Mechanisms of conjoint failure of the somatotropic and gonadal axes in ageing men

J. D. Veldhuis*, A. Iranmaneshf, T. Mulligan{ and C. Y. Bowers}

*Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202, {Endocrine Section, Salem Veterans Affairs Medical Center, Salem, Virginia 24153, { Geriatrics and Extended Care Service, McGuire Veterans Affairs Medical Center, Richmond, Virginia 23249, and }Department of Medicine SL53, Tulane University Medical Center, New Orleans, Louisiana 70112-2699, USA

Abstract. Endogenous growth hormone (GH) production falls by 50% every 7 years and bioavailable testosterone concentrations decline concomitantly by 12—15% every decade in ageing men. Despite this temporal parallelism, the neuroendocrine bases of the somatopause and gonadopause are not known. This knowledge deficit contrasts with the recent unfolding of new insights into the nature of oestrogen-dependent control of the GH—insulin-like growth factor (IGF)1 axis in pre- and postmenopausal women. The present overview examines the postulate that the pathophysiology of somatopause and gonadopause in ageing men is bidirectionally linked. According to this broader thesis, hyposomatotropism accentuates Leydig cell steroidogenic failure and, conversely, progressive androgen deficiency exacerbates the decline in GH—IGF1 output in ageing.

2002 Endocrine facets of ageing. Wiley, Chichester (Novartis Foundation Symposium 242) p98-124

Clinical features of ageing include variably impaired psychological well being, cognitive function and quality of life; decreased libido and/or sexual function; reduced physical productivity; diminished muscle and bone mass; and increased visceral obesity, dyslipidemia and risk of cardiovascular events. These attributes collectively heighten the potential for frailty, disability, suffering and loss of independent living status. From an endocrine perspective, ageing in the male is accompanied by a progressive and dual decline in the bioavailability of growth hormone/insulin-like growth factor (IGF)1 and testosterone, which otherwise jointly support tissue anabolism (Iranmanesh et al 1994, Veldhuis et al 1995; Fig. 1). The terms somatopause and gonadopause highlight the foregoing age-related impoverishment of GH/IGF1 and androgen output, respectively.

° concentration (ng/dL)

FIG. 1. (Left) Relationship between overnight serum bioavailable testosterone and GH concentrations in a group of 10 young and older healthy men (Mulligan et al 1999a, Veldhuis et al 1999b, 2000b). (Right) Correlations between serum total testosterone and 24 h GH and IGF1 output in a cohort of 46 healthy pubertal boys (Martha et al 1992).

° concentration (ng/dL)

FIG. 1. (Left) Relationship between overnight serum bioavailable testosterone and GH concentrations in a group of 10 young and older healthy men (Mulligan et al 1999a, Veldhuis et al 1999b, 2000b). (Right) Correlations between serum total testosterone and 24 h GH and IGF1 output in a cohort of 46 healthy pubertal boys (Martha et al 1992).

However, virtually nothing is known about the basic clinical pathophysiology underlying the interlinked attrition of these pivotal trophic—hormone axes in ageing.

The present overview develops the bipartite thesis that ageing-associated hyposomatotropism and hypogonadism arise from conjoint pathophysiologies. We hypothesize that failing GH/IGF1 output worsens the age-related decline in luteinizing hormone (LH)-stimulated testicular steroidogenesis, and, conversely, that waning androgen availability blunts hypothalamo—pituitary drive of the GH/ IGF1 axis. This notion reflects extensive basic science and clinical data (examined below), which collectively indicate that GH and androgen show anabolic synergy and mechanistic coupling in normal physiology.

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