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Background: Chemotherapy efficacy in early-stage hormone receptor-positive (HR+) breast cancer (BC) according to menopausal status needs a biological explanation., Methods: We compared early-stage HR+ BC biological features before and after (neo)adjuvant chemotherapy or endocrine therapy (ET), and assessed oestrogen receptor (ER) pathway activity in both pre- and post-menopausal patients. The nCounter platform was used to detect gene expression levels., Findings: In 106 post-menopausal patients with HR+/HER2-negative BC randomized to neoadjuvant chemotherapy or ET (letrozole+ribociclib), a total of 19 oestrogen-regulated genes, including progesterone receptor (PGR), were found downregulated in the ET-based arm-only. We confirmed this finding in an independent dataset of 20 letrozole-treated post-menopausal patients and found, conversely, an up-regulation of the same signature in HR+/HER2-negative MCF7 cell line treated with estradiol. PGR was found down-regulated by 2 weeks of ET+anti-HER2 therapy in pre-/post-menopausal patients with HR+/HER2-positive (HER2+) BC, while anti-HER2 therapy alone increased PGR expression in HR-negative/HER2+ BC. In 88 pre- and post-menopausal patients with newly diagnosed HR+/HER2-negative BC treated with chemotherapy, the 19 oestrogen-regulated genes were found significantly downregulated only in pre-menopausal patients. In progesterone receptor (PR)+/HER2-negative BC treated with neoadjuvant chemotherapy (n=40), tumours became PR-negative in 69.2% of pre-menopausal patients and 14.8% of post-menopausal patients (p=0.001). Finally, a mean decrease in PGR levels was only observed in pre-menopausal patients undergoing anti-HER2-based multi-agent chemotherapy., Interpretation: Chemotherapy reduces the expression of ER-regulated genes in pre-menopausal women suffering from hormone-dependent BC by supressing ovarian function. Further studies should test the value of chemotherapy in this patient population when ovarian function is suppressed by other methods., Funding: Instituto de Salud Carlos III, Breast Cancer Now, the Breast Cancer Research Foundation, the American Association for Cancer Research, Fundació La Marató TV3, the European Union's Horizon 2020 Research and Innovation Programme, Pas a Pas, Save the Mama, Fundación Científica Asociación Española Contra el Cáncer, PhD4MDgrant of "Departament de Salut", exp SLT008/18/00122, Fundación SEOM and ESMO. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s)., Competing Interests: Declaration of Competing Interest Dr. Prat reports grants and personal fees from Pfizer, grants and personal fees from Lilly, personal fees from Nanostring tecnologies, grants and personal fees from Amgen, grants from Roche, personal fees from Oncolytics Biotech, personal fees from Daiichi Sankyo, personal fees from PUMA, personal fees from BMS, from Daiichi Sankyo, outside the submitted work. Dr. Perou reports personal fees from Bioclassifier LLC, outside the submitted work; in addition, Dr. Perou has a U.S. Patent No. 12,995,459 with royalties paid. Dr. Saura reports personal fees from AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, Puma, Roche Farma, Sanofi-Aventis, SeaGen, and Zymeworks outside the submitted work. Dr. Ciruelos reports personal fees from Roche, Pfizer, Lilly, Novartis, Astra-Zeneca/Daiichy Sankio and from MSD outside the submitted work. Dr. Gavilá reports grants from Novartis, Pfizer, Astra-Zeneca and Lilly, outside the submitted work. Dr. Soberino reports grants and personal fees from MSD, grants from Sanofi and personal fees from Roche outside the submitted work. Dr. Carey reports uncompensed relationship with Sanofi, G1 Therapeutics, Genentech/Roche, AstraZeneca/Daiichi Sankyo, Apitude Health and Exact Sciences; in addition Dr. Carey declared that Companies who have provided research funds to her institution in the past 1–2 years were Syndax, Immunomedics, Novartis, Nanostring technologies, Abbvie, Seattle Genetics and Veracyte, outside the submitted work. Dr Bellett declares advisory board participation for Lilly, Pfizer and Novartis, as well as travel expenses from Pfizer, outside the submitted work. Dr. Muñoz reports expert testimony for Eisai, Novartis and Roche, advisory board for Pierre Fabre and travel grants from Lilly, Pfizer and Roche, outside the submitted work. Dr. Oliveira reports grants from Pfizer, grants, personal fees and non-financial support from Roche, grants and personal fees from Genentech, grants, personal fees and non-financial support from Novartis, grants and personal fees from Seattle Genetics, grants and personal fees from Astra-Zeneca, grants and personal fees from PUMA Biotechnolgy, grants from Immunomedics, grants from Boehringer-Ingelheim, non-financial support from Eisai, Grunenthal, GP Pharma and Pierre Fabre, outside the submitted work. Dr. Pernas reports personal fees and non-financial support from Novartis, personal fees from AstraZeneca, Daiichi-Sankyo, Polyphor, Seattle Genetics, Eisai, Roche and Pierre-Fabre, outside the submitted work. Dr. Cortes reports personal fees and travel expenses from Pfizer, personal fees from Lilly, Servier, Athenex, personal fees and travel expenses and advisory/honoraria from Roche, personal fees from Polyphor, personal fees and travel expenses from Daiichi Sankyo, Novartis and Eisai, personal fees from MSD, GSK, Astra-Zeneca, Celgene, Cellestia, Biothera, Merus, Seattle Genetics, Erytech, Leuko, Bioasis, Clovis Oncology, Boerhinger-Ingelheim, Samsung Bioepis, and stocks from MedSIR, outside the submitted work. The other authors have nothing to declare., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The skin is the body's primary defence against the external environment, preventing infection and desiccation. Therefore, alterations to skin homeostasis, for example with skin ageing, increase susceptibility to skin disease and injury. Skin biological ageing is uniquely influenced by a combination of intrinsic and extrinsic (primarily photoageing) factors, with differential effects on skin structure and function. Interestingly, skin architecture rapidly changes following the menopause, as a direct result of reduced circulating 17β-estradiol. The traditional clinical benefit of estrogens are supported by recent experimental data, where 17β-estradiol supplementation prevents age-related decline in the skin's structural and mechanical properties. However, the off-target effects of 17β-estradiol continue to challenge therapeutic application. Here we discuss how ageing alters the physiological and structural properties of the dermal extracellular matrix, and explore how estrogen receptor-targeted therapies may restore the mechanical defects associated with skin ageing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

All women undergo the menopause transition (MT), a neuro-endocrinological process that impacts aging trajectories of multiple organ systems including brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. Yet, little is known of how this process impacts the human brain. This multi-modality neuroimaging study indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-menopause, peri-menopause, and post-menopause). These effects involved brain regions subserving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer's disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile during midlife endocrine aging of the female brain.

The decrease in ovarian hormone secretion that occurs during menopause results in an increase in body weight and adipose tissue mass. Probiotics and soy isoflavones (SIFs) could affect the gut microbiota and exert anti-obesity effects. The objective of this study was to investigate the effects of probiotics and a diet containing SIF (SIF diet) on ovariectomized mice with menopausal obesity, including the gut microbiome. The results demonstrate that Bifidobacterium longum 15M1 can reverse menopausal obesity, whilst the combination of Lactobacillus plantarum 30M5 and a SIF diet was more effective in alleviating menopausal lipid metabolism disorder than either components alone. Probiotics and SIFs play different anti-obesity roles in menopausal mice. Furthermore, 30M5 alters the metabolites of the gut microbiota that increase the circulating estrogen level, upregulates the expression of estrogen receptor α in abdominal adipose tissue and improves the production of short-chain fatty acids (SCFAs). A SIF diet can significantly alter the structure of the fecal bacterial community and enrich the pathways related to SCFAs production. Moreover, 30M5 and a SIF diet acted synergistically to effectively resolve abnormal serum lipid levels in ovariectomized mice, and these effects appear to be associated with regulation of the diversity and structure of the intestinal microbiota to enhance SCFAs production and promote estrogen circulation.

During aging and menopausal transition in women, a progressive muscle degeneration ( i.e. decrease in quality and muscle function) occurs. This muscle dysfunction, caused by decreased proliferation of muscle satellite cells, increased levels of inflammatory markers, and altered levels of sex hormones, exposes women to a raised incidence of sarcopenia. In this regard, hormonal balance and, in particular, estradiol, seems to be essential in skeletal muscle function. The role of the estradiol on satellite cells and the release of inflammatory cytokines in menopausal women are reviewed. In particular, estradiol has a beneficial effect on the skeletal muscle by stimulating satellite cell proliferation. Skeletal muscle can respond to estrogenic hormonal control due to the presence of specific receptors for estradiol at the level of muscle fibers. Additionally, estradiol can limit inflammatory stress damage on skeletal muscle. In this review, we primarily focused on the role of estradiol in sarcopenia and on the possibility of using Estradiol Replacement Therapy, which combined with nutritional and physical activity programs, can counteract this condition representing a valid tool to treat sarcopenia in women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BS declared a shared affiliation with some of the authors, RC and EM, to the handling editor at time of review., (Copyright © 2021 Geraci, Calvani, Ferri, Marzetti, Arosio and Cesari.)

Ovarian hormone deficiency leads to increased body weight, visceral adiposity, fatty liver and disorders associated with menopausal metabolic syndrome. To better understand the underlying mechanisms of these disorders in their early phases of development, we investigated the effect of ovariectomy on lipid and glucose metabolism. Compared to sham-operated controls, ovariectomized Wistar female rats markedly increased whole body and visceral adipose tissue weight ( p ˂ 0.05) and exhibited insulin resistance in peripheral tissues. Severe hepatic triglyceride accumulation ( p ˂ 0.001) after ovariectomy preceded changes in both serum lipids and glucose intolerance, reflecting alterations in some CYP proteins. Increased CYP2E1 ( p ˂ 0.05) and decreased CYP4A ( p ˂ 0.001) after ovariectomy reduced fatty acid oxidation and induced hepatic steatosis. Decreased triglyceride metabolism and secretion from the liver contributed to hepatic triglyceride accumulation in response to ovariectomy. In addition, interscapular brown adipose tissue of ovariectomized rats exhibited decreased fatty acid oxidation ( p ˂ 0.01), lipogenesis ( p ˂ 0.05) and lipolysis ( p ˂ 0.05) despite an increase in tissue weight. The results provide evidence that impaired hepatic triglycerides and dysregulation of some CYP450 proteins may have been involved in the development of hepatic steatosis. The low metabolic activity of brown adipose tissue may have contributed to visceral adiposity as well as triglyceride accumulation during the postmenopausal period.

Non-melanoma skin cancers (NMSC) are more frequent among men, but women (especially those aged < 40 years) have experienced steeper growth in their incidence rates in recent years. Hormonal factors were hypothesized to be playing a role in modulating NMSC risk, but the studies published to date provided conflicting results. We systematically reviewed and meta-analysed the studies focusing on the association between hormone-related characteristics (use of exogenous sex hormones, and aspects of menstrual and reproductive history) and the risk of NMSC among women. We included observational and experimental studies published in PubMed and EMBASE until February 2020. We calculated summary relative risk (SRR) and 95% confidence intervals (CI) by applying random effects models with maximum likelihood estimation, and used the I 2 statistics to quantify the degree of heterogeneity of risk estimates across studies. Eleven independent studies encompassing a total of over 30,000 NMSC cases were included in quantitative analyses. No evidence of an increased NMSC risk emerged among ever vs. never users of oral contraceptives (SRR 1.13, 95% CI 0.88-1.45) or hormones for menopause (SRR 1.09, 95% CI 0.87-1.37). Likewise, age at menarche or at menopause and parity were not associated with NMSC risk. Heterogeneity across studies was low, and pooled results were comparable between NMSC subtypes. We found no evidence that hormonal factors play a role in the pathogenesis of NMSC among women.

Background: Little is known about the estrogen exposure measurement and mutual effect of age at menarche and age at menopause in the risk of cardiovascular disease (CVD) events., Objectives: To evaluate estrogen exposure measurement and describe mutual effect of age at menarche and age at menopause in the risk of CVD events., Search Strategy: Systematic review of literature in PubMed, Embase and Web of Science for studies published up to 28 June 2020., Selection Criteria: Observational studies related to estrogen exposure measurement, including mutual effect of age at menarche and age at menopause and risk of CVD events., Data Collection and Analysis: Synthesis of evidence was conducted by reviewing individual estimates, followed by meta-analysis. The study received no external funding., Main Results: A total of 75 studies were included in synthesis of evidence, of which 17 studies were included in meta-analysis. Reproductive lifespan (age at menopause - age at menarche), endogenous estrogen exposure and total estrogen exposure were used for estrogen exposure measurement. Reproductive lifespan was by far the most commonly used method for estrogen exposure measurement. A shorter reproductive lifespan was associated with a higher risk of CVD events; the pooled relative risk (95% CI) was 1.31 (1.25-1.36) for stroke events. Robust epidemiological studies with measurement of estrogen exposure and associated health risk would strengthen the evidence., Conclusions: Reproductive lifespan was the most commonly used method for estrogen exposure measurement in epidemiological studies. A shorter reproductive lifespan was associated with a higher risk of CVD events, particularly stroke., Tweetable Abstract: A systematic review and meta-analysis found that women with a shorter reproductive lifespan have a higher risk of stroke events., (© 2020 John Wiley & Sons Ltd.)

Purpose: This study aimed to find the associations between vasomotor symptoms (VMS) and metabolic syndrome (MetS) in Chinese middle-aged women in a cross-sectional study., Methods: A total of 675 participants were recruited from an urban Chinese community. MetS was defined by the 2009 criteria of the Joint Interim Statement. VMS including hot flashes and sweats, blood pressure, weight, height, waist circumference (WC), serum glucose, triglycerides, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), estradiol, and follicle-stimulating hormone (FSH) were collected., Results: The presence of hot flashes was independently associated with the risk of MetS after adjusting for age, menopausal status, FSH log , estradiol log , and physical activity (odds ratio: 1.98, 95% confidence interval: 1.21-3.24, p  = 0.006). Both hot flashes and sweats were also independently associated with WC (for hot flashes, p  = 0.016; and for sweats, p  = 0.007) and triglycerides (for hot flashes, p  = 0.041; and for sweats, p  = 0.014) significantly. However, VMS were not significantly associated with blood pressure, glucose, HDL, and LDL., Conclusion: Women with hot flashes had a higher risk of MetS. Both hot flashes and sweats were related to a higher amount of central fat indicated by WC and higher triglycerides, but were not related to blood pressure, glucose, and HDL in Chinese women.

After menopause, women experience declines in ovarian sex hormones, an event that has recently been associated with increased amyloid-β peptides, a main feature of Alzheimer's disease. Diet-induced insulin resistance also increases amyloid-β peptides; however, whether this process is exacerbated with ovarian sex hormone loss remains unknown. Female C57BL6/J mice received either bilateral ovariectomy (OVX; n = 20) or remained intact ( n = 20) at 24 wk of age and were placed on either a low- or high-fat diet (LFD, n = 10 for OVX and intact; HFD, n = 10 for OVX and intact) for 10 wk. Independently, OVX led to increases in the amyloidogenic marker, soluble amyloid precursor protein β (sAPPβ). The HFD in combination with OVX led to lower insulin degrading enzyme (IDE) protein content and activity in the prefrontal cortex, indicative of decreased amyloid-β degradation; however, no differences in amyloid-β content were observed. Data from this study provide novel evidence of independent effects of peripheral insulin resistance and ovarian sex hormone loss in decreasing brain markers of amyloid-β degradation. Furthermore, findings indicate how the loss of ovarian sex hormones can promote the formation of amyloidogenic APP cleavage products, independent of diet-induced insulin resistance. NEW & NOTEWORTHY This study provides novel insight into the effect of peripheral insulin resistance and ovarian hormone loss in decreasing brain markers of amyloid-β degradation. Results demonstrate that ovarian hormone loss through ovariectomy increased the amyloidogenic marker, sAPPβ, while the high-fat diet in combination with ovariectomy led to lower IDE protein content and activity in the prefrontal cortex, indicative of decreased amyloid-β degradation. These original results provide important information for future targets in early AD pathogenesis.

Objective: To investigate the impact of age, obesity and metabolic parameters on 13 circulating steroids in reproductive and menopausal age. To define reference intervals (RIs)., Design: Cross-sectional., Methods: Three hundred and twenty five drug-free, healthy and eumenorrheic women were selected from the general population. Independent relationships of LC-MS/MS-determined steroid levels with age, BMI and metabolic parameters were estimated. Reference sub-cohorts were defined for calculating upper and lower limits in reproductive age, menstrual phases and menopause, and these were compared with limits in dysmetabolic sub-cohorts., Results: Lower androgens, pro-androgens and estrogens, but higher cortisol and metabolites were found in menopausal compared to reproductive age women. Androgens and precursors decreased during reproductive age (P < 0.001-P = 0.002) but not after menopause. 17OH-progesterone decreased with BMI (P = 0.006) and glucocorticoids with waist circumference (P < 0.001P = 0.002) in reproductive age, but increased with triglycerides (P=0.011P=0.038) after menopause. Inverse associations of dihydrotestosterone with BMI (P=0.004) and HDL-cholesterol (P=0.010), estrone with total cholesterol (P=0.033) and estradiol with triglycerides (P=0.011) were found in reproductive age. After menopause, estrone increased with waist circumference (P<0.001) and decreased with insulin resistance (P=0.012). Ovarian steroid RIs were estimated in menstrual phases and menopause. Age- and reproductive status-specific RIs were generated for androgens, precursors and corticosteroids. Lower limits for reproductive age cortisol (P=0.020) and menopausal 11-deoxycortisol (P=0.003) in dysmetabolic sub-cohorts were reduced and increased, respectively, compared to reference limits., Conclusions: Obesity and dysmetabolism differently influence circulating steroids in reproductive and menopausal status. Age, menstrual and menopausal status-specific RIs were provided by LC-MS/MS for a broad steroid panel.

Postmenopausal depression is mainly caused by the deprivation of ovarian hormones during menopausal transition, it is of great importance to study on the treatment that could effectively relieve symptoms of menopausal depression with fewer side effects. Activation of G-protein-coupled estrogen receptor (GPER) has long been reported to facilitate neuronal plasticity and improve cognition in animals. Meanwhile, it could participate in regulation of intracellular signaling pathways through the characteristic of GPER, ameliorate intracellular mitochondrial function and oxidative stress. However, the impact of GPER on regulating estrogen deprived-depressant and anxious behaviors is still largely unknown. Here we used the ovariectomized female rats to imitate the condition of menopause. Owing to the lateral ventricle administration of G-1 which specifically react with GPER receptor intracerebrally, Ovariectomized (OVX) female rats showed depressive- or anxiety-like phenotypes with attenuated mitochondrial function. In addition, G-1 facilitated PKA activation, which further accelerated TSPO phosphorylation and alleviated menopausal depression- and anxiety-like behaviors. Moreover, PKA inhibitor PKI could partially antagonized the anti-anxiety and anti-depression effects of G-1. Taken together, we concluded that GPER activation might exhibit antidepressant and anxiolytic effect by elevating TSPO phosphorylation via protein kinase A signaling and rescuing the redox status in menopausal female rats., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In this study, we investigated steroidogenic gene mRNA expression in human vaginas and verified the ability of human vagina smooth muscle cells (hvSMCs) to synthesize androgens from upstream precursor dehydroepiandrosterone (DHEA). As a readout for androgen receptor (AR) activation, we evaluated the mRNA expression of various androgen-dependent markers. hvSMCs were isolated from vagina tissues of women undergoing surgery for benign gynecological diseases. In these cells, we evaluated mRNA expression of several steroidogenic enzymes and sex steroid receptors using real time reverse transcription-polymerase chain reaction. Androgen production was quantified with liquid chromatography tandem-mass spectrometry (LC-MS/MS). In vaginal tissues, AR mRNA was significantly less expressed than estrogen receptor α, whereas in hvSMCs, its mRNA expression was higher than progestin and both estrogen receptors. In hvSMCs and in vaginal tissue, when compared to ovaries, the mRNA expression of proandrogenic steroidogenic enzymes (HSD3β1/β2, HSD17β3/β5), along with 5α-reductase isoforms and sulfotransferase, resulted as being more abundant. In addition, enzymes involved in androgen inactivation were less expressed than in the ovaries. The LC-MS/MS analysis revealed that, in hvSMCs, short-term DHEA supplementation increased Δ4-androstenedione levels in spent medium, while increasing testosterone and DHT secretion after longer incubation. Finally, androgenic signaling activation was evaluated through AR-dependent marker mRNA expression, after DHEA and T stimulation. This study confirmed that the human vagina is an androgen-target organ with the ability to synthesize androgens, thus providing support for the use of androgens for local symptoms of genitourinary syndrome in menopause., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cancer treatment-induced bone loss is a known side effect of cancer therapy that increases the risk of osteoporosis and bone fracture. Women with gynecologic cancer are at increased risk of bone loss secondary to the combined effect of oophorectomy and adjuvant therapies. Data regarding bone loss in women with gynecologic cancers are overall lacking compared to other cancer populations. Consequently, guidelines for osteoporosis screening in women with cancer are largely based on data generated among non-gynecologic cancer survivors. This article reviews current available data of bone health in women with gynecologic cancer, summarizes best-available guidelines for screening for osteoporosis in women with cancer, and provides guidance for osteoporosis screening in women with gynecologic cancers based on best available evidence., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier Inc.)

Background/aim: Hormone replacement therapy during menopause increases the risk of thromboembolic diseases and cancer, so safety alternative therapeutic strategies are needed. 17β-Aminoestrogens are a synthetic estrogens group that possess mild anticoagulant activity that contrasts with the pro-coagulant effects showed by estradiol's (E 2 ) in rodents. Being considered an alternative to conventional hormone replacement therapy during menopause without thrombogenic risks producing. The present study aimed to determine the estrogenic profile and anxiolytic activity of 17β-[hydroxy-ethylimine]-1,3,5(10)-estratrien-3-ol (IE 2 ), a related compound unknown until now., Methods: IE 2 was assessed in immature rats by uterotrophic assay administering IE 2, E 2, or vehicle. In ovariectomized adult Wistar rats (Ovx) to facilitating the lordotic behavior compared with E 2, estradiol benzoate, or vehicle. The effect of IE 2 on anxiety was estimated in Ovx animals treated with IE 2 , E 2 , or vehicle group and evaluated in the elevated plus-maze model., Results and Conclusion: IE 2 produced an uterotrophic effect, lordotic behavior, and anxiolytic effect in a dose-dependent manner, similar to E 2 . IE 2 depicted estrogenicity, indicating potential clinical use as hormone replacement therapy during menopause.

Background and Aims: Menopause is a physiological process in nature and hence, variations in the age of menopause are not expected. Hence, the study was conducted with an objective to calculate the reliable estimates of age at menopause for India, and understand the differentials in women's age at menopause throughout the country., Methods: A total of 202 studies of age at menopause, covering the period 2009-2020, were accessed from PubMed database and Google. Of these only ten studies met the selection criteria for this paper, which is that the data for these studies must be collected from house-to-house surveys., Results: The average age at menopause in India, with minimal publication bias, is 46.6 years (95% CI: 44.83, 48.44). In one study slightly above 1.96 Standard Deviation, was observed, as ascertained by Funnel Plot and Egger's test. The mean age ranged from a minimum of 44.69 years (95% CI: 35.01, 54.37) to a maximum of 48.95 (95% CI: 42.29, 55.61) years. Furthermore, the age at menopause did not exhibit any significant variation by age at menarche, although the association was positive., Conclusions: The age at menopause showed positive association with age at menarche. In India, during the period 2009-2020, it was 46.6 years, which significantly lower than the age in some developed countries. The differences may be methodological since no information was found regarding the distribution of age at menopause in the studies that were considered for meta-analysis., Competing Interests: Declaration of competing interest This is to certify that we the authors of article hereby declare that we do not have any conflict of interest in the article entitled “Age at Menopause in India: A Systematic Review”., (Copyright © 2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Background: Kisspeptin (KP) neurons in the rostral periventricular region of the 3rd ventricle (RP3V) of female rodents mediate positive estrogen feedback to gonadotropin-releasing hormone neurons and, thus, play a fundamental role in the mid-cycle luteinizing hormone (LH) surge. The RP3V is sexually dimorphic, and male rodents with lower KP cell numbers are unable to mount estrogen-induced LH surges., Objective: To find and characterize the homologous KP neurons in the human brain, we studied formalin-fixed post-mortem hypothalami., Methods: Immunohistochemical techniques were used., Results: The distribution of KP neurons in the rostral hypothalamus overlapped with distinct subdivisions of the paraventricular nucleus. The cell numbers decreased after menopause, indicating that estrogens positively regulate KP gene expression in the rostral hypothalamus in humans, similarly to several other species. Young adult women and men had similar cell numbers, as opposed to rodents reported to have more KP neurons in the RP3V of females. Human KP neurons differed from the homologous rodent cells as well, in that they were devoid of enkephalins, galanin and tyrosine hydroxylase. Further, they did not contain known KP neuron markers of the human infundibular nucleus, neurokinin B, substance P and cocaine- and amphetamine-regulated transcript, while they received afferent input from these KP neurons., Conclusions: The identification and positive estrogenic regulation of KP neurons in the human rostral hypothalamus challenge the long-held view that positive estrogen feedback may be restricted to the mediobasal part of the hypothalamus in primates and point to the need of further anatomical, molecular and functional studies of rostral hypothalamic KP neurons., (© 2020 S. Karger AG, Basel.)

The cardioprotective association of high-density lipoprotein cholesterol (HDL-C) may vary by menopause stage or estradiol level. We tested whether associations of comprehensive HDL metrics (HDL subclasses, phospholipid and triglyceride content, and HDL cholesterol efflux capacity [HDL-CEC]) with coronary artery calcium (CAC) score and density vary by menopause stage or estradiol level in women transitioning through menopause. Participants (N = 294; mean age [SD]: 51.3 [2.9]) had data on HDL metrics and CAC measures at one or two time points during the menopause transition. Generalized estimating equations were used for analyses. Effect modifications by menopause stage or estradiol level were tested in multivariable models. In adjusted models, menopause stage modified the associations of specific HDL metrics with CAC measures. Higher small HDL particles (HDL-P) concentrations (p-interaction = 0.008) and smaller HDL size (p-interaction = 0.02) were associated with greater odds of CAC presence in late perimenopause than in pre/early perimenopause stage. Women in the highest estradiol tertile, but not the lower tertiles, showed a protective association of small HDL-P with CAC presence (p-interaction = 0.007). Lower large HDL-P concentrations (p-interaction = 0.03) and smaller HDL size (p-interaction = 0.03) were associated with lower CAC density in late perimenopause than in postmenopause stage. Associations of HDL phospholipid and triglyceride content and HDL-CEC with CAC measures did not vary by menopause stage or estradiol level. We concluded that HDL subclasses may impact the likelihood of CAC presence and the stability of coronary plaque differently over the menopause transition. Endogenous estradiol levels may contribute to this observation., Competing Interests: Conflict of interest D. J. R. is the founder of VascularStrategies. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Traditionally sex hormones have been associated with reproductive and developmental processes only. Since the 1950s we know that hormones can have organizational effects on the developing brain and initiate hormonal transition periods such as puberty. However, recent evidence shows that sex hormones additionally structure the brain during important hormonal transition periods across a woman's life including short-term fluctuations during the menstrual cycle. However, a comprehensive review focusing on structural changes during all hormonal transition phases of women is still missing. Therefore, in this review structural changes across hormonal transition periods (i.e., puberty, menstrual cycle, oral contraceptive intake, pregnancy and menopause) were investigated in a structured way and correlations with sex hormones evaluated. Results show an overall reduction in grey matter and region-specific decreases in prefrontal, parietal and middle temporal areas during puberty. Across the menstrual cycle grey matter plasticity in the hippocampus, the amygdala as well as temporal and parietal regions were most consistently reported. Studies reporting on pre- and post-pregnancy measurements revealed volume reductions in midline structures as well as prefrontal and temporal cortices. During perimenopause, the decline in sex hormones was paralleled with a reduction in hippocampal and parietal cortex volume. Brain volume changes were significantly correlated with estradiol, testosterone and progesterone levels in some studies, but directionality remains inconclusive between studies. These results indicate that sex hormones play an important role in shaping women's brain structure during different transition periods and are not restricted to specific developmental periods., (© 2020 S. Karger AG, Basel.)

Women around menopause are vulnerable to present psychiatric and metabolic disorders; thus, therapies that contribute to treat both pathologies are required. Previous reports showed that an aqueous extract of pomegranate (Punica granatum), enriched in ellagitannins, exerts an antidepressant-like effect in ovariectomized rats. We analyze whether this aqueous extract of P. granatum (AE-PG) prevents the anxiety-like behavior induced by a cafeteria diet (CAF) in middle-aged ovariectomized rats at the same time that it prevents an increase in body weight, glucose, lipids, and the changes on mRNA expression of the peroxisome proliferator-activated receptor-gamma (PPAR-γ) in the liver. Also, the effects of AE-PG on the protein levels of PPAR-γphospho-PPAR-γ, extracellular signal-regulated protein kinase (ERK1/2) and phospho-ERK1/2 were measured in the hippocampus and amygdala. CAF induced anxiety-like behavior, augmented lipids and glucose blood levels, body weight, visceral fat, insulin resistance, and decreased mRNA expression of PPAR-γ in the liver. In rats fed with the CAF, AE-PG prevented the anxiety-like behavior, reduced body weight, lowered lipid levels, reduced insulin resistance, and increased PPAR-γ mRNA expression in the liver. In the hippocampus, ERK1/2 but not PPAR-γ protein levels were decreased by CAF, while AE-PG prevented these effects. In the amygdala, CAF increased the phosphorylation of PPARγ, and AE-PG prevented it. In contrast, AE-PG rescued the decreased ERK1/2 protein level in the hippocampus caused by CAF. In conclusion, AE-PG treatment prevented anxiogenic and metabolic effects induced by CAF, and its effects appear to be mediated by ERK1/2 and PPARγ depending on the brain area studied., (Copyright © 2020. Published by Elsevier Ltd.)

Ethnopharmacological Relevance: TG-decoction (Tiao Geng decoction) is the extract of a Chinese herb mixture that has been used for treating menopausal symptoms for over 30 years. We have previously reported anti-aging and anti-oxidative effects of the TG-decoction on hypothalamic neurons in ovariectomized (OVX) rats., Aim of the Study: The present study further investigates the effects of TG-decoction on the prevention of aging-related ultrastructural changes in menopausal hypothalamic neurons and the likely molecular mechanism., Materials and Methods: A total of 120 four-month-old female SPF Sprague Dawley rats were divided into six groups. Five groups were ovariectomized (OVX) and one group served as a sham control. Three OVX groups received TG-decoction at three different doses. The remaining two OVX groups served as positive and negative controls by receiving estradiol valerate and saline solution. The sham group received saline. After one month, aging-related ultrastructural alterations in hypothalamic neurons were evaluated using transmission electron microscopy. Nissl staining was used to assess the pathomorphological changes of the hypothalamic neurons. Cell apoptosis was evaluated by TUNEL. Expression of Bcl-2 family genes was studied using qRT-PCR. Expression of the apoptosis-related proteins ASK1, MKK7, JNK, c-Jun, Bax, Casp3 and Bcl-2 was studied using western blotting., Results: Ovariectomy of female rats led to visible damage and aging-like alterations in the mitochondria and endoplasmic reticulum as well as large deposits of lipofuscin in hypothalamic tissue. TG-decoction treatment prevented this visible damage and lipofuscin deposition, increased the number of nerve cells and normally-shaped Nissl bodies, and reduced the number of TUNEL-positive cells. Expression of Bcl-2 gene was increased, while Bax gene reduced. Expression of the proteins ASK1, MKK7, JNK, c-Jun, Bax and Casp3 was reduced, while that of Bcl-2 was increased., Conclusion: TG-decoction reduces aging-related ultrastructural changes in hypothalamic neurons, likely by suppressing ASK1/MKK7/JNK-mediated apoptosis in neuronal mitochondria or nuclei., (Copyright © 2020. Published by Elsevier B.V.)

The peri-menopause or menopausal transition-the time period that surrounds the final years of a woman's reproductive life-is associated with profound reproductive and hormonal changes in a woman's body and exponentially increases a woman's risk of cerebral ischemia and Alzheimer's disease. Although our understanding of the exact timeline or definition of peri-menopause is limited, it is clear that there are two stages to the peri-menopause. These are the early menopausal transition, where menstrual cycles are mostly regular, with relatively few interruptions, and the late transition, where amenorrhea becomes more prolonged and lasts for at least 60 days, up to the final menstrual period. Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-β). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. This review will present an overview of the menopausal transition as an inflammatory event, with associated systemic and central nervous system inflammation, plus regulation of the innate immune response by ER-β-mediated mechanisms.

Objective: To assess the efficacy of acupoint therapy combined with spine pinching in patients with menopausal syndrome., Methods: This is a parallel, randomized, controlled, investigator-blinded trial. A total of 132 participants were randomly assigned to receive either acupoint therapy combined with spine pinching (intervention group) or tibolone therapy alone (control group). The intervention group received acupoint therapy combined with spine pinching three times per week for 4 weeks. The control group received 2.5 mg of tibolone once daily for 4 weeks. The primary outcome was the improved Kupperman score. The WHO quality of life scale was also used. The secondary aim was to identify those who would benefit from acupoint therapy combined with spine pinching based on the levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH)., Results: In the intervention group, the improved Kupperman score was significantly decreased after treatment compared with before treatment. However, there were no differences between the intervention and control groups for any outcome. Changes in the physiology score presented negative outcomes in patients with a low FSH level with increasing body mass index (BMI) (P = 0.0). In contrast, changes in the physiology score presented positive outcomes in patients with a moderate LH level with increasing BMI (P = 0.0). The mean change in the physiology score of patients with a low FSH level and a BMI of ≥25.7 kg/m2 was -7.17 (range -10.94 to-3.40) after adjustments for age and disease duration., Conclusion: Acupoint therapy combined with spine pinching is effective in treating menopausal syndrome, especially in women with a moderate LH level. However, patients with a low FSH level had a negative outcome after acupoint therapy combined with spine pinching. In addition, patients with a BMI of > 25.7 kg/m2 had a negative outcome after the intervention, regardless of hormone levels.

Tibolone (TIB), a selective tissue estrogenic activity regulator (STEAR) in clinical use by postmenopausal women, activates hormonal receptors in a tissue-specific manner. Estrogenic activity is present mostly in the brain, vagina, and bone, while the inactive forms predominate in the endometrium and breast. Conflicting literature on TIB's actions has been observed. While it has benefits for vasomotor symptoms, bone demineralization, and sexual health, a higher relative risk of hormone-sensitive cancer has been reported. In the brain, TIB can improve mood and cognition, neuroinflammation, and reactive gliosis. This review aims to discuss the systemic effects of TIB on peri- and post-menopausal women and its role in the brain. We suggest that TIB is a hormonal therapy with promising neuroprotective properties., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

As type 2 diabetes mellitus (T2DM) reaches epidemic proportions in the developed world and the age at diagnosis decreases, more women of reproductive age are being affected. In this article, we provide a synoptic view on potential mechanisms and relevant factors underlying menstrual cycle disorders and fertility issues in women with T2DM. The article discusses the function of the hypothalamic-pituitary-ovarian (HPO) axis, the central role of the hypothalamus in the homeostasis of this system, the central modulators of the axis, and the peripheral metabolic signals involved in neuroendocrine control of reproduction. The available literature on the relationship between T2DM and the female reproductive lifespan, menstrual cycle disorders, fertility issues, and gestational health in women with T2DM are also discussed. The data so far indicate that there is a "U-shaped" relationship between menarche, menopause, and T2DM, both early and late menarche/menopause being risk factors for T2DM. Hyperglycemia and its consequences may be responsible for the effects of T2DM on reproductive health in women, but the exact mechanisms are not as yet fully understood; thus, more studies are needed in order to identify factors causing disruption of the HPO axis.

Many women with no history of cognitive difficulties experience executive dysfunction during menopause. Significant adversity during childhood negatively impacts executive function into adulthood and may be an indicator of women at risk of a mid-life cognitive decline. Previous studies have indicated that alterations in functional network connectivity underlie these negative effects of childhood adversity. There is growing evidence that functional brain networks are not static during executive tasks; instead, such networks reconfigure over time. Optimal dynamics are necessary for efficient executive function; while too little reconfiguration is insufficient for peak performance, too much reconfiguration (supra-optimal reconfiguration) is also maladaptive and associated with poorer performance. Here we examined the impact of adverse childhood experiences (ACEs) on network flexibility, a measure of dynamic reconfiguration, during a letter n-back task within three networks that support executive function: frontoparietal, salience, and default mode networks. Several animal and human subject studies have suggested that childhood adversity exerts lasting effects on executive function via serotonergic mechanisms. Tryptophan depletion (TD) was used to examine whether serotonin function drives ACE effects on network flexibility. We hypothesized that ACE would be associated with higher flexibility (supra-optimal flexibility) and that TD would further increase this measure. Forty women underwent functional imaging at two time points in this double-blind, placebo controlled, crossover study. Participants also completed the Penn Conditional Exclusion Test, a task assessing abstraction and mental flexibility. The effects of ACE and TD were evaluated using generalized estimating equations. ACE was associated with higher flexibility across networks (frontoparietal β = 0.00748, D = 2.79, p = 0.005; salience β = 0.00679, D = 3.02, p = 0.003; and default mode β = 0.00910, D = 3.53, p = 0.0004). While there was no interaction between ACE and TD, active TD increased network flexibility in both ACE groups in comparison to sham depletion (frontoparietal β = 0.00489, D = 2.15, p = 0.03; salience β = 0.00393, D = 1.91, p = 0.06; default mode β = 0.00334, D = 1.73, p = 0.08). These results suggest that childhood adversity has lasting impacts on dynamic reconfiguration of functional brain networks supporting executive function and that decreasing serotonin levels may exacerbate these effects., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Estrogen is a hormone responsible for modulating several physiological processes such as immune response and bone homeostasis. Physiological fluctuations of estrogen concentration are one of the defining principles behind its mechanism. In cases of estrogen deficiency, such as in menopausal women, a more intense bone resorption may occur due to an increase in osteoclast activity. One of the main factors that influence osteoclast formation and response is the immune system, mainly through cytokines secreted by B and T cells. The purpose of this review is to highlight how estrogen can modulate the secretion of cytokines that can alter bone physiology, thereby establishing an axis between estrogen, immune cells, and osteoclastogenesis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Our goal is to understand how loss of circulating estrogens and estrogen replacement affect brain physiology and function, particularly in brain regions involved in cognitive processes. We recently conducted a large metabolomics study characterizing the effects of rodent models of menopause and treatment with estrogen receptor (ER) agonists on neurochemical targets in hippocampus, frontal cortex, and striatum. Here we characterize effects on levels of several key enzymes involved in glucose utilization and energy production, specifically phosphofructokinase, glyceraldehyde 3-phosphate dehydrogenase, and pyruvate dehydrogenase. We also evaluated effects on levels of β-actin and α-tubulin, choline acetyltransferase (ChAT) activity, and levels of ATP citrate lyase. All experiments were conducted in young adult rats. Experiment 1 compared the effects of ovariectomy (OVX), a model of surgical menopause, and 4-vinylcyclohexene diepoxide (VCD)-treatments, a model of transitional menopause, with tissues collected at proestrus and at diestrus. Experiment 2 used a separate cohort of rats to evaluate the same targets in OVX and VCD-treated rats treated with estradiol or with selective ER agonists. Differences in the expression of metabolic enzymes between cycling animals and models of surgical and transitional menopause were detected. These differences were model-, region- and time- dependent, and were modulated by selective ER agonists. Collectively, the findings demonstrate that loss of ovarian function and ER agonist treatments have differing effects in OVX vs. VCD-treated rats. Differences may help to explain differences in the effects of estrogen treatments on brain function and cognition in women who have experienced surgical vs. transitional menopause., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: It is a common belief that menopausal women have greater difficulty losing weight. The aim of this study was to assess the efficacy of a Mediterranean diet (MD) to promote weight loss in postmenopausal women. All participants were prescribed a hypocaloric traditional MD, tailored to the individual. Subjects were asked not to begin any kind of physical activity. Body composition was measured at the beginning and after 8 weeks of treatment. In total, 89 women (age 52.8 ± 4.5 years, BMI 30.0 ± 5.2 kg/m 2 , fat mass 31.6 ± 10.5 kg) were divided into two groups: the first group consisted of fertile women over 45 years of age, the second group consisted of those diagnosed as menopausal. All women had an improvement in body composition (fat mass -2.3 ± 2.1 kg, p < 0.001; protein -0.1 ± 0.7 kg, p = 0.190) and blood pressure values. No differences were found between the two groups except for a higher reduction of low-density lipoprotein in the menopausal group ( p = 0.035). A positive significant correlation between plant to animal protein ratio and fat-free mass variation was found in the menopausal group. These data suggest that a high adherence to a traditional MD would enable menopausal women to lose fat mass and maintain muscle mass with no significant difference to younger women. Fat mass reduction provides menopausal women with improved cardiovascular and metabolic risk factors.

Laboratory studies have observed chemopreventive effects of black and green tea on breast cancer development, but few epidemiologic studies have identified such effects. We investigated the association between tea consumption and breast cancer risk using data from 45,744 U.S. and Puerto Rican women participating in the Sister Study. Frequency and serving size of black and green tea consumption were measured at cohort enrollment. Breast cancer diagnoses were reported during follow-up and confirmed by medical record review. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We further investigated potential variation according to estrogen receptor (ER) status, menopausal status and body mass index (BMI). Overall, 81.6 and 56.0% of women drank black or green tea, respectively. A total of 2,809 breast cancer cases were identified in the cohort. The multivariable model suggested an inverse association between black (≥5 vs. 0 cups/week: HR = 0.88, 95% CI 0.78, 1.00, p-trend = 0.08) and green tea (≥5 vs. 0 cups/week: HR = 0.82, 95% CI 0.70, 0.95, p-trend < 0.01) consumption and breast cancer risk. We did not observe differences by ER characteristics, menopausal status or BMI. In conclusion, our study suggests drinking at least five cups of green or black tea per week may be associated with decreased breast cancer risk., (© 2019 UICC.)

Purpose: Hormone receptor (HR)-positive, Human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) requires a therapeutic approach that takes into account multiple factors, with treatment being based on anti-estrogen hormone therapy (HT). As consensus documents are valuable tools that assist in the decision-making process for establishing clinical strategies and optimize the delivery of health services, this consensus document has been created with the aim of developing recommendations on cretiera for hormone sensitivity and resistance in HER2-negative luminal MBC and facilitating clinical decision-making., Methods: This consensus document was generated using a modification of the RAND/UCLA methodology, which included the definition of the project and identification of issues of interest, a non-exhaustive systematic review of the literature, an analysis and synthesis of the scientific evidence, preparation of recommendations, and external evaluation with a panel of 64 medical oncologists specializing in breast cancer., Results: A Spanish panel of experts reached consensus on 32 of the 32 recommendations/conclusions presented in the first round and were accepted with an approval rate of 100% about definition of metastatic disease not susceptible to local curative treatment, definition of hormone sensitivity and hormone resistance in metastatic luminal disease and therapeutic decision-making., Conclusion: We have developed a consensus document with recommendations on the treatment of patients with HER2-negative luminal MBC that will help to improve therapeutic benefits.

Alteration in reproductive hormones profile is associated with the increasing risk of menopausal depression in women. Serum follicle-stimulating hormone (FSH) level is changed during the menopause transition, while the effect of FSH on menopausal depression has remained undefined. In this study we investigated whether or how FSH affected menopausal depression in postmenopausal (ovariectomized) FSHR knockout mice (Fshr -/- ). We found that Fshr -/- mice displayed aggravated depression-like behaviors, accompanied by severe oxidative stress in the whole brain, resulted from significantly reduced glutamate cysteine ligase modifier subunit (GCLm) in glutathione synthesis and glucose-6-phosphate dehydrogenase (G6PD) in NADP/NADPH transition. Importantly, administration of ROS scavenger N-acetyl cysteine (NAC, 150 mg · kg -1  · d -1 , i.p. for 12 weeks) attenuated the depression-like behaviors of Fshr -/- mice. Consistent with these in vivo experiment results, we found that pretreatment with FSH (50, 100 ng/mL) dose-dependently increased protein levels of GCLm and G6PD, and decreased the ROS production in N2a mouse neuroblastoma cells. These findings demonstrate that FSH signaling is involved in pathogenesis of menopausal depression, and likely to maintain the redox-optimized ROS balance in neurons.

Menopause is a major factor involved in dyslipidemia increasing the risk of atherosclerosis which may be reversed by a routine of aerobic physical activity. Thus, this study aimed to analyze the effects of aerobic training on the thoracic aorta of female LDL-receptor knockout mice submitted to estrogen deprivation. Fifteen genetically modified female mice, knockout for the low-density lipoprotein receptor (LDL-Knockout group) were used as experimental groups and fifteen wild female mice (C57BL/6 J) were used as control groups. Animals were divided as (n = 5/per group): sedentary control (SC); sedentary control ovariectomized (SCO); trained control ovariectomized (TCO); LDL-Knockout sedentary (KS); LDL-Knockout sedentary ovariectomized (KOS); and LDL-Knockout trained ovariectomized (KOT). Immunohistochemical techniques for TIMP-1 and metalloproteinases 2 and 9 were used to evaluate thoracic aorta remodeling. Picrosirius stain was used to highlight the collagen fibers. Verhoff-Van Gienson was used for the quantitative analyses of elastic lamellae. Our results demonstrate a positive remodeling promoted by physical exercise in ovariectomized and dyslipidemic animals. However, further studies are needed including the evaluation of inflammatory markers present in dyslipidemia., Competing Interests: Declaration of Competing Interest The authors declare not competing or financial interest., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Purpose: The purpose of this study was to evaluate the predictive performance of OncoOVARIAN Dx algorithm, which takes into account tumor markers (beta HCG, CA 19.9, CEA, AFP, CA 125, HE4), general biochemistry and clinical data (age, menopause, comorbidities) in patients scheduled for surgical removal of a suspicious adnexal tumor in comparison with the Risk of Malignancy Algorithm (ROMA) model., Methods: Consecutive women diagnosed with an adnexal tumor mass and scheduled for surgical intervention at a single tertiary cancer between October 2018 - June 2019 were enrolled. Preoperative values of tumor markers and general biochemistry (ASAT, ALAT, GGT, total bilirubin, creatinine) were determined. Following surgery with adequate surgical staging, a definite pathological diagnosis was made and used as reference., Results: A total of 50 patients were selected, including 20 benign, 5 borderline and 25 malignant epithelial ovarian cancer (EOC) cases on final pathology. Borderline tumors comprised 3 serous and 2 mucinous FIGO stage I cases. Malignant tumors included 17 high grade serous, 4 endometrioid and 4 mucinous types, FIGO stage IA-IIIC. The two models demonstrated very good correlation (Phi 0.78, p<0.001). The sensibility (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) of OncoOVARIAN Dx versus ROMA model were 76.66% vs. 60%, 95% vs. 100%, 95.83% vs. 100%, 73.07% vs. 62.5%, respectively. In postmenopausal patients higher Se (85.71%), Sp (100%) and PPV (100%) were observed for OncoOVARIAN Dx., Conclusions: OncoOVARIAN Dx model demonstrated higher Se and NPV compared to ROMA and could be a useful marker in the preoperative management of adnexal masses; however larger studies are warranted to validate and further refine this algorithm.

Objectives: Menopausal women suffer from various menopausal symptoms due to estrogen deficiency caused by the decline of ovarian function. Estrogen plays a key role in regulating body metabolism in women. Its effects on skeletal muscle metabolism, however, need to be elucidated. The aim of our study was to investigate the effects of 17β-estradiol (E2) and/or running exercise on skeletal muscle metabolism in ovariectomized (OVX) mice. Methods: Female C57BL/6J mice were divided into five groups: sham operated, OVX, OVX with running, OVX with E2, and OVX with running and E2. The estrous cycle, body weight, and body composition of the mice were monitored after the operation. The animals were sacrificed after treatment for 7 weeks. The serum and tissue samples were collected. Results: The results showed increased fat mass, reduced lean mass, impaired mitochondrial function, and inhibited mammalian target of rapamycin complex 1 signaling pathway in skeletal muscle of OVX mice. The treatment of OVX mice with E2 and running had better effects on ameliorating these impairments than running exercise or E2 alone. Conclusions: The combined intervention of E2 and running exercise ameliorated energy metabolism of skeletal muscle and body composition in OVX mice, which exceled over E2 treatment or running exercise alone.

Many postmenopausal women individually experience varying degrees of climacteric symptoms. Among the many influencing factors, body weight and diet are recognized as important contributors to the incidence and severity of these symptoms. This study was performed to investigate the interaction effect of BMI (body mass index) and dietary consumption on the risk of climacteric symptoms among Korean women. Approximately half of the subjects (48.8%) experienced climacteric symptoms. After adjusting for the covariates, the subjects who are overweight or obese showed significantly greater total scores of climacteric symptoms ( p = 0.010) and subscales of symptoms ( p = 0.027 for physical climacteric symptoms and p = 0.007 for psychological climacteric symptoms), except for urogenital climacteric symptoms ( p = 0.085), than those subjects at a normal weight. When subjects were divided into groups according to dietary macronutrient consumption, those who are overweight or obese were 2.84-fold (adjusted odds ratio, 95% CI = 1.18-6.80, p = 0.019) more likely to experience climacteric symptoms than those at a normal weight among the subjects with high fat consumption. However, the BMI category did not affect the adjusted odds ratio for experiencing climacteric symptoms among subjects who consumed a low-fat diet.

The life history pattern of recent humans is uniquely derived in many of its aspects including an extended post-reproductive lifespan combined with short interbirth intervals. A number of theories have been proposed to explain the evolution of this unusual pattern. However most have been difficult to test due to the fragmentary nature of the hominin fossil record and the lack of methods capable of inferring such later life history events. In search of a method we tested the hypothesis that the physiologically impactful events of parturition and menopause are recorded in dental cementum microstructure. We performed histomorphological analyses of 47 teeth from 15 individuals with known life history events and were able to detect reproductive events and menopause in all females. Furthermore, we found that other stressful events such as systemic illnesses and incarceration are also detectable. Finally, through the development of a novel analytical method we were able to time all such events with high accuracy (R-squared = 0.92).

Clinical Treatment Score post-5 years (CTS5) is a promising prognostic tool to evaluate late recurrence risk for breast cancer. Our study aimed to validate its prognostic value in large-scale population and explore the impact of menopausal and HER2 status on CTS5 model. We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Survival analyses were conducted to assess the prognostic value of CTS5 in different breast cancer subgroups in terms of overall survival (OS) and breast cancer specific survival (BCSS) after five years. A total of 23,168 breast cancer patients with positive hormone receptor (HoR) were enrolled. Postmenopausal and premenopausal patients were 13,686 and 9,482, respectively. Taking CTS5 score as a continuous variable, it had significant positive correlation with poor prognosis beyond five years in both postmenopausal and premenopausal subgroups. Nevertheless, for HER2+ postmenopausal patients, the model has less effective prognostic value on long-term BCSS [HR1.177 (95%CI 0.960-1.443), p = 0.117]. Using CTS5 score as a categorical variable, HER2- patients with high-risk level revealed significant poor survival in terms of both BCSS and OS, irrespective of menopausal status. Our study showed the CTS5 model could be a useful prognostic tool for predict long-term survival in HoR+/HER2- patients. And further large-scale studies are warranted to assess its prognostic value for HER2+ patients and develop novel prediction model for late recurrence risk estimation.

Background: Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI., Methods and Findings: We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8-9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109-131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also similar in both populations (8.1 (IQR: 7.1-9.4) versus 7.9 (IQR: 7.1-8.4), p = 0.21). In addition, cIMT was lower in women with POI compared to controls (550 μm (500-615) versus 684 μm (618-737), p < 0.01). The calculated 10-year CVD risk was 5.9% (IQR: 3.7-10.6) versus 6.0% (IQR: 3.9-9.0) (p = 0.31) and current CHS was 6.1 (1.9) versus 6.5 (1.6) (p = 0.07), respectively in POI versus controls., Conclusions: Middle age women with POI presented with more unfavorable cardiovascular risk factors (increased waist circumference and a higher prevalence of hypertension and MetS) compared to age and BMI matched population controls. In contrast, the current study reveals a lower cIMT and similar 10-year cardiovascular disease risk and cardiovascular health score. In summary, neither signs of premature atherosclerosis nor a worse cardiovascular disease risk or health score were observed among middle age women with POI compared to population controls. Longer-term follow-up studies of women of more advanced age are warranted to establish whether women with POI are truly at increased risk of developing CVD events later in life., Trial Registration: ClinicalTrials.gov Identifier: NCT02616510., Competing Interests: During the most recent 4 year period B.C.J.M.F. has received fees or grant support from the following organizations (in alphabetic order); Abbott, Controversies in Obstetrics & Gynecology (COGI), Dutch Heart Foundation (Hartstichting), Dutch Medical Research Counsel (ZonMW), Ferring, London Womens Clinic (LWC), Menogenix, Myovant, OvaScience, Pantharei Bioscience, PregLem/Gedeon Richter, Reproductive Biomedicine Online (RBMO), Teva/Theramex, World Health Organisation (WHO). J.S.E.L. has received fees and grant support from the following organizations (in alphabetic order): Danone, Dutch Heart Foundation, Euroscreen, Ferring, Roche, Titus Healthcare and ZonMW. C.B.L. has over the most recent 5-year period received fees and grant support from the following organizations (in alphabetic order): Amsterdam UMC, Ferring, Merck and ZonMW. E.B., Y.A has over the most recent 4 year period received grant support from the Ducht Heart Foundation., M.K. is supported by the VENI grant (91616079) from ZonMw. J.R.v.L has over the most recent 5 year period received fees and grant support from the following organizations (in alphabetic order): Amgen, Amryt, Dutch Heart Foundation and Erasmus MC. M.G. received scientific congress fees from Merck and Gedeon Richter. The above mentioned competing interest does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction : Dyspareunia caused by vulvovaginal atrophy is a primary symptom of genitourinary syndrome of menopause (GSM), a chronic, progressive medical condition that results from estrogen and androgen deficiency at menopause. Dehydroepiandrosterone (DHEA, prasterone) is an endogenous precursor steroid hormone that is metabolized into both androgens and estrogens that has been recently been approved by the FDA for the treatment of moderate to severe dyspareunia caused by vulvovaginal atrophy secondary to menopause. Areas covered : This is a comprehensive drug evaluation describing the chemical composition, pharmacokinetics, metabolism, clinical efficacy and safety of dehydroepiandrosterone (prasterone) in the treatment of dyspareunia and VVA secondary to menopause. Preclinical and clinical data suggesting further potential uses, benefits, and contraindications in the genitourinary health of postmenopausal women are also considered. Expert opinion : Intravaginal dehydroepiandrosterone (prasterone) is effective for the management of dyspareunia secondary to menopause and may be effective in the treatment of other types of sexual dysfunction that are secondary to menopause. Further studies should explore additional dosing regimens and different indications.

Licorice ( Glycyrrhiza uralensis ) contains several compounds that have been reported to alleviate menopausal symptoms via interacting with estrogen receptors (ERs). The compounds exist mainly in the form of glycosides, which exhibit low bioavailability and function. To bioconvert liquiritin and isoliquiritin, the major estrogenic compounds, to the corresponding deglycosylated liquiritigenin and isoliquiritigenin, respectively, licorice was fermented with Monascus, which has been demonstrated to deglycosylate other substances. The contents of liquiritigenin and isoliquiritigenin in Monascus -fermented licorice increased by 10.46-fold (from 38.03 µM to 379.75 µM) and 12.50-fold (from 5.53 µM to 69.14 µM), respectively, compared with their contents in non-fermented licorice. Monascus -fermented licorice exhibited 82.5% of the ERβ binding activity of that observed in the positive control (17 β-estradiol), whereas the non-fermented licorice exhibited 54.1% of the binding activity in an in vivo ER binding assay. The increase in the ERβ binding activity was associated with increases in liquiritigenin and isoliquiritigenin contents. Liquiritigenin acts as a selective ligand for ERβ, which alleviates menopausal symptoms with fewer side effects, such as heart disease and hypertension, compared with a ligand for ERα. In addition, Monascus -fermented licorice contained 731 mg/kg of monacolin K, one of the metabolites produced by Monascus that reduces serum cholesterol. Therefore, Monascus -fermented licorice is a promising material for the prevention and treatment of menopausal syndrome with fewer side effects.

One of the leading causes for the development of adverse metabolic effects, including type 2 diabetes, dyslipidemia, and cardiovascular diseases, is the accumulation of excess body weight, often measured by body mass index (BMI). Although BMI, calculated using weight and height, is the standard measure used to determine body adiposity in clinical and public health guidelines, an inherent limitation is that BMI does not distinguish where in the body adiposity is deposited. Central obesity, characterized by greater accumulation of adiposity in the abdominal region, has been associated with a higher risk of mortality, independent of BMI. Importantly, one of the determinants of body fat distribution is sex hormones. Both estrogens and androgens appear to directly and indirectly influence body fat distribution. Our review will focus specifically on the role of estrogens and their influence in determining body fat distribution and overall health of adipose tissues, and the role of epigenetic mechanisms in regulating the production and function of estrogens., (© 2019 New York Academy of Sciences.)

Ethnopharmacological Relevance: Liuwei Dihuang (LWDH) is a classic prescription that has been used as a traditional medicinal formula for more than 1000 years in China. In clinical, LWDF is used for treating functional decline associated with senile disease and menopausal syndrome. Studies have demonstrated that LWDH could significantly improve estrogen level and ER expression, and suspend the process of atherosclerosis. However, the under mechanism of how LWDH suppressing VSMCs phenotypic conversion and proliferation through ER is still unknown., Aim of the Study: This study was to reveal the under mechanism of how LWDH inhibits the phenotypic conversion of VSMCs., Materials and Methods: 24 ApoE-/- mice were divided into 4 groups: sham group, model group, E 2 group, and LWDH group, and 6 C57BN/L6 mice were used as control group. The primary VSMCs were divided into control group, model group, E 2 group, LWDH group, LWDH + MPP group, and LWDH + PHTPP group with or without control siRNA, ERα siRNA, ERβ siRNA, and myocardin siRNA. Oil red staining was used to evaluate the lipid deposition in the cardiac aorta. Serum chemistry analysis to test serum TG, TC, LDL, and HDL. Immunofluorescence staining was used to test α-SMA, osteopontin and F-actin. Immunohistochemical staining was performed to check out the myocardin in the cardiac aorta. The mRNA levels of α-SMA, osteopontin, ERα, ERβ, SRC3 and myocardin were detected by Real Time-PCR, and the protein expression levels of them were detected by Western blotting. Co-immunoprecipitation was proceed to test the interaction between ERα and SRC3 and SRC3 and myocardin. Flow cytometry was used to check out the cell cycle. Wound healing assay and Transwell were managed to evaluate the migration capacity of VSMCs., Results: In vivo administration of LWDH suppressed AS symptoms, decreases phenotypic marker of vascular endothelial cell, and increases phenotypic marker of VSMC in ovariectomized ApoE-/- female mice. Moreover, LWDH significantly increased the mRNA and protein expression levels of ERα, ERβ, SRC3 and myocardin in the cardiac aorta of ovariectomized ApoE-/- female mice. In vitro, LWDH altered cell cycle and reduced the elevated cyclinD protein expression migration capacity and in the model VSMCs. In addition, LWDH inhibited phenotypic conversion and promoted the expression of ER, SRC3, and myocardin of the primary VSMC phenotypic conversion model. Inhibition of ERα almost completely eliminated the impacts of LWDH on α- SMA and osteopontin. Furthermore, LWDH promoted the interaction between ERα and SRC3 and up-regulated the co-activation of SRC3 and myocardin., Conclusions: LWDH could inhibit the phenotypic conversion of VSMCs in vitro and in vivo by increasing the activity of myocardin through up-regulating the expression of ERα and promoting the interaction between ERα and SRC3. Our research reveals the under mechanism of how LWDH inhibits the phenotypic conversion of VSMCs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Menopause impairs calcium(Ca) metabolism and reduces bone mineral density (BMD), but the interaction of menopause with Ca deficiency in energy, glucose, lipid, and bone metabolism has not been studied. Herein we hypothesized that Ca deficiency at levels for post-menopausal women would impair energy, glucose, lipid, and bone metabolism in estrogen-deficient rats. This hypothesis was examined in ovariectomized (OVX) rats fed high-fat diets with different Ca levels for 12 weeks. OVX rats were allocated into either very low Ca (0.02%, VLCA), low Ca (0.7%, LCA), adequate Ca (1.18%, ACA, control), or excessive Ca (2.1%, EXCA). Sham-operated rats had the same diet as ACA (Normal-control). Ca intake was 37, 107, 190, and 311 mg/kg bw/d in the VLCA, LCA, ACA, and EXCA groups. The ACA group had higher serum parathyroid hormone concentrations than the Normal-control but were highest in VLCA. VLCA decreased BMD and lean body mass compared to ACA. Fasting serum glucose concentrations, even with higher serum insulin concentrations, were higher in the VLCA than ACA, indicating increased insulin resistance in VLCA. VLCA deteriorated glucose tolerance after oral glucose administration and impaired lipid profiles. LCA and EXCA had similar effects on metabolism as ACA, but LCA did not improve insulin sensitivity and lipid profiles as much as ACA. Expressions of hepatic genes related to fatty acid and cholesterol synthesis (FAS and SREBP-1c and HMGCR) were much higher in the VLCA than ACA and expressions of genes related fatty acid degradation(CPT1 and CYP7A1) were much lower in VLCA than ACA. In conclusion, we accepted the hypothesis. Very low Ca intake (350-400 mg/d as a human equivalent) exacerbated estrogen-deficiency-induced impairments of energy, glucose, and lipid metabolism by elevating serum parathyroid hormone levels and inducing visceral fat accumulation and insulin resistance in estrogen-deficient rats, but there was no added benefit of excessive Ca., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Why a postfertile stage has evolved in females of some species has puzzled evolutionary biologists for over 50 years. We propose that existing adaptive explanations have underestimated in their formulation an important parameter operating both at the specific and the individual levels: the balance between cancer risks and cancer defenses. During their life, most multicellular organisms naturally accumulate oncogenic processes in their body. In parallel, reproduction, notably the pregnancy process in mammals, exacerbates the progression of existing tumors in females. When, for various ecological or evolutionary reasons, anticancer defenses are too weak, given cancer risk, older females could not pursue their reproduction without triggering fatal metastatic cancers, nor even maintain a normal reproductive physiology if the latter also promotes the growth of existing oncogenic processes, e.g., hormone-dependent malignancies. At least until stronger anticancer defenses are selected for in these species, females could achieve higher inclusive fitness by ceasing their reproduction and/or going through menopause (assuming that these traits are easier to select than anticancer defenses), thereby limiting the risk of premature death due to metastatic cancers. Because relatively few species experience such an evolutionary mismatch between anticancer defenses and cancer risks, the evolution of prolonged life after reproduction could also be a rare, potentially transient, anticancer adaptation in the animal kingdom., Competing Interests: The authors have declared that no competing interests exist.

Researchers have long assumed that systematic estrogen fading might contribute to the sustained progression of menopausal degenerate syndromes, although definitive evidence has not been presented. Whether such findings represent a causal contribution or are the result of opportunistic messengers sent from the reproductive system to the brain is also a vital question. We constructed a multiscale network of the ovariectomy (OVX) induced estrogen receptors depletion (ER-depletion) model and integrated targeted proteomic, targeted lipidomic, cytochemical, and histopathological data across three tissues from the ovariectomy rodent model. We found that compared to control rats, OVX rats showed increased renal and uterine prostaglandin D2 synthase (Ptgds) expression and decreased hypothalamic Ptgds expression, abnormal Ptgds metabolites, the degenerate renal function profiles and decreased cognitive ability (learning and memory) in Morris water maze test. Importantly, we observed a regulatory relationship among ER (particularly ERβ), the degree of the pathological phenotype, learning behavior test and the 'hypothalamus-uterus-kidney (HUK) axis functions. Collectively, this study elucidates that ER depletion promoted HUK aging is mostly attributed to a renal ERβ/Ptgds signalling imbalance.

Menopause is an important physiological event associated with structural and functional changes in the kidneys. An animal model of bilateral ovariectomy was used to study the effects of estrogen depletion, replacement and antiestrogen on renal structure and endocrine function. Sixty female rats were divided into six groups; group I was the control group, the remaining five groups underwent ovariectomy: group II received no treatment. The other groups received estradiol in group III, tamoxifen in group IV, estradiol followed by tamoxifen in group V and tamoxifen followed by estradiol in group VI. Serum creatinine, blood urea nitrogen, and endocrine functions of kidney were measured. Tissue samples were examined both microscopically for beta estrogen receptors and ultrastructurally for cell changes. Groups II, IV & VI showed a significant increase in creatinine, blood urea nitrogen, renal malondialdehyde, renal erythropoietin, plasma renin and plasma prostaglandin E2 and a significant decrease in renal antioxidants and serum vitamin D3. Groups III &V had a significant decrease in creatinine, blood urea nitrogen, renal malondialdehyde and renal erythropoietin with an increase in renal antioxidants, plasma prostaglandin E2 and serum vitamin D3. Histopathological and ultrastructural examinations revealed atrophic tubular changes in group II. The changes were less marked in groups III &V and more extensive in groups IV & VI. Estrogen receptor beta staining showed progressively increased expression in the absence of estrogen. Structural and most endocrine functions of the kidney were significantly affected by estradiol deficiency. Estradiol replacement exhibited a protective effect on renal tissue and endocrine functions.

Acceleration of remodeling activity after menopause leads to bone loss and fragility, however, whether this is associated with modifications of bone matrix quality has been less studied. The impact of variation in bone remodeling rate on bone matrix has been studied mainly in pathologies or anti-osteoporotic treatments. However, in healthy women this has been less studied. We analyzed, at the global level, bone matrix quality in bone biopsies from 3 groups of healthy women (20 per group): 1) before menopause (PreM), 2) 1 year after menopause (PostM, paired biopsies with preM), and 3) 14 (±9) years after menopause (LT-PostM). The mean degree of mineralization (DMB) and heterogeneity index (HI) of mineralization were assessed by X-ray microradiography on whole bone matrix; intrinsic properties (mineral/organic ratio, mineral maturity, mineral crystallinity, collagen maturity) were assessed by Fourier Transform Infrared microspectroscopy, microhardness by microindentation, both at a global level and calculated by mean of several measurements over the whole tissue area. In PostM compared to PreM (bone remodeling rate had doubled), mean DMB measured on the entire bone plane (whole bone matrix) of the sample was not different. HI was increased in trabecular bone indicating a higher heterogeneity of mineralization. However, in PostM, mineral/organic ratio (trabecular) and microhardness (cortical and trabecular) were decreased, whereas mineral/collagen maturation or crystal size/perfection were unchanged. Thus, in PostM, the local mineral content and microhardness were first affected. In LT-PostM (bone remodeling rate was 3 times higher), the mean DMB was still not different. However, the mineral/organic ratio, microhardness, mineral maturity, crystallinity all were lower compared to PreM and PostM, in both cortical and trabecular bone. Bone remodeling rate was negatively correlated with microhardness, DMB, mineral/organic and crystallinity. This suggests that increases in bone remodeling rates after menopause have a direct impact on bone quality by inducing the formation of more extensive "immature" bone areas, but the amount of immature bone does not cause modification of the global DMB., (Copyright © 2019 Elsevier Inc. All rights reserved.)