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The Journal of Biological Chemistry Jun 1982The effects of estrogens on ovarian aromatase activity were investigated in vitro using granulosa cells from immature hypophysectomized estrogen-primed rats. The cells...
The effects of estrogens on ovarian aromatase activity were investigated in vitro using granulosa cells from immature hypophysectomized estrogen-primed rats. The cells were cultured for 3 days in an androgen-free medium in the presence of follicle-stimulating hormone (FSH), with or without the specified estrogen. After washing, the cells were reincubated for 5 h with 10(-7) M androstenedione, and the formation of estrogens was measured. Estrogen production by control and diethylstilbestrol-treated cells was negligible, while FSH stimulated aromatase activity. Furthermore, concomitant treatment with diethylstilbestrol led to dose-dependent increases in the FSH-induced aromatase activity with an ED50 value of 4 X 10(-9) M and an apparent Vmax value 12- to 16-fold higher than those induced by FSH alone. The direct stimulatory effect of estrogens was time-dependent and was not accounted for by increases in cell protein. Various native and synthetic estrogens also augmented the FSH induction of aromatases (native estrogens: estradiol-17 beta = estrone greater than estradiol-17 alpha greater than estriol; synthetic estrogens: hexestrol greater than moxestrol greater than ethinyl estradiol much greater than chlorotrianisene and mestranol). The effect of estradiol-17 beta was dose-dependent with an ED50 value of 9 X 10(-9) M, which is within the physiological levels of follicular estradiol-17 beta. Although treatment with androgens also enhanced the FSH-induced aromatases, treatment with a progestin (R5020) or a mineralocorticoid (aldosterone) was without effect. Thus, estrogens directly augment the stimulation of granulosa cell aromatase activity by FSH. Follicular estrogens may activate intraovarian autoregulatory positive feedback mechanisms to enhance their own production, resulting in selective follicle maturation and the preovulatory estrogen surge.
Topics: Aldosterone; Animals; Aromatase; Diethylstilbestrol; Enzyme Induction; Estradiol; Estrogens; Estrone; Female; Follicle Stimulating Hormone; Granulosa Cells; Ovary; Oxidoreductases; Rats; Rats, Inbred Strains
PubMed: 6804461
DOI: No ID Found -
Cancer Causes & Control : CCC May 2017Oral contraceptives (OCs) have been consistently associated with a reduced ovarian cancer risk; however, most previous studies included women in older birth cohorts...
PURPOSE
Oral contraceptives (OCs) have been consistently associated with a reduced ovarian cancer risk; however, most previous studies included women in older birth cohorts using high-dose OC formulations. We assessed OC use, including type and dose, and ovarian cancer risk among women born between 1947 and 1964 using more recent formulations.
METHODS
We included 110,929 Nurses' Health Study II participants. Women reported duration of OC use and brands used from age 13 to baseline (1989) and every 2 years thereafter through 2009. We categorized brands by estrogen and progestin type, dose, and potency, and used Cox proportional hazards models, adjusted for age, calendar time, reproductive factors, and body mass index, to assess associations with ovarian cancer.
RESULTS
Over 2,178,679 person-years of follow-up, we confirmed 281 cases. At baseline, 83% of participants reported ever using OCs. Compared to never use, we observed an increased risk of ovarian cancer with ≤6 months of OC use (HR 1.82; 95% CI 1.13-2.93) but a non-significant 57% (95% CI 0.18-1.03) decreased risk with ≥15 years of OC use. The increased risk among short-term users (≤1 year) was restricted to OCs containing mestranol (HR 1.83; 95% CI 1.16-2.88) and first-generation progestin (HR 1.72; 95% CI 1.11-2.65).
CONCLUSION
The associations between OCs and ovarian cancer observed for this younger birth cohort differ substantially from the results of previous cohort studies, possibly reflecting changes in OC formulations and use patterns over time, although these results could be due to chance. Additional studies should evaluate newer OC formulations and ovarian cancer risk.
Topics: Adolescent; Adult; Contraceptives, Oral; Female; Health Surveys; Humans; Incidence; Middle Aged; Ovarian Neoplasms; Prospective Studies; United States; Women's Health; Young Adult
PubMed: 28290016
DOI: 10.1007/s10552-017-0876-0 -
British Journal of Clinical Pharmacology Mar 1980
Topics: Ethinyl Estradiol; Humans; In Vitro Techniques; Intestinal Mucosa; Jejunum; Mestranol; Norgestrel
PubMed: 7362737
DOI: 10.1111/j.1365-2125.1980.tb04841.x -
Journal of Bacteriology Nov 1967Norethindrone has been examined in vitro for antibacterial activity against 10 microorganisms. Turbidimetric techniques were used to assay the antibacterial activity of...
Norethindrone has been examined in vitro for antibacterial activity against 10 microorganisms. Turbidimetric techniques were used to assay the antibacterial activity of norethindrone. The organisms tested included Staphylococcus aureus, S. epidermidis, Micrococcus conglomeratus, Listeria monocytogenes, Streptococcus faecalis, Salmonella typhosa, Shigella flexnerii, Klebsiella pneumoniae, Escherichia coli, and Proteus vulgaris. Bacteriostatic action was shown only against the gram-positive microorganisms when they were grown anaerobically in Tryptic Soy Broth containing 10 to 50 mug of norethindrone per ml. The bacteriostatic action of norethindrone was exerted primarily during the first 8 hr of incubation and it was reduced by the presence of oxygen. Mestranol at a concentration of 1 to 10 mug/ml failed to exert any significant action on S. aureus. However, incorporation of 5 mug of mestranol per ml in the culture medium enhanced the bacteriostatic action of norethindrone on staphylococci. Enhancement of the bacteriostatic action of norethindrone could not be obtained by the addition of a concentration of 5 mug/ml of testosterone, 17alpha-estradiol, and 17beta-estradiol. Progesterone and 4-pregnen-20beta-ol-3-one under similar conditions showed an additive bacteriostatic effect when they were incorporated into the culture medium containing norethindrone. In vivo studies indicated that female, adult New Zealand rabbits, injected subcutaneously with two injections of 10 to 20 mug of norethindrone, 24 hr apart, and challenged intradermally with S. aureus 4 hr after the second injection, had fewer lesions with smaller areas of swelling and erythema as compared to control, nontreated rabbits. The protective effect of norethindrone on the development of staphylococcal lesion seemed related to hormone concentration. Thus, it was demonstrated with doses of 20, 15, and 10 mug, but not with doses of 1 and 5 mug. When the lesions were excised 48 to 92 hr after infection and when viable cell counts were made, rabbits treated with norethindrone showed significantly lower staphylococcal counts than the control rabbits. During the 1st day after infection with S. aureus, leukocytic counts of the norethindrone-treated rabbits remained normal, whereas control animals showed elevated leukocytic counts.
Topics: Animals; Drug Synergism; Enterococcus faecalis; Escherichia coli; Estradiol; Female; Klebsiella; Leukocyte Count; Listeria monocytogenes; Mestranol; Micrococcus; Norethindrone; Oxygen; Photometry; Pregnenolone; Progesterone; Proteus; Rabbits; Salmonella typhi; Shigella; Staphylococcal Infections; Staphylococcus; Testosterone
PubMed: 4964476
DOI: 10.1128/jb.94.5.1353-1358.1967 -
British Medical Journal Dec 1967
Topics: Adult; Budd-Chiari Syndrome; Contraceptives, Oral; Female; Humans; Lynestrenol; Mestranol
PubMed: 6059263
DOI: 10.1136/bmj.4.5580.660 -
Fertility and Sterility Mar 1977Amenorrhea is a symptom having many possible causes. Since amenorrhea can result from disturbed function anywhere in the hypothalamic-pituitary-ovarian-uterine axis, a...
Amenorrhea is a symptom having many possible causes. Since amenorrhea can result from disturbed function anywhere in the hypothalamic-pituitary-ovarian-uterine axis, a specific etiologic diagnosis must be made if treatment is to be effective. For this purpose, a diagnostic scheme for the differential diagnosis of the etiology of primary and secondary amenorrhea is proposed. This scheme includes a progestin test, a cyclic estrogen and progestin test, a luteinizing hormone-releasing hormone (LH-RH) loading test, and a gonadotropin (human menopausal gonadotropin and human chorionic gonadotropin) loading test. A specific pattern of responses to LH-RH and gonadotropins exists in patients with hypothalamic, pituitary, and ovarian amenorrheas, respectively, and the character of the response may facilitate the etiologic diagnosis of amenorrhea. The clinical usefulness and/or value of the scheme in the diagnosis and treatment of amenorrheas is discussed.
Topics: Adult; Amenorrhea; Chlormadinone Acetate; Chorionic Gonadotropin; Diagnosis, Differential; Endocrine System Diseases; Estrogens; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Menotropins; Mestranol; Progesterone
PubMed: 65298
DOI: 10.1016/s0015-0282(16)42430-1 -
Canadian Medical Association Journal Jan 1966Sequential oral contraceptive therapy was devised to inhibit ovulation by a potent estrogen alone. A progestational agent was added at the end of the course of therapy...
Sequential oral contraceptive therapy was devised to inhibit ovulation by a potent estrogen alone. A progestational agent was added at the end of the course of therapy to prepare the endometrium for adequate withdrawal bleeding. The program consisted of giving 80 mug. of metranol daily for 15 days and then a combination of 80 mug. of mestranol and 2 mg. of chlormadinone acetate for five additional days. Such a regimen proved to be effective in 6070 patients carefully observed for 82,085 cycles of therapy at 25 medical centres.INCREASED CYCLE REGULARITY WAS NOTED: 98.1% of the cycles were 25 to 31 days long. In 80.1% of cycles, the withdrawal interval was two to five days in length. Duration of flow was four to six days in 85.3% of the therapeutic cycles. The amount of flow decreased as compared with pretreatment values. The incidence and severity of dysmenorrhea during sequential therapy were significantly lower than before treatment. Side effects, usually infrequent, diminished as therapy was continued; the average incidence of breakthrough bleeding was 1.9% and nausea was 2.9%. Extensive laboratory studies showed no consistent abnormalities. For oral contraception, sequential therapy has proved to be virtually 100% effective when taken as directed.
Topics: Adult; Chlormadinone Acetate; Contraceptives, Oral; Endometrium; Estrogens; Female; Humans; Menstruation; Menstruation Disturbances; Mestranol; Progestins
PubMed: 4159184
DOI: No ID Found -
Fertility and Sterility Nov 1978Ethynyestradiol and mestranol, in doses ranging from 50 to 100 microgram/day, were given to women in 21-day cycles; baboons and beagle dogs received 1 and 4... (Comparative Study)
Comparative Study
Comparative studies of the ethynyl estrogens used in oral contraceptives. VII. Effects with and without progestational agents on ultracentrifugally fractionated plasma lipoproteins in humans, baboons, and beagles.
Ethynyestradiol and mestranol, in doses ranging from 50 to 100 microgram/day, were given to women in 21-day cycles; baboons and beagle dogs received 1 and 4 microgram/kg/day in a similar regimen. After a number of such cycles, megestrol acetate, norethindrone acetate, or dl-norgestrel was given concomitantly. Protein, cholesterol, triglyceride, and phospholipid levels were determined in total plasma and in ultracentrifugally separated lipoprotein fractions. Over the dosage range studied, the effects of the two kinds of estrogen were indistinguishable. Except for human total plasma triglyceride, no dose-related differences were observed. The lowering of serum protein and the increase in cholesterol induced by estrogen were more pronounced in baboons and beagles than in human subjects. The cholesterol-depressing effect of progestational compounds observed in humans was very pronounced in baboons but absent in beagles. In all three species, estrogen increased the lipoprotein fraction cholesterol, except for human low-density lipoprotein cholesterol, which was decreased. Human plasma triglyceride and phospholipid increased on estrogen administration and were decreased by the progestins; in the two animal species, triglyceride is normally very low and the estrogen-induced changes were negligible; the phospholipid rose with estrogen but was unaffected by progestins. In sum, the two animal species show many similarities to, as well as important differences from, the human response of plasma lipids to various contraceptive steroids.
Topics: Animals; Blood Proteins; Cholesterol; Contraceptives, Oral; Contraceptives, Oral, Synthetic; Dogs; Dose-Response Relationship, Drug; Estradiol Congeners; Ethinyl Estradiol; Female; Haplorhini; Humans; Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Megestrol; Mestranol; Norethindrone; Norgestrel; Phospholipids; Progesterone Congeners; Triglycerides; Ultracentrifugation
PubMed: 214353
DOI: 10.1016/s0015-0282(16)43632-0 -
British Heart Journal Dec 1976The effect of three oestrogens (including an oestrogen-progestogen combination) on the postexercise electrocardiogram was studied in 33 men and 18 women who earlier had...
The effect of three oestrogens (including an oestrogen-progestogen combination) on the postexercise electrocardiogram was studied in 33 men and 18 women who earlier had shown ST segment abnormalities after exercise. When pretreatment exercise tests were compared with tests after two weeks of treatment, the postexercise ST segments which were abnormal before treatment became even more abnormal in 18 (90%) of 20 subjects treated with conjugated oestrogens 10 mg daily, in 16 (89%) of 18 subjects treated with stilboestrol 5 mg daily, and in 12 (92%) of 13 subjects treated with norethynodrel (9-85 mg) and mestranol (0-15 mg)1 daily. The ST segment abnormalities reverted to pretreatment appearance within 6 weeks of stopping oestrogens. When 10 subjects with normal near-maximal exercise tests were treated for 2 weeks with conjugated oestrogens 10 mg daily, the tests remained unchanged in 9. The hypothesis favoured to explain these findings is that of an oestrogen-induced increase in coronary artery smooth muscle tone. An increase in arterial tone would also account for the increased incidence of myocardial (and cerebral) infarction that has been reported among individuals treated with oestrogen, either alone or in combination with progestogen.
Topics: Adult; Aged; Electrocardiography; Estrogens, Conjugated (USP); Exercise Test; Female; Heart; Humans; Male; Middle Aged; Time Factors
PubMed: 188435
DOI: 10.1136/hrt.38.12.1299 -
British Journal of Pharmacology 19801 The oestrogenic and antioestrogenic activities of tamoxifen and monohydroxytamoxifen have been compared with those of para-methoxy, -methyl, -fluoro, and -chloro...
1 The oestrogenic and antioestrogenic activities of tamoxifen and monohydroxytamoxifen have been compared with those of para-methoxy, -methyl, -fluoro, and -chloro tamoxifen in the 3 day immature rat uterine weight test.2 The oestrogenic activity of mestranol, a steroid with low oestrogen receptor binding affinity which is believed to be demethylated to ethinyl oestradiol before exerting its effects, was less potent than ethinyl oestradiol when assayed in the 3 day immature rat uterine weight test. Similarly, para-methoxytamoxifen was less active than monohydroxytamoxifen in oestrogenic and antioestrogenic tests.3 The introduction of a para-methoxy group into tamoxifen did not affect oestrogenic or antioestrogenic activity.4 All the derivatives of tamoxifen were partial oestrogen agonists when compared with oestradiol benzoate in the 3 d immature rat uterine weight test. All test compounds inhibited the uterotrophic activity of oestradiol benzoate (0.16 mug daily) in a dose-related manner. The order of potency was: monohydroxytamoxifen > tamoxifen identical with methoxytamoxifen > p-fluoro identical with p-chloro identical with p-methyltamoxifen.5 Tamoxifen was approximately equiactive with its p-methyl, p-fluoro and p-chloro derivatives in the ability to inhibit [(3)H]-oestradiol binding to rat uterine oestrogen receptors in vitro.6 Tamoxifen was approximately equiactive with its p-methyl and p-fluoro derivatives in the ability to inhibit vaginal cornification of ovariectomized rats upon intravaginal administration with oestradiol (3.2 ng total dose).7 Since tamoxifen in vivo was more active as a partial oestrogen agonist and antagonist than the para substituted fluoro, chloro and methyl derivatives that cannot undergo metabolic hydroxylation to monohydroxytamoxifen, whereas the antioestrogenic activity of the compounds upon local application in the vaginal cornification test was equivalent as was their ability to inhibit [(3)H]-oestradiol-17beta binding to the oestrogen receptor in vitro, it is suggested that at low doses; i.e. over the range of the partial agonist dose-response curve, the biological activity of tamoxifen is the net result of the activities of the parent compound and its metabolites.8 The results demonstrate that metabolic activation of non-steroidal antioestrogens is only an advantage and not a requirement for antioestrogenic activity.
Topics: Animals; Biotransformation; Estradiol; Estrogen Antagonists; Female; In Vitro Techniques; Organ Size; Rats; Structure-Activity Relationship; Tamoxifen; Uterus
PubMed: 7470748
DOI: 10.1111/j.1476-5381.1980.tb10912.x