cyproterone and Breast-Neoplasms

Antiandrogens, substances that prevent androgens from expressing their activity at target cells, play an important role in the treatment of prostate cancer. The most frequently used substances have either a steroidal structure (cyproterone acetate) or a non-steroidal structure (Flutamide or Anandron). Antiandrogens have been tested both alone and in combination with treatments aimed at inhibiting testicular secretion (castration, LH-RH analogs), thereby producing complete blockade of androgen secretion and action. Patients treated by such combination protocols have often shown an improvement in the percentage of remissions and, less often, improvement in survival. Administration of antiandrogens improves the clinical symptoms of patients with benign prostatic hypertrophy, but the exact mechanism of their action requires further investigation. Cutaneous manifestations due to hyperandrogenicity (hirsutism, alopecia, acne) have also been improved by cyproterone acetate, which is often given together with estrogens (reversed sequential regime), by spironolactone or topically applied products. Finally, antiandrogens have been successfully used to treat breast cancer in men, early puberty, hypersexuality and sexual deviations.

Topics: Androgen Antagonists; Breast Neoplasms; Cyproterone; Cyproterone Acetate; Female; Flutamide; Humans; Imidazoles; Imidazolidines; Male; Prostatic Hyperplasia; Prostatic Neoplasms; Puberty, Precocious; Skin Diseases; Spironolactone

Postoperative adjuvant hormone therapy and hormone therapy in disseminated breast cancer will be discussed systematically. The classical ablative and additive endocrine therapeutic measures--with the exception of ovarectomy and gestagen therapy--are increasingly being replaced by antagonists. Individual chapters discuss recent experience with combined hormone-radiotherapy or hormone-chemotherapy. In addition, a successful therapy scheme for the treatment of disseminated breast cancer will be presented.

Topics: Adrenal Cortex Hormones; Adrenalectomy; Aminoglutethimide; Androgens; Breast Neoplasms; Castration; Cyproterone; Estrogens; Female; Gonadotropins; Hormones; Humans; Hydrocortisone; Hypophysectomy; Menopause; Neoplasm Metastasis; Progesterone; Tamoxifen

The aim of the present study was to compare the ability of natural progesterone and synthetic progestins to stimulate local growth hormone (GH) and insulin-like growth factor I (IGF-I) secretion by breast cancer explants. Explants obtained during surgery were divided according to their estrogen/progesterone receptor phenotype - ER(+)PR(-); ER(+)PR(+); ER(-)PR(+) - as determined by immunocytochemistry. Natural progesterone (10(-5) mol/l) and synthetic progestins (cyproterone acetate (5 x 10(-7) mol/l), norethindrone (10(-5) mol/l), medroxyprogesterone acetate (10(-7) mol/l), and levonorgestrel (10(-7) mol/l) were tested in vitro for their ability to induce secretion of proliferation-promoting agents such as human GH (hGH) and IGF-I. All hormone-dependent breast cancer cell types responded to progesterone stimulation with increased local hGH secretion, while in the non-malignant tissue this effect was observed only in PR(+) cells. Moreover, progesterone in only PR(+) cells in vitro stimulated local IGF-I secretion by both malignant and non-malignant tissue. Medroxyprogesterone and levonorgestrel increased GH secretion by both malignant and non-malignant ER(-)PR(+) breast cancer explants, while cyproterone stimulated it only in non-malignant tissue. None of the synthetic progestins tested in this experiment exerted an effect on GH secretion by both malignant and non-malignant tissue of ER(+) breast cancer explants. The present data additionally showed that, apart from cyproterone, which increased IGF-I secretion in the same manner as progesterone by both malignant and non-malignant ER(-)PR(+) breast explants, other progestins tested had either no effect on IGF-I local secretion or decreased it. Medroxyprogesterone and levonorgestrel induced a decrease in IGF-I secretion noted in ER(+) explants of non-malignant tissue and in malignant ER(-)PR(+) breast tissue. All progestins tested decreased IGF-I secretion by malignant ER(+)PR(+) explants. Taken together, the tested synthetic progestins widely used as oral contraceptives and in hormone replacement therapy were less potent than progesterone in inducing secretion of proliferation-promoting agents such as hGH and IGF-I in ER-containing breast tissue. Despite the lack of confirmation of the link between the use of progestins and breast cancer risk, patients should be informed that the use of certain estrogen/progestin preparations is of no influence on breast cancer risk while others may increase it.

Topics: Breast; Breast Neoplasms; Cyproterone; Female; Human Growth Hormone; Humans; Immunohistochemistry; Insulin-Like Growth Factor I; Levonorgestrel; Medroxyprogesterone; Norethindrone; Progesterone; Progesterone Congeners; Receptors, Estrogen

Male breast cancer (MBC) is considered an androgen-dependent tumor, and as in prostatic cancer, responses have been reported with use of antiandrogens or gonadotropin-releasing hormone analogs. Thus, it is reasonable to postulate that better results could be achieved by combining these two agents.. Eleven men with recurrent or progressive carcinoma of the breast have been treated with buserelin 1500 micrograms subcutaneously daily in the first week and 600 micrograms daily subsequently and cyproterone acetate (CPA) 100 mg twice a day orally starting 24 hours before the first dose of buserelin.. Objective responses have been observed in seven patients with a median duration of 11.5 months (range, 9-24+ months). Responses were not correlated to the dominant site of disease. Three patients had stable disease lasting 5 months. Median survival was 18.5 months. Side effects primarily were decrease or loss of libido, impotence, and hot flushes.. Total androgen blockade with buserelin and CPA seems effective in the treatment of patients with advanced cancer of the male breast, but its superiority over standard androgen suppression remains to be demonstrated.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Buserelin; Cyproterone; Drug Administration Schedule; Humans; Male; Middle Aged; Neoplasm Metastasis; Treatment Outcome

The regulation of the human androgen receptor (AR) by steroid hormones in human mammary cancer cells was investigated using immunocytochemical and ligand binding assays for its protein and Northern blot analyses for the corresponding mRNA. MFM-223 cells contain high levels of ARs and are growth-inhibited by dihydrotestosterone (DHT). The AR protein is down-regulated to 57% of the control by 10 nM DHT after 24 h, and the corresponding mRNA is also reduced. The nonsteroidal antiandrogen hydroxyflutamide had no effect on the AR level, whereas after incubation with 1 microM cyproterone acetate a slight down-regulation was observed. The AR level was restored completely after release from a 7 day treatment with DHT. However, only 60% of the control level was restored, if the cells wer grown in the presence of DHT for 6 weeks. In androgen-pretreated cells the proliferation rate remained decreased even after the withdrawal of DHT. Concomitantly the distinct growth inhibition was lost. Transfection experiments demonstrated a reduced activity of the residual androgen receptor in these pretreated cells. In addition to the AR, EFM-19 cells also contain significant amounts of estrogen and progesterone receptors. EFM-19 cells are not growth inhibited by physiological concentrations of DHT. Autoregulation of AR was also found in this cell line. Additionally, reduced levels of AR protein and mRNA were found in EFM-19 cells after treatment with the synthetic progestin R5020. The maximum effect of R5020 was observed at the high concentration of 1 microM. Estrogen treatment with 10 nM 17 beta-estradiol for 3 days reduced the AR level only by 25%.

Topics: Blotting, Northern; Breast Neoplasms; Cyproterone; Dihydrotestosterone; Estradiol; Flutamide; Gene Expression Regulation, Neoplastic; Hormones; Humans; Immunohistochemistry; Progesterone Congeners; Radioligand Assay; Receptors, Androgen; RNA, Messenger; Steroids; Tumor Cells, Cultured

We have studied the effects of various steroids on DNA synthesis in MCF-7 human breast carcinoma cells, which have aromatase activity and which exert an oestrogen receptor-mediated growth, to assess the significance of intracellular aromatase on growth stimulation as well as inhibition by aromatase inhibitors. The cells were cultured for 96 h in phenol red-free medium containing 10% charcoal-treated fetal bovine serum and test reagents and pulse-labelled with [3H]thymidine. Physiological concentrations of oestradiol, oestrone, testosterone (T) and androstenedione (AD) stimulated thymidine incorporation. However, oestrone-sulphate and dihydrotestosterone (DHT) only stimulated at concentrations greater than the physiological levels. T and DHT stimulation was blocked by tamoxifen, but not by cyproterone acetate, suggesting that the stimulation was mediated via the oestrogen receptor but not by the androgen receptor. Stimulation by T and AD was reduced by aminoglutethimide and 14 alpha-hydroxy-4-androstene-3,6,17-trione, both of which inhibit aromatase activity, however, stimulation by nonaromatizable DHT was not reduced by the inhibitors, suggesting that androgens were converted by the intracellular aromatase to oestrogens which stimulated the thymidine incorporation. It is suggested that intracellular aromatase significantly contributes to the stimulation of DNA synthesis and that aromatase inhibitors suppress the stimulation.

Topics: Androgens; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Cyproterone; DNA, Neoplasm; Estrogens; Humans; Receptors, Estrogen; Tamoxifen; Tumor Cells, Cultured; Water

A series of heterocyclic quinones, 6-substituted and 6,7-disubstituted 4-(alkylamino)-5,8-quinazolinediones, have been synthesized in order to evaluate their in vitro cytotoxicity on L1210 leukemia cells. Among 14 derivatives that have been prepared and studied for the structure-activity relationship, the most potent cytotoxic compound on L1210 leukemia cells was the 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione (24). This compound has been tested with the use of a cell-image processor on MCF-7 human mammary and HBL human melanoma cell lines. The results show that compound 24 influences cell proliferation and blocks both cells lines in the S phase. In vivo antineoplastic activity of compound 24 has been demonstrated on a broad spectrum of murine experimental models, but it was found highly toxic and produced long-delayed deaths.

Topics: Animals; Antineoplastic Agents; Aziridines; Breast Neoplasms; Cell Division; Cell Line; Drug Screening Assays, Antitumor; Female; Humans; Leukemia L1210; Leukemia, Experimental; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Molecular Structure; Neoplasms, Experimental; Quinazolines; Sarcoma, Experimental; Structure-Activity Relationship

MCF-7 cell line is a model for estrogen-dependent tumors that have both aromatase activity and estrogen receptor. We studied the contribution of aromatase to cell growth and DNA synthesis by means of aromatase inhibitors. MCF-7 cells were cultured in phenol red-free medium containing 10% charcoal-treated fetal bovine serum and test reagents for 96 hours and pulse-labeled with [3H]thymidine for 1 hour. Physiological concentrations of estradiol, estrone, testosterone(T) and androstenedione(delta 4A) increased [3H] thymidine incorporation. Stimulation by T or dihydrotestosterone (DHT) was reduced by tamoxifen, but not by androgen receptor blocker cyproterone acetate, suggesting that T and DHT stimulated cellular proliferation via estrogen receptor but not via androgen receptor. Stimulation by T or delta 4A was reduced by aromatase inhibitors (aminoglutethimide and 14 alpha-hydroxy-4-androstene-3,6,17-trione), but stimulation by nonaromatizable DHT was not reduced by aromatase inhibitors. These results have suggested that estrogens which are biosynthesized from androgens by the intracellular aromatase play a significant role in growth stimulation of MCF-7 cells and that aromatase inhibitors block this pathway. These methods are useful in assessing the ability of aromatase inhibitors to suppress cell growth.

Topics: Aminoglutethimide; Aromatase Inhibitors; Breast Neoplasms; Cyproterone; Cyproterone Acetate; Female; Humans; Neoplasms, Hormone-Dependent; Receptors, Estrogen; Tamoxifen; Tumor Cells, Cultured

Often the male transsexual takes hormonal drugs, sometimes under medical prescription but most frequently by his personal choice. They wish to obtain a development of mammary gland and the disappearance of hair from facial skin. Prolonged hormonal and incorrect treatments, mainly for too high dosage and absence of association with progesterone, assumption of oestrogens, can cause the growth of mammary tumours. The Authors present the results of a clinical and radiological study on 15 patients, 12 in treated with hormonal drugs for two years and 3 without any therapy.

Topics: Adult; Breast Neoplasms; Cyproterone; Cyproterone Acetate; Estrogens; Fibrocystic Breast Disease; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Middle Aged; Radiography; Transsexualism

A reversed-phase high-performance liquid chromatographic method with ultraviolet detection of megestrol acetate and cyproterone acetate in human sera is described. The proposed assay is linear up to 1400 ng/ml (r = 0.999) and has a detection limit of 5 ng/ml. Recoveries of both compounds in spiked sera were ca. 95%; inter-assay coefficients of variation were 4.0 and 3.1% and intra-assay values were 1.3 and 1.4%, respectively. For validation of the method we also developed a gas chromatographic-mass spectrometric method for both steroids. The results obtained by the two methods showed good correlation: for megestrol acetate r = 0.98, n = 31, p less than 0.0001, and for cyproterone acetate r = 0.94, n = 0, p less than 0.0001. Large inter-individual differences in the serum concentrations of both substances were found in groups of patients with metastatic breast cancer receiving the same oral load of either steroid.

Topics: Antineoplastic Agents; Breast Neoplasms; Chromatography, High Pressure Liquid; Cyproterone; Cyproterone Acetate; Gas Chromatography-Mass Spectrometry; Humans; Megestrol; Megestrol Acetate

Topics: Adenocarcinoma; Adult; Breast Neoplasms; Buserelin; Combined Modality Therapy; Cyproterone; Cyproterone Acetate; Femoral Neoplasms; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Male; Tamoxifen; Triptorelin Pamoate

A phase II study with cyproterone acetate (CPA) was done as the primary treatment in female breast cancer patients. Twenty-three patients, mean age 64 years, range 52-75 years, were entered and treated with CPA 400 mg daily. Twenty patients were evaluable and responses were sparse. There was one partial and one complete remission, 17 patients were stable and one patient progressed within 3 months. Side-effects were frequent: five patients complained of nausea, three had severe weight loss, one suffered from depression and seven showed disturbed liver function tests. Six patients had to stop treatment for side-effects, while two other patients were taken off treatment because they developed an acute necrotizing hepatitis. The hepatitis recovered after drug withdrawal in both patients. The serum levels of CPA, cortisol, androstenedione, DHAS, LH, FSH and prolactin were measured during CPA treatment. The levels of cortisol and androstenedione did not change, while LH, FSH and DHAS were suppressed. The DHAS showed an inverse relation to serum CPA concentrations. The prolactin levels rose uniformly. The therapeutic effect of CPA in postmenopausal patients with advanced breast cancer is disappointing, and inferior to that of other progestins. Side-effects are frequent, possibly as a result of the high dosage used in this study. The hormonal changes are different from those of other progestins, which may explain the different efficacies.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Chemical and Drug Induced Liver Injury; Cyproterone; Cyproterone Acetate; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Drug Evaluation; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Middle Aged

The proliferation of three mammary carcinoma cell lines was explored for the effectiveness of dihydrotestosterone (DHT) and the antiandrogenic substances cyproterone acetate (CPA) or hydroxyflutamide. The cell growth, determined in multiple experimental cultures of the estrogen-sensitive lines MCF-7 and EFM-19, was stimulated by 10(-9) M to 10(-6) M DHT, whereas estrogen-resistant MFM-21 cells were unresponsive to the hormonal factors applied. Growth-promoting effects of 10(-8) M to 10(-6) M CPA were detected in cultures of those cell lines which were sensitive to estrogen and androgen. Competition experiments with DHT and the antiandrogens suggested involvement of the androgen receptor in the stimulation of cell growth by CPA. Participation of the estrogen receptor was excluded by lack of competition between CPA and the enhancement of proliferation by estradiol-17 beta. At the receptor level the antiandrogens were able to compete with androgen binding. The results of the study demonstrate androgenic properties of CPA in regard to the growth of human mammary carcinoma cells.

Topics: Androgen Antagonists; Androgens; Breast Neoplasms; Cell Division; Cyproterone; Cyproterone Acetate; Dihydrotestosterone; Estrenes; Estrogens; Female; Humans; Metribolone; Receptors, Androgen; Tumor Cells, Cultured

Topics: Acute Disease; Aged; Breast Neoplasms; Chemical and Drug Induced Liver Injury; Cyproterone; Cyproterone Acetate; Female; Humans

14 males with disseminated cancer of breast received a total of 35 endocrine trials, mainly in the form of hormonal supplementation. Overall, a 43% response rate was observed. In particular, remissions occurred in 7 of 11 instances with cyproterone acetate, in 3 of 7 with tamoxifen, in 2 of 5 with estrogens, in 2 of 5 with aminoglutethimide, in none of 3 with high-dose medroxyprogesterone acetate, in none of 1 with androgens, and in 1 of 3 with castration. The response to additive hormonal therapy was 44%. Median overall response duration was 10 months, 11 months following additive hormonal therapy. Median survival from start of therapy was longer in responding than in nonresponding patients (23.5 vs. 11 months). A disease-free interval did not appear to influence hormonal response. Patients responding to one form of hormonal treatment had a greater likelihood of responding to subsequent hormonal manipulations. Additive hormonal therapy may provide effective palliation in males with advanced breast cancer, and should be considered as a valid alternative to orchiectomy.

Topics: Adult; Aminoglutethimide; Androgen Antagonists; Antineoplastic Agents; Breast Neoplasms; Castration; Cyproterone; Cyproterone Acetate; Estrogens; Hormones; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Middle Aged; Neoplasm Recurrence, Local; Tamoxifen; Time Factors

Ten male patients with advanced cancer of the breast were treated with cyproterone acetate, an anti-androgenic compound with additional progestational properties. Seven patients achieved a response, for a median duration of 8 months. Plasma testosterone and estradiol levels fell significantly during therapy, but quantitatively this drop was not related to the therapeutic response. Cyproterone acetate is an effective and well-tolerated treatment for metastatic male breast cancer.

Topics: Aged; Breast Neoplasms; Cyproterone; Drug Evaluation; Erectile Dysfunction; Estradiol; Humans; Male; Middle Aged; Neoplasm Metastasis; Prolactin; Testosterone

Three male patients of 55, 63 and 71 years of age, with metastatic breast cancer, were treated with cyproterone acetate. Two patients showed complete remission, one lasting 21 months, another 51+ months and a third achieved partial remission lasting 9 months. These results suggest that cyproterone acetate may be useful in the treatment of advanced male breast cancer.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Cyproterone; Cyproterone Acetate; Drug Evaluation; Humans; Lung Neoplasms; Male; Middle Aged; Prognosis

We have examined five human breast cancer cell lines in continuous tissue culture for androgen responsiveness. One of these cell lines shows a 2- to 4-fold stimulation of thymidine incorporation into DNA, apparent as early as 10 hr following androgen addition to cells incubated in serum-free medium. This stimulation is accompanied by an acceleration in cell replication. Antiandrogens [cyproterone acetate (6-chloro-17alpha-acetate-1,2alpha-methylene-4,6-pregnadiene-3,20-dione) and R2956 (17beta-hydroxy-2,2,17alpha-trimethoxyestra-4,9,11-triene-1-one)] inhibit both protein and DNA synthesis below control levels and block androgen-mediated stimulation. Prolonged incubation (greater than 72 hr) in antiandrogen is lethal. The MCF- cell line contains high-affinity receptors for androgenic steroids demonstrable by sucrose density gradients and competitive protein binding analysis. By cross-competition studies, androgen receptors are distinguishable from estrogen receptors also found in this cell line. Concentrations of steroid that saturate androgen receptor sites in vitro are about 1000 times lower than concentrations that maximally stimulate the cells. Changes in quantity and affinity of androgen binding to intact cells at 37 degrees as compared with usual binding techniques using cytosol preparation at 0 degrees do not explain this difference between dissociation of binding and effect. However, this difference can be explained by conversion of [3H]-5alpha-dihydrotestosterone to 5alpha-androstanediol and more polar metabolites at 37 degrees. An examination of incubation media, cytoplasmic extracts and crude nuclear pellets reveals probable conversion of [3H]testosterone to [3H]-5alpha-dihydrotestosterone. Our data provide compelling evidence that some human breast cancer, at least in vitro, may be androgen dependent.

Topics: Androgen Antagonists; Androgens; Binding Sites; Binding, Competitive; Breast Neoplasms; Cell Division; Cell Line; Cells, Cultured; Cyproterone; Cytoplasm; Dihydrotestosterone; DNA, Neoplasm; Estradiol; Estrenes; Female; Humans; Neoplasm Proteins; Receptors, Androgen; Receptors, Estrogen; Receptors, Steroid; Testosterone

Specific receptor binding of estradiol (E-2) and dihydrotestosterone (DHT) was studied in human myometrial tissue and in human mammary cancer tissue. The inhibition of binding for E-2 and DHT by E-2, testosterone (T), DHT, dehydroepiandosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), androstendione (A) and 5-androstene-3beta, 17beta-diol (Adiol) was tested with the use of dextran-coated charcoal separation of bound and free E-2, respectively, and DHT. The percentage of binding inhibition was calculated with reference to the inhibition obtained with nafoxidine in a molar concentration ratio of 1,000 for E-2 binding, respectively, with cyproterone acetate in a molar concentration ratio of 10,000 for DHT binding. In 15 samples of myometrium tested, receptors were found for both E-2 and DHT. From 19 samples of mammary carcinoma tissue one showed no binding activity, three samples did bind E-2 only, five samples DHT only, and ten samples showed binding of both steroids. A 50% inhibition of E-2 binding, in myometrial as well as in tumor tissue, required a molar concentration ratio of 40 for Adiol, of more than 2,000 for DHEA. No significant inhibiting activity could be found for A up to a molar concentration ratio of 10,000 and for DHEA-S up to 40,000. With regard to DHT binding, Adiol is more active than E-2 and less active than T. Of the substances tested Adiol is therefore the only one which exerts a significant inhibiting influence at a molar ratio not far beyond the physiological range. This signifies that Adiol might interfere at the receptor level in the estrogenic stimulation of mammary cancer cells.. Specific receptor binding of estradiol-17beta (E2) and dihydrotestosterone (DHT) was studied in human myometrial tissue and in human mammary cancer tissue. The inhibition of binding for E2 and DHT by E2, testosterone (T), DHT, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), androstenedione (A) and 5-androstene-3beta, 17beta-diol (Adiol) was tested with the use of dextran-coated charcoal separation of bound and free E2, respectively, and DHT. The percentage of binding inhibition was calculated with reference to the inhibition obtained with nafoxidine in a molar concentration of 1000 for E2 binding, respectively, with cyproterone acetate in a molar concentration ratio of 10,000 for DHT binding. In 15 samples of myometrium tested, receptors were found for both E2 and DHT. From 19 samples of mammary carcinoma tissue 1 was without binding activity, 3 samples bound E2 only, 5 samples DHT only, and 10 showed binding of both. A 50% inhibition of E2 binding in myometrial as well as in tumor tissue, required a molar concentration ratio of 40 for Adiol, of more than 2000 for T and for DHT, and of about 20,000 for DHEA. Significant inhibiting activity for A up to a molar concentration ratio of 10,000 was absent. This was also true for DHEA-S up to 40,000. With regard to DHT binding, Adiol is more active than E2 and less active than T. Thus Adiol was the only substance which exerted a significant inhibiting influence at a molar ratio near physiological range. Adiol might interfere at the receptor level in the estrogenic stimulation of mammary cancer cells.

Topics: Adult; Aged; Androstenediols; Androstenedione; Binding, Competitive; Breast Neoplasms; Cyproterone; Dehydroepiandrosterone; Dihydrotestosterone; Estradiol; Female; Humans; Middle Aged; Nafoxidine; Receptors, Cell Surface; Testosterone; Uterus

Topics: Acne Vulgaris; Adult; Alopecia; Animals; Breast Neoplasms; Chlormadinone Acetate; Contraception; Contraceptives, Oral; Contraceptives, Postcoital; Cyproterone; Delayed-Action Preparations; Dermatitis, Seborrheic; Dogs; Estrogens; Ethinyl Estradiol; Female; Hirsutism; Humans; Injections, Intramuscular; Norgestrel; Progestins