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Sex hormone signaling declines during aging, from early midlife through menopause, as a consequence of reduced circulating estrogens and decreased receptiveness to these hormones in target tissues. Estrogens preserve energy homeostasis and promote metabolic health via coordinated and simultaneous effects throughout the brain and body. Age-associated loss of estrogen production during menopause has been implicated in a higher risk for metabolic diseases and increased mortality. However, it remains unclear whether age-associated changes in homeostasis are dependent on reduced estrogen signaling during menopause. Although menopausal hormone therapies containing estrogens can alleviate symptoms, concerns about the risks involved have contributed to a broad decline in the use of these approaches. Non-hormonal therapies have emerged that target tissues or pathways with varying levels of selectivity, reducing risk. We summarize here the broad effects of estrogen loss on homeostasis during menopause, current and emerging therapies and opportunities for understanding homeostatic disruptions associated with menopause., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Springer Nature America, 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).)

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).)

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.

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.

Despite significant decreases in cardiovascular disease (CVD) mortality in the past three decades, it still remains the leading cause of death in women. Following menopause and the accompanying loss of estrogen, women experience a unique, accelerated rise in CVD risk factors. Dysfunction of the endothelium represents an important antecedent to CVD development, with rapid declines in endothelial vasodilator function reportedly taking place across the menopause transition. Importantly, the decline in endothelial function is independent of chronological age and is associated with estrogen deficiency. Estrogen-mediated effects, including increasing nitric oxide bioavailability and attenuating oxidative stress and inflammation, contribute to preserving endothelial health. This review will discuss studies that have probed the role of estrogen on endothelial vasodilator function in women at discrete stages of the menopause transition and the effects of estradiol supplementation in postmenopausal women. Estrogen receptor signaling is also an important aspect of endothelial function in women, and studies suggest that expression is reduced with both acute and prolonged estrogen deficiency. Changes in regulatory mechanisms of estrogen receptor-α expression as well as sensitivity to estrogen may underlie the differential effects of estrogen therapy in early (≤5 yr past final menstrual period) and late postmenopausal women (>5 yr past final menstrual period). Lastly, this review presents potential therapeutic targets that include increasing l-arginine bioavailability and estrogen receptor activation to prevent endothelial dysfunction in postmenopausal women as a strategy for decreasing CVD mortality in this high-risk population.

Age and sex are two of the three major risk factors for Alzheimer's disease (ApoE-e4 allele is the third), with women having a twofold greater risk for Alzheimer's disease after the age of 75 years. Sex differences have been shown across a wide range of cognitive skills in young and older adults, and evidence supports a role for sex steroids, especially estradiol, in protecting against the development of cognitive decline in women. Sleep may also be a protective factor against age-related cognitive decline, since specific electrophysiological sleep events (e.g. sleep spindle/slow oscillation coupling) are critical for offline memory consolidation. Furthermore, studies in young women have shown fluctuations in sleep events and sleep-dependent memory consolidation during different phases of the menstrual cycle that are associated with the levels of sex steroids. An under-appreciated possibility is that there may be an important interaction between these two protective factors (sex steroids and sleep) that may play a role in daily fluctuations in cognitive processing, in particular memory, across a woman's lifespan. Here, we summarize the current knowledge of sex steroid-dependent influences on sleep and cognition across the lifespan in women, with special emphasis on sleep-dependent memory processing. We further indicate gaps in knowledge that require further experimental examination in order to fully appreciate the complex and changing landscape of sex steroids and cognition. Lastly, we propose a series of testable predictions for how sex steroids impact sleep events and sleep-dependent cognition across the three major reproductive stages in women (reproductive years, menopause transition, and post-menopause)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Osteocyte survival is key to bone homeostasis and is perturbed in menopause and aging. However, it remains unknown how osteocyte-mediated maintenance of the skeleton is regulated by the osteoprotective factor semaphorin 3A (Sema3A), a secreted protein that is known to reduce bone resorption and enhance bone formation. Here, we show that estrogen induces osteocyte expression of Sema3A, which acts on its receptor on osteocytes to promote their survival and maintain bone homeostasis. Postnatal global and conditional deletion of Sema3a in osteoblastic cells resulted in a severe osteoporotic phenotype marked by fewer osteocytes. This phenotype was recapitulated by osteocyte-specific deficiency of either Sema3A or its receptor component neuropilin-1 (Nrp1). A stimulator of soluble guanylate cyclase-cGMP signaling mimicked Sema3A action and ameliorated bone loss after ovariectomy. We further show that serum levels of SEMA3A decreased with age or after menopause in humans. Thus, we provide a mechanistic insight into the estrogen action and a promising therapeutic approach to protect against bone-related aging., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pancreatic fat fraction has been shown to increase in many pathological situations. However, pancreatic fat fraction and its physiological changes in healthy women are still unclear. The aim of this study is to investigate the effect of aging and menopause on pancreatic fat fraction in healthy female population.This was a cross-sectional study. A phantom of fat-water mixtures was established. One hundred sixty-seven healthy women (20-70 years) were recruited. Fat fraction was quantified with double-echo chemical shift magnetic resonance imaging with T1 and T2* correction. The association between measured and actual fat fractions was determined with Pearson correlation. Linear regression analysis was used to establish the calibration curve. Fat fractions were analyzed via analysis of variance.A significant positive linear correlation was revealed between the measured and actual fat fractions on the phantom (r = 0.991, P < .001). There was no significant difference in fat fractions among caput, corpus, and cauda of the pancreas. Pancreatic fat fraction remained constant during the age of 20 to 40 years (4.41 ± 0.79%) but significantly increased during the ages of 41 to 50 and 51 to 70 years (7.49 ± 1.10% and 9.43 ± 1.51%, respectively, P < .001). Moreover, pancreatic fat fractions of the healthy women aged 41 to 70 years were still significantly higher than these in the groups aged 20 to 40 years when postmenopausal healthy women were removed (P < .001). For volunteers aged 46 to 49 years, pancreatic fat fraction of the postmenopausal women was significantly increased compared with that of their premenopausal counterparts (P < .001).We found that an even distribution of pancreatic fat in healthy women, aging and menopause as 2 independent risk factors for pancreatic steatosis, a fatty infiltration in the pancreas beginning in the fifth decade in women.

This article reviews the role of endogenous estrogen in neural and cognitive processing, followed by an examination of longitudinal cognitive data captured in various stages of the menopausal transition. The remaining text reviews the contradictory results from major hormone therapy trials to date, evidence for the "timing hypothesis," and closes with recommendations for future research and for practicing clinicians., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Evidence supports that the physical disablement process starts earlier than previously thought, in midlife when women still have many years to live. Physical activity participation and interventions have been successful in preventing disability in older adults and may be promising for maintaining function at younger ages. Changing the conversation to more relevant topics in midlife, like positive changes in body composition, sleep, and improved mood, may move the dial on participation, as midlife women do not meet guidelines for physical activity. Exploring the role of reproductive aging beyond chronologic aging may provide gender-specific insights on both disablement and participation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Both chronologic aging and menopause affect the physical, physiologic, and microbiological characteristics of the genitourinary tract. The genitourinary syndrome of menopause, characterized by vulvovaginal and lower urinary tract signs and symptoms, is prevalent and has a significant negative impact on women's lives. In this article, the authors detail the genitourinary tract changes associated with menopause and/or aging. They also review the 2014 North American Menopause Society's definition of the genitourinary syndrome of menopause and present the epidemiology and impact of genitourinary aging in midlife and older women, namely, vulvovaginal, urinary, and sexual symptoms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Key cycle changes occur as women transition from reproductive life to menopause, and they can be roughly linked to menopausal staging. It is important to understand the types of studies that inform the current knowledge. Patterns of symptoms within menstrual cycles (sleep, headache) generally favor worsening in association with the perimenstrual phase of the cycle, and patterns of chronic symptoms, such as hot flashes and adverse mood, appear to be worse when hormones are more variable., (Copyright © 2018 Elsevier Inc. All rights reserved.)

One in three American women will die from cardiovascular disease (CVD), making it the leading cause of death among women in the United States. Traditionally, CVD has been seen as a disease of postmenopausal women, yet increasingly, risk factors for CVD are being characterized earlier. Although menopause, and its associated hypoestrogenism, has been consistently linked to CVD risk, accelerated ovarian aging among premenopausal patients has become a focus of attempts to identify women with increased CVD risk earlier. We present a review of the evidence for the association between early menopause and diminished ovarian reserve with CVD and its risk factors., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) constitutes a major socioeconomic challenge due to its disabling features and the rise in prevalence (especially among (peri)menopausal women and type 2 diabetes patients). The precise etiopathogenesis of AD remains poorly understood. Importantly, its neurodegenerative perspective has been challenged towards a more "systemic" view. Amyloid-β (Aβ) and hyperphosphorylated Tau protein (P-Tau) (the main AD neuropathological features) affect and are affected by peripheral and brain insulin signalling dysfunction, leading to glucose dysmetabolism, synaptic loss and AD-related cognitive deficits. This may be anticipated and exacerbated by the progressive loss of estrogen (and interactions, e.g., with insulin) during females' aging, increasing their risk for AD, especially during menopause. Under this perspective, we aimed to discuss the recent findings (and controversies) behind the peripheral view of AD, and the role for insulin deficits and brain glucose dysmetabolism in such diseased brain. We also focused on the metabolic shift and the putative effects of gender (especially during midlife/perimenopause) herein. We finally discussed AD as the potential "type 3 diabetes", and the therapeutic potential of restoring brain insulin levels or glucose energy metabolism via administration of intranasal insulin and use of ketogenic diets. In sum, AD appears to lie on an intricate crosstalk between age-related metabolic, hormonal and specific genetic changes that challenge its traditional view. Hence, clarification of AD risk factors (besides aging and gender) and pathophysiological mechanisms will allow to establish accurate preventive strategies, biomarkers and more efficient drugs - all urgent medical needs in our increasingly aged societies. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.', (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The aim of the study was to test the hypothesis that the development of luteal phase dominant follicles (LPDFs) as women age is associated with abnormal luteal function., Methods: Luteal and antral follicle diameter were quantified in ovulatory women of midreproductive age (MRA; 18-35 y; n = 9) and advanced reproductive age (ARA; 45-55 y; n = 16) every 1 to 3 days during one complete interovulatory interval. Blood was drawn at each visit and assayed for progesterone, estradiol, inhibin A, follicle-stimulating hormone, and luteinizing hormone. Luteal diameter and hormone profiles were compared within MRA and ARA women with versus without LPDFs., Results: Luteal growth and regression profiles were similar in MRA women with typical versus no LPDFs (13.9, 14.8 mm; P > 0.1); however, luteal phase estradiol and progesterone were greater in MRA women with typical (91.1 ng/L, 8.81 μg/L) versus no (48.8 ng/L, 7.32 μg/L) LPDFs, respectively (LPDF effect, P < 0.1). In the ARA group, mean luteal diameter was lowest in women with atypical LPDFs (12.3 mm), greatest in those with typical LPDFs (16.0 mm), and moderate in those with no LPDFs (13.6 mm), (P < 0.1). Reduced luteal growth in ARA women with atypical versus typical and/or no LPDFs occurred simultaneously to greater luteal phase estradiol (199 vs 69.0, 78.4 ng/L) lower progesterone (7.38 vs 10.7, 13.8 ug/L), and lower inhibin A (36.3, 35.6, 51.2) (P < 0.1)., Conclusions: The development of LPDFs as women age was associated with reduced luteal growth, greater estradiol, lower progesterone, and lower inhibin A. These findings provide preliminary evidence that variations in antral folliculogenesis contribute to luteal insufficiency during the menopausal transition.

The biochemical ageing status of women in the menopausal transition was studied using quantitative analysis of age- and autophagy-related gene activities (CDC42 and MAP1LC3 genes were selected as target genes). Free estradiol and progesterone levels in saliva were estimated. General linear models were used to determine the relationship between lifestyle, health status, socioeconomic factors and CDC42 and MAP1LC3 gene expression levels. Gene expression analysis revealed (1) an increasing expression of CDC42 gene after 45years in women, (2) expression level of CDC42 gene associated with menopausal status, (3) while endocrine status was found to associate with the expression of both of the studied age-related genes, (4) the "never used hormonal contraceptives" and "obese nutritional status" were the strongest factors for increased level of age-related gene expressions, and (5) changes in gene expression levels by ageing should be studied by considering not only chronological, but also biological ages. Gene expression profile of ageing has mostly been studied in model systems or human blood samples, but rarely in human saliva samples. The concordance of results between the present and former gene expression analyses, and the simplicity of saliva sample collection emphasizes the importance of saliva tissue samples in gene expression analyses especially in epidemiological surveys., (Copyright © 2017. Published by Elsevier Inc.)

Objective: This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men., Methods: Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18 F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (β-amyloid [Aβ] deposition, a hallmark of AD pathology)., Results: As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Aβ deposition, and reduced gray and white matter volumes in AD-vulnerable regions ( p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women ( p < 0.001). Aβ deposition was exacerbated in APOE4 -positive MENO women relative to the other groups ( p < 0.001)., Conclusions: Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process., (© 2017 American Academy of Neurology.)

Female mammals undergo natural fluctuations in sex steroid hormone levels throughout life. These fluctuations span from early development, to cyclic changes associated with the menstrual or estrous cycle and pregnancy, to marked hormone flux during perimenopause, and a final decline at reproductive senescence. While the transition to reproductive senescence is not yet fully understood, the vast majority of mammals experience this spontaneous, natural phenomenon with age, which has broad implications for long-lived species. Indeed, this post-reproductive life stage, and its transition, involves significant and enduring physiological changes, including considerably altered sex steroid hormone and gonadotropin profiles that impact multiple body systems, including the brain. The endocrine-brain-aging triad is especially noteworthy, as many paths meet and interact. Many of the brain regions affected by aging are also sensitive to changes in ovarian hormone levels, and aging and reproductive senescence are both associated with changes in memory performance. This review explores how menopause is related to cognitive aging, and discusses some of the key neural systems and molecular factors altered with age and reproductive hormone level changes, with an emphasis on brain regions important for learning and memory., (Copyright © 2017. Published by Elsevier Inc.)

Aging and its underlying pathophysiological background has always attracted the attention of the scientific society. Defined as the gradual, time-dependent, heterogeneous decline of physiological functions, aging is orchestrated by a plethora of molecular mechanisms, which vividly interact to alter body homeostasis. The ability of an organism to adjust to these alterations, in conjunction with the dynamic effect of various environmental stimuli across lifespan, promotes longevity, frailty or disease. Endocrine function undergoes major changes during aging, as well. Specifically, alterations in hormonal networks and concomitant hormonal deficits/excess, augmented by poor sensitivity of tissues to their action, take place. As hypothalamic-pituitary unit is the central regulator of crucial body functions, these alterations can be translated in significant clinical sequelae that can impair the quality of life and promote frailty and disease. Delineating the hormonal signaling alterations that occur across lifespan and exploring possible remedial interventions could possibly help us improve the quality of life of the elderly and promote longevity., (© 2017 European Society of Endocrinology.)

Menopause is characterized by the depletion of estrogen that has been proposed to cause oxidative stress. Circadian rhythm is an internal biological clock that controls physiological processes. It was analyzed the gene expression in peripheral blood mononuclear cells and the lipids and glucose levels in plasma of a subgroup of 17 pre-menopausal women, 19 men age-matched as control group for the pre-menopausal women, 20 post-menopausal women and 20 men age-matched as control group for the post-menopausal women; all groups were matched by body mass index. Our study showed a decrease in the expression of the oxidative stress-related gene GPX1, and an increase in the expression of SOD1 as consequence of menopause. In addition, we found that the circadian rhythm-related gene PER2 decreased as consequence of menopause. On the other hand, we observed a decrease in the expression of the oxidative stress-related gene GPX4 and an increase in the expression of CAT as a consequence of aging, independently of menopause. Our results suggest that the menopause-induced oxidative stress parallels a disruption in the circadian clock in women, and part of the differences in oxidative stress observed between pre- and post-menopausal women was due to aging, independent of menopause. Clinical Trials.gov.Identifier: NCT00924937., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Age- and menopause-related impairment in working memory mediated by the dorsolateral prefrontal cortex (dlPFC) occurs in humans and nonhuman primates. Long-term cyclic 17β-estradiol treatment rescues cognitive deficits in aged ovariectomized rhesus monkeys while restoring highly plastic synapses. Here we tested whether distributions of G protein-coupled estrogen receptor 1 (GPER1) within monkey layer III dlPFC synapses are sensitive to age and estradiol, and coupled to cognitive function. Ovariectomized young and aged monkeys administered vehicle or estradiol were first tested on a delayed response test of working memory. Then, quantitative serial section immunoelectron microscopy was used to determine the distributions of synaptic GPER1. GPER1-containing nonperforated axospinous synapse density was reduced with age, and partially restored with estrogen treatment. The majority of synapses expressed GPER1, which was predominately localized to presynaptic cytoplasm and mitochondria. GPER1 was also abundant at plasmalemmas, and within cytoplasmic and postsynaptic density (PSD) domains of dendritic spines. GPER1 levels did not differ with age or treatment, and none of the variables examined were tightly associated with cognitive function. However, greater representation of GPER1 subjacent to the PSD accompanied higher synapse density. These data suggest that GPER1 is positioned to support diverse functions key to synaptic plasticity in monkey dlPFC., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Pulsatile secretion of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) decreases during aging. Kisspeptin (encoded by Kiss1) neurons in the arcuate nucleus coexpress neurokinin B (Tac3) and dynorphin (Pdyn) and are critical for regulating the GnRH/LH pulse. We therefore examined kisspeptin neurons by histochemistry and pulsatile LH release in rats aged 2-3 (Young), 12-13 (Young-Middle), 19-22 (Late-Middle), and 24-26 (Old) months. Total LH concentrations, sampled for 3 hours, decreased in both sexes with aging. In females, numbers of Tac3 and Pdyn neurons were significantly reduced in all aging rats, and numbers of Kiss1 neurons were significantly reduced in Late-Middle and Old rats. In males, numbers of all 3 neuron-types were significantly decreased in all aging rats. GnRH agonist induced LH release in all animals; however, the increased LH concentration in all aging rats was less than that in Young rats. These results suggest that expression of each gene in kisspeptin neurons may be controlled individually during aging, and that reduction of their expression or change in pituitary responsiveness may cause attenuated pulsatile LH secretion., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: The preponderance of dementia among postmenopausal women compared with same-age men and the female sex hormones neuroprotective properties support a tentative role of their deficiency in the dementia pathogenesis., Methods: Pairs of independent reviewers screened 12,323 publications derived from a search strategy for MEDLINE to identify articles investigating the association of age at menopause/reproductive period with (i) dementia and (ii) cognitive function; a snowball of eligible articles and reviews was conducted and authors were contacted for additional information. Random-effect models were used for the meta-analysis., Results: Age at menopause (13 studies; 19,449 participants) and reproductive period (4 studies; 9916 participants) in the highest categories were not associated with odds of dementia (effect size [ES]: 0.97 [0.78-1.21]) and Alzheimer's disease (ES: 1.06 [0.71-1.58]). Significant heterogeneity was however noted in both analyses (I 2 : 63.3%, p=0.003 and I 2 : 72.6%, p=0.01, respectively). Subgroup analyses by outcome assessment, study design, level of adjustment and study quality did not materially change the findings. In 9/13 studies assessing cognitive function, advanced age at menopause/longer reproductive period was significantly associated with better cognitive performance/lower decline. Due to statistical differences, no meta-analysis was possible for cognitive function., Conclusions: Existing evidence does not support an association between indices of prolonged exposure to female hormones and lower dementia risk. There are indications, however, for better cognitive performance and delayed cognitive decline, supporting a link between female hormone deficiency and cognitive aging. Current literature limitations, indicated by the heterogeneous study-set, point towards research priorities in this clinically relevant area., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This study investigates the effects of aging and/or ovariectomy on vascular reactivity to thromboxane A2 (TXA2) receptor stimulation with U46619, and the modulation by nitric oxide (NO) and cyclooxygenase (COX) in aorta from female senescence-accelerated mice (SAMP8) and from senescence resistant mice (SAMR1). Five-month-old female SAMR1 and SAMP8 were divided into three groups: sham-operated, ovariectomized and ovariectomized plus estradiol. Twenty-eight days after surgery, thoracic aortic rings were mounted for isometric recording of tension and concentration-response curves for U46619 (10(-10)-3 × 10(-7) M) were performed in the absence and in the presence of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) and/or COX inhibitor indomethacin (10(-5)M). Vascular superoxide production was detected by dihydroethidium staining on sections of thoracic aorta. NO bioavailability in response to U46619 was suppressed by estrogen withdrawn in young and senescent mice and was restored by the administration of estradiol. In the presence of indomethacin, contractions to U46619 decreased in all groups indicating an aging- and estrogen-dependent modulation of contractile prostanoids. The simultaneous incubation of L-NAME and indomethacin did not change the maximal responses and sensitivities to TXA2 in any group in comparison with untreated aortic segments. The superoxide generation induced by TXA2 was greater in aorta from SAMP8 than in SAMR1. Moreover, in ovariectomized groups superoxide production was further increased and treatment with 17β-estradiol reverted the effects of the ovariectomy. Inhibition of COX with indomethacin prevented the U46619-induced increase in superoxide formation. Our results indicate that NO bioavailability in response to TP receptor activation is both estrogen- and aging-dependent. TXA2 induced contractions are partially mediated by COX activation. Both aging and ovariectomy enhanced COX-dependent component of the TXA2-induced contraction. It is noteworthy that in the absence of estrogen, COX inhibition induces an increase of NO bioavailability. Therefore, in senescent female mice with an experimental menopause, TP-receptor stimulation is responsible for COX activation and enhanced superoxide generation, which may result in reduced NO bioavailability. These effects were reversed by estrogen administration., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The menopause transition is associated with various symptoms, which can interact to produce morbidity. Vasomotor symptoms are the most commonly reported, but vaginal dryness/dyspareunia, sleep difficulties and adverse mood changes have all been shown to worsen as women approach menopause. For postmenopausal women changes in cognition are more likely to be related to aging and not to hormones. This article reviews the symptoms of hot flashes (vasomotor symptoms), vaginal dryness/dyspareunia, adverse mood, poor sleep/insomnia, and cognitive complaints, describing their epidemiology, diagnosis, and treatment. This article thus reviews the epidemiology, pathophysiology, diagnosis, and treatment of these common menopausal symptoms., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Estrogen facilitates higher cognitive functions by exerting effects on brain regions such as the prefrontal cortex and hippocampus. Estrogen induces spinogenesis and synaptogenesis in these two brain regions and also initiates a complex set of signal transduction pathways via estrogen receptors (ERs). Along with the classical genomic effects mediated by activation of ER α and ER β, there are membrane-bound ER α, ER β, and G protein-coupled estrogen receptor 1 (GPER1) that can mediate rapid nongenomic effects. All key ERs present throughout the body are also present in synapses of the hippocampus and prefrontal cortex. This review summarizes estrogen actions in the brain from the standpoint of their effects on synapse structure and function, noting also the synergistic role of progesterone. We first begin with a review of ER subtypes in the brain and how their abundance and distributions are altered with aging and estrogen loss (e.g., ovariectomy or menopause) in the rodent, monkey, and human brain. As there is much evidence that estrogen loss induced by menopause can exacerbate the effects of aging on cognitive functions, we then review the clinical trials of hormone replacement therapies and their effectiveness on cognitive symptoms experienced by women. Finally, we summarize studies carried out in nonhuman primate models of age- and menopause-related cognitive decline that are highly relevant for developing effective interventions for menopausal women. Together, we highlight a new understanding of how estrogen affects higher cognitive functions and synaptic health that go well beyond its effects on reproduction., (Copyright © 2015 the American Physiological Society.)

Objective: The aim of this study was to investigate the anti-aging effects of exogenous estrogen on telomerase activity in ovariectomized female Sprague-Dawley rats., Methods: Thirty-three 12-week-old female rats were divided into three groups: the ovariectomized-Treated group (Treated, n = 11), the ovariectomized control group (OVX, n = 11) and the Sham-operated group (Sham, n = 11). The rats in the Treated group were given 0.21 mg/kg estradiol valerate intragastric administration while other two groups were given the amount of physiological saline daily. All of the animals were euthanized 12 weeks after treatment, and abdominal aortic blood samples were taken to assess the level of estradiol (E2), follicle stimulating hormone (FSH). Telomerase activity and telomerase reverse transcriptase (TERT) mRNA expression in the heart, liver, brain tissues of all rats were measured by reverse transcriptional polymerase chain reaction (RT-PCR) and competitive enzyme-linked immunosorbent assay (ELISA)., Results: Compared to the OVX and Sham group, telomerase activity and TERT mRNA levels were significantly increased in the heart, liver and brain tissues of rats in the Treated group (p < 0.05). The telomerase expression was significantly higher in the heart than in liver and brain tissues in the Treated group (p < 0.05)., Conclusion: Based on the findings in the ovariectomized female rats model, exogenous estrogen can significantly up-regulate telomerase activity and TERT mRNA expression to exert the effects of anti-aging.

Do men die young and sick, or do women live long and healthy? By trying to explain the sexual dimorphism in life expectancy, both biological and environmental aspects are presently being addressed. Besides age-related changes, both the immune and the endocrine system exhibit significant sex-specific differences. This review deals with the aging immune system and its interplay with sex steroid hormones. Together, they impact on the etiopathology of many infectious diseases, which are still the major causes of morbidity and mortality in people at old age. Among men, susceptibilities toward many infectious diseases and the corresponding mortality rates are higher. Responses to various types of vaccination are often higher among women thereby also mounting stronger humoral responses. Women appear immune-privileged. The major sex steroid hormones exhibit opposing effects on cells of both the adaptive and the innate immune system: estradiol being mainly enhancing, testosterone by and large suppressive. However, levels of sex hormones change with age. At menopause transition, dropping estradiol potentially enhances immunosenescence effects posing postmenopausal women at additional, yet specific risks. Conclusively during aging, interventions, which distinctively consider the changing level of individual hormones, shall provide potent options in maintaining optimal immune functions., (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

The ageing of the global population calls for a better understanding of age-related metabolic consequences. Here we report the effects of age, sex and menopause on serum metabolites in 26,065 individuals of Northern European ancestry. Age-specific metabolic fingerprints differ significantly by gender and, in females, a substantial atherogenic shift overlapping the time of menopausal transition is observed. In meta-analysis of 10,083 women, menopause status associates with amino acids glutamine, tyrosine and isoleucine, along with serum cholesterol measures and atherogenic lipoproteins. Among 3,204 women aged 40-55 years, menopause status associates additionally with glycine and total, monounsaturated, and omega-7 and -9 fatty acids. Our findings suggest that, in addition to lipid alterations, menopause may contribute to future metabolic and cardiovascular risk via influencing amino-acid concentrations, adding to the growing evidence of the importance of amino acids in metabolic disease progression. These observations shed light on the metabolic consequences of ageing, gender and menopause at the population level.

In the research of a number of biochemical indicators in 858 men and 899 women aged from 20 till 70 years divided into 6 compared groups depending on age and gender clear distinctions in the dynamics of the components of the lipid status, status of lipid peroxidation and antioxidant activity of the blood system, the content of middlemolecular peptides are revealed. Simultaneous determination of the biological age of the subjects also revealed a distinct gender differencies testifying to lower rate of aging of men, despite the probability of earlier, in comparison with women, development of dislipidemia and atherosclerosis. Association of the received gender distinctions both with changes of level of estrogen in women due to menopause and with the peculiarities of stressful impacts on male and female organism in different age periods is supposed.

Over the last four decades, animal and cell culture studies have shown that sex steroids can have protective effects on the ageing brain. Limited short-term positive effects (2-4 months) of oestrogen treatment were found in women without (as well as with) dementia. By contrast to these initial promising findings, several large treatment studies showed that longer-term oestrogen treatment, particularly when given in combination with progesterone, could exert negative effects on cognitive function in women aged over 65 years. Several observational studies of older women and men also suggest that longer exposure to higher endogenous oestrogen levels at an older age might confer risk for accelerated cognitive decline and dementia. However, health of participants may modify this association and, in women closer to the age at the onset of menopause, positive associations of oestrogens with cognition were also found. The 'healthy cell bias' theory suggests that oestrogens have protective effects in healthy neurones, although cells undergoing pathological change show acceleration in their demise when exposed to oestrogens. In older men, most studies reported higher bioavailable testosterone levels to be associated with better cognitive function. Other studies have reported optimal testosterone levels for better global cognitive function and a reduced risk of cognitive decline. Variation in health status over time and the use of (in)sensitive cognitive tests and hormone assays may explain why this was not always found. In older women, this association (of testosterone with cognition) is less clear. Small studies reported some benefits of testosterone treatment in combination with oestrogen on cognition, although these were of short duration. Several observational studies, on the other hand, found negative associations between high testosterone levels and worse cognitive function in older women. Age, health status, duration of treatment and sex may thus modify effects of longer-term elevated sex steroid levels on brain function., (© 2013 British Society for Neuroendocrinology.)

Menopause is the permanent cessation of menstruation that results from depletion of ovarian germ cells and follicles. Although most animals experience reproductive senescence, the mechanisms differ from that in women, who may live more than one-third of their lives after menopause and consequently face the risk of a number of menopause-associated health problems. Understanding factors that influence ovarian aging may provide strategies to delay or alleviate physiological alterations that take place in postmenopausal women. The germ cell-deficient Wv mice recapitulate follicle loss, prolong postreproductive lifespan, and model many physiological changes that take place in postmenopausal women. Here, using genetic and pharmacological approaches, we found that inhibition of cyclooxygenase-1 but not cyclooxygenase-2 in Wv mice delays germ cell depletion and preserves ovarian follicles. Cyclooxygenase-1 inhibition slows down follicle maturation at the conversion of primary to secondary follicles and prolongs postnatal ovarian follicle lifespan. The current study suggests that inhibition of cyclooxygenase-1 may be able to delay ovarian aging and modulate menopausal timing.

Improved medical, economic and socio-cultural conditions have increased life expectancy, especially for women. The incidence of hypertension, diabetes mellitus, psychiatric and degenerative brain diseases, especially stroke and dementia, are more frequently seen in older people. Each of these conditions can separately, or in combination, result in similar signs and symptoms of cognition, memory, mood and motor function disorders. Therefore, it is important to understand the effects of normal ovarian ageing and the menopause on the nervous system, as well as the hallmarks of disease entities; many of these are described here. Also, the complexity of these issues is increased by the similarity of their effects to those of the polypharmacy and metabolic imbalances that are common in this population. These are complex issues, and it may be difficult and time-consuming to discern between normal brain functional changes and specific pathology in practice. Early evaluation of correctable possibilities, including imaging studies, may be key to management. Referral to specialists for diagnosis before starting clinical treatment is useful to address these issues., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The role of metabolism in ovarian aging is poorly described, despite the fact that ovaries fail earlier than most other organs. Growing interest in ovarian function is being driven by recent evidence that mammalian females routinely generate new oocytes during adult life through the activity of germline stem cells. In this perspective, we overview the female reproductive system as a powerful and clinically relevant model to understand links between aging and metabolism, and we discuss new concepts for how oocytes and their precursor cells might be altered metabolically to sustain or increase ovarian function and fertility in women., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The aim of this study is to demonstrate the relationship between the expression of the Duffy antigen receptor for chemokine (DARC) gene in peripheral blood leucocytes and epithelial cells of the oral cavity and the level of bone mineral density (BMD) in the mandible of women during menopause. A special radiographic method for measuring mandible density was used. Studies of DARC gene expression in the epithelial cells of the oral cavity and peripheral blood leucocytes did not confirm a significant correlation between expression of DARC and the level of BMD of the mandible in patients from the study groups, both in assessing the level of gene expression (ΔC(T) DARC) in the epithelium and leucocytes, as well as the value of relative expression (RQ) of DARC epithelium and lymphocytes. Significant differences were found between the values of ΔC(T) DARC marked in leucocytes and the epithelium of the control and study groups. Regarding RQ, the tests showed no significant differences between the values marked in the epithelial cells and leucocytes. The influence of DARC gene expression on bone mineral density of the mandible was not confirmed., (Copyright © 2012 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Menopause is a key point moment in the specific aging process of women. It represents a universal evolution in life. Its initiation is defined by a 12-month amenorrhea following the ultimate menstrual period. It encompasses a series of different biologic and physiologic characteristics. This period of life appears to spot a decline in a series of skin functional performances initiating tissue atrophy, withering, and slackness. Any part of the skin is possibly altered, including the epidermis, dermis, hypodermis, and hair follicles. Hormone replacement therapy (oral and nonoral) and transdermal estrogen therapy represent possible specific managements for women engaged in the climacteric phase. All the current reports indicate that chronologic aging, climacteric estrogen deficiency, and adequate hormone therapy exert profound effects on various parts of the skin.

Background: The intricate interactions between the immune, endocrine and central nervous systems shape the innate immune response of the brain. We have previously shown that estradiol suppresses expression of immune genes in the frontal cortex of middle-aged ovariectomized rats, but not in young ones reflecting elevated expression of these genes in middle-aged, ovarian hormone deficient animals. Here, we explored the impact of menopause on the microglia phenotype capitalizing on the differential expression of macrophage-associated genes in quiescent and activated microglia., Methods: We selected twenty-three genes encoding phagocytic and recognition receptors expressed primarily in microglia, and eleven proinflammatory genes and followed their expression in the rat frontal cortex by real-time PCR. We used young, middle-aged and middle-aged ovariectomized rats to reveal age- and ovariectomy-related alterations. We analyzed the expression of the same set of genes in the postcentral and superior frontal gyrus of pre- and postmenopausal women using raw microarray data from our previous study., Results: Ovariectomy caused up-regulation of four classic microglia reactivity marker genes including Cd11b, Cd18, Cd45 and Cd86. The change was reversible since estradiol attenuated transcriptional activation of the four marker genes. Expression of genes encoding phagocytic and toll-like receptors such as Cd11b, Cd18, C3, Cd32, Msr2 and Tlr4 increased, whereas scavenger receptor Cd36 decreased following ovariectomy. Ovarian hormone deprivation altered the expression of major components of estrogen and neuronal inhibitory signaling which are involved in the control of microglia reactivity. Strikingly similar changes took place in the postcentral and superior frontal gyrus of postmenopausal women., Conclusions: Based on the overlapping results of rat and human studies we propose that the microglia phenotype shifts from the resting toward the reactive state which can be characterized by up-regulation of CD11b, CD14, CD18, CD45, CD74, CD86, TLR4, down-regulation of CD36 and unchanged CD40 expression. As a result of this shift, microglial cells have lower threshold for subsequent activation in the forebrain of postmenopausal women.

The changes in the relationships between circulating antimüllerian hormone, the size of the primordial follicle pool, and follicular recruitment before and through the reproductive years have now been clarified, and show dynamic changes through sexual development. The constant relationship between the number of follicles and circulating antimüllerian hormone exists only after the age of 25 years, implying that the association between follicular recruitment and follicular survival to the later stages of development is not constant across the reproductive life course. This commentary assesses the factors that may underlie these relationships and their clinical implications for reproductive health., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this article is to summarize the recommended updates to the 2001 Stages of Reproductive Aging Workshop (STRAW) criteria. The 2011 STRAW + 10 reviewed advances in understanding of the critical changes in hypothalamic-pituitary-ovarian function that occur before and after the final menstrual period., Methods: Scientists from five countries and multiple disciplines evaluated data from cohort studies of midlife women and in the context of chronic illness and endocrine disorders on change in menstrual, endocrine, and ovarian markers of reproductive aging including antimüllerian hormone, inhibin-B, follicle-stimulating hormone, and antral follicle count. Modifications were adopted by consensus., Results: STRAW + 10 simplified bleeding criteria for the early and late menopausal transition, recommended modifications to criteria for the late reproductive stage (Stage -3) and the early postmenopause stage (Stage +1), provided information on the duration of the late transition (Stage -1) and early postmenopause (Stage +1), and recommended application regardless of women's age, ethnicity, body size, or lifestyle characteristics., Conclusions: STRAW + 10 provides a more comprehensive basis for assessing reproductive aging in research and clinical contexts. Application of the STRAW + 10 staging system should improve comparability of studies of midlife women and facilitate clinical decision making. Nonetheless, important knowledge gaps persist, and seven research priorities are identified.

Objective: The aim of this article is to summarize the recommended updates to the 2001 Stages of Reproductive Aging Workshop (STRAW) criteria. The 2011 STRAW + 10 reviewed advances in understanding of the critical changes in hypothalamic-pituitary-ovarian function that occur before and after the final menstrual period., Methods: Scientists from five countries and multiple disciplines evaluated data from cohort studies of midlife women and in the context of chronic illness and endocrine disorders on change in menstrual, endocrine, and ovarian markers of reproductive aging including antimüllerian hormone, inhibin-B, follicle-stimulating hormone, and antral follicle count. Modifications were adopted by consensus., Results: STRAW + 10 simplified bleeding criteria for the early and late menopausal transition, recommended modifications to criteria for the late reproductive stage (Stage -3) and the early postmenopause stage (Stage +1), provided information on the duration of the late transition (Stage -1) and early postmenopause (Stage +1), and recommended application regardless of women's age, ethnicity, body size, or lifestyle characteristics., Conclusions: STRAW + 10 provides a more comprehensive basis for assessing reproductive aging in research and clinical contexts. Application of the STRAW + 10 staging system should improve comparability of studies of midlife women and facilitate clinical decision making. Nonetheless, important knowledge gaps persist, and seven research priorities are identified.

The ovarian aging, a dynamic process that precedes the clinical manifestations of menopause, can be assessed using ovarian reserve biomarkers. It is well-known that reproduction during the later years of reproductive life has known limitations that challenge the success of assisted reproduction. Therefore, a review of the neuroendocrine modifications during this critical period of reproductive life may help to elucidate the ovarian aging process and its impact on reproduction. In this review, we aim to further the discussion of neuroendocrine changes taking place during the ovarian aging process that may impact reproductive function.

With advancing age, the balance between the amounts of old bone removed and new bone formed during the remodelling process becomes negative. In the past, it was commonly thought that skeletal involution was the result of age-related changes in other organs, and in particular from the decline in ovarian function in women at menopause. Nonetheless, with regard to emerging epidemiologic studies, the hypothesis suggesting that age-related changes such as inflammatory modifications importantly account for age-related bone loss is gaining increasing interest. Aging is indeed associated with immune dysfunction that coexists with a chronic subclinical inflammatory status. The latter is illustrated by a 2-4-fold increase in the levels C-reactive protein (CRP) or interleukin (IL)-6. This inflammatory status, which has been referred to by the neologism "inflammaging", is of sufficient magnitude to impact health and survival time, and correlates with age-related diseases such as atherosclerosis, insulin resistance and Alzheimer's disease. In this article, we first present the factors that condition inflammaging, and propose the hypothesis that inflammaging may be the driving force in age-related bone loss and may even be responsible for osteoporosis due to estrogen deficiency. Finally, we discuss the possibility that pro-inflammatory biomarkers may be used to provide clinical information for identifying patients at risk for osteoporosis, and the possibility that inflammatory cytokines may be targeted to improve bone formation in aged patients undergoing orthopaedic surgery., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background and Objective: To determine whether patterns of change in serum estradiol (E2) and FSH across the menopausal transition were associated with age at the final menstrual period (FMP)., Design and Setting: The Study of Women's Health Across the Nation (SWAN) is a seven-site, multiethnic, longitudinal study of the menopausal transition being conducted in 3302 menstruating women who were aged 42-52 yr at the 1996 study baseline., Measurements: Annually collected serum was assayed for E2 and FSH levels. Patterns of hormone change were evaluated in the 1215 women with a documented natural FMP by follow-up visit 9 (2006) using semiparametric stochastic and piecewise linear mixed modeling., Results: The FSH pattern across the menopausal transition began with an increase 6.10 yr before the FMP, an acceleration 2.05 yr before the FMP, deceleration beginning 0.20 yr before the FMP, and attainment of stable levels 2.00 yr after the FMP, independent of age at the FMP, race/ethnicity, or smoking status. Obesity attenuated the FSH rise and delayed the initial increase to 5.45 yr before the FMP. The mean E2 concentration did not change until 2.03 yr before the FMP when it began decreasing, achieving maximal rate of change at the FMP, then decelerating to achieve stability 2.17 yr after the FMP. Obesity, smoking behavior, and being Chinese or Japanese were associated with some variation in E2 levels but not the pattern of E2 change., Conclusions: Time spans and overall patterns of change in serum FSH and E2 across the menopausal transition were not related to age at FMP or smoking, whereas time spans but not overall patterns were related to obesity and race/ethnicity.

Background: In addition to its primary role in reproduction estrogen impacts brain areas important for cognition, including the hippocampus and prefrontal cortex. It has been hypothesized that decline in estrogen levels in women following menopause is associated with, or can exacerbate, age-related cognitive decline. However, clinical evidence to support a role for estrogen in preventing cognitive decline in women as they age is equivocal. The critical period hypothesis of estrogen effects on cognition, which proposes that estrogen administration has to be initiated within a critical time period following the loss of ovarian function in order for it to exert positive effects on the central nervous system, is offered as one explanation for inconsistencies across studies., Scope of Review: This review details results from basic research using rodent models investigating the effects of estrogen on cognition in the aging female. Emphasis is placed on work investigating effects of timing of initiation of estrogen administration on its subsequent efficacy., Major Conclusions: Results of basic research provide support for the critical period hypothesis. Furthermore, results of work in rodent models suggest mechanisms by which the response to estrogen is altered if treatment is initiated following long-term ovarian hormone deprivation., General Significance: Understanding if and under what conditions hormone administration following the loss of ovarian function positively affects the brain and behavior could have important implications with regard to female cognitive aging. Results of basic research can contribute to this understanding and provide insight into the complex mechanisms by which estrogen affects cognition., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Unlabelled: Theoretically, the degree of (18)F-FDG uptake in the glandular tissues of the normal breast can affect the detection of breast cancer. The aim of this prospective study was to investigate relationships among age, menopausal state, and breast density and determine whether they affect (18)F-FDG uptake in normal glandular breast tissue., Methods: Among 250 newly diagnosed breast cancer patients, 149 patients (mean age +/- SD, 50.9 +/- 9.70 y; range, 32-77 y) were analyzed because they had normal contralateral breasts confirmed by MRI, mammography, and (18)F-FDG PET examinations. PET images were acquired 60 +/- 2 min after the administration of (18)F-FDG (5.2 MBq/kg of body weight). The maximum and average standardized uptake value (SUVmax and SUVavg, respectively) of (18)F-FDG were calculated in the normal breast. Patients were divided into groups according to qualitative breast density and menopausal state. Descriptive statistics and 2-factorial analysis of covariance were used to assess the effects of qualitative breast density, menopausal state, and age on SUVmax and SUVavg. Pearson chi(2) was used to test the relationship between menopausal state and qualitative breast density., Results: The average age of patients with nondense breasts was significantly higher than that of patients with dense breasts (P < 0.01). Also, breast density related to menopausal state (P < 0.05). Dense breasts had an average SUVmax of 1.243 and mean SUVavg of 0.694, whereas nondense breasts had a mean SUVmax of 0.997 and mean SUVavg of 0.592. Analysis of covariance indicated that density and the linear effect of age were significant with regard to both SUVmax and SUVavg. After removing the linear effect of age, menopausal state had no effect on SUVmax and SUVavg., Conclusion: (18)F-FDG uptake significantly decreases as age increases and breast density decreases. Age and qualitative breast density are independent factors and significantly affect (18)F-FDG uptake for both SUVmax and SUVavg. Menopausal state had no effect on SUVmax and SUVavg.

Unlabelled: The relationship between the levels of gonadotropic hormones and bone metabolism in Chinese adult women is unclear. Our research shows that a significant positive correlation exists between the levels of gonadotropic hormones and various bone turnover indicators. Follicle-stimulating hormone (FSH) has been found to have a greater influence on all types of bone turnover indicator than luteinizing hormone (LH). Further, FSH has a greater influence on bone formation indicators than on bone resorption indicators., Introduction: The aim of this study was to investigate the relationship between serum FSH and LH and biochemical markers of bone turnover in native Chinese adult women., Methods: We conducted a cross-sectional study of 694 healthy Chinese women aged between 20 and 82 years. Serum FSH, LH, bone-specific alkaline phosphatase (BAP), osteocalcin (OC), N-terminal telopeptides of type I collagen, C-terminal telopeptides of type I collagen, urinary NTX, urinary CTX, and urinary deoxypyridinoline (uDPD) were determined., Results: All types of bone turnover indicator were significantly positively correlated with FSH (r = 0.164-0.626, all P = 0.000) and LH (r = 0.130-0.618, all P = 0.013-0.000). The correlation coefficient between serum FSH and BAP was the highest (r = 0.626), and that between serum FSH and uDPD was the lowest (r = 0.164). The serum gonadotropic hormone levels were higher; concentrations of bone turnover indicators were higher. The extent of the influence of FSH on various bone turnover indicators was approximately seven to 20 times greater than that of LH on these indicators. FSH could explain 43% and 22% of the changes in BAP and OC, respectively; whereas, LH could explain only 2.1% and 1.1%, respectively. FSH could explain approximately 1.9-11.8% of the changes in bone resorption indicators; however, LH had almost no effect on them., Conclusions: Gonadotropic hormone levels are correlated with the rate of bone turnover in Chinese women: the higher the serum gonadotropic hormone levels in circulation, the higher the levels of bone turnover indicators. FSH has a greater influence on all types of bone turnover indicator than LH; moreover, it has a greater influence on bone formation indicators than on bone resorption indicators.

Coronary heart disease is less prevalent in pre-menopausal women than in men, but increases at the onset of menopause. This delay is due to estrogen protective effects. The rise of cholesterolemia is one of the main risk factors for coronary disease. Since 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme of the cholesterol biosynthetic pathway, it plays a pivotal role in cholesterol homeostasis maintenance. Aim of this study is to investigate whether HMGR is involved in the cholesterolemia increase that occurs during aging, and to consider its potential role as a target for estrogen protective effects. "In vivo" studies have been performed using the livers of 12-month-old female rats (whose estrogen level decrease is comparable to the one detected at the occurrence of human menopause), 12-month-old female rats treated with 17-beta-estradiol, and 3-month-old untreated male and female rats. The results indicated hypercholesterolemic status and a significant increase of HMGR activity according to a reduced activation of AMPK detected in treated rats compared to controls. Furthermore, 17-beta estradiol treatment reduced HMGR activity restoring AMPK activation. These findings highlight the correlation between estrogen and HMGR short-term regulation, and suggest the presence of another mechanism underlying the protective role of estrogen in age-related diseases., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

The human vitreous body undergoes structural changes with aging. This can be followed by a posterior vitreous detachment, which can result in ocular pathology. As in many collagenous tissues, age-related changes in the vitreous could be caused by the formation of advanced glycation end products (AGEs). The goal of this study was to find out whether the AGE pentosidine accumulates in the human vitreous with aging. With this data we were able to estimate the half-life of vitreous collagen. Furthermore, we analyzed whether there was a gender difference in pentosidine accumulation, as this was seen in other tissues as well. Using high performance liquid chromatography, pentosidine contents were determined in whole vitreous bodies and in separate parts of vitreous bodies, which were all obtained from human donor eyes. Our results show that pentosidine accumulates in the human vitreous. From the rate of accumulation we could roughly estimate that vitreous collagen has as a similar or shorter half-life compared to skin collagen. This supports the concept of collagen turnover in the vitreous. In general, the female vitreous experiences a faster pentosidine accumulation than the male vitreous, and most of the pentosidine accumulation in the former occurs after 50 years of age.

This chapter describes current definitions of the climacteric, perimenopause, menopausal transition and menopause, and discusses the 2001 Stages of Reproductive Aging (STRAW) criteria in relation to more recently proposed categorization criteria for reproductive aging. Data from endocrine studies on women throughout the menopausal transition are discussed from earliest to most recent. The earlier studies focused on the changes in levels of steroid hormones and gonadotrophins, and established that follicle-stimulating hormone undergoes the first detectable change while menstrual cycles remain regular. Erratic and less predictable changes in steroid hormones follow, especially with the onset of irregular cycles. Later serum hormone studies on the inhibins and anti-Mullerian hormone established that diminishing ovarian follicle number contributes to the endocrine changes with advancing reproductive age. A classification system of cycle types incorporating all available endocrine data and their associated menstrual cycle patterns is proposed, and the application of biological markers as diagnostic tools for reproductive staging is discussed.