RESUMO
Aging results in insidious decremental changes in hypothalamic, pituitary and gonadal function. The foregoing three main anatomic loci of control are regulated by intermittent time-delayed signal exchange, principally via gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and testosterone/estradiol (Te/E(2)). A mathematical framework is required to embody these dynamics. The present review highlights integrative adaptations in the aging male hypothalamic-pituitary-gonadal axis, as assessed by recent objective ensemble models of the axis as a whole.
Assuntos
Envelhecimento/fisiologia , Retroalimentação Fisiológica/fisiologia , Gônadas/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Fluxo Pulsátil/fisiologia , Envelhecimento/sangue , Envelhecimento/metabolismo , Animais , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismo , Masculino , Modelos Biológicos , Testosterona/sangue , Testosterona/metabolismoRESUMO
Testosterone (Te) production declines in the aging male, albeit for unknown reasons. Plausible mechanisms include reduced secretion of GnRH, less feedforward by LH, and/or altered feedback by systemic Te. The present study tests all three postulates in a cohort of 10 young (20-35 yr old) and eight older (50-72 yr old) men. The experimental paradigm comprised graded blockade of the GnRH receptor to create four distinct strata of LH and Te pulsatility in each subject. A novel analytical formalism was developed to reconstruct implicit dose-response functions linking 1) virtual GnRH outflow positively to LH secretion, 2) LH pulses positively to Te secretion, and 3) Te concentrations negatively to the size and number of LH secretory bursts. Validation was by direct pituitary sampling in the horse and sheep. Statistical comparisons disclosed that age decreased the efficacy of each of 1) virtual GnRH outflow (P < 0.01), 2) LH drive of Te secretion (P < 0.01), and 3) total, bioavailable and free Te feedback on GnRH-driven LH secretion (P = 0.015). In contrast, age increased the potency of virtual GnRH feedforward (P = 0.013) and did not affect Te's inhibition of LH pulse frequency. Unexplained variance was less than 10%. Robustness was shown by resampling techniques. Accordingly, competitive silencing of one locus of control and ensemble-based analyses identified triple regulatory deficits in the aging male gonadal axis. The generality of the present integrative model suggests utility in parsing interlinked adaptations in other physiological networks.