Sex Hormones in Older Women Study (The SHOW Study)

Chief Investigators: Susan R Davis, Robin J Bell, Rory Wolfe, together with the ASPREE team

Androgens have a crucial role in female physiology. Whereas we know that androgen levels decline steeply during the reproductive years and are unaffected by natural menopause, little is known about androgen levels in older women. Nonetheless, several studies have implicated low testosterone as an important risk factor for cardiovascular disease (CVD) and all-cause mortality in women.  These studies have been limited by various factors including size, the number of years between measurement of testosterone and the outcomes, measurement only of testosterone, as opposed to also measuring its precursors and metabolites, and most importantly, measurement of testosterone by methods that lack precision at the low concentrations seen in older women.  As CVD is the leading cause of death in women in developed countries (25.3% of all deaths) and of women aged 65 and over, clarification of the relationship between androgens and CVD is an important step towards determining whether androgen physiology contributes to the pathophysiology of CVD in women.

ASPREE (ASPirin in Reducing Events in the Elderly) is a randomised placebo-controlled trial (RCT) of aspirin (100 mg enteric coated daily) in people aged 70 years and older (70+). 16,500 Australians, screened to confirm normal cognition and no prior cardiovascular event at study entry, and followed on average for 5 years, have been recruited through partnerships with over 2500 General Practitioners. The large representation of women in the ASPREE cohort (~56%) provides a unique opportunity to, for the first time, establish age-specific reference ranges for each of main sex steroids in a large sample of community-dwelling, older women using gold standard methodology (liquid chromatography tandem mass spectrometry [LCMS]). Sex hormone binding globulin (SHBG) strongly binds sex steroids in the blood, and hence is a determinant of circulating unbound sex steroids. SHBG has been independently associated with diabetes and CVD. Measurement of the sex steroids and SHBG will provide the unique opportunity for the investigation of the associations these and main clinical outcomes being measured in ASPREE : all cause mortality and cardiovascular events.

Our hypotheses are:

  1. That in women aged 70 years and older (70+), low total and free testosterone levels are associated with all cause mortality and cardiovascular events
  2. That low SHBG, but not circulating androgen levels, is associated with an adverse CV risk profile (adverse lipid profile, obesity and type 2 diabetes).
  3. That androgen levels do not decline beyond the age of 70 years in ‘well’ community dwelling women;

To address these hypotheses our research objectives are to:

  1. Investigate the associations between sex steroids measured in blood collected at recruitment to ASPREE and the following ASPREE outcomes in women randomised to placebo as well as women randomised to aspirin:
    1. All-cause mortality
    2. Fatal and non-fatal cardiovascular events including
      1. coronary heart disease death,
      2. non-fatal myocardial infarction
      3. fatal and non-fatal stroke and
      4. hospitalisation for heart failure
  2. This will be done after the study is unblinded in April 2018.
  3. Explore the associations between blood sex steroid levels (listed in 3) and SHBG and anthropomorphic measures and other cardiovascular risk factors.
  4. Document circulating sex steroid levels in baseline blood drawn from female ASPREE participantsand establish reference ranges for each of these by 5 year age intervals.
  5. Explore whether changes in sex steroid levels after a period of 3 years, as opposed to baseline levels, are associated with outcomes of ASPREE listed in (3).