+Model ANDO-614; No. of Pages 4
ARTICLE IN PRESS Disponible en ligne sur
ScienceDirect www.sciencedirect.com Annales d’Endocrinologie xxx (2014) xxx–xxx
Journées Klotz 2014
Andropause – lessons from the European Male Ageing Study Andropause : le¸cons de l’étude européenne sur l’homme vieillissant Ilpo T. Huhtaniemi a,b,∗ a
Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom b Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland
Abstract Andropause or late-onset hypogondism (LOH) is a situation where a middle-aged or older man has low serum testosterone (T) in conjunction with diffuse symptoms reminiscent of those of genuine male hypogonadism (e.g. reduced sexual function, loss of vigor, muscle weakness, depression). Opinions about the diagnostic criteria, prevalence and treatment options of andropause vary considerably amongst experts. We review here some salient findings on the prevalence, diagnostic criteria and impact on health of andropause, obtained from the European Male Ageing Study (EMAS), a multicenter study of ageing among community-dwelling middle-aged and older men. © 2014 Elsevier Masson SAS. All rights reserved. Keywords: Ageing; Sexual function; Serum testosterone; Late-onset hypogonadism
Résumé L’andropause ou hypogonadisme de survenue tardive est une situation dans laquelle un homme d’âge moyen ou plus âgé présente des taux de testostéronémie bas en conjunction avec une symptomatologie évocatrice d’un authentique hypogonadisme masculin (e.g. diminution de la fonction sexuelle, perte de vitalité, faiblesse musculaire, dépression). Les avis concernant les critères diagnostiques, la prévalence et les stratégies thérapeutiques de l’andropause varient considérablement parmi les experts. Nous revoyons ici les points les plus marquants de la prévalence, des critères diagnostiques et du retentissement sur la santé de l’andropause à partir des données de l’étude européenne des hommes vieillissants (EMAS), étude multi-centrique sur le vieillissement dans une population masculine européenne d’âge moyen ou plus âgée. © 2014 Elsevier Masson SAS. Tous droits réservés. Mots clés : Vieillissement ; Dysfonction sexuelle ; Testostérone sanguine ; Hypogonadisme tardif
DOIs of original articles: http://dx.doi.org/10.1016/j.ando.2014.03.007, http://dx.doi.org/10.1016/j.ando.2014.04.010, http://dx.doi.org/10.1016/j.ando.2014.03.004, http://dx.doi.org/10.1016/j.ando.2014.04.011, http://dx.doi.org/10.1016/j.ando.2014.04.006, http://dx.doi.org/10.1016/j.ando.2014.03.008, http://dx.doi.org/10.1016/j.ando.2014.03.010, http://dx.doi.org/10.1016/j.ando.2014.04.002, http://dx.doi.org/10.1016/j.ando.2014.04.004, http://dx.doi.org/10.1016/j.ando.2014.03.001, http://dx.doi.org/10.1016/j.ando.2014.03.003, http://dx.doi.org/10.1016/j.ando.2014.03.009, http://dx.doi.org/10.1016/j.ando.2014.04.001, http://dx.doi.org/10.1016/j.ando.2014.03.011, http://dx.doi.org/10.1016/j.ando.2014.04.003, http://dx.doi.org/10.1016/j.ando.2014.04.005, http://dx.doi.org/10.1016/j.ando.2014.03.002. ∗ Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom. E-mail address: [email protected] http://dx.doi.org/10.1016/j.ando.2014.03.005 0003-4266/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Huhtaniemi IT. Andropause – lessons from the European Male Ageing Study. Ann Endocrinol (Paris) (2014), http://dx.doi.org/10.1016/j.ando.2014.03.005
+Model ANDO-614; No. of Pages 4 2
ARTICLE IN PRESS I.T. Huhtaniemi / Annales d’Endocrinologie xxx (2014) xxx–xxx
1. Introduction It is a well-documented fact that there is a slow gradual decline in testicular testosterone (T) production as the man ages. When the decrease is associated with symptoms of androgen deficiency, the condition is usually termed andropause or lateonset hypogonadism (LOH). The decline of T is usually small, 1–2% per year, but in some men it is more profound and may lead to clinical hypogonadism. In men with perfect health, the decline may not be detectable at all [1]. Andropause has recently received much attention, and T replacement therapy is aggressively marketed for its treatment, especially in the United States [2]. To obtain more scientific information about andropause we launched more than 10 years ago a study, The European Male Ageing Study (EMAS) [3], whose purpose was to examine in a large cohort of community-dwelling European men the extent of ageing-related alterations in T and other reproductive and metabolic hormones, other laboratory parameters, anthropometry and health status, and to refine the diagnostic criteria and clinical significance of andropause/LOH. In this review we summarize some of the salient findings of the EMAS study. 2. Definition and pathogenesis of andropause Andropause is associated with a wide array of largely nonspecific physical, psychological and sexual symptoms often associated with hypogonadism of young men and ageing in general. Several questionnaires have been constructed to score the magnitude of andropausal symptoms, but they are generally considered inaccurate [4–6]. In EMAS we observed that the only symptoms that were significantly associated with serum total T or free T were the three sexual symptoms, i.e. erectile dysfunction and decreased sexual thoughts and morning erections [7]. Frequencies of other physical and psychological symptoms used in the andropause questionnaires showed no significant association with circulating T levels, occurring at roughly similar frequency throughout the range of measured T concentrations. We can therefore almost categorically state that if a man does not have reduced sexual function, he does not have andropause and that the other symptoms he may have, such as insomnia, depression, muscle weakness, irritability, are not alone associated with genuine andropause. Hence, sexual function is a window into the health of an ageing man. 3. Pathogenesis and diagnosis of andropause It is obvious that low T must be one of the criteria of the diagnosis of andropause. The simplest parameter is serum total T, which should be below the lower limit of the references range, roughly about 10 nmol/L. Another useful parameter is measured or calculated free T, which is often considered a more accurate measure, but opinions vary about the accuracy of the formulas used to calculate free T [8], and the methods of direct free T measurement are expensive and/or often not accessible in clinical practice. Low T alone is not sufficient, because often men with T below the reference range are totally asymptomatic. The EMAS criteria for T to fulfill criteria of andropause are total T
below 8 nmol/L, or if total T is in the gray zone of 8-11 nmol/L, then in addition calculated free T should be below 220 pmol/L [7]. With these T levels, sexual symptoms of men (see above) are significantly more frequent than in men with T above these limits. However, even men with low T may have sexual symptoms independently of low T, because there is a high background prevalence of sexual symptoms in about 25% of men irrespective of their circulating T concentration [7]. According to the strict EMAS criteria [7], i.e. low serum total and/or free T (see above) and three sexual symptoms, the frequency of andropause/LOH in 40–79-year-old communitydwelling men is only 2.1%, increasing from 0.15 to 5.1% between 40 and 79 years. However, if a man visits a physician complaining andropausal symptoms, it has been estimated that the likelihood of genuine LOH in this selected population is about 15% [9]. Low T alone with diffuse symptoms does not justify the diagnosis of andropause, neither do sexual symptoms in men with normal T. If low T is associated with elevated LH, the man has primary hypogonadism, and if LH is either low or inappropriately normal in the face of low T, hypogonadism is secondary, caused by a disturbance at the hypothalamic-pituitary level. Both conditions are observed in andropause. According to the EMAS study, secondary hypogonadism is associated with overweight and obesity, but not with ageing, whereas primary hypogonadism is an ageing-related condition [10]. Altogether 73% of the men fulfilling the strict criteria of andropause were overweight or obese. In the rest, the lean men with andropause have often chronic health conditions (e.g. cardiovascular disease, diabetes, frailty), which could explain the finding. The condition remains idiopathic only in a minority of men, which means that there are targets for treatment, including lifestyle modification with weight loss and good treatment balance of comorbidities. T replacement therapy should not be the automatic first option. We also identified a third diagnostic group, which was termed ‘compensated hypogonadism’ [11]. These men have normal T but elevated LH, and they accounted for 9.5% of the EMAS cohort. They have signs of androgen deficiency, in particular limited physical capacity. Our recent (unpublished) followup data suggest that compensated hypogonadism represents an interphase in the trajectory from eugonadism to primary hypogonadism, and it is totally distinct from the obesity related secondary hypogonadism. Classification into the three diagnostic subgroups by combining LH with T may improve the diagnosis and management of andropause. 4. Impact of andropause on health Low T has been associated with increased mortality in a number of studies [12]. However, the natural history of symptomatic LOH, especially its relationship to mortality, remains poorly explored. We recently investigated in the prospective part of EMAS the associations between andropause, low T, and sexual symptoms with mortality in 2599 men [13]. All-cause, cardiovascular, and cancer-related mortality was measured during an average follow-up of 4.3 years. Fifty-five men (2.1%) were identified as having LOH (31 moderate and 24 severe). After
Please cite this article in press as: Huhtaniemi IT. Andropause – lessons from the European Male Ageing Study. Ann Endocrinol (Paris) (2014), http://dx.doi.org/10.1016/j.ando.2014.03.005
+Model ANDO-614; No. of Pages 4
ARTICLE IN PRESS I.T. Huhtaniemi / Annales d’Endocrinologie xxx (2014) xxx–xxx
adjusting for age, centre, body mass index (BMI), current smoking, and poor general health, compared with men without LOH, those with severe LOH (T < 8 nmol/L + sexual symptoms) had over 5-fold (hazard ratio 5.5; 95% confidence interval 2.7, 11.4) higher risk of all-cause mortality. Similar risks were observed for cardiovascular mortality. When only low T (15%) the change was significant (in the same direction as total T). Smoking cessation was associated with a greater decline in T than being a non-smoker, independent of weight change. Changes in number of comorbid conditions or physical activity did not influence function of the hypothalamic–pituitary–testicular (HPT) axis. We were able to conclude from these observations that weight and lifestyle factors do influence HPT axis function in ageing. Weight loss increases and weight gain decreases T, free T and SHBG levels. Weight management is therefore important in maintaining circulating T in ageing men, and obesity-associated changes in HPT axis hormones can be reversed by weight reduction. These observations leave us with the ‘hen and egg’ conundrum between serum T and health. Is low T the cause or consequence of ill health? The causality is apparently at least to some extent bidirectional, but the evidence is mounting that low T is simply an indicator of ill health, not the cause of it. 6. Controversies in the treatment of andropause There are in principle two treatment options for LOH, which are:
3
• T replacement therapy; • lifestyle modification, weight loss and good treatment balance of comorbidities. It is tempting to conceptualise andropause as an ageingrelated deficiency state of T that is the cause for associated health problems, and that simply replacing the reduced T production with exogenous hormone will reverse the situation and correct the health problems. This approach is based on the conjecture that low T is the cause of health problems. However, this is far from being convincingly shown. Admittedly, there are conditions where reduction of T production leads to symptoms common in LOH, for example upon androgen blockage therapy of prostate cancer [15]. It is equally possible that low T is the harbinger of ill health, and it could even be the body’s desired adaptation phenomenon to ill health, in which case its reversal by exogenous T would not only be undesirable but could even be harmful. Several recent studies have warned about cardiovascular complication in ageing men during T replacement therapy [16–18]. Numerous studies have shown health benefits of T replacement in andropause, but these studies are invariably small, short in duration, retrospective, non-randomized and either uncontrolled or having biased controls. A typical study is where T is offered for a group of men with variable reduction of T and selected purportedly andropausal symptoms, and the men who for any reason (e.g. contraindications) do not receive T form the controls. Very telling is one placebo-controlled study where both placebo and T had similar statistically significant suppressive effects on andropausal symptoms [19]. The largely anecdotal information or poor quality research data do not justify recommending T replacement as standard treatment of andropause at this moment. We have to wait for better information before the issue can be solved. Such a definitive treatment trial is currently underway in the US (NCT00799617 on 2008 11 30), and we should see its results in 2015. 7. Conclusions Andropause can be defined according to the strict EMAS criteria as a condition where an ageing man has low T (
ARTICLE IN PRESS Disponible en ligne sur
ScienceDirect www.sciencedirect.com Annales d’Endocrinologie xxx (2014) xxx–xxx
Journées Klotz 2014
Andropause – lessons from the European Male Ageing Study Andropause : le¸cons de l’étude européenne sur l’homme vieillissant Ilpo T. Huhtaniemi a,b,∗ a
Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom b Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland
Abstract Andropause or late-onset hypogondism (LOH) is a situation where a middle-aged or older man has low serum testosterone (T) in conjunction with diffuse symptoms reminiscent of those of genuine male hypogonadism (e.g. reduced sexual function, loss of vigor, muscle weakness, depression). Opinions about the diagnostic criteria, prevalence and treatment options of andropause vary considerably amongst experts. We review here some salient findings on the prevalence, diagnostic criteria and impact on health of andropause, obtained from the European Male Ageing Study (EMAS), a multicenter study of ageing among community-dwelling middle-aged and older men. © 2014 Elsevier Masson SAS. All rights reserved. Keywords: Ageing; Sexual function; Serum testosterone; Late-onset hypogonadism
Résumé L’andropause ou hypogonadisme de survenue tardive est une situation dans laquelle un homme d’âge moyen ou plus âgé présente des taux de testostéronémie bas en conjunction avec une symptomatologie évocatrice d’un authentique hypogonadisme masculin (e.g. diminution de la fonction sexuelle, perte de vitalité, faiblesse musculaire, dépression). Les avis concernant les critères diagnostiques, la prévalence et les stratégies thérapeutiques de l’andropause varient considérablement parmi les experts. Nous revoyons ici les points les plus marquants de la prévalence, des critères diagnostiques et du retentissement sur la santé de l’andropause à partir des données de l’étude européenne des hommes vieillissants (EMAS), étude multi-centrique sur le vieillissement dans une population masculine européenne d’âge moyen ou plus âgée. © 2014 Elsevier Masson SAS. Tous droits réservés. Mots clés : Vieillissement ; Dysfonction sexuelle ; Testostérone sanguine ; Hypogonadisme tardif
DOIs of original articles: http://dx.doi.org/10.1016/j.ando.2014.03.007, http://dx.doi.org/10.1016/j.ando.2014.04.010, http://dx.doi.org/10.1016/j.ando.2014.03.004, http://dx.doi.org/10.1016/j.ando.2014.04.011, http://dx.doi.org/10.1016/j.ando.2014.04.006, http://dx.doi.org/10.1016/j.ando.2014.03.008, http://dx.doi.org/10.1016/j.ando.2014.03.010, http://dx.doi.org/10.1016/j.ando.2014.04.002, http://dx.doi.org/10.1016/j.ando.2014.04.004, http://dx.doi.org/10.1016/j.ando.2014.03.001, http://dx.doi.org/10.1016/j.ando.2014.03.003, http://dx.doi.org/10.1016/j.ando.2014.03.009, http://dx.doi.org/10.1016/j.ando.2014.04.001, http://dx.doi.org/10.1016/j.ando.2014.03.011, http://dx.doi.org/10.1016/j.ando.2014.04.003, http://dx.doi.org/10.1016/j.ando.2014.04.005, http://dx.doi.org/10.1016/j.ando.2014.03.002. ∗ Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom. E-mail address: [email protected] http://dx.doi.org/10.1016/j.ando.2014.03.005 0003-4266/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Huhtaniemi IT. Andropause – lessons from the European Male Ageing Study. Ann Endocrinol (Paris) (2014), http://dx.doi.org/10.1016/j.ando.2014.03.005
+Model ANDO-614; No. of Pages 4 2
ARTICLE IN PRESS I.T. Huhtaniemi / Annales d’Endocrinologie xxx (2014) xxx–xxx
1. Introduction It is a well-documented fact that there is a slow gradual decline in testicular testosterone (T) production as the man ages. When the decrease is associated with symptoms of androgen deficiency, the condition is usually termed andropause or lateonset hypogonadism (LOH). The decline of T is usually small, 1–2% per year, but in some men it is more profound and may lead to clinical hypogonadism. In men with perfect health, the decline may not be detectable at all [1]. Andropause has recently received much attention, and T replacement therapy is aggressively marketed for its treatment, especially in the United States [2]. To obtain more scientific information about andropause we launched more than 10 years ago a study, The European Male Ageing Study (EMAS) [3], whose purpose was to examine in a large cohort of community-dwelling European men the extent of ageing-related alterations in T and other reproductive and metabolic hormones, other laboratory parameters, anthropometry and health status, and to refine the diagnostic criteria and clinical significance of andropause/LOH. In this review we summarize some of the salient findings of the EMAS study. 2. Definition and pathogenesis of andropause Andropause is associated with a wide array of largely nonspecific physical, psychological and sexual symptoms often associated with hypogonadism of young men and ageing in general. Several questionnaires have been constructed to score the magnitude of andropausal symptoms, but they are generally considered inaccurate [4–6]. In EMAS we observed that the only symptoms that were significantly associated with serum total T or free T were the three sexual symptoms, i.e. erectile dysfunction and decreased sexual thoughts and morning erections [7]. Frequencies of other physical and psychological symptoms used in the andropause questionnaires showed no significant association with circulating T levels, occurring at roughly similar frequency throughout the range of measured T concentrations. We can therefore almost categorically state that if a man does not have reduced sexual function, he does not have andropause and that the other symptoms he may have, such as insomnia, depression, muscle weakness, irritability, are not alone associated with genuine andropause. Hence, sexual function is a window into the health of an ageing man. 3. Pathogenesis and diagnosis of andropause It is obvious that low T must be one of the criteria of the diagnosis of andropause. The simplest parameter is serum total T, which should be below the lower limit of the references range, roughly about 10 nmol/L. Another useful parameter is measured or calculated free T, which is often considered a more accurate measure, but opinions vary about the accuracy of the formulas used to calculate free T [8], and the methods of direct free T measurement are expensive and/or often not accessible in clinical practice. Low T alone is not sufficient, because often men with T below the reference range are totally asymptomatic. The EMAS criteria for T to fulfill criteria of andropause are total T
below 8 nmol/L, or if total T is in the gray zone of 8-11 nmol/L, then in addition calculated free T should be below 220 pmol/L [7]. With these T levels, sexual symptoms of men (see above) are significantly more frequent than in men with T above these limits. However, even men with low T may have sexual symptoms independently of low T, because there is a high background prevalence of sexual symptoms in about 25% of men irrespective of their circulating T concentration [7]. According to the strict EMAS criteria [7], i.e. low serum total and/or free T (see above) and three sexual symptoms, the frequency of andropause/LOH in 40–79-year-old communitydwelling men is only 2.1%, increasing from 0.15 to 5.1% between 40 and 79 years. However, if a man visits a physician complaining andropausal symptoms, it has been estimated that the likelihood of genuine LOH in this selected population is about 15% [9]. Low T alone with diffuse symptoms does not justify the diagnosis of andropause, neither do sexual symptoms in men with normal T. If low T is associated with elevated LH, the man has primary hypogonadism, and if LH is either low or inappropriately normal in the face of low T, hypogonadism is secondary, caused by a disturbance at the hypothalamic-pituitary level. Both conditions are observed in andropause. According to the EMAS study, secondary hypogonadism is associated with overweight and obesity, but not with ageing, whereas primary hypogonadism is an ageing-related condition [10]. Altogether 73% of the men fulfilling the strict criteria of andropause were overweight or obese. In the rest, the lean men with andropause have often chronic health conditions (e.g. cardiovascular disease, diabetes, frailty), which could explain the finding. The condition remains idiopathic only in a minority of men, which means that there are targets for treatment, including lifestyle modification with weight loss and good treatment balance of comorbidities. T replacement therapy should not be the automatic first option. We also identified a third diagnostic group, which was termed ‘compensated hypogonadism’ [11]. These men have normal T but elevated LH, and they accounted for 9.5% of the EMAS cohort. They have signs of androgen deficiency, in particular limited physical capacity. Our recent (unpublished) followup data suggest that compensated hypogonadism represents an interphase in the trajectory from eugonadism to primary hypogonadism, and it is totally distinct from the obesity related secondary hypogonadism. Classification into the three diagnostic subgroups by combining LH with T may improve the diagnosis and management of andropause. 4. Impact of andropause on health Low T has been associated with increased mortality in a number of studies [12]. However, the natural history of symptomatic LOH, especially its relationship to mortality, remains poorly explored. We recently investigated in the prospective part of EMAS the associations between andropause, low T, and sexual symptoms with mortality in 2599 men [13]. All-cause, cardiovascular, and cancer-related mortality was measured during an average follow-up of 4.3 years. Fifty-five men (2.1%) were identified as having LOH (31 moderate and 24 severe). After
Please cite this article in press as: Huhtaniemi IT. Andropause – lessons from the European Male Ageing Study. Ann Endocrinol (Paris) (2014), http://dx.doi.org/10.1016/j.ando.2014.03.005
+Model ANDO-614; No. of Pages 4
ARTICLE IN PRESS I.T. Huhtaniemi / Annales d’Endocrinologie xxx (2014) xxx–xxx
adjusting for age, centre, body mass index (BMI), current smoking, and poor general health, compared with men without LOH, those with severe LOH (T < 8 nmol/L + sexual symptoms) had over 5-fold (hazard ratio 5.5; 95% confidence interval 2.7, 11.4) higher risk of all-cause mortality. Similar risks were observed for cardiovascular mortality. When only low T (15%) the change was significant (in the same direction as total T). Smoking cessation was associated with a greater decline in T than being a non-smoker, independent of weight change. Changes in number of comorbid conditions or physical activity did not influence function of the hypothalamic–pituitary–testicular (HPT) axis. We were able to conclude from these observations that weight and lifestyle factors do influence HPT axis function in ageing. Weight loss increases and weight gain decreases T, free T and SHBG levels. Weight management is therefore important in maintaining circulating T in ageing men, and obesity-associated changes in HPT axis hormones can be reversed by weight reduction. These observations leave us with the ‘hen and egg’ conundrum between serum T and health. Is low T the cause or consequence of ill health? The causality is apparently at least to some extent bidirectional, but the evidence is mounting that low T is simply an indicator of ill health, not the cause of it. 6. Controversies in the treatment of andropause There are in principle two treatment options for LOH, which are:
3
• T replacement therapy; • lifestyle modification, weight loss and good treatment balance of comorbidities. It is tempting to conceptualise andropause as an ageingrelated deficiency state of T that is the cause for associated health problems, and that simply replacing the reduced T production with exogenous hormone will reverse the situation and correct the health problems. This approach is based on the conjecture that low T is the cause of health problems. However, this is far from being convincingly shown. Admittedly, there are conditions where reduction of T production leads to symptoms common in LOH, for example upon androgen blockage therapy of prostate cancer [15]. It is equally possible that low T is the harbinger of ill health, and it could even be the body’s desired adaptation phenomenon to ill health, in which case its reversal by exogenous T would not only be undesirable but could even be harmful. Several recent studies have warned about cardiovascular complication in ageing men during T replacement therapy [16–18]. Numerous studies have shown health benefits of T replacement in andropause, but these studies are invariably small, short in duration, retrospective, non-randomized and either uncontrolled or having biased controls. A typical study is where T is offered for a group of men with variable reduction of T and selected purportedly andropausal symptoms, and the men who for any reason (e.g. contraindications) do not receive T form the controls. Very telling is one placebo-controlled study where both placebo and T had similar statistically significant suppressive effects on andropausal symptoms [19]. The largely anecdotal information or poor quality research data do not justify recommending T replacement as standard treatment of andropause at this moment. We have to wait for better information before the issue can be solved. Such a definitive treatment trial is currently underway in the US (NCT00799617 on 2008 11 30), and we should see its results in 2015. 7. Conclusions Andropause can be defined according to the strict EMAS criteria as a condition where an ageing man has low T (
