menopause years before the start of the HRT. Thus, it is possible that starting HRT in women during perimenopause may prove more beneficial. 11 In addition, the many previous studies that showed positive effects of HRT on CVD in postmenopausal women were usually small cohorts of women who were mostly healthy and active, were of middle socioeconomic status or higher, followed good dietary regimens, and did not have diabetes. In contrast, the cohort in WHI, although excluding women who had previous CV events, included all types of postmenopausal women independent of body weight and activity. Thus, the WHI cohort was more reflective of the general population of postmenopausal women in the United States. Obesity and subsequent type II diabetes is becoming an epidemic in the United States, and weight gain with aging is commonly found in postmenopausal women. To our knowledge, there is no information that female gender or estradiol supplements protect against the complications of diabetes. In type I diabetic subjects, women have complications such as diabetic nephropathy, retinopathy, and cardiovascular disease at a similar rate as men. In fact, in one study, type I diabetic women younger than age 40 years had a higher incidence of ischemic heart disease than did men. 12 Women with type 2 diabetes also have a greater incidence of aortic stiffening13 and left ventricular hypertrophy, 14 and similar15 or higher risk of cardiovascular mortality than men. 16 It is not clear why premenopausal women are not protected from the complications of diabetes. However, one possibility is that estradiol biosynthesis may be compromised somewhat in chronic diseases, such as diabetes, just as testosterone biosynthesis is in men. To our knowledge, studies to evaluate serum estradiol levels in premenopausal diabetic women, especially women who do not have strict glycemic control, have not been performed. So, it is possible that in premenopausal women with type I or II diabetes, the reason that they are not protected from CVD is that their bioavailable estradiol levels are reduced. This hypothesis remains to be evaluated in clinical studies.