In 5,535 women aged 70 or older enrolled in the Sex Hormones in Older Women (SHOW) Study — a sub-study of the ASPREE trial — endogenous oestradiol levels measured via the gold-standard liquid chromatography-tandem mass spectrometry showed no independent association with major adverse cardiovascular events (MACE) or all-cause mortality over approximately 4.5 years. Notably, 66% of participants had oestradiol below the detection threshold of 11 pmol/L. Neither very low nor higher circulating oestradiol (tertile 3) significantly altered MACE risk compared to the middle reference group, with hazard ratios spanning 0.83–1.11 and wide confidence intervals.
This finding challenges a long-standing hypothesis that declining endogenous oestrogen is a primary cardiovascular risk driver in post-menopausal women. Earlier observational data and the 'timing hypothesis' from the Women's Health Initiative suggested oestrogen's cardioprotective role may be time-sensitive — potentially relevant only when initiated near menopause. The SHOW results suggest that among already post-menopausal women well past the transition, residual circulating oestradiol levels carry little prognostic weight for hard cardiovascular endpoints.
Important limitations apply: participants were relatively healthy at baseline, excluding those with prior cardiovascular events, which may limit generalisability. The median follow-up of 4.5 years may be insufficient to detect modest long-term associations. Clinically, this reinforces that measuring oestradiol in older women is unlikely to refine cardiovascular risk stratification — a valuable null finding for clinical practice.