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.

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.

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.

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.

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.

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.

Efficacy and safety of non-hormonal remedies for vaginal dryness: open, prospective, randomized trial.

OBJECTIVES: To prove non-inferiority of the first non-hormonal vaginal cream in Germany, Vagisan(®) Moisturising Cream (CREAM), compared to a non-hormonal vaginal gel (GEL) for vulvovaginal atrophy (VVA) symptom relief. METHOD: This was a 12-week multicenter, open-label, prospective, randomized, two-period, cross-over phase-III trial. The primary endpoint was the cumulative VVA subjective symptom score of the respective treatment period. Secondary endpoints were assessment of single VVA subjective and objective symptoms, VVA objective symptom score, vaginal pH, safety parameters, overall assessment of efficacy, tolerability and evaluation of product properties. In total, 117 women were randomly allocated to either one of the two treatments, each administered for 4 weeks; 92 women were included in the per-protocol analysis (primary analysis). The main outcome measure was cumulative VVA subjective symptom score. RESULTS: Regarding VVA symptom relief, results confirmed non-inferiority of CREAM compared to GEL and even indicated superiority of CREAM. Frequency and intensity of subjective symptoms and objective findings were clearly reduced, with CREAM showing better results compared to GEL. Mean VVA objective symptom score significantly decreased; improvement was significantly greater with CREAM. Vaginal pH decreased only following CREAM treatment. Tolerability was superior for CREAM: burning and itching, mostly rated as mild, occurred markedly less often with CREAM than with GEL. Overall satisfaction with treatment efficacy, tolerability and most product properties were rated significantly superior for CREAM. CONCLUSIONS: Subjective and objective VVA symptoms were reliably and safely reduced by both non-hormonal topical products. However, efficacy and tolerability of CREAM were shown to be superior to GEL.

Ultra-low dose - new approaches in menopausal hormone therapy.

Despite increasing life expectancy, the age of onset of natural menopause has not significantly changed in recent decades. Thus, women spend about one-third of their lives in an estrogen-deficient state if untreated. There is a need for appropriate treatment of acute symptoms and prevention of the sequelae of chronic estrogen deficiency. International guidelines call for the use of the lowest effective hormone dosage for vasomotor symptom relief, the major indication for menopausal hormone therapy (MHT). In 2011, an oral continuous combined ultra-low-dose MHT was approved in Switzerland. This publication was elaborated by eight national menopause specialists and intends to review the advantages and disadvantages of ultra-low-dose MHT after the first years of its general use in Switzerland. It concludes that, for many women, ultra-low-dose MHT may be sufficient to decrease vasomotor symptoms, but not necessarily to guarantee fracture prevention.

Gonadotrophin stimulation for in vitro fertilization significantly alters the hormone milieu in follicular fluid: a comparative study between natural cycle IVF and conventional IVF.

STUDY QUESTION: Is the steroid hormone profile in follicular fluid (FF) at the time of oocyte retrieval different in naturally matured follicles, as in natural cycle IVF (NC-IVF), compared with follicles stimulated with conventional gonadotrophin stimulated IVF (cIVF)? SUMMARY ANSWER: Anti-Mullerian hormone (AMH), testosterone (T) and estradiol (E2) concentrations are ∼3-fold higher, androstenedione (A2) is ∼1.5-fold higher and luteinizing hormone (LH) is ∼14-fold higher in NC-IVF than in cIVF follicles, suggesting an alteration of the follicular metabolism in conventional gonadotrophin stimulated IVF. WHAT IS KNOWN ALREADY: In conventional IVF, the implantation rate of unselected embryos appears to be lower than in NC-IVF, which is possibly due to negative effects of the stimulation regimen on follicular metabolism. In NC-IVF, the intrafollicular concentration of AMH has been shown to be positively correlated with the oocyte fertilization and implantation rates. Furthermore, androgen treatment seems to improve the ovarian response in low responders. STUDY DESIGN, SIZE, DURATION: This cross-sectional study involving 36 NC-IVF and 40 cIVF cycles was performed from 2011 to 2013. Within this population, 13 women each underwent 1 NC-IVF and 1 cIVF cycle. cIVF was performed by controlled ovarian stimulation with HMG and GnRH antagonists. PARTICIPANTS/MATERIALS, SETTING, METHODS: Follicular fluid was collected from the leading follicles. AMH, T, A2, dehydroepiandrosterone (DHEA), E2, FSH, LH and progesterone (P) were determined by immunoassays in 76 women. Aromatase activity in follicular fluid cells was analysed by a tritiated water release assay in 33 different women. For statistical analysis, the non-parametric Mann-Whitney U or Wilcoxon tests were used. MAIN RESULTS AND ROLE OF CHANCE: In follicular fluid from NC-IVF and from cIVF, median levels were 32.8 and 10.7 pmol/l for AMH (P < 0.0001), 47.2 and 18.8 µmol/l for T (P < 0.0001), 290 and 206 nmol/l for A2 (P = 0.0035), 6.7 and 5.6 pg/ml for DHEA (n.s.), 3292 and 1225 nmol/l for E2 (P < 0.0001), 4.9 and 7.2 mU/ml for FSH (P < 0.05), 14.4 and 0.9 mU/ml for LH (P < 0.0001) and 62 940 and 54 710 nmol/l for P (n.s.), respectively. Significant differences in follicular fluid concentrations for AMH, E2 and LH were also found in the 13 patients who underwent both NC-IVF and cIVF when they were analysed separately in pairs. Hormone analysis in serum excluded any relevant impact of AMH, T, A2, and E2 serum concentration on the follicular fluid hormone concentrations. Median serum concentrations were 29.4 and 0.9 mU/ml for LH (P < 0.0001) and 2.7 and 23.5 nmol/l for P (P < 0.0001) after NC-IVF and c-IVF, respectively. Positive correlations were seen for FF-AMH with FF-T (r = 0.35, P = 0.0002), FF-T with FF-LH (r = 0.48, P < 0.0001) and FF-E2 with FF-T (r = 0.75, P < 0.0001). The analysis of aromatase activity was not different in NC-IVF and cIVF follicular cells. LIMITATION, REASONS FOR CAUTION: Any association between the hormone concentrations and the implantation potential of the oocytes could not be investigated as the oocytes in cIVF were not treated individually in the IVF laboratory. Since both c-IVF and NC-IVF follicles were stimulated by hCG before retrieval, the endocrine milieu in the natural cycle does not represent the pure physiological situation. WIDER IMPLICATIONS OF THE FINDINGS: The endocrine follicular milieu and the concentration of putative markers of oocyte quality, such as AMH, are significantly different in gonadotrophin-stimulated conventional IVF compared with natural cycle IVF. This could be a cause for the suggested lower oocyte quality in cIVF compared with naturally matured oocytes. The reasons for the reduced AMH concentration might be low serum and follicular fluid LH concentrations due to LH suppression, leading initially to low follicular androgen concentrations and then to low follicular AMH production. STUDY FUNDING/COMPETING INTERESTS: Funding for this study was obtained from public universities (for salaries) and private industry (for consumables). Additionally, the study was supported by an unrestricted grant from MSD Merck Sharp & Dohme GmbH and IBSA Institut Biochimique SA. The authors are clinically involved in low-dose monofollicular stimulation and IVF therapies, using gonadotrophins from all gonadotrophin distributors on the Swiss market, including Institut Biochimique SA and MSD Merck Sharp & Dohme GmbH. Otherwise, the authors have no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.