Experts' view on the role of oestrogens in combined oral contraceptives: emphasis on oestetrol (E4).

Introduction: The evolution of contraception has been crucial for public health and reproductive well-being. Over the past 60 years, combined oral contraceptives (COCs) have remained an important part of the contraceptive landscape worldwide; continued development has worked toward maintaining efficacy and improving safety. Methods: Seven global experts convened to discuss the clinical relevance of the oestrogen in COCs, focusing on the impact of the new oestrogen, oestetrol (E4). Participants then commented through an online forum on the summary content and other participants' feedback. We prepared this report to describe the experts' views, their follow-up from the open forum and the evidence supporting their views. Results: Ethinylestradiol (EE) and oestradiol (E2) affect receptors similarly whereas E4 has differential effects, especially in the liver and breast. Adequate oestrogen doses in COCs ensure regular bleeding and user acceptability. EE and E4 have longer half-lives than E2; accordingly, COCs with EE and E4 offer more predictable bleeding than those with E2. Oestrogen type and progestin influence VTE risk; E2 poses a lower risk than EE; although promising, E4/DRSP VTE risk is lacking population-based data. COCs alleviate menstrual symptoms, impact mental health, cognition, libido, skin, and bone health. Conclusion: Oestrogens play an important role in the contraceptive efficacy, bleeding patterns, and overall tolerability/safety of COCs. Recent studies exploring E4 combined with DRSP show promising results compared to traditional formulations, but more definitive conclusions await further research.

Impact of vaginal estriol on serum hormone levels: a systematic review.

The genitourinary syndrome of menopause (GSM) affects up to 84% of postmenopausal women and may significantly reduce the quality of life in some. For symptom relief, there are several non-hormonal and hormonal vaginal products available. In Europe, vaginal estriol (E3) is the most frequently chosen estrogen for GSM treatment. The aim of this systematic review was to assess the impact of vaginal E3 on serum sex hormone levels, an outcome that has been previously used to assess safety in similar products. In our review, we did not find any alterations in serum estrone, estradiol, testosterone, progesterone and sex hormone binding globulin levels after vaginal E3 application. In contrast, some studies showed a minimal and transient decrease in serum gonadotropin levels, which however remained within the postmenopausal range. Similarly, only a few studies reported a minimal and transient increase of serum E3 levels, with the rest reporting no changes. The lack of clinically relevant long-term changes in serum sex hormone levels supports the current literature providing evidence about the safety of vaginal E3 products.

Quality of life in menopausal women in the workplace - a systematic review.

Menopausal women are a large and economically relevant group in the workforce. Yet their quality of life (QoL) and needs in the workplace have been neglected. Thus, the aim of this systematic review was to provide an overview of QoL of menopausal women in the workplace. Systematic literature searches were executed, yielding 1211 references. After abstract screening, 156 articles remained for full-text screening. Finally, 12 articles fulfilled the inclusion criteria and were included in this review. Age, educational level, type of work, working environment (e.g. crowding, confined spaces, noise, workstation design), permanent place of residency, mental factors (e.g. stress level, workload, work pattern), comorbidities, menopausal symptoms, time since menopause and physical activity have repeatedly been shown to affect QoL in the workplace in menopausal women. Low-threshold access to medical and psychological support as well as individual adaptation of the workplace environment are, among others, retrieved recommendations for employers from these findings. Further raising of awareness of special needs of menopausal working women as well as further systematic research programs are needed.

Clomiphene citrate stimulated cycles - additional gonadotrophin stimulation increases endometrium thickness without increasing implantation rate.

It is known that Clomiphene citrate (CC) reduces endometrial thickness, but it is unknown if additional gonadotrophin stimulation increases endometrial thickness and if this has an effect on implantation rate in in vitro fertilization (IVF). The retrospective study included 263 minimal stimulation IVF-cycles stimulated with 25 mg CC per day (CC-IVF), and 161 IVF-cycles stimulated with CC plus 75IU hMG (human Menopausal Gonadotrophin) per day (CC/hMG-IVF). Endometrial and oestradiol (E2) measurements were analysed between day -4 and 0 (0 = day of oocyte retrieval) and the association of endometrial thickness and treatment on implantation rates were studied after multiple adjustments. It was shown that on day 0, endometrium was significantly thicker in CC/hMG-IVF versus CC-IVF cycles (9.81 ±2.68 versus 9.06 ±2.54 mm, p = 0.005). However, increased endometrial thickness did not have an effect on implantation and live birth rates. In conclusion, gonadotrophins should not be added to low dose CC treated IVF cycles just to increase endometrial thickness as increased endometrial thickness does not increase implantation rate.

Impact of progesterone on the gastrointestinal tract: a comprehensive literature review.

Women are more prone to gastrointestinal symptoms than men. A comprehensive literature search was performed to assess the impact of sex steroid hormone, especially progesterone, on the (healthy and diseased) gastrointestinal tract. Overall, 37 articles were identified. Based on these we conclude that progesterone has a dose-dependent and sex-dependent effect on gastric emptying (especially in mammals), slows down gastrointestinal motility, reduces the gallbladder's response to contractile stimulants, may support gastroesophageal reflux by reducing the esophageal sphincter pressure, may protect from Helicobacter pylori infection gastrointestinal sequelae (especially in mammals) and does not affect inflammatory bowel disease-specific symptoms. However, for several gastrointestinal symptoms and diseases no studies have yet been performed addressing the impact of sex hormone steroids.

The impact of micronized progesterone on cardiovascular events - a systematic review.

Biologically identical menopausal hormone therapy (MHT) including micronized progesterone (MP) has gained much attention. We aimed to assess the impact of MP in combined MHT on venous and arterial thromboembolism (VTE/ATE) (e.g. deep venous thrombosis/pulmonary embolism, myocardial infarction [MI] and ischemic stroke). Articles were eligible if they provided endpoints regarding cardiovascular events and use of exogenous MP. Literature searches were designed and executed for the databases Medline, Embase, CINAHL, the Cochrane Library, ClinicalTrials.gov and interdisciplinary database Web of Science. Twelve studies consisting of randomized controlled trials (RCTs), case-control studies and prospective or retrospective cohort studies were included, and risk of bias was assessed. Only a minority assessed thromboembolic events as a primary endpoint, showing that in contrast to norpregnane derivatives, primary and recurrent VTE risk was not altered by combining estrogens with MP, which was also true for ischemic stroke risk. Similarly, in placebo-controlled RCTs assessing VTE/ATE as adverse events there were no significant intergroup differences. Studies on MI as a primary endpoint are missing. In conclusion, while available data suggest that MP as a component in combined MHT may have a neutral effect on the vascular system, more RCTs investigating the impact of MP alone or in combined MHT on vascular primary endpoints are needed.

Limitations in functioning in climacteric syndrome: a systematic literature review using the ICF.

INTRODUCTION: This study is the first of four preparatory studies in the process to develop an International Classification of Functioning, Disability and Health (ICF) Core Set for climacteric syndrome. The aim was to identify perimenopausal and postmenopausal limitations in functioning reported in the scientific literature. METHODS: A systematic literature review was performed on MEDLINE, PsycInfo, Embase and CINAHL including publications from 2010 to 2020. Meaningful concepts were identified from the included studies and linked to the ICF using standardized linking rules. RESULTS: From the 6935 unique publications found, 300 articles were randomly selected for abstract screening and 48 studies met the inclusion criteria. From these, 1836 meaningful concepts were identified and linked to 158 different ICF categories. Most of them could be linked to the ICF chapter 'Body Functions'. Emotional, sleep, energy and drive as well as thermoregulatory functions and sensation of pain were addressed in >80% of all publications. CONCLUSION: Climacteric syndrome involves all four components of the ICF, but the focus of scientific research lies on limitations in body functioning. Limitations in body structures, activities and participation and environmental factors were less frequently assessed. The ICF is a valuable tool to describe the multidimensional phenotype of climacteric syndrome.

Swiss consensus on the role of DHEA in the management of genitourinary syndrome of menopause.

Genitourinary syndrome of menopause (GSM) has a significantly negative impact on affected women's lives. However, despite the increasing number of GSM treatment options (e.g. non-hormonal vaginal products, vaginal hormones [estrogens], dehydroepiandrosterone [DHEA; prasterone], vaginal laser therapy, oral ospemifene), many women remain untreated. The goal of the Swiss interdisciplinary GSM consensus meeting was to develop tools for GSM management in daily practice: a GSM management algorithm (personalized medicine); a communication tool for vaginal DHEA (drug facts box); and a communication tool for understanding regulatory authorities and the discrepancy between scientific data and package inserts. The acceptance and applicability of such tools will be further investigated.

Sustainability of vaginal estrogens for genitourinary syndrome of menopause - a systematic review.

Genitourinary syndrome of menopause (GSM) is a highly prevalent, not self-limiting condition displaying a major negative impact on sexual function and emotional well-being. Various non-hormonal and hormonal treatment options are available. Many women consider GSM treatment to be a short-term interval cure rather than a long-term or lifelong treatment. The aim of this systematic literature search was to assess the sustainability of vaginal estrogens for GSM treatment after treatment cessation. We found that objective GSM signs mostly deteriorated within approximately 4 weeks after vaginal estrogen treatment cessation, while vaginal estrogens had a more sustainable impact on subjective GSM symptoms up to 3-6 months. However, overall, scientific evidence on sustainability of vaginal estrogens was low. Thus, GSM treatment should not be considered a short-term interval cure but long-term therapy. Further studies in an internationally harmonized setting (Core Outcomes in Menopause [COMMA]) are needed.

Impact of progesterone on skin and hair in menopause - a comprehensive review.

In clinical practice, micronized progesterone (MP) is frequently recommended to treat signs and symptoms of skin and hair aging in menopausal women. The aim of this comprehensive review was to evaluate whether topically or systemically applied MP may effectively prevent or slow down signs of skin and hair aging. Three out of six identified studies reported an impact of MP on skin aging markers in menopausal women. Of these, two studies reported a benefit: one for topically applied MP, another for systemically applied combined menopausal hormone therapy (MHT) comprising MP as progestogen for endometrial protection. Tolerability and safety of MP were good. However, there was no study investigating the impact of MP on menopausal scalp hair. In conclusion, delay of skin aging comprises lifestyle adjustment, antioxidants, and several esthetic procedures. In menopausal women, MHT displays beneficial effects on skin aging. There is poor quality but promising scientific evidence for MP displaying anti-aging skin effects in menopausal women. However, good quality studies are needed.

The impact of menopausal hormone therapy on overall mortality - a comprehensive review.

Menopausal hormone therapy (MHT) is indicated for menopausal symptom relief. However, MHT has also been shown to be beneficial for prevention of long-term estrogen deficiency sequelae including mortality. Based on a comprehensive literature review on MHT and mortality, the authors' recommendations are as follows: in postmenopausal women, MHT appears to confer a (significant) reduction in overall mortality; the benefit especially applies to women who initiate long-term MHT early after menopause; in women with prevalent cardiovascular risk factors (except for diabetes mellitus, where results are mixed), the benefit of MHT on overall mortality is even more pronounced; and, however, study results are difficult to compare due to heterogeneous study designs.

An extended Menopause Rating Scale II: a retrospective data analysis.

OBJECTIVE: This study aims to discuss a statistically reasonable inclusion of additional questions in the Menopause Rating Scale II (MRS II) for daily use in clinical practice. METHODS: Retrospective data analysis was performed (cantonal ethics committee No. 2016-01179). The MRS II was extended with the parameters 'changes in weight', 'headaches', 'skin changes', 'changes in hair growth', 'hair loss', and whether therapy was desired. Data from 419 women seeking medical advice in our menopause center were collected between April 2009 and April 2017. Cronbach's alpha was used to measure internal consistency of the extended questionnaire. RESULTS: For the conventional MRS II (N = 340 of 419, 81.1%), the internal consistency measured with Cronbach's alpha increased from 0.805 to 0.820 considering 'changes in weight' (N = 237, 56.6%), to 0.815 considering 'headaches' (N = 247, 58.9%), and to 0.815 considering 'skin changes' (N = 236, 56.3%) if these additional parameters were added separately. Cronbach's alpha increased from 0.805 to 0.835 (N = 224, 53.5%) if these parameters were added at once. Desire for therapy varied between 42.1% for 'changes in hair growth' (N = 38, 9.1%) and 60.6% for 'hair loss' (N = 33, 7.9%). CONCLUSION: We suggest including the items 'changes in weight', 'headaches', and 'skin changes' in the MRS II as our results show even higher internal consistency with these symptoms and as the wish for therapy was high.

Impact of endogenous and exogenous progesterone exposure on stress biomarkers: a systematic review.

Stress activates the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal axis (HPAA). Based on a systematic literature review of the impact of endogenous and exogenous exposure with natural progesterone on the stress response in healthy premenopausal and postmenopausal women, the following conclusions can be drawn: the HPAA activity was not relevantly affected by endogenous progesterone exposure across the menstrual cycle, but might be reduced by exogenous micronized progesterone application; in contrast, the ANS has a sympathetic predominance in the (progesterone-dominated) luteal phase of the menstrual cycle. Future studies should assess various stress biomarkers under various hormonal conditions to, for example, allow for cardiovascular risk stratification in hormone users.

Impact of micronized progesterone on body weight, body mass index, and glucose metabolism: a systematic review.

In women, body weight increases with age. Often menopausal hormone therapy (MHT) is blamed for enhancing this effect. In recent years, the debate on bioidentical MHT including micronized progesterone (MP) has increased. Among others, the question has been raised of whether MHT containing MP has an impact on body weight and glucose metabolism. Based on a systematic literature review on the impact of MHT containing MP on body weight, body mass index (BMI), and glucose metabolism, the following conclusions can be drawn: estrogens combined with MP (1) either do not change or reduce body weight in normal weight postmenopausal women, (2) do not change BMI in normal and overweight postmenopausal women, (3) do not change or improve fasting serum glucose levels in (non-)diabetic postmenopausal women, (4) do not change or improve fasting serum insulin levels in (non-)diabetic postmenopausal women, and (5) do not have an impact on serum glycated hemoglobin in postmenopausal diabetic women. This beneficial effect is probably mostly due to the estrogen MHT component.

The impact of micronized progesterone on breast cancer risk: a systematic review.

Postmenopausal women with an intact uterus using estrogen therapy should receive a progestogen for endometrial protection. The debate on bioidentical hormones including micronized progesterone has increased in recent years. Based on a systematic literature review on the impact of menopausal hormone therapy (MHT) containing micronized progesterone on the mammary gland, an international expert panel's recommendations are as follows: (1) estrogens combined with oral (approved) or vaginal (off-label use) micronized progesterone do not increase breast cancer risk for up to 5 years of treatment duration; (2) there is limited evidence that estrogens combined with oral micronized progesterone applied for more than 5 years are associated with an increased breast cancer risk; and (3) counseling on combined MHT should cover breast cancer risk - regardless of the progestogen chosen. Yet, women should also be counseled on other modifiable and non-modifiable breast cancer risk factors in order to balance the impact of combined MHT on the breast.

Measuring Active and Healthy Ageing: Applying a GENERIC Interdisciplinary Assessment Model Incorporating ICF.

OBJECTIVES: In this study we compared the chronological and bio-functional age between two German speaking cohorts 30 years apart applying a comprehensive and generic Active and Healthy Aging (AHA) assessment model incorporating ICF. METHODS: Single-centre, cross-sectional, observational, non-interventional, non-randomized trial at an University based women's hospital, division of Gynecological Endocrinology and Reproductive Medicine. All participants followed a standardized, holistic battery of biopsychosocial assessments consisting of bio-functional status (BFS), bio-functional age (BFA) and additional validated psychometric questionnaires. RESULTS: 462 non-pediatric, non-geriatric females were in the BeCS-14 cohort. The measured mean BFA was lower than the chronological age within the BeCS-14 cohort (regression coefficient 0.58) and comparable in the female LeCS-84 subcohort (regression coefficient age 0.85, communality age 76%). In detail, within the decades 35-45 years and 55-65 years the gradient of BFA increase (aging rate) was similar in both cohorts (decade 35-45 years: LeCS-84 4.08 ± 1.03 year equivalents and BeCS-14 4.78 ± 1.67 year equivalents; decade 55-65 years: LeCS-84 6.21 ± 1.29 year equivalents and BeCS-14 5.25 ± 1.18 year equivalents). Remarkably, within the LeCS-84 cohort the mean aging rate within the decade 45-55 years was significantly different from all other aging rates in both cohorts: 13.02 ± 1.05 year equivalents. However, within the BeCS-14 cohort the corresponding value was 4.83 ± 1.02 year equivalents thus indicating a continuous aging process across the adult life course. In BeCS-14, there was a significant age-related effect for cardiovascular performance and social stress exposition and younger age was associated with better cardiovascular performance while level of social stress exposition decreased in aging women. CONCLUSION: When comparing BeCS-14 and LeCS-84, the aging process seemed to be accelerated in women in LeCS-84 between 45 and 54 years of age. We can only speculate on the reasons, such as differences in the health care, political and social system. However, the differences observed support the use of our BFS/BFA assessment tool not only on an individual level (strengths/resources) but also population level following EIP-AHA requirements. Yet, it remains to be developed how the assessed health strengths/resources-profile may be integrated into AHA management.

Follicular flushing in natural cycle IVF does not affect the luteal phase - a prospective controlled study.

In contrast to multifollicular IVF, follicular flushing seems to increase the efficacy of monofollicular IVF treatments such as natural cycle IVF (NC-IVF). However, because follicular flushing causes loss of granulosa cells, it might negatively affect luteal phase length and endocrine function of the luteal body. A prospective cohort Phase II study was performed in 24 women undergoing NC-IVF. Women underwent a reference cycle with human chorionic gonadotrophin-induced ovulation without follicle aspiration and analysis of the length of the luteal phase and luteal concentrations of progesterone and oestradiol. In addition, they underwent a NC-IVF cycle which was performed identically but follicles were aspirated and flushed three times. The luteal phase was shorter in 29.2%, equal in 16.7% and longer in 50.0% of cases following flushing of the follicles. Overall, neither difference in luteal phase length was significant [median duration (interquartile range) in reference cycle: 13 (12; 14.5), IVF (flushing) cycle: 14 (12.5; 14.5), median difference (95% CI): 0.5 (-0.5 to 1.5)] nor median progesterone and oestradiol concentrations. In conclusion, follicular flushing in NC-IVF affects neither the length of the luteal phase nor the luteal phase concentrations of progesterone and oestradiol, questioning the need for luteal phase supplementation.

The impact of micronized progesterone on the endometrium: a systematic review.

Postmenopausal women with an intact uterus using estrogen therapy should receive a progestogen for endometrial protection. International guidelines on menopausal hormone therapy (MHT) do not specify on progestogen type, dosage, route of application and duration of safe use. At the same time, the debate on bioidentical hormones including micronized progesterone increases. Based on a systematic literature review on micronized progesterone for endometrial protection, an international expert panel's recommendations on MHT containing micronized progesterone are as follows: (1) oral micronized progesterone provides endometrial protection if applied sequentially for 12-14 days/month at 200 mg/day for up to 5 years; (2) vaginal micronized progesterone may provide endometrial protection if applied sequentially for at least 10 days/month at 4% (45 mg/day) or every other day at 100 mg/day for up to 3-5 years (off-label use); (3) transdermal micronized progesterone does not provide endometrial protection.

Impact of endo- and exogenous estrogens on heart rate variability in women: a review.

Measurement of heart rate variability (HRV) is an established method to assess the activity of the autonomic nervous system. The aim of this review was to examine the link between HRV, reproductive life stages and menopausal hormone therapy. A literature review was performed using the Medline database. Based on title and abstract, 45 studies were extracted out of 261 citations screened. Due to different study designs and evaluation methods, HRV indices were not directly comparable. Qualitative comparisons in between the vast majority of studies, however, demonstrated a decrease of the vagal dominance on the heart from the follicular to the luteal cycle phase, although some studies asserted no change. The intake of oral contraceptives appeared not to alter the vagal modulation of the heart. All investigations agreed on a decline of HRV towards higher sympathetic control after menopause. Different menopausal hormone therapy approaches showed a supporting impact of estrogen on HRV in most studies. A combined therapy of estrogen and progestogens revoked this benefit. Further research is needed to demonstrate how this process might be attenuated by different menopausal hormone therapies.