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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.

Summary. Background: The metabolism of estrogen contained within hormone replacement therapy (HRT) is influenced by the route of administration, and this may affect the risk of venous thromboembolism. Thrombin generation, a global coagulation assay, is a marker of hypercoagulability and is of potential use in determining the thrombotic risk associated with particular HRT administration routes. Objectives: To determine whether any effect of oral and transdermal HRT on thrombin generation is related to the plasma estrogen profile. Methods: We investigated the effects of oral, transdermal and no HRT (controls) in 52, 39 and 52 postmenopausal women, respectively, on thrombin generation, standard markers of thrombophilia, estradiol level and estrone level. Results: All parameters of thrombin generation were altered in women using oral HRT as compared with controls (P < 0.001 for all comparisons). No such differences were found in women using transdermal HRT. Estrone levels correlated with peak thrombin generation (R = 0.451, P < 0.001) in women using oral HRT, but there was no correlation in women using the transdermal route. Conclusions: Thrombin generation is significantly increased in women who use HRT administered by the oral route. This is probably mediated by the hepatic first-pass metabolism of estrone, the main metabolite of oral estradiol, which is avoided by the transdermal route. The effect of estrone on thrombin generation may provide the explanation for the higher thrombotic risk seen in women using oral rather than transdermal HRT.

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