About 40%-50% of infertility problems are said to be due to dysfunction of the male reproductive system. Male infertility can be due to hormonal etiology (either lack of gonadotropin or suppression of spermatogenesis), nonhormonal factors affecting spermatogenesis, primary testicular disease, obstruction to sperm passages, disorders of sperm motility or viability or presence of antisperm antibodies (see the box on this page). About 30%-40% is reported to be associated with varicocele. Diagnosis and investigation of etiology usually begins with physical examination (with special attention to the normality of the genitalia and the presence of a varicocele), semen analysis (ejaculate quantity, number of sperm, sperm morphology, and sperm motility), and serum hormone assay (testosterone, LH, and FSH).

Some Important Causes of Male Infertility, Classified According to Primary Site of the Defect

Insufficient hypothalamic gonadotropin (hypogonadotropic eunuchoidism)
Insufficient pituitary gonadotropins (isolated LH deficiency [“fertile eunuch”] or pituitary
Prolactin-secreting pituitary adenoma
Excess estrogens (cirrhosis, estrogen therapy, estrogen-producing tumor)
Excess androgens
Excess glucocorticosteroids
Nonhormonal factors affecting testis sperm production
Poor nutrition
Diabetes mellitus
Excess heat in area of testes
Stress and emotion
Drugs and chemicals
Febrile illnesses
Cryptochism(undescended testis, unilateral or bilateral)
Spinal cord injuries
Primary testicular abnormality
Maturation arrest at germ cell stage
“Sertoli cell only” syndrome
Klinefelter’s syndrome and other congenital sex chromosome disorders
Testicular damage (radiation, mumps orchitis, inflammation, trauma)
Myotonic dystrophy
Posttesticular abnormality
Obstruction of sperm passages
Impaired sperm motility
Antisperm antibodies

Testicular function tests. Male testicular function is based on formation of sperm by testicular seminiferous tubules under the influence of testosterone. FSH is necessary for testicular function because it stimulates seminiferous tubule (Sertoli cell) development. Testosterone secretion by the Leydig cells (interstitial cells) of the testis is necessary for spermatogenesis in seminiferous tubules capable of producing sperm. LH (in males sometimes called “interstitial cell-stimulating hormone”) stimulates the Leydig cells to produce testosterone. Testosterone is controlled by a feedback mechanism whereby testosterone levels regulate hypothalamic secretion of GnRH, which, in turn, regulates pituitary secretion of LH. The adrenals also produce androgens, but normally this is not a significant factor in males. In classic cases, serum levels of testosterone and gonadotropins (LH and FSH) can differentiate between primary testicular abnormality (failure of the testis to respond to pituitary gonadotropin stimulation, either congenital or acquired) and pituitary or hypothalamic dysfunction (either congenital or acquired). In primary gonadal (testis) insufficiency, pituitary gonadotropin levels are usually elevated. Of the various categories of primary gonadal insufficiency, the Klinefelter’s xxy chromosome syndrome in its classic form shows normal FSH and LH gonadotropin levels during childhood, but after puberty both FSH and LH levels are elevated and the serum testosterone level is low. Klinefelter’s syndrome exists in several variants, however, and in some cases LH levels may be within reference range (single LH samples also may be confusing because of the pulsatile nature of LH secretion). Occasionally patients with Klinefelter’s syndrome have low-normal total serum testosterone levels (due to an increase in SHBG levels) but decreased free testosterone levels. Elevated pituitary gonadotropin levels should be further investigated by a buccal smear for sex chromatin to elevate the possibility of Klinefelter’s syndrome. Some investigators may perform a chromosome analysis because of possible inaccuracies in buccal smear interpretation and because some persons with Klinefelter’s syndrome have cell mosaicism rather than the same chromosome pattern in all cells, or a person with findings suggestive of Klinefelter’s syndrome may have a different abnormal chromosome karyotype. In the “Sertoli cell only syndrome,” testicular tubules are abnormal but Leydig cells are normal. Therefore, the serum FSH level is elevated but LH and testosterone levels are usually normal. In acquired gonadal failure (due to destruction of the testicular tubules by infection, radiation, or other agents), the FSH level is often (but not always) elevated, whereas LH and testosterone levels are often normal (unless the degree of testis destruction is sufficient to destroy most of the Leydig cells, a very severe change). In secondary (pituitary or hypothalamic) deficiency, both the pituitary gonadotropin (FSH and LH) and the testosterone levels are low.

Although serum testosterone is normally an indicator of testicular Leydig cell function and, indirectly, of pituitary LH secretion, other factors can influence serum testosterone levels. The adrenal provides much of the precursor steroids for testosterone, and some types of congenital adrenal hyperplasia result in decreased levels of testosterone precursors. Cirrhosis may decrease serum testosterone levels. Increase or decrease of testosterone-binding protein levels may falsely increase or decrease serum testosterone levels, since the total serum testosterone value is being measured, whereas assay of free (unbound) testosterone is not affected.

Stimulation tests. Stimulation tests are available to help determine which organ is malfunctioning in equivocal cases.

1. HCG directly stimulates the testis, increasing testosterone secretion to at least twice baseline values.
2. Clomiphene stimulates the hypothalamus, producing increases in both LH and testosterone levels. The medication is given for 10 days. However, clomiphene does not stimulate LH production significantly in prepubertal children. Serum testosterone and LH values must be close to normal pubertal or adult levels before the test can be performed, and the test can be used only when there is a mild degree of abnormality in the gonadal-pituitary system.
3. The GnRH stimulation test can directly evaluate pituitary capability to produce LH and FSH and can indirectly evaluate testicular hormone-producing function that would otherwise depend on measurement of basal testosterone levels. Normally, pituitary LH stimulates testosterone production from Leydig cells of the testis, and the amount of testosterone produced influences hypothalamic production of GnRH, which controls pituitary LH. When exogenous (test) GnRH is administered, the pituitary is stimulated to produce LH. The release of testosterone from the testis in response to LH stimulation inhibits further LH stimulation to some degree. In most male patients with primary gonadal failure, basal serum LH and FSH become elevated due to lack of inhibitory feedback from the testis. However, some patients may have basal serum LH and FSH levels in the lower part of the population reference range, levels that are indistinguishable from those of some normal persons; although preillness values were higher in these patients, their preillness normal levels are rarely known. In these patients, a GnRH stimulation test may be useful. Some investigators have found that the degree of inhibition of LH production in response to GnRH administration is more sensitive in detecting smaller degrees of testicular hormone production insufficiency than basal LH levels. The decreased testosterone levels decrease feedback inhibition on the hypothalamus and administration of GnRH results in an exaggerated LH or FSH response (markedly elevated LH and FSH levels compared to levels in normal control persons). The test is performed by obtaining a baseline serum specimen for LH and FSH followed by an intravenous (IV) bolus injection of 100 µg of synthetic GnRH. Another serum specimen is obtained 30 minutes later for LH and FSH. Certain factors can influence or interfere with GnRH results. Estrogen administration increases GnRH effect by sensitizing the pituitary, and androgens decrease the effect. Patient sex and age (until adult pulsatile secretion schedule is established) also influence test results. When used as a test for pituitary function, some patients with clinically significant degrees of failure show a normal test result; therefore, only an abnormal result is definitely significant.

Semen analysis. Semen analysis is an essential part of male infertility investigation. Semen findings that are highly correlated with hypofertility or infertility include greatly increased or decreased ejaculate volume, very low sperm counts, greatly decreased sperm motility, and more than 20% of the sperm showing abnormal morphology. However, the World Health Organization (WHO) recently changed its definition of semen morphologic abnormality, and now considers a specimen abnormal if more than 70% of the sperm have abnormal morphology. One particular combination of findings is known as the “stress pattern” and consists of low sperm count, decreased sperm motility, and more than 20% of the sperm being abnormal in appearance (especially with an increased number of tapering head forms instead of the normal oval head). The stress pattern is suggestive of varicocele but can be due to acute febrile illness (with effects lasting up to 60 days), some endocrine abnormalities, and antisperm agents. An abnormal semen analysis should be repeated at least once after 3 weeks and possibly even a third time, due to the large variation within the population and variation of sperm production even within the same person as well as the temporary effects of acute illness. Most investigators recommend that the specimen be obtained 2-3 days after regular intercourse to avoid artifacts that may be produced by prolonged sperm storage. The specimen should be received by the laboratory by 1 hour after it is obtained, during which time it should be kept at room temperature.

Semen analysis: sperm morphology

Fig. 31-1 Semen analysis: sperm morphology. a, acrosome; b, nucleus (difficult to see); c, post-acrosomal cap; d, neckpiece; e, midpiece (short segment after neckpiece); f, tail. A, normal; B, normal (slightly different head shape); C, tapered head; D, tapered head with acrosome deficiency; E, acrosomal deficiency; F, head vacuole; G, cytoplasmic extrusion mass; H, bent head (bend of 45° or more); I, coiled tail; J, coiled tail; K, double tail; L, pairing phenomenon (sperm agglutination); M, sperm precursors (spermatids); N, bicephalic sperm.

Testicular biopsy. Testicular biopsy may be useful in a minority of selected patients in whom no endocrinologic or other cause is found to explain infertility. Most investigators agree that complete lack of sperm in semen analysis is a major indication for biopsy but disagree on whether biopsy should be done if sperm are present in small numbers. Biopsy helps to differentiate lack of sperm production from sperm passage obstruction and can suggest certain possible etiologies of testicular dysfunction or possible areas to investigate. However, none of the histopathologic findings is specific for any one disease. The report usually indicates if spermatogenesis is seen and, if so, whether it is adequate, whether there are normal numbers of germ cells, and whether active inflammation or extensive scarring is present.

Serum antisperm antibody studies. In patients with no evidence of endocrine, semen, or other abnormality, serum antisperm antibody titers can be measured. These studies are difficult to perform and usually must be done at a center that specializes in reproductive studies or therapy. Serum antisperm antibodies are a common finding after vasectomy, being reported in about 50% of cases (literature range, 30%-70%). The incidence and significance of serum antisperm antibodies in couples with infertility problems are somewhat controversial. There is wide variance of reported incidence (3.3%-79%), probably due to different patient groups tested and different testing methods. In men, one report suggests that serum antibody titer is more significant than the mere detection of antibody. High titers of antisperm antibody in men were considered strong evidence against fertility; low titers were of uncertain significance, and mildly elevated titers indicated a poor but not hopeless prognosis. In women, serum antisperm antibodies are said to be present in 7%-17% of infertility cases but their significance is rather uncertain, since a considerable percentage of these women can become pregnant. Antisperm antibody detected in the cervical mucus of women is thought to be much more important than that detected in serum. A test showing ability of sperm to bind to mannose may be available.