A Phase II Prospective, Randomized, Double‐Blind , Placebo‐Controlled and Multicenter Clinical Trial to Assess the Safety of 0.005% Estriol Vaginal Gel in Hormone Receptor–Positive Postmenopausal Women With Early Stage Breast Cancer in Treatment With Aromatase Inhibitor in the Adjuvant Setting

Lessons learned: The levels of circulating follicle-stimulating hormone, luteinizing hormone, estriol, estradiol, and estrone remained unchanged after a 12-week treatment with 0.005% estriol vaginal gel in postmenopausal women receiving nonsteroidal aromatase inhibitors for hormone receptor-positive early breast cancer. These results support the safety of 0.005% estriol vaginal gel for the treatment of bothering symptoms of vulvovaginal atrophy in breast cancer survivors. The results provide clinicians with confidence in the use of this product in women who do not experience symptom relief with nonhormonal remedies. Background: Symptoms of vulvovaginal atrophy associated with treatment with nonsteroidal aromatase inhibitors (NSAIs) negatively impact patients' quality of life and may affect adherence to NSAIs. Vaginal estrogens effectively improve these symptoms, although their safe use in breast cancer survivors remains unclear. Methods: Postmenopausal women with hormone receptor-positive early breast cancer receiving NSAI and moderate-to-severe vaginal dryness were randomized to 0.005% estriol vaginal gel or placebo for 12 weeks. Circulating estrogens, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), were analyzed at baseline and at weeks 1, 3, 8, and 12. The primary safety outcome was the variation in serum FSH from baseline to week 12. Results: Sixty-one women (mean age, 59 years) enrolled in the study. Small oscillations were observed in FSH and LH, although they were always maintained within the postmenopausal range. No significant differences were found in the variation of FSH and LH between baseline and week 12 from the physiological variation observed before treatment. Women receiving 0.005% estriol vaginal gel had slightly increased estriol levels at weeks 1 and 3, with a subsequent reduction until normalizing at week 12; estradiol and estrone remained the below limit-of-quantitation in almost all samples. Conclusion: Ultralow-dose 0.005% estriol vaginal gel did not significantly influence estrogens, FSH, and LH levels in women with breast cancer receiving NSAI. A transient negligible absorption of estriol and a nonsignificant variation of FSH after 12 weeks were observed. These findings provide confidence for the safe use of 0.005% estriol vaginal gel in women with breast cancer with an indication for treatment with vaginal estrogens

Perceived impact of the menstrual cycle and hormonal contraceptives on physical exercise and performance in 1,086 athletes from 57 sports

Female athletes train and compete under the potential influence of hormonal fluctuations during the menstrual cycle or during use of various hormonal contraceptives. Dysmenorrhea and premenstrual symptoms are common in the general population, as well as side effects of hormonal contraceptives. More detailed knowledge concerning prevalence and perceived impact of these symptoms on training and performance in different sports is required. The aim of the study was to 1) characterize perceptions of training and performance during the menstrual cycle phases and by hormonal contraceptive use in a large population of female athletes; 2) explore whether symptoms experienced are related to perceived performance; and 3) examine potential differences in these factors between athletes at different levels of performance. The study was based on self-reported data from 1,086 athletes from 57 sports at different performance levels via a web-based questionnaire. Thirty-seven percent (n = 407) of the athletes did not use hormonal contraceptives. In this group, menstrual cycle related symptoms were common across all athlete levels, particularly dysmenorrhea (74%, n = 300) and premenstrual symptoms (78%, n = 318), which also influenced perceived performance of aerobic fitness, muscle strength, mental sharpness, balance, and sleep quality. Sixty-three percent (n = 679) of the athletes used various hormonal contraceptives and 40% (n = 272) perceived a variety of side-effects. Physical performance was experienced equally independent of time-point of the pill-chart except for the period of inactive pills, which was associated with more negative impact. Nonetheless, only 18% (n = 191) of the athletes considered menstrual cycle or hormonal contraceptive issues when planning their training or competitions. These results indicate that greater focus is needed to identify and effectively treat different menstrual cycle and hormonal contraceptive related symptoms on an individual level

Offered Support and Knowledge about the Menstrual Cycle in the Athletic Community: A Cross-Sectional Study of 1086 Female Athletes

Many female athletes perceive that symptoms related to the menstrual cycle such as dysmenorrhea, premenstrual symptoms, amenorrhea or side-effects of hormonal contraceptives negatively impact their training, performance, and general well-being. Knowledge and communication about female athletes’ health is therefore important in the sport community. The aims of this study were to explore the level of knowledge and communication about menstrual cycle issues and use of hormonal contraceptives in the athletic community and to describe the kinds of medical support offered to female athletes. A total of 1086 Swedish and Norwegian athletes from 57 different sports responded to a web-based questionnaire. Of these, 58% (n = 627) practiced team sports and 42% (n = 459) individual sports. Twenty-six percent (n = 278) of the athletes perceived their knowledge about female athlete health to be poor/very poor and the knowledge was most often acquired from medical staff. Fifty-three percent (n = 572) of the athletes perceived the knowledge acquired of their coaches as poor/very poor, even though a significantly (p < 0.001) higher proportion of athletes with a female coach (30%, n = 31) rated their coach’s knowledge as very good/good, compared to athletes with a male coach (5%, n = 31). Only 11% (n = 116) of the athletes discussed female health issues with their coach. The majority (81%, n = 842) of the athletes partly to strongly agreed that female athlete health is considered a taboo topic in the athletic community. Forty-seven percent (n = 510) of the athletes had access to a physiotherapist, while only three percent (n = 29) had access to a gynecologist. Low perceived knowledge, lack of communication and support demonstrate the need for a multi-professional medical team and enhanced educational efforts focused on female athlete health in the athletic community

Comparison of selected exercise training modalities in the management of PCOS: a systematic review and meta-analysis to inform evidence-based guidelines

Summary: Background: Polycystic ovary syndrome (PCOS) is a common endocrine condition in women of reproductive age that often presents with reproductive, metabolic, and psychological symptoms. While exercise is part of the management of PCOS, it is unclear which form of exercise may be most effective and for which outcomes. Aim: In order to inform the updated 2023 International evidence-based guideline for the assessment and management of polycystic ovary syndrome, this systematic review aimed to determine the exercise modality that provides the greatest improvement in anthropometric, metabolic, hormonal/reproductive, and psychological outcomes in adult women with PCOS. Methods: Five databases were searched from inception to July 2022. Studies eligible for inclusion consisted of those in a PCOS population, that compared two exercise modalities, and reported at least one anthropometric, metabolic, hormonal/reproductive, and/or psychological outcome. Screening, data extraction, and methodological quality assessments were conducted by two independent reviewers. Methodological quality assessment was performed using the Cochrane Risk of Bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines were used to determine the certainty of evidence. Meta-analysis was performed utilising Comprehensive Meta-Analysis software, Version 3. Results: Of the 4739 records identified, five unique studies were eligible for inclusion in the systematic review and meta-analysis, comprising a total of 216 individuals. Meta-analyses comparing high-intensity interval training (HIIT) to moderate-intensity continuous training (MICT) on anthropometric, metabolic, and hormonal/reproductive parameters found no statistically significant differences in outcomes between groups, and the certainty of evidence was graded as low or very low. Results from single studies showed that HIIT was more effective than MICT for menstrual regularity (odds ratio [95% confidence interval] ​= ​7.875 [1.105, 56.125], p ​= ​0.039, very low certainty). HIIT vs resistance training, and diet ​+ ​MICT vs diet ​+ ​MICT ​+ ​resistance training were examined by a single study each, and no statistically significant differences were found for any outcome, with the certainty of evidence ranked as very low. Conclusion: To date, there are insufficient RCTs comparing exercise modalities in individuals with PCOS to establish with certainty whether one form of exercise is superior to another for the management of PCOS

Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome

Study question What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? Summary answer International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. What is known already The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from 6 continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low- to low-quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus-based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, the evidence quality was low, and evidence-practice gaps persist. Study design, size, and duration The 2023 International Evidence-based Guideline update re-engaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation, and ultimately recommendation strength, and diversity and inclusion were considered throughout. Participants/materials, setting, and methods This summary should be read in conjunction with the full guideline for detailed participants and methods. Governance included a 6-continent international advisory and management committee, 5 guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health, and other experts, alongside consumers, project management, evidence synthesis, statisticians, and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and 5 face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across 5 guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council. Main results and the role of chance The evidence in the assessment and management of PCOS has generally improved in the past 5 years but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpin 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include the following: (1) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm, and inclusion of anti-Müllerian hormone levels as an alternative to ultrasound in adults only; (2) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnoea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; (3) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care, and shared decision-making to improve patient experience, alongside greater research; (4) maintained emphasis on healthy lifestyle, emotional well-being, and quality of life, with awareness and consideration of weight stigma; and (5) emphasizing evidence-based medical therapy and cheaper and safer fertility management. Limitations and reasons for caution Overall, recommendations are strengthened and evidence is improved but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. Wider implications of the findings The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input, and consumer preferences. Research recommendations have been generated, and a comprehensive multifaceted dissemination and translation programme supports the guideline with an integrated evaluation programme

Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome

STUDY QUESTION What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. WHAT IS KNOWN ALREADY The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. STUDY DESIGN, SIZE, DURATION The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations, with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout. PARTICIPANTS/MATERIALS, SETTING, METHODS This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). MAIN RESULTS AND THE ROLE OF CHANCE The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION Overall, recommendations are strengthened and evidence is improved, but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. WIDER IMPLICATIONS OF THE FINDINGS The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the Guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S) This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the partnering organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker’s fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker’s fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker’s fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker’s fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker’s fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC

Maturitas Sex hormones, appetite and eating behaviour in women

a b s t r a c t Sex hormones play essential roles in the regulation of appetite, eating behaviour and energy metabolism and have been implicated in several major clinical disorders in women. Estrogen inhibits food intake, whereas progesterone and testosterone may stimulate appetite. This review describes recent findings concerning interactions between sex hormones and neuroendocrinological mechanisms in the control of appetite and eating in women. Furthermore, we are gaining insights into the roles played by sex hormones in the development of eating disorders and obesity. For instance, androgens may promote bulimia by stimulating appetite and reducing impulse control, a proposal supported by the observation that antiandrogenic treatment attenuates bulimic behaviour. Androgens are also involved in the pathophysiology of abdominal obesity in women. On the other hand, hormone replacement therapy with estrogen counteracts the weight gain and accumulation of abdominal fat associated with the menopausal transition. In conclusion, sex hormones and/or agents that exhibit similar activities may provide novel strategies for the treatment of eating disorders and android obesity, two of the most serious health problems for women today

Urinary Steroid Profile in Elite Female Athletes in Relation to Serum Androgens and in Comparison With Untrained Controls

IntroductionIn female athletes, the interpretation of doping tests is complex due to hormonal variations during the menstrual cycle and hormonal contraceptive use, both influencing the urinary steroid profile. Exercise is suggested to affect circulating steroid hormone levels, and in women, the urinary steroid profile differs between in competition testing and out of competition testing. No previous study has investigated the relationship between amount of exercise and the urinary steroid profile in female elite athletes.PurposeTo compare the urinary steroid profile between female Olympic athletes and age- and BMI-matched untrained controls, and to study the urinary steroid profile in relation to serum hormones and amount of exercise.MethodsIn this cross-sectional study conducted at the Women’s Health Research Unit, Karolinska University Hospital, Stockholm, 94 female elite athletes and 86 untrained controls were included. Serum estrogens and testosterone and the urinary steroid profile were analyzed by liquid chromatography–tandem mass spectrometry and gas chromatography-tandem mass spectrometry, respectively. Exercise hours/week were evaluated by questionnaire.ResultsAlthough serum steroid hormones were comparable between groups, the athletes demonstrated approximately 30% lower urinary steroid metabolites of testosterone, epitestosterone, androsterone, etiocholanolone, 5α-androstan-3α, 17β-diol, and 5β-androstan-3α, 17β-diol compared to the controls. The urinary steroid metabolites correlated positively with serum steroid hormones. In the athletes, urinary steroid metabolites: androsterone (rs = −0.28, p = 0.007), epitestosterone (rs = −0.22, p = 0.034), 5αAdiol (rs = −0.31, p = 0.002) and testosterone (rs = −0.24, p = 0.026), were negatively correlated with amount of training (hours per week).ConclusionThe urinary concentrations of steroid metabolites were lower in elite athletes than in sedentary controls, although serum steroids were comparable between groups. Moreover, exercise time was negatively associated with the urinary concentrations. Our findings suggest alternative excretion routes of androgens in the athletes related to training

Changes in premenstrual symptoms in women starting or discontinuing use of oral contraceptives

It is not clear whether oral contraceptive (OC) treatment affects premenstrual symptoms in women. The aim of the present study was to evaluate changes in premenstrual symptoms (PMS) in women starting to use or discontinuing the use of OCs. Twenty-four healthy women with no previous diagnosis of premenstrual dysphoric disorder were included in this study with a prospective crossover design. Nineteen women completed daily ratings of somatic and mood symptoms during two hormonally different cycles, during a normal menstrual cycle and while using OCs. The menstrual cycle phases were hormonally verified and the low-dose, monophasic OCs were used in a 21/7 regimen. The onset of OC use significantly decreased premenstrual somatic symptoms, but it did not affect mood symptoms. In the women who discontinued OC use, no significant changes in neither somatic nor mood symptoms appeared in the premenstrual phase