gestodene and etonogestrel

Among new forms of hormonal contraception, three interesting exemples are described with a high level of effectiveness and low dosage regimen that allow improved safety and tolerance: a very low-dose estrogen-progestogen combination of ethinylestradiol and gestodene for 24-day cyclical administration; a progestogen-alone subcutaneous implant containing etonogestrel; and a levonorgestrel-releasing intrauterine system. These preparations appear to be particularly interesting as they provide additional possibilities for individualizing contraceptive therapy.

Topics: Contraceptive Agents, Female; Contraceptives, Oral, Combined; Desogestrel; Drug Implants; Ethinyl Estradiol; Female; Humans; Intrauterine Devices; Levonorgestrel; Norpregnenes; Vinyl Compounds

The objective of this study was to compare cycle control, tolerability and sexual well-being with the use of three hormonal contraceptives.. In this prospective randomized study, the effects of two combined oral contraceptives [20 microg of ethinylestradiol (EE)/100 microg of levonorgestrel and 15 microg of EE/60 microg of gestodene] were compared with those of the vaginal ring (15 microg of EE/120 microg of etonogestrel). One-year data from 280 women were obtained. We investigated the pattern of menstrual cycle and the incidence of weight gain, nausea, headache, breast tenderness, irritability, depression and vaginal dryness. Moreover, desire and sexual satisfaction were evaluated. Finally, the cumulative rate of discontinuation in the three groups was estimated.. The analysis of adverse events revealed two crucial points for acceptability, compliance and continuation: poor cycle control and disturbance of sexual intercourse due to vaginal dryness and loss of desire.

Topics: Administration, Intravaginal; Adult; Affect; Contraceptive Agents, Female; Contraceptives, Oral; Desogestrel; Ethinyl Estradiol; Female; Humans; Levonorgestrel; Libido; Menstrual Cycle; Norpregnenes; Prospective Studies; Reproduction; Uterine Hemorrhage

A cross-over study of two oral contraceptive formulations, containing 30 micrograms ethinylestradiol in combination with 150 micrograms desogestrel (Marvelon) or 75 micrograms gestodene (Femovan), has been performed to compare the serum distribution and pharmacokinetics of gestodene and the active metabolite of desogestrel, namely 3-ketodesogestrel. Serum concentrations of both sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) were also measured and were increased more than 3-fold and 2-fold, respectively, on day 21 of the treatment cycle, with no statistically significant difference between treatment groups. In addition, 35 days after ingestion of either oral contraceptive had ceased, the serum SHBG and CBG concentrations were similar to the pretreatment values. During treatment cycles, increased serum SHBG levels were associated with a redistribution of 3-ketodesogestrel and gestodene such that the non-protein-bound (NPB) and albumin-bound fractions were reduced in concert with an increase in the relative proportions bound to SHBG. The proportion of gestodene bound to SHBG was consistently higher than that observed for 3-ketodesogestrel, and this undoubtedly reflects the higher affinity of SHBG for gestodene (Kd = 1.2 nM at 37 degrees C) when compared to 3-ketodesogestrel (Kd = 4.7 nM at 37 degrees C). It also probably accounts, in part, for the much higher total serum levels of gestodene (8.58 nmol/L) when compared to 3-ketodesogestrel (2.37 nmol/L) during the treatment cycles. Consequently, the absolute amounts of NPB, non-SHBG-bound, and SHBG-bound gestodene are significantly higher than those measured for 3-ketodesogestrel. It is concluded that ethinylestradiol-induced increases in serum SHBG levels during treatment with Marvelon or Femovan, influenced the distribution and total amount of 3-ketodesogestrel and gestodene in serum, respectively, and that this, combined with the higher affinity of SHBG for gestodene, results in a greater amount of bioavailable gestodene compared to 3-ketodesogestrel, despite the smaller dose of gestodene administered.

Topics: Adult; Biological Availability; Contraceptives, Oral, Combined; Cross-Over Studies; Desogestrel; Ethinyl Estradiol; Female; Humans; Kinetics; Norpregnenes; Sex Hormone-Binding Globulin; Transcortin

The serum concentrations of 3-ketodesogestrel (KDG) and gestodene have been measured in 30 and 31 women respectively who took low dose oral contraceptives containing 30 micrograms ethinylestradiol together with either 150 micrograms desogestrel or 75 micrograms gestodene for 6 months. On days 1, 10 and 21 of the first third and sixth treatment cycles blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4 and 24 h. KDG and gestodene levels were measured by radioimmunoassays and were evaluated for Cmax (peak serum concentration), tmax (time to Cmax), and AUC (area under the curve) to 4 and 24 h. The overall total gestodene concentrations were higher and the accumulation of the steroid throughout a cycle greater than that of KDG. For example, the AUC0-4 of gestodene increased in cycle 1 by a factor of 2.8 (day 10 vs. day 1) and 3.6 (day 21 vs. day 1) compared to 2.3 and 2.6 for KDG. The higher concentration of gestodene reflects a lower volume of distribution than KDG, and is consistent with gestodene binding to sex hormone binding globulin (SHBG) with a higher affinity than KDG. Concentrations of KDG and gestodene were higher on day 1 of cycles 3 and 6 than on day 1 of cycle 1. The serum concentrations of KDG and gestodene during multiple dosing cannot be predicted on the basis of single dose pharmacokinetics.

Topics: Adolescent; Adult; Blood Proteins; Contraceptives, Oral, Combined; Desogestrel; Ethinyl Estradiol; Female; Humans; Kinetics; Norpregnenes; Protein Binding; Sex Hormone-Binding Globulin

During one year of treatment with oral contraceptives containing 30 micrograms ethinylestradiol and 150 micrograms desogestrel (EE/DG) or 30 micrograms EE and 75 micrograms gestodene (EE/GSD), the serum concentrations of EE, 3-keto-desogestrel (KDG) and GSD were determined on day 1, 10 and 21 of the 1st, 3rd, 6th and 12th cycle. The areas under the time-versus-concentration curves were calculated from the levels before and 0.5, 1, 1.5, 2, 3, 4 and 24 hours after intake of a tablet. There were large intra- and interindividual variations both revealing coefficients of variation (C.V.) between 25% and 80% (EE),, 30% and 50% (KDG) and 30% and 65% (GSD). During each cycle, the EE levels increased significantly between day 1 and 10 by 70% on average reaching a steady-state, while the progestogen concentrations rose by 100% (KDG) and 150% (GSD) up to a steady-state between day 10 and 21. After reaching the steady-state, the C.V. were generally lower. The ratios between the levels of EE and the progestogens showed still higher variations indicating different influences on the estrogen and progestogen component. There was no correlation between the steroid levels and weight, height or age. In spite of the large intraindividual variations, most of the women showed a distinct pattern of the levels of EE and the progestogens throughout the year of treatment indicating a genetic or acquired predisposition. The difference in the average AUC of EE, KDG and GSD between the women was 300% at most. During the first cycle of treatment with EE/DG and EE/GSD, about half of the women recorded intermenstrual bleedings which decreased thereafter. There was no relation between the occurrence of irregular bleedings and the average serum levels of EE and the progestogens of the individual women, neither during the first cycle nor during the whole treatment period of 12 cycles. It is concluded that spottings or breakthrough bleedings during treatment with oral contraceptives are not dependent on a distinct pattern of the serum levels of EE and the progestogen.

Topics: Adolescent; Adult; Contraceptives, Oral, Combined; Desogestrel; Ethinyl Estradiol; Female; Humans; Multivariate Analysis; Norpregnenes; Progesterone Congeners; Uterine Hemorrhage

To establish a sensitive and specific method for simultaneous determination of gestodene, etonogestrel and ethinylestradiol in plasma by LC-MS/MS, plasma samples were extracted and derivatized before injection. An ESI ion source was used and operated in the positive ion mode with multiple reaction monitoring (MRM). Norgestrel was chosen as internal standard and performed on a C18 (100 mm x 2.1 mm, 5 microm) column. The concentrations of gestodene, etonogestrel and ethinylestradiol were measured, using step-gradient mobile phase and step-gradient flow rate. The method was validated over the concentration range of 0.1-20 ng x mL(-1) for gestodene and etonogestrel and 0.01-2 ng x mL(-1) for ethinylestradiol, and showed excellent linearity. The intra- and inter-assay accuracy and precision were below 10.0% and recovery was 93.6%-110.9% over the three concentration levels evaluated. The method was applied in pharmacokinetic study of the compound gestodene patch and the compound etonogestrel patch in rabbits. The LC-MS/MS method was selective, accurate and sensitive, especially the LOQ were 100 pg x mL(-1) for gestodene and etonogestrel and 10 pg x mL(-1) for ethinylestradiol. The method was successfully applied in pharmacokinetic study for contraceptives.

Topics: Animals; Chromatography, Liquid; Desogestrel; Ethinyl Estradiol; Norpregnenes; Rabbits; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization

The use of sex steroids in oral contraception or hormonal replacement therapy is associated with an increased risk of cardiovascular thromboembolic complications. Although both the estrogen and the progestin components have been involved, the underlying mechanisms responsible are unclear.. This study examined whether sex steroids promote hemostasis indirectly by increasing the procoagulant activity of blood vessels. Treatment of vascular smooth muscle cells with several progestins (progesterone, 3-keto-desogestrel, gestodene, and medroxyprogesterone acetate) upregulated proteolytically activatable thrombin receptor (PAR-1) expression, resulting in a potentiated thrombin-induced tissue factor expression and surface procoagulant activity. In contrast, neither the progestins levonorgestrel, norethisterone, and norgestimate nor the synthetic estrogen 17alpha-ethinylestradiol had such effects. The effect of the stimulatory progestins, which induce glucocorticoid-like effects in several cell systems, was mimicked by dexamethasone and inhibited by the progesterone and glucocorticoid receptor antagonist RU-38486. In addition, long-term administration of progesterone, 3-keto-desogestrel, or medroxyprogesterone acetate to ovariectomized rats increased PAR-1 protein level in the arterial wall, resulting in an increased responsiveness of isolated aortic rings to thrombin.. These data demonstrate that several progestins markedly potentiate the vascular procoagulant effects of thrombin by increasing the availability of membrane thrombin receptors in the smooth muscle, an effect that is most likely due to their glucocorticoid-like activity.

Topics: Animals; Aorta; Blood Coagulation; Blotting, Northern; Blotting, Western; Cells, Cultured; Desogestrel; Dexamethasone; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Gene Expression Regulation; Humans; In Vitro Techniques; Medroxyprogesterone Acetate; Mifepristone; Muscle, Smooth, Vascular; Norpregnenes; Ovariectomy; Progesterone; Progestins; Rats; Rats, Wistar; Receptor, PAR-1; Receptors, Glucocorticoid; Receptors, Progesterone; Receptors, Thrombin; RNA, Messenger; Thrombin; Vasoconstriction

The progestin and oestrogen component of oral contraceptives have been involved in the development of venous thromboembolic events in women. In the present study we determined the vasoactive effects of sex steroids used in oral contraceptives in isolated preconstricted rabbit jugular veins in the presence of diclofenac and examined the underlying mechanisms. The natural hormone progesterone, the synthetic progestins levonorgestrel, 3-keto-desogestrel, gestodene and chlormadinone acetate, and the synthetic estrogen 17 alpha-ethinyloestradiol induced concentration-dependent relaxations of endothelium-intact veins constricted with U46619. Levonorgestrel also inhibited constrictions evoked by either a high potassium (K(+)) solution or phorbol myristate acetate (PMA) in the absence and presence of extracellular calcium (Ca(2+)). In addition, levonorgestrel depressed contractions evoked by Ca(2+) and reduced (45)Ca(2+) influx in depolarized veins. Relaxations to levonorgestrel in U46619-constricted veins were neither affected by the presence of the endothelium nor by the inhibitor of soluble guanylyl cyclase, NS2028, but were significantly improved either by the selective cyclic AMP phosphodiesterase inhibitor rolipram or in the absence of diclofenac, and decreased by the protein kinase A inhibitor, Rp-8-CPT-cAMPS. Rolipram also potentiated relaxations to levonorgestrel in PMA-constricted veins in the presence, but not in the absence of extracellular Ca(2+). Levonorgestrel increased levels of cyclic AMP and inhibited PMA-induced activation of protein kinase C in veins. These findings indicate that levonorgestrel caused endothelium-independent relaxations of jugular veins via inhibition of Ca(2+) entry and of protein kinase C activation. In addition, the cyclic AMP effector pathway contributes to the levonorgestrel-induced relaxation possibly by depressing Ca(2+) entry.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Calcium; Calcium Chloride; Chlormadinone Acetate; Cyclic AMP; Cyclic GMP; Desogestrel; Dose-Response Relationship, Drug; Endothelium, Vascular; Ethinyl Estradiol; In Vitro Techniques; Jugular Veins; Levonorgestrel; Male; Norpregnenes; Potassium Chloride; Progesterone Congeners; Protein Kinase C; Rabbits; Rolipram; Tetradecanoylphorbol Acetate; Thionucleotides; Vasodilation

The effect of the synthetic estradiol, 17 alpha-ethinylestradiol, and three progestogens on calcium influx was investigated in cell cultures of human aortic smooth muscle. Neither the synthetic estrogen nor the progestogens levonorgestrel, 3-keto-desogestrel, and gestodene showed, in the concentration range of 10(-9) to 10(-6) M, a significant effect on calcium influx both alone or in equimolar estrogen-gestagen combinations. The results indicate that these substances, commonly used in contraceptive pills, do not change vasotonus interfering with calcium homeostasis.

Topics: Aorta; Calcium; Calcium Channels; Calcium Radioisotopes; Cells, Cultured; Desogestrel; Dose-Response Relationship, Drug; Estradiol Congeners; Ethinyl Estradiol; Humans; Levonorgestrel; Muscle, Smooth, Vascular; Norpregnenes; Progesterone Congeners

The effects of two classes of progestagens, e.g. pregnane [Org 2058, medroxyprogesterone acetate (MPA), R5020, progesterone (PROG)] and 19-nortestosterone derived progestagens [3-ketodesogestrel (KDG), levonorgestrel (LNG), gestodene (GES), norethisterone (NE), Org 30659] on proliferation of three estradiol (E2)-dependent human breast tumor MCF-7 cell lines of different origin [Van der Burg (B), Litton bionetics (L) and McGrath (M)] were studied. The pregnane derivatives hardly stimulated cell growth at 10(-6) M in MCF-7 B and L cells except for Org 2058 in B cells, whereas in M cells a statistically significant growth induction was observed except for PROG. The 19-nortestosterone derivatives induced cell growth at doses at 10(-7) M or higher in all three cell lines. NE, GES and Org 30659 were more potent stimulators than KDG and LNG at 10(-7) M. E2 already showed maximal stimulation at 10(-10) M. For all three cell lines, the effects and ranking of the individual progestagens were similar. Antiprogestagens, like RU 38486 and Org 31710 could not block these stimulatory effects while antiestrogens like 4-hydroxytamoxifen and ICI 164,384 could. This suggests that cell growth by the above-mentioned progestagens occurs via an interaction with the estrogen receptor. Indeed, displacement studies with cytosol from MCF-7 M cells revealed that at very high concentrations NE, GES and Org 30659 were able to displace 50% of the radiolabelled E2, while KDG and LNG could not. Relative binding affinities (RBAs) were 0.010, 0.025 and 0.015% for NE, GES and Org 30659, respectively. The effect of the two classes of progestagens on cell proliferation was also investigated at several dose levels in combination with E2 (10(-10) M) in the MCF-7 B cell line. This resulted in a statistically significant inhibition of cell growth with R5020, MPA and most of the 19-nortestosterone derivatives at concentrations of 10(-8) M. Org 2058 and NE did not have any influence on E2-induced growth. The inhibitory effects could not be blocked by antiprogestagens. In summary these studies with 3 subclones of MCF-7 cells show that the pregnane derived progestagens stimulate growth only in one subclone, whereas the 19-nortestosterone derived progestagens do so in all three subclones. The progestagens possess estrogenic activity only at high pharmacological doses, being 10,000 times weaker than estradiol. In combination with estrogens most progestagens gave a reduction of E2-stimulated growth in t

Topics: Adenocarcinoma; Breast Neoplasms; Cell Division; Desogestrel; Estradiol; Estrogen Antagonists; Female; Humans; Levonorgestrel; Medroxyprogesterone Acetate; Models, Statistical; Nandrolone; Norethindrone; Norpregnenes; Pregnanes; Pregnenediones; Progesterone; Promegestone; Receptors, Androgen; Receptors, Estrogen; Receptors, Progesterone; Tumor Cells, Cultured

Two classes of progestagens, e.g. pregnane [Org 2058, progesterone (PROG), R5020, medroxyprogesterone acetate (MPA)] and 19-nortestosterone derived progestagens [norethisterone (NE), levonorgestrel (LNG), 3-ketodesogestrel (KDG), gestodene (GES), Org 30659] were studied for their effect on cell growth of two human breast tumor T47D cell lines of different origin, i.e. from ATCC (A) and Sutherland (S) et al. [Sutherland et al., Cancer Res. 48 (1988) 5084-5091]. The effect of estradiol (E2) and progestagens alone as well as the combined effect of E2 (10(-10) M) and progestagens were investigated at several dose levels. Compared with E2-induced growth at 10(-10) M, pregnane and 19-nortestosterone derived progestagens at 10(-6) M alone did enhance cell growth in T47D-A cells up to 25 and 100% respectively, whereas in T47D-S cells they did not influence growth. All these progestagens at 10(-6) M did not affect E2-induced growth in T47D-A cells, whereas in T47D-S cells they completely reduced cell proliferation at doses between 10(-10) and 10(-8) M. The involvement of progestagen (PR) and estrogen (ER) receptors with respect to growth stimulation was studied by using specific antihormones. In T47D-A cells, the antiprogestagens RU 38486 and Org 31710 could not block progestagen-induced growth. Antiestrogens, like 4-hydroxytamoxifen and ICI 164,384, inhibited the 19-nortestosterone derivative-induced cell growth by approx. 50%. Remarkably, both antiprogestagens alone could also inhibit E2-induced growth in T47D-A cells by about 50%. In T47D-S cells, E2-induced cell growth was completely blocked by both antiprogestagens and antiestrogens. Both antiprogestagens in T47D-S cells were equipotent to 4-hydroxytamoxifen and 10-fold more potent than ICI 164,384. In conclusion pregnane and 19-nortestosterone-derived progestagens stimulated cell growth in T47D-A cells at high unphysiological concentrations, whereas they did not affect cell growth in T47D-S cells. The 19-nortestosterone derivative induced growth in T47D-A cells could partially be inhibited by antiestrogens. In T47D-A cells, E2-induced cell growth was not influenced by both classes of progestagens, whereas in T47D-S cells all tested progestagens, antiprogestagens, and antiestrogens inhibited E2-induced cell growth completely. These results with T47D cells as well as those obtained previously with MCF-7 cells show that subclones of cell lines may respond differently to various types of progestagens in the pres

Topics: Breast Neoplasms; Carcinoma; Cell Division; Desogestrel; Dose-Response Relationship, Drug; Estradiol; Estrenes; Estrogen Antagonists; Female; Furans; Humans; Levonorgestrel; Medroxyprogesterone Acetate; Mifepristone; Nandrolone; Norethindrone; Norpregnenes; Pregnanes; Pregnenediones; Progesterone; Promegestone; Tumor Cells, Cultured

The serum protein binding of levonorgestrel, gestodene and 3-keto-desogestrel has been determined during several clinical studies with different oral contraceptive formulations and one in vitro study. The results of these studies were combined in order to assess the relation between changes in the concentration of sex hormone-binding globulin (SHBG) and the effect on the free fraction of the progestins as well as on their distribution with respect to the binding proteins albumin and SHBG. Although marked differences in protein binding were seen for the three progestins at low concentrations of SHBG, these differences became less pronounced at high levels of SHBG which were reached during established oral contraceptive therapy. A nonlinear relation could be shown for either the free or the protein-bound fraction of the progestins and the concentration of SHBG in the serum, respectively.

Topics: Adult; Clinical Trials as Topic; Desogestrel; Female; Humans; Levonorgestrel; Norpregnenes; Progesterone Congeners; Protein Binding; Serum Albumin; Sex Hormone-Binding Globulin

Two low-dose oral contraceptives, both containing the same dose of ethinyl estradiol (EE2, CAS 57-63-6) but different progestins--gestodene (CAS 60282-87-3) and desogestrel (CAS 54024-22-5), respectively--were administered to 18 women in a single dose, cross-over study. The serum concentrations of gestodene (GEST, one of the components of Femovan) and 3-keto-desogestrel (KDG) have been measured by specific radioimmuno-assays and the pharmacokinetics of both progestins were assessed. The serum protein binding of both compounds was also investigated and although the free fraction was the same for GEST and KDG, the distribution with respect to the binding proteins albumin and sex hormone binding globulin (SHBG) was slightly different. GEST was mainly bound to SHBG, while KDG was predominantly bound to albumin. Maximum concentrations of GEST were observed after 0.7 +/- 0.2 h and amounted to 4.9 +/- 2.4 ng/ml. A biphasic pattern of disposition was observed, with half lives of 0.13 +/- 0.06 h and 14.6 +/- 4.2 h, respectively. The AUC was 32.9 +/- 18.3 ng.ml-1.h. For KDG, maximum serum levels of 1.7 +/- 0.8 ng/ml were observed 1.5 +/- 0.8 h post administration. Drug levels declined with half-lives of 0.5 +/- 0.2 h and 17.0 +/- 9.3 h, respectively, and the AUC was 15.2 +/- 10.9 ng.ml-1.h.. In Berlin, Germany and Liverpool, England health workers took blood samples from 18 24-34 year old women who took either a single oral contraceptive pill (Femovan) with 75 mcg gestodene and 30 mcg ethinyl and 30 mcg ethinyl estradiol or a single oral contraceptive pill with 150 mcg desogestrel and 30 mcg ethinyl estradiol followed 7 days later by a single pill with 75 mcg gestodene and 30 mcg ethinyl estradiol. Researchers aimed to determine the serum protein binding traits of both progestins and their pharmacokinetics. They used specific radioimmunoassays and ultrafiltration to measure levels and serum protein binding of gestodene and the active metabolite of desogestrel, 3-keto-desogestrel (KDG). The free faction of both progestins was the same 91.9% for gestodene and 1.7% for KDG). The percent gestodene bound to albumin was not significantly different from that of KDG (47.8% vs. 63.7%). Similarly there was no significant difference between the percent gestodene and percent KDG bound to sex hormone binding globulin (SHBG) while gestodene tended to bind more with SHBG than albumin. The SHBG binding of gestodene was not as strong as that of albumin binding of KDG, however. After pill administration, KDG reached maximum levels later than did gestodene (1.5 hours vs. 7 hours). Mean maximum level of gestodene was 4.9 ng/ml. Post maximum levels of gestodene fell biphasically with half lives at a mean of 0.13 hours and 14.7 hours, respectively. The area under the cure of gestodene was 32.9 ng x ml-1 x h. Mean maximum level of KDg was 1.7 ng/ml. Post-maximum levels of gestodene fell biphasically with half lives at a mean of 0.5 and 17 hours, respectively. The area under the curve of gestodene was 15.2 ng x ml-1 x h. Lower bioavailability of KDG (60-80% vs. 100% for gestodene) may have accounted for the slightly greater interindividual variation of drug levels for KDG than gestodene.

Topics: Adult; Blood Proteins; Contraceptives, Oral; Desogestrel; Half-Life; Humans; Male; Norpregnenes; Protein Binding; Radioimmunoassay

Two low-dose oral contraceptives, both containing the same dose of ethinyl estradiol (EE2) but different progestins (gestodene and desogestrel, respectively), were compared with respect to the relative bioavailability of EE2. The study was conducted with 31 women as an open intraindividual comparison with the ingestion of both preparations for 3 months, respectively. On days 1, 10 and 21 of the 1st, 3rd and 6th cycle, blood was sampled at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h following administration. The concentrations of EE2 were determined in the serum samples of each individual and the area under the serum concentration versus time curves, AUC (0-4 h) and AUC (0-24 h), were calculated. Corresponding parameters obtained on days 1, 10 and 21 of the 3rd and 6th month of treatment were compared on a statistical basis, and no differences were found. This result was in concordance with a previously performed study, where both formulations were administered to 18 women in a single-dose cross-over design. However, the results of the previous and the present study are at variance with the result of one other study, reporting higher EE2 levels in the serum of women taking the gestodene-containing formulation as compared to those taking the desogestrel-containing formulation.

Topics: Adult; Biological Availability; Contraceptives, Oral; Desogestrel; Ethinyl Estradiol; Female; Humans; Kinetics; Norpregnenes

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

Serum levels of 3-ketodesogestrel and ethinyl estradiol were analyzed by radioimmunoassay in a balanced crossover study with two tablet formulations containing desogestrel (0.150 mg) and ethinyl estradiol (0.030 mg) in 25 women under steady-state conditions after 21 days of treatment. The pharmacokinetic properties of desogestrel were characterized by the following parameters: (1) maximum serum concentration, (2) time to maximum serum concentration, (3) total area under the serum concentration versus time curve, and (4) serum half-life of elimination. The interindividual variation in these parameters was comparable with that observed with other contraceptive combinations containing ethinyl estradiol and norethisterone, levonorgestrel, or gestodene. The serum distribution of contraceptive progestogens is known to be determined by their affinity to sex hormone-binding globulin and the concentration of sex hormone-binding globulin. We analyzed the structural features that determine binding to sex hormone-binding globulin. The 18-methyl group increased and the 11-methylene group weakened the binding to sex hormone-binding globulin. The double bond at C-15 reinforced the binding only when combined with an 18-methyl group. Therefore, the binding of levonorgestrel (the 18-methyl derivative of norethisterone) and gestodene (the delta-15,18 methyl derivative of norethisterone) to sex hormone-binding globulin was much stronger than that of 3-keto-desogestrel and norethisterone.. Serum levels of 3-ketodesogestrel and ethinyl estradiol (EE) were analyzed by radioimmunoassay in a balanced crossover study with 2 tablet formulations containing desogestrel (0.150 mg) and EE (0.030 mg) in 25 women under steady-state conditions after 21 days of treatment. The pharmacokinetic properties of desogestrel were characterized by the following parameters: maximum serum concentration, time to maximum serum concentration, total area under the serum concentration vs time curve, and serum 1/2 life of elimination. The interindividual variation in these parameters was comparable with that observed with other contraceptive combinations containing EE and norethisterone, levonorgestrel, or gestodene. The serum distribution of contraceptive progestogens is known to be determined by their affinity to sex hormone- binding globulin (SHBG) and the concentration of SHBG. The authors analyzed the structural features that determine binding to SHBG; the 18- methyl group increased and the 11-methylene group weakened the binding to SHBG. The double bond at C-15 reinforced the binding only when combined with an 18-methyl group. Therefore, the binding of levonorgestrel (the 18-methyl derivative of norethisterone) and gestodene (the delta-15, 18 methyl derivative of norethisterone) to SHBG was much stronger than that of 3-ketodesogestrel and norethisterone.

Topics: Administration, Oral; Adult; Contraceptives, Oral, Hormonal; Desogestrel; Ethinyl Estradiol; Female; Half-Life; Humans; Levonorgestrel; Norethindrone; Norgestrel; Norpregnenes; Radioimmunoassay; Sex Hormone-Binding Globulin

The time-dependent alterations in the serum concentrations of ethinyl estradiol, gestodene, and 3-keto-desogestrel during treatment with 30 micrograms of ethinyl estradiol + 75 micrograms of gestodene or 30 micrograms of ethinyl estradiol + 150 micrograms of desogestrel were investigated during 12 months. The levels of gestodene and 3-keto-desogestrel increased between days 1 and 21 of each cycle, reaching maximal levels during the third and sixth cycles. The serum concentrations of gestodene were fourfold to fivefold higher than those of 3-keto-desogestrel. The ethinyl estradiol levels increased significantly between days 1 and 10 during each cycle and were significantly higher by 70% during intake of ethinyl estradiol/gestodene compared with ethinyl estradiol/desogestrel, although the dose was identical. Intake of gestodene, in addition to 35 micrograms of ethinyl estradiol + 2 mg of cyproterone acetate, caused a rise in ethinyl estradiol levels. During treatment with ethinyl estradiol/gestodene and an additional 150 micrograms of levonorgestrel, there was a continuous increase in gestodene levels, although sex hormone-binding globulin level did not change. During treatment with 30 or 35 micrograms of ethinyl estradiol and 75 micrograms of gestodene, 150 micrograms of desogestrel, or 2 mg of cyproterone acetate, there were large intraindividual and interindividual variations in the steroid levels and ratios of estrogen: progestogen levels. There was no correlation with the occurrence of intermenstrual bleedings. It is concluded that ethinyl estradiol and nortestosterone derivatives may inhibit steroid-metabolizing enzymes in the liver, which results in a rise in the serum levels of contraceptive steroids. The cause of the large intraindividual variations is as yet unknown, but it is probably from changes in steroid metabolism.

Topics: Adolescent; Adult; Contraceptives, Oral, Hormonal; Cyproterone; Cyproterone Acetate; Desogestrel; Ethinyl Estradiol; Female; Humans; Kinetics; Levonorgestrel; Menstrual Cycle; Norgestrel; Norpregnenes; Sex Hormone-Binding Globulin

Some progesterones widely used in oral contraceptives are characterized at the level of high-affinity receptor binding as well as binding to sex hormone-binding globulin and corticosteroid-binding globulin. With regard to binding to sex hormone-binding globulin, gestodene, levonorgestrel, and to a lesser extent 3-ketodesogestrel (which is only formed from the prodrug desogestrel in the body), show a behavior that is manifested in the relatively high affinity to sex hormone-binding globulin, whereas desogestrel and norgestimate do not display any measurable affinity for this specific steroid-binding serum protein. Furthermore, levonorgestrel and gestodene dissociate very much more slowly from the binding sites of sex hormone-binding globulin than 3-ketodesogestrel. A natural affinity of all these synthetic progestogens tested for corticosteroid-binding globulin could not be established. Gestodene, levonorgestrel, and 3-ketodesogestrel bind to the progesterone, glucocorticoid, and androgen receptor with high affinity, apart from slight differences, whereas estrogen receptor affinity could not be demonstrated in any of the progestogens investigated. In relation to aldosterone, the relative binding affinity values of gestodene, levonorgestrel, and the natural progestogen progesterone are relatively high, whereas 3-ketodesogestrel does not display any measurable affinity for this receptor species.

Topics: Animals; Binding, Competitive; Blood Proteins; Contraceptives, Oral, Hormonal; Cytoplasm; Desogestrel; Female; Humans; Kinetics; Levonorgestrel; Male; Norgestrel; Norpregnenes; Pregnancy; Progesterone; Progesterone Congeners; Progestins; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Sex Hormone-Binding Globulin; Transcortin; Uterus

The protein binding of ethinylestradiol (EE2), gestodene (GEST) and 3-keto-desogestrel (KDG) has been determined by ultrafiltration in the serum of women who had either taken a gestodene (n = 37) or desogestrel (n = 28) containing oral contraceptive for a time period of at least 3 months. GEST and KDG were analyzed in individual serum pools whereas EE2 was repeatedly measured in two serum pools, each one representing one treatment group. The respective free fractions of the three steroids were 0.6 +/- 0.1% (GEST), 2.5 +/- 0.2% (KDG), 1.7 +/- 0.6% (EE2, in the gestodene-group) and 1.5 +/- 0.2% (EE2, in the desogestrel-group). EE2 was exclusively bound to albumin, whereas GEST and KDG were also bound to sex-hormone-binding globulin (SHBG). The distribution of the two progestins over the serum binding proteins was determined after heat-treatment of serum samples. For GEST, the contribution of albumin and SHBG was 24.1 +/- 9.1 and 75.3 +/- 9.1%, respectively and for KDG it was 65.9 +/- 11.9 and 31.6 +/- 12.0%, respectively. SHBG and corticosteroid-binding globulin (CBG) concentrations were measured in the serum samples obtained from both treatment groups. In the gestodene-group 180 +/- 61 nmol/l (SHBG) and 89 +/- 13 mg/l (CBG) were measured, the corresponding values in the desogestrel-group were 226 +/- 64 nmol/l (SHBG) and 93 +/- 14 mg/l (CBG). SHBG concentrations were correlated with the total concentration of GEST and its free fraction and a positive (r = 0.395) and negative (r = -0.491) correlation respectively was found. Only a weak negative correlation (r = -0.291) was found for SHBG and the free fraction of KDG in the serum. These data demonstrate that the three contraceptive steroids EE2, GEST and KDG were all bound extensively to serum proteins, however, with pronounced differences concerning their distribution over the various binding proteins.. The protein binding of ethinyl estradiol (EE2), gestodene (GEST), and 3- keto-desogestrel (KDG) has been determined by ultrafiltration in the serum of women who had either taken a gestodene (n=37) or desogestrel (n=28) containing oral contraceptives for a time period of at least 3 months. GEST AND KDG were analyzed in individual serum pools whereas EE2 was repeatedly measured in 2 serum pools, each representing a treatment group. The respective free fractions of the 3 steroids were 0.6 +or- 0.1% (GEST), 2.5 +or- 0.2% (KDG), 1.7 +or- 0.6% (EE2, in the gestodene group), and 1.5 +or- 0.2% (EE2 in the desogestrel group). EE2 was exclusively bound to albumin, whereas GEST and KDG were also bound to sex-hormone binding globulin (SHBG). The distribution of the 2 progestins over the serum binding proteins was determined after heat treatment of serum samples. For GEST, the contribution of albumin and SHBG was 24.1 +or- 9.1 and 75.3 +or- 9.1%, respectively and for KDG it was 65.9 +or- 11.9 and 31./6 +or- 12.0%, respectively. SHBG and corticosteroid-binding globulin (CBG) concentrations were measured in the serum samples obtained from both treatment groups. In the gestodene-group, 180 +or- 61 nmol/1 (SHBG) and 89 +or- 13 mg/1 (CBG) were measured, the corresponding values in the desogestrel-group were 226 =or- 64 nmol/1 (SHBG) and 93 =or- 14 mg/1 (CBG). SHBG concentrations were correlated with the total concentration of GEST and its free fraction and a positive (r=0.395) and negative (r=0.491) correlation respectively was found.

Topics: Blood Proteins; Contraceptives, Oral, Hormonal; Desogestrel; Ethinyl Estradiol; Female; Humans; Norpregnenes; Protein Binding; Radioimmunoassay

The relative binding affinities (RBAs) of four progestational compounds (norethisterone, levonorgestrel, 3-keto-desogestrel and gestodene) for the human progesterone and androgen receptors were measured in MCF-7 cytosol and intact MCF-7 cells. For the binding to the progesterone receptor, both Org 2058 and Org 3236 (or 3-keto-desogestrel) were used as labelled ligands. The following ranking (low to high) for the RBA of the nuclear (intact cells) progesterone receptor irrespective of the ligand used is found: norethisterone much less than levonorgestrel less than 3-keto-destogestrel less than gestodene. The difference between the various progestagens is significant with the exception of that between 3-keto-desogestrel and gestodene, when Org 2058 is used as ligand. For the cytosolic progesterone receptor, the same order is found with the exception that similar RBAs are found for gestodene and 3-keto-desogestrel. The four progestagens clearly differ with respect to binding to the androgen receptor using dihydrotestosterone as labelled ligand in intact cells; the ranking (low to high) is: norethisterone less than 3 keto-desogestrel less than levonorgestrel and gestodene. The difference between 3-keto-desogestrel and levonorgestrel or gestodene is significant. The selectivity indices (ratio of the mean RBA for the progesterone receptor to that of androgen receptor) in intact cells are significantly higher for 3-keto-desogestrel and gestodene than for levonorgestrel and norethisterone. From these results we conclude that the introduction of the 18-methyl in norethisterone (levonorgestel) increases both the binding to the progesterone and androgen receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cell Line; Cytosol; Desogestrel; Dihydrotestosterone; In Vitro Techniques; Levonorgestrel; Norethindrone; Norgestrel; Norpregnenes; Pregnenediones; Receptors, Androgen; Receptors, Progesterone; Tritium