Demers, R; Blais, J A; Pretty, H
A cause de l'effet favorable de la grossesse sur l'activité de l'arthrite rhumatoïde, on s'est demandé si une pseudo-grossesse, produite par un progestatif de synthèse n'entraînerait pas une rémission du moins partielle de cette maladie.Noréthynodrel associée à mestranol (Enovid), 30 mg./jour, a été administrée à 44 femmes pendant quatre à 24 mois. A cause d'effets secondaires indésirables, 11 patientes furent soustraites de l'investigation. Les résultats s'appuient sur 33 cas. Une rémission apparente complète s'est manifestée chez sept patientes aux stades précoces de la maladie; chez 15, une amélioration objective des signes inflammatoires a été observée; chez quatre, une amélioration subjective seule a été notée; chez sept, il n'y a eu aucune amélioration. Dix-sept femmes sur 36 ont présenté une altération d'un ou plusieurs tests hépatiques. Trois présentèrent un ictère cholestatique. Les 17-OH plasmatiques se sont élevés à trois ou quatre fois la normale.De cette étude il ressort que noréthynodrel associée à mestranol peut produire une atténuation des signes inflammatoires de l'arthrite rhumatoïde. L'effet est palliatif, mitigé et non curatif et ne résulte pas nécessairement de l'état de pseudo-grossesse en soi.
Oesterheld, Jessica R; Cozza, Kelly; Sandson, Neil B
Nearly 50 years ago, the introduction of Enovid (norethynodrel 10 microg and mestranol 150 microg), which provided convenient and reliable contraception, revolutionized birth control. Reports of interactions between oral contraceptives (OCs) and other drugs began to trickle into the literature. At first, these drug interactions appeared to be random and unrelated. Increased understanding of P450 enzymes and phase II reactions of sulfation and glucuronidation has permitted preliminary categorization and assessment of the clinical relevance of these drug interactions.
Stimson, W H
Alpha-macroglobulin was quantitated in patients with malignant disease, steroid treatment, pregnancy, and in normal subjects using the rocket technique of Laurell. Women treated with combined estrogen/progestogen and with mestranol and men treated with stilbesterol showed rises in alpha-macroglobulins. Those treated with norethynodrel did not, indicating that the estrogen is the responsible agent. The level increased during pregnancy and decreased sharply in the first 2 days postpartum. 30% of normal women and 10% of normal men had detectable quantities of the protein (up to 4 mg/100 ml) in their serum. 92% of patients with malignant disease had detectable levels of protein--6 mg/100 ml or higher.
Dugois, P; Amblard, F; Manent, J; Bignicourt B, D E
Incidence of vaginitis due to Candida albicans confirmed by culture was 46 of 496 (9.3%) French women taking contraceptive pills. The women had used pills for a total of 5198 cycles, in which 1991 were combined lynestrenol-mestranol, 804 were norethynodrel, 525 were ethynodiol and 473 were norethisterone combinations. The study group varied widely in age, economic class, marital status and parity, but no relationship could be found between yeast infection and age, parity, marital status, miscarriages or product used. This 9.3% incidence is about the same as that in healthy women not using pills. The authors thought that virulence was increased in these pill users, although all responded to local treatment without recurrence.
Ladinsky, H; Consolo, S; Bianchi, S; Peri, G; Garattini, S
Acetylcholine and choline levels were found not to fluctuate with the phase of the estrus cycle in the cerebral hemispheres, deincephalon and mesencephalon in the rat and mouse. Choline acetyltransferase activity was not altered in these brain areas in the mouse while in the rat there was a small but significant decrease in the cerebral hemispheres during proestrus (p less than 0.01), and in the mesencephalon during estrus (p less than 0.05), both with respect to diestrus. Chronic 30-day treatment with steroid contraceptive drug combinations (lynestrenol, 5 mg/kg+ mestranol, 0.3 mg/kg; lynestrenol, 2.5 mg/kg+ mestranol, 0.15 mg/kg; norethindrone, 4 mg/kg+ mestranol, 0.2 mg/kg; norethynodrel, 4 mg/kg+ mestranol, 0.06 mg/kg) did not alter cholinergic parameters in the brain areas of these two species except for minor changes in rare instances.
Markiewicz, L; Gurpide, E
The progestin-specific stimulation of alkaline phosphatase (AP) activity in cells of the T47D human breast cancer line was applied to the development of a sensitive microtiter plate bioassay for the quantitative evaluation of progestagenic and antiprogestagenic potencies of natural and synthetic compounds. Some of the steroids tested (viz. progesterone, medroxyprogesterone acetate, norethynodrel) behaved as full-agonists, capable of inducing AP activities to the same maximal levels (equal efficacy), while others (norethindrone, gestrinone, R5020, norgestrel, Org OD 14 and its 4-ene metabolite) behaved as partial agonists, eliciting lower maximal effects. Efficacy, EC50 values (concentrations at which they induce one-half of the maximal response) and "slope factors" serve to characterize agonistic effects. Relative progestagenic potencies among the full-agonists were evaluated by comparing EC50 concentrations. Several 19-nor synthetic progestins (norethynodrel, norethindrone, Org OD 14 and its 4-ene isomer, dl-norgestrel, levo-norgestrel, RU2323), but none of the tested progestins with the pregnane structure, showed intrinsic estrogenic activity, as evaluated by using a similar in vitro bioassay based on a previously reported estrogen-specific induction of AP in human endometrial adenocarcinoma cells of the Ishikawa Var-1 line. Maximal estrogenic effects of all the tested progestins with dual activity were as high as those of estradiol. However, these compounds widely varied in their EC50 values for estrogenic activity. Consequently, the in vitro bioassays can reveal differences in the ratio of progestagenic and estrogenic activities intrinsic to these compounds. The reduced capability of the partial agonists to exert progestagenic or estrogenic effects on AP expression may reflect an impeded, receptor-mediated action, a mechanism that would also account for their inhibitory effects on the induction of AP activity by full agonists. Partial progestagenic agonists
Kuhl, H; Wiegratz, I
, norethynodrel, tibolone) can readily be aromatized in the adult human liver. This leads to the formation of the potent estrogens ethinylestradiol from norethisterone or norethynodrel and 7 alpha-methyl-ethinylestradiol from tibolone. This may have clinical consequences, e.g. the elevated risk of venous thromboembolic disease in premenopausal women treated with high doses of norethisterone for bleeding disorders, or the elevated risk of stroke or endometrial disease in postmenopausal women treated with tibolone.
The effects of oral contraceptives and estrogen replacement drugs on blood lipids that affect cardiovascular disease (atherogenic effects) are reviewed by comparing their androgenicity and progestin potency. Although early oral contraceptives with high doses of estrogen were indicted for increasing risk of thromboembolic disorders and heart attacks, today's pills low in estrogen still bear the same risk for cardiovascular events. A brief explanation of the lipoproteins is presented, emphasizing the importance of High Density Lipoprotein (HDL) in protecting against heart disease and stroke. Menstruating women have naturally high HDL. The estrogen in oral contraceptives and postmenopausal estrogen replacements increases HDL as much as 30%, while decreasing LDL, the component carrying most of the cholesterol. It seems that the progestin in oral contraceptives will lower HDL, and studies show that this action is related to androgenicity and dose of the progestin. Progestins such as levonorgestrel and norgestrel are more androgenic, while norethynodrel, ethynodiol diacetate and norethindrone are less so. When used in combination with estrogens, progestins are less androgenic, but when used alone, the androgenic and atherogenic effects dominate. The lower the estrogen dose in the combination, say around 20-35 mcg ethinyl estradiol, the more atherogenic the progestin. These actions are confirmed theoretically by measurements of sex hormone binding globulin, a blood protein that reflects estrogen activity, as well as by epidemiologic studies in Sweden and Great Britain, where rates of heart attack and stroke in pill users remain as high as they were when pills contained high doses of estrogen.
Chihal, H J; Peppler, R D; Dickey, R P
The estrogen potencies of 9 oral contraceptive pills, Enovid-E, Enovid-5, Ovulen, Demulen, Norinyl+80, Norinyl+50, Ovral, Norlestrin 1 mg. and Norlestrin 2.5 mg., were determined by bioassay. Relative estrogen potency was determined by analysis of variance. Enovid-5, the most estrogenic compound, had a potency of 4.88 compared to ethinyl estradiol, 50 mcg. equal 1.00; Ovral, the least estrogenic compound, had a potency of 0.81, a sixfold difference. Estrogen potencies at a fractional dose of 0.00155 correlate with reports of the incidence of minor side effects and thromboembolic disease. The effect of progestins on estrogen potency was purely additive (norgestrel and norethynodrel), purely antagonistic, or additive at low concentrations and antagonistic at high concentrations (norethindrone, norethindrone acetate, and ethynodiol diacetate). These results suggest that pills with a greater margin of safety might be developed by utilizing greater ratios of progestin to estrogen. In addition, differences in relative estrogen potency of oral contraceptive pills may be used as a basis for better clinical selection.
Jayaraman, Anusha; Pike, Christian J
Progesterone and other progestagens are used in combination with estrogens for clinical purposes, including contraception and postmenopausal hormone therapy. Progesterone and estrogens have interactive effects in brain, however interactions between synthetic progestagens and 17β-estradiol (E2) in neurons are not well understood. In this study, we investigated the effects of seven clinically relevant progestagens on estrogen receptor (ER) mRNA expression, E2-induced neuroprotection, and E2-induced BDNF mRNA expression. We found that medroxyprogesterone acetate decreased both ERα and ERβ expression and blocked E2-mediated neuroprotection and BDNF expression. Conversely, levonorgestrel and nesterone increased ERα and or ERβ expression, were neuroprotective, and failed to attenuate E2-mediated increases in neuron survival and BDNF expression. Other progestagens tested, including norethindrone, norethindrone acetate, norethynodrel, and norgestimate, had variable effects on the measured endpoints. Our results demonstrate a range of qualitatively different actions of progestagens in cultured neurons, suggesting significant variability in the neural effects of clinically utilized progestagens.
Kistner, R W
Infertility has a 30-40% incidence in women with endometriosis. However, conservative surgical procedures can result in pregnancy for 40-90% of these patients. The pregnancy rate is influenced by 5 factors: 1) extent of the disease, 2) age, 3) history of previous surgery for endometriosis, 4) duration of infertility before surgery, and 5) length of postsurgical follow-up. The factor responsible for infertility among women with endometriosis is believed to be an inadequacy of the tubo-ovarian motility secondary to fibrosis and scarring, which results in imperfect ovum acceptance by the fimbriae. Therapy encompasses 4 approaches: 1) prophylaxis, 2) observation and analgesia, 3) suppression of ovulation, and 4) surgical treatment. Pregnancy is suggested as the optimal prophylactic treatment for endometriosis since the symptoms and signs regress during gestation and for varying periods thereafter. This regression is probably due to a combination of anovulation and amenorrhea caused by adenohypophyseal suppression. It may also be due to a transformation of functioning endometriotic tissue into decidua by increasing levels of chorionic estrogen and progesterone. If pregnancy is not desired, anovulation can be secured by the administration of sex hormones. Pseudopregnancy for 6 months, induced by norgestrel plus ethinyl estradiol or norethynodrel plus mestranol, can lead to pregnancy in 50% of patients whose only abnormality is surface ovarian endometriosis within 1 year of cessation of therapy. Short periods of pseudopregnancy are also advocated after conservative surgery if all areas of endometriosis cannot be excised. 40-50% of these patients can expect to become pregnant within 24 months. The incidence of postoperative tubo-ovarian adhesions may be diminished by use of dexamethasone and promethazine.
Assessment of a robust model protocol with accelerated throughput for a human recombinant full length estrogen receptor-alpha binding assay: protocol optimization and intralaboratory assay performance as initial steps towards validation.
Freyberger, Alexius; Wilson, Vickie; Weimer, Marc; Tan, Shirlee; Tran, Hoai-Son; Ahr, Hans-Jürgen
Despite about two decades of research in the field of endocrine active compounds, still no validated human recombinant (hr) estrogen receptor-alpha (ERalpha) binding assay is available, although hr-ERalpha is available from several sources. In a joint effort, US EPA and Bayer Schering Pharma with funding from the EU-sponsored 6th framework project, ReProTect, developed a model protocol for such a binding assay. Important features of this assay are the use of a full length hr-ERalpha and performance in a 96-well plate format. A full length hr-ERalpha was chosen, as it was considered to provide the most accurate and human-relevant results, whereas truncated receptors could perform differently. Besides three reference compounds [17beta-estradiol, norethynodrel, dibutylphthalate] nine test compounds with different affinities for the ERalpha [diethylstilbestrol (DES), ethynylestradiol, meso-hexestrol, equol, genistein, o,p'-DDT, nonylphenol, n-butylparaben, and corticosterone] were used to explore the performance of the assay. Three independent experiments per compound were performed on different days, and dilutions of test compounds from deep-frozen stocks, solutions of radiolabeled ligand and receptor preparation were freshly prepared for each experiment. The ERalpha binding properties of reference and test compounds were well detected. As expected dibutylphthalate and corticosterone were non-binders in this assay. In terms of the relative ranking of binding affinities, there was good agreement with published data obtained from experiments using a human recombinant ERalpha ligand binding domain. Irrespective of the chemical nature of the compound, individual IC(50)-values for a given compound varied by not more than a factor of 2.5. Our data demonstrate that the assay was robust and reliably ranked compounds with strong, weak, and no affinity for the ERalpha with high accuracy. It avoids the manipulation and use of animals, i.e., the preparation of uterine cytosol as