FERTILITY AND STERILITY
4, October 1991
Copyright<> 1991 The American Fertility Society
The basic infertility investigation
Sharon B. Jaffe, M.D.
Raphael Jewelewicz, M.D.
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology,
College of Physicians and Surgeons of Columbia University, New York, New York
The demand for infertility investigations and
treatment has increased dramatically from approx-
imately 600,000 physician visits in 1968 to over 2
million in the early 1980s. 1 In response to this de-
mand, which has reportedly escalated since 1981,
fertility service centers have developed and ex-
panded, along with assisted reproductive technology
(ART) programs. Unfortunately, in vitro fertiliza-
tion (IVF) has sometimes been used to treat incom-
pletely evaluated patients. 2 The basic infertility in-
vestigation of the 1990s modifies and expands the
traditional work-up. Nevertheless, care must be
taken to avoid exploitation of the infertile couple
with expensive, unnecessary tests, procedures, and
treatment.
PREVALENCE OF INFERTILITY
In the United States today, approximately 10%
to 20% of couples are infertile. 1•3 •4 Infertility is de-
fined as the inability to conceive after 1 year of reg-
ular coitus without contraception. The definition of
infertility is based on a monthly conception rate of
20% to 25% in normal couples actively attempting
pregnancy. 4 In 1956, Guttmacher1 reported that 85%
of normal couples conceived after 1 year of exposure
and 93% after 2 years. Others have reported a 95%
conception rate after 1 year of exposure based on a
20% monthly fecundity. 4 Recently, Page5 surveyed
250 couples by mail. Of the 82% who responded,
20% to 35% took longer than 1 year to conceive at
some stage in their reproductive history.
Numerous factors may be responsible for low
conception rates. Conception and pregnancy depend
on complex physiological, anatomic, and immuno-
logical factors. The male needs normal spermato-
Vol. 56, No. 4, October 1991
Vol. 56, No.
Printed on acid-free paper in U.S.A.
genesis, reproductive anatomy, and sexual function
to deposit an adequate number of morphologically
normal, motile spermatozoa in the upper vagina. The
female needs a functionally intact hypothalamic-pi-
tuitary-ovarian axis to regulate the menstrual cycle
and provide normal folliculogenesis, ovulation, and
luteal phase hormonal milieu. For the ovum and
spermatozoa to meet in the fallopian tube, the sper-
matozoa must initially penetrate periovulatory cer-
vical mucus, and the fallopian tube must be ade-
quately mobile and functional to pick up and trans-
port the ovum. Once fertilization has occurred, the
pre-embryo is transferred to the uterus, where suc-
cessful implantation depends on a hormonally stim-
ulated endometrium maintained by a functional
corpus luteum (CL).
ETIOLOGY
A disruption in any aspect of these processes can
result in infertility. A male factor is responsible in
40% to 50% of infertile couples; some form of ovu-
latory dysfunction in 30%; uterine or tubal disease
in 20%; cervical problems, immunological factors,
and infectious disease in about 5%. 3 The prevalence
of unexplained infertility in various studies ranges
from 6% to 60%, with an average of 20%. 6 The in-
cidence of any individual factor as a cause of infer-
tility can only be estimated and varies with the study
population.4 Furthermore, infertility in many cou-
ples has multiple etiologies.
EPIDEMIOLOGY
Several epidemiologic factors contribute to infer-
tility. Because many women are delaying childbear-
Jaffe and Jewelewicz The basic infertility investigation 599
ing, age is a major factor. Fertility rates have been
shown to decline with age of spouse and duration of
marriage, presumably secondary to decrease in sex-
ual activity. 7
In addition to the inherent effects of age on the
reproductive organs, advancing age increases the
interval of time available for exposure to diseases
with potentially damaging effects on fertility, in-
cluding endometriosis, sexually transmitted dis-
eases, and pelvic inflammatory disease (PID). Stud-
ies have shown that the risk of infertility becomes
greater with each episode of PID.8 •9 Infections can
also cause deficient spermatogenesis and blockage
in the male. Use of an intrauterine device (IUD) has
been shown to increase the risk of PID and subse-
quent tubal infertility.7·8
Exercise programs have become routine for many
women and can be associated with menstrual ab-
normalities and decreased fecundity. 10 A large per-
centage of women who participate in strenuous
sports have amenorrhea or oligomenorrhea. Stren-
uous exercise can adversely affect gonadotropins,
androgens, estrogens (Es), and progesterone (P),
culminating in menstrual dysfunction. 10·11 In
addition, the low weight-for-height of female ath-
letes is associated with ovulatory dysfunction and
infertility .10
Cigarette smoking and illicit drug use have also
been associated with infertility. Approximately 30%
of women smoke cigarettes.8 The Oxford Family
Planning Association contraceptive study showed a
consistent and significant trend of decreasing fer-
tility with increasing number of cigarettes smoked. 12
In this study, ex-smokers did not show any evidence
of a decrease in fertility related to lifetime non-
smokers. Stillman et al. 13 provides an excellent re-
view of the epidemiologic studies on the effects of
cigarette smoking on fecundity. These studies dem-
onstrate a decreased ability to conceive during a
given menstrual cycle.
Nicotine and other components of smoke may
have adverse effects on the reproductive system.
Nicotine and cotinine, a nicotine metabolite, are
present in cervical mucus of smokers and may be
toxic to sperm. 14 Some human and animal studies
support the possibility of alterations in tubal phys-
iology and transport. 13·14 Smoking may result in de-
creased E and altered tubal ciliogenesis and cervical
mucus. 14 Experimental evidence supports the hy-
pothesis that smoke and its toxic components, in-
cluding nicotine and polycyclic aromatic hydrocar-
bons, result in oocyte follicle destruction. 13 An ep-
600 Jaffe and Jewelewicz The basic infertility investigation
idemiologic study of well-educated, affluent women
showed a lower pregnancy rate (PR) per cycle among
smokers compared with nonsmokers (0.22 versus
0.32, respectively). 15
In addition to the adverse effects of cigarette
smoking on female fertility, studies have shown an
impairment of sperm density, motility, and mor-
phology among male smokers. 13 In experimental an-
imals, exposure to nicotine, cigarette smoke, and
polycyclic aromatic hydrocarbons leads to testicular
atrophy, blocks spermatogenesis, and alters sperm
morphology. However, some authors have found no
statistically significant effect of smoking on sperm
density, motility, and morphology in healthy
males. 12,16
Animal studies clearly show that delta-9-tetra-
hydrocannabinol, the principal psychoactive ingre-
dient in marijuana, inhibits the secretion of lutein-
izing hormone (LH), follicle-stimulating hormone
(FSH), and prolactin (PRL), thereby inhibiting
ovulation at the hypothalamic level. 17 Approxi-
mately 20% of young adults use marijuana more than
five times per month. 8 In the human, marijuana has
been associated with shorter menstrual cycles and
shorter luteal phases, but one study revealed the de-
velopment of tolerance with regular use and sub-
sequent return of normal hormone levels and cy-
clesP Human studies indicate a temporary decrease
in sperm counts with marijuana usage.
Illicit use of narcotics can modify hypothalamic-
pituitary control of gonadotropins and PRL with
subsequent effects on reproduction because of
change in libido, sexual dysfunction, and menstrual
irregularityP Alcohol may also have an adverse ef-
fect on fertility. Approximately 5% of child-bearing
females drink at least two drinks that contain al-
cohol per dayP Chronic alcohol use has been as-
sociated with infertility and menstrual disorders. 17
In the male, alcohol affects testicular synthesis and
secretion of testosterone (T) and can result in sexual
dysfunction and abnormal sperm morphology .17
Chronic alcoholism may result in permanent im-
potence.17
Environmental and occupational exposures have
adverse effects on fertility. In Denmark, a case-con-
trol study of female infertility and occupational ex-
posures demonstrated increased risks for idiopathic
infertility associated with noise, dry cleaning chem-
icals, mercury, cadmium, and textile dyes. 8 In the
male, heat, vibration, ionizing radiation, and nu-
merous chemicals have been associated with alter-
Fertility and Sterility
ations in sperm morphology and decrease in sperm
production.8
Finally, legalized abortion and social acceptance
of single parenthood has decreased the availability
of babies for adoption, thus increasing the demand
for fertility services. Of note, legal abortion per-
formed in the United States does not carry an excess
risk for future tubal infertility. 18
HISTORY AND PHYSICAL EXAMINATION
A knowledge of the epidemiology of infertility is
important when taking the couple's history. At the
initial visit, a comprehensive medical and surgical
history of both partners should be obtained to help
direct the infertility evaluation. The history of the
female includes menstrual, pregnancy, contracep-
tive, and sexual history. It is important to inquire
about coital frequency and timing, sexual dysfunc-
tion, and possible use of lubricants that may be
spermicidal. Questions are directed at endocrinologic
etiologies of infertility, including galactorrhea,
weight fluctuations, acne, frontal balding, and hir-
sutism. Hirsutism may not be apparent on physical
examination if the patient has had electrolysis or
uses epilatory agents. The male partner's history
should include known prior fertility and sexual his-
tory. A social history and prior exposure to envi-
ronmental and occupational toxins need to be elic-
ited from both partners. The history may reveal
clues to the underlying etiology of infertility in the
couple. Finally, the history must include any prior
work-up or treatment for infertility. Any pertinent
records should be obtained and, if available, films
of a previous hysterosalpingogram (HSG) should be
reviewed.
Findings on the initial physical examination will
help direct the infertility work-up. The general ex-
amination should be complete, keeping in mind that
the gynecologist is usually the woman's primary care
physician. Special attention should be directed at
height and weight (lean mass), presence of galac-
torrhea, acne, breast size, and hair distribution. The
pelvic exam should screen for an anatomic or patho-
logical abnormality, including masses, infections,
and suggestive evidence of adhesions or endometri-
osis. In addition to a Papanicolaou smear, appro-
priate cultures include mycoplasma and ureaplasma,
chlamydia, and gonorrhea, if indicated. An exami-
nation of the male's external genitalia is important
if there is evidence of abnormal semen or abnormal
postcoital test (PCT) results. The examination in-
Vol. 56, No. 4, October 1991
eludes testicular size, position of urethral opening,
and identification of a possible varicocele.
Before initiating further diagnostic evaluation, the
menstrual cycle, fertile period, and reproductive
anatomy and physiology should be briefly outlined
for the couple so that they understand the impor-
tance and timing of the diagnostic tests and have
time to ask questions. The work-up should be in-
dividualized and not prolonged. Tests should be
performed expediently but should allow adequate
time for conception after certain procedures.
A thorough endocrine investigation is done if in-
dicated by history and physical examination. A full
discussion is beyond the scope of this article, but a
few basic concepts will be reviewed. In the presence
of galactorrhea or irregular cycles, a serum prolactin
(PRL) level is needed. In view of the daily and cyclic
fluctuations of PRL level, an elevated level warrants
a repeat sample obtained in the morning after a quiet
period and without a high protein meaU 9 In addi-
tion, thyroid function should also be evaluated. In
the presence of virilization, hirsutism, or acne, an-
drogen production needs evaluation. Hyperandro-
genism may lead to the impairment of folliculoge-
nesis and subsequent anovulation20 and may prevent
conception. 21 High androgen levels may indicate
polycystic ovaries or adrenal hyperplasia, which can
cause ovulatory disorders. 21 Some findings show that
determination of androgen levels is indicated in the
initial evaluation of all infertile females. 21 Latent,
cryptic, or adult-onset congenital adrenal hyperpla-
sia may lead to infertility. The gene for nonclassical
21-hydroxylase deficiency is prevalent. Jews of Ash-
kenazi descent have a 1 in 30 chance of having this
disorder; Hispanics have a 1 in 40 chance; Yugoslavs
have a 1 in 50 chance. 1 The importance for infertility
is currently under investigation.22
SEMEN ANALYSIS
Ideally, the couple should be present at the initial
visit because cooperation of the male partner is
mandatory for a proper infertility investigation. To
determine the adequacy of the spermatozoa, the male
must submit a semen sample for analysis. After 3
to 7 days of sexual abstinence, 23 he obtains this
sample by masturbation into a clean glass or plastic
jar. If he is unable to masturbate because of religious
or personal reasons, silicon condoms can be used to
obtain a specimen through intercourse; however, la-
tex condoms must not be used because they are
spermicidal. 3 The sample must be kept warm and
Jaffe and Jewelewicz The basic infertility investigation 601
delivered to a reliable laboratory within 1 hour. A Table 2 Relative Risk of Infertility According
to Sperm Count•
history of past paternity or adequate PCT does not
eliminate the need for a semen analysis. Sperm count Relative risk Significance
The basic semen analysis assesses the physical
<10 10.3 <1o-•
characteristics of the semen, the sperm density, mo- 10 to 19 5.2 <10- 5
tility, and morphology. Table 1 defines the 1987 20 to 39 3.1 <0.001
World Health Organization (WHO) criteria for 40 to 59 1.7 <0.02
60 to 159 1.0
normal values of semen variables. 24 It is difficult to
160 to 199 1.3
determine exact parameters for a normal semen 200+ 1.5
analysis. The conventional semen analysis has been
used for approximately 60 years, and numerous a Unit risk is that obtained for counts of 60 to 159 X 106 /mL.
b NS, not significant.
studies show that couples can conceive with an ab- (From Nelson et al26 and DeCherney. 27 Reprinted by permission
normal semen analysis. 25 The sperm density is the of the publisher.)
parameter that has been investigated most exten-
sively. A German investigation published in 1977
demonstrated a substantial decrease in fertility with superior form of spermatozoal motion. 25 They hy-
counts < 20 X 106 sperm/mL and a larger decrement pothesized that rapid movement may be less effec-
with counts < 10 X 106 sperm/mL. The relative risk tive and may be associated with decreased longevity
of infertility according to sperm count was calculated and decreased fertilization. 25 As for morphology, an
by Nelson and Bunge in 1974. 26 The relative risk of in vitro study revealed enhanced fertilization with
infertility according to sperm density was compared a greater degree of normal morphology. 28
with 60 to 159 X 106 sperm/mL and is illustrated in Nevertheless, numerous variables affect the qual-
Table 2. It is important to note that up to 20% to ity of the semen sample, and it is important to eval-
25% of proven fertile men have sperm counts< 20 uate more than one sample as well as a PCT, which
X 106 sperm/mL. 4 Normal motility is generally ac- will be discussed at length. An artificially poor sam-
cepted as 50% or more. Dunphy et al. 25 classified ple can occur secondary to stress or lack of adequate
sperm motility as grades based on progressive mo- stimulation. 29 Variables reported to adversely affect
tility, linearity, and velocity. They concluded that spermatogenesis include frequent hot baths, wearing
slow or sluggish linear or nonlinear motility is the tight underwear, certain medications, and recre-
ational drugs including alcohol, tobacco, and mari-
juana, as previously discussed. 30 The effect of avoid-
Table 1 Normal Values of Semen Variables•
ance or abstinence from these factors can take a
Volume 2.0 mL or more minimum of 3 to 4 months to show because sper-
pH 7.2 to 7.8 matozoa require about 74 days to develop and an-
Sperm concentration 20 X 106 spermatozoa/mL or other 2 weeks to pass through the testis and epidi-
more
Total sperm count 40 X 106 spermatozoa or more dymis.28 Numerous drugs and toxins have also been
Motility 50% or more with forward implicated in male infertility. 29
progression of 25% or more The male factor is reportedly significant in up to
with rapid linear progression
within 60 minutes after 50% of couples. In 20% to 25% of couples, both the
collection male and female have reproductive abnormalities. 28
Morphology 50% or more with normal Cooperation and coordination of care between the
morphology
Viability 50% or more live gynecologist and urologist is important. Therefore,
White blood cells <1 X 106 /mL knowledge of male reproductive physiology and the
Zinc (total) 2.4 ILM or more per ejaculate
diagnostic infertility work-up is critical. Problems
Citric acid (total) 52 !LM (10 mg) or more per
ejaculate can occur at any level, from spermatogenesis to co-
Fructose (total) 13 ILM or more per ejaculate itus. Several reviews that elaborate on this topic are
Mixed antiglobulin test <10% spermatozoa with adherent available in the current literature. 23 ·28·29 Abnormal
particles
Immunobead test <10% spermatozoa with adherent semen parameters can arise from changes in hor-
beads monal levels, from genetic or congenital abnormal-
ities, including retrograde ejaculation, and from drug
a (From World Health Organization: WHO Laboratory Manual
for the Examination of Human Semen and Semen-Cervical Mucus use, exposure to occupational and environmental
Interaction. 24 Reprinted by permission of the publisher.) toxins, infections, and surgical sequelae.

602 Jaffe and Jewelewicz The basic infertility investigation Fertility and Sterility
 In the presence of persistent oligospermia or azo-
ospermia, the male needs an endocrine evaluation,
including T, FSH, and PRL levels. If hormone levels
are normal and there is a suspicion of retrograde
ejaculation, one does a postejaculatory urinalysis.
Next, a vasogram and a testicular biopsy are per-
formed to evaluate for obstruction of the ductile
system or congenital abnormality. Current tech-
nology permits removal of spermatozoa retrograde
to an obstruction for use in IVF.
Finally, the relevance of a varicocele to infertility
remains controversial. A varicocele is present in 8%
to 23% of the male population and in 17% of men
with proven fertility. 31 Of men attending infertility
clinics, 19% to 41% had a varicocele.31 Some authors
advocate a spermatic vein ligation in the presence
of a varicocele associated with infertility if the semen
analysis reveals persistent oligospermia, astheno-
spermia, or teratospermia. 32 Possible mechanisms
responsible for disturbed spermatogenesis in the
presence of a varicocele include: (1) diminished ox-
ygenation of testis; (2) increased scrotal tempera-
ture; and (3} influence of catecholamines and steroid
from the left adrenal gland. 32 According to Model et
al., 32 improvement in semen parameters and PR af-
ter a spermatic vein ligation was first reported by
Tulloch in 1952. Subsequent studies have produced
contradictory results. According to Peng et al., 31 the
cofactor effect may be responsible. They proposed
that the varicocele may require cofactors, such as
various gonadotoxins, to cause male infertility. 31
Nicotine and cigarette smoke may be among these
gonadotoxins.
OVULATION ASSESSMENT AND
THE LUTEAL PHASE
In contrast to the direct assessment of the avail-
ability of spermatozoa, ovulation is evaluated indi-
rectly. Ovulation disorders account for approxi-
mately 20% of all infertility. 1 Definitive proof of
ovulation involves establishment of pregnancy or
recovery of an ovum from the oviduct. 33 For an in-
fertility work-up, the investigator usually relies on
presumptive evidence of ovulation, which is gener-
ally determined by basal body temperature (BBT),
steroid or gonadotropin hormone assays, ultrasound
(US), cervical mucus changes, or endometrial biopsy.
Ovulation should be evaluated in several cycles by
different methods. The history can be helpful in the
evaluation of ovulation. Monthly menstruation,
Vol. 56, No.4, October 1991
premenstrual symptoms, and dysmenorrhea are
usually indicative of ovulation.
The BBT is the oldest, most widely used method
of ovulation detection. 34 The BBT has the advan-
tages of being a simple, cost effective, noninvasive
method of retrospectively identifying that ovulation
has occurred. 34 It is, however, not an accurate or
reliable predictor of ovulation. 34-36 Ovulation has
been reported to occur in 3% to 20% of monophasic
BBTs and may be absent in a small percent of hi-
phasic BBTs. 3 •34 The temperature is taken upon
awakening, before any activity, and recorded on a
BBT graph, reading to the closest tenth of a degree.
The BBT serves several functions: (1) indicates the
probable occurrence of ovulation; (2) aids in timing
and interpretation of diagnostic tests; and (3) in-
dicates coital frequency and evaluates timing when
the patient is asked to mark days of intercourse.
Several factors that influence the day-to-day vari-
ability of the temperature include accuracy of the
reading, cycle variability, illness, diet, medication,
and sleeping pattern alterations. 35 The te:q1perature
elevation is secondary to the thermogenic effects of
P on the hypothalamus. 37 The nadir, or dip in the
curve, signals the approach of ovulation and should
be at least 0.1 °F (0.06°C) lower than the six previous
days. 35 A sharp rise of0.4° to 0.6°F (0.22° to 0.33°C)
between 2 consecutive days indicates ovulation.
However, it is important to note that in up to 39%
of graphs, the temperature shift is <0.4 °F (0.22°C). 35
The inaccuracy of the nadir for predicting ovu-
lation was demonstrated by Vermesh et al., 38 who
evaluated the BBT in predicting and detecting ovu-
lation in 31 cycles, 14 spontaneous and 17 clomi-
phene citrate (CC)-induced. Ovulation occurred on
the day of the nadir in 10%, 1 day after in 20%, and
within the following 3 days in the remaining 70%,
according to daily transvaginal US and hormonal
assays. Quagliarello and Arn~9 measured LH levels
and blindly read BBT charts of 21 patients for 60
total cycles to predict when the LH surge occurred.
The BBT predicted the LH surge within a 2 to 3-
day period on either side of the surge.
In 1980, the WHO multicenter collaborative study
estimated ovulation to occur 16 to 48 hours after
the onset of the serum LH surge. 398 The LH surge
represents a threefold increase in LH over the av-
erage of the three previous days. 36 The midcycle
serum LH surge is the most reliable predictor of
ovulation, but the need for frequent blood sampling
and expensive radioimmunoassays (RIA) makes the
test less desirable. 36 Urinary LH kits are noninva-
Jaffe and Jewelewicz The basic infertility investigation 603
sive, convenient, rapid, self-administered, and less
expensive. 36 The evening RIA urine LH kit was
found to detect the day of surge correctly in 98%.
The enzyme-linked immunosorbent assay kit de-
tected the day of the surge in 18% and the subse-
quent day in 82%. 36 The midcycle serum LH surge
begins between 5 A.M. and 9 A.M. and is detectable
in the urine shortly thereafter. Vermesh et al. 38
found a late morning urine LH kit test more reliable
in predicting ovulation than a first morning urine
LH kit test, 87.5% versus 53.3% predicted ovulation
correctly, respectively. It is important to remember
that the urinary kit results can be affected by the
patient's motivation and ability to read and follow
instructions correctly. Determination of the LH
surge is not essential for the basic infertility work-
up because ovulation can be determined by BBT
and endometrial biopsy.
In addition to confirming ovulation, the endo-
metrial biopsy evaluates the adequacy of the luteal
phase. The endometrial biopsy provides histologic
evidence of normal endometrial development and
acts as a bioassay of P production. 40·41 To allow for
full endometrial development, the biopsy should be
performed 2 to 3 days before the subsequent men-
ses.40 Menstrual history and BBT graph aid in
scheduling the endometrial biopsy.
The histologic characteristics of the endometrial
biopsy are dated according to the criteria established
in 1950 by Noyes et al. 42 The endometrial biopsy
can also rule out unsuspected pathology such as pol-
yps or endometritis. Sugkraroek and Chatura-
chinoa43 found 4% of patients to have endometrial
abnormalities. The tissue must be obtained from the
anterior or posterior wall of the fundus because the
tissue from the poorly vascularized lower segment
has a high incidence of being out-of-phase. 44·45
The endometrial biopsy entails minimal risk. An
analysis of 774 patients who had endometrial biopsy
for infertility revealed complications in 3.6% (28),
including difficulty obtaining the biopsy secondary
to cervical stenosis (12), excessive bleeding (5), fever
(4), excessive pain (2), vasovagal reaction (2), uterine
perforation (2), and interruption of pregnancy (1). 46
Wentz et al. 44 studied patients who had an endo-
metrial biopsy done in the cycle of conception and
concluded that the procedure did not appear to in-
crease fetal wastage. The incidence of performing
an endometrial biopsy in the cycle of conception is
3% to 5%; the overall incidence of interrupting a
pregnancy is 0.067%, and <2% if the implantation
site is biopsied.44 A sensitive pregnancy test or use
604 Jaffe and Jewelewicz The basic infertility investigation
of a barrier contraceptive method is recommended
in the cycle of the endometrial biopsy for a patient
who does not want to take this minimal risk.
Is the endometrial biopsy necessary? Driessen et
al. 47 reported that the endometrial biopsy findings
had no effect on the diagnosis or outcome of infer-
tility, whereas several others have shown that the
diagnosis of luteal phase inadequacy and its therapy
have improved reproductive outcome. 40·48•49
Diagnosis and treatment of luteal phase defect
(LPD) remains controversial. Some authors define
an LPD as two endometrial biopsies 2 or more days
out of phase,50-52 whereas others define it as >2 days
out of phase. 40·42·49·52-57 It is current practice to date
the endometrial biopsy with cycle day 28 defined as
the 1st day of the subsequent menses. Some authors
advocate that prospective dating of the endometrial
biopsy more accurately corresponds to the sequence
of endometrial maturation. 58 They claim that the
LH surge or transvaginal US defines the day of ovu-
lation or onset of the luteal phase more accu-
rately. 58,59
As determined by customary methods, the luteal
phase is inadequate in up to 30% of cycles in normal
females. 1·55 The incidence of recurrent LPD in the
infertile population ranges from 3% to 14%.1·54•55·57·60
Factors associated with an increased incidence of
out-of-phase biopsy include hyperprolactinemia, re-
current abortions, extremes of reproductive life, and
use of human menopausal gonadotropins (hMGs)
or CC. 40·60 Nevertheless, half of patients with LPD
do not have predisposing factors. 40
Luteal phase inadequacy may be a defect of P
secretion by the CL or a defect in the endometrial
response to hormonal stimulation. 42 The defect may
occur in either the follicular, periovulatory, or luteal
phase. It may initially be a problem of ovarian
folliculogenesis 52·5s-63 or inherent in the endome-
trium.41·58·60·64 Table 3 lists postulated and proven
causes of luteal phase deficiency. 41 A full discussion
of possible pathophysiology of LPD is beyond the
scope of this discussion; the interested reader is re-
ferred to the review by McNeely and SoulesY
Although endometrial histology is the most reli-
able method of evaluating the luteal phase, other
available modalities include midluteal P levels or
the BBT graph. Most women with LPD have normal
appearing BBT graphsY Persistent elevation in
temperature for ~11 days usually correlates with an
extremely out-of-phase biopsy. 41 Because P is re-
leased in a pulsatile fashion, random serum P levels
are not useful in diagnosing LPDY Some authors,
Fertility and Sterility
Table 3 Postulated and Proven Causes
of Luteal Phase Deficiency
Neuroendocrine
Increased LH pulse frequency
Follicular phase FSH deficiency
Inadequate LH surge
Abnormal follicular phase LH/FSH ratio
Mild hyperprolactinemia
Deficient luteal LH levels
Ovarian
Reduced number of primordial follicles
Accelerated luteolysis
Uterine
Inadequate endometrial steroid (P) receptors
Endometritis
Other
Physiological (postpartum, postmenarchal, premenopause)
Chronic hypoxia
Drugs (e.g., CC, hMGs)
Chronic systemic disease (e.g., renal or liver failure)
Thyroid disease
Over- or under-weight
Exercise
Psychosocial stress
(Modified from McNeely and Soules. 41 Reprinted by permission
of the publisher.)
however, advocate use of a single serum P level of
10 to 15 ng/mL, a midluteal phase mean of 12 to 13
ng/mL, or a sum of > 15 ng/mL for three samples
obtained on alternate days in the midluteal
phase.41·55 A single serum P level of ~3 ng/mL in
the luteal phase is presumptive evidence of ovula-
tion.65 In the presence of an equivocal BBT graph,
the P level can be used to ascertain if the patient
has ovulated before performing an endometrial bi-
opsy to rule out an LPD.
Finally, recording of alterations in the amount,
physical characteristics, and chemical constituents
of cervical mucus has been successfully used to de-
tect and predict ovulation. 33 These alterations are
regulated by ovarian hormones. Cervical mucus ap-
pears on cycle days 8 to 10 and peaks at ovulation
when the peak estradiol (E 2) level results in pro-
duction of a large amount of thin, watery, alkaline,
acellular cervical mucus with ferning, spinnbarkheit,
and sperm receptivity. After ovulation, P inhibits
secretory activity ofthe cervical epithelium. Cervical
mucus becomes scant, viscous, cellular, and impen-
etrable to sperm,33 with minimal spinnbarkheit and
no ferning. This change is presumptive evidence that
ovulation has occurred. Ovulation can occur from 3
days before to 3 days after peak mucus output. 33
Sperm receptivity of the cervical mucus is of prime
importance for the PCT.
Vol. 56, No.4, October 1991
CERVICAL FACTOR
A cervical factor accounts for 5% to 10% of in-
fertility.28 Although the PCT, also known as the
Simms-Huhner test, is generally accepted as an in-
tegral part of the infertility work-up, controversy
exists concerning its interpretation, reliability, and
correlation to pregnancy. It does, however, provide
concrete evidence of coital adequacy.
Normal, midcycle mucus facilitates the passage
of normal, motile spermatozoa, and it acts as a filter,
restricting entry of morphologically abnormal sper-
matozoa. 66 The cervical crypts fill with mucus and
provide storage for viable sperm to be gradually re-
leased to the uterus and fallopian tubes. The first
stage of capacitation may also occur in the crypts. 67
The PCT assesses the cervical mucus and the sperm-
mucus interaction.
The PCT should be performed close to ovulation
as predicted by BBT, change in cervical mucus, LH
surge, or US. The couple is instructed to abstain
from intercourse for 48 hours before the test. The
optimum time to perform the test after intercourse
is debatable. Some authors report no decrease in the
number of sperm after 24 hours, whereas others re-
port a decrease after only 8 hours. 1 Some authors
suggest performing the test within 2 hours to obtain
maximum information; however, complement-de-
pendent reactions that immobilize sperm require 8
to 10 hours. Thus, performing the PCT earlier than
8 to 10 hours after intercourse may not detect this
potential problem:68 To optimize the information
obtained from a PCT, we recommend at least an 8-
hour time span after intercourse.
After wiping the external os, the mucus is obtained
with a polyp forceps or aspirated with a tuberculin
syringe or 16-gauge angiocath. Because sperm dis-
tribution is uniform throughout the cervical canal,
there is no need for selective sampling. 1 Grossly, the
quantity, color, and viscosity are assessed. The mu-
cus should be clear and abundant. Spinnbarkheit or
stretchability is assessed when obtaining the spec-
imen from the cervix or by stretching it between the
slide and coverslip and measuring the length in cen-
timeters before it breaks. Eight to ten centimeters
is normal. 1 The microscopic examination assesses
fern pattern, cellularity, debris, white blood cells,
and number and motility of spermatozoa. Cellular
elements and an atypical fern pattern indicate a
possible underlying chronic cervicitis. 67 If cervicitis
is suspected, treatment with a course of doxycycline
may improve a subsequent PCT.69
Jaffe and Jewelewicz The basic infertility investigation 605
 The number of motile sperm considered adequate
remains debatable. 1•70 Several authors have pub-
lished definitions of a normal PCT71 : (1) 7 motile
sperm progressing purposefully; (2) ;;:::10 sperm per
high-power field (hpf) when >50% show purposeful
motility; (3) ;;:::10 sperm per hpf with directional
motility 24·33 ; (4) >20 sperm per hpf1•70; and (5) a sin-
gle sperm. 1•70 According to Speroff et al., 1 the ma-
jority use 5 motile sperm per hpf.
What is the prognostic value of the PCT for the
infertile couple? The PCT provides assessment of
coital technique. Jette and Glass 70 examined there-
lation of the quality of cervical mucus to subsequent
pregnancy and found aPR of 53.8% and 37% for
good and repeatedly poor mucus, respectively. A
previous study reported 43% and 14.5%, respec-
tively.70 Clear, watery mucus without white blood
cells was good, and thick, tenacious cloudy mucus
loaded with white blood cells was poor. Some authors
support the view that a good PCT implies a good
PR, whereas others report no correlation between
PCT results and pregnancy in fertile couples or in-
fertile couples. 1 •28·72 Several studies report no differ-
ence in PR with 1 to 5 sperm/hpf compared with 11
to 20 sperm/hpf. 28 In addition, the association of
postcoital motility with pregnancy has not been
shown to be statistically significant. 72 Although a
correlation between the concentration of sperm in
the semen and the number of spermatozoa in cer-
vical mucus has been found (over 20 sperm per hpf
has been associated with counts> 20 X 106/mL), 68
a semen analysis is still necessary to evaluate mor-
phology.70
Next, does an abnormal PCT indicate that sperm
did not reach its destination, the ovum? Apparently
not, because peritoneal aspirates, obtained via the
laparoscope up to 28 hours after an abnormal PCT
have revealed sperm in the cul de sac. 73 One author
has proposed use of endometrial aspiration to more
accurately determine that sperm has entered the
uterine cavity. 67
Nevertheless, the PCT is valuable in assessing
coital technique, hostile cervical mucus, and anti-
sperm antibodies. If the PCT reveals good mucus
but no sperm or only immotile sperm, the use of
spermicidal lubricants (K-Y Jelly; Johnson and
Johnson, New Brunswick, NJ and Surgilube; E.
Fougera and Co., Melville, NY) must be ruled out. 1
Vegetable oil is not spermicidal and can be used if
a lubricant is necessary for intercourse. Hostile cer-
vical mucus may be secondary to inappropriate tim-
ing of the PCT, hyporesponsiveness of the cervix to
606 Jaffe and Jewelewicz The basic infertility investigation
E 2, inadequate E levels, vaginal or cervical infection,
acid mucus, or presence of sperm antibodies. Several
PCTs, serum E and P, or the LH surge kit can be
used to improve timing. Exposure to diethylstilbes-
trol in utero or before cervical surgery can affect
mucus production. 34 As already discussed, disorders
of folliculogenesis produce inadequate E levels lead-
ing to poor mucus. In addition, CC can have an anti-
E effect on cervical mucus. Supplementary E in the
late follicular phase may improve the PCT results.
In the presence of acid cervical mucus, Ansari et
al. 74 showed that the PCT result improves ifthe mu-
cus is alkalinized by douching with sodium bicar-
bonate (1 tablespoon/quart of water) 30 to 60 min-
utes before intercourse. Possible mechanisms of ac-
tion of the sodium bicarbonate include: (1) alteration
of vaginal pH; (2) alteration of cervical pH; (3) al-
teration of cervical mucus electrolytes; (4) removal
of excess vaginal discharge; and (5) reduction of
pathogenic organisms. 74 Douching with tap water
alone did not yield favorable results. 74
The presence of white blood cells in the cervical
mucus may implicate an underlying infection. The
importance of microbial colonization for sperm-mu-
cus interactions and the benefit of antimicrobial
therapy in asymptomatic couples is controversial
and will be reviewed briefly later.
Sperm antibody testing may play a role in the
infertility investigation if the PCT reveals no sperm
or nonmotile sperm without explanation on shaking
sperm with good mucus. 1 The immunological aspects
of infertility will be elaborated on later in this review.
Table 4 summarizes the etiologies of abnormal
sperm-cervical mucus interaction. 75 Intrauterine
insemination is an option in the presence of a cer-
vical factor.
UTERINE, TUBAL,
AND PERITONEAL FACTORS
In a patient at low risk for tubal disease, detection
and treatment of other causes of infertility should
precede invasive tests. Numerous historical factors
alert the physician to possible existence of tubal
damage. These include a history of pelvic PID, septic
abortion, IUD usage, ruptured appendix, pelvic or
tubal surgery, or history of an ectopic pregnancy.
According to Westrom's data, 9 the incidence of in-
fertility after salpingitis is 11% to 12%, 23% and
54% for one, two, and at least three episodes of PID,
respectively. Epidemiologic studies link use of an
IUD with an increased risk of PID and subsequent
Fertility and Sterility
Table 4 Etiologic Classification of Abnormal Sperm-Cervical Although the tubal factor can play a role in 30%
Mucus Interaction
to 50% of infertility, 78 uterine abnormalities are re-
Female-related causes Male-related causes sponsible for infertility in only about 2%.79 Infertility
may result when leiomyomas enlarge and distort the
Inappropriate timing Deposition problems uterine cavity enough to cause interference with
Ovulatory disorders Impotence
Anovulation Retrograde ejaculation sperm transport or cause abnormal endometrial
Subtle anomalies of Hypospadias vascularity sufficient to interfere with implantation.
ovulatory process Semen abnormalities In addition, synechiae may block sperm transport.
Deposition problem Low concentration
Dyspareunia Low motility The current procedure for initial evaluation of
Prolapse High percentage of uterine and tubal factors is the HSG. The techniques
Congenital and anatomical abnormal forms and contrast media have evolved over the years. 80
anomalies High volume (>8 mL)
Anatomical and organic Low volume (<1 mL) The current techniques of hysterosalpingography
causes N onliquefying semen have about a 75% correlation with laparoscopy or
Amputation or deep Antisperm antibodies in hysteroscopy for accuracy. The procedure should be
conization of the cervix serum or seminal plasma
Deep cauterization or done in the early follicular phase after menses has
cryotherapy stopped. If the patient has tenderness, masses, or
Tumors: polyps, leiomyoma an elevated erythrocyte sedimentation rate, the HSG
Severe stenosis
Endocervicitis should be postponed. The risk of infection is <1%
Hostile cervical mucus in a low-risk population and 3% with a high-risk
Increased viscosity population. 1 Anaerobic bacteria are responsible for
Increased cellularity
(infection) the majority of infections. 1 Use of prophylactic an-
Acid mucus tibiotics is at the physician's discretion. Some feel
Presence of sperm post-HSG antibiotic therapy is indicated in the
antibodies
presence of hydrosalpinges. 81 A prostaglandin (PG)
(From Moghissi. 75 Reprinted by permission of the publisher.) inhibitor administered 30 to 60 minutes before the
procedure decreases the discomfort. Under fluoros-
copy, the gynecologist injects dye slowly to observe
subtle filling defects in the cavity and prevent in-
tubal infertility. 76 Based on a review of 159 nulli-
travasation. Injection of contrast material may in-
gravida females with known tubal infertility who
duce localized uterine or tubal spasms. This reaction
were questioned concerning IUD usage and com-
can be avoided by counseling the patient to reduce
pared with a control group of patients who conceived
tension that can contribute to spasm and by inject-
at approximately the same time, the relative risk of ing dye slowly and steadily. 82 If tubal spasm occurs,
tubal infertility is 2.6-fold greater for patients who administration of 10 mg of glucagon followed by a
ever used an IUD compared with patients who never 5-minute delay before continuing the injection of
used an IUD. 77 The actual relative risk varied de- contrast media results in 80% relief of tubal spasm.83
pending on the type of IUD used. 77 It was highest Complications of the HSG include uterine perfo-
for the Dalkon Shield (Robbins, Baltimore, MD) ration, hemorrhage, hypersensitivity to iodine, ex-
and only slightly elevated for the copper IUD. 77 Cra- acerbation of PID, and pain. 80
mer et al. 76 showed that women who reported having Two types of contrast media are available; oil-
only one sexual partner had no increased risk of soluble and water-soluble. The oil-soluble media
primary tubal infertility associated with IUD use. provides a sharper film image; it flows more slowly
Mueller et al. 78 demonstrated no excess risk of tubal and is claimed to fill in contours of the uterine cavity
infertility associated with simple appendectomy and tubes more extensively.80 In addition, peritoneal
without rupture but calculated that a ruptured ap- spill results in a lower incidence of pain than water-
pendix imposed a relative risk of 4.8 or 3.2 for the soluble media. 80 •84 Because oil-contrast media is
nulligravida or multiparous patient. Patients with slowly absorbed, it offers the option of a delayed
tubal disease are generally older, less educated, more film to detect peritubal disease. 80·84 The disadvan-
likely to be smokers, and have more sexual part- tages are increased radiation to the gonads, possible
ners. 76 Nevertheless, about half of the patients with granuloma formation, because of the slow absorp-
tubal damage or pelvic adhesions have a negative tion, the prevalence of which is unknown, and in-
history of PID. 1 travasation.80·84 Intravasation of oil-soluble contrast

Vol. 56, No.4, October 1991 Jaffe and Jewelewicz The basic infertility investigation 607
media occurs in 0% to 6.3% of cases80 and has a
1.1% risk of embolization that in most instances has
been innocuous84 ; however, lipoid pneumonia and
death have been associated with the use of oil-con-
trast media.80 Use of fluoroscopy allows detection of
intravasation, which requires immediate termina-
tion of the procedure. Advocates of water-soluble
contrast media report nearly as good a radiographic
image as with an oil medium, without potential se-
rious adverse effects.80
The therapeutic effects of HSG remain contro-
versial. Oil-soluble contrast media are reported to
be associated with a higher incidence offertility.1·80•84
Theoretical mechanisms for enhanced fertility after
HSG include: (1) bacteriostatic effect of the iodine;
(2) enhancement of ciliary action; and (3) hydro-
tubation effect with mechanical lavage straightening
tubes and breaking peritoneal adhesions. 1 In addi-
tion, ethiodol has been shown in vitro to decrease
phagocytosis of peritoneal macrophages; this finding
implies a possible in vivo decrease in phagocytosis
of spermatozoa.1 Therefore, the HSG may have
beneficial effects, and it provides additional infor-
mation about the tubal mucosa and uterine cavity.
If the HSG is normal, a 6-month interval should
elapse to allow time for these fertility-enhancing ef-
fects to occur before proceeding with operative pro-
cedures.1
Hysteroscopy and laparoscopy are the final di-
agnostic procedures of the basic infertility work-up.
Over the past 30 years, improvement in instrumen-
tation and distention media has resulted in increased
interest in hysteroscopy. 82 Preferably, the hyster-
oscopy should be done after menses and before ovu-
lation. It should not be done in the presence of
bleeding, infection, or pregnancy. Possible compli-
cations include bleeding, infection, anesthesia risks,
possible endometriosis, and risks associated with
distention media. Carbon dioxide has the risk of gas
intravasation with acidosis and possible embolus.
The most commonly used media in the United
States, high molecular weight Dextran, has the po-
tential risk of cardiovascular overload associated
with intravenous or excess Dextran. Hysteroscopy
accurately identifies the nature of the intrauterine
lesion suspected from the HSG and may reveal syn-
echiae not apparent on HSG. 2·82 Hysteroscopy
should be performed by an experienced gynecologist
who can perform an operative procedure if indicated.
The hysteroscopy adds little additional time to the
laparoscopy.
608 Jaffe and Jewelewicz The basic infertility investigation
The laparoscopy, when performed at the end of
the infertility work-up, has a high incidence of de-
tecting endometriosis or pelvic adhesions. In the
1990s, laser or operative laparoscopy should be
readily available for use by the trained specialist.
UNEXPLAINED INFERTILITY?
The prevalence of unexplained infertility has been
reported to account for 6% to 60% of infertility in
couples, with an average of 20%. Criteria for the
diagnosis of unexplained infertility includes: (1) in-
fertility of at least 2 years; (2) normal history and
physical examination; (3) adequate coital frequency;
(4) three normal semen analyses; (5) regular
monthly menstrual cycles with biphasic BBT and
luteal phase~ 12 days; (6) adequate cervical mucus
and a normal PCT; (7) normal LH, FSH, PRL, T,
and P; and (8) normal HSG and laparoscopy.85 Ad-
ditional techniques are currently advocated to fur-
ther the infertility investigation. These include bac-
teriologic, immunological, sperm penetration, major
histocompatibility complex, and US studies.
Microbial Colonization
Studies on the importance of microbial coloni-
zation in infertility or subfertility remain contro-
versial. Mycoplasma are microorganisms the size of
large viruses having no cell wall.86 Two types recov-
ered from the genital tract are mycoplasma homines
and ureaplasma urealyticum, formerly T-myco-
plasma.86 Ureaplasma was first considered as a cause
of infertility in 1970. Several studies reported a
greater prevalence of genital mycoplasma in cervical
mucus and semen of infertile couples than fertile
couples.1·86-88 Some have reported decreased sperm
quality associated with poor motility and increased
abnormal morphology associated with genital urea-
plasma.86·86 Upon successful treatment of urea-
plasma urealyticum, the same authors found im-
proved motility with a decrease in certain abnormal
morphology. Other studies report no significant in-
fluence of genital mycoplasma on sperm quality or
sperm-mucus interaction in infertile couples.811--91 In
addition, genital mycoplasma colonization has been
found in up to 50% of normal males. 92 However,
several studies report increased conceptions after
eradication of ureaplasma.86 Although the correla-
tion of genital mycoplasma with male or female
unexplained infertility remains debatable, a positive
culture for genital mycoplasma warrants treatment
Fertility and Sterility
with a course of doxycycline and delay of invasive
procedures until the organism is eradicated.
Immunological Etiology
In the male, infection, vasectomy, testicular tor-
sion, or trauma may result in breakdown of the
blood-testis barrier, resulting in an immunological
reaction and subsequent formation of antisperm
antibodies. In the female, sexual activity results in
constant exposure to the antigenic stimuli of sper-
matozoa or seminal plasma and may cause devel-
opment of sperm antibodies in genital tract fluids
or serum. Infections or inflammation of the female
genital tract increase the probability that sperm will
interact with systemic immune system compo-
nents. 93 Immunological factors have been found in
5% to 17% of infertile couples28 and in up to 40%
of couples with unexplained infertility.94 Immuno-
logical factors should be considered when sperm are
absent or immotile in the PCT but normal on semen
analysis, when sperm show shaking movement in
the PCT, when infertility persists after a vasectomy
reversal, when spontaneous sperm agglutination oc-
curs on semen analysis, and when there is a long-
standing history of unexplained infertility.94•95 Im-
mune infertility could result from: (1) depletion or
destruction of gametes; (2) inhibition of transport
of sperm in the female genital tract; (3) inhibition
of gamete interaction; or (4) prevention of embryo
cleavage or implantation. 28•96
There are no standard methods of detecting an-
tisperm antibodies and interpreting test results. 97
Several studies have shown discordance between re-
sults of sperm antibody tests in matched serum and
sperm samples.98 Treatment has produced variable
PRs. Proposed treatments include abstinence or use
of condoms to decrease sensitivity to sperm, corti-
costeroids, in vitro manipulation of semen, and IVF
with possible micromanipulation of oocyte. 28•96 The
clinical significance of immune factors in infertility
remains in dispute, and the possibility of an inter-
mittent phenomenon has been raised. 28•96
Fertilization Capacity
A functional test of the fertilizing capacity of
sperm was described in 1976 by Uehara and Yana-
gimachi.99 The sperm penetration assay evaluates
the interaction of sperm with hamster egg after
the removal of the zona pellucida by enzymatic
digestion with trypsin. 99 Standards or a normal range
have not been established for this assay. 28 The clin-
Vol. 56, No.4, October 1991
ical significance remains controversial because hu-
man IVF and pregnancy have occurred with a poor
or negative zona-free hamster egg penetration
test. 3,6,23,28
Histocompatibility Leukocyte Antigens
Another controversial issue exists concerning
histocompatibility leukocyte antigens (HLA). A
negative association between certain haplotype
combinations and infertility and a higher frequency
of the HLA-B5 locus in females with unexplained
infertility has been reported. Homozygosity at the
B locus also has been shown to occur more frequently
among couples with unexplained infertility than
among fertile controls. However, some studies have
shown no significant distribution of HLA antigens
or increased sharing among couples with unex-
plained infertility.6 The value of HLA tests in an
infertility investigation is unknown.
Luteinized Unruptured Follicle
The improved resolution of the transvaginal probe
has expanded the role of US in infertility investi-
gations and treatment. Ultrasound is currently being
used to monitor ovulation induction, IVF, gamete
intrafallopian tube transfer, and follicular growth
for diagnosis of dysfolliculogenesis, anovulation, and
the luteinized unruptured follicle syndrome.
In luteinized unruptured follicle syndrome, the
follicle does not collapse after the LH surge and may
increase in size during the luteal phase. 1 Follicular
rupture appears to involve functional smooth muscle
cells, proteolytic enzymes, and PGs. 37 Although the
complete pathophysiology of luteinized unruptured
follicle syndrome is unclear, a patient with unex-
plained infertility probably should not take PG syn-
thetase inhibitors.
Some authors have reported an increased inci-
dence of luteinized unruptured follicle syndrome in
women with unexplained infertility, endometriosis,
pelvic adhesions, and after CC therapy. 1•100 The
overall frequency of luteinized unruptured follicle
syndrome is controversial. It has been reported to
have occurred in from 5% to 18% of cycles in infertile
patients. 6•100- 102 Some studies report an even higher
incidence in patients with unexplained infertility or
endometriosis. 101 Luteinized unruptured follicle
syndrome has been found to occur in 5% to 11% of
cycles of fertile women, 101•103 and pregnancy has oc-
curred during presumed luteinized unruptured fol-
licle syndrome cycles. 37
Jaffe and Jewelewicz The basic infertility investigation 609
 Ultrasound can detect follicular rupture in the
presence of any of the following features: (1) partial
or total collapse with disappearance of the follicle;
(2) development of internal echoes; or (3) increased
fluid in the cul de sac. 104 Follicular size is not a major
factor because the maximum preovulatory diameter
varies from 15 to 29 mm. 104 Other diagnostic meth-
ods to evaluate luteinized unruptured follicle syn-
drome includes early luteal laparoscopy to identify
ovulation stigmata and profiles of E 2 and P levels
in early luteal peritoneal fluid compared with plasma
levels. 37 The existence of luteinized unruptured fol-
licle syndrome remains disputable, and it may only
be a variation of normal because it is rarely recur-
rent. Inappropriate luteinization may result from
luteinized unruptured follicle syndrome or from de-
velopment of multiple small follicles bringing about
premature luteinization.
Coulam et al. 6 evaluated 57 couples with unex-
plained infertility and found that 5% had luteinized
unruptured follicle syndrome, 5% had sperm anti-
bodies, 11% had low sperm penetration, and 37%
had HLA-locus homozygosity. The use of immu-
nological tests, US, and the sperm penetrance assay
thus reduced the diagnosis of unexplained infertility
by about 60%.
CONCLUSION
Life table analysis shows that 64% of women with
primary unexplained infertility and 79% with sec-
ondary infertility will conceive within 9 years. 86 This
does not imply that the physician should wait 9 years
before instituting treatment or embarking on other
diagnostic tests. The decision to perform additional
investigations of the infertile couple before adequate
follow-up should be made on an individual basis.
Part of the work-up of the couple with unexplained
infertility involves repeating previous tests, es-
pecially if performed by an unfamiliar physician or
laboratory. Education, relaxation exercises, and self-
help groups may decrease stress associated with in-
fertility.
Several studies have shown that PRs are inde-
pendent of treatment for infertility. 105 Pregnancy
has occurred in patients with unexplained infertility,
as well as in patients whose fallopian tubes appeared
obstructed or whose male partners seemed severely
infertile. 105 Nevertheless, shorter duration of infer-
tility is associated with a better prognosis. Sugges-
tions have been made to treat patients with unex-
plained infertility with CC, antibiotics, thyroid
610 Jaffe and Jewelewicz The basic infertility investigation
medications, danazol, and mucolytic agents. 94 None
of these empirical treatments have been proven, and
they should not be advocated.
The need to individualize an infertility investi-
gation and proceed efficiently cannot be overem-
phasized. Use of a flow sheet can be helpful. In ad-
dition, the patient should be made aware of the social
support systems available today. The role of the
physician is not only to counsel and perform diag-
nostic tests but to be realistic and suggest adoption
or ART after allowing appropriate time for concep-
tion to occur after each diagnostic step.
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West 168th Street, New York, New York 10032.
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