An Ensemble Model of the Male Gonadal Axis: Illustrative Application in Aging Men

Abstract

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.

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…Several studies have provided evidence that loss of Leydig cell population in the adult human testis as a function of increasing age is caused by Leydig cell hyperplasia, dedifferentiation, degeneration and dissolution [151][152][153]. In addition, there is evidence for an impaired hypothalamic GnRH outflow and decreased pulse generation of GnRH, with pulses being generated more irregularly, normal or enhanced LH secretion when stimulated by exogenous GnRH pulses, reduced pulsatile LH-stimulated testosterone synthesis, and decreased negative feedback in older men [131,132,[154][155][156]. From the above discussion, it is quite apparent that multiple alterations in hypothalamic-pituitary-testicular axis lead to the age-related decline in testosterone synthesis and secretion.…”

Age-associated changes in hypothalamic–pituitary–testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study

“…Individual hormones of the hypothalamic-pituitary-testicular (HPT) axis are tightly regulated by feedback / feedforward relationships (16). Different components of HPT function may 'age' differently and/or respond differentially to health and lifestyle modifications.…”

Analysis of the impact of intravenous LH pulses versus continuous LH infusion on testosterone secretion during GnRH-receptor blockade

“…Whether small frequent LH pulses or continuous LH delivery into the bloodstream is less effective than larger infrequent LH pulses in driving T secretion is not known. The issue is central to the broader theme of pulsatility regulation and action in endocrine systems (17,20,54). Indeed, growth hormone (GH), ACTH, parathyroid hormone (PTH), insulin, and oxytocin drive certain target-tissue responses in a pulse-dependent fashion (54).…”

“…Selected analytical tools (deconvolution analysis, exponential T recovery rate, and approximate entropy) were used to quantify T responses more precisely than mean T concentrations alone (19,20,29).…”

“…The issue is central to the broader theme of pulsatility regulation and action in endocrine systems (17,20,54). Indeed, growth hormone (GH), ACTH, parathyroid hormone (PTH), insulin, and oxytocin drive certain target-tissue responses in a pulse-dependent fashion (54).…”