Commentary J Epidemiol Community Health: first published as 10.1136/jech-2015-206336 on 9 December 2015. Downloaded from immortal time,21 which may generate Could androgens be relevant to partly findings at variance with meta-analysis of – RCTs.20 22 24 The only observational explain why men have lower life study of testosterone prescription that used a self-comparison and a control expectancy than women? exposure is probably the most convincing: it found, specifically, that testosterone pre- 1,2 C Mary Schooling scription was associated with a higher risk of non-fatal myocardial infarction.25 Evidence about the effects of androgens Life expectancy is about 5 years shorter gonads and longer life;6 interestingly mice 1 6 from RCTs is limited because the US for men than for women. At any given prefer a higher protein diet. In humans, Institute of Medicine advised, in 2004, age, men are more vulnerable than the reproductive axis in women is that no large scale trials of testosterone fi women to death from most major causes, suppressed at menopause, and arti cial should be undertaken until benefits over including infections, cancer and cardiovas- supplementation with reproductive hor- 1 existing treatments had been established cular disease. Lifestyle and stress mones in postmenopausal women is not in small trials.26 Health comparisons fi 7 undoubtedly play the same role in this dis- bene cial for lifespan. In contrast, men between men with genetically higher or parity as in other health disparities, par- continue to be fertile throughout adult lower androgens using Mendelian ran- ticularly given historically higher smoking life; little consideration has been given to domisation are limited because androgens rates for men than for women. Whether whether lifelong fertility in men relates to are rarely measured, so few genetic var- these factors provide a comprehensive or trades off against lifespan. Given the iants reliably determining androgens have explanation and actionable targets of shorter lifespan for men than for women, been identified.27 28 intervention is less clear, particularly as consideration is given here to how male Nevertheless, information about the these factors do not fully explain men’s reproductive hormones, namely, andro- ’ 2 role of androgens in men s health is cardiovascular disadvantage. Here, to gens, affect health in men beyond repro- slowly emerging. Below, the effects of provide another perspective, the sexual duction, and whether androgens could androgens on major contributors to global disparity in life expectancy is considered have any relevance to the sexual disparity mortality are considered, including in the context of an existing well- in life expectancy, or any implications for immune function, cancer, cardiovascular established theory from evolutionary the prevention and treatment of the disease and diabetes. Given the focus on biology. Life history theory suggests that leading causes of mortality. the effects of androgens, greatest emphasis copyright. animals, including humans, employ envir- is placed on evidence about likely causal onmentally driven strategies to maximise NON-REPRODUCTIVE EFFECTS OF effects from RCTs, Mendelian randomisa- Darwinian fitness, that is, reproductive 3 ANDROGENS IN MEN tion, experiments, natural experiments success. Optimal strategies for reproduct- Currently, the non-reproductive effects of and knockout animal models, rather than ive success likely differ by sex, because androgens on men’s health is little observed associations. men may have far more children than 8 4 researched. The published literature also women but reproductive costs are far suffers from citation bias towards studies Immune function higher for women. As such, not only does putting testosterone in a positive light.9 Androgens are generally understood to fi – a strategy aimed at tness differ from the Observational evidence concerning suppress the immune system;29 32 whereas public health goal of long and healthy life endogenous testosterone is difficult to oestrogen promotes immune response.33 fi but may also have sex-speci c implica- interpret because the most commonly For example, testosterone may inhibit tions, and so be relevant to the shorter measured androgen biomarker, serum tes- CD4 T-cell function,30 while androgen http://jech.bmj.com/ lifespan in men than in women. tosterone, falls in men with obesity and deprivation is associated with enlargement fi Speci cally, life history strategies may ill-health.10 Observed inverse associations of the thymus, which promotes immune involve trading off growth or reproduc- 29 3 of serum testosterone with major causes function. Experiments in rodents tion against longevity, with the role of of mortality, such as cardiovascular suggest androgens are pro-inflammatory less growth well known but suppressing disease, may be confounded in men by and delay wound healing.34 35 the reproductive axis may also increase fi 5 health status and so be dif cult to inter- Men tend to be more vulnerable to lifespan; and promoting the reproductive pret, as the authors of the relevant system- infections than women.33 36 37 Lifestyle on September 30, 2021 by guest. Protected axis may reduce lifespan. For example, a atic reviews and meta-analyses have been undoubtedly plays a part. However, the – high-protein diet in mice results in bigger careful to note.11 13 Other androgen bio- male vulnerability is most evident at ages gonads and shorter life, while a high- markers that give observational associa- when sexual dimorphism in sex hormones carbohydrate diet results in smaller tions more similar to results from is greatest, those being, early infancy, randomised controlled trials (RCTs) for puberty and young adult life, and includes ischaemic heart disease or its risk factors periods, such as early infancy, when life- 1School of Urban Public Health at Hunter College and are rarely reported.14 Similarly, observa- style choices are unlikely to differ by City University of New York School of Public Health, 37 New York, USA; 2Li Ka Shing Faculty of Medicine, tionally, androgens do not predict prostate sex. Male disadvantage is less evident School of Public Health, The University of Hong Kong, cancer,15 but genetic studies have for infections where a pathological Hong Kong Special Administrative Region, Hong Kong, removed doubts about a role for andro- immune response occurs.37 China gens in prostate cancer.16 Observational On the other hand, androgens may have Correspondence to Professor C Mary Schooling, evidence concerning exogenous testoster- the benefit of suppressing autoimmune School of Urban Public Health at Hunter College and 17–20 29–31 City University of New York School of Public Health, one prescription in men is mixed, responses, consistent with men being 2180 Third Avenue, New York, NY 10035, USA; and difficult to interpret because of the less vulnerable to autoimmune diseases [email protected] possibility of bias by indication and/or than women,29 31 with the difference 324 Schooling CM. J Epidemiol Community Health April 2016 Vol 70 No 4 Commentary J Epidemiol Community Health: first published as 10.1136/jech-2015-206336 on 9 December 2015. Downloaded from emerging at puberty. Androgen administra- 2014, the US Food and Drug numerical error (reporting on 308 instead tion has shown some promise in trials as a Administration (FDA) added a warning of 485 men).69 Notably, the most recent treatment for rheumatoid arthritis.38 39 about venous blood clots to the testoster- trial of testosterone found 12 major Whether biological treatments for auto- one product label.57 In July 2014, Health adverse cardiovascular events among 155 immune diseases, such as tumour necrosis Canada warned about “serious and pos- men in the treatment arm and 4 among factor-α inhibitors, operate via a similar sible life-threatening heart and blood 151 men in the placebo arm, OR 3.08, mechanism, is unknown. vessel problems such as heart attack, 95% CI 0.97 to 9.79.72 Men with lower stroke, blood clot in the lungs or legs; and endogenous testosterone due to legal cas- Cancer increased or irregular heart rate with the tration have relatively lower rates of spe- Given androgens’ suppressive effects on use of testosterone replacement pro- cifically myocardial infarction.73 Similarly, – immune function,29 32 androgens are ducts”.58 The European Medicines men with lifelong low testosterone due to thought to play a role not only in prostate Agency was less clear in November Klinefelter’s syndrome have low rates of and testis cancer, but also in cancer more 2104,59 but advised that testosterone ischaemic heart disease,74 despite well- generally,29 although evidence in men is should be restricted to men with patho- known vulnerability to diabetes.75 scarce. Based on androgen knockout logical hypogonadism.59 In March 2015, models, androgens could play a permissive the US FDA warned about “the possible Diabetes role in several cancers with a male pre- increased risk of heart attacks and strokes Diabetes is a strong, well-established risk pondrance,40 including cancer of the associated with testosterone use” and factor for cardiovascular disease, although bladder,41 kidney,42 liver43 and lung,44 as required a label change.60 Sales of testos- sex differences in diabetes rates are minor well as, perhaps, of the esophagus45 and terone are already falling in the USA61 and inconsistent.76 RCTs suggest andro- colorectum.46 Castration protects male and litigation against pharmaceutical com- gens improve glucose metabolism,77 rats against colonic adenomas.46 Whether panies is underway.62 perhaps through building muscle mass, androgens contribute to men’s vulnerabil- These warnings from regulators about which is a sink for glucose disposal. ity to cancer, and whether cancers with the cardiovascular risk of testoster- Whether treatments for diabetes operate male predominance share features, has one57 58 60 suggest that substantially by raising androgens has rarely been not been comprehensively investigated. higher androgens in men than women assessed.