Essentials of Diagnosis

++
Both male and female evaluation are needed to reach diagnosis.
Male partner:
History
Semen analysis
If semen analysis abnormal, referral to urology, endocrine evaluation, and
karyotyping in severe cases
State-mandated infectious disease panel if treatment includes intrauterine
insemination or in vitro fertilization
Female partner:
History, confirm ovulation
Physical exam to assess cervix, uterus, and adnexa for pathology
Cycle day 3 blood work and ultrasound to assess ovarian reserve
Hysterosalpingogram to evaluate uterine cavity and fallopian tubes
Possible saline sonogram to evaluate uterine cavity
Laparoscopy to assess endometriosis when indicated
State-mandated infectious disease panel if undergoing in vitro fertilization
+
Infertility: Introduction
++
The number of infertility visits has increased over the past decades. In some cases,
couples have voluntarily delayed childbearing in favor of establishing careers and
may experience an age-related decline in fertility. There have been significant
advances in assisted reproductive technologies (ART), from improved embryo
culture media to intracytoplasmic sperm injection (ICSI) and preimplantation genetic
diagnosis (PGD), which have resulted in remarkable increases in in vitro fertilization
embryo transfer (IVF-ET) pregnancy rates. These advances coupled with increasing
public awareness and acceptance of ART have spurred women or couples with
infertility to seek medical care.

++
Definition
++
Infertility is defined as the inability of a couple to conceive within 1 year. Sterility
implies an intrinsic inability to achieve pregnancy, whereas infertility implies a
decrease in the ability to conceive and is synonymous with subfertility. Primary
infertility applies to those who have never conceived, whereas secondary infertility
designates those who have conceived at some time in the past.
++
Fecundity is the probability of achieving a live birth in 1 menstrual cycle.
Fecundability is expressed as the likelihood of conception per month of exposure.
Fertility, as well as infertility, of a woman or couple is best perceived as
fecundability, as few infertile patients are sterile. It also allows for a direct
comparison of treatment options over a more functional time frame.
++
The prevalence of women diagnosed with infertility is approximately 13%, with a
range from 7 to 28%, depending on the age of the woman. It has remained stable
over the past 40 years; ethnicity or race appears to have little effect on prevalence.
However, the incidence of primary infertility has increased, with a concurrent
decrease in secondary infertility, most likely as a result of social changes such as
delayed childbearing.
++
In normal fertile couples having frequent intercourse, the fecundability is estimated
to be approximately 2025%. Approximately 8590% of couples with unprotected
intercourse will conceive within 1 year. Sterility affects 12% of couples.
+
Pathogenesis
++
Infertility can be due to either partner or both. Overall, an etiology for infertility can
be found in 80% of cases with an even distribution of male and female factors,
including couples with multiple factors. A primary diagnosis of male factor is made
in approximately 25% of cases. Ovulatory dysfunction and tubal/peritoneal factors
comprise the majority of female factor infertility. In 1520% of infertile couples, the
etiology cannot be found, and a diagnosis of unexplained infertility is made.

+
Prevention
++
Prevention of infertility is difficult to achieve and thus discuss, as a couple isn't
really aware of the diagnosis until they try to achieve pregnancy. Although difficult
to do, there are a few steps one can take to possibly decrease risk of infertility.
++
Although infertility is defined as the failure to achieve pregnancy after 12 months or
more, earlier evaluation may be justified depending on one's history and is
warranted for women over the age of 35. Because fertility is related to aging in
women and perhaps in men after the age of 50, one should be aware of these risks
when considering delaying childbearing. Therefore, it is the responsibility of the
primary care provider or gynecologist to openly discuss fertility and aging during a
well-woman visit. The new techniques of oocyte cryopreservations hold a great
promise for women who would like to delay childbearing and should be addressed
with women to increase awareness.
++
Weight extremes have also been associated with infertility in women, mainly due to
anovulation. Thus a healthy lifestyle may improve fertility for women with ovulatory
dysfunction. However, beyond what has been mentioned previously, there is little
evidence that dietary variations enhance fertility. Women should also be advised to
take folic acid supplement (at least 400 g daily) when trying to conceive.
++
Smoking has a substantial adverse effect on female fertility demonstrated by a
recent meta-analysis and also causes abnormalities in male semen parameters.
Thus couples who smoke and are trying to conceive should be advised accordingly.
Moderate alcohol and caffeine consumption has no adverse effect on fertility;
however. higher levels of alcohol and recreational drugs should be discouraged for
couples trying to conceive.
++
Lastly, couples trying to conceive should be advised to avoid using vaginal
lubricants as these can be toxic to sperm based on their effect demonstrated in
vitro. If needed, it may be better to recommend mineral oil, canola oil, or
hydroxyethylcellulose-based lubricants.
Differential Diagnosis & Clinical Findings

++
The armamentarium of diagnostic tests available for the evaluation of an infertile
couple is large. Therefore, a clinician should be judicious in his/her use of tests. The
history and physical exam shape the endocrinologic and radiologic testing algorithm
specific to each patient. Other factors to consider include patient age, risks
associated with the test, invasiveness, expense, and probabilities of significant
findings (Table 531). The patient(s) should be included in the decision-making
process.
++
Table Graphic Jump Location

Table 531. Causes of Infertility.

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Table 531. Causes of Infertility.
Male Factor

Ovulatory Factor (cont.)

Endocrine disorders

Peripheral defects

Hypothalamic dysfunction (Kallmann's

syndrome)

Gonadal dysgenesis

Pituitary failure (tumor, radiation,

surgery)

Premature ovarian failure

Hyperprolactinemia (drug, tumor)

Ovarian tumor

Exogenous androgens

Ovarian resistance

Thyroid disorders
Adrenal hyperplasia
Anatomic disorders

Metabolic disease
Thyroid disease
Liver disease

Congenital absence of vas deferens

Renal disease

Obstruction of vas deferens

Obesity

Congenital abnormalities of ejaculatory

system

Androgen excess, adrenal or neoplastic

Abnormal spermatogenesis
Chromosomal abnormalities

Pelvic Factor
Infection

Mumps orchitis

Appendicitis

Cryptorchidism

Pelvic inflammatory disease

Chemical or radiation exposure

Uterine adhesions (Asherman's

syndrome)

Abnormal motility
Absent cilia (Kartagener's syndrome)

Endometriosis
Structural abnormalities

Varicocele

Diethylstilbestrol (DES) exposure

Antibody formation

Failure of normal fusion of the

reproductive tract

Sexual dysfunction

Myoma

Retrograde ejaculation

Cervical Factor

Impotence

Congenital

Decreased libido
Ovulatory Factor
Central defects

DES exposure
Mllerian duct abnormality
Acquired

Chronic hyperandrogenemic
anovulation

Surgical treatment

Hyperprolactinemia (drug, tumor,

empty selia)

Infection

Hypothalamic insufficiency
Pituitary insufficiency (trauma, tumor,
congenital)
++
New Patient Assessment
++
The initial aspect of the interview includes discussion of the factors (ie, ovulation,
sperm concentration, ovarian reserve, etc.) that affect fertility so that the patient(s)

is aware of the potential etiologies. In this light, the physician can present an
algorithm for the diagnostic evaluation that the patient will understand. This will
help the patient grasp the peculiarities of the specific tests, such as timing the
hysterosalpingogram to the day of the menstrual cycle, and provide an opportunity
for the patient(s) to ask fertility-related questions and to address any information
learned from friends, family, or the Internet.
++
The initial clinical assessment should begin with a thorough history of both partners.
Factors to consider while obtaining the medical history are outlined in Table 532 for
the female and in Table 533 for the male. The history should guide the physical
examination beyond the general evaluation; for example, a rectovaginal exam to
detect uterosacral ligament nodularity associated with endometriosis is indicated if
a woman presents with a history of severe dysmenorrhea. However, a thorough
physical exam may divulge key information such as acanthosis nigricans and its
association with insulin resistance.
++
Table Graphic Jump Location

Table 532. Medical History for Female Factor Infertility.

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Table 532. Medical History for Female Factor Infertility.
In utero diethylstilbestrol (DES) exposure
History of pubertal development
Present menstrual cycle characteristics (length, duration, molimina)
Contraceptive history
Prior pregnancies, outcomes
Previous surgeries, especially pelvic
Prior infection
History of abnormal Papanicolaou (Pap) smear, treatment
Drugs and medications

General health (diet, weight stability, exercise patterns, review of systems)

++
Table Graphic Jump Location

Table 533. Medical History for Male Factor Infertility.

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Table 533. Medical History for Male Factor Infertility.
Congenital abnormalities
Undescended testes
Prior paternity
Frequency of intercourse
Exposure to toxins
Previous surgery
Previous infections, treatment
Drugs and medications
General health (diet, exercise, review of systems)
Decreased frequency of shaving
++
The laboratory and radiologic tests assess 4 key aspects for fertility in a couple: the
sperm (male factor), the oocyte (ovulatory factor and ovarian reserve), transport
(pelvic factor including fallopian tubes), and implantation of ova (uterus). In many
cases, the couple will be attempting to absorb significant amounts of information,
some of which may be highly technical, at a time of heightened emotion. It is
therefore helpful to offer literature or a written summary of the discussion.
Frequently, the initial history will indicate a probable diagnosis or a contributing
cause of infertility, but it is important to complete a basic evaluation of all of the
major factors so a secondary diagnosis is not ignored.
++
Evaluation of Male Partner

++
Male factor is diagnosed in 2540% of infertile couples. The majority of the
diagnoses involve testicular pathology such as varicocele. Although validation is
incomplete, there is a trend toward increasing use of molecular techniques to
quantify the fertility potential of semen as our knowledge of fundamental molecular
genetics expands. Experience and investigation have relegated several tests
previously used to assess fertilization to historical interest. Beyond the history and
physical exam, the initial evaluation of male factor is through semen analysis. If
abnormal, the semen analysis should be repeated in 4 weeks or more to confirm
findings. Normal semen analysis excludes any important male factor, whereas
abnormal semen analysis suggests the need for further evaluation (endocrine,
urological, or genetic).
++
Semen Analysis
++
The male partner should abstain from coitus for 25 days before collecting the
sample, and the specimen should be received in the lab within 1 hour of collection.
Table 534 lists normal sperm values. If fundamental parameters of count and
motility are normal, the assessment of the morphology of the sperm becomes more
critical. Specialized expertise in determining sperm morphology and strict
application of criteria should be used before declaring the semen normal.
++
Table Graphic Jump Location

Table 534. Normal Semen Parameters.

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Table 534. Normal Semen Parameters.
Liquefaction

30 minutes

Count

20 million/mL or more

Motility

>50%

Volume

2 mL or more

Morphology
WHO criteria

>30% normal

Kruger Strict Criteria

>14% normal

pH

7.27.8

White blood cell count

<1 million/mL

++
The semen parameters in normal fertile males may vary significantly over time, and
the first response to any abnormal result should be to wait an interval of several
weeks and repeat the test. A normal semen analysis will usually exclude significant
male factor. Although low counts, decreased motility, and increased numbers of
abnormal forms are most frequently associated with infertility, unfavorable semen
parameters may still be found in 20% of males undergoing vasectomy after having
completed their families. If the semen analysis reveals abnormal or borderline
parameters, the history should be reviewed for any proximate cause of an
abnormality, keeping in mind that the cycle of spermatogenesis takes
approximately 74 days. A male with <5 million sperm per milliliter warrants an
endocrinologic evaluation including follicle-stimulating hormone (FSH), luteinizing
hormone (LH), and testosterone, or a karyotype in selected cases. The patient
should be referred to a urologist with a special interest and expertise in infertility as
indicated.
++
DNA Assays
++
Several tests, including sperm chromatin structure assay (SCSA), comet, and
terminal deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL), have been
developed to quantify the damage to DNA or chromatin (packaged DNA). There is
some evidence associating increased DNA damage as determined by these tests
with poor fertility outcome. The SCSA determines the percent of chromatin that is
fragmented by exposing sperm DNA to acid denaturation (fragmented DNA is more
vulnerable). Clinical experience has not matched initial expectations, although the
test may be useful for couples with unexplained infertility with repeated in vitro
fertilization (IVF) failures. The comet assay consists of placing the sperm DNA on gel
electrophoresis; DNA with increased strand breaks will be smaller and therefore
travel further on the slide. The TUNEL assay identifies DNA strand breaks by their
incorporation of labeled dUTP. The comet and TUNEL assay are not in wide clinical
use.

++
Other Tests
++
More detailed assessment of sperm function may include postcoital test, antibody
studies, a sperm penetration assay (hamster egg penetration assay). Such
assessments are designed to investigate more subtle problems or abnormalities of
function not revealed by the assessment of sperm number and motility. Although
helpful in some cases, the sensitivity of these assays in detecting fertility is still
uncertain and varies with the particular laboratory where the test is performed.
Because no universal methodology has yet been accepted, the interpretation of
these tests requires close communication with the laboratory selected.
++
Cervical mucus is a heterogeneous secretion containing more than 90% water. It
has intrinsic properties including consistency, spinnbarkeit (stretchability), and
ferning. When mucus is obtained from the cervical canal in the preovulatory phase,
it normally exhibits a response to the high estrogen environment. The mucus is thin,
watery, and acellular; it dries in a crystalline pattern (ferning), and acts as a
facilitative reservoir for the sperm.
++
The functional sperm must interact normally with the egg and surrounding cells in
the uterine tube. The normal migration of sperm is affected by attrition and filtering,
and it is estimated that fewer than 1000 sperm will be found in the environment of
the oocyte. The initial interaction of sperm and female genital tract can be
determined by postcoital examination of the cervical mucus (Sims-Huhner test).
++
The purpose of the postcoital test is to determine the number of active spermatozoa
in the cervical mucus and the length of sperm survival (in hours) after coitus. The
test should be performed as close to ovulation as possible, but not after. The test
involves aspirating cervical mucus with a syringe 68 hours after coitus and
checking under a microscope for the number and the motility of the sperm; fewer
than 10 motile sperm per high-power field is considered abnormal. The postcoital
test is controversial and has limited use in the infertility workup. Its value in
assessing cervical hostility to sperm has never been proven.
++
Tests developed to predict the fertilizing ability of sperm include the zona-free
hamster egg penetration test (the sperm penetration assay) and the hemizona test.

These assays compare the ability of sperm to penetrate the zona-free hamster egg
(a hamster egg in which the zona pellucida has been enzymatically digested) or to
bind to human zona with sperm from a known fertile donor. The value of these tests
remains controversial, and they are not in general clinical use.
++
Sperm possess antigens and semen may contain antibodies including spermagglutinating, sperm-immobilizing, or cytotoxic antibodies. The antibodies can be
measured in semen or in serum. The immunobead test is the antibody assay used in
most labs and is considered positive when only 20% or more of motile spermatozoa
have immunobead binding. However, the test is considered to be clinically
significant when 50% of sperm are coated with immunobeads.
++
Evaluation of Female Partner
++
Ovulatory Factor
++
An ovulatory dysfunction is responsible for approximately 2025% of infertility cases
(~40% of female factor infertility). The problem should be investigated first by
review of historical factors, including the onset of menarche, present cycle length
(intermenstrual interval), and presence or absence of premenstrual symptoms
(molimina), such as breast tenderness, bloating, or dysmenorrhea. Signs and
symptoms of systemic disease, particularly of hyperthyroidism or hypothyroidism,
and physical signs of endocrine disease (ie, hirsutism, galactorrhea, and obesity)
should be noted. The degree and intensity of exercise, a history of weight loss, and
complaints of hot flushes all are clinical clues to possible endocrine or ovulatory
dysfunction.
++
Follicular Pool
++
Early in gestation, the germ cells undergo mitosis to produce oogonia. The oogonia
undergo meiosis in their transformation to oocytes but arrest at prophase of meiosis
I until the time of ovulation. A layer of granulosa cells encircles the oocytes, creating
the follicle. A female will have the highest number of germ cells, approximately 6
million, in her ovaries at 20 weeks' gestational age. Henceforth, atresia depletes the
follicular pool at a brisk pace, with only 12 million oocytes remaining at the time of
birth. The ovaries contain approximately 500,000 oocytes at the time of first

ovulation. Menopause signals the complete depletion of germ cells, with a woman
having ovulated approximately 500 oocytes during her reproductive years.
++
Ovarian Reserve
++
An inverse relationship exists between fecundity and the age of the woman. The
decline in fecundity is a result of progressive follicular atresia through apoptosis,
which accelerates in the early thirties and progresses rapidly in the late thirties and
early forties. Concomitantly, there is a decrease in follicular quality as a result of an
increase in oocytes with chromosomal anomalies and progressive deletions in
mitochondrial DNA. The concept of ovarian reserve represents the remaining
follicular pool of the ovaries. As ovarian reserve decreases, the ovaries'
responsiveness to gonadotropins decreases, necessitating higher amounts of FSH to
achieve follicular growth and maturation.
++
Ovarian reserve should be evaluated in women older than 35 years of age who are
seeking fertility. Evaluation of the level of FSH and estradiol in the early follicular
phase (cycle days 24) may provide helpful guidance in terms of the likelihood of
achieving success, as mild elevations in either FSH or estradiol may precede overt
ovulatory dysfunction but still indicate a poor prognosis for successful pregnancy.
Use of the clomiphene challenge test has gone out of favor, whereas newer tests
such as inhibin-B and anti-mllerian hormone (AMH) remain to be validated in large
studies. The specific cause of oligo-ovulation or anovulation is determined by the
history, the physical examination, and appropriate laboratory studies.
++
Confirmation of Ovulation
++
If the patient reports a history of mittelschmerz and/or regular menses with
molimina (headaches, bloating, cramping, and emotional lability) and mild
dysmenorrhea occurring at intervals of 2832 days, the likelihood of the patient
having regular ovulatory cycles is very high. Otherwise, ovulation can be confirmed
with a serum progesterone assay performed in the mid-luteal phase or the third
week of the cycle. Progesterone levels of 3 ng/mL or greater are consistent with
ovulation.
++

Pelvic ultrasonography can provide evidence for ovulation. In the follicular phase,
the developing follicle can be monitored to maturation and subsequent rupture. The
disappearance of, or change in, the follicle and free fluid in the cul-de-sac can
document ovulation.
++
To detect the LH surge, the patient can use commercially available urinary LH kits or
serum LH assay. Ovulation occurs 2436 hours after the onset of the LH surge and
1012 hours after the peak of the LH surge. The kits can be used to time intercourse
or intrauterine insemination.
++
The basal body temperature (BBT) is the temperature obtained in the resting state
and should be taken shortly after awakening in the morning after at least 6 hours of
sleep and before ambulating. Progesterone has a central thermogenic effect; it
elevates the BBT by an average of 0.8 F during the luteal phase. The luteal phase
is thus characterized by a temperature elevation lasting about 10 days. When a
biphasic monthly temperature pattern is recorded, it is confirmatory evidence of
luteinization, but the absence of a biphasic pattern may be seen in ovulatory cycles.
++
The finding of secretory endometrium confirms ovulation. The use of an endometrial
biopsy (EMB) near the end of the luteal phase can provide reassurance of an
adequate maturational effect on the endometrial lining. Within 48 hours of
ovulation, the cervical mucus changes under the influence of progesterone to
become thick, tacky, and cellular, with loss of the crystalline fernlike pattern on
drying.
++
The only absolute documentation of release of an oocyte is pregnancy. In the case
of oligomenorrhea, amenorrhea, short or very irregular menstrual cycles, or when
ovulation is not confirmed, evaluation of the hypothalamicpituitaryovarian axis is
warranted. A usual initial assessment includes the serum concentrations of FSH,
estradiol, prolactin, and thyroid-stimulating hormone.
++
Luteal Phase Defect
++
The subject of the inadequate luteal phase remains an area of controversy. There is
disagreement on how to make the diagnosis, when the diagnosis is significant, and
how best to treat the problem if diagnosed. Luteal phase defect is a histologic

diagnosis made when the endometrium lags 3 days or more behind the expected
pattern at the time of EMB. EMB to assess luteal phase defect is rarely performed
nowadays due to high levels of variability in histologic diagnosis.
++
The Pelvic Factor
++
The pelvic factor includes abnormalities of the uterus, fallopian tubes, ovaries, and
adjacent pelvic structures. Factors in the history that are suggestive of a pelvic
factor include any history of pelvic infection, such as pelvic inflammatory disease or
appendicitis, use of intrauterine devices, endometritis, and septic abortion.
Endometriosis is included as a pelvic factor in infertility and may be suggested by
worsening dysmenorrhea, dyspareunia, or previous surgical reports. Any history of
ectopic pregnancy, adnexal surgery, leiomyomas, or exposure to diethylstilbestrol
(DES) in utero should be noted as possibly contributory to the diagnosis of a pelvic
factor. A pelvic examination can be informative, yielding information such as a fixed
uterus suggestive of adhesions, leiomyomas, or adnexal masses.
++
A transvaginal ultrasound examination can be an efficient means of supplementing
information gained from the standard bimanual examination. Hydrosalpinges,
leiomyoma, and ovarian cysts, including endometriomas, can often be observed,
and the appropriate focused evaluations initiated.
++
A hysterosalpingogram (HSG) is a fluoroscopic study performed by instilling
radiopaque dye into the uterine cavity through a catheter to determine the contour
of the endometrial cavity and patency of the fallopian tubes. Sensitivity and
specificity of an HSG are approximately 65% and 85%, respectively. Abnormal
findings include congenital malformations of the uterus, submucous leiomyomas,
intrauterine synechiae (Asherman's syndrome), intrauterine polyps, salpingitis
isthmica nodosa, and proximal or distal tubal occlusion. The hysterosalpingogram
can be obtained in an outpatient setting with minimal analgesia consisting of
premedication with a nonsteroidal anti-inflammatory drug. The test is usually
scheduled for the interval after menstrual bleeding and before ovulation. Either
water- or oil-based dye may be selected; Table 535 summarizes the advantages
and disadvantages of each. There is evidence for a fertility-enhancing effect of HSG
using the oil-based dye.
++
Table Graphic Jump Location

Table 535. Comparison of Oil-Based versus Water-Based Dye Used in the

Hysterosalpingogram.
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Table 535. Comparison of Oil-Based versus Water-Based Dye Used in the
Hysterosalpingogram.
Fertility enhancement

Oil: higher pregnancy rates

Patient discomfort

Water: less cramping

Image quality

Water: rugae seen

Oil: better image

Embolization

Minimal risk with either dye

Granuloma

Greater risk for retained oil

++
Peritonitis is a risk of the procedure observed in up to 13% of patients; many
clinicians use a short-course doxycycline during the immediate period before and
after the procedure to minimize risk. An HSG is contraindicated in the presence of
an adnexal mass or an allergy to iodine or radiocontrast dye.
++
A sonohysterogram, a transvaginal ultrasound of the uterus with instillation of saline
into the uterine cavity, is a sensitive and specific test for the detection of
intrauterine lesions, specifically space-occupying lesions. Hysterosalpingo contrast
sonography, transcervical injection of sonopaque material during ultrasonography,
is used to determine tubal patency as well as detect intrauterine defects; more
commonly used in Europe, the procedure's sensitivity is comparable to that of HSG.
++
Laparoscopy with chromotubation (dye instillation) is the gold standard for the
evaluation of tubal factor, and when performed in conjunction with hysteroscopy,
information on uterine contour can be obtained simultaneously. Tubal abnormalities
such as agglutinated fimbria or adhesions (which restrict motion of the tubes) or
peritubal cysts may suggest tubal disease that would not necessarily be detected
on hysterosalpingogram. The diagnosis of endometriosis is usually based on
laparoscopic findings.

++
The necessity of laparoscopy in an infertility workup is controversial. There is
significant evidence that pelvic pathology may exist in almost one-third of patients
with normal HSG and ultrasound; consequently, some believe that with laparoscopy
one can treat the pathology (such as adhesions) found at the time of procedure or
can spare a patient needless cycles of ovulation induction that are unlikely to
succeed by providing knowledge of severe pelvic disease. Others believe that
although pelvic disease may be present, a stepwise empiric approach is more costeffective.
++
The Cervical Factor
++
A cervical factor may be indicated by a history of abnormal Papanicolaou (Pap)
smears, postcoital bleeding, cryotherapy, conization, or DES exposure in utero. The
major evaluation of the cervical factor is by speculum examination, which may
reveal evidence of cervicitis that may require further evaluation and treatment, or
cervical stenosis, especially in a patient with prior history of cervical conization. If
none of these findings are present, it is unlikely that cervical mucous presents a
major obstacle. The postcoital test has been part of the assessment of cervical
factor for many years in the past; however, the current consensus is that it is no
longer required due to high variability in its methodology and interpretation.
Moreover, treatment for otherwise unexplained infertility generally is a combination
of ovarian stimulation and intrauterine insemination (IUI), which therefore bypasses
the cervical factor. Therefore, postcoital test may only be reserved for patients in
whom results will actually influence the treatment strategy.
++
Combined Factors & Unexplained Infertility
++
After the completion of the diagnostic workup, the findings should be reviewed with
the patients and a treatment plan finalized based on guidance from the physician
and input from the patient(s). In approximately 20% of couples, a combination of
factors found may be suboptimal, and multiple therapies may need to be instigated,
either sequentially or simultaneously.
++
Diagnosis of unexplained infertility, on the other hand, generally implies normal
uterine cavity, bilateral patent tubes, normal semen analysis, and evidence of

ovulation. Postcoital tests and endometrial biopsy are no longer necessary in order
to diagnose unexplained infertility. For the couple with unexplained infertility, an
empiric stepwise approach is an excellent option. However, depending on the
history, workup, and individual situation, additional test(s) including surgery to rule
out endometriosis should be discussed.
Treatment
++
Male Factor Infertility
++
Treatment options progress from least to most invasive or use of donor sperm. Mild
to moderate disease can be treated with intrauterine insemination (IUI). Before the
insemination, the semen is prepared to select for highly motile sperm, concentrate
sperm, and remove seminal fluid (with prostaglandins). The prepared sperm is
transcervically injected into the uterus.
++
ICSI is used in conjunction with IVF for treatment of severe disease (<2 million
motile sperm or <4% normal sperm). In this procedure, a sperm is individually
injected into each oocyte. The sperm can be retrieved from the testes by
microsurgical epididymal sperm aspiration (MESA) or testicular sperm aspiration
(TESA); a minimum number of sperm is necessary.
++
Indications for ICSI include poor semen analysis parameters (low number of motile
sperm, poor morphology), fertilization failure with standard IVF, and spermatozoal
defects leading to poor fertilization. A decade of experience with the procedure has
proven its overall safety. However, offspring conceived using ICSI may be at
increased risk of imprinting disorders (eg, Angelman's syndrome), and male children
are at risk for inheriting the genetic disorder (eg, Y chromosome microdeletions)
that rendered their father infertile.
++
The initial evaluation of FSH, LH, testosterone, and prolactin helps to differentiate
between obstructive defects, primary hypogonadism (testicular defect), and
secondary hypogonadism (hypothalamic or pituitary). Obstructive defects may be
addressed through surgical reanastomosis or through retrieval of sperm via MESA or
TESA for use with ICSI. Retrograde ejaculation can be treated with alpha
sympathomimetics or urine can be centrifuged to collect sperm for IUI. Patients with

primary hypogonadism should have a karyotype, as Klinefelter's syndrome (47,XXY)

is the most common etiology.
++
Secondary hypogonadism, or hypogonadotropic hypogonadism, may be a result of a
pituitary lesion such as prolactinoma or a hypothalamic etiology such as Kallmann's
syndrome. Most prolactinomas respond to medical management. Pulsatile
gonadotropin-releasing hormone (GnRH) administration with a pump or FSH
replacement restores testosterone and sperm production in disorders leading to
hypogonadotropic hypogonadism.
++
A varicocele is a dilatation of scrotal veins in the pampiniform plexus and is
postulated to impair fertility through elevation of scrotal temperature. A clinical
varicocele is one that is detected by examination and is present in 15% of men.
Subclinical varicoceles can be detected by ultrasound or venography. There is
contradicting evidence regarding whether ligation of clinical varicoceles leads to
improved pregnancy rates; infertility is a questionable indication for the correction
of subclinical varicoceles.
++
When male infertility is not amenable to therapy, donor sperm for insemination or
IVF offers an opportunity for pregnancy. The use of donor sperm is common in
clinical practice, and experience has lessened some of the medical, emotional,
ethical, and legal issues. The American Society for Reproductive Medicine (ASRM)
advocates use of frozen semen to reduce risk of transmission of infectious disease.
++
Female Factor Infertility
++
The Ovulatory Factor
++
The treatment and success of specific ovulatory disorders is determined by the age
of the patient and the etiology of the anovulation. A stepwise approach, from least
to most invasive (and expensive), usually starts with clomiphene citrate and
progresses to ovulation induction with gonadotropins and, ultimately, IVF. The risk to
the patient, cost of therapy, and fecundability increase with each step closer to IVF.
If premature ovarian failure or early menopause is the etiology, the options include
oocyte or embryo donation.

++
Induction of ovulation can be accomplished in 9095% of patients with chronic
anovulation, normal ovarian reserve, and absence of other endocrine abnormalities
(eg, hyperprolactinemia or hypothyroidism). Clomiphene citrate is the agent of
choice for women younger than 36 years of age with oligomenorrhea or amenorrhea
and normal FSH, including women with polycystic ovary syndrome (PCOS).
Clomiphene citrate blocks the feedback inhibition of estradiol on the hypothalamus
and pituitary, leading to an increase in endogenous FSH. It is administered orally for
5 days starting on day 35 of the cycle; approximately half of the patients will
ovulate at 50 mg/d and another 25% at 100 mg/d. Ultrasonographic and hormonal
monitoring of follicular development is an option, which provides more information
and allows greater control of the cycle. After a regimen has achieved ovulation, 3
cycles with either timed intercourse or IUI should be attempted. Side effects with
clomiphene are common, including hot flushes, emotional lability or depression,
bloating, and visual changes; most are mild and all disappear with discontinuation
of the drug. The incidence of twin gestation is 8% and triplets or higher-order
multiple pregnancy is <1%.
++
Aromatase inhibitor letrozole is an alternative option for patients who do not
respond to clomiphene citrate or instead of clomiphene citrate. It was first used to
induce ovulation in 2001. Letrozole works by inhibiting estrogen biosynthesis, thus
releasing the hypothalamus/pituitary from negative feedback and increasing
endogenous FSH secretion by the pituitary. It is also administered orally for 5 days
starting on day 35. The starting dose is 2.5 mg, but studies have revealed
improved response and higher pregnancy rates with 5 mg. The dose can be
increased to up to 7.5 mg daily. As in the case of clomiphene citrate, ultrasound and
hormonal monitoring is an option and may provide more information on individual
response and how to proceed with future cycles. Letrozole has fewer side effects
than clomiphene, and studies reveal at least similar if not better success rates than
clomiphene. Lastly, letrozole has less thinning effect on the endometrium than
clomiphene.
++
A patient in whom there is no response to clomiphene or letrozole, response but no
pregnancy, pituitary insufficiency, or hypothalamic insufficiency should undergo
ovulation induction with gonadotropins, often used in conjunction with IUI. Human
menopausal gonadotropin (hMG) consists of FSH and LH isolated from the urine of
postmenopausal women to various levels of purification (and LH content);
recombinant FSH (rFSH) contains purely FSH. Gonadotropins are administered by
subcutaneous (rFSH) or intramuscular injection (hMG), and the overall evidence
indicates that the 2 preparations have similar efficacy.

++
Because of an increased risk of side effects such as multiple gestation and ovarian
hyperstimulation syndrome (OHSS), the use of gonadotropins requires close
monitoring with ultrasonography and estradiol levels. Consequently, it is more timeconsuming and expensive than clomiphene or letrozole. The monitoring reveals
both the number of developing follicles and their level of maturity. Mimicking the
effects of the LH surge, human chorionic gonadotropins (hCG) is used to trigger
ovulation. With perseverance, cumulative pregnancy rates of 4590% can be
achieved over 34 cycles with gonadotropin treatment; but even with careful
monitoring there is a 25% risk of a multiple gestation. OHSS is a rare complication
that occurs in <2% of cycles.
++
If pregnancy is not achieved with ovulation induction, IVF/embryo transfer (ET) is
the next modality in the treatment algorithm. Development of the follicular cohort is
induced with higher doses of FSH (hMG or rFSH). Follicular growth is monitored by
ultrasonography and estradiol levels. When the leading follicles are mature,
ovulation is triggered with hCG. The oocytes are retrieved from the follicles before
ovulation by ultrasound-guided transvaginal aspiration of the follicular fluid. The
oocytes are incubated with sperm for fertilization. Alternatively, ICSI is performed if
male factor is also a concern. On average, several (from 1 to >3) embryos are
transferred into the uterine cavity on day 35 after retrieval of the oocytes. OHSS is
minimized by withholding hCG if there is a high number of follicles or elevated
estradiol levels. Another option to limit the extent of OHSS is to cryopreserve the
embryos for transfer at a later time, as pregnancy can prolong the course of OHSS.
++
When modification of lifestyle or body habitus does not successfully restore
ovulation in the patient diagnosed with hypothalamic insufficiency, pulsatile GnRH is
another viable option with high likelihood of restoring normal ovulation. Normal
fertility is then restored during cycles of treatment, and most pregnancies occur
within 36 cycles.
++
Hypothyroidism and hyperprolactinemia can lead to ovulatory dysfunction. Primary
hypothyroidism leads to elevated thyroid-stimulating hormone levels, which is a
secretogogue of prolactin. Elevated prolactin levels inhibit GnRH secretion, causing
oligomenorrhea or amenorrhea. If elevated prolactin levels are detected in a woman
with normal thyroid function, a full workup including thorough history (to rule out
drugs such as psychotropics), physical exam (galactorrhea), and imaging (magnetic
resonance imaging to rule out a prolactinoma or other central nervous system

tumors) is likely to reveal the etiology. The elevated prolactin can be medically
managed with dopamine agonist, leading to normalization of the cycle.
++
The Pelvic Factor
++
Adhesions resulting from endometriosis or tubal occlusion after salpingitis are 2 of
the most common problems confronting infertile couples. With increasing pregnancy
rates, IVF represents improved fecundability and lower risk over surgical repair
except in unique circumstances. The role of surgical treatment is mostly limited to
what can be accomplished at the time of diagnostic laparoscopy. There is some
evidence to suggest that resection of mild endometriosis results in improved
pregnancy rates. Laparoscopic resection or ablation of moderate or advanced
endometriosis enhances fecundity in infertile women for the period immediately
after surgery. Reversal of tubal sterilization is indicated in young women with
adequate residual tubal length. Tubal interruption or resection increases IVF
pregnancy rates in women with hydrosalpinx.
++
The role of fibroids in infertility is unclear, and most surgeons reserve myomectomy
for treatment of recurrent abortion, repeated implantation failure, or with distortion
of the endometrial cavity by a submucosal leiomyoma. The fibroids that distort the
endometrial cavity are considered to be significant. These may be diagnosed by
hysterosalpingogram, sonohysterogram, hysteroscopy, or magnetic resonance
imaging.
++
The Cervical Factor
++
The absence of nurturing mucus at midcycle can be treated by bypassing the mucus
with IUI. When the cervical mucus appears to be affected by cervicitis and
inflammatory changes, some physicians advocate empiric treatment of patient and
partner with doxycycline. When the cervix is altered by congenital malformation or
past surgical treatment that has rendered endocervical glands absent or
nonfunctional, IUI with washed sperm can be anticipated to result in pregnancy in
2030% of patients per cycle in each of the first 3 cycles of treatment. Cervical
factor patients who do not respond to these therapies can be offered IVF, gamete
intrafallopian transfer (GIFT), or zygote intrafallopian transfer (ZIFT), although GIFT
and ZIFT are now rarely used.

++
Unexplained Infertility
++
A diagnosis of unexplained infertility is assigned to couples with normal results of a
standard infertility workup. The main treatment options include expectant
observation with timed intercourse, ovarian stimulation with or without IUI, and IVF.
Studies support the use of clomiphene with IUI for up to 4 cycles. The next step is
usually hMG with intrauterine insemination for 3 cycles; if unsuccessful, IVF should
be considered. The rationale for treatment with superovulation in women with
documented ovulation is that by increasing the number of oocytes available, the
likelihood of pregnancy is increased. In instances in which unexplained infertility
may be the result of a fundamental defect in fertilization or in embryo transfer to
the uterus, IVF may play a role in treatment. Donor oocytes or donor sperm may be
considered in couples with continued difficulties in achieving pregnancy. For many,
the hardest course to contemplate is no therapy at all.

Complications
++
The major complication associated with ovarian stimulation is OHSS. It has a broad
spectrum of disease, ranging from mild to extremely severe cases. The
pathophysiology of the disease is due to increased capillary permeability resulting
in fluid shift from the intravascular to extravascular spaces. Risk factors for OHSS
include young age, PCOS, higher doses of gonadotropins, and high serum estradiol
levels. Severe cases of hyperstimulation warrant very careful monitoring and
hospitalization, as it can lead to electrolyte abnormalities, abnormal liver function
tests, respiratory distress, and hyponatremia. There are several methods used
nowadays in order to prevent OHSS, including gentler stimulation protocols,
coasting until lower estradiol levels are achieved, and most recently, GnRH agonist
instead of hCG trigger.
++
There is also a concern about a possible association between ovulation induction
agents, specifically >12 cycles of clomiphene citrate, and ovarian cancer. The
possibility that ovulation induction increases the risk of ovarian cancer remains
unproven. Primary infertility and endometriosis are independent risk factors for
ovarian cancer. Although additional investigation is necessary, the low incidence of

ovarian cancer makes it difficult to design an adequate study to detect an

association of infertility drugs with ovarian cancer.
+
Prognosis
++
The success rates of treatment for infertility depends on a variety of factors,
including cause of infertility, woman's age, duration of infertility, and treatment
modality. Health insurance plans vary a great deal in the amount and type of
infertility treatments that are covered. For those couples without infertility
coverage, treatment choices are dictated by medical and financial considerations.
Not uncommonly, infertility treatment does not actually make the difference
between conceiving and not conceiving, but allows for conception in the more
immediate future rather than at a delayed point of time (increasing fecundability).