Published: June 2012
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.
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.
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|
|Toxins: alcohol, heavy metals|
|Box 2 Secondary (Hypogonadotropic) Hypogonadism: Major Causes|
|Congenital or acquired|
|Isolated or combined pituitary disease|
|Space-occupying lesions of pituitary, hypothalamus|
|Hyperprolactinemia per se|
|Gonadotropin-releasing hormone analogues|
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|
|Acquired immunodeficiency syndrome (AIDS)|
|Chronic renal failure|
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).
A semen analysis should be performed when fertility is in question.
Androgen replacement therapy is relatively straightforward; see Box 4 for testosterone preparations currently available in the United States. Typically, the depot esters are administered by the deep intramuscular route once every 2 weeks at a dose of 200 mg in adults. A usual dosage for the transdermal or the buccal preparations results in the systemic absorption of 2.5 to 10 mg daily. If the parenteral route is chosen, patients should and can be taught to self inject. The major disadvantage with the parenteral route is that testosterone levels exhibit a saw-toothed pattern, with high-normal or supranormal levels on days 2 to 4 and low-normal or borderline low trough values before the next injection. Mood, sense of well-being, and libido may vary accordingly in some patients.
|Box 4 Testosterone Preparations Available in the United States|
|Depot esters (Depo-Testosterone, Delatestryl)|
|Genital skin patch (Testoderm)|
|Nongenital skin patch (Androderm)|
|Gel (AndroGel, Testim)|
Dosages may be adjusted by aiming for midnormal (400- 600 ng/dL) testosterone levels after 1 week or at the low end (250-350 ng/dL) just before the next injection is due at 2 weeks. Values are stable within a few days or weeks of the skin patch, gel, or newer buccal preparation. It must be ascertained that the preparation was actually used on the day the sample was drawn; again, a value in the midnormal range (400-600 ng/dL) is the goal. Although comparable testosterone levels are reached by the patch and the gels, skin reactions at the application site are much more common with the patch. Also, the buccal preparation is difficult for patients to get used to. Alkylated oral androgens should be viewed as potentially hepatotoxic and should not be used. Useful criteria for selecting preparations for individual patients are summarized in Table 1.
|Type of Preparation|
|Parameter||Intramuscular||Gel||Patch (Genital and Nongenital)||Buccal|
|Side effects||Systemic||Local, +||Local, +++||Local, ++|
+, ++, and +++ are semiquantitative assessments of effect.
© 2002 The Cleveland Clinic Foundation.
In addition to monitoring testosterone levels periodically, prostate screening and measurement of hemoglobin and hematocrit levels must also be performed at intervals when the patient is on therapy.2
Levels of prostate-specific antigen (PSA) should be checked at 3, 6, and 12 months. If the patient is truly hypogonadal to begin with, expect a significant rise at the 3-month assessment. Thereafter, the usual criteria apply regarding the possible presence of an underlying malignancy (>4 ng/mL, or rate of increase >1.5 ng/mL/2 yr or >2 ng/mL overall). These criteria continue to be revised by our urology colleagues, tending to become more stringent with time. For example, a PSA rise of more than 1 ng/mL/year has been suggested as an early warning guide, and closer surveillance has been recommended, even at rates of 0.7 to 0.9 ng/mL/year.2 A digital rectal examination should be performed at 3 to 6 months and at 1 year after therapy is initiated. A urologic consultation should be obtained if indicated.
Hemoglobin (Hb) and hematocrit (Hct) levels should be checked periodically. Incremental increases are to be expected, but an Hb level higher than 17.5 g/dL, Hct higher than 55%, or both suggests overtreatment, occasionally abuse. Greater increments tend to occur more frequently with the intramuscular than with the transdermal preparations. If dosage adjustments do not solve the problem, look for another underlying cause.
Physicians Box 5). It should be noted that no long- term studies in large numbers of patients (neither young or old) have been performed, so potential risks and benefits need to be individualized.
|Box 5 Contraindications for Testosterone Replacement|
|Breast carcinoma (history or presence)|
|Prostate carcinoma (history or presence)|
|Severe benign prostatic hyperplasia|
|Abnormal digital rectal examinations|
|Elevated levels of prostate-specific antigen|
|Age (no limit established; possibly older than 80 years)|
|Sleep apnea (potential for worsening)|
|Polycythemia (hematocrit >51%)|
In genuinely hypogonadal men, testosterone administration can be expected to result in improvements in a variety of clinical areas (Box 6). Least predictable are the effects on sexual function, cognitive function, and muscle strength.
|Potential Benefits of Testosterone Therapy|
|Increase in lean body mass|
|Decrease in fat mass|
|Increased bone density|
|No fracture data available|
|Muscle strength, physical function|
© 2002 The Cleveland Clinic Foundation.
Concerns regarding the use of testosterone have been noted in Box 5 and by Rhoden and Morgentaler.2 There is no evidence that the incidence of prostate cancer is increased by testosterone replacement. The underlying concern is that it might alter the course of an occult malignancy estimated to be present in more than 50% of men older than 50 years. On the other hand, no one would recommend prophylactic castration to prevent prostate cancer so that, in my view, testosterone replacement in the hypogonadal man should not be avoided. Although there are genuine concerns about worsening of benign prostatic hyperplasia, this may apply only to severe cases with large prostate volumes. Indeed, one study in older men has even suggested improvement in benign prostatic hyperplasia symptoms, although not statistically significant and by an unknown mechanism.3
The aging man represents a special case and has been the subject of a review.4 There is a well-known decline in testosterone production with aging in otherwise healthy men. This decline in mean values can be seen in free testosterone levels, beginning in the mid-40s (some clinicians suggest even earlier), as a consequence of increasing SHBG levels, mechanism unknown. Total testosterone levels decline on average beyond 70 years. The diurnal rhythm, seen in younger men, is lost beyond 60 years.5 Although testicular volume also declines in this age group, spermatogenesis may be well maintained into the 80s or even beyond. Gonadotropin levels tend to rise after 70 years, indicating that the testosterone deficiency is usually primary.6 Figure 4 schematically presents these hormonal changes with age. Using the criterion of a low testosterone value, and remembering that there is considerable variability in commercially available tests regarding normal young adult ranges, it has been estimated that 7% of 40- to 60-year-olds, 22% of 60- to 80-year-olds, and 36% of 80- to 100-year-olds are hypogonadal.7
The ultimate issue as to whether these changes are normal and physiologic or should be considered pathologic, thus demanding therapy, remains unresolved. Indeed, it is a situation analogous to the ongoing dilemma of hormone replacement therapy for postmenopausal women, although in this group the hormonal deficiency state is usually more abrupt and symptomatic.
The scientific basis to help formulate guidelines for dealing with the issue of hormone replacement therapy in men was reviewed in a December 17, 2003, conference by the Institute of Medicine’s Committee on Testosterone and Aging (IMCTA).8 Many of the potential benefits of therapy (see Box 6) have been realized in small, well-controlled studies of older men. Moreover, none of the risks has been proven in a clinical trial. The IMCTA has not recommended a large-scale study to determine whether the risk for prostate cancer would be increased, because the costs of such a study were deemed to be too prohibitive.
In the meantime, practical guidelines for dealing with hypogonadism in older men have been suggested.9 I have found the recent overview in the Cleveland Clinic Men’s Health Advisor newsletter to be useful for patients.10
The American Association of Clinical Endocrinologists has published 2002 updated guidelines for the evaluation and treatment of hypogonadism in adult male patients.11 This review, geared particularly for endocrinologists, expands on some of the areas reviewed in this chapter and provides a more detailed look into aspects of male infertility.
|Box 7 Endocrine Society Clinical Practice Guidelines for Testosterone Replacement Therapy|
|Recommend diagnosis of androgen deficiency only in men with consistent symptoms and signs and with unequivocally low serum testosterone levels.|
|● Measure morning total testosterone level by a reliable assay as an initial test.|
|● Confirm with repeat total testosterone and free or bioavailable testosterone using accurate assays.|
|Do not start testosterone therapy in patients with the following:|
|● Breast or prostate cancer|
|● Palpable prostate nodule or induration or prostate-specific antigen level >3 ng/mL without urologic evaluation|
|● Severe lower urinary tract symptoms|
|● Hematocrit >50% or hyperviscosity (not defined)|
|● Untreated obstructive sleep apnea|
|● Severe coronary heart failure (Class III or IV)|
|Treatment goal and comments (no comments about age or duration limits)|
|● Aim to achieve testosterone levels in midnormal range.|
|● Men receiving testosterone therapy should be monitored using a standardized plan.|
Adapted from Bhasin S, Cunningham GR, Hayes FJ, et al: Testosterone therapy in adult men with androgen deficiency syndromes: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006;91:1995-2010.