these sub-
stances allow for increases in gonadotropin-releasing hormone (GnRH)
pulse frequency. This increase in GnRH pulsatility begins in the late luteal
phase with the decline in serum progesterone, estrogen, and inhibin A that
occurs if a pregnancy has not developed and the corpus luteum involutes.
GnRH pulses increase from 3 per day to 14 per day. This increase in GnRH
pulse frequency results in an increase in follicle-stimulating hormone (FSH)
production from the anterior pituitary, which also begins to increase in the
previous late luteal phase. The increased GnRH pulse frequency selectively fa-
vors FSH production over LH. Mean levels of FSH increase from 4 to 15 IU/L
compared with a mean of 4.8 to 8 IU/L for LH. FSH levels begin increasing
2 days before menstrual bleeding. The late luteal phase increase in FSH is
only 30% greater than the usual midluteal level, but this minimal increase
is sufficient to recruit a cohort of follicles, one of which is destined to be the
dominant follicle that eventually ovulates a mature oocyte. The late luteal
phase increase in GnRH pulsatility increases LH pulse frequency from one
LH pulse every 4 hours in the late luteal phase to one every 90 minutes in
the early follicular phase.
20 The primordial follicles that ultimately give rise to the single dominant
follicle originate as primordial germ cells. Primordial germ cells are derived
embryologically from the endoderm cell layer and migrate from the yolk sac,
allantois, and hindgut to the gonadal ridge region at 5 to 6 weeks of ges-
tation. When in the gonadal ridge area, the primordial germ cells undergo
mitotic division with a maximum number of 6 million to 7 million achieved
by 16 to 20 weeks of gestation. There is a large decline in the number of
primordial germ cells to 2 million at birth. A continual decrease in germ cell
number occurs until there are approximately 300,000 oocytes remaining at
puberty. This tremendous atresia of germ cells occurs via programmed cell
death known as apoptosis. Depending on a woman’s pregnancy and lacta-
tion history and use of hormonal contraceptives, it is estimated that only
about 400 follicles are ovulated during a woman’s reproductive lifespan.
When the primordial germ cells have reached the gonadal ridge region
and are surrounded by a single layer of granulosa cells, they are called
primordial follicles or germinal vesicles. Primordial follicles are composed
of the oocyte at the diplotene stage of prophase of the first meiotic divi-
sion and a single layer of granulosa cells. The primordial follicles individu-
ally undergo growth or atresia throughout the lifespan of the woman. It is
unknown what triggers the growth of a specific cohort or what determines
the number of primordial follicles to be recruited each cycle. It also is unclear
how the dominant follicle is selected from this cohort of follicles. Ultimately,
one follicle wins the race because of its greater ability to respond to the late
luteal/early follicular increase in FSH and the local autocrine or paracrine
environment that optimizes its response to this stimulation. Many auto-
crine/paracrine factors have been found to play a role in the regulation of
this follicular development, including various peptides, growth factors, and
cytokines (Table 2-1).
The dominant follicle that ultimately ovulates is recruited and develops its
competitive advantage over the rest of the recruited cohort of follicles dur-
ing the transition from the luteal to follicular phase and during the first few
days of the menstrual cycle. The remainder of the cohort of follicles that do
not reach dominant follicle status undergo apoptosis. It takes 85 days for the
follicle that is ultimately ovulated to mature. Most of this maturation is inde-
pendent of hormonal stimulation. Hormonal stimulation becomes dominant
Table 2-1 Role of Cytokines and Growth Factors in the Normal Menstrual Cycle
Ovary: Granulosa Cell Ovary: Theca Cell Endometrium
Factor Follicular Luteal Follicular Luteal Proliferative Secretory Pituitary
Inhibin A (LH induces) ↓ FSH ↑ LH-induced A, ↓ FSH
T production
Inhibin B (FSH induces) ↓ FSH ↑ LH-induced A, ↓ FSH
↓ Activin T production
↑ Follistatin
Activin (FSH induces) ↑ FSH ↑ FSH ↓ LH-induced A, ↑ VEGF ↑ FSH
↑ Inhibin T production ↑ GnRH

↑ Aromatase
↓P
↑ E2
↑ Follistatin
Follistatin (FSH induces) ↓ Activin →↓ FSH ↓ Activin
↑ Inhibin activity →↓ FSH
TGF-β ↓ Cell growth ↓ A, T production ↓ A, T ↑ VEGF Inhibits
↑ FSH-induced FSH MMP
and LH receptors
↓ Angiogenesis
↑ E2
FGF ↑ GC growth ↑ A, T ↑ A, T
↓ FSH-induced FSH
and LH receptors
↑ Angiogenesis
↓ E2
Continued
21
22
Table 2-1 Role of Cytokines and Growth Factors in the Normal Menstrual Cycle—cont’d
Ovary: Granulosa Cell Ovary: Theca Cell Endometrium
Factor Follicular Luteal Follicular Luteal Proliferative Secretory Pituitary
AMH ↓ GC growth ↓ growth
Inhibits oocyte meiosis
↓ EGF cell growth
TNF-α ↑ Apoptosis ↑ Apoptosis ↑ VEGF
↓ E2 ↑ Luteolysis
EGF ↓ FSH-induced inhibin, ↑P
E2, and LH receptors
↓ Aromatase
↑ Cell growth
TGF-α ↓ E2
↑ Cell growth
IGF-I (FSH, LH, GH, E2, ↑ FSH-induced ↑P ↑ A, T ↑ A, T ↑ A, T
EGF induces) LH receptors

↑ Inhibin B ↑ Theca cell growth ↑ Theca cell growth ↑ VEGF
↑ Aromatase
↑ E2
↑ GC growth
IGF-II (FSH, LH, ↑ GC growth ↑P ↑ A, T ↑ A, T
GH induces) ↑ Aromatase ↑ Theca cell growth ↑ Theca cell growth
↑ E2
VEGF (induced by LH) ↑ Angiogenesis ↑ Angiogenesis ↑ Angiogenesis ↑ Endometrial
of GC mitosis
↑ Angiogenesis
↓ = decreases or inhibits; ↑ = increases or induces; → = leads to; A, androstenedione; AMH, antimüllerian hormone; E2, estradiol; EGF, epidermal growth factor; FGF, fibroblast
growth factor; FSH, follicle-stimulating hormone; GC, granulosa cell; GH, growth hormone; GnRH, gonadotropin-releasing hormone; IGF-I, insulin-like growth factor I; IGF-II,
insulin-like growth factor II; LH, luteinizing hormone; MMP, matrix metalloproteinase; P, progesterone; T, testosterone; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis
factor-α; VEGF, vascular endothelial growth factor.
only in the late stages of oocyte maturation. If FSH secretion and stimulation
does not occur at the appropriate time, and if maintenance of this secretion
does not occur, the cohort of follicles undergoes atresia. Even without FSH
stimulation, some of the primordial follicles develop into primary or prean-
tral follicles. Preantral follicles are composed of the oocyte surrounded by
multiple layers of granulosa cells. Preantral follicles are unable to progress
to the antral or secondary follicle stage of development without the presence
of FSH.
Two-Cell With the FSH-induced increase in granulosa cell number, gap junctions
Ovarian develop between the granulosa cells and between the granulosa cells and the
Physiology oocyte. Gap junctions increase communication between the cells surround-
ing the oocyte and with the oocyte itself. The stromal layer surrounding the 23
granulosa cells also undergoes differentiation into two cell layers, an inner
theca interna and an outer theca externa. The theca layer is separated
from the granulosa layer by a basal lamina. The oocyte also enlarges and
is encased in the zona pellucida membrane layer. As the number of granu-
losa cells increases, an increase in estradiol level is noted, and FSH recep-
tors are seen for the first time on the granulosa cells. FSH and estradiol play
a role in increasing FSH receptor number and granulosa cell number. FSH
also increases the secretion of aromatase, which further increases estro-
gen production. Aromatase is produced by granulosa cells and aromatizes
the androgens produced by the theca cell layer to maximize an estrogenic
follicular milieu.
The granulosa cells are capable of producing androgens, estrogens, or
progesterone, but FSH stimulation in concert with the aromatization of
androgens pushes steroid production decidedly toward estradiol production.
Estradiol stimulates preantral follicular growth, prevents follicular apopto-
sis, and increases the action of FSH on granulosa cells. Androgens have the
opposing effect, and this balance between androgens and estrogens in the
microfollicular environment ultimately determines if a follicle undergoes
atresia or continues to develop. Preantral follicles have FSH receptors only
on the granulosa cell layer and LH receptors only on the theca cell layer.
Theca cells produce androgens in response to LH, and granulosa cells pro-
duce estrogens in response to FSH. An androgenic microenvironment is seen
early on in follicular development and changes to an estrogenic microenvi-
ronment in response to the late luteal and early follicular increase in FSH
secretion. If an androgenic microenvironment persists, programmed cell
death and follicular atresia occur. The dominant follicle produces the great-
est amount of estradiol and increases its own FSH receptor number. The
increased estradiol level ultimately downregulates the surrounding cohort
of the follicle’s FSH receptor number, however. The increasing serum level
of estradiol also begins to exert a negative feedback effect on FSH production
at the level of the pituitary. The granulosa cells also produce inhibin B with
feedback inhibition effect on FSH production. The decrease in FSH has a neg-
ative effect on the nondominant follicles and contributes to their atresia. The
dominant follicle continues to have a competitive advantage because of its
much higher FSH receptor level and estrogenic environment. Additionally,

the dominant follicle’s theca cell layer is more vascular, and FSH is better
able to reach the dominant follicle’s FSH receptors. This results in a contin-
ued competitive advantage for the dominant follicle to aromatize androgens
into estradiol within its own microenvironment.
Midfollicular/ Ovary
Proliferative As the granulosa cells continue to proliferate, follicular fluid is produced.
Phase This follicular fluid eventually accumulates sufficiently to form a fluid-filled
cavity within the substance of the granulosa cells. When the fluid-filled fol-
licular cavity forms, the follicle is now designated an antral follicle. By cycle
day 7, multiple antral follicles can be visualized on transvaginal ultrasound
as 9- to 10-mm follicles. The granulosa cells that remain in close proxim-
24 ity and surround the oocyte differentiate and are now called the cumulus
oophorus. The follicular fluid is an efficient system to maximize an estrogenic
microenvironment around the oocyte and essentially functions as an “estra-
diol sink.” Estradiol concentrations are significantly higher within the fol-
licular fluid compared with levels measured in the serum. LH acts on the
theca cell layer to produce androgens that can be aromatized to estrogens by
the granulosa cells, and FSH increases the number of theca LH receptors to
enhance this effect.
In late stages of follicular development, FSH also induces development of
LH receptors on granulosa cells, which are necessary for the granulosa cells
to be able to respond to the midcycle LH surge. Serum inhibin B, produced
by granulosa cells from the entire cohort of follicles, is at its maximum
during the early follicular phase. Inhibin B levels steadily increase to reach
a peak by cycle day 7 to 8 (see Fig. 2-3) and, in combination with increas-
ing estradiol levels, result in negative feedback at the hypothalamus and
pituitary with resulting decreases in FSH. Inhibin also reduces the num-
ber of pituitary GnRH receptors and contributes to the degradation of the
gonadotropins. Inhibin B and insulin-like growth factor I (IGF-I) increase
LH production of theca cell androgens that increase the substrate avail-
able for aromatase action and further increase follicular estradiol. The FSH
suppression induced by estradiol and inhibin gives the dominant follicle a
further developmental advantage because the smaller follicles have fewer
FSH receptors and undergo atresia. The dominant follicle is selected by cycle
days 5 to 7. A slow, steady increase in estradiol accompanies the selection of
the dominant follicle, and serum estradiol begins to increase substantially
by cycle day 7.
When the remainder of the cohort of follicles begins to undergo atresia,
local cytokines and growth factors start to play an important role. A com-
plete understanding of the role for each of these factors is still evolving and is
complex. The role for these factors becomes even more confusing when their
interaction with each other is included. These polypeptide growth factors act
locally as autocrine and paracrine regulators of endocrine and cellular func-
tion. Because they may have stimulatory or inhibitory roles, depending on
the phase of the menstrual cycle and the animal species studied, their precise
role and understanding of their function are ever evolving. The following
description is a simplification of their role in ovarian physiology, as it is cur-

rently understood (see Table 2-1).
Inhibin A and B have been described previously as important inhibitors of
FSH. In general, inhibin B is the predominant peptide produced in the follicu-
lar phase, and inhibin A is the predominant product of the luteal phase. The
inhibins are regulated further locally via epidermal growth factor (EGF) and
GnRH. Both of these peptides decrease inhibin production. IGF-I increases
inhibin production, however. IGF-II seems to be the dominant IGF in the
human follicle and is involved in granulosa cell proliferation, increased ovar-
ian steroidogenesis via enhanced aromatase activity, and gonadotropin stim-
ulation. Both IGF factors stimulate proliferation and differentiation of cells.
To complicate the IGF role in ovarian physiology further, there are also at
least six IGF binding proteins. These binding proteins and the tissue expres-
sion of the IGF receptors regulate IGF function. FSH decreases IGF binding 25
protein synthesis, which results in increased IGF availability. The overall
roles for the IGFs are to facilitate the action of FSH and LH at the appropriate
phase of the cycle and to ensure an estrogen-dominant microenvironment
for the dominant follicle.
Activin also is produced by the granulosa cells in response to FSH stim-
ulation and, as expected based on its name, “activates” or augments FSH
action within the ovary. It also increases GnRH receptor formation in the
pituitary, and its action is blocked by inhibin. Activin also plays a role in LH-
induced androgen production by inhibiting theca cell androgen production.
Follistatin binds activin to inhibit pituitary FSH secretion. Activin increases
the production of follistatin, and inhibin blocks follistatin action.
Tumor necrosis factor-␣ (TNF) inhibits estradiol production in the non-
dominant follicles. TNF-␣ levels are significantly decreased in the dominant
follicle, augmenting estradiol production at this site. Antimüllerian hormone
augments the success of the dominant follicle by inhibiting nondominant
primordial follicle growth. EGF (granulosa) and its homologue transform-
ing growth factor (TGF)-α (theca) suppress FSH receptor upregulation and
increase granulosa cell proliferation. Vascular endothelial growth factor
(VEGF) also is produced by the granulosa and is responsible for the increased
vascularity of the theca cell layer, which is especially pronounced for the
dominant follicle and improves its competitive advantage over the remaining
cohort of follicles.
Numerous other hormones and cytokines are found within the follicular
fluid. The role for these additional substances is still being elucidated. The
regulation of the menstrual cycle will continue to become more complex as
their role is defined.
Endometrial Changes
The increasing levels of estrogen stimulate endometrial gland and stroma
proliferation and thickening of the stratum functionale. Stromal and glan-
dular mitotic activity steadily increases, and pseudostratification of glandu-
lar nuclei is seen (Fig. 2-4). Growth factors also play a role in endometrial
development, with VEGF promoting endometrial mitotic activity. VEGF is
induced by TNF, TGF-β, and IGF-I. On ultrasound, a trilaminar appearance
Figure 2-4 Early Mid Late Early Mid Late

Patterns of histologic Menses
change throughout Proliferative Secretory
the menstrual cycle.
(Modified from
Gland mitosis
Noyes RW, Hertig AT,
Rock J: Dating the
endometrial biopsy.
Fertil Steril 1950;1:3.)
Pseudostratification
of nuclei
Basal vacuolation
26
Secretion
Stomal edema
Pseudodecidual
reacton
Stomal mitoses
Leukocytic
infiltration
Early Mid Late Early Mid Late

Menses
Proliferative Secretory
to the endometrium is noted, and the endometrial thickness increases from

a mean of 1 to 2 mm after menstruation to an average of 6 mm by cycle day
7 (Fig. 2-5).
Late Follicular/ Ovary

Proliferative The follicle grows 1 to 2 mm/day when it has reached the antral stage. On
Phase ultrasound, the dominant follicle reaches 20 to 26 mm before the onset of
the LH surge, and the LH surge does not occur unless the dominant follicle
reaches 15 mm mean diameter. Local factors prevent premature luteiniza-
Figure 2-5
Early follicular phase
ultrasound image of
the endometrium.
(Image courtesy of
Martin KA: Randal
Robinson, M.D.)
27
tion and ovulation, such as oocyte maturation inhibitor and luteinization

inhibitor factor. The estradiol level in the late follicular phase increases
steadily initially, but increases dramatically 24 to 36 hours before ovulation
when estradiol is at its peak. As the levels of estrogen and inhibin B continue
to increase from the midfollicular into the late follicular phase, further sup-
pression of FSH occurs. With the further increase in estradiol, however, a
change in LH feedback occurs. The initial suppression of LH seen with low
levels of estradiol in the early follicular and midfollicular phases switches to
positive feedback when estradiol reaches 200 pg/mL for approximately 50
hours. The high estrogen levels also increase production of a more bioactive
form of FSH and LH. The 10-fold increased level of LH seen during the LH
surge is from an increase in amplitude of the LH pulse. The exact mechanism
that results in this switch from negative to positive feedback is not completely
understood.
The preovulatory granulosa cells continue to enlarge and acquire lipid
inclusions. The oocyte resumes its march toward completion of the first mei-
otic reduction division. The increased number of FSH-induced LH receptors
found on the granulosa cells allows the surge in LH to begin the process of
luteinization of the granulosa cells. The surge in LH further androgenizes
the remaining cohort of smaller follicles and ensures they undergo atresia,
whereas the luteinization of the granulosa cells in the dominant follicle
results in the production of progesterone. LH also induces progesterone
receptor formation on the granulosa cells. Progesterone in an estrogenic
environment contributes to the positive feedback of estrogen on LH. If pro-
gesterone is found in higher levels (>2 ng/mL) or without an estrogenic envi-
ronment, it can block the LH surge. An appropriately timed and low level of
progesterone production has a positive feedback effect on FSH and accounts
for the midcycle surge of FSH. Preovulatory estrogen production and LH

receptor formation on granulosa cells are maximized by this second surge
of FSH. The LH surge leads to increased androgen production by the theca
cell layer. This increase in androgens may serve to increase female libido and
sexual activity around the time of ovulation.
Inhibin B production begins to decrease by cycle day 7, and inhibin
A production starts to increase slowly (see Fig. 2-3). Some theca cells are
luteinized and contribute to progesterone production, whereas others con-
tinue to produce androgens. IGF-I also facilitates LH-stimulated progester-
one production by luteinized granulosa cells and androgen production by
the theca.
Endometrial Changes
28 The trilaminar endometrium continues to thicken and frequently measures
greater than 8 mm on ultrasound evaluation immediately before ovulation.
The mean endometrial stripe thickness on ultrasound is 12 mm. Women
usually notice an increase in cervical mucus production and an increased
“stringiness” (spinnbarkheit) of the cervical mucus. This change in cervical
mucus is the crucial factor monitored by women who use natural family plan-
ning methods of fertility regulation. Histologically, the endometrial glands
increase in tortuosity, and the stromal and glandular mitotic figures are at a
peak. Pseudostratification of the cells lining the glandular epithelium also is
at a peak (see Fig. 2-4).
Ovulation When the LH surge begins, ovulation is expected within 34 to 36 hours after
LH surge onset and peak estradiol levels. Ovulation occurs approximately
12 hours after the LH peak. The LH surge lasts about 48 hours and must
be maintained for a minimum of 14 to 27 hours for oocyte maturation to
be complete. Progesterone production continues to increase after ovulation
and is probably responsible for the termination of the LH surge. Completion
of metaphase I and extrusion of the first polar body occur after the LH surge
and simultaneously with ovulation. When LH levels reach their peak, there
is a precipitous decrease in estradiol levels as steroid production shifts from
estradiol to progesterone production. This dramatic decline in estrogen
occasionally can result in midcycle spotting for some women secondary to
estrogen withdrawal bleeding.
The midcycle LH and FSH surge also stimulates production of plasminogen
activator. Plasminogen is converted into plasmin by plasminogen activator.
Plasmin aids in detachment of the cumulus oophorus from the surround-
ing granulosa cells. Hyaluronic acid also increases in response to FSH and
facilitates release of the cumulus-oocyte complex from the surrounding
granulosa cells and leads to a free-floating cumulus-oocyte cell mass within
the follicular fluid. Immediately before ovulation, there is an increase in fol-
licular fluid volume, and the follicular wall thins. FSH, LH, and progesterone
stimulate production of proteolytic factors, such as collagenase, which digest
the follicular wall. Plasmin also increases collagenase production to facilitate
follicular rupture and oocyte release. The midcycle gonadotropin surge also
stimulates the production of prostaglandins (PGs), PGF2α and PGE2, and his-
tamine. These products all seem to play a role in extrusion of the cumulus-
oocyte complex at the time of ovulation. Growth factors, such as EGF and
interleukin-1β, also regulate synthesis of the proteolytic enzymes. Extrusion
of the oocyte and cumulus oophorus is not an explosive event. Progesterone
acts directly on the follicular wall to increase its distensibility, and the follicu-
lar wall becomes thin and stretched. The follicular levels of the PGs, proteo-
lytic enzymes, and histamine are significantly elevated and result in erosion
of the collagenous matrix in the region of the follicular wall that ruptures
and extrudes the oocyte. PGs also assist in extrusion of the oocyte by induc-
ing ovarian smooth muscle cell contraction. Histologically, the granulosa
cell and theca cell layers take up lipids and lutein pigment and develop the
characteristic, yellow appearance of the corpus luteum. 29
LUTEAL/SECRETORY PHASE
Early Luteal/ Ovary

Secretory Phase The granulosa cell layer becomes vascularized only after ovulation. The vas-
cularization of the luteinized granulosa cells is crucial for adequate corpus
luteum function. Progesterone and estradiol production depends on ade-
quate cholesterol delivery to the luteinized granulosa cells by low-density
lipoprotein (LDL). LH regulates this process by increasing LDL receptors and
LDL receptor binding and modulating postreceptor processing. Oxytocin also
may play a role in the function of the corpus luteum by increasing intercel-
lular, gap junction communication; this suggests a paracrine role for oxy-
tocin to maximize corpus luteum steroidogenesis. Vascular development is
mediated via the action of VEGF and other angiogenic growth factors. By
day 8 to 9 after ovulation, peak vascularization is noted and correlates with
peak luteal phase estrogen and progesterone blood levels. Just as estradiol
is the predominant steroid produced in the follicular phase, progesterone
is the dominant steroid in the luteal phase. Estrogen levels, although lower
than their preovulatory peak, remain substantial after ovulation. Peak luteal
estradiol levels measure 100 to 150 pg/mL (see Fig. 2-3).
Endometrial Changes
Steadily increasing progesterone levels result in profound changes within the
endometrium. Glandular mitoses end, and glycogen-rich subnuclear vacu-
oles appear in the glandular cells at their base. Subnuclear vacuolization is
the first histologic evidence of progesterone effect, but does not mean ovula-
tion has occurred. When the progesterone levels increase in the early luteal
phase, the glycogen-laden vacuoles migrate toward the glandular lumen (see
Fig. 2-4). On ultrasound, shortly after ovulation, the late follicular, trilami-
nar pattern is lost, and an increased and uniform echogenicity of the endo-
metrial stripe is visualized. Ultrasonographers describe this as hyperechoic.
The mean endometrial thickness on ultrasound is 12 mm.
Midluteal to Ovary
Late Luteal/ Progesterone levels continue to increase as long as LH is present. Progesterone
Secretory Phase plateaus about 1 week after ovulation if a pregnancy does not develop.
and Menstrual Progesterone production is also pulsatile and occurs after each pulse of LH
Phase secretion; this can result in measurements of relatively low serum proges-
terone values in a normal midluteal phase. Progesterone measurements fre-
quently are used incorrectly to determine the adequacy of the luteal phase
and should be used clinically only to determine if ovulation has occurred.
Loss of LH or failure of human chorionic gonadotropin (hCG) to be produced
results in luteolysis. Luteolysis occurs approximately 14 days after the LH
surge, with a normal luteal phase range of 11 to 17 days. In the absence
of hCG, the lifespan of the corpus luteum cannot be extended even with LH
supplementation; this suggests that an active luteolysis mechanism exists
30 in primates. No definitive luteolytic factor has been identified in primates,
however, in contrast to other mammals, in which PGF2α, endothelin-1, and
TNF-α mediate luteolysis. Experiments suggest that estradiol might mediate
its luteolytic action via nitric oxide, which has been shown in humans to
induce PG production and decrease progesterone concentrations. The actual
process of luteolysis involves the matrix metalloproteinases (MMPs), which
are proteolytic enzymes. Throughout the luteal phase, tissue inhibitors of
metalloproteinases (TIMPs) are produced by the corpus luteum and inhibit
the MMPs. Toward the end of the luteal phase, MMPs increase without a
concomitant increase in TIMPs resulting in luteal cell proteolysis.
If a successful pregnancy occurs, hCG stimulates progesterone production
by acting on hCG receptors on the corpus luteum. hCG also suppresses MMP
formation and may increase TIMP expression to prevent luteolysis. The cor-
pus luteum is a dynamic tissue and includes other cell lines besides luteal
cells, including leukocytes, fibroblasts, and endothelial cells. These other
cell lines produce substances such as interleukin-1β and TNF-α, which are
important local regulators of corpus luteum activity.
The progressive increase in luteal phase progesterone leads to gradual
slowing of LH pulses to one every 4 hours by the late luteal phase. This pro-
gressive decline in LH secretion eventually leads to gradual decreases in estro-
gen and progesterone concentrations in the late luteal phase. Progesterone
and estradiol levels begin to decrease 4 to 6 days before menses. This decline
in luteal phase steroids and inhibin concentrations results in the luteal-to-
follicular transition and allows for the initial increase in FSH immediately
before the onset of the next menses.
Endometrial Changes
The mid to late secretory endometrial glands become increasingly tortu-
ous, and the stroma becomes edematous and vascular. If implantation of
the blastocyst into the endometrium does not occur, and hCG is not pres-
ent, the glands begin to fragment and collapse in the late luteal phase.
Neutrophils and monocytes begin to infiltrate the endometrial glands and
stroma. Macrophages and neutrophils produce inflammatory proteases.
Interleukin-8 seems to play a key role in recruitment of these endometrial
immunologic cells. Neutrophils degranulate and release a wide variety of
cytokines and proteases that contribute to the degradation of the extracel-

lular matrix. Progesterone seems to inhibit endometrial production of inter-
leukin-8; declining progesterone levels permit its increase, which increases
endometrial levels of macrophages and neutrophils. Matrix metallopepti-
dases, such as collagenase, also are inhibited by progesterone via proges-
terone’s action on TGF-β. Declining levels of progesterone decrease TGF-β,
which increases matrix metallopeptidase production. The end result of the
release of these enzymatic degradative substances is disruption of the vascu-
lar endometrium with PG release, vascular thrombosis, platelet deposition,
extravasation of red blood cells, and ultimately tissue necrosis.
The current theory of endometrial sloughing is different from the classic
view that the onset of menstrual bleeding primarily resulted from hypoxia
secondary to ischemic necrosis of the endometrium. This vascular theory pro-
posed that withdrawal of estrogen and progesterone led to vasoconstriction of 31
the spiral arteries that supplied the upper two thirds of the endometrium with
resulting necrosis and sloughing of the endometrium. It is now understood
that estrogen/progesterone withdrawal results in an enzymatic degrada-
tion of the stratum compactum and some portions of the stratum spongio-
sum. Steroid withdrawal releases intracellular lysosomal enzymes, activates
inflammatory proteases, and increases the activity of proteolytic MMPs. Each
of these substances contributes to the enzymatic digestion of the stratum
functionale and results in disruption of the underlying capillary and venous
endometrial vessels. Late luteal phase progesterone withdrawal permits lyso-
somal membrane instability and the release of lysosomal intracellular prod-
ucts. These substances promote cytoplasmic digestion and degradation of the
structural elements of the extracellular matrix and basement membrane; this
results in interstitial hemorrhage and eventual sloughing of the functionale
layer and bleeding. A cleavage plane is found between the stratum functionale
and the basal layer. Menstruation begins in different areas of the endome-
trium at different times. Sloughing of the endometrium occurs predominantly
in the fundus and minimally in the isthmus or cornual regions. Autolysis with
subsequent desquamation of the stratum functionale layer begins.
Cessation of menses occurs via local vasoconstriction of the denuded spi-
ral arteries, clotting, and re-epithelialization of the sloughed endometrium.
Vasoconstriction is mediated via endothelins and PGF2α. Regeneration of the
endometrium begins 36 hours after menses onset and begins even as endo-
metrial shedding continues in other areas of the uterus. Regeneration occurs
from epithelial outgrowth from the mouths of the basal glands and ingrowth
of endometrium from the cervical and cornual regions. Bleeding ceases after
complete re-epithelialization of the endometrium is accomplished, which is
usually by cycle day 5.
SUMMARY OF KEY POINTS

1. Menarche occurs at an average age of 12.8 years in the United States.
The mean length of the menstrual cycle is 28.1 days. Great variability
exists in menstrual cycle length; 24 to 35 days is considered normal.
2. The menstrual cycle is divided into two main phases: follicular/prolifera-

tive and luteal/secretory. The follicular/proliferative phase begins with
the onset of menstrual bleeding and ends with the onset of the LH
surge. The luteal/secretory phase begins with the onset of the LH surge
and ends with the onset of the next menses.
3. The endometrium consists of two main cell layers, the deeper stratum
basale and the more superficial stratum functionale. The stratum basale
does not slough with menses. The stratum functionale proliferates in
response to estrogen and sloughs with progesterone withdrawal.
4. The dominant follicle attains its competitive advantage from the cohort
of primordial follicles during the luteal-to-follicular transition. The
dominant follicle succeeds over the surrounding follicles by its ability to
respond preferentially to FSH and local autocrine/paracrine factors to
32
maximize its production of estradiol in the follicular phase.
5. The two-cell theory of ovarian follicular development suggests that FSH
acts on granulosa cells to maximize estrogen production, and LH acts on
theca cells to produce the correct amount of androgens to maximize aro-
matization of androgens into estrogens and ultimately optimize microfol-
licular estrogen production by the dominant follicle.
SUGGESTED READINGS
Auletta FJ, Flint APF: Mechanisms controlling corpus Lockwood GM, Muttukrishna S, Ledger WL: Inhibins
luteum function in sheep, cows, nonhuman primates, and activins in human ovulation, conception and
and women especially in relation to the time of lute- pregnancy. Hum Reprod Update 1998;4:284.
olysis. Endocr Rev 1988;9:88. Munster K, Schmidt L, Hahm P: Length and variation
Brannian JD, Stouffer RL: Cellular approaches to in the menstrual cycle: a cross-sectional study from a
understanding the function and regulation of the Danish country. Br J Obstet Gynaecol 1992;99:422.
primate corpus luteum. Semin Reprod Endocrinol Pall M, Friden BE, Brannstrom M: Induction of
1991;9:341. delayed follicular rupture in the human by the
Erickson GF: An analysis of follicle development selective COX-2 inhibitor rofecoxib: a randomized
and ovum maturation. Semin Reprod Endocrinol double-blind study. Hum Reprod 2001;16:1323.
1986;4:233. Regulation of the menstrual cycle. In Speroff L, Fritz
Giudice LC: Insulin-like growth factors and ovarian MA (eds): Clinical Gynecologic Endocrinology and
follicular development. Endocr Rev 1992;13:641. Infertility, 7th ed. Philadelphia: Lippincott Williams
Hedricks C, Piccinino LJ, Udry JR, Chimbira TH: & Wilkins; 2005:195.
Peak coital rate coincides with onset of luteinizing Shaw ST Jr, Roche PC: Menstruation. In Finn CA (ed):
hormone surge. Fertil Steril 1987;48:234. Oxford Reviews of Reproduction and Endocrinology,
Katt JA, Duncan JA, Herbon L, et al: The frequency vol 2. London: Oxford University Press; 1980.
of gonadotropin-releasing hormone stimulation Welt CK, Pagan YI, Smith PC, et al: Control of
determines the number of pituitary gonadotropin- follicle-stimulating hormone by estradiol and the
releasing hormone receptors. Endocrinology inhibins: critical role of estradiol at the hypothala-
1985;116:2113. mus during the luteal-follicular transition. J Clin
Liu JH, Yen SS: Induction of midcycle gonadotropin Endocrinol Metab 2003;88:1766.
surge by ovarian steroids in women: a critical evalua-
tion. J Clin Endocrinol Metab 1983;57:797.
3
NORMAL AND
ABNORMAL PUBERTY
Stephen M. Scott
DEFINITIONS
33
Precocious Early pubertal initiation, traditionally defined as younger than 8 years of
puberty age; more recent modifications of this definition are controversial
Central preco- Early pubertal development as a result of premature development of the
cious puberty hypothalamic-pituitary-ovarian axis
Peripheral pre- Early pubertal development resulting from stimulation independent of
cocious puberty the hypothalamic-pituitary-ovarian axis
Mixed preco- Peripheral precocious puberty that triggers central precocious puberty
cious puberty owing to persistent exposure to elevated estrogen levels
Premature Isolated breast tissue development
thelarche
Premature Pubic hair development without any other evidence of sexual
adrenarche development before age 8 in girls and 9 in boys
Puberty marks a time when young women experience some of the most
intense physical, emotional, and social changes of their lives. Puberty reflects
a complex mechanism of signaling between the brain, adrenal gland, and
ovaries that is influenced by genetic, nutritional, and health factors. In con-
trast to other animal species, the initiation of pubertal changes in humans
can vary over a span of 4 to 5 years. This individual variability is due to differ-
ences in genetic signaling and other environmental influences. Alterations
in the timing of this signaling can have a profound impact on final adult
height, sexual development, self-image, and psychosocial interactions with
others.
HORMONAL RESPONSES IN CHILDHOOD AND PUBERTY
The hormonal mechanisms that initiate and maintain the physical changes
of puberty include gonadotropin-releasing hormone (GnRH) signaling from
the hypothalamus that stimulates the pituitary gland to secrete follicle-stimu-
lating hormone (FSH) and luteinizing hormone (LH). The pituitary hormones
stimulate ovarian production of androgens, estrogens, and progesterone to
bring about the end-organ changes seen in pubertal development and adult
function. Hypothalamic and pituitary signals also stimulate androgen pro-

duction from the adrenal glands during this time. The hypothalamic-pitu-
itary-ovarian (HPO) axis signaling system develops in fetal life and is able to
function at any point thereafter if the proper stimuli are present. Within a
short time, however, the system undergoes profound inhibition and is kept in
check until late in childhood or early teenage years, when it is reawakened.
Gonadotropin- GnRH release, in pulsatile bursts, is the key to turning on the HPO axis sys-
Releasing tem. GnRH is produced from neurons that migrate from the olfactory area
Hormone into hypothalamic areas of the midbrain early in fetal development. Pulsatile
release from these cells is coordinated by a mechanism called the GnRH pulse
generator. The pulse generator is active in the newborn under the influence
34 of maternal and placental hormonal exposure. The intensity and frequency
of GnRH pulses (indirectly measured through LH pulse levels) are compa-
rable to adults during this time. The pulse generator is quickly dampened
and GnRH release is held in check throughout childhood. Inhibition of the
pulse generator is achieved through upstream signaling from the brain and
other outside sources. In girls, the small amount of estrogen produced by
the ovary provides a strong negative feedback signal to the pulse genera-
tor. Estrogen is not the primary mechanism preventing GnRH pulse release,
however. It has been shown in humans with nonfunctioning gonads and
primate animal models with gonadectomies that GnRH pulse suppression
in childhood and its release in adolescence are maintained. Although the
mechanisms behind a primary pulse suppressor are not completely under-
stood, there are currently two substances that seem to be leading candidates
for that role—neuropeptide Y (NPY) and leptin. Male primate animal models
(and female models to a lesser extent) have shown that NPY, a polypeptide
produced in the hypothalamus, exerts suppressive effects on GnRH pulses.
NPY plays a role in nutritional regulation. It is elevated in starvation states
and stimulates a hyperphagic response thought to aid in caloric intake. NPY
levels decrease as fat stores accumulate. This possible mechanism is intrinsi-
cally appealing because of its obvious bridge between nutritional status and
reproductive function. Puberty is a time of intense metabolic expenditure
(pregnancy being even greater). It is important to have adequate calorie
supplies before initiating HPO axis function. Studies in female primates also
have shown γ-aminobutyric acid to suppress GnRH pulse activity. Further
studies are needed to understand better how NPY and γ-aminobutyric acid
function in suppressing the reproductive system in childhood.
In late childhood, the mechanism that was suppressing GnRH pulses is
withdrawn, and the HPO axis reawakens. It has been known for some time
that a link exists between nutrition and the initiation of puberty. The average
age at menarche in the United States and the beginning of the 20th century
was around 16 years. Currently, the average age is around 12½ years in the
United States and other industrialized countries. Improved nutritional sta-
tus over this time is thought to have a significant influence on pubertal tim-
ing. Some investigators linked an absolute weight or body mass index with
the start of puberty. Other investigators thought that attaining a specific
Normal and Abnormal Puberty
fat proportion was necessary. The discovery of leptin and its interaction
with NPY has led to research linking its role in release of GnRH suppres-
sion. Leptin is a polypeptide that is produced by the so-called “ob” gene in
adipose cells. As fat accumulates with increased caloric intake, leptin levels
increase. Leptin is thought to promote satiety by negative feedback signal-
ing on NPY production from the hypothalamus. Nutritional homeostasis is
influenced by their interaction. Initially, it was assumed that leptin was the
signal that released the GnRH pulse generator from its suppression to initi-
ate puberty. Researchers found that LH pulses begin after a critical level of
leptin is attained, and administering adult doses of leptin to achieve GnRH
pulse responses in agonadal states has achieved variable results. It is cur-
rently thought that leptin plays a permissive role in initiating the timing of
puberty, but it is not the primary signal that restarts the GnRH pulse genera-
tor. As with its suppression, the mechanism behind the reawakening is not 35
completely understood, and further investigation is required.
Pituitary Gland When suppression of the pulse generator is removed, the hypothalamus
begins secreting GnRH into the portal blood system of the pituitary. Pituitary
secretion of FSH and LH are detected. Gonadotropin pulses initially occur at
night. Late in puberty, FSH and LH pulses are detected at night and during
the day.
Ovary LH receptors on theca cells in the stroma of the ovary stimulate the conver-
sion of cholesterol to androgens. These androgens travel by diffusion to the
granulosa cells within ovarian follicles. FSH binding in these cells stimulates
aromatase enzyme activity to convert androgens into estrogens. Estradiol
and androgen levels increase over time and result in end-organ stimulation
and physical changes seen in puberty. Ovulatory cycles and progesterone
production do not occur initially and may take up to 4½ years to develop.
Adrenal Gland Although the physical sign of pubic and axillary hair growth occurs within
the time frame of other pubertal changes, the androgen production that stim-
ulates this seems to be separate from ovarian production. The maturation of
the adrenal cortex, adrenarche, seems to be the source of androgens that
produce sexual hair growth or pubarche. Adrenarche begins approximately
2 years before the reactivation of the HPO axis. In contrast to the gonad,
which is quiet during childhood because of GnRH pulse suppression, the
adrenal glands seem to increase androgen secretion steadily, but gradually, as
the zona reticularis of the adrenal cortex matures. Dehydroepiandrosterone
and dehydroepiandrosterone sulfate are the primary androgens secreted
from this area of the adrenal gland. This process occurs in parallel with, but
independent from, gonadal hormone production. Investigations supporting
this view note that secondary hair growth continues in the face of gonadal
agenesis and hypothalamic hypogonadism. Isolated premature pubarche is
not associated with increased gonadal hormone production, and patients
with adrenal insufficiency continue to go through the appropriate pubertal

changes governed by gonadal hormone production.
Growth Growth hormone (GH) plays an important role in pubertal development.

Hormone Delays in growth are seen in patients with gonadal insufficiency or GH-
deficient states highlighting the need of both systems to achieve optimal
growth. Bone maturation is mediated by insulin-like growth factor produced
by GH stimulation of the liver. GH secretion tends to remain steady during
childhood, but increases fivefold at the onset of puberty. GH stimulation at
puberty seems to be regulated by estrogen in girls and boys. Low levels of
estrogen seem to increase GH activity, whereas high levels may exert an
inhibitory response. The earlier onset of ovarian hormone production fol-
36 lowed by relatively higher estradiol production in girls compared with boys
explains the GH-mediated growth acceleration that occurs approximately
2 years earlier in girls and the extended growth period seen in boys lead-
ing to an average final height difference of 13 cm between genders. GH also
plays a role in gametogenesis in the gonad and increased sensitivity of the
follicle to gonadotropic stimulation.
PHYSICAL SIGNS OF PUBERTY
The physical changes of puberty are produced by estrogens from gonadal

production and androgens from the adrenal gland. Variations in onset of
puberty are determined by genetic predisposition, environmental factors,
gender, and ethnicity. Adrenarche, the increase in adrenal androgen produc-
tion, begins around age 6. Ovarian estradiol production begins nearer to 8
years of age (Table 3-1).
Breast The earliest physical sign of puberty is breast development, or thelarche. The
median age of thelarche in the United States is 9.8, years, with differences
seen between ethnic groups. The start of breast maturation can range from
age 8 to 12. Tanner describes five stages of development from prepubertal
to adult appearance (Box 3-1). Tanner stage I is prepubertal, II has small
mounds of breast tissue under the areola, III has further enlargement, IV has
a secondary mound of areola tissue above the breast, and V has a recession of
the areola mound and final adult contour. Completion of breast development
occurs over a 5-year period.
Sexual Hair Although adrenal androgens begin to increase 2 years before ovarian hor-
mones, pubarche is usually the second physical sign of puberty. Sexual hair
growth becomes evident at a median age of 10.5 years in girls living in the
United States. Timing of initial hair growth ranges from age 9 to 13. Tanner
staging also describes progression of hair growth (Box 3-2). Stage I is pre-
pubertal. Stage II has sparse hair along the labia majora. Stage III has dark,
Table 3-1
Median Ages at Entry Age at Entry
into Each Maturity
Stage and Fiducial Non-Hispanic White Non-Hispanic Black Mexican-American
Limits (FL)* in Years Stage Median FL Median FL Median FL
for Pubic Hair and
Breast Development Pubic Hair
in Girls by Race PH2 10.57† 10.29-10.85 9.43† 9.05-9.74 10.39 —
PH3 11.80† 11.54-12.07 10.57† 10.30-10.83 11.70† 11.14-12.27
PH4 13.00† 12.71-13.30 11.90† 11.38-12.42 13.19† 12.88-13.52
PH5 16.33† 15.86-16.88 14.70† 14.32-15.11 16.30† 15.90-16.76
Breast Development
B2 10.38† 10.11-10.65 9.48† 9.14-9.76 9.80 0-11.78
B3 11.75† 11.49-12.02 10.79† 10.50-11.08 11.43 8.64-14.50
B4 13.29† 12.97-13.61 12.24† 11.87-12.61 13.07† 12.79-13.36
B5 15.47† 15.04-15.94 13.92† 13.57-14.29 14.70† 14.37-15.04 37
*
Calculated 98.3% FLs to adjust for multiple comparisons between races for an overall α of
0.05.
†
Significant pair-wise racial difference, P<.05.
From Sun SS, Schubert CM, Chumlea WC, et al: National estimates of the timing of sexual
maturation and racial differences among US children. Pediatrics 2002;110:911-919.
coarse hair over the mons. Stage IV has abundant adult hair limited to the
labia and mons. Stage V has adult type hair spread above the mons and over
the inner thighs. Typically, complete hair development is seen within 3 years.
Growth Spurt The median age of maximal growth velocity is 11½ years (range of 9½-14
years). Growth typically slows just before puberty, then accelerates approxi-
mately 2 years into puberty. A period of acceleration is seen for a little more
than 2 years. Further growth ceases in girls when the bone age approaches
15 years, and the epiphyseal plates close. Girls begin their growth spurts
approximately 2 years earlier than boys and gain an average of 25 cm during
puberty. Significant weight gain also is seen during puberty. Fifty percent of
Box 3-1 Tanner Staging System for Breast Development

I—preadolescent, papilla elevation only
II—breast bud palpable, increased areolar diameter
III—breast contour diffusely enlarged
IV—secondary mound formed by areola and papilla
V—adult breast contour, areola and breast continuous
Box 3-2 Tanner Staging System for Pubic Hair Development

I—none
II—sparse, long coarse hair on labia
III—coarse, darkly pigmented, curly, spread to pubis
IV—adult-quality hair over pubis
V—adult distribution with spread to medial thighs
adult body weight is gained during adolescence. Weight gain in boys paral-
lels their growth spurt while lagging by 6 months compared with girls. Peak
weight gain velocity reaches 8.3 kg/yr by 12.5 years of age, then decelerates
with the deceleration in height velocity later in puberty.
Menarche Continued estrogen exposure leads to increased endometrial cell mitosis and
the proliferation of the endometrial layer in the uterus. Shedding of estro-
gen-primed endometrium, or menarche, occurs with variations in estrogen
levels. Menarche is usually the last physical sign of puberty. The normal age
range of menarche in the United States is 9 to 17½ years with a median age
of 12½ years. Ethnic differences are associated with varying times of men-
arche. African-American girls achieve menarche an average of 8.5 months
38 before white girls. The HPO axis does not mature immediately, and 12 to
18 months may pass before ovulation, progesterone production, and regular
menstrual cycles occur.
INFLUENCES IN THE TIMING OF PUBERTY
The onset of puberty in girls can be difficult to track because of various

internal and external influences. Improvement in environmental condi-
tions led to a steady decrease in timing of menarche from the early 1900s
to the 1960s. A reduction of approximately 4 months per decade has been
calculated. Since 1960, the timing of menarche has reached a plateau in
industrialized countries. Although the overall variability is remarkably small
(1 year), the range in age of menarche in industrialized countries may nor-
mally be 5 years. Studies comparing monozygotic twins, dizygotic twins,
nontwin sisters, and unrelated groups note progressive variance in timing
of menarche. These findings suggest that genetic factors, including ethnic-
ity, constitute approximately three quarters of the influence on timing of
puberty, whereas environmental factors contribute the remaining quarter.
Environmental factors may include locale, climate, light-dark cycles, nutri-
tion, intrauterine growth restriction, stress, illness, and toxin exposure.
ABNORMAL PUBERTAL DEVELOPMENT
Abnormal pubertal development can be divided into conditions that initiate

pubertal changes too early or prevent timely development. Early or preco-
cious puberty can occur at any stage in childhood. Girls constitute most chil-
dren with this condition. Delayed puberty is seen more frequently in boys.
Precocious It has long been established that the lower limit of normal for pubertal ini-
Puberty tiation is 8 years of age. Normative curves in several populations have set
this age limit. The Pediatric Research in Office Settings (PROS) study noted,
however, that a large percentage of girls starting puberty when younger
than the established limit achieved normal adult height and had no long-
term physical sequelae. This led the PROS authors to recommend redefining
precocious puberty as thelarche beginning by age 6 in African-American
girls and by age 7 in white girls. Other groups have not embraced this recom-
mendation and continue to use 8 years of age as the lower limit of normal.
They cite concerns regarding the accuracy of the study methods in dating
thelarche. Multiple observers could have led to unreliable variance. Staging
was decided using visual inspection of the breast instead of palpation. Visual
inspection may not distinguish reliably true breast tissue development from
visual changes of general increased adiposity in overweight children, inac-
curately decreasing the age of thelarche. Other studies have noted that in
children 6 to 8 years old who would have been classified as normal under
the revised criteria, nearly half had an underlying disease. Concerns about
the psychosocial impact that untreated pubertal changes may have on such 39
young children also have been raised.
Precocious puberty may be divided into central or peripheral causes.
Central precocious puberty (CPP) is mediated by the premature awakening
of hypothalamic signals that stimulate ovarian hormone production. Most
CPP, approximately three quarters, is idiopathic in etiology (Fig. 3-1). The
remaining causes are due to a mass effect in the hypothalamic or pituitary
Figure 3-1
A 2-year-old girl with
idiopathic central
precocious puberty.
areas of the brain leading to stimulation of GnRH or FSH and LH produc-

tion. Because a brain mass may have serious consequences, idiopathic CPP
should be a diagnosis of exclusion. Masses that arise from the brain to cause
CPP include pituitary hamartomas (the most common tumor in CPP occur-
ring in children <6 years old), craniopharyngiomas, gliomas, adenomas,
and arachnoid cysts. Pressure and inflammation may stimulate gonado-
tropin release owing to hydrocephalus, abscess, sarcoidosis, tuberculosis,
trauma, radiation, or chemotherapy (Table 3-2).
Peripheral precocious puberty (PPP) does not depend on GnRH or pituitary
hormone signaling to produce ovarian sex hormones. Causes include estro-
gen-producing tumors of ovary or adrenal glands and exogenous estrogen
sources (Table 3-3). McCune-Albright syndrome is associated with excessive
secretion of estrogen from the ovary and benign cyst formation, which also
40 may secrete estrogen independent from gonadotropin signals (Fig. 3-2).
Diagnosis of The physical signs of estrogen stimulation, breast development and pubic
Precocious hair growth before age 8 years, may make the diagnosis of precocious
Puberty puberty obvious. Occasionally, menarche may occur before breast and hair
growth, however. Inspection of the vaginal tissue during the workup of
childhood vaginal bleeding may reveal signs of estrogen stimulation of the
Table 3-2
Etiology of Central Category Underlying Disease
Precocious Puberty
(Gonadotropin- Permanent precocious puberty
Dependent, True) Idiopathic Sporadic
Familial
CNS abnormalities or lesions Hypothalamic hamartoma
Tumors: astrocytoma, craniopharyngioma,
ependymoma, glioma, LH-secreting adenoma,
pinealoma
Congenital malformations: arachnoid cyst,
suprasellar cyst, phakomatosis, hydrocephalus
(with or without spina bifida), septo-optic
dysplasia
Acquired disease: inflammatory CNS disease,
abscess, radiation, chemotherapy, trauma
Dysmorphic syndromes Williams-Beuren syndrome
Klinefelter’s syndrome (rare)
CNS maturation with central Congenital adrenal hyperplasia
precocious puberty Sex steroid–producing tumors
secondary to prolonged Male-limited precocious puberty (constitutively
sex steroid exposure activated LH receptor
Transient precocious puberty Sporadic
Idiopathic Arachnoid cyst
Hydrocephalus
Variants of pubertal Premature thelarche
development (partial Premature pubarche
or incomplete precocity) Premature menarche
CNS, central nervous system; LH, luteinizing hormone.

From Partsch CJ, Sippell WG: Pathogenesis and epidemiology of precocious puberty. Effects of
exogenous oestrogens. Hum Reprod Update 2001;7:292-302.
Table 3-3
Etiology of Peripheral
Category Underlying Disease
Precocious Puberty
(Gonadotropin- Ovarian disorders Granulosa cell tumor
Independent, Theca cell tumor
Pseudopuberty) Other estrogen-secreting tumors: teratoma, teratocarcinoma,
dysgerminoma, luteoma, mixed cell tumor, lipoid tumor
Sex cord or Sertoli cell tumor of the ovary with annular tubuli
seminiferi (SCTAT) and aromatase activity in Peutz-Jeghers
syndrome
McCune-Albright syndrome (ovarian cysts)
Autonomous isolated ovarian cysts
Testicular disorders Leydig cell adenoma
Constitutively activating LH receptor mutation (male-limited
precocious puberty = testotoxicosis)
Adrenal disorders Adrenal adenoma
Adrenal carcinoma (usually virilizing) 41
Congenital adrenal hyperplasia (21-hydroxylase or
11β-hydroxylase deficiency)
hCG-secreting Dysgerminoma, teratoma, chorioepithelioma,
tumors choriocarcinoma, hepatoblastoma, pinealoma
Exogenous Sex-steroid exposure: pills (estrogens, anabolics), food
additives, cosmetics, creams
Transient Autonomous isolated ovarian cysts (self-limiting)
precocious Exogenous (interruption of exposure)
puberty
hCG, human chorionic gonadotropin.
From Partsch CJ, Sippell WG: Pathogenesis and epidemiology of precocious puberty. Effects of
exogenous oestrogens. Hum Reprod Update 2001;7:292-302.
mucosa (Box 3-3). A wet preparation of the mucosa may be done to perform
a maturation index. Abundance of superficial epithelial cells suggests the
presence of estrogen production. Growth curve plots may reveal acceleration
in height and change to a higher percentile. Current estradiol assays are not
always accurate in diagnosing precocious puberty. A bone age derived from
wrist x-rays, compared with age-standardized films, helps to dif ferentiate
progressive precocious puberty from more benign forms of early thelarche
and pubarche.
When the diagnosis of precocious puberty is suspected, LH and FSH levels
should be drawn to differentiate between CPP and PPP. Elevated values into
the pubertal range are consistent with CPP. Equivocal results may require a
subsequent GnRH stimulation test. LH and FSH levels, drawn 30 minutes
after a 100-μg injection of GnRH, lead to exaggerated serum levels in cases
of CPP. A peak LH level of more than 15 IU/L or a peak LH-to-peak FSH
ratio of more than 0.66 is consistent with a pubertal GnRH test with 96%
sensitivity, 100% specificity, and no false-positive results. The independent
estrogen production in PPP leads to suppressed LH and FSH levels.
Imaging of the head should be performed in all cases of CPP to rule out
a mass. Magnetic resonance imaging (MRI) has been shown to have the
highest sensitivity in detecting masses in the pituitary and hypothalamic
regions. When PPP is suspected, a thorough history should be taken to rule
out exogenous estrogen consumption. Also, imaging of the ovary and adre-
nal glands should be performed to rule out a tumor in those organs.
Figure 3-2
A 4-year-old girl with
McCune-Albright
syndrome. Note café-
au-lait spots on mons
and inner thigh.
42
Box 3-3 Useful Methodologies in the Diagnosis of Precocious Puberty

● Maturation index of vaginal mucosa
● Growth curve
● Right radial bone age
● Serum LH, FSH
● GnRH stimulation test
● MRI of head
● Ovarian ultrasound
● Adrenal computed tomography
Treatment of Any girl younger than age 8 with physical signs of puberty, significantly
Precocious advanced bone age, decreased predicted height, and a pubertal response
Puberty to GnRH stimulation should be treated to suppress CPP progression and
improve adult height (Box 3-4). Surgical therapy is limited to a few cases of
CPP in which there is a lesion present. Only lesions that arise from a pedun-
culated stalk are usually amenable to surgical removal. It may be too difficult
to remove nonpedunculated lesions without sacrificing some normal tissue
surrounding these lesions.
Box 3-4 Possible Treatments of Precocious Puberty

● Surgery if accessible central lesion identified
● GnRH-agonist therapy
● GH
● Removal of ovarian or adrenal tumors
● Removal of exogenous source of estrogen
● Removal of cysts in McCune-Albright syndrome
● Aromatase inhibitors in McCune-Albright syndrome
Medical therapy is the treatment of choice for most lesions and idio-
pathic CPP. Therapy involves continuous doses of GnRH agonists in the
form of daily nasal spray inhalation or monthly or quarterly intramus-
cular injections. The continuous GnRH agonist levels override the pulsa- 43
tile GnRH signals coming from the hypothalamus and suppress ovarian
hormone production. Serial examinations during treatment should reveal
reversal of pubertal signs, decrease in growth velocity, and slowing of bone
maturation. Laboratory values should revert to prepubertal values. This
monitoring may include LH, FSH, and estradiol levels drawn 12 hours
after the next monthly injection of GnRH agonists or a random ultrasensi-
tive estradiol.
GH secretion also may be suppressed when brain lesions are present.
Decreased GH levels also have been noted in idiopathic CPP. Reduced GH
stimulation of bone may reduce height velocity when GnRH treatment is
initiated. If height velocity is suppressed, and a shortened adult height is pre-
dicted, GH administration combined with GnRH treatment may re-establish
bone growth and improve final adult height.
Treatment of PPP involves removal of the independent estrogen source
through surgical removal in the cases of ovarian or adrenal tumors or dis-
continuation of an exogenous estrogen source. As estrogen levels begin to
decrease with treatment, breast development and genital mucosal changes
often revert to prepubertal appearance. Height acceleration should dimin-
ish, and if epiphyseal plate closure has not occurred, growth along the
established curves should continue. Removal of cysts in patients with
McCune-Albright syndrome may provide temporary reductions in estro-
gen production. Treatment with aromatase inhibitors has achieved limited
success.
Early diagnosis and treatment of precocious puberty is essential to opti-
mize final adult height. When Tanner stage III breasts develop, it becomes
difficult to achieve significant gains in height. Treatment of girls with short
stature who began puberty on the early end of the normal age range does
not result in additional final height.
Mixed High levels of estrogen eventually can stimulate the hypothalamus to begin
Precocious secreting GnRH pulses. An initial PPP etiology may lead to CPP. This com-
Puberty bination of stimulation is known as mixed precocious puberty. Monitoring
pubertal progression is important after treatment has been initiated to
prevent overlooking this phenomenon. Initial laboratory tests noting an ele-

vation in FSH and LH levels suggest a CPP. If progression in pubertal changes
continues despite adequate GnRH suppression, however, an ovarian, adre-
nal, or exogenous source of estrogen should be ruled out. If a PPP source is
initially found and treated, follow-up evaluations are needed to ensure the
reversal of pubertal changes. If progression continues, a repeat evaluation
of the FSH and LH levels should be considered to rule out secondary stimu-
lation of the hypothalamus; this may require initiating GnRH treatment to
address the new central source of ovarian stimulation.
Premature Premature thelarche is a benign condition that can be seen at a very early
Thelarche age. It consists of isolated breast tissue development. Areolar development
44 usually is unaffected. It tends to be self-limited and does not show signs of
progressive precocious puberty. Pubic hair growth, height and bone age
acceleration, early epiphyseal closure, and shortened adult stature are not
seen. The initial presentation of premature thelarche cannot be distin-
guished easily from early stages of progressive precocious puberty. Both con-
ditions may show mild increases in serum estradiol, normal basal FSH levels,
and an exaggerated FSH response to GnRH stimulation with a less drastic
increase in LH levels. Elevated basal FSH and LH levels and predominant LH
stimulation from GnRH administration do not occur until late stages of pre-
cocious puberty are established. Premature thelarche and central precocious
puberty may represent different points of severity along a spectrum of early
HPO axis activation. Serial monitoring of puberty changes, growth accel-
eration, and bone age may be needed to document stabilization or regression
and to confirm the final diagnosis of isolated premature thelarche.
Premature Premature adrenarche refers to early development of pubarche with no other

Adrenarche signs of sexual development before the age 8 in girls and 9 in boys. Girls are
affected more often than boys by a ratio of 10:1. Premature adrenarche is
due to an early isolated maturation of the adrenal gland. Gonadotropins do
not play a role in the development of premature adrenarche. Hair growth
usually is limited to the labia majora, clitoral enlargement is usually absent,
and breasts remain prepubertal. Mild increases in androgen levels, growth
velocity, and bone age can be seen. Progressive androgenizing disorders,
such as progressive precocious puberty, a virilizing adrenal or ovarian
tumor, adult-onset congenital adrenal hyperplasia, and exogenous andro-
gen administration, must be ruled out before making the diagnosis of iso-
lated premature adrenarche. Acceleration in growth and bone maturation
seems to be transient. There is no difference in onset of puberty or final adult
height compared with controls. Premature adrenarche has been associated
with hyperandrogenism, reduced ovulatory function, polycystic ovary syn-
drome, hyperinsulinemia, and alterations in triglyceride levels later in adult-
hood. Patients with premature adrenarche should be monitored for these
conditions as they progress through adolescence.
Delayed Puberty Delayed puberty is diagnosed when there is no breast development by 13.4
years in girls and no testicular development by 14 years in boys. Causes
include constitutional delay, chronic illness, hypothalamic or pituitary fail-
ure from destructive lesions, hypothyroidism, hyperprolactinemia, excessive
exercise, inadequate caloric intake, and ovarian failure. A constitutional delay
is more common in boys. It should be a diagnosis of exclusion. Evaluation of
delayed puberty is considered further in Chapter 4.
Abnormal Breast Normal breast development begins early in fetal life. A primary mammary
Development bud grows into surrounding mesenchyme from the epidermis of the pectoral
region by week 6. In the second trimester, 15 to 25 secondary buds form and
lead to lactiferous ducts that end at the nipple. Fibrous stroma and fat from
the mesenchyme surround the duct systems. Late in the third trimester, the 45
nipple and areola arise from the mammary pit. The breast remains virtually
unchanged during childhood. Pubertal breast development occurs over 3 to
5 years during puberty under the primary influence of estrogen. FSH, LH,
GH, and adrenocorticotropic hormone contribute to duct growth. In most
cases, an unknown mechanism arrests further breast development late in
puberty.
Breast hypoplasia describes a condition in which breast tissue fails to
grow despite the presence of normal structures such as nipples. Amastia
signifies the complete absence of breast tissue, including the nipples. Some
asymmetry of the breasts can be seen in most women and does not require
intervention. Significant asymmetry can be quite troubling and may war-
rant intervention. Hypoplasia has been associated with chromosomal aber-
rations, trauma, congenital defects of the pectoralis major muscle (Poland’s
syndrome), and hormone receptor abnormalities. Attempts to stimulate
growth with estrogen may provide some improvement in breast size, but sur-
gical therapy with implants or autologous tissue may be required.
Juvenile gigantomastia usually presents with rapid growth of one or both
breasts to massive proportions. Enlargement begins during the early pubertal
period. Accelerated growth lasts 3 to 6 months followed by slower, but steady
growth indefinitely. Symptoms include breast pain, back and neck pain,
slouching posture, shoulder grooving from bra straps, hygienic difficulties,
and orthopnea. Physical changes may include skin necrosis and changes in
spinal alignment. Psychosocial concerns also are significant. Breast reduc-
tion surgery is the primary initial treatment, but recurrent hypertrophy
often occurs without additional therapy. Repeat reductive surgery is often
required. Definitive treatment involves mastectomy with implants to prevent
recurrence. Tamoxifen has shown some success in slowing recurrent growth
after initial surgery.
Labial Before puberty, the labia minora appear as small prominences extending
Hypertrophy just inferior from the clitoral hood. Proliferation in size and shape occurs
at puberty under the influence of estrogen. Asymmetry is common, and in
some instances the tissue may grow quite large. Lengths of 4 to 5 cm are
generally regarded as hypertrophic, but significance is related primarily
to symptoms of pain with sitting or intercourse or patient concerns about
appearance. Histologic examination shows dilated blood vessels and edema-
tous stroma. Infiltration of lymphocytes in close proximity to blood vessels
also suggests a possible inflammatory process. The cause of labial hypertro-
phy is unknown. Filaria sanguinis-hominis infection may cause blockage of
the lymph channels, and consequently labial edema may occur to mimic
true hypertrophy. Chronic stimulation from constant pulling, myelodyspla-
sia, and chronic diaper use have been associated with the condition. Surgical
correction is usually successful.
46 SUMMARY
A complex pathway of signals between the brain, adrenal gland, and ovaries
initiates puberty at the end of the first decade of life. The system has the abil-
ity to activate at any time in childhood, but is held in check by several regu-
latory mechanisms. Timing of puberty is influenced by genetics, nutrition,
the environment, and health factors. Alterations in the timing of puberty
are usually idiopathic, but can herald underlying lesions within the brain,
adrenal gland, or ovary. Failure to identify these lesions may result in serious
injury in the short-term. Failure to treat precocious puberty in a timely man-
ner may affect potential height, sexual development, self-image, and social
interactions later in life. Asymmetry of breast and labial tissue is common
and in most cases does not require treatment. Surgical intervention usually
is required to treat rare cases of severe, symptomatic growth abnormalities.

1. The HPO axis has the capacity to function at any point after fetal life,
but is kept in check until puberty by an unclear mechanism outside of
the system.
2. Nutritional homeostasis, regulated by NPY and leptin, may play a role in
the timing of pubertal development.
3. Adrenarche, and its subsequent development of sexual hair, occurs in
parallel to, but separate from, secondary sexual developments regulated
by the ovaries—breast development, growth spurt, and menarche.
4. Pubertal changes typically begin with thelarche between ages 8 and 12.
The time from early breast development until menarche is generally
2½ years. It may take another 2 years after menarche to begin ovulatory
cycles.
5. The timing of puberty in industrialized countries has stabilized since
the 1960s with little variation in average age of pubertal development.
Individual variations of pubertal timing range from 4 to 5 years within a
group. Developing countries continue to have wider ranges of puberty
timing secondary to various nutritional and environmental factors.
6. Precocious puberty is more common in girls. Delayed puberty is more

common in boys.
7. Idiopathic precocious puberty is the most common cause of early
puberty, but should remain a diagnosis of exclusion until other, more
health-threatening causes have been ruled out.
8. GH levels should be monitored before treatment for CPP. Failure to
diagnose and treat a coexistent GH deficiency hinders maximum growth
potential.
9. Serial monitoring should be performed during the treatment of preco-
cious puberty to rule out a mixed etiology.
47
SUGGESTED READINGS
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pulse generator activity during pubertal transition Endocrinol Metab 2002;87:2090-2094.
in girls: pulsatile and diurnal patterns of circu- Lee PA, Guo SS, Kulin HE: Age of puberty: data from
lating gonadotropins. J Clin Endocrinol Metab the United States of America. APMIS 2001;109:81-88.
1993;76:940-949. Marshall WA, Tanner JM: Variations in patterns
Cunningham MJ, Clifton DK, Steiner RA: Leptin’s of pubertal changes in girls. Arch Dis Child
actions on the reproductive axis: perspectives and 1969;44:291-303.
mechanisms. Biol Reprod 1999;60:216-222. Oerter KE, Uriarte MM, Rose SR, et al: Gonadotropin
Frisch RH: Pubertal adipose tissue: is it necessary for secretory dynamics during puberty in normal
normal sexual maturation? Evidence from the rat and girls and boys. J Clin Endocrinol Metab 1990;
human female. Fed Proc 1980;39:2395-2400. 71:1251-1258.
Grumbach MM: Estrogen, bone, growth, and sex: a sea Pasquino AM, Municchi G, Pucarelli I, et al: Combined
change in conventional wisdom. J Pediatr Endocrinol treatment with gonadotropin-releasing hormone
Metab 2000;13(suppl 6):1439-1455. analog and growth hormone in central precocious
Herman-Giddens ME, Slora EJ, Wasserman RC, et puberty. J Clin Endocrinol Metab 1996;81:948-951.
al: Secondary sexual characteristics and menses in Rosenbaum M, Leibel RL: Leptin: a molecule integrat-
young girls seen in office practice: a study from ing somatic energy stores, energy expenditure and
the Pediatric Research in Office Settings network. fertility. Trends Endocrinol Metab 1998;9:117-124.
Pediatrics 1997;99:505-512. Spiliotis BE: Growth hormone insufficiency and its
Jaffe RB: Fetal neuroendocrinology. In Mancusco S impact on ovarian function. Ann N Y Acad Sci
(ed): Achievements in Gynecology. Basel/ New York: 2003;997:77-84.
Karger; 1989:104-110. Sun SS, Schubert CM, Chumlea WC, et al: National
Kaplowitz PB, Oberfield SE: Reexamination of the age estimates of the timing of sexual maturation and
limit for defining when puberty is precocious in girls racial differences among US children. Pediatrics
in the United States: implications for evaluation and 2002;110:911-919.
treatment. Drug and Therapeutics and Executive Tanner JM: Fetus into Man: Physical Growth from
Committees of the Lawson Wilkins Pediatric Conception to Maturity. Cambridge, MA: Harvard
Endocrine Society. Pediatrics 1999;104:936-941. University Press; 1989.
Lazar L, Kauli R, Pertzelan A, Phillip M: Terasawa E, Fernandez DL: Neurobiological mecha-
Gonadotropin-suppressive therapy in girls with nisms of the onset of puberty in primates. Endocrinol
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4
EVALUATION AND
TREATMENT OF
AMENORRHEA
Bruce R. Carr
49
DEFINITIONS
Amenorrhea Cessation of menstrual flow
Androgen Rare disorder resulting in external female appearance, but with absent
insensitivity uterus, ovaries, and a large part of the vagina, caused by the absence of
syndrome functional androgen receptors
Kallmann’s Low gonadotropin levels, amenorrhea, and anosmia (absent sense of
syndrome smell); the constellation is due to the failure of normal migration of
olfactory and gonadotropin neurons during embryologic development
Sheehan’s Postpartum pituitary necrosis caused by hemorrhage and resulting
syndrome profound hypovolemia
DEFINITION
The usual definition of amenorrhea is the cessation of menstrual flow.

Primary amenorrhea is a condition characterized by absence of menstrua-
tion by age 16 in phenotypic females, commonly due to gonadal dysgene-
sis. Secondary amenorrhea is a condition characterized by the cessation of
menstruation for periods of 3 months or longer in a woman who previously
has experienced spontaneous menstruation (Box 4-1). A common cause of
secondary amenorrhea is polycystic ovarian syndrome (PCOS). Although
these definitions are useful, there is significant overlap between different
disorders that manifest with primary amenorrhea. Women with PCOS may
present with a history of no bleeding, and women with gonadal dysgenesis
may have occasional menses. We prefer to classify patients with amenorrhea
in functional groups as described in Box 4-2 and Table 4-1.
CLASSIFICATIONS OF AMENORRHEA
Women who present with delayed puberty also have amenorrhea and
should not be considered as a separate entity. Women who present with
Box 4-1 Definition of Amenorrhea

● Primary amenorrhea: failure of menarche by age 16
● Secondary amenorrhea: absence of menstruation for 3 months in a woman with
previous spontaneous menses
Box 4-2 Classifications of Amenorrhea

1. Gonadal failure
2. Chronic anovulation
With estrogen present
With estrogen absent
3. Defects of female reproductive tract
50
Table 4-1
Classification of I. Anatomic defects (outflow tract)
Amenorrhea (Not A. Labial agglutination/fusion
Including Disorders B. Imperforate hymen
of Congenital Sexual C. Transverse vaginal septum
Ambiguity) D. Cervical agenesis—isolated
E. Cervical stenosis—iatrogenic
F. Vaginal agenesis—isolated
G. Müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome)
H. Complete androgen resistance (testicular feminization)
I. Endometrial hypoplasia or aplasia—congenital
J. Asherman’s syndrome (uterine synechiae)
II. Gonadal failure (hypergonadotropic hypogonadism)
A. Gonadal agenesis
B. Gonadal dysgenesis
1. Abnormal karyotype
a. Turner’s syndrome 45,X
b. Mosaicism
2. Normal karyotype
a. Pure gonadal dysgenesis
i. 46,XX
ii. 46,XY (Swyer syndrome)
C. Ovarian enzymatic deficiency
1. 17α-Hydroxylase deficiency
2. 17,20-Lyase deficiency
D. Premature ovarian failure
1. Idiopathic—premature aging
2. Injury
a. Mumps oophoritis
b. Radiation
c. Chemotherapy
3. Resistant ovary (Savage syndrome)
4. Autoimmune disease
5. Galactosemia
III. Chronic anovulation with estrogen present
A. Polycystic ovarian syndrome
B. Adrenal disease
1. Cushing’s syndrome
2. Adult-onset adrenal hyperplasia
Evaluation and Treatment of Amenorrhea
C. Thyroid disease
1. Hypothyroidism
2. Hyperthyroidism
D. Ovarian tumors
1. Granulosa-theca cell tumors
2. Brenner tumors
3. Cystic teratomas
4. Mucinous/serous cystadenomas
5. Krukenberg’s tumors
IV. Chronic anovulation with estrogen absent (hypogonadotropic hypogonadism)
A. Hypothalamic
1. Tumors
a. Craniopharyngioma
b. Germinoma
c. Hamartoma
d. Hand-Schüller-Christian disease 51
e. Teratoma
f. Endodermal sinus tumors
g. Metastatic carcinoma
2. Infection and other disorders
a. Tuberculosis
b. Syphilis
c. Encephalitis/meningitis
d. Sarcoidosis
e. Kallmann syndrome
f. Idiopathic hypogonadotropic hypogonadism
g. Chronic debilitating disease
3. Functional
a. Stress
b. Weight loss/diet
c. Malnutrition
d. Psychological
i. Eating disorders (anorexia nervosa, bulimia)
e. Exercise
B. Pituitary
1. Tumors
a. Prolactinomas
b. Other hormone-secreting pituitary tumors (adrenocorticotropic
hormone, thyrotropin-stimulating hormone, growth hormone)
c. Nonfunctional tumors (craniopharyngioma)
d. Metastatic carcinoma
2. Space-occupying lesions
a. Empty sella
b. Arterial aneurysm
3. Necrosis
a. Sheehan’s syndrome
b. Panhypopituitarism
4. Inflammatory/infiltrative
a. Sarcoidosis
b. Hemochromatosis
From Carr BR: Disorders of the ovary and female reproductive tract. In Wilson JD, Foster D (eds):
Williams Textbook of Endocrinology. Philadelphia: WB Saunders; 1992:764.
sexual ambiguity since birth or significant virilization also may present with
amenorrhea, but these should be evaluated as separate disorders. Using this
approach, the diagnosis and treatment are simplified. Classifications consist-
ing of primary and secondary amenorrhea are not used because they do not
describe the pathophysiology. The largest category is chronic anovulation,
which includes women who have the ability to ovulate but do not; subcate-
gories include women who produce estrogen (eugonadotropism) and women
who do not produce estrogen (hypogonadotropic hypogonadism). The second
category is gonadal failure (hypergonadotropic hypogonadism), in which the
germ cells are usually absent. The third category includes abnormalities and
defects in development of the female reproductive tract. Table 4-1 lists all the
possible disorders.
52
GONADAL FAILURE
Gonadal (ovarian) failure is associated with increased gonadotropins, and

the term hypergonadotropic hypogonadism is used. The development of amen-
orrhea and hypoestrogenism associated with elevated gonadotropins before
the age of 40 defines ovarian failure. Cessation of ovarian function as a
result of loss of germ cells and follicles in the ovary can occur at any age,
however, even in utero, such as in gonadal dysgenesis or ovarian agenesis.
When ovarian failure occurs before puberty, the presentation is that of a
phenotypic female with primary amenorrhea and lack of secondary sexual
development. When it occurs after pubertal development, the presentation
is secondary amenorrhea with the primary complaint being hot flashes.
As is true for disorders of chronic anovulation, ovarian failure can result
from several causes (see Table 4-1), including gonadal agenesis or dysgen-
esis. Gonadal dysgenesis can be associated with normal or abnormal karyo-
types. Women harboring Y chromosome material have an increased risk of
gonadal tumors, and the gonads should be removed (Box 4-3). Rare causes
Box 4-3 of ovarian failure include 17α-hydroxylase deficiency, resistant ovary syn-
Gonadal Failure drome, autoimmune disorders associated with galactosemia, and iatrogenic
FSH >40 mIU/mL causes secondary to chemotherapy or radiation therapy. The diagnosis of
Age <35: Obtain ovarian failure should be suspected in all cases of primary amenorrhea and
chromosomes
sexual infantilism and in women with secondary amenorrhea who develop
hot flashes and other signs of estrogen deficiency. This diagnosis is con-
firmed by documenting an increased follicle-stimulating hormone (FSH) in
the menopausal range (<30-40 IU/L).
CHRONIC ANOVULATION
The major cause of amenorrhea is chronic anovulation. In this disorder,

women have ovaries and follicles, but for various reasons do not ovulate
normally. With appropriate therapy, however, they can ovulate and later
conceive. In women with chronic anovulation, the ovaries do not secrete
estrogen and progesterone in the normal cyclic pattern. Women who exhibit
bleeding after receiving an oral or intramuscular progestin challenge are

producing estrogen and fall into the category of chronic anovulation with
estrogen present. Women who fail to exhibit a menstrual bleed after a pro-
gestin challenge have low levels of estrogen and are categorized as chronic
anovulation with estrogen absent.
Chronic Women with chronic anovulation who experience withdrawal menstrual

Anovulation bleeding after a progestin challenge and exhibit normal FSH levels are said to
with Estrogen be in a chronic estrous cycle because of a cyclic production of estrogen. The
Present ovarian follicles of women with this disorder do not secrete large amounts
of estrogen, but instead secrete androgens, such as androstenedione, which
are converted in peripheral tissues by extraglandular aromatase into the
weaker estrogen, estrone. This condition may be due to problems primarily 53
Box 4-4 in the ovary or in the hypothalamic-pituitary-gonadal feedback loops. The
Polycystic Ovarian consequence is that these women fail to ovulate and produce estrogen and
Syndrome do not experience cyclic withdrawal bleeding. The primary cause of chronic
PCOS is a state anovulation with estrogen present is PCOS (Box 4-4).
of chronic PCOS is a complex disorder (probably inherited and related to insulin resis-
anovulation
tance) characterized by the development of hirsutism or androgen excess;
with acyclic
production obesity; and menstrual disturbances, including amenorrhea, oligomenor-
of estrogen rhea, or dysfunctional uterine bleeding at the time of expected puberty (Box
(estrone) 4-5). The clinical picture varies, and laboratory tests may be helpful, but are
formed by only supportive in confirming the diagnosis. In most women with PCOS,
extraglandular plasma luteinizing hormone (LH) levels are elevated at the same time the
aromatization
of androgens
plasma FSH levels are normal or low. Some have suggested that a ratio of
(androstene- LH to FSH of greater than 2 to 3 may be a useful laboratory distinction. The
dione). evaluation of a single sample of gonadotropins may lead to the wrong diag-
nosis, however, and only 80% of women may exhibit this finding. In addition,
most women with PCOS have moderately elevated serum androgen levels.
An ultrasound showing multiple superficial small follicles surrounding the
surface of the ovary in a ringlike pattern associated with increased stromal
density in a woman with amenorrhea supports the diagnosis (Fig. 4-1).
As stated previously, the diagnosis of PCOS is not based on pathologic
changes in the ovaries or plasma hormone abnormalities, but is primarily
based on the clinical evidence of chronic anovulation with varying degrees
Box 4-5 Polycystic Ovarian Syndrome Clinical Characteristics

1. Wide spectrum
2. At or just before menarche
Androgen excess
Obesity
Menstrual disturbance
● Amenorrhea
● Oligomenorrhea
● Dysfunctional uterine bleeding
Infertility
Insulin resistance
Figure 4-1
Vaginal ultrasound
shows classic
polycystic ovaries.
Note the peripheral
location of multiple
small ovarian cysts
(ring surrounding
ovarian stroma).
54
of androgen excess and menstrual disturbances. The etiology of this dis-

order is multifactorial and is not yet clearly understood. Chronic anovula-
tion with estrogen present, obesity, hirsutism, and polycystic ovaries can be
seen in a variety of other endocrine disorders in addition to PCOS (see Table
4- 1). These women may present with Cushing’s syndrome, hyperthyroid-
ism, hypothyroidism, or late adult-onset adrenal hyperplasia secondary to
21-hydroxylase or 11β-hydroxylase deficiency. Rarely, patients with chronic
anovulation with estrogen present have ovarian tumors, such as Brenner’s
tumor or cystic teratomas and even ovarian cancers in which the ovary or
tumor or both secrete increased amounts of androstenedione, which aro-
matize in extraglandular sites to estrogen. As a result, such patients may pre-
sent with a pattern similar to that of a woman with PCOS that resolves at the
time of the removal of the tumor or the treatment of the primary disorder.
Chronic Women with chronic anovulation with estrogen absent owing to low or
Anovulation absent estrogen production fail to experience withdrawal bleeding or experi-
with Estrogen ence only vaginal spotting after a progestin challenge. Usually the FSH level
Absent is normal or low; this is an important point because evaluating the FSH level
alone (if within the normal range, e.g., 4-8 IU/mL) does not confirm the
cause of amenorrhea. Chronic anovulation with estrogen absent is a result
of hypogonadotropic hypogonadism that is secondary to organic or func-
tional disorders of the central nervous system hypothalamic-pituitary axis.
It may be clinically helpful but not always practical to subdivide these into
hypothalamic or pituitary causes (see Table 4-1). Hypothalamic tumors or
other destructive disorders of the hypothalamus are relatively rare causes of
amenorrhea and require radiographic evaluation, such as computed tomog-

raphy (CT) or magnetic resonance imaging (MRI). In women with tumors,
headaches and other neurologic symptoms and signs are often present. The
most common cause of chronic anovulation with estrogen absent is a func-
tional disorder of the hypothalamus or central nervous system in the pres-
ence of a normal MRI or CT study. In these cases, the diagnosis of chronic
anovulation is one of exclusion. A history of stress or a stressful event often
can be obtained. These events include loss of a loved one, entering a stressful
work environment, or going off to college. In these cases, the stress reduces
hypothalamic secretion of gonadotropin-releasing hormone (GnRH), lead-
ing to reduced gonadotropin secretion followed by reduced ovarian estrogen
secretion, and amenorrhea results. This can happen even in women with
normal body weight.
Other causes related to stress and emotional disorders include weight loss 55
and dieting, which is particularly common in teenage girls. The most severe
form of weight loss–induced amenorrhea is in anorexia nervosa, which is
characterized by distorted attitudes toward eating and weight, self-induced
vomiting, extreme emaciation, and distorted body images. Women who
exercise excessively, such as marathon runners, ballet dancers, or extreme
gym exercisers, and who use exogenous steroids to reduce percent body fat
may develop amenorrhea. Amenorrhea is more likely to develop in women
with a previous history of abnormalities in menstruation before the onset
of excessive exercise or weight loss. Women who develop amenorrhea asso-
ciated with stress, exercise, or dieting exhibit alterations in the menstrual
cycle that are associated with the start of their new activities. Later, as the
disorder progresses, problems in the luteal phase production of progesterone
occur followed by anovulatory cycles associated with oligomenorrhea, and
finally amenorrhea develops.
In some of these women, a withdrawal bleed after progestin challenge
may occur in the anovulatory phase with some estrogen being produced,
but in most women the failure to exhibit a withdrawal bleed after a progestin
challenge suggests that the disease is more severe. If untreated, it may lead
to problems of estrogen deficiency, such as osteoporosis. After a reduction
of stress or exercise and increased weight gain, reversal from amenorrhea
to ovulatory menstrual cycles may occur requiring no further treatment.
Other chronic debilitating diseases, such as acquired immunodeficiency
syndrome, malabsorption, or cancer, may result in hypogonadotropic hypo-
gonadism. A relatively rare cause of hypothalamic amenorrhea in women is
due to Kallmann’s syndrome, which has been shown to be associated with
defects in olfactory bulb development. GnRH neurons develop in the same
rostral part of the brain as the olfactory bulbs, and women with Kallmann’s
syndrome exhibit not only low gonadotropins and amenorrhea but also
lack of the sense of smell, or anosmia. As stated previously, the diagnosis of
functional disorders of the central nervous system hypothalamic-pituitary
axis resulting in amenorrhea may be suggested by the history, but usually
requires some form of imaging using MRI or CT.
Disorders of the pituitary include not only tumors but also Sheehan’s
syndrome, or postpartum necrosis of the pituitary, which is due to
hemorrhage, spontaneous necrosis of the pituitary, congenital absence of

the pituitary, empty sella, or inflammatory or infiltrative disorders (see Table
4-1). The most common causes of amenorrhea associated with the pitu-
itary are disorders associated with increased prolactin secretion. Women
present with amenorrhea plus galactorrhea associated with an increased
prolactin level. In women with amenorrhea and elevated prolactin levels,
imaging of the pituitary is required, and a thyrotropin level is obtained.
Hyperprolactinemia and galactorrhea may be associated with antidepres-
sant drugs or recent breastfeeding. Most women with hyperprolactinemia
do not exhibit demonstrable pituitary tumors. It has often been questioned
at what level of serum prolactin head imaging should begin. Some have
suggested prolactin levels exceeding 50 μg/L. Women with prolactin levels
greater than 50 μg/L have about a 20% chance of presenting with a pitu-
56 itary tumor, whereas women who have 100 μg/L prolactin have a 50% risk,
and women with greater than 200 μg/L prolactin have an approximately
90% to 100% chance of harboring a prolactin-secreting tumor (Box 4-6).
DEFECTS OF THE FEMALE REPRODUCTIVE TRACT
Defects of the female reproductive tract can result in amenorrhea by

obstruction or absence of endometrial tissue. Some of these defects may
be developmental, and some may be due to iatrogenic causes. Women with
anatomic defects have normal ovaries and ovarian function and develop
secondary sexual characteristics. Ovulation can be proven by changes in
the basal body temperature or by elevated serum progesterone levels in the
luteal phase. These women also have a normal female 46,XX karyotype. The
logical approach to the evaluation and classification of anatomic defects is
to start from the lowest entry at the opening of the reproductive tract and
move upward (Fig. 4-2). Anatomic causes include labial agglutination or
labial fusion and imperforate hymen. If the obstruction is farther up into
the vagina, it is known as a transverse vaginal septum. Rarely, a complete
absence of the cervix may be suspected. Women with all of these conditions
often present with increasing abdominal pain, which is the result of accumu-
lation of blood behind the obstruction. In such instances, the pain is cyclic
and predictable in nature associated with the onset of menstruation. If the
diagnosis is delayed, endometriosis, adhesions, and infertility may result.
Two additional disorders are not associated with obstruction and pain, but
Box 4-6 Hyperprolactinemia (Increased Prolactin)

1. Thyrotropin
2. Radiographic imaging (MRI)
3. Prolactin levels (ng/mL) correlated with tumor risk
20-50—5-10% tumor risk
>50—20% tumor risk
Figure 4-2 5. Intrauterine adhesions

Diagrammatic (Asherman’s syndrome)
representation
of causes of
amenorrhea resulting
from defects of the
female reproductive
(outflow) tract.
6. Müllerian
agenesis
4. Cervical stenosis
3. Transverse vagina septum 57
2. Imperforate hymen
1. Labial fusion-agglutination
result from absence of development of the uterus and vagina; these include
müllerian agenesis or dysgenesis associated with a 46,XX karyotype and
testicular feminization or complete androgen resistance, in which there is
a testis and a 46,XY karyotype (Box 4-7). This diagnosis is easily confirmed,
however, by the observation of the absence of pubic and axillary hair owing
to the androgen resistance. Individuals with testicular feminization should
have the testes removed to prevent tumor development after completion of
breast development, which occurs at age 12 to 14. Rarely, a woman may
have absence of the uterus and lack of female secondary sexual characteris-
tics. In such individuals, a karyotype should be obtained. Individuals with a
46,XY karyotype have androgen deficiency most commonly as a result 17α-
hydroxylase, testicular regression, or gonadal dysgenesis. Individuals with
Box 4-7 Differential Diagnosis of Phenotypic Female with Secondary Sexual

Development and No Uterus
Complete Androgen Resistance
Feature Müllerian Agenesis (Testicular Feminization)
1. Occurrence More common Rare
2. Hereditary pattern Sporadic X-linked recessive
3. Gonad Ovary Testis
4. Chromosomes 46,XX 46,XY
5. Serum testosterone Low Male
6. Serum LH Normal Increased
7. Breasts Present Present
8. Pubic/axillary hair Present Absent
9. Other anomalies Present Absent
a 46,XX karyotype have müllerian agenesis plus another disorder, such as

ovarian failure or hypogonadotropic hypogonadism or both.
In addition, reproductive tract defects may be due to iatrogenic causes,
such as scarring and stenosis of the cervix after dilation and curettage, con-
ization, laser, or loop electrosurgical excision procedures to treat cervical
dysplasia. Destruction of the endometrium after a vigorous curettage after
postpartum hemorrhage or therapeutic abortion or after infection associated
with a missed abortion results in scar tissue or uterine synechiae (Asherman’s
syndrome). The diagnosis of this defect is rare in the absence of a previous
surgical procedure or pregnancy. The diagnosis of female reproductive tract
defects is established by history and physical examination. Labial agglutina-
tion, fusion, imperforate hymen, and transverse vaginal septum are easily
recognized. An ultrasound can be obtained to confirm the location of the
58 blockage and presence or absence of the uterus. To evaluate and confirm the
diagnosis of Asherman’s syndrome, sonohysterography, office hysteroscopic
procedure, or occasionally hysterosalpingography may be indicated. Rarely,
a laparoscopy may be required to confirm the final diagnosis of the repro-
ductive tract anomaly, particularly with regard to fundal appearance.
CLINICAL EVALUATION OF AMENORRHEA
Evaluation of amenorrhea should begin with a thorough history and

physical examination. If a woman presents with primary amenorrhea and
absence of secondary sexual characteristics, this may suggest a primary
gonadal problem or ovarian failure. In contrast, a woman who presents with
previous regular menstrual periods but develops amenorrhea after a dilation
and curettage for hemorrhage suggests the diagnosis of uterine adhesions.
The evaluation of amenorrhea requires knowledge of the classification as
vdescribed previously (see Table 4-1). Figure 4-3 shows a flow chart that aids
in evaluating women with amenorrhea. This evaluation includes women
with a female phenotype, but excludes women with disorders of virilization
or sexual ambiguity (Box 4-8).
Figure 4-3 1. History and physical examination

Flow diagram used to 2. R/O pregnancy
evaluate amenorrhea. 3. FSH, PRL, TSH
4. Progestin administration
+ Withdrawal menses − Withdrawal menses
FSH PRL FSH or FSH FSH
Chronic anovulation Radiographic Ovarian Anatomic

Estrogen present evaluation failure defect
(PCOS) (gonadal (müllerian
Chronic anovulation dysgenesis dysgenesis)
Estrogen absent
(functional hypothalamic
amenorrhea, prolactinoma)
Box 4-8 The laboratory tests required include a pregnancy test, FSH, prolactin
Amenorrhea— and thyrotropin. We find it helpful to evaluate the estrogen status based
When to Evaluate on the progestin withdrawal test as discussed earlier. This evaluation is
1. No menses by helpful before determining therapy for infertility as well. Evaluation of the
age 16 estrogen status includes two parts: (1) The patient is examined looking for
2. No evidence signs of previous estrogen secretion, such as breast development, and cur-
of sexual rent estrogen secretion, which includes the presence of a well-rugated, moist
development
(i.e., breasts) by
vagina with abundant clear stretchable cervical mucus known as spin-
age 14 nbarkeit (Box 4-9). (2) The estrogen status can be confirmed by a proges-
3. If sexual tin challenge using medroxyprogesterone acetate (5-10 mg daily for 5-10
ambiguity or days) or progesterone in oil (100-200 mg) administered intramuscularly.
virilization is Intramuscular injection is useful, particularly when patient compliance is
present
an issue (Box 4-10). Depo-Provera should not be used because this form of
4. If the patient or
family is greatly medroxyprogesterone acetate causes amenorrhea. 59
concerned The one exception to this overall evaluation is a woman who is known on
physical examination to have an absent uterus; in this case, it is more pru-
dent and cost-effective to perform a few tests to confirm the diagnosis and to
Box 4-9 differentiate müllerian agenesis from complete testicular feminization syn-
Initial Physical drome. After the initial visit, the patient returns and the physician assesses
Examination for the level of FSH, prolactin, and response to progestin challenge. If the FSH is
Amenorrhea
elevated, the evaluation is directed toward ovarian failure or hypergonado-
1. Degree of tropic hypogonadism (Box 4-11). If the FSH is low or normal, the evaluation
maturation of
of the progestin challenge test is used to differentiate the two categories of
the breasts,
pubic and chronic anovulation (Boxes 4-12 and 4-13). Finally, if the serum prolactin is
axillary hair,
and external Box 4-10 Progestin Challenge
genitalia
Medroxyprogesterone acetate (Provera) 10 mg orally twice daily × 5-10 days
2. Current
Progesterone in oil 200 mg intramuscularly
estrogen status
3. Presence or
absence of a
uterus Box 4-11 FSH Is Elevated
− Withdrawal menses
FSH
Ovarian failure (gonadal dysgenesis)
Box 4-12 FSH Is Low or Normal
PRL FSH or
Radiographic
evaluation
Chronic anovulation, estrogen absent (functional hypothalamic amenorrhea, prolactinoma)

Box 4-13 FSH Is Normal

+ Withdrawal menses
FSH
Chronic anovulation, estrogen present (polycystic ovarian syndrome)
Box 4-14 Evaluation of Outflow Tract or Reproductive Tract

1. History and physical examination
2. Rule out pregnancy
60 3. FSH and prolactin
4. Progestin administration
FSH
Anatomic defect (müllerian dysgenesis)
elevated, thyrotropin should be measured, and the pituitary should be evalu-

ated further by MRI or CT.
Most women with significant elevations of prolactin do not respond to a
progestin challenge and are included in the category of chronic anovulation
with estrogen absent. These women should experience withdrawal bleeding
after a cycle of estrogen plus progestin, but this test and results are confus-
ing because a high percentage of women would not bleed after one cycle
of therapy. Evaluation of the outflow tract or reproductive tract is done on
physical examination, and hysterosalpingography, ultrasound, or hysteros-
copy is done if needed (Box 4-14). During the physical examination, if the
patient exhibits a vagina, a patent cervix (which can be confirmed by uterine
sounding), and a uterus without a history of pregnancy or operative pro-
cedure, a disorder of the female reproductive tract is unlikely. After disor-
ders of the reproductive tract are ruled out, a normal or low FSH indicates a
disorder of the hypothalamus or pituitary. Most of these women have func-
tional disorders of the hypothalamus, although lesions of the hypothalamus
and pituitary may be present. The use of MRI or CT, as discussed previously,
depends on the history, clinical presentation, and prolactin level. The algo-
rithm in Figure 4-3 is quite useful in most cases with the diagnosis simplified
and easily obtained.
TREATMENT OPTIONS
In general, the management of amenorrhea depends not only on the cause

but also on the current desires of the patient.
Gonadal Failure Most cases of gonadal or ovarian failure are permanent, and patients should
be started on hormone replacement therapy, particularly estrogen, as soon
as possible (Box 4-15). Estrogen maintains secondary sexual characteris-
tics and prevents premature osteoporosis and coronary heart disease. If the
diagnosis of gonadal failure is made in a woman before breast development,
Box 4-15 such as in Turner’s syndrome, a regimen of low-dose estrogen gradually
Treatment of increased over time may be important in producing normal breast develop-
Ovarian Failure ment. Growth hormone also may be used before estrogen therapy in achiev-
Hormone ing greater height if indicated. In women with gonadal dysgenesis, estrogen
replacement treatment begins with low-dose conjugated estrogens (0.3 mg) for 3 to 6
Donor egg—in months, slowly increasing from 0.625 to 1.25 mg over 1 year to augment
vitro fertilization breast development. It is necessary to initiate progestin therapy after approx-
imately 1 year of estrogen therapy to induce withdrawal bleeding to prevent
endometrial hyperplasia. If progestin is started before initiation of breast 61
development, breast development may be abnormal. Women with disorders
such as 17α-hydroxylase deficiency should be treated with glucocorticoids
and hormone therapy. Women with autoimmune ovarian failure have been
treated with a variety of medicines, but none seem to be successful, so hor-
mone replacement therapy seems appropriate. Occasionally, repositioning of
the ovary, or oophoropexy, may be helpful before a woman receives abdomi-
nal-pelvic radiation therapy. In addition, it has been hypothesized but not
proven that pretreatment with GnRH analogues or oral contraceptive pills
before chemotherapy may be successful in maintaining ovarian function.
Women with amenorrhea resulting from ovarian failure are rarely able to
conceive on their own. In some cases, ovarian follicular depletion may be in-
complete, and spontaneous ovulation and a rare pregnancy may occur. The
current treatment for infertility secondary to ovarian failure is to use donor
oocytes obtained from normal ovulatory women that are retrieved followed
by in vitro fertilization in which the sperm of the patient’s husband is used
to fertilize the donor eggs. The fertilized embryo is transferred to the recipi-
ent with ovarian failure, who has been treated appropriately with exogenous
estrogen and progesterone synchronized to mimic the normal ovulatory
cycle.
Chronic The treatment of women with chronic anovulation can be subdivided to

Anovulation match the classification of women who produce estrogen and women who
do not produce estrogen. In women who are producing estrogen but are
not ovulating, the treatment depends on the desires of the patient. If the
patient is obese, weight loss should be encouraged, and this may improve the
overall clinical situation, including insulin resistance, if present, and hyper-
cholesterolemia. If the woman is not hirsute and does not desire pregnancy,
monthly withdrawal menses should be induced by progesterone therapy or
more simply with oral contraceptive pills, which reduces the risk of hem-
orrhage secondary to dysfunctional uterine bleeding and endometrial neo-
plasia. If the woman is hirsute but does not desire pregnancy, excess male
hormone production can be suppressed through oral contraceptive pills or
antiandrogens or both. Oral contraceptives pills also are indicated if there
Box 4-16 Treatment of Chronic Anovulation—Estrogen Present (Polycystic

Ovarian Syndrome)
What concerns the patient:
1. Amenorrhea—progestin withdrawal, oral contraceptive pills
2. Infertility—ovulation induction
3. Abnormal bleeding—oral contraceptive pills
4. Hirsutism—oral contraceptive pills, spironolactone
5. Insulin resistance—metformin
are disorders in menstruation, such as dysfunctional uterine bleeding.

Finally, if pregnancy is desired, ovulation can be induced with clomiphene
62 citrate, metformin, or gonadotropins or occasionally laparoscopic ovarian
wedge resection (Box 4-16).
In women who are not producing estrogen with chronic anovulation,
treatment needs to be directed at eliminating the primary cause, such as
Box 4-17 weight loss, exercise, or stress. Treatment in women with amenorrhea and
Treatment
of Chronic
low estrogen should be aggressive because this condition can lead to reduced
Anovulation— bone mass development and early osteoporosis. In women with elevated
Estrogen Absent prolactin levels but in the absence of prolactin-secreting tumors, cyclic
1. Human estrogen-progestin therapy or, more commonly, oral contraceptive pills can
menopausal be prescribed. Oral contraceptive pills and hormone replacement therapy
gonadotropin/ not only prevent bone loss but also maintain secondary sexual character-
human istics. If pregnancy is desired, it is important that body weight and nutri-
chorionic tional requirements for the potential developing fetus be returned to normal
gonadotropin
2. GnRH pump
before induction of ovulation. If the amenorrhea persists despite reduction
3. Long-term oral in stress, increasing body weight, and percent body fat, gonadotropins or
contraceptive pulsatile GnRH therapy is often successful in inducing ovulation and preg-
pill/hormone nancy. In women who present with pituitary tumors that secrete prolactin,
replacement the treatment of choice is pharmacologic using dopamine agonists such as
therapy
bromocriptine (Box 4-17).
Defects The primary treatment of outflow tract disorders is surgical, including the
of Female incision of labial fusion, imperforate hymen, and vaginal septum, and can
Reproductive lead to return of regular menstrual periods and fertility. With respect to
Tract specific disorders, chronic labial adhesions in children can be treated with
intermittent estrogen cream. A functional vagina in women with mülle-
rian agenesis or testicular feminization is more difficult to achieve. First,
an attempt at nonsurgical dilation of a blind-ending vaginal pouch or peri-
neal dimple is indicated. If this fails, reconstruction of the vagina using skin
grafts is performed. Disorders of cervical obstruction can be treated by dila-
tion of the cervix, and pregnancy can be achieved by intrauterine insemi-
nation. If the cervix is absent, a hysterectomy is usually required because
retained blood behind the obstruction can cause significant pain and infec-
tion. Uterine scarring or Asherman’s syndrome is best treated by direct
hysteroscopic resection of the adhesions.

1. Amenorrhea is best categorized functionally with chronic anovulation
being the largest category; this category can be subdivided into women
who produce estrogen and women who do not. A second category is
women with gonadal (ovarian) failure (hypergonadotropic hypogonad-
ism). Women with defects in the development of the reproductive tract
constitute the third category.
2. The phenotypic appearance of a woman and the extent of her second-
ary sexual development are related to the timing of ovarian failure in
relation to her reproductive life.
3. Women with chronic anovulation with normal estrogen levels are best
diagnosed using progesterone withdrawal testing.
4. Women with chronic anovulation and low estrogen levels (hypogonado- 63
tropic hypogonadism) should undergo CT or MRI to rule out the pres-
ence of central nervous system tumors.
5. Defects of the female reproductive tract leading to amenorrhea often
require surgical treatment.
SUGGESTED READINGS
Abraham SF, Beaumont PJV, Fraser IS, et al: Body Speroff L, Fritz MA (eds): Clinical Gynecologic
weight, exercise and menstrual status among ballet Endocrinology and Infertility, 7th ed. Philadelphia:
dancers in training. Br Obstet Gynaecol 1982;89:607. Lippincott Williams & Wilkins; 2005:401-464.
Blackwell RE, Boot LR, Goldenberg RL, Younger JB: Stein IF, Leventhal ML: Amenorrhea associated with
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Gynecol 1982;143:862.
5
POLYCYSTIC OVARIAN
SYNDROME
Jani R. Jensen and Ruben Alvero
DEFINITIONS 65
Androgens Steroids that stimulate development of male secondary
sexual characteristics; the major androgens are testosterone,
dihydrotestosterone, androstenedione, dehydroepiandrosterone, and
dehydroepiandrosterone sulfate; in nonpregnant women, androgens
are produced by the ovaries and adrenal glands and via peripheral
conversion of steroid intermediates
Amenorrhea No menses for 3 or more consecutive months
Anovulation Failure of the development and release of a dominant ovarian follicle
Hirsutism Excess, thickly pigmented, terminal hair growing in a male pattern, such
as on the upper lip, chin, sideburns, periareolar region, upper abdomen,
or inner thighs
Oligomenorrhea Fewer than nine menstrual periods per year, or menstrual cycles
occurring more than 35 days apart
Polycystic ovar- A common endocrinopathy characterized by menstrual irregularity and
ian syndrome hyperandrogenism
Virilization Signs of severe androgen excess, which may include deepening of the
voice, clitoromegaly, cystic acne, increased muscle mass, or male-pattern
baldness
Polycystic ovarian syndrome (PCOS) is a common endocrinopathy charac-

terized by menstrual irregularity and hyperandrogenism that is estimated
to affect 5% to 10% of reproductive-age women. When initially described
by Stein and Leventhal in the 1930s, the hallmarks of PCOS were reported
to be hirsutism, oligomenorrhea, obesity, and the histopathologic finding of
cystic ovaries. It is now recognized, however, that only about one third of
patients with PCOS fulfill the classic clinical presentation, and the remaining
women with this condition fall along a clinical spectrum. Although histori-
cally there has been confusion over the actual definition of PCOS, a 1990
National Institutes of Health consensus committee defined it as a condition
characterized by oligo-ovulation and evidence of clinical or biochemical
hyperandrogenism, with the exclusion of secondary causes, such as con-
genital adrenal hyperplasia (CAH) and Cushing’s syndrome. This is the defi-
nition that most clinicians and researchers in the United States use today.
Box 5-1 Polycystic Ovarian Syndrome Diagnostic Criteria

● Menstrual irregularity owing to oligo-ovulation or anovulation
● Clinical or biochemical evidence of hyperandrogenism
● Exclusion of other causes of hyperandrogenism and menstrual irregularity
Box 5-2 Differential Diagnosis of Polycystic Ovarian Syndrome

● Exogenous androgenic steroid ingestion
● Thyroid disease (particularly hypothyroidism)
● Hyperprolactinemia
● Androgen-secreting ovarian or adrenal tumor
● Late-onset CAH (21α-hydroxylase deficiency)
● Cushing’s syndrome
● Ovarian hyperthecosis
66
Although the etiology of this condition is unknown, hypotheses include a

dysregulated hypothalamic-pituitary axis, abnormal ovarian responsive-
ness, excess adrenal androgen production, and peripheral insulin resistance.
PCOS is a diagnosis of exclusion after other causes of hyperandrogenism
are eliminated. In addition, PCOS is a significant cause of infertility, largely
owing to absence of ovulation (Boxes 5-1 and 5-2).
PHYSIOLOGY
Although oligo-ovulation or anovulation is the hallmark of PCOS, the pre-

cise reason for ovulatory failure is unknown. For normal ovulation to occur,
a single dominant graafian follicle grows from approximately 5 mm to about
24 mm in diameter, progressing through a series of hormonally controlled
maturation steps until it is released from the ovary. In patients with PCOS, this
orderly process does not occur. There is an arrest in follicular development,
which prevents the follicle from completing the later stages of maturation
required for successful ovulation. The progression from several developing
follicles to the emergence of a single, dominant follicle destined for ovula-
tion largely depends on serum follicle-stimulating hormone (FSH) levels, and
there has been much discussion about the role of FSH in arrested follicular
development. Serum FSH levels in PCOS patients are typically within the nor-
mal range, but the midcycle FSH surge may be lacking. Several studies have
shown that ovulation can be induced by therapeutically increasing FSH lev-
els, suggesting that a deficiency of FSH may be intrinsic to the arrest of fol-
licular development. This mechanism alone is unlikely, however, to explain
the abnormal pattern of follicle growth observed in PCOS patients.
Researchers have suggested that hyperinsulinemia may be the cause of
premature follicular arrest. Insulin may function as a secretagogue for ovar-
ian androgens, disrupting the normally delicate balance among ovarian
steroid hormones. With an increase in ovarian androgen secretion, which
is peripherally aromatized to the weak estrogen, estrone, feedback to the
pituitary leads to an increase in luteinizing hormone (LH) production; when
Polycystic Ovarian Syndrome
bound to ovarian theca cells, LH elicits the production of more androgens.

With an increase in circulating androgens, there is also a decrease in sex
hormone–binding globulin, which increases free androgen concentration,
perpetuating the vicious cycle.
The stunted development of numerous graafian follicles leads to the char-
acteristic ultrasound appearance of ovaries containing multiple small fol-
licles, none of which is usually greater than 8 mm in diameter. Histologic
changes associated with PCOS include a thickened ovarian capsule contain-
ing multiple follicular cysts with a surrounding hypertrophic theca interna.
Despite abnormal follicular growth, cystic ovaries are able to maintain the abil-
ity to convert some of the circulating serum androgens to estrogens. Likewise,
peripheral adipose tissue is able to convert androgens to estrogens, and the
combination of these results in a continuous state of mild hyperestrogen-
ism. Elevated estrogen levels in the absence of progesterone lead to constant 67
stimulation of the uterine lining, placing women with PCOS at higher risk
for endometrial hyperplasia or intermittent, unpredictable menstrual bleed-
ing that is noncyclic in nature.
Studies in the early 1980s first showed that many women with PCOS have
higher circulating insulin levels than normal women. This observation is
independent of body weight because obese and nonobese women with PCOS
may have evidence of hyperinsulinism. Further studies linked hyperinsu-
linemia with underlying insulin resistance, and it is now estimated that 50%
to 70% of women with PCOS have evidence of insulin resistance compared
with age-matched controls. This observation translates to an increased risk
of glucose intolerance or the development of type 2 diabetes, which is esti-
mated to be 5-fold to 10-fold higher than in normal women. Several mecha-
nisms have been proposed to explain this finding, including enhanced insulin
first phase secretion, a defect in hepatic insulin sensitivity, abnormal insu-
lin receptors, and increased abdominal obesity (central obesity) compared
with controls. Although this is an active area of investigation, the molecular
mechanisms behind insulin resistance currently are unknown.
Women with PCOS usually have clinical evidence of hyperandrogenism,
with the most common finding being hirsutism (excess terminal hair growth
in a male pattern). Other physical manifestations of hyperandrogenism
include acne, male-pattern baldness, voice deepening, increased muscle bulk,
and clitoromegaly. Androgen excess directly leads to hair growth by the con-
version of dehydroepiandrosterone (DHEA), androstenedione, and testoster-
one in the hair follicle by the enzyme 5α-reductase to dihydrotestosterone, a
potent androgen that promotes increased hair growth and the conversion of
vellus to terminal hair. Excess androgens also stimulate the sebaceous glands
in the skin, resulting in increased oil production and development of acne.
CLINICAL PRESENTATION
Although the classic description of a patient with PCOS is an obese, hirsute

woman with oligomenorrhea or amenorrhea, the actual presentation varies.
Women with PCOS typically present with menstrual disorders or infertility. An
increased waist-to-hip ratio, often described as central obesity or “apple body”

habitus, is commonly associated with PCOS. Review of the patient’s history
should include careful questioning of menstrual history, including if the patient
has ever had regular menstrual cycles. Other important information includes
comorbidities (diabetes, thyroid disease, or other endocrine disorders), medica-
tion use (including use of exogenous androgens), lifestyle considerations (diet,
exercise, smoking, and alcohol use), the onset and duration of signs of andro-
gen excess, and family history (diabetes or dyslipidemia or other cardiovascu-
lar disease). The patient’s height and weight should be measured, and a body
Box 5-3 mass index should be calculated (Box 5-3). A body mass index greater than
Calculation of 25 indicates overweight, whereas a body mass index greater than 30 indicates
Body Mass Index obesity. Physical examination should look for evidence of hirsutism or other
Weight (kg) signs of hyperandrogenism. The degree of hirsutism can be determined using
68 Height (m)2 the Ferriman-Gallwey scoring system, which evaluates hair growth on the lip,
chin, chest, arms, abdomen, inner thighs, back, and buttocks. The abdomen
should be inspected for striae, particularly the purple variety associated with
Cushing’s syndrome, and the vulva should be examined for clitoromegaly.
Further screening for Cushing’s syndrome includes evaluation of blood pres-
sure and assessment of the presence of a dorsocervical fat pad (so-called buf-
falo hump), centripetal obesity, and peripheral muscle wasting. Acanthosis
nigricans, a condition characterized by thickened, velvety, and hyperpigmented
skin, is a sign of insulin resistance that may be seen on the back of the neck, in
the axillae, beneath the breasts or pannus, or on the vulva.
DIAGNOSTIC TESTING
Diagnosis of PCOS is primarily clinical and is based on a patient having

oligo-ovulation or anovulation and clinical or biochemical signs of hyperan-
drogenism. Other etiologies leading to similar symptoms must be excluded,
such as late-onset CAH, thyroid disease, hyperprolactinemia, Cushing’s dis-
ease, ingestion of certain drugs (danazol or androgenic steroids), ovarian
hyperthecosis, or an androgen-producing tumor.
Signs of virilization, such as clitoromegaly or deepening of the voice, should
prompt the clinician to search for an androgenic tumor because these mani-
festations occur rarely with PCOS. Many types of ovarian tumors can pro-
duce androgens or estrogens, including Sertoli-Leydig tumors, hilar (Leydig)
tumors, granulosa cell tumors, Brenner’s tumors, Krukenberg’s tumors,
cystadenoma, or cystadenocarcinoma. Adrenal tumors rarely may cause
hirsutism. The most common lesion of the adrenal gland is an adenoma. Most
adenomas are unilateral and greater than 1 cm in diameter. Adrenal adeno-
mas can produce DHEA, dehydroepiandrosterone sulfate (DHEAS), or andro-
stenedione. Androgen-producing adrenal or ovarian tumors can largely be
ruled out by measuring serum DHEAS and total testosterone concentrations.
Although historically DHEAS values of less than 700 μg/dL and total testos-
terone of 200 ng/dL were believed to rule out these conditions, the sensitiv-
ity and specificity of these levels have been called into question. If DHEAS is
abnormal, an abdominal computed tomography scan should be performed.
Late-onset CAH is an autosomal recessive disorder that may be confused

with PCOS. CAH is estimated to affect 1% to 5% of women who present with
hirsutism and is more common in certain ethnic groups (Ashkenazi Jewish,
Hispanic, Serbo-Croatian or American Eskimo). The most common form of
CAH is characterized by a deficiency in 21α-hydroxylase enzyme activity,
resulting in a failure to synthesize cortisol from its precursor 17α-hydroxy-
progesterone. In response to low serum cortisol levels, the pituitary secretes
excess adrenocorticotropic hormone (ACTH), which acts on the adrenals to
produce intermediaries in the cortisol pathway. Because of inherited enzyme
defects associated with CAH, however, the intermediaries build up and are
variably diverted from the cortisol pathway and shuttled to produce excess
androgens, resulting in increased serum concentrations of testosterone and
androstenedione. A 17α-hydroxyprogesterone level should be drawn in the
early morning, immediately on awakening. Normal levels are less than 200 69
ng/dL. Although a 17α-hydroxyprogesterone level greater than 400 ng/dL
is associated with increased risk for late-onset CAH, an ACTH stimulation
test should be performed to confirm the diagnosis. Unless there is compelling
clinical evidence, Cushing’s syndrome is extremely rare, and testing for this
condition with a 24-hour urine free cortisol should not be performed.
Other laboratory tests to consider when evaluating a patient with sus-
pected PCOS include free testosterone, thyrotropin, prolactin, fasting blood
glucose and 2-hour blood glucose after a 75-g glucose load, and a fasting
lipid panel. Approximately 75% of women with PCOS have elevated levels
of circulating androgens, particularly free testosterone. Elevated thyrotropin
levels are associated with hypothyroidism, and a free thyroxine level should
be obtained to confirm the diagnosis. Prolactin may be modestly elevated in
women with PCOS, but severe elevations (>100 μg/dL) warrant evaluation
with central nervous system imaging for a prolactinoma. A 2-hour oral glu-
cose tolerance test with a 75-g glucose load and fasting lipid panel are used
to screen for type 2 diabetes and dyslipidemia (Box 5-4). Investigations sug-
gest that 12% of PCOS subjects have type 2 diabetes mellitus. Insulin levels
or complex tests of insulin resistance (e.g., euglycemic clamp test) are not
required to make a diagnosis of PCOS. The 2-hour glucose tolerance test also
is useful to assess insulin resistance (Box 5-5).
Box 5-4 Laboratory Tests in the Evaluation of Polycystic Ovarian Syndrome

● Urine pregnancy test
● Total testosterone
● Free testosterone
● DHEAS
● Prolactin
● Thyrotropin
● 17-Hydroxyprogesterone (basal)
● ACTH stimulation test if 17-hydroxyprogesterone level is elevated
● 2-hour oral glucose tolerance test with 75-g glucose load
● Fasting lipid panel
● Endometrial biopsy for prolonged oligoamenorrhea
Box 5-5 Oral Glucose Tolerance Test

A fasting (baseline) blood glucose is measured, followed by ingestion of a 75-g
oral glucose load. Serum glucose is remeasured 2 hours after ingestion. A fasting
glucose >126 mg/dL or a 2-hour value >200 mg/dL indicates diabetes. A 2-hour
value >140 mg/dL but <200 mg/dL indicates impaired glucose tolerance.
Although early discussions of PCOS included testing of serum LH and

FSH, this is no longer routine. The classic finding suggesting PCOS was a
ratio of LH to FSH of greater than 3:1, but 50% of women who otherwise
would meet criteria for diagnosis of PCOS have normal serum LH values.
Measurement of serum LH is of limited diagnostic value.
According to the 1990 National Institutes of Health consensus criteria,
70 radiologic imaging is not necessary to confirm or exclude a diagnosis of PCOS
because 25% of normal women have polycystic-appearing ovaries on ultra-
sound. In Europe, diagnostic criteria may include radiologic imaging, with
transvaginal ultrasound being the preferred modality to identify polycystic
ovaries. Earlier descriptions of PCOS required the presence of eight or more
small follicles (measuring 2-8 mm) in each ovary to make a diagnosis. The
revised “Rotterdam” criteria now define PCOS with findings of 12 or more small
(2-9 mm) follicles in each ovary or an ovarian volume of greater than 10 mL
(calculated using the formula of ovarian length × width × thickness × 0.5).
In the United States, the aforementioned ultrasound criteria are less often
used to make a diagnosis of PCOS because these criteria alone are thought
to be nonspecific.
Hirsutism is an excess of thickly pigmented, terminal hair growing in a
male pattern, such as on the upper lip, chin, sideburns, periareolar region,
upper abdomen, or inner thighs. Most women with PCOS display some degree
of hirsutism. Many patients attempt to remove unwanted or embarrassing
hair growth through shaving, waxing, depilatory creams, laser treatments,
or other modalities, so there may actually be little or no evidence of hirsutism
on clinical examination. Patients should be asked directly if they have excess
hair and what, if any, means of removal have been used. There also may be
considerable ethnic differences in hirsutism, with women of Mediterranean
descent having significantly greater degrees of hair growth than Northern
European or Asian women.
Women with PCOS also often have risk factors are adverse for atheroscle-
rotic coronary artery disease. Elevated levels of total cholesterol, triglyc-
erides, and low-density lipoprotein and low serum levels of high-density
lipoprotein have been shown in women with PCOS. Screening of fasting
serum lipids should be performed, with appropriate intervention initiated if
dyslipidemia is identified.
THERAPEUTIC INTERVENTIONS
Weight loss of 5% to 10% alone may be enough to restore ovulation, reduce

serum testosterone, and improve fertility in women with PCOS. One study
reported that a mean weight loss of 9.7 kg (achieved through a low-calorie

diet ranging from 1000 to 1500 kcal/day) was associated with a 45%
decrease in serum LH, 40% decrease in fasting insulin, and 40% decrease in
testosterone. Most of the women in the study also resumed ovulating, and
some previously infertile women became pregnant.
When fertility is not desired, the oligo-ovulation and oligomenorrhea asso-
ciated with PCOS usually are treated with a combination oral contraceptive
pill. Combination pills have been shown to increase the level of circulating
sex hormone–binding globulin and suppress ovarian androgen secretion. An
oral contraceptive pill containing 30 to 35 μg of ethinyl estradiol combined
with a minimally androgenic progestin (e.g., norethindrone, desogestrel,
norgestimate, or drospirenone) should be selected. Risks and side effects of
oral contraceptive use are similar to those in normal women. Although one
large study showed that combination oral contraceptive pill use was associ- 71
ated with increased triglyceride and high-density lipoprotein levels in PCOS
patients, there is no evidence suggesting that women with PCOS have more
adverse cardiovascular events while taking these pills than normal women.
Cyclic oral progesterone also may be used to induce withdrawal bleeding,
although these regimens do not have the antiandrogen benefits of oral
contraceptive pills and do not provide contraception. Before initiating oral
contraceptives, a urine pregnancy test should be performed to exclude preg-
nancy. If the patient has not had a menstrual period within the preceding 8
weeks, a course of medroxyprogesterone acetate (5-10 mg daily for 10 days)
may be used to induce withdrawal bleeding before beginning therapy.
Clomiphene citrate, a weak antiestrogenic compound that stimulates
endogenous FSH secretion, is the first-line therapy for ovulation induction
in PCOS patients desiring pregnancy. Clomiphene citrate is composed of
two isomers, each of which has distinct estrogen receptor agonist-antago-
nist actions. The drug’s antiestrogen effects on the hypothalamus lead to
increased gonadotropin-releasing hormone release, which drives increased
LH and FSH output and pulsatility. Elevated peripheral FSH concentrations
lead to the progressive development of ovarian follicles and increasing estra-
diol levels, which positively feed back to the hypothalamic-pituitary axis and
result in an LH surge that triggers ovulation. Clomiphene is orally adminis-
tered, usually beginning with a dose of 50 mg/day for menstrual cycle days 3
to 7 after a spontaneous or progesterone-induced withdrawal bleed. Follicle
development and ovulation during the first cycle can be monitored via endo-
vaginal ultrasound, home urinary LH predictor kits, or serum progesterone
levels. Patients who fail to ovulate on the 50 mg/day dose of clomiphene
can be titrated in a stepwise fashion to a maximum dose of 150 to 200 mg/
day during subsequent menstrual cycles. The lowest dose of clomiphene
that allows the patient to ovulate should be used because increasing the
clomiphene dose beyond what facilitates ovulation results in little gain in
fecundity. Overall, ovulation occurs in approximately 75% of patients with
clomiphene therapy, and 50% to 70% of women achieve pregnancy within
six cycles.
Women who fail to ovulate despite maximum dosage of clomiphene
present a more difficult challenge. Induction of ovulation in PCOS women
with conventional doses of exogenous gonadotropins has been associated

with lower rates of ovulation and pregnancy, but with an increased chance
of developing multiple follicles, ovarian hyperstimulation syndrome, and
a higher rate of miscarriage compared with hypogonadotropic women.
Many centers have advocated a low-dose regimen for ovulation induction
in PCOS patients. Exogenous gonadotropin medications (human meno-
pausal gonadotropin or recombinant FSH preparations) are administered
in daily, usually subcutaneous, injections after the onset of spontane-
ous or progesterone-induced menses. Monitoring of ovarian response is
achieved by serial transvaginal ultrasound and serum estradiol levels.
When a dominant follicle emerges and reaches a diameter of about 20
mm, ovulation is triggered by an intramuscular dose of human chorionic
gonadotropin. Although a variety of dosing regimens and protocols is
72 available, overall estimates of ovulatory treatment cycles approach 70%.
Pregnancy rates of 20% per cycle have been reported, with multiple ges-
tation rates of approximately 6% to 25%. If the patient does not become
pregnant after three to six cycles of injectable gonadotropins despite evi-
dence of ovulation, most practitioners would recommend offering intra-
uterine inseminations or transition to in vitro fertilization. Successful in
vitro pregnancy rates are similar for women with PCOS compared with
women without PCOS.
Metformin, a drug initially developed for use in patients with type 2
diabetes, has been used to treat adult and adolescent women with PCOS.
Metformin is a biguanide oral antihyperglycemic agent with several
therapeutic effects, including decreased hepatic glucose production and
intestinal absorption of glucose and improved peripheral glucose uptake
and use, which leads to increased insulin sensitivity. In contrast to sul-
fonylureas, metformin does not produce hypoglycemia. In addition to
blood glucose regulation, metformin is reported to have other benefits in
PCOS treatment. Several studies have shown that metformin can restore
ovulation and regular menses in approximately 50% of women with
PCOS. This observation was seen in lean and obese women with PCOS.
Metformin also has been used in combination with clomiphene citrate to
induce ovulation, usually in women with PCOS who have failed to achieve
ovulation with clomiphene alone. Several randomized trials have shown
that the combination of metformin plus clomiphene can achieve ovula-
tory rates of 90% in previously oligo-ovulatory or anovulatory women
with PCOS.
Metformin use during pregnancy also may decrease the rate of first-
trimester bleeding and pregnancy loss in women with PCOS. One study
reported an early pregnancy loss rate of approximately 9% in women tak-
ing metformin in the first trimester, whereas women in the control group
who did not take metformin had an early pregnancy loss rate of nearly 42%.
This difference was even more pronounced in women who had a prior his-
tory of miscarriage; the early pregnancy loss rate was 11.1% in the metfor-
min group compared with 58.3% in the control group. These results are still
preliminary. Another prospective analysis of 126 women with PCOS who
were treated with metformin throughout their pregnancy (1500-2550 mg
daily) reported a reduced rate of gestational diabetes compared with con-

trols; showed no evidence of teratogenicity; and reported no adverse effects
on birth length and weight, growth, or motor development of children in the
first 18 months of life. These favorable findings suggest that in the future,
metformin’s use in pregnancy may be expanded. Metformin is classified as a
class B agent in pregnancy.
Dosage of metformin is initiated at 500 mg orally per day, with titra-
tion to the usual effective dose of 1500 to 2550 mg daily. Metformin’s side
effects are primarily gastrointestinal and include nausea, diarrhea, vomit-
ing, indigestion, flatulence, and generalized abdominal cramping or dis-
comfort. Rarely, lactic acidosis may occur, and metformin should not be
used in patients with conditions predisposing them to this condition, such
as chronic renal insufficiency, heart failure, or sepsis. A normal serum
creatinine should be documented before initiating therapy to avoid lactic 73
acidosis.
Laparoscopic ovarian drilling may be a therapeutic option for women
with PCOS who fail to achieve pregnancy with medical ovulation induc-
tion alone. This procedure is associated with less postoperative adhesion
formation than with ovarian wedge resection, a procedure requiring lap-
arotomy that has largely now been abandoned. Various modalities have
been used, including laser and electrosurgery, which have comparable
efficacy. Laparoscopic ovarian drilling can be done as a same-day surgi-
cal procedure and results in impressive postoperative decreases in serum
androstenedione and testosterone concentrations, but these effects are
most often transient. Reported ovulation and pregnancy rates may be 80%
and 50% to 60%, respectively.
Hirsutism associated with PCOS may be treated with combination
oral contraceptive pills alone or with antiandrogenic agents such as spi-
ronolactone or flutamide. Oral contraceptives work to lower serum tes-
tosterone levels by decreasing gonadotropin secretion and increasing
sex hormone–binding globulin concentrations, which binds testoster-
one and lowers circulating free testosterone levels. There is a reported
50% to 60% decrease in hair growth in women taking oral contra-
ceptive pills, although it may take several months before results are
seen. Spironolactone is a diuretic with aldosterone antagonist actions,
including inhibition of ovarian and adrenal androgen synthesis, direct
inhibition of 5α-reductase activity (which converts testosterone to dihy-
drotestosterone), and competition for androgen receptors in the hair fol-
licle. Spironolactone usually is given in a range of 50 to 200 mg daily, in
divided doses. Higher doses of spironolactone have been associated with
improved outcomes, with 200 mg daily being the most commonly used
dose. Maximal effect usually occurs after 6 months of treatment. Known
side effects include hypotension and hyperkalemia, although these are
rarely seen. Flutamide is a nonsteroidal antiandrogen that competes for
androgen receptor binding in target tissues. Although it is a highly effec-
tive treatment for hirsutism, it is usually reserved for difficult or resistant
cases because it may rarely cause hepatotoxicity. Flutamide is typically
given as 250 mg daily. Liver enzymes should be monitored periodically.
Spironolactone and flutamide may be used in conjunction with oral con-

traceptives for maximal effect.
Cyproterone acetate, an androgen receptor antagonist, has been used suc-
cessfully in Europe to treat hirsutism. Efficacy rates of 50% to 75% have been
reported, although there may be significant side effects, including the risk of
hepatotoxicity. Cyproterone acetate is currently unavailable in the United
States. Regardless of which treatment for hirsutism is selected, efficacy of
therapy can be monitored by comparing pretreatment and current Ferriman-
Gallwey scores or by measuring serum androgen levels. Because hair growth
is cyclic, and treatment is effective only in the involutional phase, it may take
several months for patients to see a clinical response. When patients embark
on therapy, but before seeing results, unwanted hair may be removed or cam-
ouflaged with shaving, electrolysis, chemical depilatories, waxing, tweezing,
74 or laser treatments. Eflornithine, an ornithine decarboxylase inhibitor, has
been shown to be highly effective.
An important long-term risk to patients with PCOS is the estimated 5-
fold to 10-fold increased risk of developing type 2 diabetes. Primary care
providers should screen women with PCOS periodically for diabetes and
dyslipidemia. Monitoring of blood pressure and smoking cessation should
be encouraged to enhance cardiovascular protection because women with
PCOS often have several risk factors for the development of atherosclerotic
cardiac disease.
Chronic anovulation and unopposed estrogen stimulation of the endo-
metrium can lead to excess proliferation of the uterine lining, placing
patients at risk for endometrial hyperplasia or cancer. Additionally, women
with PCOS are often overweight or have evidence of diabetes, both of
which are independent risk factors for endometrial cancer; their actual
risk of developing abnormal endometrial pathology may be potentiated.
Endometrial biopsy should be performed in all patients with long-standing
anovulation and amenorrhea, almost regardless of age. Oral contracep-
tive pills or intermittent progesterone-induced withdrawal bleeds can be
administered to decrease the risk of endometrial hyperplasia.

1. PCOS is a common endocrinopathy characterized by menstrual irregu-
larity and hyperandrogenism that is estimated to affect 5% to 10% of
reproductive-age women.
2. Diagnosis is based on clinical findings of menstrual irregularity and evi-
dence of androgen excess.
3. Secondary causes that may mimic PCOS, such as 21α-hydroxylase defi-
ciency, should be excluded.
4. The finding of polycystic ovaries on ultrasound is nonspecific and should
not be used alone to make a diagnosis of PCOS because 25% of normal
women may have polycystic-appearing ovaries on ultrasound.
5. Health risks associated with PCOS include obesity, infertility, endometrial
hyperplasia or cancer, type 2 diabetes, and hyperlipidemia.
Polycystic Ovary Syndrome
6. Overall treatment goals include the induction of ovulation, normalization

of the endometrium, prevention of hyperandrogenism and its sequelae,
and decreasing insulin resistance.
7. Weight loss of 5% to 10% of initial body weight can result in ovulation
and improved fertility.
8. Therapy should be individualized based on the patient’s symptoms and
desire to attempt pregnancy.
9. Treatment modalities may include weight loss and lifestyle modification,
oral contraceptive pills, insulin-sensitizing agents, antiandrogens, or a
combination of these.
10. Hirsutism associated with PCOS may be treated with combination oral
contraceptive pills or antiandrogenic agents, such as spironolactone or
flutamide. Additionally, unwanted hair may be removed or camouflaged
with shaving, electrolysis, chemical depilatories, waxing, tweezing, or 75
laser treatments.
SUGGESTED READINGS
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with polycystic ovary syndrome. Cochrane Database evaluation. J Clin Endocrinol Metab 2000;85:139-146.
Syst Rev 2001;2:CD002121. National Institutes of Health Consensus Meeting
Burghen GA, Givens JR, Kitabchi AE: Correlation of on PCOS. In Dunaif A (ed): Current Issues in
hyperandrogenism with hyperinsulinism in poly- Endocrinology and Metabolism. Boston: Blackwell
cystic ovarian disease. J Clin Endocrinol Metab Scientific; 1992.
1980;50:113-116. Pasquali R, Casimirri F, Vicennati V: Weight control
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on clinical features, endocrine and metabolic profiles,
6
ABNORMAL UTERINE
BLEEDING
Kirsten J. Lund
DEFINITIONS
Abnormal Any bleeding that deviates from regular, cyclic (every 24-35 days) 77
uterine bleeding bleeding of normal amount (≤80 mL) and duration (2-8 days)
Dysfunctional Abnormal bleeding without clear anatomic cause
uterine bleeding
Polycystic Anovulation combined with clinical or laboratory evidence of
ovarian hyperandrogenism
syndrome
Menorrhagia Excessive uterine bleeding at regular intervals
Metrorrhagia Bleeding between regular menstrual periods
Polymenorrhea Irregular bleeding at frequent intervals
Oligomenorrhea Irregular bleeding at infrequent intervals
Abnormal uterine bleeding (AUB) is one of the most common complaints of

patients seeking gynecologic care, whether through an obstetrics/gynecology
specialist or a primary care provider. It is a frustrating symptom for the patient
and the clinician. For patients, AUB can be a significant lifestyle issue and a
health risk. Because uterine bleeding is a complex outcome of interactions
between systemic hormones and an end organ, the uterus, there are myriad
underlying causes of AUB. This wide differential diagnosis can lead clinicians to
feel overwhelmed when attempting to evaluate and treat patients with AUB. In
past decades, hysterectomy was a frequently used treatment for AUB, even when
the uterus itself was absolutely normal. Heavy menstrual bleeding accounts for
two thirds of all hysterectomies, and in 50% of those cases, no abnormality of
the uterus is found on pathologic analysis. Although there is still much about
the pathophysiology of uterine bleeding that is not well understood, it is pos-
sible through thoughtful history taking and judicious use of diagnostic tests to
diagnose and treat most cases of AUB efficiently (Box 6-1).
PHYSIOLOGY
The pathophysiology of AUB is complex, not entirely understood, and

often multifactorial. Bleeding, whether normal or abnormal, results from
Box 6-1 Abnormal Uterine Bleeding

Anatomic abnormality
Submucous fibroid
Endometrial polyp
Hormonal dysfunction (dysfunctional uterine bleeding)
Hyperandrogenic (PCOS)
Hypothalamic anovulation
Perimenopausal
Thyroid
Prolactin
Coagulopathy
von Willebrand’s disease
Iatrogenic
Long-term OCP use
Medroxyprogesterone acetate (Depo-Provera)
78 IUD
interactions between circulating reproductive hormones and the uterus.

Abnormalities on either side of this interaction can lead to abnormal bleed-
ing patterns. High levels of uterine prostaglandins have been associated with
menorrhagia or excessive menstrual blood loss.
It is helpful to review the physiology of normal, cyclic menstrual bleeding
to understand deviations from this pattern. Cyclic bleeding of normal amount
and duration indicates that not only is the hypothalamic-pituitary-ovarian
(HPO) axis intact but also that the target organs, the uterus and endome-
trium, are responding in a normal way to hormonal input. (The physiology
of the normal menstrual cycle is covered in greater depth in Chapter 2.)
Generally, the menstrual cycle can be divided into follicular, ovulatory, and
luteal phases. In the follicular phase, growth and maturation of ovarian fol-
licles occurs under the influence of follicle-stimulating hormone (FSH) and
luteinizing hormone (LH) release from the pituitary. Selection of a dominant
follicle results in increased estradiol production, which causes marked growth
of the endometrial lining. Immediately before ovulation, there is a surge in
gonadotropin-releasing hormone (GnRH) in response to high estradiol levels,
resulting in a subsequent surge in LH and FSH levels and subsequent ovula-
tion approximately 36 hours later. The corpus luteum, which remains at the
site of the ovarian follicle, produces progesterone along with estradiol for the
remainder of the ovarian cycle (the luteal phase). The luteal phase is char-
acterized by high serum levels of progesterone and estrogen, which act on
the endometrium to halt proliferation and induce secretory changes, making
the endometrium an appropriate environment for implantation of a fertil-
ized embryo. In the absence of implantation, the corpus luteum regresses, the
endometrium deteriorates, and the resultant shedding of endometrium mani-
fests as menstrual bleeding.
Disruption of this normal ovarian cycle results in abnormal bleeding
patterns. Anovulation is the most common cause of dysfunctional uterine
bleeding. Women who do not ovulate regularly generally have significant
estrogen production from ovarian follicles, and endometrial proliferation
occurs similar to that seen in a normal follicular phase. Without ovulation
Abnormal Uterine Bleeding
and subsequent progesterone production, however, this proliferation contin-

ues without secretory changes and without a clear signal from the ovary
for endometrial deterioration and shedding. The endometrium becomes
thickened and unstable and may slough superficially and unpredictably.
Anatomic abnormalities of the uterus also cause abnormal bleeding. The
endometrium overlying an anatomic lesion, such as a fibroid, may receive
differential perfusion and hormonal input and become unable to respond in
a normal manner to cyclic ovarian hormone production. Finally, coagulation
defects, such as von Willebrand’s disease, may give rise to menorrhagia.
History When evaluating and managing patients with AUB, it is imperative to 79

remember that AUB is a symptom, not a diagnosis, and warrants careful
evaluation. Although the evaluation of any medical complaint begins with
a good history, in the case of abnormal bleeding this part of the evaluation
can be particularly challenging. Nevertheless, an accurate, focused history
is crucial in guiding further workup. Frequently, patients are frustrated and
tired of their bleeding before they arrive for their first appointment. It is
the responsibility of the physician to guide the patient through a thorough
review of the present complaint. Although there are many causes of AUB,
they tend to “cluster” into a lesser number of interrelated categories, and a
good history often points to the correct category of diagnosis. When obtain-
ing a history of abnormal bleeding, several standard areas should be covered
in addition to those that the individual patient may bring up.
Current Hormonal Status

Knowledge of baseline hormonal status is an essential step in the evaluation
of AUB. Is the patient premenopausal, perimenopausal, or postmenopausal?
The average age of menopause is 50 to 52 years (range 48-55 years), and
menopause is a clinical diagnosis consisting of 1 year of amenorrhea.
Menopause is not a laboratory diagnosis, and often patients are referred for
“postmenopausal bleeding” based on an elevated serum FSH, without ever
having a diagnostic period of amenorrhea. Such patients should be consid-
ered premenopausal or perimenopausal for purposes of evaluation.
Historical Bleeding Profile

When did the patient go through menarche? Were cycles regular and pre-
dictable? If so, when exactly did this change? Was the change sudden or
gradual? If the patient has had unpredictable cycles for a long time, what has
changed to cause her to present for evaluation?
Contraceptive and Hormonal History

A good contraceptive history alerts the clinician to patients who may be
at increased risk of pregnancy-related bleeding. It also often sheds light
on the patient’s current complaint. What is the patient’s current method
of contraception? Did this change at or around the time of the onset of
AUB? Has the patient been on hormonal contraception in the past? Was
she placed on oral contraceptive pills (OCPs) as an adolescent to “regulate
her periods”? Many patients have been on some type of hormonal con-
traceptive for most of their lives, which obscures the natural history of a
developing process of AUB.
History of Heavy Nonmenstrual Bleeding

Coagulation defects should be considered in women who give a history of
excessive bleeding during childbirth or with surgical procedures.
Ensure That Physician and Patient Are Speaking the Same Language
In addition to a working knowledge of the normal range of menstrual bleed-
ing patterns, the physician must ensure that he or she and the patient are
80 assigning the same meaning to the words used to describe bleeding. The
physician should take time to ensure that when the patient states that men-
strual periods are “irregular,” she means that the intervals between bleeding
episodes are unpredictable. To many patients, “irregular” may simply mean
bleeding that is different from their usual pattern. An increase in menstrual
flow in the setting of 28-day cycles may qualify to a patient as “irregular.”
Similarly, the amount of blood lost during a period of bleeding must be, as
far as possible, quantifiable because patients often have differing perspectives
on what “heavy” bleeding means. Although there are standardized pictorial
scales for this estimation, by careful questioning one often can arrive at a
fairly good idea of the amount of bleeding.
Physical After obtaining an adequate history, a physician may have generated a

Examination hypothesis as to the etiology of bleeding. In addition to an examination of
uterine size and shape, the following elements are often skipped, but should
be included in the physical examination.
Body Mass Index

Because estrogens are produced in fatty tissue in amounts that may affect
endometrial proliferation, the body mass index is a useful tool to guide
differential diagnosis and to identify patients who may be at particular risk
for endometrial hyperplasia.
Examination of External Genitalia and Vagina

Examination of the external genitalia and vagina not only rules out discrete
lesions that may be contributing to bleeding but also provides information
about the patient’s hormonal status. A thick, rugated vaginal mucosa indi-
cates adequate circulating estrogen levels, whereas a thin, pale, smooth vag-
inal vault signals relative estrogen deficiency.
Examination of the Cervix

Not all bleeding is uterine in origin. Although the patient may be up to date
on cervical cancer screening, one must look at the cervix to rule out cervical
polyps and assess for clinical evidence of cervicitis.
Differential After the history and physical examination, the physician may tailor the
Diagnosis diagnostic workup to the likely cause of the bleeding. It is useful to consider
six major categories of AUB and the differential diagnosis suggested by each:
pregnancy-related bleeding, disorders of coagulation, iatrogenic bleeding,
ovulatory bleeding, oligo-ovulatory bleeding, and postmenopausal bleeding.
Disorders of Pregnancy
Pregnancy should be ruled out in any woman of reproductive age. When
combined with a thoughtful contraceptive history, a simple office urine preg-
nancy test is economical and highly sensitive. Although bleeding may occur
in a normal intrauterine pregnancy, the possibility of an ectopic pregnancy
or threatened abortion should be considered.
Disorders of Coagulation 81
The classic presentation for patients with inherited clotting disorders is that
of menorrhagia, associated with anemia, at the time of menarche. The
prevalence of clotting disorders among patients admitted to the hospital for
menorrhagia and severe anemia ranges from 19% to 45%. In addition to
von Willebrand’s disease, other disorders of impaired platelet aggregation,
including factor XI deficiency and thrombocytopenia, are common diagno-
ses in patients with menorrhagia. Although the classic presentation of von
Willebrand’s disease is that of menorrhagia at menarche or obstetric hemor-
rhage, women may not be correctly diagnosed until later in the reproductive
years.
Iatrogenic Causes
Patients on hormonal medications are at increased risk for abnormal bleed-
ing patterns. This effect is most recognized with oral and injectable contra-
ceptive preparations. The breakthrough bleeding patterns associated with
hormonal contraceptives are thought to be due to endometrial atrophy asso-
ciated with continuous, or near-continuous, progestin administration. Use
of the intrauterine contraceptive device (IUD) also is associated with abnor-
mal bleeding patterns. Perimenopausal patients who are placed on hormone
replacement therapy for treatment of vasomotor symptoms also may exhibit
abnormal bleeding patterns because standard hormone doses (in contrast to
OCP doses) are insufficient to suppress the HPO axis in patients who are still
ovulating, and hormone replacement therapy may destabilize the normal
cyclic development of the endometrium. Finally, patients on anticoagulant
therapy are prone to heavier bleeding because of the anticoagulation.
Ovulatory Bleeding
Patients who have an intact HPO axis and who ovulate regularly typically
describe a cyclic pattern to their bleeding. This bleeding may manifest as sim-
ple menorrhagia; intermenstrual, premenstrual, or postmenstrual spotting;
or ongoing bleeding with an identifiable “period” of heavier bleeding that
occurs once per month or occasionally hormonal symptoms that suggest
cyclic ovarian function in the setting of unpredictable bleeding. AUB that is
ovulatory suggests a limited range of diagnoses.
Anatomic The uterus is an end organ for ovarian steroid hormones. A normal uterus
Abnormalities should respond appropriately to cyclic hormonal input, with regular with-
of the Uterus drawal bleeding as the corpus luteum regresses each month. An abnormal
uterus may respond to cyclic hormones by bleeding more heavily during
menses or by bleeding between menstrual periods. The exact pathophysiol-
ogy by which anatomic abnormalities, such as uterine myomas, polyps, and
adenomyosis, cause abnormal bleeding of the overlying endometrium is the
subject of ongoing study.
Relative Estrogen As women enter the later reproductive years, several interrelated changes
Excess Related to occur in the HPO axis. Inhibin levels decrease, and ovaries become increas-
Perimenopausal ingly resistant to pituitary FSH. These changes result in higher follicular phase
Changes estradiol levels and higher levels overall throughout the cycle. In addition,
corpus luteum function may become inadequate, leading to lower proges-
82 terone levels during the luteal phase and shorter luteal phase overall. Taken
together, all these changes may result in a shift in the estrogen-progesterone
balance during a menstrual cycle. Although patients still may ovulate regu-
larly, menstrual blood loss becomes heavier, and cycle length may shorten.
Change in It has been widely recognized that OCP use generally leads to decreased men-
Contraceptive strual blood loss and to regular, 28-day withdrawal bleeding. Discontinuation
Method from of OCPs, conversely, may lead to a return of heavier menstrual bleeding.
Hormonal to The onset of menorrhagia and dysmenorrhea after tubal ligation, dubbed
Nonhormonal “the post–tubal ligation syndrome,” was thought to be an effect of compro-
mised ovarian blood supply after tubal sterilization. More recent studies and
meta-analyses have not found any correlation between tubal sterilization
and such symptoms. This phenomenon illustrates, however, that patients
may experience changes in menstrual function when they change their
contraceptive method.
Oligo-ovulatory Bleeding
Patients who give a history of oligomenorrhea or unpredictable cycle inter-
vals are likely to be anovulatory or to ovulate rarely. Anovulation may be
a lifelong issue for some patients; for others, it may be a transient condi-
tion. The characteristic that distinguishes anovulatory bleeding is the lack
of cyclic symptoms, such as cyclic bleeding or moliminal symptoms (e.g.,
breast tenderness). Anovulatory bleeding is caused by dysregulation of the
normal cyclic hormone patterns, whether at the level of the hypothalamus,
the pituitary, or the ovary.
Hypothalamic anovulation is perhaps the least well-understood pathway
for anovulatory bleeding. Patients who are under chronic stress, whether
from chronic disease, poor diet, or excessive physical activity, may ovulate
infrequently. The mechanism mediating the effect of stress on ovulation
is poorly understood, but related to decreased pulsatile GnRH secretion.
Patients with hypothalamic dysfunction may exhibit signs and symptoms of
low estrogen status and often have amenorrhea rather than AUB.
Thyroid dysfunction may be associated with abnormal menstrual bleeding
patterns. Hyperthyroidism increases the rate of metabolism of ovarian ste-
roid hormones, such as estradiol, and hypothyroidism increases thyrotropin
from the hypothalamus (resulting in increased stimulation of thyrotropin and

prolactin). Hyperprolactinemia is a well-recognized cause of oligo-ovulation
among lactating women and among patients with pituitary prolactinomas.
The syndrome of chronic estrogenized anovulation, with clinical or
laboratory evidence of associated hyperandrogenism, is common and well
described as polycystic ovarian syndrome (PCOS). A detailed discussion of
PCOS is beyond the scope of this chapter (see Chapter 5), although it is a fre-
quent cause of anovulatory bleeding. Because the ovaries produce estrogen
from multiple follicles and do not produce progesterone on a monthly basis
owing to anovulation, patients with PCOS-like anovulation are hyperestro-
genic and at increased risk for endometrial hyperplasia.
Anovulatory cycles occur frequently at the extremes of reproductive age.
The HPO axis is not fully mature for 5 years after the onset of menarche.
Similarly, decreasing ovarian function preceding menopause may result in 83
intermittent ovulation.
Postmenopausal Bleeding
A clear history of menopause (>1 year of amenorrhea) shifts the differential
diagnosis of AUB away from hormonal causes and toward anatomic causes.
The exception is a patient who is taking exogenous hormones because uter-
ine bleeding is a common side effect of hormone therapy. Aside from this,
patients may have postmenopausal bleeding as a result of uterine hyperpla-
sia or malignancy, myomata, polyps, or atrophy.
Finally, when considering the likely category of diagnosis for AUB, the
clinician should bear in mind that a patient may have more than one con-
tributing factor for the bleeding. Patients with small uterine fibroids may
have many years of normal cyclic bleeding, which changes as they reach the
later reproductive years and begin to have intermittent anovulatory cycles.
Although ultrasound evaluation diagnoses fibroids, perhaps for the first
time, the patient might respond to medical treatment for the anovulation,
rather than surgical treatment of the fibroids.
Diagnostic The workup of AUB is directed by the limited differential diagnosis generated by
Testing the history and physical examination. When pregnancy, coagulation disorders,
and iatrogenic causes have been ruled out, a suggested workup is as follows.
Patients who are ovulatory but who have AUB are more likely to have an
anatomic lesion of the uterus, such as uterine polyps, fibroids, or adenomyo-
sis. The best radiologic method for evaluating the uterus is pelvic ultrasound.
Traditional endovaginal ultrasound is helpful for diagnosing most fibroids,
although it is less sensitive in pinpointing whether the fibroids have a sub-
mucosal component (sensitivity 21-100%). When sonohysterography is
performed, the sensitivity for detecting submucous fibroids increases to 57%
to 100%, with specificity 96% to 100% (Fig. 6-1). The sensitivity of sono-
hysterography for diagnosis of intrauterine polyps (Fig. 6-2) is similarly high
and approaches that of the gold standard, hysteroscopy, at a fraction of the
cost and with less discomfort for the patient. In addition, myometrial defects
are seen more easily than with hysteroscopy.
Figure 6-1
A, Fluid contrast
ultrasound of
submucous fibroid.
B, Hysteroscopic
view of same
submucous fibroid.
84
Figure 6-2
A, Fluid contrast
ultrasound of
endometrial polyp.
B, Hysteroscopic
view of same
endometrial polyp.
85
A history of anovulation implies a hormonal cause for bleeding. The

differential diagnosis of anovulatory bleeding is extensive (see earlier).
Investigation of the HPO axis generally should include studies of thyroid
and prolactin production. Clinical evidence of hyperandrogenism (hirsut-
ism, acne) would be an indication for serum androgen testing, including free
and total testosterone, dehydroepiandrosterone sulfate, and 17α-hydroxy-
progesterone levels. In many patients, serum testing is normal, and there
is no apparent cause for anovulation. Frequently, this anovulation is due
to complex hypothalamic factors for which there are currently no practical
diagnostic tests. Any patient who is anovulatory and has other risk factors
for endometrial hyperplasia should undergo endometrial biopsy. In addition
to chronic anovulation, risk factors for endometrial hyperplasia include any
other condition that exposes the patient to high levels of estrogens. Such
86 conditions include obesity, late menopause, and exposure to unopposed
exogenous estrogens.
If a patient seems clearly anovulatory by history, and the physical exami-
nation is not suggestive of an anatomic abnormality, such as uterine fibroids,
it is reasonable (although uncommon) to embark on a course of treatment
without obtaining a pelvic ultrasound. If the patient does not respond to
adequate treatment as discussed subsequently, ultrasound may be useful in
diagnosing a second, structural problem.
Patients with postmenopausal bleeding, few or no risk factors for endo-
metrial cancer, and a normal examination initially may be evaluated
by pelvic ultrasound. Patients with risk factors initially may undergo
endometrial biopsy, followed by ultrasound if the biopsy is negative for
malignancy. Sonohysterography provides information regarding not only
endometrial thickness but also the presence of benign causes of bleeding,
such as myomata or uterine polyps. When the endometrial thickness is
5 mm or less on transvaginal ultrasound, the negative predictive value
for detecting endometrial cancer is 96% and for detecting any endome-
trial pathology is 92%. Because this rate is less than 100%, however, any
postmenopausal patient with a thin endometrium who continues to be
symptomatic or who fails to respond to treatment should be considered for
endometrial biopsy. Endometrial thickness in premenopausal women var-
ies, and 5 mm or greater thickness is much less predictive of endometrial
or uterine abnormalities.
Treatment modalities fall into two major categories: surgical therapy and
hormonal therapy (Box 6-2).
Surgical Therapy Surgical treatments are most useful for patients with structural abnormali-
ties as the cause of bleeding. The list of surgical options is increasing in
length each year as new technologies are tested and approved.
Box 6-2 Treatment of Dysfunctional Uterine Bleeding

OCP therapy
Progestin
Oral
Intrauterine
GnRH agonist
Uterine artery embolization
Endometrial ablation
Hysterectomy
Hysteroscopy with Resection

Patients with uterine polyps or fibroids that are primarily intracavitary are 87
excellent candidates for hysteroscopic resection of lesions. Returning the
uterine cavity to a normal shape allows the uterus to respond normally to
cyclic ovarian steroid hormone output. Patients with fibroids that are pri-
marily intramural are not good candidates for this procedure because it is
impossible to resect most of the fibroid, and the recurrence rate of bleeding
is higher.
Uterine Artery Embolization

Uterine artery embolization involves catheterizing the uterine artery, under
radiologic guidance, then embolizing the uterine arteries or, in some cases,
the single artery feeding the fibroid, with particles such as polyvinyl alcohol
or gelatin microspheres. Analysis of uterine artery embolization has shown
a decrease in menorrhagia for 80% to 90% of patients. Although there are
reports of normal pregnancy outcomes after uterine artery embolization,
there are no substantial data to predict the chances of successful pregnancy
after the procedure. Uterine artery embolization is not recommended as a
treatment of choice for patients wishing to preserve fertility.
Global Endometrial Ablation

Endometrial ablation may be an attractive alternative for patients with
ovulatory bleeding and a relatively normal uterine cavity. The aim of endo-
metrial ablation is to destroy as much of the endometrium as possible,
rendering it unable to regenerate under the influence of ovarian steroid
hormones. Traditional technologies, such as laser vaporization, rollerball
ablation, and endometrial resection with electrocautery, have been joined
by “second-generation” techniques, such as cryotherapy, microwave energy,
and various forms of heated liquid. In practice, a few patients are amenor-
rheic after endometrial ablation, although most experience a return to “nor-
mal” or light menstrual flow. Patient satisfaction rate with most of these
methods is generally high, ranging from 93% to 100%. A Cochrane review
of endometrial destruction techniques did not find a significant difference
between any of the techniques in reduction of heavy menstrual bleeding.
Anovulatory patients at risk for endometrial hyperplasia generally are not
considered good candidates for this procedure because cases of endometrial

cancer after endometrial ablation have been reported, and the diagnosis is
sometimes delayed by masking the uterine bleeding patterns.
Hysterectomy
By definition, hysterectomy eliminates uterine bleeding in any patient. This
procedure is a more invasive and costly option, however, with a higher risk
of surgical complications. Patients who are finished with childbearing and
who have significant anatomic abnormalities of the uterus are appropriate
candidates for hysterectomy. Patients should be given appropriate counsel-
ing as to risks, benefits, and alternatives.
88 Hormonal Medical treatment of AUB is particularly useful for patients with anovu-
Therapy latory bleeding or for patients who are ovulatory and have a relatively
normal uterus. Occasionally, patients with structural abnormalities of the
uterus also respond well to medical management. The list of possible medi-
cal treatments, similar to the list of surgical options, is growing as we begin
to understand better the effects of various hormones on the endometrium.
Oral Contraceptive Pill Therapy

It is well recognized that combination OCP use is associated with decreased
menstrual flow. By providing progestins throughout the cycle, OCPs limit
endometrial proliferation. OCP therapy is appropriate for patients who are
anovulatory, to provide regular withdrawal bleeding, and for patients with
menorrhagia, to decrease blood loss. There is now an overwhelming num-
ber of OCP brands on the market, but most combination OCPs work in simi-
lar ways (i.e., by ovarian suppression). Therapy should be tailored to the
patient’s individual needs and side effect profile; almost any monophasic pill
is appropriate for the treatment of AUB. Patients should be counseled to have
a 3-month trial of therapy; if bleeding patterns are improved but side effects
are unacceptable, a change in type of OCP may be considered at that time.
Oral Progestin Therapy

For patients in whom estrogen use is contraindicated, such as smokers older
than age 35 or women with hypercoagulable states, progestins alone can
control AUB. Any progestin dose with sufficient strength to suppress ovu-
lation potentially renders a patient amenorrheic when used in continuous
fashion. Although cyclic monthly progestin therapy also often is used in the
treatment of AUB, it should be limited to patients who are truly chronically
anovulatory. Treatment of ovulatory or oligo-ovulatory patients with pro-
gestins 10 to 14 days out of the month is likely to exacerbate AUB because
it is difficult to synchronize the therapy with the patient’s own, sometimes
unpredictable, luteal phase. There are at least four oral progestins currently
on the market: medroxyprogesterone acetate, norethindrone, megestrol,
and micronized progesterone. When prescribing progestins for control of
AUB, the most important consideration is to administer a potent enough
dose to control bleeding. These progestins differ widely in terms of potency
Table 6-1
Treatment Options Diagnosis Treatment A Treatment B Treatment C Treatment D
for Abnormal
Uterine Bleeding Anovulatory
Thyroid Thyroid
disease replacement
Prolactinoma Suppression OCPs
versus surgery
Idiopathic/ OCPs Oral progestins LNG IUS
PCOS
Ovulatory—anatomic
Polyp Hysteroscopic
resection
Intracavitary Hysteroscopic Hysterectomy*
myoma resection
Intramural Open/ UAE* Hysterectomy* LNG IUS
myoma laparoscopic 89
resection
Ovulatory— OCPs Endometrial LNG IUS Oral
idiopathic ablation* progestins
Coagulation Factor OCPs
disorder replacement
Postmeno- Discontinue Change Expectant/
pausal, HRT E/P ratio reassurance
normal of HRT
uterus
*Incompatible with future fertility.

E/P, estrogen/progestin; HRT, hormone replacement therapy; LNG IUS: levonorgestrel
intrauterine system; OCPs, oral contraceptive pills; UAE, uterine artery embolization.
at the progesterone receptor and the amount necessary to induce secretory

changes in endometrium (Table 6-1). Dosing of any progestin may be limited
by patient side effects.
Intrauterine Progestin
Patients with a relatively normal uterine cavity are excellent candidates for
control of AUB with a progestin-containing intrauterine system. Although
marketed as a contraceptive device, the levonorgestrel-containing intrauter-
ine system is associated with a marked decrease in menstrual blood loss.
Randomized studies have found that the efficacy of this method in terms
of reducing heavy menstrual bleeding approaches that of thermal balloon
endometrial ablation. By providing continuous progestin activity at the level
of the endometrium, the risk of hyperplasia is greatly reduced for patients
with chronic anovulation. Patients with ovulatory bleeding also may ben-
efit from reduced blood loss. Because systemic levels of progestin are not as
high as with the oral progestins, the intrauterine system is a good option for
patients who cannot tolerate oral progestin side effects.
Gonadotropin-Releasing Hormone Agonists

GnRH agonists are extremely effective agents for control of bleeding, whether
for anatomic or hormonal reasons. Their mechanism of action is through
downregulation of pituitary GnRH receptors. This results in decreased out-

put of FSH and LH and decreased stimulation of ovarian steroid hormone
production. This marked decrease in estrogen and progesterone production
brings with it potential undesirable side effects, however, including vasomo-
tor symptoms, urogenital atrophy, and, when used over a long time, loss of
bone density. Because of these side effects, GnRH agonists are not gener-
ally recommended as a long-term treatment for AUB. Ideal candidates for
GnRH agonist therapy include patients who are perimenopausal and wish to
attempt to control heavy bleeding until they are fully menopausal (although,
as menopause is a retrospective diagnosis, it may be difficult to determine the
length of treatment necessary). Patients with uterine myomata who wish
to undergo less invasive surgical treatments are good candidates for a lim-
ited course of GnRH agonists. In randomized trials, GnRH agonists reduce
90 uterine volume by 30% to 50% so that a patient with a moderately enlarged
uterus may undergo a simple vaginal hysterectomy after GnRH agonist ther-
apy, rather than an open or laparoscopic procedure. GnRH agonists also are
associated with a significant decrease in bleeding, which allows patients to
recover from anemia before a planned surgical procedure.
SUMMARY
AUB can have many different causes. The clinician should attempt to iden-
tify the cause on the basis of history first. Lifelong abnormal menses may
be related to coagulopathy. In the absence of clear features, a fluid contrast
ultrasound can establish the presence of such anatomic causes as endome-
trial polyps or distorting fibroids. In the absence of any of these abnormali-
ties, dysfunctional uterine bleeding secondary to hormonal disturbance is
likely, and the patient can attempt exogenous hormones to control the bleed-
ing. More aggressive therapies, such as the levonorgestrel-containing intra-
uterine system, uterine artery embolization, and endometrial ablation, can
be attempted. Many of these modalities are incompatible with future child-
bearing. If all of these attempts fail, a hysterectomy can be considered in
women who have completed childbearing.

1. A thorough history needs to be taken, with particular attention to the
presence or absence of risk factors for endometrial hyperplasia and to
determining whether the patient is having ovulatory cycles.
2. The diagnostic workup should be tailored to the individual patient’s pre-
sentation. If an anatomic cause for bleeding is suspected, imaging should
be ordered first. If a hormonal etiology is suspected, treatable causes of
anovulation should be ruled out first, such as thyroid or pituitary disease.
3. Patients with a lifelong history of menorrhagia have a high incidence of
coagulation defects, such as von Willebrand’s disease.
4. Treatment of AUB should reflect and be consistent with the pathophysi-

ology of the problem. Hormonal causes of bleeding, such as anovulation,
are amenable to hormonal remediation. Patients with anatomic causes
for bleeding respond best to the restoration of normal uterine anatomy.
5. Because AUB can be a lifestyle issue and a health problem, it is important
to include the individual needs of the patient and overall cost and risk
in deciding on a course of therapy. Unless patients are at risk for cancer
or severe anemia, one should err on the side of less invasive treatments
or conceivably expectant management in a patient who is not greatly
inconvenienced by her symptoms.
91
SUGGESTED READINGS
Barington JW, Arunkalaivanan AS, Abdel-Fattah M: Lethaby A, Hickey M: Endometrial destruction tech-
Comparison between the levonorgestrel intrauterine niques for heavy menstrual bleeding: a Cochrane
system (LNG-IUS) and thermal balloon ablation in review. Hum Reprod 2002;17:2795-2806.
the treatment of menorrhagia. Eur J Obstet Gynecol McGurgan P, O’Donovan P: Endometrial ablation.
Reprod Biol 2003;108:72-74. Curr Opin Obstet Gynecol 2003;15:327-332.
Farquhar C, Ekerona A, Furness S, Arroll B: A system- Oehler MK, Rees MC: Menorrhagia: an update. Acta
atic review of transvaginal ultrasonography, sonohys- Obstet Gynaecol Scand 2003;82:405-422.
terography and hysteroscopy for the investigation of Strickand JL, Wall JW: Abnormal uterine bleeding
abnormal uterine bleeding in premenopausal women. in adolescents. Obstet Gynecol Clin North Am
Acta Obstet Gynaecol Scand 2003;82:493-504. 2003;30:321-335.
Ferenczy A: Pathophysiology of endometrial bleeding. Worthington-Kirsch RL, Siskin GP: Uterine artery
Maturitas 2003;45:1-14. embolization for symptomatic myomata. J Intensive
Jensen JT, Speroff L: Health benefits of oral contracep- Care Med 2004;19:13-21.
tives. Obstet Gynecol Clin North Am 2000;27:705-
721.
7
THE CLIMACTERIC
Michael D. Wittenberger
and William H. Catherino
DEFINITIONS
Climacteric The period of a woman’s life when she is transitioning from the
reproductive years to the postmenopausal years 93
Perimenopause The variable period of time before complete cessation of menses
characterized by menstrual irregularity in cycle length and amount
of flow and increasing periods of amenorrhea; the World Health
Organization has divided perimenopause into early and late phases
Early Women with previously predictable cycles begin to experience
perimenopause alterations in their cycle regularity, but they have not gone for more than
3 months without menstruation; during this stage, women may or may
not experience symptoms related to hormonal deprivation
Late Absence of menstruation increases beyond 3 months
perimenopause
Menopause Permanent cessation of menses determined retrospectively after 12
consecutive months of amenorrhea without any other underlying
pathologic or physiologic cause; longitudinal studies supporting this
definition show less than a 2% chance of spontaneous menstruation
after 12 months of amenorrhea
Postmenopause The period of time after the final menses, representing the state of
permanent amenorrhea
Although the age of menarche has decreased over the years largely as a result
of improvements in nutrition and general health, the age a woman transi-
tions into reproductive senescence seems to be relatively unchanged. Most
women begin to experience changes leading to menopause sometime during
their 40s and 50s. With life expectancy for women entering the climacteric
nearing 86 years, women can anticipate spending greater than one third of
their lives in the postmenopausal period. Many women are poorly informed
about the changes that occur in their bodies and the health concerns asso-
ciated with these changes. They also may be uncertain about the potential
interventions available and the true risks associated with them. The climac-
teric represents a singular opportunity for a woman’s health care provider
to educate the patient and have a positive impact on the remainder of her
life. Treatment and lifestyle interventions introduced at this crucial period of
physiologic change could alleviate symptoms significantly, promote physical
and psychological well-being, and potentially prevent chronic health prob-

lems related to the ensuing changes in the woman’s hormonal milieu.
Because perimenopause represents the earliest opportunity to intervene,
investigators have sought to clarify its onset and duration. The Massachusetts
Women’s Health Study group followed a cohort of 2750 women age 45 to
55 over a 5-year period to determine the number who were perimenopausal
and postmenopausal each year (Fig. 7-1). These investigators determined the
median age of onset of perimenopause was 47.5 years, and the median age
of menopause was 51.3 years. The median duration of perimenopause was
3.8 years. The investigators noted that 10% of the sample stopped menstru-
ating abruptly without evidence of preceding cycle irregularity. Their find-
ings suggested age, smoking, and nulliparity affected the onset and duration
of perimenopause. Women who were older at the onset of perimenopause
94 had shorter transitions to menopause, smokers had earlier onset and shorter
transitions to menopause, and nulliparous women had earlier onset of peri-
menopause. Other studies have elucidated further factors that may be asso-
ciated with early menopause, including family history of early menopause,
history of regular cycles, shorter cycle length during adolescence, history of
type 1 diabetes mellitus, unilateral oophorectomy, presence of a variant form
of galactose 1-phosphate uridyltransferase, and presence of estrogen recep-
tor polymorphisms. Regardless of the inherent interplay of patient genetics
and specific risk factors, only about 2% of women have not entered into the
climacteric by age 55. Armed with knowledge of when this important tran-
Figure 7-1
Percentage of
Perimenopausal
women entering
perimenopause and Postmenopausal
postmenopause
by age. By age 100
51, nearly half
of all women 90
have a cessation
of menstrual 80
periods. Nearly 9
of 10 women reach 70
menopause by their
mid-50s. (Adapted 60
from McKinlay
Percent
SM, Brambilla DJ, 50

Posner JG: The
normal menopause 40
transition. Maturitas
1992;14:107.) 30
20
10
0
45 46 47 48 49 50 51 52 53 54 55
Age
The Climacteric
sition occurs and what factors influence its onset and duration, it is impor-
tant to consider the physiologic processes at work in the climacteric period.
PHYSIOLOGY
Although hormonal changes and ovarian physiology leading to the climac-

teric are not completely understood, it is known that there is a sharp decline
in fertility rates beginning after age 30. In addition, there is a decline in the
quality and quantity of oocytes associated with a concomitant increase in
basal follicle-stimulating hormone (FSH) levels years before the onset of the
climacteric. The climacteric presumably begins when a critical number of
functional follicles are lost through the process of follicular atresia.
During a woman’s reproductive years, hormone production by ovarian 95
follicles maintains a delicately balanced feedback system with the pituitary
and the hypothalamus. As the production of ovarian hormones decreases,
compensatory changes in the hypothalamus and the pituitary seek to re-
establish homeostasis. At the onset of the climacteric (perimenopause),
ovarian production of inhibins decreases, paralleling a decline in functional
ovarian follicles. Initially, levels of inhibin B are affected. Normal levels of
FSH levels in inhibin A are conserved until just before menopause. Because inhibins func-
premenopausal and tion to decrease the synthesis and secretion of FSH and to decrease the num-
perimenopausal
ber of gonadotropin-releasing hormone receptors on pituitary gonadotropes,
women. Because
of decreasing circulating levels of FSH begin to increase (Fig. 7-2). Despite elevated levels of
negative feedback of
estradiol, FSH levels
remain elevated Figure 7-2
in perimenopausal
45
women throughout
the menstrual
cycle. Using FSH 40
levels to diagnose
perimenopause 35 Perimenopausal
can be misleading,
however, because FSH
30
measurements can
reach premenopausal
FSH level
levels, and with 25

infrequent menstrual
periods, it may be 20
difficult to time
FSH measurements
accurately. (Adapted 15
from Santoro N,
Brown JR, Adel T, 10 Premenopausal
Skurnick JH:
Characterization
5
of reproductive
hormonal dynamics in
the perimenopause. J 0
Clin Endocrinol Metab −10 −9 −8 −7−6 −5 −4 −3 −2 −1 0 1 2 3 4 5 6 7 8 9 10 1112 13 14 15 16 17 18
Day of menstrual cycle
1996;81:1497.)
FSH, ovarian response to FSH becomes progressively more blunted. Initially,

the ovary responds to the elevated levels of FSH by increasing production of
estradiol, resulting in levels greater than those seen during the reproductive
years. Ovarian response per unit of FSH continues to decline, however, until
estradiol levels are markedly reduced. In addition to fluctuations in estra-
diol, the perimenopause is marked by reduced progesterone production in
the luteal phase until, with cessation of ovulation, progesterone production
ends. This vacillation in ovarian hormone secretion continues until meno-
pause, at which time a new steady state is reached. By menopause, estradiol
and estrone are markedly decreased, FSH and luteinizing hormone (LH) are
elevated, and testosterone is reduced by 20%.
The most observable consequence of this hypothalamic-pituitary-
ovarian axis perturbation is the changes in a woman’s menstrual cycle.
96 Perimenopause is characterized by ovulatory cycles interspersed with
anovulatory cycles of varying lengths. Normal to elevated levels of estradiol
and altered estradiol to progesterone levels may lead to menorrhagia, endo-
metrial hyperplasia, dysfunctional uterine bleeding, and growth of uterine
leiomyomata. Early on, there may be a shortening of the cycle by 2 to 7 days
secondary to a shorter follicular phase as enhanced FSH recruitment of a
dominant follicle occurs. There also may be increased quantity of menstrual
bleeding as a result of luteal insufficiency and anovulation. Later, the cycle
typically lengthens secondary to decreased follicular recruitment and fur-
ther anovulation. Before menopause, menstrual bleeding decreases as estro-
genic stimulation of the endometrium decreases; however, irregular spotting
may increase. At menopause, the functional pool of follicles is depleted, and
estradiol production declines further. As a result, there is minimal estrogenic
stimulation of the uterus, the endometrium becomes atrophic, and menses
cease.
Although menstrual disorders are often cited as the most bothersome initial
symptom of the climacteric, elsewhere in the body fluctuations and ultimate
withdrawal of ovarian hormones are responsible for many clinical symp-
toms that have a significant impact on a woman’s life.
Vasomotor Vasomotor disturbances (hot flashes and night sweats) are common cli-
Disturbances macteric symptoms. Nearly 75% of perimenopausal and postmenopausal
women report vasomotor symptoms. Hot flashes typically occur early in
perimenopause, peak at menopause, and persist into postmenopause for
approximately 1 to 5 years. They are characterized by a sudden sensation
of heat in the upper body, especially the face, neck, and chest, which rap-
idly becomes generalized. Often they are associated with profuse sweating
and palpitations and may be followed by shivering and chills. They last a
few seconds to several minutes and occur several times per day. They may
occur once per hour throughout the day and night. Physiologic studies show
The Climacteric
that hot flashes are associated with an inappropriate peripheral vasodilation

with shunting of blood to the skin and perspiration resulting in rapid heat
loss and a drop in core body temperature. Shivering ensues to restore the
core body temperature to normal.
The exact etiology of hot flashes is unknown, although there is evidence
to suggest they arise secondary to a centrally mediated dysfunction in ther-
moregulation. This dysfunction is likely triggered by a decrease in estrogen
during the climacteric years. The major thermoregulatory center in mam-
mals (the medial preoptic area) lies in close proximity to a high density of
gonadotropin-releasing hormone–secreting neurons in the hypothalamus.
In addition, hot flashes are shown to have a temporal relationship to peaks in
LH secretion—also dependent on gonadotropin-releasing hormone release.
Women with Turner’s syndrome, who have constitutionally high levels of
FSH and LH, do not experience hot flashes unless they are first treated with 97
and then withdrawn from estrogen. This finding suggests that it is not ele-
vated FSH and LH per se, but estrogen withdrawal via its interplay with the
hypothalamus that seems to play a major role in the mechanism of vasomo-
tor symptoms.
Sleep Change in hormonal patterns that occur in the climacteric may contribute to
Disturbances sleep disturbances. Studies indicate that the number of women complaining
of sleep disturbances increases after age 40 and plateaus by age 50. Sleep dis-
turbances were increased only among perimenopausal and postmenopausal
women who were not taking hormone replacement therapy. Nocturnal hot
flashes invariably disrupt sleep, either by affecting sleep quality or by repeti-
tive awakening. Perimenopausal and postmenopausal women who have
hot flashes have decreased sleep efficiency and an increased latency to REM
sleep. Because the restorative value of sleep is directly affected by sleep con-
tinuity (the ability to remain asleep) and the circadian phase (regulated by
core body temperature cycles and melatonin) at which it occurs, disruptions
caused by nocturnal hot flashes can lead to daytime drowsiness and fatigue
and may exacerbate other problems common to the climacteric.
Depression Although women do not develop depression during the climacteric transi-
tion, studies suggest that perimenopause is a period of increased susceptibil-
ity to depression. Studies are mixed on the relative importance of vasomotor
symptoms in women with depression; some studies indicate women expe-
riencing menopausal symptoms (irregular bleeding and vasomotor symp-
toms) have higher rates of depression than women who are symptom-free,
whereas others report depression occurred independent of vasomotor symp-
toms. Regardless, one of the strongest predictors for depression during the
climacteric is a preceding history of depression. Perimenopausal women
have a variety of other psychosocial stressors that also may predispose
them to depression. They may be at the peak of their professional careers,
balancing career decisions with changes in family dynamics and caregiv-
ing responsibilities related to egress of older children and care of elderly
family members. Women who view themselves primarily as mothers may

mourn the loss of their reproductive years. Negative cultural images of the
aging woman may promote pessimism in women undergoing this transition.
Whether this increase in depression results from hormonal or life changes,
the risk of depression seems to normalize in the postmenopausal years.
Urogenital As circulating estrogen levels decrease toward the end of the climacteric,
Symptoms numerous changes occur in the genitourinary system. Vaginal epithelium is
relatively estrogen dependent, and estrogen depletion leads to thinning and
atrophy of the vaginal mucosa. On examination, the vagina may appear
pale with absence of normal rugae and presence of petechiae and superfi-
cial vessels. Vaginal elasticity also may decrease resulting in a loss of cali-
98 ber and length unless sexual intercourse is maintained. In addition, there
is decreased production of vaginal fluid and decreased glycogen production
by vaginal epithelium. Lactobacilli, which previously suppressed competi-
tive bacterial growth by metabolizing glycogen to acidic by-products, may be
gradually replaced, and vaginal pH may increase. The increase in vaginal pH
around menopause may promote growth of potential pathogenic organisms
and increase the likelihood of infection. Collectively, all these changes intro-
duced by estrogen depletion subsequently lead to vaginal irritation, pruritus,
and dyspareunia.
Similarly, estrogen depletion leads to atrophy of the superficial and inter-
mediate layers of the urethra epithelium and to atrophy of the bladder tri-
gone. Ensuing changes that occur may result in decreased urethral seal and
tonicity and loss of bladder compliance and irritation, which result in dysuria
from atrophic urethritis, urinary frequency, and incontinence. Combined
with a change in vaginal flora favoring colonization by pathogenic or fecal
organisms, postmenopausal women also are at increased risk for urinary
tract infections.
Risk for pelvic organ prolapse is another condition associated with estro-
gen deficiency. This malady is more likely to manifest itself after menopause,
however, and usually is associated with several other risk factors. Other risk
factors for pelvic organ prolapse include advanced age, multiparity, obesity,
birth trauma associated with dystocia or operative vaginal delivery, prior
pelvic surgery, connective tissue disorders, neurogenic dysfunction affecting
the pelvic floor, chronic constipation secondary to anal atresia, and other
conditions that chronically increase intra-abdominal pressure. Together
with racial differences in the incidence of pelvic organ prolapse, these risk
factors suggest that prolapse does not chiefly represent an estrogen defi-
ciency syndrome, but injury of pelvic support structures that are exacer-
bated over time.
Sexual Problems with sexual function are common among women in the climacteric
Dysfunction period and may be associated with physiologic, emotional, and iatrogenic
causes. Discomfort during intercourse may be exacerbated by vaginal atro-
phy, dryness, and decreased compliance resulting from estrogen deficiency.
The Climacteric
In addition, it is known in animals that estrogen deficiency also causes a

reversible neuropathy in the distribution of the pudendal nerve. Similarly,
estrogen deprivation may result in decreased skin sensitivity in the geni-
tal region in women. During the climacteric transition, libido also may be
affected by the changing hormonal milieu. Although still controversial in its
exact contribution to sexual function and dysfunction, androgen production
is known to decline during this transition and may affect sexual interest and
desire. Women also may have decreased interest in sexual activity if they
are experiencing haphazard bleeding, hot flashes, and sleep disturbances.
Emotional issues during this period also may interfere with normal sexual
function. Body image concerns associated with weight gain during this
phase, the availability of a functional partner, and the onset of chronic ill-
nesses all may affect a woman’s sense of femininity and her sexual receptiv-
ity. Many medications given to treat these conditions actively interfere with 99
normal sexual functioning. Medications that affect the autonomic nervous
system may affect desire and orgasm, whereas medications that affect the
parasympathetic nervous system and alter concentrations of acetylcholine
may affect arousal.
Connective As a woman ages, the amount of collagen in her skin and bones decreases.
Tissue Changes After the time of menopause, changes apparent in the skin include thin-
ning, increased wrinkling, decreased hydration, decreased sebaceous secre-
tion, and decreased elasticity. These changes are probably estrogen mediated
because the skin is rich with estrogen receptors, and multiple studies have
shown increased collagen content and thickness after estrogen therapy.
Osteoporosis Although not typically associated with the early climacteric when estrogen
levels are still conserved, osteoporosis is a significant health problem begin-
ning with the menopausal and postmenopausal years. An individual’s ulti-
mate bone mass seems to be influenced by heredity and hormonal factors
and is amassed over a relatively short window of time during their reproduc-
tive life. With the onset of menopause and subsequent estrogen deprivation,
bone remodeling increases with bone resorption by osteoclasts exceeding
bone formation by osteoblasts. As a consequence, 1.5% of the total skeletal
mass and 5% of trabecular bone can be lost per year in the first few years
after menopause. Depending on the woman’s bone mass entering meno-
pause, osteoporosis could occur in 10 years. Osteoporosis is characterized
by low bone density and microarchitectural deterioration of bone tissue,
with an increase in bone fragility and susceptibility to fracture. For measure-
ment purposes, it is defined as greater than a 2.5 SD in bone mass from the
average, same gender, peak bone mass. Osteopenia is defined as a reduction
between 1 and 2.5 SDs from the average peak bone mass and, in the pres-
ence of other risk factors for osteoporosis or documented progressive bone
loss, may represent an increased risk for fracture. Because trabecular bone
in the axial skeleton experiences a greater decline in mass, it is particularly
susceptible to fracture. Vertebral fractures may lead to chronic pain, loss of
height, kyphosis (dowager’s hump), and other postural deformities with their
attendant pulmonary, gastrointestinal, and bladder dysfunctions. Similarly,
hip fracture is associated with significant morbidity and mortality. After hip
fracture, approximately 20% of women die within 1 year, 25% require long-
term care, and 50% experience long-term loss of mobility. Accelerated bone
loss during the climacteric period represents a significant threat to health
and quality of life for women at risk for osteoporosis. Osteoporosis is covered
in greater detail in Chapter 8.
Cardiovascular Similar to osteoporosis, cardiovascular disease does not begin to increase

Disease until after menopause. Relative to age-matched men, women during their
reproductive years show decreased risk for cardiovascular disease (Fig. 7-3).
100 Progression through menopause is associated with an increase in total cho-
lesterol, low-density lipoprotein cholesterol, and triglycerides—all risk fac-
tors for heart disease. The incidence of myocardial infarction also increases
after menopause. Coronary heart disease is two to three times more likely to
occur in women after menopause than in women of the same age who have
not entered menopause; this has led many clinicians to postulate a protec-
tive role of estrogen in the prevention of cardiovascular disease.
Cognitive Aging is associated with a general decline in memory and cognition. In addi-
Decline tion, there is a threefold increase in Alzheimer’s disease in women compared
with men. In the brain, estrogen is believed to promote synaptic and neu-
ronal growth and to guard against oxidative neuronal cytotoxicity and to
Figure 7-3 Men

Incidence of
myocardial infarction Women
by age and sex.
Before the climacteric
(age 35-44), women 35
have 1⁄10 the risk of
myocardial infarction 30
compared with age-
Two year rate per 1000
matched men. This 25

risk increases to 1⁄7.5
at the climacteric 20
and to less than ½
by age 80. (Adapted 15
from Lerner DJ,
Kannel WB: Patterns 10
of coronary heart
disease morbidity 5
and mortality in
the sexes: a 26- 0
year follow-up of 35-44
45-54
the Framingham 55-64
population. Am Heart Age at exa 65-74
mination 75-84
J 1986;111:386.)
The Climacteric
reduce the glycoprotein found in Alzheimer’s lesions. Despite this evidence,

studies do not uniformly support a decline in cognition through the meno-
pausal transition, and they do not show a protective effect of estrogen on
cognitive decline or development of dementia.
Summary Physiologic changes of the climacteric period can precipitate many clinical
symptoms. These symptoms seem to be related to the short-term and long-
term effects of ovarian hormone withdrawal. Symptom and risk factor rec-
ognition and subsequent initiation of therapy are paramount because of the
impact these problems have on a woman’s general health and quality of life.
DIAGNOSTIC TESTING 101
Markers for Collectively, the many health issues associated with the climacteric can
Menopause have a dramatic impact on current social functioning and long-term health.
The diagnosis of menopause is made in hindsight, after a full year of ovar-
ian quiescence. During this year, women experience many of the negative
side effects of decreasing estrogen, including hot flashes, night sweats, and
bone loss. Early identification of impending menopause would allow for
preemptive intervention to prevent such symptoms.
In the final stages of ovarian failure, the ovaries respond poorly to FSH
stimulation. As a result, FSH levels increase to drive the ovarian follicles to
produce estradiol. Ultimately, when the ovaries are exhausted of oocytes
and are unable to produce estradiol, the FSH levels increase dramatically.
Overproduction of FSH could serve as a marker for entry into menopause.
FSH is not a reliable marker for the transition to menopause. This hor-
mone is produced in a pulsatile fashion, and blood levels may be relatively
low in menopausal women or relatively high in women who have not yet
reached menopause, depending on whether FSH production is at its peak or
nadir. Also, given this variability, it is difficult to select a clinically useful FSH
level that can be used to diagnose menopause. If the FSH cutoff is too high,
women reaching this level would most certainly be in menopause, but there
would be many other women who experience the perimenopausal symptoms
but do not achieve this cutoff. Conversely, if the level is too low, there would
be women who have not reached menopause who would be incorrectly cate-
gorized as menopausal. It has been shown that there is no statistical increase
in the likelihood of undergoing menopause over the next 10 years in women
with a basal FSH of greater than 10 IU/L compared with women with basal
FSH levels less than 10 IU/L.
In the absence of an effective blood test to diagnose menopause accu-
rately, clinicians are obliged to evaluate symptoms to determine whether
their patients have progressed into and beyond the climacteric. Because this
strategy can place a woman at risk for several months, it is important to use
the established relationship between age and onset of perimenopause to
begin screening for the health problems that she is likely to encounter and to
intervene as necessary to minimize these risks.
Osteoporosis Fracture risk, as described previously, represents one of the greatest risks of
Screening the menopausal period. The development of osteopenia and ultimately osteo-
porosis is relatively silent and inevitable with age, and patients frequently
present with a life-threatening bone fracture. Current technology provides
reasonable options for diagnosis and treatment of osteoporosis.
The gold standard for assessment of bone loss is the dual-energy x-ray
absorptiometry (DEXA) scan. DEXA involves exposure of x-rays at two dif-
ferent energies that are absorbed differently by bone of different densities.
Results typically are presented as T-scores, which are simply SDs from the
mean of the peak bone mass of an average young adult. Each SD from the
mean increases the risk of fracture twofold. Data from DEXA scans also can
be presented as Z-scores, which represent SDs from an age-matched mean.
Z-scores can be misleading, in that mean bone mass decreases with age, and
102 individuals who are elderly but near the mean are at increased risk of bone
fracture.
In addition to DEXA scanning, there are several blood and urine tests to
identify products of bone turnover. Markers that increase with bone resorp-
tion include N-telopeptide, C-telopeptide, pyridinoline, deoxypyridinoline,
and hydroxyproline, and markers that increase with bone formation include
N-propeptide, C-propeptide, alkaline phosphatase, and osteocalcin. These
markers may provide some information on the effectiveness of therapy, but
there are currently no well-accepted measurements that can be used for
prognosis.
Cardiovascular As women progress through the climacteric period, their risk of cardiac and
Risk Screening vascular disease rapidly approaches the risk encountered by men. Before the
climacteric, men experience coronary heart disease at a rate 6.5 times greater
than age-matched women (Box 7-1). By menopause, this ratio decreases to
3, and by 75 years of age or older, women carry the same risk as men. There
remains a bias, however, that men are at risk of cardiovascular disease and
Box 7-1
Relative Risk of that women are protected from it. In reality, cardiovascular disease is the
Cardiovascular most common cause of death in women from the climacteric and beyond.
Disease in Men Typical symptoms that define impending myocardial infarction are well
Compared with defined in men, but may differ in women. As a result, clinicians need to have
Women by Age a high level of suspicion when a perimenopausal or postmenopausal woman
Preclimacteric—6.5 presents with vague symptoms. In an asymptomatic patient, studies such
Menopause—3.0 as electrocardiogram or exercise stress testing have low positive predictive
≥75 years—1.0
value and are not helpful as screening tests. Evaluation of risk factors for car-
diac disease such as cholesterol, high-density lipoprotein, low-density lipo-
protein, and triglycerides is warranted. For patients with symptoms, stress
testing and electrocardiogram along with creatine kinase–MB and troponin
blood testing provide invaluable information on current and future risk.
Carotid artery Doppler also may be helpful in women who are experienc-
ing central nervous system symptoms, such as transient ischemic attacks.
Evidence of cardiovascular disease should be evaluated further and treated
in conjunction with a cardiologist.
The Climacteric
Numerous management strategies exist to treat symptoms associated with

the climacteric and to maintain the healthy functioning of a woman as she
continues on into her postmenopausal years. These approaches consist of
lifestyle interventions and hormonal and nonhormonal pharmacotherapy.
Lifestyle The climacteric transition is an excellent opportunity to educate women

Intervention and reinforce the concept of a healthy lifestyle. As part of a healthy lifestyle,
women should be instructed in proper nutrition. With the cessation of ovar-
ian hormone production, a woman’s metabolic requirements change. To
maintain a desirable body weight and minimize her risk of different chronic
diseases associated with obesity, her total caloric intake should be decreased 103
to 1900 calories per day. Approximately 30% of recommended calories
should be fats with no more than 300 mg of cholesterol per day. High-fat
diets may increase the risk of cardiac disease and are associated with sev-
eral cancers. Conversely, dietary fiber is linked to a decreased risk for cardiac
disease and cancer. Adequate intake of calcium and other minerals impor-
tant in bone maintenance, such as zinc, magnesium, and phosphorus, also
should be encouraged. Daily calcium intake should be increased from 1000
mg/day to 1500 mg/day, and vitamin D may be added if a patient has inad-
equate sun exposure. Caffeine and alcohol negatively affect bone density via
calcium absorption and estrogen metabolism. Dietary changes that limit
alcohol and caffeine may be helpful in ameliorating symptoms associated
with osteoporosis.
Because smoking increases a woman’s risk of cardiovascular disease,
osteoporosis, bronchitis, emphysema, and cancer, smoking cessation dur-
ing this period of increasing susceptibility should be strongly encouraged.
Studies show that patients have greater success at quitting when physicians
encourage them to stop. The health care provider’s effectiveness as deter-
mined by actual cessation rates depends, however, on a systematic approach
to identifying smokers and supporting tobacco cessation. A woman’s health
care provider should be prepared to assist with smoking cessation by intro-
duction of behavioral therapy and supplementing with nicotine patch and
bupropion therapy as needed.
The positive effects of exercise on cardiovascular disease and bone mineral
density are well documented. As a woman ages, cardiovascular endurance
decreases at a rate of 1 mm3 oxygen/kg body weight per year, and maximum
heart rate decreases by 1 beat/min per year. Although maximal heart rate
does not change, cardiovascular endurance can be improved through physi-
cal activity. Studies indicate a 30% to 40% risk reduction in cardiovascular
disease in women participating in vigorous physical activity such as brisk
walking. In addition, exercise stimulates osteoblastic, or bone-forming, activ-
ity in bone and decreases the age-related decline in muscle mass. Regular
physical activity should be encouraged. Physical activities should include a
combination of aerobic weight-bearing and resistance exercises to maximize
cardiovascular and musculoskeletal benefits. Posture and balance training

also is important and may decrease the risk of falls as a woman ages. It is
recommended that women get 30 minutes of cumulative physical activity at
least 3 days per week.
In addition to proper nutrition, smoking cessation, and exercise, health
screening is an important component of lifestyle intervention. Various medi-
cal organizations have recommended health screening measures for women.
The American College of Obstetrics and Gynecology has recommended the
measures listed in Table 7-1 based on age groups and specific risk factors for
asymptomatic women based on test accuracy, risks, and cost. Symptomatic
women would require further evaluation as dictated by their complaint.
104 Hormonal Phar- Many of the symptoms associated with the climacteric (hot flashes, night
macotherapy sweats, sleep disturbances, sexual dysfunction, and collagen changes)
and some of the long-term health issues of the postmenopausal period
(osteoporosis) result from hormone deprivation that occurs with ovarian
failure. These symptoms and diseases can be minimized or eliminated with
hormonal supplementation. Early retrospective studies suggested a wide
range of benefits from hormone replacement therapy, including prevention
Table 7-1
Health Screening Evaluation Timing
Recommendations
for Women in the History—including full medical Annually
Climacteric and family histories; evaluation
of sexuality, fitness, and nutrition;
psychosocial evaluation; and
cardiovascular risk factors
evaluation
Physical—including measurement Annually
of height, weight, and blood
pressure and oral cavity, thyroid,
breast, abdomen, pelvic, and
skin examinations
Pap smear Annually, then physician discretion after
3 consecutive normal tests if low risk
Mammography Every 1-2 yr until age 50, annually
thereafter
Cholesterol testing Every 5 yr beginning at age 45
Fecal occult blood testing Annually
Flexible sigmoidoscopy Every 5 yr beginning at age 50
Or
Colonoscopy Every 10 yr beginning at age 50
Or
Double-contrast barium enema Every 5-10 yr beginning at age 50
Fasting glucose testing Every 3 yr after age 45
Influenza vaccine Annually beginning at age 50
Tetanus-diphtheria booster Every 10 yr
Modified from American College of Obstetricians and Gynecologists: Guidelines for Women’s
Health Care, 2nd ed. Washington, D.C.: ACOG; 2002:130-131.
The Climacteric
of cardiovascular disease, dementia, and other long-term ailments. Various

prospective trials have not validated these findings, however, and hormone
replacement therapy can no longer be considered a panacea.
Cardiovascular disease is the most common cause of morbidity and mortal-
ity in postmenopausal women, and early studies suggested that markers for
long-term cardiovascular risk improved in women taking hormone replace-
ment therapy. Placebo-controlled, randomized, prospective trials (Heart and
Estrogen/progestin Replacement Study II and the Women’s Health Initiative)
showed, however, that hormone replacement therapy provided no benefit
for primary or secondary prevention of cardiovascular disease, stroke, or
deep venous thromboembolus. The combination (Premarin/Provera) form
of hormone replacement therapy used seemed to increase the risk of these
outcomes, although overall mortality was no different in either arm of the
study. 105
Although the Women’s Health Initiative validated hormone replacement
therapy as reducing the risk of vertebral and hip fractures by 34%, these
investigators concluded that overall risks outweighed the merits of hormone
replacement therapy in this setting. Then what conditions should be treated
preferentially with hormone replacement therapy? The above-mentioned
studies did not, and by design could not, assess the impact of hormone
replacement therapy on the vasomotor symptoms associated with the cli-
macteric. Because of the dramatic improvement in hot flashes caused by
hormone replacement therapy, it was impossible to do a blinded study. For
women with severe hot flashes, night sweats, and sleep disturbances, hor-
mone replacement therapy is an effective short-term therapeutic option. In
addition, for women at high risk for osteoporosis, the risk/benefit assessment
may favor hormone replacement therapy use. For women previously tak-
ing hormone replacement therapy primarily for nonvasomotor complaints,
alternative formulations exist.
Other Pharma- Other agents have not proved as effective in treating vasomotor symptoms.
cotherapy When evaluated by randomized placebo-controlled trials, only selective
serotonin reuptake inhibitors and gabapentin have shown improvement in
vasomotor symptoms over placebo. Because of the perceived danger in tak-
ing hormonal preparations, many women have resorted to using soy prod-
ucts, herbs, and other complementary and alternative therapies to manage
menopausal symptoms. Although black cohosh and some phytoestrogen
preparations initially appeared promising, randomized controlled trials have
not borne out their efficacy. In addition, there are no long-term safety data
for these formulations.
Selective estrogen receptor modulators (SERMs) are one class of non-
hormonal agents shown to be beneficial in remedying some of the effects
of ovarian hormone withdrawal. SERMs selectively bind estrogen recep-
tors and, based on the tissue type, may exert an agonistic or antagonistic
response. Raloxifene has been shown to maintain bone density in postmeno-
pausal women without adverse stimulation of the breast or endometrium.
In addition, raloxifene was associated with reduced risk for breast cancer.
It also was associated with an increase in thromboembolic events and a

significant increased risk of hot flashes, however. At this time, no commer-
cially available SERM has proved effective at relieving vasomotor symptoms.
Bisphosphonates are another group of medications that have shown efficacy
in increasing bone mass and reducing fractures when used to treat osteopo-
rosis. These agents preferentially bind hydroxyapatite crystals in mineralized
bone matrix and inhibit osteoclastic activity. Bisphosphonates approved for
use in the United States include alendronate, risedronate, and ibandronate.
For patients at risk for osteoporosis-related fractures who are unable to toler-
ate bisphosphonates, calcitonin and teriparatide (an injectable parathyroid
hormone) may be viable options.
106 Summary Multiple therapeutic modalities exist to treat the short-term and long-term
effects of ovarian hormone withdrawal initiated in the climacteric period.
Early diagnosis and intervention potentially can prevent significant morbid-
ity and preserve overall well-being of women reaching this transition point
in life.

1. It is important to identify the beginning of the climacteric period to inter-
vene appropriately.
2. Fluctuations of estradiol during perimenopause potentially may lead to
pathologic conditions, such as endometrial hyperplasia, dysfunctional
uterine bleeding, and enlargement of uterine tumors. Bleeding during
perimenopause needs to be investigated with endometrial sampling.
3. Estrogen deprivation underlies most of the physical symptoms experi-
enced by women passing through the climacteric.
4. Long-term hormonal replacement may not be beneficial, but short-term
use may be justified to control symptoms related to hormonal depriva-
tion.
5. Alternatives to hormonal supplementation exist, but the benefits of some
of these products, particularly those sold without prescription, have not
been carefully evaluated.
SUGGESTED READINGS
American College of Obstetricians and Gynecologists: Barbieri RL, Derman RJ, Gass MLS, et al (eds): APGO
Clinical updates in women’s health care—care of aging Educational Series on Women’s Health Issues:
women. ACOG vol III, no 1; January 2004. Current Strategies for Managing Osteoporosis.
Barbieri RL, Berga SL, Chang RJ, Santoro NF (eds): Beachwood, Ohio: Current Therapeutics; 2003.
APGO Educational Series on Women’s Health Barbieri RL, Lobo RA, Walsch BW, Santoro NF (eds):
Issues: Managing the Perimenopause. Beachwood, APGO Educational Series on Women’s Health
Ohio: Current Therapeutics; 2001. Issues: Improving Quality of Life during Menopause:
The Climacteric
The Role for Hormone Replacement Therapy. Managing Insomnia and Sleep Disorders in Women.
Beachwood, Ohio: Current Therapeutics; 2002. Beachwood, Ohio: Current Therapeutics; 2000.
Diagnosis and clinical manifestations of menopause. Speroff L, Fritz RA (eds): Menopause and the peri-
UpToDate Online Version 12.2; 2004. menopausal transition. In Clinical Gynecologic
Grady D, Herrington D, Bittner V, et al: Cardiovascular Endocrinology and Infertility, 7th ed. Philadelphia:
disease outcomes during 6.8 years of hormone Lippincott Williams & Wilkins; 2005:621-688.
therapy: Heart and Estrogen/progestin Replacement Writing Group for the Women’s Health Initiative
Study follow-up (HERS II). HERS Research Group. Investigators: Risks and benefits of estrogen plus
JAMA 2002;288:49-57. progestin in healthy postmenopausal women. JAMA
Ling FW, Buysse DJ, Ciotti MC, et al (eds): APGO 2002;288:321-333.
Educational Series on Women’s Health Issues:
107
8
OSTEOPOROSIS AND
BONE METABOLISM
Rocio I. Pereira and Linda A. Barbour
DEFINITIONS
Bisphosphonates Pharmacologic agents that bind to hydroxyapatite at active sites in the 109
bone and inhibit osteoclastic activity
Bone strength The characteristic of bone that, when compromised, predisposes patients
to increased fracture risk; bone strength depends on bone mineral
density and bone quality (determined by architecture, mineralization,
microdamage accumulation, and turnover rate)
Osteomalacia A condition of defective mineralization of mature bone that occurs
in adults when insufficient calcium or phosphorus is available for the
formation of the primary bone mineral, hydroxyapatite
Osteopenia Bone mineral density compromise with a T-score of −1 to −2.5
Osteoporosis A skeletal disorder characterized by compromised bone strength,
predisposing an individual to increased risk of bone fracture, defined by
the World Health Organization as a T-score of −2.5 or less
T-score Bone mineral density reported as the number of SDs from the normal
young adult mean density value
Z-score Bone mineral density reported as the number of SDs from the normal
mean value for age-matched and sex-matched control subjects
Osteoporosis affects numerous individuals who often are not diagnosed until
significant morbidity occurs. Although osteoporosis most often affects white
women, men and women of all races and ethnic backgrounds can be affected.
According to the World Health Organization, one in three postmenopausal
women have osteoporosis, but 70% are undiagnosed and untreated. The
cumulative lifetime fracture risk for whites is approximately 50%. One in five
postmenopausal women have vertebral fractures, usually with no symptoms,
yet this single event increases their relative risk of mortality eightfold. Most
women are deeply concerned about the effects of bone fracture on quality
of life, as evidenced by the finding that owing to the unfavorable prospect
of nursing home placement, 80% of women older than 75 years preferred
death to a bad hip fracture.
Osteoporosis is defined as a skeletal disorder characterized by compro-
mised bone strength predisposing an individual to increased risk of bone
fracture. Bone strength depends on bone mineral density (BMD) and bone
quality (determined by architecture, mineralization, microdamage accumu-

lation, and turnover rate). BMD accounts for 70% of bone strength and is
used as a proxy measure of overall bone strength.
Osteoporosis can be classified as primary, secondary, or idiopathic.
Primary osteoporosis results from an age-related acceleration of bone resorp-
tion. It can affect men and women, but most often affects postmenopausal
women. Secondary osteoporosis is unrelated to menopause and results from
medications or certain clinical disorders. Idiopathic osteoporosis results
from an inability to achieve adequate peak bone mass during childhood and
adolescence.
Osteoporosis-associated fractures can occur in any bone, but usually
occur at sites of low bone mass and are related to a fall or injury. A fragility
fracture is a fracture occurring from trauma that usually would not cause a
110 fracture or from a force less than or equal to that resulting from a fall from
standing height. Common sites of fractures are the vertebral bodies (verte-
bral compression fracture), proximal femur (hip fracture), and distal forearm
(Colles’ fracture).
Vertebral compression fractures are diagnosed by a 15% to 20% reduc-
tion in anterior, mid, or posterior vertebral body height. Possible adverse
effects related to vertebral fractures include loss of height, kyphosis, crowd-
ing of internal organs, back pain (acute and chronic), prolonged disability,
and increased mortality. Hip fractures are the most serious complication of
osteoporosis, resulting in pain, disability, and greatly increased mortality.
Among women with hip fractures, approximately 25% die within 1 year,
greater than 50% spend time in a nursing home, and 90% are no longer
able to climb stairs independently. The risk of fracturing the opposite hip is
approximately 30%.
PHYSIOLOGY
Bone remodeling is the ongoing process of bone formation and breakdown

(resorption) necessary for the skeleton to provide optimal support and for the
repair of damage occurring from daily activities. During childhood and ado-
lescence, bone formation predominates, and bone mass gradually increases.
Peak bone mass is achieved by 30 years of age in men and women. Peak bone
mass is determined by multiple factors, including genetics (50-80% contribu-
tion), nutrition, physical activity, health, and sex hormones. In healthy young
adults, the bone remodeling process is in balance, and bone density remains
stable. The highest rate of calcium accrual occurs at age 12 to 13 years in
girls, and many do not achieve their predicted peak bone mass because of an
increase in the incidence of calcium and vitamin D deficiency in children.
With menopause and aging, bone resorption occurs at a greater rate than
bone formation, and a loss in bone density occurs. An accelerated decline in
bone density of 1% to 3% loss per year is seen for the first 5 to 10 years after
menopause and tapers to approximately 0.75% per year in the elderly.
Risk factors for developing low bone mass can be categorized as modifiable
or nonmodifiable (Table 8-1). Although nonmodifiable risk factors, such as
Osteoporosis and Bone Metabolism
Table 8-1
Modifiable Modifiable Risk Factors Nonmodifiable Risk Factors
and Nonmodifiable
Risk Factors for Calcium deficiency (vitamin D deficiency, Female gender
Low Bone Mass malabsorption, hypercalciuria) Age >50 yr
Smoking White race
Low weight (<127 lb) and body mass index Family history
Estrogen deficiency (menopause <45 yr, History of prior fracture
amenorrhea) History of falls
Alcohol intake (>2 drinks/day) Dementia
Chronic diseases (see Box 8-1)
Medications (see Box 8-2)
Low activity level and muscle strength
Balance problems
Poor vision
111
genetic makeup and age, account for most osteoporosis risk, modifiable fac-
tors, such as inadequate vitamin D and calcium, smoking, excess alcohol
and caffeine intake, and inactivity, should be identified and addressed in
all women receiving routine medical care. Multiple medical conditions and
medications also have been associated with an increased risk of osteoporosis
(Boxes 8-1 and 8-2). Early identification of these risk factors and appropriate
intervention can help prevent the development of secondary osteoporosis in
these patients.
Although BMD is an important predictor of fracture risk, the propensity
to fall also contributes markedly to the overall risk of osteoporotic fracture
in postmenopausal women. Age is the most powerful risk factor. Despite the
exact same bone density measurements, an 85-year-old woman has four times
the fracture risk compared with a 65-year-old woman, and hip fracture risk
increases more than 10-fold from age 50 to age 70. In women with known
osteoporosis, it is important to address other risk factors for falls, including
poor eyesight, frailty, alcoholism, balance problems, and dementia.
Box 8-1 Chronic Diseases Associated with an Increased Risk of Osteoporosis

● Anorexia/bulimia
● Celiac sprue
● Cerebrovascular accident
● Chronic obstructive pulmonary disease
● Chronic renal insufficiency
● Cushing’s syndrome
● Hyperparathyroidism
● Hyperthyroidism
● Hypogonadism
● Inflammatory bowel disease
● Liver disease
● Multiple myeloma
● Multiple sclerosis
● Rheumatoid arthritis
● Type 1 diabetes
Box 8-2 Medications Associated with an Increased Risk of Osteoporosis

● Aluminum
● Medroxyprogesterone
● Glucocorticoids
● Heparin
● Immunosuppressants
● Lithium
● Phenobarbital
● Phenytoin
● Sedatives
● Supraphysiologic thyroxine replacement
112 CLINICAL PRESENTATION
Osteoporosis is most commonly silent, and the diagnosis is often not made
until an individual sustains a fragility fracture. Even when a patient is hos-
pitalized for a fragility fracture, only approximately 25% of patients undergo
the appropriate diagnostic evaluation and treatment for osteoporosis.
Vertebral fractures may present as an insidious loss of height or as acute and
chronic pain associated with a stooped posture.
African-American women have a higher bone density than white non-
Hispanic women throughout their life and experience lower hip fracture
rates. Japanese women often have a lower peak bone density than white
women, but for unclear reasons, they have a lower hip fracture rate. Mexican-
American women have bone densities intermediate between those of white
non-Hispanic women and African-American women. Limited available
information on Native American women suggests they have a lower BMD
than white non-Hispanic women.
DIAGNOSTIC TESTING
Bone Mineral Measurement of BMD is integral to the evaluation of osteoporosis and should
Density be performed on all younger postmenopausal women (>50 years) who have
Measurements risk factors and in all women 65 years old or older (Box 8-3). Several dif-
ferent techniques have been developed for measuring BMD, including dual-
energy x-ray absorptiometry (DEXA), quantitative computed tomography
(CT), peripheral quantitative CT, single x-ray absorptiometry, quantitative
ultrasonography, and radiographic absorptiometry.
Measurements of central BMD (hip and spine) done by DEXA and quanti-
tative CT are most sensitive and most useful in the diagnosis of osteoporosis
and in assessing a response to treatment. DEXA has become the technical
standard for measurement of BMD because of its ability to measure clini-
cally important sites, relative affordability, reproducibility, and low exposure
to radiation. Quantitative CT of the spine is measured in three dimensions
(g/cm3) rather than in two dimensions. Although most sensitive, its preci-
sion may not be as high as DEXA, and it is mainly used as a research tool
Box 8-3 National Osteoporosis Guidelines for Bone Density Measurement

All women >65 years old
All women with a history of fragility fracture
Postmenopausal women <65 years old with at least one risk factor other than
menopause or white race
Patients receiving glucocorticoids for >3 months
Monitoring therapy
because of its high cost (three times the cost of DEXA) and significant radi-
ation. Measurements of peripheral (e.g., forearm, heel) BMD by the other
techniques are less sensitive but less expensive and more widely available.
Peripheral BMD measurement can be useful in screening for fracture risk
when DEXA is unavailable and in low-risk populations. Peripheral measure- 113
ments cannot be used to monitor response to therapy, however, because
of lower sensitivity and the small changes seen in peripheral bone density
compared with the precision of the device. Until standards of comparabil-
ity of different devices and sites for assessing fracture are established, DEXA
remains the gold standard to confirm the diagnosis of osteoporosis and to
monitor the response to treatment.
BMD data are reported as T-scores, representing the number of SDs
from the normal young adult mean density values; Z-scores, representing
the number of SDs from the normal mean value for age-matched and sex-
matched control subjects; and absolute BMD (Figs. 8-1 and 8-2). The T-score
Figure 8-1
Bone densitometry 0
report: T-score
calculation. The
T-score represents −0.5
the number of SDs
from the normal
young adult mean −1
density value. The
T-score predicts −1.5
fracture risk.
SD (T-score)
−2
−2.5
−3 T-score = −3.0
X
−3.5
−4
20 30 40 50 60 70 80 90 100
Age (years)
Figure 8-2
Bone densitometry 0
report: Z-score
calculation. The
Z-score represents −0.5
the number of SDs
from the mean
density value for −1
age-matched and
sex-matched control −1.5
subjects. The Z-score
SD (Z-score)
predicts likelihood of
secondary cause. −2
−2.5
114
−3 Z-score = −1.5
X
−3.5
−4
20 30 40 50 60 70 80 90 100
Age (years)
is used to diagnose osteoporosis or osteopenia and is useful in predicting

fracture risk.
The World Health Organization has defined osteopenia as a T-score of −1
to −2.5 and osteoporosis as a T-score of equal to or less than −2.5 (Box 8-4).
These definitions are based on normal values for DEXA hip scores in white
postmenopausal women, but have become generalized to other patient
groups, including men and nonwhite women. In women older than 60 years
of age, fracture risk doubles with each unit decrease in T-score (Fig. 8-3).
The presence of a vertebral fracture doubles this risk further. T-scores from
peripheral measurements do not correlate well with central DEXA T-scores
and should not be used for true World Health Organization classification of
osteoporosis or osteopenia.
The Z-score compares a patient’s BMD with that of age-matched controls
and is useful in identifying patients with abnormally low BMD for their age.
Women with Z-scores less than 2 should undergo comprehensive evalua-
tions for secondary causes of bone loss. Premenopausal women with signifi-
Box 8-4 Bone Density Criteria for Diagnosis of Osteoporosis in

Postmenopausal Women
Normal: T-score >−1.0
Osteopenia: T-score −1.0 to −2.5
Osteoporosis: T-score ≤−2.5
Premenopausal women: not established; use Z-scores
Figure 8-3
Bone density and 16
fracture risk. The Osteoporosis
T-score can be
used to determine 14
relative fracture risk
in women older than
60 years.
Relative fracture risk 12
10
6
115
0
−4 −3 −2 −1 0
Bone mineral density (T-score)
cant underlying medical diseases placing them at high risk for osteoporosis
should be diagnosed using a Z-score rather than a T-score.
The absolute BMD value is expressed in g/cm2 and can be used to determine
whether a change in BMD is likely a true change or due to the precision error
of the instrument. The precision error for DEXA equipment is usually approxi-
mately 1.5% to 2%. To be confident that a true change in bone mass has
occurred, the change must be greater than 2.5 times the precision error, which
often translates into a 3% to 4% change overall. If possible, serial measurements
over time are most accurately assessed using the same DEXA machine.
Bone Turnover Bone turnover markers provide useful information in identifying patients
Markers with high bone turnover and evaluating response to treatment. These mark-
ers cannot replace BMD measurements, however, and do not make a diagno-
sis of osteoporosis. Bone formation can be assessed by measurement of serum
bone-specific alkaline phosphatase, serum osteocalcin, and serum procolla-
gen I extension peptides. Bone resorption can be assessed through measure-
ment of urinary and serum N-telopeptides, collagen crosslinks, and urinary
deoxypyridinoline and hydroxyproline. A therapy-induced decrease in bone
resorption markers can indicate response to therapy even before signifi-
cant changes in BMD are observed. A patient with osteopenia by DEXA and
increased resorption markers seems to have a higher likelihood of develop-
ing more rapid bone loss over time, but there are inadequate fracture data to
recommend the use of bone markers in routine clinical practice at this time.
SCREENING
The most significant barrier to osteoporotic fracture risk reduction is the

failure of primary and specialty care physicians to implement screening in
appropriate populations. Fewer than 30% of “high-risk” women receive bone
density testing, and fewer than 2% of women older than 60 years of age were
diagnosed by their primary care physicians with osteoporosis (although the
expected prevalence is approximately 20-30%). The National Osteoporosis
Foundation recommends BMD testing for all women age 65 and older regard-
less of risk factors, younger postmenopausal women with one or more risk
factors (other than being white, postmenopausal, and female), and post-
menopausal women who present with fractures (to confirm diagnosis and
determine disease severity). In addition, BMD can be useful when monitoring
116 therapy to ensure that there is no decrease in BMD (see Box 8-3). Women
receiving hormone replacement therapy should be followed especially closely
because 25% have a decrease in bone density on therapy. Measurement
of BMD also should be considered when it might help the patient to decide
whether to institute a treatment that might prevent a fracture.
Age is the most powerful risk factor for fracture and is the reason that
screening strategies prioritize obtaining bone density measurements for
women older than 60 to 65 years of age. Screening 10,000 women age
70 to 74 would result in identifying 2025 women with T-scores of −2.5,
and the number needed to treat to prevent one hip fracture is 51. Screening
the same number of women age 55 to 59 would result in identifying 445
women with T-scores of −2.5, and the number needed to treat to prevent
one hip fracture is 193. Owing to a paucity of prospective trials on screening
and treatment in premenopausal women and the rarity of fragility fractures,
bone density measurements should be reserved for premenopausal women
who have high-risk medical conditions (including amenorrhea) or who are
taking medications associated with bone loss.
Changes in postmenopausal bone density occur first at the spine as a
result of the high metabolic activity of vertebral trabecular bone. To detect
early postmenopausal changes in bone loss, central spine bone density is
most sensitive until about age 65 years, when degenerative joint disease can
falsely elevate the measurement. Given that a spine bone density can overes-
timate bone mass after age 65 years, it should not be used as the sole site for
screening in this age group. Hyperparathyroidism may affect cortical bone
before trabecular bone, and a wrist DEXA is the most sensitive measurement
in this subset of patients at a high risk for osteoporosis. A low central or
peripheral bone density predicts risk of fracture at other sites. However, low
BMD of the hip is the best predictor of future hip fracture.
Screening should be done with DEXA of the spine and hip, unless this
technique is unavailable. Peripheral BMD measurement can be used to
screen low-risk populations for fracture risk, but should not be used in the
high-risk groups mentioned previously or to diagnose osteoporosis. Women
with normal peripheral BMD still should be considered for follow-up central
DEXA if they have significant risk factors (Box 8-5).
Box 8-5 Who Should Have a Central Measurement with Normal Peripheral
Bone Density
● Postmenopausal women >65 years old not on estrogen replacement therapy
who would consider treatment
● Women with history of fragility fractures
● Women with two or more risk factors for bone loss other than menopause
● Women with medical conditions associated with bone loss
● Women taking medications that cause bone loss
EVALUATION
All women with postmenopausal osteoporosis should have an evaluation to

exclude other common causes of low BMD (e.g., vitamin D deficiency, hyper-
117
thyroidism, or hyperparathyroidism) and to detect coexisting medical con-
ditions or factors contributing to low BMD. Secondary causes of decreased
BMD include endocrine disorders, medications, immobilization, renal fail-
ure, and malignancy (see Table 8-1).
Osteomalacia is a condition of defective mineralization of mature bone
that occurs in adults when insufficient calcium or phosphorus is available
for the formation of the primary bone mineral hydroxyapatite; this results
in inadequate or delayed mineralization of newly formed osteoid (bone pro-
tein matrix). Rickets is the same process, but it occurs in immature bone in
children. Rickets causes defective mineralization in the bones and in the car-
tilage of epiphyseal growth plates, resulting in growth retardation and skel-
etal deformities not seen in osteomalacia. More than 50 different diseases
and conditions associated with abnormal vitamin D metabolism or action or
abnormalities of phosphorus may result in osteomalacia or rickets. Vitamin
D deficiency is extremely common in the outpatient and inpatient popula-
tions and occurs in 50% of patients on medical wards and 80% in nursing
homes.
SECONDARY CAUSES OF OSTEOPOROSIS
Secondary causes are present in more than 50% of cases of perimeno-

pausal osteoporosis and should be sought in patients with a T-score less
than −2.5 and especially in patients with a Z-score less than −2.0. Before
osteoporosis treatment, the following conditions should be ruled out: idio-
pathic hypercalciuria, hyperparathyroidism, hyperthyroidism, premature
hypogonadism, low vitamin D levels or calcium malabsorption, and chronic
medical conditions or medications that can cause osteoporosis. Minimum
laboratory studies should include calcium and phosphorus (to evaluate for
hyperparathyroidism or severe vitamin D deficiency), alkaline phosphatase
(to determine increased bone turnover or metastatic disease), serum creati-
nine (to screen for renal failure), thyrotropin (to rule out hyperthyroidism),
and a complete blood count and erythrocyte sedimentation rate to screen
for malignancy (Box 8-6). In younger patients with limited sun exposure
Box 8-6 Evaluation for Postmenopausal Osteoporosis

Serum laboratory values, including calcium, phosphorus, alkaline phosphatase,
creatinine, thyrotropin, complete blood count, PTH
Consider 25-hydroxyvitamin D and serum protein electrophoresis for older women
Consider 24-hour urine for calcium and creatinine
Lateral spine films if any history of height loss
and poor nutrition and in all older patients, a 25-hydroxyvitamin D level

should be checked. A 24-hour urine is extremely useful to rule out hypercal-
ciuria (which can occur in approximately 10% of patients with secondary
causes and is effectively treated with hydrochlorothiazide diuretics), hyper-
parathyroidism (normal to high 24-hour calcium excretion), and vitamin D
118 deficiency (low 24-hour calcium excretion). For patients with unexplained
vitamin D deficiency, consideration should be given to rule out celiac sprue,
especially in patients with affected first-degree relatives, patients with type 1
diabetes, patients with hypothyroidism, and any patient with weight loss or
diarrhea. Older patients with unexplained osteoporosis should have a serum
protein electrophoresis study to rule out multiple myeloma.
Women who could be perimenopausal may benefit from having follicle-
stimulating hormone and estradiol levels ordered because estradiol levels
less than 30 to 50 pg/mL place women at risk for estrogen deficiency–related
bone loss. Estradiol levels may decrease below this level even before menses
ceases in perimenopausal women and before hot flashes occur in women
with a hysterectomy. Women with estradiol levels less than 5 pg/mL have a
seven to eight times increased risk of hip and spine fracture.
The most common offending medications causing osteoporosis include
excess thyroid hormone supplementation, anticonvulsants, glucocorticoid
therapy, and immunosuppressant agents (see Box 8-2). Even subclinical
hyperthyroidism (suppressed thyrotropin but normal levels of thyroid hor-
mones) can cause postmenopausal osteoporosis. Glucocorticoids are potent
direct antiresorptive agents and cause calcium wasting and decreased cal-
cium absorption. Patients treated with only 10 mg of prednisone for 20
weeks experienced an 8% loss of spine bone density. Many experts suggest
that any patient receiving the daily equivalent of 5 mg of prednisone for
more than 3 months is at high risk for excessive bone loss.
Lateral spine films should be obtained to rule out asymptomatic ver-
tebral fractures in patients with height loss. More than 50% of vertebral
fractures are asymptomatic. The presence of a vertebral fracture is sufficient
to diagnose osteoporosis regardless of T-score value.
Bone remodeling markers may be useful to determine whether a patient
has “high turnover” or “low turnover” osteoporosis and possibly for moni-
toring the effectiveness of antiresorptive therapy. Bone resorption can be
assessed through measurement of urine N-telopeptides and C-telopeptides,
which are collagen degradation products of osteoclasts. Urine crosslinked
deoxypyridinoline can be collected at the same time that calcium excretion
is evaluated to rule out hyperparathyroidism, hypercalciuria, or vitamin D
deficiency.
High-turnover osteoporosis (high bone resorption with normal or high

bone formation) is found in one third of patients and seems to be a risk factor
for fractures independent of bone density compared with low turnover osteo-
porosis (low-normal or low bone resorption with low bone formation). High-
turnover osteoporosis is associated with a rapid bone loss of 3% to 5% per year
and may result in increased bone fragility independent of bone mass owing
to an increase in resorptive depth of individual bone remodeling units, with
disruption of the trabecular framework. High-turnover osteoporosis may be
more responsive to antiresorptive treatment than low-turnover osteoporosis.
In patients with suspected osteomalacia, the disease can be confirmed with
a bone biopsy using tetracycline labeling. Histologic features of osteomalacia
include wide osteoid seams and an increased mineralization lag time (time
necessary for newly deposited matrix to mineralize). Mineralization lag time
is assessed by administering two short courses of tetracycline several weeks 119
apart and measuring the distance between the two tetracycline-labeled min-
eralization fronts in the biopsy specimen.
PREVENTION AND TREATMENT
Prevention of The National Osteoporosis Foundation recommends several interventions to

Osteoporosis reduce fracture risk in the general population, including adequate calcium
and Bone and vitamin D intake, regular weight-bearing exercise, fall prevention, and
Fracture avoidance of tobacco use and alcohol abuse. All individuals should be advised
to obtain at least 1200 mg/day of calcium and 400 to 800 IU/day of vitamin
D. Adequate calcium intake during the first 2 decades of life is essential for
the acquisition of peak bone mass. In addition, continued adequate calcium
intake after peak bone mass is achieved is necessary to prevent accelerated
bone resorption. Postmenopausal women should receive at least 1500 mg/
day of calcium, including supplements if necessary, and 400 to 800 IU/day
of vitamin D.
Adequate calcium and vitamin D therapy can prevent secondary hyper-
parathyroidism and the accelerated resorption that occurs in this condition.
Elderly women are at increased risk of vitamin D deficiency because of low
sunlight exposure, decreased skin synthesis of vitamin D, and low vitamin
D intake. Randomized controlled trials have shown that therapy with 800
IU of vitamin D and 1200 mg of calcium decreased hip fractures in elderly
women, many of whom had vitamin D levels less than 15 ng/mL.
Calcium is present in a variety of foods, but the major bioavailable sources
are dairy products and calcium-fortified drinks. Increasing the consumption
of low-fat dairy products is the safest way to increase calcium intake with-
out increasing the risk of kidney stones. The approximate calcium content
of 1 oz of cheese or 8 oz of milk, yogurt, or fruit juice with calcium is 200
to 300 mg (Box 8-7). These sources along with 300 mg of calcium from
the nondairy diet (owing to small amounts of calcium in an assortment of
foods) give a reasonable estimate of dietary calcium intake. The chief dietary
sources of vitamin D are vitamin D–fortified milk (400 IU per quart) and
cereals (40-50 IU per serving).
Box 8-7 Calcium Content of Foods

1 cup milk (125 IU vitamin D) ~300 mg
8 oz yogurt ~300 mg
1 oz cheese ~200 mg
½ cup raw tofu ~250 mg
6 oz calcium-fortified orange juice ~200 mg
1 cup cottage cheese ~125 mg
½ cup broccoli ~35 mg
All women should be encouraged to participate in weight-bearing exer-

cises and muscle-strengthening exercises. Bone is a dynamic tissue, which
is constantly being formed and resorbed. Weight-bearing exercise stim-
120 ulates the accrual of bone mineral content in the skeleton. In addition,
exercise can decrease fall risk by improving agility, strength, and balance.
Sit-ups should be avoided in women with osteoporosis of the spine or ver-
tebral fractures because this type of exercise puts excessive pressure on the
anterior vertebral bodies.
Preventing osteoporotic fractures depends not only on maintaining BMD
but also on fall prevention. Factors that increase the risk of falls (poor eye-
sight, physical obstacles in the living space, orthostatic hypotension, balance
problems, and sedating medications) should be identified and corrected if
possible. Also, in frail, elderly women with high risk for fracture, hip protec-
tors (SAFEHIP, HIPS, HipGuard, all from e-pill, B wellestey, MA; ImpactWear,
from High Tech Bodywear Lt Auckland, New Zeal) have been shown to
decrease hip fractures by approximately 60%.
In addition to calcium and vitamin D, several pharmacologic agents have
been approved by the U.S. Food and Drug Administration (FDA) for the pre-
vention of osteoporosis, including bisphosphonates, estrogen, and selective
estrogen receptor modulators. These agents are discussed subsequently.
Indications for The National Ambulatory Medical Care Survey found that appropriate
Treatment therapy for osteoporosis is offered to only approximately one third of all
diagnosed patients. Therapy for osteoporosis should be initiated in all post-
menopausal women with DEXA T-scores of −2.0 or less (Box 8-8). Women
with one or more risk factors for osteoporosis other than menopause should
begin treatment when the T-score is equal to or less than −1.5. Therapy for
prevention of osteoporosis should be started when the T-score is equal to or
less than −1.0 in patients on a glucocorticoid regimen equivalent to 5 mg/
day of prednisone or in patients who will be receiving glucocorticoids for
more than 3 months. Women who have sustained a vertebral or hip fracture
Box 8-8 When to Initiate Treatment

T-score −2.0 in all postmenopausal women
T-score ≥−1.5 with risk factors (other than menopause)
T-score ≥−1.0 in patients on steroids or if duration >3 months
should be assumed to have osteoporosis and started on treatment regardless

of T-score.
Some experts would consider initiating pharmacologic intervention in
osteopenic women with high rates of bone resorption (as identified by urinary
N-telopeptides >1 SD above the limit of normal for the premenopausal popu-
lation). These women seem to be at risk for losing bone more quickly, and
rates of bone loss may not be constant. It is never too late to initiate therapy
in a woman with osteoporosis. Bisphosphonate studies show a decrease in
hip fracture rate by 18 months after initiation of therapy. Bisphosphonate
therapy should be considered in elderly women with osteoporosis as long as
life expectancy is more than 2 to 3 years.
Pharmacologic Therapeutic agents for the prevention and treatment of osteoporosis fall into 121
Agents two main categories: antiresorptive agents, which inhibit bone resorption
(including estrogens, bisphosphonates, calcitonin, and raloxifene), and ana-
bolic agents, which stimulate bone formation (including sodium fluoride,
androgens, parathyroid hormone [PTH], growth hormone, and growth fac-
tors). Antiresorptive agents significantly reduce bone resorption without
initially affecting bone formation. As a result, bone formation temporarily
exceeds bone resorption, and bone mass increases. This increase in bone
mass is greater in patients with high-turnover osteoporosis than in patients
with low-turnover osteoporosis. Six to 18 months after the initiation of ther-
apy, bone formation rates gradually decline to the level of resorption, and
bone mass stabilizes.
Calcium and Vitamin D

As discussed previously, adequate calcium and vitamin D intake is essen-
tial for the maintenance of healthy bone. The most common side effects
of calcium are intestinal gas and constipation. These problems occur most
frequently with calcium carbonate and are less likely with calcium citrate.
Calcium and vitamin D therapy can slow down, but not prevent, the progres-
sion of cortical bone resorption and does not prevent spine fractures. Calcium
and vitamin D therapy should not be used as single therapy in patients with
known osteoporosis. Women with documented vitamin D deficiency should
be treated with higher doses of vitamin D (ergocalciferol) than that used for
prevention or with 25-hydroxyvitamin D (calcifediol) or 1,25-hydroxyvita-
min D (calcitriol). Hypercalcemia, hyperphosphatemia, and hypercalciuria
can occur unless 25-hydroxyvitamin D levels and 24-hour calcium excre-
tion are carefully monitored.
Bisphosphonates
Bisphosphonates are currently the first-line therapy for osteoporosis and
the most powerful antiresorptive agents. These agents bind to hydroxyap-
atite at active sites of remodeling on the bone surface and inhibit osteo-
clastic activity by reducing the production of hydrogen ions and lysosomal
enzymes. Bisphosphonates also inhibit the differentiation of osteoclasts
and induce osteoclast apoptosis. By reducing the activation frequency
(rate of formation of bone remodeling units), bisphosphonates reduce

the depth of resorption, which may result in improved bone quality and
maintenance of BMD.
The two oral bisphosphonates currently approved by the FDA for osteo-
porosis treatment are alendronate (Fosamax) and risedronate (Actonel).
Alendronate can be used in doses of 5 mg daily or 35 mg weekly for preven-
tion and 10 mg daily or 70 mg weekly for treatment of osteoporosis. This
agent increases bone density by 8% to 9% in the spine and 6% in the femoral
neck after 2 years. Alendronate reduces the incidence of spine and hip frac-
ture by about 50% over 3 years in patients with or without prior fractures.
Risedronate is approved for the prevention and treatment of osteoporosis at
doses of 5 mg daily and 35 mg weekly and has been shown to increase BMD
by 6% in the spine and 5% in the femoral neck over 2 years. Risedronate has
122 fracture data comparable to that of alendronate, with a reduced incidence
of spine and hip fractures by 40% to 50%. Alendronate and risedronate are
approved for treatment of steroid-induced osteoporosis and decrease verte-
bral fractures by 60% to 70% after 2 years of treatment in patients receiving
long-term steroids.
Because of their poor intestinal absorption and potential for gastro-
intestinal toxicity, alendronate and risedronate must be given on an empty
stomach, first thing in the morning, with 8 oz of water and with the patient
remaining upright for at least 30 minutes after the dose. Large clinical trials
have failed to show an increased incidence of side effects in patients treated
with alendronate or risedronate compared with placebo. Clinical experience
suggests, however, that these drugs may cause some gastrointestinal symp-
toms, including heartburn, indigestion, and rarely esophageal ulceration or
bleeding. Once-weekly administration of either agent results in similar bone
density increases with fewer gastrointestinal side effects.
Patients who are unable to tolerate treatment with oral bisphosphonates
or who are unable to absorb oral bisphosphonates because of gastrointes-
tinal disease can be considered for treatment with an intravenous bisphos-
phonate. Currently available intravenous bisphosphonates are pamidronate
(Aredia) and zoledronic acid (Zometa). These agents have not been approved
by the FDA for prevention or treatment of osteoporosis and are currently
used “off label” when necessary. Pamidronate can be given by intravenous
infusion, 30 mg over 2 hours, followed by a 30-mg infusion every third
month. Zoledronic acid, when given at a dose of 2 mg every 6 months or 4
mg every year, increased bone density in the spine by approximately 5%, but
there are fewer data compared with pamidronate. Patients should be given
1000 mg of calcium at the beginning of the intravenous infusion because of
the hypocalcemic effect of these drugs.
The duration of therapy for bisphosphonates is a subject of ongoing
study. Stable bone markers and bone density persist at least for 2 years in
postmenopausal women. A study showed, however, that discontinuation
of alendronate after 5 years resulted in a loss of bone density at years 6 to
10 associated with an increase in bone resorptive markers compared with
women who remained on the bisphosphonate for 10 years. Until more defin-
itive studies are available, bisphosphonates probably should be continued
indefinitely unless financial concerns are prohibitive. If bisphosphonates

are discontinued after 5 years of therapy, bone resorption markers and bone
density should be monitored, and if these are increased, therapy should be
reinstituted.
Estrogens
Estrogens probably inhibit osteoclastic bone resorption by inhibiting cyto-
kines, which activate and promote the growth of osteoclasts or alter the
expression of molecules directly involved in osteoclast differentiation.
Estrogen in oral, transdermal, and combined estrogen/progesterone (hor-
mone replacement therapy) formulations are FDA approved for the pre-
vention of bone loss in recently menopausal women. The usual dose of
conjugated estrogens prescribed for prevention of osteoporosis is 0.625 mg
daily, but lower doses also may be effective. 123
The Women’s Health Initiative, a prospective, randomized, double-blind,
placebo-controlled trial that studied more than 16,000 postmenopausal
women, showed a 34% reduction in vertebral and hip fractures after 5 years
of hormone replacement therapy (specifically, conjugated equine estrogen,
0.625 mg, plus medroxyprogesterone acetate, 2.5 mg daily [Prempro]).
Clinical experience has shown, however, that approximately 25% of women
on estrogen or hormone replacement therapy still sustain an osteoporotic
fracture.
The Women’s Health Initiative also reported an increased risk of myo-
cardial infarction, stroke, pulmonary emboli, and breast cancer in women
treated with Prempro. Although the absolute number of women affected was
small, these results have led most expert panels to recommend that the use
of estrogen and hormone replacement therapy be limited to the lowest pos-
sible doses for the shortest possible duration necessary to control hot flashes.
Estrogen should not be used in patients with breast cancer or in patients
with thrombophlebitis or thromboembolic disease. It also is recommended
that other approved nonestrogen agents be considered first before starting
women on estrogen or hormone replacement therapy solely for the purpose
of treating osteoporosis.
Phytoestrogens
Phytoestrogens are mixed estrogen agonists and antagonists consisting of
more than 20 different compounds found in parsley, garlic, soybeans, wheat,
rice, dates, pomegranate, cherries, coffee, and many herbs. Phytoestrogens
are usually much weaker than natural estrogens, are easily broken down,
and are not stored in the tissues. No reduction in fractures has ever been
documented with the use of phytoestrogens.
Isoflavonoids are a class of soybean-based foods that have estrogen-like
activity. One small study of 56 women less than 5 years postmenopausal
with low BMD showed no loss of BMD (0.4% increase versus a 5% loss in
the placebo group) in women treated with ipriflavone (a synthetic derivative
of a natural isoflavone). Many early menopausal women lose bone density
despite treatment with phytoestrogens. The effects of phytoestrogens on the
uterus, heart, brain, and breast are still unknown.
Selective Estrogen Receptor Modulators

Selective estrogen receptor modulators work by binding to the estrogen recep-
tors in target organs and have estrogen agonist effects in some tissues, but estro-
gen antagonist effects in other tissues. Raloxifene (Evista) has been approved
by the FDA for the prevention and treatment of postmenopausal osteoporo-
sis. This agent has been shown to decrease vertebral fractures by about 40%
after 3 years of treatment in women with and without prior vertebral fracture.
At 3 years, raloxifene increased BMD in the spine by 2.6% and in the femoral
neck by 2.1%. Raloxifene also has been found to reduce bone turnover mark-
ers to premenopausal levels. No hip fracture data are available yet.
Raloxifene should be given as 60 mg daily for the treatment of osteoporo-
sis. Minor side effects attributed to raloxifene include hot flashes, leg cramps,
and peripheral edema. In contrast to estrogen, which may increase breast
124 cancer risk, raloxifene has been shown to decrease the incidence of breast
cancer and can be considered for patients who wish to stop hormone replace-
ment therapy because of concern for breast cancer. The same thromboem-
bolic risk of estrogen has been observed with raloxifene, and cardiovascular
disease end points currently are being studied.
Calcitonin
Salmon calcitonin (Miacalcin) works by inhibiting osteoclastic bone resorp-
tion and is FDA approved for the treatment of osteoporosis in women who
are postmenopausal. It is available as an intranasal spray (200 IU [one spray]
daily) and a subcutaneous or intramuscular injection (100 IU/every other
day). Several prospective, randomized, double-blind, placebo-controlled tri-
als have shown the injectable formulation of calcitonin to increase BMD
modestly, but there are no fracture data. The 200-IU intranasal formulation
of calcitonin decreased vertebral fractures by approximately 40%, although
bone density did not significantly change. There was no dose-response rela-
tionship, and no such benefit was seen with either the 100-IU or 400-IU
dose. Studies have not yet been done to look at the effect of intranasal calci-
tonin on hip or other nonvertebral fractures, and the preparation should be
considered a third-line treatment.
Combination Therapy
Small additional increments in bone density occur (1-3%) when bisphospho-
nates are combined with estrogen or raloxifene, but the effects are not addi-
tive or synergistic. When bone turnover is normalized by one antiresorptive
drug, there is little left for an additional agent to accomplish. Whether the
small increases in bone density translate to any fracture benefit is unproven.
It is unclear whether further suppression of bone remodeling is beneficial, or
whether this promotes or harms bone health. Combining a bisphosphonate
with an anabolic agent (PTH) is not recommended because of what seems to
be a blunting of the bone formation effect when given simultaneously.
Parathyroid Hormone
Recombinant human PTH (teriparatide) is the only anabolic agent approved
by the FDA for the treatment of osteoporosis in postmenopausal women.
PTH stimulates bone resorption and bone formation, but when given as daily
injections its effect on bone formation is greater than that on bone resorp-
tion, resulting in significant increases in BMD. Teriparatide (Fortéo) is given
in a daily dose of 20 μg injected subcutaneously and is supplied in a dispos-
able multiple-dose pen device, which holds 28 doses of the drug.
Teriparatide given at the approved therapeutic dose has been shown to
decrease the risk of vertebral fractures by 65% and of nonvertebral fractures
by 53% in postmenopausal women treated for 19 months. Spine bone density
increased by 9% and hip bone density by 3%. Mild side effects, including
nausea and orthostatic hypotension, have been observed with teriparatide
treatment. These side effects tend to occur only with the first few doses of the
drug and do not usually require the discontinuation of therapy. Transient
asymptomatic calcium elevations also have been observed.
Teriparatide caused an increased incidence of osteosarcoma when studied 125
in rats, although this complication has not been seen in humans. Because
of this observation, the use of teriparatide is contraindicated in patients at
increased risk of osteosarcoma, including patients with Paget’s disease, open
epiphyses, bone metastases, hypercalcemia, a history of radiation therapy to
the skeleton, or an elevation in bone-specific alkaline phosphatase.
Teriparatide is approved by the FDA for individuals at “high risk” for frac-
ture and in patients who fail to respond to antiresorptive therapy for 2 years
or more. It was shown in two trials that combining PTH with alendronate
was inferior to using PTH alone to increase the density of the trabecular
bone at the spine. Alendronate seemed to impair the ability of PTH to induce
bone formation by decreasing bone turnover. If teriparatide is used, all anti-
resorptive agents, including bisphosphonates, should be discontinued before
starting therapy.
Monitoring It is recommended to assess the response to therapy by repeating central

Treatment BMD measurements every 1 to 2 years. Because the average increase in
BMD in the spine is 5% to 8% and only modestly exceeds the smallest change
between two measurements that can be detected in individual subjects
(3-4%), many patients seem to have no appreciable increase in bone den-
sity with treatment. No appreciable response is usually seen in the proximal
femur. BMD in patients using bisphosphonates did not predict fracture pre-
vention. Patients who seemed to lose bone density in the first year after alen-
dronate therapy still had a 48% lower fracture rate and often gained it in
the second year. Patients who gain bone density in the first 2 years usually
have no further significant increase, and bone density remains stable over
subsequent years.
Patients who do not show an increase in bone density on bisphosphonates
should not be considered nonresponders. Not observing a response is not
indicative of treatment failure, but compliance should be questioned, and a
search for metabolic factors that could impair the response should be consid-
ered (Box 8-9). In addition to noncompliance, the most common underlying
disorder not initially identified is vitamin D deficiency resulting in second-
ary hyperparathyroidism. It may be useful to obtain a 24-hour urine for
Box 8-9 Osteoporosis Treatment Failures

Taking medication improperly
Poor compliance with medication
Underlying disorder not identified
Secondary hyperparathyroidism from vitamin D deficiency
Patient is actually responding (regression to the mean)
calcium and bone resorption markers. If the 24-hour urine shows hypocal-
ciuria, inadequate calcium and vitamin D should be suspected. If the cal-
cium excretion is normal, but bone resorption markers are not suppressed,
the possibility of other metabolic conditions or drug noncompliance should
126 be re-examined.
BMD should not be measured more frequently than every 1 to 2 years
except in patients on glucocorticoids, who are likely to have significant
changes in 6 months. Urinary markers of bone resorption may be useful
in evaluating the response to antiresorptive therapy 3 to 6 months after
treatment. Bone resorptive markers should decrease by greater than 30%
compared with baseline or to within the premenopausal reference range.
Because of the precision errors of the markers, however, the study may need
to be repeated before concluding a nonresponse.

1. Age is a more powerful risk factor for fracture than bone density.
2. Approximately 50% of perimenopausal women with osteoporosis have
underlying secondary causes.
3. Approximately 50% of vertebral fractures are asymptomatic, but their
occurrence doubles the risk of sustaining a hip fracture and increases
mortality by eightfold.
4. Vitamin D deficiency resulting in secondary hyperparathyroidism is a
common cause of bone loss in older women or an inadequate response
to therapy.
5. Bisphosphonates are the most powerful antiresorptive agents currently
available.
6. Combination therapy with two antiresorptive agents results in only a
modest increase in bone density.
7. An absence of change in bone density after 1 to 2 years of treatment
with an antiresorptive agent does not indicate a lack of response to
therapy.
8. Teriparatide (PTH) is the first anabolic agent to be FDA approved, but it
should not be combined with an antiresorptive agent.
SUGGESTED READINGS
American Association of Clinical Endocrinologists in combination, on bone mass and markers of bone
(AACE) Osteoporosis Task Force: American turnover in elderly women with osteoporosis. J Clin
Association of Clinical Endocrinologists medical Endocrinol Metab 2004;89:626-631.
guidelines for clinical practice for the prevention and Hodsman AB, Hanley DA, Ettinger MP: Efficacy
treatment of postmenopausal osteoporosis: 2001 edi- and safety of human parathyroid hormone-(1-84)
tion, with selected updates for 2003. Endocr Practice in increasing bone mineral density in postmeno-
2003;9:545-563. pausal osteoporosis. J Clin Endocrinol Metab
Black DM, Greenspan SL, Ensrud KE: The effects 2003;88:5212-5220.
of parathyroid hormone and alendronate alone or McClung MR: Bisphosphonates. Endocrinol Metab Clin
in combination in postmenopausal osteoporosis. N Am 2003;32:253-271.
N Engl J Med 2003;349:1207-1215. National Institutes of Health: Osteoporosis, prevention,
Bone HG, Hosking D, Devogelaer JP: Ten years’ diagnosis, and therapy. NIH Consensus statement,
experience with alendronate for osteoporosis in post- vol 17, no 1; March 27-29, 2000.
menopausal women. N Engl J Med 2004;350: Simon JA: Osteoporosis. ACOG practice bulletin, no
1189-1199. 50; January 2004. 127
Evio S, Titinen A, Laitinen K, et al: Effects of alendro- Stein E, Shane E: Secondary osteoporosis. Endocrinol
nate and hormone replacement therapy, alone and Metab Clin N Am 2003;32:115-134.
9
HUMAN SEXUALITY
William D. Petok
DEFINITIONS
Sex A fundamental difference to distinguish is between sex and gender.
Sex can refer to a physical activity and to physical characteristics. The
latter definition often is confused with gender or the sense of maleness 129
or femaleness that individuals experience. With regard to physical
characteristics, sex is the anatomic and physiologic difference between
males and females.
Males The genome for most males contains an X and a Y chromosome.
Females Females have two X chromosomes.
Gender Gender is perceived on an internal level and is the combination of
socially learned behavior, meanings, and cues that are a reflection of
society’s notion of masculine and feminine. Gender is the biologic sex
and the more subjective sense one has of being either masculine or
feminine. Because the male sex is defined by physical characteristics
such as penile development, and male gender is defined by social and
psychological issues, there is room for confusion.
Gender identity On a psychological level, an individual’s gender identity is the individual’s
subjective perception of maleness and femaleness. Consequently, an
individual’s gender identity is psychological in nature. A physiologic male
can perceive himself as female and vice versa.
Sexual function is an important component of the lives of most adults.

Generally, sexual activity serves three primary purposes: procreation, rela-
tionship enhancement, and pleasure. Members of each gender seem to differ
in what is most important to them in their sexual relationships. Men seem to
value the physical release component of sex, whereas women tend to desire
intimacy as the end goal. Although the differences are obvious, many cou-
ples are capable of integrating them into mutually satisfying interactions
and find great comfort and pleasure in their sexual interactions. Sex is not
one-dimensional and comprises more than intercourse leading to orgasm.
A wide variety of behaviors, which include tactile stimulation of many erog-
enous zones on the body, kissing, and loving words, are included in sexual
activity. All of these activities can lead to sexual satisfaction.
SEXUAL ANATOMY
Male external reproductive organs consist of the penis, scrotum, and tes-
tes (Fig. 9-1). The penis is composed of two parts: the shaft and the glans.
The glans is highly enervated and is very sensitive to tactile stimulation.
Uncircumcised men have a prepuce or foreskin that covers a portion of the
glans. The prepuce retracts when the penis becomes erect. The penis is com-
posed of three cylindrical bodies that allow for erection. The two corpora
cavernosa are located dorsally. They are surrounded by a sheathlike mem-
brane, the tunica albuginea. The third body, the corpus spongiosum, lies on
the ventral plane and contains the urethra. Vasocongestion, the result of
physical or psychological stimulation or both, occurs rapidly. As the erec-
tile tissue expands, it presses against the tunica albuginea and mechanically
130 prevents outflow of blood through veins and capillaries. Erections are main-
tained as long as the smooth muscles surrounding the corpora cavernosa
remain relaxed, keeping blood trapped within.
The scrotum, a thin sack of skin, forms a pouch that contains the testes.
The outer layer of skin is darker than the body and contains sweat glands.
The inner layer is composed of involuntary muscle that contracts with sex-
ual excitement, cold weather, or exercise. The muscle layer relaxes when the
body becomes hot. This relaxing and contracting function allows for tem-
perature regulation of the testes and protects sperm, which are sensitive to
extreme temperature change.
The scrotal sac is partitioned into two components, which each contains a
testis, epididymis, and spermatic cord. The cord supports the testis and con-
Figure 9-1 Seminal

Male genitalia. (From vesicle Rectum
Lauver D, Welch MB: Ureter
A biopsychosocial
approach to sexuality. Bladder Ejaculatory
In Fogel CI, Lauver duct
D [eds]: Sexual
Health Promotion.
Philadelphia: WB
Saunders; 1990:41.)
Urethra
Vas deferens
Corpus
cavernosum
Corpus
spongiosum Prostate
Epididymis Penile bulb Bulbourethral gland
Pupuce (Cowper’s gland)
(foreskin)
Scrotum Testis
Human Sexuality
tains the vas deferens, blood vessels, nerves, and muscle fiber. The vas defer-
ens provides the duct for sperm delivery from the scrotum to the ejaculatory
duct. In addition to sperm production, the testes are responsible for secretion
of testosterone, made in Leydig cells. These bodies are located between the
seminiferous tubules in the scrotum.
Three additional organs are important to male sexual functioning: the
prostate, seminal vesicles, and Cowper’s glands. The prostate produces alka-
line prostatic fluid, which composes 20% of ejaculate. Sperm are protected
from the acidity of the vagina by this fluid. Sixty percent of the ejaculate is
seminal fluid produced in the seminal vesicles, which join at the vas defer-
ens to form the ejaculatory duct. Contained in the seminal fluid are prosta-
glandins that may stimulate uterine contractions and subsequent migration
of the sperm to the fallopian tubes. Cowper’s glands, located inferior to the
prostate, secrete a small amount of pre-ejaculatory fluid that is also alkaline 131
in nature. This fluid protects sperm from the acidity of the urethra.
Female external sexual organs include the vulva comprising the mons
pubis, labia majora and minora, vaginal orifice, and clitoris (Fig. 9-2). The
mons pubis is a fatty tissue that becomes more pronounced with puberty. It
provides some cushioning during the thrusting of intercourse. Sensitive to
pressure and touch, stimulation of this area can be very arousing for some
women. Labia majora cover the outer entrance to the vagina. Sweat and
sebaceous glands cover their lateral and medial surfaces. The labia majora
provide a protective covering for the urethra and vagina.
Interior to and between the labia majora are the labia minora. At their
anterior aspect, they join to form the clitoral hood. Posterior and slightly
deeper is the frenulum or lower fold of the clitoris. The labia minora also
cover the urethral opening, vaginal opening, and openings of Bartholin’s
glands. The sebaceous glands contained on them provide some lubrication.
Highly vascularized and containing many tactile nerve endings, the labia
minora are very sensitive.
The clitoris, from the Greek for “key,” is an extremely erotic area for women.
Composed of a body and a glans, it is ½ to 1 inch long. Similar to the penis, it
is composed of erectile tissue and is richly vascularized and innervated. The
only known function of the clitoris is to provide sexual pleasure.
At the entrance to the vaginal opening is the hymen. Normally perforated
to allow for menses, the hymen can be visualized as an irregular fold around
the introitus. It serves no physiologic purpose. It can be broken during vig-
orous exercise or remain intact even with intercourse. Much cultural and
emotional importance has been attached to an intact hymen. The belief that
a woman with a torn hymen must not be a virgin is false.
Two sets of glands are contained in the female genitalia: Bartholin’s and
Skene’s glands. Bartholin’s glands, located at the posterior surface of the
vaginal introitus, are analogous to Cowper’s glands in the male. They secrete
a drop or two of fluid when a woman is sexually aroused, slightly moistening
the labia. Skene’s glands are located on either side of the urethra. Skene’s
glands can vary in size from woman to woman. Fluid released by Skene’s glands
has been described as analogous to prostatic fluid and seems to be similar
in chemical makeup. Some believe that release of this fluid occurs during
Figure 9-2
A and B, Female A
genitalia. (From
Lauver D, Welch MB:
A biopsychosocial
approach to sexuality.
In Fogel CI, Lauver
D [eds]: Sexual
Health Promotion. Mons pubis
Philadelphia: WB Clitoral shaft
Saunders; 1990:431.) Urethra
Clitoral hood
Clitoral head Skene’s glands

(glans)
Labium majus Location of
132 Bartholin’s glands
Labium minus
Vagina Perineum
Hymenal
caruncles Anus
Urethra
Position of
Skene’s glands
Vagina
Rectum
female ejaculation, a controversial topic. No other known purpose for Skene’s

glands exists.
Internal female reproductive organs consist of the ovaries, fallopian
tubes, uterus, and vagina. The vagina is the conduit between the internal
and external structures. With sexual excitement, the walls of the vagina
become distended. Its length and diameter can increase 50% during arousal.
A multilayer structure, the vagina’s inner layer is mucosal in nature and
Human Sexuality
well supplied with blood and is affected by hormonal levels. The lining thins
dramatically with the onset of menopause and can become a source of pain
during intercourse. The middle layer is musculature and allows for expan-
sion and contraction that occur with childbirth. Pubococcygeal muscles cir-
cle the outer one third to one half of the vagina. The inner two thirds contain
a limited amount of tactile receptors and are more sensitive to pressure. The
outermost layer is thin mucosa. The entire vagina is lined with squamous
epithelium cells that are the source of vaginal lubrication or transudate.
Internal female reproductive structures include two ovaries that are
responsible for producing ova and estrogen and progesterone. Testosterone
also is produced in the ovaries and the adrenal glands. The fallopian tubes,
although essential for conception, have nothing to do with the pleasure
component of sexual behavior.
The uterus can experience contractions during orgasm. Otherwise, its role 133
in sexual expression is physiologically negligible. Psychologically and socio-
logically, the uterus can carry great importance because of its association
with the onset of reproductive sexuality via menstruation and pregnancy.
SEXUAL RESPONSE
Masters and According to Masters and Johnson, human sexual response proceeds in an
Johnson’s invariable linear fashion. Although the assumptions, sampling variables, and
Sexual Response other components of their research have been criticized, it remains ground-
Cycle breaking in nature and provides the first scientific data on sexual response.
Four stages of the response cycle are described for men and women. The typi-
cal pattern of male response is shown in Figure 9-3. Female response shows
greater variability than male response. Examples are shown in Figure 9-4.
Excitement is characterized by the onset of erotic feeling (erection in men
and vaginal lubrication in women); sexual tension, which also is character-
ized by vasocongestion and myotonia; increased respiration rate; increased
heart rate; blood pressure elevation; and certain changes in skin coloring.
This skin response, called mottling, is often observed more easily in women
than in men. In addition, female breasts swell, and nipples become erect.
Men also can experience nipple erection. Some women also experience a
Figure 9-3
The male sexual
response cycle per
Orgasm
Masters and Johnson.
(From Masters W, Refractory
Johnson V: Human period
Plateau
Sexual Response.
Boston: Little, Brown;
R es
Refractory
1966:5.
period
Res
olut
Excitement
ion
o
lutio
n
Figure 9-4
The female sexual
response cycle per Orgasm
Masters and Johnson.
(From Masters W,
Johnson V: Human
Sexual Response.
Boston: Little, Brown; Plateau
1966:5. Re
so
lut
ion
Re
Resolutio
s ol u
Excitement
tion
(B)
n
134
(A)
A B C (C)
clitoral erection from vasocongestion within this structure. In preparation

for coitus, several pelvic changes take place. The uterus becomes enlarged
and begins to rise from its resting position on the pelvic floor, and the vagina
enlarges to accept an erect penis more easily. Vaginal lubrication, a dis-
tinct sign of female response, results from a transudate, caused by vascular
engorgement of the vaginal walls. Transudate typically forms within 10 to
30 seconds after the onset of sexual stimulation. Additional changes in men
include elevation and swelling of the testicles, tightening of the scrotal sac,
and secretion of a lubricating liquid by the Cowper’s glands.
Plateau, in which the maximum level of arousal is reached, is a misleading
label because during this phase the arousal is not continuously high, but fluc-
tuates on the way to orgasm. Vasocongestion peaks in this stage. Maximum
genital vasocongestion in the woman causes swelling and deepened coloration
in the labia minora, and a thickened plate of congested tissue (the “orgasmic
platform”) surrounds the entrance to the lower portion of the vagina; the
erect clitoris retracts behind the symphysis pubis just before orgasm.
Orgasm is the most intensely pleasurable of the four stages. Involuntary
muscle contractions, heightened blood pressure and heart rate, rapid intake
of oxygen, and sudden forceful release of sexual tension characterize the
orgasmic phase. Male ejaculation consists of two steps. During the first step,
or emission, seminal fluid builds up in the urethral bulb of the prostate. As
the fluid accumulates, the man senses he is about to ejaculate, sometimes
known as the point of ejaculatory inevitability. During the second step, or
expulsion, the urinary bladder closes to block the possibility of urine mixing
with semen. At this point, muscles at the base of the penis begin a steady
rhythmic contraction that expels the semen from the urethral opening at
the head of the penis. After ejaculation, men enter a refractory period dur-
ing which further response to stimulation is not possible. Women do not
experience a refractory period and are capable of multiple orgasms dur-
ing a single period of stimulation. Contractions of the circumvaginal and
Human Sexuality
perineal muscles at rhythmic 0.8-second intervals characterize this stage

for women. Despite the touted social mythology of the “vaginal orgasm,” it
seems that female orgasm is almost always the result of some form of clitoral
stimulation.
Resolution is the final stage defined by Masters and Johnson. During this
phase, all sex-specific responses subside, and the body returns to its basal
state; somatic responses to sexual stimuli diminish rapidly; heart rate, blood
pressure, respiration, and skin vascularity become normal within minutes.
Postorgasm, somatic responses recede rapidly, and the clitoris returns to its
normal position within 5 to 10 seconds. Although the vagina may take 10
to 15 minutes to return to its normal state, the orgasmic platform rapidly
becomes detumescent. Probably as a result of blood draining from the geni-
tal area, the labia minora revert to normal coloration within 10 to 15 sec-
onds after the end of orgasmic contractions. The resolution phase is marked 135
by a general sense of well-being and enhanced intimacy and possibly fatigue.
Men, especially as they age, experience a refractory period of varying dura-
tion after orgasm during which they cannot achieve orgasm, although
partial or full erection sometimes may be maintained. The duration of the
refractory period varies from a few minutes to several days. There is great
variability in the length of the refractory period within and between men.
Kaplan and Desire, which sets the stage for further sexual activity, is discrete and sepa-
Desire rate from the genital components of sexuality according to Kaplan. Her con-
tribution to theory is the result of examining the limitations of the original
theory of the human sexual response cycle. She found that many patients
had little desire for sexual activity, and no amount of intervention for other
problems would effectively help them.
Sexual desire can be influenced by physiologic drive, mood states, psycho-
logical perceptions, and sociocultural factors. In addition, sexually explicit
material from visual images, sounds, or internal fantasies can elicit arousal.
Sexual desire can be conceptualized, regardless of its source, as the stimulus
that leads the individual to initiate or be receptive to sexual activity. Physical
activation of a specific neural system produces the desire or libido that drives
the individual for sexual activity. A “horny” person has such an active sys-
tem and can feel genital sensation or just vaguely sexy. This appetite for
sexual activity is the trigger for the remaining sexual responses. Following
Kaplan’s contribution, the human sexual response cycle can be organized as
a triphasic grid (Table 9-1).
Table 9-1
Sexual Response Stage Components
Cycle as Redefined
by Kaplan Desire Cognitive and hormonal motivating factors leading to an interest in
sexual activity
Arousal Vasocongestion of the genitalia, associated changes in respiration,
attention focused on erotic stimuli
Orgasm Release of vasocongestion and myotonia developed in the prior stages
Unique Noting that many women in long-term monogamous relationships are not
Components of motivated in the same way as men with regard to sexual interaction, Basson
Women’s Sexual proposed a different model of female sexual response (Fig. 9-5). Receptivity
Response to sexual stimulation is not preceded by sexual thoughts or fantasies.
Emotional intimacy is the goal that women seek from their sexual interac-
tions in this model. Intimacy is enhanced by the emotional and physically
rewarding outcomes and is necessary in a sexual experience. The nongeni-
tal components of a woman’s sexual experience lead to her satisfaction and
are driven by intimacy needs and nurture intimacy. A lack of tenderness,
excessive focus on intercourse, physical and emotional discomfort, and other
factors can prohibit the attainment of the overriding goal of enhanced inti-
macy. Finally, this desire, primarily receptive in nature, depends on whatever
sexual stimuli are necessary for a particular woman. Context may be more
136
Figure 9-5
Traditional sex
response cycle of
Masters, Johnson, Orgasm
Sexual excitement/tension
and Kaplan, Plateau

alongside new
intimacy-based
female sex response
cycle. (From Basson
R: Female sexual Arousal
response: the role
of drugs in the
management of
sexual dysfunction. Resolution
Obstet Gynecol Desire
2001;98:351.)
Time
Emotional intimacy
+
motivates the sexually
+ neutral woman
Emotional and physical

satisfaction
to find/be
responsive to
Sexual stimuli
Arousal and sexual

psychological and
desire
biological factors
govern “arousablity”
Sexual arousal
Human Sexuality
important to a woman in terms of the effectiveness of sexual stimulation

than the stimulation itself.
Neuronal The vasocongestive and orgasmic reflexes that compose the sexual response
Influences on can be found in separate but related portions of the nervous system. The
Sexual Response innervation of the genitals is somatic and autonomic in nature. Sensory
afferents provide information on tactile stimulation that instigate the local
sexual responses that are vascular and glandular after their synapse in the
sacral portion of the spinal cord. Information of a sensory nature is projected
to suprasacral regions and contributes to additional reflex activity that influ-
ences awareness and sexual excitation.
In men, erectile response is initiated by parasympathetic efferents that
travel through the pelvic plexus and the cavernosal nerves. It is possible 137
for an erectile pathway to be formed via the hypogastric nerves. This phe-
nomenon has been observed in men with lesions to sacral and pelvic nerve
segments and is termed psychogenic erection.
Ejaculation seems to be served by portions of T11-L2 nerve segments
that are sympathetic in nature. Continued stimulation of the penis triggers
orgasm with seminal emission and the rhythmic 0.8-second contractions
of the perineal and pelvic floor muscles. Emission begins during arousal.
Smooth muscle contraction of the seminal vesicles, vas deferens, and pros-
tate is influenced by sympathetic outflow producing emission. Similarly,
smooth muscle contraction in the bladder neck prevents retrograde ejacu-
lation. Higher centers of the brain can modify, augment, or inhibit genital
vasocongestion and orgasm.
Genital neuromuscular activation of female sexual response seems to be
similarly controlled. Parasympathetic activity produces clitoral erection,
labial engorgement, and vaginal lubrication. Sympathetic activity produces
orgasmic contractions, at 0.8-second intervals, of the uterus, fallopian
tubes, and paraurethral glands and contractions of the pelvic floor muscles.
Several neural pathways have been proposed as important in female sexual
response: the pudendal nerve for clitoral stimulation, the hypogastric plexus
and pelvic nerve for vaginal stimulation, and potentially the vagus nerve
directly from the cervix to the brain.
Similar to male response, female sexual response is influenced by the
brain. Research has shown women’s ability to have orgasm through fantasy
alone and hypnotically induced and direct stimulation of brain areas.
Hormonal Knowledge of the hormonal influences on sexual response is growing. An

Influences on exhaustive review of the data is not possible in this chapter. Androgens and
Sexual Response estrogen play an important role in sexual response of men and women.
Androgens increase sensitivity for sexual stimuli and seem to have impor-
tant effects on women’s sexual fantasies, desire, and arousal. Androstenedione
is the major androgen in the serum of cycling women. Most androstenedi-
one circulates bound to sex hormone–binding globulin and albumin. Half is
produced in the ovaries and half in the adrenal glands. Testosterone is the
other major circulating androgen in cycling women. The ovaries produce

about 25% of testosterone. The remainder is produced in approximately
equal proportions by conversion from androstenedione in the liver, spleen,
and adipose tissue and adrenal secretion. There is an age-related decline in
female testosterone levels by a factor of 50% between ages 20 and 40.
Research data indicate that surgically menopausal women experience a
decline in desire from presurgical levels that can be restored with the addi-
tion of supraphysiologic levels of testosterone. Naturally menopausal women
have sexual interest that is positively correlated with their androgen levels.
The picture is less clear with premenopausal healthy women. Androgen levels
influence sexual desire, but androgens alone are insufficient for the experience
of sexual desire. The effects of testosterone on female arousal are similarly
unclear with some data supporting a positive role for higher levels of vaginal
138 blood flow in response to erotic stimuli with higher versus lower levels of circu-
lating testosterone. At the same time, other research reported no differences in
subjective levels of arousal or vaginal blood flow in women administered acute
levels of dehydroepiandrosterone versus placebo controls.
There are abundant data with hypogonadal men that show reduced lev-
els of testosterone produce a rapid and marked decrease in sexual interest.
Adolescent boys’ level of sexual thoughts can be predicted by level of free
testosterone. In normal men, wide individual variability exists in the level of
circulating testosterone and levels of drive or sexual behavior. It is believed
that the level of testosterone necessary for sexual interest and activity in
men is lower than the levels of circulating testosterone found in normal men.
Variability above threshold levels in testosterone would not produce sexual
interest or behavior. Testosterone restores erectile responses in hypogonadal
men with impaired nocturnal penile tumescence. In men with normal tes-
tosterone levels, additional testosterone has not been shown to aid erection.
Estrogen has a role in sexuality for men and women. Relatively high lev-
els of exogenous estrogen have been useful in suppressing sexual desire in
sex offenders and men with uncontrollable sexual urges. Estrogen seems to
play a minimal role in female sexual desire with studies finding fluctuations
in desire across the menstrual cycle to be independent of estrogen levels.
The estrogen deficiency that occurs after menopause is related, however,
to deficits in genital vasocongestion and lubrication and reductions in the
thickness of the vaginal epithelium. These changes can impair physiologic
arousal in women and lead to dyspareunia; they also can have an adverse
effect on arousal as it is experienced psychologically.
The effect of progesterone on male sexuality has been poorly studied.
Increased levels of progesterone from certain oral contraceptives are corre-
lated with decreased sexual desire in women. It is generally agreed, however,
that progesterone treatment does not substantially influence sexual desire in
premenopausal or postmenopausal women.
Abnormally high levels of prolactin can lead to reports of decreased sexual
interest in men and women. Additional data suggest that lactating women
evidence decreased desire compared with their prepregnancy reports. Other
psychological factors could be at work given the research that associates
mood disturbances, including anxiety and depression, with high levels of
Human Sexuality
prolactin. Erectile problems have been noted in men with elevated and low-
ered prolactin levels. Some evidence exists that prolactin levels decrease
immediately after sexual arousal. Contradictory evidence from more pre-
cisely controlled research showed increased prolactin levels after mastur-
bation-induced sexual arousal in men. A doubling of prolactin levels after
orgasm in women also has been shown.
Oxytocin increases during sexual arousal and orgasm have been shown
in men and women. Oxytocin seems to have positive erection effects because
it activates excitatory nerve pathways from the spinal erection-generating
center to the penis. Intensity of orgasmic contractions, but not their dura-
tion, also has been correlated positively with oxytocin levels in both genders.
Some evidence exists that inasmuch as positive mood and sexual desire may
be related, oxytocin could play an indirect role in sexual desire.
Nitric oxide is essential to the production of penile erections. It also may 139
play a role in clitoral vasocongestion. The primary effect of nitric oxide is
that it stimulates the release of guanylate cyclase, which converts guanosine
triphosphate to cyclic guanosine monophosphate (cGMP), which enhances
relaxation of the smooth muscles of the penile arteries and corpus caverno-
sum yielding increased blood flow into the penis. Men with erectile dysfunc-
tion may have a disruption in this process. Phosphodiesterase type 5 (PDE5)
inhibitors, such as sildenafil, vardenafil, and tadalafil, prolong the action
of cGMP by inhibiting its metabolism, resulting in more stable erections. A
significant body of literature exists establishing the effectiveness of PDE5
inhibitors for male erectile dysfunction. There is no similarly well-controlled
research supporting the use of PDE5 inhibitors in women with sexual dys-
function. The use of PDE5 inhibitors does not produce an erection in the
absence of effective psychological or sensory sexual stimulation.
CLINICAL PRESENTATION AND THERAPEUTIC INTERVENTIONS
Many individuals have difficulty with their sexual lives. National probability
survey data suggest that 43% of women and 31% of men between the ages
of 18 and 59 experienced some form of sexual dysfunction in the year pre-
ceding the survey. Sources of these difficulties can be complex and usually
are multiply determined. Sources can include inadequate sexuality educa-
tion, conflicting values and beliefs, medical problems, medication side effects
(Box 9-1), and relationship problems. Consequently, the remediation of
Box 9-1 Medication Side Effects on Sexual Function

● Reduced libido—alcohol, anticonvulsants, antipsychotics (chlorpromazine,
thioridazine, haloperidol, thiothixene), benzodiazepines, β-blockers, diuretics,
MAOIs, opiates, SSRIs, tricyclic antidepressants
● Reduced arousal—alcohol, anticholinergics, antihistamines, β-blockers, MAOIs
● Reduced orgasm—β-blockers, clomipramine, SSRIs (men and women),
thioridazine (men)
MAOIs, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors.

these problems can require interventions that involve medical and psycho-
social components. In addition, most sexual problems are best treated in the
context of a couple because they involve interaction between partners.
It is essential that patients have reasonable expectations about sexual
function. Popular cultural representations of sexual interactions tend to
misrepresent reality. Mind-numbing, explosive orgasms are not the norm,
and mutual orgasm with penile thrusting occurs in a small percentage of
instances. Similarly, myths about erections that are “rock hard and instantly
ready” have literary value, but do not approach actual experience. Some
therapists suggest that, at best, 20% of sexual interactions reach the heights
suggested by movies, magazines, or television. More realistically, 60% to
70% of sexual interactions may be “good enough.” An additional 10% to
20% may be unsatisfying. It is best to focus patients on non–performance-
140 oriented goals for therapy. Mutual satisfaction and sexual comfort are more
appropriate outcomes at which to direct patients than frequency or intensity
objectives.
Patients frequently consider only intercourse leading to orgasm as “sex.”
It is good practice to educate patients that being sexual comprises a wide
range of behaviors that can include but is not limited to hugging, caress-
ing, kissing, manual and oral stimulation of erogenous zones that include
genitals, and intercourse. An expanded range of options can increase the
probability that patients will be able to achieve treatment goals of mutual
comfort and satisfaction.
Sexual problems are best categorized based on where in the sexual response
cycle they occur. Table 9-2 presents a schema for this categorization. In addi-
tion to descriptive categories, sexual dysfunction can be conceptualized along
two additional dimensions (Table 9-3). First, sexual problems can be primary,
meaning they are lifelong, or secondary, meaning they are acquired. Second,
Table 9-2
Categories of Sexual Stage of Response
Dysfunction Cycle Involved Male Female
Desire Hypoactive sexual desire Hypoactive sexual desire
disorder disorder
Sexual aversion disorder Sexual aversion disorder
Arousal Erectile disorder Female arousal disorder
Orgasm Male orgasmic disorder Female orgasmic disorder
Premature ejaculation
Pain Dyspareunia Dyspareunia
Vaginismus
Table 9-3
General Subtypes of Type of Onset Type of Context
Sexual Dysfunction
Lifelong Generalized
Acquired Situational
Human Sexuality
sexual problems can be generalized and occur in all situations or situational

and be limited to certain environments or specific partners.
Desire Phase Hypoactive sexual desire disorder (HSDD) can occur in men and women and is
Disorders most often multiply determined. HSDD can be secondary to other dysfunc-
tions. A woman with dyspareunia may develop HSDD in response to the pain
she experiences during intercourse. HSDD occurs clinically with a high fre-
quency and is one of the most difficult disorders to treat. HSDD patients do
not normally have sexual fantasies or any desire for sexual activity. Although
hormone levels, medication side effects, developmental stage of life, illness,
and other medical factors all can play a role in the HSDD development and
maintenance, psychological factors are often intertwined with these physi-
cal sources of the disorder. Religious orthodoxy, anhedonic or obsessive- 141
compulsive disorder, gender identity or sexual object choice, fear of loss of
control over sexual urges, depression, and age-related concerns all could be
implicated. Relationship factors also can contribute to HSDD development
and maintenance. Lack of attraction to a partner, poor partner sexual skills,
marital conflict, couple differences regarding the point of optimal closeness
and other factors appear in the literature.
Treatment, often lengthy owing to the multivariate nature of potential
causes, can be complicated. Referral to a specialist is often advisable. Work
with testosterone and estrogen/testosterone combinations in naturally and
surgically postmenopausal women has shown promise for HSDD. Hormonal
therapies without exploration of other factors may be ineffective, however,
because, for example, no amount of hormonal intervention can override the
effects of an abusive relationship with a partner. Additional interventions of
a psychosocial nature can include correction of misinformation about sex,
cognitive therapies, development of positive sexual experiences and expec-
tations through the use of sensate focus exercises (originally developed by
Masters and Johnson), and fantasy material.
Sexual aversion disorder (SAD), although rare, can occur in men and
women. SAD patients have or develop an aversion to all genital sexual con-
tact with a sexual partner. The aversion may manifest itself as revulsion,
fear, or anger. Patients with SAD do not present saying they are averse to sex.
Women are likely to report dyspareunia or vaginismus instead. These condi-
tions may be secondary to the aversion.
Physical causes of SAD include any illness or other condition that might
cause genital pain. Vulvar vestibulitis may cause such excruciating pain that
a woman shudders at the mere thought of someone touching her genitals.
When well established, this aversion to genital contact may persist long after
the physical cause has been resolved. Case reports of men who have impaled
their penises on the tail of an improperly trimmed intrauterine device and
subsequently become averse to sexual activity are found in the literature.
Survivors of rape or other sexual trauma, including men who have been
sexually assaulted, are particularly vulnerable to SAD. Symptoms may
include flashbacks similar to those in post-traumatic stress disorder. In some
cases, each attempt at sex reactivates the memory of the traumatizing event,
resulting in flashbacks when a partner attempts to be physically intimate in

any way. Naturally, such patients work very hard to avoid sex.
Arousal Phase Erectile disorder is the best understood of the sexual dysfunctions. It is defined
Problems as the inability to obtain or maintain an erection satisfactory for the com-
pletion of sexual activity. As men age, normal changes occur in erectile
capacity as a result of changing vascular, neurologic, and endocrine fac-
tors. Many men believe that their youthful sexual experiences, when erec-
tion was autonomous and stimulation from a partner was unnecessary, will
last forever. If a man is unaware that it is normal for an older man (45-50
years old) to require more physical stimulation to achieve the same type of
erection, he can become frustrated and anxious. Anxiety is a contributor to
142 many instances of erectile disorder, and performance anxiety can maintain
it. Consequently, some education about what is normal can have a positive
therapeutic effect.
Medical treatments for erectile disorder may include the use of vasoac-
tive intracavernosal injections of agents such as alprostadil, papaverine
hydrochloride, phentolamine mesylate, and prostaglandin E1. All of these
agents have proved effective for erectile dysfunction and have a significant
dose-response relationship: the higher the dose, the stronger the erection.
Transurethral suppositories also have been used with limited success and
reports of discomfort from patients. These treatments focus on performance,
rather than on enhancement of the broader intimate relationship between
the partners. Some men define their sexuality as their ability to maintain an
erection sufficient for intercourse and intravaginal orgasm.
PDE5 inhibitors have become a first-line therapy for many men with erec-
tile disorder. Dropout rates and outcome satisfaction can be influenced by
carefully explaining the proper use of these agents relative to the expected
onset of effects, expected half-life, and the fact it is rare for a man to achieve
100% effectiveness as evidenced by an erection sufficient for penetra-
tion. Interpersonal and intrapersonal variability is more likely and to be
expected.
PDE5 inhibitors can be a useful adjunct in treating men with psychosocial
erectile dysfunction. It is useful to advise patients to test out their response
with masturbation to determine what, if any, side effects may exist and to
get used to the medication. PDE5 inhibitors are contraindicated for anyone
taking nitrate-based medications and for men with retinitis pigmentosa.
Surgical treatments for erectile dysfunction include implantable prostheses,
penile arterial revascularization, and penile venous ligation. The data on out-
comes with these procedures are usually limited to nondescriptive “satisfac-
tory” and “unsatisfactory.” When comparing vascular surgery with implants
with vascular surgery that is effective, the patient has “normal” erections
when he desires sex and there is sufficient erotic stimulation. Implant patients
are able to achieve erection whenever they wish. Some men and their partners
are dissatisfied because the erotic or affection components of sex are not a nec-
essary component. For many patients for whom medication interventions are
inappropriate, surgical interventions are highly desirable.
Human Sexuality
Vacuum device therapy is another treatment for erectile dysfunction. In

this treatment, a tube is placed over the flaccid penis, and after a tight seal is
made, the air is pumped out. The resulting change in pressure draws blood
into the penis. The blood is trapped with a constricting device. This proce-
dure requires some degree of manual dexterity to make the seal, pump the
device, and get the band off the device and onto the penis. The band may be
uncomfortable, and some men report bruising with this technique.
Interfering thoughts and emotional issues can accompany erectile dys-
function. Men can become upset and embarrassed about this problem. Men
who experience normal arousal and erection usually think erotic thoughts
that focus on their or their partner’s body parts, seductive behavior, and
anticipation of arousal and pleasure. A man with interfering thoughts
is focused on the firmness of his erection; his partner being disappointed,
angry, or even ridiculing; and palpable feelings of anxiety, embarrassment, 143
and depression. Cognitive-behavioral interventions can be employed in
conjunction with medication therapies and may provide a more powerful
treatment than one or the other in isolation. It is important to work with
partners in these cases. Frequently, partners have their own set of interfer-
ing thoughts about the dysfunction. Common problematic thoughts have to
do with the partner’s attractiveness to the patient, loss of love, infidelity, or
loss of desire for the partner. Asking the partner what he or she thinks is the
cause of the erectile dysfunction can allow explanations of likely etiology
and clear up any misunderstandings.
Female sexual arousal disorder (FSAD) refers to arousal phase problems of
the engorgement-lubrication response. Because the primary location for
these phenomena is internal, however, women are less likely than men to
notice a physiologic arousal deficiency. Diagnosis of the physiologic changes
that occur during arousal is difficult. Vasocongestion is monitored most
accurately by vaginal photoplethysmograph measurements obtained while
the patient is exposed to erotic and neutral stimuli. In addition, research
indicates that physiologic measures of female arousal have a limited or non-
significant correlation with subjective measures. When questioned, patients
complaining of FSAD say they rarely, if ever, think about sex or get “turned
on.” They may be interested in sex—but in a theoretical, conceptual way.
Patients may present for treatment when they notice reduced arousal in the
genital region. More likely, they seek therapy because they are not having
“sexy” thoughts. FSAD patients have a hard time focusing on erotic stimuli,
such as fantasies or sexual cues from a partner, and seldom report having
the experiences of sexual excitement, pleasure, and romance that other
people report.
Treatment of premenopausal women rarely employs medical interven-
tion. Women with estrogen deficiency and impaired arousal can benefit
from hormone replacement therapy, however. A variety of artificial lubri-
cants also are available to help these patients. The psychological portion of
treatment is directed at teaching how to focus on pleasurable thoughts and
feelings about sex and methods of improving intimacy. Because electric and
battery operated vibrators can be effective in enhancing all phases of female
sexual response, they may prove useful for FSAD treatment. An integrated
approach of medical and psychosocial interventions is considered the most

effective therapy.
Orgasm Phase Premature ejaculation, more recently termed rapid ejaculation, is the most
Problems common male sexual problem. Early in their sexual experience, before they
acquire ejaculatory control, most men ejaculate sooner than they or their
partners would wish. About 30% of sexually experienced men have this
problem. Definitional differences have limited the complete understanding
of rapid ejaculation from a research point of view. Popular myths about the
length of the average intercourse event create unrealistic expectations in
many men and their partners about what is “normal.” A good definition of
rapid ejaculation is that the man does not have voluntary, conscious control or
144 the ability to choose in most encounters when to ejaculate.
From a skill-based point of view, men with rapid ejaculation have diffi-
culty identifying the point of ejaculatory inevitability at which orgasm is no
longer voluntary. The abilities to relax during sexual encounters, focus on
pleasure and arousal in his own body, and use arousal pacing strategies are
essential for ejaculatory control. In addition, anxiety disorders, obsessive-
compulsive disorder, and fear of pregnancy are possible etiologic factors.
Relationship factors can have a role in the onset and maintenance of rapid
ejaculation that is acquired. Nonpsychological explanations also are possi-
ble. Physiologic predisposition to rapid ejaculation has been linked to greater
penile sensitivity and a shorter bulbocavernosus reflex nerve response
latency. Medical problems, such as prostatitis, can predispose a man to rapid
ejaculation. Certain physical injuries, neurologic trauma, and pelvic surger-
ies also can have an impact. Use of or withdrawal from some medications
can produce a rapid ejaculation as well.
Nonscientific remedies for rapid ejaculation have existed for decades.
Men have been encouraged to think “nonsexy” thoughts or apply anes-
thetic creams to their penises. Inevitably, these interventions fail or pro-
duce discomfort or lack of pleasure for the man and his partner. Behavioral
strategies, such as the stop-start or squeeze technique, have been employed
with a good deal of initial success, although their long-term effectiveness
has come into question. In each of these therapies, the man’s partner
stimulates his penis until just before the point of ejaculatory inevitabil-
ity. He tells her when he reaches that point, and she either stops stimula-
tion or squeezes the head of the penis below the glans between her thumb
and forefinger. After a period of nonstimulation, she resumes for a second
and then third trial. On the third trial, he is allowed to reach ejaculation.
Over time, the man learns to predict his ejaculation better and control his
behavior to prolong it.
Selective serotonin reuptake inhibitors (SSRIs) have known side effects on
sexual response. Increased serotonin levels are thought to inhibit ejacula-
tion. Tricyclic antidepressants also have been used with effectiveness, but
tend to have other less desirable side effects than SSRIs. Because withdrawal
of these medications can cause a reversion to prior patterns of ejaculation,
a combination of behavioral and pharmacologic interventions may be more
Human Sexuality
powerful. Inclusion of the partner in therapy is essential because ejaculatory

problems can distress relationships.
Male orgasm disorder is a persistent difficulty in attaining orgasm despite
adequate physical and cognitive/erotic stimulation. Most men are readily
orgasmic. Consequently, it is unusual for a man not to experience orgasm
with proper stimulation. These men obtain erections with sexual stimula-
tion. This stimulation is apparently insufficient, however, to produce an
orgasm. It is not unusual for men to describe a history that is low in sex drive
or interest or filled with negative sex messages. They also may participate in
sex without allowing adequate time to create a sexual mood. It is not unusual
for such men to have developed idiosyncratic masturbatory methods of vig-
orous stimulation that cannot be replicated in intercourse. Psychological
factors, such as conflict about sexual activity, fear of pregnancy, or obses-
sive-compulsive or passive-aggressive personality traits, can contribute to 145
the etiology. Finally, surgical disruption or diseases that interfere with the
sympathetic nervous system, such as diabetes, multiple sclerosis, and alco-
holic neuropathy, can be implicated.
When no biologic or pharmacologic causal explanations exist, male
orgasm disorder is difficult to treat. It is not unusual for a man to present
for therapy when his partner insists on it, often because she wants to get
pregnant. Therapy for male orgasm disorder frequently addresses the issue
of creating and maintaining a sexual mood and allowing sufficient time and
increasing erotic input. Erotic components might include fantasy, lubrica-
tion, vibrators, or sex play. These therapeutic interventions are based on a
belief that men with delayed orgasm do not take the time to focus on their
own eroticism.
Orgasmic responsiveness is something that women tend to develop over
time. They learn how to be orgasmic alone or with a partner and adapt their
sexual interaction to achieve release. Female orgasmic disorder can be the
psychological mirror of erectile dysfunction. Performance anxiety can play a
major role in maintaining the problem. Worry about the outcome interferes
with enjoyment of the total sexual experience, and the harder the woman
tries to reach the goal of orgasm, the more difficult it is to achieve. Because
the dysfunction can be so frustrating, it can lead a woman to avoid all sexual
interaction. Orgasm in men is readily detected because it typically is accom-
panied with ejaculation. Female orgasm is a more subjective experience even
though muscular contractions occur when it is achieved.
The normal range of stimulation required to trigger orgasm is wide.
Consequently, the diagnosis of this disorder must take into account whether
the woman’s orgasmic capacity is less than would reasonably be expected,
based on her age, her sexual experience, and the adequacy of the stimula-
tion she receives. A woman may be orgasmic during masturbation, but not
during intercourse, or she may be orgasmic with one partner, but not with
another.
Possible etiologic factors for female orgasmic disorder include abnormal
pubococcygeus muscle tone, hormonal imbalances, diabetes, and spinal
cord injuries. Psychiatric medications, such as SSRIs, antipsychotics, and
anxiolytics, and antihypertensives can produce anorgasmia. Psychological
explanations have not been consistently supported by adequate research.

Although relationship variables can play a role, they have not been quanti-
fied adequately to be meaningful.
When female orgasmic disorder is lifelong and generalized, directed mas-
turbation is a preferred treatment technique. Education, self-exploration
and body awareness, and encouraging the patient to masturbate to experi-
ence orgasm initially on her own before she does with a partner are sequen-
tial components of the therapy. The objective is for the woman to become
comfortable with orgasm when alone and transfer that comfort to partner-
related sexual activity that can include manual or oral stimulation or inter-
course. In addition, by learning how to bring herself to orgasm she is more
able to teach her partner how to do the same. Several books and videotapes
describe this empirically validated approach. Acquired or situation-specific
146 female orgasmic disorder is infrequent in healthy women. Investigation of
medication-related or health-related issues should guide intervention efforts.
Pain Problems Controversy exists about the inclusion of pain during sex as a sexual dysfunc-
tion. It is unclear why painful genital sexual activity is a sexual dysfunction
when other pain syndromes that interfere with sexual activity, such as low
back pain, are not so classified. Nevertheless, the sexual pain problems of
dyspareunia and vaginismus are diagnosed as sexual problems, rather than
pain problems. There is significant overlap between female dyspareunia and
vaginismus. Vaginismus can be secondary to painful intercourse.
Although it is quite rare, male dyspareunia can be the result of Peyronie’s
disease. Plaques develop on the midshaft of the penis and cause it to bow.
Sexual activity, including masturbation and intercourse, can be painful.
There is no generally accepted, standard nonsurgical treatment for Peyronie’s
disease. In addition, the success of treatment may be difficult to determine
because 20% to 50% of patients with Peyronie’s disease experience sponta-
neous resolution. Other causes of penile pain include prostatitis and urinary
tract infections. Obstructed ejaculatory ducts can cause testicular pain. It is
rare for a man to experience testicular pain solely in conjunction with sex
and not at other times.
Recurrent or persistent female genital pain on intercourse often has a
medical etiology. Dyspareunia also places a woman at risk, however, for devel-
oping vaginismus and secondary disorders of desire, arousal, and orgasm. An
accurate diagnosis requires a thorough physical examination. Sometimes,
patients whose examinations are negative for physical factors still complain
of pain. Whatever their cause, pain symptoms can cause the patient to avoid
sexual encounters with a partner, stressing the relationship.
Most often, dyspareunia has multiple etiologies. Numerous physical fac-
tors require consideration when making the diagnosis: hymenal remnants;
pelvic tumor; endometriosis; prolapsed ovaries; pelvic inflammatory disease;
vulvar vestibulitis; surgical scar tissue from episiotomy; and infections of
the vagina, lower urinary tract, cervix, or fallopian tubes. Anatomic rela-
tionships, such as ovarian fixation to a retroverted uterus, also may be the
source of the pain. Postmenopausal women can experience dyspareunia as
Human Sexuality
a result of changes to the vulvovaginal area, including reduced vaginal tran-

sudate during sexual arousal, owing to decreasing estrogen levels. Cancer
treatments that involve radiation to the pelvic region also reduce estrogen
production with similar results.
Psychological factors also may drive or contribute to the etiology of the
disorder. Many patients complaining of dyspareunia report guilt or shame
about sex, religious proscriptions that arouse shame or guilt, poor body
image, or a combination of those factors. Sexual trauma also may contrib-
ute and should be carefully and gently investigated. Sometimes patients
complain that a partner does not provide enough foreplay to produce
adequate arousal. Other presenting issues include a partner’s lack of sexual
skill, feelings of resentment toward a partner, and anxiety about sex.
Detailed information about the location and quality of pain are essen-
tial diagnostic components. Other factors evaluated include the degree of 147
interference with sexuality, relationships, and well-being of the patient.
Assessment by a physical therapist who specializes in pelvic floor muscula-
ture also is advisable.
Cognitive-behavioral techniques for pain management, biofeedback, ves-
tibulectomy, trigger point injections, topical and systemic medications, and
lubricants all have been used for treatment of dyspareunia. Inclusion of the
partner in treatment planning is advisable because the pain typically affects
the sexual relationship between the two.
Patients with vaginismus experience a recurrent or persistent involun-
tary spasm of the perineal and levator ani muscles of the outer third of the
vagina. When her partner attempts intromission, these muscles clamp down
preventing intercourse. These women may report fear not only of coitus, but
also of vaginal penetration of any kind, making routine vaginal examina-
tion impossible. Vaginismus patients frequently can be aroused by sexual
stimuli and achieve orgasm via masturbation or stimulation from a part-
ner. This can make the problem all the more frustrating for them and their
partners. Etiologic hypotheses include the contribution of many physical
factors, including atrophic vaginitis, episiotomy, prior surgery, Monilia or
Trichomonas vaginitis, constipation, pelvic congestion, a rigid hymen, pelvic
inflammatory disease, hemorrhoids, stenosis of the vagina, pelvic tumors,
childbirth pathologies, and urethral carbuncle.
These physiologic conditions seldom are the direct cause of the vaginismus,
but can become associated with the disorder through a classic condition-
ing paradigm: The pain the patient experiences initially becomes associated
with intercourse; she reports that her vaginal muscles clamp down, almost
automatically, when her partner approaches her for sex; sometimes even
thoughts about intercourse can initiate this conditioned muscle response.
The psychological etiology of vaginismus can include inhibitions introduced
via religious orthodoxy, prior sexual trauma, fear of pregnancy or parenting,
or response to a partner’s sexual dysfunction.
If local pathology is the cause of the vaginismus, it must be ameliorated
before treatment of any underlying psychological causes or contributors can
be attempted. The goal of treatment for vaginismus is the elimination of the
reflexive muscle spasms through a series of treatments, including relaxation
techniques to help control the onset of muscle spasms and physical dilation
of the vaginal entrance. This constitutes an in vivo desensitization. Patients
also may receive pelvic floor physical therapy. Graduated dilator sets are used
in the patient’s home with specific directions on how to lubricate and insert
them. Eventually, the partner can be introduced to the process, inserting the
dilator under the patient’s guidance. It may be more comfortable for patients
to have digital insertion rather than dilators and move to penile insertion
without thrusting.
Obtaining It is clear that patients want to discuss their sexual problems with health
Historical and care professionals. They expect physicians to take the lead in asking about
Diagnostic sexual health matters. The impetus for screening for sexual health problems
148 Information includes not only concern about sexually transmitted diseases and HIV/AIDS
but also the ability of physicians to reduce their incidence through preven-
tive education. Screening also pays attention to the fact that other disorders,
such as depression and diabetes, can have an impact on sexual function.
Finally, evidence exists that sexual activity and good health are related.
Taking a complete sex history may be precluded by time limitations in gen-
eral practice. It is useful, however, to have a set of screening questions to initiate
discussion about sexuality issues. Screening for sexual problems is best accom-
plished during a review of systems or during a personal and social history.
Finally, sex-related questions can be introduced during a physical examina-
tion, although it is the least desirable time of the three because the unclothed
patient is the most defenseless, and the appearance of impropriety exists.
When taking a history, screening for sexual problems, or initiating therapeutic
interventions, some basic assumptions can guide a physician’s behavior. Basic
assumptions about patients when taking a history are listed in Box 9- 2. Four
screening questions for sexual problems are listed in Box 9-3; these questions
are brief and direct. It is essential first to obtain permission to ask about sex-
ual matters. All other questions flow from this starting point. The specificity
Box 9-2 Basic Assumptions About Patients

1. Patients are embarrassed about and have difficulty discussing sexual matters.
2. Patients have a limited understanding of and do not use medically accurate
terminology.
3. Patients are misinformed about sexual functioning.
4. Patient couples have not been open with each other and do not discuss sexual
matters easily.
Box 9-3 Sex Screening Questions

1. Can I ask you a few questions about sexual matters?
2. Have you been sexually active (or involved) with a partner in the past 6
months?
3. Have you been sexually active with women, with men, or both?
4. Do you or your partner have any sexual difficulties, (for a man) such as with
your level of interest, erections, or ejaculations, (for a woman) such as with
your level of interest, vaginal lubrication, orgasms, or intercourse pain?
Human Sexuality
of the questions is designed to elicit the maximum amount of information.

The second question gives the option of “active” or “involved.” Some patients
may not understand active and think of it as the opposite of “passive” and
may be confused. If the patient responds affirmatively, the third question
provides information about the gender of the patient’s partner or partners.
Finally, the fourth question provides detailed information from which more
detailed information can flow. If little time is available, the fourth question is
the single best question to ask.
More detailed questionnaires and instruments have been devised for
obtaining sexual history and sexual problem description. Examples are
listed in Box 9-4. Finally, many sexual problems are best treated by special-
ists. Resources for making a referral and finding out more information about
sexuality and sexual problems are listed in Box 9-5.
149
Infertility and Infertility, with its direct link to procreative sexual behavior, is a life crisis that
Sexuality is ripe for sexual dysfunction. The infertile couple in treatment is faced with
a failure experience every time they have intercourse and do not become
Box 9-4 Representative Sexuality Questionnaires

Brief Index of Sexual Functioning for Women (BISF-W). Taylor JF, Rosen RC,
Leiblum SR: Self-report assessment of female sexual function: psychometric
evaluation of the Brief Index of Sexual Functioning for women. Arch Sex Behav
1994;23:627-643.
Derogatis Sexual Functioning Inventory (DSFI). Derogatis LR, Melisaratos N: The
DSFI: a multidimensional measure of sexual functioning. J Sex Marital Ther
1979;5:244-281.
Female Sexual Function Index (FSFI). Rosen R, Brown C, Heiman J, et al: The
Female Sexual Function Index (FSFI): a multidimensional self-report instrument
for the assessment of female sexual function. J Sex Marital Ther 2000;26:
191-208.
International Index of Erectile Function (IIEF). Rosen RC, Riley A, Wagner G, et al:
The International Index of Erectile Function (IIEF): a multidimensional scale for
assessment of erectile dysfunction. Urology 1997;49:822-830.
Sexual Desire Inventory (SDI). Spector IP, Carey MP, Steinberg L: The Sexual Desire
Inventory: development, factor structure, and evidence of reliability. J Sex
Marital Ther 1996;22:175-190.
Box 9-5 Referral Sources for Sex Therapy Specialists

American Association of Sexuality Educators, Counselors, and Therapists: Available
at: http://www.aasect.org/
The American Board of Sexology: Available at: http://www.sexologist.org/
The Society for the Scientific Study of Sexuality: Available at: http://www.ssc.wisc.
edu/ssss/
SSTAR—Society for Sex Therapy and Research: Available at: http://www.sstarnet.
org/
International Society for the Study of Women’s Sexual Health: Available at: http://
www.isswsh.org/
Table 9-4
Interface of Sexual Infertility causing sexual dysfunction Hypoactive sexual desire disorder
Dysfunction and Female orgasmic disorder
Infertility Erectile dysfunction
Sexual dysfunction causing infertility Vaginismus
Erectile dysfunction
Male orgasmic disorder
Premature ejaculation
Incidental findings Reduced sexual satisfaction
Guilt about sex
Impaired marital adjustment
Based on Elstein M: Effect of infertility on psychosexual function. BMJ 1975;3:296-299.
150
pregnant. It would be difficult to imagine that the repeated pairing of sex
and failure would not begin to take a toll on the sexual image and behavior
of the individuals involved. Sex can become routine, lacking in emotion and
devoid of excitement, when couples are in infertility treatment. Patients talk
about it as though the physician was with them in the bedroom. Romance,
intimacy, and spontaneity can evaporate under such circumstances.
Estimates of sexual dysfunction in the infertile population range from
10% to 37%. At the same time, infertile couples can score in the normal
range on measures of marital and sexual satisfaction. For men, increasing
age is positively associated with erectile problems and a decreased desire for
sexual interaction. National survey data found that the oldest group of men
(50-59) was more than three times as likely to experience erection difficul-
ties and to report low desire as the cohort of men 18 to 29 years of age. The
opposite is true for women, whose sexual problems, with the exception of
trouble with lubrication, tend to decrease with age. Given that the infertile
population tends to be younger than the overall population studied in these
more recent national estimates of sexual function disturbance, the estimates
for sexual dysfunction with infertile individuals may reflect a more signifi-
cant problem because lower rates of dysfunction would be expected, at least
for men. It is possible to conceptualize the interface of sexual dysfunction
and infertility as the matrix displayed in Table 9-4, with possible presenta-
tions of infertility leading to sexual dysfunction, sexual dysfunctions leading
to a diagnosis of infertility, and finally incidental findings of sexual problems
in cases of infertility.

1. Sexual interaction is multidimensional. It is more than intercourse leading
to orgasm and can include a wide range of erotic behavior. Men and
women seem to find different aspects of sexual interaction important.
2. Human reproductive organs are located internally and externally, sug-
gesting that internal structures function more for reproduction, whereas
external structures function more for physical pleasure.
Human Sexuality
3. Sexual response can be conceptualized in three phases: desire, arousal,

and orgasm. Diagnosis of a problem based on where it occurs in the
response cycle guides intervention strategies.
4. Neuronal, hormonal, physical, and psychological factors all play impor-
tant roles in sexual response, and all must be taken into account when
diagnosing problems and providing interventions.
5. Infertility, with its focus on sexual interaction and the failure to repro-
duce, can be the source of sexual problems.
SUGGESTED READINGS
151
Basson R: Using a different model for sexual response McCarthy B, McCarthy E: Couple Sexual Awareness.
to address women’s problematic low sexual desire. J New York: Carroll & Graf; 1998.
Sex Marital Ther 2001;27:395-403. Meston C: The psychophysiological assessment of
Basson R: Female sexual response: the role of drugs female sexual function. J Sex Educ Ther 2000;25:
in the management of sexual dysfunction. Obstet 6-16.
Gynecol 2001;98:350-353. Meston CM, Frolich PF: The neurobiology of sexual
Burns LH: Sexual counseling and infertility. In Burns function. Arch Gen Psychiatry 2000;57:1012-1030.
LH, Covington SN (eds): Infertility Counseling. Metz ME, Pryor JL: Premature ejaculation: a psycho-
New York: Parthenon; 1999:149-178. physiological approach for assessment and manage-
Crenshaw TL, Goldberg JP: Sexual Pharmacology: ment. J Sex Educ Ther 2000;26:293-320.
Drugs That Affect Sexual Function. New York: Reissing ED, Binik YM, Khalife S: Does vaginismus
Norton; 1996. exist? A critical review of the literature. J Nerv Ment
Heiman JR, LoPiccolo J: Becoming Orgasmic: A Sexual Dis 1999;187:261-274.
and Personal Growth Program for Women, rev ed. Schover LR, Jensen SB: Sexuality and Chronic Illness: A
New York: Prentice Hall; 1988. Comprehensive Approach. New York: Guilford; 1988.
Leiblum SR, Rosen RC (eds): Principles and Practice of Tiefer L: Historic, scientific, clinical and feminist criti-
Sex Therapy, 3rd ed. New York: Guilford; 2000. cisms of “the human sexual response cycle” model.
Kaplan HS: The New Sex Therapy. New York: Bruner/ Ann Rev Sex Res 1991;2:1-23.
Mazel; 1974. Weeks GR, Gambescia N: Erectile Dysfunction:
Kaplan HS: Disorders of Sexual Desire. New York: Integrating Couple Therapy, Sex Therapy and
Bruner/Mazel; 1979. Medical Treatment. New York: Norton; 2000.
Masters W, Johnson V: Human Sexual Response. Zilbergeld B: The New Male Sexuality, rev ed. New
Boston: Little, Brown; 1966. York: Bantam; 1999.
10
EVALUATION OF
FEMALE INFERTILITY
Seth G. Derman and David B. Seifer
DEFINITIONS
Clomiphene A test of ovarian reserve in which a menstrual day 3 and day 10 serum 155
citrate challenge follicle-stimulating hormone (FSH) is drawn, and clomiphene citrate at
test a dose of 100 mg is given daily on days 5 through 9; its advantage is
improved sensitivity compared with basal FSH alone
Diminished Reduction in female fecundity owing to loss of reproductively competent
ovarian reserve oocytes
Hysterosalpin- A radiologic procedure using iodine-based contrast material and
gogram fluoroscopy to assess intrauterine anatomy and tubal patency and
anatomy
Infertility The inability to conceive despite 1 year of adequately timed intercourse;
an evaluation may be started earlier if the female patient is older (≥35
years old) or the couple has an obvious defect
Sims-Huhner A test to assess sperm–cervical mucus interaction, performed after
test intercourse at the midcycle; the mucus is assessed for stretchability and
motile sperm; this test has largely fallen out of favor because of poor
predictive value
Saline infusion A radiologic test to assess the anatomic integrity of the uterine cavity;
sonography the test uses ultrasonography and instillation of saline into the cavity via
a small catheter
Infertility, defined as the inability to conceive after 1 year of unprotected

intercourse, is a common problem in gynecologic practice. This problem has
been estimated to affect one in six couples at some point in their lives. With
more couples delaying childbearing, infertility has become more common.
As modern therapies have become more successful and more commonly dis-
cussed in the media and in casual conversation, infertile couples are more
likely to seek out care. An understanding of how to evaluate an infertile
couple is important to the practicing obstetrician/gynecologist.
Reproductive failure may be due to the man or the woman, or a combination
of the two. It has been estimated that 40% of human infertility is attributable
to female causes, 40% to male causes, and the other 20% to a combination
of male and female causes. Evaluation of male and female causes for infertil-
ity is essential in the evaluation of an infertile couple. Evaluation of the male
partner, including semen analysis and other diagnostic modalities, is discussed

in Chapter 11. This chapter reviews the essential components of the workup
of the female partner of the infertile couple. The essential components of the
history and physical examination, the various diagnostic tests available, and
the physiologic basis of these tests are discussed.
NORMAL HUMAN REPRODUCTION AND REPRODUCTIVE FAILURE
To understand best how to approach the evaluation of an infertile couple,

it is essential to understand the physiologic events that accompany normal
human reproduction. In a woman with normal regular menstrual cycles,
an oocyte is released from one of the ovaries at midcycle. In a woman with
156 28-day menstrual cycles, ovulation usually occurs on or around day 14. As
the dominant follicle reaches maturity, circulating estradiol levels increase,
which, through a positive feedback mechanism, leads to a surge in lutein-
izing hormone (LH). Shortly after ovulation, the oocyte is picked up by the
fimbriated end of the ipsilateral fallopian tube, and the oocyte begins its
journey down toward the uterus. This transport is facilitated by the cilia in
the endosalpinx, and its viability is supported by endosalpingeal secretions.
Around the same time, the couple has intercourse, and the male partner
releases an ejaculate into the vagina. This ejaculate contains tens, or even
hundreds, of millions of motile sperm. These sperm travel into the cervix
where the mucus has become thin, watery, and generally hospitable to sperm
(in contrast to the vagina). Some of these sperm find their way into the glan-
dular crypts of the endocervix, whereas others enter the uterus and eventu-
ally the fallopian tubes. Although scores of sperm surround the oocyte and
attempt to penetrate, only a single sperm actually penetrates the zona pellu-
cida and fertilizes the mature oocyte. After fertilization, the oocyte completes
the second meiotic division and continues its journey down through the fal-
lopian tube. Embryo migration lasts approximately 6 days, and the zygote
progresses from the pronuclear to the blastocyst stage. At the end of the trip,
the blastocyst begins to implant itself into the endometrium, the lining of
the uterus. This process is facilitated by hormones from the ovary.
After ovulation, the ovarian follicle, which contains steroidogenic cells,
becomes the corpus luteum, which produces high levels of the steroid
hormones that help support the early pregnancy. Chief among these luteal
hormones are progesterone and estradiol. If a pregnancy is not established,
the cells of the corpus luteum undergo apoptosis, or programmed cell death,
and the progesterone levels wane. If a conceptus implants, the trophoblast
begins to secrete human chorionic gonadotropin. Human chorionic gonado-
tropin acts to rescue the corpus luteum, steroid secretion continues, and the
pregnancy is maintained.
There are many steps at which this process can be interrupted, any of
which may result in infertility. The causes for infertility are summarized
in Box 10-1. One can encounter disruption of the ovulatory process. It is
possible that an egg may not be released at all, or that ovulation occurs on
an infrequent basis, significantly lowering the odds for conception. It also
Evaluation of Female Infertility
Box 10-1 Causes of Infertility
Ovulatory
Polycystic ovarian syndrome
Hypothalamic amenorrhea
Prolactinoma
Other endocrinopathies
Luteal phase deficiency
Tubal/Peritoneal
Proximal tubal obstruction
Hydrosalpinx
Peritubal adhesions
Endometriosis
Uterine
Submucosal fibroids 157
Synechiae
Septum/congenital anomalies
Luteal phase deficiency
Cervical
Hostile mucus
Antisperm antibodies
Ovarian Reserve
Ovarian failure/menopause
Diminished ovarian reserve
is possible that the oocyte quality may be poor because of an unfavorable

hormonal milieu in the ovarian follicle (e.g., as a result of hyperandrogen-
ism) or because of an aged oocyte. The corpus luteum also may be unable to
produce adequate levels of progesterone to support the early pregnancy. The
latter situation is referred to as a luteal phase deficiency.
The fallopian tubes may be absent or damaged by infectious or fibrotic pro-
cesses. This situation may result in mechanical inability for the oocyte and
sperm to come in contact or result in the inability of the fertilized pre-embryo
to be transported out of the fallopian tube into the uterus. Endometriosis,
defined as the presence of endometrial glands and stroma in an ectopic loca-
tion, also may contribute to this process. Advanced cases of endometriosis
may result in mechanical barriers to conception, as described previously.
There are numerous theories on why minimal and mild cases of endome-
triosis might cause infertility, such as abnormalities in fertilization and luteal
phase deficiency; none of these has been proven.
In the male partner, there may be a defect in sperm production in quan-
tity or quality. There also may be difficulty in ejaculation or intercourse. The
causes of male reproductive failure are discussed in Chapter 11.
The cervix also may be a barrier to conception. It may be stenotic or have
sustained damage to the endocervical glands from surgical treatment of
cervical dysplasia (e.g., cryosurgery or loop electrosurgical excision proce-
dures). Such damage may prevent the production of adequate mucus from
the endocervical glands. The presence of thick hostile mucus may prevent
sperm from being able to penetrate the cervix and survive for prolonged peri-
ods in the endocervical crypts. Many investigators also believe that antisperm
antibodies may prevent viable sperm from reaching the oocyte.
When the oocyte is fertilized and migrates to the uterus, several problems
still may be encountered. There may be anatomic defects inside the uterus
that prevent proper implantation or do not provide for sufficient blood sup-
ply to allow the pregnancy to develop to the clinical stage. Submucosal
fibroids, synechiae (intrauterine adhesions), and uterine septa are examples
of such intrauterine anomalies. Additionally, a luteal phase insufficiency
owing to inadequate progesterone production may prevent the conceptus
from surviving to the point where a pregnancy can be detected.
158
HISTORY AND PHYSICAL EXAMINATION
One cannot overstate the importance of obtaining a thorough history on the

infertile couple. Physical examination also may be helpful in determining the
causes for infertility, although to a lesser degree than the history. The salient
points in obtaining a history in the infertile couple are listed in Box 10-2.
The infertility history begins with a discussion of the age of the male and
female partners and the duration of their infertility. The age of the female
partner is crucial. A woman in her mid to late 40s is unlikely to conceive
(without use of donated oocytes), whereas a woman in her 20s is far more
likely to have issues other than oocyte age as the cause for her infertility.
The female partner’s age also determines at which point a workup might
be appropriate. Infertility generally is considered to exist when pregnancy
fails to occur after 1 year of unprotected intercourse. In patients older than
35 years of age, it is common to begin the workup after 6 months of unpro-
tected intercourse.
It is important to obtain a complete menstrual history, including the age
of menarche, the cycle length and duration, the regularity and predictability
of the cycle, and the presence or absence of moliminal symptoms and dys-
menorrhea, which suggest adequate ovulation. Additionally, it is important
to inquire about symptoms of menorrhagia, metrorrhagia, severe dysmen-
orrhea, and dyspareunia, which are associated with pathologic conditions.
Box 10-2 Essential Components in the Infertility History

● Age
● Detailed pregnancy history
● Menstrual history
● Sexually transmitted disease and pelvic infections
● Androgenic symptoms
● Medical history
● Surgical history
● Substance abuse
● Infertility testing
● Treatment
The clinician also should inquire about history of intrauterine device use,
sexually transmitted diseases, or history of pelvic inflammatory disease.
Irregularity of the cycle suggests ovulatory disturbance, whereas symp-
toms of severe dysmenorrhea and dyspareunia are seen frequently with
endometriosis. A history of sexually transmitted diseases, such as chlamydia
or gonorrhea, or of pelvic inflammatory disease should alert the physician to
the possibility of tubal causes for a couple’s inability to conceive.
The clinician should inquire about other symptoms of endocrinopathies,
such as those of hyperandrogenism. Hyperandrogenic women, such as
women who have polycystic ovarian syndrome, may complain of hirsutism,
male-pattern alopecia, and acne. Additionally, the clinician should inquire
about the symptoms of hypoglycemia and thyroid disease and galactorrhea.
Symptoms of hyperandrogenism or hyperinsulinemia suggest the possibility
of polycystic ovarian syndrome, whereas galactorrhea suggests the possibil- 159
ity of hyperprolactinemia.
A thorough obstetric history is important, including history of all preg-
nancies, the method of delivery, and any complications related to the preg-
nancy. This history includes vaginal births, cesarean sections, spontaneous
abortions, ectopic gestations, and elective terminations of pregnancy. Certain
complications during the pregnancy may suggest various endocrine distur-
bances or pelvic infections. Women who develop gestational diabetes are
more likely to be insulin resistant, a metabolic state that frequently coexists
with polycystic ovarian syndrome. A postpartum or postabortal fever or
curettage may result in tubal damage or the development of intrauterine
synechiae.
Patients with recurrent spontaneous abortions require further evalua-
tion (see Chapter 16). Past medical and surgical histories also are relevant.
Abdominal or pelvic surgeries may suggest the possibility of tubal damage
or pelvic adhesive disease. A history of surgical intervention, such as cryo-
surgery or cone biopsy of the cervix, may suggest the possibility of cervical
etiologies for infertility. Additionally, one should inquire about abdominal
pain and any family history of reproductive failure, genetic anomalies, or
mental retardation.
It is important to obtain a sexual history, including the frequency and tim-
ing of intercourse. A couple who is not sexually active during the periovula-
tory period will not conceive, regardless of how often they have intercourse
throughout the remainder of the month. Additionally, when the male part-
ner is unable to ejaculate reliably during coitus, pregnancy is far less likely
to occur. Obtaining a sexual history also provides an opportunity to counsel
the couple on when to have intercourse. In general, the couple should be
advised to start having intercourse 2 to 3 days before anticipated ovulation
and continue until the day after ovulation. Some physicians recommend
daily intercourse to maximize the number of available sperm, whereas oth-
ers recommend every-other-day intercourse to maximize counts. The total
exposure to sperm (or total area under the curve) seems to be the most
important predictor of success.
Physical examination of the female partner should not be limited to gyne-
cologic examination. On general examination, the examiner should take note
of the patient’s weight and body mass index. Examination of skin may reveal
acanthosis nigricans (a sign of insulin resistance), hirsutism, male-pattern
alopecia, or acne, all of which suggest a hyperandrogenic state. Additionally,
signs of other endocrinopathies, such as thyromegaly and abdominal striae
(suggestive of cortisol excess), should be noted. Breast examination should
be performed to look for masses, tenderness, and lymphadenopathy and to
evaluate for discharge. Any breast discharge expressed should be examined
under the microscope for fat droplets diagnostic of galactorrhea.
The most important part of the physical examination is the pelvic exami-
nation. The clinician should inspect for clitoromegaly (a sign of hyperan-
drogenism) and evidence of congenital defects, such as an imperforate hymen
or a transverse or longitudinal vaginal septum. The uterus and adenexa
should be evaluated for shape, size, position, and tenderness. Additionally,
160 the cul-de-sac should be palpated for nodularity and tenderness, which may
be more apparent on rectovaginal examination. The presence of pelvic ten-
derness or nodularity suggests the possibility of endometriosis. Tenderness
also may be found in patients with prior or recent infectious processes, such
as pelvic inflammatory disease.
If the patient’s history and physical examination point to a specific etiol-
ogy, it is appropriate to focus the workup in that direction. If the history does
not point to any specific issue, a more comprehensive evaluation is in order.
EVALUATION OF OVULATION AND THE LUTEAL PHASE
As described earlier, ovulation is essential for normal human conception.

Most women with predictable menstrual cycles have regular cyclic ovula-
tion. Nevertheless, it is still possible, albeit unlikely, that such patients may
be anovulatory. Many different modalities are available to the clinician in
the office setting and patient at home to confirm the presence of ovulation
(Box 10-3).
One of the simplest and least expensive methods for evaluating ovulation
is the basal body temperature chart. The patient checks her temperature by
a basal thermometer on first rising in the morning, before getting out of bed,
on a daily basis. Several days after ovulation, there may be an increase in the
temperature (approximately 0.5°C) mediated by an increase in serum pro-
gesterone levels, a finding that strongly suggests ovulation. The advantages
of basal body temperature testing are its relatively low cost and simplicity.
There are, however, several drawbacks to basal body temperature testing.
A woman who takes her temperature on first rising in the morning starts
Box 10-3 Methods to Document Ovulation

● Basal body temperature charts
● Urine LH kits
● Clear Plan Easy device (Unipath, Waltham, MA)
● Midluteal serum progesterone
● Endometrial biopsy
each day reminded that she and her partner have been unable to have chil-
dren. It has been well established that stress may contribute to infertility, and
temperature charting in itself is likely to increase the patient’s stress levels.
Basal body testing cannot direct the timing of intercourse because the tem-
perature increase occurs after the peak fertility period is complete.
Ovulation also may be confirmed by an over-the-counter ovulation pre-
diction kit. These kits work by detecting the midcycle LH surge in the urine.
In response to the preovulatory increase in estradiol, LH levels surge in the
bloodstream and spill into the urine. Each of the test kits measures the LH
as it accumulates in the urine. Ovulation prediction kits are made by various
manufacturers and have varying levels of reliability. These home kits con-
firm the presence of an LH surge only and do not directly confirm ovulation.
Women with chronically elevated LH levels, such as patients with polycystic
ovarian syndrome, may have kits that indicate a positive LH surge every day 161
of the month, rendering them less useful in such patients. A fertility moni-
tor called the Clear Plan Easy device (Unipath, Waltham, MA) measures
LH along with a metabolite of estradiol in the urine. The monitor indicates
periods of elevated fertility and peak fertility. These are reflective of LH and
estriol glucuronide (an estradiol metabolite) levels only and are not direct
measures of ovulation. Even though the monitor and ovulation prediction
kits indicate several days of “peak” fertility, the true window for fertilization
actually is short (usually <24 hours). The ability of sperm to be stored in the
cervical mucus for 72 hours explains the fertility period that extends beyond
this narrow window. Many couples find the ovulation prediction kits useful
in helping them time intercourse. Nevertheless, the fertile period in women
with regular, predictable cycles can be predicted easily using menstrual
cycle timing alone. Women with longer cycles are more likely to benefit from
urinary LH testing.
Ovulation also may be confirmed by serum testing of progesterone levels in
the midluteal phase. It is widely believed that a level of 3 ng/mL is confirma-
tory of ovulation. Nevertheless, such low levels may not be associated with
pregnancy cycles, and many clinicians consider levels of 10 ng/mL indica-
tive of an adequate luteal phase. Levels of 10 ng/mL correlate well with nor-
mal in-phase endometrial histology. When interpreting progesterone levels,
one should keep in mind that serum progesterone levels vary considerably
based on the laboratory technique used (e.g., radioimmunoassay, sandwich
assay) and the day of the cycle on which they are drawn.
Historically, clinicians used endometrial histology to diagnose luteal phase
insufficiency, which is essentially a mild ovulatory defect. The expense, dis-
comfort, and relatively poor reliability of the endometrial biopsy make it an
increasingly unpopular test.
It is important to inquire about ovulation when obtaining a history and
use an objective method to confirm the presence of ovulation even in patients
whose history suggests they are ovulatory. Many modalities are available to
investigate this. Basal body temperature charting and over-the-counter ovu-
lation prediction kits are easily accessible to patients. Midluteal serum pro-
gesterone levels provide the clinician with more definite proof of ovulation.
Endometrial histology is less commonly used in clinical practice.
EVALUATION OF THE FALLOPIAN TUBE AND PERITONEUM
Tubal patency and proper tubal function are essential to enable transport
of the sperm to the oocyte and to allow the fertilized zygote to travel back to
the uterus. The patient history may help in determining which patients are
likely to have tubal causes for infertility. Patients with prior pelvic inflamma-
tory disease, sexually transmitted diseases such as gonorrhea or Chlamydia
trachomatis, or a history of septic abortions are most likely to have tubal dis-
ease. Serum antibody testing for chlamydia (IgG) may help alert the clinician
to the possibility of an undiagnosed infection in the past. Many patients with
extensive tubal disease have an unremarkable history.
With the possible exception of ovulatory dysfunction and azoospermia, all
patients who are seeking evaluation for infertility at some point need to have
162 fallopian tube patency established. Even anovulatory patients should be
assessed if infertility persists despite successful ovulation induction. Couples
who use donor sperm insemination for azoospermia also should be assessed
if they do not conceive after several treatment cycles. The most common test
for determining tubal patency is hysterosalpingography (HSG). With this
procedure, a catheter is introduced into the cervix and iodine-based contrast
material is injected into the uterus under fluoroscopic evaluation. The physi-
cian is able to observe filling of the uterus, evaluate the uterine cavity, and
observe the radiopaque dye passing into the fallopian tubes and freely spill-
ing into the peritoneum. The dye may be water-based or oil-based. Because
of concerns about the risks of emboli from oil-based dye, most physicians
use only water-based contrast media. Examples of HSG images are shown
in Figure 10-1. Tubal problems, such as proximal or distal tubal obstruction
with or without hydrosalpinx, may be diagnosed. In some cases, intratubal
and extratubal adhesions may be noted. An obstruction of the fallopian
tube diagnosed on HSG profoundly affects the direction of evaluation and
treatment. Although HSG is excellent at determining tubal patency, occa-
sionally the fallopian tubes appear to be patent on HSG, but there are signifi-
cant pelvic adhesions present. Post-tubal loculations also can be suspected
on the basis of retention of contrast material in what appear to be pockets
near the tubal fimbriae. HSG carries a low risk of pelvic infection, and many
physicians instruct the patient to take prophylactic antibiotics.
The gold standard in evaluating the fallopian tube is laparoscopy. This
surgical procedure, with which most obstetrician/gynecologists and general
surgeons are quite familiar, involves insufflation of the abdominal cavity
with carbon dioxide gas followed by introduction of a trochar and laparo-
scope into the abdominal cavity. A uterine manipulator, such as a Humi or
Jarcho catheter, is inserted into the cervix. The external surface of the ova-
ries, fallopian tube, uterus, and cul-de-sac may be evaluated to an extent
that is impossible with HSG. As with HSG, tubal patency can be confirmed.
In contrast to HSG, the external surface of the fallopian tube may be visu-
alized as well; pelvic adhesions can be clearly diagnosed and treated. The
health of the fimbriated end of the tube may be assessed. It is possible to have
patent tubes with fimbriae that are incapable of ovum pickup.
Figure 10-1
HSG findings.
A, Normal.
B, Midsegment
obstruction.
C, Hydrosalpinx.
D, Submucosal
fibroids.
A B
Normal Midsegment obstruction
163
C D
Hydrosalpinx Submucosal fibroids
Equally important, endometriosis can be diagnosed at the time of laparos-

copy. Endometriosis is a condition in which glands and stroma that line the
uterus are located in ectopic locations (see Chapter 14). The most common of
these locations is around the ovary, in the cul-de-sac, and on the uterosacral
ligaments. These structures can be visualized directly at the time of laparos-
copy. Laparoscopy also provides the opportunity for fulguration or excision
of such lesions. Patients with moderate or severe endometriosis benefit from
surgical treatment of endometriosis. There is also likely a benefit to patients
with minimal to mild disease, although more study is warranted. Discussion
of the relationship between endometriosis and infertility is beyond the focus
of this chapter.
Other factors that should be noted with laparoscopy include the presence of
abdominal and perihepatic adhesions, which suggest previous pelvic inflam-
matory disease. Laparoscopy carries with it the risks of general anesthesia,
bleeding, infection, and damage to the adjacent organs. Because of the risks
and costs associated with laparoscopy and the increasing success of in vitro
fertilization, many reproductive endocrinologists are abandoning routine
laparoscopy in infertility patients with no abnormal findings in their workup.
There are other ways to evaluate tubal patency, although some of these
methods are not established to be of benefit. Sonohysterography is a procedure
commonly used to evaluate the uterine cavity in which saline is infused

into the uterus at the time of pelvic sonography. Although visualization of
the uterine cavity is excellent, it is more difficult to visualize the fallopian
tube at ultrasound. There has been some success in using albumin mixed
in with saline infusion and color flow Doppler to visualize the tubes. At this
time, sonohysterography is not used routinely to document tubal patency.
Additionally, evaluation of the fallopian tube, whether by HSG or laparos-
copy, does not adequately visualize the interior of the fallopian tube. The cilia
and function of the tube are essential to proper tubal function. Techniques
such as falloposcopy and salpingoscopy have been developed to visualize the
endosalpinx, and some centers use these techniques to evaluate the fallo-
pian tube. The increasing success rate of in vitro fertilization as a treatment
for tubal disease has made the importance of such an evaluation less impor-
164 tant. It is essential to establish that the fallopian tubes are patent as part of
a complete infertility evaluation. Most commonly, this is done by use of HSG
or laparoscopy.
EVALUATION OF THE UTERINE CAVITY
The uterine cavity plays an important role in normal human reproduction.

A normal endometrium allows the fertilized embryo to implant, allowing the
conceptus to continue to develop. There are two aspects of uterine function
that are of interest to the clinician evaluating an infertile couple. One con-
cerns the cyclic changes that occur in the endometrial thickness and histol-
ogy in response to hormonal fluctuations throughout the menstrual cycle.
Such changes in endometrial receptivity are largely related to ovarian rather
than uterine function; evaluation of endometrial histology and progester-
one was considered earlier in this chapter.
The second aspect of uterine function relevant to reproduction is ana-
tomic integrity. Anatomic abnormalities in the endometrium, such as sub-
mucosal fibroids, endometrial polyps, uterine septa, and uterine synechiae,
may interfere with the implantation process. Although many congenital
uterine anomalies have not been associated with infertility, most have been
associated with recurrent pregnancy loss and are still important in the man-
agement of an infertile couple. The most commonly used test to evaluate the
uterine cavity anatomy is HSG. HSG is effective at determining tubal patency
and delineating uterine anatomy.
Even more sensitive and specific for evaluation of the cavity is sonohys-
terography, also known as the saline infusion sonography. A soft plastic
catheter is inserted into the internal os, saline is injected, and transvaginal
sonography is performed preinfusion and postinfusion. Sonohysterography
provides an excellent view of the uterus in general and the endometrial
cavity in particular. Alternatively, one may perform hysteroscopy, in which
an endoscope is introduced into the uterine cavity along with gas (car-
bon dioxide) or liquid (saline, glycine, sorbitol) distending medium. Both
procedures provide excellent imaging of the endometrium, but they are of
limited or no use in evaluating tubal patency. Additionally, major müllerian
anomalies may be diagnosed reliably by pelvic magnetic resonance imaging

or three-dimensional sonography.
EVALUATION OF CERVICAL FUNCTION
The postcoital test is performed by aspirating a sample of cervical mucus

via a hollow catheter, such as an intravenous angiocatheter. The aspirate
is evaluated for stretchability (also known as spinnbarkeit), pH, and vol-
ume. Under the microscope, the clinician looks for the presence of sperm
and confirms that the sperm are motile and forwardly progressive. Although
standards vary from center to center, the clinician should look for forwardly
progressive sperm, adequate volume, and spinnbarkeit of at least 10 cm.
The problem with this test is that it is not uniformly predictive for pregnancy. 165
Many women with abnormal postcoital tests go on to achieve pregnancy.
Additionally, there remain a variety of normal values in the medical litera-
ture and little consensus on what constitutes a normal test. If the postcoital
test is not performed at precisely the right time, even a patient with excellent
quality cervical mucus would have an abnormal postcoital test. As a result
of the poor reproducibility and a low positive predictive value, the postcoital
test has largely fallen out of favor with reproductive endocrinologists and is
not recommended for routine use by the American Society for Reproductive
Medicine.
Many reproductive endocrinologists also check infertile couples for anti-
sperm antibodies. Antibodies directed at the sperm are thought to prevent
adequate numbers of sperm from passing through the cervical mucus and
reaching the oocyte and prevent the sperm that do manage to get through
from fertilizing the egg. Antisperm antibodies may be assayed in the female
partner by serum testing or in the man by testing of serum or seminal fluid.
The validity of such testing in predicting infertility is controversial.
EVALUATION OF OVARIAN RESERVE
In recent years, reproductive endocrinologists have come to realize the

importance of the role that ovarian aging plays when assessing an infertile
couple. Many women with otherwise unexplained infertility may be unable
to conceive because of diminished numbers or quality of the remaining
oocyte pool. Although natural fertility potential and pregnancy rates from
in vitro fertilization are quite good in women in their early 20s, they are poor
in women in their late 40s, a phenomenon clearly related to aging of the
cohort of ovarian follicles. This aging of the ovary is known as diminished
ovarian reserve, and a battery of tests has been devised to provide a quanti-
tative estimate of ovarian reserve (Box 10-4).
The most long-standing test for determining ovarian reserve is the basal
follicle-stimulating hormone (FSH) level. Serum is drawn on day 2 or 3 in the
early follicular phase for FSH assay. A normal value in most centers is con-
sidered to be less than 10 mIU/mL and is considered diagnostic of normal
Box 10-4 Methods to Assess Ovarian Reserve

● Basal FSH levels
● Basal estradiol levels
● Clomiphene citrate challenge test
● Ultrasound
● Inhibin levels
● MIS/antimüllerian hormone levels
ovarian reserve, although each clinic should determine its own normative
values. Elevated basal FSH levels in older patients indicate significantly
diminished chances for success with assisted reproductive technology and
in spontaneous conception. In younger patients, it is unclear whether an
166 elevated basal FSH level is indicative of lower pregnancy rates, or whether
such patients simply have poorer responses to gonadotropin treatment and a
higher chance for cycle cancellation. More significantly, basal FSH levels can
be interpreted only in light of the laboratory in which the assay is run, and
there is significant intercycle variability among patients. Individuals with
even one elevated basal FSH value have a markedly decreased chance for
success.
Taking the basal FSH concept a step further, the clomiphene citrate chal-
lenge test was developed in 1987. This is a provocative test of ovarian reserve
during which basal FSH levels are drawn. The patient is given clomiphene,
100 mg/day, on days 5 to 9 of the cycle, and repeat FSH levels are checked
on day 10. The basis of this test is that patients with normal ovarian reserve
with a normal cohort of follicles producing adequate estradiol and inhibin
levels are able to suppress FSH levels back into the normal range between
days 9 and 10. This test has been shown to be predictive for a general infer-
tility population and patients undergoing in vitro fertilization. It seems to be
much more sensitive than the basal FSH alone.
Other tests have been developed for evaluation of ovarian reserve in addi-
tion to the basal FSH and clomiphene citrate challenge test. Estradiol levels
frequently are obtained with the basal FSH, and women with elevated basal
estradiol levels have been shown to have reduced fertility. It is unclear at this
time whether an elevated basal estradiol level is suppressing the FSH level or
is itself predictive of diminished ovarian reserve.
Inhibin B also has been studied as a measure of diminished ovarian
reserve. This peptide growth factor from the transforming growth factor-β
superfamily is produced by granulosa cells and expressed in the ovarian folli-
cle. Diminished inhibin B production is the physiologic basis of elevated FSH
levels noted in patients with diminished ovarian reserve and the clomiphene
citrate challenge test. The decrease in inhibin B occurs before elevations in
basal FSH, suggesting that diminished inhibin B levels may be an earlier sign
of diminished ovarian reserve.
Another member of the transforming growth factor-β superfamily, mül-
lerian inhibin substance (MIS), also known as antimüllerian hormone, may
be used to test for ovarian reserve. MIS is best known for its role in embryonic
sexual differentiation. The hormone is produced in follicles at various stages
of development and is unlikely to be affected by the cycle. In the available

studies, low MIS levels suggested poor response to gonadotropin therapy.
Nonetheless, MIS remains an experimental diagnostic test.
Ultrasound evaluation of ovarian reserve also has been studied. Various
authors have looked at total ovarian volume, volume of the largest ovary, and
the investigators noted that patients with smaller ovaries produced smaller
numbers of follicles. What is unclear is whether patients with diminished ovar-
ian size on ultrasound have diminished pregnancy rates or only poor oocyte
yields at in vitro fertilization. Additionally, ultrasound can be used to perform
counts of early antral follicles. Antral follicle counts seem to correlate with
ovarian response to stimulation and perhaps with pregnancy outcome.
CONCLUSION 167
Infertility is a common problem among women of reproductive age. A couple

who has been attempting pregnancy for 1 year should undergo evaluation;
couples in whom the female partner is older than age 35 should undergo
evaluation after attempting pregnancy for 6 months. Various tests have been
used to evaluate infertility. As in all areas of clinical medicine, the first step is
to obtain an adequate history.
Evaluation of the female partner of an infertile couple typically includes
evaluation of ovulation, confirmation of tubal patency, evaluation of the
semen, and evaluation of ovarian reserve. In many modern reproductive
centers, the workup has often been pared down to a basal FSH, midluteal
progesterone, semen analysis, and HSG. The postcoital test, a standard for
infertility testing over the past century, has generally fallen out of favor.
It is helpful for the clinician and the patient to understand the reasons for
reproductive failure before beginning therapy. This information may direct
therapy, avoid treatments that are likely to be ineffective, and make the infer-
tile couple active participants in their care. Despite diagnostic efforts, how-
ever, about 10% of couples have unexplained infertility. In these couples,
empiric therapy with clomiphene citrate or gonadotropin superovulation
may be effective. Patient age plays an important role, and in vitro fertiliza-
tion should be considered early in couples in whom the woman is older than
35 years old.

1. Female causes and mixed male and female causes account for more than
half of the cases of human infertility.
2. Evaluation of the female partner is essential in determining the cause of
a couple’s infertility and directing the course of therapy.
3. A thorough history can help to pare down the workup, reduce costs, and
bring the patient to treatment sooner.
4. Minimal evaluation of the female partner includes confirmation of ovula-
tion, tubal patency, and adequate ovarian reserve.
5. The use of the postcoital test in evaluation for cervical causes in infertility
is controversial.
6. Ovulation may be confirmed by various means, including basal body
temperature charting, urinary LH testing, midluteal progesterone levels,
and endometrial biopsy.
7. Tubal patency may be shown by HSG or chromoperturbation at the time
of laparoscopy.
8. Ovarian reserve is a measure of aging of the ovaries and can predict a
woman’s ability to conceive with contemporary therapies. It is commonly
assessed using a basal FSH and estradiol level or a clomiphene citrate
challenge test.
168
SUGGESTED READINGS
ASRM Practice Committee Report: Optimal evaluation of Wathen NC, Perry L, Lilford RJ, Chard T:
the infertile female. Birmingham, AL: American Society Interpretation of single progesterone measurement
of Reproductive Medicine; June 2000. in a diagnosis of anovulation and defective luteal
Griffith CS, Grimes DA: The validity of the postcoital phase: observations on analysis of the normal range.
test. Am J Obstet Gynecol 1990;162:615-620. BMJ 1984;288:7.
Mosher WD, Pratt WF: Fecundity and infertility in Wilcox AJ, Weinberg CR, Baird DD: Timing of sexual
the United States: incidents and trends. Fertil Steril intercourse in relation to ovulation—effects on the
1991;56:192. probability conception, survival of the pregnancy and
Noyes RW, Hertig AW, Rock J: Dating the endometrial sex of the baby. N Engl J Med 1995;333:1517.
biopsy. Fertil Steril 1950;1:3.
Sharara FI, Scott RT Jr, Seifer DB: The detection of
diminished ovarian reserve in infertile women. Am J
Obstet Gynecol 1998;179(3 pt 1):804-812.
11
EVALUATION
AND TREATMENT
OF MALE INFERTILITY
Jesse N. Mills, Sheri M. Dey,
and Randall B. Meacham
169
DEFINITIONS
Oligospermia Sperm density less than 20 million/mL
Asthenozoo- Sperm motility less than 50%
spermia
Severe astheno- Total motility of 0% to 5%
zoospermia
Teratozoo- Normal sperm morphology less than 15%
spermia
Azoospermia Absence of sperm in the ejaculate
Primary infertility affects approximately 15% to 18% of couples. Male infer-

tility is responsible for approximately 40% of these cases. This chapter dis-
cusses the evaluation, including history, physical examination, laboratory
testing, and radiologic evaluation, and treatment of male factor infertility.
A section on genetic factors of male infertility and genetic screening consid-
erations is included.
HISTORY
Evaluation of an infertile man begins with a detailed history. The patient

should be asked about childhood illnesses and abnormalities, including the
presence of an undescended testicle, performance of an orchiopexy, testicu-
lar torsion, and trauma. Men with a history of testicular cancer also may
have impaired fertility. Testicular cancer is an independent risk factor for
infertility, and the various treatment options can result in impaired fertil-
ity. Chemotherapy, radiotherapy, and retroperitoneal lymph node dissection
all can adversely affect sperm function and transport. The effects of chemo-
therapy and radiation can last 5 years post-treatment, and improvement
after that time is rare. Retroperitoneal lymph node dissection can interrupt
the sympathetic chain and cause absence of seminal emission or retrograde

ejaculation.
The history should include questions about past and current medical prob-
lems. Chronic respiratory infections may suggest a diagnosis of immotile
cilia syndrome, Kartagener’s syndrome, cystic fibrosis, or Young’s syndrome.
Young’s syndrome produces an obstructive azoospermia by blocking the epi-
didymis with inspissated debris. Immotile cilia syndrome and Kartagener’s
syndrome, a subset of immotile cilia syndrome associated with situs inver-
sus, affects sperm motility. Cystic fibrosis can show variable penetrance in
which the patient may experience only frequent respiratory infections or be
completely asymptomatic. Physical examination subsequently may reveal
congenital absence of the vas deferens. This finding has a strong correlation
with a mutation of the cystic fibrosis transmembrane receptor (CFTR) gene.
170 Endocrine abnormalities are responsible for some cases of male infertil-
ity. Congenital adrenal hyperplasia is associated with precocious puberty
and impaired fertility. Family and personal history of diabetes mellitus may
manifest as disturbances in emission or retrograde ejaculation. It has been
reported that men with diabetes mellitus can present with decreased ejacu-
late volume as the sole complaint. Delayed puberty can be a sign of hypo-
gonadotropic hypogonadism. Patients with Kallmann’s syndrome, a form
of hypogonadotropic hypogonadism associated with anosmia, can present
with a history of decreased olfaction. Hyperthyroidism can cause reversible
reduction in sperm motility. Hypothyroidism, rare in men, is less likely to
contribute to infertility. It was found, however, that 3% of men with idio-
pathic infertility had subclinical hypothyroidism. A subset of these men was
found to have positive thyroid autoantibodies and decreased sperm counts.
Visual disturbances, galactorrhea, anosmia, and sudden decrease in libido
suggest the presence of a pituitary tumor.
Scrotal trauma, whether surgically corrected or not, is a reported cause
of infertility. Past scrotal and inguinal surgeries are important to investigate.
More recent literature has focused on bilateral inguinal hernia repairs as a
cause of infertility. In one study, 14% of men with severe oligozoospermia
had undergone bilateral inguinal hernia repairs. Men who have low-volume
ejaculate and sperm in a postejaculatory urine specimen may have under-
gone bladder neck surgery in their childhood.
History of recent illnesses also must be elicited. Fever or viremia can cause
impaired testicular function that may last 3 months after the initial insult.
This delay in recovery is due to the normal time course of sperm matura-
tion because it takes approximately 74 days for immature spermatogonia
to develop into spermatozoa in the ejaculate. When a man gives a history
of recent illness and his semen quality is subnormal, he should return in 4
months for re-evaluation. Sexually transmitted diseases in men can cause
obstructive azoospermia, ranging in cause from a strictured urethra to
obstructed vas deferens or epididymis. Although far less common in the
United States, genitourinary tuberculosis can lead to obstruction of the vas
deferens and epididymis.
Much has been made of environmental toxins causing abnormal and
reduced semen parameters. A widely discussed article from 1992 asserted
Evaluation and Treatment of Male Infertility
that sperm quantity and quality had declined over the last half of the 20th
century. This study was a meta-analysis of semen quality from European
and American fertility centers, which showed average sperm densities in
1940 were 113 × 106 mL and in 1990 were 66 × 106 mL. Many authors
challenged the study’s methodology, and the topic remains controversial.
Although a responsible agent has yet to be identified, possible toxins include
pesticides, particularly the nematocide dibromochloropropane, ethylene
dibromide, carbaril, lead, and chlordecone. Occupations in which these
chemicals are encountered include agriculture, welding, and ceramics.
Numerous lifestyle factors can contribute to male infertility. The most quoted
in the popular literature and least scientifically supported is the type of under-
wear a man wears. Wearing boxer shorts instead of briefs offers no advantage
to successful procreation. Other hyperthermic environments may play a minor
role, however. Discontinuing use of saunas and hot tubs is prudent advice for a 171
man with borderline semen parameters. Long-distance cycling often has been
associated with male infertility, although the evidence is scant. One study
identified reduced sperm motility during the training season of professional
cyclists with return to normal parameters in the off-season.
Smoking seems to have relatively little effect on semen quality. Data sug-
gest that smoking causes oxidative DNA damage in human spermatozoa,
which may lead to birth defects and an increased cancer risk in offspring.
This information offers another opportunity for the clinician to advise a
patient to quit smoking. Obesity is a potential risk factor. Excess fat enhances
peripheral conversion of testosterone to estrogen via aromatase. There also
is an increased prevalence of varicocele, diabetes, and erectile dysfunction
in obese men.
It is important to inquire about erectile function early in the history to
rule out inadequate vaginal penetration as a cause of male factor infertility.
The diagnosis of erectile dysfunction often has a significant impact on male
self-esteem, which can lead to significant relationship stressors and couple
anxiety. Similarly, premature ejaculation is rarely a source of infertility, but
is often a source of male reproductive anxiety.
Many medications have been implicated. Recreational and illicit drugs
potentially contributing to male infertility include marijuana, opiates,
cocaine, and alcohol. Acute alcohol intoxication can transiently impair
sperm morphology. Chronic alcoholism alters testosterone clearance by the
liver and causes gynecomastia and feminization. There is no evidence, how-
ever, that moderate alcohol consumption is detrimental to sperm quality.
Anabolic steroids, such as those taken by bodybuilders, have direct gonado-
toxic effects in addition to altering the hypothalamic-pituitary-gonadal axis.
Testosterone supplementation is an increasingly common practice for men
with subclinical hypogonadism and can impair spermatogenesis by feedback
inhibition, altering the function of the hypothalamic-pituitary-gonadal axis.
Men with decreased serum testosterone who wish to achieve conception
should not be treated with testosterone.
Chemotherapeutic regimens have variable effects on fertility. As a class,
all chemotherapeutic agents are potentially gonadotoxic, but some are
more detrimental than others. Recovery of fertility is better with doxorubicin,
methotrexate, estrogens, and androgens. Improvement is less likely after

vincristine and the testicular cancer combination of bleomycin, etoposide,
and cisplatin. There is a poor chance of recovery after cyclophosphamide,
chlorambucil, procarbazine, and the combination of nitrogen mustard,
vincristine, procarbazine, and prednisone, a regimen used in Hodgkin’s
lymphoma. Men anticipating cancer chemotherapy should be counseled to
consider cryopreserving sperm. Antihypertensives as a class have deleteri-
ous effects on penile erections, with nonselective β-blockers, such as pro-
pranolol, being the worst offenders. Calcium channel blockers may interfere
directly with the capacitation process and acrosome reaction; there is a case
report of a previously infertile couple conceiving after the man stopped his
calcium channel blocker. The α-blocker agents, a class of antihypertensives
and prostatic smooth muscle relaxants, cause retrograde ejaculation in
172 approximately 10% of patients. Angiotensin-converting enzyme inhibitors,
including enalapril and lisinopril, do not seem to have any adverse effects on
fertility or male sexual function.
Antipsychotics and antidepressants can lead to infertility by inhibiting
erectile function. Most antipsychotics act on central dopamine pathways,
which can suppress the hypothalamic-pituitary-gonadal axis and depress
libido. Selective serotonin reuptake inhibitors are commonly prescribed for
even mild depression because of their excellent safety profile. They may have
a marked impact on decreasing libido, however, and leading to delayed ejac-
ulation or even anejaculation. Fluoxetine (Prozac), paroxetine (Paxil), and
sertraline (Zoloft) are so effective in delaying ejaculation that clinicians pre-
scribe these medications to men with premature ejaculation. These agents
also can cause hyperprolactinemia, which can impair sexual function and
semen quality.
Antibiotics also can contribute to infertility. High doses of nitrofurantoin
cause maturation arrest. Erythromycin and tetracycline can affect sperm
motility. Spermatogenesis can be inhibited by gentamicin and neomycin.
A few commonly prescribed miscellaneous drugs can affect fertility.
Cimetidine, a common H2 blocker, interrupts the pulsatile release of luteiniz-
ing hormone (LH) from the anterior pituitary. The gout medications colchicine
and allopurinol impair the sperm’s ability to penetrate the egg. Sulfasalazine,
a common treatment for inflammatory bowel disease, decreases sperm den-
sity and motility and alters morphology. Mesalazine, an alternative drug, does
not seem to have these adverse effects. There has been some concern over
the statin class of cholesterol-lowering drugs. The hypothesis is that these
medications reduce the availability of cholesterol, an essential component in
steroidogenesis. Animal and human studies have not supported these con-
cerns. Table 11-1 summarizes the effects of commonly used drugs on fertility.
PHYSICAL EXAMINATION
A brief but thorough general physical examination must be included in the

evaluation of an infertile man, followed by a more detailed examination of
the genitalia. Inadequate virilization can be suggested by scant body hair,
Table 11-1
Medications and Altered Decreased Erectile
Recreational Drugs Medication/Drug Gonadotoxic HPG Axis Libido Dysfunction
and Their Impact
on the Male Alcohol Yes Yes Yes Yes
Reproductive Axis Tobacco Yes No No Yes
and Sexual Function Marijuana Yes No No No
β-blockers No No Yes Yes
Calcium channel No, but can No No No
blockers inhibit
capacitation
SSRIs No No Yes Yes
Anabolic steroids Yes Yes No Yes
Chemotherapy Yes No No No
Nitrofurantoin Yes Yes No No
Cimetidine Yes Yes No No
Sulfasalazine Yes Yes No No 173
HPG, hypothalamic-pituitary-gonadal; SSRIs, selective serotonin reuptake inhibitors.
gynecomastia, and a eunuchoid appearance. Examination of the penis

should assess curvature, plaques, and position of the meatus. Hypospadias,
if proximal enough, can result in inadequate deposition of semen in the
vagina.
The scrotum is examined with the patient standing for testicular size and
consistency. The adult testicle in a normospermic man should be greater
than 4 cm in length with an estimated volume greater than 20 mL. Testes
smaller than this suggest abnormal spermatogenesis. By volume, 85% of the
testis is involved in spermatogenesis. The testes also should be palpated for
tumors. Testicular cancer is the most common malignancy in men younger
than age 35, the prime age for infertility. Testicular cancer is associated with
subfertility, and the subfertility often manifests before the cancer. The scrotal
examination also includes assessment for the presence of a varicocele and
palpation of the vasa deferentia. Varicoceles, thought to result from engorge-
ment of the pampiniform complex secondary to faulty venous valves, are
thought by some to cause defects in sperm motility. Of men presenting with
primary infertility, 40% have a varicocele. Varicocele represents a surgically
correctable cause of infertility; this is controversial because a substantial
percentage of fertile men also have varicoceles. As a result of the drainage
of the left testicular venous system into the left renal vein, varicoceles are
more common on the left. Occasionally, a unilateral right-sided varicocele
can indicate abdominal pathology, which needs evaluation by computed
tomography scan. The vasa must be identified on physical examination
because congenital bilateral absence of the vas deferens occurs in 1.4% of
infertile men.
Finally, a digital rectal examination should be performed to evaluate the
prostate and the seminal vesicles. Enlarged seminal vesicles or a midline
prostatic cyst may indicate obstructive azoospermia necessitating transrec-
tal ultrasound for further evaluation.
LABORATORY EVALUATION
A thorough history and physical examination should guide the clinician

in performing a focused laboratory evaluation. Endocrine panels including
follicle-stimulating hormone (FSH), LH, and prolactin are often ordered, but
frequently are not helpful. In one study involving two infertility centers, less
than 10% of more than 1000 subfertile men were found to have any endo-
crinologic abnormalities. Most of these men had isolated elevated levels of
FSH. Less than 2% had a clinically relevant finding that could affect fertil-
ity treatment. Although general endocrine screening may not yield many
patients, directed serum assays may be useful. Men presenting with delayed
puberty, low libido, or erectile dysfunction should have testosterone, FSH,
and LH drawn to investigate hypogonadotropic hypogonadism. A man pre-
174 senting with visual disturbances and galactorrhea needs a serum prolactin
assessment to rule out pituitary tumors.
Although serum hormone assessments may not often prove useful, the
semen analysis is an essential component of the male infertility evalua-
tion. The quality of semen analyses is influenced by the collection techni-
que (Box 11-1). The patient should not have ejaculated for 48 to 72 hours
before collecting the sample. Prolonged abstinence beyond 72 hours also
may be detrimental to sperm quality. Specimens should be brought to the
evaluating facility within 1 hour of ejaculation. Suitable containers must be
clean, but not sterile. Masturbation is the preferred method of collection, but
intercourse with a spermicide-free condom is acceptable. Initial evaluation
should consist of at least two separate semen analyses.
The semen parameters of greatest interest are outlined in Table 11-2.
Briefly, volume measured to the nearest 0.1 mL, sperm density, percent motile
sperm, forward progression, and percent normal morphology are assessed.
Sperm density is determined with a microscope at 400× power using an
appropriate counting chamber on the device’s stage. All equipment, includ-
ing pipettes used to prepare the sperm, should be calibrated periodically to
ensure accuracy. Motility is a quantification of the average percentage of
sperm moving in 10 randomly selected high-power fields. Forward progres-
sion, a subset of motility, is classified using a variety of scales. One com-
monly used scheme designates “a” as rapidly progressive, “b” as progressive,
“c” as motile but not progressive, and “d” as nonmotile. An alternative but
similar score grades the sperm from 0 to 4+, with each increment indicating
an improvement in forward motility.
Morphology is a more complex assessment to make. The World Health
Organization (WHO) requires that even slightly aberrant sperm are assigned
Box 11-1 Semen Collection

● Abstinence for 2 to 3 days
● Delivery to laboratory within 1 hour of collection
● Keep sample at body temperature (37°C)
● Masturbation preferred
● Avoid normal condoms or lubricants
Table 11-2
World Health Parameter Normal Value (WHO)
Organization (WHO)
Criteria for Semen Ejaculate volume >2 mL
Analysis Sperm density >20 million/mL
Motility >50%
Morphology ≥15% normal
pH 7.5-8.5
Adapted from World Health Organization: WHO Laboratory Manual for the Examination of
Human Semen and Sperm-Cervical Interaction, 4th ed. Cambridge: Cambridge University Press;
1999.
as abnormal. A normal semen analysis should contain greater than 14% of

sperm with normal morphology using the WHO criteria. These criteria are
increasingly employed, particularly in laboratories that support assisted repro- 175
ductive technique centers, abandoning the older methods that assess sperm
morphology using moving sperm. With the so-called strict criteria, sperm are
immobilized and evaluated; using this standard, 15% or greater normal forms
constitutes a normal assay. Providers should be aware of which criteria their
laboratory uses. There should be few white blood cells in a normal semen spec-
imen. The WHO allows for 1 × 106 white blood cells/mL. In one study, 23%
of infertile men had white blood cell counts higher than the WHO criteria,
suggesting that pyospermia contributes to male infertility. Although normal
values are specified when semen analyses are performed, the provider should
understand that, other than azoospermia, deviation from these standards does
not suggest sterility, but rather an increase in the relative risk of subfertility.
RADIOGRAPHIC EVALUATION
Men with low-volume ejaculate who are found not to have retrograde ejacula-
tion should undergo transrectal ultrasound evaluation to assess for the pres-
ence of ejaculatory duct obstruction. Cysts of wolffian or müllerian origin can
be found in the midline of the prostate and may be associated with ejaculatory
duct obstruction. One controlled study found müllerian duct cysts in 11% of
infertile men with an incidence of 0% in the control group. Ejaculatory duct
obstruction can be treated successfully with a transurethral repair.
Vasography is an invasive diagnostic procedure that also can diagnose
an obstructive process. Its risks include vasal scarring, which can lead to
obstruction. Because of the success of transrectal ultrasound in diagnosing
distal obstructions, vasography typically is reserved for detecting obstruc-
tion of the inguinal vas. It also may be performed at the time of a micro-
scopic vasovasostomy or vasoepididymostomy to ensure a patent system.
TREATMENT OF INFERTILITY
Treatment of male factor infertility should begin with identifying revers-

ible medical conditions amenable to pharmacologic management. Treatable
conditions include hyperthyroidism or hypothyroidism, isolated testosterone

deficiency, hypogonadotropic hypogonadism, congenital adrenal hyperpla-
sia, hyperprolactinemia, retrograde ejaculation, and genital tract infection.
If the history suggests a diagnosis of hypogonadism, targeted therapies can
help restore fertility. Although sexual dysfunction associated with isolated
testosterone deficiency may respond to testosterone replacement therapy,
induction of spermatogenesis is unlikely. Patients with hypogonadotropic
hypogonadism often respond to injections of human chorionic gonadotro-
pin, 1500 IU three times weekly, and human menopausal gonadotropin, 75
IU three times weekly.
Congenital adrenal hyperplasia causes elevated androgen levels that sup-
press gonadotropin production by the pituitary and inhibits spermatogen-
esis. This disease is rare in adults, but there are case reports of glucocorticoid
176 therapy inducing spermatogenesis in affected men. Hyperprolactinemia,
almost as uncommon as congenital adrenal hyperplasia, also can adversely
affect fertility. Pituitary tumors, hypothyroidism, liver disease, and various
medications (e.g., tricyclic antidepressants, phenothiazines) can cause hyper-
prolactinemia. After ruling out a pituitary tumor by computed tomography
or magnetic resonance imaging, a trial of bromocriptine (5-10 mg/day), a
dopamine agonist, can reduce serum prolactin and lead to an increase in
sperm counts.
Antisperm antibodies, seen in high titers in men with a history of testicu-
lar cancer, genitourinary infections, or after vasectomy, can cause decreased
sperm motility and inability to penetrate the oocyte. Treatment with cortico-
steroids is usually ineffective and can lead to untoward side effects, including
hyperglycemia, acne, and aseptic necrosis of the hip. Because of this, many
fertility centers use intracytoplasmic sperm injection (ICSI) in the manage-
ment of this condition.
Retrograde ejaculation, a condition seen in men with a history of testicu-
lar cancer and subsequent retroperitoneal lymph node dissection, bladder
neck surgery, spinal cord injury, or diabetes mellitus, is an identifiable cause
of infertility that can be addressed with medication. The aim of pharmaco-
logic therapy is to increase adrenergic activity at the bladder neck and pro-
pel semen forward. Common agents include phenylpropanolamine (75 mg
twice daily), pseudoephedrine (60 mg four times daily), ephedrine sulfate (50
mg four times daily), and imipramine hydrochloride (50 mg at bedtime), to
be started 1 week before the start of ovulation and continued 3 days beyond.
Success with this therapy may be 40%. If medical management is unsuc-
cessful, retrieval of sperm from the bladder can be used in combination with
sperm processing and intrauterine insemination or assisted reproductive
techniques.
If a thorough evaluation fails to identify a treatable cause of oligozoo-
spermia, empiric therapy historically has been considered. Empiric therapy
generally has provided inconsistent results at best. Clomiphene citrate, an
antiestrogen that increases gonadotropin production and increases serum
testosterone, has been used empirically to treat male infertility. Numerous
small trials have suggested efficacy with various dosages and dosing inter-
vals. A well-performed randomized controlled trial showed no efficacy, how-
ever. Tamoxifen, similar in its endocrine function, but devoid of the estrogenic
side effects, also has been used in the treatment of idiopathic oligozoosper-
mia. It too has undergone close scrutiny with poor results. Empiric medical
therapy has no place in modern male factor infertility treatments.
SURGICAL TREATMENT
As previously mentioned, varicocele is the most common surgically correct-

able abnormality in an infertile man, but significant controversy exists as
to its efficacy. Three main surgical approaches are available for varicocele
repair: scrotal, inguinal, and retroperitoneal. Scrotal repairs are hindered by
the uncertainty of the venous plexus anatomy at that level. There are mul-
tiple veins within the pampiniform plexus, and it may be difficult to ascer- 177
tain whether all veins contributing to the varicocele have been ligated. The
scrotal approach is the least popular of the three approaches.
The retroperitoneal, or high ligation, approach is performed through a
transverse incision made just medial to the anterior superior iliac spine at the
level of the internal ring. Dissection is carried through the external oblique
fascia, and the dilated veins usually are found adherent to the reflected peri-
toneum. The inguinal, or low ligation, approach is performed through an
incision approximately 3 to 4 cm above and lateral to the symphysis pubis.
The spermatic cord is identified and mobilized, and the dilated veins are
identified. Each vein is ligated. Use of intraoperative Doppler can help iden-
tify the arterial supply to the testis and avoid its ligation.
Laparoscopic varicocelectomy also has been described. More recent data
suggest the laparoscopic approach offers shorter operative and recovery time
and decreased surgical costs. Other varicocele repair techniques include per-
cutaneous embolization. Interventional radiologists can localize venograph-
ically the varicocele and inject wire coils or sclerosing agents to occlude the
vessels.
Some retrospective reviews of surgically treated patients show a 50% to
70% improvement in semen parameters and a 30% to 50% rate of preg-
nancy within 6 to 9 months of surgery. Many studies are uncontrolled,
however. The literature suggests that azoospermic men with unilateral or
bilateral varicoceles may benefit from repair. In one series, 43% of azoosper-
mic men with varicoceles were noted to have return of sperm to the ejacu-
late after repair.
Approximately 500,000 vasectomies are performed yearly in the United
States. Approximately 50% to 67% of first marriages end in divorce, so it
is not surprising that vasovasostomy is a relatively common surgical proce-
dure. The most important factor in predicting the success of a vasovasostomy
is time since the original vasectomy. The greatest success is achieved with an
interval less than 3 years, with a patency rate of 97% and a pregnancy rate
of 76%. The least successful interval is greater than 15 years, with a patency
rate of 71% and a pregnancy rate of 30%. At the time of vasectomy rever-
sal, men should be offered the option of sperm extraction and cryopreserva-
tion for future use in assisted reproductive technologies in the event that the
vasectomy reversal is unsuccessful. Occasionally, the surgeon performing

a vasectomy reversal encounters obstruction at the level of the epididymis
gland. Performance of an epididymovasostomy is indicated to bypass the
obstruction. Although more technically demanding than a vasovasostomy,
in experienced hands, epididymovasostomy still can yield favorable results.
The pregnancy rates for this procedure approach 30% to 40%. Motile sperm
often return to the ejaculate within 2 months after vasovasostomy and 6
months after epididymovasostomy. The time course varies, however, so it is
prudent to wait 6 months after vasovasostomy and 1 year after epididymo-
vasostomy before intervening for persistent azoospermia.
The growing success of in vitro fertilization and ICSI has fostered increased
interest in sperm retrieval. Many methods are available to obtain sperm from
azoospermic men (Table 11-3). Microsurgical epididymal sperm aspiration
178 (MESA) entails an incision in the scrotum and aspiration of sperm under
direct vision. The technique of MESA usually involves working from the dis-
tal epididymis to the proximal portion or caput in search of viable sperm. This
technique allows for minimal disruption of normal tissue. The procedure
can be done under general anesthesia or conscious sedation and local anes-
thetic. The main advantage of MESA is the ability to retrieve large amounts
of sperm sufficient for multiple cycles of in vitro fertilization. Because it is
an open procedure, MESA also minimizes trauma to normal structures. The
downsides to MESA compared with percutaneous procedures are the need
for an incision, longer recovery time (2-3 days), and added expense.
Percutaneous epididymal sperm aspiration employs a 21-gauge or
23-gauge needle to extract sperm from the epididymis. The patient under-
goes conscious sedation and local anesthetic, and the surgeon makes mul-
tiple passes with the needle under negative pressure into the epididymis. The
aspirate is placed in sperm buffer and analyzed. Percutaneous epididymal
sperm aspiration is an office procedure, and because no incision is made, it is
less expensive than MESA. Because there is no incision, it is by nature a blind
approach. This potentially increases the risk of damaging the epididymis to
Table 11-3
Invasive Sperm Technique Advantages Disadvantages Pregnancy Rate
Retrieval Techniques
Microsurgical High sperm yield, Open surgery, 30%
epididymal sperm technically precise expensive
aspiration
Percutaneous Fast recovery, Epididymal 30%
epididymal sperm office procedure scarring, lower
aspiration sperm yield
Testicular sperm Diagnostic ability, Open surgery, 33%
extraction good sperm risk of
yield testicular
atrophy
Testicular sperm Office procedure, Multiple 11% with ICSI
aspiration reduced costs procedures,
hematoma
ICSI, intracytoplasmic sperm injection.
the point where reconstructive procedures are impossible. The quantity of

sperm retrieved is usually less than with MESA, making the need for repeat
procedures more likely. Testicular epididymal sperm aspiration is a percuta-
neous approach similar to percutaneous epididymal sperm aspiration. The
testis is aspirated with multiple passes under negative pressure with a fine-
gauge needle. The yield of sperm is low with this technique, and multiple
procedures may be required.
The above-described procedures for sperm harvesting are applicable only
to men with obstructive azoospermia. Testicular epididymal sperm extrac-
tion performed through an open testicular biopsy is an option, however, for
some men with testicular failure. Testicular epididymal sperm extraction
offers diagnostic information regarding the nature of the patient’s testicular
failure in addition to providing tissue for attempted sperm extraction. If there
is asymmetry between the testicles, the larger testicle typically is selected 179
for biopsy and sperm extraction first. There is some controversy regarding
whether to perform bilateral biopsies automatically on all men undergoing
this procedure. Approximately 30% of the time, there can be major histo-
logic differences between the right and left testicle. Focal spermatogenesis
can be missed in unilateral biopsies.
GENETIC CONSIDERATIONS IN AZOOSPERMIC

OR SEVERELY OLIGOZOOSPERMIC MEN
Genetic abnormalities accounted for 5.8% of male factor infertility in one

survey of 9766 infertile men. Of these men, 4.2% showed sex chromosome
abnormalities, and 1.5% had autosomal abnormalities. A large percentage
of subfertile men (approximately 30-40%) are labeled as having idiopathic
infertility; genetic factors probably contribute to many of these cases. Efforts
have been made to bridge the gap between basic science and clinical prac-
tice in dealing with genetic causes of male infertility. In 1998, the Practice
Guidelines Committee of the American Urological Association, Inc., com-
missioned a team to provide recommendations for the optimal evaluation
of the infertile man. These guidelines provide urologists, gynecologists, and
other health care providers practical assistance in newer, less standardized,
and rapidly changing areas of male infertility.
It is recommended that men with azoospermia secondary to testicular
failure and men with severe oligospermia undergo genetic evaluation. One
purpose of genetic testing in such patients is to identify uncorrectable condi-
tions. Identification of men in this group allows counseling on therapeutic
donor insemination and adoption, while saving the couple the inconve-
nience, expense, and risk associated with invasive procedures if the potential
for sperm acquisition is extremely low. In addition, genetic testing and coun-
seling allow couples to be informed regarding potential genetic transmission
of anomalies to offspring. In one study, it was observed that many infertile
men fear that they are responsible for their infertility problem by their own
behaviors, environmental factors, or previous sexual experiences and were
relieved to learn their infertility was a result of genetic factors.
When considering genetic abnormalities, it is helpful to categorize disor-

ders into the following categories: numerical chromosomal abnormalities;
structural chromosomal abnormalities; and pretesticular, testicular, and
post-testicular genetic causes of infertility. The most common numerical
chromosomal disorder encountered in practice is Klinefelter’s syndrome.
Klinefelter’s syndrome has an overall incidence of 1 in 500 live male births
and contributes to 14% of all cases of azoospermia. The syndrome is a result
of nondisjunction of either the maternal or the paternal chromosome. Most
cases result in a 47XXY configuration that is easily detected on karyotyp-
ing. Mosaic patterns have been described and are associated with less severe
phenotypes. Men with Klinefelter’s syndrome may present with increased
height, deficient maturation of secondary sexual characteristics, small
firm testes, gynecomastia, obesity, decreased intelligence, and infertility.
180 Laboratory studies may show increased FSH, normal or increased estradiol
and testosterone, and decreased or absent spermatogenesis. Klinefelter’s
mosaic patients may be treated with assisted reproductive techniques includ-
ing ICSI with the option of preimplantation genetic testing of the embryo to
ensure a normal karyotype before implantation.
Men with XYY karyotype are another relatively common numerical chro-
mosomal anomaly with an incidence of 1 in 1000 live births. Males are
usually phenotypically normal, although of increased stature and possibly
lower than average IQ. Infertility is associated with spermatogenic impair-
ment and may be associated with hormonal abnormalities. Less common is
mixed gonadal dysgenesis with a mosaic pattern of 45X/46XY. These indi-
viduals can present with a male, female, or ambiguous phenotype. Patients
with ambiguous phenotypes often have intra-abdominal testes, which carry
a high risk of malignancy. Structural chromosomal abnormalities resulting
in defective sperm function and production can result from translocations,
reciprocal exchange of visible lengths between two or more autosomes or
sex chromosomes, or reciprocal attachment of the long arms of two acro-
centric chromosomes, termed robertsonian translocation.
Y chromosome microdeletions that are not detectable through normal
karyotyping but are detectable through polymerase chain reaction testing
have shown that the long arm of the Y chromosome is required for sper-
matogenesis. Microdeletions result in variable sperm production. The most
common microdeletions include abnormalities of the SRY (sex determining
region on the Y chromosome) and DAZ (deleted in azoospermia) regions.
More than 30 deletions have been identified, and testing is currently available
at specialized facilities. Men with Y chromosomal microdeletions are pheno-
typically normal but often infertile and may be candidates for reproductive
assistance with counseling that the genetic abnormality may be transmit-
ted to their offspring. One case series evaluated the four sons, products of
ICSI, of three men with Y chromosomal microdeletions who all expressed
the same Y microdeletion. Another study indicated that 7% of azoospermic
or severely oligozoospermic men without non–sex chromosomal abnormali-
ties, endocrinopathies, or obstructive azoospermia have a Y chromosomal
microdeletion. These authors recommend routine screening of azoospermic
and severely oligozoospermic men for Y microdeletions owing to the high

prevalence in that population.
Another example of a structural chromosomal abnormality associ-
ated with male infertility is the XX male syndrome with an incidence of
1 in 20,000 births. The SRY is believed to be translocated to the X chromo-
some. Phenotypically, individuals present as men in 90% of cases and with
ambiguous genitalia in 10% of cases. All affected individuals, regardless of
phenotype, are azoospermic.
Defects, mutations, deletions, or polymorphic expansions of genes that deter-
mine function at any point in the hypothalamic-pituitary-gonadal axis can have
an impact on spermatogenesis. These pretesticular causes of infertility can be
detected by abnormalities in testosterone, LH, FSH, estradiol, and prolactin.
The most common X-linked disorder associated with infertility is Kallmann’s
syndrome, which results in hypogonadotropic hypogonadism and has an inci- 181
dence of 1 in 10,000 to 1 in 60,000 births. The deficiency in this syndrome is
a failure of gonadotropin-releasing hormone secretion from the hypothalamus
as a result of a mutation in KAL-1, which is thought to code for neuronal cell
adhesion. Patients often present with failure to initiate puberty. Physical signs
of Kallmann’s include increased stature, small testes, micropenis, anosmia,
and cryptorchidism. Treatment is with testosterone to allow maturation and
sexual function and gonadotropin therapy if fertility is desired.
Genetic factors also may manifest as post-testicular ductal and ejaculatory
system abnormalities. As mentioned previously, congenital bilateral absence
of the vas deferens is commonly associated with cystic fibrosis. Cystic fibrosis
is an autosomal recessive disorder affecting 1 in 2000 live births. To date,
more than 500 mutations in the large CFTR have been identified. Patients
with cystic fibrosis mutations can present with hypoplastic, nonfunctional
seminal vesicles and absent vasa. Other, less common disorders associated
with male infertility include Young’s syndrome, which is associated with
respiratory tract abnormalities, including chronic sinusitis and bronchiec-
tasis; epididymal obstruction; spina bifida, which is associated with failure of
normal ejaculation and defects in spermatogenesis; prune belly syndrome;
and genitourinary tract malformations, such as bilateral cryptorchidism
and bladder exstrophy/epispadias.
Impairments of sperm production and function can be related to disorders
such as muscular dystrophy that cause seminiferous tubule damage. Sperm
motility also can be affected by primary ciliary dyskinesia in syndromes
such as Kartagener’s syndrome and Usher’s syndrome. These also cause
extratesticular problems, such as chronic sinusitis, bronchiectasis, and deaf-
ness. Both of these disorders can be treated by ICSI and in vitro fertilization
because the problem is one of motility and not production.
Systemic disorders that damage the testis or the pituitary can result in
infertility. Common examples include sickle cell anemia and β-thalassemia.
These disorders themselves do not cause infertility, but treatment with mul-
tiple blood transfusions increases total body iron, which can be deposited
in the testis and pituitary. Hematochromatosis can result in infertility by a
similar mechanism.
SUMMARY
Male factor infertility is a common cause of infertility in couples and com-

prises many diagnoses. Idiopathic male factor infertility is one of the most
common subcategories of this disorder, although a genetic cause for many
of these individuals is suggested. When no correctable diagnosis is identified,
empiric therapy with techniques such as intrauterine insemination may be
attempted. Realistically, ICSI should be attempted from the outset with mod-
erate to severe male factor patients or when intrauterine insemination fails.
ICSI has revolutionized male factor treatment, improving what was previ-
ously a dismal success rate to parity with all other diagnoses using assisted
reproductive techniques. Nevertheless, concern has arisen that genetic
transmission of disorders now may be possible because ICSI bypasses one of
182 the barriers to fertilization in these previously infertile individuals. Further
research is needed to address these concerns.

1. Male infertility is responsible for 40% of all cases of difficulty conceiving.
2. Endocrine abnormalities are an unusual cause of male factor infertility.
3. Intracytoplasmic sperm injection has dramatically improved the success
rates of moderate-to-severe male factor patients.
4. Men with severe oligospermia or azoospermia should be offered genetic
testing.
5. The semen analysis is crucial in assessing an infertile couple and should
be performed in virtually all men involved in an infertile relationship.
SUGGESTED READINGS
Anguiano A, Oates RD, Amos JA, et al: Congenital Lenzi A, Lombardo F, Salacone P, et al: Stress, sexual
bilateral absence of the vas deferens: a primarily dysfunctions, and male infertility. J Endocrinol Invest
genital form of cystic fibrosis. JAMA 1992; 2003;26(3 suppl):72-76.
267:1794. Maduro MR, Lamb DJ: Understanding the new genet-
Carlsen E, Giwercman A, Keiding N, et al: Evidence ics of male infertility. J Urol 2002;168:2197-2205.
for decreasing quality of semen during past 50 years. Meacham RB, Lipshultz LI, Howards SS: Male infertil-
BMJ 1992;305:609. ity. In Gillenwater JY, Grayhack JT, Howards SS,
Howell SJ, Shalet SM: Testicular function following Duckett JW (eds): Adult and Pediatric Urology, 4 ed.
chemotherapy. Hum Reprod Update 2001; Philadelphia: Lippincott Williams & Wilkins; 2002:
7:363-369. 1747-1802.
Jarow J, Sharlip I, Belker A, et al: Best practice policies Munkelwitz R, Gilbert BR: Are boxer shorts really bet-
for male infertility. J Urol 2002;167:2138-2144. ter? A critical analysis of the role of underwear type
Joffe M: Infertility and environmental pollutants. Br in male subfertility. J Urol 1998;160:1329.
Med Bull 2003;68:47-70. Mydlo J: The impact of obesity in urology. Urol Clin
Johnson MD: Genetic risks of intracytoplasmic sperm North Am 2004;31:275-287.
injection in the treatment of male infertility: recom- Nudell D, Monoski M, Lipshultz L: Common medica-
mendations for genetic counseling and screening. tions and drugs: how they affect male fertility. Urol
Fertil Steril 1998;70:397. Clin North Am 2002;29:965-973.
Oates RD, Amos JA: Congenital bilateral absence of SS (eds): Infertility in the Male, 3rd ed. St. Louis:
the vas deferens in cystic fibrosis. World J Urol Mosby; 1997:530.
1993;11:82. Thompson ST: Prevention of male infertility: an
Rucker G, Mielnik A, King P, et al: Preoperative screen update. Urol Clin North Am 1994;21:365-376.
for genetic abnormalities in men with nonobstructive World Health Organization: WHO Laboratory Manual
azoospermia before testicular sperm extraction. for the Examination of Human Semen and Sperm-
J Urol 1998;160:2068-2071. Cervical Interaction, 4th ed. Cambridge: Cambridge
Sigman M, Lipshultz LI, Howards SS: Evaluation University Press; 1999.
of the subfertile male. In Lipshultz LI, Howards
183
12
OVULATION
INDUCTION
Lynda J. Wolf
185
DEFINITIONS
Aromatase An alternative to clomiphene citrate ovulation induction; when estrogen
inhibitor levels are suppressed by the medication, the pituitary increases release of
follicle-stimulating hormone to enhance follicular development
Clomiphene A selective estrogen receptor modulator with a structure that allows
citrate it to bind to hypothalamic estrogen receptors; the hypothalamus is
deceived into sensing a hypoestrogenic state, which enhances pulsatile
gonadotropin-releasing hormone secretion
Human A naturally occurring glycoprotein that is used as a luteinizing hormone
chorionic surrogate to “trigger” ovulation when a mature graafian follicle is
gonadotropin identified
Human A glycoprotein derived from postmenopausal women or synthesized
menopausal with recombinant technologies; consisting of either follicle-stimulating
gonadotropin hormone (FSH) alone or a combination of FSH and luteinizing
hormone, the glycoprotein is used to stimulate anovulatory women or
hyperstimulate them for use in assisted reproductive technologies
Ovulation The precise coordination of hypothalamic, pituitary, and ovarian
hormonal events to facilitate the expulsion of a fertilizable oocyte from
the ovary
Ovulation requires the precise coordination of hormonal events in three loca-

tions: hypothalamus, pituitary gland, and ovary. Any interference in the com-
plex interactions between these three organs results in the failure to develop
and release an egg (Box 12-1). Ovulatory cycles vary from 24 to 35 days.
Anovulatory cycles can be shorter or longer. Women with anovulation often
have oligomenorrhea, or fewer than six spontaneous menstrual cycles in a
year. The reduction in the number of ovulatory events prolongs the interval
to conception. The goal of ovulation induction is to optimize the environment
within the follicle to facilitate ovulation during each menstrual cycle.
Box 12-1 World Health Organization Classification of Ovulatory Deficiencies

Type I: hypothalamic-pituitary failure/hypogonadotropic hypogonadism
Hypothalamic amenorrhea
Kallmann’s syndrome
Isolated gonadotropin deficiency
Type II: hypothalamic-pituitary dysfunction
Normogonadotropic normogonadism
Chronic anovulation secondary to hyperandrogenism (polycystic ovarian
syndrome)
Type III: ovarian failure/hypergonadotropic hypogonadism
Couples attempting to conceive during a spontaneous ovulatory cycle

with a fertile male partner and patent fallopian tubes achieve a pregnancy
186 in only 15% to 25% of cycles. It may take multiple attempts at ovulation
induction to achieve a pregnancy.
EVALUATION
The first step in the treatment of anovulation is the screening and correc-
tion of occult underlying medical conditions. A single fasting serum sample
of thyroid-stimulating hormone, prolactin, dehydroepiandrosterone sulfate,
2-hour glucose tolerance test, and insulin are reasonable first steps.
In women who have experienced prolonged anovulation without proges-
tin treatment alone or with combined oral contraceptive preparations, an
endometrial sampling to assess for endometrial hyperplasia is performed
before initiating ovulation induction. Male partners are evaluated with a
semen analysis. Tubal patency may be confirmed by hysterosalpingography,
but some practitioners defer this until ovulation is established.
PHYSIOLOGY
Ovulatory dysfunction is the cause of infertility in 40% of women present-

ing for treatment. Most of these women have hyperandrogenism resulting in
anovulation, a condition referred to as polycystic ovarian syndrome (Fig. 12-1).
Insulin resistance is the most common cause of hyperandrogenism. Obesity
often exacerbates hyperandrogenism and must be treated to optimize ther-
apy. Obesity impairs insulin receptor sensitivity. To compensate, the pancreas
overproduces insulin, resulting in sustained elevations of circulating insulin
levels (hyperinsulinemia). As weight increases, so does insulin resistance.
Insulin receptors are ubiquitous, and chronic stimulation of these receptors
leads to widespread pathology.
In the liver, excess insulin suppresses the production of sex hormone–bind-
ing globulin resulting in a higher percentage of free circulating testosterone.
In addition, insulin decreases hepatic insulin-like growth factor binding pro-
tein I production leading to increased bioavailable insulin-like growth factor
I contributing to anovulation. In the ovary, insulin stimulates stromal cell
Ovulation Induction
Figure 12-1
A and B,
Unstimulated
ultrasound
appearance of
the ovaries in
a woman with
chronic anovulation
secondary to
hyperandrogenism
(polycystic ovarian
syndrome).
187
proliferation. The combination of elevated insulin levels and normal lutein-

izing hormone (LH) release from the hypothalamus amplifies the production
of testosterone by thecal cells and contributes to premature arrest of follicu-
lar growth. In the adrenal gland, insulin increases sensitivity to adrenocor-
ticotropic hormone stimulation, increasing the production and release of
dehydroepiandrosterone sulfate.
TREATMENT OF CHRONIC ANOVULATION

SECONDARY TO HYPERANDROGENISM
Lifestyle For an obese insulin-resistant woman undergoing ovulation induction, life-

Alterations style alterations to bring about weight loss are an important part of therapy.
188 Dietary interventions should focus on restricting calories and simple carbo-
hydrates and increasing protein and fiber. Sustained physical activity is
essential for weight loss. A minimum of 30 minutes of moderately intense
exercise at least three times per week is recommended; daily exercise is
strongly encouraged. Daily exercise promotes the uptake of insulin by the
skeletal muscle. The sequestered insulin can remain in the skeletal muscle
for 24 hours. Women participating in structured weight loss programs that
include a behavior modification component do better than women attempt-
ing weight loss on their own. Women participating in a structured weight
loss program of 6 months’ duration experienced an average weight loss of
15 lb. These previously anovulatory women had a 92% spontaneous ovu-
lation rate and a 33% to 45% spontaneous pregnancy rate. Spontaneous
abortions were reduced from 75% to 18%. These findings prove that lifestyle
alterations that lead to weight loss of even a small percentage of the woman’s
total weight can have a dramatic impact on the ability to achieve and carry
a pregnancy.
Insulin- Metformin is an oral biguanide insulin-sensitizing agent that improves the

Sensitizing action of insulin at the cellular level without affecting insulin secretion.
Agents It works through second messengers within the cells. Metformin inhibits
hepatic glucose production without inducing hypoglycemia, while enhanc-
ing glucose uptake by skeletal muscle. Metformin decreases intestinal
absorption of glucose. This action leads to an increase in the severity of
gastrointestinal symptoms when the patient ingests meals high in simple
carbohydrates.
Gastrointestinal symptoms, including nausea, vomiting, bloating, and
diarrhea, are common when initiating therapy. Taking metformin with
meals, increasing the dosage slowly to 1.5 to 2 g/day, or changing to an
extended-release formulation can reduce side effects. Reducing the ingestion
of simple carbohydrates also reduces gastrointestinal symptoms.
Many women taking metformin experience weight loss; women taking it
for more than 6 months experienced an average weight loss of 16 lb. Many
women taking metformin have an increase in sex hormone–binding globu-
lin and a decline in insulin and androgen levels, which improve menstrual
Ovulation Induction
cyclicity. Spontaneous ovulation rates of 87% have been reported with preg-
nancy rates of 5% to 20%. Several small studies have shown a reduction in
spontaneous abortion.
Clomiphene Clomiphene citrate is a selective estrogen receptor modulator with a

Citrate structure that allows it to bind to estrogen receptors. Clomiphene citrate
occupies the receptor for weeks rather than hours. This prolonged bind-
ing interferes with estrogen receptor replenishment within the hypothala-
mus. With the binding of clomiphene citrate, the hypothalamus is unable
to recognize the endogenous estrogen level and mistakenly interprets it as
low. In response, the hypothalamus alters the pulsatility of the gonadotro-
pin-releasing hormone secretion, resulting in increased pituitary release
of follicle-stimulating hormone (FSH). This increased FSH initiates ste- 189
roidogenesis and folliculogenesis, resulting in growth of the ovarian fol-
licle and an increase in the circulating level of estradiol. Ovulation occurs
5 to 10 days after the last pill in each course of therapy. After ovulation,
progesterone and estradiol levels increase and decrease as they would in a
normal ovulatory cycle. The actions of clomiphene citrate facilitate ovula-
tion in 80% of women. Although not absolute, weight influences the dose
at which an ovulatory response can be expected. Empirically, clomiphene
citrate is initiated at a dose of 50 mg for 5 days during the early follicular
phase (cycle days 3-5). In obese women weighing more than 200 lb, less
than 20% ovulate when treated with a 50-mg course, with most requiring
much larger doses. In these women, initiating therapy at a dose greater
than 50 mg is acceptable.
The dose of clomiphene citrate is increased by 50-mg increments to a
maximum dose of 250 mg until ovulation is achieved. The package insert
for clomiphene citrate stipulates that increasing the dose beyond 100 mg
for 5 days is not recommended, and that if ovulation does not occur after
three courses of therapy, further treatment is not recommended. In clinical
practice, these recommendations would exclude from optimizing treatment
many patients who ultimately conceive with clomiphene citrate. Doses of clo-
miphene citrate of 150 to 250 mg are used commonly and safely, although
outside the dose approved by the Food and Drug Administration.
In women who conceive with clomiphene citrate, 75% of pregnancies
occur in the first three ovulatory cycles. Urinary LH surge detection is more
sensitive than basal body temperature charting to confirm ovulation. In addi-
tion to home urinary LH screening, ultrasound may be used to help ascer-
tain the appropriate dose to facilitate ovulation. To optimize the information
gained from a single ultrasound study, it is best scheduled at least 5 days
after the last pill of the clomiphene citrate course. Important indicators of a
conception cycle include the number and size of preovulatory follicles. The
lead follicle in a clomiphene citrate cycle grows to a larger mean diameter
before the ovum is ready for release compared with a spontaneous cycle
(Fig. 12-2). During the clomiphene citrate cycle, the preovulatory follicle reaches
a mean diameter of 25 mm compared with 19 mm in a spontaneous ovula-
tory cycle. In ovulatory clomiphene citrate cycles in which the endometrium
Figure 12-2
Lead follicle in an
ovulatory clomiphene
citrate cycle with a
mean diameter of
24 mm.
190
has been exposed to appropriate estrogen levels for an adequate duration,

the endometrial lining has the same thickness compared with spontaneous
ovulatory cycles, reaching an average thickness of 11 mm (Fig. 12-3).
Even with an approximately 30% rate of multifollicular development,
pregnancies achieved with clomiphene citrate are usually singletons, with
a multiple pregnancy rate of only 8%. Most multiple pregnancies are twins.
Triplet pregnancies account for only 0.5% of pregnancies, and quadruplets
account for only 0.3% of pregnancies.
The most common side effect of clomiphene citrate is hot flashes.
Uncommonly, women taking clomiphene citrate may experience visual
changes. The visual changes resolve without intervention by 1 week after the
last pill. Headaches are another common side effect of clomiphene citrate.
After ovulation, women may report discomfort including a sensation of
abdominal fullness or bloating, pelvic pain, breast tenderness, and menorrhagia
in a nonconception cycle.
After a nonconception cycle, there may be a persistence of one or more
corpora lutea cysts. These cysts are usually asymptomatic. There are no
studies on the effect of these cysts on the outcome of subsequent clomiphene
citrate cycles. Stimulation of an existing large ovarian cyst prevents resolu-
tion, however. A 1-month hiatus from clomiphene citrate allows for spon-
taneous resolution of the cyst. There is no role for the use of combined oral
contraceptives to suppress ovarian cysts because they do not resolve the cyst
any faster. Ovarian cysts that persist for more than 9 weeks are neoplasms or
endometriomas rather than physiologic cysts. These persistent ovarian cysts
should be removed before proceeding with additional ovulation induction.
Ovulation Induction
Figure 12-3
Endometrial thickness
in an ovulatory
clomiphene citrate
cycle.
191
Clomiphene Citrate and Ovarian Cancer

The relationship between the use of clomiphene citrate and the subsequent
development of ovarian cancer is controversial. Infertility may be the early
expression of an underlying process that increases the risk of ovarian can-
cer. Women who are never able to conceive have an increased incidence
of ovarian cancer. There are likely many cellular processes that culminate
in ovarian cancer. Genetic, environmental, hormonal, and viral etiologies
all have been implicated in the development of ovarian cancer. Clomiphene
citrate induces ovulation disrupting the ovarian epithelium. The process
of ovarian repair involves the invagination and entrapment of the surface
epithelium rendering the epithelial cells vulnerable to malignant transfor-
mation. Other theories suggest that stimulation by estrogen, growth factors,
follicular fluid, or gonadotropins may result in differentiation, proliferation,
and ultimately malignant transformation.
The published literature is contradictory. The most commonly cited study
showing an increased risk of ovarian cancer in women exposed to clomi-
phene citrate is a retrospective study. The investigators relied on patient recall
to ascertain the clomiphene citrate exposure. This study suggested that the
use of 12 or more cycles of clomiphene citrate increased the risk of develop-
ing ovarian cancer. In this study, exposure to 1 to 11 cycles decreased the
risk of ovarian cancer. The risk of ovarian cancer was increased only when
borderline (low malignant potential) tumors were included, but the inci-
dence of invasive cancer was not increased. Additional studies investigating
clomiphene citrate use and the subsequent formation of borderline ovarian
neoplasms have shown no increased risk. Many studies that have followed
fertility patients and monitored them for the development of ovarian cancer
have found no increased risk of invasive ovarian cancer.
Patients receiving clomiphene citrate for ovulation induction should be
advised of a potential increased risk of ovarian cancer if they never conceive.
Pregnancy reduces this risk, likely offsetting any risk incurred by the use of
clomiphene citrate. The uninterrupted extended use of clomiphene citrate is
discouraged. Some patients repeat therapy after a pregnancy; risk of ovarian
cancer in these patients is lowered by the previous pregnancy, and it is appro-
priate to repeat the clomiphene. When previous users of clomiphene citrate
are not actively attempting to conceive, the use of combined oral contracep-
tives reduces their risk of ovarian cancer.
Adjuvants to Clomiphene Citrate Therapy

192 Glucocorticoids The first medical treatment of chronic anovulation was adrenal suppres-
sion with cortisone. Since the introduction of clomiphene citrate, it has
been combined with adrenal suppression to optimize ovulation induction.
Adrenal androgens, particularly dehydroepiandrosterone sulfate and andro-
stenedione, along with their metabolites estrone and testosterone, interfere
with the hypothalamic-pituitary-ovarian axis. Suppression of the adrenal
androgens is theorized to augment clomiphene citrate’s actions on the
hypothalamus.
In addition to suppressing adrenal androgens, glucocorticoids exacerbate
insulin resistance. Hyperinsulinemia is detrimental to the developing follicle.
The adjuvant use of glucocorticoids should be limited to patients with low
insulin levels and high adrenal androgens.
Human Human chorionic gonadotropin as an LH surrogate is an appropriate adju-
Chorionic vant to clomiphene citrate therapy in women without a detectable urinary
Gonadotropins LH surge despite ultrasound-confirmed adequate follicular development and
endometrial proliferation. It is given as a 5000-U or 10,000-U intramuscu-
lar injection when a mature graafian follicle is identified.
Human A threshold of FSH is required to support follicular development through
Menopausal ovulation. Some clomiphene citrate nonresponders initiate follicular devel-
Gonadotropins opment, but are unable to sustain adequate FSH to reach ovulation. These
women may benefit from sequential clomiphene citrate and human meno-
pausal gonadotropins (HMG). Clomiphene citrate is administered in the
early follicular phase for 5 days immediately followed by a daily injection of
HMG. Sequential cycles require careful monitoring to minimize the risk of
multiple pregnancies and ovarian hyperstimulation syndrome. Monitoring
with ultrasound is initiated after the fourth injection and continued until
adequate follicular development is documented.
Aromatase The aromatase enzyme is the last step in the formation of estrogens.
Inhibitors for Blockage of the aromatase enzyme suppresses estrogen synthesis, resulting
Ovulation in markedly lower levels of estradiol and estrone. Administration of aroma-
Induction tase inhibitors in the early part of the menstrual cycles reduces estrogen
Ovulation Induction
levels, and in response the hypothalamus increases pituitary release of FSH,

which enhances ovarian follicular development. Aromatase inhibitors have
a shorter half-life than clomiphene citrate. There is no downregulation of
estrogen receptors. Early studies using aromatase inhibitors showed ovula-
tion in clomiphene citrate–resistant women.
Superovulation Some women with chronic anovulation secondary to hyperandrogenism

do not respond to clomiphene citrate despite the appropriate use of
adjuvants or aromatase inhibitors or both. These women require HMG.
Caution must be used in the administration of these preparations because
of the large pool of recruitable follicles. These preparations have a narrow
therapeutic range; the difference between the dose required to support
adequate follicular development and hyperstimulation is small. Ovulation 193
induction with HMG requires careful monitoring. The judicious use of
ultrasound and estradiol levels optimizes pregnancy rates, while minimizing
complications.
Severe ovarian hyperstimulation syndrome complicates 1% to 2% of HMG
cycles. This syndrome is characterized by an increase in ovarian and perito-
neal capillary permeability resulting in a fluid shift from the intravascular
space to third space compartments. Vascular endothelial growth factor is
one protein implicated in this process. This protein is produced in sponta-
neous ovulatory cycles to promote the rapid ingrowth of blood vessels into
the corpus luteum to facilitate progesterone transport to the endothelium
for secretory transformation, embryo attachment and implantation, and
placentation. Ovarian hyperstimulation syndrome is a life-threatening con-
dition (Box 12-2). It must be diagnosed and treated early (Box 12-3).
Box 12-2 Clinical Features of Severe Ovarian Hyperstimulation Syndrome

● Pain
● Rapid weight gain
● Ascites
● Orthostatic hypotension
● Tachycardia
● Tachypnea
● Oliguria
● Hyponatremia
● Hyperkalemia
Box 12-3 Management of Severe Ovarian Hyperstimulation Syndrome

● Intravenous hydration with normal saline
● Antiemetics
● Analgesics
● Paracentesis/culdocentesis
OVULATION INDUCTION IN WOMEN WITH

HYPOTHALAMIC AMENORRHEA
Options for ovulation induction in women with hypothalamic amenorrhea

are limited to HMG or gonadotropin-releasing hormones. Exogenous HMG
response in women with hypothalamic amenorrhea varies. Some women
are sensitive to low doses for a short time. Many women with hypothalamic
amenorrhea require a prolonged stimulation, however, and high doses to
prime the follicles. Women with hypothalamic amenorrhea also are at risk
of multiple pregnancy and ovarian hyperstimulation syndrome and must be
monitored appropriately with ultrasound studies and estradiol levels.
Luteal phase and early pregnancy support is required for women with
hypothalamic amenorrhea. The pituitary gland is unable to release LH,
194 which is required to maintain the corpus luteum for progesterone produc-
tion to prepare the endometrium for attachment, implantation, and early
placentation. Progesterone alone or in combination with repeated low-
dose human chorionic gonadotropins may be used for this necessary luteal
support.
Gonadotropin-releasing hormone is administered in pulses by a portable
pump with an intravenous needle. Monitoring is similar to that required for
HMG cycles. The pump, human chorionic gonadotropin, or progesterone
can provide luteal support.
SUMMARY
Anovulation is a common cause of infertility. Women with chronic anovula-

tion secondary to hyperandrogenism are often able to conceive with a com-
bination of lifestyle alterations and clomiphene citrate. In women who are
resistant to clomiphene citrate, the use of combination therapy or aromatase
inhibitors often results in pregnancy. Some women respond only to HMG.
These women are at a higher risk of ovarian hyperstimulation syndrome
and multiple pregnancies. In contrast, women with hypothalamic amenor-
rhea have limited options for ovulation induction, and their luteal phase and
early pregnancy must be supported with hormones.

1. The goal of ovulation induction is to optimize the environment within
the follicle to facilitate ovulation during each menstrual cycle.
2. The first step in the treatment of anovulation is the screening and correc-
tion of occult underlying medical conditions, including insulin resistance,
which is common.
3. Lifestyle alterations, including dietary interventions and exercise that lead
to weight loss, are an important part of therapy.
4. Insulin-sensitizing drugs work in synergy with ovulation induction
agents.
Ovulation Induction
5. Clomiphene citrate is a first-line agent in the treatment of anovulation in

women with chronic anovulation secondary to hyperandrogenism. If clo-
miphene citrate alone is unsuccessful, adjuvants can be used to facilitate
ovulation.
6. Aromatase inhibitors can be used for ovulation induction in clomiphene
citrate–resistant women.
7. Superovulation with human menopausal gonadotropins has the highest
risk of ovarian hyperstimulation syndrome and multiple pregnancy.
8. Women with hypothalamic amenorrhea have limited options for ovulation
induction, and their luteal phase and early pregnancy must be supported
with hormones.
SUGGESTED READINGS 195
Balen AH, Braat DDM, West C, et al: Cumulative Mitwally MFM, Casper RF: Use of an aromatase
conception and live birth rates after the treatment inhibitor for induction of ovulation in patients with
of anovulatory infertility: safety and efficacy of an inadequate response to clomiphene citrate. Fertil
ovulation induction in 200 patients. Hum Reprod Steril 2001;75:305.
1994;9:1563. Mosgaard BJ, Lidegaard O, Kjaer SK, et al: Infertility,
Daly DC, Walters CA, Soto-Albors CE, et al: A fertility drugs, and invasive ovarian cancer, a case-
randomized study of dexamethasone in ovulation control study. Fertil Steril 1997;67:1005.
induction with clomiphene citrate. Fertil Steril Novat D, Goldstein N, Mor-Joseph S, et al: Multiple
1984;41:844. pregnancies: risk factors and prognostic variables
Dickey RP, Olar TT, Taylor SN, et al: Relationship during ovulation induction with human menopausal
of endometrial thickness and pattern to fecundity gonadotropins. Hum Reprod 1991;6:1152.
in ovulation induction cycles: effect of clomiphene Opsahl MS, Robins ED, O’Connor DM, et al:
citrate alone and with human menopausal gonadotro- Characteristics of gonadotropin response, follicular
pin. Fertil Steril 1993;59:756. development, and endometrial growth and matura-
Filicori M, Flamigni C, Dellai P, et al: Treatment of tion across consecutive cycles of clomiphene citrate
anovulation with pulsatile gonadotropin-releasing treatment. Fertil Steril 1996;6:533.
hormone: prognostic factors and clinical results in Practice Committee of the American Society for
600 cycles. J Clin Endocrinol Metab 1994;79(04):1215. Reproductive Medicine: Ovarian hyperstimulation
Hoeger KM, Kochman L, Wixom N, et al: A random- syndrome. Fertil Steril 2003;80:1309.
ized, 48-week, placebo-controlled trial of intensive Steinkampf MP, Hammond KR, Blackwell RE, et al:
lifestyle modification and/or metformin therapy in Hormonal treatment of functional ovarian cysts:
overweight women with polycystic ovary syndrome: a a randomized, prospective study. Fertil Steril
pilot study. Fertil Steril 2004;82:421. 1990;54:775.
13
ANATOMIC INFERTILITY
Mark Payson and Alicia Armstrong
DEFINITIONS
Diethylstil- An oral estrogen used from the 1930s to the early 1970s for relief
bestrol of menopausal symptoms, spontaneous abortion, preterm labor, and
preeclampsia; despite no convincing data of its efficacy, it was widely
197
used and resulted in significant adverse outcomes in female infants
exposed in utero
Endometrial Overproliferation of endometrial glands and stroma; may be associated
polyps with abnormal bleeding and impaired fertility
Hysterosal- A radiologic study employing fluoroscopy and plain film x-rays to assess
pingogram the uterine cavity and patency of the fallopian tubes
Leiomyomata Benign smooth muscle tumors of the uterus, otherwise known as
uteri fibroids; although benign, their location in critical areas of the uterus,
such as the endometrial cavity, may be associated with abnormal
bleeding, infertility, and miscarriage
Saline sono- An ultrasound procedure that employs normal saline in the endometrial
hysterography cavity to delineate better irregularities in contour of the cavity that may
suggest abnormalities such as polyps and fibroids
Salpingitis Small diverticuli found in the proximal fallopian tube and associated with
isthmica nodosa infertility
Synechiae Intrauterine adhesions resulting from prior surgical trauma or infection
Uterine Failure of the embryologic septum to resorb, resulting in a fibrous
septa midline structure variably separating the two sides of the uterine cavity;
associated with recurrent spontaneous abortion
The technical definition of infertility requires 1 year of unprotected coitus

without conception, but the criteria for initiating an evaluation also should
consider the patient’s age and relevant medical diagnoses. Infertility is a
widespread problem that affects millions worldwide; nearly 15% of couples
attempting conception experience difficulty. The increase in the number
of visits from less than 1 million in the late 1960s to more than 2 million in
the early 1980s is evidence of the enormous impact of this diagnosis among
reproductive-age couples. By the mid-1990s, approximately 17% of repro-
ductive-age women sought medical help during their lifetimes as a result of
infertility; an estimated 5 million couples in the United States alone sought
help.
Excluding the category of idiopathic infertility, a diagnosis for infertility

can be made approximately 80% of the time. These diagnoses are divided
equally between male factor and female factor. Approximately 60% of
women younger than age 35 have anatomic infertility as the primary cause;
most of these women have tubal factor, with 5% or less having a diagnosis
of cervical factor. Together, tubal and pelvic pathologies are responsible for
nearly half of female factor infertility.
Numerous societal factors have played a pivotal role in the rise in tubal
factor infertility. The dramatic increase in sexually transmitted disease in the
last several decades is clearly linked to the increasing numbers of women
with tubal infertility. The impact of infections on future fertility has been well
documented by multiple investigators. One widely cited study indicated that
the incidence of tubal infertility is 12% after one pelvic infection, increas-
198 ing to 23% after two infections and 54% after three infections. In addition
to infertility, there is a sixfold to sevenfold increase in the risk of ectopic preg-
nancy, which remains a major cause of maternal mortality in the first trimes-
ter. Despite the threat of HIV transmission, at-risk sexual behavior continues
to contribute to the high prevalence of chlamydia and gonorrhea among
young adults, which contributes to the ever-increasing numbers of women
with tubal and pelvic pathologies. Although the incidence of tubal factor is
far greater than that of cervical or uterine factors, evaluation for these causes
of infertility is a crucial part of the basic infertility evaluation.
This chapter reviews the following topics:
1. Normal anatomy and congenital anomalies of the female reproductive
tract
2. Acquired pathology of the uterus, cervix, and fallopian tubes
3. Evaluation of anatomic infertility
4. New and future therapies
ANATOMY, PHYSIOLOGY, AND CLINICAL PRESENTATION

OF UTERINE FACTOR INFERTILITY
Anatomy and Congenital abnormalities of the reproductive tract occur in 1 in 200 women.
Physiology of These disorders may manifest first as reproductive problems, such as infer-
Congenital tility or recurrent pregnancy loss. Although not a common cause of infertil-
Anomalies ity, it is easy to screen for these frequently treatable anomalies in the initial
infertility evaluation.
Embryology A basic understanding of reproductive system embryology simplifies an oth-

erwise confusing array of congenital defects. These problems are the result
of failures at various stages of ontogeny: (1) failures of development, (2) fail-
ure of descent, and (3) failure of fusion or resorption or both.
Normal The genital structures begin at the indifferent stage (7 weeks) with female and
Development male embryos having two pairs of genital ducts. The mesonephric (wolffian
Anatomic Infertility
ducts) remain and develop male gonads in the presence of Y chromosome

encoded testis determining factor. In contrast, the paramesonephric (mülle-
rian ducts) persist if there is an absence of a signal to differentiate along the
male pathway.
In the female, the wolffian ducts disappear, and the müllerian ducts give
rise to the fallopian tubes, uterus, and superior vagina. The genital ducts
lengthen into paired tubular structures, which fuse in the midline. At their
caudal end, they join the urogenital sinus. The wall between the two uterine
tubes is resorbed producing the uterus, and the tissue between the distal end
of the wolffian ducts and the urogenital sinus canalizes forming a patent
vagina (Fig. 13-1).
Congenital The most severe anomaly is congenital absence of müllerian structures. 199
Anomalies Mayer-Rokitansky-Küster-Hauser syndrome has an incidence of 1 in 4000.
Individuals with this disorder have absence of the uterus and fallopian tubes
with a foreshortened vaginal pouch. As a result of the presence of normal
ovaries, affected individuals otherwise develop as phenotypically normal
women and present with primary amenorrhea. Genetic offspring are pos-
sible through the use of the patient’s oocytes and a surrogate carrier.
Failure of one of the müllerian ducts to develop produces a unicornuate
uterus on the contralateral side. If there is partial development of one side,
there is a rudimentary horn adjacent to the “normal” side. If the uterine horns
form normally, failure of the septum to resorb can leave residual tissue that
ranges from the clinically insignificant arcuate uterus to a uterine septum of
variable length that may extend to the vagina. Failure of the vagina to cana-
lize results in a transverse vaginal septum, which can range from a thin layer
of tissue to extensive replacement of the vagina with fibrous tissue.
In the evaluation of a patient discovered to have a müllerian abnormality,
it is important to evaluate the renal system because these patients are prone
to have abnormalities of the kidneys and ureters. When renal anomalies do
occur, they are likely to be ipsilateral to the müllerian abnormality because
of the intertwined development of the urinary and genital systems.
Müllerian abnormalities arise from disorders of embryologic development,
and these structural aberrations may not be discrete from each other. These
disorders occur on a continuum, and they can be seen in combination with
each other. They can be understood by applying the principles of embryo-
logic development. This explains the periodic case reports of “new” variants
that do not seem to fit classic patterns.
Congenital The impact on fertility of disorders such as outflow tract obstruction and
Anomalies and uterine agenesis is clear. Most of these patients are diagnosed before attempts
Infertility at conception, either as children or when they present with primary amenor-
rhea. More difficult are uterine abnormalities diagnosed because of difficulty
with conception or after recurrent pregnancy loss. Generally, any structural
abnormality in the uterus leads to a decrease in fertility and an increase in
abortion and preterm delivery. The diagnosis and management of anomalies
Figure 13-1
Embryology A B C
and congenital
abnormalities of
the uterus. A, The
müllerian horns have
fused side-to-side,
leaving a septum still
in place and abutting
the urogenital sinus
(9 weeks). B, The
septum has resorbed,
but the cervix has not
resorbed (12 weeks).
C, Normally formed
uterus with cervix
200 patent to vagina. D E F
D, Unicornuate
uterus (right-sided)
representing a fully
developed one-
horned uterus. E,
Bicornuate uterus.
Uterine horns fused
only at the level of
the cervix. F, Septate
uterus secondary
to lack of complete
resorption of septum
(seen in A).
that become evident as a result of an infertility evaluation or the investiga-

tion of recurrent pregnancy loss are more difficult to evaluate and to treat.
Impact of Diethylstilbestrol (DES), an oral estrogen, was first synthesized in 1933. It

Diethylstil- was used for the control of menopausal symptoms, primarily hot flashes,
bestrol in the 1930s and 1940s. In 1948, its efficacy in preventing miscarriage,
preterm labor, and preeclampsia was publicized. DES became widely used
in pregnant women in the United States in the 1950s and 1960s, despite a
series of randomized trials that showed no efficacy. DES was even included in
some prenatal vitamin formulations. Use of DES was halted in 1971 with the
discovery of an association between clear cell adenocarcinoma of the vagina
and in utero exposure to the drug. It is estimated that 2 million U.S. women
used DES during their pregnancy.
DES also caused several reproductive tract abnormalities. The uterus may
be malformed with a T-shaped hypoplastic cavity or with intrauterine adhe-
sions (synechiae). Abnormality of fallopian tubes and an increase in ectopic
pregnancy have been reported. A “cockscomb cervix” or a cervix with pseu-
dopolyps also is often present.
In the absence of reproductive tract abnormalities, the effect of in utero
DES exposure on infertility is controversial, with most women with DES
exposure having little difficulty with reproduction. In the presence of struc-

tural abnormalities, these patients have problems with maintenance of preg-
nancy often seen in patients with structural uterine anomalies.
In 2005, the youngest DES-exposed women were 34 years old. Although
this cohort of women will be seen less and less often in the evaluation of
infertility, the lessons of DES should not be forgotten: It is crucial to test new
medications properly and to adhere to careful study design.
Acquired Similar to congenital abnormalities, acquired abnormalities of müllerian

Anomalies structures can affect reproductive outcomes. Uterine fibroids can interfere
with implantation, and fallopian tube damage can inhibit egg transport.
The two most common causes of acquired anatomic infertility are fibroids
and infection. 201
Uterine Synechiae
In 1948, Asherman described intrauterine adhesions (synechiae) after
uterine curettage. This syndrome frequently is associated with a clinical
history of menstrual irregularities, abortion, and infertility. The severity
of the synechiae is measured by the degree of obliteration of the cavity
(Fig. 13-2).
Most cases of Asherman’s syndrome develop after dilation and curettage,
as part of a termination procedure, a missed abortion, or postpartum for
retained placenta. The instrumentation of the endometrium at this sensitive
phase predisposes to anterior-to-posterior scarring of the uterus. Infection
in the form of endometritis can cause adhesions, and instrumentation in the
face of infection is a particularly high-risk setting. Dilation and curettage for
a septic abortion presents the highest risk of developing Asherman’s syn-
drome. A scoring system for assessment of the severity of uterine synechiae
was published by the American Fertility Society.
Polyps
Endometrial polyps, overproliferation of endometrial glands and stroma,
are found in about 15% of asymptomatic women. These lesions are usu-
ally benign and often regress spontaneously. The most common symptom
associated with these lesions is the development of abnormal uterine bleed-
ing. Similar to intracavitary fibroids, polyps may interfere with fertility,
presumably through an effect on implantation. The ultrasound appearance
of polyps also can be similar to intracavitary fibroids. It is standard prac-
tice in many in vitro fertilization (IVF) centers to screen for and remove any
polyps found before assisted reproductive technique procedures. It also is
important that polyps be evaluated to rule out hyperplasia or malignancy,
particularly in postmenopausal women.
Leiomyomata
Commonly known as fibroids, leiomyomata are benign smooth muscle
tumors of the uterus. Leiomyomata represent an extremely common dis-
order; 25% of women have symptoms of fibroids at some time in their life.
Figure 13-2
HSG of Asherman’s
syndrome. Note the
central obliteration of
the uterine cavity.
202
The cause of fibroids is unknown; they are monoclonal and can range from
many small tumors to tumors that fill the abdominal cavity and weigh sev-
eral kilograms. Fibroids can be found in multiple locations within the uterus.
They can be polypoid masses in the uterine cavity (intracavitary), immedi-
ately beneath the endometrium (submucosal), within the wall of the uterus
(intramural), immediately beneath the uterine serosa (subserosal), arising
from the surface of the uterus (pedunculated), in the cervix, or in the broad
ligament. Rate of growth and size vary (Fig. 13-3).
Depending on size and location, fibroids can cause menorrhagia, pres-
sure, pain, and urinary frequency, all of which are gynecologic indications
for intervention. From a fertility point of view, the clinical impact of fibroids
likely is determined by their location. An intracavitary fibroid can function
as an intrauterine device and prevent pregnancy. A fibroid that pushes into
the endometrial cavity and distorts it decreases fecundity and leads to an
increased risk of abortion or preterm delivery. Intramural fibroids greater
than 2.5 cm in diameter may decrease pregnancy rates in IVF by interfer-
ing with implantation. Fibroids distorting the cervix can lead to cervical
incompetence or labor dystocia. Leiomyomata also can increase markedly
the complexity and morbidity of cesarean section. Most studies evaluating
Figure 13-3
MRI of fibroid.
203
the impact of fibroids on infertility are uncontrolled, so it is difficult to assess

their true importance.
The imaging study of choice for fibroids is transvaginal ultrasound fol-
lowed by saline sonography. The location and position of fibroids and any
distortion of the cavity can be documented, and impact of the fibroids on
the cavity can be assessed. If there are no large intramural fibroids, and the
uterine cavity distends normally, the patient can be reassured that fibroids
should not have a significant effect on fertility. Fibroids typically increase in
size during reproductive life, although the rate of growth varies.

OF TUBAL INFERTILITY
The fallopian tubes are more than conduits for oocytes. As the site of fertiliza-
tion, fallopian tubes must facilitate the passage of ova and sperm in opposite
directions and transport the zygote to the uterus. Internal and external dam-
age of the fallopian tube can inhibit these functions.
Obstruction of the fimbriated end of the fallopian tube prevents egg trans-
port and causes infertility. Intrapelvic inflammation, from any cause, often
leads to adhesions and distortion of anatomy. This anatomic distortion can
be caused by a ruptured appendix, pelvic infection, intraperitoneal spread
of infection arising from the fallopian tubes, or endometriosis. A ruptured
appendix rarely causes infertility and usually does not cause more than a
unilateral (right) tubal blockage. Endometriosis can cause significant dam-
age to the distal fallopian tube and ovaries, which are further evidence for
the theory of retrograde menstruation as a cause of endometriosis. Pelvic
inflammatory disease may cause adhesions throughout the pelvis. The
presence of adhesions localized to the liver (Fitz-Hugh-Curtis syndrome)
204 should be considered anatomic evidence of a history of chlamydial pelvic
infection.
Intraluminal The most common form of tubal disease occurs within the fallopian tube
Tubal Disease and is often the result of a chlamydial infection. Many cases of chlamyd-
ial salpingitis are clinically silent, and the patient may not be aware of
past infection. The disruption of tubal microarchitecture, important for
normal reproductive function, not only increases the risk of infertility,
but also the risk of ectopic pregnancy. It is estimated that after one epi-
sode of pelvic inflammatory disease the rate of infertility is 12%, increas-
ing to 25% and 50% after the second and third infections. The risk of
ectopic pregnancy increases in a similar fashion. The classic finding of
tubal disease is a hydrosalpinx, a fallopian tube that has been dilated to
many times its normal diameter and is filled with fluid. The presence of
a hydrosalpinx not only may explain the cause of a woman’s infertility,
but it also interferes with the success of assisted reproductive techniques;
the presence of a hydrosalpinx decreases the success rate of IVF by 30%
(Fig. 13-4).
Although less common than distal tubal occlusion, disease arising in the
proximal portion of the fallopian tube is also an important cause of ana-
tomic infertility. Salpingitis isthmica nodosa, a rare condition, is diagnosed
by the finding of small diverticuli along the proximal portion of the tube
on hysterosalpingogram (HSG). Its etiology is unknown. Salpingitis isthmica
nodosa is seen in 60% of tubal specimens removed as a result of ectopic preg-
nancy, and it has been associated with infertility (Fig. 13-5).
Tubal disease is diagnosed by HSG, which is the best method to establish
intraluminal disease. External tubal adhesive disease may be suspected on
HSG, but is best confirmed with laparoscopy.
Figure 13-4
HSG of hydrosalpinx.
Note the sausage-
shaped fallopian
tubes.
205
Figure 13-5
HSG of salpingitis
isthmica nodosa
(arrows). (From
Letterie G: Structural
Abnormalities
and Reproductive
Failure. Blackwell
Scientific, Malden,
MA: Publications;
1998:377.)

OF CERVICAL FACTOR INFERTILITY
The cervix is more than the anatomic path between the vagina and cervix.
It also serves as a barrier to ascending infection and serves as a filter and res-
ervoir of sperm in the periovulatory period. During this period in the cycle,
the cervical mucus increases in quantity and decreases in viscosity, further
facilitating sperm transport.
The concept of “cervical factor infertility” is controversial. Cervical fac-
tor infertility is based on the theoretical principle that there may be some
abnormality in the sperm–cervical mucus interaction that is responsible for
the disruption of normal sperm transport; this is evaluated by the postcoital
test, an examination that has little scientific support. The test involves sam-
206 pling periovulatory cervical mucus for ferning, cervical mucus consistency,
and the presence of motile sperm within 12 hours of intercourse. This test is
rarely used in the evaluation of infertile couples because of poor sensitivity,
poor specificity, high percentage of abnormal tests in fertile couples, and lack
of reproducibility. Perhaps the only useful purpose of the test is to document
that intercourse successfully occurred.
The one cervical abnormality that has been clearly linked to poor obstet-
ric outcomes is cervical incompetence. Women with this disorder experience
painless dilation that can lead to multiple early pregnancy losses or preterm
birth. A complex problem managed by perinatologists, cervical incompe-
tence often requires ultrasound surveillance of cervical length. Prophylactic
and emergent management frequently require operative intervention using
cervical cerclage and tocolytics. Cervical incompetence is not a cause of
infertility, but a cause of recurrent pregnancy loss. Recurrent pregnancy
loss is discussed in greater detail in Chapter 16. Surgery or trauma to the
cervix, whether from delivery, cesarean section, or removal of a portion of
the cervix for treatment of precancerous lesions, may cause cervical incom-
petence, but has little effect on fertility.
DIAGNOSTIC TESTING FOR ANATOMIC INFERTILITY
Uterine anomalies may be suspected by a history of amenorrhea, pain, or

reproductive difficulties. A physical examination determines normal exter-
nal genitalia, vagina, cervix, and the presence of a uterus. HSG delineates
whether or not the uterine cavity and tubal architecture are normal. If there
is an abnormal finding on physical examination or HSG, it is prudent to eval-
uate further with a transvaginal ultrasound and saline sonogram. In some
cases associated with developmental abnormalities, magnetic resonance
imaging (MRI) may be necessary (Fig. 13-6 and 13-7).
Hysterosal- HSG is a crucial part of the initial infertility evaluation and should be offered
pingogram to most patients. The study should be performed in the early follicular phase
after the cessation of menses. If tenderness or masses are present on physical
Figure 13-6
MRI of bicornuate
uterus (arrow and
arrowheads). (From
Letterie G: Structural
Abnormalities
and Reproductive
Failure. Blackwell
Scientific, Malden,
MA: Publications;
1998:1550.)
207
Figure 13-7
Flow chart for
evaluation of HSG
anatomic infertility.
Severe tubal Uterine cavity

Minimal
disease abnormality
tubal disease
patient > 36
patient < 35
even if minimal
IVF Laparoscopy Saline sonography MRI confirmation

with abnormal congenital
cavity abnormalities
Hysteroscopic Surgical correction

polypectomy septum; rudimentary
or myomectomy uterine horn
Myomectomy for
intramural or
large Leiomyoma
examination, or if the patient has a history of tubo-ovarian abscesses, pelvic

anatomy should be evaluated by laparoscopy. A history of pelvic infections
is not an absolute contraindication to HSG because even high-risk patients
have a less than 5% chance of serious infections. Patients with risk factors
should receive antibiotics before the HSG, however, and patients who have
evidence of tubal disease should receive postprocedure antibiotic therapy.
Doxycycline, 100 mg twice daily the day before, the day of, and the day after
the procedure, should suffice.
Numerous radiographic findings on HSG are possible in the presence of
tubal disease. Distal tubal disease can be manifested as mild dilation or large
hydrosalpinges with absent mucosal folds. Salpingitis isthmica nodosum
usually is evidenced by radiographic findings in the proximal tube.
Many congenital anomalies, such as uterus didelphys, require additional
208 studies for confirmation. Two common abnormalities, uterine synechiae and
a uterine septum, frequently can be detected by HSG. As previously men-
tioned, not all uterine anomalies should be surgically corrected, underscor-
ing the importance of an accurate diagnosis.
Cavitary abnormalities, including leiomyomata, which distort the cav-
ity, may be suggested by transvaginal ultrasound, but are best documented
by saline sonohysterography. Cavitary abnormalities found on saline sono-
hysterography can be confirmed and frequently corrected by hysteroscopy.
Hysteroscopy is best reserved for patients who are likely to need surgical
intervention.
Magnetic MRI is a noninvasive method for evaluating further uterine anomalies found
Resonance on HSG or ultrasound. Before the widespread use of this radiographic tech-
Imaging nique, laparoscopy or laparotomy was often required to differentiate such
entities as bicornuate uterus and uterine septum. Because management
depends on diagnosis, a radiographic test that does not carry the risk and
cost of surgery is invaluable. HSG technique should be part of residency
training and is one of the Council on Resident Education in Obstetrics and
Gynecology educational objectives
Abnormalities of Unicornuate Uterus

the Uterus Although term pregnancy may be achieved in the presence of a unicor-
nuate uterus, there is an increased risk of preterm birth and malpresen-
tation. Unicornuate uterus probably does not decrease long-term fertility,
but may reduce fecundity or the ability to achieve a live birth within one
menstrual cycle by increasing the time to conception. The possibility of a
uterine anomaly always should be considered in a term infant that is per-
sistently breech. In a woman with multiple early losses and a unicornuate
uterus, cervical cerclage can be considered, but because of the potential
morbidity of such a procedure, its prophylactic use in a first pregnancy is
controversial.
A unicornuate uterus with a rudimentary horn presents a greater prob-

lem. If the horn does not communicate with the vagina, it can be a source
of pain owing to retained menstrual bleeding and can lead to pain through
endometriosis that results from retrograde menstruation. Pregnancy may
occur because sperm can transmigrate from the contralateral fallopian
tube, leading to a pregnancy in the rudimentary horn. A pregnancy in the
rudimentary uterus can be life-threatening if rupture and hemorrhage
occur. It is recommended that a rudimentary horn be removed because of
these potential morbidities; this procedure often can be accomplished lapa-
roscopically.
A bicornuate uterus should not be surgically corrected. Various attempts
at uterine reunification procedures have only worsened morbidity and out-
comes. Similar to women with a unicornuate uterus, these women have the
potential for normal obstetric outcomes. 209
Uterine Septa
Uterine septa, which are a common anomaly, have a similar appearance to
a bicornuate uterus on HSG and frequently are associated with miscarriage.
After confirmation of the diagnosis, which often includes studies such as
ultrasound and MRI, a careful resection of the septum can be undertaken.
This is generally a hysteroscopic procedure. Laparoscopy can aid in the pre-
vention of and early recognition of injuries in complex cases. The finding
of “arcuate uterus,” or an indentation of the myometrium into the fundal
portion of uterine cavity, should be considered a normal variant. Although
embryologically it may be the mildest form of septum, it does not have
adverse reproductive consequences, and patients should be reassured that
surgical intervention is unnecessary.
Uterine Synechiae
Patients who have radiographic evidence of uterine synechiae are best
managed surgically. Hysteroscopic lysis of adhesions, followed by estrogen
therapy to promote regeneration of the endometrium, is the recommended
therapy for patients with this diagnosis. Hysteroscopy frequently is per-
formed under laparoscopic guidance to decrease the likelihood of uterine
injury and to facilitate the early recognition of uterine perforation. Patients
should be counseled that they may require multiple hysteroscopic proce-
dures as a result of adhesion reformation. In severe cases, it may not be pos-
sible to restore a functional endometrium.
Leiomyoma
If the primary indication for treatment of leiomyoma is fertility or pregnancy
loss, surgical removal is the treatment of choice. Intracavitary and submu-
cosal fibroids that protrude 50% or more into the cavity can be removed
hysteroscopically. Larger fibroids and intramural fibroids often require lapa-
rotomy and extensive dissection into the myometrium. In most cases, the
removal of intramural fibroids or any procedure that requires deep dissec-
tion into the myometrium requires all future births to be via cesarean section
because of an unacceptably increased risk of uterine rupture in labor.
Cervical Cervical stenosis and its impact on sperm transport and fertility have been
Abnormalities poorly studied. If the cervix remains sufficiently patent to permit menstrua-
tion, sperm transport also should be possible. The use of intrauterine insemi-
nation bypasses the cervix and is a simple and minimally invasive treatment
for infertility that is possible in most couples except in cases of severe ste-
nosis. Intrauterine insemination obviates the cervix as a possible cause of
infertility and eliminates the need for testing, which is inconvenient and
lacks scientific evidence.
Abnormalities The surgical treatment of tubal disease is often disappointing, and many
of the Fallopian patients are best served by proceeding to IVF rather than surgery. When per-
Tube formed properly, laparoscopy has been found to be just as effective as lapa-
210 rotomy in pregnancy rates achieved based on the extent of adhesions found
at the time of surgery. As would be expected, mild disease is associated with
the best outcomes, and approximately two thirds of these women achieve a
pregnancy within 3 years of the surgery. Moderate disease has an interme-
diate response with 30% to 40% of women achieving pregnancy within the
same time period. Women with severe disease rarely get pregnant, regardless
of the length of observation.
Operative correction of tubal disease does not restore pregnancy rates to
baseline. Surgery not only is associated with lower pregnancy rates com-
pared with IVF, but it also is associated with an increased risk of ectopic preg-
nancy. Pelvic infection is rarely a unilateral disease. If there is gross evidence
of unilateral tubal damage, bilateral tubal damage should be assumed. The
“unaffected” tube is likely to have histologic evidence of disruption of the
microarchitecture and would not be a normal conduit for a pregnancy. As
previously noted, the treatment of mild tubal disease with relatively normal-
appearing fimbria in a patient younger than 35 years old may be beneficial.
In light of the 30% decrease in IVF pregnancy rates associated with hydro-
salpinges, salpingectomy or proximal tubal occlusion should be considered
when they are shown by ultrasound before IVF. Although the ectopic preg-
nancy rate associated with IVF is lower than the rate associated with tubal
surgery, salpingectomy can decrease that risk further.

1. Congenital abnormalities are due to embryologic failure of development
and fusion of the paired müllerian ducts and can lead to infertility and
premature delivery.
2. Not all anomalies require surgical correction, and management and
counseling should be based on the type of anomaly.
3. DES, a synthetic estrogen, was widely used in the 1950s and 1960s.
In utero exposure leads to an increased risk of clear cell adenocarcinoma
of the vagina and structural abnormalities of the uterus, cervix, and fal-
lopian tubes.
4. HSG is the best screening method for tubal disease.
5. Patients older than age 35 and all patients with severe tubal disease have
higher pregnancy rates and lower ectopic pregnancy rates with IVF.
6. HSG is the initial screening method of choice for acquired uterine abnor-
malities. Saline sonohysterography frequently is needed to confirm these
findings before hysteroscopic correction.
7. The management of a leiomyoma that affects fertility depends on size,
location, reproductive history, and future plans for achieving conception.
8. Intrauterine insemination obviates the cervix as a possible cause of infer-
tility and eliminates the need for testing, which is inconvenient and lacks
scientific evidence.
211
SUGGESTED READINGS
Council on Resident Education in Obstetrics and Letterie, G: Structural Abnormalities and Reproductive
Gynecology: Core Curriculum in Obstetrics and Failure. Malden, MA: Blackwell Science;1998.
Gynecology, 7th ed. Washington, DC: Council on Peterson H, Walker CK, Kahn JG, et al: Pelvic inflam-
Resident Education in Obstetrics and Gynecology; matory disease: key treatment issues and options.
2002. JAMA 1991;266:2605-2611.
Donnez J, Nisolle M: An Atlas of Operative Speroff L, Fritz MA (eds): Clinical Gynecologic
Laparoscopy and Hysteroscopy, 2nd ed. New York: Endocrinology and Infertility, 7th ed. Philadelphia:
Parthenon Publishing Group; 2001. Lippincott, Williams & Wilkins; 2005.
Lepine LA, Hillis SD, Marchbanks PA, et al: Severity
of pelvic inflammatory disease as a predictor of
the probability of live birth. Am J Obstet Gynecol
1998;178:977-981.
14
ENDOMETRIOSIS
Richard Scott Lucidi and Craig A. Witz
DEFINITIONS
Dyschezia The presence of pain with defecation
Dysmenorrhea Pain or discomfort associated with menstruation
Dyspareunia The presence of pain during intercourse
Fecundability The probability of conceiving a pregnancy in one cycle 213
Fecundity The probability of conceiving a pregnancy that results in a live birth in
one cycle
Endometriosis, defined as the presence of endometrial glands and stroma

outside of the uterine cavity (Fig. 14-1), is a common benign gynecologic
disorder, affecting approximately 5% of the general population and 30% or
more of infertile women. It was first described as a disease process 300 years
ago. In the late 17th century, it was recognized as peritoneal “ulcers” occur-
ring on the surface of the bladder, intestine, and surface of the uterus. Von
Rokitansky described the disease in detail in 1860. With improvements in
microscopy, the growth of ectopic endometrial tissue was identified as the
cause of these lesions.
PATHOPHYSIOLOGY
Theories Although the cause of endometriotic lesions remains undefined, various

theories have been promulgated to explain the pathogenesis of endometrio-
sis. This section describes the different theories of histogenesis and discusses
current understanding of the contribution of the immune system to the eti-
ology of endometriosis.
Implantation Theory
The implantation theory proposes that endometrial tissue passes through the
fallopian tubes then attaches and proliferates at ectopic sites in the peritoneal
cavity. This mechanism of histogenesis is often referred to as Sampson’s the-
ory and suggests that endometriotic implants result from menstrual flow
through the fallopian tubes. More recent studies using laparoscopy have
shown that retrograde menstruation is a nearly universal phenomenon
in women with patent fallopian tubes, showing that endometrial cells can
access the peritoneal cavity through the fallopian tubes. Other studies have
Figure 14-1
Histologic
appearance of
endometriosis. The
specimen is from
a resection of the
anterior rectal wall.
Endometriosis was
seen throughout
the bowel wall from
serosa to rectal
mucosa. Endometrial
glands and stroma
are seen in this
micrograph. (Original
magnification ×100.)
214
shown that sloughed menstrual endometrial cells remain viable and have
the capacity to implant at ectopic sites.
Cases of iatrogenically derived endometriosis resulting from mechanical
transplantation of endometrium also support the implantation theory. There
are numerous case reports of endometriosis in episiotomy and laparotomy
scars after vaginal delivery and cesarean section. Similarly, endometriosis
has occurred remote from pregnancy in umbilical incisions after laparo-
scopic tubal ligation and in needle tracts after amniocentesis.
Several “natural experiments” support the implantation model of peri-
toneal endometriosis. Patients with müllerian anomalies and obstructed
menstrual flow through the vagina have an increased risk of endometrio-
sis. The anatomic distribution of endometriosis also provides evidence for
Sampson’s theory with an increased frequency of endometriotic implants
in the dependent areas of the pelvis where pooling of menstrual debris is
expected.
Coelomic Metaplasia Theory

The theory of coelomic metaplasia holds that endometriosis develops from
metaplasia of cells lining the pelvic peritoneum. Iwanoff and Meyer are rec-
ognized as the originators of this theory. This theory is based on embryologic
studies showing that müllerian ducts, germinal epithelium of the ovary,
and pelvic peritoneum all are derived from the same embryologic precursor.
A prerequisite of the coelomic metaplasia theory is that germinal epithelium
and pelvic peritoneum contain cells capable of differentiating into endome-
trial cells or that these cells may dedifferentiate and later acquire the capac-
ity for further development into endometrium.
The coelomic metaplasia theory is attractive in that it can account for the
occurrence of endometriosis anywhere in the abdominal cavity and in the
Endometriosis
thoracic cavity. In cases of pulmonary endometriosis, the pleura are most

commonly affected. Pleural endometriosis could result from local metapla-
sia of pleural epithelium. It also could result from transdiaphragmatic pas-
sage of peritoneal fragments of endometrium and vascular metastasis of
endometrium.
The rare occurrence of endometriosis in men is often taken as proof of
the coelomic metaplasia theory. In these reported cases of endometriosis,
however, the men all were undergoing estrogen therapy, and the location of
endometriosis did not exclude the possibility that it resulted from müllerian
rests stimulated by exogenous hormones.
Induction Theory
The induction theory is an extension of the coelomic metaplasia theory.
This theory postulates that retrograde menstruated endometrium produces 215
substances that induce peritoneal tissues to form endometriosis by dediffer-
entiation and subsequent metaplasia.
Embryonic Rests Theory

Von Recklinghausen and Russell are credited with the theory that endome-
triosis results from embryonic cell rests. This theory suggests that, in the
presence of a specific stimulus, cell rests of müllerian origin could be acti-
vated to form functioning endometrium. Although embryonic cell rests are
common in the ovary, there is no evidence that they develop into endome-
triosis. As described previously, however, rare cases of endometriosis have
been reported in men, and transformation of embryonic rests is a plausible
explanation for this phenomenon.
Lymphatic and Vascular Metastasis Theories

The lymphatic metastasis theory of endometriosis often is referred to as
Halban’s theory. Halban reported that endometriosis could arise in the ret-
roperitoneum and in sites not directly apposed to peritoneum. Sampson also
had suggested that endometriosis could result from lymphatic and hema-
togenous dissemination of endometrial cells. Subsequently, considerable evi-
dence has accumulated suggesting that endometrial cells can metastasize
via lymphatic and hematogenous routes.
An extensive communication of lymphatics has been shown between the
uterus, ovaries, tubes, pelvic and vaginal lymph nodes, kidney, and umbili-
cus. Metastasis of endometrial cells via the lymphatic system to these areas
is anatomically possible. Venous and lymphatic transportation of intrauter-
ine contents (i.e., trophoblasts, amniotic fluid, and fetal squames) is now a
well-recognized phenomenon. Experimental demonstration that intrave-
nous injection of endometrium can produce pulmonary endometriosis in
the rabbit further supports the theory of venous metastasis.
Lymphatic and vascular metastasis of endometrium has been offered as
an explanation for rare cases of endometriosis occurring in locations remote
from the peritoneal cavity. In addition to pleural tissue, endometriosis has
been reported in pulmonary parenchyma, bone, muscle, peripheral nerves,
and the brain.
Composite Theory
Javert proposed a composite theory of the histogenesis of endometriosis that
combines implantation and vascular/lymphatic metastasis and a theory of
direct extension of endometrial tissue through the myometrium. According
to the composite theory, the histogenesis of endometriosis depends on the
location and “type” of the endometriotic implant. Peritoneal endometriosis
can be explained by the implantation theory. Ovarian endometriomas could
be the result of coelomic metaplasia of invaginated ovarian epithelial inclu-
sions. Rectovaginal endometriosis, which often resembles adenomyosis,
could result from metaplasia of müllerian remnants located in the rectovagi-
nal septum.
The composite theory is attractive in that it recognizes a multifaceted
mechanism of histogenesis. It seems logical that a disease with such protean
216 manifestations may originate via several mechanisms, and that no single
theory can explain every case of endometriosis.
Genetic Factors It has long been thought that endometriosis has a genetic basis. Although
there does not seem to be an association with HLA haplotypes, there is an
increased prevalence of endometriosis in first-degree relatives of affected
women compared with the general population. In addition, monozygotic
twins have 88% concordance for endometriosis. It has been suggested that
endometriosis is a genetically transmitted disorder that results from an
altered immune surveillance that allows for the attachment and growth of
ectopic endometrium.
Immune Factors Convincing data exist to suggest that retrograde menstruation and implan-
tation of endometrial fragments is the most likely means of developing
endometriosis in the peritoneal cavity. Although retrograde menstruation is
a nearly universal phenomenon in women with patent fallopian tubes, the
development of endometriosis is far less common. Alterations in immuno-
logic response to this tissue have been implicated in the genesis and main-
tenance of the endometriotic lesion. To evaluate the role of the immune
system in the pathogenesis of endometriosis, investigators studied immune
cells and their secretory products in peritoneal fluid. Examination of the cel-
lular and biochemical composition of peritoneal fluid revealed differences
between women with endometriosis and without endometriosis.
Macrophages are the predominant cell type in peritoneal fluid and are
found in higher concentrations in women with endometriosis. They are
thought to contribute to the pathogenesis of endometriosis by secreting
growth factors and cytokines. Elevated levels of macrophage-derived growth
factor, tumor necrosis factor-α, interleukin-1, interleukin-6, interleukin-8,
transforming growth factor-β, and other cytokines have been found in the
peritoneal fluid of women with endometriosis.
It is currently unclear whether the increased concentration of macrophages
and cytokines contributes to the creation of endometriotic lesions, or whether
these findings represent an immunologic response to endometriosis. More recent
Endometriosis
reports have suggested evidence for a role of cytokines in the establishment and
maintenance of endometriotic lesions.
Most women with endometriosis are asymptomatic. When present, the

symptoms may take a variety of forms (Box 14-1). The type and severity
depend on the extent and location of the disease; even limited disease can
cause significant symptoms.
Pain Pain symptoms in women with endometriosis range from increasing dys-
menorrhea to chronic pelvic pain and dyspareunia. The mechanism of 217
worsening dysmenorrhea is unknown, but may be related to increased pros-
taglandin and cytokines present in peritoneal fluid of women with endome-
triosis. Pain secondary to peritoneal disease is mediated by somatic afferent
fibers that sense stretching, irritation, or injury. Endometriosis-related pain
also may be perceived by sympathetic or parasympathetic visceral nerves
that innervate the pelvic organs and are sensitive to distention, distortion,
or impression. Dyspareunia is more common in women with endometriosis
and deep posterior cul-de-sac disease.
Infertility Retrospective data demonstrate that 30% to 50% of women with endome-
triosis may be infertile. Severe disease may cause infertility by distorting pel-
vic anatomy. Severe pelvic adhesions may impair egg release from the ovary,
block sperm entry into the distal fallopian tube, and inhibit ovum pickup.
In animal models of endometriosis, pelvic adhesions seem to contribute to
the observed decreased fecundity noted in animals with advanced endo-
metriosis. The cause in less severe cases is controversial, and the literature
contains many theories regarding possible mechanisms to explain endo-
metriosis-associated infertility (Box 14-2). Many studies show that women
Box 14-1 Signs and Symptoms of Endometriosis
Signs
Tenderness in the cul-de-sac or uterosacral ligaments
Nodularity along the uterosacral ligaments
Adnexal tenderness
Pelvic masses
Symptoms
Worsening dysmenorrhea
Pelvic pain
Dyspareunia, especially with deep thrust
Dysuria
Hematuria
Dyschezia
Infertility
Box 14-2 Possible Mechanisms of Endometriosis-Associated Infertility*

● Anatomic distortion and tubal obstruction
● Anovulation
● Autoimmunity/immune dysfunction
● Corpus luteum insufficiency
● Decreased ovarian reserve
● Embryotoxicity of peritoneal fluid
● Granulosa cell apoptosis
● Implantation defects
● Luteinized unruptured follicle syndrome
● Sperm toxicity of peritoneal or follicular fluid
*For a complete discussion of these mechanisms, see the article by Burns and Schenken in
Suggested Readings.
218
with endometriosis have an increased volume of peritoneal fluid; increased

macrophage concentration and function; and increased peritoneal fluid
concentrations of prostaglandin, interleukin-l, tumor necrosis factor, and
proteases. These alterations may impair oocyte, sperm, embryo, and fallo-
pian tube function. It also has been proposed that numerous endocrine and
ovulatory disorders may be present in women with endometriosis, including
luteinized unruptured follicle syndrome, luteal phase dysfunction, abnormal
follicular growth, and premature or multiple luteinizing hormone surges.
IgG and IgA antibodies and lymphocytes may be increased in the endome-
trium of women with endometriosis. These abnormalities may alter endo-
metrial receptivity to embryo implantation. In women with endometriosis, it
is unclear whether implantation failure contributes to decreased fecundity.
Some women with endometriosis lack endometrial αvβ3 integrin expression.
This decreased endometrial integrin production in the midluteal phase may
cause infertility by impairing implantation. These observations support the
concept that endometriosis may represent one component of a disease that
is characterized by dysfunction in multiple components, including the ovary,
endometrium, fallopian tubes, and peritoneum.
DIAGNOSIS
Endometriosis should be suspected when patients present with the previ-

ously noted symptoms. Signs of endometriosis include pelvic tenderness
with nodularity, particularly over the uterosacral ligaments; pain with
uterine movement; uterine retroversion with decreased mobility; and
adnexal enlargement with tenderness. Many symptomatic women have
normal pelvic examinations. No one constellation of signs or symptoms
is pathognomonic of endometriosis. Serum antigen CA 125 levels are
helpful in detecting and monitoring more severe cases, but are not spe-
cific to this condition. Transvaginal ultrasound is helpful to confirm the
presence of endometriomas (Fig. 14-2). They appear as intraovarian cys-
tic structures, usually unilocular with hazy borders and internal echoes.
Endometriosis
Figure 14-2
Pelvic ultrasound
shows an ovarian
endometrioma.
219
The diagnosis can be substantiated only by laparoscopy or laparotomy.

Endometriotic lesions can have multiple appearances (Box 14-3). Peritoneal
biopsy is desirable because many other lesions can mimic endometriosis
(Box 14-4), and because the positive predictive value of a visual diagno-
sis is only 45%.
Box 14-3 Common Appearances of Endometriotic Lesions

● Clear vesicles
● White lesions
● Red lesions
● Red polypoid lesions
● Yellow lesions
● Powder burn lesions
● Black lesions
● Chocolate ovarian cysts
● Peritoneal windows
Box 14-4 Lesions That Visually Mimic Endometriotic Implants

● Carbon residual from prior surgical ablation
● Endosalpingiosis
● Hemangiomas
● Hemosiderin deposits
● Inflammatory changes
● Mesothelial hyperplasia
● Splenosis
It is important to assess correctly the presence and extent of disease.

Endometriosis should be documented carefully by using the revised clas-
sification of endometriosis recommended by the American Society for
Reproductive Medicine (Fig. 14-3). Although this classification scheme has
not been prospectively validated, and the score assigned to various lesions
and adhesions produced by endometriosis is arbitrary, it serves as a partially
objective means of determining the extent of the disease and provides a
quantifiable basis for follow-up comparisons.
THERAPY
Individual treatment of endometriosis should be based on the extent of the

220 disease, the severity of symptoms, the patient’s desire for childbearing, the
patient’s age, and other coexisting medical and surgical factors. Available
treatment modalities are expectant, hormonal, surgical, and combined med-
ical/surgical. Expectant management of infertile women with mild endome-
triosis has been previously recommended. More recent data suggest that
treatment at the time of laparoscopy maginally improves pregnancy rates.
Medical Endometriotic implant growth usually depends on ovarian steroids.

Treatment Medications that suppress ovarian function appear to be beneficial. Ovarian
suppression has not been shown to improve pregnancy rates for infertile
women with mild or moderate endometriosis; several studies have reported a
decreased pregnancy rate with medical management likely as a result of the
period of anovulation associated with use of these agents. Medical therapy
should not be used to enhance fertility. Medical therapy has been shown, how-
ever, to relieve pain and reduce the amount of endometriosis visible at lapa-
roscopy. Medical therapy may be indicated for women with pain. Analgesics,
oral contraceptives, progestins, danazol, and gonadotropin-releasing hor-
mone (GnRH) agonists all seem to be effective in reducing pelvic pain (Table
14-1). Medical therapy also may be effective in reducing the progression of
disease, but this benefit is not as well documented. Hormonal therapy is inef-
fective in resolving endometriomas and has no effect on adhesion formation.
Contraindications to medical therapy include hypersensitivity to any of the
individual agents and undiagnosed abnormal vaginal bleeding.
Medical therapy has been employed before and after conservative surgi-
cal treatment of endometriosis. There is no good evidence that preoperative
treatment reduces operating time or bleeding. It has no benefit over surgery
alone for endometriosis-associated pain or infertility. Postoperative treat-
ment may be beneficial for delaying pain recurrence.
Analgesics
Prostaglandin synthesis by ectopic endometrium may be responsible for
characteristic symptoms of endometriosis, such as pelvic pain and dysmenor-
rhea. Nonsteroidal anti-inflammatory drugs inhibit biosynthesis of prosta-
glandins and alleviate these symptoms. These drugs are well tolerated, safe,
Endometriosis
Figure 14-3
American Society
for Reproductive
Medicine revised
classification scale
for endometriosis.
(Courtesy of
American Society
for Reproductive
Medicine.)
221
Continued
Figure 14-3—Cont’d
222
and inexpensive and are recommended as first-line treatment in women

with mild symptoms.
Oral Contraceptive Pills

Specific contraindications to taking oral contraceptives include being a smoker
older than age 35 years and having a history of thromboembolic disease.
Treatment usually involves the use of low-dose (20–35 μg of ethinyl estradiol)
oral contraceptives continuously for 6 to 9 months. The treatment usually is
begun with one tablet daily and increased to two tablets per day only if break-
through bleeding occurs. The administration of more than two pills is not
recommended because of increasing undesirable side effects. The lowest dose
of hormone that produces amenorrhea is maintained during the course of
Endometriosis
Table 14-1
Medications Medication Dose Route
Commonly Used to
Treat Endometriosis Nonsteroidal anti- Varies Oral
inflammatory drugs
Oral contraceptives 1-2 pills daily continuous Oral
dosing
Medroxyprogesteone 20-100 mg daily Oral
acetate
Depot medroxy- 150 mg (3 mo) Depot injection
progesterone
Megestrol acetate 40 mg daily Oral
Norethindrone 5-15 mg daily (start at 5 mg Oral
acetate daily and increase dose every
2 wk if needed)
Danazol 200-800 mg daily Oral
Leuprolide acetate 3.75 mg (1 mo); 11.25 mg (3 mo) Depot injection 223
Nafarelin acetate 200 μg twice daily Intranasal
therapy. During the initial 2 to 3 months of treatment, many patients experi-

ence worsening symptoms referable to the endometriosis.
Progestins
Medroxyprogesterone acetate is the most commonly used progestin to treat
endometriosis. Oral medroxyprogesterone acetate, 20 to 100 mg/day, or injec-
tion of depot medroxyprogesterone acetate, 150 mg every 3 months, results
in significant amelioration of pain symptoms. A drawback to the use of
depot medroxyprogesterone acetate is the prolonged interval to resumption
of ovulation after cessation of therapy, which may be 1 year. The depot form
should not be used in women who desire pregnancy in the near future and
should be reserved for patients who do not want to conceive. The most prom-
inent side effects consist of spotting and breakthrough bleeding, depression,
weight gain, and bloating. Megestrol acetate and norethindrone acetate may
also be used with similar side effects.
Danazol
Danazol is a derivative of the synthetic steroid 17α-ethinyl testosterone, which
is known to have progestagenic and androgenic effects. It has a mild suppres-
sive effect on gonadotropin secretion, abolishes the luteinizing hormone surge,
and has an inhibitory effect on ovarian steroidogenic enzymes and the growth
of normal and ectopic endometrium. The drug creates an anovulatory amen-
orrheic, high-androgen, low-estrogen milieu that is hostile to the growth of
endometriotic implants. Specific contraindications to danazol include impaired
hepatic, renal, or cardiac function.
A dosage of 600 mg/day for 6 months is recommended and seems to be
effective in relieving symptoms and suppressing endometriotic lesions. In
practice, the dosage of danazol should be individualized and adjusted to
the need of the patient, extent of the disease, and severity of side effects.
The medication should be started after the completion of a normal
menstruation. Danazol should not be administered to pregnant women

because it may cause virilization of the external genitalia of a female fetus.
In patients with irregular or abnormal menstrual cycles, the presence of an
early pregnancy should be excluded before this medication is given. Patients
receiving danazol therapy should use barrier contraceptives during the
course of treatment. Menses usually recur within 6 weeks of stopping dan-
azol therapy.
Danazol use results in side effects associated with a hyperandrogenic
state, including weight gain, acne, hirsutism, oily skin, a decrease in breast
size and, rarely, a deepening of the voice. Other side effects include muscle
cramps, flushing, mood changes, depression, and edema. Patients receiv-
ing danazol are usually amenorrheic; however, breakthrough bleeding may
occur when doses of 400 mg or less are given. Because of the significant
224 side-effect profile, danazol is rarely used today.
Gonadotropin-Releasing Hormone Agonists

Administration of GnRH agonists produces an initial stimulation of pitu-
itary gonadotropes that results in secretion of follicle-stimulating hormone
and luteinizing hormone and the expected gonadal response. Continuous or
repeated administration of an agonist at supra-physiologic doses produces an
inhibition of the pituitary-gonadal axis, however. Functional changes result-
ing from this inhibition include pituitary GnRH receptor downregulation,
gonadal gonadotropin receptor downregulation, attenuated gonadotropin
secretion, and decreased steroidogenesis. The inhibitory effects of agonists
are fully reversible. The ability of GnRH agonists to produce amenorrhea
and anovulation has provided the basis for their use in the management of
endometriosis.
Side effects associated with GnRH agonist therapy are those attributable
to hypoestrogenism, including hot flashes, vaginal dryness, and some largely
reversible loss of bone mineral density. Treatment usually is limited to one
6-month course. Women who develop side effects on GnRH agonists, who
require treatment for longer than 6 months, or who require repeat treat-
ments may be candidates for “add-back” therapy. This consists of progestin
or combination low-dose estrogen and progestin. Many regimens are com-
monly used (Box 14-5). Use of oral contraceptive pills for add-back therapy
may negate the effect of GnRH agonist treatment because of the supraphysi-
ologic estrogen dose. Add-back therapy usually decreases side effects, but
may not completely prevent bone loss. Menses may take 8 to 10 weeks to be
re-established after GnRH agonist therapy.
Aromatase Inhibitors
Aromatase is an enzyme involved in the production of estrogen that acts by
catalyzing the conversion of testosterone to estradiol. Aromatase is located
in estrogen-producing cells in the adrenal glands, ovaries, placenta, testicles,
adipose tissue, and brain.
Third-generation aromatase inhibitors act by inhibiting the enzyme aro-
matase, which suppresses estrogen production locally and systemically, and
are used to treat estrogen-dependent breast cancer. Because GnRH analogue
Endometriosis
Box 14-5 Common Add-Back Regimens for Use with Gonadotropin-

Releasing Hormone Agonists
CEE 0.625 mg + MPA 2.5–5 mg

CEE 0.3 mg + MPA 2.5–5 mg
17β-E2 1 mg + MPA 2.5–5 mg
NE 5 mg ± CEE
MPA 20 mg
NE 5 mg + etidronate
CEE, conjugated equine estrogen; E2, estradiol; MPA, medroxyprogesterone acetate; NE,
norethindrone acetate.
therapy inhibits estrogen production in the ovary, but not locally in the 225
endometriotic lesion, aromatase inhibitors are currently being evaluated for
treatment of refractory cases of endometriosis. Letrozole, 2.5 mg daily for
6 months, showed promising results in a small study. Side effects of letrozole
include hot flashes and bone pain. Because bone loss is a theoretical risk of
prolonged therapy secondary to the hypoestrogenic state induced, add-back
therapy with norethindrone acetate may be given.
Surgical Surgical treatment usually can be accomplished at the initial laparoscopy

Treatment undertaken to diagnose the disease. Conservative or limited surgery is appro-
priate for women desiring future fertility and for women with pelvic pain.
Conservative procedures include excision, vaporization, and coagulation of
endometrial implants; excision of ovarian endometriomas; and lysis of adhe-
sions. These can be accomplished at laparoscopy with surgical excision, laser
(carbon dioxide, argon, potassium titanyl phosphate [KTP], or neodymium:
yttrium-aluminum-garnet [Nd:YAG]), and monopolar or bipolar electrocau-
tery. Treatment outcomes using sharp excision, carbon dioxide laser, argon
laser, KTP laser, and electrosurgery during laparoscopy seem to be compa-
rable. Conservative surgery is most often performed through the laparoscope;
however, in the case of extensive disease with cul-de-sac obliteration and
dense scarring of the ovaries to the pelvic sidewalls, or when removal of large
endometriomas, enterostomy, extensive enterolysis, bowel resection, or other
situations deemed too complex for the laparoscope are required, laparotomy
may be necessary. Adjunct procedures, including presacral neurectomy and
uterosacral nerve ablation, have been recommended for relief of central pel-
vic pain. The long-term benefit of these procedures has not been conclusively
shown. Uterosacral plication, uterine suspension, and oophoropexy have
even less clearly defined benefits. Patients with significant bowel involvement
may require resection of the affected segment and anastomosis.
Pregnancy rates are acceptable after laparoscopic surgery for endometrio-
sis (Table 14-2). Two randomized, controlled studies on the effectiveness of
laparoscopic conservative surgery report conflicting results in women with
less severe stages of endometriosis. The effectiveness of surgery for minimal
or mild endometriosis has been difficult to show. The Canadian Collaborative
Table 14-2
Pregnancy Rates
Endometriosis Stage
After Laparoscopic
Surgery for Minimal/Mild Moderate/Severe
Endometriosis- Without surgery 37.4% 3.1%
Associated Infertility After surgery 51.7% 41.3%
Group on Endometriosis reported a randomized trial of laparoscopy with

and without treatment in 341 women with minimal or mild disease. The
fecundity rate in treated patients was 4.7 versus 2.4 per 100 person-months
in controls (95% confidence interval 1.2–3.1). The Gruppo Italiano per lo
Studio dell’ Endometriosis conducted a similar study in 111 patients with
226 stage I or stage II endometriosis. One year after surgery, the pregnancy rate
was 29% in the no treatment group and 24% in the ablation/resection
group. These conflicting studies show the controversy regarding the value of
surgery for patients with mild disease. If lesions are observed at the time of
laparoscopy, however, destruction or excision of these lesions may improve
fecundity and is unlikely to cause significant morbidity.
Definitive therapy, total abdominal hysterectomy, and bilateral salpingo-
oophorectomy are indicated for patients who have completed childbearing or
have significant persistent pelvic pain after conservative treatment. One or
both ovaries may be spared if they are completely uninvolved and the endo-
metriosis can be resected completely. Approximately one third of women
treated conservatively have recurrent endometriosis and require additional
surgery within 5 years. After bilateral oophorectomy, estrogen replacement
therapy may be initiated immediately with little risk of reactivating residual
disease. There is no reason to delay replacement therapy after surgery.
Assisted In patients with persistent infertility associated with endometriosis, super-

Reproduction ovulation (with and without intrauterine inseminations) and assisted repro-
ductive technologies offer some promise. Spontaneous monthly fecundity
rates of 0.10 for stage I, 0.09 for stage II, 0.18 for stage III, and 0.0 for stage
IV endometriosis have been reported.
A significant increase in cycle fecundity was seen with four cycles of clo-
miphene citrate and intrauterine insemination compared with controls hav-
ing intercourse (0.095 versus 0.033). Cycle fecundity for gonadotropins
and intrauterine insemination also compare favorably with no treatment for
women with stage I or stage II endometriosis and infertility (0.15 and 0.045).
A report on the effects of expectant management, clomiphene citrate and
intrauterine insemination, gonadotropins and intrauterine insemination,
or in vitro fertilization and embryo transfer (IVF/ET) on cycle fecundity in
women with infertility and minimal or mild endometriosis showed improved
cycle fecundity rates with treatment (Table 14-3).
The effect of endometriosis on the outcome of IVF is controversial.
Overall, the diagnosis of endometriosis (especially previously treated dis-
ease) does not seem to decrease pregnancy rates in patients with less severe
Endometriosis
Table 14-3
Effect of Treatment Treatment Fecundity
on Fecundity in
Women with Minimal None 0.028
or Mild Endometriosis Clomiphene citrate and IUI 0.066
Gonadotropins and IUI 0.114
IVF/ET 0.320
IUI, intrauterine insemination.
stages of disease. Some investigators have suggested, however, that patients

with endometriosis undergoing IVF have a reduced implantation rate, pos-
sibly secondary to endometrial dysfunction or an embryotoxic environment.
Women with advanced endometriosis and a history of a previous oophorec- 227
tomy and a contralateral ovarian cystectomy seem to do poorly in IVF/ET
programs. It is possible that the previous ovarian surgery has depleted the
available oocyte pool, making the women perimenopausal. Women with
large endometriomas at the start of an IVF/ET cycle also may be at risk for
a poor cycle outcome. Resection of an endometrioma should be considered
before initiation of an IVF/ET cycle.

1. Although many theories have been proposed, the etiology of endome-
triosis remains unclear.
2. Medical therapy effectively treats endometriosis-associated pain symp-
toms, but is of no value for the treatment of endometriosis-associated
infertility.
3. A causal relationship between moderate or severe disease with distor-
tion of pelvic anatomy and infertility is clear; however, the relationship
between minimal or mild disease and infertility is controversial.
4. There is controversy regarding the value of surgery for patients with
mild disease; however, if lesions are observed at the time of laparoscopy,
destruction or excision of these lesions may marginally improve fertility.
5. Superovulation, with or without intrauterine insemination, and assisted
reproductive technologies improve fecundity in patients with endome-
triosis-associated infertility.
SUGGESTED READINGS
ACOG practice bulletin: medical management of endo- Gambone JC, Mittman BS, Munro MG, et al:
metriosis. Number 11, December 1999. Consensus statement for the management of
Burns WN, Schenken RS: Pathophysiology of endo- chronic pelvic pain and endometriosis: proceedings
metriosis-associated infertility. Clin Obstet Gynecol of an expert-panel consensus process. Fertil Steril
1999;42:586-610. 2002;78:961-972.
Marcoux S, Maheux R, Berube S: Laparoscopic Winkel CA: Evaluation and management of women
surgery in infertile women with minimal or mild with endometriosis. Obstet Gynecol 2003;102:
endometriosis. Canadian Collaborative Group on 397-408.
Endometriosis. N Engl J Med 1997;337:217-222. Witz CA: Pathogenesis of endometriosis. Gynecol
Surrey ES, Hornstein MD: Prolonged GnRH ago- Obstet Invest 2002;53(suppl 1):52-62.
nist and add-back therapy for symptomatic endo- Witz CA, Burns WN: Endometriosis and infertility: is
metriosis: long-term follow-up. Obstet Gynecol there a cause and effect relationship? Gynecol Obstet
2002;99:709-719. Invest 2002;53(suppl 1):2-11.
228
15
DIMINISHED OVARIAN
RESERVE
Andrew J. Levi
229
The evaluation and treatment of an infertile couple can be complex. In
the female partner, success of treatment relies on competent oocytes that
are capable of being fertilized and subsequently are able to implant and
differentiate successfully. As women age, the likelihood of conception
decreases, with a steep decline in pregnancy rates as women enter their
mid to late 30s (Fig. 15-1); this is usually secondary to the absence of
competent oocytes. Oocytes of poor quality may be a cause of in vivo or
in vitro fertilization failure, implantation failure, or early pregnancy loss.
When evaluating a subfertile woman, an evaluation of whether there
exists a potential problem with oocyte quality or quantity (which often
goes hand-in-hand with subfertility) should be performed. This investiga-
tion is termed ovarian reserve screening or screening for diminished ovarian
reserve (DOR).
FOLLICULOGENESIS AND OVARIAN AGING
A thorough understanding of ovarian physiology and folliculogen-

esis is important to comprehend the rationale behind ovarian reserve
screening. During fetal life, the ovaries contain approximately 6 million
oocytes; only a few million of these oocytes are present at birth. By men-
arche, only around 250,000 oocytes remain. When a woman reaches
the menopause, approximately 500 ovulations have occurred, yet the
oocyte pool is depleted (Fig. 15-2). During a woman’s reproductive life,
most oocytes are consumed not through ovulation, but rather through
the processes of apoptosis (programmed cell death) and atresia. In some
women, this rate of oocyte atresia can occur rapidly and prematurely,
leading to a decrease in available oocytes (quantity) and competent
oocytes (quality). Ovarian reserve screening seeks to identify women
who may be subfertile because of issues related to diminishing oocyte
quantity or quality or both.
Figure 15-1
Historical fertility 400
rates in women
as a function of
age. The natural
decline in fertility as
women age is well 300
documented. Note
the steep decline in
Number pregnant
conception rates as
women enter their
30s. This natural
200
decline in fertility is
due to diminishing
oocyte quantity and
quality. Although
230 chronologic aging
100
and reproductive
aging often progress
in parallel, the rate of
decline varies among
individuals. Women
with DOR often 0
have a rapid decline 20 25 30 35 40 45 50
in fertility potential, Female age (years)
sometimes at an early
age. (Adapted from
Menken J, Trussell J,
Larsen U: Age and
Early in fetal life, germ cell migration from the yolk sac to the gonadal ridge
infertility. Science
1986;233:1389– forms gonadal tissue. In female gonads, the primordial follicles are the first
1394.) follicles produced. These early follicles are the follicles that are recruited first
in the process of folliculogenesis and subsequently develop into preantral fol-
licles. The development of preantral follicles from primordial follicles occurs
in the absence of gonadotropin stimulation, also known as the gonadotro-
pin-independent period of folliculogenesis. Later, these preantral follicles
enlarge and fill with fluid, becoming antral follicles; in contrast to preantral
follicles, antral follicles respond to tropic pituitary hormones. This part of
follicle development is appropriately termed the gonadotropin-dependent
period of folliculogenesis.
In a given menstrual cycle, a cohort of ovarian follicles (depending on age)
is recruited in the late luteal phase under the selective stimulation of follicle-
stimulating hormone (FSH) during the stage of gonadotropin-dependent
folliculogenesis. As the corpus luteum regresses in a nonpregnant cycle,
estradiol, progesterone, and inhibin levels decrease, and suppression of the
hypothalamic-pituitary-ovarian axis no longer occurs. In the days that fol-
low, FSH levels increase as inhibin levels wane, and selection of the dominant
follicle occurs. The dominant follicle rapidly grows under the influence of
FSH in its unique microenvironment, whereas unselected follicles undergo
atresia secondary to apoptotic events that are not completely understood.
Inhibin plays an important role in the process of folliculogenesis because its
withdrawal in the early follicular phase of the menstrual cycle allows FSH
levels to increase and it directly and indirectly plays a role in follicular atresia
Diminished Ovarian Reserve
Figure 15-2
Decline in oocyte 10000000
quantity as a function
of chronologic
aging. Oocytes
are constantly Birth
lost through 1000000
the processes of
apoptosis and Optimal
atresia as a woman fertility
Number of eggs
ages. By the time a

woman is 37 years Decreasing
100000
old, only a small fertility
fraction of oocytes
remain compared
End of
with the number of fertility
oocytes present in 231
10000
early adulthood. In
women with DOR,
the oocyte pool
is typically small Menopause
and may consist
of oocytes of poor 1000
quality. Among 0 18 31 37 41 45 51
younger women with Age
DOR, the graph is
shifted to the left,
consistent with among unselected follicles. In this way, a multitude of oocytes undergo apop-
premature ovarian
tosis and atresia during the period of follicular recruitment, selection of the
senescence.
(Adapted from te dominant follicle, and ovulation. In some women, these processes are mag-
Velde ER, Scheffer nified and can lead to the accelerated loss of ovarian follicles and subsequent
GJ, Dorland M, et DOR. In many patients, DOR is manifested as subfertility and diagnosed dur-
al: Developmental ing ovarian reserve screening.
and endocrine Chronologic aging and reproductive aging do not always go together.
aspects of normal
ovarian aging. Mol
Rather, in some patients, the accelerated loss of ovarian follicles can lead to
Cell Endocrinol ovarian senescence at an early reproductive age. Whether this loss occurs
1998;145:67–73.) through apoptosis, as a consequence of environmental factors (e.g., reac-
tive oxygen species), or through other mechanisms is unknown. In some
patients, ovarian aging can occur rapidly, leading to infertility at an early
chronologic age. It is important to consider DOR as a potential diagnosis in
“young” patients with apparent unexplained infertility.
OVARIAN RESERVE SCREENING
Many screening tests exist that seek to detect DOR as a cause of subfertil-
ity in women (Box 15-1). The fact that multiple tests exist underscores the
point that no one test possesses the sensitivity and specificity to serve as
“the” screening test for prospective detection of declining ovarian function.
In many cases, abnormalities in testing portend a poor outcome. Because
many of these tests lack specificity, however, patients should not be assured
that “normal” ovarian reserve screening implies that fertility is a certainty.
Box 15-1 Ovarian Reserve Screening Tests

● Basal FSH measurements
● CCCT
● Basal AFC
● Measurement of mean ovarian volume
● Basal estradiol levels
● Basal inhibin B levels
● Ovarian biopsy
The results of the following tests commonly are employed by clinicians to

identify and counsel patients whose subfertility is likely secondary to declin-
ing ovarian reserve.
232
Basal Follicle- The measurement of basal FSH levels has been the most widely studied and
Stimulating the best characterized screening test for the detection of DOR in subfertile
Hormone Levels women. The premise for measuring basal FSH levels in the early follicular
phase of the menstrual cycle (on day 2, 3, or 4) stems from the findings that
as women age, mild elevations in basal FSH concentrations occur; these
elevations are commonly observed in women during their mid-30s. The
early manifestations of DOR may be reflected solely as increases in basal
FSH levels. FSH levels likely begin to increase secondary to waning granu-
losa cell function, which is manifested by lower concentrations of follicular
inhibin levels. FSH levels, which are normally “inhibited” by serum inhibin,
consequently increase in the early follicular phase. This phenomenon led
many investigators to study the relationship between basal FSH levels and
ovarian response to exogenous gonadotropin stimulation and subsequent
reproductive outcome.
The initial studies investigating basal FSH as a screening test for DOR were
performed in the late 1980s and 1990s. Most of these reports were from pop-
ulations of patients undergoing in vitro fertilization (IVF). Although most
of these studies were retrospective, numerous investigators showed that as
basal FSH levels increased, the odds of a successful pregnancy dramatically
decreased. At a defined FSH threshold level, ongoing pregnancy rates and live
birth rates were low. These declining pregnancy rates were attributed to DOR
because patients with elevated basal FSH levels who underwent IVF were
often poor responders to exogenous FSH (as manifested by fewer ovarian fol-
licles visualized by ultrasound), had fewer oocytes retrieved, and developed
fewer embryos that were ultimately available for transfer compared with
controls. Patient age did not predict clinical response (ovarian responsive-
ness and number of embryos) or the chances of an ongoing pregnancy as
well as did basal FSH concentrations. Although pregnancy rates declined
with advancing age, basal FSH levels were shown to predict outcome best,
independent of age. These findings were shown in subfertile women; basal
FSH levels were not a reliable screening tool in women of reproductive age
who had not yet attempted to conceive.
Subsequent studies showed other significant findings. First, FSH levels on

day 2, 3, or 4 were equivalent in terms of predicting reproductive outcome.
In addition, basal FSH levels had significant intercycle variability; FSH lev-
els could be within the “normal” range in one cycle, but could be deemed
as “abnormal” in a subsequent cycle. Women with significant DOR had the
largest deviations from cycle to cycle. Outcome in a given patient was similar
in cycles when FSH levels were elevated compared with cycles when FSH lev-
els were normal. Pregnancy rates were not enhanced by treating patients in
cycles when the FSH was normal; clinical responsiveness and outcome was
defined by patients’ highest FSH levels noted during prior screening.
Further studies suggested that women with DOR not only might have
problems conceiving, but also might have a propensity toward miscarriage.
Investigators showed that women with elevated basal FSH levels have sig-
nificantly higher miscarriage rates compared with age-matched controls. In 233
one study, women older than 40 with elevated basal FSH levels had miscar-
riage rates of 90%. It has been suggested that DOR, as manifested by elevated
basal FSH concentrations, may be an explanation for “unexplained” recur-
rent pregnancy loss. Among these patients, it is hypothesized that fertilized
oocytes of poor quality give rise to aneuploid embryos that ultimately mis-
carry. In these clinical scenarios, screening for DOR with basal FSH levels
becomes useful not only in predicting outcome, but also for preconceptual
counseling.
Despite the multitude of studies examining the relationship between
elevated basal FSH levels and poor ovarian responsiveness and reproduc-
tive outcome, follow-up studies suggested that in some clinical scenarios,
elevated basal FSH levels did not always predict a poor prognosis. Some
investigators strongly support the notion that elevated FSH levels should
not be used to exclude subfertile patients from ART. Although patients with
grossly elevated basal FSH values generally have a poor chance of achiev-
ing an ongoing pregnancy, patients with borderline elevated test results
ultimately may achieve a live birth. It may be that patients with moderately
elevated basal FSH concentrations can achieve a pregnancy, provided that
they respond well to exogenous gonadotropins. It may be that the results
of ovarian reserve screening by way of basal FSH concentrations should be
reserved for patient counseling, rather than used to dissuade these patients
from considering ART as a means to conceive.
Clomiphene The clomiphene citrate challenge test (CCCT) was next investigated as a
Citrate possible screening test for DOR. Studied in 1987 in subfertile women older
Challenge Test than 35 years, the CCCT relied on the principle that some women might
have DOR despite a “normal” screening basal FSH level (false-negative test
result). As originally described, the CCCT involved measuring the basal FSH
concentration (typically on day 3) followed by the administration of clomi-
phene citrate, 100 mg/day, on days 5 to 9 of the cycle; the FSH level was
measured again on day 10 (Box 15-2). The physiologic principle behind the
CCCT was that clomiphene citrate would increase the patient’s FSH level
Box 15-2 Clomiphene Citrate Challenge Test

Measure serum basal FSH concentration on cycle day 2, 3, or 4
Administer clomiphene citrate, 100 mg/day, from cycle day 5 through cycle
day 9
Measure serum basal FSH concentration on cycle day 10
during the course of administration, and in patients with normal ovarian

reserve, the FSH level would return to baseline on day 10 after the 5 days of
treatment. Studies of the CCCT in subfertile women showed that although
many patients had a “normal” basal FSH level, some had an elevated level on
day 10 of a CCCT. Study results showed that among patients with “normal”
basal FSH concentrations who underwent the CCCT, of women who then
234 had an abnormal day 10 level, only 6% conceived during the study period,
whereas of women with a normal day 10 value, 42% conceived.
Additional studies evaluating the CCCT as a screening test for patients
undergoing ART followed, and results from those investigations corrobo-
rated what was originally surmised: that patients with abnormal day 10
FSH levels after a course of clomiphene citrate, despite “normal” basal FSH
levels, frequently responded poorly to exogenous gonadotropins or did not
become pregnant. Similar to basal FSH screening for DOR, the CCCT was
independent of patient age. Many patients who originally had been diag-
nosed with unexplained infertility had significant DOR as manifested by an
abnormal CCCT.
Clinics should develop their own database and determine normal values
for FSH screening. Populations and testing technique vary, so individual
clinic experience should be the primary determinant for counseling patients
regarding their results.
Basal Antral Investigators have sought to determine whether the number of basal antral
Follicle Counts follicles, defined as follicles visualized in the early follicular phase of the men-
strual cycle, measuring 4 mm or less in diameter when observed by trans-
vaginal ultrasound, might predict ovarian responsiveness and pregnancy
outcome. The premise behind the significance of basal antral follicle counts
(AFCs) is that in patients with DOR, fewer antral follicles are available for
recruitment in a given menstrual cycle. It was postulated that basal AFCs
could be another method to prospectively identify patients at risk for poor
ovarian response and a low probability of conception.
Multiple studies have been performed seeking to identify a threshold basal
AFC that might predict pregnancy. Such an AFC threshold value has yet
to be ascertained. In examining the basal AFC in patients undergoing IVF,
patients with lower numbers of antral follicles had higher cycle cancellation
rates, and if they were not cancelled, these patients had lower pregnancy
rates compared with controls. The total number of antral follicles was noted
to be of greatest importance, regardless of whether more antral follicles were
visualized in one ovary or the other. In addition, basal AFCs seemed to vary
little from cycle to cycle. Although a threshold basal AFC that might predict
IVF cycle cancellation, poor ovarian response to exogenous gonadotropins,

or poor pregnancy outcome was not delineated, study results suggested that
patients with fewer than four to six total antral follicles had poor outcomes
relative to patients with higher AFCs. Basal AFCs may be used to counsel
patients regarding the likelihood of IVF cycle cancellation before starting
gonadotropins and may be used to alter treatment regimens before ovarian
stimulation for IVF, for instance increasing gonadotropin dose during ovar-
ian hyperstimulation. AFCs also can be useful as a counseling tool in the
context of an abnormal basal FSH level or abnormal CCCT; taken together,
these results may deter a patient from proceeding with IVF based on the high
likelihood of cycle cancellation and poor pregnancy outcome. The patient
may proceed instead with a donor oocyte protocol.
235
Measurement of Measuring the volume of the ovaries in the early follicular phase of the
Mean Ovarian menstrual cycle also has been investigated as a potential predictor of ovar-
Volume ian responsiveness. Investigators first recognized that women with DOR
had smaller ovarian volumes compared with controls. Studies suggested
that women with smaller mean ovarian volumes (<2 cm3) had higher cycle
cancellation rates and lower pregnancy rates compared with women with
mean ovarian volumes greater than 2 cm. These findings were observed
when controlling for age. One group of investigators hypothesized that the
mean ovarian volume reflected the number of primordial follicles remain-
ing and could predict ovarian reserve and reproductive age. Although this
is not an absolute, the mean ovarian volume, similar to the basal AFC, can
be used in conjunction with other ovarian reserve screening tests to better
counsel infertility patients regarding their chances of ovarian response to
treatment.
Basal Estradiol When measuring basal FSH levels, it is appropriate to measure the FSH
Levels and estradiol concentrations to confirm that testing is being performed
at the appropriate time of the menstrual cycle (i.e., in the earlier follicu-
lar phase). Some patients, despite screening in the early follicular phase,
have surprisingly high serum estradiol levels. Investigators postulated that
in some patients, the prematurely elevated estradiol levels could be sup-
pressing basal FSH levels into the normal range, perhaps “masking” abnor-
mal FSH levels in patients with occult DOR. In 1995, one study suggested
that in patients undergoing IVF, a basal estradiol concentration of greater
than 80 pg/mL correlated with poor IVF outcome. Follow-up studies with
larger sample sizes failed to identify a relationship between basal estradiol
levels and pregnancy rates, however. Basal estradiol levels did not predict
pregnancy outcome in patients undergoing IVF when controlling for basal
FSH (i.e., basal estradiol levels were inconsequential in the face of a normal
basal FSH). Although measuring the basal estradiol level in conjunction
with FSH is important to confirm the part of the menstrual cycle in which a
blood sample is collected, its validity as a screening test for DOR remains to
be proven.
Basal Inhibin B Inhibin B is a granulosa cell product from antral follicles that directly sup-
Levels presses pituitary FSH secretion. Investigators surmised that as ovarian func-
tion waned, early follicular inhibin B concentrations would decrease and fail
to suppress FSH secretion. Changes in inhibin B concentrations might occur
before fluctuations in basal FSH levels, and inhibin B levels might be a more
“direct” assessment of granulosa cell function. Based on this premise, it was
thought that measurements of basal inhibin B concentrations might be an
excellent screening test for DOR. Although results from one of the first stud-
ies of inhibin B as a screening test for DOR determined a threshold level for
which ART outcome was poor, it failed to control for basal FSH levels. A fol-
low-up study showed that basal inhibin B levels increased before basal FSH
levels did; however, in patients with normal basal FSH levels, inhibin B levels
in the same patients did not prognosticate ovarian response or pregnancy
236 outcome.
Similar to AFCs or ovarian volume measurements, basal inhibin B con-
centrations may be used in conjunction with other screening tests for patient
counseling. Although women with diminished ovarian reserve typically have
lower inhibin B levels compared with women who respond well to exogenous
gonadotropin administration, inhibin B levels are not by themselves predic-
tive of reproductive outcome. Although the hypothesis behind screening for
DOR with inhibin B levels makes physiologic sense, screening patients with
basal inhibin B levels seems to be inferior to other screening tests for DOR.
Ovarian Biopsy It has been suggested by some investigators that ovarian biopsy should be a
part of the infertility evaluation to rule out depletion of the pool of primor-
dial follicles as a source of declining ovarian function. Investigators observed
that patients with unexplained infertility had lower ovarian follicular den-
sity and fewer total follicles compared with patients with discernible etiolo-
gies for infertility. This observation led to the notion of ovarian biopsy as a
diagnostic tool during the infertility investigation.
Ovarian biopsy is invasive, requiring diagnostic laparoscopy. In addition,
the risk of future adhesions and further decreasing ovarian reserve as a
result of the biopsy itself exists. Perhaps most important, although the pres-
ence of appropriate numbers of follicles was reassuring for sufficient ovar-
ian reserve, a biopsy specimen showing empty cortex or few follicles was
not always consistent with declining ovarian function. The risks of ovarian
biopsy and its uncertain role as a sensitive and specific screening test for DOR
prevent this procedure from being recommended at this time.
TREATMENT AND PATIENT COUNSELING
As mentioned previously, DOR implies a significant decline in oocyte quan-

tity or quality or, in many cases, both. Although treatment options exist (Box
15-3), there are no safe, effective, proven therapies that can improve oocyte
quality. When testing suggests a diagnosis of DOR, therapy usually consists
of ovarian hyperstimulation in the hopes of recruiting multiple ovarian
Box 15-3 Treatment Options for Patients with Diminished Ovarian Reserve
● Gonadotropin stimulation with intrauterine insemination
● IVF
● Oocyte donation
follicles. Viable options include treatment with exogenous gonadotropins

followed by (1) intrauterine inseminations or (2) oocyte retrieval and IVF.
In cases of borderline DOR in which response to ovarian stimulation is ade-
quate, pregnancies do occur. Studies have shown that women with DOR (as
manifested by abnormal basal FSH or CCCT) have significantly lower preg-
nancy rates and higher miscarriage rates compared with controls; however,
investigators also have suggested that moderately elevated FSH levels should
not lead to the exclusion of subfertile patients from treatment. In one study, 237
although the pregnancy rate was lower among patients with moderately
elevated FSH levels compared with controls, the pregnancy rate was still an
acceptable 28% among patients with abnormal basal FSH levels. Based on
their data, the authors concluded that pregnancy rates were acceptable as
long as patients responded to exogenous gonadotropins and had a basal FSH
of less than 20 IU/L. Ovarian reserve testing generally should be used as a
screening and counseling tool, but should not be used routinely as a way to
dissuade patients from undergoing fertility treatment.
In patients with DOR who experience poor response to gonadotropins or
poor reproductive outcome, conceiving with donor eggs is a viable option.
Studies have unequivocally shown that the age of the oocyte, not the age
of the uterus, is more important (Fig. 15–3). In brief, egg donation can be
performed anonymously (through a clinic or agency) or directed (a known
donor, such as a friend or relative). Egg donors are extensively screened med-
ically, genetically, and psychologically before being selected by a recipient
couple and undergoing the egg donation process. An egg donor undergoes
ovarian stimulation and oocyte retrieval; the donor oocytes are fertilized with
the recipient partner’s sperm, and the resulting embryos are transferred to
the donor egg recipient. Before stimulating the egg donor, the recipient takes
sequential estrogen and progesterone supplementation to simulate the mid-
luteal phase so that implantation occurs after embryo transfer. In this way,
extremely high live birth rates are achieved in patients who otherwise would
have been unable to conceive.
Experimental methods involving cytoplasm (ooplasm) donation have
been investigated; cytoplasm is transferred from a donor oocyte to a recipient
oocyte in an attempt to enhance embryo quality and improve ART outcome
in patients with poor oocyte quality. Cytoplasm donation was first investi-
gated in the late 1990s in patients with “recurrent implantation failure.”
In these patients, small amounts of donor cytoplasm were injected into
recipient oocytes; mitochondria from the donor cytoplasm were thought to
improve respiratory processes in recipient oocytes and to enhance implanta-
tion. Although healthy children resulted from this technique, an alarmingly
increased rate of Turner’s syndrome and Down syndrome was observed
in humans; this could be due to epigenetic defects intrinsic to impaired
Figure 15-3
Live birth rate after 40
embryo transfer
using a patient’s
35
own eggs versus
using donor eggs. In
Donor eggs
patients undergoing 30
IVF using their own
eggs, there is a
Live births per transfer
significant decrease in 25
live birth rates after Own eggs
the age of 37. The 20
live birth rate remains
high regardless of
age in women who 15
conceive using donor
238 eggs. This illustrates
10
the fact that (1) egg
quality decreases
with advancing 5
age, and (2) the
age of the uterus
plays a minor role 0
25 27 29 31 33 35 37 39 41 43 45
in reproduction.
Age
(Adapted from the
CDC 2001 ART
Success Rates,
National Summary recipient oocytes that seemingly were “rescued” by donor cytoplasmic trans-
and Fertility Clinic
fer. Although initial studies were promising, the safety and efficacy of this
Reports, 48.)
technique has not yet been convincingly addressed. Additional research
into cytoplasmic donation in animals and humans is necessary before this
method to enhance oocyte quality is used further. More recently, ovarian
tissue and oocyte cryopreservation have emerged as a means to “bank”
tissue or gametes before ovarian failure; at this time, these technologies are
being considered for patients before undergoing chemotherapy or radiation
therapy and warrant further investigation.
CONCLUSION
Aging, ovarian and chronologic, remains the enemy of reproduction.

Numerous ovarian screening tests exist, and they should be interpreted in
such a way that their results can be used to affect treatment and to better
counsel patients regarding their chances of conception and achieving a live
birth. In general, the possibility of DOR should not exclude patients from
care, unless the results of testing are grossly abnormal, or patients respond
poorly to treatment, because studies have shown that patients with moder-
ately abnormal test results can conceive. The role of cytoplasmic donation
needs to be investigated further. Patients with suspected DOR as a rule should
be treated aggressively because their window of opportunity before complete
ovarian senescence occurs may be a small one. In some patients, conceiv-
ing with donor eggs is a viable option. Lastly and perhaps most importantly,
patient age always should be taken into account because age remains a
powerful predictor of reproductive outcome. Patients older than age 37 (if
not younger) should not be given a false sense of security from clinicians if
their ovarian reserve screening is “normal”; in these patients, advancing age
by itself portends that there may be “bumps in the road” as patients try to
conceive.

1. Ovarian aging and oocyte atresia is a normal part of reproductive life.
Rates of oocyte loss vary, however, among women. Women with accel-
erated oocyte atresia may encounter problems conceiving at an early
age. It is unknown why some women experience reproductive senes-
239
cence earlier than others.
2. Declining oocyte quantity and poor oocyte quality contribute to DOR,
which can be a cause of subfertility and miscarriage. DOR also is thought
to be a possible cause of “unexplained” recurrent miscarriage.
3. Patient age always should be taken into consideration when interpreting
results from ovarian reserve testing because age alone is a predictor of DOR.
4. Numerous testing methods have been proposed to detect declining
ovarian function in subfertile patients. No one test has been shown to be
the ideal screening test for detecting DOR. In many cases, a combina-
tion of different studies (i.e., the CCCT in conjunction with AFC and/or
ovarian volume), rather than a single test (basal FSH measurement), may
better detect DOR.
5. Ovarian reserve screening should be reserved for patients with a diagno-
sis of infertility. These tests have not been studied in patients who have
not yet attempted to conceive and should be interpreted with caution in
such patients.
6. Abnormal test results are usually predictive of poor reproductive out-
come. “Normal” ovarian reserve testing, although reassuring, does not
imply that a patient is fertile because some tests are subject to intracycle
variability and lack adequate specificity.
7. There are no safe, effective, proven treatments to improve oocyte qual-
ity. Treatment with exogenous gonadotropin to recruit multiple ovarian
follicles (possibly in conjunction with IVF) may be beneficial in some
cases, although reproductive outcome tends to be poor. Oocyte dona-
tion may be a possible option for patients in cases in which pregnancy
cannot be achieved using their own eggs.
8. The results of ovarian reserve screening tests should be used to coun-
sel patients regarding their chances of success with infertility treat-
ment. Abnormal testing is predictive of an increased likelihood of poor
response to ovarian stimulation, IVF cycle cancellation, and poor repro-
ductive outcome. Abnormal test results should not be used to deny
patients care; rather, test results should be discussed with patients in
the context of whether or not the probability of achieving a pregnancy
warrants proceeding with treatment.
SUGGESTED READINGS
Barnhart K, Osheroff J: Follicle stimulating hormone Scott RT Jr, Hofmann GE, Oehninger S, Muasher SJ:
as a predictor of fertility. Curr Opin Obstet Gynecol Intercycle variability of day 3 follicle-stimulating
1998;10:227-232. hormone levels and its effect on stimulation quality
Cohen J, Scott R, Alikani M, et al: Ooplasmic trans- in in vitro fertilization. Fertil Steril 1990;54:297-302.
fer in mature human oocytes. Mol Hum Reprod Scott RT, Leonardi MR, Hofmann GE, et al: A pro-
1998;4:269-280. spective evaluation of clomiphene citrate challenge
Frattarelli JL, Bergh PA, Drews MR, et al: Evaluation test screening of the general infertility population.
of basal estradiol levels in assisted reproductive tech- Obstet Gynecol 1993;82(4 Pt 1):539-544.
nology cycles. Fertil Steril 2000;74:518-524. Scott RT, Toner JP, Muasher SJ, et al: Follicle-stimu-
Frattarelli JL, Lauria-Costab DF, Miller BT, et al: Basal lating hormone levels on cycle day 3 are predic-
antral follicle number and mean ovarian diameter tive of in vitro fertilization outcome. Fertil Steril
predict cycle cancellation and ovarian responsive- 1989;51:651-654.
ness in assisted reproductive technology cycles. Fertil Seifer DB, Gardiner AC, Ferreira KA, Peluso JJ:
Steril 2000;74:512-517. Apoptosis as a function of ovarian reserve in women
240 Frattarelli JL, Levi AJ, Miller BT, Segars JH: A pro- undergoing in vitro fertilization. Fertil Steril
spective assessment of the predictive value of basal 1996;66:593-598.
antral follicles in in vitro fertilization cycles. Fertil Seifer DB, Lambert-Messerlian G, Hogan JW, et
Steril 2003;80:350-355. al: Day 3 serum inhibin-B is predictive of assisted
Frattarelli JL, Levi AJ, Miller BT, Segars JH: reproductive technologies outcome. Fertil Steril
Prognostic use of mean ovarian volume in in vitro 1997;67:110-114.
fertilization cycles: a prospective assessment. Fertil Seifer DB, Scott RT Jr, Bergh PA, et al: Women with
Steril 2004;82:811-815. declining ovarian reserve may demonstrate a decrease
Hawes SM, Sapienza C, Latham KE: Ooplasmic dona- in day 3 serum inhibin B before a rise in day 3 follicle-
tion in humans: the potential for epigenic modifica- stimulating hormone. Fertil Steril 1999;72:63-65.
tions. Hum Reprod 2002;17:850-852. Sharara FI, Scott RT: Assessment of ovarian reserve: is
Hofmann GE, Danforth DR, Seifer DB: Inhibin-B: there still a role for ovarian biopsy? First do no harm!
the physiologic basis of the clomiphene citrate Hum Reprod 2004;19:470-471.
challenge test for ovarian reserve screening. Fertil Sharara FI, Scott RT Jr, Seifer DB: The detection of
Steril 1998;69:474-477. diminished ovarian reserve in infertile women. Am J
Hofmann GE, Khoury J, Thie J: Recurrent pregnancy Obstet Gynecol 1998;179(3 Pt 1):804-812.
loss and diminished ovarian reserve. Fertil Steril Smotrich DB, Widra EA, Gindoff PR, et al: Prognostic
2000;74:1192-1195. value of day 3 estradiol on in vitro fertilization out-
Levi AJ, Raynault MF, Bergh PA, et al: Reproductive come. Fertil Steril 1995;64:1136-1140.
outcome in patients with diminished ovarian reserve. Trout SW, Seifer DB: Do women with unexplained recur-
Fertil Steril 2001;76:666-669. rent pregnancy loss have higher day 3 serum FSH and
Navot D, Drews MR, Bergh PA, et al: Age-related estradiol values? Fertil Steril 2000;74:335-337.
decline in female fertility is not due to diminished te Velde ER, Scheffer GJ, Dorland M, et al:
capacity of the uterus to sustain embryo implanta- Developmental and endocrine aspects of normal
tion. Fertil Steril 1994;61:97-101. ovarian aging. Mol Cell Endocrinol 1998;145(1–2):
Navot D, Rosenwaks Z, Margalioth EJ: Prognostic assess- 67-73.
ment of female fecundity. Lancet 1987;2:645-647. van Rooij IA, de Jong E, Broekmans FJ, et al: High
Practice Committee of the American Society for follicle-stimulating hormone levels should not neces-
Reproductive Medicine: Ovarian tissue and oocyte sarily lead to the exclusion of subfertile patients from
cryopreservation. Fertil Steril 2004;82:993-998. treatment. Fertil Steril 2004;81:1478-1485.
16
RECURRENT
PREGNANCY LOSS
Stacey Leigh Rubin and Randall Odem
Recurrent pregnancy loss (RPL) is a devastating medical problem with

far-reaching effects on the couple, their support system, and their caregivers.
Few problems strike the heart of a relationship as forcefully as pregnancy
241
loss. These emotional issues may contribute to divorce or the decision to
abandon prematurely further pregnancy attempts. To help couples work
through the fear of future pregnancies, the clinician should provide accurate
facts, an appropriate evaluation, close follow-up in subsequent pregnancies,
and continued emotional support.
RPL is defined as three or more consecutive pregnancy losses of less than
20 weeks’ gestation. Many physicians apply this diagnosis to nonconsecutive
losses before 28 weeks’ gestation. Others argue that a RPL workup should be
initiated after two consecutive miscarriages because the risk of subsequent
spontaneous abortion after two losses is similar to the risk after three or
more. For this reason, many clinical trials investigating habitual abortion
include patients with two pregnancy losses.
Of all clinically recognized pregnancies, 12% end in spontaneous abor-
tion; the miscarriage rate is 30% when unrecognized pregnancies are taken
into account. Overall, 1% of reproductive-age women have experienced
three or more losses, 5% of women have experienced two losses, and 15% to
40% of women have experienced at least one pregnancy loss. RPL may have
an etiology distinct from sporadic spontaneous abortions, with an inher-
ent factor placing some couples at greater risk for further pregnancy loss.
Numerous etiologies have been suggested by retrospective studies, and pro-
spective trials continue to yield additional information. Despite a thorough
evaluation, no etiology is identified in 30% to 40% of habitual abortion
cases. Even without treatment, a 65% to 70% chance exists of subsequently
achieving a live birth.
Obstetric history is significant in predicting future risk of spontaneous
abortion. Even a single miscarriage, without history of a viable pregnancy,
increases the risk that the next pregnancy will terminate in abortion from
12% to 20%. Two miscarriages without a live birth result in a 35% risk of
subsequent spontaneous abortion, and three miscarriages without a live
birth confer a 47% risk of subsequent loss. A history of one prior live birth
reduces the risk of miscarriage by approximately 10%.
The routine workup for RPL begins with a detailed history and physical
examination. Box 16-1 lists pertinent information to be collected. This chapter
addresses the various genetic, uterine, endocrine, infectious, thrombophilic,
immune, and environmental causes of RPL.
GENETIC ERROR
Fifteen percent of all clinically recognized pregnancies end in spontaneous

abortion, and more than half of these are due to lethal genetic defects in
the conceptus. Genetic anomalies account for 60% of first-trimester miscar-
riages, 6% of second-trimester miscarriages, and 0.6% of third-trimester
miscarriages. Genetic errors likely cause many additional early abortions
242 occurring before clinical detection. More than 50% of RPL results from
genetic etiologies, including aneuploidies, chromosomal abnormalities, and
single gene mutations.
Box 16-1 Pertinent History, Physical Examination, and Laboratory Tests for
Recurrent Pregnancy Loss
History
Detailed obstetric history
Pattern and trimester of previous pregnancy losses
Presence or absence of live embryos
Serial human chorionic gonadotropin levels
Ultrasound findings
Pathology reports of abortuses (e.g., karyotypes)
Family history of RPL
Menstrual abnormalities, including history of amenorrhea, oligomenorrhea, and
LPD
Gynecologic or obstetric infections
Exposure to occupational or environmental toxins
Social habits, including tobacco, alcohol, and caffeine use
Chronic medical illnesses, including endocrinologic disturbances
In utero DES exposure
Physical Examination
Examination of vagina and cervix
Examination of uterus with attention to uterine size and signs of DES exposure
Body habitus
Signs of metabolic disease
Diagnostic Tests
Sonohysterography, HSG, or hysteroscopy
Luteal phase endometrial biopsy
Parental karyotypes
LAC antibody
ACA
Thyrotropin
Fasting insulin and glucose
Aneuploidy The risk of aneuploidy, or an abnormal number of chromosomes, increases

with advancing maternal age. Aneuploidy occurs from maternal non-
disjunction, paternal gonadal mosaicism, translocations, and inversions.
Monosomies are almost always lethal, whereas some fetuses with trisomies
survive to birth and beyond. Parental chromosomal abnormalities occur in
4% of couples with RPL, which is five times more frequently than in the gen-
eral population. Of spontaneous abortions secondary to aneuploidy, 75%
occur in the first 8 weeks of pregnancy.
Chromosomal translocations are the most common structural abnormali-
ties associated with RPL. Sixty percent of translocations are reciprocal, or
balanced, with material exchanged between nonhomologous chromosomes.
All genetic material is preserved, but when the abnormal chromosomes seg-
regate into germ cells during meiosis, fetal aneuploidy can result (Fig. 16-1).
Of translocations, 40% are robertsonian, in which two acrocentric chromo- 243
somes fuse and lose their short arms. Robertsonian translocations always
result in fetal aneuploidy.
Inversions occur when a chromosomal segment breaks and is reinserted in
reverse order. Chromosomal inversions can result in phenotypically normal
infants. Paracentric crossovers and recombinations are more likely to result
in cytogenetically unbalanced embryos. Female translocation and inversion
carriers are twice as likely as male carriers to produce affected offspring.
Single Gene Many single gene mutations are associated with RPL, and undoubtedly
Mutations many more as yet are unidentified. The true scope of single gene mutations
is unknown. Mutations in “housekeeping genes” result in preimplantation
pregnancy failure, whereas mutations in specific adhesion molecules can
Figure 16-1 Chromosome Chromosome

Parental balanced A B
translocation
between
nonhomologous
chromosomes can
yield unbalanced
offspring.
Balanced translocation Normal
carrier
Unbalanced Unbalanced Balanced Normal

translocation translocation translocation
trisomy trisomy carrier
chromosome B chromosome A
interfere with implantation. Women with glucose-6-phosphate dehydro-

genase deficiency are twice as likely to have a spontaneous abortion. Other
important single gene mutations occur in the factor V Leiden, methylene tet-
rahydrofolate reductase (MTHFR), prothrombin, and antithrombin genes.
These are discussed in greater detail in the thrombophilias section.
Diagnosis and Structural abnormalities are diagnosed by cytogenetic testing (karyotyp-

Treatment ing). A loss at 9 weeks of gestational age is most likely to be associated with
an abnormal karyotype in the abortus, and the frequency of abnormalities
decreases sharply after 16 weeks. Beyond this period, most spontaneous
abortions are associated with maternal rather than genetic factors. After
one karyotypically abnormal abortus, subsequent losses have a 70% risk of
244 being chromosomally abnormal.
Cytogenetic testing is expensive, but karyotyping of both parents should
be included in the routine workup for couples that have experienced three
or more first-trimester losses. Routine cytogenetic analysis of the abortus is
not usually indicated, and the decision to do this analysis should be made on
an individual basis. Some distraught couples can work through their grief
more easily after knowing the cause of their loss. Still, cytogenetic testing is
incapable of detecting many genetic etiologies of RPL.
Fluorescent in situ hybridization facilitates analysis of tissue that cannot
be cultured and has identified important roles of single gene mutations, X-
inactivation, and imprinting (epigenetic chromosome modification) in the
etiology of habitual spontaneous abortion. Fluorescent in situ hybridiza-
tion is also very expensive and is still used primarily in the research setting.
Development of new molecular techniques will continue to elucidate the
genetic mechanisms of RPL.
At-risk couples should be offered genetic counseling. A trained genetic
counselor can advise couples best about their risk of abnormal pregnancy
and can be an important source of psychological support. Preimplantation
diagnosis is still under development, but allows couples to screen for karyo-
typically abnormal embryos. For preimplantation diagnosis, one or two cells
are removed from the day 3 cleavage stage embryos for testing, and only
normal embryos subsequently are transferred. Prenatal testing involves
chorionic villus sampling or amniocentesis to detect fetal abnormalities.
Elective abortion of severely affected fetuses is an option for some couples.
Comprehensive psychological support is an important part of treatment and
should not be overlooked. Box 16-2 summarizes the main points concerning
genetic error and RPL.
UTERINE ANOMALIES
Uterine anomalies affecting pregnancy have congenital and acquired

etiologies. Congenital uterine abnormalities occur in 10% to 15% of
women with RPL, but in only 3% of the general population and result from
errors in müllerian development or from in utero diethylstilbestrol (DES)
Box 16-2 Summary of Genetics and Recurrent Pregnancy Loss

● Parental chromosomal abnormalities occur in 4% of couples with RPL.
● Chromosomal translocations are the most common structural abnormalities
associated with RPL.
● Cytogenetic testing (karyotyping) should be included in the workup for couples
with RPL.
● Genetic counseling is an important treatment component in couples with
known genetic abnormalities.
exposure. Acquired uterine abnormalities include intrauterine adhesions

and leiomyomata.
245
Diagnosis Transvaginal ultrasound and sonohysterography are noninvasive and inex-

of Uterine pensive first studies for uterine abnormalities. Ultrasound alone is not as sen-
Anomalies sitive at diagnosing subtle defects in uterine architecture. Filling the uterus
with saline increases sensitivity, but this is invasive. Ultrasound is especially
useful for identifying noncommunicating or obstructed uterine horns.
Hysterosalpingogram (HSG) is a common test for diagnosis of uterine
anomalies. HSG assesses tubal patency and the internal architecture of the
uterus. This test does not differentiate between septate and bicornuate uteri
because an HSG does not elucidate the external uterine contour. In this case,
an additional modality, such as sonohysterography, three-dimensional ultra-
sound, or magnetic resonance imaging (MRI), is required. A disadvantage of
HSG is that it is invasive and involves radiation exposure. Three-dimensional
ultrasound or MRI is noninvasive and valuable for diagnosis of uterine
anomalies. The radiologist should be informed of the study’s purpose so that
proper planes of section can be obtained. MRI is very expensive and cannot
assess tubal patency.
Müllerian Development of the female reproductive tract begins in week 7 when the
Development embryonic müllerian (paramesonephric) ducts elongate and reach the uro-
genital sinus. By week 8, both ducts fuse into a single solid tube forming the
primitive uterovaginal canal. Internal canalization forms a central lumen
in each of the solid ducts. The septum is resorbed by week 20 forming the
uterine lumen. Müllerian uterine anomalies occur when elongation, fusion,
canalization, or septal resorption do not occur properly. The most common
malformations associated with RPL are variations on the double uterus
(bicornuate, septate, and didelphic). Septate and bicornuate uteri account for
more than 50% of abnormalities. Figure 16-2 shows the various müllerian
anomalies.
Inadequate uterine vascularity is associated with müllerian anomalies.
Eighty percent of women with müllerian defects have abnormal uterine
artery flow compared with 10% of anatomically normal controls. Lateral pla-
centation and poor perinatal outcome also have been correlated to müllerian
Figure 16-2
The American Society I. Hypoplasis/Agenesis
for Reproductive
Medicine
classification *
of müllerian
anomalies. (From the
American Society
for Reproductive
Medicine.) a. vaginal * b. cervical c. fundal d. tubal e. combined
II. Unicornuate
246
a. communicating b. non-communicating c. no cavity d. no horn
III. Didelphus IV. Bicornuate
a. complete b. partial
V. Septate VI. Arcuate
a. complete** b. partial
VII. DES drug related
* Uterus may be normal or take a variety of abnormal forms.

** May have two distinct cervices
defects. Uterine distortion and decreased intraluminal volume may restrict

fetal growth and increase pressure on the lower uterine segment and cervix.
Congenital anomalies are present in 30% of cases of cervical incompetence
that contribute to midtrimester pregnancy losses.
Unicornuate A unicornuate uterus results from agenesis or incomplete elongation of one

Uterus müllerian duct. It is rare but has a poor prognosis and is associated with a 51%
spontaneous abortion rate, a 15% preterm birth rate, and 40% overall fetal
survival. Intrauterine growth restriction and malpresentation are common
problems. There is no way to increase cavity size surgically. Some physicians
recommend treatment with prophylactic cervical cerclage, but there are no
good trials assessing outcome. (Some physicians elect to use a gestational car-
rier to reduce the risk of adverse pregnancy outcome.) It is necessary to look 247
for a rudimentary horn on the contralateral side and manage this as indicated.
A complete workup should include renal ultrasound because 40% of women
with a unicornuate uterus also have some degree of renal agenesis.
Uterus Uterus didelphys results from duplication of the vagina, cervix, and uterus in
Didelphys the absence of müllerian duct fusion. Each cavity has the same volume as a
unicornuate uterus, but superior blood supply results in a smaller spontane-
ous abortion rate of 40%. Many women with uterus didelphys have normal
reproductive outcome, however, so other etiologies should be examined before
attributing RPL to a uterus didelphys. Careful examination of the fundus is
required to differentiate a uterus didelphys from a septated uterus with cervi-
cal and vaginal duplication. If no other cause of RPL is identified, the uterus
didelphys can be united by metroplasty, but surgery is of unproven benefit
and is rarely performed for this abnormality. Metroplasty carries the risk of
subsequent infertility, and the patient requires a cesarean section delivery.
Bicornuate A bicornuate uterus consists of a single chamber for the vagina and cer-
Uterus vix, with partial or complete separation of the uterine bodies. It results from
incomplete fusion of the müllerian ducts at the uterine fundus. A bicornuate
uterus is associated with a 30% spontaneous abortion rate and 60% overall
fetal survival. Treatment can involve surgical unification by metroplasty, but
this is rarely performed because there are no randomized controlled trials
showing a benefit of surgical management. In cohort studies, the live birth
rate increases to 75% after metroplasty, even in women with previous losses.
Another reported treatment option is prophylactic cervical cerclage, which
has success rates in cohort studies similar to those of metroplasty without
the need for cesarean section. Cerclage must be placed before 20 weeks’
gestation to reduce the rate of intrauterine infection.
Septate Uterus In a septate uterus, there is partial or complete failure of septal resorption
in müllerian development. The septum is fibromuscular tissue and is poorly
vascularized and does not generally support placentation; this contributes to

an overall poor prognosis with spontaneous abortion rates of 85%. Treatment
should be considered for women with RPL, fetal death, preterm delivery, or
recurrent fetal malpresentation. Hysteroscopic incision of the septum with
possible laparoscopic visualization of the uterus is the preferred treatment.
In the hands of an experienced surgeon, the procedure has low morbidity
and a high success rate. Postsurgical miscarriage rates are only 20% to 30%.
Abdominal metroplasty is associated with higher morbidity and is generally
not considered because of the benefits of a hysteroscopic approach. As with
the bicornuate uterus repair, there are no randomized controlled trials that
support a benefit of surgery.
248 Arcuate Uterus An arcuate uterus has a slight fundal protrusion reminiscent of a very small
septum. It is not associated with recurrent miscarriage or reproductive risk.
Diethylstil- DES is a synthetic estrogen that was used to treat RPL, preterm delivery, and
bestrol Exposure other pregnancy complications starting in the 1940s. Its use was discontin-
ued in 1971 when it was associated with vaginal clear cell adenocarcinoma.
In addition, 70% of women exposed to DES in utero developed structural
uterine abnormalities, and 44% have cervical anomalies. DES exposure is
associated with a T-shaped uterus, widened lower uterine segment, irregular
uterine margins, uterine constrictions, and uterine hypoplasia. The smaller
endometrial surface area contributes to a spontaneous abortion rate of 24%.
Cervical incompetence is increased, ectopic pregnancy is eight times more
likely, and preterm labor is three times more likely than in the general popula-
tion. Surgery generally cannot correct the malformations. Cervical cerclage
should be considered for women with prior second-trimester losses.
Intrauterine Asherman’s syndrome is characterized by acquired intrauterine adhesions,

Adhesions which can completely ablate the uterine cavity in severe cases. Adhesions
(Asherman’s develop when the endometrium is denuded, and the regenerative basal cells
Syndrome) are destroyed by postabortal or postpartum curettage. The remaining endo-
metrium is often inadequate to support placentation and is compromised by
inflammation and fibrosis of the stroma and glands. An effort should be made
to minimize damage to the endometrium because this population under-
goes an increased number of dilation and curettage procedures. Symptoms
include amenorrhea or irregular menses, infertility, and RPL. Asherman’s
syndrome is diagnosed by multiple filling defects on HSG. There is an 80%
spontaneous abortion rate before treatment. Treatment involves hystero-
scopic lysis of adhesions, placement of a Foley catheter, and administration
of estrogens. Postoperative spontaneous abortion rate is decreased to 15%.
Success rates are based on cohort data and not randomized controlled trials.
It also is possible to lyse the adhesions blindly without hysteroscopy, but this
is not recommended because it can damage the endometrium further and
may be suboptimal.
Leiomyomata Leiomyomata, also known as fibroids, are acquired benign tumors of the uterus
and can be submucosal, intramural, subserosal, or pedunculated. Submucosal
and intramural fibroids are associated with RPL and a 41% spontaneous abor-
tion rate. Treatment involves resection of submucosal fibroids that distort the
uterine cavity or occupy a large subendometrial area. Myomectomy for intra-
mural fibroids may be performed if no other cause for RPL is identified. This
procedure often is associated with high morbidity, including intra-abdominal
adhesions, excessive blood loss, and the need for future cesarean section. The
postoperative spontaneous abortion rate is decreased to 19% in representative
cohort studies. Box 16-3 summarizes uterine anomaly issues.
ENDOCRINOPATHIES
249
Several endocrinologic conditions have been implicated in RPL, including
luteal phase defect (LPD), polycystic ovary syndrome (PCOS), hyperan-
drogenism, increased gonadotropins, hyperprolactinemia, thyroid abnor-
malities, and diabetes mellitus. In some cases, it is possible to correct the
endocrinopathy and improve pregnancy outcome.
Luteal Phase Ovarian progesterone is required for implantation and maintenance of

Defect early pregnancy. Some investigators believe that 20% to 25% of RPL
results from progesterone deficiency during the luteal phase, termed LPD.
No properly controlled trials have shown that LPD causes RPL. It is diffi-
cult to attribute losses after 8 weeks’ gestation to LPD because the placenta
begins to synthesize progesterone, and ovarian progesterone is no longer
required. In addition, many women with LPD are capable of conceiving
and carrying to term. It is more likely that decreasing progesterone levels
are a consequence of poor placental or fetal development and not the cause
of pregnancy failure.
In the past, LPD was diagnosed most commonly by out-of-phase endo-
metrial biopsy specimens, where histologic dating lagged behind menstrual
dating by at least 3 days. Diagnosis required two consecutive out-of-phase
endometrial biopsy specimens because 30% of biopsy specimens from iso-
lated cycles of normal women could be out-of-phase. There was significant
interobserver variation when dating endometrial biopsy specimens. Other
Box 16-3 Summary of Uterine Anomalies and Recurrent Pregnancy Loss

● Uterine anomalies are diagnosed by sonohysterography, HSG, or MRI.
● The most common uterine malformations associated with RPL are variations on
the double uterus.
● Inadequate uterine vascularity and decreased intraluminal volume may
contribute to pregnancy loss in women with müllerian defects.
● DES exposure in utero is associated with structural uterine abnormalities,
including T-shaped uterus.
● Acquired uterine anomalies include intrauterine adhesions and leiomyomata.
clinicians diagnose LPD with midluteal progesterone levels less than 9 ng/mL,
but this method is less accepted.
Currently, the most accepted method for evoluating the luteal phase is by using
urinary luteinizing hormone (LH) testing. If the length of time from the observed
LH change to menses is ≥13 days, then the luteal phase is felt to be adequate.
There are no convincing controlled clinical trials suggesting that proges-
terone supplementation effectively treats LPD or reduces miscarriages. Some
physicians continue to advocate empiric progesterone supplementation for
LPD because it is inexpensive with relatively few side effects. Although pro-
gesterone may not adversely affect a normal pregnancy, however, it may
prolong abnormal pregnancies and ectopic pregnancies. Although proges-
terone is not a known teratogen, potential side effects must be considered
when using any treatment during pregnancy, and medications of unproven
250 benefit should be used cautiously. Clomiphene citrate is another treatment
that has been used to treat LPD, with unproven success.
Polycystic PCOS is a disorder characterized by acyclic production of estrogen via periph-

Ovarian eral aromatization of circulating androstenedione. The clinical diagnosis is
Syndrome based on anovulatory infertility, hirsutism, obesity, acne, and amenorrhea or
oligomenorrhea. PCOS occurs in 5% to 10% of reproductive-age women and is
the most common cause of infertility. Elevated luteinizing hormone (LH) levels
contribute to increased androgen production and enlarged polycystic ovaries.
PCOS-associated hyperinsulinemia adversely affects the endometrium
and preimplantation environment by reducing glycodelin and insulin-like
growth factor I binding protein levels. Glycodelin inhibits the endometrial
immune response against the embryo and is important for embryo survival.
Insulin-like growth factor I binding protein facilitates adhesion at the mater-
nal-fetal interface and is important for implantation. Elevated plasminogen
activator inhibitor (PAI) levels also are associated with insulin resistance and
occur in 52% of women with PCOS compared with 4% of women without
PCOS. PAI inhibits fibrinolysis and may lead to thrombosis and clot forma-
tion in the placenta. All of these factors contribute to pregnancy difficul-
ties in women with PCOS. PCOS is an independent risk factor for RPL and is
associated with miscarriage rates of 30% to 50%.
Diagnostic workup should include ovarian ultrasound, fasting insulin,
testosterone, androstenedione, dehydroepiandrosterone sulfate, LH, follicle-
stimulating hormone, and PAI. Studies suggest that RPL in PCOS can be
treated effectively with metformin, an insulin-sensitizing drug. Metformin
decreases circulating androgens, minimizes the contribution of obesity to
infertility, reduces hyperinsulinemic insulin resistance, decreases PAI activity,
and improves ovulation. In one retrospective study, PCOS women treated with
metformin had an 8.8% miscarriage rate compared with the 42% loss rate
in untreated PCOS controls. Hyperandrogenism is associated with RPL, even
in the absence of PCOS. Androgens may have an antagonistic effect on ovula-
tion and estrogen priming of the endometrium. Diagnostic workup for women
with signs and symptoms of hyperandrogenism should include testing for
abnormalities in testosterone and dehydroepiandrosterone sulfate levels.
Increased Increased LH is found in 33% of women with RPL and may contribute to
Luteinizing premature luteinization. A 65% spontaneous abortion rate is associated with
Hormone increased LH compared with a 12% loss rate in controls. Diagnostic workup
should evaluate LH and follicle-stimulating hormone levels. Treatment with
gonadotropin-releasing hormone agonists to suppress LH release has been
shown to reduce loss rates in some studies. Menotropins (human meno-
pausal gonadotropins) may increase fecundity in women with difficulty
conceiving, but these pregnancies also may be predisposed to spontaneous
abortion. Some investigators theorize that this predisposition to miscarriage
may be due to the fertilization of suboptimal eggs that would have become
atretic in a natural cycle.
Hyperprolacti- Hyperprolactinemia affects the hypothalamic-pituitary-ovarian axis and 251

nemia results in insufficient folliculogenesis and oocyte maturation. Even in the
absence of ovarian or menstrual dysfunction, hyperprolactinemia has been
associated with RPL. In observational studies, treatment with bromocriptine
decreased the spontaneous abortion rate from 47.6% to 14.3%.
Thyroid Overt hyperthyroidism and hypothyroidism have been associated with recur-
rent miscarriage, but correcting thyroid hormone levels results in normal out-
come. Initial screening is by thyrotropin, with appropriate further evaluation
based on the findings.
Diabetes Uncontrolled diabetes mellitus has been associated with a threefold increase
Mellitus in pregnancy loss. Well-controlled diabetes is not a risk factor for RPL, how-
ever. Diagnosis is by oral glucose tolerance screening or by glycosylated
hemoglobin (hemoglobin A1c) levels.
Diagnosis and A pertinent endocrinologic workup should be conducted on all women with
Treatment RPL. Physicians should ensure that treatment choices are guided by well-
designed clinical trials, rather than historical practice. Box 16-4 summarizes
issues related to endocrinopathies and RPL.
INFECTIONS
Infection is a controversial cause of RPL. Although certain infections have

been linked to spontaneous abortion, few are convincingly correlated to RPL.
Bacterial vaginosis is associated with a fivefold increased risk of miscarriage
in the first 20 weeks of gestation. Bacterial vaginosis is an alteration of the
normal vaginal flora associated with loss of lactobacilli and overgrowth of
anaerobic bacteria, including Gardnerella vaginalis, Mycoplasma hominis, and
Ureaplasma urealyticum. Bacterial vaginosis is diagnosed clinically by a thin
gray discharge with fishy odor, pH greater than 4.5, the presence of “clue
Reproductive Endocrinology and Infertility: Requisites
Box 16-4 Summary of Endocrine Abnormalities and Recurrent Pregnancy Loss

● Some investigators believe that 25% of RPL are due to LPDs, but no properly
controlled trials have shown that LPD causes miscarriage.
● PCOS is associated with anovulatory infertility and RPL; studies suggest that
metformin may reduce miscarriage rates in women with PCOS.
cells,” and bacteria-encrusted epithelial cells. The presence of bacterial vagi-

nosis predicts early pregnancy loss in 36% of cases, and absence of bacte-
rial vaginosis predicts normal delivery in 93% of cases. In another study, U.
urealyticum was associated with a 44.4% spontaneous abortion rate before
treatment with erythromycin and an 11.4% rate of spontaneous abortion
after treatment.
252 One study showed that primary infection with herpes simplex virus dur-
ing pregnancy was associated with increased miscarriage, but other studies
dispute this finding. Overall, it is agreed that Toxoplasma gondii, Chlamydia
trachomatis, Treponema pallidum, Borrelia burgdorferi, Neisseria gonorrhea,
Streptococcus agalactiae, Listeria monocytogenes, and cytomegalovirus are
not associated with RPL. There is conflicting evidence regarding the role
of infection in RPL, and additional research is required. Screening for and
treating bacterial vaginosis in patients with RPL seems prudent. Some phy-
sicians advocate empiric antibiotic treatment with a tetracycline, assuming
that infection is a possible cause of RPL. Practitioners should weigh the risk
versus benefit of antibiotic treatment and endometrial culture. Box 16-5
summarizes issues related to infections and RPL.
THROMBOPHILIAS
Increased thrombus formation at the maternal-fetal interface has been impli-

cated in RPL. During pregnancy, changes in hemostasis favor thrombin for-
mation and platelet activation, resulting in a hypercoagulable state. Figure
16-3 reviews the coagulation cascade. Thrombin formation is favored by
increased levels of procoagulant factors VII, VIII, and X, beginning in week
12. With this procoagulant increase, there is no corresponding increase in
natural anticoagulants. Protein S levels decrease by 50% to 60%. In addi-
tion, resistance to activated protein C develops during pregnancy, inhibiting
fibrinolysis, which is required for placentation. A fourfold to fivefold increase
in PAI also reduces fibrinolysis and predisposes to thrombosis.
Platelet activation is favored by increased synthesis of thromboxane before
20 weeks. Coupled with decreased platelet sensitivity to the antiaggregatory
Box 16-5 Summary of Infections and Recurrent Pregnancy Loss

● Bacterial vaginosis, including infection with G. vaginalis, M. hominis, and U.
urealyticum, has been associated with pregnancy loss.
● Empiric antibiotic treatment with doxycycline or erythromycin is frequently
prescribed.
Figure 16-3 Enhances

Intrinsic
The coagulation pathway fibrinolysis
cascade. (Adapted
from Rai R, Regan L:
Thrombophilia and Villa Inhibits
adverse outcome. Activated
Semin Reprod Med protein C
Va Protein S cofactor
2000;18:370.)
Thrombin
Thrombin
AT
Protein C
Fibrinogen Fibrin
AT
253
Thrombin
Thrombomodulin
Endothelial cell
effects of prostacyclins, these platelet mediator changes result in vasospasm

and platelet aggregation, predisposing to placental infarction.
Thrombophilic defects alone may not cause thrombosis, but they decrease
the ability to cope with hypercoagulable states such as pregnancy. During
pregnancy, there is an eightfold increased risk of thrombotic events associated
with the inherited thrombophilias, and women with combined thrombophilic
defects have an even poorer prognosis. Thrombophilic defects are unlikely to
cause very early pregnancy loss because the maternal intervillous network
does not form until gestational week 8, and many of the procoagulant changes
do not begin until week 12. Many of the thrombophilic defects are associated,
however, with losses before 20 weeks (miscarriage) and later in pregnancy
(fetal death). The balance between coagulation and fibrinolysis maintains
intact placental circulation. Microthrombi in placental vasculature lead to
RPL, preeclampsia, and intrauterine growth restriction. Thrombosis of spiral
arteries leads to uterine and placental insufficiencies and fetal loss. Histologic
samples from lost pregnancies support these findings, showing increased fibrin
deposition and clotting and suggesting an underlying cause of thrombosis.
Factor V Leiden The factor V Leiden mutation (G1691A) renders factor V resistant to pro-
Mutation and teolysis and inactivation by activated protein C. Enhanced thrombin gen-
Activated eration and increased clot formation result. The factor V Leiden mutation
Protein C is present in 2% to 6% of the general population, but is probably underdiag-
Resistance nosed because most carriers are asymptomatic. Still, it is the most numeri-
cally important cause of venous thrombosis and familial thrombophilia.
Women with the factor V Leiden mutation are predisposed to spontaneous
abortion, placental infarction, severe preeclampsia, and intrauterine growth
restriction. Nineteen percent of women with RPL are heterozygous and are
at a 5-fold to 10-fold increased risk of venous thrombosis; 6% of women

with RPL are homozygous and are at a 50-fold to 100-fold increased risk
of thromboembolism. Activated protein C resistance results in increased
thrombin formation because factor V is not proteolytically cleaved. Nine
percent of women with RPL have acquired activated protein C resistance
compared with 3.3% of controls.
Prothrombin Factor II, or prothrombin, is converted to thrombin by the factor Va/Xa com-
(G20210A) plex. A single base pair substitution at base 20210 gives rise to increased
Mutation thrombin levels and arteriolar and venous thrombosis. The mutation is
autosomal dominant, and carriers have a twofold increased risk of RPL. Two
to three percent of the general population is heterozygous for the prothrom-
254 bin (G20210A) mutation, whereas 8.8% of women with RPL are heterozy-
gous. The mutation has been found in 6.7% of women with first-trimester
miscarriages compared with 0.8% of normal controls, but has been impli-
cated in early and late losses. Data are conflicting on the association of the
prothrombin (G20210A) mutation and RPL, and further studies are needed.
Methylene MTHFR allows homocysteine to be reconverted into methionine in the

Tetrahydrofolate methionine salvage pathway. Decreased MTHFR activity results in accu-
Reductase mulation of high homocysteine levels, which may cause vascular injury
(C677T) and early arteriosclerosis. Hyperhomocysteinemia has procoagulant effects
Mutation and by decreasing protein C activity and decreasing plasminogen activator.
Hyperhomo- Reduced MTHFR activity and hyperhomocysteinemia may be evident only
cysteinemia in the presence of folate deficiency, however, and adequate folate supplemen-
tation may prevent phenotypic expression of the mutation. Homozygosity
and heterozygosity for the MTHFR (C677T) mutation are associated in some
small studies with increased early fetal loss and twofold to threefold increased
risk for early RPL. Conflicting data on the association between the MTHFR
mutation and RPL necessitate further study.
Antithrombin Antithrombin binds to thrombin, inactivating thrombin and allowing it to be

Deficiency cleared, which also inhibits further thrombin formation. The autosomal domi-
nant antithrombin III mutation is the most thrombogenic of the thrombophil-
ias, but it is extremely rare. The rarity of this mutation makes it difficult to study
in controlled trials. The trials that have been conducted show an associated 44%
to 70% risk of thrombosis or fetal death in pregnancy and a fivefold increased
risk of stillbirth. Antithrombin deficiency is believed to account for 12% of
pregnancy-associated venous thromboembolic events. The exact relationship
between the antithrombin III mutation and RPL must be investigated further.
Factor XII Factor XII deficiency results in defective fibrinolytic activation, disturbed
Deficiency hemostasis, and thromboembolism at the maternal-fetal interface. In one
study, 15% of women with RPL were factor XII deficient (defined as 60%
activity) compared with 0% of control women. Further research is neces-

sary to define the exact role of factor XII deficiency in RPL.
Protein C Protein C and protein S deficiencies result from autosomal dominant muta-
and Protein S tions. The prevalence of protein C deficiency in the general population is
Deficiencies about 1 in 500, whereas the prevalence of protein S deficiency is unknown.
Both deficiencies are associated with a low but significant risk of thrombosis
and fetal death in pregnancy. The risk of postpartum thrombosis is highest.
The exact correlation to RPL requires further study.
Plasminogen PAI decreases fibrinolysis. Increased PAI levels have been found in 38% of
Activator women with RPL and PCOS. 255
Inhibitor
Diagnosis and It is debatable whether factor V Leiden, prothrombin (G20210A), MTHFR

Treatment (C677T), antithrombin III, factor XII, PAIs, and protein C and protein S defi-
ciencies should be included in the workup for RPL, owing to their relative rar-
ity and the lack of evidence associated with treatment outcome. Ultimately,
these thrombophilic disorders should be worked up only in a select popula-
tion of women with personal or familial history of thrombosis or no other
known cause of RPL.
Diagnosis of the inherited thrombophilias is by polymerase chain reaction
or by enzyme level detection. Specifically, the diagnosis of the factor V Leiden
mutation is by polymerase chain reaction amplification of exon 10 in the
factor V gene, and the MTHFR (C677T) mutation is diagnosed by polymerase
chain reaction amplification of exon 2 and the intron of the MTHFR gene.
The diagnosis of antithrombin III and protein C and protein S deficiencies is
by enzyme assay.
In one study, treatment of women with thrombophilic defects with low-
molecular-weight heparin increased the live birth rate from 20% to 75%.
Other investigators advocate the use of heparin and aspirin. Good clinical
trials measuring the outcome of anticoagulant therapy are largely lacking,
however. More trials are necessary to establish specific treatment benefits
and dosages. One known treatment for the MTHFR mutation is supplementa-
tion with vitamin B6 and folate, which has effectively suppressed phenotypic
expression of hyperhomocysteinemia in some women. Future studies aimed
at improving understanding of maternal intervillous blood flow, investi-
gating the role of fetal thrombophilic defects in pregnancy outcome, and
prospective trials with anticoagulant treatment are warranted. Box 16-6
summarizes issues related to thrombophilias and RPL.
IMMUNOLOGIC FACTORS
There are many proposed immunologic mechanisms for RPL, including auto-
immune etiologies (antiphospholipid syndrome [APS], other autoantibodies)
Box 16-6 Summary of Thrombophilias and Recurrent Pregnancy Loss

● Pregnancy is a hypercoagulable state.
● Thrombosis of spiral arteries leads to placental insufficiency and RPL in women
with thrombogenic defects.
● The clinician should test for factor V Leiden, prothrombin (G20210A), and
MTHFR (C677T) mutations in women with a personal or family history of
thrombosis and RPL.
● Future trials on anticoagulation therapy and pregnancy outcome are warranted.
and alloimmune etiologies. With the exception of APS, the immunologic

etiologies of habitual abortion are poorly understood.
256
Antiphospho- APS is an autoimmune disorder characterized by antiphospholipid antibod-
lipid Syndrome ies and one or more clinical features, including RPL, unexplained fetal death,
autoimmune thrombocytopenia, and thrombosis. The primary antiphos-
pholipid antibodies are lupus anticoagulant (LAC) antibody and anticardio-
lipin antibody (ACA). These autoantibodies inhibit prostacyclins, which are
potent vasodilators and inhibitors of platelet aggregation. Protein C activa-
tion also is inhibited, resulting in a procoagulant environment that favors
thrombosis. Fetal death most likely occurs as a result of uteroplacental insuf-
ficiency from spiral arteriolar vasculopathy. In severe cases, decreased inter-
villous blood flow leads to placental infarction. APS is the cause of recurrent
miscarriage in 5% to 10% of women and is most commonly associated with
second-trimester loss. Seven percent of women with RPL are LAC antibody
positive, and 19% are ACA positive, whereas only 2% of normal women have
antiphospholipid antibodies.
LAC antibody is found most commonly in women who do not meet the
diagnostic criteria for systemic lupus erythematosus. LAC antibody is
diagnosed by activated partial thromboplastin time, dilute Russell’s viper
venom time, kaolin clotting time, or plasma clotting time. Abnormalities are
confirmed by mixing the patient’s plasma with normal plasma, which does
not correct the abnormality if inhibitor is present. Without treatment, LAC
antibody is associated with an 80% spontaneous abortion rate.
ACA is associated with a 38% fetal loss rate. ACA IgG and IgA are diagnosed
on a continuum, but only medium-positive and high-positive titers (20 GPL
units) are associated with RPL. High titers and previous history of fetal loss
are additive risk factors influencing pregnancy outcome.
It is important to diagnose APS because it is a treatable condition. Treatment
for APS is aimed at antiplatelet, anticoagulant, or immunosuppressive activ-
ity. Heparin binds to antiphospholipid antibodies, preventing their harmful
effects. The most accepted APS treatment is heparin and aspirin therapy
for maximum anticoagulation. Combination therapy has a better outcome
than either aspirin or heparin treatment alone. With optimal treatment, the
spontaneous pregnancy loss rate is reduced to 15%. Treatment with pred-
nisone and aspirin has a similar outcome as heparin and aspirin therapy.
Glucocorticoids are discouraged, however, because they are associated with
high maternal and fetal morbidity, including premature rupture of mem-

branes and preeclampsia.
Some physicians also advocate intravenous immunoglobulin (IVIG)
immunotherapy, but there are no trials showing clinical or statistical benefit.
There have been case reports of successful pregnancy with IVIG in hepa-
rin-resistant cases. Large clinical trials show, however, that addition of IVIG
to heparin and aspirin therapy does not improve the number of live births,
preeclampsia, fetal growth impairment, birth weight, or gestational age at
delivery. The efficacy of IVIG treatment for APS is uncertain, and IVIG can-
not be advocated at this time because of its high expense and lack of proven
benefit.
Thyroid Thyroid autoantibodies (antithyroglobulin and antimicrosomal antibod- 257

Autoantibodies ies) are associated with RPL, but the pathophysiology is poorly understood.
One hypothesis is that thyroid autoantibodies are markers of abnormal T
cell function or a generalized immune reaction against the fetal allograft.
Another hypothesis is that thyroid autoantibodies are signs of mild hypo-
thyroidism or decreased thyroid reserve. A third theory states that preg-
nancy loss results directly from thyroid peroxidase autoantibodies. Thyroid
peroxidase autoantibody titers are higher at initial presentation in women
who later miscarry. The presence of antithyroglobulin or antimicrosomal
antibodies in early pregnancy, or just before pregnancy, is associated with
a 17% risk of loss compared with 8% loss rates in normal controls. Despite
this association, there is no benefit to testing routinely for thyroid autoanti-
bodies because there is no recognized treatment, and their presence is not a
modifiable risk factor.
Systemic Lupus A diagnosis of systemic lupus erythematosus is associated with a 22% total
Erythematosus pregnancy loss rate; 75% of losses secondary to systemic lupus erythemato-
sus are in the second or third trimesters. The prognosis is significantly better
for women with quiescent disease. Conception should be delayed until lupus
is in remission.
Other Antinuclear antibodies are more common in women with RPL, but the pres-
Autoantibodies ence or absence of antinuclear antibodies does not predict pregnancy out-
come. In addition, there is no proven treatment for women who test positive
for antinuclear antibody, so antinuclear antibodies should not be routinely
tested in the RPL workup. Anti-β2 glycoprotein 1 is not independently associ-
ated with increased risk of pregnancy loss and does not predict adverse out-
come. It should not be included in the routine diagnostic workup for RPL.
Alloimmunity Successful gestation depends on an immunologic milieu that allows the

mother to maintain the antigenically dissimilar fetal allograft in the uterus.
Little is known, however, about the mechanisms that prevent immunologic
rejection of the fetus in successful pregnancies. Some practitioners believe

that HLA sharing between parents contributes to pregnancy loss, as the
woman produces minimal antipaternal antibodies, which are required to
produce blocking antibodies. This model is unlikely because HLA sharing
does not preclude healthy pregnancy in most women, and there is no con-
vincing statistical difference in the degree of HLA sharing between couples
experiencing RPL and normal couples.
The cytotoxic immune rejection theory states that leukocytic antibody
activity increases in normal pregnancies, but not in women with RPL.
This activity is probably a result of the number and duration of pregnan-
cies and does not influence subsequent pregnancies. A third theory is that
the maternal humoral response is necessary to prevent rejection of the
fetal allograft. These maternal blocking antibodies are not universally
258 present in normal pregnancies, however, and are not predictive of preg-
nancy outcome.
Even in the absence of known alloimmune etiology, some physicians
administer costly immunotherapy. One treatment is paternal leukocyte
immunization to prevent paternally derived antigen expressed on embry-
onic tissue from resulting in fetal rejection. Well-designed trials have
shown this therapy to be ineffective, however, at improving pregnancy
outcome in women with recurrent miscarriage. IVIG also has been sug-
gested as treatment for alloimmune causes of RPL. As discussed earlier,
however, IVIG cannot be recommended because of lack of efficacy and
high cost.
APS remains the only known humoral cause of RPL, and it is effectively
treated with heparin and aspirin anticoagulation therapy. Future research
undoubtedly will elucidate additional immunologic mechanisms in RPL.
Box 16-7 summarizes immunologic issues related to RPL.
LIFESTYLE AND ENVIRONMENTAL FACTORS
Many couples experiencing RPL are concerned that environmental toxins

may contribute to their reproductive difficulties. Popular media coverage
often leads to exaggerated or inappropriate conclusions from research data.
It is important for physicians to relate accurate and current information
about the effects of lifestyle and the environment on pregnancy. Particular
attention should be focused on modifiable risk factors, such as alcohol and
tobacco use.
Box 16-7 Summary of Immunology and Recurrent Pregnancy Loss

● APS is the only known immunologic cause of RPL and is characterized by LAC
antibody and ACA, thrombosis, and repeated miscarriage.
● The preferred treatment of APS involves heparin and aspirin therapy.
● Little is known about alloimmune mechanisms of RPL.
Alcohol Alcohol use in the first 8 weeks of gestation is associated with consider-
able risk of miscarriage. Drinking twice weekly is associated with a twofold
increase in spontaneous abortion, and daily alcohol use is associated with
a threefold increased risk of miscarriage. Alcohol should be avoided during
pregnancy.
Tobacco Smokers have 25% to 50% more spontaneous abortions than nonsmok-
ers, and the risks are proportional to cigarettes smoked per day. Smoking
more than 14 cigarettes per day is associated with a twofold increased risk of
miscarriage. Tobacco should be avoided during pregnancy.
Caffeine Drinking fewer than 1.5 cups of coffee each day has not been associ- 259
ated with increased pregnancy loss, but drinking more than 3 cups each
day (300 mg of caffeine) is associated with a twofold increase in sponta-
neous miscarriages. The relationship between caffeine and miscarriage
may not be causal, however, because women with viable pregnancies
are more likely to experience nausea and reduce their caffeine intake.
Women with nonviable pregnancies are more likely to defer curtailment
of caffeine use, which may contribute to an overestimated relative risk.
Still, it is recommended that women with a history of RPL limit their
caffeine intake.
Radiation Ionizing radiation is an abortifacient in sufficient doses (>5 cumulative rads).

The average chest x-ray administers 8 mrads, and a barium enema deliv-
ers 800 mrads. Therapeutic radiation delivers 360 to 500 rads and almost
always causes miscarriage.
Hyperthermia Maternal hyperthermia resulting from fever or hot tub use is teratogenic and
and Fever results in neural tube defects and spontaneous abortion. Hot tub and sauna
use should be avoided during pregnancy.
Tap Water High exposure to bromodichloromethane in tap water has been associated
with a twofold increase in spontaneous abortions. In one California study,
women who drank more than 6 glasses of tap water daily had a 10% to 50%
increased risk of miscarriage. Other studies report conflicting evidence,
however, and the exact risk of drinking tap water is unknown.
Other Factors There is significant evidence that lead and mercury increase the risk of mis-
carriage. There is some evidence for the contribution of arsenic, formalde-
hyde, benzene, ethylene oxide, and nitrous oxide to pregnancy loss. Box 16-8
summarizes environmental and lifestyle issues related to RPL.
Box 16-8 Summary of Lifestyle and Environmental Factors and Recurrent

Pregnancy Loss
Evidence suggests that frequent use of alcohol, tobacco, and caffeine contribute to
spontaneous miscarriage.
CONCLUSION
Many causes of RPL have been discussed in this chapter. Table 16-1 summa-
rizes comprehensive diagnostic workups and treatments. It is unlikely that
any one couple would require all of this testing. In 30% to 40% of couples,
260 Table 16-1

Etiology, Diagnosis, Standard Diagnostic Supplemental
and Treatment of Etiology Tests Diagnostic Tests Treatment
Recurrent Pregnancy
Loss Genetic error Cytogenetic testing PCR of single gene Genetic
mutation, counseling,
clomiphene citrate prenatal
challenge test testing,
preimplantation
genetic
diagnosis
Uterine Sonohysterography Ultrasound, HSG, Surgical
anomalies MRI correction,
prophylactic
cervical
cerclage
Endocrinop- Endometrial biopsy, Androstenedione, Correction of
athies progesterone testosterone, endocrinopathy
DHEAS, prolactin, when possible
LH, FSH, thyro-
tropin, fasting
insulin
Infections None U. urealyticum, Antibiotics
G. vaginalis,
M. hominis
cultures; screen
for bacterial
vaginosis
Thrombophilias Factor V Leiden, Antithrombin, Consider
prothrombin protein C, anticoagulation
G20210A, protein S,
MTHFR C677T factor XII, PAI
Immunologic LAC antibody, ACA None Heparin and
factors IgG, ACA IgM aspirin,
prednisone
and aspirin
Environment Tobacco, alcohol, Test for lead, Avoid exposure
and lifestyle and caffeine use mercury
by history
DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; PCR, polymerase

chain reaction.
no etiology is determined after complete diagnostic workup. This situation

can be frustrating and disheartening for affected couples. Informative and
sympathetic counseling plays an essential role in this difficult situation. It is
important to explain that couples experiencing RPL have live birth rates of
70% in subsequent pregnancies, even without treatment. This figure may
provide comfort and hope to grieving couples. It is imperative to recognize
that fear for future pregnancies is a prominent emotion, and the grieving
process for lost pregnancies can last a lifetime.
Some studies suggest that a “tender loving care” approach, including weekly
ultrasound studies for assurance of fetal interval growth, improves subsequent
pregnancy outcome. Regardless, adequate psychological support should be
offered to all couples undergoing evaluation and treatment for RPL.
Given the high emotional and financial costs of some existing therapies,
proof of efficacy from well-designed randomized controlled trials should be 261
required. Patients undergoing experimental therapies should be aware of
the risks and unproven nature before receiving treatment. There is a clear
need for future clinical therapeutic trials that meet epidemiologic standards,
including randomization, double-blindedness, and placebo control. Future
studies should focus on women with unknown causes of RPL. Including
women with two consecutive losses should be considered because the
risk factors for subsequent losses seem to be similar, and this would increase
sample sizes substantially.

1. RPL is defined as three or more consecutive losses before 20 weeks’
gestation.
2. RPL can have diverse etiologies, including genetic, structural uterine,
endocrine, infectious, thrombophilic, immunologic, and environmental
factors.
3. An identifiable etiology is not found in 30% to 40% of RPL.
4. Treatment decisions should be based on evidence from well-designed
clinical trials.
5. RPL is frustrating and frightening for couples, and appropriate psycho-
logical support is important.
SUGGESTED READINGS
Clifford K, Rai R, Watson H, Regan L: An informative Medicine, 2nd ed. Stamford, CT: Appleton & Lange;
protocol for the investigating of recurrent miscar- 1998:679-692.
riage: preliminary experience of 500 consecutive Ober C, Karrison T, Odem RR, et al: Mononuclear-cell
cases. Hum Reprod 1994;9:1328-1332. immunisation in prevention of recurrent miscar-
Hill JA: Recurrent pregnancy loss. In: Creasy RK, riages: a randomised trial. Lancet 1999;354:365-369.
Resnick (eds): Maternal-Fetal Medicine, 4th ed. Rai R, Regan L: Thrombophilia and adverse pregnancy
Philadelpha: Saunders;1999. outcome. Semin Reprod Med 2000;18:369-377.
Kutteh WH: Recurrent pregnancy loss. In: Carr BR, Stephenson MD: Frequency of factors associated with habi-
Blackwell RE (eds): Textbook of Reproductive tual abortion in 197 couples. Fertil Steril 1996;66:24-29.
Stray-Pederson B, Stray-Pederson S: Etiologic Warburton D, Kline J, Stein Z, Strobino B:

factors and subsequent reproductive performance Cytogenetic abnormalities in spontaneous abor-
in 195 couples with a prior history of habitual tion of recognized conceptions. In: porter IH (ed):
abortion. Am J Obstet Gynecol 1984;148: Perinatal Genetics: Diagnosis and Treatment.
140-146. New York: Academic Press; 1986;23-40.
262
262
17
ASSISTED
REPRODUCTIVE
TECHNOLOGIES
Deborah L. Manzi-Smith
263
DEFINITIONS
In vitro Fertilizing retrieved oocytes by insemination with sperm
fertilization
Intracytoplasmic Injecting single sperm directly into ooplasm of oocyte
sperm injection
Assisted Creating a defect in zona pellucida of cleaving embryo to enhance
hatching implantation
Gamete Placing sperm and oocytes in a normal fallopian tube to achieve in vivo
intrafallopian fertilization
transfer
Embryo transfer Atraumatically placing an embryo into uterine cavity to achieve
pregnancy
Ovarian hyper- Complication of assisted reproductive technologies resulting in ovarian
stimulation enlargement, increased vascular permeability, hemoconcentration, and
syndrome ascites
Although many assisted reproductive technologies (ART) exist with a bewil-

dering array of acronyms (Box 17-1), their goal is the same. ART procedures
attempt to bring sperm and oocyte close together to increase the likelihood
of fertilization, implantation, and delivery of a healthy infant. Initially, in
vitro fertilization (IVF) was used only in patients with tubal factor infertil-
ity; however, in the 1980s, the application of IVF was broadened to include
patients with male factor infertility, endometriosis, unexplained infertil-
ity, and immunologic infertility. The technology has improved significantly
since the 1980s, and the rapid developments in the field suggest that these
improvements will continue.
Box 17-1 Acronyms for Assisted Reproductive Technologies

IVF—in vitro fertilization
GIFT—gamete intrafallopian transfer
ZIFT—zygote intrafallopian transfer
ET—embryo transfer
PGD—preimplantation genetic diagnosis
ICSI—intracytoplasmic sperm injection
AH—assisted hatching
MESA—microsurgical epididymal sperm aspiration
TESE—testicular sperm extraction
GENERAL PRINCIPLES
264
Oocytes obtained from ovarian follicles by aspiration are prepared and com-
bined with sperm in a dish in the laboratory. Fertilization occurs outside
the body with IVF (in vitro) or in the body (in vivo) with gamete intrafal-
lopian transfer (GIFT). The outstanding effort of Edwards and Steptoe that
produced the first IVF birth was achieved using a nonstimulated (natural)
cycle with timing of the oocyte retrieval based on urinary luteinizing hor-
mone (LH) levels. Nonstimulated cycles have been used to reduce costs, but
pregnancy rates are only 10%. Most patients undergoing IVF procedures
receive gonadotropins to increase the number of oocytes available for oocyte
retrieval. A careful balance between producing numerous oocytes and pre-
venting hyperstimulation is sought. Although multifollicular development
can be achieved by using clomiphene citrate, most patients require injected
preparations of follicle-stimulating hormone (FSH) to produce an adequate
number of oocytes.
CONTROLLED OVARIAN HYPERSTIMULATION
The process of creating an increased number of oocytes using medications

is called controlled ovarian hyperstimulation. This stimulation is accomplished
through the administration of medications such as clomiphene citrate,
human menopausal gonadotropins (HMG), or follitropin (FSH). There are
several formulations of HMG and FSH. Some formulations contain FSH and
LH, whereas others contain FSH only (Table 17-1). Careful patient monitor-
ing is required on a regular basis to prevent too many follicles from develop-
ing. Ultrasound of the ovaries and monitoring plasma estradiol levels are
used to evaluate the effects of the superovulation medication and to help
prevent overstimulation. The dose of medication is titrated almost daily to
achieve the desired response. Most IVF cycles involve pretreatment with
oral contraceptive pills and with a gonadotropin-releasing hormone agonist
(GnRH) or midcycle treatment with a GnRH antagonist. Human chorionic
gonadotropin is given when the lead follicles are 18 mm or greater in diam-
eter. Human chorionic gonadotropin is usually given 34 to 38 hours before
Assisted Reproductive Technologies
Table 17-1
Types, Gonadotropin Gonadotropin Content per Vial (IU)
Content, and
Brand Names of Type of Gonadotropin FSH LH Brand Name
Gonadotropin
Human Derived
Preparations Used in
HP FSH 75 <0.1 Bravelle
the United States
hFSH 75 <1 Metrodin
HMG 75 75 Pergonal,
Repronex
Recombinants
rFSHα 37.5–1200 None Gonal-f
rFSHβ 50–600 None Follistim
hFSH, human follicle-stimulating hormone; HMG, human menopausal gonadotropin; HP FSH,

highly purified follicle-stimulating hormone; rFSHα, recombinant follicle-stimulating hormone α;
rFSHβ, recombinant follicle-stimulating hormone β. 265
the planned retrieval procedure. About 15% of cycles in the United States
are cancelled before oocyte retrieval because the response to superovulation
is excessive and the risk of ovarian hyperstimulation syndrome (OHSS) is
substantial or because the response to ovarian stimulation is poor.
MEDICATIONS COMMONLY USED IN ASSISTED REPRODUCTIVE

TECHNOLOGY PROCEDURES
Oral The use of oral contraceptive pills in ART stimulation protocol is a more
Contraceptives recent innovation. Monophasic preparations of oral contraceptive pills have
been used to allow greater flexibility in the schedule of cycle start dates. Oral
contraceptive pills also are used for their known effect on ovarian cysts and
to suppress spontaneous ovulation. Patients receiving oral contraceptive
pills are less likely to have large ovarian or corpora lutea cysts at the initia-
tion of the IVF cycle. These cysts may delay cycle initiation.
Human The high degree of success with modern IVF would not be possible with-
Menopausal out the use of HMG or FSH. In 1954, pooled extracts of FSH from meno-
Gonadotropins pausal urine were noted to be clinically effective in stimulating oocyte
and Follitropin production. The process of extracting FSH was described in 1961 with
the first pregnancy from HMG occurring in 1962. There are several for-
mulations of HMG available; now recombinant FSH also is available (see
Table 17-1). Disagreement in the literature exists as to which is the better
formulation to use. Some studies have shown better oocyte quality with
FSH-only regimens compared with HMG or HMG/FSH combination regi-
mens. Other studies showed no difference in oocyte quality between the
regimens.
Gonadotropin- GnRH agonist has been used in IVF to induce a temporary hypogonadal state.
Releasing The use of GnRH agonist has led to an improvement in stimulation protocols
Hormone allowing for more synchronous development of follicles. The use of GnRH
Agonists agonist also has almost eliminated the premature LH surge and effects of
increasing progesterone on developing follicles. Before GnRH agonist was
used in IVF cycles, there was a higher cancellation rate and higher propor-
tion of postmature oocytes. GnRH agonist use has increased IVF pregnancy
rates and has allowed flexible timing of the IVF cycle. GnRH agonist induces
desensitization of the gonadotropic cells by decreasing the number of GnRH
receptors on the cell membrane.
Gonadotropin- GnRH antagonists (Cetrotide, Ganirelix) have been introduced into IVF pro-
266 Releasing tocols only more recently in the United States. These agents allow for greater
Hormone flexibility in timing IVF cycle starts and effectively eliminate LH surges. GnRH
Antagonists antagonists typically are started after stimulation with FSH/HMG has begun.
GnRH antagonists have minimal systemic side effects and have a higher bind-
ing affinity for the GnRH receptor than the native GnRH molecule. GnRH
antagonists act by competitive blockade of the GnRH receptor and are charac-
terized by an immediate suppression of pituitary gonadotropin release with-
out inducing an initial stimulatory response. There is a short recovery phase
of 2 to 4 days after GnRH antagonist use. The main application of GnRH
antagonists is the suppression of LH surges during gonadotropin stimulation;
however, GnRH antagonist use may be expanded for use in the treatment of
fibroids, endometriosis, and female genital tract cancers.
ASSISTED REPRODUCTIVE TECHNOLOGY TECHNIQUES
Oocyte Retrieval In the past, oocytes were collected using laparoscopic techniques, but now
and Oocyte transvaginal follicle aspiration guided by ultrasound is the method of choice
Identification for oocyte retrieval. Transvaginal oocyte retrieval is typically performed
using conscious sedation, although general anesthesia and spinal anesthe-
sia have also been used. Most women are able to leave the office within 1 to
2 hours after the oocyte retrieval procedure.
Oocyte retrieval is performed by aspirating each follicle in turn under
ultrasound guidance, usually through a single vaginal needle puncture for
each ovary. The follicular fluid (Fig. 17-1) collected is examined immedi-
ately under an operating microscope for the presence of a cumulus mass
that contains an oocyte (Fig. 17-2). When the oocytes are collected, they are
immediately placed in a culture medium containing the essential nutrients.
Approximately 4 to 5 hours after retrieval, the oocytes are inseminated with
sperm. A major discovery in ART was that sperm need not be added to the
oocytes immediately after retrieval, and a delay of 4 to 6 hours improves
fertilization rates.
GIFT is another ART modality that can be used only in women with at
least one patent tube. GIFT is a laparoscopic technique in which the trans-
fer of gametes to the fallopian tube allows for in vivo fertilization. GIFT was
Figure 17-1
Follicular fluid in
test tube at oocyte
retrieval.
267
first reported in 1984. By 1986, GIFT was commonly used throughout the
United States. As with IVF cycles, GIFT uses controlled ovarian hyperstimu-
lation followed by oocyte retrieval. GIFT can involve laparoscopic retrieval
of oocytes or transvaginal ultrasound–guided retrieval. The fallopian tube is
cannulated laparoscopically, and sperm and oocytes are injected into the dis-
tal fallopian tube. In the era of laparoscopic oocyte retrieval and poor embryo
culture techniques, GIFT made good sense. Now, with simplification of IVF
and improvement in culture conditions, GIFT is comparatively less effective
and more invasive. It should be used in a very select population, specifically
individuals whose religion or ethics proscribe in vitro fertilization.
Insemination of Routine Insemination

Oocytes Depending on the sperm quality, oocytes may be inseminated using “rou-
tine” fertilization (oocytes placed with sperm in a Petri dish) or through
micromanipulation techniques, such as intracyctoplasmic sperm injection
(ICSI). Sperm are prepared by washing and centrifugation. For routine fertil-
ization, 50,000 to 100,000 motile sperm are placed in a Petri dish with an
oocyte. Fertilization can be detected 12 to 20 hours after insemination by
Figure 17-2
Cumulus mass
represents single
oocyte.
268
the presence of two pronuclei found in the cytoplasm of the oocytes and the
presence of two polar bodies in the perivitelline space (Fig. 17-3). Fertilization
rates of greater than 60% of mature oocytes should be expected. Twenty-
four hours after insemination, the pronuclear membranes dissolve allowing
combination of the maternal and paternal chromatids (syngamy), which is
followed by the first cleavage division to a two-cell embryo (Fig. 17-4).
Intracytoplasmic Sperm Injection

The limited success with intrauterine inseminations for male factor infertil-
ity has led to numerous individuals pursuing ART in an attempt to achieve
pregnancy. Initial experience with IVF without sperm injection techniques
for male factor infertility was disappointing, with low fertilization and preg-
nancy rates. IVF has allowed access to the oocyte and the opportunity for IVF
technicians to facilitate entry of sperm into the oocyte. The early techniques
of facilitating sperm entry included partial zona dissection and subzonal
insertion. One of the greatest advances in IVF success can be attributed to
Van Steirteghem and coworkers in Belgium, who perfected the technique of
ICSI. With ICSI, a single sperm is injected into a mature oocyte. The possibil-
ity of achieving pregnancy with only a single sperm launched a revolution
in IVF. Sperm used for ICSI not only have been obtained from the ejaculate,
but also in men with no sperm in the ejaculate by using microsurgical epi-
didymal sperm aspiration or testicular biopsy (testicular sperm extraction).
A few sperm also have been identified in men with Sertoli cell–only syndrome
Figure 17-3
Zygote 12
to 20 hours
postinsemination
with two pronuclei
represents successful
fertilization.
269
and used for ICSI. Sperm precursors (spermatids, immotile sperm) have been
used for ICSI, but fertilization rates using immature or immotile sperm have
been lower than the rates using motile sperm. ICSI is the treatment of choice
for severe oligospermia, microsurgical epididymal sperm aspiration or testic-
ular sperm extraction derived sperm, or severe antisperm antibodies. There
is a less than 5% chance of damage to the oocyte with ICSI in experienced
laboratories.
Since the introduction of ICSI, there has been concern about its safety.
ICSI is an invasive procedure, which may bypass the “natural selection”
mechanisms that sperm encounter during the course of natural concep-
tion. Additionally, small amounts of culture medium are injected into
oocytes with the ICSI procedure, as are sperm components (i.e., acrosome)
that normally do not enter the oocyte, with unknown effects. Data suggest
that there is a slight increase in de novo sex chromosome aneuploidy (0.6%
versus 0.2%) and structural autosomal abnormalities (0.4% versus 0.07%)
with ICSI compared with the general neonatal population. There also are
an increased number of inherited structural aberrations mostly from the
infertile male partner. There seems to be no increased risk, however, for
major and minor malformations in ICSI children compared with naturally
Figure 17-4
Two-cell embryo in
culture.
270
conceived children, despite these chromosomal defects. Early studies that

have evaluated development of children born through IVF with ICSI do not
reveal significant problems.
In Vitro Culture An amazing discovery with IVF was that embryos are able to complete their
of Embryos development in vitro (Figs. 17-4 through 17-6). Tissue culture techniques
for human embryos were largely borrowed from existing animal models. The
media used to maintain the growth of embryos have changed dramatically
since the late 1980s with the recognition that the metabolic requirements of
a cleavage stage embryo that was only 24 hours old were significantly differ-
ent than the requirements of a morula or blastocyst embryo. The incubator
environment also is strictly controlled with respect to temperature, air qual-
ity, pH, and oxygen tension for optimal embryo development.
Embryo Transfer Generally, embryos are transferred to the uterus on day 2, 3, or 5 after
insemination, by which time the embryos have divided into two, four, or
eight cells or the morula/blastocyst stage. Usually one to four embryos are
transferred together in a tiny amount of embryo culture medium using a
variety of soft plastic embryo transfer catheters. The number of embryos
to transfer is based on the patient’s age, ovarian reserve, and prior history.
Transabdominal ultrasound is often used to facilitate the transfer procedure
and confirm placement of embryos in the uterine cavity. Embryos of good
Figure 17-5
Four-cell embryo in
culture.
271
morphologic grade in excess of those transferred can be cryopreserved for

future use.
Luteal Phase In natural cycles, the ovary produces progesterone after ovulation. There is evi-
Support dence, however, that premature luteolysis may occur with some IVF regimens.
Most IVF centers administer progesterone supplementation via intramuscular
injections. Human chorionic gonadotropin also can be used for luteal support.
Vaginal pessaries, gel-like formulations, suppositories, and oral micronized
progesterone have been used for postretrieval progesterone supplementation,
but there is evidence that these may not be as effective as progesterone in oil or
human chorionic gonadotropin intramuscular injections.
Embryo Cryo- Embryo cryopreservation provides couples with the option of freezing their
preservation unused embryos. The first pregnancy using cryopreserved embryos from
an earlier IVF cycle was reported in 1984. Cryopreservation of embryos
offers patients the opportunity to increase their chance of pregnancy after
a single retrieval procedure. It is possible to cryopreserve embryos from the
one-cell stage to the blastocyst stage. Cryopreservation reduces the num-
ber of HMG/FSH cycles and oocyte retrievals most patients would undergo.
Approximately 75% of women younger than age 35 with good ovarian
reserve have excess embryos to freeze compared with 20% of women older
Figure 17-6
Blastocyst in culture
approximately 5 days
after fertilization.
272
than 35. Pregnancies have resulted from embryos cryopreserved for many
years. There is no known limit on the duration of storage for a cryopreserved
embryo. There seems to be no increased risk of chromosomal abnormali-
ties or spontaneous pregnancy loss in patients achieving pregnancy with
cryopreserved embryos. Cryopreservation of embryos has contributed to
the decrease in multiple pregnancy rates with IVF. Patients can be counseled
that the freeze-thaw embryo survival rate is approximately 80%.
Assisted Failure of implantation and conception might result from inability of the
Hatching embryo at the blastocyst stage to escape from its zona pellucida. Assisted
hatching involves the use of mechanical or chemical thinning of the zona
pellucida surrounding the embryo before transfer. There is no clear evi-
dence that assisted hatching has an impact on live birth rate when used in
all IVF patients, but assisted hatching may be beneficial when used in select
patients. Assisted hatching may increase pregnancy rates in women older
than 38 years women with diminished ovarian reserve, women with poor-
quality embryos, women with previous failed IVF attempts, or women with
a thick zona pellucida.
PREIMPLANTATION GENETIC DIAGNOSIS
The detection of genetic disorders in human embryos has transformed the

diagnosis of diseases from postimplantation to the preimplantation period.
Preimplantation genetic diagnosis (PGD) is the genetic diagnosis of gametes
and conceptuses before implantation in the uterus. The techniques used in
PGD are possible only because of more recent developments in IVF coupled
with revolutionary developments in molecular biology. Although the appli-
cation of PGD has generated considerable controversy, the number of PGD
cases continues to increase.
PGD is a technically challenging procedure that requires an understand-
ing of embryology and molecular biology. During IVF, oocytes and embryos
are readily accessible, allowing a biopsy specimen to be taken from the oocyte
or embryo. Many micromanipulation techniques applied to PGD originally 273
were developed for use in animal husbandry. Three major aspects of PGD
have been applied successfully: sex determination, chromosomal analysis,
and the detection of single-gene defects. These techniques are accomplished
with the addition of micromanipulative procedures for oocyte or embryo
biopsy, fluorescent in situ hybridization (FISH) for chromosomal analysis, or
polymerase chain reaction (PCR).
PGD is initiated with collection of genetic material, which must be
accomplished without compromising embryo development (Box 17-2).
The amount of genetic material that can be removed safely is limited,
restricting the use of confirmational analysis. The complexity of PGD is
compounded by the fact that the embryos must be implanted in a synchro-
nized uterus. The entire procedure from the time of biopsy to implanta-
tion of the embryos in the uterus must be completed in a limited time. In
general, embryos should be transferred within 48 hours of embryo biopsy.
Despite its drawbacks, PGD is rapidly becoming an integral part of many
IVF programs.
Biopsy Polar body biopsy is performed before fertilization of the oocyte in an attempt
Techniques to identify maternal genetic defects. The technique of the polar body biopsy
is used for “preconception” genetic diagnosis. This technique can be used
only if the female partner is the carrier of the genetic defect. The oocyte
is arrested at the diplotene stage of meiosis until further resumption of
meiosis occurs at the time of the LH surge. At the time of ovulation, the
first meiotic division is completed, and the first polar body is extruded. This
extruded polar body does not contribute to the subsequent development
of the embryo; removal of the polar body is thought to impose minimal
Box 17-2 Techniques for Obtaining Genetic Material

● Polar body biopsy
● Blastomere biopsy
● Blastocyst trophectoderm biopsy
Reproductive Endocrinology and Infertility: Requisites
adverse effects on development after fertilization. Problems do exist with the

use of the polar body. In the second meiotic division, the chromosomes con-
taining normal and abnormal alleles from a heterozygous carrier segregate
independently into the primary oocyte and polar body. If the polar body
contains the abnormal allele, this would indicate that the oocyte contained
the complementary normal allele. Conversely, if the polar body contains the
normal allele, this would indicate that the primary oocyte contained the
abnormal allele.
The accuracy of this technique relies on the fact that homologous gene
pairs do not cross over. Crossover occurs more commonly at the telomeric
(distal) region of the chromosome than at the centromere. Location of the
gene on the chromosome becomes important for accurate diagnosis. Timing
also is important in polar body biopsy. The polar body should be retrieved
274 within 4 to 6 hours after oocyte collection. Shortly after retrieval, the oocytes
are treated with hyaluronidase to remove the cumulus cells to expose the
polar body for ease of removal, after which ICSI is performed as a means
of insemination. Conventional insemination techniques would increase
the probability of polyspermia in oocytes that have had their cumulus cells
removed.
More than 5000 known genetic mutations are associated with specific
inherited diseases for which polar body biopsy can be used. More than
two dozen have been used for PGD. Despite its theoretical drawbacks,
this technique has been used for preconception diagnosis in patients at
risk for cystic fibrosis, sickle cell anemia, hemophilia, and α1-antitrypsin
deficiency.
There is general agreement that obviating disease by preventing fertiliza-
tion of abnormal oocytes is justifiable. Public acceptance of PGD is higher
for techniques that favor early intervention. Acceptance of techniques per-
formed before fertilization is higher compared with techniques performed
before implantation.
Multicellular embryo biopsy is classified according to stage of embryo
development. Blastomere biopsy samples cleavage stage blastomeres.
Blastocyst trophectoderm biopsy involves the removal of numerous cells
from the trophectoderm. Blastomere biopsy is best used to assess chromo-
somal number, multinucleation, or polyploidy. Blastocyst trophectoderm
biopsy is best used for determining single gene defects and mosaicism.
Embryo biopsy on day 3 of development is the most common method.
Typically, when an embryo reaches the 6- to 12-cell stage, a single cell is
removed. Despite the reduction in cell number, good pregnancy rates exist
using this technique. The biopsy should be done as early as possible on day 3
before the development of tight gap junctions that occur at the start of cel-
lular compaction.
Blastocyst trophectoderm biopsy is associated with added advantages
compared with biopsy at earlier stages. This technique, used extensively in
animal science, allows for the removal of multiple cells. Blastocyst biopsy is
a technically challenging procedure. This technique and blastomere biopsy,
in contrast to polar body biopsy, can be used for male or female carriers of
the genetic disease.
Genetic Analysis After the material to be tested is obtained (i.e., polar body, embryonic cell,
trophectoderm), several techniques are used to test the genetic material,
including FISH and PCR. FISH is the preferred technique for detection of
aneuploidy. The amount of genetic material obtained is limited, generally
one polar body or one blastomere. The FISH procedure allows determination
of specific chromosomal numbers by counting fluorescent signals in inter-
phase nuclei in a single cell. The FISH technique is highly sensitive and has
an acceptable accuracy for clinical use.
PCR has revolutionized DNA analysis. The procedure involves the
repeated amplification of DNA to obtain adequate genetic material for
analysis. This technique makes it possible to detect single gene mutations
in polar bodies or blastomeres. The list of disorders for which PGD-PCR
techniques can be applied is growing rapidly. This technique is challeng-
ing because of inherent problems with the procedure, including control of 275
DNA contamination and the loss of genetic material. In clinical practice,
cystic fibrosis and sickle cell anemia are the two genetic disorders that PCR
most commonly identifies.
Other Although not considered a preimplantation genetic diagnosis technique,

Techniques another method of preconception gender selection is the use of flow cyto-
metric separation of human spermatozoa (MicroSort). This technique can be
used to decrease the likelihood of transmitting an X-linked disorder. It relies
on the 2.8% difference in DNA content between X chromosome–bearing and
Y chromosome–bearing spermatozoa, with the X chromosome being larger.
There are more than 350 X-linked diseases in humans, including Duchenne
muscular dystrophy, X-linked hydrocephalus, and hemophilia, for which
this technique may be used. The use of the DNA flow cytometry separates
the sperm sample into an X-enriched sample and Y-enriched sample. In tri-
als of the MicroSort technique, 91% of the offspring were female using an
X-enriched sample, and 76% of the offspring were male using a Y-enriched
sample, significantly decreasing the likelihood of transmitting a gender-
linked disorder. Combining the sperm separation techniques with IVF and
subsequent preimplantation embryo testing increases the chance of a suc-
cessful unaffected pregnancy.
Ethical Although public support heavily favors PGD, some people do object to PGD
Considerations even when it is used to prevent severely debilitating diseases. In public opin-
ion polls, there is greater acceptance of polar body biopsy or sperm separa-
tion techniques (before fertilization or creation of embryos) than of embryo
biopsy techniques when used to prevent diseases. Ethical concerns about
PGD primarily stem from concerns that these techniques may be used for
indications other than severe debilitating disease. As technology advances,
it may be used to predict eye color, hair color, or other “desirable” physical
characteristics that would not affect quality of life. Additionally, there is pub-
lic concern that PGD would be used for gender selection. There are programs
that use PGD for this purpose, despite statements discouraging its use by the
American Society for Reproductive Medicine. When the technology is used

for X-linked diseases, public support is high.
OOCYTE DONATION
Age is the main determinant of IVF outcome. Population-based data indi-

cate a decline in fertility as an individual ages. In the United States, 10% of
women 20 to 29 years old have an infertility problem compared with more
than 50% of women older than age 40. The decline in fertility rates is evident
in a classic study of the Hutterite population. The Hutterites are a religious
sect in which contraception is strictly prohibited. There was a 7% infertility
rate in women age 25 to 29 compared with 11% at age 30 to 34, 33% at
276 age 35 to 39, and 87% at age 40 to 44. This study is an imperfect estima-
tion of the effect of aging on reproductive potential, and it does not take into
consideration other conditions that may impair fertility (i.e., decreased coital
frequency, endometriosis, tubal disease).
For many years, physicians have debated whether aging of the uterus or
aging of the oocyte was primarily responsible for the age-related decline
in fertility. Much of the early data in animal studies suggested that the
uterus played a predominant role in limiting reproductive success, with
markedly lower pregnancy rates in older animals receiving donor oocytes
compared with matched, young recipients. Histologic assessment of the
uterus and endometrium in humans reveals no consistent change with
aging, however, when hormonal stimulation is controlled. Age-related
changes in the endometrium seen in animals may be related to a change
in hormonal function, which may affect implantation and lower preg-
nancy rates. The use of IVF and donor oocyte has provided a more direct
means of assessing uterine aging. Young women undergoing IVF with
their own oocytes have similar pregnancy rates as older women (>40
years old) using donated oocytes. This comparable success suggests that
uterine aging does not play a role in humans in hormonally controlled
cycles.
There is no question that the aging of the oocytes is the primary factor
contributing to a decline in pregnancy rates in older women. Although
there is not always a consistent morphologic difference among mature
oocytes and early embryos in older women compared with younger women,
there is a clear difference in pregnancy rates. Data suggest that the oocytes
of older women are more likely to show chromosomal abnormalities
(aneuploidy), which could explain this decline in pregnancy and implanta-
tion rates. This age-dependent increase in aneuploidy has been shown in
stimulated and unstimulated ovaries. Additionally, the percentage of chro-
mosomally abnormal embryos diagnosed by FISH is approximately 70% in
women of advanced reproductive age. Some IVF programs are performing
PGD for aneuploidy diagnosis to help older women achieve pregnancy, its
benefit is controversial. Because PGD requires the development of embryos
to the blastocyst stage, this technique cannot be applied to most women
of advanced reproductive age. There are significant age-related differences
in blastocyst formation (i.e., arrest at morula stage, diminished blastocyst

expansion) as a woman ages; this coupled with lower oocyte yield tends to
create too few embryos to use for PGD aneuploidy diagnosis in most women
of advanced reproductive age. The principal impact of PGD in older women
seems to be a reduction in spontaneous abortions, rather than improve-
ment in pregnancy rate.
Many women in their later reproductive years are able to conceive. The
transition to a less fertile state is thought to be governed primarily by the
rate at which a woman depletes her follicular reserves. At the time of birth
females have a finite number of oocytes. There is a rapid decline in oocyte
number from 20 weeks of gestation until birth. This decline in oocyte
number continues after birth until menopause. It has been suggested that
when the follicle reserve falls below a certain “available pool,” fertility is
compromised. Further declines in the available pool lead to oligo-ovula- 277
tion, perimenopause, and eventually menopause. This threshold number
of oocytes needed for normal reproduction has been documented in rats.
Although a steady rate of decline of the available pool is seen in rats, in
humans the loss of follicular reserves with advancing age is biexponential,
with an accelerated decline starting around age 35. If this biexponential
loss did not occur, and the initial rate of follicular atresia seen before age
35 continued, it is estimated that menopause would not be reached until
age 70.
The first human pregnancies after the use of donor oocytes were reported
in 1983. These pregnancies were achieved by transcervical uterine lavage
of oocyte donors 5 to 7 days after timed insemination with sperm from
the recipient’s husband. The recovered embryos were transferred to the
recipient. Presently, when a donor is selected, the donor and recipient
undergo strict screening. The American Society of Reproductive Medicine
(ASRM) has guidelines with regard to donor oocyte use. Box 17-3 presents
the ASRM’s current indications for oocyte donor use. Donors typically
undergo the same stimulation protocols and procedures as a couple hav-
ing IVF treatment. The screenings listed in Box 17-4 are currently recom-
mended by the ASRM and the Food and Drug Administration. Success with
oocyte donation is high, with pregnancy rates of 75% per cycle at some
IVF programs.
Box 17-3 Indications for Oocyte Donation

1. Hypergonadotropic hypogonadism
2. Women of advanced reproductive age
3. Diminished ovarian reserve
4. Women who are known to be affected by or are the carrier of a significant
genetic defect, or who have a family history of a condition and whose carrier
status cannot be determined
5. Women with poor oocyte or embryo quality or multiple failures during prior
attempts to conceive
Adapted from ASRM guidelines for oocyte donation. Fertil Steril 2004;82(Suppl 1):S13-S15.
Box 17-4 Recommended Screening During Oocyte Donor Cycles

Donor Screening
Age 21-34
Medical history
Family history
Genetic screening
Screen for risk factors
Sexually transmitted disease exposure
HIV exposure
Transmissible spongiform encephalopathy exposure
Organ transplant exposure
VDRL
Hepatitis B surface antigen
Hepatitis C antibody
Cervical cultures for Neisseria gonorrhoeae and Chlamydia trachomatis
278 HIV 1 and 2
Blood type, Rh
Partner of Recipient Screening
Medical history
Semen analysis
Blood type, Rh
VDRL
Cytomegalovirus IgG, IgM
HIV 1
Genetic screening
Psychological screening
Recipient Screening
Uterine evaluation
Medical history
Physical examination
Blood type, Rh
Rubella titer
Varicella titer
VDRL
Cytomegalovirus IgG, IgM
HIV 1
Genetic screening
Psychological screening
VDRL, Veneral Disease Research Laboratory
Adapted from ASRM guidelines. Fertil Steril 2004;82(Suppl 1): for oocyte donation. S13-S15.
COMPLICATIONS OF ASSISTED REPRODUCTIVE TECHNOLOGIES
Ovarian Hyper- OHSS is a serious complication of IVF affecting approximately 5% to 10% of

stimulation IVF cycles. In its most severe form, OHSS includes massive ovarian enlarge-
Syndrome ment, hemoconcentration, ascites, and oligouria and can be complicated by
renal failure, hypovolemic shock, thromboembolic events, and acute respi-
ratory distress syndrome. The intensity of OHSS is related to the degree of

the patient’s response to stimulatory medications. OHSS was first reported
in 1961 and is thought to be due to increase in capillary permeability of the
ovarian vessels. Estrogens, the renin-angiotensin system, prostaglandins,
vascular endothelial growth factor, and interleukins all have been reported
as mediators of OHSS. OHSS can be classified as mild, moderate, or severe
(Box 17-5) based on symptoms, ultrasound findings, and laboratory studies.
Factors that increase a patient’s risk of developing OHSS are listed in Box
17-6. Mild OHSS is common among most IVF patients with an average to
good response to stimulatory gonadotropins and has little clinical signifi-
cance. Many cases of severe OHSS require a short period of hospitalization
for stabilization (Box 17-7). Treatment options include albumin, aggres-
sive intravenous hydration, heparin therapy, dopamine, paracentesis, and
expectant management. 279
Box 17-5 Classification of Ovarian Hyperstimulation Syndrome

Mild OHSS
Grade 1—Abdominal distention and discomfort
Grade 2—Features of grade 1 plus nausea, vomiting, or diarrhea; ovaries enlarged
5-12 cm
Moderate OHSS
Grade 3—Features of mild OHSS plus ultrasound evidence of ascites
Severe OHSS
Grade 4—Moderate OHSS plus breathing difficulties; evidence of ascites or
hydrothorax or both
Grade 5—All of the above plus change in blood volume, increased blood viscosity
owing to hemoconcentration, coagulation abnormalities, and diminished renal
perfusion and function
Box 17-6 Risk Factors for Ovarian Hyperstimulation Syndrome
● High serum estradiol level

● Known high responder
● Luteal phase stimulation with human chorionic gonadotropin
● Numerous follicles
● Polycystic-appearing ovaries
● Polycystic ovary syndrome
● Pregnancy
Box 17-7 Criteria for Hospitalizing Patients with Ovarian Hyperstimulation

Syndrome
● Severe abdominal pain requiring narcotics

● Coagulopathy
● Electrolyte imbalance
● Hematocrit >45%
● Hemorrhage
● Oliguria/anuria
● Respiratory distress
Multiple It was noted early in the practice of ART techniques that pregnancy
Gestations rates increased as the number of embryos transferred to the uterus was
increased. In 1996, the ASRM became concerned about the increasing
number of multiple gestations among IVF couples. Multiple birth infants
are at increased risk for preterm delivery, low birth weight, congenital
malformations, neonatal death, and long-term disability. The argument
for transferring fewer embryos has gained significant momentum. In the
United States, no laws exist to limit the number of embryos transferred to
date. Box 17-8 lists the ASRM guidelines regarding the number of embryos
to implant.
PRESERVING FERTILITY FOR YOUNG WOMEN

280
Long-term survival rates for cancer have improved substantially because
of the use of aggressive therapy. Many women receiving chemotherapy or
radiation lose ovarian function, however. A technique to ensure successful
cryopreservation of oocytes would benefit these young women who wish to
retain their fertility potential. Two techniques have been used to help these
women potentially retain fertility: cryopreservation of oocytes and cryo-
preservation of ovarian tissue.
In contrast to the success of embryo freezing, which is considered rou-
tine, the cryopreservation of oocytes has been less successful. Only a few
births have been achieved since this technique was first described in 1986.
Survival of cryopreserved oocytes remains low, and more research is needed
in this area. The low surface-volume ratio thwarts efficient replacement of
cellular water with cryoprotectant, resulting in lethal crystallization.
An alternative to cryopreservation of oocytes is cryopreservation of
ovarian biopsy samples or ovarian slices. These ovarian sections may con-
tain thousands of immature oocytes. Autografting of ovarian tissue has
been attempted with limited success, although a single live birth has been
reported. A significant theoretical risk of this technique is the possibility that
Box 17-8 Number of Embryos to Transfer
1. In patients younger than age 35, no more than two embryos in the absence of
extraordinary circumstances should be transferred.
2. For patients 35 to 37 years old having a more favorable prognosis, no more
than two embryos should be transferred. All others in this age group should
have no more than three embryos transferred.
3. For patients 38 to 40 years old, no more than four embryos should be
transferred.
4. For patients older than age 40, no more than five embryos should be
transferred.
5. Patients with two or more failed IVF attempts may have additional embryos
transferred.
6. In donor oocyte cycles, the age of the donor should determine the number of
embryos to transfer.
Adapted from ASRM guidelines. Fertil Steril 2004;82(Suppl 1):S1-S2.

this biopsied tissue contains cancer, especially in patients with hematologic

cancers, and reimplantation of this tissue may lead to recurrence or metas-
tasis of the original tumors.
STEM CELLS AND THERAPEUTIC CLONING
Much media attention has surrounded the use of embryonic stem cells for
the treatment of degenerative diseases. Potential uses include restoration
of function in patients with spinal cord injury or replacement of insulin-
producing cells in patients with diabetes. Neurologic, musculoskeletal, hepatic,
and cardiac cell lines have been developed with mouse embryos. The devel-
opment of embryonic stem cell lines has been less successful in humans.
281
SUMMARY
IVF is a rapidly expanding field with continued innovations improving preg-

nancy rates. Future goals include improvements in in vitro maturation of
oocytes, oocyte freezing, and decreasing multiple pregnancy rates.

1. Controlled ovarian hyperstimulation is crucial to increase the number of
fertilizable oocytes.
2. GnRH agonists or antagonists prevent premature luteinization in ART
cycles.
3. ICSI has dramatically improved success rates in male factor infertility.
4. Oocyte donation normalizes success rates in women with compromised
ovarian reserve.
5. PGD is useful in preventing transfer of genetically abnormal embryos.
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2001;185:758-770. Endocrinology and Infertility, 6th ed. Philadelphia:
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INDEX
Note: Page numbers followed by b, f and t refer to boxes, figures and tables,
respectively.
A Albumin, 5, 5t γ-Amino butyric acid (GABA), in

Abortion, spontaneous Alcohol consumption puberty, 34
recurrent. See Recurrent preg- in climacteric, 103 Anabolic agents
nancy loss. male infertility and, 171 male infertility and, 171 283
sporadic, 241 recurrent pregnancy loss and, for osteoporosis and fracture
Acanthosis nigricans, 68 259 prevention, 124-125
Acne, in polycystic ovarian Alendronate, for osteoporosis and Analgesics, for endometriosis-
syndrome, 67 fracture prevention, 122 associated pain, 220, 222
Activated protein C resistance, Alloimmunity, recurrent Androgen receptor, 7
recurrent pregnancy loss in, pregnancy loss and, Androgen receptor antagonists,
254 257-258 for hirsutism in polycystic
Activin, in menstrual cycle, 21t, Allopurinol, male infertility and, ovarian syndrome, 74
25 172 Androgen resistance, complete,
Adrenal gland, in puberty, 35-36 Alopecia, in polycystic ovarian amenorrhea from, 57, 57b
Adrenal hyperplasia syndrome, 67 Androgens, 4, 7, 65. See also
late-onset Alzheimer’s disease, in women, 99 specific androgens, e.g.,
amenorrhea in, 54 Amastia, 45 Testosterone.
versus polycystic ovarian Amenorrhea, 49-63 elevated. See
syndrome, 68 from chronic anovulation, Hyperandrogenism.
male infertility in, 170, 176 52-56 in menstrual cycle, 23
Adrenal tumors, androgen- with estrogen absent, 51t, in puberty, 35
producing, 68 55-56, 62, 62b in sexual response, 137-138
Adrenarche, 35 with estrogen present, tumors producing, 68
Adrenergic blockers, male 50t-51t, 53-54, 61-62 weight gain and, 5
infertility and, 172 classification of, 49-52, 50b, Androstanes, 3
Adrenocorticotropic hormone 50t-51t Androstenedione, 4, 4f, 137
(ACTH) stimulation test, clinical evaluation of, 58-60, Anemia, sickle cell, male infertility
in polycystic ovarian 58f, 59b-60b and, 181
syndrome, 69 definition of, 49, 50t Aneuploidy
Age from female reproductive tract detection of, 275
bone resorption and, 110 defects, 50t, 56-58, 57b, recurrent pregnancy loss from,
diminished ovarian reserve 57f, 62 243, 243f
and, 229-231, 230f, 231f hypothalamic, anovulation in, Anovulation, 185-195
female infertility and, 158, 194 abnormal uterine bleeding
230f laboratory tests in, 59-60, from, 78-79, 82-83, 86,
maternal, chromosomal 59b-60b 89t
abnormalities and, 243 in polycystic ovarian syndrome, amenorrhea from, 52-56
menopause and, 94, 94f 53-54, 53b, 54b with estrogen absent, 51t,
myocardial infarction and, 100f treatment of, 60-62, 61b, 62b 55-56, 62, 62b
Index
Anovulation (Continued) Antithyroglobulin antibodies, Assisted reproductive technologies

with estrogen present, recurrent pregnancy loss (ART) (Continued)
50t-51t, 53-54, 61-62 and, 257 oocyte donation and, 276-277,
classification of, 186b Antral follicles, 24, 230 277b, 278b
evaluation of, 186 count of, for ovarian reserve oocyte insemination in,
hypothalamic, 82 evaluation, 167, 234-235 267-270, 268f, 269f
in hypothalamic amenorrhea, Arachidonic acid, 9-10, 10f oocyte retrieval and identifica-
194 Arcuate uterus, 209, 246f, 248 tion in, 266-267, 267f,
infertility from, 156-157 Aromatase, 23, 35 268f
physiology of, 186-188 Aromatase inhibitors ovarian hyperstimulation in,
in polycystic ovarian syndrome, for chronic anovulation, 264-265, 265t
66, 186-193, 187f 192-193 ovarian hyperstimulation
treatment of. See Ovulation for endometriosis, 224-225 syndrome and, 193,
induction. Arousal phase, 133-134, 135, 193b, 278-279, 279b
284 Anti-ß 2
glycoprotein 1, recurrent 135t, 136f, 138, 139 preimplantation genetic
pregnancy loss and, 257 sexual dysfunction during, diagnosis in, 273-276,
Antiandrogenic agents, for 142-144 273b
hirsutism in polycystic Arsenic exposure, recurrent principles of, 264
ovarian syndrome, 73-74 pregnancy loss and, 259 stem cells and therapeutic
Antibiotics, male infertility and, Asherman’s syndrome cloning and, 281
172 amenorrhea in, 58 techniques in, 266-272
Anticardiolipin antibody, recurrent infertility in, 201, 202f, 209 Asthenozoospermia, 169
pregnancy loss and, 256 recurrent pregnancy loss in, 248 Azoospermia, 169, 179-181. See
Anticoagulant therapy Aspirin, heparin plus also Infertility, male.
abnormal bleeding with, 81 for antiphospholipid syndrome,
for thrombophilias, 255 256 B
Antidepressants for thrombophilias, 255 Bacterial vaginosis, recurrent
male infertility and, 172 Assisted hatching (AH), 272 pregnancy loss and, 251-252
tricyclic, for premature Assisted reproductive technologies Barium enema, in climacteric,
ejaculation, 144 (ART), 263-281 104t
Antihypertensive drug therapy, acronyms for, 264b Bartholin’s glands, 131, 132f
male infertility and, 172 assisted hatching in, 272 Benzene exposure, recurrent
Antimicrosomal antibodies, recur- biopsy techniques in, 273-274, pregnancy loss and, 259
rent pregnancy loss and, 257 273b Beta blockers, male infertility
Antimüllerian hormone complications of, 278-280 and, 172
in menstrual cycle, 21t, 25 embryo cryopreservation in, Bicornuate uterus, 200f, 207f,
for ovarian reserve evaluation, 271-272 209, 246f, 247
166-167 embryo transfer in, 270-271 Biopsy
Antinuclear antibodies, recurrent for endometriosis, 226-227, in assisted reproductive
pregnancy loss and, 257 227t technologies, 273-274,
Antiphospholipid syndrome, ethical considerations in, 273b
recurrent pregnancy loss in, 275-276 endometrial
256-257 genetic analysis in, 275 in abnormal uterine
Antipsychotics, male infertility in vitro culture of embryo in, bleeding, 86
and, 172 270, 270f-272f out-of-phase, in luteal phase
Antiresorptive agents, for luteal phase support in, 271 defect, 249-250
osteoporosis and fracture medications in, 265-266, 265t for ovulation confirmation,
prevention, 121-124 multiple gestations and, 280, 161
Antisperm antibodies, infertility 280b for ovarian reserve evaluation,
and, 158, 165, 176 oocyte and ovarian tissue 236
Antithrombin deficiency, recurrent cryopreservation in, 238, Bisphosphonates, 106, 109,
pregnancy loss in, 254 280-281 121-123, 124
Index
Black cohosh, 105 Caffeine intake (Continued) Cervix (Continued)

Bladder exstrophy, male infertility recurrent pregnancy loss and, examination of, in abnormal
and, 181 259 uterine bleeding, 80
Blastocyst trophectoderm biopsy, Calcitonin, for osteoporosis and functional evaluation of, 165
274 fracture prevention, 124 Chemotherapeutic agents, male
Blastomere biopsy, 274 Calcium infertility and, 171-172
Bleeding dietary sources of, 119, 120b Chlamydial salpingitis, 204
menstrual intake of Cholesterol, 4f
heavy, 80, 81 in climacteric, 103 Chromosomal disorders
normal, 31 for osteoporosis and fracture male infertility in, 180-181
postpartum, 12 prevention, 119, 121 recurrent pregnancy loss in,
uterine, abnormal. See Uterine Calcium channel blockers, male 243, 243f
bleeding, abnormal. infertility and, 172 Cimetidine, male infertility and,
Blood tests, in osteoporosis, 102 Caloric intake, in climacteric, 103 172
Body mass index Cancer Clear Plan Easy device, 161 285
in abnormal uterine bleeding, 80 endometrial, in polycystic ovar- Climacteric, 93-106
calculation of, 68b ian syndrome, 74 cardiovascular disease in, 100,
in polycystic ovarian ovarian, clomiphene citrate 100f, 102, 102b
syndrome, 68 and, 191-192 clinical presentation in,
Body temperature chart, for testicular, infertility and, 96-101
ovulation confirmation, 169-170 cognitive decline in, 100-101
160-161, 160b Carboprost tromethamine, for connective tissue changes in, 99
Bone mass, peak, 110 postpartum hemorrhage, definition of, 93
Bone mineral density 12 depression in, 97-98
bone strength and, 109-110 Cardiovascular disease diagnostic tests in, 101-102
measurement of, 112-115, 113b, in climacteric, 100, 100f, 102, health screening
113f, 114b, 114f, 115f 102b recommendations in, 104,
screening recommendations risk of, in men versus women, 104t
for, 116, 117b 102, 102b hormonal therapy in, 104-105
Bone remodeling, 110 Celiac sprue, 118 lifestyle interventions in,
Bone remodeling markers, 118 Central bone mineral density 103-104
Bone resorption, 110 measurement, 112-113, menopause markers in, 101
Bone scan. See Dual-energy x-ray 116 onset and duration of, 93-95,
absorptiometry (DEXA) scan. Central obesity, in polycystic 94f
Bone strength, 109-110 ovarian syndrome, 68 osteoporosis in, 99-100, 102,
Bone turnover markers, 115 Central precocious puberty, 110, 117, 118b
Brain lesions, precocious puberty 39-40, 40t pharmacotherapy in,
and, 40, 40t, 41 Cervical cerclage, for uterine 104-106
Breast anomalies, 247, 248 physiology of, 95-96, 95f
asymmetry of, 45 Cervical factor infertility, 206, sexual dysfunction in, 98-99
development of 210 sleep disturbances in, 97
abnormal, 45 Cervical incompetence, 206 therapeutic interventions in,
normal, 36, 37b, 37t Cervical mucus 103-106, 104t
premature, 44 hostile, infertility from, urogenital symptoms in, 98
hypertrophy of, 45 157-158, 206 vasomotor disturbances in,
hypoplasia of, 45 pre-ovulatory change in, 28 96-97, 105
Bromocriptine, for Cervical stenosis Clitoral erection, 133-134
hyperprolactinemia, 176, 251 amenorrhea from, 58 Clitoris, 131, 132f
infertility and, 210 Clitoromegaly, in polycystic
C Cervix ovarian syndrome, 67, 68
Caffeine intake agenesis of, amenorrhea from, Clomiphene citrate
in climacteric, 103 56 adjuvants to, 192
Index
Clomiphene citrate (Continued) Cushing’s syndrome Dilation and curettage

for chronic anovulation, 71, amenorrhea in, 54 amenorrhea after, 58
189-192, 190f, 191f screening for, 68 infertility after, 201
and intrauterine insemination, Cyclic guanosine monophosphate Dominant follicle, 20, 26-27, 230
for endometriosis, 226, (cGMP), in sexual response, Drugs
227t 139 male infertility from, 171-172,
for male infertility, 176-177 Cycling, male infertility and, 171 173t
ovarian cancer and, 191-192 Cyclooxygenase-2 (COX-2) inhibi- osteoporosis from, 112b, 118
side effects of, 190 tor, for dysmenorrhea, 12 recreational and illicit, male
Clomiphene citrate challenge test, Cyclooxygenase pathway, 10, 10f infertility from, 171, 173t
155, 166, 233-234, 234b Cyproterone acetate, for sexual dysfunction from, 139b
Cloning, therapeutic, 281 hirsutism in polycystic Dual-energy x-ray absorptiom-
Coagulation cascade, 252-253, ovarian syndrome, 74 etry (DEXA) scan, 102
253f Cystic fibrosis, male infertility bone mineral density
286 Coagulation disorders and, 170, 181 measurements in, 112,
abnormal uterine bleeding Cytogenetic testing, in recurrent 113-115, 113b, 113f,
and, 81, 89t pregnancy loss, 244 114b, 114f, 115f
recurrent pregnancy loss and, Cytokines for osteoporosis screening,
252-255, 253f, 256b in menstrual cycle, 20, 116, 117b
Coelomic metaplasia theory of 21t-22t, 24-25 Dyschezia, 213
endometriosis, 214-215 in pathogenesis of Dyslipidemia, in polycystic
Cognitive decline, in climacteric, endometriosis, 216-217 ovarian syndrome, 70
100-101 Cytoplasm donation, for Dysmenorrhea
Colchicine, male infertility and, diminished ovarian reserve, definition of, 213
172 237-238 in endometriosis, 217
Colonoscopy, in climacteric, 104t Cytotoxic immune rejection theory primary, 11-12
Computed tomography of spine, of recurrent pregnancy loss, Dyspareunia
112-113 258 in climacteric, 98-99
Connective tissue changes, in definition of, 213
climacteric, 99 D in endometriosis, 217
Contraception, hormonal, 8, 81. Danazol, for endometriosis, etiology and treatment of,
See also Oral contraceptives. 223-224 146-147
Contraceptive method Dehydroepiandrosterone, 35 hypoactive sexual desire
change in, abnormal bleeding Dehydroepiandrosterone sulfate, disorder related to, 141
after, 82 35, 68 Dysuria, in climacteric, 98
history of, in abnormal uterine Depression, in climacteric, 97-98
bleeding, 79-80 Desire, sexual, 135, 135t, E
Corpora cavernosa, 130, 130f 136-137, 136f Ectopic pregnancy, pelvic
Corpora lutea cyst, persistence of, Diabetes mellitus inflammatory disease and,
after ovulatory clomiphene male infertility and, 170 204
citrate cycle, 190 in polycystic ovarian Ejaculation, 134
Corpus luteum, 29, 30, 156 syndrome, 67, 69 premature (rapid), 144-145,
Corpus spongiosum, 130, 130f recurrent pregnancy loss and, 171
Corticosteroid-binding globulin, 5 251 retrograde, 176
Cowper’s gland, 130f, 131 Diethylstilbestrol Ejaculatory duct obstruction, 175
Cryopreservation infertility from, 200-201 Embryo
embryo, 271-272 recurrent pregnancy loss from, cryopreservation of, 271-272
ovarian tissue and oocyte, 238, 248 in vitro culture of, 270, 270f-
280-281 Dieting, amenorrhea from, 55 272f
Cryptorchidism, male infertility Digital rectal examination, in transfer of, 270-271
and, 181 male infertility, 173 Embryology of reproductive tract,
Cumulus oophorus, 24 Dihydrotestosterone, 7 198-199, 200f
Index
Embryonic rests theory of Endometriosis (Continued) Estradiol (Continued)

endometriosis, 215 laparoscopic evaluation of, 163 in climacteric, 96
Embryonic stem cells, 281 lesions that mimic, 219b in menstrual cycle, 19, 19f, 23,
Emotional intimacy, sexual lymphatic and vascular 24, 27, 29, 30
response and, 136-137, 136f metastasis theories of, 215 in puberty, 35
Emotional issues, in erectile in male, 215 Estranes, 3-4
disorder, 143 medical treatment of, 220, Estriol, 4f, 6
Endocrinopathies 222-225, 223t Estrogen receptor-α, 6
female infertility and, 160 oral contraceptives for, Estrogen receptor-ß, 6
male infertility and, 170 222-223 Estrogens
recurrent pregnancy loss and, pain in, 217 assays for, 8, 8b
249-251, 252b pathophysiology of, 213-217, in climacteric, 8-9
Endometrial ablation, for 214f deficiency of, in climacteric, 96
abnormal uterine bleeding, pleural, 215 effects of, 6, 7t
87-88 progestins for, 223 for hormonal contraception, 8 287
Endometrial biopsy surgical treatment of, for osteoporosis and fracture
in abnormal uterine bleeding, 86 225-226, 226t prevention, 123, 124
out-of-phase, in luteal phase Endometrium for ovarian failure, 61
defect, 249-250 cancer of, 74 in sexual response, 138
for ovulation confirmation, hyperplasia of, 74, 86 types of, 6
161 layers of, 18, 18b Estrone, 4f, 6
Endometrial polyp in luteal/secretory phase, 29, in climacteric, 96
infertility and, 201 30-31 Ethical considerations, in
radiologic imaging of, 83, 85f in menstrual cycle, 19f preimplantation genetic
treatment of, 87, 89t in proliferative phase diagnosis, 275-276
Endometriosis, 213-227 early, 18 Ethylene oxide exposure, recurrent
analgesics for, 220, 222 late, 28 pregnancy loss and, 259
aromatase inhibitors for, middle, 25-26, 27f Excitement, sexual, 133-134,
224-225 re-epithelialization of, 31 133f, 134f
assisted reproductive technolo- sloughing of, theories of, 31 Exercise
gies for, 226-227, 227t Environmental factors in climacteric, 103-104
classification of, 220, male infertility and, 170-171 for osteoporosis and fracture
221f-222f recurrent pregnancy loss and, prevention, 120
clinical presentation in, 258-259, 260b
217-218, 217b Enzyme assays, in thrombophilias, F
coelomic metaplasia theory of, 255 Factor V Leiden mutation, recur-
214-215 Ephedrine, for retrograde rent pregnancy loss in,
composite theory of, 215 ejaculation, 176 253-254
danazol for, 223-224 Epidermal growth factor, in Factor XII deficiency, recurrent
diagnosis of, 218-220, 219b, menstrual cycle, 21t, 25 pregnancy loss in, 254-255
219f Epididymal sperm aspiration, Fallopian tube, 133
embryonic rests theory of, 215 178-179, 178t abnormalities of
genetic factors in, 216 Epididymovasostomy, 178 diagnosis of, 208
gonadotropin-releasing Epispadias, male infertility and, infertility and, 157,
hormone agonists for, 181 203-204, 205f, 210
224, 225b Erectile disorder, 142-143, 171 agenesis of, 199
immune factors in, 216-217 Erection, psychogenic, 137 evaluation of, 162-164, 163f
implantation theory of, Erythromycin, male infertility intraluminal disease of, 204,
213-214 and, 172 205f, 210
induction theory of, 215 Estradiol, 4f, 6 Falls
infertility from, 157, 217-218, basal, for ovarian reserve prevention of, 120
218b, 225-227, 226t, 227t evaluation, 166, 235 risk factors for, 111
Index
Fecal occult blood testing (FOBT), Fluorescence in situ hybridization Gamete intrafallopian transfer
in climacteric, 104t (FISH), in preimplantation (GIFT), 266-267, 267f, 268f
Fecundability, 213 genetic diagnosis, 275 Gap junctions, 23
Fecundity, 213 Flutamide, for hirsutism in Gardnerella vaginalis, recurrent
Female polycystic ovarian syn- pregnancy loss and,
Alzheimer’s disease in, 99 drome, 73-74 251-252
cardiovascular disease risk in, Folate supplementation, for Gender
102, 102b MTHFR mutation, 255 myocardial infarction and,
definition of, 129 Follicle stimulating hormone (FSH) 100f
dyspareunia in, 98, 141, amenorrhea and, 59, 59b-60b preconception selection of, 275
146-147, 217 in assisted reproductive sex versus, 129
infertility in, 155-168. See also technology procedures, 265 Gender identity, 129
Infertility, female. basal, for ovarian reserve Gene mutation, single, recurrent
reproductive tract of. See evaluation, 165-166, pregnancy loss and,
288 Reproductive tract. 232-233 243-244
sexual anatomy of, 131-133, for chronic anovulation, 72 Genetic counseling, in recurrent
132f in climacteric, 94f, 95-96 pregnancy loss, 244
sexual response cycle of, 133- formulations of, 264, 265t Genetic diagnosis, preimplantation,
135, 134f, 136-137, 136f as menopause marker, 101 273-276, 273b
vaginismus in, 147-148 in menstrual cycle, 19f, 20, 23, Genetics
Female orgasm disorder, 145-146 27-28 endometriosis and, 216
Female sexual arousal disorder, in ovarian failure, 52 male infertility and, 179-181
143-144 in polycystic ovarian recurrent pregnancy loss and,
Feminization, testicular, syndrome, 53, 66 242-244, 243f, 245b
amenorrhea from, 57, 57b in precocious puberty, 41 Genitalia
Ferriman-Gallwey scoring system in puberty, 35 examination of, in abnormal
for hirsutism, 68 Follicular fluid, 24 uterine bleeding, 80
Fertility. See Infertility. Follicular/proliferative phase of female, 131-133, 132f
Fertility monitor, 161 menstrual cycle innervation of, 137
Fertilization early, 18-24 male, 130-131, 130f
in vitro late, 26-28 Genitourinary system
for endometriosis, 226-227, middle, 24-26, 27f in climacteric, 98
227t Folliculogenesis, ovarian aging malformations of, male infertility
procedure for, 237, and, 229-231, 230f, 231f and, 181
267-270, 268f, 269f Follistatin, in menstrual cycle, 21t Genitourinary tuberculosis, male
normal, 156 Foreskin, 130, 130f infertility and, 170
Fever, male infertility and, 170 Formaldehyde exposure, recurrent Gentamicin, male infertility and,
Fibroblast growth factor, in pregnancy loss and, 259 172
menstrual cycle, 21t 45X/46XY karyotype, male Germinal vesicles, 20, 230
Fibroids infertility in, 180 Gestations, multiple, assisted
infertility and, 201-203, 203f, 47XXY karyotype, male infertility reproductive technologies
209 in, 180 and, 280, 280b
radiologic imaging of, 83, 84f Fracture, osteoporosis- Gigantomastia, juvenile, 45
recurrent pregnancy loss and, associated, 110, 111, 112 Glans, 130, 130f
249 bone mineral density and, 114, Glucocorticoids, adjuvant, for
treatment of, 87, 89t, 209, 249 115f chronic anovulation, 192
Filaria sanguinis-hominis prevention of, 119-120 Glucose, fasting, in climacteric,
infection, 46 Fragility fracture, 110, 112 104t
Flexible sigmoidoscopy, in Glucose tolerance test, 69, 70b
climacteric, 104t G Glycodelin, in polycystic ovarian
Flow cytometry, in preconception Galactorrhea, amenorrhea with, syndrome, 250
gender selection, 275 56 Gonadal dysgenesis, 52
Index
Gonadal ovarian failure. Gonadotropin-releasing hor- Hormone response elements, 5

See Hypergonadotropic mone stimulation test, in Hormone therapy, 8-9
hypogonadism. precocious puberty, 41 abnormal bleeding with, 81
Gonadotropin therapy Granulosa cell, 4, 23 for abnormal uterine bleeding,
adjuvant, for chronic luteinization of, 26-27 88-90
anovulation, 192 Growth factors for chronic anovulation, 62
in assisted reproductive in menstrual cycle, 20, in climacteric, 8-9, 104-105
technology procedures, 21t-22t, 24-25 for osteoporosis and fracture
264-265, 265t in pathogenesis of prevention, 123
for chronic anovulation, 62, endometriosis, 216 for ovarian failure, 61
72, 193, 194 Growth hormone Hot flashes, 96-97, 105
for hypogonadotropic for precocious puberty, 43 Hot tub use, maternal, recurrent
hypogonadism, 176 in puberty, 36 pregnancy loss and, 259
and intrauterine insemination Growth spurt, 37-38 Human chorionic gonadotropin
for diminished ovarian Guanosine monophosphate, cyclic, adjuvant, for chronic 289
reserve, 237 in sexual response, 139 anovulation, 192
for endometriosis, 226, 227t H for chronic anovulation, 62, 72
in polycystic ovarian syn- Hamartoma, pituitary, precocious definition of, 185
drome, 72 puberty and, 40 for hypogonadotropic
severe ovarian Hatching, assisted, 272 hypogonadism, 176
hyperstimulation Health screening in menstrual cycle, 30
syndrome from, 193, 193b recommendations, in before oocyte retrieval and
Gonadotropin-dependent climacteric, 104, 104t identification, 264-265
folliculogenesis, 230 Hemorrhage. See Bleeding. in polycystic ovarian
Gonadotropin-dependent Heparin syndrome, 72
precocious puberty, 39-40, for antiphospholipid syndrome, Human menopausal gonadotropin
40t 256 (HMG)
Gonadotropin-releasing hormone for thrombophilias, 255 adjuvant, for chronic
(GnRH) Herpes simplex virus, recurrent anovulation, 192
after ovulation induction in pregnancy loss and, 252 in assisted reproductive
hypothalamic amenorrhea, Hip technology procedures,
194 bone mineral density 265
for chronic anovulation, 62 measurement of, 112, 116 for chronic anovulation, 62,
in menstrual cycle, 19-20, 19f fracture of, 110 72, 193, 194
in puberty, 34-35 Hip protectors, 120 definition of, 185
Gonadotropin-releasing hormone Hirsutism, 5, 67, 68, 73-74 formulations of, 264, 265t
agonists HLA (human leukocyte in polycystic ovarian
for abnormal uterine bleeding, antigen) sharing, recurrent syndrome, 72
89-90 pregnancy loss and, 258 recurrent pregnancy loss and,
add-back therapy for use with, Homocysteinemia, recurrent 251
224, 225b pregnancy loss in, 254 severe ovarian
in assisted reproductive Hormonal contraception, 8, 81. hyperstimulation
technology procedures, 266 See also Oral contraceptives. syndrome from, 193, 193b
for endometriosis, 224, 225b Hormonal influences on sexual Hydrosalpinx, 204, 205f, 210
for precocious puberty, 43 response cycle, 137-139 17α-Hydroxyprogesterone,
for recurrent pregnancy loss, 251 Hormonal responses, in puberty, in congenital adrenal
Gonadotropin-releasing hormone 33-36 hyperplasia, 68
antagonists, in assisted Hormonal status, history of, in Hymen
reproductive technology abnormal uterine bleeding, anatomy of, 131, 132f
procedures, 266 79-80 imperforate, amenorrhea from,
Gonadotropin-releasing hormone Hormone, steroid. See Steroid 56
pulse generator, 34-35 hormones. Hyperandrogenism
Index
Hyperandrogenism (Continued) Hypogonadism (Continued) Immunoglobulin, intrave-

anovulation from, 66, male infertility in, 170, 176, nous, for antiphospholipid
186-193, 187f. See 181 syndrome, 257
also Polycystic ovarian Hypothalamic disorders Immunotherapy, in recurrent
syndrome. abnormal uterine bleeding in, pregnancy loss, 258
female infertility and, 160 82 Implantation theory of
in polycystic ovarian amenorrhea in, 51t, 54-55 endometriosis, 213-214
syndrome, 53, 67, 68, Hypothalamic-pituitary-gonadal In vitro culture of embryo, 270,
69 axis, male infertility and, 181 270f-272f
Hypercoagulable state, pregnancy Hypothalamic-pituitary-ovarian In vitro fertilization (IVF)
as, 252-253, 253f axis for endometriosis, 226-227,
Hypergonadotropic in climacteric, 96 227t
hypogonadism, amenorrhea investigation of, 86 procedure for, 237, 267-270,
in, 50t, 52, 52b, 61, 61b in puberty, 34-36 268f, 269f
290 Hyperhomocysteinemia, recurrent Hypothyroidism Incontinence, urinary, in
pregnancy loss in, 254 abnormal uterine bleeding in, climacteric, 98
Hyperinsulinemia, in polycystic 82-83 Induction theory of endometriosis,
ovary syndrome, 66-67, amenorrhea in, 54 215
186, 188, 250 male infertility in, 170 Infections
Hyperparathyroidism, wrist DXA recurrent pregnancy loss in, pelvic, infertility and, 197, 204
in, 116 251 recurrent pregnancy loss and,
Hyperprolactinemia Hysterectomy 251-252, 252b
abnormal uterine bleeding in, for abnormal uterine bleeding, urinary tract, in climacteric,
83 88 98
amenorrhea in, 56, 56b for endometriosis, 226 Infertility
female infertility in, 160 Hysterosalpingography, 155 anatomic, 197-211
male infertility in, 176 for fallopian tube evaluation, anatomy, physiology, and
in polycystic ovarian 162, 163f clinical presentation of,
syndrome, 69 for infertility evaluation, 206, 198-206
recurrent pregnancy loss in, 208 diagnostic tests for,
251 of tubal disease, 204, 205f 206-208, 207f
sexual response and, 138-139 of uterine anomalies, 245 therapeutic interventions
Hyperthermia, maternal, for uterine cavity evaluation, for, 208-210
recurrent pregnancy loss 164 cervical factor, 206, 210
and, 259 Hysteroscopy definition of, 155
Hyperthermic environment, male for abnormal uterine bleeding, endometriosis-related,
infertility and, 171 87 217-218, 218b, 225-227,
Hyperthyroidism for uterine anomalies, 248 226t, 227t
abnormal uterine bleeding in, for uterine cavity evaluation, female, 155-168
82-83 164 age and, 158, 230f
amenorrhea in, 54 causes of, 156-158, 157b
male infertility in, 170 I cervical function evaluation
osteoporosis in, 118 Illicit drugs, male infertility from, in, 165
recurrent pregnancy loss in, 171, 173t diminished ovarian reserve
251 Imipramine, for retrograde and, 229-239. See
Hypoactive sexual desire disorder ejaculation, 176 also Ovarian reserve,
(HSDD), 141 Immotile-cilia syndrome, infertility diminished.
Hypogonadism and, 170 fallopian tube and peritoneal
hypergonadotropic, amenorrhea Immune factors evaluation in, 162-164,
in, 50t, 52, 52b, 61, 61b in endometriosis, 216-217 163f
hypogonadotropic in recurrent pregnancy loss, frequency of, 155
amenorrhea in, 51t, 54-56 255-258, 258b history in, 158-159, 158b
Index
Infertility (Continued) Inguinal surgery (Continued) Intracytoplasmic sperm injection

ovarian reserve evaluation for varicocele, 177 (ICSI)
in, 165-167, 166b, Inguinal vas obstruction, for antisperm antibodies, 176
231-236, 232t radiographic evaluation of, procedure for, 268-270
ovulation and luteal phase 175 Intrauterine device, abnormal
evaluation in, 160-161, Inhibin, in folliculogenesis, bleeding with, 81
160b 230-231 Intrauterine insemination
physical examination in, Inhibin A for cervical stenosis, 210
159-160 in climacteric, 95 for diminished ovarian reserve,
in polycystic ovarian in menstrual cycle, 19, 19f, 237
syndrome, 67 21t, 25, 28 for endometriosis, 226, 227t
uterine cavity evaluation in, Inhibin B Intravenous immunoglobulin, for
164-165 basal, for ovarian reserve antiphospholipid syndrome,
incidence of, 197 evaluation, 166, 236 257
male, 169-182 in climacteric, 95 Inversion, chromosomal, recurrent 291
drugs and medications in menstrual cycle, 19f, 21t, pregnancy loss and, 243
contributing to, 24, 25, 28 Isoflavonoids, for osteoporosis
171-172, 173t Insemination and fracture prevention, 123
frequency of, 169 intrauterine
genetic considerations in, for cervical stenosis, 210 J
179-181 clomiphene citrate and, for Juvenile gigantomastia, 45
history in, 169-172 endometriosis, 226, 227t
laboratory evaluation in, for diminished ovarian K
174-175, 174b, 175t reserve, 237 Kallmann’s syndrome
pharmacologic treatment of, oocyte amenorrhea in, 55
175-177 intracytoplasmic, 176, male infertility in, 170, 181
physical examination in, 268-270 Kaplan’s redefinition of sexual
172-173 routine, 267-268, 268f, 269f response cycle, 135, 135t
radiographic evaluation in, Insulin, elevated, in polycystic Kartagener’s syndrome, male
175 ovary syndrome, 66-67, 250 infertility in, 170, 181
surgical treatment of, Insulin resistance Karyotyping, in recurrent
177-179, 178t assessment of, 69, 70b pregnancy loss, 244
pelvic inflammatory disease in polycystic ovary syndrome, Klinefelter’s syndrome, male
and, 197, 204 67, 68 infertility in, 180
sexual dysfunction and, Insulin-like growth factor binding
149-150, 150t proteins, 25 L
tubal, 203-204, 205f, 210 Insulin-like growth factor-I, in Labia majora, 131, 132f
uterine factor, 158, 198-203 menstrual cycle, 21t, 24, 25 Labia minora, 131, 132f
from acquired anomalies, Insulin-like growth factor-I Labial agglutination/fusion,
201-203, 203f binding protein, in polycystic amenorrhea from, 56
anatomy and physiology of, ovarian syndrome, 250 Labial hypertrophy, 45-46
198-199, 200f Insulin-like growth factor-II, in Laparoscopic ovarian drilling,
from congenital anomalies, menstrual cycle, 21t, 25 for polycystic ovarian
199-200 Insulin-sensitizing agents, for syndrome, 73
diagnosis of, 208 chronic anovulation, Laparoscopic surgery, for
from diethylstilbestrol, 188-189 endometriosis, 225-226, 226t
200-201 Integrin, in endometriosis-related Laparoscopic varicocelectomy,
treatment of, 208-209 infertility, 218 177
Influenza vaccine, in climacteric, Intercourse, pain during. See Laparoscopy, for fallopian tube
104t Dyspareunia. evaluation, 162-163
Inguinal surgery Intimacy, emotional, sexual Laparotomy, for endometriosis,
infertility and, 170 response and, 136-137, 136f 225
Index
Lead exposure, recurrent Luteinizing hormone (LH) Medications (Continued)

pregnancy loss and, 259 (Continued) sexual dysfunction from, 139b
Leiomyomata midcycle surge of, detection of, Medroxyprogesterone acetate, for
infertility and, 201-203, 203f, 161 endometriosis, 223
209 in polycystic ovarian syn- Megestrol acetate, for
radiologic imaging of, 83, 84f drome, 53, 70 endometriosis, 223
recurrent pregnancy loss and, in precocious puberty, 41 Men. See Male.
249 in puberty, 35 Menarche, normal onset of, 15,
treatment of, 87, 89t, 209, recurrent pregnancy loss and, 38
249 251 Menopause. See also Climacteric;
Leptin, in puberty, 35 Luteolysis, 30 Perimenopause;
Letrozole, for endometriosis, 225 Lymphatic metastasis theories of Postmenopause.
Leukocytic antibody activity, in endometriosis, 215 abnormal uterine bleeding
recurrent pregnancy loss, after, 83, 89t
292 258 M definition of, 93
Leydig cells, 131 Macrophages, in pathogenesis of markers of, 101
Libido, in climacteric, 99 endometriosis, 216 sexual desire in, 138
Lifestyle Magnetic resonance imaging Menorrhagia, 80, 81
male infertility and, 171 for infertility evaluation, 207f, Menstrual cycle
recurrent pregnancy loss and, 208 age at onset of, 15, 38
258-259, 260b in precocious puberty, 41 in climacteric, 96
Lifestyle interventions of uterine anomalies, 245 cytokines and growth factors
for chronic anovulation, 188 Male in, 20, 21t-22t, 24-25
in climacteric, 103-104 cardiovascular disease risk in, follicular/proliferative phase of
Lipid disorders, in polycystic 102, 102b early, 18-24
ovarian syndrome, 70 definition of, 129 late, 26-28
Lipoxygenase pathway, 10, 10f dyspareunia in, 146 middle, 24-26, 27f
Low-molecular-weight heparin, endometriosis in, 215 histologic change throughout,
for thrombophilias, 255 infertility in, 169-182. See also 26f
Lupus anticoagulant antibody, Infertility, male. history of, infertility and,
recurrent pregnancy loss sexual anatomy of, 130-131, 158-159
and, 256 130f length of, 16-17, 16f, 17f
Lupus erythematosus, recurrent sexual response cycle of, luteal/secretory phase of
pregnancy loss in, 257 133-135, 133f early, 29
Luteal hormones, 156 Male orgasm disorder, 145 middle to late, 30-31
Luteal phase Mammography, in climacteric, normal, 15-32, 16b, 19f, 78
defect in, 159 104t ovulation and, 28-29
recurrent pregnancy loss Masters and Johnson’s sexual in polycystic ovarian
and, 249-250 response cycle, 133-135, syndrome, 67
early, 29 133f, 134f two-cell ovarian physiology in,
evaluation of, 160-161, 160b Masturbation, directed, for female 23-24
middle to late, 30-31 orgasm disorder, 146 Menstruation
Luteal phase support Matrix metalloproteinases, in heavy bleeding during, 80, 81
after ovulation induction in menstrual cycle, 30 normal, 31
hypothalamic amenorrhea, Mayer-Rokitansky-Küster-Hauser pain during. See
194 syndrome, 199 Dysmenorrhea.
in assisted reproductive McCune-Albright syndrome, Mercury exposure, recurrent
technologies, 271 precocious puberty in, 40, 42f pregnancy loss and, 259
Luteinizing hormone (LH) Medications Mesalazine, male infertility and,
in climacteric, 96 male infertility from, 171-172, 172
in menstrual cycle, 19f, 20, 23, 173t Mesonephric (wolffian) ducts,
26-27, 28, 29 osteoporosis from, 112b, 118 198-199
Index
Metalloproteinases, matrix, in Myocardial infarction Oocyte donation, 237, 238f,

menstrual cycle, 30 in climacteric, 100, 100f, 102, 276-277, 277b, 278b
Metformin 102b Oocyte insemination
for chronic anovulation, incidence of, 100f intracytoplasmic, 176, 268-270
188-189 routine, 267-268, 268f, 269f
for polycystic ovarian N Oocyte retrieval and identification
syndrome, 72-73, 250 Neomycin, male infertility and, human chorionic gonadotropin
Methylene tetrahydrofolate 172 administration prior to,
reductase mutation, recurrent Neuropeptide Y, in puberty, 34 264-265
pregnancy loss in, 254 Night sweats, 96-97, 105 procedure for, 266-267, 267f,
Metroplasty, for uterine anomalies, Nipple erection, 133 268f
247 Nitric oxide, in sexual response, Oophorectomy, bilateral, for
Microsurgical epididymal sperm 139 endometriosis, 226
aspiration (MESA), 178, Nitrous oxide exposure, recurrent Ooplasm donation, for diminished
178t, 264b pregnancy loss and, 259 ovarian reserve, 237-238 293
Miscarriage Nonsteroidal antiinflammatory Oral contraceptives
recurrent. See Recurrent drugs for abnormal uterine bleeding,
pregnancy loss. for dysmenorrhea, 12 88
sporadic, 241 for endometriosis-associated in assisted reproductive
Misoprostol, for postpartum pain, 220, 222 technology procedures,
hemorrhage, 12 Norethindrone acetate, for 265
Mons pubis, 131, 132f endometriosis, 223 for chronic anovulation, 61-62
Mottling, skin, in sexual response, Nulliparity, menopause and, 94 discontinuation of, abnormal
133 Nutrition bleeding after, 82
Müllerian agenesis, 199 in climacteric, 103 for endometriosis, 222-223
amenorrhea from, 57-58, 57b puberty and, 34-35 for hirsutism, 73
Müllerian anomalies for polycystic ovarian
acquired, 201-203, 203f, O syndrome, 71, 73
248-249 Obesity Orgasm, 133f, 134-135, 134f,
congenital central, in polycystic ovarian 135t
anatomy and physiology of, syndrome, 68 sexual dysfunction during,
199, 200f in hyperandrogenism, 186 144-146
infertility and, 199-200 male infertility and, 171 Osteomalacia, 109, 116, 119
recurrent pregnancy loss Obstetric history Osteopenia, 99, 109, 114, 114t
and, 245-248, 246f infertility and, 159 Osteoporosis, 109-126
diagnosis of, 164-165, 245 recurrent pregnancy loss and, bone mineral density
from diethylstilbestrol, 200, 241 measurements in,
246f, 248 Oligomenorrhea, 65, 67 112-115, 113b, 113f,
recurrent pregnancy loss and, Oligo-ovulation. See also 114b, 114f, 115f
245-249, 246f, 249b Anovulation. bone turnover markers in, 115
treatment of, 208-209 abnormal bleeding from, classification of, 110
Müllerian ducts, 198-199, 245 78-79, 82-83 in climacteric, 99-100, 102,
Müllerian inhibin substance. See in polycystic ovarian 110, 117, 118b
Antimüllerian hormone. syndrome, 66 clinical presentation in, 112
Multiple gestations, assisted Oligozoospermia, 169, 176-177, definition of, 109-110
reproductive technologies 179-181. See also Infertility, diagnostic tests in, 112-115
and, 280, 280b male. evaluation for, 117, 118b
Muscular dystrophy, male infertility Oocyte(s) fractures associated with, 110,
and, 181 cryopreservation of, 238, 111, 112
Mycoplasma hominis, recurrent 280-281 bone mineral density and,
pregnancy loss and, fertilization of, 156 114, 115f
251-252 quantity of, age and, 231f prevention of, 119-120
Index
Osteoporosis (Continued) Ovarian tumors Pamidronate, for osteoporosis

high-turnover, 119 amenorrhea in, 54 and fracture prevention, 122
idiopathic, 110 androgen-producing, 68 Pap smear, in climacteric, 104t
low-turnover, 119 Ovarian volume, mean, Paramesonephric (müllerian)
physiology of, 110-111, 111b, measurement of, 235 ducts, 198-199, 245
111t, 112b Ovary(ies), 133 Parathyroid hormone
prevention of, 119-126 in follicular phase excess of, wrist DXA in, 116
primary, 110 early, 18-20, 23 recombinant, for osteoporosis
screening for, 102, 116, 117b late, 26-28 and fracture prevention,
secondary, 110, 111b, 112b, middle, 24-25 124-125
117-119 in luteal/secretory phase, 29, 30 Paternal leukocytic immunization,
treatment of in menstrual cycle, 19f in recurrent pregnancy loss,
combination therapy for, polycystic. See Polycystic ovarian 258
124 syndrome. Pelvic examination, in female
294 indications for, 120-121, in puberty, 35 infertility, 160
120b two-cell physiology of, 23-24 Pelvic inflammatory disease,
monitoring during, Ovulation, 28-29 infertility and, 197, 204
125-126, 126b deficiency of. See Anovulation. Pelvic organ prolapse, in
pharmacologic, 121-125 evaluation of, 160-161, 160b climacteric, 98
Ovarian aging, 229-231, 230f, Ovulation induction Pelvic pain, in endometriosis, 217
231f aromatase inhibitors for, Pelvic ultrasonography, in
Ovarian biopsy, for ovarian 192-193 abnormal uterine bleeding,
reserve evaluation, 236 in assisted reproductive tech- 83, 84f, 85f, 86
Ovarian cancer, clomiphene nology procedures, Penile pain, 146
citrate and, 191-192 264-265, 265t Penis, 130, 130f
Ovarian cyst, persistent, 190 clomiphene citrate for, Percutaneous epididymal sperm
Ovarian drilling, laparoscopic, 189-192, 190f, 191f aspiration, 178-179, 178t
for polycystic ovarian in hypothalamic amenorrhea, Perhydrocyclopentaphenanthrene,
syndrome, 73 194 3-4, 4f
Ovarian failure. See Anovulation; insulin-sensitizing agents for, Perimenopause
Hypergonadotropic 188-189 abnormal bleeding in, 82
hypogonadism; Menopause. lifestyle alterations for, 188 definition of, 93
Ovarian hormone production, in ovarian hyperstimulation early, 93
climacteric, 95-96, 95f syndrome after, 193, late, 93
Ovarian hyperstimulation, 193b, 278-279, 279b onset and duration of, 94, 94f
264-265, 265t. See also in polycystic ovarian syndrome, Peripheral bone mineral density
Ovulation induction. 71-72, 73, 188-193 measurement, 113, 116
Ovarian hyperstimulation syn- Ovulation prediction kit, 161 Peripheral precocious puberty,
drome, 193, 193b, Ovulatory bleeding, 81-82 40, 41t
278-279, 279b Oxytocin Peritoneum, evaluation of, in
Ovarian reserve in menstrual cycle, 29 female infertility, 162-164,
diminished, 155, 229-239 in sexual response, 139 163f
age and, 229-231, 230f, Peyronie’s disease, male
231f P dyspareunia in, 146
recurrent pregnancy loss Pain Phenylpropanolamine, for
and, 233 in endometriosis, 217 retrograde ejaculation, 176
treatment of, 236-238, during intercourse. See Phosphodiesterase-5 inhibitors,
237b Dyspareunia. 139
evaluation of, 165-167, 166b, during menstruation. See for erectile disorder, 142
231-236, 232t Dysmenorrhea. Phytoestrogen preparations, 105
Ovarian tissue cryopreservation, Pain problems, as sexual for osteoporosis and fracture
238, 280-281 dysfunction, 146-148 prevention, 123
Index
Pituitary disorders, amenorrhea Postmenopause (Continued) Progesterone (Continued)

in, 51t, 55-56 abnormal uterine bleeding in, for chronic anovulation, 61
Pituitary gland 83, 89t in climacteric, 8-9, 96
postpartum necrosis of, 55-56 age and, 94, 94f deficiency of, during luteal
in puberty, 35 bone resorption in, 110 phase, 159, 249-250
Pituitary hamartoma, precocious definition of, 93 for endometriosis, 223
puberty and, 40 osteoporosis in, 99-100, 102, for hormonal contraception,
Pituitary tumors, male infertility 110, 117, 118b 8
and, 170 Postpartum hemorrhage, 12 in menstrual cycle, 19, 19f,
Plasminogen activator, in Preantral follicles, 230 29, 30
ovulation, 28 Precocious puberty, 38-44 for ovarian failure, 61
Plasminogen activator inhibitor central (gonadotropin- for polycystic ovarian
(PAI) dependent), 39-40, 40t syndrome, 71
in polycystic ovarian definition of, 39 serum, for ovulation
syndrome, 250 diagnosis of, 40-41, 42b confirmation, 161 295
in recurrent pregnancy loss, in McCune-Albright syndrome, in sexual response, 138
255 40, 42f Progesterone receptor-A, 7
Plateau, sexual, 133f, 134, 134f mixed, 43-44 Progesterone receptor-B, 7
Platelet activation, in pregnancy, peripheral (gonadotropin- Progestin challenge, in
252-253 independent), 40, 41t amenorrhea, 55, 59, 59b
Polar body biopsy, 273-274 treatment of, 42-43, 43b Prolactin, elevated. See
Polycystic ovarian syndrome, Prednisone, osteoporosis from, Hyperprolactinemia.
65-75 118 Proliferative phase of menstrual
abnormal uterine bleeding in, Pregnancy cycle
83 disorders related to, abnormal early, 18-24
amenorrhea in, 53-54, 53b, uterine bleeding in, 81 late, 26-28
54b ectopic, pelvic inflammatory middle, 24-26, 27f
anovulation in, 66, 186-193 disease and, 204 Prostaglandin E1, for postpartum
physiology of, 186-188, 187f hypercoagulation in, 252-253, hemorrhage, 12
treatment of, 188-193 253f Prostaglandin E2, 11, 11b
clinical presentation in, 67-68 multiple, in assisted Prostaglandin F2α, 11, 11b
definition of, 65-66, 66t reproduction, 280, 280b dysmenorrhea and, 11-12
differential diagnosis in, 66t, Pregnancy loss for postpartum hemorrhage,
68-69 recurrent. See Recurrent 12
female infertility and, 160 pregnancy loss. Prostaglandin I2, 11, 11b
hirsutism in, 67, 68, 73-74 sporadic, 241 Prostaglandin receptors, 10
laboratory tests in, 68-70, 69b, Pregnancy support, early, after Prostaglandins, 9-12
70b ovulation induction in definition of, 3
physiology of, 66-67 hypothalamic amenorrhea, physiology and clinical
recurrent pregnancy loss in, 194 presentation of, 10-11,
249-250 Pregnanes, 3 11b
treatment of, 61-62, 70-74 Preimplantation genetic diagnosis production of, 9-10, 10f
Polymerase chain reaction (PGD), 273-276, 273b structure of, 10f
in preimplantation genetic Premature ejaculation, 144-145, therapeutic interventions
diagnosis, 275 171 related to, 11-12
in thrombophilias, 255 Prepuce, 130, 130f Prostate, 130f, 131
Polyp, endometrial Primordial follicles, 20, 230 examination of, in male
infertility and, 201 Primordial germ cells, 20 infertility, 173
radiologic imaging of, 83, 85f Progesterone, 4f, 6-7 Prostheses, implantable, for
treatment of, 87, 89t for abnormal uterine bleeding, erectile disorder, 142
Postcoital test, 165, 206 88-89 Protein C or S deficiency, recurrent
Postmenopause assays for, 8, 8b pregnancy loss in, 255
Index
Prothrombin mutation, recurrent Recurrent pregnancy loss Sauna use, maternal, recurrent
pregnancy loss in, 254 (Continued) pregnancy loss and, 259
Prune belly syndrome, male infer- immunologic factors in, Scrotum, 130, 130f, 131
tility and, 181 255-258, 258b examination of, in male
Pruritus, vaginal, in climacteric, 98 infections and, 251-252, 252b infertility, 173
Pseudoephedrine, for retrograde lifestyle and environmental in hyperthermic environment,
ejaculation, 176 factors and, 258-259, 260b male infertility and, 171
Pseudopuberty, 40, 41t obstetric history and, 241 repair of, for varicocele, 177
Psychogenic erection, 137 summary of, 260-261, 260t trauma to, infertility and, 170
Pubarche thrombophilia and, 252-255, Secretory phase of menstrual
normal, 36-37, 37b, 37t 253f, 256b cycle
premature, 44 uterine anomalies and, early, 29
Puberty, 33-47 244-249, 246f, 249b middle to late, 30-31
abnormal, 38-46 Refractory period, after orgasm, Selective estrogen receptor
296 delayed, 45 134, 135 modifiers (SERMs). See
hormonal responses in, 33-36 Reproduction also specific drugs, e.g.,
normal, 33-38 assisted. See Assisted Clomiphene citrate.
physical signs of, 36-38, 37b, 37t reproductive technologies in climacteric, 105-106
precocious, 38-44. See also (ART). for osteoporosis and fracture
Precocious puberty. normal, 156 prevention, 124
timing of, 38 Reproductive failure. See Selective serotonin reuptake
Pubic hair, development of Infertility. inhibitors
normal, 36-37, 37b, 37t Reproductive tract male infertility and, 172
premature, 44 anomalies of. See Müllerian for premature ejaculation, 144
anomalies. Semen
R defects of abnormalities of, environmental
Race, osteoporosis and, 112 amenorrhea from, 50t, toxins and, 170-171
Radiation, recurrent pregnancy 56-58, 57b, 57f, 62 analysis of, 174-175, 174b,
loss and, 259 evaluation of, 60, 60b 175t
Raloxifene embryology of, 198-199, 200f Seminal fluid, 131
in climacteric, 105-106 Resolution, sexual, 133f, 134f, 135 Seminal vesicle, 130f, 131
for osteoporosis and fracture Retrograde ejaculation, 176 examination of, in male
prevention, 124 Retroperitoneal surgical approach infertility, 173
Rape, sexual aversion disorder for varicocele, 177 Septate uterus, 199, 200f, 209,
after, 141-142 Rickets, 116 246f, 247-248
Rapid ejaculation, 144-145, 171 Risedronate, for osteoporosis and Serotonin reuptake inhibitors,
Recreational drugs, male infertility fracture prevention, 122 male infertility and, 172
from, 171, 173t Robertsonian translocation Severe ovarian hyperstimulation
Rectal examination, digital, in male infertility and, 180 syndrome, 193, 193b
male infertility, 173 recurrent pregnancy loss and, Sex, versus gender, 129
Recurrent pregnancy loss, 243 Sex screening questions,
241-261 148-149, 148b, 149b
cervical incompetence and, 206 S Sex therapy specialists, 149b
diminished ovarian reserve Saline infusion sonography. See Sex-hormone–binding globulin
and, 233 Sonohysterography. (SHBG), 4-5, 5t
endocrinopathies and, 249- Salpingitis, chlamydial, 204 Sexual activity
251, 252b Salpingitis isthmica nodosa, 204, desire for, 135, 135t, 136-137,
genetics and, 242-244, 243f, 205f 136f
245b Salpingo-oophorectomy, bilateral, patient expectations about, 140
history, physical examination, for endometriosis, 226 purpose of, 129
and laboratory tests in, Sampson’s theory of endometrio- response cycle in. See Sexual
242b sis, 213-214 response cycle.
Index
Sexual anatomy Sims-Huhner test, 155 Steroid hormones (Continued)

female, 131-133, 132f Skene’s glands, 131-132, 132f physiology and clinical
male, 130-131, 130f Skin presentation related to,
Sexual aversion disorder (SAD), changes of, in climacteric, 99 4-6, 5t
141-142 mottling of, in sexual response, structure of, 3-4, 4f
Sexual dysfunction, 139-150 133 therapeutic interventions
during arousal phase, 142-144 Sleep disturbances, in climacteric, related to, 8-9
categories of, 140-141, 140t 97 Steroid receptors, 5
in climacteric, 98-99 Smoking ß-Thalassemia, male infertility
during desire phase, 141-142 in climacteric, 103 and, 181
history taking in, 148-149, male infertility and, 171 Stratum basale, 18, 18b
148b, 149b menopause and, 94 Stratum compactum, 18, 18b
infertility and, 149-150, 150t recurrent pregnancy loss and, Stratum functionale, 18, 18b
from medications, 139b 259 Stratum spongiosum, 18, 18b
during orgasm, 144-146 Sonohysterography Strengthening exercise, for 297
overview of, 139-141 in abnormal uterine bleeding, osteoporosis and fracture
pain problems as, 146-148 83, 84f, 85f prevention, 120
screening for, 148-149, 148b, for fallopian tube evaluation, Stress
149b 163-164 abnormal uterine bleeding
Sexual hair, development of of uterine anomalies, 245 and, 82
normal, 36-37, 37b, 37t for uterine cavity evaluation, amenorrhea and, 55
premature, 44 164 Sulfasalazine, male infertility
Sexual history, infertility and, Sperm and, 172
159 antibodies against, infertility Superovulation. See Ovarian
Sexual infantilism, in ovarian and, 158, 176 hyperstimulation.
failure, 52 environmental toxins and, Suppositories, transurethral, for
Sexual response cycle, 133-139 170-171 erectile disorder, 142
female, 133-135, 134f, intracytoplasmic injection of Synechiae, uterine
136-137, 136f for antisperm antibodies, amenorrhea in, 58
hormonal influences on, 176 infertility in, 201, 202f, 209
137-139 procedure for, 268-270 recurrent pregnancy loss in, 248
intimacy-based, 136-137, laboratory analysis of, Systemic lupus erythematosus,
136f 174-175, 174b, 175t recurrent pregnancy loss in,
Kaplan’s redefinition of, 135, retrieval of, 178-179, 178t 257
135t Spermatic cord, 130-131, 130f
male, 133-135, 133f Spina bifida, male infertility and, T
Masters and Johnson’s, 181 Tamoxifen, for male infertility,
133-135, 133f, 134f Spine, bone mineral density 177
neuronal influences on, 137 measurement of, 112-113, Tanner stages, 36-37, 37b
sexual dysfunction categories 116 Tap water consumption, recurrent
based on, 140, 140t Spironolactone, for hirsut- pregnancy loss and, 259
Sexual trauma, sexual aversion ism in polycystic ovarian Temperature charting, for
disorder after, 141-142 syndrome, 73 ovulation confirmation,
Sexuality, 129-151 Statins, male infertility and, 172 160-161, 160b
Sexually transmitted disease, Stem cells, embryonic, 281 Teratozoospermia, 169
male infertility and, 170 Steroid hormones, 3-9. See also Teriparatide, for osteoporosis and
Sheehan’s syndrome, Androgens; Estrogens; fracture prevention,
amenorrhea in, 55-56 Progesterone. 124-125
Sickle cell anemia, male infertility anabolic, male infertility and, Testicular cancer, infertility and,
and, 181 171 169-170, 173
Sigmoidoscopy, flexible, in assays for, 8, 8b Testicular epididymal sperm
climacteric, 104t classes of, 3 aspiration, 178t, 179
Index
Testicular epididymal sperm Transurethral suppositories, for Ureaplasma urealyticum, recurrent

extraction, 178t, 179, erectile disorder, 142 pregnancy loss and,
264b Transverse vaginal septum, 56, 251-252
Testicular feminization, 200f Urinary incontinence, in
amenorrhea from, 57, 57b Trauma climacteric, 98
Testicular pain, 146 to scrotum, infertility and, 170 Urinary tract infection, in
Testis, 130, 130f, 131 sexual, sexual aversion disorder climacteric, 98
examination of, in male after, 141-142 Urine tests, in osteoporosis, 102
infertility, 173 Tricyclic antidepressants, for Urogenital symptoms, in
Testosterone, 4, 4f, 7 premature ejaculation, climacteric, 98
assays for, 8, 8b 144 Usher’s syndrome, male infertility
in climacteric, 96 T-score, 109, 113-114, 113f and, 181
in sexual response, 137-138 Tubal factor infertility, 157, Uterine artery embolization, for
supplementation of, male 203-204, 205f, 210 abnormal uterine bleeding,
298 infertility and, 171 Tube, fallopian. See Fallopian 87
Tetanus-diphtheria booster, in tube. Uterine bleeding, abnormal,
climacteric, 104t Tuberculosis, genitourinary, male 77-91
Tetracycline, male infertility and, infertility and, 170 clinical presentation in, 79-80
172 Tumor necrosis factor-α, in diagnostic tests in, 83-85, 84f,
Theca cell, 4, 23 menstrual cycle, 21t, 25 85f
Thelarche Tumors differential diagnosis in, 81-83
abnormal, 45 androgen-producing, 68 history in, 79-80
normal, 36, 37b, 37t ovarian, amenorrhea in, 54 hormonal therapy for, 88-90
premature, 44 pituitary, male infertility and, physical examination in, 80
Thoughts, interfering, in erectile 170 physiology of, 77-79, 78b
disorder, 143 Tunica albuginea, 130, 130f surgical therapy for, 86-88
Thrombin formation, in treatment of, 86-90, 87b, 89b
pregnancy, 252 U Uterine cavity, evaluation of,
Thrombophilia, recurrent Ultrasonography. See also 164-165
pregnancy loss and, Sonohysterography. Uterine fibroids
252-255, 253f, 256b for ovarian reserve evaluation, infertility and, 201-203, 203f,
Thromboxane, 11, 11b 167 209
Thyroid autoantibodies, recurrent in ovulatory clomiphene radiologic imaging of, 83, 84f
pregnancy loss and, 257 citrate cycle, 189-190, recurrent pregnancy loss and,
Thyroid disorders 190f, 191f 249
abnormal uterine bleeding in, pelvic, in abnormal uterine treatment of, 87, 89t, 209,
82-83 bleeding, 83, 84f, 85f, 86 249
amenorrhea in, 54 in polycystic ovarian Uterine polyp
male infertility in, 170 syndrome, 53, 54f infertility and, 201
osteoporosis in, 118 three-dimensional, of uterine radiologic imaging of, 83, 85f
recurrent pregnancy loss in, anomalies, 245 treatment of, 87, 89t
251 transrectal, in male infertility, Uterine synechiae
Thyrotropin, elevated, in polycystic 175 amenorrhea in, 58
ovarian syndrome, 69 transvaginal infertility in, 201, 202f, 209
Transforming growth factor-α, in in endometriosis, 218, 219f recurrent pregnancy loss in,
menstrual cycle, 22t, 25 in polycystic ovarian 248
Transforming growth factor-ß, in syndrome, 70 Uterus, 133
menstrual cycle, 21t of uterine anomalies, 245 agenesis of, amenorrhea from,
Translocation, chromosomal Underwear, male, infertility and, 56-57
male infertility and, 180 171 anatomic abnormalities of
recurrent pregnancy loss and, Unicornuate uterus, 199, 200f, abnormal bleeding from, 82,
243 208-209, 246f, 247 89t
Index
Uterus (Continued) Vaginal pruritus, in climacteric, W

acquired, 201-203, 203f 98 Weight gain
anatomy and physiology of, Vaginismus, etiology and treatment androgen level and, 5
198-199, 200f of, 147-148 in puberty, 37-38
congenital, 199-200, Vaginosis, bacterial, recurrent Weight loss
245-248, 246f pregnancy loss and, 251-252 amenorrhea from, 55
diagnosis of, 208, 245 Varicocele, infertility and, 173, for chronic anovulation, 188
from diethylstilbestrol, 177 for polycystic ovarian
200-201, 248 Varicocelectomy, laparoscopic, 177 syndrome, 70-71
infertility from, 158, Vas deferens, 130f, 131 Weight-bearing exercise, for
198-203, 208-209 Vascular endothelial growth osteoporosis and fracture
radiologic imaging of, 83, factor prevention, 120
84f, 85f in menstrual cycle, 21t, 25 Wolffian ducts, 198-199
recurrent pregnancy loss in severe ovarian Women. See Female.
from, 244-249, 246f, hyperstimulation Wrist, DXA of, 116 299
249b syndrome, 193
arcuate, 209, 246f, 248 Vascular metastasis theories of X
bicornuate, 200f, 207f, 209, endometriosis, 215 XX male syndrome, male infertility
246f, 247 Vasectomy reversal, 177-178 in, 181
embryology of, 198-199, 200f Vasomotor disturbances, in XYY karyotype, male infertility
enlargement of, in sexual climacteric, 96-97, 105 in, 180
response, 134 Vasovasostomy, 177-178
with rudimentary horn, 209 Vertebral compression fracture, Y
septate, 199, 200f, 209, 246f, 110, 112, 118 Y chromosome microdeletions,
247-248 Viremia, male infertility and, 170 male infertility in, 180-181
unicornuate, 199, 200f, Virilization Young’s syndrome, infertility
208-209, 246f, 247 inadequate, evaluation of, and, 170, 181
Uterus didelphys, 246f, 247 172-173
in polycystic ovarian Z
V syndrome, 67, 68 Zoledronic acid, for osteoporosis
Vacuum device therapy, for erectile Vitamin B6 supplementation, for and fracture prevention, 122
disorder, 143 MTHFR mutation, 255 Z-score, 109, 114-115, 114f
Vagina, 132-133, 132f Vitamin D Zygote intrafallopian transfer
agenesis of, amenorrhea from, deficiency of, 116, 117, 118, (ZIFT), 264b
56-57 125
enlargement of, in sexual dietary sources of, 119
response, 134 intake of, for osteoporosis and
examination of, in abnormal fracture prevention, 119,
uterine bleeding, 80 121
lubrication of, in sexual Voice deepening, in polycystic
response, 134 ovarian syndrome, 67, 68
thinning and atrophy of, in Von Willebrand’s disease, 81
climacteric, 98 Vulva, 131, 132f

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1600 John F. Kennedy Blvd.

REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY ISBN- 13: 978–0–323–04054–9

Library of Congress Cataloging-in-Publication Data

Acquisitions Editor: Rebecca Gaertner

Printed in the United States of America.

Last digit is the print number: 9 8 7 6 5 4 3 2 1

very commonly in many clinical practices, including family medicine, inter-

The main classes of steroid hormones are progestins, androgens, estrogens,

Basic steroid C27

SHBG, sex hormone–binding globulin.

DNA to available estrogen is decreased. Conformational changes may acti-

Progestins Progesterone is primarily synthesized by the ovary. A small amount is made

HDL, high-density lipoprotein; LDL, low-density lipoprotein.

nancy, the effects of high levels of progesterone include relaxation of the

Therapeutic Hormonal Contraception

Box 1-1 Units of Measurement for Sex Steroid Hormones

SUMMARY OF KEY POINTS—STEROIDS

Naturally occurring prostaglandins (PGs), 20-carbon fatty acid derivatives,

the cyclooxygenase pathway. The lipoxygenase pathway leads to the forma-

Box 1-2 Effects of Prostaglandins

that occurs in an obstetric patient who is undergoing cervical ripening with

Therapeutic Primary Dysmenorrhea

SUMMARY OF KEY POINTS—PROSTAGLANDINS

The idealized length of the normal human menstrual cycle is 28 days

Box 2-1 Normal Menstrual Cycle

Treloar AE, Boynton

Early Follicular/ Endometrium

Box 2-2 Endometrial Layers

Figure 2-3 Follicular Ovulation Mature corpus Corpus

Period of Period First growth Second growth Period of

Bleeding Proliferative, follicular, Secretory, luteal or Bleeding

or estrogenic phase progestational phase

↑ Inhibin T production ↑ GnRH

EGF induces) LH receptors

much higher FSH receptor level and estrogenic environment. Additionally,

description is a simplification of their role in ovarian physiology, as it is cur-

Figure 2-4 Early Mid Late Early Mid Late

Early Mid Late Early Mid Late

to the endometrium is noted, and the endometrial thickness increases from

Late Follicular/ Ovary

tion and ovulation, such as oocyte maturation inhibitor and luteinization

for the midcycle surge of FSH. Preovulatory estrogen production and LH

Early Luteal/ Ovary

cytokines and proteases that contribute to the degradation of the extracel-

SUMMARY OF KEY POINTS

2. The menstrual cycle is divided into two main phases: follicular/prolifera-

HORMONAL RESPONSES IN CHILDHOOD AND PUBERTY

function. Hypothalamic and pituitary signals also stimulate androgen pro-

with adrenal insufficiency continue to go through the appropriate pubertal

Growth Growth hormone (GH) plays an important role in pubertal development.

PHYSICAL SIGNS OF PUBERTY

The physical changes of puberty are produced by estrogens from gonadal

Box 3-1 Tanner Staging System for Breast Development

Box 3-2 Tanner Staging System for Pubic Hair Development

INFLUENCES IN THE TIMING OF PUBERTY

The onset of puberty in girls can be difficult to track because of various

ABNORMAL PUBERTAL DEVELOPMENT

Abnormal pubertal development can be divided into conditions that initiate

areas of the brain leading to stimulation of GnRH or FSH and LH produc-

CNS, central nervous system; LH, luteinizing hormone.

Box 3-3 Useful Methodologies in the Diagnosis of Precocious Puberty

Box 3-4 Possible Treatments of Precocious Puberty

prevent overlooking this phenomenon. Initial laboratory tests noting an ele-