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PubMed1976

Oral contraceptives, norethindrone and mestranol: effects on tissue levels of minerals.

The study involved three levels of dietary zinc (deficient, marginal, and adequate) and four hormonal conditions; namely, no steriods, norethindrone, mestranol, and norethindrone plus mestranol. The steroids were incorporated into diets and fed to 11-wk-old female Sprague-Dawley rats. After 10 wk of treatment, various tissues were excised for mineral assays by atomic-absorption spectrophotometry. Both steroids, reduced weight gain. Mestranol depressed plasma zinc, tibia copper and magnesium, and liver iron, but elevated the zinc levels in liver and erythrocytes, plasma copper, liver magnesium and calcium, and iron content of tibia and heart. In general, the effect was most prominent with adequate zinc but diminished in magnitude with the reduction of zinc intake. In addition, norethindrone increased heart iron and tibia calcium. Mestranol appeared to be the main causative factor and may have induced a possible shift of minerals from one pool to another. As expected, zinc deficiency resulted in the reduction of zinc concentrations of plasma, tibia, kidney, and pancreas, and the elevation of copper, iron, magnesium, and calcium concentrations of various tissues.

Animals↗
PubMed1975

Colorimetric determination of mestranol in combination with ethynodiol diacetate.

Mestranol in combination with ethynodiol diacetate, an oral contraceptive formulation, is isolated from the sample on a partition chromatographic column prior to colorimetric determination. The color reaction which is specific for estrogens is formed by shaking an aliquot of the heptane eluate of mestranol with a 30% methanol-sulfuric acid solution. A collaborative study of the method gave results of 99.8% of added mestranol for the simulated mix and 100.7% of labelled mestranol for the commercial tablet. The method has been adopted as official first aciton.

Chemical Phenomena↗
PubMedDate not supplied

The influence of mestranol and chlormadinone given separately or in combination on the effects evoked by a high-fat diet in female rabbits.

The effect of mestranol and chlormadinone, the hormones contained in oral contraceptives: on lipid metabolism, some hemostatic parameters and on morphology of aorta, liver and heart was tested after separate or combined administration to mongrel female rabbits fed on a normal or high-fat diet (HFD). HFD administration led to typical atheromatous changes in the aortal intima. The hormones given together with HFD attenuated the augmentation of lipid serum level and the extent of atheromatous plaques in the intima. The percent content of alpha-lipoproteins was significantly lower in groups receiving HFD with or without the hormones than in the controls, but it was higher than in controls in the rabbits receiving the hormones alone. Chlormadinone given together with HFD potentiated atheromatous aortal changes, which occurred not only in the intima but also in the media. Mestranol given together with HFD significantly counteracted the development of atheromatous changes. Female rabbits receiving mestranol and chlormadinone displayed a significant increase in fibrinogen content, while those receiving mestranol showed an increased time of fibrinolysis. HFD produced a hepatic damage, which was augmented in rabbits concomitantly receiving the hormones. The hormones alone also displayed some, a less pronounced hepatotoxic action.

Animals↗
PubMed1994

Effect of mestranol on pharmacokinetics of paracetamol.

The aim of this study was to investigate the effect of mestranol on pharmacokinetics of paracetamol. The study was carried out on 20 female rabbits. Paracetamol was administered to rabbits intragastrically at a dose of 50 mg/kg b.w. One group of animals was given mestranol intragastrically 0.1 mg once daily during 2 months. The method of Routh A. et al. was used to paracetamol concentration assay. Blood for the assays was collected within 24 hours after drug administration, prior to the study as well as 1 month and 2 months after continuous mestranol administration. The two compartment open model was used for calculations. The study revealed an increase in AUC and paracetamol half-life as well as decrease in the total body clearance. We conclude that there is an interaction between mestranol and paracetamol leading to a decrease in total body paracetamol clearance.

Acetaminophen↗
PubMed1990

Pharmacokinetics of ethinyl estradiol and mestranol.

Pharmacokinetally, a 50 micrograms oral dose of mestranol (which itself is inactive) is bioequivalent to a 35 micrograms dose of ethinyl estradiol. Physiologically, mestranol ranges from 50% to 100% of the activity of ethinyl estradiol, depending on the endpoint chosen. Compounds such as these, which are metabolized with a first-pass effect and are enterohepatically recirculated, demonstrate large interindividual and intraindividual variability in their pharmacokinetics. Thus a given dose of ethinyl estradiol in one person may produce an effect equivalent to a substantially larger (or smaller) dose in another person. This wide variability confounds efforts to establish tight dose-response relationships, a point rarely considered in clinical or epidemiologic studies of these compounds. The circulating levels of ethinyl estradiol sulfates may be higher than those of free ethinyl estradiol itself. It has been thought that these sulfates represent a "reservoir" of ethinyl estradiol. Our studies show that this idea is untenable because the half-life of the sulfates is not long enough for such an effect. Differences in the pharmacokinetics of ethinyl estradiol and mestranol have been observed in studies of various populations. The reality of these group differences is affirmed by analyses of urinary metabolite patterns.

Biological Availability↗
PubMed1975

Metabolism of 2-3H- and 4-14C-17alpha-ethynylestradiol 3-methyl ether (mestranol) by women.

A mixture of 2-3H and 4-14C-mestranol was administered orally to five women and 2-3H-mestranol alone to one woman. Reactions involving position 2 were extensive as judged by liberation of 3H into body water (14-45% of the dose). 17alpha-Ethynylestradiol, 2-hydroxy-17alpha-ethynylestradiol, 2-methoxy-17alpha-ethynylestradiol, 2-hydroxy-17alpha-ethynylestradiol 3-methyl ether and 16geta-hydroxy-17alpha-ethynylestradiol were measured in the "glucuronide" and pH1 fractions and mestranol, D-homoestrone-17a and D-homoestradiol-17abeta were also measured in the "glucuronide" fraction frum the urine to two of the women by reverse isotope dilution. Radioactive 2-methoxyestradiol accounted for less than 0.011% of the 14C dose in the "glucuronide" fraction of one of the women, consistent with the extent of de-ethynylation previously reported (Steroids, 25, 343 (1975).

Adult↗
PubMed1993

Arterial sodium concentration in rats with hypertension induced by mestranol.

Rats were made hypertensive by the oral ingestion of mestranol for 6 months. Carotid arteries from these hypertensive rats and from control rats were incubated in an extract of plasma from these rats, which contained 24Na and 14C-sucrose (an extracellular fluid marker). After sufficient time for equilibration, the vessels were removed and counted for 24Na; an aliquot of the incubation fluid was also counted for 24Na. At least 7 days later, after the 24Na had decayed away, the samples were counted for 14C-sucrose. By knowing the specific activity of the 24Na and the ratio of 24Na/14C in the bathing fluid, the amount of intracellular Na could be calculated for each carotid artery. The total protein content of each vessel was determined, and the results were expressed as nEq of Na per mg of vessel. The Na content of carotids from mestranol treated rats averaged 135 +/- 11 (SEM) while the carotids from the control rats averaged 125 +/- 8 nEq/mg protein. Because these values were not significantly different, this study provided no evidence that increases in arterial Na content contributed to the hypertension associated with the ingestion of mestranol in this rat model.

Animals↗
PubMed1977

The influence of thiamin deficiency on the metabolism of the oral contraceptive mestranol [3-methoxy-17-ethynyl-1,3,5(10)-estratrien-17 beta-o1] by female rat liver enzymes.

Hepatic microsomes from female rats fed a thiamin deficient diet for three weeks had approximately three times the capacity to metabolize mestranol as microsomes from similar rats fed a diet rich in thiamin. The incremental addition of thiamin to the diet depressed mestranol O-demethylation, NADPH cytochrome c reductase, and cytochrome P-450 content in a dose related manner up to 2 microgram thiamin per gram of feed. Pair-feeding experiments indicate that thiamin ingestion is responsible for the depression of mestranol O-demethylation and NADPH cytochrome c reductase activity while carbodhydrate ingestion is responsible for the decrease in cytochrome P-450. The absorbance spectra generated by the binding of ethylisocyanide to microsomes yield data which suggest that there are no qualitative alterations in cytochrome P-450 due to diet.

Animals↗
PubMed1977

Influence of rifampicin treatment on the metabolic fate of [4-14C] mestranol in women.

[4-14C] Mestranol was administered to 2 rifampicin treated and to 3 untreated hysterectomised women with normal liver functions. The urinary excretions of mestranol, ethynylestradiol, 2-hydroxy-ethynylestradiol and of the total radioactivity were measured within the following 5 days. After this period the total urinary excretion of radioactivity amounted to approx. 43% (38%-50%) of the administered dose and no difference was found for the rifampicin treated and untreated women. Moreover, in the urines of both of these groups the same amounts of radioactive mestranol (1.1%-6.3% of the urinary radioactivity) and 2-hydroxy-ethynylestradiol (0.9%-3.9% of the urinary radioactivity) were measured. In contrast, the urinary excretion of ethynyl-estradiol was definitely lower in the rifampicin treated women (3.5% and 4.9% of the urinary radioactivity) as compared to the control group (15%-23%).

Adult↗
PubMed1980

Properties of the estrogen receptor in the human oviduct and its interaction with ethinylestradiol and mestranol in vitro.

Biochemical properties of estrogen binding are investigated in the cytosol and nuclear fractions of the human Fallopian tube. Sucrose density ultracentrifugation and dextrancoated charcoal adsorption techniques are used for characterization of [3H]estradiol uptake in the human oviduct. There is indirect evidence for the presence of protease which can be inhibited by diisopropylfluorophosphate (DFP). When DFP is present in buffer of low ionic strength, the cytosol receptor sediments at 8S and 4S peaks. In the absence of DFP, the 4S peak alone is demonstrated. The proteolytic inhibitor does not alter the estrogen-binding capacity in the human oviduct. The dissociation constant (Kd) for [3H]estradiol in cytosol is 2 X 10(-10) M without DFP and 1.5 X 10(-10) M with DFP. The presence of protease in cytosol of human oviducts is confirmed by hydrolysis of benzoyl-arginine nitroanalide. The enzymatic activity is inhibited by DFP. Nuclear estrogen receptor sediments at 4S after extraction with 0.4 M KCL buffer. A rapid nuclear accumulation of [-3H]estradiol is seen at 25 C, with reciprocal depletion of cytoplasmic receptor in human oviduct tissue minces. The synthetic estrogens ethinylestradiol (17 alpha-ethynyl-1,3,5-estratriene-3,17 beta-diol) and mestranol [3-methoxy-17 alpha-ethinyl-1,3-5(10)-estratiene-17 beta-OL] are competitors for the estrogen receptor in the human Fallopian tube. Inhibition of oviductal estrogen binding is 500 times greater with ethinylestradiol than with mestranol (ki = 0.75 X 10(-9) M for ethinylestradiol; Ki = 3.74 X 10(-7) M for mestranol). The estrogen receptor in the human Fallopian tube shows properties similar to those of the estrogen receptor of the human uterus. However, the determination of the number of binding sites in the oviduct is not influenced by proteolytic enzyme activity.

Adult↗
PubMed1987

Effects of prenatal administration of mestranol and two progestins on testosterone synthesis and reproductive tract development in male rats.

The oestrogen mestranol (0, 0.01, 0.1 mg/kg body weight per day) and the progestins medroxyprogesterone-acetate and norethisterone (0, 2, 20 mg/kg body weight per day each) in sesame oil were intubated intragastrically daily during gestational days 14.5 through 19.5 to pregnant rats. Males were studied as 20.5-day-old foetuses and 4-month-old adults for serum testosterone and LH concentrations, in vitro testosterone synthesis, anogenital distance (foetuses only) and testes, seminal vesicle and ventral prostate weights. Administration of 0.1 mg mestranol decreased by 35 to 70% basal and LH-stimulated testosterone synthesis by both foetal and adult testes in vitro (P less than 0.01). Foetal body weights (P less than 0.05), but not anogenital distances, were significantly decreased. Testosterone content in adult sera was reduced significantly (P less than 0.05) to less than 50% of control. Testes, ventral prostate, seminal vesicle and epididymal weights were unaffected by treatment. Medroxyprogesterone acetate or norethisterone administration did not alter testes endocrine function in foetal or adult offspring. In a small number of rats, pregnant for 10.5, 14.5 or 18.5 days, [3H]ethinyloestradiol was intubated and foetal and placental tissue examined for appearance and content of radioactivity. Radioactivity was detected in 10.5, 14.5 and 18.5 days old placentas, and 14.5 and 18.5 days old foetal liver, gonads and external genitalia. With [3H]medroxyprogesterone acetate, radioactivity was localized in 14.5 day placenta and foetal tissues. Thin-layer chromatographic analysis showed most of the activity to migrate as authentic ethinyloestradiol or medroxyprogesterone acetate. These results demonstrate inhibition of testicular testosterone synthesis by mestranol, presumably by being transferred across the placenta and acting in the foetus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

Metabolism of oral contraceptive drugs. The formation and disappearance of metabolites of norethindrone and mestranol after intravenous and oral administration.

Previous studies from this laboratory reported that 3H-labeled metabolites with half-lives of more than 24 hours may remain in the plasmaa of women receiving an intravenous injection of 3H norethindrone or 3H mestranol. To confirm the presence of these metabolites, blood samples were collected for five days after injection of 3H norethindrone or 3H mestranol; 3H representing metabolites of norethindrone disappeared with half-life values of 42 to 84 hours (mean 67 hours), while 3H representing metabolites of mestranol declined with an average half-life of 45 hours (range 37 to 65 hours). When the 3H-labeled drugs were administered orally, metabolites of similar half-life were formed. Because these compounds exist for several days after a single administration and since oral contraceptive drugs are normally taken daily, the possiblity of the accumulation of 3H in the plasm of women receiving several consecutive doses of 3H norethindrone was investigated. The results of this study show a stepwise accumulation of the 3H metabolites when 3H norethindrone was administered in six daily oral doses. However, the 3H levels declined from the peak on the sixth and last day of the treatment at a rate equivalent to those previously measured after intravenous or oral administration.

Administration, Oral↗
PubMed1975

Radioimmunoassay of unconjugated plasma ethynylestradiol in women given a single oral dose of ethynylestradiol or mestranol.

A method for the radioimmunoassay of ethynylestradiol in plasma is described. The sensitivity is 18 pg/ml, recovery 86.5%, and precision 10.9% (coefficient of variation). Normal women, five at each dose level, were given 50 or 80 mug ethynylestradiol or 50, 80, or 100 mug mestranol of uniform bioavailability. Peak plasma levels were consistently obtained in the 1-hour plasma sample with the former compound. With mestranol, the peak levels of ethynylestradiol were lower than with the same quantity of ethynylestradiol and the time-curve of plasma levels much more variable. With this procedure, it is now possible to study certain aspects of the pharmacokinetics of these clinically important compounds.

Administration, Oral↗
PubMed1977

Comparison of ethinylestradiol and mestranol in sequential-type oral contraceptives in their effects on blood glucose and serum insulin in oral glucose tolerance tests.

Forty 3-hour oral glucose tolerance tests (OGTTs) were performed in 10 assumedly healthy female volunteers 19 to 30 years old, each serving four times as her own control. Each subject was taking a sequential type oral contraceptive containing either 50 microgram of ethinylestradiol or 80 microgram of mestranol alternatingly in four consecutive treatment cycles. The OGTTs were performed on the 6th day of each cycle, during pure estrogen medication. Blood glucose and serum insulin values did not differ significantly under either estrogen as tested by the t-test for paired observations. Our results do not support the findings of others that mestranol has a more pronounced or even exclusively adverse effect on glucose tolerance as compared with ethinylestradiol.

Adult↗
PubMed1981

Simple high-performance liquid chromatographic assay for norethindrone--mestranol in combination tablets.

A simple, sensitive, and specific high-performance liquid chromatographic procedure was developed to assay norethindrone--mestranol combination tablets. The method involves a chloroform extraction of a single pulverized tablet. After centrifugation, and aliquot of the supernate was injected into a modular high-performance liquid chromatograph. The effluent from the silica column was monitored serially with a fixed-wavelength UV detector (254 nm) for norethindrone quantitation and a fluorescence detector (230 nm for excitation and 280 nm cutoff filter for emission) for mestranol quantitation. Progesterone was used as an internal standard. The method was employed successfully in content uniformity studies of several brands of commercially available tablets.

Chromatography, High Pressure Liquid↗
PubMed1989

Hormone prevention of mammary carcinogenesis by norethynodrel-mestranol.

The observation that the susceptibility of the mammary gland to chemical carcinogenesis is inversely related to its level of hormonally induced differentiation led us to test whether treatment of virgin rats with an estrogenic-progestagenic hormone combination protected the gland against this carcinogenesis. Virgin Sprague-Dawley rats aged 45, 55, 65, or 75 days had implanted subcutaneously for 21 days a pellet containing norethynodrel-mestranol (NM) (98.5%-1.5%) at two doses, a physiological or low dose (LD) of 0.5 mg, equivalent to the dose used in Enovid for contraception in humans, and a pharmacological or high dose (HD) of 5.0 mg. Twenty-one days after NM pellet removal, the mammary glands of 5 animals per group were examined for the number of terminal end buds (TEBs), terminal ducts (TDs), alveolar buds (ABs) and lobules, and the DNA labeling index (DNA-LI). The remaining animals received 8 mg 7,12-dimethylbenz(a) anthracene (DMBA)/100 g body weight, and tumorigenesis was evaluated at 24 weeks. The percentage of TEBs decreased with age, and further with NM treatment at both doses. Treatment did not significantly modify the percentage of TDs, but increased that of ABs in most groups. The DNA-LI of TEBs remained constant, even during aging and after treatment, whereas both aging and treatment reduced DNA-LI in TDs and ABs. Tumor incidence declined with increasing age from 75% to 44% in the 45 and 75 day-old control groups respectively. Adenocarcinoma incidence followed the same trend. NM treatment had a dose-related protective effect against development of tumors in general and of adenocarcinomas in particular. LD treatment resulted in a marginally significant reduction in adenocarcinoma incidence, whereas HD-treated animals were 0.24 times as likely as controls to develop carcinomas. There was a statistically significant correlation between the percentage of TEBs present in the gland at the time of carcinogen administration and the incidence of adenocarcinomas. It was concluded that treatment of virgin rats with the hormone combination norethynodrel-mestranol resulted in long lasting structural changes in the mammary gland which protected this organ from a subsequent carcinogenic insult.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1975

Metabolism of 4-3-H- and 4-14-C-17alpha-ethynylestradiol 3-methyl ether (mestranol) by women.

A mixture of 4-3-H and 4-14-C-mestranol was administered orally to four women. Reactions involving position 4 were no greater than 1.7-3% of the dose as measured by liberation of 3-H into body water. The extent of de-ethynylation in vivo was no greater than 1-2% of the dose as measured by urinary estrone metabolites. Mestranol (0.7 and 0.32% of the dose), 17alpha-ethynylestradiol (6.6 and 11.3%) and 2-hydroxy-17alpha-ethynylestradiol (0.64 and 0.7%) were identified as metabolite aglycons by reverse isotope dilution after Ketodase hydrolysis of the urine from two of the women.

Administration, Oral↗
PubMed1985

Mestranol: the assignment of its 1H and 13C NMR spectra by means of two-dimensional NMR spectroscopy, and its photochemical decomposition.

The 1H- and 13C-nmr spectra of mestranol were assigned with the help of a 2 D-J-resolved, a 2D spin echo J-correlated (SECSY) and a 2D 1H-13C hetero-shift correlation experiment. The analysis of the spectra facilitated the identification of some of the photodecomposition products of mestranol. It was shown that, upon irradiation with UV-B light in water-ethanol (1:1, v/v), products are formed by oxidation of rings B and C of the steroid.

Carbon Isotopes↗