The aging male hypothalamic–pituitary–gonadal axis: Pulsatility and feedback

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Abstract

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/E2). 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.

Introduction

Although recognized biochemically nearly 60 years ago, the fundamental bases of androgen depletion in the aging male remain unknown (Veldhuis et al., 2004a). Testosterone (Te) deficiency has been associated epidemiologically with skeletal muscle weakness, sarcopenia, osteopenia, diminished physical stamina, erectile dysfunction, systolic hypertension, carotid artery-wall thickness, increased abdominal visceral-fat mass, insulin resistance, reduced HDL concentrations, postprandial somnolence, impaired quality of life, depressive mood, diminished working memory, and decreased executive–cognitive function (Liu et al., 2004, Liu et al., 2005a, Veldhuis et al., 2007) (Fig. 1). In meta-analyses, low Te availability correlates with reduced grip strength, decreased lean-body mass and increased visceral adiposity (Bhasin et al., 2006, Isidori et al., 2005, Liverman and Blazer, 2004), which are significantly reversed by Te supplementation. Whether androgen replacement is indicated in older men without frank hypogonadism is not established (Liu et al., 2004). Moreover, the mechanisms that mediate hypoandrogenemia in the elderly male are only partially understood.

Section snippets

Clinical Te deprivation in aging

Impoverished Te production in older men has been documented by (i) direct sampling of the spermatic vein, (ii) meta-analysis of cross-sectional data (Gray et al., 1991), and (iii) longitudinal investigations in healthy cohorts (Harman et al., 2001, Morley et al., 1997). Total Te concentrations fall by approximately 110 ng/dL (3.8 nmol/L) per decade in men after age 60, bioavailable (nonSHBG-bound) Te concentrations by 8–13% (0.7–1.0 nmol/L) per decade, and free Te concentrations by a similar

Need for mechanistic understanding of gonadal axis as a whole

As articulated by the U.S. Institute of Medicine and World Health Organization (Liu et al., 2004, Liverman and Blazer, 2004, World Health Organization, 2001), investigations are required to unveil the primary mechanisms mediating gradual Te depletion in the aging male. This is because both the absolute number and the proportion of men aged 60 or older will increase significantly over the next 50 years in industrialized countries. An important research goal is to identify potentially reversible

Theoretical feedback and feedforward models

Biomathematical constructs of feedback (inhibitory) and feedforward (stimulatory) dose–response pathways interlinking GnRH, LH and Te may assist in visualizing dynamic interactions that maintain euandrogenism (Keenan et al., 2003, Keenan and Veldhuis, 1998, Keenan and Veldhuis, 2001a, Keenan and Veldhuis, 2001b) (Fig. 4). One analytical formalism was validated by sampling hypothalamo-pituitary, jugular and spermatic-vein hormone release in three mammalian species (Keenan et al., 2004, Keenan et

Experimental insights

Although multiple sites of impaired regulation probably coexist in the aging hypothalamic–pituitary–gonadal axis, the following section for clarity reviews each potential locus of failure individually.

Utility of paradigmatic and analytical advances

Combined paradigmatic and analytical advances have resolved some earlier controversies, and introduced new research opportunities. One noninvasive paradigm entails creating four graded strata of Te and estrogen feedback by variably suppressing endogenous GnRH action with a competitive GnRH-receptor antagonist (Liu et al., 2006a, Liu et al., 2006b) (Fig. 5A). The analytical component requires estimation of a 3-dimensional dose–response surface linking GnRH outflow and LH secretion to the Te

Conclusion and future directions

Basic research provides the foundation and clinical medicine the motivation to elucidate fundamental causes of hypoandrogenism in the older male. Future studies need to quantify control mechanisms at the systems level (full hypothalamic–pituitary–gonadal axis) using increasingly innovative experimental strategies. Two major unanswered questions are whether multiple mechanisms of regulatory failure emerge sequentially or simultaneously during the aging process, and the extent to which regulatory

Acknowledgments

We thank Kay Nevinger and Donna Scott for support of manuscript preparation; Ashley Bryant for data analysis and graphics; the Mayo Immunochemical Laboratory for assay assistance; and the Mayo research nursing staff for implementing the protocol. Supported in part via the Center for Translational Science Activities (CTSA) Grant Number 1 UL 1 RR024150, RR019991 from the National Center for Research Resources (Rockville, MD), and AG23133, AG029362, DK072095 and DK063609 from the National

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