Bailliere's clinical endocrinology and metabolism最新文献

There has been much recent interest in the relationship between androgens and bone mineralization in men. Increases in serum androgens during puberty allow for skeletal maturation and the attainment of peak bone mass, and the persistence of normal testosterone secretion during adulthood is important for the maintenance of bone density. Testosterone deficiency is associated with heightened bone turnover and is a major risk factor for osteoporosis in men. The administration of testosterone to androgen-deficient men leads to an increase in bone mass, particularly in the trabecular bone compartment, and a reduction in levels of surrogate markers of bone turnover, suggesting that androgens have a dampening effect on bone remodelling. In addition, the administration of androgens to eugonadal men with idiopathic osteoporosis, with resulting supraphysiological testosterone concentrations, may lead to increases in bone mineral density. The risk of osteopenia due to androgen deficiency and the benefits of testosterone substitution therapy or supraphysiological administration on bone will be reviewed.

There are many hormonal changes that occur with ageing in humans, of which the most dramatic and intriguing change occurs for the adrenal androgenic steroid dehydroepiandosterone (DHEA). There are tantalizing epidemiological data demonstrating a significant association between the changes in circulating DHEA level and changes in the incidence of malignancy, atherosclerosis, Alzheimer's disease and other age-related changes. The pharmacological effects in animals such as rodents and rabbits have demonstrated many beneficial effects, for example increased immune function, the prevention of atherosclerosis, cancer, diabetes and obesity, and the improvement of memory. Clinical studies carried out in small groups of subjects have clearly demonstrated that the administration of DHEA to the elderly increases many hormone levels, including that of insulin-like growth factor-1, (free and total) testosterone, dihydrotestosterone, oestrone and oestradiol. It remains to be clearly defined whether these changes are clinically beneficial, and there is only insufficient information on the side-effects on long-term use. Results from short-term intervention studies in small groups of subjects have not demonstrated any convincing beneficial effects so far. A judgement on whether DHEA replacement has a place in preventing age-related disabilities could be determined only on the basis of results from studies of long-term DHEA replacement in elderly people.

Hypogonadism in HIV-infected men has been well described, having a prevalence of about 30%. Its aetiology is a combination of non-specific changes from chronic and acute illness, and specific effects due to HIV infection. A depressed serum testosterone level has been associated with viral or infectious invasion of the endocrine organs, and with medications commonly used in treating HIV infection. Recently, many have noted the association between decreased serum testosterone in men and women, and the wasting syndrome of HIV infection, particularly with a reduction in lean body mass. Our understanding of the risks and benefits of testosterone therapy in non-HIV infected men has grown significantly. Treatment in this population can improve sexual function, quality of life parameters and body composition. Based on this information, a few studies have been carried out, and more are being planned to test the hypothesis that therapy with testosterone or its analogues can benefit HIV-infected men and women with wasting and/or low circulating androgen concentrations. To date, the studies have been inconclusive. Not all studies have shown a statistical benefit of androgen therapy on weight, muscle mass or quality of life. Testosterone is now available in several forms for dosing, which has improved compliance and ease of administration. Its potential risks to the prostate or serum lipids should be monitored closely. Although the beneficial effects of androgenic steroids in HIV-infected men have not been demonstrated clearly, short-term studies suggest that testosterone supplementation may improve metabolic outcomes in HIV-infected men with androgen deficiency.

Testosterone-induced nitrogen retention in castrated male animals, eunuchoidal men, prepubertal boys and women, and the sex-related differences in the size of the muscles between male and female animals, have been cited as evidence that testosterone has anabolic effects. Recent studies have reported that replacement doses of testosterone in hypogonadal men and supraphysiological doses in eugonadal men increase fat-free mass, muscle size and strength. These effects have provided the rationale for exploring these anabolic applications in sarcopenic states. Although emerging data demonstrate modest gains in fat-free mass in HIV-infected men given replacement doses of testosterone, we do not know whether testosterone supplementation can produce clinically meaningful changes in muscle function and disease outcome in patients with wasting disorders.

Androgens have an important physiological role in women. Not only are they the precursor hormones for oestrogen production in the ovaries and extragonadal tissues, but they also appear to act directly, via androgen receptors, throughout the body. Androgen levels decline with increasing age in women, who may experience a variety of physical symptoms secondary to androgen depletion, as well as physiological changes that affect their quality of life. In this chapter, the changes in androgens as women age are reviewed, and the rationale for physiological androgen, specifically testosterone replacement, in women is addressed.

Normal ageing is associated with a decline in lean body mass, muscle mass and strength. The functional consequences of these changes may be significant and include falls, fractures, loss of mobility and increasing dependency. The anabolic actions of testosterone on muscle have been known for over 60 years, and replacement studies in young hypogonadal men have shown that testosterone can improve muscle mass and strength. In addition, the supraphysiological replacement of testosterone in young eugonadal men has also been shown to increase muscle mass and improve strength. Although the data are limited, studies of testosterone replacement in healthy older men with relative testosterone deficiency have demonstrated some modest improvements in muscle mass and strength, although the clinical and functional relevance of the muscle changes have yet to be determined. More data and experience are needed before testosterone can be advocated for the prevention or reversal of sarcopenia in the ageing male.

Puberty describes the complex physiological transition between childhood and adulthood. Dramatic physical changes occur, most notably the development of secondary sexual characteristics and the pubertal growth spurt. During the adolescent growth spurt, growth velocity increases from pre-pubertal rates of 4–6 cm per year to as much as 10–15 cm per year. Accompanying the increase in gonadal steroids is an increase in amplitude of growth hormone secretory bursts. Evidence suggests that adequate growth hormone and gonadal steroids are both necessary for the attainment of a normal pubertal growth velocity, and the complex interplay between these two hormonal axes is under intense investigation. Delayed onset of puberty, or constitutional delay of growth and adolescence, is a common phenomenon presenting particularly in boys. Physiologically, it represents an extension of the normal pre-pubertal hypogonadotropic hypogonadal state. Without intervention, these children will spontaneously undergo puberty and often reach their genetic height potential, but their delay compared with that of their peers is often of concern to the children and their families. Recent evidence suggests long-term physiological benefits of early androgen replacement therapy in these boys, including maximizing attained bone mineral density. Androgen replacement therapy in male adolescents with constitutional delay of growth and adolescence is beneficial psychologically as well as physiologically and should be initiated promptly.

Growth hormone (GH) directly stimulates proliferation and differentiated functions of cultured bone cells. In addition, temporal relationships between decreased function of the GH/IGF-1 axis and age-related bone loss have prompted some investigators to hypothesize that these two phenomena are causally related, and to test this hypothesis by evaluating the effects of GH administration on bone turnover and mineral density in older men and women. Although these studies show clearly that GH initiates bone remodelling activity, changes in bone mass have not been impressive, even when GH was given in combination with anti-resorptive therapy. Thus, it appears very unlikely that GH will offer a clinically useful means to restore skeletal deficits in patients with osteoporosis.