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PubMed1988

Lipid and lipoprotein changes associated with oral contraceptive use: a randomized clinical trial.

To determine the effects of oral contraceptives on lipids and lipoproteins over a six-month period, we randomized 266 women into four oral contraceptive groups: ethinyl estradiol 35 micrograms plus ethynodiol diacetate 1 mg, ethinyl estradiol 30 micrograms plus levonorgestrel 0.15 mg, ethinyl estradiol 35 micrograms plus norethindrone 1 mg, and ethinyl estradiol 35 micrograms plus norethindrone 0.5 and 1 mg (biphasic). For all groups, total cholesterol increased 5.9-9.1% from baseline values over the six months. Triglycerides increased with all preparations, with the ethynodiol diacetate group (37.6%) and the biphasic norethindrone group (45.3%) showing the greatest increase. Low-density lipoprotein cholesterol increased 10-15.6% among the groups; low-density lipoprotein-apolipoprotein B changed proportional to the low-density lipoprotein cholesterol increases. All groups except the ethynodiol diacetate group showed a decrease of high-density lipoprotein cholesterol, with the levonorgestrel group (8.7%) and biphasic norethindrone group (4.5%) showing the largest declines. Apolipoprotein A-1 increased in all groups, with the ethynodiol diacetate preparation (19.3%) showing the greatest increase and the levonorgestrel preparation (3.2%) showing the smallest increase from baseline values. The changes in apolipoprotein A-1 were out of proportion to the changes in high-density lipoprotein cholesterol, suggesting that the high-density lipoprotein particle may be undergoing some type of metabolic alteration.

Adult↗
PubMed1983

Effect of oral contraception by progesterone pill on lipids and glucose metabolism.

The influence of oral contraception with 0.5 mg ethynodiol diacetate (Femulen) on blood lipid and glucose tolerance test (GTT) was studied in a group of 14 nulliparous women ages 17-24 years before and 3 months after treatment. In another group of 13 women of matched age, contraception was managed by providing a combined pill (estrogen and progesterone). The continuous treatment of ethynodiol diacetate did not result in the increase in serum cholesterol and triglyceride levels and did not affect the GTT, as observed when the combined pill was administered. Femulen had no side effects, except for 2 cases of vaginal spotting. Ethynodiol diacetate does not induce the decrease in high-density lipoprotein cholesterol levels which is an anti-risk factor for the prevention of accelerated atherosclerotic disease. Oral contraception with this pill is indicated for all women, especially when there is an absolute contraindication for the use of combined pills

Biology↗
PubMedDate not supplied

The effect of progestogens on vaginal cytology.

Various progestogens were given to postmenopausal and premenopausal women. The first group consisted of 46 postmenopausal patients and in the postmenopausal atrophic smear, 17 acetoxyprogestogens produced no effect. However, the administration of two 19 nortestosterone derivatives, ethynodiol diacetate and norethisterone increased the Karyopyknotic Index and degree of proliferation of the epithelium, presumably due to their estrogenic metabolites. Low grade hypotrophic smears, consisting of parabasal and intermediate cells, reacted by a decrease in the size of the intermediate cells associated with clumping, and a disappearance from the smear of parabasal cells. In the case of ethynodiol diacetate, its estrogenic effect of elevating the Karyopyknotic Index occurred before the progestogenic effect of clumping and fusing of the intermediate cells. The second group consisted of 370 women using an oral form of sequential contraception, based on administration of 0.05 mg ethinyl estradiol daily for three weeks followed by a combined oral contraceptive containing the same amount of estrogen with varying progestogens for a further week. The anti-estrogenic effect of the various progestogens was then compared by their ability to lower the Karyopyknotic Index. This levelled out after four or five tablets. The most potent progestogen was d-norgestrel in the lowest dose of 0.25 mg and this compound exerted a greater effect than 4 mg norethisterone, 1 mg ethynodiol diacetate or 4 mg megestrol acetate.

Adolescent↗
PubMed1978

Intravenous glucose tolerance after 18 months on progestogen or combination-type oral contraceptive.

The effect of long-term use of different oral contraceptives compounds was evaluated in two groups of 36 normal women on the basis of blood glucose and plasma insulin changes measured during i.v. glucose tolerance tests. Progestogen (ethynodiol diacetate) alone or a combination-type steroid compound (norethynodrel-mestranol) were used. After 18 months of ethynodiol diacetate therapy, a mild though obvious diabetogenic effect similar to that seen with norethynodrel-mestranol was observed.

Adult↗
PubMed1977

Contribution of functional groups of 19-nor-progestogens to binding to progesterone and estradiol-17beta receptors in rabbit uterus.

The structural elements of 19-norprogestogens which may be essential for binding to progesterone and estradiol-17beta(E2) receptors were investigated in the rabbit uterine cytosol. The kinetic study showed that 19-nor-progestogens are competitive inhibitors of progesterone-receptor (8S) binding and E2-receptor binding. The affinities of steroids for the progesterone receptor were as follows: norethindrone (Ki of 2.3 X 10(-9)M) greater than 5alpha-dihydronorethindrone greater than norethindrone acetate greater than lynestrenol greater than 17alpha-ethynyl-estra-4-ene-3beta, 17beta-diol greater than ethynodiol diacetate (Ki of 1.3 X 10(-7) M). The affinities of steroids for the E2 receptor were as follows: ethynodiol diacetate (Ki of 1.3 X 10(-7)M) greater than 17alpha-ethynyl-estra-4-ene-3beta, 17beta-diol greater than norethindrone acetate greater than norethindrone greater than 5alpha-dihydronorethindrone greater than lynestrenol (Ki of 8.4 X 10(-7)M). The results indicate that 3-ketone and 17beta-hydroxyl groups, and the plane of ring A/B of 19-norprogestogen are important for binding to the progesterone receptor. The affinities of 19-nor-progestogens for the E2 receptor were very weak. Their affinities for the E2 receptor increased with addition of acetate or hydroxyl groups at the 3beta and 17beta positions, and were decreased by the elimination of a 3 oxygen function or the reduction of ring A.

Animals↗
PubMed1983

A randomized prospective study of the metabolic effects of four low-estrogen oral contraceptives.

Healthy, nonsmoking, normotensive, well-motivated young women were assigned at random to one of four different commercial, low-estrogen oral contraceptives. Measurements of biochemical parameters were made on two blood specimens collected from fasting subjects late in the pretreatment cycle, then again late in each treatment cycle for 12 months. All the women assigned to one product (0.5 mg norethindrone + 35 micrograms ethinyl estradiol) dropped out of the study before the end of the fifth cycle, but discontinuations with the other three products were few. Though the numbers of subjects were small, the groups were closely matched, and most of the metabolic differences were statistically significant. Products containing ethynodiol diacetate and norethindrone were associated with increases in serum total cholesterol and triglycerides but decreases in high-density-lipoprotein-cholesterol. In contrast, the levonorgestrel-containing preparation produced significantly less of an effect on these tests. A similar pattern was seen with a range of blood coagulation and fibrinolytic factors. Minimal alterations were seen with the levonorgestrel preparation, whereas those containing norethindrone or ethynodiol diacetate showed marked increases in factors I, VII, VIII and X and plasminogen, associated with a decrease in antithrombin III. Differences in the metabolic impact of the various commercially available low-estrogen preparations, combined with their effects on intermenstrual bleeding, allow a choice of the progestogen component most suitable for general use.

Adolescent↗
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↗
PubMed1977

The effect of different regimens of oestrogens on the clotting and fibrinolytic system of the post-menopausal woman.

The effects of six different regimens of hormone replacement therapy on coagulation, fibrinolysis and platelet aggregation were sudied in 33 symptomatic, post-menopausal women. Studies were performed before and after 3 months of therapy in the six treatment groups, Premarin, Progynova, Harmogen, Serial 28, ethynodiol diacetate and a testosterone and oestradiol implant. No changes in any parameter were detected following administration of Premarin, Progynova or an implant of testosterone and oestradiol. Serial 28 produced a significant increase in plasminogen concentration and increased the extent of platelet aggregation in 0.5 micron adrenalin solution. Harmogen produced an increase in the extent of platelet aggregation in 1.0 micron adrenalin solution, but a decrease in the rate of platelet aggregation in 1.0 micron solution. Ethynodiol diacetate caused a significant decrease in the kaolin-cephalin clotting time but decreased the extent of platelet aggregation in 0.5 and 1.0 micron solutions of adrenalin. FDPs developed following therapy in 9 of the 33 patients. These were evenly distributed between the groups. No patients had any change in anti-Xa concentration, platelet count or platelet aggregation in thrombin.

Adult↗
PubMed1980

Oral contraceptives: effects on carbohydrate metabolism, insulin like activity and histology of the pancreas.

The effect of the combination type oral contraceptive and its estrogen (mestranol) and progesterone (ethynodiol diacetate) components on the intravenous glucose tolerance test (IVGTT), intravenous tolbutamide test (IVTT), serum insulin like activity (ILA) and morphology of beta cells of the pancreas was investigated in female rabbits. The combination produced impairment of glucose tolerance in all animals after 24 weeks treatment. Fifty percent of animals in the estrogen treated group and 33.3 percent of animals in the progesterone treated group developed impairment of glucose tolerance after 24 weeks. A reduction in the glucose response to IVTT was observed in all the animals following 24 weeks treatment with the combination, estrogen or progesterone. A significant decline in fasting serum ILA and post glucose ILA was observed in animals treated with the combination and estrogen. A small but consistent decline in the serum ILA was observed in animals treated with ethynodiol diacetate. A rise in serum FFA paralleled the abnormality of glucose tolerance. Morphological changes in the cytostructure of pancreatic islets in the form of degranulation and degeneration of cells were observed in the pancreas of animals treated with the combination, and to lesser extent in animals treated with estrogen and progesterone. These observations indicate that the disturbances in carbohydrate and lipid metabolism produced by oral contraceptives may be associated with damage to beta cells and low circulating insulin in rabbits.

Animals↗
PubMed1976

The metabolic fate of chlormadinone acetate in the baboon.

The metabolic fate of chlormadinone acetate (17alpha-acetoxy-6-chloro-4, 6-pregnadiene-3, 20-dione; CAP) was studied in intact and biliary fistula baboons. The steroid was labeled with 3H at position 1 and with 14C at the carboxyl moiety of the 17alpha-acetate, thus affording the opportunity to ascertain the loss of the 17alpha-acetoxy group and the fate of both labels. The averages of the radioactivity excreted, given as percentages of the amounts injected, and the standard deviations were as follows: In the urine of intact animals after 6 hours, 5.7 +/- 0.2% and 5.5 +/- 0.7% of the 3H and 14C were recovered, respectively. After 6 days, there was 17.5% of the 3H and 16.2% of the 14C in the urine plus 15.3% of the 3H and 16.4% of the 14C in the feces. In baboons with biliary fistulas, the total radioactivity excreted was 7.8 +/- 0.7% of the 3H and 11.6% of the 14C in the urine, and 30.9 +/- 4.4% of the 3H and 30.7% of the 14C in the bile after 6 hours. Glucosiduronates were the predominant conjugates in the urine and bile. The similarity in the urinary excretion of radioactivity in the first 6 hours in intact and biliary fistula animals, the relatively low excretion of radioactivity in the bile and after 6 days in the urine, and the low fecal excretion suggest that the metabolites of CAP are not involved in an extensive enterohepatic circulation in the baboon. Deacetylation of the 17alpha-acetate in CAP was detected in the early collection periods of the urine and bile and constituted a very small percentage of the injected compound. No significant oxygenation of CAP at position 1 was detected. The metabolism of CAP is discussed and compared to our previously reported data on the metabolism of progesterone, ethynodiol diacetate and medroxyprogesterone acetate and the data on other progestogens reported in the literature. It appears that the excretion of CAP is significantly slower in the baboon than that of the other progestogens. The amounts of glucosiduronates of CAP and/or its metabolites formed in vivo are less than those formed with the other progestogens. Also, the extent of deacetylation of the 17alpha-acetate of CAP is much less than that of the 3beta-acetate of ethynodiol diacetate.

Animals↗
PubMed1995

A changing pattern in the association of oral contraceptives and the different groups of congenital limb deficiencies.

A case-control study on different groups of isolated congenital limb deficiency was performed in a ten-year population-based and revised Hungarian data set. A higher rate of one contraceptive pill type with relatively high dose (ethynodiol diacetate 1.0 mg + ethinyloestradiol 0.05 mg) used in the periconceptional period was found in the mothers of cases with terminal transverse defect (adjusted relative odds 1.9 with 95% confidence interval of 1.1-3.4). This risk is minimised by the use of recent low-dose pills.

Abnormalities, Drug-Induced↗
PubMed2003

Chemical and analytical characterization of related organic impurities in drugs.

A system is proposed for the classification of related organic impurities in drugs and drug products including among others (separated and non-separated) intermediates, various kinds of by-products, among them products of different side reactions, epimeric/diastereomeric, enantiomeric impurities, impurities in natural products, and finally degradation products. Examples are taken mainly from the author's own experience and from among the named impurities in the European Pharmacopoeia with focus on impurities in hydrocortisone, prednisolone, enalapril maleate, lisinopril, ethynodiol diacetate, pipecuronium bromide, cimetidine, and ethynylsteroids. The methodological aspects of impurity profiling from the detection to the identification/structure elucidation and quantitative determination of impurities are briefly summarized.

Cimetidine↗
PubMed1978

An open assessment of a new low dose oestrogen combined oral contraceptive.

This was a multicentre general practitioner study using a new low dose oral contraceptive, Ovamin 30 (ethinyloestradiol 30 microgram, ethynodiol diacetate 2 mg). Results showed a pregnancy rate calculated as a Pearl Index of 0.4. An analysis of bleeding patterns showed consistently acceptable cycle control. From these results it would appear that Ovamin 30 is an effective and well tolerated low dose oral contraceptive preparation.

Contraceptives, Oral↗
PubMed1976

Evaluation of an oral contraceptive containing only progestogen.

In the results from this series ethynodiol diacetate ("Femulen") was found to be a reliable and acceptable oral contraceptive with a decreased risk of severe side-effects. A review of oral contraception (Jackson, 1973) supports the view that the progestogen-only pill has a useful part to play in modern oral contraception.

Adolescent↗
PubMed1991

Estimation of impurity profiles of drugs and related materials. Part VIII: Combined application of high-performance liquid chromatography and NMR spectroscopy in the impurity profiling of drugs.

The usefulness of the joint application of HPLC and NMR spectroscopy in drug impurity profiling is demonstrated by the following examples: (1) identification of Z and E isomers of 17 alpha-ethynyl-4-oestrene-3 beta, 17-diol-3-acetate-17-(3'-acetoxy-2'-butenoate) in ethynodiol diacetate; (2) identification of the p-tolyl analogue as the impurity of enalapril maleate; (3) identification and quantification of 2'-dehydro-pipecuronium bromide in pipecuronium bromide. The possibilities of utilizing NMR spectroscopy for the identification and quantification of the impurities with and without their isolation are discussed.

Androstane-3,17-diol↗
PubMed1975

Estrogen potency of oral contraceptive pills.

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.

Animals↗
PubMed1979

Pregnancy rate of a progestogen oral contraceptive.

The results of this survey show that 0.5 mg of ethynodiol diacetate (Femulen) is a reliable oral contraceptive with a pregnancy rate calculated by the Pearl Index of 0.52 per 100 women years. This is superior to the failure rates for both 0.075 mg dl norgestrel and 0.35mg norethisterone and approximates more closely with the claimed failure rates for combined oestrogen/progestogen preparations. There is no evidence which suggests that side effects occur with prolonged use of Femulen therapy.

Adult↗