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.

High-fat diet promotes coagulation and endothelial activation in Sprague Dawley rats: Short-term effects of combined oral contraceptives / Dieta alta en grasas promueve la coagulación y la activación endotelial en ratas Sprague Dawley: efectos a corto plazo de los anticonceptivos orales combinados

Background Combined oral contraceptives (COCs), use in individuals are associated with increased risk of thrombotic events. This highlights the significance of assessing the impact of COC on promoting coagulation and endothelial activation in high-fat diet (HFD)-fed Sprague Dawley rats. Methods Twenty (20) five-weeks-old female Sprague Dawley rats weighing between 150 and 200g were subjected to both LFD and HFD-feeding for 8-weeks to determine its influence on basic metabolic status, hemostatic profile, hemodynamic parameters (blood pressure and heart rate), as well as selected biomarkers of coagulation (tissue factor and D-dimer) and endothelial activation (Von Willebrand factor and nitric oxide). Thereafter HFD-fed animals were treated with receive high dose combined oral contraceptive (HCOC) and low dose combine oral contraceptive (LCOC) for 6 weeks. Results Our results showed that beyond weight gain, HFD-feeding was associated with hyperglycemia, increased mean arterial pressure, and reduced nitric oxide levels when compared with LFD group (p<0.05). Interestingly, treatment with high dose of COC for 6-weeks did not significantly alter atherothrombotic markers (p>0.05). However, this study is not without limitation as regulation of these markers remains to be confirmed within the cardiac tissues or endothelial cells of these animals. Conclusion HFD-feeding orchestrate the concomitant release of pro-coagulants and endothelial activation markers in rats leading to haemostatic imbalance and endothelial dysfunction. Short-term treatment with COC shows no detrimental effects in these HFD-fed rats. Although in terms of clinical relevance, our findings depict the notion that the risk of CVD in association with COC may depend on the dosage and duration of use among other factors especially in certain conditions. ... (AU)

Antecedentes El uso de anticonceptivos orales combinados (AOC) en individuos se asocia con un mayor riesgo de eventos trombóticos. Esto resalta la importancia de evaluar el impacto de los AOC en la promoción de la coagulación y la activación endotelial en ratas Sprague Dawley alimentadas con una dieta alta en grasas (HFD). Métodos Veinte (20) ratas Sprague Dawley hembra de 5semanas de edad con un peso entre 150-200g fueron tratadas mediante una alimentación con dieta baja en grasas (LFD) y alta en grasas (HFD) durante 8 semanas para determinar su influencia en el estado metabólico básico, perfil hemostático, parámetros hemodinámicos (presión arterial y frecuencia cardíaca), así como biomarcadores seleccionados de coagulación (factor tisular y D-dímero) y activación endotelial (factor de von Willebrand y óxido nítrico). Posteriormente, los animales alimentados con HFD fueron tratados con dosis alta de anticonceptivo oral combinado (AOC-AL) y dosis baja de anticonceptivo oral combinado (AOC-BL) durante 6 semanas. Resultados Nuestros resultados mostraron que, además del aumento de peso, la alimentación con HFD se asoció con hiperglucemia, aumento de la presión arterial media y niveles reducidos de óxido nítrico en comparación con el grupo LFD (p<0,05). Curiosamente, el tratamiento con dosis alta de AOC durante 6 semanas no alteró significativamente los marcadores aterotrombóticos (p>0,05). Sin embargo, este estudio no está exento de limitaciones, ya que la regulación de estos marcadores aún debe confirmarse en los tejidos cardíacos o las células endoteliales de estos animales. Conclusión La alimentación con HFD orquesta la liberación concomitante de procoagulantes y marcadores de activación endotelial en ratas, lo que conduce a un desequilibrio hemostático y disfunción endotelial. El tratamiento a corto plazo con AOC no muestra efectos perjudiciales en estas ratas alimentadas con HFD. ... (AU)

Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. METHODS: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). RESULTS: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. CONCLUSIONS: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

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.

The effect of lavender on mood disorders associated with the use of combined oral contraceptives (COCs): a triple-blinded randomized controlled trial.

BACKGROUND: The use of contraceptive methods is influenced by their effectiveness, availability, and minimal side effects. OCPs are one of the most effective and widely used methods of pregnancy prevention worldwide. This method not only prevents pregnancy but also helps prevent and treat other diseases. One of the main reasons for discontinuing this method is the emotional disturbances associated with its use. Lavender is an evergreen, fragrant plant that has gained significant attention for its anti-anxiety effects. This study was conducted to investigate the effect of lavender essential oil capsules on mood disorders during the use of COCs. METHODS: This triple-blinded clinical trial was conducted on 60 married women (aged 15-49 years old) who were consumers of COCs, referring to 26 health centers in Tabriz, Iran. The participants were randomly assigned to either the intervention (consuming one gelatin capsule containing 80 mg LEO daily) or control (consuming one placebo capsule daily) group. The intervention continued for 56 days. Scores for positive and negative were determined using the Positive and Negative Affect Schedule (PANAS) questionnaire; and for stress, depression, and anxiety were measured using the DASS-21 questionnaire on day's 28th and 56th post-intervention. Data analysis was conducted using the t-test and ANOVA with repeated measures, and a p-value of < 0.05 was considered significant for all analyses. RESULTS: A statistically significant difference was observed in mood disorders, stress, and depression between women receiving LEO or placebo. The consumption of LEO increased the positive mood on day 28 [MD (95% CI): 4.5 (2.1 to 7.0), p = 0.001] and day 56 [5.9 (3.4 to 8.3), p < 0.001] while decreased the negative mood on day 28 [MD (95% CI): -3.5 (-5.3 to -1.3), p < 0.001] and day 56 [-4.3 (-6.3 to -2.2), p < 0.001], stress on day 28 [MD (95% CI): -4.9 (-7.1 to -2.8), p = 0.001] and day 56 [-5.3 (-7.6 to -3.1), p < 0. 001], and depression on day 28 [MD (95% CI): -3.0 (-4.9 to 1.1), p = 0.003] and day 56 [-3.1 (-5.0 to 1.2), p = 0.002]. There was no statistically significant difference between the two groups in terms of anxiety. CONCLUSIONS: The consumption of LEO with COCs improved mood disorders and reduced stress and depression. The use of hormonal contraceptives and mood changes should be considered by providers. Therefore, regarding the possibility of mood changes, it is expected that appropriate counseling and education will be provided to women who consume COC., providing appropriate solutions, including the simultaneous use of LEO.

Progestogen only contraception in women with congenital heart disease.

BACKGROUND: There is little information of progestogen-only contraceptives in patients with congenital heart disease (CHD) on the long-term. OBJECTIVE: To evaluate the use of contraception in patients with CHD. We studied both short-acting reversible contraceptives (SARCs), oral progestin-only pills (POPs) and long-acting reversible contraceptives (LARCs): intrauterine devices (IUD-IPs) and subdermal implants both impregnated with progestogens (SI-IPs). STUDY DESIGN: Retrospective study of all women attending the preconception clinic. Contraceptive methods were classified in three TIERs of effectiveness before and after consultation. ESC classification regarding pregnancy risk, WHOMEC classification for combined oral contraceptive safety was collected. RESULTS: Six hundred and fifty-three patients. A significant proportion of them switched from TIER 3 to TIER 2 or 1 (p < .001) after consultation. One hundred and ninety-nine patients used POPs, 53 underwent IUD-IPs implantation and 36 SI-IPs, mean duration was 58 ± 8, 59 ± 8 and 53 ± 38 months, respectively. CONCLUSIONS: Because of their safety and efficacy, IUD-IPs and SI-IPs should be considered as first-line contraception in patients with CHD.

We looked at the use of progestogen-only contraceptives in women with congenital heart disease (CHD) over a long period and determine how safe and effective these contraceptives are for such patients. We considered two types of contraceptives: short-acting ones like progestin-only pills (POPs) and long-acting ones like intrauterine devices and subdermal implants that release progestogens.We gathered information from 653 women and assessed how women's contraceptive choices changed before and after they had a consultation with us.After consulting with our clinic, a significant number of women switched from less effective contraceptives to more effective ones. Among the women who used POPs, most of them followed the prescribed regimen quite well. Additionally, 89 women used long-acting contraceptives, without failure of method.In conclusion, our findings suggest that long-acting progestogen-only contraceptives are safe and effective choices for contraception in women with CHD. Therefore, these options should be considered as the first choice.

The effects of dienogest and combined oral contraceptives on protein S-specific activity in endometriosis patients.

OBJECTIVE: One serious side effect of combined oral contraceptives (COCs) is venous thromboembolism. Reduced activity in activated protein C-related coagulation pathways is attributable to low protein S activity in one-third of Japanese patients with deep vein thrombosis. Herer, we quantified the behavior of protein S-specific activity in response to dienogest (DNG) and COCs using the protein S-specific activity assay system to explore its potential utility as a thrombosis marker. STUDY DESIGN: This was a prospective cohort study. Female patients aged 20 - 49 years who were starting drug treatment for endometriosis using DNG or COCs were enrolled. Blood samples were taken before treatment and at the first, third, and sixth months of treatment. To analyze the primary endpoints, changes in total protein S antigen levels, total protein S activity, and protein S-specific activity from baseline to each time point were estimated using a linear mixed-effects model. All statistical analyses were performed in the SAS software version 9.4 (SAS Institute, Cary, NC). A two-sided P < 0.05 was considered statistically significant. RESULTS: 64 patients took DNG and 34 patients took COCs. Protein S-specific activity did not change significantly from baseline in the six months after treatment started in either group. In the DNG group, total protein S activity and total protein S antigen levels increased slightly from baseline levels after the treatment. The means for total protein S activity and total protein S antigen levels in the COC group remained within reference limits, but they both decreased markedly in the first month and stayed low. Protein S-specific activity in four women remaind below the reference limit throughout the whole study period, suggesting they may have potential protein S deficiencies. CONCLUSION: The effects of DNG on protein S were negligible, though both total protein S activity and antigen levels decreased soon after COC treatment began and remained low. As there was no VTE event during the study, further studies with larger numbers of patients will be needed to confirm that protein S-specific activity can be a surrogate maker of VTE risk.

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.

Effect of combined oral contraceptive on cardiorespiratory function and immune activation in premenopausal women involved in exercise: A systematic review protocol.

BACKGROUND: The use of combined oral contraceptive (COC) is common among women of reproductive age despite the potential risk of them developing thrombotic events. There is a need to understand how COC affects cardiorespiratory function and markers of immune activation in premenopausal women involved in exercise. This highlights a need for a systematic review to enhance our understanding of how the use of COC affects cardiovascular health in premenopausal women subjected to exercise. METHOD: This systematic review protocol was prepared following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) 2015 statement. An extensive search of relevant literature by two independent reviewers will be conducted through the EBSCOhost interface to access databases such as MEDLINE, EMBASE, and CINAHL. Other health sources, including Cochrane CENTRAL, unpublished studies and grey literature, will also be searched. The search will include all studies that report the effect of COC on essential parameters of cardiorespiratory function and markers of immune activation in premenopausal women involved in exercise. All included studies will be appraised using appraisal tools, while appropriate extraction tools will be used for data extraction. Where possible, eligible studies will be pooled for meta-analysis. If statistical pooling is not feasible, our findings will be presented in a narrative format. The certainty of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation Assessment (GRADE) tool. TRIAL REGISTRATION: PROSPERO registration number: CRD42021265257.

Continuous combined oral contraceptive use versus vitamin E in the treatment of menstrual migraine: rationale and protocol of a randomized controlled trial (WHAT!).

BACKGROUND: Currently, there is no evidence-based hormonal treatment for migraine in women. Several small studies suggest a beneficial effect of combined oral contraceptives, but no large randomized controlled trial has been performed. As proof of efficacy is lacking and usage may be accompanied by potentially severe side effects, there is a great need for clarity on this topic. METHODS: Women with menstrual migraine (n = 180) are randomly assigned (1:1) to ethinylestradiol/levonorgestrel 30/150 µg or vitamin E 400 IU. Participants start with a baseline period of 4 weeks, which is followed by a 12-week treatment period. During the study period, a E-headache diary will be used, which is time-locked and includes an automated algorithm differentiating headache and migraine days. RESULTS: The primary outcome will be change in monthly migraine days (MMD) from baseline (weeks - 4 to 0) to the last 4 weeks of treatment (weeks 9 to 12). Secondary outcomes will be change in monthly headache days (MHD) and 50% responder rates of MMD and MHD. CONCLUSIONS: The WHAT! trial aims to investigate effectivity and safety of continuous combined oral contraceptive treatment for menstrual migraine. Immediate implementation of results in clinical practice is possible. TRIAL REGISTRATION: Clinical trials.gov NCT04007874 . Registered 28 June 2019.

Systematic analysis of combined oral contraceptive prescription patterns in psychotropic drug users across twelve European countries.

OBJECTIVE: To investigate prescription patterns of combined oral contraceptives (COC) among psychotropic drug users compared to non-psychotropic drug users in routine clinical practice in Europe. STUDY DESIGN: A pooled analysis of three large, prospective, multinational cohort studies including women with a new prescription of COC from 12 European countries. We calculated standardized mean differences (SMD) to investigate whether the status of psychotropic drug use (use/no use) or the psychotropic drug class (psycholeptics/psychoanaleptics) is associated with the healthcare professional's choice of a specific type of COC progestin. RESULTS: Our analysis comprised 143,069 non-psychotropic drug users and 2174 psychotropic drug users. Progestins with the highest frequency in the cohorts were levonorgestrel (non-psychotropic drug users: 33.8%; psychotropic drug users: 32.4%), nomegestrol/nomegestrol acetate (non-psychotropic drug users: 19.1%; psychotropic drug users: 26.4%), and drospirenone (non-psychotropic drug users: 15.9%; psychotropic drug users: 14.8%). SMD analysis indicated no substantial differences in COC prescription patterns between the two cohorts. However, we observed association signals for users of the herbal antidepressant St. John's wort in that those individuals more often received a prescription for drospirenone and less frequently for nomegestrol/nomegestrol acetate compared to non-psychotropic drug users. CONCLUSIONS: Psychotropic drug user status does not seem to affect healthcare professionals' decisions when prescribing COC. However, limited evidence suggests that the risk for drug interactions might differ by progestin type, and some COC might be more suitable for psychotropic drug users than others. Specific guidelines should be conveyed to healthcare professionals to assist them in contraceptive counseling. IMPLICATIONS: With exception of St. John's wort, our analysis showed no differential prescription behavior of combined oral contraceptives in psychotropic drug users and non-users. However, healthcare professionals should carefully consider psychotropic drug use in contraceptive counseling as it is still unclear whether drug interactions exist when co-administered with certain oral contraceptives.

Hormonal contraceptive use is associated with altered bone structural and metabolic responses to military training in women: An observational cohort study.

Military training increases tibial density and size. Female sex hormones may influence the adaption of bone to loading, but it is unknown if women using different hormonal contraceptives adapt similarly to military training. One hundred and sixteen women (57 women not using hormonal contraceptives [non-users], 38 combined oral contraceptive pill [COCP] users, 21 depot medroxyprogesterone acetate [DMPA] users) completed this study. Tibial volumetric bone mineral density (vBMD) and geometry were measured by peripheral quantitative computed tomography (4 %, 14 %, 38 %, and 66 % sites) at the start (week 1) and end (week 14) of British Army basic training. Circulating markers of bone and calcium metabolism were measured at weeks 1, 2, 4, 6, 10, and 14. Training increased trabecular vBMD at the 4 % site, periosteal perimeter at the 14 % and 66 % sites, and total area, cortical area, cortical thickness, and bone strength at all sites (0.1 to 1.6 %, p ≤ 0.009), with no differences between hormonal contraceptive groups (p ≥ 0.127). Trabecular vBMD increased at the 14 % site in non-users (0.8 %, p = 0.005), but not in COCP or DMPA users (p ≥ 0.205). Periosteal perimeter increased at the 38 % site in COCP (0.4 %, p < 0.001) and DMPA (0.5 %, p < 0.001) users, but not in non-users (p = 0.058). Training had no effect on periosteal perimeter at the 4 % site or cortical vBMD or endosteal perimeter at any site (p ≥ 0.168). ßCTX decreased and PINP increased during training with no difference between hormonal contraceptive groups. Training increased iPTH in non-users, but not COCP or DMPA users. Hormonal contraceptives may exert site-specific effects on the mechanobiology of bone, with higher endogenous oestradiol promoting trabecularisation and inhibiting periosteal expansion in non-users compared with hormonal contraceptive users.

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.

Prevalence of anxiety and depression among Lebanese women using oral contraceptives: a cross-sectional study.

BACKGROUND: Oral contraceptives (OCs) are used worldwide, including Lebanese women. However, the association between OCs use and anxiety or depression remains unclear. This study aims to assess the prevalence of anxiety and depression among Lebanese women using oral contraceptive pills and investigate the differential impact of combined oral contraceptives (COCs) versus progestogen-only pills (POPs) on mental health outcomes. METHODS: A cross-sectional study was conducted among a sample of Lebanese women using OCs between January and March 2023. Nine hundred nighty seven out of the 2051 women who took part in the survey met our criteria and were included in this study. Data on anxiety and depression were collected using validated and reliable scales, the Arabic versions of the Generalized Anxiety Disorder-7 Questionnaire (GAD-7) and the Patient Health Questionnaire-9 (PHQ-9). Statistical analyses, including multivariate analysis, were performed to assess the association between OCs type (COC vs. POP) and anxiety/depression. RESULTS: The prevalence of anxiety and depression among Lebanese women taking OCs was found to be 39.9% and 64.3%, respectively. Furthermore, the study revealed that POP users had 2.8 times higher odds of developing anxiety (adjusted odds ratio ORadj = 2.8 with 95% confidence interval CI of 1.770 to 4.435) p-value < 0.001 and 9.2 times higher odds of developing depression (adjusted odds ratio ORadj = 9.2 with 95% confidence interval CI of 5.790 to 14.506) p-value < 0.001 compared to COC users. CONCLUSION: The results of this study shed light on the elevated prevalence of anxiety and depression among Lebanese women using OCs and emphasized the varying effects of COCs and POPs on their mental health outcomes. Further research is needed to comprehensively understand this association, considering both the dosage and specific type of oral contraceptive to improve the overall well-being of women using these contraceptives.

A mouse model of oral contraceptive exposure: Depression, motivation, and the stress response.

Hormonal contraceptives, including oral contraceptives (OCs), regulate hormonal cycles and broadly affect physiological processes, including stress responsivity. Whereas many users describe overall improved mood, up to 10 % of OC users experience adverse effects, including depression and anxiety. Given the link between regulation of hypothalamic-pituitary-adrenal (HPA) axis, stress exposure, and risk for depression, it is likely that OC-effects on stress mediate increased risk or increased resilience to these disorders. In this study, we developed and characterized a tractable mouse model of OC exposure with which to identify the mechanisms underlying OC modulation of brain, behavior, and mood. Specifically, we aimed to determine whether translationally relevant doses of OC-hormones in mice mimic changes in stress responsivity observed in humans taking OCs and describe behavioral changes during OC exposure. Young adult female C57Bl/6 N mice received daily ethinyl estradiol (EE) and levonorgestrel (LVNG) in 10 % sucrose, EE and drospirenone (DRSP) in 10 % sucrose, or 10 % sucrose alone. Translationally relevant doses of EE + LVNG-exposure, but not EE + DRSP, suppressed the acute stress response, consistent with effects observed in human OC users. EE + LVNG caused a specific anhedonia-like effect, without broad changes in stress-coping behavior, other depression-like behaviors, or anxiety-like behaviors. The suppression of regular estrous cycling, together with the blunting of the corticosterone response to acute stress, demonstrate the utility of this model for future studies to identify the mechanisms underlying OC interactions with stress, motivation, and risk for depression.

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.

High-fat diet promotes coagulation and endothelial activation in Sprague Dawley rats: Short-term effects of combined oral contraceptives.

BACKGROUND: Combined oral contraceptives (COCs), use in individuals are associated with increased risk of thrombotic events. This highlights the significance of assessing the impact of COC on promoting coagulation and endothelial activation in high-fat diet (HFD)-fed Sprague Dawley rats. METHODS: Twenty (20) five-weeks-old female Sprague Dawley rats weighing between 150 and 200g were subjected to both LFD and HFD-feeding for 8-weeks to determine its influence on basic metabolic status, hemostatic profile, hemodynamic parameters (blood pressure and heart rate), as well as selected biomarkers of coagulation (tissue factor and D-dimer) and endothelial activation (Von Willebrand factor and nitric oxide). Thereafter HFD-fed animals were treated with receive high dose combined oral contraceptive (HCOC) and low dose combine oral contraceptive (LCOC) for 6 weeks. RESULTS: Our results showed that beyond weight gain, HFD-feeding was associated with hyperglycemia, increased mean arterial pressure, and reduced nitric oxide levels when compared with LFD group (p<0.05). Interestingly, treatment with high dose of COC for 6-weeks did not significantly alter atherothrombotic markers (p>0.05). However, this study is not without limitation as regulation of these markers remains to be confirmed within the cardiac tissues or endothelial cells of these animals. CONCLUSION: HFD-feeding orchestrate the concomitant release of pro-coagulants and endothelial activation markers in rats leading to haemostatic imbalance and endothelial dysfunction. Short-term treatment with COC shows no detrimental effects in these HFD-fed rats. Although in terms of clinical relevance, our findings depict the notion that the risk of CVD in association with COC may depend on the dosage and duration of use among other factors especially in certain conditions. However, additional studies are required to confirm these findings, especially long-term effects of this treatment within the cardiac tissues or endothelial cells of these animals in certain conditions relating to postmenopausal state.