We found no association of FT, TT, and SHBG levels with mortality in all postmenopausal women. In diabetic postmenopausal women referred for coronary angiography, we observed a significant association of low FT levels with increased all-cause as well as cardiovascular mortality after adjustment for various cardiovascular risk factors. Moreover, high FT levels were associated with cardiovascular risk factors including obesity, insulin resistance, and type 2 diabetes at baseline.
High testosterone levels have been shown to be associated with insulin resistance, metabolic syndrome, obesity, type 2 diabetes, and chronic inflammation in pre- as well as in postmenopausal women (1
). Our cross-sectional analyses are in line with these previous reports. In contrast, Debing et al. (12
) found a positive association between low serum androgen levels and severe carotid artery atherosclerosis in postmenopausal women. Interestingly, TT levels were positively associated with carotid artery intima-media thickness but negatively associated with high coronary calcium scores (13
). Besides the association of high androgen levels with cardiovascular risk factors, evidence regarding the association of androgen levels with mortality in women is sparse. In our cohort, we did not observe an association of TT, SHBG, and FT levels with all-cause mortality and cardiovascular mortality, which is in line with previous results from the Rancho Bernardo Study (6
). In contrast, Sievers et al. (8
) found a significant association of low TT levels with increased all-cause mortality and incident cardiovascular events in a population aged 18–75 years (mean, 58 years), which is somewhat surprising considering the fact that high testosterone levels are associated with several traditional cardiovascular risk factors, including type 2 diabetes (3
). Further, high levels of TT might increase the risk of developing breast cancer in postmenopausal women (14
). Moreover, Laughlin et al. (15
) reported that low levels of testosterone are associated with an increased risk of coronary heart disease events prospectively in a population-based study including 639 postmenopausal women, aged 50–91 years (mean, 73.8 years).
Despite the inverse associations of FT levels with cardiovascular risk factors, there was no significant association of FT levels with all-cause or cardiovascular mortality when all postmenopausal women in our cohort were analyzed. Interestingly, we observed a robust association of low FT with increased all-cause and cardiovascular mortality in diabetic postmenopausal women. Underlying pathophysiological pathways remain to be explored, but there are several mechanisms that might explain our results. First, low androgen levels might be caused by a pre-existing disease and might simply be a marker of disease or poor health. Thus, low FT levels might reflect one aspect of anabolic insufficiency, which might have an adverse impact on mortality in diabetic postmenopausal women at high cardiovascular risk. However, when deaths occurring during the first 2 years were excluded, our results did not materially change. Second, low testosterone may cause or worsen disease and therefore lead to increased mortality. This hypothesis might be supported by observations in men. Several studies (16
) indicate that low testosterone levels are associated with increased mortality, which might be attributable to direct and indirect effects of androgens on vascular tone, glucose, and lipid metabolism. In postmenopausal women, the effects of low androgens are less clear. Similar to the gradual decline of androgens observed within aging in men, an age-dependent decline in androgens also occurs in women. In postmenopausal women, androgen insufficiency may have implications for maintenance of bone density and overall quality of life (18
). Potential signs or symptoms attributable to low androgen levels in postmenopausal women are vasomotor instability or decreased vaginal lubrication, bone loss, decreased muscle strength, and changes in cognition or memory (19
). Moreover, a diminished sense of well-being or dysphoric mood, a lack of energy, as well as persistent, unexplained fatigue might be associated with androgen insufficiency in postmenopausal women (18
). However, the diagnosis of female “androgen insufficiency” might be difficult because of the lack of normative data on TT or FT levels across the life span and the poor accuracy and precision of testosterone assays available at that time (18
In men, as well as in women, it has been shown that testosterone therapy augments anabolic function, leading to increased muscle mass and physical strength (20
). Moreover, testosterone replacement therapy at physiological levels increased muscle mass and improved some cardiovascular risk factors, such as insulin resistance in women with androgen deficiency caused by hypopituitarism (21
). As reviewed by Braunstein (22
), the major adverse reactions to exogenous androgens are androgenic side effects, including hirsutism and acne; testosterone administration to postmenopausal women that results in physiological to slightly supraphysiological serum-free testosterone levels is safe for at least 2 years. Although there is substantial evidence that testosterone treatment in low-dose regimens has beneficial effects on several aspects, including bone mass, muscle mass, and quality of life, there is insufficient data concerning long-time safety and side effects of testosterone replacement therapy (19
Little is known about the clinical and biochemical features of PCOS after menopause. The definition of postmenopausal PCOS women remains to be determined because menstrual irregularity cannot be assessed in postmenopausal women and polycystic ovary morphology might change over time. Menopausal transition involves many changes regarding women’s androgen status. To the best of our knowledge, no large prospective study has been published to date investigating the association of TT or FT levels with mortality in PCOS women. Considering our results showing an inverse association of FT levels with mortality in diabetic postmenopausal women, one might question the postulated negative impact of high androgens on survival in postmenopausal women at high cardiovascular risk. Of note, there is an ongoing debate on whether the increased cardiovascular risk is caused by PCOS itself, the interaction of abdominal obesity with hyperandrogenemia, or maybe by obesity alone. In contrast, data from a recent meta-analysis indicate that the increased risk for cardiovascular events in PCOS is not completely explained by obesity (2
). Similarly, Krentz et al. (23
) demonstrated that among nondiabetic postmenopausal women with intact ovaries, prevalent atherosclerotic disease is associated with features of a putative PCOS phenotype, which includes biochemical hyperandrogenism. Because no prospective study with a long-term follow-up in PCOS women is available, evidence on mortality in PCOS women is lacking.
The results of this study should be evaluated in the context of its limitations. The data provided are restricted to women referred for coronary angiography and may therefore not be generalizable to patients at lower cardiovascular risk, population-based cohorts, and younger age-groups. Thus, the external validity of the study is limited and larger studies on more diverse populations are needed to further establish the association of FT with mortality. Furthermore, we investigated a cohort of Caucasians living in Germany, and results might not relate to other ethnicities. Because direct measurement of FT by equilibrium dialyses is impractical in routine practice, several methods such as Vermeulen, Sodergard, Nanjee-Wheeler, and Ly-Handelsman equations are used to provide clinically useful estimates of FT concentration. However, the Vermeulen equation used to calculate FT is a reasonable approximation of actual values (10
). Furthermore, TT was measured by immunoassay, and different testosterone immunoassays may give varying results. However, these methods are frequently used in large-scale studies in which assay of TT by mass spectrometry and FT via equilibrium dialysis might be impractical. Moreover, this technique has been calibrated against mass spectrometry showing a strong positive correlation. SHBG genotype (24
) and coffee consumption (25
) are known to influence SHBG levels but data concerning these aspects were not available in the cohort. Further, there was no power calculation with a priori established primary end points.
In summary, we present evidence that high FT levels are associated with cardiovascular risk factors, including obesity, insulin resistance, and type 2 diabetes. We found no association of TT or SHBG with mortality, whereas low FT levels were associated with increased all-cause and cardiovascular mortality in diabetic postmenopausal women referred for coronary angiography. The underlying mechanisms remain to be explored. Large prospective studies are warranted to explore the effect of androgens on mortality in women, with a special focus on women with PCOS.