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.
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
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.
Barron, A L; Pasley, J N; Rank, R G; White, H J; Mrak, R E
Female guinea pigs were given daily doses of a combination of oral contraceptive (OC) agents, consisting of mestranol and norethynodrel suspended in sesame oil or distilled H2O, and were infected in the genital tract with the chlamydial agent of guinea pig inclusion conjunctivitis (GPIC). Counts of chlamydial inclusions in cells of vaginal smears collected during infection, showed prolongation and enhancement of infection in OC-treated animals as compared with controls. Appearance of IgG and IgA antibodies to GPIC in genital secretions, as determined by enzyme-linked immunosorbent assay (ELISA), was also delayed in OC-treated animals as compared with controls. OC-treated infected animals were killed on days 15 and 43, and gross pathological evidence for ascending infection culminating in salpingitis was found in all of five and four of five animals, respectively. On the other hand, among untreated infected controls on each sacrifice day, only one of five animals had any evidence for ascending infection. Chlamydiae were detected by light and electron microscopy in fallopian tube tissue collected on day 15 following OC-treatment but not in tissue from control animals.
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.
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.
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.