Relationship of estradiol levels to breakthrough bleeding during continuous combined hormone replacement therapy

Objective: To determine whether serum estradiol and dydrogesterone concentr ations are associated with the occurrence of breakthrough bleeding. Methods: In a prospective, double-blind study, 194 postmenopausal women wer e allocated randomly to receive one of four doses of dydrogesterone (2.5 mg , 5 mg, 10 mg, 15 mg) continuously combined with 2 mg of micronized 17 beta -estradiol. All medication was taken orally for a total of 168 days. Vagina l bleeding was recorded on a daily basis. Serum estradiol (E2) and dihydrod ydrogesterone (the main metabolite of dydrogesterone) trough levels were me asured at day 85 and at the end of the study (day 168). Bleeding pattern an alysis was done according to the reference period method. Results: One hundred fifty-two of 177 women who completed the study supplie d valid data on drug compliance, smoking habits, bleeding episodes, and ser um hormone concentrations, which were used to assess the impact of serum E2 and dihydrodydrogesterone concentrations on the occurrence of breakthrough bleeding. Logistic regression analysis identified only the serum E2 concen tration as having an independent, statistically significant effect (P =.003 ) on the occurrence of breakthrough bleeding; no such effect was associated with dihydrodydrogesterone levels (P =.118). The relative risk for the occ urrence of breakthrough breeding was 2.7 (95% confidence interval [CI] 1.45 4, 5.609) for serum E2 concentrations greater than 40 pg/mL. Conclusion: The occurrence of breakthrough bleeding during continuous combi ned hormone replacement therapy with estradiol and dydrogesterone in postme nopausal women was related to serum estradiol levels and not to dydrogester one levels. Further studies are needed to test the hypothesis that estrogen is a major factor in the incidence of bleeding during postmenopausal hormo ne replacement therapy. (Obstet Gynecol 1999;93:551-7. (C) 1999 by The Amer ican College of Obstetricians and Gynecologists.).