Male Hypogonadism

Definition and Prevalence

Male hypogonadism is defined as the failure of the testes to produce androgen, sperm, or both. Although the disorder is exceedingly common, its exact prevalence is uncertain.
Regulation of testicular function
Figure 1: Click to Enlarge
testosterone and metabolites
Figure 2: Click to Enlarge
primary and secondary causes of MaleHypogonadism
Figure 3: Click to Enlarge

Testosterone production declines with advancing age; 20% of men older than 60 years and 30% to 40% of men older than 80 years have serum testosterone levels that would be subnormal in their younger adult male counterparts. This apparent physiologic decline in circulating androgen levels is compounded in frequency by permanent disorders of the hypothalamic-pituitary-gonadal axis (see later). These include the transient deficiency states associated with acute stressful illnesses, such as surgery and myocardial infarction, and the more chronic deficiency states associated with wasting illnesses, such as cancer and acquired immunodeficiency syndrome.

Male factor infertility is probably responsible for one third of the 10% to 15% of couples who are unable to conceive within 1 year of unprotected intercourse. Most of these male-associated cases result from diminished, absent, or faulty spermatogenesis. In addition to abnormal sperm production, other conditions, including obstructive ductal disease, epididymal hostility, immunologic disorders, and erectile or ejaculatory dysfunction should be considered. Finally, because combined female-male infertility is common, and fertility as well as psychological well-being are ultimate goals, both partners must be assessed from the outset.

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The physiologic regulation of the hypothalamic-pituitary-gonadal axis is shown in Figure 1. Circulating testosterone is largely protein-bound—the major protein is sex hormone–binding globulin (SHBG)—with only 2% present as the biologically active or free fraction. Some clinicians believe that the bioavailable fraction, the fraction present in the supernatant after ammonium sulfate precipitation, representing testosterone loosely bound predominantly to serum albumin, is more meaningful. Hepatic SHBG production rises with aging and thyroid hormone excess and declines in hyperinsulinemic states (obesity and type 2 diabetes), so that free testosterone values may not always be concordant with total testosterone values. The biologic effects of testosterone may be mediated directly by testosterone or by its metabolites 5α-dihydrotestosterone or estradiol (Fig. 2).

Male hypogonadism is caused by a primary (hypergonadotropic) testicular disorder or is secondary (hypo- or normogonadotropic) to hypothalamic-pituitary dysfunction, as illustrated in Figure 3. Combined disorders also occur. Examples of the major causes of male hypogonadism are shown in Boxes 1 and 2.
Box 1 Primary (Hypergonadotropic) Hypogonadism: Major Causes
Genetic: Klinefelter’s syndrome
Congenital: anorchia
Toxins: alcohol, heavy metals

Box 2 Secondary (Hypogonadotropic) Hypogonadism: Major Causes
Pubertal delay
Congenital or acquired
Isolated or combined pituitary disease
Space-occupying lesions of pituitary, hypothalamus
Hyperprolactinemia per se
Infiltrative, infectious
Sex steroids
Gonadotropin-releasing hormone analogues
Aging (?)

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Signs and Symptoms
Birth and Infancy

Persistent failure of the testes to descend may be an early manifestation of testicular dysfunction. In addition, a normally formed but hypotrophic penis may provide a clue to an abnormality of the hypothalamic-pituitary-gonadal axis.

Delayed, arrested, or absent testicular growth and secondary sexual characteristic development are hallmarks of pubertal disorders. Skeletal proportions may be abnormal (eunuchoid) with more than a 5-cm difference between span and height and between pubis-floor and pubis-vertex dimensions.

Manifestations in adults are generally more subtle. Perhaps the minor contribution of adrenal androgens (or androgenic precursors) may substitute for testicular deficiency once the target tissues have been fully developed. Moreover, ingrained behavior patterns may be resistant to androgenic hormone deficiency. Certainly, prolactin excess, testosterone deficiency, or both in men may result in impaired libido and erectile dysfunction. The yield of finding hyperprolactinemia or testosterone deficiency, or both, in patients presenting with these symptoms is generally considered to be low, usually less than 5%. However, a large survey of patients with erectile dysfunction presenting to a Veterans Affairs center has suggested that the prevalence of these abnormalities is substantial: 18.7% of patients with low testosterone levels and 4.6% with elevated prolactin levels.1

The first manifestation of hypogonadism may be a consequence of a large space-occupying intrasellar or parasellar lesion manifested by headaches, bitemporal hemianopia, or extraocular muscle palsy. Galactorrhea as a manifestation of hyperprolactinemia is rare, but rarely sought. Unexplained osteoporosis or mild anemia sometimes is the clue to an underlying hypogonadal state. Some common clinical conditions associated with male hypogonadism are listed in Box 3. The subject of androgen deficiency and the aging man is dealt with in greater detail later in this chapter.
Box 3 Conditions Associated with Male Hypogonadism
Chronic illness
Acquired immunodeficiency syndrome (AIDS)
Chronic renal failure
Rheumatoid arthritis
Cancer cachexia
Corticosteroid use

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Because of the well-known diurnal rhythm of serum testosterone, which appears to be lost with age (>60 years), with values 30% or so higher near 8 am versus the later day trough, a testosterone value should be determined first thing in the morning. Normal ranges vary among laboratories. Although the usually quoted range for young men is 300 to 1000 ng/dL, the lower limit reported for the Cleveland Clinic is 220 ng/dL. In general, values below 220 to 250 ng/dL are clearly low in most laboratories; values between 250 and 350 ng/dL should be considered borderline low. Because the acute effect of stressful illness may result in a transient lowering of testosterone levels, a confirmatory early morning specimen should be obtained. Measurement of free testosterone levels or bioavailable testosterone levels, determined adequately in select commercial laboratories, may provide additional information (see later, “Pathophysiology”). For example, free testosterone levels may be lower than expected from the total testosterone level as a result of aging and higher than expected in insulin-resistant individuals, such as in obesity. In addition, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin levels should be determined to help delineate the cause of the testosterone-deficient state.

If gonadotropin levels are not elevated, despite clearly subnormal testosterone values, anterior pituitary (thyroid-adrenal) function should be determined by measuring free thyroxine and thyroid-stimulating hormone levels, as well as an early morning cortisol level. A magnetic resonance imaging (MRI) scan of the brain and sella should be considered. An exception to this recommendation is the condition of morbid obesity, in which both total and free testosterone levels are typically low and gonadotropin values not elevated. Hyperprolactinemia, even of a small degree, may also warrant ordering MRI, because interference of hypothalamic-pituitary vascular flow by space-occupying, stalk-compressing lesions will lead to disruption of the tonic inhibitory influence of hypothalamic dopamine, and result in modest hyperprolactinemia (usually 20 to 50 ng/mL range).