Dose-dependent effects of synthetic progestins on the biochemistry of the estrogenized post-menopausal endometrium

Symptomatic post-menopausal women were treated with conjugated equine estrogens (Premarin; Ayerst International) 1.25 mg daily, continuously, adding either norethisterone (Primolut N; Schering Chemicals) 1, 2.5, 5 or 10 mg daily or D/L norgestrel (Wyeth Laboratories) 150 or 500 micrograms daily for 10 days each calendar month. Endometrial biopsies were obtained during estrogen therapy alone and on the 6th day of combined estrogen/progestin administration. Sensitive biochemical indices of estrogen and progestogenic activities were measured in th endometrial samples. These included measurements of DNA synthesis in epithelium and stroma by tritiated thymidine autoradiography; nuclear estradiol receptor content, and the activities of estradiol 17 beta and isocitric dehydrogenase and acid and alkaline phosphatase. Low dosages of progestins achieved maximal biochemical effects and the larger doses failed to enhance these responses. It is concluded that the dosages of progestins currently added in post-menopausal estrogen therapy are greatly in excess of those necessary to suppress endometrial proliferation effectively; lowering the daily progestin dosage is unlikely to result in any lessening of this protective effect and will probably reduce the incidence of side effects, as these appear to be dose-dependent.