Oral contraceptives in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of women of reproductive age and combined oral contraceptives (OCs) are often the first-line treatment of the syndrome by improving hyperandrogenism and regulating menstrual cycles. Oral contraceptives have some cardiovascular and metabolic effects that varies among different formulations depending upon the dose and type of the both estrogen and progestin components. These cardiometabolic effects of OCs raise some concerns about their long-term use in PCOS, but available data suggest that the benefits outweigh the risks. More studies are needed to clarify the safety of long-term use of OCs in PCOS.

[Modern combined oral contraceptive pills].

Hormonal contraceptives possess unique additional (non-contraceptive) properties that offer potential health benefits and help maintaining good quality of life. This review presents the existing notions about molecular mechanisms of the direct and side effects of combined oral contraceptive pills (COCPs), and gives a generalized classification of synthetic progestins. A new illustrative scheme, showing the androgen and corticoid properties of synthetic progestins, is presented. Main principles of the individual selection of hormonal COCPs are discussed.

Contraception, venous thrombosis and biological plausability.

Exogenous use of hormones leads to different impact on coagulation. Usually estrogen leads to an activation of coagulation, while use of progestogens alone do not. Combined oral contraceptives (COC) differs significantly regarding VTE risk depending on amount of estrogen and type of progestagen: COC containing desogestrol, gestoden or drospirenone in combination with ethinyl-estradiol (EE) (so called 3rd or 4th generation COC) are associated with a higher VTE risk than COC with EE and levonorgestrel or norethisterone (so called 2nd generation COC). The VTE risk for transdermal COC like vaginal ring (NuvaRing) or patch (Evra) is as high than than for COC of 3rd or 4th generation. 2nd generation COC should therefore be the first choice when prescribing hormonal contraception. Most PROGESTAGEN-only contraceptive methods do not increase VTE risk significantly. In patients with a history of venous thromboembolism (VTE) and /or a known thrombophilic defect COC are contraindicated, but progestagen-only contraceptives can be safely used in this patient group. New kinds of COC without EE but with Estradiolvalerat or Estradiol showed a much lower degree of coagulation activation than "classical" COC containing EE. If newer COC with Estradiolvalerat or Estradiol have a lower VTE risk, remains to be elucidated.

[Oral contraceptive pill and thrombotic risk: epidemiological studies]. / Pillola e rischio trombotico: gli studi wpidemiogici.

The venous thromboembolism (VTE) is a rare event during childbearing age and during the assumption of combined oral contraceptive. The absolute risk of VTE in users of combined oral contraceptives is 20-30 per 100000 women years. A number of case-control studies published in recent years have shown an apparent increase in the risk of VTE among users of oral contraceptives (OCs) containing desogestrel, gestodene, drospirenone and cyproterone, relative to the use of levonorgestrel. The data derived from these recent studies is of borderline statistical significance because any important factors are not considered to evaluate the real correlation between the assumption of OCs and risk of venous thromboembolism. Among the factors that should be considered, there are: EE dose, duration of use, coexistance of other risk factors of venous thromboembolism (age, BMI, familiarity, surgical interventions) and other prescription bias. The lack of these factors is likely to contribute to the increased risk of venous thromboembolism observed in users of third-generation OCs when compared to that in users of second-generation OCs. To date, because of the inadequacy of epidemiological studies, the data about the correlation between OCs and TVE, are not conclusive and it will be necessary to carry out other studies to clarify this debating point, definitively.

[Zoely, a combined oral contraceptive, monophasic pill containing estradiol and nomegestrol acetate]. / La médicament du mois. Zoely, une association monophasique d'estradiol et d'acétate de nomégestrol.

A new combined oral contraceptive called Zoely has just been marketed in Belgium. It contains nomegestrol acetate, a progestin known for its high contraceptive reliability based on its antigonadotropic power and long half-life. This progestin is associated with estradiol and Zoely is devoid of ethinyl estradiol, which is the usual component of the majority of combined oral contraceptives and is primarily responsible for thrombotic side effects of the pill. The compositon and type of regimen of this new oral contraceptive contribute to its efficacy and excellent clinical tolerance.

Types of progestogens in combined oral contraception: effectiveness and side-effects.

BACKGROUND: The progestogen component of combined oral contraceptives (COC) has undergone changes since it was first recognised that it's chemical structure could influence the spectrum of minor adverse and beneficial effects. The major determinants of effectiveness are compliance and continuation which may be influenced by cycle control and common side effects. The rationale of this review is to provide a systematic comparison of COCs containing the progestogens currently in use worldwide. OBJECTIVES: To compare currently available low-dose COCs containing ethinyl estradiol and different progestogens in terms of contraceptive effectiveness, cycle control, side effects and continuation rates. SEARCH STRATEGY: A search of PubMed, LILACS, EMBASE, Popline, CINAHL and the Cochrane Central Register of Controlled Trials databases was conducted in September 2010 to update the 2004 review. SELECTION CRITERIA: Randomised trials reporting clinical outcomes were considered for inclusion. We excluded studies comparing monophasic with multiphasic pills, crossover trials, trials in which the difference in total content of ethinyl estradiol between preparations exceeded 105 µg per cycle and those comparing continuous dosing regimens. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed methodological quality, applied inclusion criteria and extracted data. MAIN RESULTS: Thirty trials with a total of 13,923 participants were included, generating 16 comparisons. Overall the quality of trials was low. Only four trials were double-blind. At least twenty-three trials were sponsored by pharmaceutical companies. There was less discontinuation with second-generation compared with first-generation monophasic progestogens (3 trials, 2,709 women, Relative Risk (RR) 0.76, 95% Confidence Interval (CI) 0.67-0.86); this remained significant when only double-blind trials were considered (812 women, RR 0.79, 95% CI 0.66-0.94).Women using monophasic COC's containing third-generation progestogens were less likely to discontinue than the second-generation group (3 trials, 1,815 women, RR 0.77, 95% CI 0.60-0.98) but this was not significant when only double-blind trials were considered (RR 0.79, 95% CI 0.50-1.26]. Women in the third-generation group experienced less intermenstrual bleeding than the second-generation group (one double-blind trial, 456 women, RR 0.71, 95% CI 0.55-0.91).Compared to desogestrel (DSG), women in the drospirenone (DRSP) group were more likely to complain of breast tenderness (5 trials, 4,258 women, RR 1.39, 95% CI 1.04-1.86) and nausea (6 trials, 4,701 women, RR 1.46, 95% CI 0.96-2.21].Pregnancy rates overall were comparable but the trials had insufficient power to find potentially important differences. AUTHORS' CONCLUSIONS: Women using COCs containing second-generation progestogens may be less likely to discontinue than those using COCs containing first-generation progestogens. Based on one small double-blind trial, third-generation progestogens may be preferable to second-generation preparations with regard to bleeding patterns but further evidence is needed. Without blinding as to treatment group, comparisons between the various "generations" of progestogens used in COCs cannot be made. Until this widespread methodological flaw is overcome in better trials conducted according to CONSORT guidelines and internationally accepted definitions, no further conclusions can be drawn.

YAZ and the novel progestin drospirenone.

Drospirenone is a novel progestin that is structurally related to 17 alpha-spirolactone and has antimineralocorticoid and antiandrogenic activity. A 3-mg dose of drospirenone was first used in combination with ethinyl estradiol (EE) 30 microg in a combination oral contraceptive (COC) that is administered for 21 days, followed by a 7-day hormone-free interval (HFI) (drospirenone/30EE, or Yasmin). The 21/7 regimen is considered to be the standard regimen for COC delivery. A formulation with the metabolic benefit of COCs containing a lower estrogen dose has been developed combining drospirenone 3 mg with EE 20 microg and using a regimen of 24 days of active pills, followed by a 4-day HFI (drospirenone/20EE-24/4), or YAZ (Bayer HealthCare Pharmaceuticals Inc., Wayne, New Jersey). Since drospirenone has a half-life of > 30 hours, its activity extends for a prolonged time into the shortened HFI. This new COC has been shown to provide effective contraception and to have a good safety profile. Two large noninterventional studies have recently evaluated the safety of drospirenone/30EE in 2 areas of special interest: hyperkalemia and thromboembolic events. Use of a drospirenone-containing COC was not associated with an increased risk of either type of disorder in comparison with COCs containing other progestins. Drospirenone/20EE-24/4 provides a low dose of EE in combination with drospirenone in an effective and safe COC that is administered using a regimen with a shortened HFI. Drospirenone/20EE-24/4 is the only COC with 3 indications: contraception and the treatment of premenstrual dysphoric disorder in women who wish to use a COC for birth control, and the treatment of moderate acne in women who are at least 14-years-old, have achieved menarche and wish to use a COC for birth control.

Hormonal contraceptives: pharmacology tailored to women's health.

BACKGROUND: In recent years, several new oral contraceptives have become available. In some ways, they represent an evolution in terms of individualization and compliance on the part of women. The new formulations make it increasingly possible to prescribe a specific hormonal contraceptive on an individual basis. METHODS: A systematic literature search of PubMed was performed using the following combination of terms: 'oral contraceptives', 'estroprogestins' and 'combined oral contraceptive'. Only English-language papers published between January 2000 and July 2014 were included in our analysis. The present review analyzes all aspects of the choice of oral contraceptives in the different phases of a woman's life in detail. RESULTS: Regarding the estrogen component, lowering the dose of ethinylestradiol (EE) helped reduce associated side effects. Natural estradiol is now available and represents a valid alternative to EE. And regarding progestins, the dose has changed over time, as well as the endocrine and metabolic characteristics. These are the fruit of much research into improvement of old products (19-nor-progesterone-derived progestins) with androgenic effects and testing of new molecules with improved metabolic neutrality in terms of insulin sensitivity and lipid parameters. New progestins were a genuine turning point because they greatly reduced major side effects, such as water retention, and their anti-androgenic properties made them indicated for all forms of hyperandrogenism associated with acne and mild hirsutism. The associations of estradiol/dienogest and estradiol/nomegestrol acetate are the most suitable contraceptives for women with abundant menstrual bleeding and can increase the number of potential users of hormonal contraception. CONCLUSION: Progress in the provision of new oral contraceptives has improved the risk/benefit ratio, by increasing benefits and reducing risks. The present challenge is to tailor contraceptives to individual needs in terms of efficacy and protection of reproductive health.

Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA).

OBJECTIVES: This study aims to assess vaginal bleeding patterns and cycle control of oral contraceptives containing estetrol (E4) combined with either drospirenone (DRSP) or levonorgestrel (LNG). STUDY DESIGN: An open-label, multicentre, randomised, dose-finding study lasting six cycles in healthy women aged 18-35 years was used. Four treatments (15 mg or 20 mg E4, combined with either 3 mg DRSP or 150 mcg LNG) were administered in a 24/4-day regimen. A marketed dosing regimen of estradiol valerate with dienogest (E2V/DNG) served as reference since it contains (like E4) a natural oestrogen. RESULTS: A total of 396 women were randomised, of whom 389 received study medication, and 316 completed the study. By cycle 6, the frequencies of unscheduled bleeding and/or spotting and absence of withdrawal bleeding were the lowest in the 15 mg E4/DRSP group (33.8% and 3.5%, respectively). In the E2V/DNG reference group, these frequencies were 47.8% and 27.1%, respectively. By cycle 6, the frequency of women with absence of withdrawal bleeding was <20% for all E4 treatment groups: 3.5-3.8% combined with DRSP and 14.0-18.5% combined with LNG. By cycle 6, unscheduled intracyclic bleeding was reported by <20% of women in the 20 mg E4/LNG group (18.9%) and in the 15 mg E4/DRSP group (16.9%). CONCLUSION: This study showed that, of the four treatment modalities investigated, the 15 mg E4/DRSP combination has the most favourable bleeding pattern and cycle control. IMPLICATIONS: Due to its favourable bleeding pattern and cycle control, the 15 mg E4/DRSP combination is the preferred combination for further phase III clinical development.

Impact of estrogen type on cardiovascular safety of combined oral contraceptives.

OBJECTIVES: The International Active Surveillance study "Safety of Contraceptives: Role of Estrogens" (INAS-SCORE) investigated the cardiovascular risks associated with the use of a combined oral contraceptive (COC) containing dienogest and estradiol valerate (DNG/EV) compared to established COCs in a routine clinical setting. STUDY DESIGN: Transatlantic, prospective, noninterventional cohort study conducted in the United States and seven European countries with two main exposure groups and one exposure subgroup: new users of DNG/EV and other COC (oCOC), particularly levonorgestrel-containing COCs (LNG). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious cardiovascular events (SCE), particularly venous thromboembolic (VTEs) events. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. RESULTS: A total of 50,203 new COC users were followed up for up to 5.5years (mean value, 2.1years). Overall 20.3% and 79.7% of these women used DNG/EV and oCOC (including 11.5% LNG users), respectively. A low loss to follow-up of 3.1% was achieved. Based on 47 (VTE) and 233 (SCE) events, the primary analysis (European data set) yielded adjusted hazard ratios for DNG/EV vs. oCOC of 0.4 and 0.5, respectively. The upper bounds of the 95% confidence intervals were 0.98 (VTE) and 0.96 (SCE). The corresponding hazard ratios for DNG/EV vs. LNG showed similar point estimates but the confidence intervals included unity. CONCLUSION: DNG/EV is associated with similar or even lower cardiovascular risk compared to oCOC and LNG. IMPLICATION STATEMENT: A COC containing DNG and EV is associated with similar or even lower cardiovascular risk compared to COCs containing levonorgestrel or other progestogens.

Oral contraceptives and periodontal diseases: rethinking the association based upon analysis of National Health and Nutrition Examination Survey data.

BACKGROUND: Historic evidence suggests that use of high-dose combined oral contraceptives (OCs) (containing >50 microg of estrogen and>or=1mg progestin) places women at increased risk for periodontal diseases. Since the mid-1970s, OC formulations have dramatically changed. This study investigated the association between OC use and periodontal diseases among 4,930 National Health and Nutrition Examination Survey (NHANES) I and 5,001 NHANES III premenopausal U.S. women, aged 17 to 50 years, before and after the reduction of hormone levels in OCs. METHODS: Data for this cross-sectional study came from the first (NHANES I, 1971 to 1974) and third (NHANES III, 1988 to 1994) NHANES studies. RESULTS: The prevalence of OC use in the U.S. premenopausal female population in NHANES I was 22% and in NHANES III, 20%. Using multivariable logistic regression, a protective association between current OC use and gingivitis was suggestive but not significant in both NHANES I (odds ratio [OR]=0.65; 95% con- fidence interval [CI]: 0.42 to 1.01) and NHANES III (OR=0.80; 95% CI: 0.61 to 1.02) surveys. Current OC use was also associated with a decreased risk of periodontal disease in NHANES I (OR=0.36; 95% CI: 0.13 to 0.96) and a non-significant association in NHANES III (OR=0.73; 95% CI: 0.50 to 1.07). CONCLUSION: This analysis failed to validate the theory that earlier high- or current low-dose OC use is associated with increased levels of gingivitis or periodontitis and suggests an important reexamination of the perceived association between OC use and periodontal diseases.

Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contraceptives.

OBJECTIVE: To assess the relationship between venous thromboembolic disease (VTE) and use of low-estrogen dose (<50 microg) combined estrogen-progestin oral contraceptives (OC) and three thrombosis-related gene mutations in a United States population. DESIGN: This case-control study was conducted in 1998-2000 among women ages 15-44 years who were members of the Kaiser Permanente Medical Care Program [KPMCP] (Northern and Southern California). Cases were women with incident VTE; about three times as many women frequency matched for age were randomly selected as controls from the KPMCP membership in the same years. Data were collected in a 1 h face-to-face interview; blood was drawn to extract DNA to test for gene polymorphisms. The analysis data set comprised 196 cases (mean age 35.3 years) and 746 controls (mean age 36.2 years). RESULTS: The adjusted odds ratio (OR) for VTE associated with current OC use was 4.07 (95% confidence interval [CI]: 2.77-6.00). The OR associated with OC use was higher for women who were obese than in the nonobese (p = 0.01 for likelihood test for interaction) and in women without predisposing medical conditions (p = 0.02 for interaction). The adjusted OR for VTE was 7.10 (95% CI: 2.33-21.61) in women with factor V Leiden (G1691A) mutation, 2.83 (95% CI: 0.70-11.63) in women with prothrombin G20210A mutation and 0.26 (95% CI: 0.10-0.65) in women with the MTHFR C677T mutation. The OR for VTE in OC users with factor V Leiden mutation (11.32) was elevated more than in OC users without the mutation (3.20) and women with the mutation who were non-OC users (8.42), but confidence intervals overlapped. CONCLUSIONS: The risk of VTE is increased in users of low-estrogen OC formulations. Obese women appear to be at greater risk of VTE when using OCs.

Oral contraceptives and mood.

The past 40 years of research on the mood and behavioural effects of combined oral contraceptives (OCs) have yielded inconclusive results due to dramatic changes in the compounds and to methodological flaws inherent in studies undertaken to assess the effects of OCs. Since the late 1960s, the dosages of oestrogen and progestin in marketed OCs significantly declined and novel progestins were developed to deliver higher levels of progestogenic activity with a lower risk of adverse oestrogenic and androgenic effects. This review evaluates controlled, comparative studies that have focused on the efficaciousness of OCs as treatment for premenstrual syndrome (PMS) and those examining whether OCs may cause negative mood. It is suggested that the mood and behavioural effects of OCs might be attributed to different progestin compounds and possibly, their oestrogen ratios. There is a great need for more longitudinal, randomised, placebo-controlled studies to further clarify the mood and behavioural effects of OCs.

Cyclofem/Cyclo-Provera: emerging countries' perspective.

Cyclo-Provera, the original name of the combination of 25 mg medroxyprogesterone acetate and 5 mg estradiol cypionate, later known as Cyclofem and hereafter referred to MPA/E2C, has proven its use-effectiveness (pregnancy rate less than 1%) in routine service delivery conditions. Overall, the life-table discontinuation rates at 1 year ranged from 33.5% to 71.8%. Only a third of total discontinuations were attributable to the injectable contraceptive method, thus raising the importance of service delivery issues related to its continued use. The results of introductory trials in Mexico, Indonesia, Thailand, Tunisia, Jamaica and, more recently, Brazil, Colombia, Chile and Peru have demonstrated that MPA/E2C is a highly effective contraceptive that could be offered as an alternative to current fertility regulation methods for many women around the world. In addition, the results of studies were the basis for the approval of MPA/E2C by local health authorities and its inclusion in the Ministries of Health Family Planning Programs.

Effects of a contraceptive containing drospirenone and ethinylestradiol on blood pressure, metabolic profile and neurohumoral axis in hypertensive women at reproductive age.

UNLABELLED: The use of combined oral contraceptives is widespread among hypertensive women despite being associated with increased cardiovascular risk. Contraceptives containing drospirenone, which has antimineralocorticoid properties, may have a positive or neutral effect on neurohumoral activation and metabolic homeostasis of hypertensive women at reproductive age. OBJECTIVES: To evaluate the effect of combined oral contraceptive containing drospirenone+ethinylestradiol on the systemic blood pressure, metabolic variables and neurohumoral axis in hypertensive women in reproductive age. DESIGN: Prospective controlled trial with 56 hypertensive women allocated in two groups: 30 volunteers under oral combined contraceptive use and 26 volunteers using non-hormonal contraceptive methods. Subjects were tested before the introduction of the contraceptive method and 6 months after its use. For data acquisition, we used continuous non-invasive beat-to-beat blood pressure curve recordings and, for the biochemical and hormonal analyses two blood samples were obtained. Student's t test was used to determine differences between groups and moments and p<0.05 was considered statistically significant. RESULTS: Comparing antropometric and blood pressure measurements, cardiac sympatho-vagal modulation, baroreceptor sensitivity, metabolic and neurohumoral axis variables between baseline and after 6 months, no significant difference was detected in each group or between groups. Except serum triglyceride levels which increased in the group of women using EE+DRSP after 6 months of use. CONCLUSION: A contraceptive containing 20 mcg of ethinyl estradiol and 3 mg of drospirenone causes no significant changes in clinical and autonomic parameters, metabolic variables and neurohumoral axis of hypertensive women.

New metabolites from fungal biotransformation of an oral contraceptive agent: methyloestrenolone.

Fungal cell cultures were used for the first time for the biotransformation of methyloestrenolone (1), an oral contraceptive. Fermentation of 1 with Macrophomina phaseolina, Aspergillus niger, Gibberella fujikuroi, and Cunninghamella echinulata produced eleven metabolites 2-12, six of which 2-5, 11 and 12 were found to be new. These metabolites were resulted from the hydroxylation at C-1, C-2, C-6, C-10, C-11, and C-17α-CH3, as well as aromatization of ring A of the steroidal skeleton of substrate 1. The transformed products were identified as 17α-methyl-6ß,17ß-dihydroxyestr-4-en-3-one (2), 17α-(hydroxymethyl)-11ß,17ß-dihydroxyestr-4-en-3-one (3), 17α-methyl-2α,11ß,17ß-trihydroxyestr-4-en-3-one (4), 17α-methyl-1ß,17ß-dihydroxyestr-4-en-3-one (5), 17α-methyl-11α,17ß-dihydroxyestr-4-en-3-one (6), 17α-methyl-11ß,17ß-dihydroxyestr-4-en-3-one (7), 17α-methyl-10ß,17ß-dihydroxyestr-4-en-3-one (8), 17α-(hydroxymethyl)-17ß-hydroxyestr-4-en-3-one (9), 17α-methylestr-1,3,5(10)-trien-3,17ß-diol (10), 17α-methyl-3,17ß-dihydroxyestr-1,3,5(10)-trien-6-one (11), and 17α-methyl-6ß,10ß,17ß-trihydroxyestr-4-en-3-one (12).

Progestin-only contraception and venous thromboembolism.

Combined oral contraceptives (COC) are the most popular contraceptive method in developed countries. Since their introduction there have been numerous changes and modifications in its composition with the aim to improve safety and tolerability while maintaining contraceptive efficacy. Most of the changes have been conducted on the progestin component, since most of the combinations include ethinyl estradiol as oestrogen. One of the adverse effects of COC is the increased risk of venous thromboembolism (VTE) in two clinical forms of presentation: deep vein thrombosis or pulmonary embolism. This review details the changes in haemostasis induced by progestin-only contraceptives and the risk of VTE in women who utilize this type of contraception; the relationship with other risk factors such as thrombophilia; the interactions of these contraceptives with anticoagulant treatment and finally the eligibility criteria for the use of hormonal contraception in women with previous VTE or thrombophilia carriers.