New horizons in testosterone and the ageing male

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1 Age and Ageing 2015; 44: doi: /ageing/afv007 The Author Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please NEW HORIZONS New horizons in testosterone and the ageing male TOMÁS AHERN, FREDERICK C. W. WU Andrology Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Old St Mary s Building, Hathersage Road, Manchester M13 9WL, UK Address correspondence to: T. Ahern. Tel: (+44) ; Fax: (+44) tomasbahern@physicians.ie 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 188

2 0.1 nmol/l (0.04%) per year reduction in total testosterone concentrations and a 3.83 pmol/l (0.77%) per year reduction in free (not protein bound) testosterone concentrations [6]. Testosterone levels fall below the normal range in a minority of ageing men, however. Both EMAS and the Boston Area Community Health Survey (BACH) found that between 16 and 26% of men aged have a total testosterone concentration that is <10.5 nmol/l compared with a proportion of between 11 and 22% of men aged <50 [7, 8]. Interestingly, not all studies have observed lower testosterone levels in older men. Studies of healthy men describe no difference in testosterone concentrations between older and younger men [9]. Multiple mechanisms contribute to the fall in testosterone levels with ageing Testicular and hypothalamic function decline with age. Study of post-mortem specimens shows that Leydig cell number is 44% lower in men aged than in men aged [10]. Congruently, the secretory capacity of the testes is substantially lower in older men than in younger men [11]. Although declining testicular function appears to be the main cause of low testosterone levels due to ageing, hypothalamic GnRH secretion, but not pituitary LH reserve, is lower in older men [12]. Obesity contributes to the decline in testosterone levels with ageing. Total and visceral fat mass increase with ageing peaking normally at 65 years [13]. Obese men (BMI > 30 kg/m 2 ) have lower total and free testosterone concentrations than lean men (BMI kg/m 2 ), and their testosterone concentrations decline more quickly [2]. Despite lower testosterone concentrations than lean men, LH concentrations are not elevated in those with obesity suggesting a hypothalamicpituitary defect [2]. Possible explanations for hypothalamicpituitary disruption in obese men include elevated cytokine concentrations [14] and insulin resistance [15]. Chronic illness, which accompanies ageing, plays also a role in the fall in testosterone levels with ageing. Men with chronic illness have lower testosterone levels than healthy men [2]. Like men with obesity, LH concentrations are not elevated in those with chronic illness, suggesting a hypothalamic-pituitary defect [2]. Chronic illnesses, such as cardiovascular disease (CVD) and type 2 diabetes (T2DM), are associated with increased concentrations of pro-inflammatory cytokines [16], which may disrupt the hypothalamus resulting in lower testosterone levels [14]. Other possible, although less likely, causes for lower testosterone levels in older men include statin use [17] and vitamin D deficiency [18]. Testosterone and the ageing male 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 <11 nmol/l and a free testosterone concentration <220 pmol/l [1] (Figure 1). Such a syndrome appears to affect 3% of men aged and 0.1% of men aged (Figure 2) [1]. Over 9 years, the incidence rate is 10% and the remission rate is 55% [19]. LOH appears to have some features consistent with classical hypogonadism In EMAS, men with LOH were older, had higher BMI, had lower muscle mass, had lower BMD, had lower haemoglobin levels and had slower walk speeds than men without LOH, suggesting similarity with classical hypogonadism (Figure 2). These features correlate weakly with testosterone levels, however, and are mimicked by chronic illness and the ageing process. Adverse effects of low testosterone levels A commonly used definition of a low testosterone level is a level that is below the 2.5 percentile of testosterone levels in young, healthy adult men [20, 21]. Prospective observational studies of older men show that men with low testosterone levels have a substantially increased risk of developing depressive illness [22]. Low testosterone confers also an increased development of poor physical function [23] and frailty [24], although this relationship becomes non-significant when one adjusts for chronic illness [24, 25]. Men with low testosterone levels have a higher incidence of T2DM and a higher prevalence of CVD than men with normal testosterone levels [26, 27]. It is likely that obesity, which is associated with low testosterone, T2DM and CVD, plays a role in this relationship. This relationship between testosterone and obesity is likely bidirectional, with obesity effecting a decline in testosterone levels as described above and low testosterone levels increasing the risk of obesity, T2DM and CVD. Symptoms of adult onset male hypogonadism are non-specific and overlap with many symptoms that develop with normal ageing MMAS found that the prevalence of loss of libido increased, over the course of 9 years, from 30.6 to 41.1% and that the Do low testosterone levels confer an increased mortality risk? Men with hypogonadism due to a disease known to affect the HPG axis usually have testosterone levels that are well below 189

3 T. Ahern and F. C. W. Wu Figure 1. Multiple correspondence analysis (MCA) showing associations between symptoms and levels of total testosterone and free testosterone in the training and validation sets [1]. In this MCA plot, variables (including low or normal testosterone levels and the presence or absence of symptoms) are considered to be highly associated if they are at the same distance and in the same direction from the origin where the horizontal axis (Axis 1) and the vertical axis (Axis 2) cross in the training set and the validation set. Thus, the clustering of the categories of the variables in close proximity to one another is indicative of a syndromic association, which is highlighted by broken-line circle. The values along the axes are indexes of the strength of the association between variables. On Axis 1, the presence of symptoms has positive coordinates (to the right of the origin), compared with the absence of symptoms, with negative coordinates (to the left of the origin). Axis 2 helps identify symptoms that are related to a low testosterone level. The red clusters indicate the presence of the three sexual symptoms, with coordinates similar to those of a low testosterone level. The blue clusters indicate the absence of symptoms, with coordinates similar to those of a normal testosterone level. In contrast, the three psychological symptoms and, to a lesser extent, the three physical symptoms are located far from coordinates for normal and low testosterone, indicating that these symptoms are unrelated or weakly related to the testosterone level. The cluster patterns of symptoms in relation to total or free testosterone levels in the training set are virtually identical to those in the validation set. To convert the values for total testosterone to nanograms per millilitre, divide by To convert the values for free testosterone to picograms per millilitre, divide by Full colour figures are available online. the normal reference range. Men with LOH, however, tend to have testosterone levels that are just below this range [7]. As described above, obesity and chronic illness appear to contribute to this LOH and these (and maybe other factors) may be the reason for adverse consequences and not the low testosterone level per se. This is illustrated by prospective studies that found that once the data were adjusted for obesity and chronic illness, age-related low testosterone levels were not associated with increased mortality [28], unless a lower testosterone threshold (T < 8.36 nmol/l) was used [29]. The situation differs slightly for men at the upper extreme of age (aged >70) where some studies have shown an association between low 190

4 Figure 2. The prevalence of the syndrome in EMAS, overall and stratified by age, BMI and co-morbidity [1]. The syndrome of LOH as defined by at least three sexual symptoms associated with total testosterone levels of <11 nmol/l and free testosterone of <220 pmol/l. The overall prevalence of LOH is 2.1% (a), the prevalence of LOH increased with age from 0.1, 0.6, 3.2 to 5.1% at 40 49, 50 59, and >70 years, respectively (a). The prevalence of LOH also increased with BMI (b) and comorbidity (number of coexisting illnesses) (c). testosterone levels with increased mortality and some have not [30]. Testosterone therapy Before considering testosterone therapy, one should ensure that testosterone levels are low, that the patient has features consistent with hypogonadism and that assessment for hypothalamic, pituitary and testicular disease is made [20, 21]. A low testosterone level should be confirmed by second measurement due to large intra-individual variation in levels the difference between two testosterone measurements on the same person exceeds 20% about half the time [31]. Blood for the determination of testosterone levels should be taken in the early morning and in the fasting state due to the significant diurnal variation in testosterone levels and the considerable effect of food intake on decreasing testosterone levels [32]. Consideration should be given to specific therapies other than testosterone for remediable causes of hypogonadism. Dopamine agonist therapy is first-line therapy for men with hyperprolactinaemia and will increase testosterone levels [33] as will bariatric surgery for men with type 2 diabetes and/or severe obesity [34]. For the man with a low testosterone level who desires fertility, consideration should be given to gonadotrophin therapy or pulsatile gonadotrophin-releasing hormone therapy if LH levels are not elevated [35]. Transdermal, intramuscular and buccal forms of testosterone therapy are safe and effective. Transdermal and buccal forms require daily administration, whereas intramuscular preparations are given every 3 12 weeks. Oral testosterone and 17-alpha-alkylated androgen preparations are not recommended due to potential liver toxicity and variable clinical response. More detailed recommendations on the practical aspects of testosterone therapy are available in published guidelines [20, 21]. Potential benefits of testosterone therapy Sexual function A meta-analysis of 17 randomised clinical trials (RCTs) involving 656 men (mean age 57.5 years) found that testosterone therapy moderately improved sexual symptoms and sexual function in men with a total testosterone concentration <12 nmol/l [36]. Of note, testosterone therapy had no such effect in eugonadal men. Subsequent studies have shown inconsistent effects of testosterone therapy on sexual symptoms and sexual function [37, 38]. Quality of life Similarly, some studies of men with age-related low testosterone levels have found that testosterone therapy improved quality of life (QOL) questionnaire scores [38], whereas others have not [37]. A recent meta-analysis found a positive effect of testosterone therapy in hypogonadal men with depression [39]. Frailty Testosterone and the ageing male A recent double-blind RCT of 274 frail older men showed that testosterone therapy led to an increase in physical function in men aged 75 or greater and in men with two or more Fried frailty criteria (Figure 3) [38]. Other RCTs have not found improvements in physical function with testosterone therapy [40], suggesting that treatment may benefit only frail men with clearly low testosterone levels. The Testosterone in Older Men with Mobility Limitations trial, a double-blind, RCT of 209 men aged 65 or older with a total testosterone of 12.0 nmol/l or less, showed that testosterone therapy (10 mg/day, double the standard replacement dose) improved muscle strength. In this trial, the group 191

5 T. Ahern and F. C. W. Wu Figure 3. (a) Change in isometric knee extension peak torque (IME-PT), isometric knee flexion peak torque (IMF-PT), isokinetic knee extension peak torque (IKE-PT) and isokinetic knee flexion peak torque (IKF-PT) in the placebo and T groups at 6 months; (b) change in lean body mass (LBM) and fat mass (FM) at 6 months compared with baseline in the placebo and T groups; (c) change in Aging Males Symptom scale (AMS) subscale scores at 6 months compared with baseline in the placebo and T groups [38]. **Significant difference between groups (ANCOVA, comparing adjusted mean difference between placebo and T groups). of participants allocated to testosterone therapy, at a supraphysiological dose, experienced a greater incidence of cardiovascular-related events [41]. Bone and metabolic health Meta-analyses show that intramuscular testosterone therapy improves lumbar BMD by 8% and that no trials to date have determined the effect of testosterone on fracture incidence [42]. Although testosterone levels are lower in people with T2DM, the majority of double-blind, RCTs involving testosterone therapy for men with T2DM and/or metabolic syndrome have found no improvement in insulin resistance (as assessed by HOMA2-IR) or in glycaemic control (as assessed by HbA1c) [43]. Potential risks Contraindications to testosterone therapy include erythrocytosis (haematocrit >52%), prostate cancer, breast cancer, untreated obstructive sleep apnoea, uncontrolled heart failure, severe lower urinary tract symptoms (International Prostate Symptom Score >19) and desire for fertility [20, 21]. Testosterone therapy, through suppression of hepcidin, increases haemoglobin levels by 1 g/dl and haematocrit by 3% leading to a >3-fold risk of erythrocytosis [44]. Testosterone therapy increases prostate-specific antigen levels and (possibly as a result) tends to increase the risk of prostate biopsy [45]. Despite this, current data suggest no increased risk of prostate cancer [44]. Continuing caution is required with respect to the possibility of development of 192

6 prostate cancer as androgens may have a long latency in promoting the growth of pre-existing prostate cancer, and sufficiently powered RCTs are unlikely to be performed [46]. As described above, the Testosterone in Older Men with Mobility Limitations trial suggested a possible link between cardiovascular-related events with testosterone therapy (at double the recommended dose) [41]. Observational studies and a meta-analysis performed after this trial found also associations between testosterone therapy and a 30 54% increased risk of cardiovascular-related events [47]. The US Food and Drug Administration (FDA) found that all these studies had significant limitations and that currently there is insufficient evidence for an association between testosterone therapy and adverse cardiovascular outcomes. The FDA has, however, sought to make clear that a low testosterone level due to ageing is not an indication for testosterone therapy and that further cardiovascular safety monitoring of testosterone therapy in older men is required. A recent meta-analysis used the incidence of a new major adverse cardiovascular event (MACE), defined by the composite of cardiovascular death, non-fatal acute myocardial infarction and stroke, and acute coronary syndromes and/or heart failure, as its principal outcome [48]. The authors concluded that testosterone therapy did not increase the risk of MACE (OR 1.01 [ ]) overall and decreased MACE incidence in men with T2DM and/or metabolic syndrome (OR 0.19 [ ]). The effect of testosterone therapy on mortality in community-dwelling men with age-related low testosterone levels is not known No sufficiently powered, prospective, long-term, interventional studies have been performed to assess whether testosterone therapy can prolong life. A meta-analysis of 51 comparative studies that involved men with low or lownormal testosterone levels and at least 3 months of testosterone therapy found no significant effect of testosterone therapy on mortality [44]. Two retrospective studies, performed after this meta-analysis, suggested that testosterone therapy may decrease mortality by 39 50% in men with chronic illness [49, 50]. These results need to be treated with caution both studies were retrospective in nature and as such are subject to significant treatment bias. a large drop in testosterone levels through mechanisms independent to, and of greater magnitude to, those from ageing. Age-related hypogonadism appears to be different to other classical causes of hypogonadism. Testosterone levels are not unequivocally low and associated symptoms are nonspecific. 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 for QOL, physical function, bone health and metabolic health. These issues, together with the risks of testosterone therapy, make the decision to initiate testosterone therapy in older symptomatic men, a complex and challenging one generating the imperative to establish a formal diagnosis of hypogonadism, usually without identifiable underlying pathology of the HPG axis. The Testosterone Trials in which 788 men aged over 65 with a total testosterone concentration <9.4 nmol/l will receive transdermal testosterone, or placebo, for 1 year will provide important information on the short-term efficacy of testosterone [46]. There remains an urgent need for RCTs with sufficient size, duration and power to determine specific benefits and risks of testosterone therapy in older men. In a broader context, low testosterone levels should be regarded as a biomarker of obesity and chronic illness (overt or occult) thereby proffering an important portal to improving men s health. Key points Testosterone and the ageing male The prevalence of LOH among men aged is 2%. Ageing-related decline in testicular function and hypothalamic dysregulation, without specific pathologies, appear to be the mechanisms explaining the fall in testosterone levels in older men. Obesity and chronic illness in ageing men both cause a large drop in testosterone levels through mechanisms independent to, and of greater magnitude to, those from ageing. In older men with low testosterone levels, the clinically important benefits of testosterone therapy are small and/or inconsistent while the risks of potentially serious adverse risks are undefined. The Testosterone Trials in which 788 men aged over 65 with a total testosterone concentration <9.4nmol/lwillreceivetransdermal testosterone, or placebo, for 1 year, will provide important information on the short-term efficacy of testosterone. Conclusion The fall in testosterone levels with age appears to be a real phenomenon. The prevalence of LOH, among men aged 40 70, is 2%. 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 Conflicts of interest The views expressed in this article belong to the authors and are not an official position of the Central Manchester University Hospitals NHS Foundation Trust or of the University of Manchester. F.C.W.W.: Speaker, Bayer Schering Pharma, Clinical Researcher, Eli Lilly & Company, Speaker, Besins Healthcare. 193

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