Approach to the Infertile Couple

Shana L. Birnbaum

From 10% to 15% of US couples in their childbearing years are infertile, defined as a couple that has been engaging in regular sexual intercourse without conceiving, without use of contraception for at least 1 year in a woman under age 35 years or for at least 6 months in a woman over age 35 years. After 1 year, approximately 85% of couples attempting conception will succeed, at a rate of around 25% per cycle for the first three cycles, decreasing in subsequent cycles. Although the prevalence of infertility has remained relatively stable over the last 30 years, new technologies, rising expectations, and delayed childbearing have produced significant increases in the numbers of couples seeking help. The primary care clinician is often the first to be consulted and is responsible for initiating a medical evaluation of the couple, along with identifying any psychological or socioeconomic barriers to conception. Although treatment is usually carried out by practitioners specializing in infertility, the primary care physician should become proficient in performing the initial assessment and knowing when referral is indicated. Principal tasks include providing accurate advice and uncovering treatable etiologies.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5 and 6)

Any disorder involving the male or female reproductive system may interfere with function to a degree sufficient to cause infertility. Although the woman is frequently the first to seek consultation for infertility, a full evaluation needs to focus on both partners; invasive testing in a woman should not be done before her partner has undergone basic evaluation, given that up to 40% of infertility is attributable at least in part to male factors.

Men

Male infertility can be classified in terms of gonadal, gonadotropic (hypothalamic or pituitary), obstructive, and functional etiologies and considered according to whether the man presents with azoospermia, oligospermia, or normal sperm counts.

Azoospermic Etiologies

Patients with primary hypogonadism affecting both spermatogenesis and testosterone synthesis have azoospermia, a low testosterone level, and elevations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Klinefelter syndrome is the archetype, usually characterized by two × chromosomes and one Y chromosome; it occurs in up to 1 in 500 phenotypic males. Even more common are Y chromosome microdeletions and translocations, which are increasingly recognized as an etiology of azoospermia and severe oligospermia; they are seen in up to 20% of infertile men.

Men with predominantly germinal compartment failure are also azoospermic but manifest relatively normal testosterone and normal LH and elevated FSH levels. Sertoli cell-only syndrome and adult mumps orchitis and cancer therapy are among the more common congenital and acquired varieties, respectively. In a study comparing childhood and adolescent cancer survivors with sibling control subjects, overall relative fertility was 85%, with radiation therapy below the diaphragm reducing it by 25% and alkylating therapy alone causing a 40% reduction.

Hypogonadotropic hypogonadism is another cause of azoospermia that may be congenital or acquired (Table 120-1). Patients present with azoospermia and low levels of FSH, LH, and serum testosterone. Congenital disease is often associated with anosmia (Kallmann syndrome, congenital gonadotropin-releasing hormone [GnRH] deficiency) but may be associated with other rarer disorders. Hereditary hemochromatosis, a relatively common disorder, may cause postpubertal hypogonadotropic hypogonadism through the mechanism of excess iron deposition in the pituitary. Pituitary tumors account for much of the acquired disease; a prolactinoma is the most frequent etiology. Large sellar tumors (e.g., craniopharyngioma) can lead to panhypopituitarism, with features of hypothyroidism and adrenal insufficiency dominating the clinical picture. Drugs (including alcohol, opiates, and marijuana) can interfere with hypothalamic-pituitary function, as can any serious systemic illness, malnutrition, or obesity.

Azoospermia in association with normal levels of LH, FSH, and testosterone characterizes retrograde ejaculation (due to diabetes or drugs) and obstruction of the ejaculatory system. There may be congenital or acquired obstruction of the epididymis and vas deferens, or the vas deferens may be congenitally absent due to mutations in chloride channels similar to those seen in cystic fibrosis. Most other types of obstruction, including that resulting from sexually transmitted infections, are more proximal, giving normal testicular size and normal semen fructose.

Oligospermic Etiologies

Patients with a large varicocele may present with the typical “bag of worms” appearance to the testicle, but at times, the only manifestation is a faint pulsation along the spermatic vein on Valsalva maneuver or coughing. The varicocele may be unilateral (usually on the left) or bilateral. The mechanism by which varicocele results in decreased fertility is poorly understood. Varicocele is present in up to 40% of men with infertility, but 10% to 15% of fertile men also have a varicocele, prompting some authorities to question the association. Repair of a palpable varicocele by spermatic vein ligation improves sperm quantity and function, although beneficial effect on fertility has not been consistently demonstrated.

Another large group of oligospermic patients with normal LH and testosterone have no detectable pathology and are labeled idiopathic. The condition results in a quantitative or qualitative abnormality of spermatogenesis without any identifiable anatomic or endocrinologic precipitant. FSH is normal unless the sperm count falls below 20 million/mL, in which case it may begin to rise. A proportion of these men with idiopathic oligospermia are found to have Y chromosome abnormalities on genetic analysis. The acquired forms of selective tubular damage (chemotherapy, irradiation, adult mumps) may leave the patient oligospermic rather than azoospermic.

Men with a history of unilateral or bilateral cryptorchidism often have spermatogenic defects, which are believed to be congenital and related to developmental defects. They may present with oligo- or azoospermia, most typically with normal LH but elevated FSH levels. Such men are at elevated relative risk for testicular cancer, although the absolute risk is still low.

In milder forms of acquired hypothalamic-pituitary dysfunction, some spermatogenesis may be preserved. FSH and LH are low to low-normal, and testosterone is low. Prolactin may be elevated due to a microadenoma. In partial androgen resistance,
testosterone and LH are elevated, whereas FSH remains normal. Depending on the degree of insensitivity, patients may present with ambiguous external genitalia, gynecomastia, and hypogonadism. Exogenous steroid use may also lead to oligospermia with low serum LH; testosterone levels may be normal, elevated, or low, depending on the ability of the testosterone assay to measure the exogenous androgen.

TABLE 120-1 Important Causes of Male Infertility

Hypothalamic/Pituitary
	Prolactinoma
	Idiopathic
	Drugs (e.g., alcohol, marijuana)
Testicular
Klinefelter syndrome/Y chromosome microdeletion or translocation
	Sertoli cell-only syndrome
	Irradiation
	Adult mumps
	Alkylating agents
Anatomic/Functional
	Obstruction of epididymis or vas
	Impotence
	Retrograde ejaculation
	Infection
	Antisperm antibodies
	Idiopathic defects in sperm quantity or quality

Etiologies with Normal Sperm Counts

Many patients demonstrate abnormal sperm morphology or motility and suffer from many of the same conditions as those with oligospermia (e.g., varicocele, minor Y chromosome abnormalities). In addition, genitourinary tract infection may cause qualitative sperm changes; leukocytes sometimes appear in the semen, although their relation to fertility is unclear. Symptomatic infection can lead to subsequent obstruction of the efferent ducts, lowering sperm counts, and should be treated. Antisperm antibodies are noted in some patients, and an autoimmune mechanism may be clinically important when antibodies are present in high concentrations and cause sperm agglutination. Men who have had a vasectomy reversal or testicular trauma are at particularly high risk.

Impotence or erectile dysfunction ranks as a leading, although frequently overlooked, etiology. Hormone concentrations and sperm parameters are usually normal in “functional” variants (although depression and situational stress can transiently reduce sperm counts). In organic etiologies of impotence, these parameters reflect the underlying pathology (see Chapters 132 and 229). Anatomic anomalies, such as proximal location of the urinary meatus, may lead to infertility because of deposition of sperm and semen too far from the cervical os.

Women

Disorders of Ovulation

Disorders of ovulation are among the most frequent causes of failure to conceive, making up 20% to 40% of cases in which a female factor is responsible for the infertility. Anovulatory bleeding (irregular menses), amenorrhea, or infertility may be the presenting complaint. Polycystic ovary syndrome (PCOS) and various forms of hypothalamic dysfunction account for most cases (see Chapters 111 and 112). Pathophysiologically, the normal pattern of GnRH release is disrupted, impairing the normal midcycle LH surge and ovulation. Occasionally, an androgen-producing tumor or late-onset congenital adrenal hyperplasia may present with anovulation and infertility. Treatment of the primary disorder can restore fertility, as can ovulation induction with medication.

Diminished ovarian reserve is a problem as maternal age increases and now recognized as an important contributor to infertility as the age at which women have their first child increases in the United States. A higher incidence of chromosomal abnormalities is partially responsible, but declining oocyte quality with fewer, lower-quality oocytes is probably more significant. Premature ovarian failure, which may be autoimmune or idiopathic, occurs when ovarian reserve fails before the expected age of menopause. If it occurs before age 30 years, the possibility of mosaic Turner syndrome or a partial × chromosome deletion should be investigated. An increasingly recognized cause of premature ovarian failure is a premutation in the fragile × syndrome gene (FMR1). An important acquired source of ovarian failure is cancer therapy in children and adolescents (see Azoospermic Etiologies). In the study noted earlier comparing survivors of childhood and adolescent cancers with their siblings, overall relative fertility for women was 85%, with radiation therapy below the diaphragm reducing it by 25%. Conversely, alkylating therapy had relatively little effect.

Tubal Disorders

Tubal disorders account for about 25% of cases. Pelvic inflammatory disease (particularly indolent nongonococcal forms such as that due to Chlamydia trachomatis; see Chapters 116 and 117) is the leading cause of tubal damage. In a prospective study, 12% of those with a single episode of salpingitis had tubal occlusion, 35% of those with two infections had occlusion, and 75% of those with three or more had occlusion. Women without a known history of acute pelvic inflammatory disease who are found to have tubal occlusion have higher rates of antibodies against the agents that cause chlamydia and gonorrhea, suggesting that asymptomatic salpingitis occurs frequently. Other pelvic and abdominal infections or surgeries (such as a ruptured appendix) may also lead to tubal adhesions. Postpartum infection has an association with tubal occlusion, as does infection after induced abortion, particularly if it is inadequately treated or unrecognized. Endometriosis, found with much more frequency in infertile women (38% vs. 5% in one study), may cause tubal obstruction and uterine disturbances (some experts have also hypothesized an inflammatory response to account for the lower fertility rates seen in women with milder forms of endometriosis).

Uncommon causes of tubal adhesions include pelvic trauma from vehicular accidents, inflammatory bowel disease, tuberculosis, and schistosomiasis. In general, processes that cause adhesions rather than tubal epithelial damage seem to have a better prognosis.

Uterine Pathology

Uterine pathology represents about 5% of cases. Congenital anomalies, such as absence or duplication of the uterine fundus, often present as recurrent pregnancy loss. Complete duplication of cervix and uterus tends to diminish fertility but less so than anomalies causing distortion of a single uterine cavity. Septate and deeply arcuate uteri may be better able to maintain a pregnancy after hysteroscopic or operative repair. Uterine fibroids and endometriosis may distort or obstruct the uterine cavity, causing infertility or pregnancy loss. Resection and reresection of fibroids have been surprisingly successful. The forgotten intrauterine device is occasionally a cause of infertility.

Cervical Factors

Cervical factors may lead to inability to carry a pregnancy to term as well as difficulty with conception. Cervical incompetence may lead to repeated abortion or later-trimester pregnancy losses. The incompetence can result from inadequate innervation, disturbances in synthesis or breakdown of prostaglandin,
previous cervical procedures (such as a loop excision for cervical dysplasia), or defects in muscle and collagen fibers.

The precise role of cervical mucus is not well understood, but normal viscosity and ferning are essential to conception and represent evidence of adequate estrogen stimulation and response.

Both Partners

Interpersonal problems (see Chapter 229) are an important etiologic factor because they may lead to sexual dysfunction or inactivity. The desire for children may not be shared equally by both partners, there may be anxiety over how family responsibilities will interfere with career development, or one partner may not want to lose the economic and social freedom of being a childless couple. Transient situational problems also arise; the young professional person may be under considerable job pressure, and travel may interfere with optimal timing of intercourse for conception or lead to hypothalamic dysfunction.

DIFFERENTIAL DIAGNOSIS (1, 2, 3, 4 and 5)

In about one third of instances, a male factor is the predominant etiology. In another one third, a female factor predominates. In the remainder, either the cause resides with both partners or the etiology is unknown; several unfavorable factors may contribute to subfertility in a particular couple. In almost one half of cases attributed to a male factor, there is either a quantitative or a qualitative sperm defect of unknown etiology. Among female factors, ovulatory disturbances account for up to 40%, tubal disorders for 10% to 30%, cervical factors for 10%, and uterine factors for about 5%. Tables 120-1 and 120-2 list some of the most important etiologies.