ANDROPAUSE

In men and women many physiological and psychological symptoms and biochemical changes attributed to an aging-related decline in gonadal hormones. Menopause in women is based on the end of the reproductive cycle associated with ovarian failure, and is characterized by the relatively abrupt onset of well-recognized symptoms. In contrast, the term "andropause" has been used to describe the slow, steady decline of testosterone in men as they age. This process is not universal in men, is more insidious in its onset, and its clinical presentation is more subtle and varied. For these reasons it has been suggested that androgen decline in the aging male (ADAM) is a more appropriate designation for this syndrome (Morales et al.).

Changes in the aging male

The andropause syndrome is difficult to detect clinically because the symptoms are often attributed to a more general aging process in the absence of specific disease. The characteristic symptoms include weakness, depression, fatigue, and changes in body hair and skin. In addition there is loss of libido, lean body mass, and bone mass, as well as decreased intellectual activity and spatial orientation ability. The severity and frequency of each symptom are variable.

Erectile function. Male aging is associated with a decline in sexual interest and activity and an increase in erectile dysfunction. In men between the ages of forty and seventy, 52 percent reported some degree of impotence (Gooren). This aging-related impaired sexual function is multifactorial with testosterone likely playing only a minor, if any, role. Testosterone appears more important in maintaining desire and nocturnal erections (Gooren). For most men with erectile dysfunction, therapies such as sildenafil (Viagra©), penile injections, vacuum-suction devices, and penile prostheses are more effective than testosterone.

Mood and cognition. Testosterone replacement often improves men's sense of overall well-being (Vermeulen). Improvements in libido, energy, and mood; a decline in anxiety; and increased aggressiveness in business transactions have all been described in hypogonadal (having low levels of testosterone) men receiving testosterone (Tenover 1992, 1994; Wang et al.), but how these findings translate to normal aging men is not clear.

Body composition. A decrease in both muscle tissue mass and some aspects of muscle strength have been associated with male aging (Tenover 1994). An increase in percent body fat has been reported in hypogonadal men compared to eugonadal men (Katznelson et al.). A role for testosterone in these changes is supported by the fact that testosterone replacement in young, healthy, hypogonadal men increases fat-free mass, muscle size, and strength, and decreases percent body fat (Bhasin et al.; Katznelson et al.; Tenover 1992). Several studies have reported an increase in grip strength with testosterone replacement (Morley et al.; Sih et al.), but the effect on more clinically relevant measures of strength is not known.

Bone density. Osteoporosis is a significant but underrecognized cause of morbidity and mortality in elderly men. As in women, bone density decreases and osteoporotic fractures increase with male aging (Abu et al.; Swerdloff and Wang). Hypogonadism is associated with a significant decrease in bone density (Katznelson et al.) and increased risk of fractures. Testosterone replacement significantly improves bone mineral density in hypogonadal men (Behre et al.; Katznelson et al.), but a reduction in fractures following normalization of bone mineral density has not been established.

Androgen levels. Only 1-2 percent of the testosterone in the circulation is free; the remainder is bound, either tightly to sex-hormonebinding-globulin (SHBG; 60 percent), or weakly to albumin (40 percent). Bioavailable testosterone includes only the free and albumin bound components. SHBG-bound testosterone is not available for tissue uptake (Gray et al.).

Bioavailable testosterone declines, and SHBG-bound testosterone increases, with increasing age. The implication of this is that hypogonadal men may have normal or only slightly reduced total serum testosterone levels. For this reason identification of these men is best accomplished by measurement of bioavailable testosterone (Gray et al.).

The clinical significance of the age-related decline in testosterone is unclear. There is considerable variation in serum testosterone among men of all ages, such that many healthy elderly men have levels within the normal range (Vermeulen). Total testosterone levels below the normal reference level are reported in 7 percent of men age forty to sixty, 20 percent of men age sixty to eighty, and 35 percent of men over eighty (Vermeulen and Kaufman).

Complications of testosterone replacement

Prostate growth, whether malignant or benign, is highly dependent on steroid hormones. A major concern is that testosterone replacement will stimulate the onset or hasten the development of prostatic carcinoma. The inhibitory effect of removing androgens on clinically diagnosed prostate cancer is well known. Whether replacing testosterone in hypogonadal men promotes development of de novo malignancies or progression of sub-clinical carcinomas is not known. To date, the small and short-term studies have not demonstrated an increased risk (Morales et al.). However, the level of experience at this time is insufficient to conclusively rule out a causal relationship (Morales et al.). For this reason, careful monitoring of these patients with serum prostate-specific antigen (PSA) and digital rectal exams are recommended.

The effect of testosterone on benign prostatic enlargement has also been a concern. The most recent data from placebo-controlled trials of testosterone replacement in hypogonadal men suggests that the changes in PSA, prostate volume, and lower urinary tract symptoms are clinically insignificant (Tenover, 1998). Current recommendations suggest serum PSA and digital rectal exam before instituting testosterone replacement, then yearly thereafter.

The effects of hypogonadism and testosterone replacement on lipid profiles and risk of cardiovascular disease are unclear. Interestingly, low serum testosterone levels appear to be associated with increased triglycerides and decreased levels of high-density lipoprotein (HDL) cholesterol; testosterone replacement appears to restore these to more favorable levels (Zmuda et al.). Several recent studies have suggested that hypogonadism may be a risk factor for coronary artery disease, although this remains to be fully explained (Philips et al.; Uyanik et al.). The impact of testosterone therapy on cardiovascular risk is not entirely clear, however; most current data suggest it does not induce an atherogenic profile (Vermeulen and Kaufman). Careful lipid monitoring should be provided for patients on testosterone replacement, particularly those with risk factors for coronary artery disease.

Current injectable, oral, and transdermal testosterone preparations (available in the United States only) without methyltestosterone are believed not to cause the liver toxicity described with previously used methylated forms of testosterone (Morales et al.).

Testosterone stimulates erythropoiesis (production of red blood cells) through an unclear mechanism and can result in increased hematocrit, increased hemoglobin, and hypercoagulability in as many as 24 percent of patients (Jockenhovel et al.; Winkler). For this reason hematocrit assessment on a three-month basis has been recommended for men on testosterone replacement.

Types of replacement therapy

Options for replacement include oral tablets and capsules, transdermal patches (scrotal and nonscrotal), and intramuscular injections. Older methyltestosterone oral formulations are undesirable because of their significant first-pass metabolism in the liver and significant liver toxicity. Testosterone undecenoate is absorbed through the lymphatic system and is thought to be free of liver toxicity (Nieschlag). Oral doses two or three times a day can reduce serum testosterone fluctuations, and may have a lower incidence of increased red cell mass in the blood and increased hematocrit.

Injectable testosterone is generally administered as a slow-release, oil-based preparation (testosterone enanthate or cypionate) that achieves supraphysiologic concentration approximately seventy-two hours after injection, then slowly declines over ten to fourteen days to a hypogonadal range. The wide fluctuation in levels during the dosing interval can produce enlarged breasts, breast tenderness, significant mood swings, and changes in libido and sexual function.

Transdermal patches have become available that provide a more physiologic approach to testosterone replacement by mimicking the normal diurnal variation in testosterone levels. The original patches were scrotal; more recently nonscrotal patches have become available (neither is currently available in Canada). Patches are applied at bedtime so that peak testosterone levels occur in the morning, then decline during the day (Nieschlag; Schow et al.). These patches appear to have most of the benefits of injected testosterone replacement. In addition there appears to be less aggressiveness, although these effects have not been studied in long-term trials (Morales et al.). Local dermatitis and higher costs have prevented their widespread use.

Conclusions

Current evidence supports the existence of progressive hypogonadism affecting many older men which has been labeled andropause or the ADAM syndrome. The diagnostic criteria for this syndrome, however, are imprecise because many of its symptoms, such as mood and energy level, are difficult to measure and separate from "normal" aging. In addition, possible changes in the androgen receptors with aging lead to uncertainty about the exact level of androgen required for optimum health. Also, many other hormone changes and disease states affect the aging man.

Nonetheless, testosterone appears to be a prominent hormone involved in this syndrome, and testosterone replacement in this population is used with increasing frequency. Androgen replacement should be instituted on the basis of the combination of low bone density or patient symptoms and low testosterone levels, and in the absence of other causes. A DRE (digital rectal examination) and PSA (prostate-specific androgen measurment) should be performed on all men prior to instituting testosterone replacement. Patients with known prostate or breast cancer (due to conversion to estrogen), abnormal DRE or elevated PSA or severe lower urinary tract symptoms are not suitable for testosterone replacement. Others will require careful follow-up to minimize the potential for long-term complications.

Troy Sitland John Grantmyre

See also Hair; Menopause; Prostate; Sarcopenia; Sexuality.

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