Failure of Progestins to Induce Estradiol Dehydrogenase Activity in Endometrial Carcinoma, in Vitro1

Estradiol dehydrogenase (E2DH) is a well-known progester one-dependent enzyme in human endometrium, and its induc tion has been proposed as a means to test hormonal sensitivity of endometrial carcinoma. While administration of progestins to some patients with endometrial carcinoma resulted in in creased endometrial E2DH activity, efforts to induce this en zyme, in vitro, in these tumors have been unsuccessful. The reasons for such failure were investigated in the present study. Progesterone receptor (PR) concentrations and E2DH activities were simultaneously measured in proliferative and malignant endometria under organ culture conditions. Cytoplasmic PR concentrations were determined by Scatchard plot analysis of [3H]progesterone binding in fresh samples and in tissue explants incubated in nutrient medium at 37°in a humidified 5% CO2 atmosphere for various periods of time. Parallel incuba tions of expiants with and without 500 ng medroxyprogesterone acetate per ml were carried out for monitoring E2DH induction. In proliferative endometrium, the progesterone-spe cific binding sites remained stable during the culture periods, and the E2DH activities were stimulated severalfold by medroxyprogesterone acetate. In contrast, the PR concentrations in carcinoma expiants were undetectable after a 24-hr period, and this was associated with a lack of increase in E2DH activity. These findings provide evidence that progestin-induced endo metrial E2DH activity is a receptor-mediated phenomenon. In addition, these results demonstrate clearly that the ineffective ness of progestin to induce E2DH in endometrial cancer spec imens, in vitro, is related to the instability of PR under culture conditions. It is suggested that any experiment designed to follow effects of steroids on target tissues must take into account the stability of steroid receptors under in vitro condi tions.