A DOSE-RANGING STUDY OF THE USE OF CYCLICAL DYDROGESTERONE WITH CONTINUOUS 17-BETA ESTRADIOL

Objective To establish the lowest dose of cyclical dydrogesterone that protects against endometrial hyperplasia induced by continuous 2 mg 1 7 beta oestradiol, and to study the dose effect on vaginal bleeding an d side effects. Design Double-blind, prospectively randomised dose-ran ging study. Setting Menopause clinics in the UK and The Netherlands. S ubjects Three hundred and seventy-one postmenopausal women with intact uteri, aged 40 to 60. Interventions Administration of six 28-day trea tment cycles of continuous daily micronised 17 beta oestradiol with a randomly allocated dose of 5 to 20 mg of dydrogesterone added for the last 14 days of each. Main outcome measures Histological assessment of adequate progestational endometrial response, bleeding patterns and a dverse effects. Results The study was completed by 320 subjects (86%). Endometrial transformation occurred in over 94% of those taking 5 mg of dydrogesterone, and in over 97% of those on higher doses, without s ignificant differences between the 10, 15 and 20 mg groups. Acceptable bleeding patterns were found at all doses, with the incidence of with drawal bleeding rising with increasing dose. The day of onset of bleed ing was predictable from cycle to cycle, and occurred later in the 20 mg group than in the others. The incidence of noncyclic bleeding was a bout 6% at all doses. Withdrawal occurred in 3.3% due to unacceptable bleeding and in 5.4% due to side effects. There was no relation with d ose. Conclusions A dydrogesterone-17 beta oestradiol combination hormo ne replacement therapy confers endometrial protection with an acceptab le bleeding pattern and few side effects. At least 10 mg of dydrogeste rone for 14 days is required for acceptable endometrial protection.