Endometrial safety of continuous combined hormone replacement therapy with 17beta-oestradiol (1 or 2 mg) and dydrogesterone

Objectives: To determine the endometrial safety of oral 17β-oestradiol combined continuously with dydrogesterone in preventing endometrial proliferation. Methods: The low dose group comprised three 52-week (13 cycles of 28 days) studies (two of which were double blind) using a 17β-oestradiol dose of 1 mg daily combined with dydrogesterone 2.5, 5, 10 or 20 mg daily. The high dose group comprised two 24-week double-blind studies using a 17β-oestradiol dose of 2 mg daily combined with dydrogesterone 2.5, 5, 10 or 15 mg daily. Endometrial safety was verified by aspiration endometrial biopsies. Inadequate progestational response was defined as proliferative endometrium, endometrial polyp, hyperplasia and carcinoma. Results: Data was evaluable from 650 healthy postmenopausal women in the low dose group and 310 in the high dose group. Endometrial protection was achieved with dydrogesterone at doses of 5 mg or higher combined with 1 or 2 mg 17β-oestradiol. The success rate was 97%, 97% and 98% in women receiving 1/5, 1/10 and 1/20 mg, respectively, and 95%, 98% and 91% in women receiving 2/5, 2/10 and 2/15 mg, respectively. A lower success rate was achieved with the 2.5 mg dydrogesterone dosage (93% in the 1/2.5 mg group and 85% in the 2/2.5 mg group) due to more cases of proliferative endometrium. None of the women in the low dose group developed hyperplasia or carcinoma; five (0.7%) had endometrial polyps. In the high dose group, one woman given 2.5 mg dydrogesterone developed hyperplasia; there were no cases of carcinoma. Conclusion: 5 mg daily dydrogesterone appears to be the lowest effective dose to ensure endometrial safety in a continuous combined regimen with 1 or 2 mg 17β-oestradiol.