<30 30-39 40-49 50-59 60-69 70-79 80+ Age, years

FIG. 5. Changes in sex hormone binding globulin (SHBG) in ageing men. Note the progressive increase in SHBG which binds to approximately 50% of total serum oestrogen or serum testosterone, rendering it largely unavailable to target tissues. The remaining 50%, which is bound to albumin or is free, is bioavailable. Thus, the progressive increases in serum SHBG with ageing are a major reason for the progressive deficiency in bioavailable testosterone and oestrogen in ageing men. Error bars represent SEM. (With permission from Riggs et al 2000.)

mechanisms for the increase in serum SHBG are complex but are probably due, in part, to decreases in production of growth hormone and IGF1 coupled with an impaired gondal secretory reserve (Table 5). Thus, as assessed by their free or bioavailable levels, about half of elderly males have a substantial deficiency of oestrogen and testosterone, and, in general, these are the ones that are losing bone (Khoslaet al 2000).

TABLE 5 Differences between genders: mechanisms of sex steroid deficiency




Oestrogen deficiency Testosterone deficiency A, SHBG Mechanism

Begins acutely at menopause Gradual and progressive

(a) Inactivation by SHBG

(b) Impaired hypothalamic,

Ovarian failure pituitary, gonad axis

Data from several recent 'experiments of nature' are consistent with the concept that oestrogen plays a major role in maintaining bone mass in men. A young adult who was unable to respond to oestrogen because of homozygous mutations of oestrogen receptor a genes (Smith et al 1994) and two young adults who were unable to synthesize oestrogen because of homozygous mutations of the aromatase genes (Carani et al 1997, Morishima et al 1997) had osteopenia despite normal or elevated levels of testosterone. Moreover, Vanderschueren et al (1997) found no differences in the effects of orchiectomy or treatment with aromatase inhibitor on decreasing bone density in aged male rats, suggesting that the aromatization of androgens to oestrogens was playing a major role in skeletal maintenance.

Four recent population-based, observational studies (Khosla et al 1998, Slemenda et al 1997, Center et al 1997, Greendale et al 1997) involving an aggregate total of 1410 men from young adulthood to old age found by multivariate analysis that free serum oestrogen rather than free serum testosterone was the main predictor of bone mass at all measured sites except some cortical bone sites in the appendicular skeleton. Khosla et al (2000) have also demonstrated that this also applies to the rate of bone loss in elderly men. Finally, our group (Falahati-Nini et al 2000) has recently shown that when a group of elderly men were pharmacologically rendered hypogonadal and their aromatase activity was blocked, oestrogen, but not testosterone, prevented an increase in bone resorption markers. Collectively, these studies provide convincing evidence that a deficiency in oestrogen is a major cause of bone loss in ageing men. Interestingly, Bernecker et al (1995) found that mean levels of serum oestrogen but not testosterone were significantly reduced in 56 men with established idiopathic osteoporosis.

Collectively, these data support the hypothesis that oestrogen deficiency plays a major role in involutional bone loss in men as well as in women. However, testosterone clearly accounts for the sexual dimorphism of the skeleton that develops following puberty and probably also stimulates the subsequent periosteal growth of cortical bone (Seeman 1997). In addition, we (Khosla et al 1998) have found that testosterone deficiency is the main determinant of the predominantly cortical bone mass of the appendicular skeleton. More studies must be made to define the additional effects of testosterone on the male skeleton and to determine the relative contributions of deficiencies of oestrogen and testosterone in causation of the slow phase of bone loss in ageing men.

The probable mechanisms by which sex steroid deficiency produces bone loss in ageing men are shown in Fig. 2B.

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