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.

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).

Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes.

A number of different progestogens, levonorgestrel (LNG), norethisterone (NET), gestodene (GSD), desogestrel (DG) and norgestimate (NORG) are used in combination with the oestrogen ethinyloestradiol (EE2) in oral contraceptive steroid preparations. All the progestogens are acetylenic steroids and previous studies have indicated the potential of acetylenic steroids to cause mechanism-based or "suicide" inactivation of cytochrome P-450. We have compared the effects of the different progestogens on EE2 2-hydroxylation (a reaction catalyzed by enzymes from the P-450IIC, P-450IIIA and P-450IIE gene families) and also the oxidative metabolism of other drug substrates (cyclosporin, diazepam, tolbutamide) by human liver microsomes. On coincubation with EE2 as substrate, GSD, 3-keto desogestrel (3-KD, the active metabolite of desogestrel) and LNG produced some concentration-dependent inhibition of EE2 2-hydroxylation (maximum 32% inhibition at 100 microM 3-keto desogestrel). Ki values determined for GSD and 3-KD were 98.5 +/- 12.3 and 93.2 +/- 10.3 microM (mean +/- SD; n = 4), respectively. Preincubation of progestogens in a small volume (50 microliters) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100 microM, inhibition was for GSD 39%, 3-KD 46%, LNG 46%, NET 51% and NORG 43%). Inhibitory effects were therefore comparable and also similar to the macrolide antibiotic troleandomycin. The most marked inhibition seen was of diazepam N-demethylation and hydroxylation by GSD (71 and 57%, respectively) and 3-KD (62 and 50%, respectively). In preincubation studies involving cyclosporin as the substrate, the order of inhibitory potency was GSD greater than 3-KD greater than NET greater than LNG for production of both metabolite M17 and M21. The results of the study indicate that all the progestogens in common use have the propensity to inhibit a number of oxidative pathways but there is little evidence for one progestogen being more markedly inhibitory than others.

Metabolism of the oral contraceptive steroids ethynylestradiol, norgestimate and 3-ketodesogestrel by a human endometrial cancer cell line (HEC-1A) and endometrial tissue in vitro.

Human endometrial cancer cells and human endometrial tissue have been extensively used to study steroid hormone action and metabolism. The natural estrogens estradial (E2) and estrone (E1) are known to be metabolized by both cells and tissue with the interconversion of the two steroids and the formation of sulphate conjugates. The aim of the present work was to see if the commonly used oral contraceptive steroids ethynylestradiol (EE2), norgestimate (Ngmate) and 3-ketodesogestrel (3-KDG) were metabolized by a human endometrial cancer cell line (HEC-1A) and human endometrial tissue in vitro. Metabolites were analysed by on-line radiometric HPLC. Endometrial tissue was obtained from women undergoing dilation and curettage or hysterectomy operations. In preliminary studies with endogenous estrogens, HEC-1A cells were able to interconvert E1 and E2; the equilibrium favouring the formation of E2. Normal endometrial tissue extensively converted E2 to E1, tumour tissue appeared to catalyse this reaction much less avidly. In addition sulphate conjugates were formed by normal tissue from some patients. Cell line and endometrial tissue was able to hydrolyse estrone 3-sulphate. With EE2 as substrate there was no evidence of phase I metabolism by cell line or tissue. However, conversion to the presumed 3-sulphate conjugate was observed following incubation with normal tissue from some women. Deacetylation of the progestogen Ngmate to norgestrel oxime (NgOx) was complete within 24 h. There was also some loss of the oxime moiety to give norgestrel (Ng) following incubation with HEC-1A cells. Metabolism of Ngmate was also complete within 24 h following incubation with endometrial tissue. There were both qualitative and quantitative differences in metabolite formation between tissue obtained from different women. In contrast, 3-KDG was relatively resistant to metabolism by cell line and tissue. The major metabolite formed by HEC-1A cells accounted for only 3.3 +/- 0.4% of total added radiolabelled steroid and co-chromatographed with 3 alpha-hydroxydesogestrel. Smaller amounts of other radiometabolites were formed. No phase I metabolites of 3-KDG were formed by normal endometrial tissue, however small amounts of radiometabolites appeared to be formed by malignant tissue. These studies have provided evidence to suggest that the oral contraceptives EE2, Ngmate and 3-KDG are metabolized in the human endometrium. Knowledge of the metabolism of these in target tissues such as the endometrium may be pertinent considering the possibility that metabolites may exert specific effects.

PIP: In England, pharmacologists and a biochemist at the University of Liverpool used an established human endometrial cancer cell line (HEC-1A) and human endometrial tissue in vitro to confirm that HEC-1A and tissue metabolize oral contraceptive (OC) steroids. They used on-line radiometric high-performance liquid chromatography to analyze metabolic activity. Surgeons obtained the endometrial tissue from women undergoing dilatation and curettage or hysterectomy at the Royal Liverpool University Hospital. Earlier research showed that HEC-1A cells interconvert estrone (E1) and 17 beta-estradiol (E2), with E2 predominating in the equilibrium. In this in vitro study, healthy endometrial tissue extensively changed E2 to E1, while malignant tissue caused this conversion to a much lesser extent. The healthy endometrial tissue of some patients formed sulphate conjugates. Both HEC-1A and endometrial tissue hydrolyzed E1 3-sulphate. They did not bring about phase I metabolism when ethinyl estradiol (EE2) was the substrate. Yet, incubation with healthy tissue from some women did lead to conversion of the presumed 3-sulphate conjugate. Incubation with HEC-1A cells completely removed the acetyl group from norgestimate, resulting in mainly norgestrel oxime (55.1% of metabolites) within 24 hours. It also resulted in some norgestrel (16.3%). Incubation with endometrial tissue also brought about complete metabolism of norgestimate within 24 hours. The tissue from different women brought about qualitative and quantitative differences. HEC-1A and endometrial tissue did not metabolize much of 3-ketodesogestrel (3-KDG). In fact, the major metabolite formed by HEC-1A was 3 alpha-hydroxydesogestrel, which made up 3.3% of total added radiolabeled steroid. Healthy endometrial tissue did not produce any phase I metabolites of 3-ketodesogestrel, while tumor tissue may have produced a small amount of radiometabolites. These findings indicate that the endometrium does metabolize the OC EE2, 3-KDG, and norgestimate.

Cyclic fluctuations in human serum lipid and apolipoprotein levels during the normal menstrual cycle: comparison with changes occurring during oral contraceptive therapy.

The influence of menstrual cycle phases and hormonal contraception on serum lipid and apolipoprotein (apo) levels was investigated in a group of normally menstruating young women. The study period covered a normal menstrual cycle (pretherapy), the fourth cycle of treatment with a triphasic oral contraceptive (OC) preparation, and the cycle immediately following interruption of therapy (cycle 5, posttherapy). Cycle phases were defined on the basis of serum hormone levels and basal body temperature determinations. Significant differences in cholesterol (free and esterified) levels were observed during the menstrual phase of both the normal menstrual cycle (lower) and the OC cycle (higher), when compared with the other phases. Triglycerides, which were higher under OCs, fluctuated similarly throughout the two cycles, but phase differences did not reach statistical significance. Apo AI and apo B were both higher under OCs, and apo B followed a trend similar to cholesterol during the two cycles. During the first month after discontinuation of OCs, cholesterol levels returned progressively to baseline values, while triglycerides were only partially decreased. We conclude that cyclic fluctuations in lipid levels do occur under the influence of both endogenous and exogenous sex hormones.

PIP: Total and free cholesterol, triglycerides, and apolipoproteins apo-A1 and B were determined at precise phases of a pre-therapy menstrual cycle, the 4th cycle on a triphasic oral contraceptive, and in the 1st post-therapy menstrual cycle in 18 women. The triphasic pill contained 5 mcg ethinyl estradiol and 180, 215 and 250 mcg norgestimate for 7 days each (ORF 10131 Triphasic, Ortho Pharmaceuticals, Raritan, NJ). Total cholesterol and triglycerides were measured enzymatically by autoanalyzer (Abbott Bichromatic Analyzer 100), free cholesterol by commercial kit (Boehringer-Mannheim, Mannhein, Germany), and apolipoproteins by electroimmunoassay (Hydragel Apo A1/B, Sebia, Issy- les-Moulineaux, France), with strict quality control using commercial standards. Sera were sampled in 4 phases: Days 3, 4 or 5 of menses, in the follicular phase during rising or peak estradiol levels, at ovulation at peak or highest LH level, and in luteal phase at peak progesterone level. In pill cycles, sera were sampled during each week. Total cholesterol was significantly lower in the menstrual phase, rose on average 9.2% in follicular phase (range -6.8% to +34.4%, in 13 of 18 women), and declined only slightly in luteal phase. Free and esterified cholesterol showed a similar pattern. Triglycerides similarly were lowest in menstrual phase, but were not significantly higher during menstrual cycles. In oral contraceptive cycles, total cholesterol fell an average of 10.7% in the 1st week, and remained at that level until the next pill-free interval or upon discontinuation, when cholesterol rose 11.2%. After discontinuation of the pill, all women resumed normal ovulatory cycles and showed stepwise normalization of cholesterol. Apo-A1 was significantly higher in pill cycles and pill-free intervals than in normal menstrual cycles (p0.001 at all 4 sample points); apo-B was also significantly higher in all samples form pill cycles (p0.05-0.001). There was no correlation between cholesterol levels and any of the hormone levels measured, estradiol, progesterone, LH or FSH.

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

The new era in oral contraception: pills containing gestodene, norgestimate, and desogestrel.

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)

Risks of estrogens and progestogens.

PIP: The risks and benefits of specific types of postmenopausal estrogens and progestogens are explored: those affecting serum lipids, clotting elements, hepatic proteins synthesis, blood pressure, glucose tolerance, endometrial, breast and cervical cancer. Ethinyl estradiol taken orally is the only estrogen likely to cause gall bladder disease. It also induces liver protein synthesis when taken orally or vaginally. Natural estrogens do not heighten coagulation factors, and may shift towards fibrinolysis. Both ethinyl estradiol and equine estrogens may increase blood pressure, while natural estrogens may decrease it. Similarly natural estrogens induce prostacyclin synthesis, while ethinyl estradiol activates both prostacyclin and thromboxanes. Progestagens, especially so the norprogestins, disturb carbohydrate metabolism and tend to reverse the beneficial effects of estrogens on serum lipids, a 40-70% reduction in risk of mortality from coronary heart disease. A meta- analysis of 23 studies concluded that menopausal estrogens do not increase the risk of breast cancer by a measurable degree, except in high doses and in those predisposed by family history. There is an increased risk of endometrial carcinoma for those taking unopposed estrogens for more than 3-6 years. This can be attenuated by taking combined estrogen-progestins, which will eventually result in absence of bleeding, or a 12-day progestogen course every 4-6 cycles. Oral micronized progesterone decreases blood pressure. The relative androgenic effects of progestins other than the norprogesterone derivatives are less significant. As an alternative to taking a progestogen, a woman could have regular endometrial sampling or abdominal or vaginal sonograms to detect endometrial cancer.^ieng

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

New progestogens in oral contraception.

The major developments in combined oral contraceptives (COCs) have been a reduction in the total dose of both the oestrogen and progestogen administered per cycle and the introduction of new progestogens which are claimed to be more 'selective' than the older ones. This review examines in detail the clinical efficacy of the new COCs, where possible in comparison with those containing levonorgestrel or norethisterone, and their pharmacological effect on carbohydrate and lipid metabolism, haematological factors, pituitary-ovarian function and serum protein and androgen concentrations. Based mainly on the pharmacological evidence, the newer COCs are an improvement over the older low-dose formulations and are clearly preferable to the high-dose ones. However, the older low-dose COCs, despite many years of use, have not resulted in a high incidence of adverse effects. The increasing use of the new COCs, as evidenced by their increasing market share throughout Europe, does indicate that they have been well accepted in clinical practice.

PIP: European researchers have conducted most of the clinical tests of the 3 new progestogens used in low-dose, combined oral contraceptive (OC) formulations: desogestrel (DSG), gestodene (GSD), and norgestimate (NGM). Enough clinical trial data for GSD and DSG OCs exist to compare with those of other low-dose OCs. The newer OCs are at least as effective and have at least as good cycle control as other low-dose OCs. Minor side effects of the newer OCs correspond to those of other OCs. Various flaws in studies make it hard to compare major adverse side effects of the different OCs. To compare OCs, parameters must be accurately measured. Continuation rates, measurement of blood pressure, and incidence of specific side effects can be accurately measured, but only in large comparative trials using standardized assessment methods. Other possible comparative parameters are metabolic parameters, but trials must be well-designed and adequately controlled. Almost all studies show that the new OCs do not affect fasting levels of glucose and insulin. More research is needed on the validity of a glucose tolerance test to stimulate any changes in carbohydrate metabolism, however. Recent data show that lipid metabolism may vary among the new OCs, but the research is largely limited to assessing the serum levels of various lipids. Yet, assessment of various ratios or an assay of the apoproteins are better indicators of the risk of cardiovascular disease. An assay of just high density lipoprotein-cholesterol allows researchers to distinguish between OCs. Hematologic factors are not a good basis for comparison, due to a variety of problems with measurement. Accurate measurements of serum proteins (e.g., sex hormone binding globulin) can be made, however. New OC use has increased 2-fold in 4 years in some European countries, attesting to their popularity and acceptability.

Characteristics of the new progestogens in combination oral contraceptives.

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.

PIP: 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 reported.

Systemic availability of levonorgestrel after single oral administration of a norgestimate-containing combination oral contraceptive to 12 young women.

Norgestimate is a novel progestin which undergoes both in vivo and in vitro metabolic conversions to a number of metabolites, of which the most important are levonorgestrel acetate, levonorgestrel oxime and levonorgestrel itself. It has been claimed that the progestogenic activity of norgestimate in clinical studies is almost exclusively based on the parent drug and its major metabolite, levonorgestrel oxime, and that levonorgestrel does not make an important contribution. However, to date, no data on the presence of levonorgestrel in the serum of women who have received oral doses of norgestimate have been presented. In the present study, 12 young female volunteers received single oral doses of 250 micrograms levonorgestrel in combination with 50 micrograms ethinylestradiol and 250 micrograms norgestimate in combination with 35 micrograms ethinylestradiol in an open, randomized, intraindividual comparison. Blood samples were taken at regular time intervals after each treatment, and the serum samples were analyzed for their content of levonorgestrel. Basic pharmacokinetic parameters of levonorgestrel were calculated and from the ratio of the AUC values obtained after both administrations, the bioavailability of norgestimate-derived levonorgestrel was calculated. About 22 +/- 6% of the dose of norgestimate administered became systemically available as levonorgestrel. Thus, it was concluded that levonorgestrel is a major metabolite of orally administered norgestimate, and that at least part of the pharmacologic activity of norgestimate in women is due to the presence of levonorgestrel.

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.

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.