Atam B. Singh

Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men.

OBJECTIVES: To examine the effect of graded doses of testosterone on physical function and muscle performance in healthy, older men.

The Effects of Injected Testosterone Dose and Age on the Conversion of Testosterone to Estradiol and Dihydrotestosterone in Young and Older Men

BACKGROUND During testosterone (T) therapy, T is partly converted to 17beta-estradiol (E2) and 5alpha-dihydrotestosterone (DHT). Effects of age, testosterone dose, and body composition on total and free E2 and DHT levels are unknown. OBJECTIVE We evaluated age and dose-related differences in E2 and DHT levels in response to graded doses of testosterone enanthate in young and older men. METHODS Fifty-one young (aged 19-35 yr) and 52 older (aged 59-75 yr) men completed treatment with monthly injections of a GnRH agonist plus randomly assigned weekly doses of testosterone enanthate (25, 50, 125, 300, or 600 mg) for 5 months. RESULTS During testosterone administration, total and free E2 levels increased dose-dependently (dose effect, P<0.001) in both young and older men. Total and free E2 levels and E2:T ratios during T administration were higher in older than young men, but age-related differences in free E2 and free E2:T ratios were not significant after adjusting for testosterone levels, percentage fat mass, and SHBG. DHT levels and DHT:T ratios were dose-related but did not differ between young and older men. Mechanistic modeling of free hormone data revealed that the conversions of T to E2 and DHT were both consistent with saturable Michaelis-Menten kinetics. The in vivo Km values were estimated to be 1.83 nm for aromatase and 3.35 nm for 5alpha-reductase, independent of age. The Vmax parameter for E2 was 40% higher in older men than younger men, but Vmax for DHT was not significantly different between age groups. CONCLUSIONS During im testosterone administration, E2 and DHT levels exhibit saturable increases with dose. The rate of whole body aromatization is higher in older men, partly related to their higher percentage fat mass, SHBG, and testosterone levels.

Effects of a supraphysiological dose of testosterone on physical function, muscle performance, mood, and fatigue in men with HIV-associated weight loss

Testosterone increases fat-free mass (FFM) in men infected with human immunodeficiency virus (HIV), but its effects on muscle performance, physical function, mood, and quality of life are poorly understood. Sixty-one HIV-infected men with weight loss were randomized to receive weekly intramuscular injections of 300 mg of testosterone enanthate or placebo for 16 wk. The primary outcome of interest was physical function (walking speed, stair-climbing power, and load-carrying ability). Secondary outcome measures included body weight and composition, muscle performance, sexual function, mood, and quality of life. Serum nadir free and total testosterone levels increased (+188.0 +/- 29.6 and +720 +/- 86 ng/dl) in the testosterone, but not placebo, group. Testosterone administration was associated with increased FFM (2.8 +/- 0.5 kg), which was significantly greater than in the placebo group (P < 0.0001). Leg press strength increased significantly in testosterone-treated (P = 0.027), but not placebo-treated, men; the difference between groups was not significant. Other measures of muscle performance and physical function did not change significantly in either group. Men receiving testosterone demonstrated significantly greater improvements in mental health and quality-of-life scores than those receiving placebo and improvements in fatigue/energy and mood scores that were not significantly different from those receiving placebo. Sexual function scores did not change in either group. In HIV-infected men with weight loss, a supraphysiological dose of testosterone significantly increased FFM but did not improve self-reported or performance-based measures of physical function. Improvements in mood, fatigue, and quality-of-life measures in the testosterone group, although clinically important, need further confirmation.

NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION

Functional derangement of every endocrine organ system has been reported in association with HIV infection. The changes in endocrine function may be related to the viral infection of the gland, to systemic effects of HIV or an opportunistic infection, to infiltration by a neoplasm such as Kaposis sarcoma, to a complication of treatment, or generation of cytokines. A wide spectrum of endocrine abnormalities is observed in HIV-infected patients. Some of these abnormalities are similar to those seen in other systemic illness, whereas others are unique to HIV infection. The clinical significance of many of these endocrine abnormalities is not well understood.

Physiology and pathophysiology of male sex hormones

There is currently great interest in understanding the role of androgens in both men and women. It is well established that testosterone levels decline with age in men but whether this is a physiologic or pathologic process remains to be determined. Many older men who have low testosterone levels also have symptoms suggestive of hypogonadism. The role of androgens on androgen-dependent target organs is well documented, particularly for younger patients who have androgen deficiency. It is speculated that women who have testosterone deficiency could benefit from testosterone therapy.

Androgen Administration in Sarcopenia Associated with Chronic Illness

The anabolic applications of testosterone in sarcopenia associated with human immunodeficiency virus (HIV)-infection and other chronic illnesses are based on a series of assumptions that are illustrated in Fig. 1. The premise is that these agents increase muscle mass and that androgen-induced changes in muscle mass translate into improvements in skeletal muscle performance, physical function, and other health-related outcomes. Although there is agreement that testosterone supplementation increases muscle mass in a variety of settings (1–14), but we do not know whether testosterone improves muscle performance or physical function. The mechanisms by which testosterone increases muscle mass are unknown.

Male Reproductive Endocrinology

This 23-yr-old man was referred to our Endocrinology Clinic for the management of adrenal insufficiency. The patient was born of a full-term uncomplicated delivery, and grew up normally in early childhood. At 6 yr of age, he became ill, stopped growing, and developed increased pigmentation of the skin. He was evaluated at a local hospital in Mexico and diagnosed as having adrenal insufficiency. After initiation of glucocorticoid replacement therapy with 5 mg prednisone daily, his condition improved and growth resumed, but the increased skin pigmentation persisted.