Laboratoire des ricepteurs el des steroides kormonaux, Institut Paoli-Calmettes, Marseilles; and CliniqueHaving examined the steroid receptor (SR) ' system i n normal and neoplastic endometrium from pre-and postmenopausal women, we investigated the effect of progestin therapy on estrogen and progestin receptors in neoplastic endometrium with respect t o histopathological changes and clinical responses of the lesions. I n normal endometrium of premenopausal women the estrogen receptor (ER) maximum occurred just before the estradiol (E) peak which i s associated with a decrease i n ER. I n pre-and postmenopausal women, a high progesterone receptor (PR) value was never associated with a high ER value although i n postmenopausal women, PR was only detected when the ER level was high and when there was histological evidence of estrogenic influence. I n neoplastic endometrium, a high degree of histological differentiation was associated with simultaneous low ER and high PR valuer, and vice-verso. Progestin therapy results i n virtually no change either i n ER level o r i n pathological state of the lesions where PR was initially undetectable. I n contrast, a positive clinical response was observed i n a PR-positive lesion revealing a differentiated histological type. The effect of P therapy i s a fall in both ER and PR t o a low level for the former and an undetectable level for the latter. The reasons for PR disappearance involve a nuclear translocation (detected 4 t o 8 h after treatment) and a non-replenishment of PR. Since the clinically responding patients were those with PR and ER positive lesions, the relationship between the presence of PR and a differentiated histological state could reflect the hormonal sensitivity of the tissue. These data also suggest that the effectiveness of P therapy i s due t o a redifferentiation and t o a reduction of the estrogen-dependent growth of neoplastic endometrial cells.The administration of progestins to patients with endometrial carcinoma has led to inhibition of tumor growth in about one-third of patients, in particular in those with well-differentiated tumors (Anderson, 1965;Kelley and Baker, 1965;Kistner and Griffiths, 1968;Wentz, 1964). Concerning progestin therapy of endometrial carcinomas, this work was undertaken with a two-fold purpose.The first was to examine the effect of progesterone therapy on the concentration of estrogen and progestin receptors in the cytosol and at the nuclear level. It has previously been demonstrated (Pollow et al., 1975a(Pollow et al., ,b, 1976(Pollow et al., , 1977Evans et al., 1974; Bayard et al., 1975; Limpaphayom et al., 1971) that variations in these levels occur in normal endometrium from pre-menopausal women according to cycle phase, in normal endometrium from post-menopausal women according to the estrogenic influence and in neoplastic endometrium from postmenopausal women according to the degree of tumor differentiation. Secondly, events at the molecular level were compared with the clinical response of patients who underwen...