Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium

To study the effects of exogenous estrogens on the postmenopausal endometrium, and to determine the time course and minimum dosage of added progestins necessary to oppose estrogen stimulation, we obtained endometrial specimens from symptomatic postmenopausal women being treated with various preparations of estrogens and progestins. Morphologic changes were assessed with light and electron microscopy, and biochemical effects through measurement of DNA synthesis, estradiol and progesterone receptors, and isocitric and estradiol dehydrogenase activity. For comparison, identical studies were carried out on specimens from premenopausal women in the proliferative and secretory phases of their cycle. All the estrogens exerted stimulatory effects in the postmenopausal specimens that were comparable to those observed in the premenopausal proliferative-phase specimens. Estropipate, subcutaneous estradiol, and conjugated estrogens had some hyperphysiologic effects. Maximal progestational effects occurred in the postmenopausal specimens only after norethindrone was administered for six days, and a constant level of activity equal to that in premenopausal secretory-phase specimens was then observed until the 10th day of exposure. Similar maximal effects occurred after six days of treatment with D/L-norgestrel (150 and 5 mg daily [10 mg daily produced less complete changes]). We conclude that many estrogen preparations subject the endometrium to a potent stimulus. Norethindrone and norgestrel are protective because they counteract the proliferative effects of estrogens, but the currently recommended daily dosages of these progestins can be greatly reduced without loss of response.