Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort sub study of the Aspree trial.

Summary

Blood testosterone concentrations in women decline during the reproductive years and reach a nadir in the 7^th decade after which concentrations increase and are restored to those of reproductive age women in the 8^th decade. The present commented study [1], which was a prospective cohort sub-study of the longitudinal randomized ASPREE trial aimed to establish the association between the concentration of testosterone in the blood and the risk of major adverse cardiovascular events (MACE) and all-cause mortality in healthy older women. Eligible participants were women aged at least 70 years from Australia with unimpaired cognition, no previous MACE, and a life expectancy of at least 5 years. Women using hormonal or steroid therapy were ineligible for inclusion. Concentrations of sex steroids were measured with liquid chromatography-tandem mass spectrometry whilst SHBG was measured with immunoassay. Results were divided into four quartiles and lower and higher concentrations were compared. Primary endpoints were risk of MACE and all cause mortality. Associations with sex steroid concentrations were assessed using Cox proportional hazards regression that included age, body mass index, smoking status, alcohol consumption, diabetes, hypertension, dyslipidemia, impaired renal function, and treatment allocations in the Aspree trial (aspirin vs placebo). A total of 5,535 women were included in the final analysis. Median age at entry was 74.0 years (interquartile range [IQR] 71.7-77.7). During a median follow up of 4.4 years (24,553 person years) 144 (2.6%) women had a first MACE (incidence 5.9 per 1,000 person years). During a median 4.6 years (IQR 3.8-5.6) of follow up (25,295 person years) 200 (3.6%) of the 5,535 women died, an incidence rate of 7.9 per 1,000 person years. In the fully adjusted models, higher concentrations of testosterone were associated with lower incidences of MACE (quartile 4 vs quartile 1 HR 0.57 [95% CI: 0.36-0.91] as were higher concentrations of DHEA (Q4 vs Q1 0.61 [95% CI 0.38-0.97]. For Oestrone, a lower risk of MACE was observed for Q2 only when compared to Q1. No association was seen between SHBG and MACE or between any hormone or SHBG and all-cause mortality. Blood concentrations of testosterone and DHEA above the lowest quartile in older women were associated with first ever MACE. Given that physiological effects of DHEA are mediated through its steroid metabolites, if these findings were to be replicated, trials investigating testosterone therapy for the primary prevention of ischemic cardiovascular disease events in older women would be warranted.

Commentary

The present study showed that, amongst healthy postmenopausal Australian women aged 70 and over, blood concentrations of testosterone and DHEA above the lowest quartile were associated with nearly half the risk of MACE, independent of traditional risk factors for cardiovascular disease. No consistent association between circulating levels of oestrone (the major circulating postmenopausal oestrogen) and MACE was seen despite DHEA being the precursor of both oestrone and testosterone. Early emergence of the apparent protective effect of both testosterone and DHEA and the fact that results for Q2-4 tended to track together suggests that benefits seen for Q2 compared to Q1 were not additionally improved by higher concentrations of testosterone or DHEA. These findings suggest, that in older postmenopausal women, there is no cardiovascular benefit from higher endogenous levels of oestrone and that higher levels of testosterone and DHEA are not associated with an increased risk of cardiovascular disease and may indeed offer cardio protection.

Much has been made of the ‘window of opportunity’ for the use of exogenous estrogens for cardio protection in postmenopausal women with consistent data from observational studies and randomized clinical trials in recently menopausal women suggesting benefits which are not seen when estrogen therapy is initiated more than 20 years after the final menstrual period. Such may not be the case for exogenous testosterone therapy, but future research must answer that question before its use for this indication in older postmenopausal women becomes accepted in clinical practice. This interesting study raises many questions, the first being the possibility that these data be replicated in other populations of older postmenopausal women. Should that be the case it will be fascinating to follow further research to test the hypothesis that exogenous testosterone therapy administered to healthy postmenopausal women at various stages of postmenopausal life may offer cardiovascular benefit.

Meanwhile, it is important to remember that the only current indication for the use of testosterone therapy in postmenopausal women is for the relief of the hypoactive sexual desire disorder and then, only after a thorough biopsychosocial assessment [2].

Prof. Rodney Baber, B Pharm, MB, BS, FRCOG, FRANZCOG
Department of Gynecological Endocrinology,
Clinical Professor of Obstetrics and Gynaecology
Faculty of Medicine and Health, The University of Sydney, Australia
Past President IMS
Editor in Chief, Climacteric

References

1. Islam 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(2):e109-e118.
   https://pubmed.ncbi.nlm.nih.gov/35252940/

2. Davis SR, Baber R, Panay N, et al. Global Consensus Position Statement on the Use of Testosterone Therapy for Women. 2019;22(5):429-434.
   https://pubmed.ncbi.nlm.nih.gov/31474158/