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Ovamin 30, a new low-dose oral contraceptive (OC) containing 30 mcg of ethinyl estradiol and 2 mg of ethynodiol diacetate, was evaluated for efficacy and acceptability in a group of women (504 patients; 3236 woman months of use) requesting OCs from their general practitioner. 39 patients withdrew from the study because of side effects which could reasonably be associated with the pill (excessive/irregular bleeding, amenorrhea, depression/headache, and breast discomfort/weight gain), and only 18 of these were menstrual disorders. 12 patients withdrew from the trial to conceive. 1 involuntary pregnancy occurred, and 58 patients were lost to follow-up. An early establishment of acceptable bleeding cycles was maintained in later cycles. The pregnancy rate for this preparation by the Pearl Index was .4/100 woman years with 95% confidence limits of .01-2.24. Ovamin 30 appeared to be an effective and well tolerated low-estrogen OC, and further studies may determine whether side effects are reduced with 30-mcg products as opposed to those containing 50 mcg of estrogen.
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PMID:An open assessment of a new low dose oestrogen combined oral contraceptive. 62 4

Recently there have been reports that long-term use of estrogen- containing oral contraceptives (OCs) can induce folic acid and vitamin B deficiency which can lead to hematopoiesis. The symptoms are paleness, forgetfulness, sleeplessness, and euphoric and depressive states. This deficiency occurs when serum folic content falls below 8 nmol/1 or 3 ng/ml. According to a nutrition group blood folic acid level declined up to 40% in patients taking OCs. In a Sri Lanka study of healthy women aged 20-45 taking Ovulen 50 (.05 mg of ethinyl estradiol and 1 mg of ethynodiol diacetate) folic acid level dropped in the 1st 6 months stabilizing at 2.2 ng/ml in those from the lowest social classes and at 2.9 ng/ml in those from privileged classes. Prophylactic substitution of folic acid in the diet was recommended by WHO, but it is less effective since it appears in the diet as polyglutamate that has to be broken down to absorbable monoglutamate. A US study found that taking OCs for 60 months resulted in a 40% reduction of the vitamin B12 serum level, while vitamin B12 concentrations in erythrocytes and peripheral blood stayed normal. Vitamin B12 helps recover tetrahydrofolic acid from N-methyltetrahydrofolic acid. Possibly this is another manifestation of OC-induced folic acid hypovitaminosis. OCs can also influence tryptophan metabolism reducing its blood concentration whereby less 5-hydroxytryptamine (serotonin) is produced. This results in headache, concentration decreases irritability, and sleep disturbances. In addition, lower riboflavin (vitamin B2) and thiamin concentration in erythrocytes was reported after using OCs. Counseling on the possible effect on vitamin stores and on proper nutrition including folic acid as monoglutamate is necessary for women who use OCs or estrogen substitution therapy for postmenopause or for osteoporosis prophylaxis.
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PMID:[Folic acid and vitamin deficiency caused by oral contraceptives]. 192 42

From August 1988-June 1989, 983 physicians participated in a phase IV trial by following 7759 women using the monophasic oral contraceptive (OC), Demulen 1/35 (1 mg ethynodiol diacetate and 35 ug ethinyl estradiol) to evaluate its efficacy and safety. The total number of cycles for the study stood at 21,440. In addition, the total woman-years stood at 1787. Only 6382 patients could be evaluated for safety. 4.4% of the patients had adverse reactions to the OC, but only 1.7% of all patients stopped taking it. The leading side effects included nausea (67 cases), headache (45), amenorrhea (42), emotional changes (30), breast pain (19), dysmenorrhea (12), and 11 cases of weight gain, abdominal/pelvic pain, and bloating. Of the 280 reported adverse reactions, only 87 (31%) were considered severe. The leading serious adverse reactions were depression (10) and hypertension (6). Only 5412 patients could be used to determine efficacy. The physicians initially reported 121 (2.2%) pregnancies during the study. The researchers learned that 33 of the 84 returned 2nd questionnaires (response rate, 70%) reported that the women conceived after enrollment but before taking the OC. 36 conceived while taking it, but 8 did not take it daily. Noncompliance may have contributed to pregnancy for the remaining 28 cases. Therefore the 36 confirmed pregnancies made for a failure rate of .7%. 85.7% of the pregnancies happened in the 1st 3 months of taking the OC. Either patient noncompliance or true medication failure accounted for treatment failure. Therefore it is important for physicians to instruct patients on how to take OCs correctly.
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PMID:Efficacy and safety of ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms, with an emphasis on contraceptive efficacy. A phase IV trial. 204 81

Oral contraceptives (OCs, long-acting progestins (LAPs), and IUDS are reviewed in terms of new information on safety and efficacy. OC formulations are described and their mechanism of action and efficacy indicated. Reports are provided for thromboembolism, hemorrhagic and thrombotic stroke, ischemic heart diseases, alterations in lipid and hypoprotein and carbohydrate metabolism, hypertension, coagulation changes, breast and cervical cancers, and such minor side effects as menstrual irregularities, nausea, headaches, weight gain, premenstrual syndrome effects, and mood and libido changes. Noncontraceptive health benefits and clinical considerations are discussed. Norplant, as the only long acting progestin available in the US is described in terms of its formulations, mechanism of action, sequelae and metabolic effects, menstrual irregularities, metabolic effects, nuisance side effects, candidates for insertion, method of insertion and removal, and continuation rates. 2 IUD types are identified as the only ones available in the US, Progestasert T and T-Cu-380A (Paragard). Mechanism of action, efficacy, candidates, major sequelae such as salpingitis, infertility, and uterine perforation, minor sequelae such as metrorrhagia and dysmenorrhea, and other considerations are indicated. OCs in the US contain an average of 35 mg of ethinyl estradiol and assorted progestins e.g.s, ethynodiol diacetate, norethindrone acetate, nortestosterone derivatives with a complex mechanism of action. The failure rate for use effectiveness is 6 pregnancies/100 woman years. Modern formulations have combined rates of no more than 50 to 100 adverse events/100,000 users. Some of the effects are indicated as follows: Thromboembolism accounts for 60% of adverse effects and appears to be declining along with hemorrhagic and thrombotic stroke, however, modern use studies are only partially available. Myocardial infarction related to OC use may be embolic, and has a low risk at 7/100,000 users. Low-dose contraceptives substantially reduce the associated risks. Those with risk factors need close monitoring. Norplant is useful for those not wanting to take a daily regimen and is commonly accompanied by menstrual irregularity and sometimes headaches. Continuation is 80% after the 1st year and 40% after 5 years. Candidates for IUDs are parous women in monogamous relationships, who are not at risk for salpingitis, which is related to IUD use, or sexually transmitted diseases. Continuation is 70% after 1 year compared with 50% of OC users.
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PMID:Modern trends in contraception. 212 11

Mechanism of action, indications, side effects and contraindications of oral contraceptive agents (OCA) are reviewed. OCA can be divided into two groups: consecutive and combined agents. Combined OCA contain both estrogens and gestagens and are taken for 3 weeks, while consecutive OCA contain only estrogens and are taken for 2 weeks followed by 1 week of combined OCA until the onset of menstruation. Biological activity of synthetic gestagens is estimated by a dosage which results in a delay of menstruation by 2 weeks. Gestagens norethindrone and norethynodrel were shown to be equally effective, while ethinodiol diacetate and norgestrel were 15-30 times more effective. Estrogen component of OCA is represented by ethinyl estradiol or mestranol. Combined OCA are more effective than consecutive OCA; probability of undesirable pregnancy during administration of combined OCA does not exceed 0.2%. The most frequent side-effects of OCA include nausea, headache, uterine hemorrhage, and changes in libido. OCA can affect the endocrine and reproductive systems. Major endocrine effects of OCA include changes in the cortisol metabolism in the adrenal glands, increase in the level of thyroid-binding globulin in the thyroid gland, changes in the glucose metabolism in the pancreas, inhibition of the luteinizing hormone releasing hormone in the hypothalamus with simultaneous decrease in the production of pituitary gonadotropins and inhibition of the ovulation. The most serious side-effects of OCA include cholelithiasis, thrombophlebitis, thromboembolism, liver adenoma, and myocardial infarction. Absolute contraindications to the use of OCA include hypertension, hyperlipidemia, breast or endometrial cancer, pregnancy, cardio-vascular diseases, liver diseases, and kidney insufficiency.
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PMID:[Principles of the use of oral contraceptive preparations]. 307 80

437 multiparous women were given ethynodiol diacetate in continuous microdoses of .35 mg/day, .50 mg/day, .25 mg/twice a day, or .125 mg/twi ce a day. 7 pregnancies occurred during treatment, 5 due to medication failure; 2 were in the .5 mg/day group and 3 were in the .125 mg/twice a day group. Women taking .5 mg/day and .25 mg/twice a day had most menstrual irregularities (10% of the cycles). Side effects noted were: headache, nervousness, nausea and vomiting, and abdominal pain. Most of the patients lost weight; lactation did not appear to be affected by the medication. Uterine tone changed during treatment; there was a decrease in frequency, an increase in intensity and an increase in the tone of the contractions. It is concluded that the contraceptive efficacy was directly related to dosage as were menstrual and uterin disturbances, except for side effects. Ovulation was not inhibited although contraception was produced.
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PMID:Ethynodiol diacetate as a contraceptive. 442 5

Bisecurin, an oral contraceptive containing 1 mg ethynodiol diacetate and .05 mg ethinyl estradiol, was clinically evaluated for 3-10 months in 57 women aged 18-37. Side effects noted were breakthrough bleeding, spotting, nausea and vomiting, headache, gain in weight, and reduction of libido. Breakthrough bleeding and spotting were controlled with mikrofollin during and immediately after the bleeding.
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PMID:Further investigations concerning bisecurin, a peroral contraceptive of low hormonal contents. 1227 37

Conova 30 is a combination contraceptive in which each tablet consists of 2 mg ethynodiol diacetate and .03 mg ethinylestradiol. The preparation was offered to women who requested an oral contraceptive. Several who had contraindications for steroid contraceptives, especially oral ones, were not taken into the study. In all, 122 women were involved, comprising 902 women months. During the test no pregnancies occurred, giving a .0 Pearl index. The menstrual bleeding induced when the pill was stopped for 7 days each month showed a tendency to be shorter than the women's normal reported menstrual period (modal value 4 vs 5 days). Only 1 woman reported nausea and 2 a decrease in libido. 9 women reported significant (3-9 kg) weight gain and of these 6 found the gain sufficiently disturbing that they switched over to another preparation or another method. 12 women reported significant increases in headaches, 4 complied of vertigo, 2 of depression and 3 of "nervousness." 10 women reported breakthrough bleeding and of this group 3 switched over to an oral contraceptive with a higher estrogen dose. 6 women reported breast tension and 2 reported that spastic dysmenorrhea had disappeared since they started Conova 30. Among about 20 women whose lipid metabolism was investigated, no effect of Conova 30 was found and no thromboembolism phenomena were seen during this study. The results of this study suggest that Conova 30 is safe and effective.
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PMID:[Clinical study of Conova 30]. 1231 31

This paper outlines methods of therapy utilizing newer combinations of estrogens and progestins. The specific agent and length of treatment depends on the extent of disease, severity of symptoms, presence of infertility and response to pseudopregnancy. Structural formulas for 19 synthetic preparations are shown. Of 36 patients with proven endometriosis in which pseudopregnancy was induced by the use of these newer agents, satisfactory objective in 82%. Pregnancy occurred later in 6 of 10 patients who had previously been infertile and wished to become pregnant. The optimum maintenance dose is 4-6 mg of chlormadinone acetate or ethnodiol diacetate with .2 mg of mestranol and 5-10 mg of megestrol acetate with .2 mg of ethniyl estradiol. Dosage is increased only when break through bleeding occurs. Gain in weight occurred in almost 1/2 of the patients. The decidual reaction was just as great as that produced formerly by large doses of Enovid. In a more recent study 60 patients were treated with Norlestrin, 20 with Lyndiol and 20 with Ovral. Satisfactory objective and subjective remissions were obtained in 89%. Pregnancy has occurred subsequently in 17 to 43 patients who desired pregnancy. All infants have been normal. The optimum maintenance doses seem to be 10-15 mg if Norlestrin, 2.5-5 mg Lyndiol or .5-1 mg of Ovral. The most common side effect was weight gain in 35%. These agents may be used prior to conservative surgery in order to soften areas of fibrotic endometriosis or to pinpoint areas otherwise overlooked. The length of preoperative treatment depends on the extent of disease, 6 weeks being usual. The indication for prolonged pseudopregnancy is recurrent endometriosis following surgery, also proven vaginal endometriosis. Subsequent to conservative surgery, 12 to 24 weeks of therapy are given in order to inhibit ovulation and prevent reactivation of any remaining areas of endometriosis. Tables show commercial combinations and dosage regimens. Nausea, break through bleeding, breast soreness, acne, water retention, isoninia, irritability, lethargy, headaches or development of leiomyomas are side effects to be dealt with by modifying the treatment. Thromboembolic disease has not been a complication in over 500 patients but should be looked for as it has been reported by others. The effect of long-term use of these drugs has been shown to be entirely reversible without subsequent deleterious effects. Severe hepatic disease or previous mammary carcinoma are contraindications. Excessive side effects may necessitate other treatment but the newer drugs reduce this chance. The diagnosis of endometriosis should first be proven.
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PMID:Newer synthetic progestins for the treatment of endometriosis. 1233 29