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Endocrinology of the aging male

https://doi.org/10.1016/j.beem.2010.11.004Get rights and content

The endocrinology of the aging male is complex, with multiple hormones along the hypothalamic-pituitary-testicular (HPT) axis interacting with one another in feedback. As men age, there is a small and progressive (not precipitous, as in women) decline in several sex hormones, in particular testosterone and dehydroepiandrosterone, and related increases in luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin. The importance of these changes is wide-ranging because of the ubiquitous role of sex hormones in male physiology. This chapter discusses the endocrinology of the aging male. We provide an overview of the regulation of the HPT axis with an emphasis on the changes that occur with aging and the measurement of gonadal steroids, including hormone pulsatility, within-subject and circadian variations. The difficulties of assessing the symptoms of late-onset hypogonadism are highlighted. There is a comprehensive discussion of the epidemiology of sex hormone changes, including their age associations, prevalence of symptomatic hypogonadism, secular changes, risk factors, and the association of sex hormones with outcomes.

Introduction

Aging is associated with degenerative changes in multiple organ systems. The rate and extent to which these occur depend on genetics, the presence of other disease processes, and the accumulated effects of socioeconomic, lifestyle, and environmental factors. Although there is no equivalence in men of the abrupt cessation of cyclical ovarian activity that occurs in women, a variable and inconsistent decrease in testosterone with increasing age is observed, albeit that even at very advanced age, sexual and reproductive function may be within normal limits. The age-related decrease in testosterone is primarily due to testicular dysfunction, at least in the absence of disorders that affect the hypothalamic-pituitary-testicular (HPT) axis, for example obesity, although some reduction in central responsiveness of the HPT axis may also occur. The extent to which an age-related decrease in testosterone has direct consequences for physical or cognitive function as well as mood and overall quality of life, and the level of testosterone at which these occur remains incompletely resolved, as does the role of the testosterone supplementation.

This chapter discusses the endocrinology of the aging male, with particular focus on the biology and central regulation of the HPT axis, and the epidemiology of sex hormone changes, with implications for diagnosis and management of hypogonadism in aging men. Since testosterone is the most important androgen from a biological perspective and assays are widely available, this chapter focuses on testosterone, with attention paid to other androgens and other sex hormones as appropriate.

Section snippets

Gonadotrophin-releasing hormone

In a normal adult male, neurons in the preoptic area and the medial basal region of the hypothalamus secrete gonadotrophin-releasing hormone [GnRH] in a pulsatile manner. The periodicity and amplitude of GnRH secretion determine the pattern of secretion of the gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), from the gonadotroph cells of the anterior pituitary.

It has been suggested, but not proven, that neuronal GnRH outflow in healthy men is reduced by 33–50%

Measurement issues

Proper assessment of HPT axis functioning relies critically on accurate assessment of analytes in human serum, and to a lesser extent and for specific syndromes (e.g., hypogonadism), on medical history or patient self-report.

Testosterone circulates predominantly bound to the plasma proteins SHBG and albumin, with high and low affinity respectively. A small and variable fraction is said to circulate as free testosterone. One or another of these circulating fractions of testosterone have been

Age trends

Because of the complex interrelations of the sex hormones with other hormone systems, common chronic diseases of aging (cancer, CVD, diabetes, depression, hyperlipidemia, arthritis), and associated risk factors for chronic disease (obesity, sedentariness, nutritional deficiency, smoking), there is still little consensus to what constitutes a normal sex hormone profile for an aging male. There is no male equivalent of the menopause, and even in very old men with healthy active lifestyles plasma

Treatment

In men with classical hypogonadism, treatment is clearly indicated and men should be monitored appropriately. See Chapter X (Bhasin). There is considerable debate about the appropriateness of testosterone in aging men. The long-term safety or efficacy of testosterone replacement in aging men with late-onset hypogonadism has not been established, but as noted above, small-scale clinical studies suggest that testosterone may have beneficial effects.

Practice points

  • On average there is a small

Disclosures

ABA is a consultant to Lilly USA, LLC (Indianapolis, IN). GAW is a consultant to Lawley Pharmaceuticals (Perth WA, Australia) and received speaking fees and research support from Bayer Schering Pharma AG and Organon.

Acknowledgements

Supported by Award Number R01AG020727 from the National Institute on Aging. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. GAW is in receipt of project grant support from the National Health and Medical Research Council of Australia and the Australian Research Council.

References (154)

  • L.A.J. Heinemann et al.

    A new ‘Aging Male’s Symptoms’ (AMS) rating scale

    The Aging Male

    (1999)
  • J.E. Morley et al.

    Validation of a screening questionnaire for androgen deficiency in aging males

    Metabolism

    (2000)
  • J.E. Morley et al.

    Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men

    Metabolism

    (1997 Apr)
  • B.A. Mohr et al.

    Are serum hormones associated with the risk of prostate cancer? Prospective results from the Massachusetts male aging study

    Urology

    (2001 May)
  • R. Shabsigh

    Testosterone therapy in erectile dysfunction and hypogonadism

    The Journal of Sexual Medicine

    (2005 Nov)
  • V. Kupelian et al.

    Is there a relationship between sex hormones and erectile dysfunction? Results from the Massachusetts male aging study

    Journal of Urology

    (2006 Dec)
  • A. Iranmanesh et al.

    Age in men does not determine gonadotropin-releasing hormone’s dose-dependent stimulation of luteinizing hormone secretion under an exogenous testosterone clamp

    Journal of Clinical Endocrinology and Metabolism

    (2010 Jun)
  • F.C. Wu et al.

    Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European male aging study

    Journal of Clinical Endocrinology and Metabolism

    (2008 Jul)
  • B.Z. Leder et al.

    Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels

    Journal of Clinical Endocrinology and Metabolism

    (2004 Mar)
  • R.L. Goodman et al.

    Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B

    Endocrinology

    (2007 Dec)
  • M.N. Lehman et al.

    Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion

    Endocrinology

    (2010 Aug)
  • J.M. Castellano et al.

    Acute inflammation reduces kisspeptin immunoreactivity at the arcuate nucleus and decreases responsiveness to kisspeptin independently of its anorectic effects

    The American Journal of Physiology – Endocrinology and Metabolism

    (2010 Jul)
  • F. Brioude et al.

    Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype-phenotype relationships

    European Journal of Endocrinology/European Federation of Endocrine Societies

    (2010 May)
  • J. Young et al.

    TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans

    Journal of Clinical Endocrinology and Metabolism

    (2010 May)
  • Y. Wakabayashi et al.

    Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat

    Journal of Neuroscience

    (2010 Feb 24)
  • L. Wildt et al.

    Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey

    Endocrinology

    (1981 Aug)
  • J. Woerdeman et al.

    In young men, a moderate inhibition of testosterone synthesis capacity is only partly compensated by increased activity of the pituitary and the hypothalamus

    Clinical Endocrinology

    (2010 Jan)
  • T.R. Kumar

    FSHbeta knockout mouse model: a decade ago and into the future

    Endocrine

    (2009 Aug)
  • P. Kumanov et al.

    Significance of inhibin in reproductive pathophysiology and current clinical applications

    Reproductive Biomedicine Online

    (2005 Jun)
  • S.J. Meachem et al.

    Inhibin B in male reproduction: pathophysiology and clinical relevance

    European Journal of Endocrinology/European Federation of Endocrine Societies

    (2001 Nov)
  • D.H. Van Thiel et al.

    Evidence for a specific seminiferous tubular factor affecting follicle-stimulating hormone secretion in man

    Journal of Clinical Investigation

    (1972 Apr)
  • H.M. Scott et al.

    Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds

    Endocrine Reviews

    (2009 Dec)
  • J.Q. Purnell et al.

    Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women

    Journal of Clinical Endocrinology and Metabolism

    (2004 Jan)
  • Y. Koeva et al.

    Age-related changes in the expression of 11beta-hydroxysteroid dehydrogenase type 2 in rat leydig cells

    Folia Histochemica et Cytobiologica

    (2009)
  • D.M. Selva et al.

    Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene

    Journal of Clinical Investigation

    (2007 Dec)
  • D.M. Selva et al.

    Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4alpha

    Journal of Molecular Endocrinology

    (2009 Jul)
  • E. Atlantis et al.

    Demographic, physical and lifestyle factors associated with androgen status: the florey adelaide male ageing study (FAMAS)

    Clinical Endocrinology

    (2009 Aug)
  • A.D. Coviello et al.

    Differences in the apparent metabolic clearance rate of testosterone in young and older men with gonadotropin suppression receiving graded doses of testosterone

    Journal of Clinical Endocrinology and Metabolism

    (2006 Nov)
  • P.B. Grino et al.

    Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone

    Endocrinology

    (1990 Feb)
  • C.D. Toran-Allerand

    Estrogen and the brain: beyond ER-alpha, ER-beta, and 17beta-estradiol

    Annals of the New York Academy of Sciences

    (2005 Jun)
  • K.M. Lakshman et al.

    The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men

    Journal of Clinical Endocrinology and Metabolism

    (2010 Aug)
  • C.E. Roselli et al.

    Brain aromatization: classic roles and new perspectives

    Seminars in Reproductive Medicine

    (2009 May)
  • E.R. Simpson et al.

    Aromatase–a brief overview

    Annual Review of Physiology

    (2002)
  • F. Naftolin et al.

    Estrogen-induced hypothalamic synaptic plasticity and pituitary sensitization in the control of the estrogen-induced gonadotrophin surge

    Reproductive Sciences

    (2007 Feb)
  • W. Rosner et al.

    Position statement: utility, limitations, and pitfalls in measuring testosterone: an endocrine society position statement

    Journal of Clinical Endocrinology and Metabolism

    (2007 Feb)
  • W. Rosner et al.

    Toward excellence in testosterone testing: a consensus statement

    Journal of Clinical Endocrinology and Metabolism

    (2010 Oct)
  • J.D. Veldhuis et al.

    Operating characteristics of the male hypothalamo-pituitary-gonadal axis: pulsatile release of testosterone and follicle-stimulating hormone and their temporal coupling with luteinizing hormone

    Journal of Clinical Endocrinology and Metabolism

    (1987 Nov)
  • A. Vermeulen et al.

    Representativeness of a single point plasma testosterone level for the long term hormonal milieu in men

    Journal of Clinical Endocrinology and Metabolism

    (1992 Apr)
  • D.J. Brambilla et al.

    Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men

    Clinical Endocrinology

    (2007 Dec)
  • M.J. Diver et al.

    Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men

    Clinical Endocrinology

    (2003 Jun)
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