Failure of progestins to induce estradiol dehydrogenase activity in endometrial carcinoma, in vitro.
Estradiol dehydrogenase (E2DH) is a well-known progesterone-dependent enzyme in human endometrium, and its induction 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 increased endometrial E2DH activity, efforts to induce this enzyme, 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 degrees in a humidified 5% CO2 atmosphere for various periods of time. Parallel incubations of explants with and without 500 ng medroxyprogesterone acetate per ml were carried out for monitoring E2DH induction. In proliferative endometrium, the progesterone-specific 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 explants 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 endometrial E2DH activity is a receptor-mediated phenomenon. In addition, these results demonstrate clearly that the ineffectiveness of progestin to induce E2DH in endometrial cancer specimens, 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 conditions.
D015067:17-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis*; D004790:Enzyme Induction; D004960:Estradiol Dehydrogenases / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D011372:Progestins / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000032:analysis; D014594:Uterine Neoplasms / Q000201:enzymology*
D011372:Progestins; D011980:Receptors, Progesterone; D015067:17-Hydroxysteroid Dehydrogenases; D004960:Estradiol Dehydrogenases