Male hypogonadism is the clinical and/or laboratory syndrome that results from a failure of the testis to work properly. The normal testis has two functions: synthesis and secretion of testosterone from the Leydig cells and production of sperm from the seminiferous tubules. Deficiency of one or both functions is termed male hypogonadism. This condition can result from a disruption at one or more levels of the hypothalamic-pituitary-gonadal axis. Depending on the stage of development, hypogonadism may have varied manifestations.

In utero androgen deficiency leads to a female phenotype or ambiguous genitalia, most commonly caused by a block in the production of testosterone secondary to congenital testosterone biosynthetic enzyme defects. Rarely, peripheral tissues cannot respond normally to testosterone, thereby resulting in the androgen insensitivity syndromes of testicular feminization (complete) and Reifenstein’s syndrome (incomplete). Other manifestations include micropenis, hypospadias, and cryptorchidism.

Childhood androgen deficiency results in delayed, incomplete, or absent pubertal development. Common manifestations include the following:

In early adulthood, a decrease in sperm output (azoospermia or oligospermia) without deficient production of testosterone is common and results in male infertility; thus, infertility is a form of male hypogonadism. A decrease in production of testosterone in adulthood is usually accompanied by a decline in production of sperm. When it is not, the term fertile eunuch (eunuchoid proportions, low levels of luteinizing hormone [LH], low levels of testosterone, normal levels of follicle-stimulating hormone [FSH], and spermatogenesis) is appropriately applied. Libido and/or potency may be diminished.

The most frequent circumstance in which adult hypogonadism occurs is in the middle-aged or senescent man complaining of decreased libido or potency. Semen analysis is rarely performed in these men because they are usually not concerned with fertility. Other findings may include osteoporosis, diminished androgen production, and small prostate. If the onset of hypogonadism is acute, the patient may experience hot flushes and sweats.

LH is episodically secreted from the anterior pituitary in response to pulses of gonadotropin-releasing hormone (GnRH), thus stimulating production of testosterone by Leydig cells. Once testosterone is secreted into the bloodstream, it is bound by sex hormone–binding globulin (SHBG) and albumin. The non–SHBG-bound (or “free”) testosterone provides negative feedback to the hypothalamic-pituitary unit and thus inhibits output of LH. This classic endocrine feedback loop serves to maintain serum testosterone at a predetermined level; if serum testosterone falls below the set point, the pituitary is stimulated to secrete LH, which, in turn, stimulates testicular output of testosterone until serum levels return to the set point. Conversely, if serum testosterone rises above the set point, decreased output of LH results in decreased testicular output of testosterone until serum levels have declined to the set point. Although most automated total testosterone assays are reliable and are generally able to distinguish hypogonadal from eugonadal men, abnormalities in the SHBG level may give falsely low or high total testosterone levels. Equilibrium dialysis is the gold standard for measuring the free testosterone, but it is not commonly available and should be ordered to be performed only in a reliable reference laboratory. Liquid chromatography–mass spectrometry or gas chromatography–mass spectrometry is used by some reference laboratories to measure testosterone. This is a very accurate but expensive method. Analog methods for determining free testosterone are more widely available but are not accurate in the low ranges.

Moderate obesity, nephrotic syndrome, hypothyroidism, and the use of certain medications (notably glucocorticoids and androgenic steroids) decrease SHBG levels and give a low total serum testosterone level, whereas aging, anticonvulsant use, estrogen use, herbal preparations for “prostate health” that contain plant-derived estrogens, hepatic cirrhosis, human immunodeficiency virus (HIV) infection, and hyperthyroidism may all increase SHBG and cause a high total level of testosterone.

The regulation of sperm production is complex and less clearly understood than is the regulation of testosterone production. Both hormonal and nonhormonal factors are important. The Sertoli cells within the seminiferous tubules seem to play an important coordinating role. Sertoli cells respond to FSH by producing inhibin (secreted into the blood) and androgen-binding protein, transferrin, and other proteins (secreted into the seminiferous tubular lumen). Inhibin appears to inhibit the output of FSH from the pituitary gland, thus completing a feedback loop. In theory, if spermatogenesis declines, production of inhibin also should decline; thus the negative feedback effect on the pituitary would be reduced, leading to an increased output of FSH, which would then presumably stimulate spermatogenesis. However, not all aspects of this feedback loop (FSH-inhibin-spermatogenesis) have been verified experimentally. Moreover, spermatogenesis depends on intratesticular production of testosterone mediated by androgen receptors within Sertoli cells. Initiation of spermatogenesis during puberty requires both LH and FSH. However, reinitiation of the process if it is disrupted by exogenous factors (see the following) requires only LH (or human chorionic gonadotropin [hCG]), although FSH may be needed to produce a normal number of sperm.

Failure of testicular function may result from a defect either at the testis or at the hypothalamic-pituitary level. Testicular disorders leading to hypogonadism are termed primary hypogonadism (Fig. 44-1), whereas disorders of hypothalamic-pituitary function leading to hypogonadism are termed secondary hypogonadism (Fig. 44-2). This distinction has therapeutic implications. In men with secondary hypogonadism, fertility can generally be restored with appropriate hormonal treatment. Men with primary hypogonadism have fewer options and more limited success with improvement in fertility. In addition, the evaluation of secondary hypogonadism can reveal a pituitary mass or systemic illness as the underlying cause.

Primary hypogonadism resulting from a testicular disorder leads to a decline in production of testosterone and sperm, a consequent decrease in the negative feedback effects on the pituitary, and a corresponding increase in serum levels of LH and FSH. Conversely, in secondary hypogonadism resulting from a hypothalamic-pituitary disorder, serum LH and FSH may be subnormal or “inappropriately” normal (explainable, in part, by decreased bioactivity) despite a low testosterone level. A subnormal sperm count and a normal testosterone level with a normal LH and elevated FSH suggest primary hypogonadism with a dysfunction of the seminiferous tubules and sperm production but intact Leydig cell function. An algorithm for the logical evaluation of hypogonadism is shown in Figure 44-3.

 Klinefelter’s syndrome (47,XXY and mosaics)

 Microdeletions of azoospermia factor (AZF) regions of Yp telomere (15% of men with nonobstructive azoospermia; 5% to 10% of those with oligospermia)

 Cryptorchidism

 Myotonic dystrophy

 Testosterone biosynthetic enzyme deficiencies (3-beta-hydroxysteroid dehydrogenase, 17-alpha-hydroxylase, or 17-beta-hydroxysteroid dehydrogenase)

 Androgen receptor gene mutation (qualitative or quantitative)

 LH receptor mutations (male phenotype, if mild; female phenotype, if severe)

 Cancer therapy: chemotherapy (alkylating agents more than cisplatin and carboplatin) and radiation therapy (may be permanent with external radiation; usually transient with radioactive iodine)

 Drugs (e.g., ketoconazole, 5-alpha-reductase inhibitors)

 Testicular injury

 Hyperthyroidism

 Infiltrative disease (e.g., hemochromatosis)

 Infections (e.g., HIV [may be multifactorial], mumps orchitis)

 Systemic illness (e.g., uremia, cirrhosis); may be multifactorial

Symptomatic hypogonadism, defined by at least three sexual symptoms and a low total testosterone (< 320 ng/dL) and/or low free testosterone (< 64 pg/mL) level, is present in about 2% of men between 40 and 79 years of age. When only biochemical criteria are used, the prevalence is higher (2%–6%) in that age range and 18% to 30% in men more than 70 years old. Multiple cross-sectional studies have noted that older men have mildly reduced levels of total serum testosterone but significantly reduced levels of free testosterone (because of a rise in SHBG with age) compared with younger men. This decline is associated with a rise in LH and FSH, a finding suggesting a primary gonadal cause. Studies have demonstrated an average 1% to 2% decline in total serum testosterone and an even greater reduction in free testosterone (because of elevations in SHBG) per year associated with normal aging. Further complicating the situation is the observation that there has been a population-level decrease in serum testosterone levels in men in the United States since the early 1990s.