ethisterone and Breast-Neoplasms

In 1950 a trial was set up to evaluate the effects of large doses of stilboestrol and ethisterone on rates of fetal loss in pregnant diabetic women. Eighty women were allocated at random to receive the hormonal treatment and 76 to receive inactive tablets of identical appearance. At follow-up 27 years later, information was obtained about 97% of the women, all but four being traced. All respondents were unaware of who had received hormones. The overall mortality was 4.5 times that of women of comparable age in England and Wales, most deaths being from complications of diabetes. More tumours, mainly benign, of the reproductive tract were reported in the hormone-exposed than the non-exposed group (14 (18%) and two (3%) respectively). Four cases of malignant breast disease were reported in the hormone-exposed women and none in the non-exposed. These findings support other evidence linking oestrogen treatment and breast cancer and suggesting that the latent period before the tumour becomes clinically apparent may be 15 years or longer.

Topics: Breast Neoplasms; Clinical Trials as Topic; Diabetes Mellitus; Diethylstilbestrol; Ethisterone; Female; Fetal Death; Follow-Up Studies; Genital Neoplasms, Female; Humans; Pregnancy; Pregnancy in Diabetics; Random Allocation; Time Factors

The function and clinical significance of the androgen receptor (AR) in human breast cancer are still not clear. The synthetic progestins, norgestimate and norelgestromin, were designed to minimize the adverse effects such as acne, hirsuitism and metabolic changes observed with older oral contraceptives while maintaining contraceptive effectiveness and cycle control. AR-mediated effects of these synthetic progestins were studied in an in vitro transactivation assay, employing DNA co-transfection of an AR expression vector and luciferase reporter gene construct in the MDA-MB 231 human breast cancer cell line. Testosterone acetate and 5alpha-dihydrotestosterone induced the reporter gene transcription, whereas incubation of the transfected cells with the natural progestin 17alpha-hydroxyprogesterone did not markedly induce luciferase activity. The progestins norgestimate and norelgestromin exerted a very low androgenic activity. Our data suggest that norgestimate and its metabolite norelgestromin possess weak androgen-like properties. The use of these compounds for clinical application may be of great advantage in the treatment of breast cancer as well as hyperandrogenism in women.

Topics: 17-alpha-Hydroxyprogesterone; Breast Neoplasms; Contraceptives, Oral, Combined; Dihydrotestosterone; Drug Combinations; Ethisterone; Genetic Vectors; Humans; Luciferases; Norgestrel; Oximes; Receptors, Androgen; Testosterone; Transfection; Tumor Cells, Cultured

Human breast cancer tissue contains enzymes (estrone sulfatase, 17beta-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of estradiol (E(2)) formation. In this tissue, E(2) can be synthesized by two main pathways: (1) sulfatase-transforms estrogen sulfates into bioactive E(2), and the (2) aromatase-converts androgens into estrogens. Quantitative assessment of E(2) formation in human breast tumors indicates that metabolism of estrone sulfate (E(1)S) via the sulfatase pathway produces 100-500 times more E(2) than androgen aromatization. In the present study, we demonstrated in T-47D and MCF-7 human breast cancer cells that norelgestromin (NGMN) (a metabolite of norgestimate) is a potent inhibitory agent of the estrone sulfatase activity. After 24h incubation of physiological concentrations of E(1)S (5 x 10(-9)mol/l) the inhibitory effect of NGMN at concentrations of 5 x 10(-9), 5 x 10(-7) and 5 x 10(-5)mol/l was 43+/-7, 74+/-4 and 97+/-2%, respectively, in T-47D cells; 25+/-4, 57+/-5 and 96+/-2% respectively, in MCF-7 cells. Comparative studies using medroxyprogesterone acetate (MPA) showed that this progestin also has an inhibitory effect on sulfatase activity, but significantly less intense than that of NGMN. The inhibition for MPA at concentrations of 5 x 10(-9), 5 x 10(-7) and 5 x 10(-5)mol/l was 31+/-5, 47+/-3 and 61+/-3%, respectively, for T-47D cells; 6+/-3, 20+/-3 and 63+/-4%, respectively, for MCF-7 cells. In conclusion, the present data show that NGMN is a very potent inhibitory agent for sulfatase activity in the hormone-dependent breast cancer cells, resulting in decreased tissue concentration of E(2). The clinical significance of this finding remains to be elucidated.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Contraceptives, Oral, Combined; Drug Combinations; Estradiol; Ethisterone; Humans; Inhibitory Concentration 50; Medroxyprogesterone Acetate; Models, Chemical; Norgestrel; Oximes; Selective Estrogen Receptor Modulators; Sulfatases; Tumor Cells, Cultured

We have previously reported that clinical trials relating to the use of danazol in the management of benign breast disease show a positive correlation between favourable clinical response and an induction of progesterone receptors in the affected tissue which is maintained for a period of at least 6 months subsequent to the cessation of treatment. Further studies designed at elucidating more clearly the actions of danazol at the cellular and molecular levels have confirmed that progesterone receptors are down-regulated by short-term progestin action at the level of the mRNA transcript, but that danazol is subsequently able to produce an enhanced cellular response, inducing progesterone receptors in the presence of oestrogenic agents. Uteri from danazol-treated rats showed a doubling of progesterone receptor concentrations compared with the control uteri. In the mammary cancer cell line T-47D, cells treated with danazol had increased progesterone receptor concentrations of 558.4 +/- 32.0 compared with 152.6 +/- 7.0 fmol/mg protein in the control cells. In both cases, these inductions were observed following a period of progesterone receptor suppression. Short-term molecular studies on T-47D cells indicated that progesterone and danazol initially inhibit mRNA transcription, but that 24 h after treatment an induction is observed. This is especially marked in the danazol-treated cells.

Topics: Animals; Breast Neoplasms; Danazol; Down-Regulation; Estrus; Ethisterone; Female; Gene Expression; Humans; In Vitro Techniques; Rats; Receptors, Estrogen; Receptors, Progesterone; RNA, Messenger; Tumor Cells, Cultured; Uterus

Topics: Breast Neoplasms; Diethylstilbestrol; Ethisterone; Female; Follow-Up Studies; Humans; Menopause; Pregnancy; Pregnancy in Diabetics; Risk

Topics: Adolescent; Adult; Breast Neoplasms; Contraceptives, Oral; Diethylstilbestrol; Ethisterone; Female; Follow-Up Studies; Humans; Middle Aged; Pregnancy; Pregnancy Complications; Risk

Topics: Androgens; Breast Neoplasms; Diethylstilbestrol; Estrogens; Ethisterone; Female; Humans; Norethindrone; Progesterone