Phase 1 study of safety and tolerability of an oral contraceptive containing low-dose ethinyl oestradiol combined with glecaprevir/pibrentasvir treatment in healthy premenopausal women.

Glecaprevir/pibrentasvir (GLE/PIB) is an approved guideline-recommended chronic hepatitis C virus infection treatment. GLE/PIB coadministration with ethinyl oestradiol (EE) is not recommended in current labels owing to a Phase 1 study observing Grade ≥2 alanine aminotransferase (ALT) elevation in 2 out of 12 healthy women cotreated for 11 days with GLE/PIB and oral contraceptive (OC) containing 35 µg/250 µg EE/norgestimate. No Grade ≥2 elevation was observed with low-dose (20 µg) EE (n = 14). This Phase 1 study examined safety/tolerability of GLE/PIB coadministered with an OC containing low-dose EE using a larger sample size and longer treatment duration. Healthy premenopausal women were treated with EE/levonorgestrel alone (20/100 µg, Cycles 1-2), followed by coadministration with GLE/PIB (300/120 mg; Cycles 3-4). A safety criterion of special interest was a confirmed Grade ≥2 ALT elevation (>3× upper normal limit). Adverse events (AEs) and study drugs concentrations were examined. Of 85 enrolled women, 72 initiated combined GLE/PIB + EE/levonorgestrel treatment, 66 completed the study and 19 discontinued prematurely (non-safety reason, n = 16; AE [deemed unelated to GLE/PIB], n = 3). No participant met the safety criterion of special interest of confirmed Grade ≥2 ALT elevation. No serious/Grade ≥3 AEs were reported. Study drug concentrations were within the expected ranges. GLE/PIB in combination with an OC containing low-dose EE was generally well tolerated with no confirmed Grade ≥2 ALT elevation and no evidence of drug-induced liver injury. No pattern to the reported AEs and no new safety issues were identified. This was a Phase 1 study of healthy volunteers, not a registered clinical trial.

Oral contraceptives in adolescents: a retrospective population-based study on blood pressure and metabolic dysregulation.

PURPOSE: This study aimed to explore the relationship between oral contraceptive use and blood pressure values and in a national cohort of women adolescents and to investigate the level of coexistence of the high blood pressure levels, dyslipidemia or insulin resistance. METHODS: This is a retrospective cohort study that evaluated data form 14,299 adolescents aged 14 to 17 years. Crude and race-and age-adjusted analyses were performed using Poisson regression to estimate the prevalence ratios. Data clustering analysis was performed using machine learning approaches supported by an unsupervised neural network of self-organizing maps. RESULTS: We found that 14.5% (n = 2076) of the women adolescents use oral contraceptives. Moreover, an increased prevalence of high blood pressure, dyslipidemia, and insulin resistance (all P < 0.001) was observed among adolescents who use oral contraceptives as compared to those who do not. Our analysis also showed that 2.3% of adolescents using oral contraceptives had both high blood pressure levels and dyslipidemia, whereas 3.2% had high blood pressure levels combined with insulin resistance (all P < 0.001). The algorithmic investigative approach demonstrated that total cholesterol, LDLc, HDLc, insulin, and HOMA-IR were the most predicted variables to assist classificatory association in the context of oral contraceptive use among women adolescents with high blood pressure. CONCLUSIONS: These findings suggest that oral contraceptives were associated with an increased prevalence of high blood pressure, dyslipidemia, and insulin resistance among women adolescents. Although the indication of this therapy is adequate to avoid unintended pregnancies, their use must be based on rigorous individual evaluation and under constant control of the cardiometabolic risk factors.

Differential changes in appetite hormones post-prandially based on menstrual cycle phase and oral contraceptive use: A preliminary study.

This was a preliminary study that examined whether appetite regulation is altered during the menstrual cycle or with oral contraceptives. Ten naturally cycling females (NON-USERS) and nine tri-phasic oral contraceptive using females (USERS) completed experimental sessions during each menstrual phase (follicular phase: FP; ovulatory phase: OP; luteal phase: LP). Appetite perceptions and blood samples were obtained fasted, 30, 60, and 90 min post-prandial to measure acylated ghrelin, active glucagon-like peptide-1 (GLP-1), and total peptide tyrosine tyrosine (PYY). Changes were considered important if p < 0.100 and the effect size was ≥medium. There appeared to be a three-way (group x phase x time) interaction for acylated ghrelin where concentrations appeared to be greater in USERS versus NON-USERS during the OP 90-min post-prandial and during the LP fasted, and 90-min post-prandial. In USERS, ghrelin appeared to be greater 90-min post-prandial in the OP versus the FP with no other apparent differences between phases. There were no apparent differences between phases in NON-USERS. There appeared to be a three-way interaction for PYY where concentrations appeared to be greater in USERS during the FP 60-min post-prandial and during the OP 30-min post-prandial. In USERS PYY appeared to be greater 60-min post-prandial during the OP versus the LP with no other apparent differences. There were no apparent differences between phases in NON-USERS. There appeared to be no effect of group or phase on GLP-1, or appetite perceptions. These data demonstrate small effects of menstrual cycle phase and oral contraceptive use on the acylated ghrelin and total PYY response to a standardized meal, with no effects on active GLP-1 or perceived appetite, though more work with a large sample size is necessary.

Acceptability of an on-demand pericoital oral contraceptive pill: a systematic scoping review.

BACKGROUND: Access to an on-demand pericoital oral contraceptive pill - used to prevent pregnancy within a defined window around sexual intercourse - could offer women more reproductive agency. A contraceptive with this indication is not currently available in any market. This review aims to understand international user appeal for an on-demand pericoital oral contraceptive pill. METHODS: Systematic scoping review, comprising 30 peer-reviewed papers published between 2014-2023. RESULTS: Data from 30 papers reporting on research from 16 countries across five World Health Organisation regions suggests widespread user appeal for on-demand oral contraceptive pills that can be used peri- or post-coitally, especially among women who are younger, more educated or who have less frequent sex. Women of varying age, wealth, employment or relationship status, and with different prior experience of using modern contraceptives, were also interested. Women identified clear rationale for use and preference of these types of product: close alignment with women's sexual lives that comprised unplanned, spontaneous or occasional sex; perceived convenience and effectiveness; discreet use of pills to negotiate contextual circumstances that constrained their reproductive agency. Factors inhibiting use included knowledge barriers and attitudes of service providers, a lack of knowledge and misinformation among end-users, women's dislike of menstrual side effects and myths related to the effects of hormone content on future fertility. CONCLUSIONS: Introduction of an on-demand pericoital oral contraceptive pill could expand contraceptive choice for diverse women experiencing unmet need for modern contraception and constrained sexual and reproductive agency. Priorities for future research include: broadening the geographical scope of evidence to include SE Asia and the Pacific, and international rural and peri-urban settings; documenting the perspectives of adolescents and unmarried young people; identifying opportunities for innovation in the supply channels to enhance appropriate, affordable access to on-demand oral contraceptives; and unpacking how to bring new pericoital contraceptives to the market in a variety of international settings.

Access to an oral contraceptive pill that is used as needed to prevent pregnancy and taken within a defined window around sexual intercourse (i.e. an on-demand pericoital oral contraceptive pill) could offer women more reproductive agency. Though not currently available in any market, our analysis from this review of international literature reveals widespread appeal among women for using this type of contraceptive product. Clear rationale supporting use and preference included: (1) closer alignment with women's sexual lives that comprised desired but unplanned, spontaneous or occasional sex than other contraceptives; (2) perceived convenience and effectiveness, offering benefits over other modern contraceptives; and (3) women feeling able to overcome social values and beliefs that constrained their reproductive agency. There were also barriers to use of this type of product, including knowledge gaps and attitudes of service providers, a lack of knowledge and misinformation among end-users, women's dislike of the side effects, and myths and misconceptions about the impact of the hormone content in pills on future fertility. Introduction of an on-demand pericoital oral contraceptive pill could expand contraceptive choice for diverse women experiencing unmet need for modern contraception and constrained sexual and reproductive agency. Priorities for future research include: broadening the geographical scope of evidence to include SE Asia and the Pacific, and rural and peri-urban settings; documenting the perspectives of adolescents and unmarried young people; identifying opportunities for innovation in the supply channels to enhance appropriate, affordable access to this type of contraceptive; and unpacking how to bring this new contraceptive to the market in a variety of international settings.

Testing effects of partner support and use of oral contraception during relationship formation on severity of nausea and vomiting in pregnancy.

BACKGROUND: A recent study focusing on dietary predictors of nausea and vomiting in pregnancy (NVP) found that women with higher levels of partner support, and those who had used oral contraception (OC) when they met the father, both tended to report less severe NVP compared with previous non-users or those with less supportive partners. We provide a further test of these factors, using a large sample of women from four countries who retrospectively scored their NVP experience during their first pregnancy. METHODS: We recruited women who had at least one child to participate in a retrospective online survey. In total 2321 women completed our questionnaire including items on demographics, hormonal contraception, NVP, and partner support. We used general linear models and path analysis to analyse our data. RESULTS: Women who had used OC when they met the father of their first child tended to report lower levels of NVP, but the effect size was small and did not survive adding the participant's country to the model. There was no relationship between NVP and partner support in couples who were still together, but there was a significant effect among those couples that had since separated: women whose ex-partner had been relatively supportive reported less severe NVP. Additional analyses showed that women who were older during their first pregnancy reported less severe NVP, and there were also robust differences between countries. CONCLUSIONS: These results provide further evidence for multiple influences on women's experience of NVP symptoms, including levels of perceived partner support.

PK-DB: pharmacokinetics database for individualized and stratified computational modeling.

A multitude of pharmacokinetics studies have been published. However, due to the lack of an open database, pharmacokinetics data, as well as the corresponding meta-information, have been difficult to access. We present PK-DB (https://pk-db.com), an open database for pharmacokinetics information from clinical trials. PK-DB provides curated information on (i) characteristics of studied patient cohorts and subjects (e.g. age, bodyweight, smoking status, genetic variants); (ii) applied interventions (e.g. dosing, substance, route of application); (iii) pharmacokinetic parameters (e.g. clearance, half-life, area under the curve) and (iv) measured pharmacokinetic time-courses. Key features are the representation of experimental errors, the normalization of measurement units, annotation of information to biological ontologies, calculation of pharmacokinetic parameters from concentration-time profiles, a workflow for collaborative data curation, strong validation rules on the data, computational access via a REST API as well as human access via a web interface. PK-DB enables meta-analysis based on data from multiple studies and data integration with computational models. A special focus lies on meta-data relevant for individualized and stratified computational modeling with methods like physiologically based pharmacokinetic (PBPK), pharmacokinetic/pharmacodynamic (PK/PD), or population pharmacokinetic (pop PK) modeling.

Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study.

BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.

Effects of oral contraceptives on serum concentrations of adipokines and adiposity indices of women with polycystic ovary syndrome: a randomized controlled trial.

PURPOSE: To compare the effects of oral contraceptives (OCs) with different progestins, including Levonorgestrel (LNG), Desogestrel (DSG), Cyproterone Acetate (CPA), and Drospirenone (DRSP) on adipokines levels and adiposity indices in women with polycystic ovary syndrome (PCOS). METHODS: In this parallel randomized clinical trial, 120 women with PCOS randomly assigned to intervention with OCs containing LNG, DSG, CPA, or DRSP. Outcomes of interest, including serum concentrations of adiponectin, leptin, and resistin, and adiposity indices, i.e., body mass index (BMI), waist circumference (WC), obesity, central obesity, waist to hip ratio (WHR), waist to height ratio (WHtR), lipid accumulation product (LAP), a body shape index (ABSI), body roundness index (BRI), and visceral adiposity index (VAI), and lipid profiles were assessed at baseline, and 6 months of treatment. RESULTS: This study showed no significant differences in serum concentrations of adipokines between the four study groups after 6 months of treatment. Our results also showed that patients treated with various compounds of OC for 6 months had no significant differences in their adiposity indices, except for LAP (p = 0.04), and VAI (p = 0.03). PCOS patients treated with OCs containing CPA had significantly a higher mean LAP, compared to those using products containing LNG. Besides, patients treated with OCs containing CPA had significantly a higher mean VAI, compared to those treated with OCs containing DRSP. CONCLUSION: This study demonstrated that OCs with low androgenic and antiandrogenic activities had identical effects on serum concentrations of adipokines, and adiposity indices, except LAP, and VAI parameters. REGISTRATION NUMBER: IRCT20080929001281N3.

Oral Contraceptive Intake and Iodine Status in Young Women.

OBJECTIVE: Similar to pregnant women, women taking an oral contraceptive (OC) might have elevated iodine requirements due to the altered hormonal state. This is the first study aimed at investigating the prevalence of iodine deficiency and possible influences of OC intake on urine creatinine and iodine levels in young women. METHODS: One hundred fifty-five women between the age of 18 and 35 years (62 taking an OC and 93 controls) participated in a cross-sectional pilot study at the Medical University of Vienna, which included a 1-spot urine sample and a questionnaire on OC intake as well as a food questionnaire. RESULTS: The median urinary iodine concentration (UIC) in this study was 68 µg/L (41, 111 µg/L) suggesting an inadequate iodine status in the women according to the WHO guidelines. Median UIC (OC: 89 µg/L, IQR 55-120; control: 59 µg/L, IQR 39-91, p = 0.010) and urine creatinine (OC: median = 99.0 µg/L, IQR 74.9-175.5; control: 77.0 µg/L, IQR 49.6-147.2, p = 0.030) levels were significantly higher in OC women than in the control group. UIC corrected for urine creatinine was comparable between both groups. CONCLUSION: With similar creatinine-corrected UICs in both groups, OC intake might not have a significant impact on iodine status. However, the low median UIC in a vulnerable group of young women potentially conceiving in the following years points at the necessity of optimizing the iodine intake in the Austrian population and reiterates the insufficiency of the current iodine supplementation measures.

Effects of oral contraceptive for different responder women before GnRH antagonists: a systematic review and meta-analysis.

This analysis aimed to compare the efficacy of oral contraceptive pill (OCP) pretreatment for gonadotropin-releasing hormone antagonist (GnRH-ant) protocol, especially for different responder women. The PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) databases were searched for trials on with and without OCP pretreatment before stimulation with gonadotropins. The standardized mean differences (SMDs) or pooled risk ratios (RRs) with 95% confidence intervals (CIs) were used for statistical analysis. Fifteen studies with 5326 in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles were summarized. The clinical pregnancy rate, moderate or severe ovarian hyper-stimulation syndrome (OHSS) rate, and miscarriage rate was not found to be significantly different between patients with and those without OCP pretreatment, even after sensitivity analyses. In addition, there were still no statistically significant differences for the subgroups analyses of hyper-responders, poor responders, and normal responders. No significant differences were detected in the duration of ovarian stimulation, gonadotropin dose consumed, endometrial thickness on day of oocyte collection, or number of oocytes. This meta-analysis did not find an unequivocally beneficial effect of OCP pretreatment for different responder women with using a GnRH-ant protocol. The clinician should weigh the advantages and disadvantages of OCP pretreatment and guide the treatment scheduling considering the patient's own situation.

The use of oral contraceptive is inversely associated with the risk of type 2 diabetes mellitus among middle-aged women.

OBJECTIVE: To assess the cross-sectional association between oral contraceptive (OC) use and type 2 diabetes mellitus (T2DM) risk among US women. METHODS: The data was obtained from the National Health and Nutrition Examination Survey (NHANES 2007-2018). OC use was assessed by questionnaires and the diagnosis of T2DM was confirmed by the glycosylated hemoglobin, fasting blood glucose, and self-report. Binary logistic regression models and the restricted cubic spline model were adopted to evaluate whether OC use was associated with T2DM. RESULTS: Compared with non-users, the odds ratio (OR) with 95% confidence interval (CI) of T2DM risk for the OC users was 0.71 (0.57-0.89) in unadjusted Model. The association remained significant in fully adjusted models, and the OR with 95%CI was 0.78 (0.62-0.99). In the stratified analyses, there was an inverse association of OC use with T2DM risk when women were overweight. Dose-response analysis also revealed an inversely nonlinear relationship between the duration of OC use and T2DM (p-value for linearity = .589). CONCLUSIONS: Our findings suggested that OC use may be inversely associated with T2DM risk.

Cardiorespiratory response to exercise in endurance-trained premenopausal and postmenopausal females.

PURPOSE: To assess the influence of different hormonal profiles on the cardiorespiratory response to exercise in endurance-trained females. METHODS: Forty-seven eumenorrheic females, 38 low-dose monophasic oral contraceptive (OC) users and 13 postmenopausal women, all of them endurance-trained, participated in this study. A DXA scan, blood sample tests and a maximal aerobic test were performed under similar low-sex hormone levels: early follicular phase for the eumenorrheic females; withdrawal phase for the OC group and at any time for postmenopausal women. Cardiorespiratory variables were measured at resting and throughout the maximal aerobic test (ventilatory threshold 1, 2 and peak values). Heart rate (HR) was continuously monitored with a 12-lead ECG. Blood pressure (BP) was measured with an auscultatory method and a calibrated mercury sphygmomanometer. Expired gases were measured breath-by-breath with the gas analyser Jaeger Oxycon Pro. RESULTS: One-way ANCOVA reported a lower peak HR in postmenopausal women (172.4 ± 11.7 bpm) than in eumenorrheic females (180.9 ± 10.6 bpm) (p = 0.024). In addition, postmenopausal women exhibited lower VO2 (39.1 ± 4.9 ml/kg/min) compared to eumenorrheic females (45.1 ± 4.4 ml/kg/min) in ventilatory threshold 2 (p = 0.009). Nonetheless, respiratory variables did not show differences between groups at peak values. Finally, no differences between OC users and eumenorrheic females' cardiorespiratory response were observed in endurance-trained females. CONCLUSIONS: Cardiorespiratory system is impaired in postmenopausal women due to physiological changes caused by age and sex hormones' decrement. Although these alterations appear not to be fully compensated by exercise, endurance training could effectively mitigate them. In addition, monophasic OC pills appear not to impact cardiorespiratory response to an incremental running test in endurance-trained females.

Fasted plasma asprosin concentrations are associated with menstrual cycle phase, oral contraceptive use and training status in healthy women.

PURPOSE: Asprosin, an orexigenic hormone that stimulates hepatic glucose release, is elevated in insulin resistance and associated with obesity. Plasma asprosin concentrations may also be related to female sex hormone levels; higher levels are reported in women with polycystic ovary syndrome (PCOS) but this may be related to peripheral insulin resistance also associated with PCOS. Clarification of female-specific factors influence on the plasma asprosin response is crucial for studies investigating asprosin. Therefore, this study determined the association of menstrual phase, oral contraceptive (OC) use (as a pharmacological influence on sex hormone levels) and training status (as a physiological influence on sex hormone levels) on plasma asprosin levels in pre-menopausal women. METHODS: Fasting plasma asprosin, 17ß-estradiol (E2) and progesterone, were assessed in 32 healthy untrained and trained women with regular menstrual cycles (non-OC; n = 8 untrained, n = 6 trained) or using OC (n = 10 untrained, n = 8 trained) during early follicular, late follicular and mid-luteal menstrual phases (or the time-period equivalent for OC users). RESULTS: Asprosin was lower in OC (0.75 ± 0.38 ng mL-1) than non-OC users (1.00 ± 0.37 ng mL-1; p = 0.022). Across a cycle, asprosin was highest in the early follicular equivalent time-point in OC users (0.87 ± 0.37 ng mL-1) but highest in the mid-luteal phase in non-OC users (1.09 ± 0.40 ng mL-1). Asprosin concentrations varied more across a cycle in untrained than trained women, with higher concentrations in the early follicular phase compared to the late follicular and mid-luteal (training status-by-menstrual phase interaction p = 0.028). CONCLUSION: These findings highlight the importance of considering OC use, menstrual cycle phase and to a lesser extent training status when investigating circulating asprosin concentrations in females.

Contraceptive use and fertility behaviour among Syrian migrant women.

OBJECTIVES: This study aimed to investigate fertility behaviours and contraceptive use among Syrian migrant women in western Turkey. METHODS: An epidemiological, single-centre, cross-sectional, descriptive study was conducted. The survey collected data on sociodemographic characteristics and types of marriage, use of contraceptive methods and fertility behaviours among 223 Syrian migrant women. RESULTS: The women's mean (± standard deviation) age range was 29.6 ± 9.1 (range 18-49) years; 29.6% had no formal marriage status; 61.0% had had an arranged marriage. The mean age at first pregnancy was 19.5 ± 3.4 (13-39) years; 26.4% had become pregnant before the age of 18. In total, 94.2% of participants had knowledge of contraceptive methods. However, 47.5% did not use contraception and the main reason for this was to become pregnant again. Intrauterine devices and oral contraceptive pills were known as contraceptive methods by 67.7% and 72.2% of women, but used by only 16.1% and 8.5%, respectively. Withdrawal (22.0%) was the most used contraceptive method. There was a risk of unwanted pregnancy in 13.0% of participants. Arranged marriage and low educational level were determined to be risk factors for adolescent pregnancy. CONCLUSION: Although Syrian migrant women were aware of contraceptive methods, the rate of method use was low.

The difficult journey to treatment for women suffering from heavy menstrual bleeding: a multi-national survey.

PURPOSE: Up to 30% of women of reproductive age experience HMB, which has a substantial impact on their quality of life. A clinical care pathway for women with HMB is an unmet need, but its development requires better understanding of the factors that characterise current diagnosis and management of the condition. MATERIALS AND METHODS: This observational, survey-based study assessed the burden, personal experiences, and path through clinical management of women with HMB in Canada, the USA, Brazil, France and Russia using a detailed, semi-structured online questionnaire. After excluding those reporting relevant organic pathology, responses to the questionnaire from 200 women per country were analysed. RESULTS: Around 75% of women with HMB had actively sought information about heavy periods, mostly through internet research. The mean time from first symptoms until seeking help was 2.9 (Standard deviation, 3.1) years. However, 40% of women had not seen a health care professional about the condition. Furthermore, 54% had never been diagnosed or treated. Only 20% had been diagnosed and received appropriate treatment. Treatment was successful in 69% of those patients currently receiving treatment. Oral contraceptives were the treatment most commonly prescribed for HMB, although the highly effective levonorgestrel-intrauterine system was used by only a small proportion of women. CONCLUSIONS: This study provides insight into the typical journey of a woman with HMB which may help patients and health care professionals improve the path to diagnosis and treatment, although further research with long-term outcomes is needed.

The influence of birth cohort and calendar period on global trends in ovarian cancer incidence.

Ovarian cancer is the eighth most common cancer in women worldwide and incidence rates vary markedly by world region. Our study provides a comprehensive overview of ovarian cancer incidence trends globally, examining the influence of birth cohort and period of diagnosis on changing risk. We presented current patterns and trends of ovarian cancer incidence until 2012 using data from successive volumes of Cancer Incidence in Five Contents. The incidence of ovarian cancer is highest in northern and eastern European countries and in northern America. Declining trends were observed in most countries with the exception of a few central and eastern Asian countries. Marked declines were seen in Europe and North America for women aged 50-74 where rates have declined up to 2.4% (95% CI: -3.9, -0.9) annually in Denmark (DNK) over the last decade. Additionally, declines in the incidence rate ratio (IRR) were observed for generations born after the 1930s, with an additional strong period effect seen around 2000 in United States and DNK. In contrast, IRRs increased among younger generations born after the 1950s in Japan and Belarus. Overall, the favorable trends in ovarian cancer incidence is likely due to the increase use of oral contraceptive pills, and changes in the prevalence of other reproductive risk and protective factors for ovarian cancer over the years studied. Changes in disease classifications and cancer registry practices may also partially contribute to the variation in ovarian cancer incidence rates. Thus, continuous cancer surveillance is essential to detect the shifting patterns of ovarian cancer.

Effect of eliglustat on the pharmacokinetics of digoxin, metoprolol, and oral contraceptives and absorption of eliglustat when coadministered with acid-reducing agents.

Eliglustat is an oral substrate reduction therapy indicated for patients with Gaucher disease type 1. Based on in vitro data, clinical trials were conducted to assess the potential for drug-drug interactions between eliglustat and digoxin (P-glycoprotein substrate), metoprolol (sensitive CYP2D6 substrate), a combined oral contraceptive (CYP3A substrate), and acid-reducing agents. Healthy subjects were enrolled in four Phase 1 clinical studies to evaluate the effect of eliglustat on the pharmacokinetics, safety, and tolerability of digoxin (N = 28), metoprolol (N = 14), and a combined oral contraceptive (N = 30) and the effect of acid-reducing agents on eliglustat pharmacokinetics, safety, and tolerability (N = 24). Coadministration resulted in increased exposure to digoxin (1.49-fold) and metoprolol (2-fold) with eliglustat, negligible effects on oral contraceptive pharmacokinetics with eliglustat, and a negligible effect of acid-reducing agents on eliglustat pharmacokinetics. Across all studies, eliglustat was well-tolerated. One serious adverse event (spontaneous abortion) and one discontinuation due to an adverse event (urinary tract infection) were reported, both during the acid-reducing agents study. When eliglustat is coadministered with medications that are P-glycoprotein or CYP2D6 substrates, lower doses of these concomitant medications may be required. Eliglustat may be coadministered with oral contraceptives and acid-reducing agents without dose modifications for either drug.

Breastfeeding and the risk of epithelial ovarian cancer among women with a BRCA1 or BRCA2 mutation.

OBJECTIVE: BRCA mutation carriers face a high lifetime risk of developing ovarian cancer. The strong inverse association between breastfeeding and the risk of ovarian cancer is established in the general population but is less well studied among women with a germline BRCA1 or BRCA2 mutation. METHOD: Thus, we conducted a matched case-control analysis to evaluate the association between breastfeeding history and the risk of developing ovarian cancer. After matching for year of birth, country of residence, BRCA gene and personal history of breast cancer, a total of 1650 cases and 2702 controls were included in the analysis. Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI) associated with various breastfeeding exposures. RESULTS: A history of ever-breastfeeding was associated with a 23% reduction in risk (OR = 0.77; 95%CI 0.66-0.90; P = 0.001). The protective effect increased with breastfeeding from one month to seven months after which the association was relatively stable. Compared to women who never breastfed, breastfeeding for seven or more months was associated with a 32% reduction in risk (OR = 0.68; 95%CI 0.57-0.81; P < 0.0001) and did not vary by BRCA gene or age at diagnosis. The combination of breastfeeding and oral contraceptive use was strongly protective (0.47; 95%CI 0.37-0.58; P < 0.0001). CONCLUSIONS: These findings support a protective effect of breastfeeding for at least seven months among women with a BRCA1 or BRCA2 mutation, that is independent of oral contraceptive use.

Female reproductive factors and the risk of Parkinson's disease: a nationwide cohort study.

There are conflicting finds in the literature regarding the association of female estrogen status and the incidence of Parkinson's disease (PD). We aimed to investigate whether female reproductive factors are associated with PD. Using the Korean National Health Insurance System database, 4,729,546 postmenopausal women without PD were identified. The new incidence of PD was defined as subjects with an ICD-10 code for PD (G20) and with a rare intractable disease registration code for PD (V124). The Cox proportional hazard models were used to evaluate the associations of various reproductive factors with incidence of PD. During the median follow-up of 5.84 years, 20,816 individuals were diagnosed with PD. An increased risk of PD was observed in subjects with a later age at menarche (≥ 17 years) compared with reference subjects (13 years ≤ age at menarche ≤ 14 years) (adjusted hazard ratio, aHR 1.10, 95% confidence interval, CI 1.05-1.16). As age at menopause increased, risk of PD decreased (P for trend 0.019). Consistently, decreased risk of PD was observed (aHR 0.91, 95% CI 0.85-0.96) in subjects with longer duration of fertility (≥ 40 years of age) compared with shorter duration of fertility (< 30 years of age). Hormone replacement therapy and oral contraceptives independently increased the risk of PD by 17% and 7%, respectively. Female reproductive factors are independent risk factors for PD, with higher risk associated with shorter lifetime exposure to endogenous estrogen.

Progestogen-releasing intrauterine systems for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) impacts the quality of life of otherwise healthy women. The perception of HMB is subjective and management depends upon, among other factors, the severity of the symptoms, a woman's age, her wish to get pregnant, and the presence of other pathologies. Heavy menstrual bleeding was classically defined as greater than or equal to 80 mL of blood loss per menstrual cycle. Currently the definition is based on the woman's perception of excessive bleeding which is affecting her quality of life. The intrauterine device was originally developed as a contraceptive but the addition of progestogens to these devices resulted in a large reduction in menstrual blood loss: users of the levonorgestrel-releasing intrauterine system (LNG-IUS) reported reductions of up to 90%. Insertion may, however, be regarded as invasive by some women, which affects its acceptability. OBJECTIVES: To determine the effectiveness, acceptability and safety of progestogen-releasing intrauterine devices in reducing heavy menstrual bleeding. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL (from inception to June 2019); and we searched grey literature and for unpublished trials in trial registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in women of reproductive age treated with LNG-IUS devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and conducted GRADE assessments of the certainty of evidence. MAIN RESULTS: We included 25 RCTs (2511 women). Limitations in the evidence included risk of attrition bias and low numbers of participants. The studies compared the following interventions. LNG-IUS versus other medical therapy The other medical therapies were norethisterone acetate, medroxyprogesterone acetate, oral contraceptive pill, mefenamic acid, tranexamic acid or usual medical treatment (where participants could choose the oral treatment that was most suitable). The LNG-IUS may improve HMB, lowering menstrual blood loss according to the alkaline haematin method (mean difference (MD) 66.91 mL, 95% confidence interval (CI) 42.61 to 91.20; 2 studies, 170 women; low-certainty evidence); and the Pictorial Bleeding Assessment Chart (MD 55.05, 95% CI 27.83 to 82.28; 3 studies, 335 women; low-certainty evidence). We are uncertain whether the LNG-IUS may have any effect on women's satisfaction up to one year (RR 1.28, 95% CI 1.01 to 1.63; 3 studies, 141 women; I² = 0%, very low-certainty evidence). The LNG-IUS probably leads to slightly higher quality of life measured with the SF-36 compared with other medical therapy if (MD 2.90, 95% CI 0.06 to 5.74; 1 study: 571 women; moderate-certainty evidence) or with the Menorrhagia Multi-Attribute Scale (MD 13.40, 95% CI 9.89 to 16.91; 1 trial, 571 women; moderate-certainty evidence). The LNG-IUS and other medical therapies probably give rise to similar numbers of women with serious adverse events (RR 0.91, 95% CI 0.63 to 1.30; 1 study, 571 women; moderate-certainty evidence). Women using other medical therapy are probably more likely to withdraw from treatment for any reason (RR 0.49, 95% CI 0.39 to 0.60; 1 study, 571 women, moderate-certainty evidence) and to experience treatment failure than women with LNG-IUS (RR 0.34, 95% CI 0.26 to 0.44; 6 studies, 535 women; moderate-certainty evidence). LNG-IUS versus endometrial resection or ablation (EA) Bleeding outcome results are inconsistent. We are uncertain of the effect of the LNG-IUS compared to EA on rates of amenorrhoea (RR 1.21, 95% CI 0.85 to 1.72; 8 studies, 431 women; I² = 21%; low-certainty evidence) and hypomenorrhoea (RR 0.98, 95% CI 0.73 to 1.33; 4 studies, 200 women; low-certainty evidence) and eumenorrhoea (RR 0.55, 95% CI 0.30 to 1.00; 3 studies, 160 women; very low-certainty evidence). We are uncertain whether both treatments may have similar rates of satisfaction with treatment at 12 months (RR 0.95, 95% CI 0.85 to 1.07; 5 studies, 317 women; low-certainty evidence). We are uncertain if the LNG-IUS compared to EA has any effect on quality of life, measured with SF-36 (MD -14.40, 95% CI -22.63 to -6.17; 1 study, 33 women; very low-certainty evidence). Women with the LNG-IUS compared with EA are probably more likely to have any adverse event (RR 2.06, 95% CI 1.44 to 2.94; 3 studies, 201 women; moderate-certainty evidence). Women with the LNG-IUS may experience more treatment failure compared to EA at one year follow up (persistent HMB or requirement of additional treatment) (RR 1.78, 95% CI 1.09 to 2.90; 5 studies, 320 women; low-certainty evidence); or requirement of hysterectomy may be higher at one year follow up (RR 2.56, 95% CI 1.48 to 4.42; 3 studies, 400 women; low-certainty evidence). LNG-IUS versus hysterectomy We are uncertain whether the LNG-IUS has any effect on HMB compared with hysterectomy (RR for amenorrhoea 0.52, 95% CI 0.39 to 0.70; 1 study, 75 women; very low-certainty evidence). We are uncertain whether there is difference between LNG-IUS and hysterectomy in satisfaction at five years (RR 1.01, 95% CI 0.94 to 1.08; 1 study, 232 women; low-certainty evidence) and quality of life (SF-36 MD 2.20, 95% CI -2.93 to 7.33; 1 study, 221 women; low-certainty evidence). Women in the LNG-IUS group may be more likely to have treatment failure requiring hysterectomy for HMB at 1-year follow-up compared to the hysterectomy group (RR 48.18, 95% CI 2.96 to 783.22; 1 study, 236 women; low-certainty evidence). None of the studies reported cost data suitable for meta-analysis. AUTHORS' CONCLUSIONS: The LNG-IUS may improve HMB and quality of life compared to other medical therapy; the LNG-IUS is probably similar for HMB compared to endometrial destruction techniques; and we are uncertain if it is better or worse than hysterectomy. The LNG-IUS probably has similar serious adverse events to other medical therapy and it is more likely to have any adverse events than EA.