Clinical consequences of the decline in activity of the hormonal systems

Andropause

Testosterone has long been known for its anabolic effects (Brodsky et al 1996). Muscle weakness, anaemia, lowered bone mass, and mood disturbances rapidly normalize in mid-adult hypogonadal men during T replacement therapy. Since the decrease in serum T concentrations occurs in parallel with the decrease in muscle mass, strength and bone mass, it has been suggested that these are causatively related. Several cross-sectional and longitudinal studies have demonstrated relationships in older men between serum T levels and muscle strength, changes in body composition and bone mineral density (Rudman & Shetty 1994, Murphy et al 1993, Ongphiphadhanakul et al 1995). In agreement, in a cross-sectional study of 403 elderly men, we found positive relationships between non-SHBG-bound T and muscle strength and bone mineral density, and an inverse relationship with fat mass. A cross-sectional study among 856 elderly men demonstrated that bioavailable T levels were significantly lower for the 25 men with categorically defined depression than levels observed in all other men (Barrett-Connor et al 1999). This suggests that T treatment might improve depressed mood in older men who have low levels of bioavailable testosterone. On the other hand, in the population of elderly men we studied, no significant relation was observed between general life satisfaction and T levels. However, non-SHBG-bound T was positively related to some separate questions of the questionnaire, like the satisfaction related to mobility, physical performance and independency.

It is not known whether T therapy in older men has beneficial effects on muscle function, sexual function, sense of well-being and quality of life, and whether this therapy can be done safely. Studies involving physiological replacement therapy of testosterone in older men are limited. However, the results of these studies are consistent; reported are treatment-related declines in body fat mass ranging from

6.4-14%, and increases in lean mass ranging from 3.2—5.0% are both reported (Tenover 1998, Snyder et al 1999a). Several studies evaluating muscle strength in older men during testosterone replacement have demonstrated a statistically significant increase in strength with therapy (Tenover 1998, Sih et al 1997). However, Snyder et al (1999a) evaluated lower extremity strength in a doubleblind, placebo-controlled study involving 108 men, and did not demonstrate a significant change compared to the placebo group, nor did they observe an increase in physical performance in response to testosterone (Snyder et al 1999a). In the same study, testosterone replacement did not increase lumbar spine bone density in the overall group, but it did in men with low pretreatment serum testosterone concentrations (Snyder et al 1999b). It has to be mentioned, however, that the men in this study did not have very low T concentrations.

Although it has been thought for years that T administration adversely affects serum lipid concentrations, recent research shows that T probably has a favourable effect on total and LDL cholesterol concentration, and probably also on triglycerides concentration (Tenover 1992). So far it is unclear whether T replacement in older men can be considered safe with regard to cardiovascular risk. In young men, T administration generally decreases HDL cholesterol levels, while LDL and triglycerides levels remain unchanged. Physiological doses of androgens in elderly men reduced total and LDL cholesterol and had no effect on HDL cholesterol (Zgliczynski et al 1996).

Additionally, the effect of T supplementation on the prostate remains unclear. It has been claimed that about 50% of men aged over 50 years have a subclinical prostate carcinoma, which can be activated by T administration (Jackson et al 1989). However, Snyder et al (1999b) reported that T treatment was associated with a small increase in mean serum prostate-specific antigen concentrations, but not with increases in other parameters that reflect prostate disease (Snyder et al 1999b). Furthermore, it is known that T increases haematocrit within the normal range (Sih et al 1997), while a negative role in the sleep apnoea syndrome has been reported in a few individuals (Matsumoto et al 1985). Overall, the beneficial effects of T replacement in older men seem to be promising, and T administration can probably be given safely to elderly men, provided they are monitored frequently. However, since only few double-blind placebo-controlled studies have been done on T replacement in the elderly, more research is necessary to define dose, form and subjects for T therapy.

In our study of 403 elderly men, serum LH levels were inversely related to muscle strength and lean mass, and positively to self-reported disability (van den Beld et al 1999). All relationships were independent of T, suggesting that LH reflects the serum androgen activity in a different manner than T, possibly more closely reflecting the combined feedback effect of T, dihydrotestosterone and oestrogen.

In most women, the period of decline in oestrogens during menopause is accompanied by vasomotor reactions, depressed mood, and changes in skin and body composition (increase in body fat and decrease in muscle mass). In the subsequent years, the loss of oestrogen is followed by a high incidence of cardiovascular disease, loss of bone mass and cognitive impairment (Lindsay et al 1996). Only recently has it become evident that oestrogens may not only play an important role in regulating bone turnover in women, but also in men. Smith et al (1994) described a male with a homozygous mutation in the oestradiol receptor gene who, even in the presence of normal T levels, had unfused epiphysis and marked osteopenia, along with elevated indexes of bone turnover. A few studies now have demonstrated significant relations between serum (bioavailable) oestradiol levels and bone mineral density in elderly men (Khosla et al 1998).

In normal men small amounts of oestradiol (15% of the total daily production) are derived from direct secretion from the testis; about equal amounts of oestradiol are synthesized in adipose tissue, muscle, skin, breast and liver, as well as indirectly from adrenal androgens via the conversion of androstenedione to oestrone to oestradiol or by peripheral aromatization of testosterone to oestradiol (MacDonald et al 1979). Bioavailable oestradiol decreases dramatically with age in community-dwelling men, independent of body size, health and chronic disease (Ferrini & Barrett-Connor 1998). In our population of elderly men, we also found strong positive relations between serum oestradiol and bone mineral density. In addition, however, we observed a strong positive relation between serum oestradiol concentrations and life satisfaction. It remains to be examined whether oestradiol has a central action on the brain, or whether this relationship represents an indirect effect of oestradiol on physical characteristics, which in turn lead to a better quality of life. Only a few studies have examined the relation between oestrogens and atherosclerosis in men (Price et al 1997). Oestrogens may offer some degree of protection against cardiovascular disease by influencing the lipid profile (Bagatell et al 1994, Giri et al 1998). The relationship between this decline in endogenous oestradiol levels and fragility, impaired functioning and chronic diseases (such as osteoporosis, diabetes, cancer, prostate and heart disease) should be the focus of future research.

Adrenopause

DHEA in its free, sulfated and lipoidal forms is the most abundant steroid secreted by the zona reticularis of the adult human adrenal. Circulating DHEAS levels in healthy adults are more than 10 times higher than those of cortisol (Ravaglia et al

1996). It is well known that ageing is associated with a marked decrease of the adrenal androgens DHEA and its sulfate (Orentreich et al 1984, Labrie et al

1997). DHEA is a universal precursor for androgenic and oestrogenic steroid formation in peripheral tissues, which contain a number of DHEA-metabolizing enzymes (Herbert 1995). A variety of factors influence Cortisol and DHEA levels: obesity, meals, insulin, stress, alcohol and smoking all alter adrenal steroid levels.

DHEA has been called 'the Fountain of Youth'. However, despite the abundance of DHEA and DHEAS in human serum, it remains unclear whether they play a functional role in the ageing process, either directly or through conversion into other steroids. Our knowledge of the functions of adrenal hormones is mainly derived from animal studies. Studies in rodents, which have very low circulating DHEAS levels, suggest that DHEA administration prevents obesity, diabetes mellitus, cancer and heart disease, while it enhances immune function. Supportive data in humans are limited, highly controversial and as yet unresolved.

Functional parameters of daily living in males over 90 years old were lowest in those with the lowest DHEAS levels (Ravaglia et al 1996). In a group of independent community-dwelling older men, men in the highest quartile of serum DHEAS concentrations were leaner, more fit and had a favourable lipid profile compared with those in the lowest quartile (Abbasi et al 1998). In our population of independently living men, a significant relationship between serum DHEAS and bone mineral density became non-significant after adjustment for oestradiol or testosterone, suggesting that any potential effect on bone mineral density is indirect through the conversion of DHEAS into androgens and oestrogens. Serum DHEA(S) levels in the same population were not related to self-reported disability, physical performance, muscle strength or body composition, nor to quality of life.

Administration of 50 mg DHEA to elderly men leads to serum DHEAS concentrations similar to those in healthy adults, while circulating serum oestrogens significantly increase (Arlt et al 1999). This DHEA-induced increase in oestrogenic activity may contribute to the beneficial effects of DHEA in men. Two randomized placebo-controlled studies support the concept that oral administration of DHEA has beneficial effects (Baulieu 1995). Three months of daily treatment with 50 mg of DHEA in 20 adults, most of whom were non-elderly individuals (40—70 years old), increased DHEA(S) levels to young adult levels, increased plasma androgen and IGF1 concentrations, and induced a remarkable increase in perceived physical and psychological well-being in both sexes without an effect on libido. In a subsequent study, 100 mg of DHEA given daily for 6 months to 9 men and 10 women increased lean body mass in both sexes but increased muscle strength in men only (Morales et al 1998). In a randomized, double-blind, placebo-controlled trial among 140 elderly men and 140 elderly women (Baulieu et al 2000) it appeared that 50 mg DHEA a day for one year led to changes in bone mineral density in women but not in men. In addition, no effect of DHEA administration on vascular properties in elderly men was observed. A

nine month cross-over study in 39 elderly men, did not confirm the effects of the drugs publicized by others, such as on the sense of well-being (Flynn et al 1999). DHEA might influence CNS activity (Wolf et al 1998), although short-term DHEA replacement does not appear to improve cognition, memory, mood or well-being (Wolf et al 1997,1998).

Higher DHEAS levels are accompanied by a modestly reduced risk of death from cardiovascular disease in males (Barrett-Connor & Goodman-Gruen 1995, Feldman et al 1998). Data with regard to a protective effect of DHEA on cardiovascular disease in humans are conflicting and unresolved; studies using animal models, however, are quite promising. Animal studies also show that DHEA reverses the immuno-incompetence of aged animals. One study in humans indeed shows an activation of the immune system in elderly men. DHEA administration increased the number of monocytes and natural killer cells, and the functional activation of T cells (Khorram et al 1997).

Although neither Flynn et al (1999) or Baulieu et al (2000) demonstrated a change in prostate specific antigen concentration after DHEA replacement, it is so far unknown whether the increase in sex steroid levels induced by DHEA is safe with regard to the development of prostate, or other types of cancer.

DHEA has received great attention from the general population as potentially being able to increase the sense of well-being and sexual function, and to partially reverse the ageing process. So far, however, results are neither clear nor consistent. It seems prudent to await more trials, in order to be certain that exogenous DHEA is beneficial and can be used safely.

Somatopause

Growth hormone (GH) is an important anabolic hormone with stimulatory effects on protein synthesis and on lipolysis. In man both ageing and GH deficiency are associated with reduced protein synthesis, decreases in lean body mass and bone mass, and increases in body fat (Corpas et al 1993). In several studies of healthy individuals of a broad age range, an association was observed between the maximum aerobic capacity and circulating IGF1 levels (Papadakis et al 1995). Within the elderly population, however, cross-sectional studies have demonstrated weak or no correlations between measures of body composition and bone mass on the one hand, and serum IGF1 or GH levels on the other (Goodman-Gruen & Barrett-Connor 1997, Rudman & Shetty 1994). Similarly, largely negative findings have been reported concerning the association between IGF1 and muscle strength, and measures of functional ability (Papadakis et al 1995, Welle et al 1996). In our study in elderly men, we also failed to demonstrate a significant relationship between IGF1 and IGFBP3, and measures of physical functional status. We did, however, demonstrate strong inverse relationships between serum IGFBP2 concentrations and physical performance, muscle strength, lean body mass, fat mass and bone mineral density. A positive relationship was observed between IGFBP2 and self-reported disability. Serum IGFBP2 levels in an individual represent an integrative response to the nutritional state, 24 h GH-secretion, serum IGF1 and IGF2 concentration and, to a lesser extent, serum insulin concentrations (Clemmons 1997). Therefore low IGFBP2 levels might serve as an indicator of better overall functional physical status. As mentioned above, we did not find an association between the physical characteristics of ageing and serum IGFBP3 levels, which are mainly regulated by GH and therefore serve as an indicator of serum GH levels. We did, however, find a positive relationship between serum IGFBP3 levels and quality of life, measured with the questionnaire developed by Herschbach and Huber (Herschbach 1995, Huber et al 1988). In a study of 52 elderly men and 80 elderly women, positive correlations were observed between HDL cholesterol and IGFBP3 concentrations, which served as an index of GH secretion (Ceda et al 1998).

The expectation that somatopause contributes to the decline of functional capacity in the elderly is mainly derived from studies in which GH replacement therapy of GH-deficient adults was shown to increase muscle mass, muscle strength, bone mass and quality of life. A beneficial effect on the lipid profile and an important decrease in fat mass were also observed in such patients (Salomon et al 1989). The GH/IGF1 axis may also play a role in the age-related decline of certain cognitive functions (Aleman et al 1999).

GH administration for 3 to 6 months to healthy elderly individuals increased IGF1 levels to those observed in control individuals half their age, while muscle strength, muscle mass, skin thickness and bone mineral content significantly increased and fat mass decreased (Rudman et al 1990, Welle et al 1996). Unfortunately, GH replacement in 52 healthy older men did not improve muscle strength and functional ability (Papadakis et al 1996). If GH was administered in combination with resistance exercise training, however, a significant positive effect on muscle mass, muscle strength and bone mineral density was recorded but did not differ from that seen with placebo treatment, which suggests that GH does not add to the beneficial effects of exercise (Yarasheski et al 1995, 1997). Preliminary results of a randomized placebo-controlled trial of 6 weeks GH administration in elderly individuals with an acute hip fracture indicate that in individuals over 75 years old, GH administration causes a statistically significant earlier return to independent living after the fracture. Finally, it has to be mentioned that side effects of GH therapy are common, namely carpal tunnel syndrome, gynaecomastia and hyperglycaemia.

Other components in the regulation of the GH/IGF1 axis are effective in activating GH and IGF1 secretion. Long-acting derivates of the hypothalamic peptide growth hormone-releasing hormone (GHRH), given twice daily subcutaneously for 14 days to 70 year old healthy men, increased GH and IGF1 levels to those encountered in 35 year olds (Corpas et al 1992). These studies support the concept that somatopause is primarily hypothalamically driven and that pituitary somatotrops retain their capacity to synthesize and secrete high levels of GH. GH-releasing peptides (GHRPs) are oligopeptides with even more powerful GH-releasing effects. Originally developed by design, it has recently been suggested that they mediate their GH-secretory effects through endogenous specific receptors (Howard et al 1996). Non-peptide analogues such as MK-677 and L-692,429 have powerful GH-releasing effects, restoring IGF1 secretion in the elderly to levels encountered in young adults (Chapman et al 1996). Long-term oral administration of MK-677 to healthy elderly individuals increased lean body mass but not muscle strength. If proven to be GH-specific, these orally active GHRP derivates might be important alternatives to subcutaneously administered GH in the reversal of somatopause, the prevention of frailty, and the reversal of acute catabolism. The long-term safety of the activation of GH/IGF1 levels remains uncertain with regard to tumour growth, as most human solid cancers express IGF1 receptors (Chapman et al 1996).

Andro-, adreno- andsomatopause

Some of the changes in hormones concentrations of the different hormonal axes which take place during ageing occur in parallel. However, it is not known whether interrelations exist between the hormones of the different axes, or whether they independently influence the physiological changes during ageing. Interactions between these hormonal systems may play a physiologically relevant role in the elderly population in the management of age-associated alterations in physical performance, muscle strength and body composition. Compared with healthy young men, 80% of healthy young men are hyposomatomedinaemic (lowered IGF1 levels) and hypogonadal (lowered testosterone levels); compared with healthy old men, 30% of chronically institutionalized old men are both hyposomatomedinaemic and hypogonadal. In institutionalized old men, hyposomatomedinia and hypogonadism are usually of central origin, but their occurrences are not significantly associated (Abbasi et al 1993). Although few relationships were present between hormones of the different axes in the study of 403 independently living elderly men, the associations between hormone concentrations and physical characteristics were all independent. This implies that subjects with low IGF1/GH levels do not necessarily have low androgens or adrenal hormones. This suggests that changes in hormones concentrations of the different axes influence the ageing process independently, which is extremely important for the selection of subjects for the respective replacement therapies.

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