Infertility is defined as one year of frequent, unprotected intercourse during which pregnancy has not occurred. According to data from the National Survey of Family Growth, an estimated 10 to 15 percent of couples in the United States are infertile.¹ Many of these couples present first to their primary care physician, who may initiate evaluation and treatment. Infertility can be attributed to any abnormality in the female or male reproductive system. In most cases, the etiology is distributed fairly equally among male factors, ovarian dysfunction, and tubal factors. A smaller percentage of cases are attributed to endometriosis, uterine or cervical factors, or other causes. In approximately one fourth of couples, the cause is uncertain and is referred to as “unexplained infertility” (Table 1).² The etiology is multifactorial for some couples.

Evaluation

In general, an infertility evaluation is initiated after 12 months of unprotected intercourse during which pregnancy has not been achieved.^3,4 Earlier investigation may be considered when historical factors, such as previous pelvic inflammatory disease or amenorrhea, suggest infertility, although physicians should be aware that earlier evaluation may lead to unnecessary testing and treatment in some cases.^3,4 Evaluation also may be initiated earlier when the female partner is older than 35 years, because fertility rates decrease and spontaneous miscarriage and chromosomal abnormality rates increase with advancing maternal age.^5,6 Partners should be evaluated together and separately, because each person may want to reveal information about which their partner is unaware, such as previous pregnancy or sexually transmitted disease.⁷

EVALUATION OF THE COUPLE

Important topics to address include the frequency and timing of intercourse, and the use of lubricants or other products that may impair fertility.^8–10 The duration of infertility and history of previous fertility for the couple and for each partner individually also need to be addressed, because they affect prognosis and may help in determining etiology.^2,7

EVALUATION OF THE MALE PARTNER

Any condition that results in impaired sperm quality, quantity, or both can lead to male factor infertility. Testicular failure or dysfunction, also referred to as primary hypogonadism, is the most common identifiable cause.¹¹ Less common causes are hypothalamic-pituitary dysfunction, also referred to as secondary hypogonadism, and conditions that affect sperm transport.¹¹ The etiology remains unclear in nearly one half of cases (Table 2).^4,7,11–13

Important historical and physical examination details and laboratory tests in the evaluation of the male partner are outlined in Table 3.^4,7,12,13 Normal semen parameters, as established by the World Health Organization, are shown in Table 4.¹² If hypogonadism is suspected based on the semen analysis (severe oligospermia or azoospermia), evaluation of morning follicle-stimulating hormone (FSH) and total serum testosterone levels can help distinguish between primary and secondary causes.⁷ Elevated levels of FSH in the presence of low testosterone levels correlate with primary hypogonadism. Low levels of both hormones suggest secondary hypogonadism. Measurement of prolactin levels is indicated if secondary hypogonadism is suspected, to rule out hyperprolactinemia as the underlying cause.⁷

In patients with a low volume of ejaculate, postejaculatory urinalysis and transrectal ultrasonography may be performed to rule out retrograde ejaculation and ejaculatory duct obstruction, respectively.⁴ Scrotal ultrasonography also can be helpful in evaluating suspected testicular and scrotal abnormalities such as hydroceles and tumors.¹³ Specialized semen tests, including testing for sperm vitality, sperm culture, and analysis of sperm biochemistry and function, should be considered if evaluation of the female partner fails to reveal a cause.¹²

EVALUATION OF THE FEMALE PARTNER

As previously noted, causes of infertility in the female partner include disorders of ovulation, tubal disease, and uterine or cervical factors.^2,3 Endometriosis also has been implicated as an independent cause of infertility (Table 5).^2,3,7,14,15

Important historical and physical examination details, laboratory tests, and additional studies to consider for the female partner are outlined in Table 6.^{3,5,7,8,16–21} Details of the menstrual cycle can help determine whether the cycles are ovulatory or anovulatory. A menstrual cycle length of 22 to 35 days suggests ovulatory cycles, as does the presence of mittelschmerz and premenstrual symptoms.¹⁴ During review of the woman's substance use history, caffeine intake should be assessed; high levels of caffeine use by the female partner have been associated with lower fertility rates.¹⁵

Basal body temperature charting is a simple and inexpensive means of documenting ovulation. In ovulatory cycles, the first morning body temperature often increases from 97°F to 98°F (36.1°C to 36.6°C) to greater than 98°F as a woman's menstrual cycle progresses from the follicular phase to the luteal phase. The rise in temperature is generally noted two days after a surge in luteinizing hormone (LH) occurs.^3,22 In recent years, basal body temperature charting for documentation of ovulation has largely been replaced by use of the less cumbersome urinary LH prediction kit. During ovulatory cycles, an LH surge can be detected in the urine 14 to 48 hours before ovulation.^8,16 Additionally, a single midluteal progesterone level, measured at the midpoint between ovulation and the start of the next menstrual cycle, can provide further confirmation as well as information about the adequacy of the luteal phase. A level greater than 6 ng per mL (19 nmol per L) implies ovulation and normal corpus luteal production of progesterone.¹⁷ Of the three tests, the urinary LH kit provides the greatest accuracy in predicting ovulation.¹⁷

If ovulatory dysfunction is suspected based on the results of initial evaluation, focused laboratory investigation and other testing can help determine the underlying cause. Testing in patients with amenorrhea, irregular menses, or galactorrhea should involve checking FSH, prolactin, and thyroid-stimulating hormone (TSH) levels.^7,18 Low or normal FSH levels are most common in patients with polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea.¹⁸ The presence or absence of obesity and androgenization, generally occurring in women with PCOS, can be used to distinguish between the two disorders.¹⁸ The usefulness of the progesterone challenge test is limited because of high false-positive and false-negative rates with respect to the presence or absence of estrogen production.¹⁸ A high FSH level correlates with ovarian failure.¹⁸ Evaluation of prolactin level is useful to rule out pituitary tumor, and measurement of TSH is necessary to rule out hypothyroidism.¹⁸ Measurement of 17α-hydroxyprogesterone and serum testosterone levels is helpful in evaluating patients with hyperandrogenism for late-onset congenital adrenal hyperplasia and androgen-secreting tumors.²³

Women older than 35 years may benefit from testing of FSH and estradiol levels on day 3 of their menstrual cycle to assess ovarian reserve.⁵ An FSH level of less than 10 mIU per mL (10 IU per L), combined with an estradiol level of less than 80 pg per mL (294 pmol per L), suggests favorable follicular potential.⁵ The clomiphene citrate challenge test, in which the FSH level is obtained on day 3 of the cycle, then again on day 10 after administration of clomiphene citrate (Clomid; 100 mg per day) on days 5 to 9, also can be helpful in assessing ovarian reserve.⁵ Normal and abnormal values vary by laboratory. Obtaining an antral follicle count via transvaginal ultrasonography can be useful in evaluating ovarian reserve; it also can help predict ovarian responsiveness to gonadotropin stimulation, which is useful when considering treatment options.^5,19 The optimal test to assess ovarian reserve has not yet been determined.⁵ Circulating inhibin B levels and the gonadotropin-releasing hormone test are not recommended for routine use in the assessment of ovarian reserve because of limited data regarding their prognostic value.⁵

If the initial history and physical examination suggest tubal dysfunction or a uterine abnormality, or if other testing has failed to reveal an etiology, hysterosalpingography is indicated.^3,7 The contour of the uterine cavity, including the presence or absence of any abnormalities, as well as tubal patency can be assessed. Ultrasonography can also be used to evaluate for pelvic pathology.³ If abnormalities are detected, hysteroscopy and/or laparoscopy, depending on the location of the abnormality, can be pursued for confirmation and further assessment.^3,7 Laparoscopy may be performed as a final step in the infertility evaluation because it can reveal additional causes not otherwise seen, including endometriosis and pelvic adhesions.^3,7,20 The use of postcoital testing to evaluate for factors of cervical mucus has been abandoned by most physicians because of its lack of effect on pregnancy outcome.²¹

Management

TREATMENT OF THE COUPLE

Ideal coital frequency, consisting of intercourse on multiple days during the “fertile window,” which includes the five days preceding and the day of anticipated ovulation, should be reviewed with the couple.⁸ Using the Clear Plan Easy Fertility Monitor, checking for E-type vaginal mucous discharge (i.e., clear, stringy), or both, may be the most helpful in determining optimal timing of intercourse, because they reflect the increase in estrogen before the LH surge and are more prospective than basal body temperature charting or the urinary LH kit.⁸

The importance of avoiding lubricants and douches should be stressed.¹⁰ Both partners should be encouraged to avoid alcohol consumption and use of tobacco and street drugs and, as mentioned earlier, the woman should be counseled to limit caffeine intake.^3,4,7,15 The use of fertility-impairing medications should be avoided by both partners if possible (Tables 3 and 6).^{2,3,7,12,14,15}

The couple should be offered emotional support because infertility often produces significant stress and sadness in one or both partners. Groups such as RESOLVE: the National Fertility Association can provide additional support and information to assist the couple (http://www.resolve.org).

MANAGEMENT OF MALE FACTOR INFERTILITY

Dopamine agonists such as bromocriptine (Parlodel) can be useful in patients with hyperprolactinemia.²⁴ Agents to treat erectile dysfunction can be employed if indicated.²⁵ If obstruction or a varicocele is found to be associated with seminal fluid abnormalities, surgical repair may be pursued. Varicocele repair has been shown to improve semen parameters, although it has not yet been shown to increase the chance of conception.^26,27 In general, seminal fluid abnormalities warrant referral to a fertility specialist for treatment. Depending on findings, treatment options available to the specialist include gonadotropin injections, intrauterine insemination, and in vitro fertilization (IVF) with or without intracytoplasmic sperm injection, using testicular sperm extraction if indicated.^25,28

MANAGEMENT OF OVULATORY DYSFUNCTION

Underlying causes of ovulatory dysfunction, such as thyroid dysfunction, should be corrected if possible.²⁹ As with men, women who have hyperprolactinemia can be treated with dopaminergic agents, which may restore ovulation.³⁰ Insulin-sensitizing agents, most commonly metformin (Glucophage), have been shown to increase ovulation and pregnancy rates in patients with PCOS, although these agents are not yet approved by the U.S. Food and Drug Administration (FDA) for the treatment of infertility.³¹ Laparoscopic ovarian drilling for ovulation induction also may be considered for patients with PCOS if other treatments are unsuccessful.^29,32

In most women with ovulatory dysfunction without evident cause or that is not otherwise correctable, the condition can be managed with use of the oral ovulation-inducing agent clomiphene citrate.²⁹ Clomiphene citrate can be used in patients with PCOS as well, with or without the coadministration of insulin-sensitizing agents.³¹ Treatment with clomiphene citrate is ineffective in patients with ovulatory dysfunction caused by hypothalamic amenorrhea, however, because its mechanism of action occurs at the hypothalamus.²⁹ These patients are more likely to respond to gonadotropin therapy.¹⁴ Women with limited ovarian reserve also are unlikely to benefit from ovulation induction. Currently, only oocyte donation has been proven successful for these patients.⁵

Clomiphene citrate is generally well tolerated and effective; 80 percent of appropriately selected patients will ovulate with this treatment.²⁹ Major risks associated with the use of clomiphene citrate include ovarian hyperstimulation syndrome and twinning. Higher-order multiple gestation is a rare consequence.²⁹ Generally, a dosage of 50 mg per day is administered starting on day 3 to day 5 of the menstrual cycle and is continued for five days.²⁹ Documentation of ovulation can be accomplished fairly easily with basal body temperature charting or use of a urinary LH kit.²⁹ If a dosage of 50 mg per day is insufficient to induce ovulation, it can be increased to 100 mg per day. Higher dosages generally should be managed by a fertility specialist because 100 mg per day is the maximal dosage approved by the FDA.²⁹ If clomiphene citrate therapy is unsuccessful, additional treatment options include IVF and injectable ovulation-inducing agents such as human menopausal gonadotropin, exogenous FSH, and gonadotropin-releasing hormone.³³

MANAGEMENT OF TUBAL, UTERINE, AND PELVIC DISEASE

Tubal disease may be treated with tubal reparative surgery, although success rates are generally low and are compromised by increased risk of subsequent ectopic pregnancy.^14,34 IVF is an alternative, especially in patients with markedly damaged tubes.¹⁴ Patients with endometriosis may benefit from laparoscopic ablation or laparotomy, depending on the severity of disease.^35,36 Ovulation induction with or without intrauterine insemination and IVF also can be used in these patients.^35,37,38

MANAGEMENT OF UNEXPLAINED OR PERSISTENT INFERTILITY

Options for patients with unexplained infertility include intrauterine insemination, clomiphene citrate therapy, and intrauterine insemination with either clomiphene citrate or gonadotropin therapy.^39,40 To date, the benefit of IVF has not been proven in patients with unexplained infertility.⁴¹ IVF may be useful in patients with persistent infertility in whom treatments for specific diagnoses have been unsuccessful.¹⁴

PROGNOSIS

The overall likelihood of successful treatment for infertility is nearly 50 percent, but this varies by cause, age of the female partner, history of previous fertility, and duration of infertility.⁴² Of the various etiologies, infertility attributed to ovulatory dysfunction has the best prognosis, with treatment success rates approaching 50 percent overall. Infertility caused by tubal factors or severe endometriosis has the least likelihood for success (i.e., 21 and 17 percent, respectively).⁴² A shorter duration of infertility and previous fertility increase the chance of achieving pregnancy, as does age younger than 30 years in the female partner.^2,7,42