Hormone Replacement Therapy and Glycemic Control: Evidence from Observational Studies and Randomized Clinical Trials: Response to Dr. Aquilar-Salinas et al.

We thank Aguilar-Salinas et al. (1) for their interest in our paper (2), and we agree that the cross-sectional associations between hormone replacement therapy (HRT) and lower HbA_1c levels we reported do not establish causality. We concur with the need of long-term clinical trials among women with diabetes in order to understand whether and to what extent HRT may improve glycemic control. However, our findings are consistent with small and short-term randomized trials in women with diabetes (3,4,5). We demonstrated a number of differences between HRT users and nonusers in our report and went to great lengths to balance these covariates, including the use of the propensity score approach (6). As we mentioned in our discussion, HRT remained significantly associated with lower HbA_1c levels (P < 0.001) in the propensity score–adjusted Generalized Estimating Equation models.

Aguilar-Salinas et al. (1) found, in contrast with the previous randomized trial of unopposed estrogen in women with diabetes, that conjugated estrogens at 0.625 mg/day plus the cyclical medrogestone at 5 mg/day (for 10 days) may have slightly worsened HbA_1c levels in women with good glycemic control at baseline.

In our study (2), women using unopposed estrogen as well as women using opposed estrogen had lower HbA_1c levels then women not using HRT. A recent publication (7) of the results from a short-term randomized controlled cross-over study of 61 women with type 2 diabetes with acceptable glycemic control (mean HbA_1c 7.1%) receiving daily 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone or placebo showed that although HbA_1c levels were not significantly different between treatment periods, fructosamine levels were significantly lower during treatment with this HRT regime. Another recent publication (8) of a randomized placebo-controlled trial among 43 women with type 2 diabetes showed no difference in glycemic control among women assigned to continuous transdermal estradiol in combination with oral norethisterone (1 mg daily) or in women assigned to identical placebos.

Along with the data of Aguilar-Salinas et al. (1), these recent studies suggest that the type of progestin and whether treatment is continuous or cyclic may influence the effect of HRT on glycemic control in women with diabetes. It is also interesting to note that clinical trials (9,10) in women without diabetes have shown that although fasting glucose and insulin levels decrease after estrogen therapy (with or without progestins), the addition of progestins worsens postchallenge glucose levels.

In conclusion, we strongly agree with Aguilar-Salinas et al. (1) on the need for long-term randomized trials of various HRT regimes among diabetic women with a broad spectrum of glycemic control. Results from large observational studies such as ours can provide data on the potential expected magnitude of the effect of HRT on HbA_1c and therefore facilitate calculations of the minimum required sample size for future randomized controlled trials.