Aging in men results in progressive impoverishment of systemic androgen availability. Epidemiological data establish a close association between hypoandrogenemia and sarcopenia, osteopenia, visceral adiposity, insulin resistance, dyslipidemia, reduced quality of life and institutionalization. However, the precise mechanistic bases of reduced testosterone production in the older male are not known. The present proposal is predicated on the thesis that the male gonadal axis is regulated via reciprocal interactions among all three of GnRH, LH and testosterone. Interpreted from this vantage and compelling preliminary data, we postulate that the primary mechanisms of aging-related testosterone depletion include the following: HYPOTHESIS I: Restricted hypothalamic GnRH drive, which reduces the mass of LH contained in pulses. HYPOTHESIS II: Impaired Leydig-cell steroidogenesis, which enforces systemic hypoandrogenemia. HYPOTHESIS III: Reduced negative feedback by testosterone, which unleashes high-frequency, low- amplitude and irregular LH release. The immediate objective is to elucidate the relative timing, importance and prevalence of the foregoing putative regulatory deficits in the same 40 individuals as a function of age within the continuum 18-80 yr. These data will drive formulation of an R01 to investigate age-related adaptations in the gonadal axis longitudinally. The long-term goal is to stimulate novel insights into mechanistically selective preventive strategies to preserve anabolic support and enhance quality of life, physical and cognitive function and capable independent activities of older citizens. PUBLIC PRECIS. Studies focus on what causes low sex-hormone levels in older men. Low testosterone is important, because it predicts relative physical frailty (thin bones, reduced muscle strength and stamina), less life satisfaction, greater abdominal fat gain and increased cardiovascular risk. Knowing why testosterone falls should help foster new and safer ways to prevent the problem. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG023777-02
Application #
7229802
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Sherman, Sherry
Project Start
2006-03-01
Project End
2009-02-28
Budget Start
2007-06-15
Budget End
2009-02-28
Support Year
2
Fiscal Year
2007
Total Cost
$176,776
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Keenan, Daniel M; Clarke, Iain J; Veldhuis, Johannes D (2011) Noninvasive analytical estimation of endogenous GnRH drive: analysis using graded competitive GnRH-receptor antagonism and a calibrating pulse of exogenous GnRH. Endocrinology 152:4882-93
Iranmanesh, Ali; Mulligan, Thomas; Veldhuis, Johannes D (2010) Age in men does not determine gonadotropin-releasing hormone's dose-dependent stimulation of luteinizing hormone secretion under an exogenous testosterone clamp. J Clin Endocrinol Metab 95:2877-84
Veldhuis, Johannes D; Keenan, Daniel M; Liu, Peter Y et al. (2010) Kinetics of removal of intravenous testosterone pulses in normal men. Eur J Endocrinol 162:787-94
Veldhuis, Johannes D; Keenan, Daniel M; Pincus, Steven M (2010) Regulation of complex pulsatile and rhythmic neuroendocrine systems: the male gonadal axis as a prototype. Prog Brain Res 181:79-110
Veldhuis, Johannes D; Takahashi, Paul Y; Keenan, Daniel M et al. (2010) Age disrupts androgen receptor-modulated negative feedback in the gonadal axis in healthy men. Am J Physiol Endocrinol Metab 299:E675-82
Liu, Peter Y; Keenan, Daniel M; Kok, Petra et al. (2009) Sensitivity and specificity of pulse detection using a new deconvolution method. Am J Physiol Endocrinol Metab 297:E538-44
Liu, Peter Y; Takahashi, Paul Y; Roebuck, Pamela D et al. (2009) Testosterone's short-term positive effect on luteinizing-hormone secretory-burst mass and its negative effect on secretory-burst frequency are attenuated in middle-aged men. J Clin Endocrinol Metab 94:3978-86
Aksglaede, Lise; Jensen, Rikke Beck; Carlsen, Elisabeth et al. (2008) Increased basal and pulsatile secretion of FSH and LH in young men with 47,XXY or 46,XX karyotypes. Eur J Endocrinol 158:803-10
Veldhuis, Johannes D; Keenan, Daniel M; Pincus, Steven M (2008) Motivations and methods for analyzing pulsatile hormone secretion. Endocr Rev 29:823-64
Takahashi, Paul Y; Votruba, Patrick; Abu-Rub, Mohammed et al. (2007) Age attenuates testosterone secretion driven by amplitude-varying pulses of recombinant human luteinizing hormone during acute gonadotrope inhibition in healthy men. J Clin Endocrinol Metab 92:3626-32

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