Continuous combined hormone replacement therapy usually consists of an estrogen combined with medroxyprogesterone acetate taken on a daily basis to counter the effects of unopposed estrogen on the endometrium. This form of hormone replacement therapy is increasingly prescribed to postmenopausal women who have not undergone hysterectomy in order to prevent vaginal bleeding during hormone therapy. Since vaginal bleeding is cited as the most common reason for discontinuation of hormone replacement therapy, establishing the optimal dosage of progesterone to achieve amenorrhea is important. Nand and colleagues compared the efficacy of three different dosages of medroxyprogesterone acetate in achieving amenorrhea when given with 1.25 mg of estrone sulfate.

In the multicenter trial, 557 postmenopausal patients were randomly assigned to receive one of three continuous hormone replacement regimens for two years. Menopausal status was evaluated on the basis of amenorrhea, symptoms and levels of follicle-stimulating hormone. Women were excluded from the study if they had hypertension or severe metabolic, endocrine or gastrointestinal disease. Women with a history of thromboembolism also were excluded. After a complete history, physical examination and baseline blood measurements, the patients began therapy with 1.25 mg of estrone sulfate plus medroxyprogesterone acetate in dosages of 2.5, 5.0 or 10.0 mg daily. Patients were given identical instructions and were followed every three months. Patients maintained a diary of symptoms, particularly of vaginal bleeding or spotting, which was recorded on a four-point scale. In addition to physical examinations, blood monitoring and compliance checks, the follow-up included endometrial sampling performed three times during the study and bone density measurements that were taken twice.

The three treatment groups were comparable in all respects at the beginning of the study. At the three-month stage, 42 percent of women reported some degree of vaginal bleeding. By six months, the percentage of women achieving amenorrhea was 76.5, 80.1 and 80.9 percent for the 2.5-, 5.0- and 10.0-mg dosages of medroxyprogesterone acetate. At one year, the amenorrhea figures were 80.0, 87.8 and 85.8 percent. At two years, 91.5, 89.9 and 94.3 percent of women reported amenorrhea. None of the differences between the three dosages reached statistical significance. Approximately 10 percent of women reported persistent bleeding, but this did not appear to be related to the dosage of medroxyprogesterone acetate. About 95 percent of the women had atrophic endometrium at baseline, and no endometrial hyperplasia was detected during the study.

The authors conclude that all three dosages of medroxyprogesterone acetate provided adequate endometrial protection and achieved amenorrhea in approximately 80 percent of women by six months of continuous therapy. Most women achieved amenorrhea or experienced only very slight bleeding or spotting within the first three months of therapy. Since the incidence of atrophic endometrium was so high at the beginning of the study, the authors do not believe baseline endometrial biopsy is necessary before hormone replacement therapy is initiated.