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Bone's resistance to fracture depends on its amount and quality, the latter including its structural and material/compositional properties. Bone material properties are dependent on bone turnover rates, which are significantly elevated immediately following menopause. Previously published data reported that following menopause, the amount of organic matrix synthesized at actively forming surfaces is significantly decreased, while glycosaminoglycan content was also modulated at resorbing surfaces, in the cancellous compartment. In the present study, we used Raman microspectroscopic analysis of paired iliac crest biopsies obtained before and shortly after menopause (1 year after cessation of menses) in healthy females to investigate changes in material/compositional properties due to menopause, in the cortical compartment. Specifically, the mineral/matrix ratio, the relative proteoglycan content, the mineral maturity/crystallinity, and the relative pyridinoline collagen cross-link content were determined at actively forming intracortical surfaces (osteons) as a function of tissue age, as well as in interstitial bone. Results indicated that it is the freshly synthesized organic matrix content that significantly declines following menopause, in agreement with what was previously reported for the cancellous compartment. This decline was not evident in the freshly deposited mineral content. None of the compositional/quality properties were altered following menopause either. Finally, no differences in any of the monitored parameters were evident in cortical interstitial bone., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The mechanism(s) underlying obesity-related postmenopausal (PM) breast cancer (BC) are not clearly understood. We hypothesized that the increased local presence of 'obese' mammary adipocytes within the BC microenvironment promotes the acquisition of an invasive and angiogenic BC cell phenotype and accelerates tumor proliferation and progression. BC cells, treated with primary mammary adipocyte secretome from premenopausal (Pre-M) and PM obese women (ObAdCM; obese adipocyte conditioned-media) upregulated the expression of several pro-tumorigenic factors including VEGF, lipocalin-2 and IL-6. Both Pre-M and PM ObAdCM stimulated endothelial cell recruitment and proliferation and significantly stimulated BC cell proliferation, migration and invasion. IL-6 and LCN2 induced STAT3/Akt signaling in BC cells and STAT3 inhibition abrogated the ObAdCM-stimulated BC cell proliferation and migration. Expression of proangiogenic regulators including VEGF, NRP1, NRP2, IL8RB, TGFβ2, and TSP-1 were found to be differentially regulated in mammary adipocytes from obese PM women. Comparative RNAseq indicated an upregulation of PI3K/Akt signaling, ECM-receptor interactions and lipid/fatty acid metabolism in PM versus Pre-M mammary adipocytes. Our results demonstrate that irrespective of menopausal status, cross-talk between obese mammary adipocytes and BC cells promotes tumor aggressiveness and suggest that targeting the LCN2/IL-6/STAT3 signaling axis may be a useful strategy in obesity-driven breast tumorigenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Context: Ectopic fat depots are related to the deregulation of energy homeostasis, leading to diseases related to obesity and metabolic syndrome (MetS). Despite significant changes in body composition over women's lifespans, little is known about the role of breast adipose tissue (BrAT) and its possible utilization as an ectopic fat depot in women of different menopausal statuses., Objective: We aimed to assess the relationship between BrAT and metabolic glycemic and lipid profiles and body composition parameters in adult women., Methods: In this cross-sectional study, we enrolled adult women undergoing routine mammograms and performed history and physical examination, body composition assessment, semi-automated assessment of breast adiposity (BA) from mammograms, and fasting blood collection for biochemical analysis. Correlations and multivariate regression analysis were used to examine associations of BA with metabolic and body composition parameters., Results: Of the 101 participants included in the final analysis, 76.2% were in menopause, and 23.8% were in premenopause. The BA was positively related with fasting plasma glucose, glycated hemoglobin, homeostasis model assessment of insulin resistance, body mass index, waist circumference, body fat percentage, and abdominal visceral and subcutaneous fat when adjusted for age among women in postmenopause. Also, the BA was an independent predictor of hyperglycemia and MetS. These associations were not present among women in premenopause., Conclusion: The BA was related to different adverse body composition and metabolic factors in women in postmenopause. The results suggest that there might be a relevant BrAT endocrine role during menopause, with mechanisms yet to be clarified, thus opening up research perspectives on the subject and potential clinical implications., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Menopause, as a consequence of ovarian follicular decline, induces estrogen deficiency and metabolic changes that increase the cardiovascular risk in women. In particular, there is an increase in blood pressure during menopause. Menopausal hormonal therapy can be prescribed to women with symptoms of menopause to improve their quality of life. This article reviews the current literature on the pathophysiological mechanisms that explain blood pressure changes at menopause and describes the impact of menopausal hormone therapy on blood pressure., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Lower urinary tract symptoms (LUTS) are common in postmenopausal women. These symptoms are often linked to decreased estrogen levels following menopause. This study investigated the relationship between estrogen levels, alterations in bladder tissue structure, bladder function, and the incidence of urinary frequency. An age-appropriate bilateral ovariectomized mouse model (OVX) was developed to simulate conditions of estrogen deficiency. Mice were divided into three groups: a sham-operated control group, OVX, and an estradiol-treated group. The assessments included estrogen level measurement, urination frequency, cystometry, histological analysis, immunofluorescence staining, and real-time quantitative PCR. Additionally, we quantified the expression of the mechanosensitive channel proteins Piezo1 and TRPV4 in mouse bladder tissues. Lower estrogen levels were linked to increased voiding episodes and structural changes in mouse bladder tissues, notably a significant increase in Collagen III fiber deposition. There was a detectable negative relationship between estrogen levels and the expression of Piezo1 and TRPV4 , mechanosensitive proteins in mouse bladder tissues, which may influence voiding frequency and nocturia. Estrogen treatment could improve bladder function, decrease urination frequency, and reduce collagen deposition in the bladder tissues. This study explored the connection between estrogen levels and urinary frequency, potentially setting the stage for novel methods to address frequent urination symptoms in postmenopausal women.

Menopause is a normal stage in the human female aging process characterized by the cessation of menstruation and the ovarian production of estrogen and progesterone hormones. Menopause is associated with an increased risk of several different diseases. Cardiovascular diseases are generally less common in females than in age-matched males. However, this female advantage is lost after menopause. Cardiac hypertrophy is a disease characterized by increased cardiac size that develops as a response to chronic overload or stress. Similar to other cardiovascular diseases, the risk of cardiac hypertrophy significantly increases after menopause. However, the exact underlying mechanisms are not yet fully elucidated. Several studies have shown that surgical or chemical induction of menopause in experimental animals is associated with cardiac hypertrophy, or aggravates cardiac hypertrophy induced by other stressors. Arachidonic acid (AA) released from the myocardial phospholipids is metabolized by cardiac cytochrome P450 (CYP), cyclooxygenase (COX), and lipoxygenase (LOX) enzymes to produce several eicosanoids. AA-metabolizing enzymes and their respective metabolites play an important role in the pathogenesis of cardiac hypertrophy. Menopause is associated with changes in the cardiovascular levels of CYP, COX, and LOX enzymes and the levels of their metabolites. It is possible that these changes might play a role in the increased risk of cardiac hypertrophy after menopause., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

As both perimenopausal and menopausal periods are recognized critical windows of susceptibility for breast carcinogenesis, development of a physiologically relevant model has been warranted. The traditional ovariectomy model causes instant removal of the entire hormonal repertoire produced by the ovary, which does not accurately approximate human natural menopause with gradual transition. Here, we characterized the mammary glands of 4-vinylcyclohexene diepoxide (VCD)-treated animals at different time points, revealing that the model can provide the mammary glands with both perimenopausal and menopausal states. The perimenopausal gland showed moderate regression in ductal structure with no responsiveness to external hormones, while the menopausal gland showed severe regression with hypersensitivity to hormones. Leveraging the findings on the VCD model, effects of a major endocrine disruptor (polybrominated diphenyl ethers, PBDEs) on the mammary gland were examined during and after menopausal transition, with the two exposure modes; low-dose, chronic (environmental) and high-dose, subacute (experimental). All conditions of PBDE exposure did not augment or compromise the macroscopic ductal reorganization resulting from menopausal transition and/or hormonal treatments. Single-cell RNA sequencing revealed that the experimental PBDE exposure during the post-menopausal period caused specific transcriptomic changes in the non-epithelial compartment such as Errfi1 upregulation in fibroblasts. The environmental PBDE exposure resulted in similar transcriptomic changes to a lesser extent. In summary, the VCD mouse model provides both perimenopausal and menopausal windows of susceptibility for the breast cancer research community. PBDEs, including all tested models, may affect the post-menopausal gland including impacts on the non-epithelial compartments., (© 2024. The Author(s).)

Background: Estrogen has a protective impact on acute kidney injury (AKI); moreover, reducing the daily intake of calories impedes developing diseases. The present study aimed to determine the effects of calorie restriction (CR) and time restriction (TR) diets on the expression of silent information regulator 2 homolog 1 (SIRT1), transforming growth factor beta 1 (TGF-β1), and other indicators in the presence and absence of ovaries in AKI female rats., Methods: The female rats were divided into two groups, ovariectomized (OVX) and sham, and were placed on CR and TR diets for eight weeks; afterward, AKI was induced by injecting glycerol, and kidney injury indicators and biochemical parameters were measured before and after AKI., Results: After AKI, the levels of urine albumin excretion rate, urea, and creatinine in serum, and TGF-β1 increased, while creatinine clearance and SIRT1 decreased in kidney tissue. CR improved kidney indicators and caused a reduction in TGF-β1 and an increase in SIRT1 in ovary-intact rats. Moreover, CR prevented total antioxidant capacity (TAC) decrease and malondialdehyde (MDA) increase resulting from AKI. Before AKI, an increase in body weight, fasting blood sugar (FBS), low-density lipoprotein (LDL), triglyceride (TG), and total cholesterol (TC), and a decrease in high-density lipoprotein (HDL) were observed in OVX rats compared to sham rats, but CR prevented these changes. The effects of TR were similar to those of CR in all indicators except for TGF-β1, SIRT1, urea, creatinine, and albumin., Conclusion: The present study indicated that CR is more effective than TR in preventing AKI, probably by increasing SIRT1 and decreasing TGF-β1 in ovary-intact animals., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

A variety of progestogens are widely used by women for contraception and menopausal hormone therapy. The progestogens undergo extensive metabolism by oral and parenteral routes of administration to form many metabolites. Although a small number of metabolites have been shown to be biologically active, most have not been tested for biologic activity. The present review shows that we know most about progesterone metabolism, followed by the metabolism of levonorgestrel and norethindrone. Very few studies have been carried out on metabolism of most of the progestogens. The clinical significance of this deficiency is that those progestogen metabolites that bind to the progesterone receptors may also bind to other steroid receptors and be responsible for some of the well-documented side effects of administered progestogens. We also discuss how obesity and genetic polymorphisms alter progestogen metabolism, and how development of oral progestogen formulations that are targeted to the colon, where the concentration of steroid-metabolizing enzymes is much lower than in the proximal gut, may have a beneficial effect on progestogen metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

17β-estradiol, the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo brain 18 F-fluoroestradiol ( 18 F-FES) Positron Emission Tomography (PET) study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age, plasma estradiol and sex hormone binding globulin, and were highly consistent, correctly classifying all women as being postmenopausal or premenopausal. Higher ER density in target regions was associated with poorer memory performance for both postmenopausal and perimenopausal groups, and predicted presence of self-reported mood and cognitive symptoms after menopause. These findings provide novel insights on brain ER density modulation by female neuroendocrine aging, with clinical implications for women's health., (© 2024. The Author(s).)

A significant decrease in estrogen levels puts menopausal women at high risk for major depression, which remains difficult to cure despite its relatively clear etiology. With the discovery of abnormally elevated inflammation in menopausal depressed women, immune imbalance has become a novel focus in the study of menopausal depression. In this paper, we examined the characteristics and possible mechanisms of immune imbalance caused by decreased estrogen levels during menopause and found that estrogen deficiency disrupted immune homeostasis, especially the levels of inflammatory cytokines through the ERα/ERβ/GPER-associated NLRP3/NF-κB signaling pathways. We also analyzed the destruction of the blood-brain barrier, dysfunction of neurotransmitters, blockade of BDNF synthesis, and attenuation of neuroplasticity caused by inflammatory cytokine activity, and investigated estrogen-immuno-neuromodulation disorders in menopausal depression. Current research suggests that drugs targeting inflammatory cytokines and NLRP3/NF-κB signaling molecules are promising for restoring homeostasis of the estrogen-immuno-neuromodulation system and may play a positive role in the intervention and treatment of menopausal depression., (© 2024. The Author(s).)

Navigating menopause involves traversing a complex terrain of hormonal changes that extend far beyond reproductive consequences. Menopausal transition is characterized by a decrease in estradiol-17β (E2), and the impact of menopause resonates not only in the reproductive system but also through the central nervous system, musculoskeletal, and gastrointestinal domains. As women undergo menopausal transition, they become more susceptible to frailty, amplifying the risk and severity of injuries, including traumatic brain injury (TBI). Menopause triggers a cascade of changes leading to a decline in muscle mass, accompanied by diminished tone and excitability, thereby restricting the availability of irisin, a crucial hormone derived from muscles. Concurrently, bone mass undergoes reduction, culminating in the onset of osteoporosis and altering the dynamics of osteocalcin, a hormone originating from bones. The diminishing levels of E2 during menopause extend their influence on the gut microbiota, resulting in a reduction in the availability of tyrosine, tryptophan, and serotonin metabolites, affecting neurotransmitter synthesis and function. Understanding the interplay between menopause, frailty, E2 decline, and the intricate metabolisms of bone, gut, and muscle is imperative when unraveling the nuances of TBI after menopause. The current review underscores the significance of accounting for menopause-associated frailty in the incidence and consequences of TBI. The review also explores potential mechanisms to enhance gut, bone, and muscle health in menopausal women, aiming to mitigate frailty and improve TBI outcomes., Competing Interests: Declaration of competing interest None, (Published by Elsevier Ltd.)

Background: Estrogen homeostasis is crucial for bladder function, and estrogen deprivation resulting from menopause, ovariectomy or ovarian dysfunction may lead to various bladder dysfunctions. However, the specific mechanisms are not fully understood., Methods: We simulated estrogen deprivation using a rat ovariectomy model and supplemented estrogen through subcutaneous injections. The metabolic characteristics of bladder tissue were analyzed using non-targeted metabolomics, followed by bioinformatics analysis to preliminarily reveal the association between estrogen deprivation and bladder function., Results: We successfully established a rat model with estrogen deprivation and, through multivariate analysis and validation, identified several promising biomarkers represented by 3, 5-tetradecadiencarnitine, lysoPC (15:0), and cortisol. Furthermore, we explored estrogen deprivation-related metabolic changes in the bladder primarily characterized by amino acid metabolism imbalance., Conclusion: This study, for the first time, depicts the metabolic landscape of bladder resulting from estrogen deprivation, providing an important experimental basis for future research on bladder dysfunctions caused by menopause., 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., (Copyright © 2024 Zhang, Yang, Song, Liu and Li.)

A large body of scientific research accumulated over the past twenty years documents the cardiovascular (CV) benefits of estradiol (E2) and progesterone (P4) in reproductive aged women. In contrast, accelerated development of CV disease (CVD) occurs in the absence of ovarian produced E2 and P4. Hormone replacement therapy (HRT) with E2 and P4 has been shown to cause no harm to younger menopausal women. This robust scientific data supports a reconsideration of the prescriptive use of E2 and P4 as preventative therapeutics for the reduction of CVD, even without additional large-scale studies of the magnitude of the Women's Health Initiative (WHI). With the current expanded understanding of the critical modulatory role played by E2 on a multitude of systems and enzymes impacting CVD onset, initiation of HRT shortly after cessation of ovarian function, known as the "Timing Hypothesis", should be considered to delay CVD in recently postmenopausal women., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

The menopause transition is a vulnerable period for developing both psychiatric and metabolic disorders, and both can be enhanced by stressful events worsening their effects. The present study aimed to evaluate whether a cafeteria diet (CAF) combined with chronic variable stress (CVS) exacerbates anxious- or depressive-like behavior and neuronal activation, cell proliferation and survival, and microglia activation in middle-aged ovariectomized (OVX) rats. In addition, body weight, lipid profile, insulin resistance, and corticosterone as an index of metabolic changes or hypothalamus-pituitary-adrenal (HPA) axis activation, and the serum pro-inflammatory cytokines IL-6, IL-β, and TNFα were measured. A CAF diet increased body weight, lipid profile, and insulin resistance. CVS increased corticosterone and reduced HDL. A CAF produced anxiety-like behaviors, whereas CVS induced depressive-like behaviors. CVS increased serum TNFα independently of diet. A CAF and CVS separately enhanced the percentage of Iba-positive cells in the hippocampus; the combination of factors further increased Iba-positive cells in the ventral hippocampus. A CAF and CVS increased the c-fos -positive cells in the hippocampus; the combination of factors increased the number of positive cells expressing c-fos in the ventral hippocampus even more. The combination of a CAF and CVS generates a slight neuroinflammation process and neuronal activation in a hippocampal region-specific manner and differentially affects the behavior.

Background: About two-thirds of those with Alzheimer's disease (AD) are women, most of whom are post-menopausal. Menopause accelerates dementia risk by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (obesity, diabetes/prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents., Objective: Our goal was to determine the effects of a high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of AD and assess the effects of menopause., Methods: First, 3-month-old AppNL-F and WT female mice were placed on either a control or a high fat diet until 10 months of age then assessed for metabolic outcomes. Next, we did a more extensive assessment in AppNL-F mice that were administered VCD (4-vinylcyclohexene diepoxide) or vehicle (oil) and placed on a control or high fat diet for 7 months. VCD was used to model menopause by causing accelerated ovarian failure., Results: Compared to WT controls, AD female mice had worse glucose intolerance. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. There were interactions between diet and menopause on some metabolic health serum biomarkers and the expression of hypothalamic markers related to energy balance., Conclusions: This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD.

Melatonin is an indolamine secreted to circulation by the pineal gland according to a circadian rhythm. Melatonin levels are higher during nighttime, and the principal function of this hormone is to organize the temporal night and day distribution of physiological adaptive processes. Besides hormonal pineal production, melatonin is synthesized in various organs and tissues like the ovaries or the placenta for local utilization. In addition to its function as a circadian messenger, melatonin is also associated with many physiological functions. For example, melatonin has antioxidant properties and is involved in the regulation of energy and bone metabolism, and reproduction. Melatonin impacts several stages of reproduction and the action across the hypothalamus-pituitary-gonadal axis is well described. However, it is not well understood how those actions impact the female reproductive hormones secretion nor the consequent physiological outcomes. Thus, the first part of this chapter describes the regulation of female reproductive hormone synthesis by melatonin. Moreover, melatonin and female reproductive hormones have coincident physiological functions. Life stages like pregnancy or menopause are characterized by alterations in the reproductive hormones secretion that may be associated with certain physiological stages. Therefore, the second part discusses whether melatonin fluctuations could have an overlapping role with reproductive hormones in contributing to clinical outcomes associated with pregnancy and menopause., (Copyright © 2024. Published by Elsevier Inc.)

Postmenopausal women represent an important target population in need of preventative cardiometabolic approaches. The loss of estrogen following the menopause eliminates protections against metabolic dysfunction, largely due to its role in the health and function of adipose tissue. In addition, some studies associate the menopause with reduced physical activity, which could potentially exacerbate the deleterious cardiometabolic risk profile accompanying the menopause. Meanwhile, exercise has adipocyte-specific effects that may alleviate the adverse impact of estrogen loss through the menopausal transition period and beyond. Exercise thus remains the best therapeutic agent available to mitigate menopause-associated metabolic dysfunction and represents a vital behavioral strategy to prevent and alleviate health decline in this population.

Increasing evidence implicates sex and endocrine aging effects on brain bioenergetic aging in the greater lifetime risk of Alzheimer's disease (AD) in women. We conducted 31 Phosphorus Magnetic Resonance Spectroscopy ( 31 P-MRS) to assess the impact of sex and menopause on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters/phosphodiesters (PME/PDE)] in 216 midlife cognitively normal individuals at risk for AD, 80% female. Ninety-seven participants completed amyloid-beta (Aβ) 11 C-PiB PET. Women exhibited higher ATP utilization than men in AD-vulnerable frontal, posterior cingulate, fusiform, medial and lateral temporal regions (p < 0.001). This profile was evident in frontal cortex at the pre-menopausal and peri-menopausal stage and extended to the other regions at the post-menopausal stage (p = 0.001). Results were significant after multi-variable adjustment for age, APOE-4 status, midlife health indicators, history of hysterectomy/oophorectomy, use of menopause hormonal therapy, and total intracranial volume. While associations between ATP/PCr and Aβ load were not significant, individuals with the highest Aβ load were post-menopausal and peri-menopausal women with ATP/PCr ratios in the higher end of the distribution. No differences in Pi/PCr, Pi/ATP or PME/PDE were detected. Outcomes are consistent with dynamic bioenergetic brain adaptations that are associated with female sex and endocrine aging., (© 2022. The Author(s).)

Background: The menopause transition is associated with unfavourable alterations in health. However, postprandial metabolic changes and their mediating factors are poorly understood., Methods: The PREDICT 1 UK cohort (n=1002; pre- n=366, peri- n=55, and post-menopausal females n=206) assessed phenotypic characteristics, anthropometric, diet and gut microbiome data, and fasting and postprandial (0-6 h) cardiometabolic blood measurements, including continuous glucose monitoring (CGM) data. Differences between menopausal groups were assessed in the cohort and in an age-matched subgroup, adjusting for age, BMI, menopausal hormone therapy (MHT) use, and smoking status., Findings: Post-menopausal females had higher fasting blood measures (glucose, HbA1c and inflammation (GlycA), 6%, 5% and 4% respectively), sugar intakes (12%) and poorer sleep (12%) compared with pre-menopausal females (p<0.05 for all). Postprandial metabolic responses for glucose 2hiauc and insulin 2hiauc were higher (42% and 4% respectively) and CGM measures (glycaemic variability and time in range) were unfavourable post- versus pre-menopause (p<0.05 for all). In age-matched subgroups (n=150), postprandial glucose responses remained higher post-menopause (peak 0-2h 4%). MHT was associated with favourable visceral fat, fasting (glucose and insulin) and postprandial (triglyceride 6hiauc ) measures. Mediation analysis showed that associations between menopause and metabolic health indicators (visceral fat, GlycA 360mins and glycaemia (peak 0-2h )) were in part mediated by diet and gut bacterial species., Interpretation: Findings from this large scale, in-depth nutrition metabolic study of menopause, support the importance of monitoring risk factors for type-2 diabetes and cardiovascular disease in mid-life to older women to reduce morbidity and mortality associated with oestrogen decline., Funding: Zoe Ltd., Competing Interests: Declaration of interests TDS, JW and GH are co-founders of ZOE Ltd (ZOE). AMV, FA, LMD, NS, PWF, SEB, TDS receive payments as consultants to ZOE. GH, IL, JW, KK, RD are employed by ZOE. AMV, GH, IL, JW, KK, LMD, NS, PWF, RD, SEB, TDS also receive options in ZOE. Other authors have no conflict of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Hyperthyroidism is a health problem characterized by an overactive thyroid gland, resulting in extra triiodothyronine (T3) and thyroxine (T4) production, as well as a decrease in thyroid-stimulating hormone (TSH). The oxidative stress indicators in hyperthyroid patients and the relationship with impaired metabolism of lipid are still controversial, especially in menopausal women suffering from a lack of ovulation hormones. In this study, blood samples were withdrawn from 120 subjects, including healthy premenopausal (n=30) and postmenopausal women (n=30) as control groups (G1 and G2), as well as 30 hyperthyroid women in each group of premenopausal and postmenopausal patient groups (G3 and G4). The levels of T3, T4, and TSH, blood pressure, and lipid profiles, such as triglyceride, total cholesterol (TC), high-density lipoprotein, and low-density lipoprotein, superoxide dismutase (SOD) activity, malondialdehyde (MDA), and advanced oxidation protein products (AOPP) in the two healthy control groups and patient groups with hyperthyroidism were measured. In addition, serum progesterone levels were measured by the Bio-Merieux kit France, according to the manufacturer's instructions. The results revealed a significant decrease in SOD activity in the postmenopausal group, as compared to that in premenopausal women and control groups. Hyperthyroidism groups demonstrated a significant increase in MDA and AOPP levels, compared to control groups. Patient groups reported a decreased level of progesterone, in comparison with control groups. Moreover, there was a significant increase in T3 and T4 in patient groups (G3 and G4), compared to that in control groups (G1 and G2). There was a significant increase in systolic and diastolic blood pressure in menopausal hyperthyroidism (G4), compared to that in other groups. The TC decreased significantly in G3 and G4, compared to that in both control groups ( P <0.05); nonetheless, there was no significant difference between patient groups (G3 and G4), as well as between control groups (G1 and G2). The study suggested that hyperthyroidism causes an increase in oxidative stress, which negatively affects the antioxidant system and drops levels of progesterone in both premenopausal and postmenopausal female patients. Therefore, low levels of progesterone are linked with hyperthyroidism, leading to aggravating symptoms of the disease., Competing Interests: The authors declare that they have no conflict of interest.

Background: If menopause is really independent risk factor for cardiovascular disease is still under debate. We studied if ovariectomy in the model of insulin resistance causes cardiovascular changes, to what extent are these changes reversible by estradiol substitution and if they are accompanied by changes in other organs and tissues., Methods: Hereditary hypertriglyceridemic female rats were divided into three groups: ovariectomized at 8th week ( n = 6), ovariectomized with 17-β estradiol substitution ( n = 6), and the sham group ( n = 5). The strain of abdominal aorta measured by ultrasound, expression of vascular genes, weight and content of myocardium and also non-cardiac parameters were analyzed., Results: After ovariectomy, the strain of abdominal aorta, expression of nitric oxide synthase in abdominal aorta, relative weight of myocardium and of the left ventricle and circulating interleukin-6 decreased; these changes were reversed by estradiol substitution. Interestingly, the content of triglycerides in myocardium did not change after ovariectomy, but significantly increased after estradiol substitution while adiposity index did not change after ovariectomy, but significantly decreased after estradiol substitution., Conclusion: Vascular and cardiac parameters under study differed in their response to ovariectomy and estradiol substitution. This indicates different effects of ovariectomy and estradiol on different cardiovascular but also extracardiac structures.

Background: In women, metabolic health deteriorates after menopause, and the role of physical activity (PA) in mitigating the change is not completely understood. This study investigates the changes in indicators of metabolic health around menopause and evaluates whether PA modulates these changes., Methods: Longitudinal data of 298 women aged 48-55 years at baseline participating in the ERMA and EsmiRs studies was used. Mean follow-up time was 3.8 (SD 0.1) years. Studied indicators of metabolic health were total and android fat mass, waist circumference, waist-to-hip ratio (WHR), systolic (SBP) and diastolic (DBP) blood pressure, blood glucose, triglycerides, serum total cholesterol, and high- (HDL-C) and low-density (LDL-C) lipoprotein cholesterol. PA was assessed by accelerometers and questionnaires. The participants were categorized into three menopausal groups: PRE-PRE (pre- or perimenopausal at both timepoints, n = 56), PRE-POST (pre- or perimenopausal at baseline, postmenopausal at follow-up, n = 149), and POST-POST (postmenopausal at both timepoints, n = 93). Analyses were carried out using linear and Poisson mixed-effect models., Results: At baseline, PA associated directly with HDL-C and inversely with LDL-C and all body adiposity variables. An increase was observed in total (B = 1.72, 95% CI [0.16, 3.28]) and android fat mass (0.26, [0.06, 0.46]), SBP (9.37, [3.34, 15.39]), and in all blood-based biomarkers in the PRE-POST group during the follow-up. The increase tended to be smaller in the PRE-PRE and POST-POST groups compared to the PRE-POST group, except for SBP. The change in PA associated inversely with the change in SBP (-2.40, [-4.34, -0.46]) and directly with the change in WHR (0.72, [0.05, 1.38])., Conclusions: In middle-aged women, menopause may accelerate the changes in multiple indicators of metabolic health. PA associates with healthier blood lipid profile and body composition in middle-aged women but does not seem to modulate the changes in most of the studied metabolic health indicators during the menopausal transition., (© 2021. The Author(s).)

Recent reports have acknowledged the underrepresentation of women in the field of dietary nitrate (NO 3 - ) research. Undoubtedly, greater participation from women is warranted to clarify potential sex differences in the responses to dietary NO 3 - interventions. However, careful consideration for the effects of sex hormones - principally 17β-estradiol - on endogenous nitric oxide (NO) synthesis and dietary NO 3 - reductase capacity is necessary for improved interpretation and reproducibility of such investigations. From available literature, we present a narrative review describing how hormonal variations across the menstrual cycle, as well as with menopause, may impact NO biosynthesis catalyzed by NO synthase enzymes and NO 3 - reduction via the enterosalivary pathway. In doing so, we address methodological considerations related to the menstrual cycle and hormonal contraceptive use relevant for the inclusion of premenopausal women along with factors to consider when testing postmenopausal women. Adherence to such methodological practices may explicate the utility of dietary NO 3 - supplementation as a means to improve vascular function among women across the lifespan., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Every year, 2 million women reach menopause in the United States, and they may spend 40% or more of their life in a postmenopausal state. In the years immediately preceding menopause-known as the menopause transition (or perimenopause)-changes in hormones and body composition increase a woman's overall cardiometabolic risk. In this narrative review, we summarize the changes in weight, body composition, and body fat distribution, as well as the changes in energy intake, energy expenditure, and other cardiometabolic risk factors (lipid profile, glucose metabolism, sleep health, and vascular function), that occur during the menopause transition. We also discuss the benefits of lifestyle interventions in women in the earlier stages of menopause before these detrimental changes occur. Finally, we discuss how to include perimenopausal women in research studies so that women across the life-span are adequately represented., (© 2021 The Obesity Society.)

Context: Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons)., Objective: We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood-brain barrier) and impedes their downstream effects., Design: Case/control., Setting: Academic medical center., Participants: Mice., Interventions: Administration of peripherally restricted kappa receptor agonists and frequent blood sampling to determine hormone release and body temperature., Main Outcome Measures: LH pulse parameters and body temperature., Results: First, chronic administration of a PRKA to bilaterally ovariectomized mice with experimentally induced hyperactivity of KNDy neurons reduces the animals' elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity., Conclusion: The inhibition of kisspeptin neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Melatonin, an indolamine mainly released from the pineal gland, is associated with many biological functions, namely, the modulation of circadian and seasonal rhythms, sleep inducer, regulator of energy metabolism, antioxidant, and anticarcinogenic. Although several pieces of evidence also recognize the influence of melatonin in the reproductive physiology, the crosstalk between melatonin and sex hormones is not clear. Here, we review the effects of sex differences in the circulating levels of melatonin and update the current knowledge on the link between sex hormones and melatonin. Furthermore, we explore the effects of melatonin on gonadal steroidogenesis and hormonal control in females. The literature review shows that despite the strong evidence that sex differences impact on the circadian profiles of melatonin, reports are still considerably ambiguous, and these differences may arise from several factors, like the use of contraceptive pills, hormonal status, and sleep deprivation. Furthermore, there has been an inconclusive debate about the characteristics of the reciprocal relationship between melatonin and reproductive hormones. In this regard, there is evidence for the role of melatonin in gonadal steroidogenesis brought about by research that shows that melatonin affects multiple transduction pathways that modulate Sertoli cell physiology and consequently spermatogenesis, and also estrogen and progesterone production. From the outcome of our research, it is possible to conclude that understanding the correlation between melatonin and reproductive hormones is crucial for the correction of several complications occurring during pregnancy, like preeclampsia, and for the control of climacteric symptoms., (© 2021 S. Karger AG, Basel.)

Context: Novel metrics of high-density lipoprotein (HDL) (subclasses, lipid content, and function) may improve characterization of the anti-atherogenic features of HDL. In midlife women, changes in these metrics vary by time relative to the final menstrual period (FMP), supporting a contribution of estradiol (E2) and follicle-stimulating hormone (FSH)., Objective: We tested associations of endogenous E2 and FSH with novel HDL metrics and assessed whether these associations varied by time relative to FMP., Methods: This study was a longitudinal analysis from the Study of Women's Health Across the Nation (SWAN) HDL study, using a community-based cohort of 463 women, baseline mean age 50.2 (2.7) years. The main outcome measures were HDL cholesterol efflux capacity (HDL-CEC), HDL phospholipids (HDL-PL), HDL triglycerides (HDL-Tg), HDL particles (HDL-P), HDL size, and HDL cholesterol (HDL-C)., Results: In multivariable analyses, E2 was positively associated with HDL size, large HDL-P, HDL-CEC, and HDL-Tg, but negatively with medium HDL-P (P values < 0.05). The positive association between E2 and HDL-Tg was stronger 2 years post-FMP than before, (interaction P = 0.031). FSH was positively related to total and medium HDL-P, but negatively to HDL size, large HDL-P, and HDL-CEC per particle (P values < 0.05). Associations of higher FSH with greater total HDL-P and smaller HDL size were only evident at/after menopause (interaction P values < 0.05)., Conclusion: Some of the associations linking E2 and FSH with novel HDL metrics were vulnerable to time relative to menopause onset. Whether a late initiation of hormone therapy relative to menopause could have a detrimental effect on lipid content of HDL particles should be tested in the future., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Aging is associated with significant changes in fat distribution and menopause may alter this process. This study aimed to investigate the longitudinal effect of menopause on changes in adiposity indices (AI)., Methods: A total number of 3876 non-menopausal women, aged > 20 years, who participated in the Tehran Lipid and Glucose study, were selected for the present study. They were followed from 1998 to 2018 at a 3-year interval and their adiposity indices were measured. Throughout the study, participants were categorized into two groups according to their menopausal status as group 1): women who reached menopause and group 2): women who did not reach menopause. The generalized estimation equation (GEE) models were used to compare the trend of changes in AIs between these two groups., Results: At the end of the study, a total number of 1479 (38.2%) participants reached menopause. The odds of general obesity decreased by 5% (OR: 0.95, 95% CI: 0.90-0.99), and the odds of central obesity increased by 6% in group1 compared to group2 (OR: 1.06, 95% CI: 1.01-1.12)., Conclusions: Menopause alters the impact of aging on central fat distribution. Increasing awareness of the related risk in menopausal women and their healthcare professional may prevent adverse related outcomes., (© 2021. Italian Society of Endocrinology (SIE).)

Objective: Loss of sex hormones has been suggested to underlie menopause-associated increment in cardiovascular risk. We investigated associations of sex hormones with arterial stiffness in 19-58-years-old women. We also studied associations of specific hormonal stages, including natural menstrual cycle, cycle with combined oral contraceptives (COC) and menopausal status with or without hormone therapy (HT), with arterial stiffness., Methods: This study includes repeated measurements of 65 healthy women representing reproductive (n=16 natural, n=10 COC-users) and menopause (n=5 perimenopausal, n=26 postmenopausal, n=8 HT-users) stages. Arterial stiffness outcomes were aortic pulse wave velocity (PWVao) and augmentation index (AIx%) assessed using Arteriograph-device. Generalized estimating equation models were constructed to investigate associations of each hormone (wide age-range models) or hormonal stage (age-group focused models) with arterial stiffness. PWVao models with cross-sectional approach, were adjusted for age, relative fitness, fat mass and mean arterial pressure, while models with longitudinal approach were adjusted for mean arterial pressure. AIx% models used the same approach for adjustments and were also adjusted for heart rate., Results: Negative and positive associations with arterial stiffness variables were observed for estradiol and follicle-stimulating hormone, respectively, until adjustment for confounding effect of age. In naturally menstruating women, AIx% was higher at ovulation (B=3.63, p<0.001) compared to the early follicular phase. In COC-users, PWVao was lower during active (B=-0.33 - -0.57, p<0.05) than inactive pills. In menopausal women, HT-users had higher PWVao (B=1.43, p=0.03) than postmenopausal non-HT-users., Conclusions: When using wide age-range assessments covering reproductive to menopausal lifespan it is difficult to differentiate age- and hormone-mediated associations, because age-mediated influence on arterial stiffness seemed to overrule potential hormone-mediated influences. However, hormonal status associated differentially with arterial stiffness in age-group focused analyses. Thus, the role of sex hormones cannot be excluded. Further research is warranted to resolve potential hormone-mediated mechanisms affecting arterial elasticity., 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., (Copyright © 2021 Laakkonen, Karppinen, Lehti, Lee, Pesonen, Juppi, Kujala, Haapala, Aukee, Laukkanen and Ihalainen.)

Postmenopausal syndrome refers to symptoms caused by the gradual decrease in female hormones after mid-40 years. As a target organ of estrogen, decrease in estrogen causes various changes in brain function such as a decrease in choline acetyltransferase and brain-derived neurotrophic factor; thus, postmenopausal women experience cognitive decline and more depressive symptoms than age-matched men. Radix Polygalae has been used for memory boosting and as a mood stabilizer and its components have shown neuroprotective, antidepressant, and stress relief properties. In a mouse model of estrogen depletion induced by 4-vinylcyclohexene diepoxide, Radix Polygalae was orally administered for 3 weeks. In these animals, cognitive and depression-related behaviors and molecular changes related to these behaviors were measured in the prefrontal cortex and hippocampus. Radix Polygalae improved working memory and contextual memory and despair-related behaviors in 4-vinylcyclohexene diepoxide-treated mice without increasing serum estradiol levels in this model. In relation to these behaviors, choline acetyltransferase and brain-derived neurotrophic factor in the prefrontal cortex and hippocampus and bcl-2-associated athanogene expression increased in the hippocampus. These results implicate the possible benefit of Radix Polygalae in use as a supplement of estrogen to prevent conditions such as postmenopausal depression and cognitive decline.

Introduction: Background: peri- and post-menopausal women exhibit a high tendency towards obesity and visceral fat deposition, which increases cardiometabolic risk. Objective: to evaluate through a prospective nutritional study the effect of carotenoid consumption on cardiometabolic risk biomarkers in peri- and post-menopausal women. Material and methods: twelve peri- and post-menopausal women without previous symptoms of cardiovascular disease, but with some cardiometabolic risk factor, were recruited. Their diet was supplemented during 4 weeks with orange-carrot juice, tomato juice, and boiled spinach, providing 415 mg of total carotenoids/week (carotenes, cryptoxanthin, lycopene, and lutein + zeaxanthin). At the beginning (TI) and at the end (TF) of the intervention period blood samples were drawn to measure biochemical parameters, oxidative stress, inflammation and endothelial function biomarkers, and plasma carotenoid levels. Results: at TF a significant decrease (p < 0.05) in LDL-cholesterol and atherogenic index, and an increase in HDL-cholesterol were observed. Plasma carotenoids increased significantly (p < 0.05) from 0.56 µg/mL at TI to 1.22 µg/mL at TF. Concurrently, a shift in oxidative stress and inflammation biomarkers was detected, with a decrease in plasma C-reactive protein and malonaldehyde levels, and an increase in adiponectin. However, endothelial dysfunction biomarkers (sVCAM and sICAM) and total antioxidant capacity remained unchanged. Conclusions: dietary supplementation with carotenoids leads to an increase in plasma carotenoids, a decrease in atherogenic dyslipidemia, and an improvement in oxidative stress and inflammation biomarkers, which indicates a reduction in cardiometabolic risk.

It has been widely observed that adult men of all ages are at higher risk of developing serious complications from COVID-19 when compared with women. This study aimed to investigate the association of COVID-19 positivity and severity with estrogen exposure in women, in a population based matched cohort study of female users of the COVID Symptom Study application in the UK. Analyses included 152,637 women for menopausal status, 295,689 women for exogenous estrogen intake in the form of the combined oral contraceptive pill (COCP), and 151,193 menopausal women for hormone replacement therapy (HRT). Data were collected using the COVID Symptom Study in May-June 2020. Analyses investigated associations between predicted or tested COVID-19 status and menopausal status, COCP use, and HRT use, adjusting for age, smoking and BMI, with follow-up age sensitivity analysis, and validation in a subset of participants from the TwinsUK cohort. Menopausal women had higher rates of predicted COVID-19 (P = 0.003). COCP-users had lower rates of predicted COVID-19 (P = 8.03E-05), with reduction in hospital attendance (P = 0.023). Menopausal women using HRT or hormonal therapies did not exhibit consistent associations, including increased rates of predicted COVID-19 (P = 2.22E-05) for HRT users alone. The findings support a protective effect of estrogen exposure on COVID-19, based on positive association between predicted COVID-19 with menopausal status, and negative association with COCP use. HRT use was positively associated with COVID-19, but the results should be considered with caution due to lack of data on HRT type, route of administration, duration of treatment, and potential unaccounted for confounders and comorbidities., Competing Interests: Zoe Global Limited co-developed the app pro bono for non-commercial purposes. JCP and JW work for Zoe Global, and TDS is a consultant to Zoe Global. IB is Chief Data Scientist Advisor for AstraZeneca. These do not alter our adherence to PLoS ONE policies on sharing data and materials.

The present work was aimed to evaluate the effect of different administration modes of sodium valproate (VPA) on bone strength, bone mass and bone mineral density in ovariectomized (OVX) rats and further investigation of the possible mechanism. 60 female SD rats were randomly divided into 4 groups: Sham group (Sham, n = 15), OVX group (OVX, n = 15), OVX rats received intermittent VPA treatment group (IVPA, n = 15) and OVX rats received daily VPA treatment group (EVPA, n = 15). After 12 weeks of treatment, the rats were sacrificed, and serum and femur samples were harvested. DEXA, Micro-CT, history, biomechanical testing, biochemical index and western blot analysis were used to observe the therapeutic effect and explore the possible mechanism. Micro-CT and DEXA analysis of bones revealed better BMD and higher BV/TV, Tb. Th, Tb. N, Conn. D and lower Tb. Sp at femoral metaphysis evaluated in IVPA when compared with OVX and EVPA group (P < 0.05). Histological, fluorescent analysis and biological strength revealed more trabecular bone and higher relative mineral apposition rate, maximal load, elastic modulus and energy at break with evaluated in IVPA when compared with OVX and EVPA group (P < 0.05). The levels of P1NP, estrogen, CTX, TRAP-5b and RANKL of the IVPA group showed a significant increase when compared with the OVX and EVPA group (P < 0.05). We confirm adverse effects on protein expressions including Notch1, Jagged1, HEY1, Wnt 1, β-catenin and RUNX2 following daily VPA treatment in OVX female rats. Our current study demonstrated that intermittent administration of sodium valproate has a protective effect on bone health in OVX rats and these effects may be achieved by activating Notch/Wnt/β-catenin/RUNX2 signal axis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The rapid decline of circulating 17β-estradiol (E2) at menopause leads to negative neurological consequences, although hormone therapy paradoxically has both harmful and positive effects depending on the age at which it is delivered. The inconsistent response to E2 suggests unappreciated regulatory mechanisms for estrogen receptors (ERs), and we predicted it could be due to age-related differences in ERβ phosphorylation. We assessed ERβ phosphorylation using a sensitive mass spectrometry approach that provides absolute quantification (AQUA-MS) of individually phosphorylated residues. Specifically, we quantified phosphorylated ERβ in the hippocampus of women (aged 21-83 years) and in a rat model of menopause at 4 residues with conserved sequence homology between the 2 species: S105, S176, S200, and Y488. Phosphorylation at these sites, which spanned all domains of ERβ, were remarkably consistent between the 2 species, showing high levels of S105 phosphorylation (80%-100%) and low levels of S200 (20%-40%). Further, S200 phosphorylation decreased with aging in humans and loss of E2 in rats. Surprisingly, Y488 phosphorylation, which has been linked to ERβ ligand-independent actions, exhibited approximately 70% phosphorylation, unaltered by species, age, or E2, suggesting ERβ's primary mode of action may not require E2 binding. We further show phosphorylation at 2 sites directly altered ERβ DNA-binding efficiency, and thus could affect its transcription factor activity. These findings provide the first absolute quantification of ERβ phosphorylation in the human and rat brain, novel insights into ERβ regulation, and a critical foundation for providing more targeted therapeutic options for menopause in the future., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous midlife estradiol treatment, like continuous treatment, improves memory and results in lasting increases in hippocampal levels of estrogen receptor (ER) α and ER-dependent transcription in ovariectomized rodents. We hypothesized that previous and continuous midlife estradiol act to specifically increase levels of nuclear ERα, resulting in transcriptional regulation of proteins that mediate estrogen effects on memory. Ovariectomized middle-aged rats received estradiol or vehicle capsule implants. After 40 days, rats initially receiving vehicle received another vehicle capsule (ovariectomized controls). Rats initially receiving estradiol received either another estradiol (continuous estradiol) or a vehicle (previous estradiol) capsule. One month later, hippocampi were dissected and processed. Continuous and previous estradiol increased levels of nuclear, but not membrane or cytosolic ERα and had no effect on Esr1. Continuous and previous estradiol impacted gene expression and/or protein levels of mediators of estrogenic action on memory including ChAT, BDNF, and PSD-95. Findings demonstrate a long-lasting role for hippocampal ERα as a transcriptional regulator of memory following termination of previous estradiol treatment in a rat model of menopause., Competing Interests: Disclosure statement None., (Copyright © 2021. Published by Elsevier Inc.)

Menopause is related to a decline in ovarian oestrogen production, affecting the perception of the somatosensory stimuli, changing the immune-inflammatory systems, and triggering depressive symptoms. It has been demonstrated that the inhibition of the kinin B 1 and B 2 receptors (B 1 R and B 2 R) prevented the depressive-like behaviour and the mechanical allodynia that was induced by immune-inflammatory mediators in mice. However, there is no evidence regarding the role of the kinin receptors in the depressive-like and nociceptive behaviour in female mice that were subjected to bilateral ovariectomy (OVX). This study has shown that the OVX mice developed time-related mechanical allodynia, together with an increased immobility time as indicative of depression. Both of these changes were reduced by the genetic deletion of B 1 R, or by the pharmacological blockade of the selective kinin B 1 R antagonist R-715 (acute, i.p.). The genetic deletion or the pharmacological inhibition of B 2 R (HOE 140, i.p.) did not prevent the OVX-elicited behavioural changes. The data has suggested a particular modulation of kinin B 1 R in the nociceptive and depressive-like behaviour in the OVX mice. The selective inhibition of the B 1 R receptor may be a new pharmacological target for treating pain and depression symptoms in women during the perimenopause/menopause period., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Context: The relation between the menopause transition (MT) and changes in regional fat distribution is uncertain., Objective: To determine whether the MT is associated with the development of central adiposity., Design: Longitudinal analysis from the Study of Women's Health Across the Nation, spanning 1996-2013 (median follow-up 11.8 years)., Setting: Community-based., Participants: 380 women with regional body composition measures by dual energy X-ray absorptiometry. Mean baseline age was 45.7 years; racial/ethnic composition was 16% Black, 41% Japanese and 43% White., Outcomes: Changes in android, gynoid and visceral fat and waist and hip circumferences., Results: Android fat increased by 1.21% per year (py) and 5.54% py during premenopause and the MT, respectively (each P < 0.05). Visceral and gynoid fat began increasing at the MT, annualized changes were 6.24% and 2.03%, respectively (each P < 0.05). Postmenopausal annual trajectories decelerated to 1.47% (visceral), 0.90% (android), and -0.87% (gynoid), (all non-zero, P < 0.05). Waist girth grew during premenopause (0.55% py), the MT (0.96% py), and postmenopause (0.55% py) (all non-zero, P < 0.05; not statistically different from each other). Hip girth grew during premenopause (0.20% py) and the MT (0.35% py) (each non-zero, P < 0.05; not statistically different from each other) and decelerated to zero slope in postmenopause. Results are for the White referent; there were statistically significant differences in some trajectories in Black and Japanese women., Conclusions: The MT is associated with the development of central adiposity. Waist or hip circumferences are less sensitive to changes in fat distribution., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Obesity and its related metabolic disorders have become prevalent and fatal, which are faced by the entire human beings since decades. An energy equilibrium is urgently important for human metabolic health, which requires the participation of multiple organs, such as adipose tissues, liver and skeletal muscles. It seems that both sex and age play a role in the above processes. In this review, we focus on the sexual dimorphism in energy metabolism mediated by adipose tissues, including white and thermogenic (brown/beige) adipose tissues. Remarkably, past investigations have focused on targeting brown/beige adipose tissues to combat obesity because of their contributions to non-shivering thermogenesis. However, sex differences in the regulation of adipose tissue metabolism are likely overlooked. Particularly, increasing data show that males display more visceral fat than females, and females show increased visceral fat after menopause. Visceral adiposity is more deleterious and closely related to metabolic disorders, such as cardiovascular diseases. In this review, we discuss current findings on sexual dimorphism in WAT and BAT biology for a better metabolic balance in humans., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Menopause, probably the most important natural change in a woman's life and a major component of female senescence, is characterized, inter alia, by cessation of ovarian estrogen and progesterone production, resulting in a gradual deterioration of the female immune system. Hormone replacement therapy (HRT) is used in postmenopausal women to relieve some of the peri- and postmenopausal symptoms, while there is also evidence that the therapy may additionally partially reverse menopausal immune senescence. Flavonoids, and especially isoflavones, are widely used for the treatment of menopausal symptoms, although it is not at present clear whether they can reverse or alleviate other menopausal changes. HRT reverses the menopausal CD4/CD8 ratio and also limits the general peri- and postmenopausal inflammatory state. Moreover, the increased levels of interleukins (IL)-1β, IL-6, and IL-8, as well as of tumor necrosis factor-α (TNF-α) are decreased after the initiation of HRT. However, some reports show no effect of HRT on IL-4, IL-10, and IL-12. It is thus evident that the molecular pathways connecting HRT and female immune senescence need to be clarified. Interestingly, recent studies have suggested that the anti-inflammatory properties of isoflavones possibly interact with inflammatory cytokines when applied in menopause treatments, thereby potentially reversing immune senescence. This narrative review presents the latest data on the effect of menopausal therapies, including administration of flavonoid-rich products, on age-associated immune senescence reversal with the aim of revealing possible directions for future research and treatment development.

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.)

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.)

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.)