Age and Ageing Advance Access published February 9, 2015 Age and Ageing 2015; 00 : 1–8 doi: 10.1093/ageing/afv007
© The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: [email protected]
NEW HORIZONS
New horizons in testosterone and the ageing male TOMÁS AHERN, FREDERICK C. W. WU
Address correspondence to: T. Ahern. Tel: (+44) 1612766295; Fax: (+44) 1612766363. Email: [email protected]
Abstract The fall in testosterone levels with age appears to be a real phenomenon. Declining testicular function and hypothalamic dysregulation appear to be the mechanisms explaining the fall in testosterone levels with age. The increased prevalence of obesity and chronic illness in ageing men both cause a large drop in testosterone levels independent of ageing. Age-related hypogonadism appears to be different to other ‘classical’ causes of hypogonadism. Testosterone levels are not unequivocally low and associated symptoms are non-specific. In frail older men with low testosterone levels, testosterone therapy appears to improve QOL and physical function. In less frail men, however, effects of testosterone therapy in the ageing male are small and/or inconsistent. There remains an urgent need for randomised clinical trials with sufficient size, duration and power to determine specific benefits and risks of testosterone therapy in older men. Keywords: ageing, hypogonadism, older people, testosterone
Introduction The fall in testosterone levels with ageing has generated considerable interest among healthcare providers, the pharmaceutical industry and the general population. The clinical features of ageing and hypogonadism overlap, and it is tempting to assume that falling testosterone levels are a remediable contributor to poor life quality, frailty and premature death. The fall in testosterone levels appears to be brought about by the effects of ageing on the hypothalamic-pituitary-gonadal (HPG) axis as well as by an increasing prevalence of obesity and chronic illness. In only a small minority of ageing men do testosterone levels fall below the normal range. Whether testosterone therapy for men with late-onset hypogonadism (LOH) can ameliorate safely life quality and/or frailty remains controversial with studies failing to show consistent beneficial effects. These inconsistent data make challenging the provision of a clear explanation of potential risks and benefits of testosterone therapy. Male hypogonadism is a clinical syndrome resulting from sub-physiological testosterone concentrations due to disruption of the HPG axis [1, 2]. Klinefelter’s syndrome (KS) exemplifies hypogonadism that manifests before or during puberty. KS is a congenital chromosomal aberration (mostly 47,XXY) affecting 0.2% of male newborns [3]. In addition to markedly low testosterone
levels and elevated gonadotrophin levels (primary hypogonadism), men with KS have small testes and tend to have decreased libido, erectile dysfunction, poor beard growth, infertility (with azoospermia), tall stature, sparse pubic hair, gynaecomastia, decreased muscle mass, decreased muscle strength, low bone mineral density (BMD) and anaemia [3]. In later life, men with KS have decreased physical function, an increased risk of diabetes, obesity and bone fracture and have increased mortality [3]. Hypogonadism that arises after puberty is exemplified by hypothalamic-pituitary disease (e.g. tumour, infiltration, trauma, radiation). In addition to low testosterone levels and low gonadotrophin levels (secondary hypogonadism), men who develop hypopituitarism after puberty tend to develop the same features as men with KS, with the exceptions of small testis, poor beard growth and abnormal height [4]. Hypogonadism can occur also due to disruption at more than one level of the HPG axis. Opioids, for example, inhibit secretion of gonadotropin-releasing hormone (GnRH), luteinizing hormone and testosterone through action on the hypothalamus, pituitary and testis [5]. Testosterone levels fall with ageing
The European Male Ageing Study (EMAS) followed 2,736 men aged >40 for an average of 4.4 years and found a
1
Downloaded from http://ageing.oxfordjournals.org/ at Library - Faculty of Medicine Ramathibodi Hospital on February 18, 2015
Andrology Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Old St Mary’s Building, Hathersage Road, Manchester M13 9WL, UK
T. Ahern and F. C. W. Wu
Multiple mechanisms contribute to the fall in testosterone levels with ageing
prevalence of erectile dysfunction increased from 37.4 to 42.3% [19]. Counterintuitively, symptoms of hypogonadism do not correspond to low testosterone concentrations ( poor positive predictive value) and are not sensitive [7, 8]. This is exemplified in BACH where among men aged over 50 only 20.2% of those with symptoms of hypogonadism had a low total testosterone level (≤10.5 nmol/l), and of men with a low testosterone level, only 20.1% reported low libido and only 29.0% reported erectile dysfunction [8]. To overcome these difficulties, EMAS investigators defined LOH as the presence of three sexual symptoms (decreased frequency of morning erection, erectile dysfunction and decreased frequency of sexual thoughts) together with a total testosterone concentration
© The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: [email protected]
NEW HORIZONS
New horizons in testosterone and the ageing male TOMÁS AHERN, FREDERICK C. W. WU
Address correspondence to: T. Ahern. Tel: (+44) 1612766295; Fax: (+44) 1612766363. Email: [email protected]
Abstract The fall in testosterone levels with age appears to be a real phenomenon. Declining testicular function and hypothalamic dysregulation appear to be the mechanisms explaining the fall in testosterone levels with age. The increased prevalence of obesity and chronic illness in ageing men both cause a large drop in testosterone levels independent of ageing. Age-related hypogonadism appears to be different to other ‘classical’ causes of hypogonadism. Testosterone levels are not unequivocally low and associated symptoms are non-specific. In frail older men with low testosterone levels, testosterone therapy appears to improve QOL and physical function. In less frail men, however, effects of testosterone therapy in the ageing male are small and/or inconsistent. There remains an urgent need for randomised clinical trials with sufficient size, duration and power to determine specific benefits and risks of testosterone therapy in older men. Keywords: ageing, hypogonadism, older people, testosterone
Introduction The fall in testosterone levels with ageing has generated considerable interest among healthcare providers, the pharmaceutical industry and the general population. The clinical features of ageing and hypogonadism overlap, and it is tempting to assume that falling testosterone levels are a remediable contributor to poor life quality, frailty and premature death. The fall in testosterone levels appears to be brought about by the effects of ageing on the hypothalamic-pituitary-gonadal (HPG) axis as well as by an increasing prevalence of obesity and chronic illness. In only a small minority of ageing men do testosterone levels fall below the normal range. Whether testosterone therapy for men with late-onset hypogonadism (LOH) can ameliorate safely life quality and/or frailty remains controversial with studies failing to show consistent beneficial effects. These inconsistent data make challenging the provision of a clear explanation of potential risks and benefits of testosterone therapy. Male hypogonadism is a clinical syndrome resulting from sub-physiological testosterone concentrations due to disruption of the HPG axis [1, 2]. Klinefelter’s syndrome (KS) exemplifies hypogonadism that manifests before or during puberty. KS is a congenital chromosomal aberration (mostly 47,XXY) affecting 0.2% of male newborns [3]. In addition to markedly low testosterone
levels and elevated gonadotrophin levels (primary hypogonadism), men with KS have small testes and tend to have decreased libido, erectile dysfunction, poor beard growth, infertility (with azoospermia), tall stature, sparse pubic hair, gynaecomastia, decreased muscle mass, decreased muscle strength, low bone mineral density (BMD) and anaemia [3]. In later life, men with KS have decreased physical function, an increased risk of diabetes, obesity and bone fracture and have increased mortality [3]. Hypogonadism that arises after puberty is exemplified by hypothalamic-pituitary disease (e.g. tumour, infiltration, trauma, radiation). In addition to low testosterone levels and low gonadotrophin levels (secondary hypogonadism), men who develop hypopituitarism after puberty tend to develop the same features as men with KS, with the exceptions of small testis, poor beard growth and abnormal height [4]. Hypogonadism can occur also due to disruption at more than one level of the HPG axis. Opioids, for example, inhibit secretion of gonadotropin-releasing hormone (GnRH), luteinizing hormone and testosterone through action on the hypothalamus, pituitary and testis [5]. Testosterone levels fall with ageing
The European Male Ageing Study (EMAS) followed 2,736 men aged >40 for an average of 4.4 years and found a
1
Downloaded from http://ageing.oxfordjournals.org/ at Library - Faculty of Medicine Ramathibodi Hospital on February 18, 2015
Andrology Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Old St Mary’s Building, Hathersage Road, Manchester M13 9WL, UK
T. Ahern and F. C. W. Wu
Multiple mechanisms contribute to the fall in testosterone levels with ageing
prevalence of erectile dysfunction increased from 37.4 to 42.3% [19]. Counterintuitively, symptoms of hypogonadism do not correspond to low testosterone concentrations ( poor positive predictive value) and are not sensitive [7, 8]. This is exemplified in BACH where among men aged over 50 only 20.2% of those with symptoms of hypogonadism had a low total testosterone level (≤10.5 nmol/l), and of men with a low testosterone level, only 20.1% reported low libido and only 29.0% reported erectile dysfunction [8]. To overcome these difficulties, EMAS investigators defined LOH as the presence of three sexual symptoms (decreased frequency of morning erection, erectile dysfunction and decreased frequency of sexual thoughts) together with a total testosterone concentration
