Effective bleeding control and symptom relief by lower dose regimens of continuous combined hormone replacement therapy: A randomized comparative dose-ranging study

Objectives: We compared two different continuous combined hormone replacement therapy (HRT) regimens of estradiol valerate (E₂V) and medroxyprogesterone acetate (MPA) with a combination of micronized estradiol (E₂) and norethisterone acetate (NETA) to determine bleeding pattern, control of climacteric symptoms, lipid profile, endometrial and general safety in a 1-year multicenter study. Methods: 440 postmenopausal women were randomized to three treatment groups to receive: 1 mg E₂V+2.5 mg MPA; 1 mg E₂V+5 mg MPA; or 2 mg of E₂+1 mg NETA. After the first 6 months, the E₂V dose was increased to 2 mg in both E₂V/MPA groups. Information on bleeding was recorded on diaries by the women and intensity of climacteric symptoms was assessed using VAS scales. Physical and laboratory examinations, endometrial biopsy and vaginal ultrasonography were performed at baseline and follow-up visits. Results: Significantly fewer bleeding days were experienced in the first 3 months by women taking E₂V/MPA compared with women taking E₂/NETA. When the dose of E₂V was increased in the E₂V/MPA groups, an increase in maximum bleeding intensity was observed in the group receiving 2.5 mg of MPA, but not in the group taking 5 mg of MPA. All dose combinations effectively relieved climacteric symptoms and beneficial effects on the lipid profile were seen after 6 months in all groups. Tolerability and endometrial safety were good and no cases of hyperplasia were observed. More women discontinued treatment prematurely in the E₂/NETA group compared with either of the E₂V/MPA groups. The overall continuation rates ranged from 70 to 86%. Conclusions: These results confirm that lower dose combinations of continuous combined HRT are usually sufficient to control symptoms or avoid breakthrough bleeding. However, if higher E₂V dose is needed for symptom control, it should be combined with the higher dose of progestin (5 mg) to avoid bleeding disturbances. Flexible treatment regimens should be available for individualized HRT.