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A Primary Care Approach to the Infertile Couple

Article  in  The Journal of the American Board of Family Practice / American Board of Family Practice · November 2000
Source: PubMed

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CLINICAL REVIEW

A Primary Care Approach to the Infertile Couple

Gail F. Whitman-Elia, MD, and Elizabeth G. Baxley, MD

Background: Approximately 20% of reproductive age couples have difficulty conceiving or maintaining
an established pregnancy. The family physician is in a unique position to provide patient education,
begin initial evaluation, make appropriate referrals, and offer ongoing counseling and support to cou-
ples who experience problems with fertility.
Methods: And extensive clinical review was conducted based on a MEDLINE search, the Cochrane
database of systematic reviews, and other supporting evidence.
Results: Major physiologic influences affecting live birth rates include age, coital frequency, and du-
ration of infertility. Male factor is associated with approximately 40% of these cases and should be ad-
dressed early in the evaluation.
Conclusion: Many conditions once considered untreatable can now be routinely corrected. As man-
aged care programs expand coverage to include infertility services, primary care providers will be
asked to participate in the initial phase of this care. This article offers a practical approach. (J Am
Board Fam Pract 2001;14:33– 45.)

Family physicians are frequently the first clinicians mathematical models exist to describe fecundability
consulted by patients concerned about potential in so-called normal populations. For example, the
infertility. Because of the anxiety that often accom- interconceptual period of Hutterite women, a reli-
panies early attempts to conceive, it is important gious group refusing access to birth control, is
for providers to have accurate knowledge about often compared with other populations.2 Other
what represents normal fecundity, when a couple’s models are based on observations of fertile women
fertility should be investigated, and the availability undergoing artificial donor insemination for treat-
of various treatment options. Establishing a good ment of male azoospermia and on otherwise
referral network of specialists is essential in dealing healthy women seeking routine gynecologic care.3,4
with difficult cases and in helping couples achieve From these studies, probability of conception
successful pregnancies. curves have been constructed and provide a basis
for deciding when extensive investigation is war-
Methods ranted or when a proposed therapy is efficacious.
Using MEDLINE, the Cochrane database of sys- Only one in five (20%) couples actively trying to
tematic reviews, and other supporting evidence, we conceive will be successful in a given month. Yet,
undertook an extensive review of the published the other 80% can be reassured by the knowledge
literature, applying the key words “infertility” and that more than 85% will become pregnant within
“habitual abortion.” the first year.3,4
Once couples are able to conceive, a live birth is
Aspects of Fertility anticipated. Unfortunately, many pregnancies re-
Fecundability is the ability to achieve a recognized sult in spontaneous abortion. The ability to deliver
pregnancy within one menstrual cycle.1 Many a liveborn is affected most by maternal age.5– 8 The
risk of having a clinically recognized spontaneous
Submitted, revised, 23 March 2000. abortion increases from approximately 10% for
From the Department of Obstetrics and Gynecology those younger than 30 years, to 18% for those in
(GFW), and the Department of Family and Preventive
Medicine (EGB), University of South Carolina School of their late 30s, to 34% for those in their early 40s.9
Medicine, Columbia. Address reprint requests to Gail F. Women older than 35 years are more likely to have
Whitman-Elia, MD, Department of Obstetrics and Gyne-
cology, University of South Carolina School of Medicine, 2
difficulty with chromosomal nondisjunction and as-
Richland Medical Park, Suite 208, Columbia, SC 29203. sociated aneuploidy. Depending on the karyotype

Infertile Couple 33
Figure 1. Initial screening evaluation.

of the conceptus, these patients can give birth to setting. Examining diagnoses of couples undergo-
genetically compromised infants or experience still- ing infertility investigation shows that male factor
birth, miscarriage, and failed implantations.7 causes are found up to 40% of the time.10 Among
Genetics aside, the older patient has had more women, pelvic conditions (endometriosis, tubal dis-
time to develop pelvic adhesions secondary to un- ease, pelvic adhesions, etc) account for 30% to 40%
treated pelvic infection or occult endometriosis.6 of cases, while ovulatory dysfunction and cervical
Additionally, this group is at increased risk for factors each contribute another 10% to 15%. A
ovulatory dysfunction and associated luteal phase smaller percentage (5%) relate to other causes,
abnormalities.8 Coital frequency often decreases such as hypothyroidism, immunologic factors, and
with age, potentially enhancing the contribution luteal phase defect. Roughly 10% remain unex-
that timing of intercourse makes in cases of infer- plained even after thorough investigation.10
tility.5 By the time a woman is 35 years old, the Knowledge of these factors and their relative
quoted live birth rate for her age-group is one-half contribution to the problem of infertility will help
that of the younger population. The likelihood of a the family physician begin a directed screening
successful outcome in these women is lower even if evaluation of affected couples in the ambulatory
actual pathologic conditions are diagnosed and setting. Women older than 35 years or those at
treated. high risk for infertility based on medical history
The length of time a couple has been attempting should be promptly evaluated as soon as the ques-
to conceive has an independent impact on progno- tion of infertility arises. On the other hand, young
sis, especially for those couples with normal find- couples with normal medical histories who have
ings on evaluation. Couples with infertility span- been trying to conceive for less than 1 year can be
ning 4 or more years tend to have a poor observed for an appropriate time based on antici-
prognosis.9 pated fecundability rates. For these patients, a
Local referral patterns clearly affect the respec- screening semen analysis and documentation of
tive infertility diagnoses encountered in a particular ovulation can be initiated as a means of reassurance

34 JABFP January–February 2001 Vol. 14 No. 1

Table 1. Important History and Physical Findings.
Type of Problem Specific Indicators

Sexual techniques Vaginal lubricants

Douching after coitus
Poor timing related to actual fertile period
Sexual dysfunction Incomplete penetration:
Male: erectile dysfunction, premature ejaculation
Female: vaginismus, chronic vaginitis
Frequency of intercourse ⬍2 times a month
Pelvic mechanical problems Exposure to sexually transmitted disease
Pelvic inflammatory disease or endometriosis
Previous pelvic or abdominal surgery
History of induced abortion or postpartum complications
Intrauterine device use
Severe dysmenorrhea or chronic pelvic pain
Exposure to tuberculosis
Enlarged or irregular shaped uterus
Cervical hood or history of in utero exposure to diethylstilbestrol
Chronic vaginal discharge
Scant menses
Endocrine problems affecting fertility History of abnormal puberty
Abnormal menstrual cyclicity (outside the 24- to 35-day range)
History of amenorrhea
Abnormal basal body temperature charts (monophasic or luteal phase ⬍10 days)
History of nonpuerperal galactorrhea
Abnormal pattern of hair growth
Acne
History, signs, or symptoms of thyroid, adrenal, or other systemic disorder
Potential genetic problems Known or suspected hereditary disease in patient or family
Consanguinity
Two losses or one pregnancy with documented anomalies
Birth defects
Unexplained mental retardation
Advanced maternal age
Teratogen exposure
Ethnic groups at special risk

Adapted from Blankstein et al.11

or, in the case of abnormal results, to recognize reveal to the other. Complete records of any past
those in need of early referral (Figure 1). investigation or treatment for infertility should be
obtained and subsequently reviewed with the cou-
Step 1: The Screening Evaluation ple.
A complete medical, reproductive, and sexual his- The aim of the physical examination is to look
tory should be the initial step in the evaluation of for evidence of systemic disease, genetic abnormal-
couples complaining of infertility, focusing on elic- ities, or androgen dysfunction in either partner.11
iting historical signs or symptoms associated with In women, a breast examination should be done to
infertility (Table 1). Many clinicians find the use of assess for the presence of occult galactorrhea or
preprinted educational material and questionnaires abnormal breast masses. Pelvic examination should
helpful in this regard. Both partners should be be directed toward detecting signs of hyperandro-
interviewed separately, as well as jointly, to elicit genism (eg, enlarged clitoris); vaginitis or pelvic
important facts that one partner might not wish to infection; or congenital anomalies (eg, absent va-

Infertile Couple 35
gina or uterus, longitudinal or transverse vaginal Table 2. Basic Semen Analysis: Summary of Lower
septum, cervical changes consistent with in utero International Normal Values.
diethylstilbestrol exposure). Parametrial thickness, Characteristic Value
detection of uterosacral ligament nodularity, and
uterine mobility should be noted on bimanual ex- Volume 2–6 mL
amination, because abnormalities in these areas can Sperm count ⱖ20 ⫻ 106/mL
Motility ⱖ40.0%
indicate past pelvic inflammatory disease or endo-
Forward progression ⱖ3.0
metriosis.9
Morphology ⱖ40% normal
The examination should not be limited to fe-
male reproductive organs. A detailed skin examina-
tion can reveal signs of androgen excess, such as
hirsutism, seborrhea, acne, and acanthosis nigri- Ovulation that occurs at reasonable intervals is crit-
cans.12 Vitiligo or other forms of depigmentation ical for successful conception to take place. Women
can suggest autoimmune systemic disease.13 Docu- with oligo-ovulation or whose menstrual cycles are
mentation of body composition (weight, height, less than 24 days or longer than 35 days require
body mass index) and blood pressure measurements further evaluation.
should also be reviewed, as obesity is often associ- An initial semen analysis should be obtained
ated with androgen excess.14 from the male partner early in the infertility eval-
In the male partner, an attempt should be made uation, before any invasive tests are done on the
to look for endocrine stigmata consistent with hy- woman (Table 2). Once a determination about se-
pogonadism and associated undermasculinization, men adequacy is made, a directed evaluation can be
including gynecomastia, immature secondary sex- undertaken. If the semen analysis is satisfactory, the
ual characteristics, and small testes.15 Location and remainder of the screening evaluation will center
condition of the urethral opening and prepuce on the female partner.
should be noted. The scrotum should be palpated
for content, consistency, and tenderness. The testes Step 2: The Directed Investigation
should be carefully measured by stretching the Male Partners With Unsatisfactory Findings on
scrotal skin over both testicles, defining their con- Semen Analysis
tour separate from the epididymal head by palpa- Although the period of abstinence necessary to
tion, and estimating the testicular size. The testes obtain an optimal semen specimen has been the
of an adult male should be greater than 10 mL in subject of debate, 2 to 4 days is usually recom-
volume by orchidometer, which corresponds to a mended.18 An abnormal initial sperm count neces-
palpable longitudinal axis of 4 to 5 cm and an sitates that more than one sample be analyzed to
anteroposterior diameter of 2 cm.16 Scrotal hernias, determine a trend. If there has been a history of
hydroceles, or lymphoceles, if present, should be febrile illness or major physiologic or psychologic
noted. Cysts, tenderness, or thickening in the epi- stress within the previous 3 months, one full cycle
didymis and vas deferens can suggest inflammatory of spermatogenesis (approximately 72 days) should
or infectious causes. Evaluating the patient in an be allowed before repeating the analysis.18
upright standing position and having him perform To diagnose male factor infertility, the semen
a Valsalva’s maneuver will help make scrotal vari- analysis should be standardized and performed ac-
cosities obvious. cording to the guidelines of the World Health
Initial laboratory investigation of the female Organization.18 Unfortunately, the predictive value
partner generally includes a complete blood count, of the semen analysis is limited, even when prop-
urinalysis, Papanicolaou smear, vaginal wet mount, erly performed, and reliable tests for sperm func-
appropriate cultures should infection be suspected, tion do not yet exist.19 Most andrologic disorders
and an assessment of ovulation. In the ambulatory are treated empirically.20
setting, the latter can be accomplished by charting Based on treatment approach, male factor infer-
basal body temperature, obtaining a serum proges- tility can be divided into the following six catego-
terone approximately 7 days after expected ovula- ries: genetic causes, gonadotropin deficiency, ana-
tion, or using commercially available urinary lu- tomic defects, infections, immunologic causes, and
teinizing-hormone-surge ovulation predictor kits.17 idiopathic causes.

36 JABFP January–February 2001 Vol. 14 No. 1

Genetic varicocele have been associated with infertility. Af-
It has been estimated that 30% of male factor fected men have normal follicle-stimulating hor-
infertility is genetic. Affected men frequently have mone, luteinizing hormone, and testosterone lev-
azoospermia or oligospermia associated with low els. They have normal testicular volume but
motility and a predominance of abnormal forms. abnormal semen findings. If there is azoospermia
Genetic disorders include chromosomal aneu- or severe oligospermia, and the patient has nor-
ploidy and mutations in the genes associated with mally functioning gonads based on gonadotropin
spermatogenesis, which can be inherited or arise and testosterone levels, the male genital tract could
from new mutations. Klinefelter syndrome be obstructed. Checking the semen for the absence
(47,XXY) is encountered in approximately 1 in 700 of fructose can determine whether the patient’s
to 1,000 newborns, representing the most common ejaculatory duct is absent or obstructed.18
numerical chromosome anomaly in infertile men.21 Congenital bilateral absence or atrophy of the
Classic Klinefelter syndrome arises from meiotic vas deferens is found both in men with cystic fibro-
nondisjunction of the X chromosome. These pa- sis and in those men with an isolated Wolffian duct
tients usually have small firm testes, low serum anomaly.21 Azoospermic men with the isolated
testosterone levels, and azoospermia. If gonadotro- anomaly have a 60% increase in mutations for the
pin levels are elevated in a male partner with sperm CFTR gene. Identification of these mutations be-
counts consistently less than 10,000,000/mL, comes clinically relevant in such cases when preg-
karyotyping should be done to rule out Klinefelter nancy through assisted reproduction is contem-
syndrome.22 plated, because cystic fibrosis is the most common
Other more recently recognized genetic ab- autosomal recessive disorder with a carrier fre-
normalities associated with male factor infertility quency of 1:20.21
include translocations, inversions, Y chromosome- Retrograde ejaculation occurs when the lumbar
specific deletions, androgen receptor gene muta- sympathetic nerves are injured through surgery or
tions, and cystic fibrosis (CFTR) gene.21 disease process. A urine specimen should be
scanned for spermatozoa in those men suspected of
Gonadotropin Deficiency having retrograde ejaculation, particularly those
Men who are hypothalamic or have pituitary dys- with diabetes.19 Alpha-adrenergic agonists, anti-
function are frequently hypogonadal and have cholinergics, and imipramine have been used to
azoospermia or oligospermia and low motility. Se- reverse the condition. When medical therapy fails,
rum follicle-stimulating hormone, luteinizing hor- spermatozoa can be recovered for use with assisted
mone, and testosterone levels are low in these men, reproduction technologies either by electrovibra-
and the testes are usually small and soft. Beyond the tion or by surgery.19
genital examination, a finding of anosmia might be Some 3% to 6% of men will have undescended
encountered in hypogonadal men who have had testes at birth.19 It is preferable that such malposi-
gonadotropins suppressed from puberty (Kallman tion be corrected within the first year of life, as
syndrome).23 In hypogonadal men treatment with germ cell degeneration and dysplasia start in early
GnRH or gonadotropin therapy can be successful infancy.19 Because of the push to early correction,
after several months of therapy.19 Consequently, if few such cases will be encountered in the infertility
signs and symptoms of hypogonadism are present, setting.
an endocrine investigation should include a thy- Varicoceles are believed to cause decreased fer-
roid-stimulating hormone measurement to rule out tility as a result of hypoxia, stasis, increased pres-
subclinical hypothyroidism, total and free testoster- sure, increased catecholamines, and increased tem-
one and gonadotropin measurements to assess perature in the testicle.19 Varicoceles are the most
testicular-pituitary-hypothalamic function, and a frequent physical finding in subfertile men, al-
prolactin measurement to screen for occult hyper- though they are often not detected on routine
prolactinemia.11 physical examination and can require referral for
ultrasound evaluation.24 Varicocelectomy has be-
Anatomic Defects come the most frequent operation for male infer-
Absence or obstruction of the ejaculatory ducts, tility.19,20 Unfortunately, it remains highly ques-
testicular maldescent, retrograde ejaculation, and tionable whether this clinically invasive procedure

Infertile Couple 37
results in better outcomes than observation alone. nosuppressant medications, such as glucocorti-
Currently, it appears that surgery should be recom- coids, have been used to treat immunologic infer-
mended for those men with scrotal pain or swelling tility. Unfortunately, severe side effects, such as
but not for improvement of pregnancy rates. muscle wasting, aseptic necrosis of the femoral
heads, infection, and gastritis, can override any po-
Infection tential benefit.19,20 Affected men should be referred
Symptomatic bacterial infection or venereal disease for assisted reproduction. Intracytoplasmic sperm
of the male genital tract should be treated to avoid injection, a technique that microinjects a single
subsequent obstruction of the efferent ducts. Fur- spermatozoa or spermatocyte into each oocyte ob-
ther evaluation of the ejaculate after prostatic mas- tained from follicular aspiration during in vitro
sage might be indicated if the semen analysis sug- fertilization cycles, is a highly successful method of
gests infection. If the patient has a history of treatment for these patients.25,26
urethritis, both partners should have genital speci-
mens cultured and receive antibiotic therapy based Idiopathic Infertility
on identification of a specific organism. Male pa- Unexplained male infertility probably has many
tients have traditionally been screened for gonor- underlying causes. Various treatment regimens
rhea, chlamydia, mycoplasma, and Ureaplasma or- have been used, including gonadotropin-releasing
ganisms, and some clinics routinely screen for any hormone, gonadotropins, testosterone, bromocrip-
anaerobic bacterial infection, particularly when leu- tine, clomiphene citrate, vitamin C, and vitamin E,
kocytes are found in sperm on semen analysis. The to name a few. Unfortunately, not one of these
importance of asymptomatic genital tract infec- approaches used empirically has been shown to
tions, however, remains ambiguous. Incidental leu- improve pregnancy rates in subfertile men.19,20
kocytes in sperm found on semen analysis has a When the semen analysis is consistently abnor-
high spontaneous resolution rate without treat- mal, therapy can be directed at correcting the un-
ment.19,20 Additionally, few randomized controlled derlying disorder while completing the female eval-
studies have been done to clarify the influence of uation. Artificial insemination by donor sperm will
antibiotic treatment on subsequent pregnancy rates be required when the male partner has frank tes-
in asymptomatic men. When studies using preg- ticular failure as documented by azoospermia with
nancy as an outcome parameter are considered, no castrate-level gonadotropin levels.26 On the other
significant differences have been found between hand, unsatisfactory sperm counts secondary to hy-
those groups on antibiotic therapy and those under pogonadotropic hypogonadism can self-correct
observation alone.19,20 Thus, the practice of ob- once the primary endocrine disorder is ad-
taining routine cultures in asymptomatic men dressed.19,20,27
should be questioned. Treatment with timed intrauterine insemination
in an ovulation-induction cycle can be offered to
Immunologic Infertility many couples with male factor infertility.19,20,28 In
This condition is diagnosed when antisperm anti- vitro fertilization might be required, however, par-
bodies are found in the seminal fluid and no other ticularly if fewer than 1,000,000 motile spermato-
cause of infertility has been detected. Immunologic zoa or high antisperm antibody titers are discov-
testing for antisperm antibodies should be consid- ered.19,20,25,26 Many conceptions in this group have
ered when there is evidence of poor sperm motility resulted from oocyte micromanipulation with in-
or agglutination on semen analysis or a history of tracytoplasmic sperm injection (ICSI).
serious scrotal trauma. Men who have had a vasec-
tomy with subsequent vasovasostomy are at partic- Women With Amenorrhea
ular risk for antisperm antibody formation, which Once pregnancy is ruled out, the evaluation of a
might hamper subsequent fertilization attempts.25 woman with amenorrhea is directed toward deter-
Concentrations of antisperm immunoglobulin G or mining whether she is estrogen deficient, because
immunoglobulin A above 50% gave been associ- one of several covert conditions can exist in the
ated with greatly reduced pregnancy rates, and con- hypogonadal patient. Hypogonadism can be ruled
centrations above 90% virtually exclude the chance out immediately and inexpensively in the office if
of spontaneous pregnancy. Until recently, immu- there is evidence of endogenous estrogen produc-

38 JABFP January–February 2001 Vol. 14 No. 1

tion on a vaginal cytologic sample (more than 15% sufficiency, an occult craniopharyngioma, severe
superficial cells with small, pyknotic nuclei and hypothyroidism, or an expanding pituitary tumor.
large amount of cytoplasm). Hypogonadism is sug- If the fasting prolactin level is elevated to more
gested by the predominance of parabasal cells. than 100 ng/mL, and the patient gives no history of
Smaller parabasal cells, which have a nuclear to excessive breast stimulation or psychoactive medi-
cytoplasmic ratio of 50:50, suggest hypogonadism.29 cation usage, pituitary studies by magnetic reso-
Response to a progestational challenge test (10 nance imaging or computed tomography are indi-
mg of medroxyprogesterone acetate daily for 13 cated.35,36 Alternatively, lower elevations of
days orally, or a single intramuscular injection of prolactin might indicate compression or injury to
100 mg progesterone in oil) also will be indicative the tuberoinfundibular stalk and should not be ig-
of the adequacy of endogenous estrogen.9,29 If nored.37 In some patients, more extensive provoc-
enough circulating estrogen is present to prolifer- ative endocrine testing might be indicated depend-
ate the endometrial lining, exposure to progester- ing on the clinical history and screening laboratory
one will induce the lining to undergo secretory results. It is imperative that these women receive a
maturation and induction of menstrual bleeding.9 thorough evaluation of their endocrine status be-
At the same time, thyroid-stimulating hormone fore attempting ovulation induction. Patients with
and prolactin levels should be measured to assess amenorrhea secondary to hyperprolactinemia will
for systemic disorders that adversely affect ovula- usually begin ovulatory cycles once normal prolac-
tory function. tin levels are established with the use of bromocrip-
Failure to bleed after this challenge suggests that tine.35 Most hypogonadal patients with suppressed
the patient might be hypogonadal, and serum go- gonadotropins are able to conceive successfully
nadotropin levels should be measured. If the go- when managed with exogenous gonadotropin ther-
nadotropins are elevated to castrate levels on two apy.
separate occasions, ovarian failure is diagnosed.30
Women younger than 36 years in whom ovarian
failure is discovered should have a karyotype inves- Women With Presumptive Ovulation
tigation to rule out the presence of occult Y chro- If the woman has a history of normal menstrual
mosomal material or evidence of sex chromosome cycles, and no abnormalities are found during the
mosaicism. Women with a Y chromosome are at physical examination, a presumed diagnosis of ovu-
increased risk for the development of gonadal ridge lation is reasonable. In these cases, the workup
tumors and require gonadectomy.31 Those without should be directed at documenting ovulatory cy-
Y material but with chromosomal mosaicism (eg, cles, tubal patency, endometrial receptivity, and
hospitable cervical mucus. Most of these proce-
45,X/46,XX; 45,X/46,X,i(Xq)) can have occult re-
nal or cardiac abnormalities or autoimmune condi- dures require specific and appropriate timing
tions that might not become manifest until later in within the menstrual cycle (Table 3), and it is help-
adulthood.32 These women are sterile and should ful to sequence them rapidly within 3 to 4 months
be encouraged to consider fertility treatment so that therapy can be initiated if needed. Although
through oocyte or embryo donor programs.33 referral to a reproductive specialist might be war-
If the patient appears to have functioning gonads ranted at this point for invasive procedures, the
based on both clinical examination and normal go- family physician should remain informed of the
nadotropins, failure to withdraw to progestogen patient’s progress and be available to provide on-
challenge could be secondary to endometrial scar- going support of the couple, as well as to facilitate
ring (Asherman syndrome).34 In this situation, giv- referral for second opinion, assisted reproduction,
ing a priming dose of estrogen and repeating the or specialized reproductive surgery in appropriate
progestational challenge will clarify whether an cases.
end-organ problem exists. Failure to respond to
this combination suggests a uterine cause of amen- Women With Chronic Eugonadal Anovulation,
orrhea; a hysterosalpingogram or hysteroscopy will Irregular Ovulation, or Signs of Androgen Excess
confirm the diagnosis. For women who are clinically anovulatory (based
A hypogonadal woman with abnormally low go- on history, basal body temperature charts, urinary
nadotropins could be suffering from pituitary in- luteinizing hormone ovulation predictor kit, or

Infertile Couple 39
Table 3. Timing of Screening Evaluation.
Test Phase of Cycle Expected Normal Results

Hysterosalpingogram Early follicular phase Tubal patency, normal uterus

Laparoscopy, hysteroscopy Early follicular phase Normal pelvis and endometrium
Postcoital test Just before the midcycle luteinizing hormone Mucus with good spinnbarkeit
surge More than 10 motile sperm per high-power field
Serum progesterone Mid luteal phase Luteal assay range defined by kit
Endometrial biopsy Late luteal phase Late secretory endometrium

Adapted from Speroff et al.9

properly timed luteal progesterone level) serum populations, making preconceptual counseling and
prolactin and thyroid-stimulating hormone levels testing appropriate, because the homozygous con-
should be measured. Therapy can then be directed dition is the most frequent form of genital ambi-
to correct the hormonal imbalance as indicated. guity and the most frequent endocrine cause of
Additionally, if physical signs suggesting androgen neonatal death.9 It has been estimated that 1 in 3
excess are found, serum total testosterone and di- eastern European Jews, 1 in 4 Hispanics, 1 in 5
hydroepiandrostendione sulfate (DHEAS) levels Slavs, and 1 in 9 Italians are heterozygous carriers.9
should be determined to rule out ovarian and ad- Screening with blood 17-hydroxyprogesterone
renal androgen-producing tumors, particularly if level has become the primary form of assessment.
rapid masculinization within several months has Affected individuals will have levels many times
occurred.9 A presumptive diagnosis of polycystic higher than normal. Routine screening is recom-
ovarian disease can be made if the results of these mended for at-risk populations, for patients with
tests fall within tumor range (testosterone ⬎ 200 pedigrees containing unexplained neonatal death,
ng/dL or DHEAS ⬎ 700 ␮g/dL), excluding other or for those with genital ambiguity.
causes of anovulation.9 Acute, rapid virilization, Eugonadal anovulation will most often be man-
however, requires a full investigation even if the aged with ovulation induction through use of drugs
testosterone and DHEAS concentrations are less like clomiphene citrate. Pregnancy success rates are
than cutoff levels described. high when ovulatory dysfunction is the only infer-
In selected patients, additional screening for el- tility factor.39
evated 17-hydroxyprogesterone can also be useful
in ruling out late-onset adrenogenital syndrome
(congenital adrenal hyperplasia).38 Congenital ad- Recurrent Pregnancy Loss
renal hyperplasia is caused by a specific adrenal Today, 1 in 5 women in the United States gives
enzyme defect inherited in an autosomal recessive birth to her first baby when she is older than 35
fashion. The 21-hydroxylase defect is the most years.40 These women are at increased risk for
common and, when inherited in the severe form, aneuploid conceptions and hence have lower take-
can result in newborn ambiguity with or without home baby rates.41 Unfortunately, more than one
severe salt wasting. It has been estimated that from clinical loss is not that unusual in this age-group.
1% to 5% of women with hirsutism have late-onset Most pregnancy loss occurs in the first trimester
congenital adrenal hyperplasia. Little or no mani- and is associated with random genetic events.42
festation of the condition is evident before puberty. Habitual abortion has been classically defined as
As the adrenal glands become more active at pu- three or more consecutive losses, but the chance of
berty, progressive hirsutism and disordered menses a successful live birth after three consecutive losses
soon occur. At the clinical level patients with late- remains hopeful at 55% to 60%.9,43 These odds are
onset congenital adrenal hyperplasia are clinically improved up to 70% when habitual abortion occurs
indistinguishable from other patients with eugo- following at least one normal liveborn.9
nadal anovulation and androgen excess. It is best to customize the clinical approach to a
Management of the ovulatory dysfunction is fre- couple with recurrent pregnancy loss based on the
quently treated the same in both groups. The ge- woman’s age and level of anxiety, rather than to the
netic carrier status, however, is higher in certain number of previous miscarriages, as most evalua-

40 JABFP January–February 2001 Vol. 14 No. 1

Table 4. Habitual Abortion Considerations. tion.54 The association of early pregnancy loss with
Genetic Consider pedigree caffeine use has been controversial. The safety of
Offer karyotype and genetic counseling low levels of caffeine intake (less than 5 cups of
Environmental Eliminate tobacco, alcohol, caffeine, coffee per day) has recently been supported
occupational toxins, stress through measurement of maternal serum paraxan-
Endocrine Rule out luteal phase insufficiency, thine levels and correlation with rates of spontane-
thyroid disease, diabetes
ous abortion in women who were part of the Na-
Anatomic Consider cavity study to rule out septate
uterus, partial Asherman syndrome, tional Collaborative Perinatal Project.55 In this
incompetent cervix, leiomyomata study, only very high serum paraxanthine concen-
Infectious Cultures often inconclusive trations (equivalent to more than 6 cups per day)
Consider antibiotic treatment?
were associated with an increased abortion risk.
Immunologic Consider antiphospholipid and lupus
screening Based on available evidence, it is therefore safe to
Refer for more complex testing as reassure women about low-to-moderate caffeine
indicated intake in the first trimester.
Anesthetic gasses, certain dry-cleaning fluids,
isotretinoin (Accutane), and petrochemical occupa-
tions will result in normal findings. Obtaining a tional exposures have also been implicated.56,57 In-
family pedigree from both partners should be a first fectious agents, such as Chlamydia trachomatis,
step.44 Clinical testing should be aimed at detecting Ureaplasma urealyticum, Toxoplasma gondii, Listeria
causes that can be documented (Table 4). In ap- monocytogenes, Mycoplasma hominis, herpesvirus, and
proximately 8% of couples with recurrent loss, one cytomegalovirus, have been associated with recur-
partner will be found to carry a balanced chromo- rent loss, but causation has not been substantiated.9
somal translocation.44 Karyotyping of both part- Treatment, if rendered, has been largely empiri-
ners is particularly important if the couple has had cal.20
a malformed fetus or liveborn in addition to recur-
rent losses. Couples should be informed that nor-
mal parental karyotyping does not exclude genetic Therapy Considerations
causes, since many losses result from undetectable There are few absolutes when dealing with the
single-gene defects. If the karyotype is abnormal, infertile couple. Therapy should be directed at
referral for genetic counseling is indicated. In most shifting the couple’s fecundity curve toward that of
situations, there is a 50% chance of normal off- the normal population in their age-group. Inter-
spring in subsequent pregnancies, although gamete pretation of the literature regarding intervention-
donor therapy can be offered as an alternative.45 specific prognosis must be done cautiously. It is
Failed or faulty implantation and embryonic insufficient to look at the pregnant versus nonpreg-
growth secondary to a suboptimal endometrium nant percentages, particularly if repetitive treat-
has been postulated as a cause of recurrent preg- ment cycles are considered. Life table analysis stud-
nancy loss. Treatment approaches traditionally ies are more appropriate when comparing
have been directed at progesterone supplementa- repetitive treatment cycles, because this approach
tion or ovulation induction.46 – 48 adjusts for patient dropout rates and conceptions
Other causes of recurrent loss include müllerian that occur during early treatment cycles.58
anomalies (eg, septate uterus), intrauterine syn- Choice of therapy often comes down to issues of
echiae (Asherman syndrome), and antiphospholipid efficacy, cost, ease of use, and side effects. An esti-
syndrome, or other immune causes.49 –51 More mated 28% of all couples seeking reproductive as-
commonly, subclinical thyroid disease and uncon- sistance will have normal findings on evaluation,
trolled diabetes mellitus can also be associated with making the unexplained group a more common
pregnancy loss.52,53 Contrary to common belief, no finding in recent years. Empiric therapy options
conclusive evidence exists linking endometriosis become important in these situations, as few cou-
with an increased risk of spontaneous abortion.9 ples want to be observed after several years of
Environmental factors, such as heavy smoking trying unsuccessfully to conceive. In epidemiologic
and alcohol and coffee consumption, have been terms, couples with unexplained infertility who are
associated with an increased risk of recurrent abor- cared for without treatment have a cumulative

Infertile Couple 41
pregnancy rate of 60% to 70% within 3 years, with support, and motivations for seeking pregnancy in
some variation in rates by age and duration of the first place.66 Beyond these issues, one of the
infertility.59,60 There have been no large, random- most important factors in determining how well a
ized clinical trials investigating the efficacy of em- couple copes with infertility evaluation and treat-
piric therapy in this group, although generally an- ment is the skill level of the providers who care for
ticipated per-cycle pregnancy rates for this group them.
are 5% for timed intercourse, 10% for superovula- Psychological support is critical for all families
tion with intrauterine insemination, and 15% to who are confronted with a diagnosis of infertility. It
25% for assisted reproduction therapies.61 These should be emphasized from the initial office visit
rates must be adjusted downward for older women that infertility is a couple-family problem, and the
and will be influenced negatively as the duration of discussion should not focus entirely on medical
infertility increases. It is important for both pa- diagnosis and treatment. For the family physician
tients and providers to remain realistic about prog- involved in the care of these patients, information
nosis, considering that even if every diagnosed regarding past mental health problems, coping
problem were corrected, conception is not likely to styles, partner and family support, and basic per-
occur at a higher rate than Mother Nature nor- sonality structure is often known. This knowledge
mally allows. is valuable in the early stages of counseling, while
assessing the personal and family aspects of the
diagnosis. As partners often differ in their response
Counseling to what they are told, the impact of the information
There is no evidence that infertile couples have
will likely be felt differently. The family physician
higher levels of psychopathology compared with
can provide or refer patients for counseling to im-
fertile couples, and most cope well with excellent
prove communication between partners through-
compliance through difficult and sometimes
out this process.
lengthy evaluation and treatment efforts.62 Yet,
Anyone counseling patients regarding infertility
throughout this process it is not unusual for pa-
must first be familiar with the causes, workup, and
tients to experience some level of frustration, sad-
treatment options available to couples who are ex-
ness, loss of control, and other depressive symp-
periencing difficulty achieving pregnancy. An ini-
toms.63 Infertility, for these couples, is a life
tial assessment of their response to the diagnosis
crisis.64 Early in the evaluation, either partner
and a discussion of the implications of evaluation
might feel guilt or shame regarding his or her
contribution to the diagnosis that renders the cou- and treatment should take occur. At the outset,
ple infertile. As treatment begins, couples can ex- anticipatory guidance should be provided regarding
perience cycles of hope and despair with each pass- the expected emotional responses the couple can
ing menstrual cycle. As the duration of treatment experience and the symptoms that might occur
lengthens, psychological distress is likely to in- while on specific hormonal and other treatment
crease. In some cases, patients might become ob- regimens. The couple should be reassured that the
sessed with their infertility, “making a career out of feelings each partner might experience are normal.
pursuit of pregnancy.”66 This obsession is detri- Patients should be encouraged from the beginning
mental to other aspects of their lives, from which to attend to their own personal care needs, includ-
marital and sexual problems frequently result. Ad- ing nutrition, rest, exercise, and work schedules.
ditional behaviors associated with infertile couples Tips on how to deal with family and friends, as well
include the avoidance of family functions in which as how to respond in public gatherings, can be
other children are present and unrealistic optimism helpful for couples who do not raise this as an issue
regarding their prognosis in light of appropriately themselves. It is important to differentiate between
delivered information to the contrary. the common dysphoria that occurs among infertile
How well couples cope with the psychological couples and true dysfunction that can result during
stress of infertility depends on many factors, in- the process of an infertility evaluation.62 The fam-
cluding age at diagnosis, basic personality struc- ily physician should be prepared to assist in referral
ture, coping styles and defense mechanisms, preex- to appropriate counseling resources should a more
isting mental health diagnoses, family and friend formal support mechanism be required.

42 JABFP January–February 2001 Vol. 14 No. 1

 Finally, it is important to recognize that an of- Many of these cases have been settled out of court.
ten-neglected goal of counseling couples is to help In a recent Supreme Court decision, Bragdon v
them deal with ending unsuccessful therapy. This Abbott, the court confirmed the viewpoint that
decision can be particularly difficult for the unex- reproduction constitutes a major life activity under
plained infertile group, because there is no obvious the ADA.70 It is hoped that more test cases will
pathologic condition on which to base the decision expand access to infertility therapy.
to end therapy. Couples need to be able to share
their feelings in a safe environment so they can
make the right personal decision about stopping
Summary
The initial evaluation of a couple that is unable to
therapy or initiating adoption procedures. Support
conceive can be easily and effectively conducted in
groups, such as those organized by RESOLVE,
an ambulatory, primary care setting. As more cou-
Inc, can be helpful in this regard. Patients consid-
ples are seeking reproductive assistance, primary
ering adoption must prepare for the rigors of social
care providers will frequently be asked to partici-
agency evaluation and can become disappointed
pate in the early stages of this treatment. Many
early in the process. An alternative is private adop-
conditions once considered untreatable can now be
tion.67– 69
routinely corrected, typically in conjunction with a
referral specialist. Throughout the process, the
family physician is in a unique position to provide
Ethics, Insurance, and the Law
patient education and ongoing psychosocial sup-
The concept of patient autonomy would dictate
port to these couples.
that the role of providers is to offer medically ap-
propriate technology to the infertile patient with-
out making judgments about who should be a par- References
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Infertile Couple 45

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