Low free testosterone levels are associated with all-cause and cardiovascular mortality in postmenopausal diabetic women

OBJECTIVE

Hyperandrogenemia is associated with cardiovascular risk factors in women but evidence about the relationship of testosterone levels with mortality is sparse. We aimed to evaluate whether total testosterone (TT), free testosterone (FT), and sex hormone–binding globulin (SHBG) are associated with all-cause and cardiovascular mortality in a cohort of postmenopausal women.

RESEARCH DESIGN AND METHODS

We measured TT and SHBG levels in 875 postmenopausal women who were referred for coronary angiography (during 1997–2000). FT was calculated according to the Vermeulen method. The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes and from cardiovascular causes.

RESULTS

After a median follow-up time of 7.7 years, 179 women (20.5%) had died. There were 101 deaths due to cardiovascular disease (56.4% of all deaths). We found no association of FT, TT, and SHBG levels with mortality in all postmenopausal women. In postmenopausal diabetic women, multivariable-adjusted HRs (with 95% CIs) in the fourth compared with the first FT quartile for all-cause and cardiovascular mortality were 0.38 (0.08–0.90), P = 0.025, and 0.28 (0.08–0.90), P = 0.032, respectively. We found no association of TT and SHBG with mortality in diabetic postmenopausal women.

CONCLUSIONS

In postmenopausal diabetic women referred for coronary angiography, low FT levels are independently associated with increased all-cause and cardiovascular mortality.Hyperandrogenemia is associated with adverse metabolic features, including insulin resistance, central obesity, dyslipidemia, and chronic inflammation in premenopausal women, which might lead to an increased cardiovascular risk (1). Hyperandrogenemia in premenopausal women is most frequently caused by polycystic ovary syndrome (PCOS). In a recent meta-analysis (2), a twofold increased risk for arterial disease was observed in patients with PCOS relative to women without PCOS. BMI adjustment did not affect this finding, suggesting that the increased risk for cardiovascular events in PCOS might rather be a consequence of hyperandrogenemia than of obesity per se. High testosterone levels, which indicate an increased risk of type 2 diabetes in postmenopausal women (3), may underlie this association when considering that type 2 diabetes is associated with a 3.5-fold increased mortality (4). On the other hand, low levels of testosterone have been reported in women with atherosclerotic disease (5). Little is known about the association of androgen levels with mortality in pre- as well as postmenopausal women. The few studies conducted so far revealed conflicting results. Results from the Rancho Bernardo Study (6) indicate no association of testosterone levels with mortality, whereas Shaw et al. (7) demonstrated that hyperandrogenemia and a history of irregular menses were associated with angiographic coronary artery disease and increased mortality. In contrast, Sievers et al. (8) demonstrated that low total testosterone (TT) levels were associated with increased all-cause mortality and incident cardiovascular events in a primary care cohort of 2,914 female patients. These latter studies were, however, limited by use of TT for assessment of androgen status. This may not be the best approach because free testosterone (FT), and not TT, is the biologically active form.Hence, our aim was to study the association of TT, sex hormone–binding globulin (SHBG), and FT levels with all-cause as well as cardiovascular mortality in postmenopausal women referred for coronary angiography. Considering previous data suggesting a possible association of testosterone status and type 2 diabetes, we performed analyses stratified by diabetes status.