gestodene and norgestimate

Acne and seborrhea (or facial oiliness) are related androgenic skin disorders which affect a high proportion of women after menarche. They can have a negative effect on psychological well-being and social life. Androgens play an important role in the pathogenesis of acne through the stimulation of sebum secretion, increasing sebaceous gland size and possibly through follicular hyperkeratinization. Conversely, estrogens decrease sebum production by suppressing gonadotropin release and androgen production and increasing sex hormone binding globulin production. One of the treatment options for these conditions is hormonal therapy, especially for women who require contraception. The effect of combined oral contraceptives in androgenic skin disorders depends on their estrogen:progestogen balance and on the antiestrogenic activity of the progestogen component. Improved understanding of what women value about oral contraceptives suggests that the choice of product should be tailored as much as possible to the individual. Several combined oral contraceptives containing new-generation progestogens (e.g. desogestrel, gestodene) or progestational antiandrogens (e.g. cyproterone acetate, chlormadinone acetate) have demonstrated efficacy in the treatment of women with acne, although comparisons between trials are difficult because of differing endpoints. Seborrhea has been less well studied, but the few studies that are available show an improvement in women with this condition using combined oral contraceptives.

Topics: Acne Vulgaris; Contraceptives, Oral; Contraceptives, Oral, Combined; Dermatitis, Seborrheic; Desogestrel; Ethinyl Estradiol; Female; Humans; Norgestrel; Norpregnenes; Safety; Treatment Outcome

The purpose of the present report is to summarize the most important pharmacokinetic features of the new progestogens. In addition, the question of whether or not gestodene, in comparison to desogestrel, has an influence on the pharmacokinetics of ethinylestradiol (EE2) will be addressed.

Topics: Desogestrel; Ethinyl Estradiol; Female; Humans; Kinetics; Norgestrel; Norpregnenes; Progesterone Congeners

Topics: Contraceptives, Oral, Synthetic; Humans; Norgestrel; Norpregnenes

Progestins have played an important role in hormone replacement therapy (HRT). This article reviews the history, structure, and pharmacology of synthetic progestins, including the new progestins, norgestimate, gestodene, and desogestrel. The benefits and potential effect on carcinoma of the breast for each HRT are summarized. Current treatment alternatives are addressed.

Topics: Breast Neoplasms; Cardiovascular Diseases; Desogestrel; Endometrium; Estrogen Replacement Therapy; Female; Humans; Norgestrel; Norpregnenes; Osteoporosis, Postmenopausal; Progesterone Congeners; Risk Factors; Structure-Activity Relationship

To assess the differences and similarities in efficacy, safety, and metabolic effects of oral contraceptives (OCs) containing the new progestins desogestrel, gestodene, and norgestimate. All formulations reviewed contained no more than 35 micrograms ethinyl estradiol.. Data were reported from approximately 100 published reports, dating from 1980, of comparative and noncomparative clinical studies on phasic and fixed-dose preparations culled from computer searches of several sources, including MEDLINE and Excerpta Medica.. An attempt was made to select the most meaningful studies in terms of length, size, methodology, and quality of description. All clinical studies were considered; in general, review articles were not. Some preclinical studies were also included. No abstracts were used.. The indices chosen for examination were contraceptive efficacy, cycle control, coagulation, carbohydrate and lipid metabolism, and androgenicity.. The new formulations were found to be comparable in efficacy to each other and to established agents. They also appeared to be less androgenic than current OCs and to have less impact on carbohydrate and lipoprotein metabolism. Cycle control was similar to that of older products. Changes in coagulation-promoting and antithrombotic factors were minor. Clinical relevance of the results could not be determined because of small sample size and methodologic differences between studies.

Topics: Androgens; Blood Coagulation; Blood Glucose; Contraceptives, Oral; Desogestrel; Female; Humans; Insulin; Lipid Metabolism; Norgestrel; Norpregnenes; Progesterone Congeners

Desogestrel, gestodene, and norgestimate represent a new generation of progestins designed for use in oral contraceptives. A high degree of efficacy has been retained in these progestins, and the adverse metabolic impact exhibited by older progestins has been reduced considerably. The clinical profile of each progestin, as it is marketed in Europe in combination with ethinyl estradiol, is reviewed. Direct comparisons are made whenever applicable. The major advantages of these formulations over the older combined oral contraceptives are that they have less effect on lipid metabolism and on carbohydrate metabolism, and they are less androgenic. The clinical implications of these findings are discussed.

Topics: Contraceptives, Oral; Desogestrel; Female; Humans; Norgestrel; Norpregnenes

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)

Topics: Contraceptives, Oral, Combined; Contraceptives, Oral, Synthetic; Desogestrel; Dose-Response Relationship, Drug; Female; Humans; Norgestrel; Norpregnenes; Pregnancy; Progesterone Congeners

This review details the characteristic features of three new progestogens which soon will be available in low-dose combination oral contraceptive agents in the United States. Available data suggest that desogestrel, gestodene, and norgestimate are extremely potent progestogens with few androgenic side effects. The smaller changes in lipids induced by these progestogens seem to confer some advantage to the use of preparations containing one of these agents. Whether this advantage is also present clinically remains to be determined.. 3 about-to-be marketed progestogens (desogestrel, gestodene, and norgestimate) are discussed in terms of their structural characteristics and metabolism, biological activity, effects on carbohydrate and lipid metabolism, and effects on coagulation. There appears to be little difference in clinical efficacy between the new progestogens and those currently available in the US. What difference, there is to be that the androgenic metabolic effects are minimized with the new progestogens. It is though that a comparison of the clinical benefits of these agents would be difficult. Synthetic progestogens are used in oral contraceptives (OC) in order to inhibit ovulation. In combination with estrogen, they can have antiestrogenic properties. Steroid dose and potency in OCs is noted as an important consideration in comparing progestogens. The new progestogens, like the US-marketed DL-norgestrel and levonorgestrel, are gonanes, which like estranes are structured with the absence of a methyl group between rings A and B and the presence of an ethinyl group in position 17 alpha. Each is different metabolically. Studies of the biological activity of these new progestogens are difficult to compare because of labeling, dose, experimental methods, measurement errors, and the inclusion of the estrogen component, which is known to be contributory to the side effects. Only potency can be compared and gestodene has the strongest effect on inhibiting ovulation an transforming the endometrium into secretory endometrium. All have little estrogenic effects an are weak antiestrogens, with little androgenic activity as measured by the increase in seminal vesicle or prostatic weight of laboratory animals. Circulatory bonding is found in various forms. Although not clinically demonstrated, it is possible that gestodene, which is a competitive inhibitor to aldosterone, may be useful to those with hypertension. Because of the marked increase in circulating concentrations of SHBG of gestodene and desogestrel, it may be useful to those with hirsutism upon additional clinical testing. The selected review of studies on the effects of the new progestogens on carbohydrate and lipid metabolism, including the HDL and LDL cholesterol levels, suggests small effects of questionable clinical significance. Based on clinical trials of gestodene in Europe, there appears to be no greater incidence of thromboembolic activity or effects on coagulation an fibrinolysis than previously reporte

Topics: Blood Coagulation; Carbohydrate Metabolism; Contraceptives, Oral, Combined; Desogestrel; Humans; Lipid Metabolism; Norgestrel; Norpregnenes; Progesterone Congeners

There is limited information on the metabolism of levonorgestrel, norethindrone and structurally related contraceptive steroids. Both levonorgestrel and norethindrone undergo extensive reduction of the alpha, beta-unsaturated ketone in ring A. Levonorgestrel also undergoes hydroxylation at carbons 2 and 16. The metabolites of both compounds circulate predominantly as sulfates. In urine, levonorgestrel metabolites are found primarily in the glucuronide form, whereas norethindrone metabolites are present in approximately equal amounts as sulfates and glucuronides. Of the progestogens structurally related to norethindrone, norethindrone acetate, ethynodiol diacetate, norethindrone enanthate, and perhaps lynestrenol, undergo rapid hydrolysis and are converted to the parent compound and its metabolites. There is no convincing evidence that norethynodrel is converted to norethindrone. Of the progestogens structurally related to levonorgestrel, it appears that neither desogestrel nor gestodene are transformed to the parent compound. However, there is evidence that norgestimate can be, at least partly, converted to levonorgestrel. Further studies on the metabolism of these progestogens are required before we can understand their mechanism of action.

Topics: Animals; Contraceptives, Oral, Combined; Desogestrel; Female; Humans; Levonorgestrel; Norethindrone; Norgestrel; Norpregnenes

Three new 19-nortestosterone progestogens, which are chemically related to levonorgestrel, are now clinically available in combination oral contraceptives in Europe. Desogestrel and norgestimate must be transformed to metabolites for all or part of their biologic activity; gestodene is active in its original form. Compared with present low-dose monophasic and triphasic levonorgestrel formulations, the new combinations appear to be equivalent in efficacy and type and frequency of side effects. Cycle control may be slightly improved with the gestodene preparation and somewhat poorer with the desogestrel regimen. As with the present triphasics, most changes reported in coagulation indexes for the new combinations remained within normal limits, as did changes in carbohydrate and lipid metabolism. There is no present evidence that either the norgestimate or aesogestrel formulation provides a clinical improvement over the levonorgestrel triphasic. In the gestodene combination, the progestogen's increased biologic activity allows further reduction of total steroid dose.. 3 new progestogens are now available in combination oral contraceptives (OCs) in Europe: desogestrel, gestodene, and norgestimate. All are 19-nortestosterone derivatives that are chemically and biologically related to levonorgestrel. Desogestrel and norgestimate must be transformed to metabolites for all or part of their biologic activity, while gestodene is active in its original form and can be administered in the lowest dose. Numerous studies have been carried out to determine whether these new progestogen compounds provide a clinical advantage over compounds presently available in the US such as Nordette and Triphasil. The new regimens appear to be equivalent in efficacy (use effectiveness rate of less than 1 pregnancy/100 woman-years) to current low-dose monophasic and triphasic combinations. Compared with levonorgestrel monophasic OC data, the gestodene compound appears to offer slightly better menstrual cycle control and the desogestrel compound somewhat less control. The type and frequency of side effects seem to be the same as those commonly seen with low-dose monophasic and triphasic OCs. As with the present triphasics, most changes in coagulation indexes for the new combinations remain within normal limits, as do changes in carbohydrate and lipid metabolism. Overall, there is as yet no evidence that either the norgestimate or the desogestrel formulation offers any significant improvements over the levonorgestrel triphasic. On the other hand, gestodene has the advantage of allowing a further reduction of the total steroid dose.

Topics: Carbohydrate Metabolism; Desogestrel; Drug Evaluation; Female; Humans; Lipid Metabolism; Menstrual Cycle; Norgestrel; Norpregnenes; Pregnancy; Progesterone Congeners; Proteins

The pharmacology and the application in oral hormonal contraceptives of four new progestogens--gestodene, desogestrel, norgestimate, and dienogest--are described in a survey. Although derived from 19-norethisterone these progestogens exhibit in clinical dosages no androgenic effects. Both in animal and in human tests gestodene possesses the highest progestogenic potency followed by levonorgestrel, desogestrel, norgestimate, and dienogest. The monophasic preparations with the new progestogens (femovan--gestodene, marvelon--desogestrel, cilest--norgestimate, certostat--dienogest) are safe contraceptives and the incidence of bleeding disturbancies amount to about 5%. After administration of these monophasic contraceptives the concentration of SHBG in serum increases and as a result of this the level of free testosterone decreases. Further a favourable effect on lipid metabolism is observed. In spite of a different progestogen content these combination pills are almost without influence on biochemical parameters and carbohydrate metabolism.

Topics: Contraceptives, Oral, Hormonal; Desogestrel; Female; Humans; Nandrolone; Norgestrel; Norpregnenes; Progesterone Congeners

Complementary to the epidemiological knowledge on the association between oral contraceptive use and the occurrence of venous thromboembolism, a study was designed to obtain more conclusive data regarding the effect of estrogen dose and progestogen type of oral contraceptives on risk markers for the occurrence of venous thromboembolism. The protocol for this multicenter, randomized, open label, parallel group, comparative study is outlined in the present article. A total of 730 healthy, nonsmoking, mulliparous women were treated for six cycles with one of the seven monophasic oral contraceptives tested in this study. The effects of progestogen type (desogestrel, gestodene, levonorgestrel, and norgestimate) and the effects of ethinyl estradiol dose (50, 30, and 20 micrograms) on various hemostatic variables was assessed, including the key components of the anticoagulant and fibrinolytic system, as well as the coagulation system. The primary outcome variables in the study were prothrombin fragment 1 + 2 and D-dimer.

Topics: Blood Coagulation; Contraceptives, Oral; Desogestrel; Ethinyl Estradiol; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Hemostasis; Humans; Levonorgestrel; Norgestrel; Norpregnenes; Peptide Fragments; Prothrombin; Thrombin; Venous Thrombosis

The effect of a triphasic oral contraceptive containing ethinyl estradiol and gestodene (EE/GSD) on various lipid and lipoprotein parameters was compared with that of a monophasic formulation containing 35 micrograms ethinyl estradiol and 250 micrograms norgestimate (EE/NGM). Blood samples were collected from 46 women on days 2, 11, and 21 of the preceding control cycle and of the third, sixth, and twelfth treatment cycles. There was no significant difference between formulations with regard to the influence on any measured parameter. As compared with controls, a significant increase was observed in the plasma levels of total triglycerides (24-78%), total phospholipids (7-20%), very low density lipoprotein (VLDL) triglycerides (61-76%), VLDL-phospholipids (14-60%), low density lipoprotein (LDL) triglycerides (8-35%), LDL-phospholipids (28-30%), high density lipoprotein (HDL) cholesterol (8-16%), HDL 3-cholesterol (11-20%), HDL-triglycerides (17-66%), HDL-phospholipids, HDL 3-phospholipids (7-11%), apolipoprotein (apo) A-I (5-20%) and apo A-II (10-40%) during treatment with both formulations. In contrast, the LDL-cholesterol levels were significantly decreased. These changes in lipid metabolism appear to reflect a predominance of the effect of the estrogen component. The results indicate that both low dose oral contraceptives containing different progestins and different amounts of EE do not exert a deleterious effect on lipoprotein metabolism, as high HDL-cholesterol and low LDL-cholesterol levels are known as low risk factors of cardiovascular disease. In contrast to endogenous hypertriglyceridemia, an EE-induced rise in triglyceride levels does not appear to increase cardiovascular risk if LDL is not increased.. Oral contraceptives (OCs) that contain a progestogen with high androgenic activity have been shown to have an atherogenic effect on lipid and lipoprotein metabolism. The present study compared the effect of a triphasic OC containing ethinyl estradiol and gestodene on selected lipid and lipoprotein parameters with that of a monophasic OC containing 35 mcg of ethinyl estradiol and 250 mcg of norgestimate. 46 healthy volunteers from Frankfurt, Germany, were enrolled and randomly assigned to receive one of the two OCs. Serum samples were collected on days 2, 11, and 21 of the control cycle and treatment cycles 3, 6, and 12. No significant differences between formulations were observed for any of the measured parameters. Significant increases were recorded during OC use in plasma levels of total triglycerides (24-78%), total phospholipids (7-20%), very low density lipoprotein (VLDL) triglycerides (61-76%), VLDL phospholipids (14-60%), low density lipoprotein (LDL) triglycerides (8-35%), LDL phospholipids (28-30%), high density lipoprotein (HDL) cholesterol (8-16%), HDL 3-cholesterol (11-20%), HDL triglycerides (17-66%), HDL phospholipids (7-11%), apolipoprotein (apo) A-I (5-20%), and apo A-II (10-40%). In contrast, LDL-cholesterol levels were significantly decreased during treatment with both formulations. These changes appear to reflect a predominance of the effect of the estrogen component.

Topics: Adolescent; Adult; Apolipoproteins B; Cholesterol; Contraceptives, Oral, Combined; Contraceptives, Oral, Synthetic; Drug Evaluation; Ethinyl Estradiol; Female; Humans; Lipids; Lipoproteins; Norgestrel; Norpregnenes; Phospholipids; Reference Values; Triglycerides

In the present study the effect of oral contraceptive (OC) treatment on selected factors involved in the activation, i.e. circulating activated factor VII (cFVIIa), and in the inhibition of blood coagulation, i.e. plasma protein S activity and circulating thrombomodulin (cTM), were for the first time measured in OC users in a prospective study. Beside other coagulation variables, these parameters were measured during treatment with three low estrogen formulations containing different gestagen components (norgestimate, gestodene). During OC treatment increases in the activation markers prothrombin fragment F1 + 2 and D-Dimer were found, suggesting an increased activation of blood coagulation and fibrinolysis. Along with elevated plasma levels of FVII antigen, cFVIIa was also found increased in all three treatment groups, while inhibitory components of blood coagulation, plasma protein S activity and cTM, significantly and similarly decreased during treatment in all three treatment groups. We conclude that low dose estrogen pills induce similar changes in the plasma levels of main regulatory components of blood coagulation, despite differences in their gestagen components. Increased levels of activators and decreased activities of inhibitors may contribute to arterial and venous thrombotic complications seen in predisposed OC users.. The effect of oral contraceptive (OC) treatment on selected factors involved in the activation and inhibition of blood coagulation was measured in a prospectively randomized parallel-group centralized-center study. These were circulating activated factor VII (cFVIIa) as well as plasma protein S activity and circulating thrombomodulin (cTM). In addition to other coagulation variables these parameters were measured during treatment with 3 low-estrogen formulations containing different gestagen components (norgestimate, gestodene). 60 healthy women 19-37 years old were included. The women in Group I used Cileste tablets containing 35 mcg ethinyl estradiol (EE) and 250 mcg norgestimate (NG). Group II women used the 3-phase preparation Tri-Cileste containing EE and different doses of NG; and Group II women used the 3-phase preparation Triodena containing different doses of EE and gestodene (GS). 21 days on treatment were followed by 7 days off of treatment before the next cycle was started. Participants were treated for 6 cycles. Blood samples were obtained during the luteal phase before treatment and on days 18-22 of the 3rd and 6th treatment cycle. The plasma levels of various coagulation parameters, such as fibrinogen (Cileste, Tri-Cileste p 0.05; Triodena p 0.0005); fibrin-split product D-Dimer (Cileste p 0.05; Tri-Cileste, Triodena p 0.005), prothrombin fragment F1+2 (Cileste p 0.0005); Tri-Cileste, Triodena p 0.05); Factor VII antigen (Cileste, Triodena p 0.0005; Tri-Cileste p 0.005); FVII clotting activity (Cileste p 0.0005; Tri-Cileste p 0.05; Triodena p 0.005), and activated factor VII (Cileste p 0.0005; Tri-Cileste p 0.05; Triodena p 0.005) were significantly higher during the 3rd treatment cycle compared with the pretreatment values. A significant decrease was also found in the plasma levels of total and free protein S antigen (total protein S: Cileste p 0.05; Tri-Cileste, Triodena p 0.005; free protein S: Cileste, Tri-Cileste p 0.0005; Triodena p 0.05) and circulating thrombomodulin (Cileste p 0.05; Tri-Cileste p 0.0005; Triodena p 0.005).

Topics: Adult; Blood Coagulation; Blood Proteins; Contraceptives, Oral, Combined; Contraceptives, Oral, Hormonal; Contraceptives, Oral, Synthetic; Ethinyl Estradiol; Factor VIIa; Female; Humans; Norgestrel; Norpregnenes; Prospective Studies; Protein S; Risk Factors; Thromboembolism; Thrombomodulin

The effect of a triphasic oral contraceptive containing ethinylestradiol and gestodene (EE/GSD) on various serum hormonal parameters was compared with that of a monophasic formulation containing 35 micrograms ethinylestradiol and 250 micrograms norgestimate (EE/NGM). Blood samples were collected from 46 women on days 2, 11, and 21 of the preceding control cycle and of the third, sixth and twelfth treatment cycle. There was no significant difference in the influence on any hormonal parameter between both formulations. Both EE/GSD and EE/NGM caused a time-dependent suppression of serum dehydroepiandrosterone sulphate (DHEA-S) by 20-30% (p < 0.01) and a reduction of 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide by 50-60% (p < 0.01) during each treatment cycle, while androstenedione levels were reduced by 25% (p < 0.01). There was also a significant decrease in the levels of total testosterone by 30-35% (p < 0.01) and free testosterone by 60% (p < 0.01), while sex hormone-binding globulin (SHBG) was increased by 200-240% on days 11 and 21 (p < 0.01). During the pill-free interval the SHBG levels were reduced to a certain degree but remained elevated by 100% as compared to the pretreatment values. The serum levels of corticosteroid-binding globulin (CBG) which is known to be influenced only by the estrogenic component of combination pills, increased significantly by 170% (p < 0.01) during each treatment cycle. During the pill-free interval of 7 days, the CBG levels decreased but were still elevated by 90-100% as compared to the control cycle. Similarly, the serum levels of cortisol were significantly elevated by 110-140% (p < 0.01) during treatment with both preparations. The results demonstrate a profound suppression of androgen levels and peripheral androgen metabolism.. At the J. W. Goethe University Hospital in Frankfurt am Main, Germany, researchers randomly allocated 46 women to use either the triphasic oral contraceptive (OC) containing 30 mcg ethinyl estradiol (EE) and 50 mcg gestodene or the monophasic OC containing 35 mcg EE and 250 mcg norgestimate. They wanted to compare the effects of the two OCs on different serum hormonal parameters and serum binding proteins. Health workers took blood samples from the women on days 2, 11, and 21 of the cycle before OC use and of treatment cycles 3, 6, and 12. The two groups had similar hormonal parameters. Both OCs suppressed serum levels of dehydroepiandrosterone sulphate (DHEA-S) by 20-30% (p 0.01). They reduced 5alpha-androstane-3alpha, 17beta-diol glucuronide by 50-60% (p 0.01) during each treatment cycle. Both OCs also reduced androstenedione serum levels by 25% (p 0.01). Both OCs reduced serum levels of total testosterone by about 30% and of free testosterone by 60% (p 0.01-0.05 and p 0.01, respectively). The 200% increase of serum levels of sex hormone binding globulin (SHBG) on days 11 and 21 of each cycle in both groups (p 0.01) caused the more pronounced decrease of serum levels of free testosterone. Suppression of ovarian androgen synthesis also contributed to the more pronounced decrease of free testosterone. SHBG levels fell during the pill-free interval but remained 100% higher than pretreatment values. Serum levels of corticosteroid binding globulin (CBG) increased by 170% during each treatment cycle (p 0.01). CBG levels fell during the pill-free interval, but remained higher by 90-100% than the pretreatment cycle. Only the estrogenic component affected the increase in CBG. Both OCs increased cortisol serum levels by 110-140% (p 0.01). These findings show that both OCs significantly suppressed some androgen parameters and peripheral androgen metabolism.

Topics: Adolescent; Adult; Androgens; Androstane-3,17-diol; Androstenedione; Carrier Proteins; Contraceptives, Oral; Contraceptives, Oral, Combined; Corticosterone; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Estradiol Congeners; Ethinyl Estradiol; Female; Humans; Hydrocortisone; Norgestrel; Norpregnenes; Radioimmunoassay; Sex Hormone-Binding Globulin; Testosterone

Changes in endogenous androgen metabolism were compared in healthy women taking one of four low-dose modern oral contraceptives (OCs). One hundred women were randomized to (1) 35 micrograms ethinyl estradiol (EE) + 250 micrograms norgestimate (Cilest); (2) 20 micrograms EE + 150 micrograms desogestrel (Mercilon); (3) 30 micrograms EE + 150 micrograms desogestrel (Marvelon); or (4) 30 micrograms EE + 75 micrograms gestodene (Femodene). During the luteal phase of the pretreatment cycle, body weight and blood pressure were recorded, and plasma levels of the following variables were recorded: sex-hormone-binding globulin (SHBG), cortisol-binding globulin (CBG), testosterone, free testosterone, dihydrotestosterone, androstenedione, dihydroepiandrosterone sulfate (DHEAS), and hydroxyprogesterone. The free androgen index was also calculated. These variables were remeasured during the third week of OC intake and during the fourth and sixth cycles. There were no statistically significant differences in androgenic variables among the four OCs. The DHEAS concentration decreased less with the 20 micrograms EE + desogestrel formulation compared with either 30 micrograms EE + desogesterel or norgestimate-containing formulations (20% vs. 45%). Concentrations of SHBG and CBG increased significantly in all four groups (average 263 +/- 119% and 94 +/- 26%, respectively); CBG increased less in women taking 20 micrograms EE + desogestrel (about 75%) than in the other formulations (about 100%). The four modern, low-dose OCs tested had similar impacts on endogenous androgen metabolism, yielding significant decreases in testosterone, dihydrotestosterone, androstenedione, and DHEAS. All of these formulations may be beneficial in women with androgen-related syndromes such as acne and hirsutism. Large studies are under way to establish which of the third-generation OCs is the least androgenic. In vitro studies suggest that norgestimate has the least androgenic profile.

Topics: Adult; Androgens; Blood Pressure; Body Weight; Carrier Proteins; Contraceptives, Oral, Combined; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Desogestrel; Dihydrotestosterone; Dose-Response Relationship, Drug; Ethinyl Estradiol; Female; Humans; Hydroxyprogesterones; Norgestrel; Norpregnenes; Progesterone Congeners; Prospective Studies; Serum Albumin; Sex Hormone-Binding Globulin; Testosterone

The alterations in lipid metabolism that occur with the use of oral contraceptives (OCs) have aroused considerable concern that OCs might increase the risk of premature atherosclerosis. However, most studies examining the role of OCs in atherogenesis were performed using earlier-generation preparations employing larger doses of sex hormones than present formulation. Therefore, we undertook a comparative and standardized determination of the effects on lipid metabolism of six modern, low-dose OCs. This open, randomized, comparative study included patients recruited at 21 study centers throughout Europe. Four hundred sixty-six women, aged 18-38 years, participated. They were randomly assigned to the following OC formulations:(1) norgestimate 250 micrograms + ethinyl estradiol (EE) 35 micrograms (Cilest); (2) norgestimate 180/215/250 micrograms + EE 35 micrograms (Tricilest); (3) desogestrel 150 micrograms + EE 20 micrograms = (Marvelon); (4) desogestrel 150 micrograms + EE 30 micrograms (Mercilon); (5) gestodene 75 micrograms + EE 30 micrograms (Femovan); and (6) gestodene 50/70/100 micrograms + EE 30/40/30 micrograms (Trifemovan). There were three parallel studies with six parallel patient groups. Fasting blood samples were drawn at baseline (between days 24 and 28) and on days 18-22 of cycle 6, and cycle 12. Sample were analyzed for total cholesterol,high-density lipoprotein (HDL) cholesterol, HDL2 cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein (apo)A1, and apoB at one central laboratory. Two hundred eighty-two women completed all 12 cycles and were included in the final evaluation. As expected, triglyceride and total cholesterol concentrations increased in all study groups but to lesser levels with the formulations containing gestodene. All OCs, except the monophasic gestodene preparation, slightly but significantly increased HDL. The HDL2 subfraction did ot change significantly except in the group using the monophasic gestodene preparation; in this group, the HDL2 subfraction slightly but significantly decreased. The LDL concentration increased slightly with the monophasic and triphasic norgestimate preparations and with desogestrel + 20 micrograms EE. The LDL/HDL ratio did not change significantly except with the use of the triphasic norgestimate preparation, in which case it decreased slightly. ApoA1 and apoB levels increased only slightly with all formulations. Importantly, while all of the OCs tested altered li. The changes in lipid metabolism which occur with the use of oral contraceptives (OCs) have prompted concern about the potential for OCs to increase the risk of premature atherosclerosis. Findings are reported from the study of the effects on lipid metabolism of six modern low-dose OCs. 466 women aged 18-38 years recruited from 21 study centers throughout Europe participated. Subjects were randomly assigned to the following OC formulations: norgestimate 250 mcg and 35 mcg ethinyl estradiol (EE), 180/215/250 mcg of norgestimate and 35 mcg EE, 150 mcg desogestrel and 20 mcg EE, 150 mcg desogestrel and 30 mcg EE, 75 mcg gestodene and 30 mcg EE, and 50/70/100 mcg gestodene and 30/40/30 mcg EE. There were three parallel studies with six parallel patient groups. Fasting blood samples were drawn for the analysis of cholesterol, lipoproteins, and triglycerides between days 24 and 28 and on days 18-22 of cycles 6 and 12. 282 women completed all 12 cycles and were included in the final evaluation. Triglyceride and total cholesterol concentrations increased in all study groups, but to lesser levels with the formulations containing gestodene. All OCs, except the monophasic gestodene preparation, slightly but significantly increased high-density lipoprotein (HDL) cholesterol. The HDL(2) cholesterol subfraction slightly, but significantly, decreased among women using the monophasic gestodene preparation. The low-density lipoprotein (LDL) cholesterol concentration increased slightly with the monophasic and triphasic norgestimate preparations and with desogestrel combined with 20 mcg EE. The only significant change, a slight decrease, in the LDL/HDL ratio occurred with the use of the triphasic norgestimate preparation. While all of the OCs tested altered lipid levels, after 12 cycles there were no statistically significant differences in lipid effects among OC preparations. These findings suggest that, although modern combined OCs containing norgestimate, desogestrel, or gestodene all have some impact upon lipid levels, they probably do not contribute to atherogenesis in healthy women.

Topics: Adolescent; Adult; Cholesterol, HDL; Cholesterol, LDL; Contraceptives, Oral; Desogestrel; Dose-Response Relationship, Drug; Ethinyl Estradiol; Female; Humans; Lipid Metabolism; Lipids; Norgestrel; Norpregnenes; Progesterone Congeners

Two monophasic oral contraceptives containing gestodene (GTD, 75 micrograms) and ethinylestradiol (EE, 30 micrograms) or norgestimate (NGS, 250 micrograms) and EE (35 micrograms) were compared during the first six cycles of use. The subjects were randomly assigned to receive either type: 97 received GTD/EE and 92 NGS/EE. Six women in the GTD/EE group and nine in the NGS/EE group withdrew from the study; three (3%) and two (2%), respectively, withdrew because of adverse reactions. A total of 562 cycles for GTD/EE and 523 for NGS/EE were available. No woman became pregnant during the study. Overall, 94.4% of cycles in the GTD/EE group and 92.8% in the NGS/EE group were normal. A similar incidence of breakthrough bleeding (0.2% of cycles for GTD and 1.6% for NGS) and spotting (5.4% vs. 5.6%) was observed. Amenorrhea was never reported. Duration of withdrawal bleeding tended to be slightly longer in the NGS/EE group, significantly so for cycles 2 (0.5 days, p = 0.016), 4 (0.5 days, p = 0.031) and 5 (0.4 days, p = 0.045). Cycle 2 was significantly longer in the GTD/EE group (0.3 days, p = 0.027). Side-effects were reported by 12 (12%) women in the GTD/EE group and 13 (14%) in the NGS/EE group. The most common side-effects were headache (five cases (5%) in the GTD/EE group and two (2%) in the NGS/EE group) and breast pain (three (3%) and eight (9%) cases respectively). There were no statistically significant differences between the two groups with respect to change in body weight or changes in blood pressure and in laboratory data.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Contraceptives, Oral, Combined; Ethinyl Estradiol; Female; Humans; Italy; Menstrual Cycle; Norgestrel; Norpregnenes

In order to compare the secondary effects of oral contraceptive pills during the first cycle of application, 308 women between the age of 25 and 45 were interrogated by questionnaires about their subjective complaints. The patients received a contraceptive within an In-vitro-Fertilization-program (IVF-program) in preparation for a stimulation treatment to follow. The study consisted of two parts: at the beginning a pilot study was carried out in which retrospectively a pill containing 0.150 mg Desogestrel and 0.030 mg Ethinylestradiol and a contraceptive containing 0.075 mg Gestoden and 0.030 mg Ethinylestradiol were compared. In a following prospective randomized examination a product, new on the market, containing 0.250 mg Norgestimat and 0.035 mg Ethinylestradiol, was included. The most common secondary effects, occurring in 34% of our patients, were spottings and break through bleedings. Regarding the secondary effects--during the first cycle of application--no significant difference between the contraceptives could be established.

Topics: Adult; Contraceptives, Oral, Combined; Desogestrel; Dose-Response Relationship, Drug; Ethinyl Estradiol; Female; Fertilization in Vitro; Humans; Norgestrel; Norpregnenes; Pilot Projects; Prospective Studies; Retrospective Studies

Recent studies have indicated that the risk of thromboembolic disease (VTE) in users of combined oral contraceptive pills (COCs) varies not only with estrogen dose, but also with the progestogen in pills with the same estrogen dose. The aim of this article is to discuss sex hormone binding globulin (SHBG) as a marker of estrogenicity and as a surrogate indicator for the potential risk of VTE in users of COC.. Using data from the literature, we investigated the relationship between the risk of VTE with various COCs and their effects on SHBG. We also collected data on the effects on SHBG by some combined preparations, where there are no VTE data.. There appears to be a relationship between the risk of VTE and the effect on SHBG. Monophasic preparations containing levonorgestrel, having the lowest risk of VTE, cause an average SHBG increase of around 50%. COCs containing desogestrel or gestodene cause an average SHBG increase of 200-300%. A preparation with cyproterone acetate, carrying a higher risk of VTE than desogestrel and gestodene, cause a 300-400% SHBG increase. With the recently developed combined preparations, there is a 150% SHBG increase with norgestimate and a 250-300% increase with drosperinone and dienogest.. We propose that the change in SHBG with a COC could be interpreted as a measure of total estrogenicity and used as a predictor of the risk of VTE. Preparations containing drosperinone, dienogest, cyproterone acetate and norgestimate are equally or more estrogenic than the more thoroughly studied COCs, containing desogestrel or gestodene and should not be considered a safer substitute.

Topics: Biomarkers; Contraceptives, Oral, Combined; Cyproterone Acetate; Desogestrel; Female; Humans; Levonorgestrel; Norgestrel; Norpregnenes; Predictive Value of Tests; Risk Factors; Sex Hormone-Binding Globulin; Venous Thrombosis

The epidemiological studies that assessed the risk of venous thromboembolism (VTE) associated with newer oral contraceptives (OC) did not distinguish between patterns of OC use, namely first-time users, repeaters and switchers. Data from a Transnational case-control study were used to assess the risk of VTE for the latter patterns of use, while accounting for duration of use. Over the period 1993-1996, 551 cases of VTE were identified in Germany and the UK along with 2066 controls. Totals of 128 cases and 650 controls were analysed for repeat use and 135 cases and 622 controls for switching patterns. The adjusted rate ratio of VTE for repeat users of third generation OC was 0.6 (95% CI:0.3-1.2) relative to repeat users of second generation pills, whereas it was 1.3 (95% CI:0.7-2.4) for switchers from second to third generation pills relative to switchers from third to second generation pills. We conclude that second and third generation agents are associated with equivalent risks of VTE when the same agent is used repeatedly after interruption periods or when users are switched between the two generations of pills. These analyses suggest that the higher risk observed for the newer OC in other studies may be the result of inadequate comparisons of pill users with different patterns of pill use.

Topics: Adult; Body Mass Index; Case-Control Studies; Contraceptives, Oral, Synthetic; Desogestrel; Estrogens; Ethinyl Estradiol; Female; Humans; Levonorgestrel; Logistic Models; Norgestrel; Norpregnenes; Risk Factors; Venous Thrombosis

Topics: Adolescent; Adult; Contraceptives, Oral, Synthetic; Desogestrel; Female; Humans; Levonorgestrel; Norgestrel; Norpregnenes; Odds Ratio; Time Factors

Epidemiological studies have shown that women who use third-generation oral contraceptives (OC) containing desogestrel, gestodene or norgestimate have a higher risk of venous thrombosis than women who use second-generation OC containing levonorgestrel. It is also known that a mutation in factor V (factor V(Leiden)), which results in resistance to activated protein C (APC) and which is the most common cause of hereditary thrombophilia, potentiates the prothrombotic effect of OC. Effects of APC on thrombin generation in the plasma of women using OC were compared to the response to APC in non-OC users and in individuals that were heterozygous or homozygous for factor V(Leiden). The response towards APC was evaluated on basis of the ratio (APC-sr) of the time integrals of thrombin formation determined in the presence and absence of APC. Compared with women not using OC, women who used OC exhibited a significantly decreased sensitivity to APC (P<0.001), independent of the kind of OC used. Women who used third-generation monophasic OC were significantly less sensitive to APC than women using second-generation OC (P<0.001) and had APC-sr that did not significantly differ from heterozygous female carriers of factor V(Leiden) who did not use OC. Women who were heterozygous for factor V(Leiden) and used OC had APC-sr in the range of homozygous carriers of factor V(Leiden). Two women who started OC therapy had significantly elevated APC-sr within 3 d. Acquired APC resistance may explain the epidemiological observation of increased risk for venous thrombosis in OC users, especially in women using third-generation OC.

Topics: Adolescent; Adult; Aged; Contraceptives, Oral, Combined; Desogestrel; Factor V; Female; Hemostasis; Heterozygote; Humans; Levonorgestrel; Male; Middle Aged; Norgestrel; Norpregnenes; Protein C; Thrombin; Thrombophlebitis

Topics: Adult; Blood Coagulation Factors; Contraceptives, Oral, Combined; Cross-Sectional Studies; Desogestrel; Female; Fibrinolysis; Humans; Lipids; Middle Aged; Norgestrel; Norpregnenes; Progesterone Congeners; Thromboembolism

A matched case-control study was undertaken in 10 centers in Germany and the United Kingdom to explore the association of current use of major combination oral contraceptives with the occurrence of venous thromboembolism. The cases recruited were 505 women aged 16-44 years with venous thromboembolism, controls were 1877 women (at least 3 controls per case) matched for 5-year age group and region without VTE. The main outcome measures were odds ratios derived by comparing current use of a specific oral contraceptive or group of OC against current use of other groups or against no current use of OC. The odds ratios (95% confidence intervals) for venous thromboembolism were: for third generation products (low dose ethinyloestradiol, gestodene and desogestrel) versus second generation products (low dose ethinyloestradiol, no gestodene and desogestrel, 1.5 (1.1 to 2.0), for third versus second generation products with norgestimate included in third generation, 1.6 (1.2 to 2.2). The odds ratios for current use for women aged 16-44 of specific progestagens versus levonorgestrel-containing compounds were 1.7 (1.1 to 2.6) for gestodene, 1.8 (1.2 to 2.6) for desogestrel, 1.9 (1.0 to 3.6) for norgestimate and 1.3 (0.7 to 2.5) for progestagen-only pills. For women aged 25 to 44 likely to be exposed to any of these progestagens, odds ratios for the comparison of progestagens versus levonorgestrel showed a successive increase by market introduction ranging from 1.5 (0.9 to 2.5) for desogestrel with 30 micrograms oestrogen content (introduced 1981) to 2.8 (1.3 to 6.5) for desogestrel with 20 micrograms oestrogen content (introduced 1992) significant in linear trend analysis (p = 0.00012). The influence of norgestimate classification as third or second generation product does not significantly alter the results regarding the association of third generation products and venous thromboembolism. A direct comparison of current use of norgestimate (which is primarily metabolized to levonorgestrel) versus levonorgestrel shows an increased odds ratio. The trend of increasing risk of progestagens by recency of market introduction when compared with levonorgestrel is strongly indicative of the existence of external bias due to attrition of susceptibles.

Topics: Adolescent; Adult; Bias; Contraceptives, Oral, Synthetic; Desogestrel; Female; Humans; Levonorgestrel; Norgestrel; Norpregnenes; Odds Ratio; Progesterone Congeners; Risk Factors; Thromboembolism

The European Society of Contraception developed a survey to examine birth control methods in the 12 countries++ of the European Community. Responses to those questions relating to prescribing++ practices of oral contraceptives (OCs) are presented herein. The survey was sent to 400 physicians. One hundred two responded, most from France, Belgium, and the United Kingdom. The responses revealed that the most popular OCs are modern combined formulations containing low doses of ethinyl estradiol and progestogens such as norgestimate, desogestrel, gestodene, and levonorgestrel. More than half of physicians prescribe a particular formulation because of its tolerability and 20% because of its hormonal content. More than 90% prescribe OCs to healthy, nonsmoking women over 40. However, three fourths will not prescribe OCs to smokers over 35. Half of physicians recommend mammography for their older OC patients. Half also recommend cholesterol screening, but 8% only for women over 30. Most physicians are no longer reluctant to prescribe OCs to their diabetic patients: 61% prescribe OCs for women with non-insulin-dependent diabetes, 56% for those with insulin-dependent diabetes, and 85% for those with a history of gestational diabetes. Despite recent studies showing no relation between past OC use and cardiovascular disease, 42% of physicians said that their greatest OC-related health concern is cardiovascular disease. One third cited noncompliance as their greatest concern. These results reveal inhomogeneous prescribing practices for OCs among European physicians. ¿Over-screening¿--not prescribing the pill because of perceived (but not necessarily real) health risks--may be depriving many women of the contraceptive and noncontraceptive benefits of OCs. Complete and accurate information--as promoted by the European Society of Contraception--is one way to combat such overscreening.. Findings are presented from the 1993 European Society of Contraception Oral Contraceptive Survey conducted in 12 member countries among 102 physicians. Findings are considered suggestive because of the low response rate of 25% to the mailed questionnaire to 400 physicians. The aim is to determine the prescribing practices of oral contraceptives. Over 50% of physicians prescribed the following modern, low-dose combined formulations: Marvelon, Mercilon, Minulet, Gynera, Cilest, and Femodene. 66% of physicians prescribed monophasic pills containing 20-30 mcg of ethinyl estradiol and low doses of desogestrel, gestodene, levonorgestrel, or norgestimate. 58% preferred oral pills because of their tolerability. Other desirable features were the cost, hormonal content, and other factors. 94% prescribed oral pills for women aged over 40 years who were healthy and did not smoke. 75% would not prescribe oral pills to women who were over the age of 35 years and who smoked. Over 50% of physicians recommended mammograms for women aged over 35 years who used oral pills. 45% routinely performed lipoprotein screening of oral pill users. 8% did so only for patients aged over 30 years. 42 physicians out of the 102 responding had a protocol based on the total cholesterol level. 61% prescribed oral pills for women with non-insulin-dependent diabetes. The majority prescribed oral pills for women with insulin-dependent diabetes. 38% of physicians who prescribed oral pills for women with diabetes prescribed very-low-dose monophasic oral contraceptives. 85% prescribed oral pills for women with gestational diabetes. 42% were concerned about patient risk of cardiovascular disease. The study revealed a range of practices among physicians.

Topics: Adult; Aging; Cardiovascular Diseases; Contraception; Contraceptives, Oral; Data Collection; Desogestrel; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Estradiol Congeners; Ethinyl Estradiol; Europe; Female; Humans; Levonorgestrel; Norgestrel; Norpregnenes; Progesterone; Progesterone Congeners; Risk Factors; Smoking; Surveys and Questionnaires

The relative binding affinity of norgestimate for human sex hormone-binding globulin was compared with that of its metabolites and other progestins by measuring their abilities to displace [3H]testosterone from this carrier protein in vitro. Norgestimate and its 17-deacetylated and 3-keto metabolites did not significantly displace [3H]testosterone from sex hormone-binding globulin at concentrations up to 10,000 nM, whereas gestodene, levonorgestrel, and 3-keto desogestrel displaced [3H]testosterone from sex hormone-binding globulin with IC50 concentrations of 23.1, 53.4, and 91.0 nM, respectively. Since it is believed that a progestin may exert androgenic effects by displacing testosterone from sex hormone-binding globulin, thereby increasing circulating levels of free, active testosterone, these data are consistent with the results of preclinical and clinical studies demonstrating the selective progestational activity of norgestimate.

Topics: Binding, Competitive; Desogestrel; Humans; Levonorgestrel; Norgestrel; Norpregnenes; Progesterone; Progestins; Sex Hormone-Binding Globulin; Testosterone

The aim of using new synthetic progestogens (gestodene and norgestimate) in oral hormonal contraceptives is to find a combination that has a more beneficial effect on metabolism and endometrium than presently available formulations. Our studies with low-dose pills containing 30 micrograms ethinyl estradiol/150 micrograms levonorgestrel or 30 micrograms ethinyl estradiol/150 micrograms desogestrel compared with the new pills with 35 micrograms ethinyl estradiol/250 micrograms norgestimate or 30 micrograms ethinyl estradiol/75 micrograms gestodene revealed no significant alterations of serum glucose after glucose loading. With all four combination pills, insulin levels were slightly elevated when compared with controls. Studies of the lipid metabolism showed that depending on the type and estrogen combination, progestogens have different effects on lipid metabolism. The new progestogens seem to have a more pronounced effect on triglycerides, whereas total cholesterol and high-density lipoprotein cholesterol remain almost unchanged. In general, it could be shown that low-dose oral contraceptives have little impact on lipid metabolism. Studies with low-dose monophasic preparations, including the new formulations, reveal only a low effect on blood coagulation. According to our and other data on the new progestogens in oral contraceptives available so far, it can be expected that such low-dose monophasic and triphasic combination pills will be beneficial during longtime use with respect to side effects on the cardiovascular system and control of the menstrual cycle.

Topics: Contraceptives, Oral, Combined; Desogestrel; Ethinyl Estradiol; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Levonorgestrel; Lipids; Lipoproteins; Norgestrel; Norpregnenes; Progesterone Congeners