Norethindrone Acetate Prevents Endometrial Hyperplasia When Used in Continuous Combinations with Ethinyl Estradiol in Postmenopausal Women

Abstract

Objectives: Estrogen replacement therapy (ERT) is effective in preventing and treating acute menopausal symptoms, e.g., vasomotor instability, as well as the long-term consequences of hypoestrogenism including osteoporosis and cardiovascular disease. Unopposed ERT is contraindicated in women with intact uteri due to the increased probability of endometrial hyperplasia and adenocarcinoma. Consequently, various progestins are routinely used to protect the endometrium. This approach has proven effective when the progestins are administered either cyclically or continuously. A newly available continuous combined hormone replacement therapy (femhrt™), a combination of norethindrone acetate (NA) and ethinyl estradiol (EE) prevents endometrial hyperplasia compared to unopposed ethinyl estradiol (Speroff, et al, 1996). The present study was undertaken to determine whether lower doses of NA would be effective in preventing endometrial hyperplasia when given continuously with either 5 or 10 mcg of EE. Design: A 1-year, double-blind, placebo-controlled, multicenter randomized clinical trial. Materials and Methods: 945 postmenopausal women were enrolled in the study. All subjects were free of endometrial pathology as determined by biopsy and transvaginal ultrasound. After determining their eligibility, subjects were randomized to 1 of 8 treatment groups: placebo, 5 mcg EE, 10 mcg EE, 0.25 mg NA/5 mcg EE, 1 mg NA/5 mcg EE, 0.5 mg NA/10 mcg EE, 1 mg NA/10 mcg EE or Prempro (0.625 mg CEE/2.5 mg MPA). Endometrial biopsies were performed at baseline and again at the end of 6 and 12 months of treatment or as medically indicated. Results: This study confirms prior results. No hyperplasia occurred in study subjects receiving 1 mg NA per day in combination with either 5 or 10 mcg of EE. Lower doses of NA per day in combination with EE appear to provide endometrial hyperplasia protection but suggest less bleeding control and more proliferation. Conclusions: Norethindrone acetate provides endometrial protection at the 1 mg dose, a dose also associated with excellent vaginal bleeding control. It is unknown whether continued exposure to even lower doses would provide long-term endometrial protection.