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PubMed1985

Renin-angiotensin mechanisms in oral contraceptive hypertension in conscious rats.

Rats were placed on powdered chow containing either no additives (controls), mestranol (a synthetic estrogen), norethynodrel (a synthetic progestin), or both mestranol and norethynodrel. After 6 mo on these diets, catheters were placed in the carotid artery and jugular vein of each rat. An arterial blood sample was obtained for plasma renin activity (PRA), plasma renin concentration (PRC), and plasma renin substrate concentration (PRS). Mean arterial pressure was measured in each rat. The angiotensin II (ANG II) antagonist, [Sar1-Ile8]ANG II, was infused intravenously for 30 min while blood pressure was recorded. Rats treated with mestranol and/or norethynodrel had PRA and PRC values that were not different from the control rats; however, mestranol-treated rats and rats treated with mestranol plus norethynodrel had PRS values that were substantially (P less than 0.01) higher than the controls. Arterial pressures in rats treated with mestranol and with mestranol plus norethynodrel were significantly (P less than 0.01) elevated when compared with the controls and with the rats treated with norethynodrel alone. Infusion of the ANG II antagonist failed to alter arterial pressure in any of the groups of rats. These results indicated that, in the steroid combination found in the oral contraceptive Enovid, it is the estrogenic component that results in hypertension in this rat model. Also this study found no evidence that ANG II plays a role in maintaining the elevated arterial pressure following long-term treatment with mestranol in rats.

Angiotensin II↗
PubMed1983

Oral contraceptive steroids as promoters or complete carcinogens for liver in female Sprague-Dawley rats.

Published reports have described an increased incidence of adenomas and of hepatocellular carcinomas in livers of women with a history of long-term oral contraceptive use. Evidence derived from human and experimental animals suggests that oral contraceptive steroids may be liver tumor promoters. Experiments were designed to determine the initiating and/or promoting potential of two oral contraceptive steroids, namely mestranol and norethynodrel. The results show that: mestranol and norethynodrel can promote DEN-initiated hepatocarcinogenesis, as indicated by increased numbers of gamma-glutamyl transpeptidase-positive, putative preneoplastic lesions and by the appearance of carcinomas. Various synthetic estrogens fail to cause detectable levels of DNA damage in hepatocytes. Mestranol has weak, if any, initiating potential. Neither mestranol nor norethynodrel exhibits antiglucocorticoid activity. Mestranol and norethynodrel inhibit metabolic cooperation in V-79 Chinese hamster cells. Taken together, these results and those reported by others demonstrate that oral contraceptive steroids are relatively strong promoters of hepatocarcinogenesis and have little if any genotoxic effect.

Animals↗
PubMed1979

Tolerance of estrogen-treated rats to acute cold exposure.

Female rats treated chronically with ethynylestradiol (36 micrograms/kg per day) alone, and in combination with the progestational agent, norethynodrel (253 micrograms/kg per day), cooled significantly faster than controls when lightly restrained and exposed to air at 5 degrees C. Rate of cooling of rats given only norethynodrel was similar to that of the control group. In other studies, rate of oxygen consumption was determined for all groups during acute exposure to cold (14 degrees C). All estrogen-treated groups achieved the same maximal rate of oxygen consumption as control and norethynodrel-treated groups during cold exposure, but cooled significantly faster. Two groups of female rats were treated chronically with ethynylestradiol at two separate doses (36 and 61 micrograms/kg per day). An untreated group served as controls. Rate of oxygen consumption of all animals were measured during restraint and exposure to cold (18 degrees C). The estrogen-treated groups again achieved the same maximal rate of oxygen consumption as the control group, but also cooled significantly faster despite the fact that the cold stress was less severe than in the previous experiment. That estrogen-treated rats cooled faster than controls in both studies despite achieving a maximal rate of heat production which did not differ from controls suggests that reduced cold tolerance of estrogen-treated rats may be related to increased heat loss.

Animals↗
PubMed1992

The hormonal regulation of platelet-activating factor-acetylhydrolase in the rat.

Platelet-activating factor-acetylhydrolase (PAF-AH), the enzyme that inactivates PAF, is decreased in the plasma of both rabbits and humans during the latter stages of pregnancy. The activity of the enzyme was decreased in rats by the administration of 1,3,5(10)-estratrien-17 alpha-ethynyl-3,17 beta-diol (17 alpha-ethynylestradiol) and increased by dexamethasone treatment. In the present study, we have further defined the hormonal regulation of PAF-AH levels in plasma of adult and juvenile rats. Estrone (E1), 17 beta-estradiol (E2), estriol (E3), and various progestins [4-pregnen-6 alpha-methyl-17 alpha-ol-3,20-dione (medroxyprogesterone), 4-estren-17 alpha-ethynyl-17 beta-ol-3-one (norethindrone), and 5(10)-estren-17 alpha-ethynyl-17 beta-ol-3-one (norethynodrel)] were administered to adult rats, and the plasma PAF-AH activities were assayed. E1, E2, and E3 administration to adult female rats lowered the plasma PAF-AH activity, E3 being the most effective. After administration of these estrogens the activity returned to the preinjection level within 4 days. The administration of medroxyprogesterone resulted in a 2-fold increase in plasma PAF-AH activity in adult female rats, and the activity remained elevated for up to 30 days. When adult male rats were treated with similar doses only a 20% increase was observed and the PAF-AH activity returned to control values by day 10. In contrast, norethindrone and norethynodrel administration resulted in a reduction of the enzyme activity in adult female rats. The plasma PAF-AH activity in juvenile male and female rats (3 weeks of age, 45-60 g body wt) was two times higher than that in adult rats of both sexes and spontaneously decreased up to the time of puberty. When juvenile male or female rats were injected with either 17 alpha-ethynylestradiol or medroxyprogesterone, a minimal change in PAF-AH activity was observed. In contrast, when dexamethasone was administered to juvenile male and female rats the plasma PAF-AH activity increased in a manner similar to adult animals. It is suggested that estrogens cause a decrease and medroxyprogesterone an increase in plasma PAF-AH activity. It is suggested that the different responsiveness to medroxyprogesterone between adult female and male rats and juvenile animals may depend on the concentration of the hormone receptor in the tissue responsible for the synthesis of PAF-AH. The decrease in PAF-AH activity after the administration of norethindrone and norethynodrel may be due to the known estrogenic activity of these steroids.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1976

Reduced beta adrenergic responsiveness in rats treated with estrogenic agents.

Chronic treatment with ethynyl estradiol alone (48-50 mug/kg/day) and in combination with several doses of norethynodrel either attenuated or prevented the increase in tail skin temperature accompanying sC. administration of isoproterenol (200 mug/kg b.wt.) to male and female rats. Dietary administration of an oral contraceptive containing norethynodrel and mestranol (7.5 mg/kg of food) was also accompanied by an attenuated response to isoproterenol. Attenuation of the tail skin temperature response was present in all groups after 3 to 5 weeks of treatment but was detectable in the oral contraceptive-treated group after 1 week of treatment. All steroids and combinations, except norethynodrel administered alone (154 mug/kg/day), reduced body weight gain.

Animals↗
PubMed1975

Effect of ethynodiol diacetate and combination--type oral contraceptive compounds on carbohydrate metabolism. I. Six month intravenous glucose tolerance study.

In order to evaluate long-term effects of different types of oral contraceptive compounds, blood glucose and plasma insulin levels were measured during an intravenous glucose tolerance test in 2 groups of normal, nondiabetic patients: 36 women using a progesterone-alone oral contraceptive, ethynodiol diacetate, and 36 women using a combination-type drug, containing norethynodrel and mestranol. Each patient was tested before and after 6 months of treatment. There were no significant differences from pre-treatment glucose and insulin values in the first group of women (on ethynodiol diacetate). In the second group (on norethynodrel and mestranol), there was a significant elevation of mean blood glucose levels at 15, 30 and 120 min of the glucose tolerance test. Nevertheless, a significant elevation of plasma insulin was seen only at 60 min of the test. Patients participating in this study will continue this treatment, and monitoring of carbohydrate metabolism is contemplated over a period of several years.

Adult↗
PubMed1985

Effect of some synthetic steroids on rat liver function.

Norethynodrel proved to have moderately potent effects on hepatic function in female rats. It causes (a) loss of body mass, (b) increase in the relative liver mass, (c) rise in the protein content of liver, (d) increase in the cytochrome P-450 level, (e) reduction in the length of pentobarbital-induced sleep, and (f) increase in the rate of biotransformation of (i) aniline and (ii) aminopyrine. In contrast, ethynyl estradiol was shown to have little or no effect as judged by the same criteria, but, like norethynodrel, progesterone and estradiol, caused loss of body mass.

Aminopyrine N-Demethylase↗
PubMed1983

Enhancement of mutagenic activity in Salmonella by contraceptive steroids.

Two oral contraceptive steroids, mestranol and norethynodrel, were evaluated for mutagenicity in the Salmonella histidine reversion assay. The pure forms of the hormones were not mutagenic when tested with either missense (TA1535, TA100) or frameshift (TA98, TA1538, TA1537) strains. In vitro activation of the hormones with liver homogenates from rats induced either with phenobarbital or Aroclor did not influence these results. However, mestranol was capable of enhancing the mutation yield obtained by an ineffective subthreshold dose of 2-acetylaminofluorene. Dimethyl sulfoxide extracts of two contraceptive pills, Ovulen-21 (containing mestranol) or Enovid-E (containing mestranol or norethynodrel), also were nonmutagenic. But again, both these extracts were capable of enhancing the mutation yield induced with an ineffective dosage of 2-acetylaminofluorene and N-nitrosopiperidine. These studies point to the possible promotional effect and subsequent potential hazard to the female consumers who use these hormones as a means of pregnancy control.

Contraceptives, Oral↗
PubMed1983

Further characterization of estrogen receptors in the human oviduct.

Estrogen binding in human oviducts was studied in vitro by the dextran-coated charcoal assay and sucrose density ultracentrifugation. Estrogen binds with high affinity and limited capacity to cytosol of the human oviduct. The concentration of competitive inhibitors to produce 50% reduction in estrogen binding was 8 x 10(-8) M for the antiestrogen CI-628, 8 x 10(-7) M for the progestogen norethynodrel, and 3 x 10(-6) M for the testosterone derivative danazol at the ligand concentration of 1 nM estradiol. Nuclear estrogen binding was not inhibited by a 100-fold excess of progesterone or by a 10-fold excess of norethynodrel. Estrogen-binding protein with a sedimentation coefficient of 4S was seen in oviductal cytosol of all three anatomic segments. The nuclear 4S peak of estrogen binding was demonstrated in the ampullary tubal segment.

Binding, Competitive↗
PubMed1977

Comparative metabolism of 17alpha-ethynyl steroids used in oral contraceptives.

The metabolism of mestranol, ethynylestradiol, norethynodrel, norethindrone, ethynodiol diacetate, lynestrenol, and norgestrel is reviewed. The estrogenic components of the oral contraceptives, mestranol or ethynylestradiol, have nearly identical metabolic pathways since mestranol is rapidly and almost completely converted to ethynylestradiol The major fraction of the drugs plus metabolites is excreted in the urine as conjugated materials. All of the 17beta-ethynyl progestins reviewed follow similar metabolic paths. For three of these, norethynodrel, ethynodiol diacetate and lynestrenol, a principal metabolite is norethindrone. Biotransformation to more polar metabolites and conjugation proceed rapidly for these three precursor drugs and norethindrone. Norgestrel follows metabolic paths similar to those of norethindrone. However, the ethyl moiety at the C-13 position appears to slow the metabolism of this steroid so that biotransformation to more polar metabolites and the conjugation of these steroids does not proceed as rapidly as that of the other progestins. The high progestational potency of norgestrel may be attributed to this slow rate of biotransformation. Some of the pharmacokinetic parameters derived from the research reports reviewed here are summarized. The compounds appear to be readily absorbed, and they and their metabolites are excreted to a greater extent in the urine than in the feces.

Animals↗
PubMed1976

Effects of contraceptive agents on drug metabolism in various animal species.

The effect on liver microsomal enzyme activity of three steroid contraceptive drug (SCD) combinations was compared in rats, mice and guinea-pigs. Lynestrenol plus mestranol, norethisterone plus mestranol and norethynodrel plus mestranol were given orally for 4 consecutive days (acute treatment) or 30 days (chronic treatment) at various doses eliciting an experimentally controlled antifertility activity which varied in its extent. In rats and mice all the combined treatments (with the exception of norethynodrel plus mestranol in mice) were active as inducers of liver microsomal enzymes. This induction seems to be mediated mainly by the progestogenic compounds. Oestrogens showed a very poor effect bordering on significance only in a few cases. No effect on liver microsomal protein or cytochrome P 450 concentration was obtained after treatment with doses capable of increasing the microsomal enzyme activity. The activity of the liver microsomal enzymes did not appear to be reduced immediately (2 h) after the last administration of the SCD given during 4 or 30 days. Contraceptive treatments at doses capable of eliciting complete antifertility activity were inactive on liver microsomal enzyme activity in guinea-pigs.

Animals↗
PubMed2005

Stereoselectivity in metabolic 3-reduction of tibolone in healthy Chinese female volunteers.

AIM: To investigate the stereoselectivity in human metabolic 3-reduction of tibolone. METHODS: Twenty healthy Chinese female volunteers were given a single oral dose of tibolone (2.5 mg), and serial blood samples were collected after treatment. The plasma concentrations of the two pharmacologically active 3-hydroxyl metabolites of tibolone, 3alpha-hydroxyl-7-methyl- norethynodrel (3alpha-HMN) and 3beta-hydroxyl-7-methyl- norethynodrel (3beta-HMN) in plasma were determined by using a validated liquid chromatography-mass spectrometry (LC-MS) method. RESULTS: The apparent elimination half-life (T(1/2) of 3alpha-HMN was 1.43+/-0.52 h, and that of 3beta-HMN was 1.53+/-0.60 h. Maximum plasma concentrations (C(max)) were found to be 8.75+/-4.36 microg/L for 3alpha-HMN and 3.59+/-1.81 microg/L for 3beta-HMN. Areas under the plasma concentration versus time curve (AUC(0-t)) were 26.30+/-12.14 microg.h(-1).L(-1) for 3alpha-HMN and 9.89+/-4.93 microg.h(-1).L(-1) for 3beta-HMN. CONCLUSION: Stereo-selective differences exist in the pharmacokinetics of tibolone metabolism in humans.

Administration, Oral↗
PubMed1978

The metabolism and motility of human spermatozoa in the presence of steroid hormones and synthetic progestagens.

The metabolism and motility of human ejaculated spermatozoa incubated in vitro with steroids were studied. Progesterone and norethynodrel depressed the respiration, glycolytic metabolism and the motility of washed spermatozoa. Lynoestrenol did not affect the respiration or glycolysis of the spermatozoa, but did inhibit motility. Oestradiol did not cause any consistent alteration of the sperm metabolism, and did not affect the motility. Progesterone and norethynodrel appeared to act on the plasma membrane of human spermatozoa to increase its permeability and hence to facilitate the loss of essential cofactors required for the glycolytic and oxidative processes.

Energy Metabolism↗