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Introduction: Data suggest that micronised progesterone (mP) in menopausal hormone therapy is safer for the breast than synthetic progestins, while protection of the endometrium appears to be less effective. However, comparative randomised trial data are lacking. The objective of the Progesterone Breast Endometrial Safety Study is to investigate breast and endometrial safety of mP versus norethisterone acetate (NETA) in continuous combination with oral oestrogen., Methods and Analysis: This multicentre trial, conducted at three University Hospitals in Stockholm and Uppsala, Sweden, consists of two phases: part 1 focuses on breast safety and is designed as a double-blind, randomised controlled trial. 260 postmenopausal women will be randomised to 100 mg mP or 0.5 mg NETA per day in continuous combination with 1 mg oestradiol. The primary objective is to compare the treatments with respect to percentage change in mammographic breast density after 12-month treatment. Secondary outcomes are breast proliferation, endometrial histology and proliferation, bleeding pattern, gut and vaginal microbiome, hormone levels and coagulation and metabolic factors, mood, and health-related quality of life. Part 2 features an open, single-arm design to study endometrial safety of 1-year treatment with mP in continuous combination with oestradiol on endometrial pathology (hyperplasia and cancer). We will treat 260 additional women with 100 mg mP/1 mg oestradiol resulting in an endometrial safety population of 390 women. The total number of participants in part 1 and part 2 will be 520., Ethics and Dissemination: The study protocol was approved by the Swedish Ethical Review Authority (2021-03033) on 29 June 2021 with amendment (2023-01480-02, protocol version 3.1) on 14 March 2023. Results of the study will be published in peer-reviewed journals and presented at scientific meetings., Trial Registration Number: NCT05586724., Competing Interests: Competing interests: This is an investigator-initiated study. The company Besins healthcare Ireland has provided financial support and study medication but has not been involved in the preparation of the study protocol and will not be involved in the evaluation and publication of study results., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Pregnancy outcomes of different ovarian stimulation protocols for in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) in patients with adenomyosis are not explicit. This meta-analysis aimed to systematically evaluate the effects of different IVF/ICSI protocols on pregnancy outcomes., Design: Meta-analysis., Data Sources: PubMed, Web of Science and Cochrane library were searched up to October 2023., Eligibility Criteria: Comparative studies on IVF/ICSI outcomes in the adenomyosis population were eligible. Studies on preimplantation genetic testing, reviews, case reports and animal experiments were excluded., Data Extraction and Synthesis: Valid information was extracted by two independent authors according to a standard data format. All analyses were conducted using Review Manager (RevMan, V.5.3)., Results: Compared with the non-adenomyosis population, adenomyosis was responsible for a 26% reduction in clinical pregnancy rate (CPR; 42.47% vs 55.89%, OR: 0.74, 95% CI: 0.66 to 0.82, p<0.00001), a 35% reduction in live birth rate (LBR; 30.72% vs 47.77%, OR: 0.65, 95% CI: 0.58 to 0.73, p<0.00001) and a 1.9-fold increase in miscarriage rate (MR; 27.82% vs 13.9%, OR: 1.90, 95% CI: 1.56 to 2.31, p<0.00001). Subgroup analysis suggested that, in fresh embryo transfer (ET) cycles, the CPR (34.4% vs 58.25%) in the long/short/antagonist protocol group was poorer than that in the ultralong protocol group. In frozen ET (FET) cycles, there were no statistical differences in CPR ((GnRHa+FET) AM(adenomyosis) vs non-AM: 51.32% vs 43.48%, p=0.31; (non-GnRHa+FET) AM vs non-AM: 50.25% vs 60.10%, p=0.82), MR ((GnRHa+FET) AM vs non-AM:12.82% vs 12.50%, p=0.97; (non-GnRHa+FET) AM vs non-AM: 30.5% vs 15.54%, p=0.15) and LBR ((GnRHa+FET) AM vs non-AM:44.74% vs 36.96%, p=0.31; (non-GnRHa+FET) AM vs non-AM: 34.42% vs 50.25%, p=0.28). The MR in the adenomyosis group was high in the fresh ET and FET cycles., Conclusions: FET might be a better choice for women with adenomyosis, especially those pretreated with GnRHa. In fresh ET cycles, pregnancy outcomes of the long/short/antagonist protocols were poorer than those of the ultralong protocol., Trial Registration Number: CRD42022340743., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The use of androgenic anabolic steroids (AASs) among recreational athletes is steadily increasing. However, knowledge regarding the potentially harmful effects of AAS primarily originates from case reports and small observational studies. This large-scale study aims to investigate the impact of AAS use on vascular plaque formation, preclinical coronary disease, cardiac function, circulating cardiovascular risk markers, quality of life (QoL) and mental health in a broad population of illicit AAS users., Methods and Analyses: A nationwide cross-sectional cohort study including a diverse population of men and women aged ≥18 years, with current or previous illicit AAS use for at least 3 months. Conducted at Odense University Hospital, Denmark, the study comprises two parts. In part A (the pilot study), 120 recreational athletes with an AAS history will be compared with a sex-matched and age-matched control population of 60 recreational athletes with no previous AAS use. Cardiovascular outcomes include examination of non-calcified coronary plaque volume and calcium score using coronary CT angiography, myocardial structure and function via echocardiography, and assessing carotid and femoral artery plaques using ultrasonography. Retinal microvascular status is evaluated through fundus photography. Cardiovascular risk markers are measured in blood. Mental health outcomes include health-related QoL, interpersonal difficulties, body image concerns, aggression dimensions, anxiety symptoms, depressive severity and cognitive function assessed through validated questionnaires. The findings of our comprehensive study will be used to compose a less intensive investigatory cohort study of cardiovascular and mental health (part B) involving a larger group of recreational athletes with a history of illicit AAS use., Ethics and Dissemination: The study received approval from the Regional Committee on Health Research Ethics for Southern Denmark (S-20210078) and the Danish Data Protection Agency (21/28259). All participants will provide signed informed consent. Research outcomes will be disseminated through peer-reviewed journals and scientific conferences., Trial Registration Number: NCT05178537., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The study aimed to explore the lived experiences of women with severe obesity before and after undergoing bariatric surgery with a special focus on possible effects of changed sex hormone levels., Design: A qualitative interview study with transcribed text analysis based on Gadamer's hermeneutics., Setting: Regional hospital and outpatient bariatric clinic in central Sweden., Participants: Ten women (age 23-38 years) having undergone Roux-en-Y gastric bypass surgery between 2016 and 2019 were interviewed., Results: The transcribed interviews were analysed according to Gadamer's hermeneutics. Text horizons, interpreter horizons and fact horizons were derived and formed the fusions 'Recognition of unhealthy body weight', 'Dealing with other people's opinions and society's norms', 'Life has changed in a positive way' and 'Accepting inner self and bodily changes'., Conclusion: Women highlighted weight and body size in their responses. The study provided a deeper understanding of the situation of women living with obesity and pros and cons of having undergone bariatric surgery. Experiences of changes in sex hormones and fertility were discussed but not central to the informants. Participants emphasised the need to be prepared and properly supported in dealing with changes in life after bariatric surgery and subsequent weight loss., Competing Interests: Competing interests: TO participated in advisory boards and educational activities for Johnson & Johnson and Novo Nordisk unrelated to the submitted article, and reimbursements were directed to his academic institution. All other authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Hormonal contraceptive use might impair bone health and increase the risk of stress fracture by decreasing endogenous oestrogen production, a central regulator of bone metabolism. This cross-sectional study investigated bone density and biochemical markers of bone metabolism in women taking hormonal contraceptives on entry to basic military training., Methods: Forty-five female British Army recruits had biochemical markers of bone metabolism, areal bone mineral density (aBMD) and tibial speed of sound (tSOS) measured at the start of basic military training. Participants were compared by their method of hormonal contraception: no hormonal contraception (NONE), combined contraceptive pill (CP) or depot-medroxyprogesterone acetate (DMPA) (20±2.8 years, 1.64±0.63 m, 61.7±6.2 kg)., Results: aBMD was not different between groups (p≥0.204), but tSOS was higher in NONE (3%, p=0.014) when compared with DMPA users. Beta C-terminal telopeptide was higher in NONE (45%, p=0.037) and DMPA users (90%, p=0.003) compared with CP users. Procollagen type 1 N-terminal propeptide was higher in DMPA users compared with NONE (43%, p=0.045) and CP users (127%, p=0.001), and higher in NONE compared with CP users (59%, p=0.014). Bone alkaline phosphatase was higher in DMPA users compared with CP users (56%, p=0.044)., Conclusions: DMPA use was associated with increased bone turnover and decreased cortical bone integrity of the tibia. Lower cortical bone integrity in DMPA users was possibly mediated by increased intracortical remodelling, but trabecular bone was not affected by contraceptive use., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The use of oral contraceptives (OCs) is linked to an increased risk of cardiovascular diseases (CVDs) in women of reproductive age. CVD remain one of the top causes of death worldwide, with at least three-quarters of deaths occurring in low-income and middle-income nations. The impact of various types of combined oral contraceptive (COC) on several modifiable risk factors associated with CVDs in premenopausal women is inconsistent regardless of genetic mutations. The aim of this systematic review will be to provide a comprehensive synthesis of the available evidence on the impact of COC usage on modifiable risk factors associated with CVDs and assess ethnic and geographic disparities in the reported prevalence of CVD., Methods and Analysis: This systematic review protocol was prepared in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocols 2015 statement. An extensive search on the Embase, MEDLINE and Cochrane Library will be conducted from inception until. Two reviewers will independently screen for eligible studies using a predefined criterion. The risk of bias and quality of included studies will be assessed using the modified Downs and Black's checklist. Whereas the overall quality of included studies will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation assessment tool., Ethics and Dissemination: This is a review of existing studies and will not require ethical approval. The findings will be disseminated through peer-reviewed publication. The use of OC and the risk of CVDs including arterial and venous thrombosis remain a major concern among women of reproductive age. Thus, given the impact of COCs on the risk variables linked with CVDs, this review may provide an insight and assistance during COC use., Prospero Registration Number: CRD42020216169., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The use of gender-affirming oestrogen therapy (GAOT) is an integral part of the gender-affirming transition process for transgender women (assigned male at birth who identify as women) and gender-diverse individuals. However, its use may present significant cardiovascular implications, which may be influenced by systemic oestradiol levels. Therefore, we aim to establish the association between serum oestradiol levels and incidence of adverse cardiovascular events in individuals using GAOT., Methods and Analysis: We will conduct a systematic review addressing the association between serum oestradiol levels and risk of adverse cardiovascular events in individuals using GAOT. Our primary outcome is the incidence of adverse cardiovascular events, our secondary outcome is the incidence of cardiovascular-related mortality and our tertiary outcome is cardiovascular-related risk factors. Electronic databases (Cochrane Central Register of Controlled Trials, Embase, MEDLINE and Web of Science) will be searched from inception until September 2022. Two investigators will independently complete screening to determine appropriateness of inclusion. Extracted data will include information on serum sex hormone levels (oestradiol and testosterone), participants, GAOT (route of administration, formulations, dosages and duration of exposure), incidence of cardiovascular outcomes, study quality and risk of bias. Inter-reviewer reliability will be calculated at both phases. Data will be presented both descriptively and meta-analysed using a random effects model, if appropriate. Heterogeneity will be explored and meta-regressed if noted., Ethics and Dissemination: Ethics approval is not needed. We will disseminate findings through international conferences, distributions to transgender and gender-diverse support organisations, decision-makers and key stakeholders. The final systematic review will be published in a peer-reviewed journal., Trial Registration Number: CRD42021247717., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Infertility is a common complication of endometriosis. While in vitro fertilisation-embryo transfer (IVF) successfully treats endometriosis-associated infertility, there is some evidence that pregnancy rates may be diminished in women seeing fertility treatment for endometriosis-associated infertility compared with other etiologies of infertility. The use of gonadotropin releasing hormone (GnRH) agonist prior to IVF has been suggested to improve success, however studies have been small and rarely reported live birth rates. Recent approval of an oral GnRH antagonist for endometriosis provides a novel option for women with endometriosis who are undergoing IVF. There have been no studies on the efficacy of GnRH antagonists for the treatment of endometriosis-related infertility., Methods and Analysis: This study is a multicentre, prospective, randomised, double-blind, placebo-controlled trial to study the efficacy of GnRH antagonist pretreatment for women with endometriosis who are undergoing IVF. A total of 814 patients with endometriosis undergoing fertility treatment will be enrolled and randomised 1:1 into two groups: elagolix 200 mg two times per day or placebo for 8 weeks, prior to undergoing IVF. All participants will then undergo IVF treatment per local protocols. The primary outcome is live birth. Secondary outcomes include oocyte number, fertilisation rate, embryo morphology and implantation rates, as well as rates of known endometriosis-related obstetrical outcomes (pregnancy-induced hypertension, antepartum haemorrhage, caesarean delivery and preterm birth)., Ethics and Dissemination: The PREGnant trial was approved by the Institutional Review Board at Johns Hopkins University. Results will be published in a peer-reviewed journal., Trial Registration Number: NCT04173169., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Gender affirming hormone therapy (GAHT) is increasingly used by transgender individuals and leads to shifts in sex hormone levels. Skeletal muscle is highly responsive to hormone activity, with limited data on the effects of GAHT on different human tissues. Here, we present the protocol for the GAME study (the effects of G ender A ffirming hormone therapy on skeletal M uscle training and E pigenetics), which aims to uncover the effects of GAHT on skeletal muscle 'omic' profiles (methylomics, transcriptomics, proteomics, metabolomics) and markers of skeletal muscle health and fitness., Methods and Analysis: This study is a prospective age-matched cohort study in transgender adults commencing GAHT (n=80) and age-matched individuals not commencing GAHT (n=80), conducted at Austin Health and Victoria University in Victoria, Australia. Assessments will take place prior to beginning GAHT and 6 and 12 months into therapies in adults commencing GAHT. Age-matched individuals will be assessed at the same time points. Assessments will be divided over three examination days, involving (1) aerobic fitness tests, (2) muscle strength assessments and (3) collection of blood and muscle samples, as well as body composition measurements. Standardised diets, fitness watches and questionnaires will be used to control for key confounders in analyses. Primary outcomes are changes in aerobic fitness and muscle strength, as well as changes in skeletal muscle DNA methylation and gene expression profiles. Secondary outcomes include changes in skeletal muscle characteristics, proteomics, body composition and blood markers. Linear mixed models will be used to assess changes in outcomes, while accounting for repeated measures within participants and adjusting for known confounders., Ethics and Dissemination: The Austin Health Human Research Ethics Committee (HREC) and Victoria University HREC granted approval for this study (HREC/77146/Austin-2021). Findings from this project will be published in open-access, peer-reviewed journals and presented to scientific and public audiences., Trial Registration Number: ACTRN12621001415897; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Corticosteroids are an important pillar in many anti-inflammatory and immunosuppressive treatment regimens and are available in natural and synthetic forms, which are considered equipotent if clinical bioequivalence data are used. Current clinical bioequivalence data are however based on animal studies or studies with subjective endpoints. Furthermore, advancement in steroid physiology with regard to metabolism, intracellular handling and receptor activation have not yet been incorporated. Therefore, this study aims to re-examine the clinical bioequivalence and dose effects of the most widely used synthetic corticosteroids, prednisolone and dexamethasone., Methods and Analysis: In this double-blind, randomised cross-over clinical trial, 24 healthy male and female volunteers aged 18-75 years, will be included. All volunteers will randomly receive either first a daily dose of 7.5 mg prednisolone for 1 week, immediately followed by a daily dose of 30 mg prednisolone for 1 week, or first a presumed clinical bioequivalent dose of 1.125 mg dexamethasone per day, immediately followed by 4.5 mg of dexamethasone per day for 1 week. After a wash-out period of 4-8 weeks, the other treatment will be applied. The primary study endpoint is the difference in free cortisol excretion in 24 hours urine. Secondary endpoints will include differences in immunological parameters, blood pressure and metabolic measurements., Ethics and Dissemination: This study has been approved by the Medical Ethics Committee of the University Medical Center Groningen (METC 2020.398). The results of this study will be submitted for publication in peer-reviewed journals., Trial Registration Number: ClinicalTrials.gov (Identifier: NCT04733144), and in the Dutch trial registry (NL9138)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: There has been a global increase in demand for gender-specific healthcare services and a recognition that healthcare access is complex and convoluted, even in countries with well-developed healthcare services. Despite evidence in Ireland supporting the improvement in physical and mental health following access to gender care, little is known about the local healthcare navigation challenges. Internationally, research focuses primarily on the experience of service users and omits the perspective of other potential key stakeholders. Youth experiences are a particularly seldom-heard group., Methods and Analysis: This study will use a sequential exploratory mixed-methods design with a participatory social justice approach. The qualitative phase will explore factors that help and hinder access to gender care for young people in Ireland. This will be explored from multiple stakeholders' perspectives, namely, young people, caregivers and specialist healthcare providers. Framework analysis will be used to identify priorities for action and the qualitative findings used to build a survey tool for the quantitative phase. The quantitative phase will then measure the burden of the identified factors on healthcare navigation across different age categories and gender identities (transmasculine vs transfeminine vs non-binary)., Ethics and Dissemination: This study has been approved by St Vincent's Hospital Research Ethics Committee (RS21-019), University College Dublin Ethics Committee (LS-21-14Kearns-OShea) and the Transgender Equality Network Ireland's Internal Ethics Committee (TIECSK). We aim to disseminate the findings through international conferences, peer-review journals and by utilisation of expert panel members and strategic partners., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Determine whether augmentation of oestrogen in postmenopausal women decreases the risk of death following COVID-19., Design: Nationwide registry-based study in Sweden based on registries from the Swedish Public Health Agency (all individuals who tested positive for SARS-CoV-2); Statistics Sweden (socioeconomical variables) and the National Board of Health and Welfare (causes of death)., Participants: Postmenopausal women between 50 and 80 years of age with verified COVID-19., Interventions: Pharmaceutical modulation of oestrogen as defined by (1) women with previously diagnosed breast cancer and receiving endocrine therapy (decreased systemic oestrogen levels); (2) women receiving hormone replacement therapy (increased systemic oestrogen levels) and (3) a control group not fulfilling requirements for group 1 or 2 (postmenopausal oestrogen levels). Adjustments were made for potential confounders such as age, annual disposable income (richest group as the reference category), highest level of education (primary, secondary and tertiary (reference)) and the weighted Charlson Comorbidity Index (wCCI)., Primary Outcome Measure: Death following COVID-19., Results: From a nationwide cohort consisting of 49 853 women diagnosed with COVID-19 between 4 February and 14 September 2020 in Sweden, 16 693 were between 50 and 80 years of age. We included 14 685 women in the study with 11 923 (81%) in the control group, 227 (2%) women in group 1 and 2535 (17%) women in group 2. The unadjusted ORs for death following COVID-19 were 2.35 (95% CI 1.51 to 3.65) for group 1 and 0.45 (0.34 to 0.6) for group 2. Only the adjusted OR for death remained significant for group 2 with OR 0.47 (0.34 to 0.63). Absolute risk of death was 4.6% for the control group vs 10.1% and 2.1%, for the decreased and increased oestrogen groups, respectively. The risk of death due to COVID-19 was significantly associated with: age, OR 1.15 (1.14 to 1.17); annual income, poorest 2.79 (1.96 to 3.97), poor 2.43 (91.71 to 3.46) and middle 1.64 (1.11 to 2.41); and education (primary 1.4 (1.07 to 1.81)) and wCCI 1.13 (1.1 to 1.16)., Conclusions: Oestrogen supplementation in postmenopausal women is associated with a decreased risk of dying from COVID-19 in this nationwide cohort study. These findings are limited by the retrospective and non-randomised design. Further randomised intervention trials are warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Several studies have suggested the influence of exogenous hormones on asthma, but the results are still conflicting. Moreover, there has been little associated research on Asian population. This study aimed to assess the association between use of exogenous female sex hormones and asthma in Korean women., Design: Korea National Health and Nutrition Examination Survey (KNHANES) is a nationwide programme to assess national health and nutritional status in Korea. A population-based study was conducted to analyse the relationship between self-reported asthma and exogenous hormones using the KNHANES between 2007 and 2012., Participants: The study sample included 6874 premenopausal and 4912 postmenopausal women aged 30-65., Outcome Measures: KNHANES data comprised health interviews and physical examinations. Questionnaires regarding asthma, reproductive factors and exogenous hormones were included., Results: Among postmenopausal women, 3.4% reported doctor-diagnosed asthma. Hormone replacement therapy (HRT) was associated with increased odds of doctor-diagnosed asthma (OR 1.56; 95% CI 1.04 to 2.35), while the association between HRT and wheeze in the last 1 year was not significant (OR 1.37; 95% CI 0.95 to 1.96). In premenopausal women, the prevalence of asthma was 2.3%. Use of oral contraceptives (OCs) was associated with an increased odds of doctor-diagnosed asthma (OR 1.67; 95% CI 1.01 to 2.76) and wheeze in the last 1 year (OR 1.88; 95% CI 1.31 to 2.69). These associations were dominant among non-obese women (body mass index <25 kg/m 2 ; OR 2.36; 95% CI 1.34 to 4.17 for asthma and OR 2.15; 95% CI 1.43 to 3.23 for wheeze)., Conclusions: HRT and OCs were associated with increased asthma in postmenopausal and premenopausal women, respectively. The association between OC use and asthma was strong in non-obese premenopausal women., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: As of November 2021, COVID-19 has killed more than 5 million people globally, including over 750 000 in the USA. Apart from corticosteroids, most available therapeutic options are at best marginally efficient in reducing disease severity and are extremely expensive. The systematic investigation of clinically approved drugs is a priority to determine what does mitigate disease severity. Oestradiol (E2) and progesterone (P4) produce a state of anti-inflammatory immune responses and immune tolerance, and enhanced antibody production. The goal of this trial is to evaluate the efficacy of a short E2 and P4 therapy, in addition to standard of care (SOC), in mitigating disease severity in COVID-19 hospitalised patients., Methods and Analysis: Phase 2, randomised, double blind, placebo-controlled, single-centre trial. Patients hospitalised for confirmed COVID-19, with scores 3-5 on the 9-point WHO ordinal scale are randomised between two arms: (1) Oestradiol cypionate intramuscular (IM) and micronised progesterone oral (PO), in addition to SOC, and (2) placebo, in addition to SOC. The primary outcome is the proportion of patients improving to scores 1 or 2 on the WHO scale through day 28. Secondary outcomes include length of hospital stay, duration of mechanical ventilation, cause of death, readmission rates, change in inflammatory biomarkers between admission and occurrence of primary endpoint, and adverse events. Study sample size will be up to 120 participants. The trial is currently recruiting subjects., Ethics and Dissemination: The sponsor of this study is the Center of Excellence in Sex-Based Biology & Medicine at Tulane University, New Orleans, Louisiana, USA. Ethical approval was obtained from the Tulane institutional review board on 14 May 2021. The study was reviewed by the US Food and Drug Administration and granted Investigational New Drug #152 499. Results of the study will be submitted for publication in a peer-reviewed journal., Trial Registration Number: NCT04865029; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The overall study aim is to clarify the relation of endogenous sex hormones with major health outcomes in men. This paper reports a systematic review focusing on published estimates for testosterone associations., Setting: Community-dwelling men., Participants: 20 180 adult men participated in the final set of studies identified and selected from a systematic review. Eligible studies included prospective cohort studies with plasma or serum testosterone concentrations measured for adult men using mass spectrometry with at least 5 years of follow-up data and one of the specified outcome measures recorded. Only published or grey literature items written in English were considered., Primary and Secondary Outcome Measures: Planned prospective outcome measures: cardiovascular disease (CVD) events, CVD deaths, all-cause mortality, cancer deaths, cancer diagnoses, cognitive decline, dementia. Meta-analyses were of the most frequently reported outcomes in selected studies: CVD deaths and all-cause mortality. Succinct characterisations of testosterone associations with other outcomes are also presented., Results: Screening of 1994 deduplicated items identified 9 suitable studies, with an additional 2 identified by colleagues (11 in total). Summary estimates of mean testosterone concentration and age at recruitment for 20 180 adult men were 15.4±0.7 nmol/L and 64.9±3.3 year. Despite considerable variation in mean testosterone, a metaregression estimated no significant dependence on mean age at recruitment among studies (slope=-0.03, 95% CI -0.11 to 0.06). Meta-analyses demonstrated negligible heterogeneity and no significant effect of a 5 nmol/L increase in testosterone on the risk of all-cause mortality (HR=0.96, 95% CI 0.89 to 1.03) or death from CVD (HR=0.95, 95% CI 0.83 to 1.08)., Conclusions: Analyses of published estimates did not demonstrate associations of endogenous testosterone with CVD deaths or with all-cause mortality. Suggested further research includes the planned individual participant data meta-analyses for selected studies, enabling the investigation of non-linear summary effects., Prospero Registration Number: PROSPERO: CRD42019139668., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: From a reproductive justice framework, we aimed to investigate how a possible association between hormonal contraceptive (HC) and antidepressants use (as a proxy for depression) is distributed across intersectional strata in the population. We aimed to visualise how intersecting power dynamics may operate in combination with HC use to increase or decrease subsequent use of antidepressants. Our main hypothesis was that the previously observed association between HC and antidepressants use would vary between strata, being more pronounced in more oppressed intersectional contexts. For this purpose, we applied an intersectional multilevel analysis of individual heterogeneity and discriminatory accuracy approach., Design: Observational prospective cohort study using record linkage of national Swedish registers., Setting: The population of Sweden., Participants: All 915 954 women aged 12-30 residing in Sweden 2010, without a recent pregnancy and alive during the individual 1-year follow-up., Primary Outcome Measure: Use of any antidepressant, meaning being dispensed at least one antidepressant (ATC: N06A) during follow-up., Results: Previously mentally healthy HC users had an OR of 1.79 for use of antidepressants compared with non-users, whereas this number was 1.28 for women with previous mental health issues. The highest antidepressant use were uniformly found in strata with previous mental health issues, with highest usage in women aged 24-30 with no immigrant background, low income and HC use (51.4%). The largest difference in antidepressant use between HC users and non-users was found in teenagers, and in adult women of immigrant background with low income. Of the total individual variance in the latent propensity of using antidepressant 9.01% (healthy) and 8.16% (with previous mental health issues) was found at the intersectional stratum level., Conclusions: Our study suggests teenagers and women with immigrant background and low income could be more sensitive to mood effects of HC, a heterogeneity important to consider moving forward., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Many patients demonstrate an insufficient endogenous luteinising hormone (LH) concentration during ovarian stimulation. With traditional fixed or flexible gonadotropin-releasing hormone (GnRH) antagonist protocols, antagonist administration may further reduce LH activity. Previously, we proved that LH can be used as an indicator for the timing and dosage of antagonist. Patients with a persistently low LH concentration during ovarian stimulation may not require antagonists, whereas antagonist administration can affect reproductive outcomes. To further explore this hypothesis, we designed a randomised clinical trial to compare the LH-based flexible GnRH antagonist protocol with traditional flexible GnRH antagonist protocol in women with normal ovarian response., Methods and Analysis: This study was a multicentre, parallel, prospective, randomised, non-inferiority study. The primary efficacy endpoint was cumulative ongoing pregnancy rate per cycle. The study aimed to prove the non-inferiority of cumulative ongoing pregnancy rate per cycle with an LH-based flexible GnRH antagonist protocol versus traditional flexible GnRH antagonist protocol. Secondary endpoints were the high-quality embryo rate, clinical pregnancy rate and cancellation rate. Differences in cost-effectiveness and adverse events were evaluated. The cumulative ongoing pregnancy rate per cycle in women with normal ovarian response was 70%. Considering that a non-inferiority threshold should retain 80% of the clinical effect of a control treatment, a minimal clinical difference of 14% (one-sided: α, 2.5%; β, 20%) and a total of 338 patients were needed. Anticipating a 10% drop-out rate, the total number of patients required was 372., Ethics and Dissemination: This trial has been approved by the Institutional Ethical Committee of Beijing Chao-Yang hospital. All participants in the trial will provide written informed consent. The study will be conducted according to the principles outlined in the Declaration of Helsinki and its amendments. Results of this study will be disseminated in peer-reviewed scientific journals., Trial Registration Number: ChiCTR1800018077., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Hormone replacement therapy (HRT) can help women experiencing menopausal symptoms, but usage has declined due to uncertainty around risks of cancer and some cardiovascular diseases (CVD). Moreover, improved cancer survival rates mean that more women who survive cancer go on to experience menopausal symptoms. Understanding these relationships is important so that women and their clinicians can make informed decisions around the risks and benefits of HRT. This study's primary aim is to determine the association between HRT use after cancer diagnosis and the risk of cancer-specific mortality. The secondary aims are to investigate the risks of HRT on subsequent cancer, all-cause mortality and CVD., Methods and Analysis: We will conduct a population-based longitudinal cohort study of 18-79 year-old women diagnosed with cancer between 1998 and 2020, using the QResearch database. The main exposure is HRT use, categorised based on compound, dose and route of administration, and modelled as a time-varying covariate. Analysis of HRT use precancer and postcancer diagnosis will be conducted separately. The primary outcome is cancer-specific mortality, which will be stratified by cancer site. Secondary outcomes include subsequent cancer diagnosis, CVD (including venous thrombo-embolism) and all-cause mortality. Adjustment will be made for key confounders such as age, body mass index, ethnicity, deprivation index, comorbidities, and cancer grade, stage and treatment. Statistical analysis will include descriptive statistics and Cox proportional hazards models to calculate HRs and 95% CIs., Ethics and Dissemination: Ethical approval for this project was obtained from the QResearch Scientific Committee (Ref: OX24, project title 'Use of hormone replacement therapy and survival from cancer'). This project has been, and will continue to be, supported by patient and public involvement panels. We intend to the submit the findings for peer-reviewed publication in an academic journal and disseminate them to the public through Cancer Research UK., Competing Interests: Competing interests: JH-C is an unpaid director of the Qresearch database (partnership between the University of Oxford and EMIS, commercial supplier of GP computer systems). She is shareholder and former director of ClinRisk Ltd outside the submitted work. PST reports consulting with AstraZeneca and Duke-NUS outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Enzyme-inducing antibacterial drugs can impair the efficacy of hormonal contraceptives. Suspicion that other antibiotics might do likewise led to advice that extra contraceptive precautions should be taken during a course of antibiotics. However, current advice is that the purported interaction does not occur, based on small studies observing few pregnancies, assuming that all women are susceptible, and without measuring unbound hormone concentrations., Objective: To test the null hypothesis that antibiotics do not impair the effectiveness of oral contraceptives., Design: A database review of Yellow Card reports to the UK's Medicines and Healthcare products Regulatory Agency., Data: Spontaneous reports of suspected adverse drug reactions in people taking antibacterial drugs (n=74 623), enzyme-inducing medicines (n=32 872), or control medicines (n=65 578)., Main Outcome Measures: Reports of the primary outcome-unintended pregnancies; reports of cardiac arrhythmias and headaches (control events); reports of congenital abnormalities (positive control events); and reports of diarrhoea (a possible confounding factor)., Results: Compared with control medicines, unintended pregnancies were seven times more commonly reported with antibiotics and 13 times more commonly reported with enzyme inducers (the positive controls). Congenital abnormalities were reported seven times more often with enzyme inducers but were not more common with antibiotics. Diarrhoea was not a confounding factor., Conclusion: This study provides a signal that antibacterial drugs may reduce the efficacy of hormonal contraceptives. Women taking hormonal contraceptives should be warned that antibiotics may impair their effectiveness. Extra precautions can be taken during a course of antibiotics; an unintended pregnancy is a life-changing event., Competing Interests: Competing interests: JKA and REF have both written widely about adverse drug reactions and interactions and have from time to time received fees for legal reports, payments for articles, and royalties on books that they have written on the subject., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Low levels of income and education are risk factors for metabolic syndrome in the population of Northeast China, which has a high incidence of metabolic syndrome and cardiovascular diseases. This study aimed to determine sex-based differences associated with the prevalence of and risk factors for metabolic syndrome among people older than 40 years in Northeast China; this has not been previously investigated., Design: This study analysed a portion of the large sample data of the national cross-sectional screening of China from 2016. Metabolic syndrome was defined as the presence of any three of the following five risk factors: abnormal waist circumference; high levels of triglycerides, high-density lipoprotein cholesterol or fasting plasma glucose; and elevated blood pressure. Multiple regression analysis was used to investigate sex-based differences in the prevalence of, and risk factors for metabolic syndrome., Setting: The study was conducted in Dehui City, Jilin Province, China., Participants: A total of 4052 participants with complete questionnaire information and laboratory examination results were included., Results: The prevalence of metabolic syndrome was 50.1% overall (38.4% in men and 57.9% in women; p < 0.001). High body mass index and hip circumference were associated with metabolic syndrome in both sexes. In addition, physical inactivity (OR and 95% CI 1.44 (1.06 to 1.97); p = 0.022) in men and advanced age (OR and 95% CI 1.54 (1.15 to 2.04); p=0.003) in women were factors associated with metabolic syndrome. Women with junior high school education or above and living in rural areas were less likely to have metabolic syndrome. For men, education and rural or urban living had no association with metabolic syndrome., Conclusions: The risk factors for metabolic syndrome have similarities and differences in different sexes; thus, the prevention and treatment of metabolic syndrome should be based on these sex differences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The number of individuals with gender dysphoria seeking gender-affirming treatment is increasing. The short-term and long-term effects of masculinising treatment with testosterone are debated as serum testosterone increases up to 20-fold compared with cisgender women. We will investigate short-term and long-term effects of masculinising testosterone treatment on preclinical and clinical coronary disease, muscle strength and power, oxygen consumption (VO 2 ) max, cardiac and respiratory function and quality of life including aggression in transgender men., Methods and Analyses: Prospective, single-centre, observational cohort study at the Body Identity Clinic (BIC), Odense University Hospital, Denmark. Investigations are performed at inclusion and following 1, 3, 5 and 10 years of testosterone therapy. Non-calcified coronary plaque volume and calcium score are estimated by coronary CT angiography. CT is only performed at inclusion and following 1 and 10 years. Upper body muscle strength and power are measured by a 'low row' weight stack resisted exercise machine. Evaluation of aggression and quality of life is assessed by questionnaires, VO 2 max is estimated by maximal testing on bike ergometer, and cardiac and respiratory functions are measured by echocardiography and spirometry, respectively. Markers of cardiovascular risk and inflammation and also cortisol and cortisone are assessed in blood, diurnal urine and/or hair samples. Our cohort (BIC), including dropouts, will be an embedded subcohort in a future national registry study in all individuals with gender dysphoria and controls. Data are available on International Statistical Classification of Diseases and Related Health Problems 10 th version diagnostic codes, prescriptions, socioeconomics and causes of death., Ethics and Dissemination: The Regional Committee on Health Research Ethics for Southern Denmark (S-20190108) and the Danish Data Protection Agency (19/27572) approved the study. Signed informed consent will be obtained from all participants. All findings will be published in peer-reviewed journals or at scientific conferences., Trial Registration Number: NCT04254354., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: This study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at least three Australian, two European and four North American population-based cohorts involving approximately 20 000 men., Methods and Analysis: Eligible studies include prospective cohort studies with baseline testosterone concentrations measured using mass spectrometry and 5 years of follow-up data on incident cardiovascular events, mortality, cancer diagnoses or deaths, new-onset dementia or decline in cognitive function recorded. Data for men, who were not taking androgens or drugs suppressing testosterone production, metabolism or action; and had no prior orchidectomy, are eligible. Systematic literature searches were conducted from 14 June 2019 to 31 December 2019, with no date range set for searches. Aggregate level data will be sought where individual participant data (IPD) are not available. One-stage IPD random-effects meta-analyses will be performed, using linear mixed models, generalised linear mixed models and either stratified or frailty-augmented Cox regression models. Heterogeneity in estimates from different studies will be quantified and bias investigated using funnel plots. Effect size estimates will be presented in forest plots and non-negligible heterogeneity and bias investigated using subgroup or meta-regression analyses., Ethics and Dissemination: Ethics approvals obtained for each of the participating cohorts state that participants have consented to have their data collected and used for research purposes. The Androgens In Men Study has been assessed as exempt from ethics review by the Human Ethics office at the University of Western Australia (file reference number RA/4/20/5014). Each of the component studies had obtained ethics approvals; please refer to respective component studies for details. Research findings will be disseminated to the scientific and broader community via the publication of four research articles, with each involving a separate set of IPD meta-analyses (articles will investigate different, distinct outcomes), at scientific conferences and meetings of relevant professional societies. Collaborating cohort studies will disseminate findings to study participants and local communities., Prospero Registration Number: CRD42019139668., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)