The use of a pill containing ethinylestradiol-norgestimate improves female sexuality despite the decrease in circulating androgens: a pilot study.

PURPOSE: To evaluate the initial impact of a combined oral contraceptive (COC) containing norgestimate (NGM) on female sexuality and on circulating androgen levels in users. MATERIALS AND METHODS: Six months modification in the McCoy Female Sexuality Questionnaire (MFSQ) and testosterone (T) and dehydroepiandrosterone sulphate (DHEAS) serum levels in women starting a monophasic pill containing ethinyl-estradiol (EE) 35 µg and NGM 0.250 mg. RESULTS: The study was completed by 36 subjects. There was a significant increase in MFSQ during treatment (p < 0.0001) (and its domains with the exclusion of vaginal lubrication domain) with concomitant decreases in T (-4.45%, p < 0.0001) and DHEAS (-19.41%, p < 0.0001) serum levels. CONCLUSIONS: Contraception with EE/NGM was associated with a short term non-deteriorating effect on sexuality despite the evident decrease in androgen levels. Female sexuality during COC use is a complex topic and is not only linked with changes in serum androgen levels.

EE/NGM treatment has a short term non-deteriorating effect on sexuality despite the evident decrease in androgen serum levels.

Effects of rimegepant 75 mg daily on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate in healthy female participants.

OBJECTIVE: To assess the effect of single and multiple doses of rimegepant 75 mg dose on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol (EE)/norgestimate (NGM) in healthy females of childbearing potential or non-menopausal females with tubal ligation. BACKGROUND: Females of childbearing age experience the highest prevalence of migraine and frequently inquire about the concomitant use of anti-migraine medications and contraceptives. Rimegepant, a calcitonin gene-related peptide receptor antagonist, demonstrated efficacy and safety for treating an acute migraine attack and preventing migraine. METHODS: This open-label, single-center, phase 1, drug-drug interaction study explored the effects of rimegepant 75 mg daily dose on the pharmacokinetics of an oral contraceptive containing EE/NGM 0.035 mg/0.25 mg in healthy females of childbearing potential or non-menopausal females with tubal ligation. During cycles 1 and 2, participants received EE/NGM once daily for 21 days followed by placebo tablets with inactive ingredients for 7 days. Rimegepant was administered during only cycle 2 for 8 days, from days 12 through 19. The primary endpoint was the effect of single and multiple doses of rimegepant on the pharmacokinetics of EE and norelgestromin (NGMN), an active metabolite of NGM, at steady state, including area under the concentration-time curve for 1 dosing interval (AUC0-τ,ss ) and maximum observed concentration (Css[max] ). RESULTS: The study enrolled 25 participants, with pharmacokinetic data assessed for 20 participants. A single 75 mg dose of rimegepant co-administered with EE/NGM increased exposures of EE and NGMN by ≤16% (geometric mean ratio [GMR], 1.03; 90% confidence interval [CI], 1.01-1.06; and GMR, 1.16; 90% CI, 1.13-1.20, respectively). After 8 days of co-administering EE/NGM with rimegepant, EE pharmacokinetic parameters, AUC0-τ,ss and Css(max) , increased by 20% (GMR, 1.20; 90% CI, 1.16-1.25) and 34% (GMR, 1.34; 90% CI, 1.23-1.46), respectively, and NGMN pharmacokinetic parameters increased by 46% (GMR, 1.46; 90% CI, 1.39-1.52) and 40% (GMR, 1.40; 90% CI, 1.30-1.51), respectively. CONCLUSIONS: The study identified modest elevations in overall EE and NGMN exposures after multiple doses of rimegepant, but these elevations are unlikely to be clinically relevant in healthy females with migraine.

The role of combined oral contraceptives containing norgestimate for acne vulgaris treatment: a review.

INTRODUCTION: Both Food and Drugs Administration and European Medicine Agency (EMA) approve the use of a triphasic combined oral contraceptive (COC) containing ethinyl-oestradiol (EE) and norgestimate (NGM) for acne vulgaris treatment in women requiring an effective contraception. COCs can target sebum production and may also play a role in decreasing follicular hyperkeratinisation. RESULTS: Specific advantages of the use of an anti-androgenic progestin such as NGM in this condition are presented in this review, including the lowest venous thrombosis risk in the COCs scenario, as established by the EMA, associated with a very satisfactory cycle control. The results of aggregate analysis of published data (n = 163 vs. n = 161 treated subjects) demonstrate a significant effect in comparison with the placebo of a greater than 50% reduction, in terms of inflammatory lesions (from 19.0 to 8.2), comedones (from 35.2 to 17.7) and total lesions (from 54.3 to 25.9) count. CONCLUSIONS: The choice of a triphasic combination of EE/NGM seems a referenced, highly effective, easy-to-use and safe therapeutic approach for acne vulgaris, alone or in combination with different targeted drugs.

Triphasic ethinyl-oestradiol and norgestimate is on label for mild to moderate acne vulgaris treatment worldwide, in women requiring an effective contraception. This combination demonstrated a significant effect in comparison with the placebo of a greater than 50% reduction, in terms of inflammatory lesions, comedones and total lesions count.

The paradigm of norgestimate: a third-generation testosterone-derivative progestin with a peripheral anti-androgenic activity and the lowest risk of venous thromboembolism.

INTRODUCTION: Norgestimate (NGM) is a testosterone derivative with peculiar receptor activities. AREAS COVERED: This is a narrative review of the available data on the pharmacotherapy of NGM in combined hormonal contraceptives (CHCs) in terms of contraceptive efficacy, venous thromboembolism (VTE) risk, safety, tolerability and bleeding patterns. A comprehensive literature review was conducted in August 2020 using PubMed with the keyword 'norgestimate'. EXPERT OPINION: NGM shows a mild estrogenic activity associated with anti-mineralocorticoid and anti-androgenic properties, largely responsible for the cardiovascular safety profile. The anti-androgenic property depends on the androgen receptor (AR) nuclear translocation (AR trafficking and its subnuclear distribution), the inhibition of 5α-reductase activity (it possesses higher activity compared to other available progestins), and the increase on sexual hormone binding globulin (SHBG) levels if combined with an estrogenic counterpart. NGM is one of the molecules that best modulates the power of ethinyl-estradiol on the thromboembolic risk, being associated with the lowest VTE risk between different CHCs. NGM has the advantage of retaining peripheral anti-androgenic activity, demonstrated by the impact on lipid and glucose metabolism, and it should be preferred if compared with other similar progestins of the same class of risk which are much more androgenic, such as levonorgestrel.

UPLC-MS/MS assay for the simultaneous determination of ethinyl estradiol, norgestimate and 17-Desacetyl norgestimate at low pg/mL in human plasma.

Previously, because of the difficulty of measuring very low levels (pg/mL) of norgestimate (NGM) due to rapid metabolism to its active and major metabolite, 17-Desacetyl norgestimate (DNGM), only DNGM and the co-administered ethinyl estradiol (EE2) were required to be analyzed in bioequivalence (BE) studies for oral contraceptive NGM/EE2 tablets. Recently, with more sensitive assays available, health authorities have requested that bioequivalence of NGM be also demonstrated in addition to DNGM and EE2. Therefore, it was important to establish a 3-in-1 method for the quantitation of EE2, NGM and DNGM in human plasma. Here a UPLC-MS/MS method for the simultaneous quantitation of EE2, NGM and DNGM in human plasma at low pg/mL range is described. EE2, NGM, DNGM and their isotopic labeled internal standards (IS) EE2-d4, NGM-d6 and DNGM-d6 in 0.4mL of human plasma were extracted with hexane/ethyl acetate. The extracts were evaporated to dryness and derivatized with dansyl chloride, to enhance the mass spec response. The derivatives were reconstituted with methanol and analyzed by UPLC-MS/MS. In order to minimize the ex-vivo conversion of NGM to DNGM, sodium fluoride/potassium oxalate was used as anti-coagulant. To achieve desirable throughput for sample analysis, UPLC-MS/MS with a run time of 4.4min was utilized. The calibration curve ranges were 5-500pg/mL for EE2 and NGM, and 25-2500pg/mL for DNGM, respectively. The chromatographic separation was achieved on a Waters Acquity UPLC HSS T3 (100×2.1mm, 1.8µm) column with a gradient elution. Assay accuracy, precision, linearity, selectivity, sensitivity and analyte stability covering sample storage and analysis were established. This validated UPLC-MS/MS method has been applied to a BE study for the determination of EE2, NGM and DNGM concentrations in human plasma.

Simultaneous determination of estrogens (ethinylestradiol and norgestimate) concentrations in human and bovine serum albumin by use of fluorescence spectroscopy and multivariate regression analysis.

The endocrine disruption property of estrogens necessitates the immediate need for effective monitoring and development of analytical protocols for their analyses in biological and human specimens. This study explores the first combined utility of a steady-state fluorescence spectroscopy and multivariate partial-least-square (PLS) regression analysis for the simultaneous determination of two estrogens (17α-ethinylestradiol (EE) and norgestimate (NOR)) concentrations in bovine serum albumin (BSA) and human serum albumin (HSA) samples. The influence of EE and NOR concentrations and temperature on the emission spectra of EE-HSA EE-BSA, NOR-HSA, and NOR-BSA complexes was also investigated. The binding of EE with HSA and BSA resulted in increase in emission characteristics of HSA and BSA and a significant blue spectra shift. In contrast, the interaction of NOR with HSA and BSA quenched the emission characteristics of HSA and BSA. The observed emission spectral shifts preclude the effective use of traditional univariate regression analysis of fluorescent data for the determination of EE and NOR concentrations in HSA and BSA samples. Multivariate partial-least-squares (PLS) regression analysis was utilized to correlate the changes in emission spectra with EE and NOR concentrations in HSA and BSA samples. The figures-of-merit of the developed PLS regression models were excellent, with limits of detection as low as 1.6×10(-8) M for EE and 2.4×10(-7) M for NOR and good linearity (R(2)>0.994985). The PLS models correctly predicted EE and NOR concentrations in independent validation HSA and BSA samples with a root-mean-square-percent-relative-error (RMS%RE) of less than 6.0% at physiological condition. On the contrary, the use of univariate regression resulted in poor predictions of EE and NOR in HSA and BSA samples, with RMS%RE larger than 40% at physiological conditions. High accuracy, low sensitivity, simplicity, low-cost with no prior analyte extraction or separation required makes this method promising, compelling, and attractive alternative for the rapid determination of estrogen concentrations in biomedical and biological specimens, pharmaceuticals, or environmental samples.

Quantification of 17-desacetyl norgestimate in human plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application to bioequivalence study.

A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the estimation of 17-desacetyl norgestimate in human plasma using solid-phase extraction technique. 17-desacetyl norgestimate D6 was used as the internal standard. Simple gradient chromatographic conditions and mass spectrometric detection enabled accurate and precise measurement of 17-desacetyl norgestimate at sub-picogram levels. The proposed method was validated for a linear range of 20-5000 pg/mL with a correlation coefficient ≥0.9988. The intra-run and inter-run precision and accuracy were within 10%. The overall recoveries for 17-desacetyl norgestimate and 17-desacetyl norgestimate D6 were 96.30% and 93.90%, respectively. The total run time was 4.5 min. The developed method was applied for the determination of the pharmacokinetic parameters of 17-desacetyl norgestimate following a single oral administration of a norgestimate and ethinyl estradiol 0.250 mg/0.035 mg tablets in 35 healthy female volunteers.

Importance of levonorgestrel dose in oral contraceptives for effects on coagulation.

Combined oral contraceptives show clear differences in effect on the tissue factor-initiated coagulation test of activated protein C resistance, which is dependent on the presence and dosage of levonorgestrel. Multiphasic levonorgestrol oral contraceptives differ from monophasic contraceptives and resemble third-generation contraceptives.

PIP: The significance of levonorgestrel dose in oral contraceptives for effects on coagulation is presented. A study in Germany was conducted to test the activated protein C resistance and assess the differences induced by various combined oral contraceptives (COCs). A resistance to activated protein C of monophasic COCs with desogestrel, gestodene, or norgestimate close to the value of women heterozygous for factor V Leiden was confirmed. Higher concentrations of levonorgestrel counteract the increase in resistance. Thus, monophasic and multiphasic COCs with levonogestrel were distinguished according to their effects on tissue-factor-initiated resistance to activated protein C. A more detailed comparison of in-vitro coagulation effects and epidemiology will further assess the plausibility and mechanisms of resistance in relation to activated protein C acquired by COC use and venous thromboembolism.

Nomenclature of the gonane progestins.

PIP: The use of gonane nomenclature can be traced back to the early 1960s, when the first compound submitted for trial, the carbon-18 homologue of the anabolic agent Nilevar was named bisnortestosterone. However, the confusion about how this compound was named led scientists to introduce the gonane system for naming bisnortestosterones and structurally related compounds. Use of the terms gonane and estrane to classify the levonorgestrel and norethindrone families of progestins, respectively, originates from the systemic name of these compounds. Levonorgestrel is 17beta-hydroxy-17alpha-ethinyl-13beta-ethyl-4-gonen-3-one, while norethindrone is 17beta-hydroxy-17alpha-ethinyl-4-estren-3-one. The term gonane signifies that levonorgestrel and the related progestins are a separate class of steroids that differ from other steroids. Levonorgestrel and the related progestins form a structural category of 18-homologated 19-nortestosterones. Thus, it would be better to categorize levonorgestrel and the structurally related progestins such as desogestrel, norgestimate, gestodene as carbon-18-homologated 19-nortestosterones. Alternatively, it is simpler to refer to these compounds as the levonorgestrel family of progestins. In a similar manner, norethindrone and the related progestins can be referred to as the norethindrone (norethisterone) family of progestins.^ieng

Effect of two oral contraceptives containing ethinyl estradiol and gestodene or norgestimate on different lipid and lipoprotein parameters.

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.

PIP: 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.

WHO scientific group meeting on cardiovascular disease and steroid hormone contraceptives.

PIP: More than 100 million women worldwide are thought to use steroid hormone contraceptive methods, with an estimated 93 million women using combined oral contraceptives (COCs). The composition and use of these contraceptive preparations, especially those of COCs, have changed dramatically over the years. The World Health Organization (WHO) convened a Scientific Group Meeting on Cardiovascular Disease and Steroid Hormone Contraception during November 3-7, 1997, to review current scientific data on the use of steroid hormone contraception as they relate to the risk of myocardial infarction, ischemic and hemorrhagic stroke, and venous thromboembolic disease. The group also reviewed the incidence of cardiovascular disease among women of reproductive age in general, how the effect of risk factors for cardiovascular disease may be changed using hormonal contraceptives, and whether different compositions of COCs have different cardiovascular risk profiles. The group was comprised of the authors of background papers prepared for the meeting and experts from around the world. The scientific group's conclusions are presented. The incidence and mortality rates of all cardiovascular diseases are very low among reproductive-age women. For women who do not smoke, who have their blood pressure checked, and who do not have hypertension or diabetes, the risk of myocardial infarction in COC users is not increased regardless of age. While current users of COCs have a low absolute risk of venous thromboembolism, their risk is still 3-6 times greater than that of nonusers, with the risk probably being highest during the first year of use.^ieng

Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris.

BACKGROUND: An excess of androgen is believed to contribute to development of acne in some patients. Because oral contraceptives (OCs) may reduce the active androgen level, hormonal therapy with OCs has been used successfully to treat patients with acne, although this treatment has previously not been studied in placebo-controlled trials. OBJECTIVE: Our purpose was to evaluate the efficacy of a triphasic, combination OC (ORTHO TRI-CYCLEN [Ortho-McNeil Pharmaceutical, Raritan, N.J.], norgestimate/ethinyl estradiol) compared with placebo in the treatment of moderate acne vulgaris. METHODS: Two hundred fifty-seven healthy female subjects, 15 to 49 years of age with moderate acne vulgaris, were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects received either 3 consecutive weeks of the OC (i.e., tablets containing a fixed dose of ethinyl estradiol [0.035 mg] and increasing doses of norgestimate [0.180 mg, 0.215 mg, 0.250 mg]) followed by 7 days of inactive drug or placebo (color-matched tablets). Efficacy was assessed by facial acne lesion counts, an investigator's global assessment, a subject's self-assessment, and an analysis of within-cycle variation (cycle 6) in lesion counts. RESULTS: Of the 160 subjects in whom efficacy could be evaluated, the OC group showed a statistically significantly greater improvement than the placebo group for all primary efficacy measures. The mean decrease in inflammatory lesion count from baseline to cycle 6 was 11.8 (62.0%) versus 7.6 (38.6%) (p = 0.0001), and the mean decrease in total lesion count was 29.1 (53.1%) versus 14.1 (26.8%) (p = 0.0001) in the OC and placebo groups, respectively. In the investigator's global assessment, 93.7% of the active treatment group versus 65.4% of the placebo group were rated as improved at the end of the study (p < 0.001). Six of the seven secondary efficacy measures (total comedones, open comedones, closed comedones, papules, pustules, and the subject's self-assessment of study treatment) were also significantly more favorable in the OC group compared with the placebo group. CONCLUSION: An OC containing 0.035 mg of ethinyl estradiol combined with the triphasic regimen of norgestimate is a safe and effective treatment of moderate acne vulgaris in women with no known contraindication to OC therapy.

PIP: To evaluate the efficacy of a triphasic combined oral contraceptive (OC) in the treatment of moderate acne vulgaris, 231 healthy US volunteers 15-49 years of age with this dermatologic condition were enrolled in a phase III, multicenter, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects (n = 110) received either 3 consecutive weeks of Ortho Tri-Cyclen (containing a fixed dose of 0.035 mg of ethinyl estradiol and 0.180, 0.215, and 0.250 mg of norgestimate) followed by 7 days of inactive drug or placebo. The OC group showed significantly greater improvement than controls on all efficacy measures. The mean decrease in inflammatory lesion count from baseline to the sixth cycle was 11.8 (62.0%) among cases and 7.6 (38.6%) in controls, while the mean decrease in total lesion count was 29.1 (53.1%) versus 14.1 (26.8%) in the OC and placebo groups, respectively. In the investigator's global assessment, 93.7% of women in the treatment group and 65.4% of controls were rated as improved at the end of the study. Similarly, more cases than controls considered their acne "improved" at the study's end and expressed a preference for this therapy over other forms of acne treatment. These findings indicate that treatment of moderate acne vulgaris with a low-dose triphasic OC is safe and effective in women with no contraindications to OC use.

Increased levels of activated factor VII and decreased plasma protein S activity and circulating thrombomodulin during use of oral contraceptives.

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.

PIP: 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).

Oral contraceptives and venous thromboembolism: should epidemiologic associations drive clinical decision making?

PIP: New studies linking use of oral contraceptives (OCs) containing a third generation progestogen with venous thromboembolism (VTE) have stirred controversy. Epidemiologists face the task of separating a direct effect of the OC from the confounding effect of a pre-existing factor (e.g., smoking). Only 1-2% of VTE cases are fatal. The percentage of VTE cases that are diagnosed and treated in the hospital is low and falling. A major challenge in the epidemiologic study of non-fatal conditions is that clinical and social factors will also affect whether or when or where the diagnosis is made. The newest studies of OCs and VTE were based on cases diagnosed and treated in the hospital. They found the risks for non-fatal VTE among OC users to be about 2-4 times higher than those for non-users and 1.5-2 times higher for those using levonorgestrel-containing OCs. In the past, laboratory and epidemiologic studies have pointed to the estrogen dose as the main risk factor for VTE and thus the lower estrogen dose OCs are less likely to contribute to VTE than the older higher estrogen dose OCs. Yet the new studies found an increased risk of VTE with lower doses of estrogen. There has been consistency in the findings, leading some to conclude that causation explains the findings. A re-analysis of the data from these studies found that the highest relative risks occurred with the recently introduced desogestrel-containing OC that has only 20 mcg ethinyl estradiol. Yet it would have been expected to be safer than the other OCs. The authors concluded that clinicians may have assumed that each new OC should be safer, and thus they have been selectively prescribing them to higher risk women. Since the association between the third generation OCs and VTE risk is weak and there is no biologic explanation for the association, one should not consider the association causal. Physicians should consider all the evidence before changing OC prescription practices. Clinical actions based on weak associations undermine their credibility and that of epidemiologists.^ieng

Norgestimate.

PIP: Norgestimate (NGM) is one of a class of newer, more selective progestins. The authors describe its structure and biologic activity, contraceptive effectiveness, cycle control, metabolic effects, carbohydrate metabolism, coagulation factors, and clinical side effects. NGM-containing oral contraceptives (OC), either as a monophasic or triphasic formulation, perform as well as pills using older progestins. Androgenic side effects, however, are somewhat lower with NGM, but not enough to be of in clinical importance. Clinicians who believe in the potential for clinical consequences associated with changes in lipid and carbohydrate metabolism should make NGM their first choice OC progestin. Although no study has ever demonstrated a long-term superiority of one OC over another with respect to atherogenesis, there is some evidence that changes in HDL and LDL cholesterol, especially over a 20-year period secondary to pill use, may play a role in accelerating or retarding atherosclerosis. There are also multiple influences upon cardiovascular risk, including direct effects of estrogens upon the endothelium. The prudent healthcare professional should therefore choose, with the patient, the preparation which has the most favorable impact upon lipid metabolism.^ieng

[Pharmacology of oral contraceptives]. / Pharmacologie des contraceptifs oraux.

Oral contraceptives include two types of steroids; ethinyl-estradiol as the main estrogenic component which dose vary from 20 to 50 micrograms per tablet (mostly 30 to 35 micrograms) and progestins essentially derivatives of 19 nortestosterone. Derivatives of 19 norprogesterone such as nomegestrol acetate or ST 1435 are not used as oral contraceptives but are being evaluated through parenteral administration, e.g. implants or transdermal systems. The assessment of the pharmacological properties of these progestins indicate a high antigonadotropic and a high antiestrogenic properties for levonorgestrel and for the newer gestagens as well. Therefore very low doses are being used in the current oral contraceptives. However, there is a lower margin of security with the low dose contraceptives than with previous standard combinations and especially when concomitant medications are ingested such as enzyme-inducing agents. Selection of contraceptive methods should be discussed when specific co-medications are necessary.

PIP: Oral contraceptives (OCs) contain two types of steroids: ethinyl estradiol (the estrogenic component [20-50 mcg/pill]) and progestins derived essentially from 19-nortestosterone. The progestins derived from 19-norprogesterone (e.g., nomegestrol acetate or ST 1435) are not yet used in OCs, but are being evaluated for parenteral administration. The study of pharmacologic properties of progestins suggests that levonorgestrel and its derivatives have a powerful antigonadotropic and antiestrogenic effect, which allow them to be effective at very low doses in new OCs. These derivatives are desogestrel, gestodene, and norgestimate. The margin of safety for levonorgestrel and its derivatives is limited, especially when taken with other medication, however. Drugs that reduce the efficacy of OCs include rifampicin, antiepileptic drugs (e.g., phenobarbital), antibiotics (neomycin, lincomycin, and ampicillin), griseofulvin (an enzyme-inducing drug), antimalarials, and antacids. Thus, selection of contraceptive methods must be discussed when certain concomitant medications are required.

Desogestrel, norgestimate, and gestodene: the newer progestins.

OBJECTIVE: To review and compare the newer progestins desogestrel, norgestimate, and gestodene with regard to chemistry, pharmacokinetics, efficacy, and tolerability. DATA SOURCES: Primary literature on desogestrel, norgestimate, and gestodene was identified from a comprehensive MEDLINE English-literature search from 1984 through 1994, with additional studies selected by review of the references. Indexing terms included progestins, desogestrel, gestodene, norgestimate, levonorgestrel, and norgestrel. STUDY SELECTION: Only human clinical and pharmacokinetic trials performed in Europe, Canada, and the US were included. DATA EXTRACTION: All available data from human studies were reviewed; both comparative and noncomparative studies were included because of the paucity of direct comparative information available. DATA SYNTHESIS: The newer progestins were designed to minimize the adverse effects (e.g., acne, hirsuitism, nausea, carbohydrate and lipid metabolism changes) observed with older oral contraceptives (OCs) while maintaining efficacy and good menstrual cycle control. Desogestrel, norgestimate, and gestodene have minimal amounts of androgenicity and antiestrogenic potential. All of these agents are pharmacokinetically similar to older agents: they are highly bioavailable when administered orally, hepatically metabolized, and obtain steady-state concentrations after 8-10 days of continuous administration. The newer agents have similar Pearl Indexes and slightly better cycle control. Furthermore, the new progestins appear to cause fewer adverse effects, such as acne and hirsuitism, and similar rates of weight gain, blood pressure changes, and lipid and carbohydrate metabolism changes. CONCLUSIONS: Desogestrel, norgestimate, and gestodene appear to offer clinical advantages because of their decreased androgenicity. Women whose cycles are currently well controlled with other OCs should not be switched to a newer progestin. However, any of the combination OC products that contain these progestins may be prescribed for women intolerant of older agents or to first-time users of OCs. The newer progestins appear to be efficacious and offer similar cycle control, improved safety and tolerability profiles, and comparable price with the older agents.

PIP: The objective was to review and compare the chemistry, pharmacokinetics, efficacy, and tolerability of the newer progestins desogestrel, norgestimate, and gestodene. Data sources were primary literature on desogestrel, norgestimate, and gestodene identified from a comprehensive MEDLINE English-literature search from 1984 through 1994, with additional studies selected by review of the references. Only human clinical and pharmacokinetic trials performed in Europe, Canada, and the US were included. All available data from human studies were reviewed; both comparative and noncomparative studies were included. The newer progestins were designed to minimize the adverse effects (e.g., acne, hirsutism, nausea, blood pressure elevation, carbohydrate and lipid metabolism changes, hemostatic changes) observed with older oral contraceptives (OCs) while maintaining efficacy and good menstrual cycle control. Desogestrel, norgestimate, and gestodene have minimal amounts of androgenicity and antiestrogenic potential. All of these agents are highly bioavailable when administered orally, hepatically metabolized, and obtain steady-state concentrations after 8-10 days of continuous administration. These agents have similar Pearl Indexes and slightly better cycle control than older agents. They appear to cause fewer adverse effects such as acne and hirsutism, and similar rates of weight gain, blood pressure changes, and lipid and carbohydrate metabolism changes. Desogestrel, norgestimate, and gestodene appear to offer clinical advantages because of their decreased androgenicity; however, available data are based on relatively small studies of short duration. Women whose cycles are currently well controlled with other OCs should not be switched to a newer progestin. However, any of the combination OC products that contain these progestins may be prescribed for women intolerant of older agents or to first-time users of OCs because of their apparent efficacy, improved cycle control, superior safety, tolerability, and comparable prices. Patients who have significant acne or hirsutism with older products and diabetic women may experience clinically significant benefit with the newer agents.

Ovarian function during low-dose oral contraceptive use.

Lowering the total steroid dose in modern oral contraceptives (OCs) has been connected with a higher incidence of ovarian follicle and cyst formation. To investigate the presence of ovarian follicles and cysts by means of vaginal ultrasonography and serum hormone determinations during use of two low-dose OCs, 65 volunteers were randomized to receive either 20 micrograms ethinylestradiol (EE) + 150 micrograms desogestrel (group A) or 35 micrograms EE + 250 micrograms norgestimate (group B) for a 2-month study period. At baseline, 39% of women in group A and 31% in group B exhibited at least one follicle < 35 mm in diameter. By the end of the second treatment cycle, the frequency of these follicles had decreased to 14% in each group. Only one subject in the higher estrogen group developed an ovarian cyst > 35 mm. One subject in each group demonstrated hormone levels characteristic of ovulation; no pregnancy occurred in either group. The 20 micrograms EE preparation was not found to lead more often to ovarian follicles or cysts when compared with a 35 micrograms EE preparation, possibly because of the type and dose of the progestogen used.

PIP: In Austria, health workers randomly allocated 28 women to the group using the low-dose oral contraceptive (OC) Mercilon (20 mcg ethinyl estradiol [EE] + 150 mcg desogestrel) and 35 women to the group using the low-dose OC Cilest (35 mcg EE + 250 mcg norgestimate). No one had used OCs for at least one month before the study. Clinicians used vaginal ultrasonography and serum hormone levels to learn the degree of ovarian suppression during use of these two low-dose OCs by looking for ovarian follicles and cysts. Before beginning to use the OCs, 39% of women in the Mercilon group and 31% of those in the Cilest group had at least one ovarian follicle. By the second treatment cycle, the frequency of ovarian follicles (35 mm) had fallen significantly to 14% in both groups as compared to baseline (p 0.05). No one in the Mercilon group developed a follicle larger than 35 mm in diameter that remained for more than 4 weeks (i.e., ovarian cyst). One woman in the Cilest group did develop an ovarian cyst (46 mm), however. It appeared during the pill-free week after the first pill cycle and steadily decreased to 40 mm during the second pill cycle. One woman in each group had hormone levels indicative of ovulation. No one in either group became pregnant. These findings suggest that the type and dose of progestogen in the Mercilon OC (desogestrel) were responsible for the lower frequency of ovarian follicles and cysts in the lower-dose OC group than that in the higher-dose OC.

Effect of two oral contraceptives containing ethinylestradiol and gestodene or norgestimate upon androgen parameters and serum binding proteins.

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.

PIP: 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.

[Clinical effectiveness of Marvelon]. / Analiza kliniczna stosowania Marvelonu.

Clinical results of a new contraceptive pills--Marvelon (Organon) were studied. 32 women, ages 30 +/- 5 years, participated in the study during at least 6 cycles. Marvelon was good tolerated and subjective side-effects were very low. The cycles were regular, duration of withdrawal bleeding was 3-5 days and the amount of the blood lost were unchanged or milder. Marvelon didn't affect body weight and blood pressure. Favourable lipid profile--increased a mean level of HDL-Cholesterol and decreased a mean level of LDL-Cholesterol were noticed. Pearl Index was 0,0.

PIP: Marvelon is an oral contraceptive of the third generation of contraceptives introduced in the 1980s. These preparations contain progestagens (desogestrel, gestodene, and norgestimate) and ethinyl estradiol. Marvelon contains .03 mg of ethinyl estradiol and .15 mg of desogestrel. The results of clinical use of Marvelon (made by Organon), were studied in 32 women aged 30 +or- 5 years in the course of at least six cycles. Marvelon was well tolerated and the subjective side effects were minor. The cycles were regular and withdrawal bleeding lasted 3-5 days. The duration of menstrual cycles with the use of Marvelon constituted 27-30 days. The amount of bleeding did not change in 26 women, while it became less in 6 women. Marvelon did not affect body weight and blood pressure. The weight of the patients varied within the limit of +or- 2 kg. It produced a favorable lipid profile by increasing the mean level of high density lipoprotein (HDL) cholesterol and lowering the mean level of low density lipoprotein (LDL) cholesterol. The level of HDL cholesterol was 1.56 mmol/l in cycle 0 compared with 1.85 in cycle 6. The average level of LDL cholesterol was statistically lower in the 6th cycle of Marvelon use (2.73 mmol/l) in comparison to cycle 0 (3.29 mmol/l). Marvelon did not significantly influence the values of glucose, total cholesterol, and triglycerides. The Pearl Index was 0.0.