Mechanistic bases for age-related androgen deficiency

Summary

Principal Investigator: Johannes Veldhuis
Abstract: [unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-03-01 - 2009-02-28
more information: NIH RePORT

Top Publications

  1. pmc Age disrupts androgen receptor-modulated negative feedback in the gonadal axis in healthy men
    Johannes D Veldhuis
    Mayo School of Graduate Medical Education, Mayo Clinic, 200 First St SW Mayo Clinic, Rochester, MN 55905, USA
    Am J Physiol Endocrinol Metab 299:E675-82. 2010
  2. ncbi Regulation of complex pulsatile and rhythmic neuroendocrine systems: the male gonadal axis as a prototype
    Johannes D Veldhuis
    Department of Medicine, Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota, United States of America
    Prog Brain Res 181:79-110. 2010
  3. pmc Age in men does not determine gonadotropin-releasing hormone's dose-dependent stimulation of luteinizing hormone secretion under an exogenous testosterone clamp
    Ali Iranmanesh
    Endocrine Section, Department of Medicine, Salem Veterans Affairs Medical Center, Salem, Virginia 24153, USA
    J Clin Endocrinol Metab 95:2877-84. 2010
  4. pmc Kinetics of removal of intravenous testosterone pulses in normal men
    Johannes D Veldhuis
    Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota 55905, USA
    Eur J Endocrinol 162:787-94. 2010
  5. pmc 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
    Peter Y Liu
    Endocrine Research Unit, Mayo Medical School, Mayo School of Graduate Medical Education, Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905, USA
    J Clin Endocrinol Metab 94:3978-86. 2009
  6. pmc Sensitivity and specificity of pulse detection using a new deconvolution method
    Peter Y Liu
    Endocrine Research Unit, Department of Internal Medicine, Mayo Medical School, Mayo School of Graduate MedicalEducation, Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905, USA
    Am J Physiol Endocrinol Metab 297:E538-44. 2009
  7. pmc Motivations and methods for analyzing pulsatile hormone secretion
    Johannes D Veldhuis
    Endocrine Research Unit, Department of Internal Medicine, Mayo Medical School, Mayo School of Graduate Medical Education, Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905, USA
    Endocr Rev 29:823-64. 2008
  8. pmc Increased basal and pulsatile secretion of FSH and LH in young men with 47,XXY or 46,XX karyotypes
    Lise Aksglaede
    University Department of Growth and Reproduction GR, Rigshospitalet, University of Copenhagen, Section 5064, Blegdamsvej 9, DK 2100 Copenhagen Ø, Denmark
    Eur J Endocrinol 158:803-10. 2008
  9. ncbi A noninvasive measure of negative-feedback strength, approximate entropy, unmasks strong diurnal variations in the regularity of LH secretion
    Peter Y Liu
    Endocrine Research Unit, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, MN 55905, USA
    Am J Physiol Endocrinol Metab 293:E1409-15. 2007
  10. ncbi Age attenuates testosterone secretion driven by amplitude-varying pulses of recombinant human luteinizing hormone during acute gonadotrope inhibition in healthy men
    Paul Y Takahashi
    Endocrine Research Unit, Department of Internal Medicine, General Clinical Research Center, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
    J Clin Endocrinol Metab 92:3626-32. 2007

Scientific Experts

  • Johannes Veldhuis
  • Lise Aksglaede
  • Peter Y Liu
  • Daniel M Keenan
  • Ali Iranmanesh
  • Paul Y Takahashi
  • Pamela D Roebuck
  • Thomas Mulligan
  • Joy N Bailey
  • Petra Kok
  • Kevin T O'Byrne
  • Vasantha Padmanabhan
  • Mohammed Abu-Rub
  • Steven M Pincus
  • Patrick Votruba
  • Kristi Mielke
  • Ajay X Nehra

Detail Information

Publications11

  1. pmc Age disrupts androgen receptor-modulated negative feedback in the gonadal axis in healthy men
    Johannes D Veldhuis
    Mayo School of Graduate Medical Education, Mayo Clinic, 200 First St SW Mayo Clinic, Rochester, MN 55905, USA
    Am J Physiol Endocrinol Metab 299:E675-82. 2010
    ..001). These data suggest the hypothesis that topographically selective androgen receptor pathways mediate brain-predominant and pituitary-dependent feedback mechanisms in healthy men...
  2. ncbi Regulation of complex pulsatile and rhythmic neuroendocrine systems: the male gonadal axis as a prototype
    Johannes D Veldhuis
    Department of Medicine, Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota, United States of America
    Prog Brain Res 181:79-110. 2010
    ..In this manner, each neuroendocrine system is viewed as a whole, rather than the sum of individual parts...
  3. pmc Age in men does not determine gonadotropin-releasing hormone's dose-dependent stimulation of luteinizing hormone secretion under an exogenous testosterone clamp
    Ali Iranmanesh
    Endocrine Section, Department of Medicine, Salem Veterans Affairs Medical Center, Salem, Virginia 24153, USA
    J Clin Endocrinol Metab 95:2877-84. 2010
    ..Aging is associated with a decline in incremental LH pulse amplitude, which could be due to decreased GnRH secretion or impaired GnRH action...
  4. pmc Kinetics of removal of intravenous testosterone pulses in normal men
    Johannes D Veldhuis
    Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota 55905, USA
    Eur J Endocrinol 162:787-94. 2010
    ....
  5. pmc 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
    Peter Y Liu
    Endocrine Research Unit, Mayo Medical School, Mayo School of Graduate Medical Education, Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905, USA
    J Clin Endocrinol Metab 94:3978-86. 2009
    ..Testosterone (T) production declines and LH pulses become smaller and more frequent in middle-aged men. The mechanisms underlying these changes are not known...
  6. pmc Sensitivity and specificity of pulse detection using a new deconvolution method
    Peter Y Liu
    Endocrine Research Unit, Department of Internal Medicine, Mayo Medical School, Mayo School of Graduate MedicalEducation, Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905, USA
    Am J Physiol Endocrinol Metab 297:E538-44. 2009
    ..We conclude that an objective automated pulse detection deconvolution procedure has high sensitivity and specificity, thus offering a platform for quantitative neuroendocrine analyses...
  7. pmc Motivations and methods for analyzing pulsatile hormone secretion
    Johannes D Veldhuis
    Endocrine Research Unit, Department of Internal Medicine, Mayo Medical School, Mayo School of Graduate Medical Education, Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905, USA
    Endocr Rev 29:823-64. 2008
    ..This review will focus on the motivations driving and the methodologies used for such analyses...
  8. pmc Increased basal and pulsatile secretion of FSH and LH in young men with 47,XXY or 46,XX karyotypes
    Lise Aksglaede
    University Department of Growth and Reproduction GR, Rigshospitalet, University of Copenhagen, Section 5064, Blegdamsvej 9, DK 2100 Copenhagen Ø, Denmark
    Eur J Endocrinol 158:803-10. 2008
    ..The aim of this study was to investigate the neuroendocrine integrity of the pituitary-gonadal axis in patients with primary testicular failure due to supernumerary X chromosomes...
  9. ncbi A noninvasive measure of negative-feedback strength, approximate entropy, unmasks strong diurnal variations in the regularity of LH secretion
    Peter Y Liu
    Endocrine Research Unit, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, MN 55905, USA
    Am J Physiol Endocrinol Metab 293:E1409-15. 2007
    ..These outcomes suggest that ApEn may have general utility in probing dynamic mechanisms mediating feedback in other endocrine systems...
  10. ncbi Age attenuates testosterone secretion driven by amplitude-varying pulses of recombinant human luteinizing hormone during acute gonadotrope inhibition in healthy men
    Paul Y Takahashi
    Endocrine Research Unit, Department of Internal Medicine, General Clinical Research Center, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
    J Clin Endocrinol Metab 92:3626-32. 2007
    ..Whether testosterone (Te) depletion in aging men reflects deficits in the testis, hypothalamus, and/or pituitary gland is unknown...
  11. ncbi An ensemble model of the male gonadal axis: illustrative application in aging men
    Daniel M Keenan
    Department of Statistics, University of Virginia, Charlottesville, Virginia 22903, USA
    Endocrinology 147:2817-28. 2006
    ..The generality of the present integrative model suggests utility in parsing interlinked adaptations in other physiological networks...