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Even though oral contraceptives (OCs) with the new 3 progestins are the most widely prescribed OCs in the world, especially in Europe, they still are not available to US women. Gestodene's, desogestrel's, and norgestimate's effective daily dose are only 75 mcg, 150 mcg, and 250 mcg, respectively, while the daily dose of norethindrone in OCs used in the US ranges from 350-1000 mcg. The older progestins alter lipid metabolism, thus increasing cardiovascular disease risks. Some studies indicate that the new progestins induce fewer lipid metabolic changes than the older progestins. A 1988 study in West Germany suggests, however, that women who use gestodene may be at increased risk of thromboembolism. Yet, similar research in the UK and also in West Germany did not find this association. There has been concern for many years about OCs' ability to change glucose metabolism and insulin resistance. 5 studies show that OCs with desogestrel cause fewer such disturbances than those with levonorgestrel. 1 study also finds that OCs with gestodene do not alter glucose and insulin levels. On the other hand, 1 study suggests, that OCs with gestodene increase glucose and insulin levels over 6 months. European studies of the new progestins demonstrate their low 1-year method failure rates (gestodene, 0.07/100 users; desogestrel, 0.04/100 users; and norgestimate, [pregnancy rate] 0.25/100 users). Further, the 3 progestins result in a smaller proportion of women who have side effects (breakthrough bleeding or spotting, 3-9%, breast discomfort or headaches, 10-13%). Yet, researchers have not directly compared the effectiveness and acceptability of the 3 new progestins. A legal dispute between 2 pharmaceutical companies prevented the marketing of norgestimate in 1990. 1 company claims patent infringement. The US Food and Drug Administration is now evaluating gestodene and desogestrel. It probably will not approve gestodene until the question of apparent excess of thromboembolism is resolved.
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PMID:The new pills: awaiting the next generation of oral contraceptives. 142 86

The latest advance in the 30-year evolution of oral contraceptives (OCs) is the development of three new progestogens: desogestrel, norgestimate, and gestodene. These three new agents are derivatives of levonorgestrel, a gonane hormone, and have been used to develop pills that provide effective pregnancy prevention at lower doses than oral contraceptives using the older steroids. Desogestrel is a prohormone that must first be metabolized into its biologically active form. Norgestimate is already active, but it will be metabolized in part to levonorgestrel. Gestodene is biologically active in its native form. Among the improvements in metabolic parameters seen with this new generation of progestogens are a lack of impact on blood pressure, a balanced effect on coagulation, and a reduced impact on carbohydrate metabolism compared with earlier, higher-dose formulations. The new pills also seem to produce no negative effects on lipid and lipoprotein biosynthesis, and perhaps even improve the ratio of low-density lipoprotein to high-density lipoprotein. Cycle control with all three progestogens is improved, with much lower incidence of intermenstrual bleeding (IMB). Efficacy is as good as with other OCs. Another benefit of the new low-dose progestogens, however, is the low incidence of minor side effects observed in women using these contraceptives. Low incidences of weight gain, headache, and nausea were reported, and the dropout rate because of side effects was low in both international and US trials. Serious side effects are rarely seen with pills containing the new progestogens.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The new era in oral contraception: pills containing gestodene, norgestimate, and desogestrel. 143 6

Femovan contains 30 mcg of ethinyl estradiol and 75 mcg of gestodene. Gestodene has been used in combination oral contraceptives since 1987 in 38 countries with hardly any effect on carbohydrate and lipid metabolism or fibrinolysis. Its contraceptive reliability for menstrual cycle control and tolerance was examined. A total of 102.769 women aged 18-35 with 593.455 menstrual cycles were included in 2 phases. Most of the women were German women, but the study included women from Europe and Latin America. Although 2-8% of the women took Femovan irregularly, only 3 pregnancies occurred in 414 English women (4704 cycles), 7 in 3267 German women (36.711 cycles), and 124 in 95.906 German women (523.477) as a result of forgetfulness. The pearl index reached .16 and .22 in the 2 phases, respectively, under client failure, and .07 and .06 under method failure. Bleeding ranged from .6-2.8% of cycles, while spotting was 4.5-8.2%. The omission of menstrual bleeding occurred in less than 1% of this population. Tension in the breasts, headache, and nausea with nervousness occurred in up to 10% of the women. Nervousness, vertigo, and depression was significantly less frequent. Acne and edema occurred only in a few cases. The average increase of body weight was a maximum of .8 kg. Blood pressure was unchanged for a few cases. There were 2 and 26 cases, respectively, of thromboembolitic diseases in the 2 phases amounting to .3 and .6/1000 woman years of use which compares to .4-1.7/1000 of the Oxford-Family Planning Association cohort study results. Femovan was discontinued on medical grounds (headache, nausea, and irregular bleeding) in 10.3% of 3267 German women and in 7.5% of 95.906 German women. Femovan's acceptance rate was remarkably high, and it proved to reliable and well-tolerated.
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PMID:[Clinical experiences with femovan (Gynera)]. 209 80

Results of a survey of gynecologists and general practitioners in France concerning their opinions of the advantages and drawbacks of oral contraceptives (OCs) and a brief history of the successive improvements in OCs over the past 3 decades are presented. The 300 gynecologists and 600 general practitioners interviewed in all regions of France felt that OCs were an important contraceptive method. Almost all reported they were very concerned about possible longterm effects: 78% with cardiovascular risks, 77% with lipid metabolic effects, 63% with glucose metabolic effects, and 62% with androgenic effects. Fewer than 1/2 were very concerned about shortterm clinical problems such as weight gain, spotting, and dermatological effects which have less serious prognoses. Almost 90% of the physicians considered that too high a dose of estrogen dominance was a very important cause of problems. Over 1/2 of the physicians felt that information furnished them regarding OCs should be more detailed and precise. Enovid, the 1st combined OC commercially available in the US, contained 150 mcg of mestranol and 9.85 mg of norethynodrel. Isolated cases of serious vascular problems began to be reported soon after its introduction. In 1961 a formulation with half the estrogen dose was developed, and in 1964 ethinyl estradiol, a better tolerated synthetic estrogen, replaced mestranol and is still the only estrogen used. New and better tolerated progestins were subsequently synthesized, as were formulations with lower steroid doses. Results of large epidemiological studies demonstrated that estrogens were responsible for venous thromboembolic accidents while progestins were directly correlated with arterial accidents. No increased risk of breast cancer has been found in OC users in the most recent controlled studies. Hepatic or biliary problems are possible because of the hepatic catabolism of the steroids, justifying the contraindication for women who have had hepatic accidents. Headaches are usually but not always harmless. Weight gain is due not to increased adipose mass but to water retention and is often responsible for termination of use. Benefits of OCs include effective fertility control and regular medical surveillance of users, which allows medical problems to be discovered at earlier stages. OCs have favorable effects on dysmenorrhea, spontaneous hyperestrogenism, endometriosis and provide protection against-rheumatoid polyarthritis and osteoporosis. The recent development of biphasic and especially triphasic pills has provided better cycle control at the same time that steroid doses have been reduced. The next innovation in combined OCs will probably be the use of new progestins combining powerful antigonadotropic action with an absence of metabolic effects at contraceptive doses. Gestodene, a derivative of 19 nortestosterone, offers great promise. Its use will decrease the effects of combined OCs on different metabolic factors that influence individual cardiovascular risk.
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PMID:[Oral contraception: evolution of concepts over the last thirty years]. 1228 8

Autoimmune progesterone dermatitis (APD) is rare autoimmune response to endogenous progesterone or to earlier exposure to exogenous progesterone (1). Skin lesions typically occur due to increases in progesterone during the luteal phase of the menstrual cycle (2). A-31-year-old mother of two children presented to our Department with a 5-year history of pruritic and painful erythematosus macules, papules, and patches on her neck, pectoral region, and face, which appeared 2-3 days before the onset of menses and gradually resolved 7-10 days later (Figure 1). The lesions first appeared 10 months after her second pregnancy and a few months after she had started using oral contraceptive pills (OCP) containing gestodene combined with ethinyloestradiol. A few months before presenting to us, the lesions had started spreading on her forearms, elbows, and pretibial areas. Since one year prior to our visit she had complained of occasional urticaria with angioedema one week prior to menses, which resolved after menses. The lesions were accompanied by malaise, headache, and fatigue. The patient was asymptomatic between the outbreaks. She reported that she had been using various local corticosteroids, peroral antihistamines, and prednisone for the treatment of her skin lesions, but this treatment had not improved her symptoms. She suffered from mild seasonal rhinoconjunctivitis. We performed multiple laboratory tests that were unremarkable. Histopathological examination of a biopsy taken from a lesion on the neck showed epidermal hyperplasia and nonspecific mild dermal inflammation. Since progesterone was not available in aqueous solution in our country, we did not perform an intradermal test, but we performed a lymphocyte transformation test (LTT) to medroxyprogesterone and estradiol. The patient's lymphocytes showed markedly enhanced proliferation to medroxyprogesterone in vitro, while being negative to estradiol. We had performed control LTT in 10 healthy controls and 10 patients with atopy, and such hyperactivity was not observed in any of them. We performed an oral provocation test with OCP containing gestodene combined with ethinyloestradiol. Two days after commencing treatment, the patient developed widespread dermatitis (Figure 2) with nausea, malaise, and angioedema. The patient was informed about treatment options and possible side-effects. She started with OCP with the lowest amount of progesterone, containing ethinyloestradiol and dropirenone for treatment of APD, but terminated treatment after the second cycle due to a worsening of the skin lesions and urticaria accompanied with angioedema. At the time of writing, our patient continues to have premenstrual flares. The typical symptoms of APD are skin lesions such as eczema, erythema multiforme, prurigo, stomatitis, papulopustular lesions, folliculitis, urticaria, angioedema, and rarely anaphylaxis (2) that develop 3-10 days before and subside 1-2 days after menses, with recurrent cyclic aggravation (1,3,4). Frequently, patients have a history of exogenous progesterone intake (1,5,6), as in our patient, which could have resulted in antibody formation. The diagnosis of APD is established by an appropriate clinical history (premenstrual flare of skin lesions), a progesterone intradermal test, an intramuscular (7), oral (8), or intravaginal (1, 6) progesterone challenge test, and circulating antibodies to progesterone. Progesterone testing has not been standardized. Most of the sex hormones are not suitable for testing since they contain an oily component that can produce an irritant test reaction. Gestodene, which was used for the oral provocation test in our patient, is a potent progesterone (9). The LTT shows reactions to circulating lymphocytes and reflects immune reactions within the body. The goal of treatment is suppression of ovulation. Currently, the first-line choice of therapy is a combination oral contraceptive (3). We believe that OCP have a limited effect because all of them contain a progesterone component. If this treatment is ineffective, patients have been treated with danazol, gonadotropin releasing hormone analogs (3,4,6), conjugated estrogens (7), tamoxifen, oophorectomy (8), and progestogen desensitization (10) with varying success.
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PMID:Autoimmune Progesterone Dermatitis Diagnosed by Lymphocyte Transformation Test and Progesterone Provocation Test. 3039 Jul 35