Sample records for norethynodrel

  1. Effect of a combination of norethynodrel and mestranol on plasma luteinizing hormone in normal women.


    Abraham, G E; Klaiber, E L; Broverman, D


    Plasma luteinizing hormone (LH) levels were measured by radioimmunoassay in 6 normal nulliparous women (ages 21-25) during 2 consecutive menstrual cycles. Cycle 1 served as the control, while a combination of 5 mg norethynodrel and .075 mg mestranol (Enovid) was administered daily during the second cycle. Midcycle LH peaks observed in all subjects during the control cycle were completely suppressed in the treated cycle. Basal LH levels during the treated cycle were significantly lower than during the follicular phase of control cycles. Mechanisms by which Enovid could affect plasma LH include decreased synthesis or release of LH and different sites of drug action with different dosages. PMID:5794834

  2. Metabolism of the Synthetic Progestogen Norethynodrel by Human Ketosteroid Reductases of the Aldo-Keto Reductase Superfamily

    PubMed Central

    Jin, Yi; Duan, Ling; Chen, Mo; Penning, Trevor M; Kloosterboer, Helenius J.


    Human ketosteroid reductases of the aldo-keto reductase (AKR) superfamily, i.e. AKR1C1-4, are implicated in the biotransformation of synthetic steroid hormones. Norethynodrel (NOR, 17α-ethynyl-17β-hydroxy-estra-5(10)-en-3-one), the progestin component of the first marketed oral contraceptive, is known to undergo rapid and extensive metabolism to 3α- and 3β-hydroxy metabolites. The ability of the four human AKR1C enzymes to catalyze the metabolism of NOR has now been characterized. AKR1C1 and AKR1C2 almost exclusively converted NOR to 3β-hydroxy NOR, while AKR1C3 gave 3β-hydroxy NOR as the main product and AKR1C4 predominantly formed 3α-hydroxy NOR. Individual AKR1C enzymes also displayed distinct kinetic properties in the reaction of NOR. In contrast, norethindrone (NET), the Δ4-isomer of NOR and the most commonly used synthetic progestin, was not a substrate for the AKR1C enzymes. NOR is also structurally identical to the hormone replacement therapeutic tibolone (TIB), except TIB has a methyl group at the 7α-position. Product profiles and kinetic parameters for the reduction of NOR catalyzed by each individual AKR1C isoform were identical to those for the reduction of TIB catalyzed by the respective isoform. These data suggest that the presence of the 7α-methyl group has a minimal effect on the stereochemical outcome of the reaction and kinetic behavior of each enzyme. Results indicate a role of AKR1C in the hepatic and peripheral metabolism of NOR to 3α- and 3β-hydroxy NOR and provide insights into the differential pharmacological properties of NOR, NET and TIB. PMID:22210085

  3. Screening for (anti)androgenic properties using a standard operation protocol based on the human stably transfected androgen sensitive PALM cell line. First steps towards validation.


    Freyberger, A; Witters, H; Weimer, M; Lofink, W; Berckmans, P; Ahr, H-J


    Despite more than a decade of research in the field of endocrine active compounds targeting the androgen receptor (AR), and although suitable cell lines can be obtained, no validated human stably transfected androgen sensitive transactivation assay is available. Bayer Schering Pharma (BSP) and the Flemish Institute for Technological Research (VITO), partners within the EU-sponsored 6th framework project ReProTect, made first steps towards such a validation. A standard operation protocol (SOP) developed at BSP based on the androgen sensitive PALM cell line was transferred to VITO and its performance and transferability were thoroughly studied. The investigation followed a generic protocol prepared for all reporter gene assays evaluated within ReProTect, and in both laboratories at least three independent experiments were performed. The highest concentration to be tested was limited to 10 microM, if needed. A few compounds, 17alpha-methyltestosterone (17alpha-MT), vinclozolin and linuron, were studied using a real world scenario, i.e., assuming that their interaction with the AR was not known: A prescreening for agonism and true, competitive antagonism was used to select conditions such as the appropriate mode of action, and the working range excluding cytotoxicity for the final screening. All other compounds were tested according to the generic protocol: Compounds screened for agonism were the reference androgen 17alpha-methyldihydrotestosterone (MDHT), levonorgestrel, norethynodrel, progesterone, o,p'-DDT, and dibutylphthalate (DBP), while compounds screened for antagonism were the reference anti-androgen flutamide, prochloraz, o,p'-DDT, progesterone, norethynodrel, and DBP. Cytotoxicity was assessed in parallel as lactate dehydrogenase release. The prescreen classified 17alpha-MT as androgenic, vinclozolin and linuron as anti-androgenic and compounds were tested accordingly. In the absence of cytotoxicity, appropriate androgenic properties of reference and test

  4. Effect of oestrogens on postexercise electrocardiogram.

    PubMed Central

    Jaffe, M D


    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. PMID:188435

  5. The mother of the pill.


    Djerassi, C


    The first synthesis of an active ingredient of the pill was performed on October 15, 1951, at Syntex in Mexico City. These preliminary results, obtained in late 1951, encouraged the submission of a synthetic progestin, norethindrone (19-nor-17alpha-ethynyltestosterone), to a number of outside investigators for more extensive biological scrutiny. Norethynodrel, together with many other steroids synthesized in the Searle laboratories, as well as Syntex's norethindrone, were examined by Pincus and collaborators for ovulation inhibition in animals and humans. Contrary to predictions, orally effective steroid ovulation inhibitors became the most widely used method of reversible birth control in most parts of the world some 40 years after their first synthesis. Toward the end of the 1960s, at least 13 international pharmaceutical companies (9 of them US) had active research and development programs dedicated to new advances in the field of contraception. Every drug to which a woman or man is exposed to for long periods of time (e.g., vaccines, systemic contraceptives, cholesterol-lowering agents, antihypertensives) in the end has to pass through large-scale postmarketing experiments. The most damaging was the requirement for 6-year toxicology in beagle dogs, which resulted in enormous development costs. Another setback was a 1986 judgment in Georgia against Ortho Pharmaceutical Company for the amount of $5,151,030 for alleged birth defects caused by the use of its spermicide Ortho-Gynol in spite of overwhelming epidemiological evidence against such a cause-effect relationship. Mifepristone (RU-486) is clearly the most significant new development in birth control as an important alternative to conventional abortion. A priority list of six new contraceptive methods for future development includes a spermicide with antiviral properties, a once-a-month menses inducer, a reliable ovulation predictor, easily reversible male sterilization, a male contraceptive pill, and an

  6. Clinically Relevant Progestins Regulate Neurogenic and Neuroprotective Responses in Vitro and in Vivo

    PubMed Central

    Liu, Lifei; Zhao, Liqin; She, Hongyun; Chen, Shuhua; Wang, Jun Ming; Wong, Charisse; McClure, Kelsey; Sitruk-Ware, Regine; Brinton, Roberta Diaz


    Previously, we demonstrated that progesterone (P4) promoted adult rat neural progenitor cell (rNPC) proliferation with concomitant regulation of cell-cycle gene expression via the P4 receptor membrane component/ERK pathway. Here, we report the efficacy of seven clinically relevant progestins alone or in combination with 17β-estradiol (E2) on adult rNPC proliferation and hippocampal cell viability in vitro and in vivo. In vitro analyses indicated that P4, norgestimate, Nestorone, norethynodrel, norethindrone, and levonorgestrel (LNG) significantly increased in rNPC proliferation, whereas norethindrone acetate was without effect, and medroxyprogesterone acetate (MPA) inhibited rNPC proliferation. Proliferative progestins in vitro were also neuroprotective. Acute in vivo exposure to P4 and Nestorone significantly increased proliferating cell nuclear antigen and cell division cycle 2 expression and total number of hippocampal 5-bromo-2-deoxyuridine (BrdU)-positive cells, whereas LNG and MPA were without effect. Mechanistically, neurogenic progestins required activation of MAPK to promote proliferation. P4, Nestorone, and LNG significantly increased ATP synthase subunit α (complex V, subunit α) expression, whereas MPA was without effect. In combination with E2, P4, Nestorone, LNG, and MPA significantly increased BrdU incorporation. However, BrdU incorporation induced by E2 plus LNG or MPA was paralleled by a significant increase in apoptosis. A rise in Bax/Bcl-2 ratio paralleled apoptosis induced by LNG and MPA. With the exception of P4, clinical progestins antagonized E2-induced rise in complex V, subunit α. These preclinical translational findings indicate that the neurogenic response to clinical progestins varies dramatically. Progestin impact on the regenerative capacity of the brain has clinical implications for contraceptive and hormone therapy formulations prescribed for pre- and postmenopausal women. PMID:20943809

  7. [Family planning with different contraceptive methods].


    Dumitrache, F; Gheorghiţă, E


    Female hormonal contraceptives, introduced commercially in 1959, contained 10 mg of norethynodrel and .15 mg of mestranol. The estrogen and progesterone doses were progressively reduced over time. In 1989, approximately 60 million couples used oral contraceptives (OCs) ranging from 1% in Japan to 40% in the Netherlands. The monophasic pill contains .01 - .04 mg of ethinyl estradiol (EE), and the biphasic pill contains increasing doses of progesterone and estroprogesterone in the course of the menstrual cycle. Triphasic combined pills contain an initially dominant estrogen dose. In oral sequential pills, estrogen is given on days 14-16 followed by a estroprogesterone for 5-7 days. Micropills with progesterone, injectables with medroxyprogesterone, and 3rd-generation OCs such as gestoden with a low progesterone dose of .04 mg/day and reduced androgenic activity are among other OCs. The OCs are administered in 21-22 day packets. Absolute contraindications include history of venous thrombosis, atherogenic lipid profile, hormone-dependent cancer, and allergy. Relative contraindications include arterial ailments, smoking, hypertension, older age, obesity, and familial history of cardiovascular and cerebrovascular accidents. Interactions with antibiotics (ampicillin and tetracycline) occur as the modified intestinal flora reduces the level of deconjugated EE. Most frequent side effects are depression, modification of libido, ocular disorders, headache, and urinary infection. Benefits include favorable modification of menstrual cycle, and reduction of endometriosis and endometrial and ovarian cancer. Systemic risks such as cardiovascular and blood coagulation effects occur mainly with high-dose OCs. Further topics addressed are the cancer risk and protective effect of OCs, postcoital OCs, traditional contraception, the IUD, RU-486, implants, vaccination with the human antigonadotropine, and the vaginal ring. PMID:1823414

  8. Bimodal binding and free energy of the progesterone receptor in the induction of female sexual receptivity by progesterone and synthetic progestins.


    Kubli-Garfias, Carlos; González-Flores, Oscar; Gómora-Arrati, Porfirio; González-Mariscal, Gabriela; Vázquez-Ramírez, Ricardo; Beyer, Carlos


    Synthetic progestins (SPs) are used for regulation of fertility, contraception and hormone replacement therapy. The acetylated medroxyprogesterone (MPA), megestrol (MGA) and chlormadinone (CLA) are related to progesterone (P). Other SPs are 19-nortestosterone derivatives such as: norethisterone (NET), norethynodrel (NED) or the 13-ethyl gonane, levonorgestrel (LNG). We studied MPA, NET, NED and LNG in a dose-response manner to induce sexual receptivity in rats. Results showed that MPA, NET and NED act as partial agonists, with similar or lower potency than P. However, LNG is a full agonist. Additionally, the molecules of MPA, MGA, CLA, NET, NED, LNG, and P, were submitted to computer calculations at ab initio quantum mechanics theory, to obtain their electronic structure and molecular properties. The aim was to correlate their behavioral effect with their physicochemical properties. In addition, the crystals of P, NET and LNG bound to the progesterone receptor (PR) were studied. The PR crystallizes as a dimer forming two monomers (mA and mB), in which Gln725 interacts in either of two possible ways with the C3-carbonyl pharmacophore of progestins. P binds differentially to both PR monomers, while NET binds exclusively as mA and LNG binds only as mB in both monomers with no difference. Energetically, binding of LNG and P to mB, is more favorable than that of NET and P to mA. Consequently, this bimodal mechanism increases the action possibilities of SPs on biological systems. Interestingly, progestin potency depends mostly on local molecular structure and electronic features, prevailing over total molecular properties. PMID:22960752

  9. Assessment of a recombinant androgen receptor binding assay: initial steps towards validation.


    Freyberger, Alexius; Weimer, Marc; Tran, Hoai-Son; Ahr, Hans-Jürgen


    Despite more than a decade of research in the field of endocrine active compounds with affinity for the androgen receptor (AR), still no validated recombinant AR binding assay is available, although recombinant AR can be obtained from several sources. With funding from the European Union (EU)-sponsored 6th framework project, ReProTect, we developed a model protocol for such an assay based on a simple AR binding assay recently developed at our institution. Important features of the protocol were the use of a rat recombinant fusion protein to thioredoxin containing both the hinge region and ligand binding domain (LBD) of the rat AR (which is identical to the human AR-LBD) and performance in a 96-well plate format. Besides two reference compounds [dihydrotestosterone (DHT), androstenedione] ten test compounds with different affinities for the AR [levonorgestrel, progesterone, prochloraz, 17alpha-methyltestosterone, flutamide, norethynodrel, o,p'-DDT, dibutylphthalate, vinclozolin, linuron] were used to explore the performance of the assay. At least three independent experiments per compound were performed. The AR binding properties of reference and test compounds were well detected, in terms of the relative ranking of binding affinities, there was good agreement with published data obtained from experiments using recombinant AR preparations. Irrespective of the chemical nature of the compound, individual IC(50)-values for a given compound varied by not more than a factor of 2.6. Our data demonstrate that the assay reliably ranked compounds with strong, weak, and no/marginal affinity for the AR with high accuracy. It avoids the manipulation and use of animals, as a recombinant protein is used and thus contributes to the 3R concept. On the whole, this assay is a promising candidate for further validation. PMID:19833195