GYNECOLOGY Dra Alenzuela

the hormones involved in reproductive endocrinology.

Inhibin.

A polypeptide dimer composed of an and a subunit

joined by disulfide bonds. This hormone is produced by
ovarian granulosa cells and inhibits FSH secretion.

Leptin.

A peptide secreted by adipose tissue. It is believed to be

a peripheral signal of amount of fat stores.

Luteinizing Hormone
(LH).

A glycoprotein with a molecular weight of 28,000 daltons

that is composed of a nonspecific subunit and a
specific subunit. The primary action of LH in the female
is to stimulate ovarian steroid synthesis.

Median Eminence
(Infundibulum).

The portion of the neurohypophysis lying in the midline

at the base of the hypothalamus. It is connected to the
infundibular stalk and the posterior (neural) lobe of the
pituitary gland.

Neurohypophysis.

The portion of the hypothalamus consisting of the

median eminence, infundibular stalk, and posterior lobe
of the pituitary.

Paracrine.

Producing hormonal effects by diffusion to contiguous

cells.

Sex Hormone-Binding
Globulin (SHBG).

A serum globulin that has a high affinity for

dihydrotestosterone, testosterone, and estradiol
estrogens and androgens (also called testosterone
estrogen-binding globulin [TeBG]).

REPRODUCTIVE ENDOCRINOLOGY
Definition of Terms:

Arcuate Nucleus.

A group of nerve cells lying in the medial portion of the

hypothalamus just above the median eminence. Nerve
cells in the arcuate nucleus are the major source of
gonadotropin-releasing hormone (GnRH) secretion.

Aromatization.

Synthesis of a phenolic, or aromatic, benzene ring, as

occurs during conversion of testosterone to estradiol

Atresia.

Process of regression of preantral follicles.

Catechol Estrogens.

Steroids that structurally resemble both estrogens and

catecholamines and have only a weak estrogenic action.

Desensitization (DownRegulation).

The condition wherein a hormone is secreted or

administered for a prolonged period and produces an
inhibitory instead of a stimulatory response because of
saturation of its receptor.

Dominant Follicle.

Follicle that enlarges to about 2 cm in diameter and

eventually ovulates.

Follicle-Stimulating
Hormone (FSH).

A glycoprotein with a molecular weight of 33,000 daltons

that is composed of a nonspecific subunit and a
specific subunit. The primary action of FSH in the
female is to stimulate granulosa cell synthesis.

GnRH Structure
A decapeptide synthesized in and secreted by the
Gonadotropin-Releasing
hypothalamus at periodic intervals to stimulate
Hormone (GnRH).
gonadotropin release from the pituitary gland.
Gonadotropin-Releasing GnRH analogues are proteins that have various amino
Hormone Analogue
acid substitutions of the 10 amino acids found in the
(GnRH Analogue).
parent molecule that increase potency and half-life.

Hormone Receptors.

Proteins on the cell membrane or within the cell of the

target tissue that bind to a specific molecule of a
hormone (ligand) for the purpose of eliciting a biologic
response. Hormone receptors bind only to ligands of a
specific hormone and thus are hormone specific.

Hypothalamus.

Portion of the base of the brain that is located just below

the optic chiasm and that has a major role in regulating

A decapeptide synthesized and released by the ARCUATE NUCLEUS

Stimulate pituitary synthesis and release of FSH and LH
GnRH-secreting cells arrive in the brain from its origins in the olfactory
area.
Beginning in the medial olfactory placode, from where the sense of smell
originates, the cells migrate along a cranial nerve projecting from the nose
to the septal-preoptic nuclei in the brain.
In Kallman's syndrome, mutations arising, which prevent normal neuronal
migration in this area, result in deficiency of GnRH and the lack of a sense
of smell.
The cell bodies of the hypothalamic neurons that produce GnRH are
concentrated mainly in two areas: the anterior hypothalamus and the
medial basal (tuberal) hypothalamus

Hypothalamic Control
Gonadotropin Stimulatory, GnRH
Prolactin Stimulatory, PRF
Inhibitory, PIF

Hypothalamus, Ant Hypothalamus, Medial Basal/

Tuberal Hypothalamus (arcuate Nucleus)

Tuberoinfdibular Tract

GnRH Secretion
Regulates secretion of FSH and LH
Secreted in a pulsatile manner to be effective (hl: 2-4min)
Amplitude of release in menstrual cycle:
1. Follicular Phase frequent small amplitude (1 pulse per hour)
2. Late Follicular Phase greater frequency, higher amplitude
(ovulation)
3. Luteal Phase decreased frequency, high amplitude
(1 pulse in 2-3 hrs)

Median Eminence

Portal Ciculation

Anterior Lobe of the Pituitary

Routes of Secretion

t
.

a
r

I.
Major Route (Cyclic)
GnRH is transported along the axons of these neurons, which terminate in the median
eminence around the capillaries of the primary portal plexus. The nerve cells that
transport GnRH from the arcuate nucleus to the median eminence are called the
The median eminence, or infundibulum, together with the
infundibular stalk and posterior (neural) lobe of the pituitary, make up the
neurohypophysis. The three components of the neurohypophysis share a common
capillary network and have a direct arterial blood supply from the hypophyseal arteries.
The capillaries of the median eminence have a fenestrated epithelium similar to that of
peripheral tissue, which allows passage of large molecules. These capillaries differ from
those present in the brain, and thus the median eminence is outside the bloodbrain
barrier.The nerve cell terminals of the tuberoinfundibular tract secrete GnRH directly
into the portal circulation, which carries the hormone to the gonadotropin-containing
cells in the anterior lobe of the pituitary. The pars tuberalis of the anterior lobe of the
pituitary (adenohypophysis) receives its vascular supply from pituitary portal vessels and
is located adjacent to the base of the hypothalamus and the pituitary stalk. Unlike the
neurohypophysis, the adenohypophysis has no direct arterial blood supply and receives
all of its blood from the portal vessels. After leaving the pituitary gland, the circulation
returns to the neurohypophyseal capillary plexus, allowing pituitary hormones to help
regulate the secretion of GnRH from the median eminence.

II.
Minor Route (Tonic)
Axons of the tuberoinfundibular tract may transport GnRH directly into the third
ventricle. A specialized ependymal cell, the tanycyte, extends from the lumen of the
third ventricle into the outermost zone of the median eminence ( Fig. 4-3 ). Because
GnRH is transported into the portal system when it is administered into the third
ventricle, it has been postulated that transport occurs via the tanycytes and their
microvilli. Thus GnRH can be released both in large amounts periodically via the
tuberoinfundibular tract (cyclic release) and in a low-grade continuous
transependymal manner (tonic release) via the tanycytes.
Hypothalamus, Ant Hypothalamus, Medial Basal/
Tuberal Hypothalamus (arcuate Nucleus)

Tuberoinfdibular Tract

Median Eminence

Tanycytes

Portal Ciculation

Anterior Lobe of the Pituitary

Regulation of Secretion

Control of episodic GnRH secretion is extremely important for the maintenance

of normal ovulatory cyclicity

I. Long Feedback Loop

Activin
(-) progesterone and (+) estradiol production
(+) FSH release only
Stimulation of thecal androgen production
Inhibits oocyte maturation
*decline in inhibin levels in the perimenopause and menopause is probably the
permissive factor in the rise of FSH levels at these times

A. Ovarian Steroids: (+/-) Estrogen and Progesterone

Metabolism
Transport Proteins

Estradiol: 0.1 to 0.5 mg (lowest during

menses, highest just before ovulation
Progesterone: 0.5mg (follicular phase by Adrenals)
20 mg (luteal phase by corpus luteum)
Kidneys and Liver
SHBG: Estrogen and Androgen
CGB: Progesterone

Clinical Application:
estradiol, obesity and hyperthyroidism (SHBG)
androgen and hypothyroidism (SHBG)
B. Non Steroidal Secretions: (+/-) Inhibin, Activin, Follistatin

k
:

n
r

Daily Secretion

Follistatin
Ovarian peptide
Aka FSH suppressing protein
(-) of FSH synthesis and secretion
(-) of FSH respose to GnRH
Binds to activin and in this maner decrease the activity of activin
L

Estrogen stimulation of synthesis of esctrogen and progesterone receptors in target

tissues such as the endometrium
Progesterone inhibition of synthesis of estrogen and progesterone receptors
- increase intracellular synthesis of estrogen dehydrogenase, converts
estradiol to less potent estrone

Transforming Growth Factor / and Epidermal Growth Factor

Transforming growth factors (TGF-) and (TGF-) share significant homology
with the subunit of the inhibin and activin molecules. Within the ovary, they both
bind with equal affinity to a common receptor. TGF- and epidermal growth factor
(EGF) are potent regulators of granulosa cell proliferation and differentiation. They
have been demonstrated to inhibit both gonadotropin-supported granulosa cell
differentiation and follicular cell steroidogenesis. TGF- promotes growth and cAMP
accumulation in granulosa cells and enhances FSH-induced increases in aromatase
and LH receptors. TGF- also inhibits follicular cell growth and thus facilitates
follicle cell growth.

Table 4-3 -- Effects of Eicosanoids

Prostaglandins

Inhibins
(+) progesterone and (-) estradiol production
Production is regulated by FSH
Preferentially inhibits FSH over LH release
(+) of thecal androgen production
(-) oocyte maturation
*decline in inhibin levels in perimenopause and menopause is probably the permissive
factor in the rise of FSH levels at these times

Effects

PGI2, PGE2, PGD2 Vasodilation

Cytoprotection
Platelet aggregation
Leukocyte aggregation
Cyclic-AMP formation
IL-1 and IL-2 formation

Prostaglandins

Effects

PGF2

Vasoconstriction
Bronchoconstriction
Smooth muscle contraction

TXA2

Vasoconstriction
Platelet aggregation
Lymphocyte proliferation
Bronchoconstriction

LTB1

Vascular permeability
Leukocyte aggregation
IL-1 formation
IL-2 formation
Natural killer cell cytotoxicity
Chemoattractant

LTC4, LTD4

Bronchoconstriction
Vascular permeability

IL, interleukin; LT, leukotriene; PG, prostaglandin; PGI2, prostacyclin; TX,

thromboxane.
II. Short Feedback Loop

This preferential inhibition of FSH release during the reproductive

years results from increasing levels both estradiol and inhibin

A. Luteinizing Hormone Function:

1. Stimulates hormone production by activating cP450SCC
a. androgen in theca cells
b. progesterone in the corpus luteum
2. Acts synergistically with FSH
a. on the granulose cells to help follicular maturation
b. to increase LH receptors and luteinizing of follicle (thus increasing
progesterone production)
3. Induces Ovulation
a. stimulating a plasminogen activator that decreases tensile strength of the
follicle wall before follicular rupture occurs
b. stimulates prostaglandin synthesis
B. Follicle Stimulating Hormone Function
1. Stimulates hormone production
a. Estrogen (E1, E2) in granulose cells by activating aromatase enzyme
b. Interconversion of androstenedione and testosterone in the theca
cells by activating 3 OHSD
2. Acts synergistically with LH
a. on the granulose cells to help follicular growth and maturation
b. to increase LH receptors and luteinization of follicle (thus
increasing progesterone production)
3. Rescue of follicles from degeneration (achieved by reducing androgenicity of
environment)
a. Indirectly by stimulating activin production
b. Directly metabolizing LH induced thecal androgen to estrogens

Gonadotropins: LH and FSH

Structurally identical subunit
14,000 daltons, 90 a.a., similar to TSH and hCG
Structurally different subunit
carbohydrates, biologic activity, amino acids

LH
FSH

Sialic Acid
Half Life
1 or 2
30 min
5
3.9 hrs
Common cell type: basophilic cells
Physiologic Secretions
FSH release is greater than LH during puberty and menopause

III. Ultra Short Feedback Loop

Inhibition by GnRH

A. Neurotransmitters:

Catecholestrogens
higher concentrations in the hypothalamus than are prostaglandins E1 and
E2
inhibition of tyrosine hydroxylase and competition for the enzyme
catechol- -methyltransferase
(-) NE = (-) GnRH

Catecholamines modulate GnRH pulsatile release by influencing

the frequency and amplitude of the pulses
Dopamine

Inhibits GnRH release and indirectly inhibit

gonadotropins
Inhibits pituitary prolactin secretion
(PrL inhibiting hormone???)

Norepinephrine Stimulatory to GnRH

Produced by conversion of tyrosine in the
midbrain by enzyme tyrosine hydoxylase
Indolamine
Serotonin

Does not affect GnRH release

Stimulates PRF, thus stimulating PrL ultimately
Inhibiting GnRH

B. Neuromodulators:
Opiods (LH, PrL, GnRH)
3 subgroups : enkephalin, endorphins, dynorphins
5 to 10 times as potent as morphine
concentrated mainly in the arcuate nucleus, median eminence of the
hypothalamus, as well as the pituitary gland
concentrations of endorphins are about 1000 times higher in the pituitary than
in the hypothalamus
Prostaglandin PGE2 (GnRH)
Administration of prostaglandin E2 significantly increases GnRH levels in the
portal blood

C. Brain Peptides:
Neuropeptide Y
Stimulates pulsatile release GnRH and gonadotropins
Absence of estrogen inhibits gonadotropin release
Increased in CSF of women with anorexia and bulimia
AngiotensinII
Affects secretion of pituitary hormones by local action
Affects ND and dopamine on the releasing factors that control
gonadotropin and prolactin secretion
Somastostatin
Inhibits the release of growth hormone, prolactin and TSH from the
pituitary
Galanin
Released into the portal circulation in pulsatile manner
Positively influences LH secretion
Inhibited by dopamine and somatostatin
Stimulated by TRH an estrogen
Activin and Inhibin
Produced by gonads
Peptide members of the transforming growth factor family
Opposes FSH secretion
Inhibin selectively diminishes FSH but not LH
Activin stimulates FSH and LH
Follistatin
FSH suppressing protein
Inhibits FSH synthesis and secretion and the FSH response to GnRH
Binds to activin and in this manner decreases he activity of activin
Melatonin
Produced by pineal gland
Secretion influenced by darkness
Important in circadian rhythm
High levels in winter months
Leptin
Produced by adipose cells

Enhance GnRH release

Exhibits a negative correlation with androgen levels DHEAS
Likely has a role in the pituitary, ovary and endometrium
Have a role in implantation

Breast cancer
Prostatic cancer
Suppression of ovarian function in polycystic ovary syndrome and in vitro
fertilization

GnRH Analogs

Premenstrual syndrome

Dysfunctional uterine bleeding including clotting disorders

Modifications of the native GnRH molecule

Increase receptor affinity
Decrese degradation
More stable and powerful compounds
Agonist
desensitization

Suppression of
Gonadotropins
Acute responses
Chronic Response
Experience
Safety

Stimulate LH/FSH
Inhibit LH/FSH
Extensive
Long History of Safety

Cost

low

Contraception
Suppression of spermatogenesis
Antagonist
Comprtitive receptor
blockade
Inhibit LH, Partially FSH
Inhibit LH/FSH
Limited
REffects of histamine
release
high

Clinical Applications of GnRH and Its Agonists

Ovulation inhibition

GnRH Mode of Action: GNRH AGONIST

GnRHa administered

GnRH receptors occupied and internalized

Initial LH and FSH surge

Activation of PituitaryGonadal Function (GnRH)

Delayed puberty

Loss os available GnRH receptors

Cryptorchidism
Functional hypothalamic amenorrhea
Hypogonadotropic hypogonadism (Kallmann's syndrome)

Decreased LH and FSH synthesis and release

PituitaryGonadal Inhibition (Agonists)

Suppression of follicular development
Precocious puberty
Hormone-dependent tumors

Decreased estradiol synthesis and release

Endometriosis
Uterine leiomyoma

Mode of Action: GnRH ANTAGONIST

Pituitary ovarian axis suppression without flare effect
Compete with GnRH for its receptors
Prevent synthesis and release of LH/FSH
Induce immediate and transient hypogonadism
Suppress gonadal steroidogenesis

Has greatest number of receptors

Has greatest mitotic activity and number of granulosa cells
More vascularized theca cells so more FSH reaches its receptor

Ovulation Occurs
*24 hrs after the first estradiol peak
*32 hours after the initial rise in LH
*12-16 hours after peak LH levels in the serum

Ovarian Gametogenesis

Theca Cells androstenedione and testosterone

Granulosa Cells estrone and estradiol
Corpus Luteum progesterone

Clinical Guidelines for Normal Menstruation

Normal Values:
Cycle Length 28+/- 7 days
Duration of flow 4+/- 2 days
Menstrual blood loss 40 +/- 20 ml
Average Iron Loss/Menses 16 mg

Two-Cell-Two Gonadotropin Hypothesis

Key Events of Menstrual Cycle (Dr Alenzuelas Note)

Hormone Production in the Graafian Follicle

Theca Cells
LH

Cholesterol

Androstenedione Testosterone

At the start of each menstrual cycle, gonadal hormones are low and has ben
declining since the end of the luteal phase of the previous cycle
With the demise of the corpus luteum of the previous cycle, FSH level begin to rise
and follicular recruitment of the next cyclebegins. Under the influence of FSH, these
follicles grow and each secrete increasing amounts of estadiol. The rising causes
proliferation of the endometrium
Estrogen stimulate growth and differentationof the functional layer of the
endometrium and work synergistically with FSH for follicular development

Granulosa Cells
Aromatization
FSH
Estrone Estradiol

The Dominant Follicle

Established by day 7 of the cycle
Secretes the highest amount of estrogen
Most sensitive to FSH

Rising levels of estradiol sends a negative feedback the pituitary and hypothalamus
resulting into inhibition of FSH release and FSH declines at midpoint of the follicular
phase. Also, the granulose cells secrete inhibin which help suppress FSH. LH on the
otherhand, is initially stimulated by secrtionof estrogen throughout the follicular
phase. The midpoint decline of FSH causes atresia of all except one follicle the
dominant follicle. The dominant follicle produces abot 80% of the daily estradiol
production of 500ug. The rapid rise of estradiol and small amounts of ptrogesterone
from the dominant follicle is the HPO signal that the follicle is ready to be ovulated.
When critical estradiol level is reached (200pg/ml or more for two or more days),
the initial negative feedback reverses into a positive one and causes the LH and FSh
surge at midcycle. The LH surge initiates ovulation

At the end of the follicular phase just befoe ovulation, FSH induced receptors appear on
the granulose cells. LH stimulation modulates progesterone secretion
LH surge initiates germinal vesicle disruption and metaphase I is completed. The oocyte
enters metaphase II and the first polar body appears (it is only upon sperm penetration
into the zona pellucida when meiosis is completed and the second polar body is
extruded)
Prior to rupture, LH stimulates synthesis of PGF2 and PGE and collagenase. FSH
stimulates production of plasminogen activator which converts plasminogen to plasmin
a proteolytic enzyme. These facilitates follicular rupture and egg extrusion.
After extrusion of the oocyte, there is a decrease in follicular fluid, the follicular wall
convolutes and there is a marked decrease in diameter and volume of the follicle. The
granulose cells become vascularized allowing LH to reach more receptors. Both
granulose and theca cells become luteinized and acquire yellow coloration.
Under LH, the corpus luteum produces significant amounts of progesterone. Estradiol
levels meanwhile decreases just before ovulation and continues to lower in the early
luteal phase. Its level pick up at midliteal phase a consequence of corpus luteum
production (second estradiol peak)
The decrease in LH frequency in the luteal phase is due to the negative feedback effect
of progesterone on the hypothalamus which decreases GnRH release. (increased
endorphin levels probably mediates this event). The decrease in LH amplitude is due to
the negative feedback of progesterone on the pituitary
Estradiol and progesterone levels remain elevated throughout the lifespan of the corpus
luteum. However, its existence is dependent on LH. With continuing decline in LH levels,
there is demise of the corpus luteum and sex steroid levels declines. In 4-6 days after
this fall menstruation ensues and the next cycle begins. If however, fertilization occurs,
there is rescue of the corpus luteum as a consequence of HCG production which acts as
a surrogate for LH.

takes place via the cyclic endoperoxides, prosta-glandins G and H (PGG

and PGH). Prostanoids are produced intracellularly shortly before they
are released and generally act locally, in contrast to steroids.

KEY POINTS

The hypothalamic hormone that controls gonadotropin release, namely

gonadotropin-releasing hormone (GnRH), is a decapeptide.

The cell bodies of the hypothalamic neurons that produce GnRH are
concentrated mainly in two areas: the anterior hypothalamus and the
medial basal (tuberal) hypothalamus.

Following a single intravenous bolus of GnRH, the LH levels peak in 30

minutes and FSH in 60 minutes.

GnRH can be released both in large amounts periodically via the

tuberoinfundibular tract (cyclic release) and in a low-grade continuous
transependymal fashion (tonic release) via the tanycytes.

With a constant infusion of GnRH there is a biphasic release of LH but

not of FSH. The initial increase of LH occurs 30 minutes, and the second,
90 minutes after the start of the infusion.

When stimulation by hormone is maximal, the unoccupied receptors

become refractory to hormone binding for 12 to 72 hours. This
phenomenon has allowed frequent administration of GnRH analogues to
be used clinically to inhibit FSH and LH levels, and thus decrease
steroidogenesis.

GnRH analogues are synthesized by substitution of amino acids in the

parent molecule at the 6 and 10 positions. The various agonists have
greater potencies and longer half-lives than the parent GnRH.

LH and FSH have the same subunit, which is similar in structure to the
subunit of thyroid-stimulating hormone (TSH) and human chorionic
gonadotropin (HCG). The subunits of all these hormones have
different amino acids and carbohydrates, which provide specific biologic
activity.

The half-life of LH is more rapid (30 minutes) than that of FSH (3.9
hours).

LH acts primarily on the theca cells to induce steroidogenesis, whereas

FSH acts primarily on the granulosa cells to stimulate follicular growth.

LH acts on the theca cells to produce androgens, which are then

transported to the granulosa cells, where they are aromatized to
estrogens.

After sufficient LH receptors have been produced by the action of FSH

and estradiol, LH acts directly on the granulosa cells to cause
luteinization and production of progesterone.

The ovary secretes three principal steroid hormones: estradiol from the
follicle, progesterone from the corpus luteum, and androstenedione
from the stroma.

Pregnenolone, 17-hydroxypregnenolone, progesterone, 17hydroxyprogesterone, and corticosteroids have 21 carbon atoms;

GnRH is secreted in a pulsatile manner. The amplitude and frequency of

the pulses vary throughout the menstrual cycle. The frequency is rapid
in the follicular phase, about one pulse per hour, and slower in the luteal
phase, about one pulse every 2 or 3 hours.

The most important neurotransmitters involved in reproductive

neuroendocrinology are two catecholamines, dopamine and
norepinephrine, as well as an indolamine, serotonin.

Infusion of -endorphin results in an increase in prolactin and a

decrease in luteinizing hormone (LH), the latter occurring by an
inhibitory effect on GnRH neurons in the hypothalamus.

Peripheral measurement of plasma -endorphin levels does not reflect

levels in the central nervous system circulation.

The peptide hormones, such as GnRH, bind to specific receptors on the

surface membrane of the target cell, in contrast to steroid hormones,
which pass through the cell membrane to bind to intracellular receptors.

When a protein hormone binds to its specific receptor, it activates or

inhibits the enzyme adenyl cyclase, the second messenger, which in turn
changes the concentration of adenosine 3,5-cyclic monophosphate
(cyclic-AMP, cAMP).

The various growth factors provide hormonal effects within the ovary by
both autocrine and paracrine mechanisms.

Inhibin inhibits pituitary follicle-stimulating hormone (FSH) release,

whereas in the ovarian follicle inhibin stimulates progesterone and
inhibits estradiol production. Activins have an opposite action to
inhibins by stimulating pituitary FSH release and opposing ovarian action
by inhibiting progesterone and stimulating estradiol.

Biosynthesis of prostanoids from arachidonic acid and other precursors

androgens (testosterone and androstenedione) have 19 carbon atoms;

estrogens have 18 carbon atoms and a phenolic ring A.

Because the ovaries lack 21-hydroxylase, 11--hydroxylase, and 18hydroxylase reductase activity, they are unable to synthesize
mineralocorticoids or glucocorticoids.

Estradiol and estrone are interconverted outside the ovary. Estrone is

then converted to estrone sulfate, which has a long half-life and is the
largest component of the pool of circulating estrogens.

The greater the amount of fat tissue present, the greater is the
percentage of androstenedione that is converted to estrone. In a normal
individual, about 1.3% of the daily 3000 g of androstenedione
produced is converted to estrone (40 g), whereas in an obese
individual as much as 7% of the 3000 g is converted (200 g).

The process by which steroids are conjugated involves the

transformation of lipophilic compounds, which are only sparingly soluble
in water, into metabolites (sulfates and glucuronides) that are readily
water-soluble and can therefore be eliminated in urine. Progesterone
first undergoes extensive reduction of its double bond and ketone
group(s) before it is conjugated. Its major urinary metabolite is
pregnanediol glucuronide. The major urinary metabolites of estradiol
and estrone are glucuronides and sulfates of estrone, estradiol, and
estriol.
Sex hormone-binding globulin (SHBG) primarily binds
dihydrotestosterone, testosterone, and estradiol. About 65% of
circulating testosterone is bound to SHBG and 30% to albumin.
Approximately 2% remains unbound or free.

Corticosteroid-binding globulin (CBG) binds with highest affinity to

cortisol, corticosterone, and 11-deoxycortisol, and to a lesser extent to
progesterone.

Estrogen stimulates the synthesis of both estrogen and progesterone

receptors in target tissues, and progestins inhibit the synthesis of both
estrogen and progesterone receptors.

Just before birth the primary oocytes, which at that time number 2 to 4
million, reach the diplotene stage, also called the germinal vesicle stage
of development.

Estradiol stimulates preantral follicle growth, reduces follicular atresia,

and increases FSH action on the granulosa cells. Testosterone increases

follicular atresia and prevents preantral follicle growth.

The follicle destined to become dominant secretes the greatest amount

of estradiol, which in turn increases the density of FSH receptors.

With ultrasound it has been found that there is a steady increase in

follicular diameter and volume that parallels the rise in estradiol. The
dominant follicle has a maximal mean diameter of about 19.5 mm, with
a range of 18 to 25 mm just before ovulation. The mean maximal
follicular volume is 3.8 mL, with a range of 3.1 to 8.2 mL.

Ovulation occurs about 24 hours after the estradiol peak, as well as 32

hours after the initial rise in LH, and about 12 to 16 hours after the peak
of LH levels in serum.

The midcycle LH surge initiates germinal vesicle disruption, and

metaphase I is completed. As the oocyte enters metaphase II, the first
polar body appears. Completion of meiosis and extrusion of the second
polar body occur only when a sperm penetrates the ovum.

By serial ultrasound observation and LH measurements, ovulation

usually occurs within 24 hours and always within 48 hours after the peak
in LH.

Beginning in the midluteal phase, progesterone is secreted in a pulsatile

manner, occurring immediately following an LH pulse.

Serum levels of estradiol rise from less than 50 pg/mL in the early
follicular phase to 200 to 500 pg/mL at midcycle and have a broad
luteal-phase peak level of about 100 to 300 pg/mL.

Progesterone levels in serum are less than 1 ng/mL before ovulation and
reach midluteal levels of 10 to 20 ng/mL.

During a normal ovulatory cycle at midcycle, the first event is a rise in

estradiol. When estradiol reaches peak levels, there is an abrupt
increase (surge) in LH and FSH. The increase in LH reaches a peak in
about 18 hours, and peak levels plateau for about 14 hours, after which
there is a decline. The mean duration of the LH surge is about 24 hours.
Beginning about 12 hours before the onset of the LH surge, there is an
increase of both progesterone and 17-hydroxyprogesterone.

With the occurrence of the LH peak, there is a decline in estradiol and a

further increase in progesterone. This shift in steroidogenesis in favor of
progesterone instead of estradiol production is brought about by the
luteinization of the granulosa cells produced by LH.

10

Menstrual cycle length is most irregular in the 2 years after menarche

and the 3 years before menopause, times of life during which
anovulatory cycles are most frequent.

The mean duration of menstrual cycle length is 28 7 days, with

menstruation in which cycles occur at more frequent intervals (<21
days) being called polymenorrhea, and that in which cycles are less
frequent (>35 days) being called oligomenorrhea. The mean duration of
menstrual flow is 4 2 days.

Only the spiral arteries that supply the upper two thirds of the
endometrium become coiled and constrict.

After menstruation, regeneration of the endometrium comes from cells

in the spongiosum that were previously a portion of the secretory
endometrium and not from the stratum basale, as previously believed.

The endometrium produces growth factors, prostaglandins, and peptide

hormones, including a specific peptide called pregnancy-associated
endometrial protein.

The subjective method of correlating the degree of maturation in the

endometrium by histologic visualization is relatively imprecise, and
more precise indices based on quantitative morphometric analysis have
been developed. To date the endometrium most accurately, the
maturation should be correlated with the days after LH peak, not the
number of days before the onset of the next menstrual period.

There are extreme variations in the amounts of endometrial shedding in

different areas of the same uterus, as well as variations among different
uteri removed by hysterectomy.

Menstruation in humans is probably a combination of some superficial

tissue shedding, brought about by ischemia and the presence of
hydrolytic enzymes and possibly relaxin, as well as mainly by tissue
regression and reorganization of the endometrial cells.

Just after ovulation, glycogen-rich subnuclear vacuoles appear in the

base of the cells lining the glands. This subnuclear vacuolization is the
first histologic indication of the effect of progesterone, but is not
evidence that ovulation has occurred.

Enzyme-linked immunosorbent assay (ELISA), or sandwich, techniques

have been developed to measure protein hor-mones (e.g., LH, FSH,
HCG), with the use of monoclonal antibodies against the and
subunits. The endpoint is a color reaction and can be read in a

spectrophotometer.

There are four characteristics of hormone assays that establish their

reliability: sensitivity, specificity, accuracy, and precision.

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