Androgen deficiency in men is associated with reduced physical stamina, relative sarcopenia, osteopenia, visceral obesity, sexual dysfunction, depressed mood, reduced sense of well-being, and detectable cognitive impairment (1-10). Impoverished testosterone production in the older male has been affirmed by (1) direct sampling of the human spermatic vein, (2) meta-analysis of cross-sectional epidemiological data (11), and (3) longitudinal investigations in healthy populations (12-15). For example, the European SENIEUR and Massachusetts Male Aging Cohort studies inferred that bioavailable (non-sex hormone-binding globulin [SHBG]-bound) testosterone concentrations decline by 0.8-1.3% annually (13,16), and, a 15-yr prospective analysis in New Mexico observed that total testosterone concentrations fall by 110 ng/dL per decade in men after age 60 (14,17). Surgery, trauma, stress, systemic illness, medication use, and chronic institutionalization exacerbate androgen depletion in elderly individuals (6,8,13,18-21). However, the fundamental mechanisms that mediate waning testosterone secretion in aging men are unknown. Indeed, a unified physiological concept has been difficult to develop in this arena.

Available data point to an array of contributing mechanisms underlying relative androgen depletion in the older male (22-33). Primary (nonexclusive) considerations include reduced hypothalamic GnRH outflow, limited gonadotrope secretory capacity, impaired Leydig cell steroidogenesis, and anomalous androgen-directed feedback control (34-37).

As a unifying approach, the male gonadal axis is viewed as an adaptive neuroendocrine ensemble. In this broader concept, testosterone availability is adjusted on a minute-by-minute basis by repeated decremental and incremental signaling interactions among GnRH, LH, and testosterone (see Fig. 1). Simplified biomathematical simulations based on this network-like perspective predict that hypoandrogenemia and altered LH secretion in aging could arise singly or jointly by way of (1) attenuated hypothalamic GnRH feedforward drive (albeit not acting alone), (2) impaired Leydig cell steroidogenesis, and/or (3) reduced negative feedback by testosterone (38-40). Figure 2 highlights the foregoing primary mechanistic considerations.

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