PIP: 177 patients were recruited between 1973 and 1977 to participate in a study to determine the endometrial response to exogenous estrogens and the modifying effect of progestogens on this response; hence, the endometrial proliferation during cyclical estrogen therapy and sequential estrogen/progestogen therapy was studied longitudinally. The patients were peri-or postmenopausal. Cyclical thereapy ranged from 2-47 months (mean, 15.1 months). With high-dose estrogen, cystic glandular hyperplasia was diagnosed in 16 (23%) patients, and atypical hyperplasia in 6 (9%); with low-dose regimens, cystic glandular hyperplasia was diagnosed in 4 (12%) and atypical hyperplasia in 2 (6%) patients. Sequentia therapy ranged from 2-50 months (mean, 16.2 months). With high dose regimens, 1 (2%) was found to have cystic glandular hyperplasia and 1 atient (2%) atypical hyperplasia; with low doses atypical hyperplasi was diagnosed in 1 patient (3%). these data therefore suggested that progestogens protected the endometrium against estrogen-induced stimulation, although complete protection was not afforded. Progestogens also depressed cytoplasmic progesterone receptor levels and induced the formation of estradiol 17-beta-dehydrogenase, as shown by the following findings: in all samples from Weeks 2 and 3, no activity of the enzyme was detectable. During norethisterone administration (Week 4), however, the activity rose to the premenopausal secretory range and was significantly higher than that in Weeks 2 and 3 (P .001 and P .001, respectively). Measurement of cytoplasmic progesterone receptor confirmed that the estrogenic stimulus being applied to the endometrium was potent.