Aging and hormones of the hypothalamo-pituitary axis: gonadotropic axis in men and somatotropic axes in men and women

Abstract

Neuroendocrinology of the aging (male) gonadal and (male and female) somatotropic axes will be reviewed. A companion chapter discusses reproductive hormonal changes in aging women. Both the gonadal and growth-hormone/insulin-like growth factor (GH/IGF-I) axes function as ensembles. The ensembles comprise tripartite interactions among the brain (hypothalamus), anterior pituitary gland (gonadotrope and somatotrope cells) and target organs (testis, liver, muscle, fat and brain). Compelling evidence indicates that combined hypothalamic and gonadal adaptations operate in the reproductive axis of older men, and multiple hypothalamic adaptations prevail in the GH axis of elderly men and women. Evolving investigative methods allow more precise parsing of the particular mechanisms that subserve such age-related changes, and suggest novel interventional strategies to evaluate the physiological impact of the dynamic alterations discerned in aging individuals.

Figure 1

Epidemiological associations reported with androgen deficiency. Unpublished summary. CNS = central nervous system, LV = left ventricle, CT = computed tomography

Figure 2

Impact of age in cross-sectional analyses of total, bioavailable and free Te concentrations in healthy men in Olmsted County, MN. To convert ng/dL to international units (nmol/L), multiply by 0.0347. Unpublished.

Figure 3

Principal mechanistic alterations in aging male gonadal axis deduced to date. Unpublished précis. CNS = central nervous system, GnRH = gonadotropin-releasing hormone, Te = testosterone, SHBG = sex-hormone binding globulin, LH = luteinizing hormone

Figure 4

Male anabolic axis from a clinical perspective (left) and analytical vantage (right). CNS, GnRH, Te, SHBG and LH are defined in Figure 3.

Figure 4

Male anabolic axis from a clinical perspective (left) and analytical vantage (right). CNS, GnRH, Te, SHBG and LH are defined in Figure 3.

Figure 5

Fifty percent reduction in fasting GH concentrations and secretion rates (Panel A) and peptide-driven GH pulses (Panel B) in postmenopausal compared with premenopausal women evaluated during a 3-week E₂ clamp emulating the late follicular phase in the young adult. Reprinted with permission from (Erickson et al. 2004).

Figure 6

Ensemble construct of core linkages among ghrelin (GHRP), GHRH, SS and GH feedback. D₁ and D₂ are feedback delays. GHRH = GH-releasing hormone, GHRP = GH-releasing peptide; SS = somatostatin; ArC = arcuate nucleus; PeV = periventricular nucleus; +, stimulatory; −, inhibitory. Adapted from (Farhy and Veldhuis 2005).

Figure 7

Summary of experimentally inferred actions of E₂ on regulated GH secretion. Unpublished compilation. GHRH, GHRP and SS are defined in the legend of Figure 6. The terms ID₅₀ and ED₅₀ denote inhibitory and stimulatory potencies, respectively.

Figure 8

Administration of recombinant human GHRH for 3 mo twice daily increases fat-free (lean-body) mass (Panel A) and total body water (tritium spaces), and decreases total abdominal fat mass (Panel B).

Figure 9

Continuous GHRP-2 (a ghrelin analog) infusion for 30 days drives 24-h GH secretion in older men and women (Bowers et al. 2004).

Figure 10

Panel A. Regression of pulsatile GH secretion on abdominal visceral fat mass (AVF) estimated by computed tomography (CT) in pre- and postmenopausal (PRE and POST) women exposed to gonadal downregulation and E₂ repletion (Erickson et al. 2004). Panel B. Unstimulated (saline/saline) and maximal paired secretagogue-induced GH secretion during an E₂ clamp in 8 POST and 10 PRE women. Note differing y-axis scales. Data are the mean ± SEM. Adapted from (Erickson et al. 2004). Panel C. Reduced baseline (saline/saline) and GHRH/GHRP-2-stimulated GH secretion in POST compared with PRE women administered leuprolide and placebo to enforce a low-E₂ clamp (Veldhuis et al. 2005b).

Figure 11

New variable-waveform deconvolution method comprising incremental smoothing to create candidate sets of pulse times, T_i (Panel A), and nonlinear estimation of all secretion and elimination parameters simultaneously (Panel B). The algorithm was validated experimentally and verified mathematically (Keenan et al. 2003; Keenan et al. 2005; Keenan et al. 2004). AIC and BIC refer to the Akaike and Bayesian information criteria, respectively. Greek symbols denote parameters of secretion, elimination and random effects. Unpublished line drawings.

Figure 12

Panel A. Illustrative 24-h GH concentration profiles in a young (23 yr-old) and older (68 yr-old) man given placebo, low Te and higher Te parenterally for 2 wk in randomly assigned order at least 6 wk apart (Gentili et al. 2002). Panel B. Six months of near-physiological testosterone supplementation compared with placebo (Pl) increases overnight pulsatile GH secretion in older men (Muniyappa et al. 2007).

Figure 13

Panel A. Reduced unstimulated (baseline) GH secretion and GHRP-2-stimulated GH secretion in older men in the absence and presence of exogenous GH feedback. Data are GH concentration profiles in one young (age 22 y), middle-aged (age 36 y) and older (age 67 y) man [rows, top-to-bottom], each studied on 4 different mornings fasting [columns, left-to-right]. The 4 sessions comprised consecutive iv infusion of saline/saline, saline/GHRP-2, rh GH/saline or rh GH/GHRP-2. Data reflect sampling every 10 min for 5 h beginning at 0800 h clock time (zero min on x axis). Panel B. Age reduces fractional (%) inhibition of GH secretion by a fixed pulse of recombinant human (rh) GH compared with saline.