An ensemble perspective of aging-related hypoandrogenemia in men

Abstract

Aging is associated with changes in pituitary testicular function in men which are partly explained by changes in the testis and by comorbidities, body weight, nutrition, and the presence of diabetes mellitus. The 0.8–1.3% annual fall in nonSHBG bound “bioavailable” testosterone levels results in a reduction of 30–50% by the sixth to eighth decades of life. Low testosterone concentrations are associated with relative sarcopenia, osteopenia, visceral fat accumulation, reduced sexual function, detectable cognitive impairment, and variable depression of mood. Accordingly, the mechanisms driving the progressive decline in androgens are important to understand. To this end, we highlight age-associated alterations in three dominant sites of physiological control; viz., the hypothalamus, pituitary gland, and testis. The cognate signals are gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and testosterone, which jointly determine androgen availability via feedback and feedforward adaptations. According to this emergent notion, no single gland acts in isolation to maintain homeostasis. We underscore an integrative concept by highlighting how aging-related testosterone depletion is an ensemble outcome of deterioration of interlinked control.