Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial.

OBJECTIVES: To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain. DESIGN: The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial. SETTING: 34 UK hospitals. PARTICIPANTS: 405 women of reproductive age undergoing conservative surgery for endometriosis. INTERVENTIONS: Participants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill. MAIN OUTCOME MEASURES: The primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment). RESULTS: 405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference -0.8, 95% confidence interval -5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). CONCLUSIONS: Postoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some. TRIAL REGISTRATION: ISRCTN registry ISRCTN97865475.

Effects of the selective AMPA modulator NBI-1065845 on the pharmacokinetics of midazolam or ethinyl estradiol-levonorgestrel in healthy adults.

This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.

Health benefits of combined oral contraceptives - a narrative review.

PURPOSE: This review presents an update of the non-contraceptive health benefits of the combined oral contraceptive pill. METHODS: We conducted a literature search for (review) articles that discussed the health benefits of combined oral contraceptives (COCs), in the period from 1980 to 2023. RESULTS: We identified 21 subjective and/or objective health benefits of COCs related to (i) the reproductive tract, (ii) non-gynaecological benign disorders and (iii) malignancies. Reproductive tract benefits are related to menstrual bleeding(including anaemia and toxic shock syndrome), dysmenorrhoea, migraine, premenstrual syndrome (PMS), ovarian cysts, Polycystic Ovary Syndrome (PCOS), androgen related symptoms, ectopic pregnancy, hypoestrogenism, endometriosis and adenomyosis, uterine fibroids and pelvic inflammatory disease (PID). Non-gynaecological benefits are related to benign breast disease, osteoporosis, rheumatoid arthritis, multiple sclerosis, asthma and porphyria. Health benefits of COCs related to cancer are lower risks of endometrial cancer, ovarian cancer and colorectal cancer. CONCLUSIONS: The use of combined oral contraceptives is accompanied with a range of health benefits, to be balanced against its side-effects and risks. Several health benefits of COCs are a reason for non-contraceptive COC prescription.

Hospital-based interventional two-arm parallel comparative study on dydrogesterone vs combined oral contraceptive pills for functional ovarian cysts.

Background: Functional ovarian cysts are common among women of reproductive age, often necessitating medical intervention. This hospital-based interventional study compares the efficacy and safety of combined oral contraceptive pills (COC) and dydrogesterone in managing functional ovarian cysts. Methods: This randomized controlled trial will be conducted over two years at the Department of Obstetrics & Gynecology, AVBRH, Datta Meghe Institute of Medical Sciences. The study population consists of reproductive-age women seeking care at the outpatient unit of Obstetrics and Gynecology at AVBRH hospital. The sample size of 46 participants per group has been calculated based on a 95% confidence interval and the estimated prevalence of functional ovarian cysts. Group A will receive low-dose COC for three menstrual cycles. At the same time, Group B will be administered dydrogesterone (10 mg twice daily) for ten days during the luteal phase, repeated across three cycles. Expected outcomes: The primary outcomes include evaluating the recession of cysts within three months, monitoring alterations in menstrual patterns (frequency, regularity, duration, and volume), assessing the necessary treatment duration, and observing potential side effects (e.g., nausea, vomiting, weight gain, and acne) and complications (e.g., thromboembolism, delayed menstrual cycles post-treatment, and interactions with other drugs). Data analysis will encompass descriptive statistics, comparative tests, and regression models to assess the primary outcomes. The significance level for hypothesis testing will be 0.05 with a two-tailed approach. Registration: CTRI/2023/04/051811.

Anti-obesity pharmacological agents for polycystic ovary syndrome: A systematic review and meta-analysis to inform the 2023 international evidence-based guideline.

This systematic review and meta-analysis evaluated the efficacy of anti-obesity agents for hormonal, reproductive, metabolic, and psychological outcomes in polycystic ovary syndrome (PCOS) to inform the 2023 update of the International Evidence-based Guideline on PCOS. We searched Medline, EMBASE, PsycInfo, and CINAHL until July 2022 with a 10-year limit to focus on newer agents. Eleven trials (545 and 451 participants in intervention and control arms respectively, 12 comparisons) were included. On descriptive analyses, most agents improved anthropometric outcomes; liraglutide, semaglutide and orlistat appeared superior to placebo for anthropometric outcomes. Meta-analyses were possible for two comparisons (exenatide vs. metformin and orlistat + combined oral contraceptive pill [COCP] vs. COCP alone). On meta-analysis, no differences were identified between exenatide versus metformin for anthropometric, biochemical hyperandrogenism, and metabolic outcomes, other than lower fasting blood glucose more with metformin than exenatide (MD: 0.10 mmol/L, CI 0.02-0.17, I2 = 18%, 2 trials). Orlistat + COCP did not improve metabolic outcomes compared with COCP alone (fasting insulin MD: -8.65 pmol/L, -33.55 to 16.26, I2 = 67%, 2 trials). Published data examining the effects of anti-obesity agents in women with PCOS are very limited. The role of these agents in PCOS should be a high priority for future research.

Venous Thromboembolic Risk of Estradiol Valerate-Dienogest Compared with Ethinyl Estradiol-Levonorgestrel Combined Oral Contraceptives.

This pooled analysis compared the risk of venous thromboembolism (VTE) associated with combined oral contraceptives (COCs) containing estradiol (E2) valerate-dienogest with those containing ethinyl E2-levonorgestrel. Data were retrieved from two large, prospective, observational cohort studies. Propensity score subclassification was applied to balance baseline parameters between the COC user cohorts. Crude and adjusted hazard ratios (HRs) were calculated based on the extended Cox model. The pooled data set included 11,616 E2 valerate-dienogest users and 18,681 ethinyl E2-levonorgestrel users, contributing 17,932 and 29,140 women-years of observation, respectively. A significantly decreased VTE risk in E2 valerate-dienogest COCs compared with ethinyl E2-levonorgestrel COCs was observed (propensity score-stratified HR 0.46, 95% CI, 0.22-0.98). This pooled analysis expands data from a previous postauthorization safety study and provides valuable real-world safety information on the relative safety of current COCs.

Gap in knowledge of health benefits and risks of combined oral contraceptives among Lebanese women.

BACKGROUND: Oral Contraceptive Pills (OCPs) are among the most commonly used forms of contraception, but they are associated with several health benefits and risks. This study aims to determine the gap in knowledge of the underlying health benefits and risks of OCPs among Lebanese women and to identify the factors that might influence their beliefs. METHODS: A questionnaire was completed by 817 Lebanese women aged 18-64 years old and assessed sociodemographic details, medical information, contraceptive practices, knowledge of underlying health benefits and risks, and information needs related to OCPs. RESULTS: Among the total participants, 41.5% of women reported using OCPs at some point in their lives yet 46.6% denied receiving information about their benefits and 48% denied receiving information about their risks. The mean total OCP knowledge score was 5.70 out of 25, the mean OCP risk knowledge score was 4.09 out of 15, and the mean OCP benefit knowledge score was 0.77 out of 6. Sociodemographic factors associated with greater total knowledge, risk knowledge and benefit knowledge included OCP usage, being a student, confidence in one's knowledge and satisfaction with one's information. Both the total and risk knowledge scores were found to be higher in women who found that receiving information related to OCPs was important. Finally, participants who lived in central governates had greater total knowledge scores, whereas those with higher levels of education and a family history of endometrial cancer demonstrated better benefit knowledge. CONCLUSIONS: This study highlighted the poor knowledge of health benefits and risks associated with OCP use among Lebanese women and the associated sociodemographic factors that might influence their beliefs.

Is the multinational, surveillance PRO-E2 study informative for all countries? The Italian data on VTE and contraceptive effectiveness.

PURPOSE: To evaluate whether the thromboembolic risk and contraceptive effectiveness of NOMAC-E2 observed in the PRO-E2 study can be extended to each participating country, as lifestyle, cardiovascular risk factors and prescribing habits may differ geographically. This analysis was performed on the PRO-E2 Italian subpopulation, where smoking habit and women over 35 years were more prevalent compared with the overall study population. MATERIALS AND METHODS: Data from NOMAC-E2 or levonorgestrel-containing COCs (COCLNG) new users were descriptively analysed. Incidence rates of thrombosis (events/10,000 women-years [WY]) and the Pearl Index (pregnancies/100 WY) were calculated. RESULTS: Overall, 11,179 NOMAC-E2 and 8,504 COCLNG users were followed up to 2 years (34,869 WY). The NOMAC-E2 cohort included more women over 35 vs. COCLNG (37.7% vs. 31.8%; p = 0.001). A comparable low risk of combined deep venous thrombosis of lower extremities (DVT) and pulmonary embolism (PE) was observed in NOMAC-E2 (1.7/10,000 WY; 95% CI: 0.21-6.2) and COCLNG users (6.6/10,000 WY; 95% CI: 2.4-14.4). Similar results were obtained by considering all thromboembolic events (VTE). Unintended pregnancies did not differ between NOMAC-E2 (0.12/100 WY; 95% CI: 0.06-0.21) and COCLNG (0.15/100 WY; 95% CI: 0.08-0.26) cohorts. CONCLUSION: Despite the higher age and tobacco use, findings from the Italian subpopulation were broadly consistent with overall PRO-E2 results, confirming a similar low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 and COCLNG. SHORT CONDENSATION: This subgroup analysis of the PRO-E2 study provides comprehensive epidemiological data on the use of combined oral contraceptives in a large Italian cohort, with a higher prevalence of women over 35 years and smokers. The study confirms the low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 pill.

Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis.

CONTEXT: Polycystic ovary syndrome (PCOS) affects more than 1 in 10 women. OBJECTIVE: As part of the 2023 International PCOS Guidelines update, comparisons between combined oral contraceptive pills (COCP), metformin, and combination treatment were evaluated. DATA SOURCES: Ovid Medline, Embase, PsycINFO, All EBM, and CINAHL were searched. STUDY SELECTION: Women with PCOS included in randomized controlled trials (RCTs). DATA EXTRACTION: We calculated mean differences and 95% CIs regarding anthropometrics, metabolic, and hyperandrogenic outcomes. Meta-analyses and quality assessment using GRADE were performed. DATA SYNTHESIS: The search identified 1660 publications; 36 RCTs were included. For hirsutism, no differences were seen when comparing metformin vs COCP, nor when comparing COCP vs combination treatment with metformin and COCP. Metformin was inferior on free androgen index (FAI) (7.08; 95% CI 4.81, 9.36), sex hormone binding globulin (SHBG) (-118.61 nmol/L; 95% CI -174.46, -62.75) and testosterone (0.48 nmol/L; 95% CI 0.32, 0.64) compared with COCP. COCP was inferior for FAI (0.58; 95% CI 0.36, 0.80) and SHBG (-16.61 nmol/L; 95% CI -28.51, -4.71) compared with combination treatment, whereas testosterone did not differ. Metformin lowered insulin (-27.12 pmol/L; 95% CI -40.65, -13.59) and triglycerides (-0.15 mmol/L; 95% CI -0.29, -0.01) compared with COCP. COCP was inferior for insulin (17.03 pmol/L; 95% CI 7.79, 26.26) and insulin resistance (0.44; 95% CI 0.17, 0.70) compared with combination treatment. CONCLUSIONS: The choice of metformin or COCP treatment should be based on symptoms, noting some biochemical benefits from combination treatment targeting both major endocrine disturbances seen in PCOS (hyperinsulinemia and hyperandrogenism).

The role of sex hormones, oral contraceptive use, and its parameters on visuospatial abilities, verbal fluency, and verbal memory.

Sex hormones can cross the blood-brain barrier and access brain regions underlying higher-order cognition. Containing synthetic sex hormones, oral contraceptives (OC) have been found to modulate visuospatial and verbal abilities, though inconsistencies have been found in the literature. Among possible explanations, certain OC use parameters (progestin androgenicity, synthetic hormone levels, duration of use) have not received consistent consideration. Thus, the objectives were to (1) examine group differences between men, combined OC users, and naturally cycling women (NC women; not using OC) in visuospatial abilities, verbal fluency, and verbal memory and (2) investigate the contribution of endogenous and exogenous sex hormones on these effects. We also aimed to (3) identify OC use parameters relevant to cognitive outcomes. In total, 70 combined OC users, 53 early follicular (EF) women, 43 pre-ovulatory (PO) women, and 47 men underwent cognitive tests. Performance was compared based on hormonal milieus (OC, EF, PO, men) and OC users' contraceptive androgenicity (anti, low, high). Correlations between performance, hormone levels and OC use duration were also conducted. OC use dampened the sex difference that typically favors men in 3D visuospatial abilities, whereas its duration of use positively predicted verbal fluency. Androgenicity and hormone levels did not predict performance in any task. These results highlight the importance of considering OC use duration. Results also did not support a role for androgenicity in cognition. Importantly, combined OC use (including prolonged use) does not impair visuospatial, verbal, and memory functions in a healthy young sample.

Comparison of estrogenic components used for hormonal contraception.

Attempts have been made over the years to replace ethinyl estradiol (EE) in combined oral contraceptives (COCs) with the less potent natural estrogen estradiol (E2), or its prodrug, E2 valerate (E2V), to improve their safety and tolerability. Recently, a COC incorporating a novel weak natural estrogen, estetrol (E4), combined with drospirenone, has become available. We present a comparative analysis of the three prevailing estrogens used in COCs, focusing on their structure-function relationships, receptor-binding affinity, potency, metabolism, pharmacokinetic parameters, and pharmacodynamics. The binding affinity of EE to estrogen receptor (ER)α is twice that of E2, whereas its affinity for ERß is about one-half that of E2. E4 has a lower binding affinity for the ERs than E2. The high potency of EE is notable in its dramatic increase in estrogen-sensitive hepatic globulins and coagulation factors. EE and E2 undergo extensive and comparable metabolism, while E4 produces only a very limited number of metabolites. E4 has the highest bioavailability among the three estrogens, with E2 having <5%. Studies demonstrate consistent ovulation inhibition, although a higher dose of E4 (15 mg) in COCs is required to achieve follicular suppression compared to E2 (1-3 mg) and EE (0.01-0.035 mg). E2 and E4 in COCs may be less stimulatory of coagulant proteins than EE. Studies with E2/dienogest suggest a comparable risk of venous thromboembolism to EE/levonorgestrel, while data assessing risk with an E4-based COC are insufficient. Nevertheless, the E4-based formulation shows promise as a potential alternative to EE and E2 due to its lower potency and possibly fewer side effects.

Influence of gender and combined estrogen-progestin oral contraceptive on parotid saliva flow rate, pH, and electrolytes concentration.

OBJECTIVES: Endocrinal variations within an individual impact the electrolyte composition, pH, and flow-rate (FR) of saliva. The aim of this study was to evaluate the gender-specific differences and the effect of combined estrogen-progestin oral contraceptives (COCs) on FR, pH, and electrolyte concentrations in the parotid saliva (PS) of a group of healthy adults. MATERIAL AND METHODS: Stimulated PS was collected from 20 healthy adults using a Lashley cup; 11 males, 8 females, and 1 female undertaking combined contraceptive therapy (levonorgestrel/ethinyloestradiol 0.1 mg + 0.02 mg). FR and pH were recorded for each saliva sample. Electrolytes concentrations (Na+ , Ca2+ , K+ , Mg2+ ) were measured using inductively coupled plasma optical emission spectrometer (ICP-OES). Statistical analysis was performed, and the significance level was set at p < .05. RESULTS: PS FR varied from 0.13 to 0.42 mL/min in females not taking any medication and from 0.08 to 0.5 mL/min in males not taking any medication. PS pH of females and males not taking any medication ranged from 6.23 to 7.50 and from 6.15 to 7.55. PS pH and FR of the female taking COCs were 6.5 and 0.1 mL/min. PS pH, FR, and electrolytes concentrations (Ca2+ , Na+ , K+ , Mg2+ ) were not statistically significantly different between females and males not taking any medication. PS concentrations of Ca2+  and Na+ were significantly higher in the females taking COCs than in the females not taking any medication. Whereas, concentrations of K+ and Mg2+ did not differ significantly between the females taking COCs and the females not taking any medication. CONCLUSIONS: There are no significant gender-specific differences in PS flow rate, pH, and electrolyte concentrations of Na+ , Ca2+ , Mg2+ , and K+ . Combined hormonal oral contraceptive has a significant effect on PS flow rate, pH, Ca2+ , and Na+ concentrations. Whereas the PS concentration of K+ and Mg2+ are not influenced by COCs. These results warrant further investigation.

Longitudinal profile of estrogen-related thrombotic biomarkers after cessation of combined hormonal contraceptives.

ABSTRACT: The persistence of risk of venous thromboembolism (VTE) due to combined hormonal contraceptives (CHCs), after their cessation, is unknown but important to guide clinical practice. The objective of this prospective cohort study was to define the time until normalization of estrogen-related thrombotic biomarkers after CHC cessation. We enrolled women aged 18 to 50 years who had decided to stop their CHC, excluding those with a personal history of VTE, anticoagulation, or pregnancy. The study started before cessation of CHC, with 6 visits afterwards (at 1, 2, 4, 6, and 12 weeks after cessation). Primary outcomes were normalized sensitivity ratios to activated protein C (nAPCsr) and to thrombomodulin (nTMsr), with sex hormone-binding globulin (SHBG) as a secondary end point. We also included control women without CHC. Among 66 CHC users, from baseline until 12 weeks, average levels of nAPCsr, nTMsr, and SHBG decreased from 4.11 (standard deviation [SD], 2.06), 2.53 (SD, 1.03), and 167 nmol/L (SD, 103) to 1.27 (SD, 0.82), 1.11 (SD, 0.58), and 55.4 nmol/L (SD, 26.7), respectively. On a relative scale, 85.8%, 81.3%, and 76.2% of the decrease from baseline until 12 weeks was achieved at 2 weeks and 86.7%, 85.5%, and 87.8% at 4 weeks after CHC cessation, respectively. Levels were not meaningfully modified throughout the study period among 28 control women. In conclusion, CHC cessation is followed by a rapid decrease in estrogen-related thrombotic biomarkers. Two to 4 weeks of cessation before planned major surgery or withdrawal of anticoagulants in patients with VTE appears sufficient for the majority of women. The trial is registered at www.clinicaltrials.gov as #NCT03949985.

Behavioral characterization of co-exposure to cannabinoids and hormonal contraceptives in female rats.

Hormonal contraceptives are among the most widely used drugs by young healthy women to block ovulation and avoid pregnancy. They reduce the ovarian secretion of estradiol and progesterone, hormones that also modulate neuronal plasticity, cognitive functions, emotions and mood. Cannabis is the most commonly used illicit drug worldwide and its use is increasing among young women, many of which regularly take the "pill". Despite evidence of a bidirectional interaction between the endocannabinoid system and gonadal hormones, only very few studies have examined the consequences of cannabis consumption in young females under hormonal contraceptives treatment. To fill this gap, this study evaluated the behavioral effects of co-exposure to chronic 1) hormonal contraceptives, i.e., ethinyl estradiol (EE) plus levonorgestrel (LNG), one of the synthetic estrogen-progestin combinations of hormonal contraceptives, and 2) cannabinoid receptor agonist, i.e., WIN 55,212-2 (WIN), on motor activity, emotional state and cognitive functions in young adult female rats (8-11/experimental group). Hormonal and cannabinoid treatment started at post-natal day (PND) 52 and 56, respectively, while behavioral testing occurred between PND 84-95. The results show that chronic EE-LNG treatment, at doses (0.020 and 0.060 mg/rat, respectively) known to drastically reduce plasma progesterone levels, and the contextual exposure to WIN, at a dose (12.5 µg/kg/infusion) known to be rewarding in the rat, alters the hormonal milieu but does not cause further changes in locomotor activity compared to EE-LNG or WIN alone, and does not modify anxiety-like state (as measured by the elevated plus maze and the marble burying tests) and cognitive abilities (as measured by the novel object recognition and the prepulse inhibition tests) in young adult female rats. Although exposure to EE-LNG and WIN tends to increase the duration of immobility and to reduce the time spent swimming in the forced swimming test, there was not a significant additive effect suggestive of a depressive-like state. These findings allow deepening the current knowledge on the interaction between cannabinoid agonists and hormonal contraceptives and suggest that low, rewarding doses of cannabinoids do not significantly alter the motor and cognitive skills and do not induce anxiety or depressive-like states in females that use hormonal contraceptives.

Contraindicated use of modern contraceptives among mothers from a Pelotas Birth Cohort

ABSTRACT OBJECTIVE To describe the prevalence of contraindicated use of combined hormonal contraceptives, progesterone-only contraceptives, and intrauterine devices in mothers participating in the 2015 Pelotas Birth Cohort according to the WHO medical eligibility criteria. METHODS The biological mothers of children belonging to the 2015 Pelotas birth cohort who attended the 48-month follow-up were studied. The 48-month follow-up data were collected from January 1, 2019, to December 31, 2019. Contraindicated use of modern contraceptives was considered to occur when these women presented at least one of the contraindications for the use of modern contraceptives and were using these methods. The prevalence of contraindicated use was calculated according to each independent variable and their respective 95% confidence intervals (95%CI). RESULTS The analyzed sample consisted of 3,053 women who used any modern contraceptive method. The prevalence of contraindicated use of modern contraceptives totaled 25.9% (95%CI: 24.4-27.5). Combined hormonal contraceptives showed the highest prevalence of contraindicated use (52.1%; 95%CI: 49.3-54.8). The prevalence of contraindicated use of modern contraceptives methods was greater in women with family income between one and three minimum wages, a 25-30 kg/m2 body mass index, indication by a gynecologist for the used method, and purchasing the contraceptive method at a pharmacy. The higher the women's education, the lower the prevalence of inappropriate use of modern contraceptives. CONCLUSION In total, one in four women used modern contraceptives despite showing at least one contraindication. Policies regarding women's reproductive health should be strengthened.

Combined Oral Contraceptive Use and the Risk of Cervical Cancer: Literature Review.

Cervical cancer (CC) is caused by persistent infection of human papillomavirus of high oncogenic risk (hr-HPV); however, several cofactors are important in its carcinogenesis, such as smoking, multiparity, and prolonged use of oral hormonal contraceptives (COCs). Worldwide, 16% of women use COCs, whereas in Brazil this rate is of ∼ 30%. The safety and adverse effects of COCs are widely discussed in the literature, including the increase in carcinogenic risk. Due to the existence of several drugs, combinations, and dosages of COCs, it is hard to have uniform information in epidemiological studies. Our objective was to perform a narrative review on the role of COCs use in the carcinogenesis of cervical cancer. Several populational studies have suggested an increase in the incidence of cervical cancer for those who have used COCs for > 5 years, but other available studies reach controversial and contradictory results regarding the action of COCs in the development of CC.

O câncer cervical (CC) é causado pela infecção persistente pelo papilomavírus humano de alto risco oncogênico (hr-HPV); entretanto, vários cofatores são importantes na sua carcinogênese, como tabagismo, multiparidade e uso prolongado de contraceptivos hormonais orais (COCs). No mundo, 16% das mulheres usam AOCs, enquanto no Brasil essa taxa é de ∼ 30%. A segurança e os efeitos adversos dos COCs são amplamente discutidos na literatura, incluindo o aumento do risco carcinogênico. Devido à existência de várias drogas, combinações e dosagens de COCs, é difícil ter informações uniformes em estudos epidemiológicos. Nosso objetivo foi realizar uma revisão narrativa sobre o papel do uso de COCs na carcinogênese do câncer cervical. Vários estudos populacionais têm sugerido aumento da incidência de câncer de colo uterino para aquelas que usam COCs há mais de 5 anos, mas outros estudos disponíveis chegam a resultados controversos e contraditórios quanto à ação dos COCs no desenvolvimento do CCU.

Combined oral contraceptive with estetrol plus drospirenone: from pharmacokinetics to clinical applications.

INTRODUCTION: Drospirenone/estetrol (DRSP/E4) is a combined oral contraceptive (COC) recently approved in several countries. It is composed of 15 mg of E4, a natural estrogen produced by human fetal liver throughout pregnancy, and 3 mg of DRSP, the first synthetic progestin used in oral contraception derived from 17-α-spirolactone. E4 and DRSP synergistically prevent pregnancy by inhibiting ovulation. E4 differs from 17-ß-estradiol or ethinylestradiol because it represents a native estrogen with selective action in tissues (NEST), therefore it displays both agonist and antagonist estrogenic effects in different tissues. AREAS COVERED: In this paper, we reviewed the scientific literature published in English prior to April 2023 and gathered information on the pharmacodynamics and pharmacokinetics of DRSP, E4 and their combination for contraception. We also proposed possible clinical applications based on the characteristics of the components of this COC. EXPERT OPINION: E4/DRSP-based COC has shown high tolerability, safety and satisfaction and may represent a viable choice in young girls in need of oral contraception and pill users who suffer from high cholesterol, breast tenderness or water retention. Moreover, this new COC shows higher scheduled bleeding rate compared to other pills containing natural estrogens. All the data are reassuring, permitting long-term use.

Pharmacological investigation of vitamin E with combined oral contraceptives on INHBA gene against PCOS that intricate through melatonin PKC pathway.

The most prevalent endocrine and metabolic condition in women of reproductive age are polycystic ovary syndrome (PCOS) with significant risk factors such as circadian rhythm and melatonin disruption. The aim of this study is to assess the effect of vitamin E in combination with a combined oral contraceptive (COC) on continuous light-induced PCOS using hormonal measures, oxidative stress (OS) indicators, and the inhibin beta-A (INHBA) gene, which targets the melatonin protein kinase C (PKC) pathway. An in silico technique anticipated INHBA's binding affinity for vitamin E and COC. For the in vivo investigation (IAEC/240/2021), female SD rats were divided into six groups and subjected to a 16-week induction period, followed by a 2-month test drug treatment with drospirenone (DRSP) as a standard. Serum testosterone, FSH, melatonin, and OS were calculated as hormonal markers. The expression of the INHBA gene was studied to see if it could be linked to the circadian rhythm and OS via the melatonin PKC pathway. According to the in silico study, vitamin E and DRSP had higher binding energy for the INHBA (-8.6 kcal/mol and -8.4 kcal/mol, respectively). When compared to the control group, in vivo results showed a substantial decrease in testosterone levels (p = .05), as well as changes in FSH (p = .78) and melatonin (p = .13). IHNBA gene expression has also dramatically increased, stimulating FSH production in the pituitary gland. Vitamin E and COC concomitantly are beneficial against PCOS because it modulates OS, which in turn influences circadian rhythm and the melatonin PKC pathway.

Oral hormonal therapy as treatment option for abnormal uterine bleeding.

BACKGROUND: abnormal uterine bleeding is a very frequent reason for referral to gynaecologists and can deeply influence the quality of life. Once organic causes requiring surgical treatment are ruled out, clinicians should be able to manage these patients conservatively in the most effective way. MATERIALS AND METHODS: a search in PubMed/MEDLINE database was conducted in order to find relevant and recent meaningful sources for this narrative review. RESULTS: LNG-IUS 52 mg is the first-line treatment for non-organic causes. Nevertheless, it could be contraindicated or declined by the patient. Combined oral contraceptives (COC) and progestin-only pills inhibit the hypothalamic-pituitary-ovarian axis, preventing ovulation, and induce endometrial atrophy. Consequently, they are effective in treating AUB. Moreover, brand new pills containing a combination of oestrogens, progestins and GnRH antagonists are now available for the management of AUB related to uterine fibroids. CONCLUSIONS: In daily clinical practice, oral hormonal therapies are convenient and reversible tools to manage AUB when LNG-IUS 52 mg is contraindicated or turn down by the patient. Many oral hormonal therapies are prescribed to treat AUB, but only a few have been approved with this specific indication, therefore further large well-designed studies are necessary in order to compare the efficacy of different pills for treating AUB.

Even though LNG-IUS 52 mg is the first-line treatment for abnormal uterine bleeding, oral hormonal therapies should be effectively managed by gynaecologists in case of contraindications or patient's decline. Contraceptive pills are practical, but further studies are necessary to compare their efficacy and to approve them with the specific AUB indication.

Combined oral contraceptives: update recommendations of the Latin American contraceptive association.

Background: In recent years, new combined oral contraceptives (COCs) have become available, representing an advance in terms of individualization and compliance by users.Objective: To provide recommendations regarding COCs: formulations, use, efficacy, benefits and safety.Method: For these recommendations, we have used the modified Delphi methodology and carried out a systematic review of studies found in the literature and reviews performed in humans, published in English and Spanish in Pubmed, Medline and advanced medicine and computer networks until the year 2021, using the combination of terms: 'oral contraceptives', 'estroprogestins' and 'combined oral contraceptives'.Results: Regarding the estrogen component, initially switching from mestranol (the pro-drug of ethinylestradiol) to ethinylestradiol (EE) and then reducing the EE dose helped reduce side effects and associated adverse events. Natural estradiol and estradiol valerate are already available and represent a valid alternative to EE. The use of more potent 19-nortestosterone-derived progestins, in order to lower the dose and then the appearance of non-androgenic progestins with different endocrine and metabolic characteristics, has made it possible to individualize the prescription of COC according to the profile of each woman.Conclusion: Advances in the provision of new COCs have improved the risk/benefit ratio by increasing benefits and reducing risks. Currently, the challenge is to tailor contraceptives to individual needs in terms of safety, efficacy, and protection of female reproductive health.