Aging in men results in progressive impoverishment of systemic androgen availability. Based on current estimates of free and bioavailable testosterone concentrations, approximately 30% of healthy men aged 60 and 50% aged 80 years are testosterone deficient by young-adult standards. Epidemiological data establish a close association between hypoandrogenemia and sarcopenia, osteopenia, increased visceral adiposity, reduced quality of life and institutionalization. However, the precise mechanistic bases of reduced testosterone production in the older male are not known. The present proposal is predicated on the thesis that the male gonadal axis operates via regulated and reciprocal interactions among all three of GnRH, LH and testosterone. Interpreted from this vantage, published literature, laboratory experiments, background data and ensemble feedback/feed forward simulations predict that hydroandrogenemia in aging men could arise nonexclusively by way of: (i) reduced hypothalamic GnRH outflow; (ii) impaired Leydig-cell steroidogenesis; and (iii) altered testosterone-enforced negative feedback. To investigate the primary mechanisms of aging-related testosterone depletion, we pose the following three testable clinical hypotheses: HYPOTHESIS I: Reduced hypothalamic GnRH drive underlies low-amplitude LH pulses in older men. This postulate will be tested by comparing inhibitory susceptibility of endogenously GnRH-driven LH secretory-burst mass to escalating doses of a selective GnRH-receptor antagonist (ganirelix) in aging and young individuals. HYPOTHESIS II: Impaired Leydig-cell steroidogenesis accentuates hypoandrogenemia in aging. To appraise this issue, we will compare the (24-h) testosterone secretory response by age to an experimentally normalized lutropic stimulus achieved by pulsatile i.v. infusion of rh LH under GnRH-receptor blockade for 5 days. HYPOTHESIS Ill: The low androgen-feedback milieu in aging men contributes to high frequency, low amplitude and irregular patterns of LH release. This concept will be examined by quantitating LH secretory adaptations in young and older men to a novel dose-stratified clamp of plasma bioavailable testosterone concentrations. The long-term goal of mechanistic understanding of aging-related hypogonadism is to stimulate novel insights into interventional strategies to preserve quality of life, physical and cognitive function and capable independent activities of older citizens. Expected corollary outcomes are enhanced diagnosis, assessment and management of more subtle pathophysiology of the male gonadal axis in puberty and adulthood.
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