Estrogen and interrupted progestin: A new concept for menopausal hormone replacement therapy

Objective: We tested a new hormone replacement formulation based on the hypothesis that interrupted administration of progestin in the presence of continuous estrogen would result in receptor up-regulation and resensitization of target tissues to both estrogen and progestin. As a result, symptom control might be possible with lower doses of steroids and in the absence of withdrawal bleeding. Study Design: Forty postmenopausal women were entered in a 6-month pilot study, including an 18-month extension. They received piperazine estrone sulfate 0.75 mg daily. Norethindrone 0.35 mg daily was added in 3-day phases, alternating with progestin-free phases of 3 days. There was no steroid-free withdrawal period. We examined symptom control, bleeding patterns, endometrial protection, and lipid profiles in the women over the 24 months of the study. Results: Hot flushes were completely eliminated in 76% of women, and 80% had no bleeding by 6 months. There were three dropouts. Thirty-three women elected to continue after the first 6 months and completed 24 months on therapy for a compliance rate of 82.5%. No endometrial hyperplasia was seen on serial biopsies, and no changes occurred in lipids except for a small but statistically significant decrease in high-density lipoproteins and triglycerides at 24 months. Conclusion: Our preliminary results of low bleeding rates, good symptom control, and endometrial protection, suggest that hormone replacement with low-dose estrogen and interrupted progestin is effective and may lead to improved compliance in menopausal women.