Mechanisms of ensemble failure of the male gonadal axis in aging

The systemic availability of testosterone (Te) falls by 35-50% after the sixth decade of life in healthy men. Intercurrent illness, trauma, surgery, stress, weight loss, diverse medications and institutionalization reduce Te concentrations further. Impoverishment of anabolic drive probably contributes to physical frailty and diminished quality of life in older individuals. However, the fundamental mechanisms that mediate hypoandrogenemia in the aging male remain unknown. Recent clinical experiments offer new clues to the mechanistic bases of Te depletion in older men. In particular, the following attributes mark aging-related Te withdrawal: (a) high-frequency and low-amplitude LH pulses; (b) disorderly LH-release patterns, consistent with feedback disruption; (c) normal or heightened LH secretion following single or repeated GnRH stimuli; (d) reduced Te secretory-burst mass with normal basal Te secretion; and (e) impaired Leydig-cell Te production in response to secreted LH pulses (stimulated by flutamide, tamoxifen, GnRH or anastrozole) and infused (recombinant human) LH pulses. The foregoing interconnected findings allow us to frame the integrative postulate that androgen deprivation in the older male reflects multisite failure in the GnRH-LH-testosterone axis. The most proximate locus of impairment is not yet known.