Androgens, Irregular Menses, and Risk of Diabetes and Coronary Artery Calcification in the Diabetes Prevention Program

Catherine Kim; Vanita R. Aroda; Ronald B. Goldberg; Naji Younes; Sharon L. Edelstein; MaryLou Carrion-Petersen; David A. Ehrmann


J Clin Endocrinol Metab. 2018;103(2):486-496. 

In This Article

Abstract and Introduction


Context: It is unclear whether relative elevations in androgens or irregular menses (IM) are associated with greater cardiometabolic risk among women who are already overweight and glucose intolerant.

Research Design and Methods: We conducted a secondary analysis of the Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS). Participants included women with sex hormone measurements who did not use exogenous estrogen (n = 1422). We examined whether free androgen index (FAI) or IMwas associated with diabetes risk during the DPP/DPPOS or with coronary artery calcification (CAC) at DPPOS year 10. Models were adjusted for menopausal status, age, race or ethnicity, randomization arm, body mass index (BMI), and hemoglobin A1c.

Results: Women had an average age of 48.2 ± 9.9 years. Elevations in FAI and IM were associated with greater BMI, waist circumference, and blood pressure and lower adiponectin. FAI was not associated with diabetes risk during the DPP/DPPOS [hazard ratio (HR) 0.97; 95% confidence interval (CI), 0.93 to 1.02] or increased odds of CAC [odds ratio (OR) 1.06;95%CI, 0.92 to 1.23]. IM was also not associated with diabetes risk during the DPP/DPPOS (HR 1.07; 95% CI, 0.87 to 1.31) or increased odds of CAC (OR 0.89; 95% CI, 0.53 to 1.49). Women who had both relative elevations in FAI and IM had similar diabetes risk and odds of CAC as women without these conditions. Differences by treatment arm and menopausal status were not observed.

Conclusions: Among midlife women who were already glucose intolerant and overweight, androgen concentrations and IM did not additionally contribute to increased risk for diabetes or CAC.


Polycystic ovary syndrome (PCOS) is a common endocrinopathy that may affect up to one in five women of reproductive age.[1] Existing definitions are based on the presence of two or more of the following criteria: relative elevations in androgens, irregular menses (IM), and polycystic ovary morphology.[1] Women with PCOS have greater insulin resistance compared with age- and weight-matched controls[2–4] and subsequently higher risk of type 2 diabetes.[5–9] However, the extent to which central PCOS components (i.e., androgens and IM) increase cardiometabolic risk among women without a diagnosis of PCOS is unclear.

Specifically, it is unknown whether these characteristics increase risk beyond the presence of impaired glucose tolerance and overweight alone. Although one meta-analysis noted that women with elevated total testosterone concentrations had higher risk of diabetes in cross-sectional analyses,[10] more recent longitudinal studies of women with a range of body mass indices (BMIs) and degrees of glucose tolerance have not observed associations between hyperandrogenism and diabetes.[11,12] Reports also conflict as to whether hyperandrogenism is associated with coronary artery calcification (CAC)[13,14] or carotid intima media thickness,[15–18] both of which are indicators of subclinical atherosclerosis. Similarly, some studies report an association of IM with incident diabetes[19,20] and incident coronary disease[21] in populations with a range of BMIs and degrees of glucose tolerance, but others have noted that these associations are no longer significant after adjustment for BMI.[13,22,23]

The Diabetes Prevention Program (DPP) randomly assigned overweight, nondiabetic glucose-intolerant participants to a program of intensive lifestyle modification (ILS), metformin, or placebo.[24] The follow-up observational cohort, the Diabetes Prevention Program Outcomes Study (DPPOS), has continued to ascertain incident diabetes semiannually and has also measured CAC. Thus, we were able to assess whether androgens or history of IM at study entry were associated with increased risk factors for cardiometabolic disease beyond their known associations with impaired glucose tolerance and increased weight. For the present report, we examined traditional and nontraditional cardiovascular risk factors, progression to diabetes, and presence of CAC. We hypothesized that women with relative androgen elevations or IM would have adverse risk factor profiles compared with other overweight and glucose-intolerant women without these conditions. We also hypothesized that the free androgen index (FAI), a measure of androgen levels, and IM would be associated with increased risk of incident diabetes and a higher prevalence of detectable CAC.