Low testosterone concentrations and risk of ischaemic cardiovascular disease in ageing: not just a problem for older men

Coronary heart disease, myocardial infarction, and ischaemic stroke increase sharply in prevalence with age in both men and women.1Virani SS Alonso A Aparicio HJ et al.American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2021 update: a report from the American Heart Association.Circulation. 2021; 143: e254-e743Crossref PubMed Scopus (1287) Google Scholar The understanding that such diseases are more likely to occur in women after the menopause has motivated research into the cardiovascular effects of low blood oestrogen concentrations. By contrast, it is less well appreciated that blood testosterone concentrations also decrease gradually with age in women, although these concentrations can rise again at the start of the seventh decade.2Islam RM Bell RJ Handelsman DJ et al.ASPREE Investigator GroupLongitudinal changes over three years in sex steroid hormone levels in women aged 70 years and over.Clin Endocrinol (Oxf). 2021; 94: 443-448Crossref Scopus (2) Google Scholar Previous studies have suggested that low circulating concentrations of testosterone might increase the risk of ischaemic cardiovascular disease in older men and women by promoting maladaptive vascular remodelling and atherosclerosis.3Moreau KL Babcock MC Hildreth KL Sex differences in vascular aging in response to testosterone.Biol Sex Differ. 2020; 11: 18Crossref PubMed Scopus (18) Google Scholar Whether a rise or fall in testosterone later in life is linked with ischaemic disease in older women remains unclear. Most previous studies measured testosterone concentrations with immunoassays; however, the ability of these immunoassays to quantify low concentrations of testosterone, such as those seen in women, has been questioned.4Gravitte A Archibald T Cobble A Kennard B Brown S Liquid chromatography-mass spectrometry applications for quantification of endogenous sex hormones.Biomed Chromatogr. 2021; 35e5036Crossref PubMed Scopus (8) Google Scholar Furthermore, the relationship between dehydroepiandrosterone (DHEA), the major precursor for testosterone in postmenopausal women, and ischaemic cardiovascular disease has not been established. In the Sex Hormones in Older Women (SHOW) study, a prospective cohort substudy of the ASPREE trial, Rakibul Islam and colleagues5Islam RM Bell RJ Handelsman DJ et al.Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial.Lancet Healthy Longev. 2022; 3: e109-e118Summary Full Text Full Text PDF Scopus (1) Google Scholar investigated the potential associations between plasma concentrations of sex steroids (oestrone, testosterone, and DHEA) and the risk of major adverse cardiovascular events (MACE) and all-cause mortality in healthy older women aged 70 years and older. The authors used state-of-the-art liquid chromatography–tandem mass spectrometry (LC–MS/MS), which precisely quantifies circulating concentrations of sex hormones. Interestingly, Islam and colleagues5Islam RM Bell RJ Handelsman DJ et al.Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial.Lancet Healthy Longev. 2022; 3: e109-e118Summary Full Text Full Text PDF Scopus (1) Google Scholar showed that women with serum testosterone and DHEA concentrations in the lowest quartile had the highest risk of MACE (eg, coronary heart disease, myocardial infarction, or ischaemic stroke), compared with women with serum testosterone and DHEA concentrations in the higher quartiles. The authors concluded that low androgen concentrations could predispose older women to MACE in these disease settings. This new research by Islam and colleagues5Islam RM Bell RJ Handelsman DJ et al.Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial.Lancet Healthy Longev. 2022; 3: e109-e118Summary Full Text Full Text PDF Scopus (1) Google Scholar is crucially important because the SHOW study provides convincing evidence that low plasma concentrations of testosterone and DHEA are detrimental to cardiovascular health in older women, especially with respect to ischaemic diseases. These findings strongly suggest that testosterone and DHEA concentrations above the lowest quartile might be cardioprotective in postmenopausal women. As a result, as long as potential benefits outweigh any related risks, testosterone supplementation could be an effective treatment strategy in this patient group. Additionally, if these promising initial results were to be replicated, this research could set the stage for future trials of testosterone therapy to prevent ischaemic cardiovascular events in postmenopausal women with low endogenous testosterone. Although the SHOW study highlights the importance of androgens in women's cardiovascular health, some questions remain. This study included fatal coronary heart disease, non-fatal myocardial infarction, and fatal or non-fatal ischaemic stroke but excluded heart failure, which is very common in older individuals.1Virani SS Alonso A Aparicio HJ et al.American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2021 update: a report from the American Heart Association.Circulation. 2021; 143: e254-e743Crossref PubMed Scopus (1287) Google Scholar Our preclinical work6Ayaz O Banga S Heinze-Milne S Rose RA Pyle WG Howlett SE Long-term testosterone deficiency modifies myofilament and calcium-handling proteins and promotes diastolic dysfunction in the aging mouse heart.Am J Physiol Heart Circ Physiol. 2019; 316: H768-H780Crossref Scopus (14) Google Scholar, 7Banga S Heinze-Milne SD Godin J Howlett SE Signs of diastolic dysfunction are graded by serum testosterone levels in aging C57BL/6 male mice.Mech Ageing Dev. 2021; 198111523Crossref Scopus (3) Google Scholar has shown that chronic exposure to low circulating concentrations of testosterone promotes diastolic dysfunction—a condition in which the heart has trouble relaxing—in ageing male mice. Diastolic dysfunction can lead to heart failure with preserved ejection fraction, a type of heart failure that is common in older people, and has few, if any, treatment options.8Pepine CJ Merz CNB El Hajj S et al.American College of Cardiology Committee on Cardiovascular Disease in Women. Heart failure with preserved ejection fraction: similarities and differences between women and men.Int J Cardiol. 2020; 304: 101-108Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar It would be interesting to explore the associations between low circulating concentrations of androgens and all types of heart failure in postmenopausal women using the elegant approaches deployed by Islam and colleagues.5Islam RM Bell RJ Handelsman DJ et al.Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial.Lancet Healthy Longev. 2022; 3: e109-e118Summary Full Text Full Text PDF Scopus (1) Google Scholar The SHOW study raises other interesting questions. For example, high ratios of testosterone to oestradiol have previously been associated with an increased risk of cardiovascular diseases (especially heart failure) in postmenopausal women, at least when hormone concentrations are assessed with immunoassays.9Zhao D Guallar E Ouyang P et al.Endogenous sex hormones and incident cardiovascular disease in post-menopausal women.J Am Coll Cardiol. 2018; 71: 2555-2566Crossref PubMed Scopus (144) Google Scholar It would be fascinating to know whether LC–MS/MS approaches could show how testosterone-to-oestradiol ratios relate to risk of adverse cardiovascular events in older women. In the long term, it could be interesting to investigate the beneficial effects of testosterone replacement therapy in postmenopausal women with low endogenous testosterone concentrations. In support of these potential effects, there is emerging evidence that testosterone therapy improves exercise capacity in older men with heart failure and reduces the risk of myocardial infarction in older men with low testosterone.10Goodale T Sadhu A Petak S Robbins R Testosterone and the heart.Methodist Debakey Cardiovasc J. 2017; 13: 68-72Crossref Scopus (36) Google Scholar Furthermore, the SHOW study5Islam RM Bell RJ Handelsman DJ et al.Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial.Lancet Healthy Longev. 2022; 3: e109-e118Summary Full Text Full Text PDF Scopus (1) Google Scholar highlights the need for additional preclinical research into the fundamental mechanisms underlying the observed cardiovascular protection in both men and women. The observation that low plasma testosterone and DHEA concentrations facilitate adverse ischaemic events in older women underscores why it is important to consider plasma androgen concentrations in ageing women, as well as in ageing men. This consideration is not only important for developing new potential treatments for ischaemic cardiovascular diseases in ageing patient populations but also for understanding the biological mechanisms of healthy ageing and longevity in both sexes. Future work in this area promises to be illuminating. We declare no competing interests. Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trialBlood concentrations of testosterone and DHEA above the lowest quartile in older women were associated with a reduced risk of a first-ever MACE. Given that the physiological effects of DHEA are mediated through its steroid metabolites, if the current findings were to be replicated, trials investigating testosterone therapy for the primary prevention of ischaemic cardiovascular disease events in older women would be warranted. Full-Text PDF Open Access

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