Ethinyl estradiol vs estradiol valerate in combined oral contraceptives - Effect on glucose tolerance: A randomized, controlled clinical trial.

Objective: To compare the effects of two formulations of combined oral contraceptives (COCs), estradiol valerate (EV) and ethinyl estradiol (EE) combined with dienogest (DNG), and DNG-only, on glucose tolerance.

Study Design: We performed a randomized, controlled 9-week clinical trial. Inclusion criteria were: age 18-35 years, regular menstrual cycle (28 ± 7 days), no polycystic ovaries, non-smoking, no contraindications for COC use and a 2-month wash-out from hormonal contraceptive use. The women were randomized to EV + DNG (n = 20), EE + DNG (n = 20), and DNG-only (n = 19), and evaluated at baseline, at 4-5 weeks and 8-9 weeks of treatment. Study medications were used continuously for 63 days. Primary outcome measure was change in the whole-body insulin sensitivity index (Matsuda index) derived from the oral glucose tolerance test (OGTT) over the treatment period. Secondary outcome measures were area under curves (AUC) of glucose and insulin, homeostatic model assessment - insulin resistance (HOMA-IR) and Insulin Sensitivity Index (ISI).

Results: Fifty-nine women enrolled, and 56 women completed the study. The Matsuda index changed from baseline as follows (mean percentage change, mean change [95%CI]): DNG-only -12%, -1.45 [95%CI -3.22-0.325] P = 0.10; EV + DNG + 2.7%, -0.10 [-1.34 to 1.14] P = 0.86; EE + DNG -5.5%, -1.02 [-2.51 to 0.46] P = 0.16, comparing the groups P = 0.27. There were no clinically significant differences in glucose tolerance between the COC groups, but the DNG-only group showed an improvement in the 2-h glucose levels (5.5 [95%CI 5.0-6.0] to 4.7 mmol/l [4.2-5.2], P = 0.001).

Conclusion: We found no clinically significant differences between EV and EE combined with DNG and DNG-only on glucose tolerance in healthy, young, normal-weight women, indicating that these preparations appear close to neutral regarding glucose metabolism when used continuously for nine weeks.

Implications: Combinations of both ethinyl estradiol and natural estradiol (estradiol valerate) with dienogest (DNG), as well as DNG-only, seem metabolically safe in young and healthy women in short-term continuous use.