Search

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.

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.)

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.

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

Postmenopausal women are at greater risk of developing cardiovascular diseases than premenopausal women. Female mice ovariectomized (OVX) at weaning display increased atherosclerotic lesions in the aorta compared with female mice with intact ovarian function. However, laboratory models involving estrogen-deficient mice with atherosclerosis-prone status are lacking. This deficit is crucial because clinical estrogen deficiency in menopausal women may aggravate the incidence of pre-existing or ongoing lipid disruption and atherosclerosis. In this study, we establish an in vivo estrogen-deficient mouse model by bilateral ovariectomy via a double dorsal-lateral incision in apolipoprotein E (apoE) -/- mice. We then compare the effects of 17β-estradiol and pseudoprotodioscin (PPD) (a phytoestrogen) perorally administered via hazelnut spread. We find that although PPD exerts some effect on reducing final body weight and plasma TG in OVX apoE -/- mice, it has anti-atherosclerotic and cardiac-protective capacities comparable with its 17β-estradiol counterpart. PPD is a phytoestrogen that has been reported to exert anti-tumor properties. Thus, the proposed method is applicable for screening phytoestrogens via peroral administration to substitute for traditional hormone replacement therapy in postmenopausal women, which has been reported to have potentially deleterious tumorigenetic capacity. Peroral administration via hazelnut spread is noninvasive, rendering it widely applicable to many patients. This article contains step-by-step demonstrations of bilateral ovariectomy via the double dorsal-lateral incision in apoE -/- mice and peroral 17β-estradiol or phytoestrogen hormone replacement via hazelnut spread. Plasma lipid and cardiovascular function analyses using echocardiography follow.

Context: Menopausal transition is associated with increased cardiovascular risks. Available data on the effect of earlier climacterium on these risks are limited., Objective: To compare cardiovascular risk-associated parameters at the ages of 14, 31, and 46 in relation to climacteric status at the age of 46., Design, Setting, and Participants: A prospective cohort study including 2685 women from the Northern Finland Birth Cohort 1966., Main Outcome Measures: Follicle-stimulating hormone, body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), blood pressure (BP), body composition, cholesterol levels, testosterone (T) levels, free androgen index (FAI), high-sensitivity C-reactive protein (hs-CRP), and liver enzymes., Results: Women who were climacteric at the age of 46 had lower BMIs (P = 0.029), T levels (P = 0.018), and FAIs (P = 0.009) at the age of 31. At the age of 46, they had less skeletal muscle (P < 0.001), a higher fat percentage (P = 0.016), higher cholesterol levels [total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), high-density lipoprotein cholesterol (HDL-C; P = 0.022), and triglycerides (P = 0.008)], and higher alanine aminotransferase (P = 0.023) and γ-glutamyltransferase (P < 0.001) levels compared with preclimacteric women. Waist circumference, WHR, BP, and hs-CRP levels did not differ between the groups. Of the climacteric women, 111/381 were using hormone-replacement therapy (HRT). In subanalysis that excluded the HRT users, triglycerides, HDL-C, and body fat percentage did not differ among the groups., Conclusions: Earlier climacterium is associated with mainly unfavorable metabolic changes., (Copyright © 2019 Endocrine Society.)

Transition to menopause is associated with an increase in cardiovascular disease (CVD) risk, mainly attributed to lipid and glucose metabolism dysregulation, as well as to body fat redistribution, leading to abdominal obesity. Indeed, epidemiological evidence suggests that both early menopause (EM, defined as age at menopause <45 years) and premature ovarian insufficiency (POI, defined as age at menopause <40 years) are associated with 1.5-2-fold increase in CVD risk. Menopausal hormone therapy (MHT) exerts a favorable effect on CVD risk factors (with subtle differences regarding oestrogen dose, route of administration, monotherapy or combination with progestogen and type of progestogen). Concerning CVD morbidity and mortality, most studies have shown a beneficial effect of MHT in women at early menopausal age (<10 years since the final menstrual period) or younger than 60 years. MHT is strongly recommended in women with EM and POI, as these women, if left untreated, are at risk of CVD, osteoporosis, dementia, depression and premature death. MHT has also a favorable benefit/ risk profile in perimenopausal and early postmenopausal women, provided that the patient is not at a high CVD risk (as assessed by 10-year calculation tools). Transdermal oestrogens have a lower risk of thrombosis compared with oral regimens. Concerning progestogens, natural progesterone and dydrogesterone have a neutral effect on CVD risk factors. In any case, the decision for MHT should be individualized, tailored according to the symptoms, patient preference and the risk of CVD, thrombotic episodes and breast cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

There is increasing evidence that menopause is associated with the progression and severity of non-alcoholic fatty liver disease (NAFLD). Estrogen deficiency worsens non-alcoholic steatohepatitis (NASH) in mice models with fatty liver. The prevalence of NAFLD seems to be higher in postmenopausal compared with premenopausal women. Although more data are needed, lower serum estradiol levels are associated with NASH in postmenopausal women. Apart from estrogen deficiency, relative androgen excess and decrease in sex hormone-binding protein are observed in postmenopausal women. These hormonal changes seem to interplay with an increase in abdominal adipose mass, also observed in postmenopausal women, and aging, which are both closely related to the severity and progressive forms of NAFLD. NAFLD adds extra morbidity to postmenopausal women, possibly increasing the risk of type 2 diabetes mellitus and cardiovascular disease. Improving parameters of the metabolic syndrome via modifications in diet and physical exercise may reduce the risk of NAFLD and its related morbidity. Limited studies have shown a beneficial effect of hormone replacement therapy (HRT) on NAFLD, although adverse hepatic effects have been attributed to progesterone in one study. Phytoestrogens may be alternatives to HRT, but their long-term efficacy and safety remain to be shown. The aim of this review was to summarize evidence linking menopause with NAFLD with a special focus on potential therapeutic perspectives., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The aim of this review is to present, critically appraise and qualitatively synthesize current evidence on the risk of type 2 diabetes mellitus (T2DM) development during menopause, the management of climacteric symptoms in women with T2DM and the management of T2DM in postmenopausal women. Menopause represents the end of reproductive life in women, as a result of ovarian aging. It is characterized by substantial decrease in the endogenous oestrogen concentrations and it is accompanied by alterations in body weight, adipose tissue distribution and energy expenditure, as well as insulin secretion, insulin sensitivity and activity that can predispose to the development of T2DM, independently of, and additively to, aging. Many women in midlife experience climacteric symptoms, including hot flushes and night sweats, resulting in an indication to receive Hormone Replacement Treatment (HRT). HRT has a favourable effect on glucose homeostasis both in women without and with T2DM. The latter was considered in the past as a cardiovascular disease (CVD) equivalent, which would suggest that women with the disease should not receive HRT. However, nowadays evidence exists to support an individualized approach of women based on their CVD risk, as some women with T2DM may be excellent candidates for HRT. Regarding T2DM management for women in menopause, lifestyle intervention, including diet and exercise, constitutes its cornerstone. However, most of these women will eventually require pharmacologic therapy. The most suitable agents should be selected according to their metabolic, cardiovascular and bone effects, taking into consideration the specific characteristics and comorbidities of each postmenopausal woman., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Menopause is a critical period during which, without timely interventions, increased risks of cardiovascular and metabolic diseases, osteoporosis, sexual dysfunction and premature cognitive decline will contribute to diminished quality-of-life in women. Hormone therapy (HT) used to be the standard of care for managing vasomotor symptoms and prevention of chronic diseases until publication of the Women's Health Initiative (WHI) in 2002. Concerned about risks highlighted in WHI publications, many symptomatic women promptly ceased HT which resulted in increased vasomotor symptoms, osteoporosis-related-fractures and insomnia. Data from post-hoc WHI analyses and newer clinical trials consistently show reductions in coronary heart disease and mortality when estrogen therapy is initiated soon after menopause, whereas administration in later years and/or in combination with progesterone carries increased risks. However, no validated primary preventive strategies are available for younger postmenopausal women (<60 years), highlighting the need to re-evaluate the use of estrogen alone for which the risk-benefit balance appears positive. In contrast, in older women (>60 years), risks associated with oral HT exceed benefits; however transdermal estrogen may offer a safer alternative and should be further evaluated. Alternative therapies such as phytoestrogens and non-hormonal prescriptions may be beneficial for older women or those who are unsuitable for HT. Long-term head-to-head comparisons of HT with alternative interventions are warranted to confirm their efficacy for chronic disease prevention., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Hormone replacement therapy (HRT) plays a large part in maintaining and improving the quality of life (QOL) of postmenopausal women. Despite this obvious role, the use of HRT has stagnated in Japan as well as the United States, since the interim report of the HRT trial of Women's Health Initiative study was published in 2002. The Japan Society of Obstetrics and Gynecology and Japan Society for Menopause and Women's Health formulated the Guidelines for Hormone Replacement Therapy in 2009, which was subsequently revised in 2012, with the aim of organizing perceptions about HRT and allowing people to provide or receive HRT with a sense of security. Later on, in light of changes in indications for HRT and attitudes toward its impact on cancer risks, amendments were made again in 2017. With the establishment of the 2017 guidelines, practitioners in Japan are able to address various issues related to HRT with more appropriate judgment. Moreover, the practice of reliable, safe and effective HRT is expected to promote further efforts toward improvement or maintenance of QOL in patients., (© 2018 Japan Society of Obstetrics and Gynecology.)

Background: Studies examining the ability of estrogen replacement therapy (ERT) to enhance memory in women, and in animal models, have not produced consistent results. However, studies examining the effects of activity and exposure to novel environments consistently find enhancement of memory., Methods: An animal model of reproductive aging was used to determine if estradiol (E2) replacement, activity, and/or exposure to an enriched environment could act synergistically to improve memory, and neural correlates of memory. Young (3 months) and reproductively senescent (12 months) female rats were ovariectomized and received either vehicle or E2 treatment. Rats were assigned to 1 of 3 exposures; control: rats remained in their cage; maze control: rats were put into a pen where they could move and explore; enriched maze: rats were put into a pen with various items to climb on or investigate. The amount of time rats were active in each environment was measured. On the third day of exposure, one of the items in the enriched environment was exchanged, and the amount of time animals spent investigating the new item was used as a measure of memory., Results: E2 increased activity, immunostaining for proliferating cell nuclear antigen, and synaptic markers, synaptophysin and spinophilin, in the hippocampus of all animals. However, E2- and activity-induced changes in these markers were more pronounced in young rats. Only young rats displayed improved recognition in response to E2., Conclusions: Older rats may need an extended period of ERT or increased activity before the benefits on memory become apparent., (© 2017 S. Karger AG, Basel.)

Background . Our previous Gräfenberg spot findings confirmed that the distal-third areas of the anterior vaginal wall bore a significantly greater number of nerves and sexual hormone may have certain degree of influence on these significant differences. However, the role of estrogen in vaginal innervations remains controversial. Methods . To investigate whether hormonal-neural interactions occur in the vagina, sixty rats were randomly divided into six groups: Sham-operated, ovariectomy, and 4 treatment groups. After 2 weeks of treatment, vaginal biopsies were prepared with hematoxylin and eosin and PGP9.5 using immunohistochemistry. Results . The density of small nerve fibers was significantly higher in the distal-half areas of intact vaginal walls than the proximal-half areas ( P = 0.001). In contrast, the overall PGP 9.5-ir fiber innervation density was significantly decreased in the OVX rats subjected to surgical menopause. Sustained estrogen administration for 2 weeks resulted in nerve fiber proliferation, with values reaching normal levels in the low-dose estradiol valerate group. Conclusion . Our findings indicate that systemic hormonal therapy with low-dose estradiol valerate is effective and safe for treating deficient vaginal innervation caused by low level of estrogen activity in menopausal women and may aid studies to identify an optimal estradiol dose to provide relief from vaginal discomfort.

Crohn's disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel diseases, are archetypical inflammatory disorders of the gastrointestinal tract with rising incidence worldwide. Although the role of genetic factors in disease development has been highlighted by genome-wide association studies, environmental risk factors likely play a pivotal role in development of CD and UC. Prior observational studies have suggested a link between exogenous hormone use and risk of CD and UC. Specifically, studies have shown an association between oral contraceptive use and risk of CD and menopausal hormone therapy and risk of UC. Although the exact mechanism of these associations is largely unknown, a number of hypotheses have been proposed. First, oral estrogen has been shown to modify intestinal permeability, a critical step in the pathophysiology of inflammatory bowel disease. Second, exogenous hormone use through its effect on endogenous levels of hormones may enhance the development of Th1- and Th2-mediated inflammatory diseases. Lastly, recent data have linked modification in the gut microbiome to endogenous levels of androgens, which are also known to be altered with exogenous hormone use and influence the development of autoimmune diseases. This supports the intriguing hypothesis that the gut microbiome lies at the crossroads of pathways linking exogenous hormone use with innate and adaptive immunity. Future studies should therefore focus on bridging these epidemiologic findings to disease pathogenesis through comprehensive understanding of the complex interaction between exogenous hormone use, sex steroid biomarkers, genetic risk loci, and alterations in the intestinal microbial environment in the etiology of CD and UC.

The increase in cardiovascular disease and metabolic syndrome incidence following the onset of menopause has highlighted the role of estrogen as a cardiometabolic protective agent. Specifically regarding the heart, estrogen induced an improvement in cardiac function, preserved calcium homeostasis, and inhibited the mitochondrial apoptotic pathway. The beneficial effects of estrogen in relation to cardiac ischemia/reperfusion (I/R) injury, such as reduced infarction and ameliorated post-ischemic recovery, have also been shown. Nevertheless, controversial findings exist and estrogen therapy is reported to be related to a higher rate of thromboembolic events and atrial fibrillation in post-menopausal women. Therefore, greater clarification is needed to evaluate the exact potential of estrogen use in cases of cardiac I/R injury. This article reviews the effects of estrogen, in both acute and chronic treatment, and collates the studies with regard to their in vivo, in vitro, or clinical trial settings in cases of cardiac I/R injury and myocardial infarction.

Premenopausal females are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease onset and severity. However, it is unknown how a fluctuating ovarian hormone environment during the transition from perimenopause to menopause impacts the onset of hypertension, and whether interventions during perimenopause prevent disease onset after menopause. A gradual transition to menopause was induced by repeated daily injections of 4-vinylcyclohexene diepoxide (VCD). ANG II (800 ng·kg(-1)·min(-1)) was infused into perimenopausal and menopausal female mice for 14 days. A separate cohort of mice received 17β-estradiol replacement during perimenopause. ANG II infusion produced significantly higher mean arterial pressure (MAP) in menopausal vs. cycling females, and 17β-estradiol replacement prevented this increase. In contrast, MAP was not significantly different when ANG II was infused into perimenopausal and cycling females, suggesting that female resistance to ANG II-induced hypertension is intact during perimenopause. ANG II infusion caused a significant glomerular hypertrophy, and hypertrophy was not impacted by hormonal status. Expression levels of aquaporin-2 (AQP2), a collecting duct protein, have been suggested to reflect blood pressure. AQP2 protein expression was significantly downregulated in the renal cortex of the ANG II-infused menopause group, where blood pressure was increased. AQP2 expression levels were restored to control levels with 17β-estradiol replacement. This study indicates that the changing hormonal environment in the VCD model of menopause impacts the severity of ANG II-induced hypertension. These data highlight the utility of the ovary-intact VCD model of menopause as a clinically relevant model to investigate the physiological mechanisms of hypertension that occur in women during the transition into menopause., (Copyright © 2015 the American Physiological Society.)

Multiple sclerosis (MS) is an autoimmune demyelinating and neurodegenerative condition of the central nervous system that preferentially afflicts women more than men. Low estrogen states such as menopause and the postpartum period favor exacerbations of multiple sclerosis in women with the disease. Existing and emerging evidence suggests a role for estrogen in the alleviation of symptoms and reversal of pathology associated with MS. While clinical evidence is sparse regarding the benefit of estrogen therapy for women at risk for MS exacerbations, scientific data demonstrates that estrogen potentiates numerous neuroprotective effects on the central nervous system (CNS). Estrogens play a wide range of roles involved in MS disease pathophysiology, including increasing antiinflammatory cytokines, decreasing demyelination, and enhancing oxidative and energy producing processes in CNS cells., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Menopausal therapy with a tissue selective estrogen complex combines estrogens with a selective estrogen receptor modulator, with the goal of blending the desirable effects of estrogens on menopausal symptoms and bone with the tissue selective properties of a selective estrogen receptor modulator. The first tissue selective estrogen complex to receive regulatory approval is a combination of conjugated estrogens (CE) with bazedoxifene (BZA). Clinical trials with CE/BZA in postmenopausal women have shown improvement in vasomotor symptoms, vulvo-vaginal atrophy, and bone mineral density, without stimulation of the endometrium or breast tissue, with a generally favorable safety and tolerability profile. CE/BZA represents a new approach to the management of menopausal symptoms in women with a uterus.

Research Objective: Development of the individual comprehensive program of follow treatment of patients with climacteric disorders complicated MMS (menopausal metabolic syndrome) with cholestasis; on the basis of application of low-dose hormone replacement therapy in combination with ursodeoxycholic acid, to improve the quality of life., Materials and Methods: We observed 101 woman with climacteric syndrome, obesity and cholestasis; conducted a comprehensive clinical and laboratory examination, ultrasound of the hepatobiliary system, measurement modified menopausal index (MMI), the measurement of the quality of life on questionnaire SF-36 before treatment and after 6 and 12 months., The Results: Positive and statistically significant changes in lipid spectrum, the activity of transaminases, bilirubin and its fractions, improvement of MMI and quality of life, the indices of coagulation remained virtually unchanged., Conclusion: Low-dose hormone replacement therapies in combination with ursodeoxycholic acid are highly effective drugs for the treatment of menopausal syndrome, which normalize lipid profile of patients and the performance of the hepatobiliary system.

Purpose of Review: Oestrogens are important modulators of lipid metabolism, inflammation and vascular homeostasis. Endogenous oestrogens contribute to the low prevalence of atherosclerotic vascular disease in premenopausal women with intact ovarian function, and cessation of oestrogen production following menopause increases cardiovascular risk. Orally administered oestrogens such as postmenopausal hormone therapy increase HDL and reduce LDL cholesterol levels, and they increase triglyceride levels. Current guidelines do not recommend postmenopausal hormone therapy for cardiovascular prevention., Recent Findings: Recent clinical studies have suggested potential benefits of natural oestrogen or selective oestrogen receptor modulators on cardiovascular outcomes, effects that are associated with lipid profile improvements. In contrast to earlier studies such as the Women's Health Initiative, the Heart and Estrogen/Progestin Replacement Study or the Estrogen Replacement and Atherosclerosis trial, in which investigators used hormone mixtures derived from horse urine (misleadingly named 'conjugated oestrogens' with unknown activity on oestrogen receptors), triphasic oestrogen therapy started early after menopause as primary prevention study protocol improved outcome. New studies suggest therapeutic potential of natural oestrogens and certain selective oestrogen receptor modulators to reduce coronary artery disease risk in postmenopausal women., Summary: Endogenous oestrogens are important regulators of lipid metabolism and inhibit inflammation, vascular cell growth and plaque progression in premenopausal women. The recent trials warrant further studies, which should also determine how much of the potential benefits are due to improvements of lipid metabolism.

The critical window hypothesis predicts that estrogen replacement therapy (ERT) must be administered early on the menopause or ovariectomy (OVX) to positively affect cognition. However, the neural substrates, underling the time dependent efficacy of ERT, are still not completely known. In order to address this issue, we submitted female mice to 12 weeks of OVX followed by 5 weeks of chronic ERT (OVX(E2)). Within the first 12 weeks, the OVX animals showed a progressive compromised performance in the object recognition memory (ORM) task. After ERT, OVXE2 mice, but not the control group (OVXoil), were able to recognize the new object in the test session. Further, we evaluated the c-Fos expression in hippocampus, perirhinal cortex (PC) and central amygdala (CeA) of OVXoil and OVX(E2) mice, after context exposure (CTX) or object exploration (OBJ). We observed that ERT increased c-Fos expression unspecifically for CTX and OBJ. In addition, only the OVX(E2) group showed significantly higher c-Fos expression in the PC and CeA after object exploration. Thus, our results showed that delayed chronic ERT improves ORM (compromised by OVX) and increases constitutive c-Fos expression in temporal lobe regions. Furthermore, we showed for the first time that PC and CeA, but not the hippocampus, present a distinct pattern of activation in response to object exploration in ovariectomized females that underwent delayed-ERT., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Flaxseed (FS) is an oilseed rich in phytoestrogens and n-3 polyunsaturated fatty acids, compounds that may attenuate bone loss during aging. We previously demonstrated using the ovariectomized (OVX) rat model of postmenopausal osteoporosis that 10% dietary FS combined with low-dose estrogen therapy (LD) preserves vertebral bone mass and strength more so than either treatment alone. However, it was prudent to also consider the effect of this intervention on uterine tissue as LD, and possibly FS, may have estrogenic, and thus negative, effects on uterine tissue. The present study investigated if FS enhances the estrogenic effect of LD on markers of uterine health in OVX rats. Three-month-old rats were randomized to groups: (1) SHAM, (2) OVX, (3) OVX+FS, (4) OVX+LD, or (5) OVX+FS+LD. Ground FS was added to the AIN-93M diet (100 g/kg of diet), and LD was delivered by subcutaneous implant (0.42 μg of 17β-estradiol/kg of body weight/day) to mimic LD in postmenopausal women. After 12 weeks, histological analyses of uterine tissue demonstrated flattened or cuboidal luminal epithelia organized in a single layer in the OVX group, while FS, LD, and FS+LD induced a single layer of elongated luminal epithelia, columnar in shape. The SHAM group had the greatest epithelial mass. Cell proliferation was similar among all OVX groups. Therefore FS and FS+LD similarly induce estrogen-like effects on the morphology of luminal epithelia that are weaker than in the SHAM group without inducing cell proliferation in OVX rats. Thus, FS does not enhance the estrogenic effect of LD on markers of uterine health in OVX rats.

The perceptions of menopausal hormone therapy (MHT) have evolved considerably. Observational studies suggested that MHT could relieve vasomotor symptoms and prevent coronary heart disease (CHD). However, randomized controlled trials later showed no reduction in CHD and an increased risk of stroke. Subsequent analyses of these trials have shown that in women younger and closer to menopause, the risks associated with MHT may not be as great as originally thought. Several organizations, including the North American Menopause Society, the International Menopause Society, and the Endocrine Society, have published guidelines and statements that help health care providers translate the research findings into clinical practice. A common theme from these organizations is the need for health care providers to tailor information to their patients so they may make informed treatment decisions (especially considering the media attention MHT has received). It is particularly important to individualize therapy, considering patients' risk factors for atherosclerotic disease, venous thromboembolic disease, osteoporosis, and breast cancer. Ongoing research in women younger than those in prior trials is evaluating lower doses of MHT and directly comparing transdermal and oral formulations. Such research should help define the population of women most likely to benefit from MHT without undue risk of adverse outcomes.

Extant research findings allow several conclusions regarding the relationship between estrogen and cognitive functioning across the female life span. First, performance on tests of verbal memory fluctuates in concert with physiological changes in ovarian hormone production during the menstrual cycle and during pregnancy and the postpartum period. Estrogen therapy (ET) prevents the decrease in verbal memory when administered immediately following the surgical removal of both ovaries in premenopausal women. Some, but relatively little evidence is available to support the idea that ET, initiated at the time of a natural or a surgical menopause for a few years, may protect against cognitive decline 30 years later and more research in this area is urgently needed. Finally, the evidence to date strongly suggests that the initiation of ET decades after the menopause has occurred does not protect against cognitive decline or dementia. Taken together, these findings support the so-called "window of opportunity" hypothesis which holds that ET will be neuroprotective only when administered closely in time to a natural or surgical menopause.

Context: The role of ovarian hormones in maintaining neuronal integrity and cognitive function is still debated. This study was undertaken to clarify the potential relationship between postmenopausal hormone use and the cholinergic system., Objective: We hypothesized that early initiated hormone therapy (HT) preserves the cholinergic system and that estrogen therapy (ET) would be associated with higher levels of acetylcholinesterase activity in the posterior cingulate cortex and hippocampus compared to estrogen plus progestin therapy (EPT) or no HT., Design and Setting: We conducted a cross-sectional study at a university teaching hospital., Patients: Fifty postmenopausal women (age, 65.2 ± 0.7 yr) with early long-term HT (n = 34; 13 ET and 21 EPT) or no HT (n = 16) participated in the study., Interventions: There were no interventions., Main Outcome Measure: We measured cholinergic activity (acetylcholinesterase) in the hippocampus and posterior cingulate brain regions as measured by N-[(11)C]methylpiperidin-4-yl propionate and positron emission tomography as a marker of cholinergic function., Results: Significant effects of treatment on cholinergic activity measures were obtained in the left hippocampus (F = 3.56; P = 0.04), right hippocampus (F = 3.42; P = 0.04), and posterior cingulate (F = 3.76; P = 0.03). No significant effects were observed in a cortical control region. Post hoc testing identified greater cholinergic activity in the EPT group compared to the no-HT group in the left hippocampus (P = 0.048) and posterior cingulate (P = 0.045), with a nonstatistically significant trend in the right hippocampus (P = 0.073)., Conclusions: A differential effect of postmenopausal ET and EPT on cholinergic neuronal integrity was identified in postmenopausal women. The findings are consistent with a preservation of cholinergic neuronal integrity in the EPT group.

Sex hormones are fundamental for female development and they are important physiologically to maintain the health and normal functioning of several organs such as the brain, heart and bone. It is now clear that the hormonal changes that occur during a woman's life, particularly her estrogen status, can modulate disease activity. This is especially true for cardiovascular and musculo-skeletal diseases, which are two leading causes of morbidity and mortality in women. With the general aging of the population they represent a serious and growing public health concern. Estrogen synthesis and blood levels fluctuate during a woman's life and in this review three broad periods will be considered: reproductive phase, transition and postmenopausal phase. Generally speaking, women in the reproductive phase of their life are at low risk of cardiovascular and musculo-skeletal disorders. However, the onset of menopause and the loss of ovarian function is associated with a significant increase in the prevalence of diseases such as coronary heart disease, osteoarthritis and osteoporosis. The prevalence of these debilitating diseases continues to increase through the postmenopausal period. Estrogen replacement is an obvious treatment approach to counter the problems associated with the loss of ovarian function and subsequent estrogen deficiency. Overall, oral and transdermal estrogen replacement are similarly effective in relieving menopausal symptoms and disorders that manifest during this period of a woman's life. Transdermal estrogen may be preferable in older women because of its lower thrombogenic potential. In this journey through a woman's life current best evidence relating to cardiovascular and musculo-skeletal risk will be reviewed in line with well documented management strategies., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Menopause is associated with sharp declines in concentrations of circulating estrogens. This change in hormone milieu has the potential to affect brain functions relevant to dementia and cognitive aging., Scope of Review: Focused review of published results of randomized clinical trials of estrogen-containing hormone therapy for Alzheimer's disease treatment and dementia prevention, observational research on cognition across the menopause transition, and observational research on the association of hormone therapy and Alzheimer's disease risk., Major Conclusions: Clinical trial evidence supports conclusions that estrogen therapy does not improve dementia symptoms in women with Alzheimer's disease and that estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Hormone therapy begun in this older postmenopausal group does not ameliorate cognitive aging. Cognitive outcomes of midlife hormone exposures are less well studied. There is no strong indication of short-term cognitive benefit of hormone use after natural menopause, but clinical trial data are sparse. Little research addresses midlife estrogen use after surgical menopause; limited clinical trial data imply short-term benefit of prompt initiation at the time of oophorectomy. Whether exogenous estrogen exposures in the early postmenopause affect Alzheimer risk or cognitive aging much later in life is unanswered by available data. Observational results raise the possibility of long-term cognitive benefit, but bias is a concern in interpreting these findings., General Significance: Estrogen-containing hormone therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging. Further research is needed to understand short-term and long-term cognitive effects of estrogen exposures closer to the age of menopause., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Many postmenopausal women question whether to start or continue hormone therapy because of recent clinical trial negative results. However, evidence from other studies of postmenopausal women, and from studies in menopausal monkeys, indicate that estrogen has neurocognitive protective effects, particularly when therapy is initiated close to the time of menopause before neural systems become increasingly compromised with age. In this review, we present studies of menopausal women and female monkeys that support the concept that estrogen therapies protect both cognitive function and neurobiological processes.

A new approach to menopausal therapy is the tissue selective estrogen complex or the pairing of a selective estrogen receptor modulator with estrogens. The clinical profile of a tissue selective estrogen complex will result from the blended tissue-selective activities of its components. An appropriate tissue selective estrogen complex may provide the therapeutic benefits of estrogens and selective estrogen receptor modulators with better tolerability and safety than either therapy alone. An ideal menopausal therapy would reduce the number and severity of hot flashes, effectively treat vulvar-vaginal atrophy and its symptoms, prevent and treat menopausal osteoporosis, and have favorable effects on lipoprotein profiles, while at the same time would not stimulate the endometrium, not cause uterine bleeding, not increase the risk of vascular events, not be associated with breast pain or tenderness, and potentially reduce breast cancer incidence. Here, we introduce the concept of a tissue selective estrogen complex and the rationale for its development as a next generation menopausal therapy.

Estrogen therapy is the most consistently effective treatment and the only therapy approved by the FDA for menopausal vasomotor symptoms. Following the safety issues reported in the primary Women's Health Initiative publications and with continued patient requests for treatment, a challenge to clinicians has been to identify the lowest effective dose of estrogen for alleviating menopausal symptoms. A number of low-dose estrogen preparations are now available, and transdermal preparations containing an ultra-low dose (25% of the previous conventional or standard dose) of estrogen have recently been approved by the FDA. These preparations effectively relieve menopausal symptoms such as vasomotor symptoms and vaginal atrophy, and potentially protect against bone loss. Compared with standard-dose estrogen therapy, these ultra-low-dose products have an improved tolerability profile and may require reduced amounts or a lower frequency of progestogen administration, potentially mitigating the apparent long-term adverse effects of estrogen-progestogen combinations, as noted in the Women's Health Initiative.

A fairly consistent finding in work on the menopause and hormone replacement therapy is the positive effect of estrogen on connective tissue and its turnover. The menopause has been shown repeatedly to have a negative effect on the connective tissue in the dermis of the skin. Such an effect is prevented and in some cases reversed with estrogen therapy. This is similar to what happens in bone matrix. Similarly, the media in the carotid has been shown to undergo the same change with the menopause and with estrogen therapy as the dermis. The carotid artery media is increased in menopausal women on estrogen therapy and is thinner in untreated women. Recently, new information has revealed that the menopause, i.e. estrogen deprivation, has similar effects on the connective tissue of intervertebral discs. In aged intervertebral discs, the predominant collagen is type III, not type I, which is the predominant collagen in skin and bone, although skin has additional type III. These negative changes are once again prevented or reversed with estrogen therapy. This effect probably also extends to the extracellular non-collagenous matrix in all these systems, i.e. skin, carotid and intervertebral discs. The common thread is that estrogen has profound effects on connective tissue turnover, no matter the site. This has far-reaching implications not only in maintaining the structure and aesthetic appearance of tissue, but also the strength and stiffness of various tissues and the functioning of neighboring and surrounding organs.

Exogenous estrogen is an effective means of prevention for postmenopausal symptoms. Estrogen treatment should be combined with progesterone in non-hysterectomized women to prevent estrogen-induced malignant transformation of the endometrium. Progesterone supplementation using continuous combined estrogen + progesterone treatment may result in an increased incidence of breast cancer and cardiovascular disease. In addition, progesterone supplementation with sequential estrogen + progesterone treatment may cause immediate adverse effects, such as irregular bleeding and spotting, breast congestion, fluid retention, abdominal distention, and a change in lipid profile. All these effects are related, at least in part, to the progesterone component of the therapy.To avoid these complications, researchers are seeking safer progestational components and different modes of administration. In this article we review the findings on the use of the novel levonorgestrel-releasing intrauterine system as a therapeutic tool for localized, rather than systemic, progesterone administration in postmenopausal women.

Objective: Parkinson disease (PD) is less common in women possibly because of hormonal or reproductive influences. The objective of this study was to evaluate the associations of reproductive factors and postmenopausal hormone use with the risk of PD among postmenopausal women., Methods: Incident cases (n = 178) and randomly selected age-matched controls (n = 189) who were members of the Kaiser Permanente Medical Care Program (KPMCP) of Northern California participated in the study conducted during the years 1994 to 1995. Statistical analyses were carried out using logistic regression., Results: The association of postmenopausal hormone use with PD risk depended on the type of menopause. Among women with history of a hysterectomy with or without an oophorectomy, estrogen use alone was associated with a 2.6-fold increased risk (adjusted odds ratio (OR) 2.6, 95% CI: 1.1 to 6.1) and significant trends in the risk of PD were observed with increasing duration of estrogen use, but disease risk was not influenced by recency of use. In contrast, among women with natural menopause, no increased risk of PD was observed with hormone use (estrogen alone or a combined estrogen-progestin regimen). Early age at final menstrual period (44 years or younger) was associated with reduction in risk (adjusted OR 0.5, 95% CI: 0.3 to 1.0). Age at menarche and parity were not associated with the risk of PD., Conclusion: Postmenopausal use of estrogen alone may increase the risk of Parkinson disease (PD) among women with a hysterectomy. Among women with natural menopause for whom the usual treatment is combined estrogen-progestin therapy, no increased risk of PD was observed.

Objectives: Changes in the hormonal milieu at the menopause are associated with an increase in total adiposity and a more android pattern of fat distribution, with the latter associated with an increased risk of the metabolic syndrome. The aim of this study was to explore potential mechanisms that might contribute to the changes in body composition associated with the menopause transition., Methods: Using real-time PCR analysis, we have compared the expression of various factors involved in fat metabolism in subcutaneous abdominal and gluteal fat in premenopausal (Group 1; n=11), postmenopausal (Group 2; n=10) and postmenopausal women taking estrogen therapy (Group 3; n=10)., Results: All subjects were of normal body mass index, euglycemic and normolipemic. The postmenopausal women were older (Group 1, 43.1+5.0 versus Groups 2 and 3, 57.9+/-7.4 years, P<0.001 and 56.1+/-4.5 years, P<0.001, respectively). Expression analysis revealed that levels of transcripts encoding adiponectin, peroxisome proliferator-activated receptor gamma and fatty acid transporter, each associated with insulin sensitivity, were significantly greater in gluteal fat from estrogen deplete postmenopausal women than in fat from the other two groups (P<0.05). In contrast, levels of transcripts for acetyl CoA carboxylase alpha, long chain acyl CoA dehydrogenase and hormone sensitive lipase were significantly greater in abdominal fat from premenopausal women than either postmenopausal groups (P<0.05)., Conclusions: These findings indicate both aging and the menopause transition are associated with changes in fat metabolism, which may contribute to the accumulation of body fat after menopause.

Purpose: After menopause, women gain abdominal fat and become less sensitive to insulin. We sought to determine whether hormone replacement therapy (HRT) reduced intraabdominal and sc abdominal fat and improved insulin sensitivity in early menopausal women., Methods: Seventy-six postmenopausal women, age 51.6 +/- 3.9 yr with body mass index of 24.9 +/- 3.2 kg/m2, were randomized to conjugated estrogens (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) or placebo daily. Women received a computed tomography scan at the L4-L5 vertebral disk space, a dual x-ray absorptiometry scan, and a euglycemic hyperinsulinemic clamp at baseline, 6 months, 1 yr, and 2 yr., Results: Fifty-one women completed the trial and were analyzed (n = 26 on HRT and n = 25 on placebo). Intraabdominal fat, sc abdominal fat, total fat, percent fat, fat-free mass, and weight did not differ between treatment groups by time. Insulin sensitivity did not change in the placebo group, but decreased by 17% in the HRT group by 6 months and persisted at 2 yr (P < 0.01 for treatment by time effect). One year after the trial, insulin sensitivity increased by 25% in women who had taken HRT (P = 0.006 for treatment by time effect), to a level similar to those women in the placebo group., Conclusions: Conjugated estrogens plus medroxyprogesterone acetate reduce insulin sensitivity in menopausal women without affecting body composition or body fat distribution. The reduction in insulin sensitivity is reversible after discontinuing HRT.

Objectives: To investigate the effects of transdermal estrogen replacement therapy (ERT) on plasma homocysteine levels in postmenopausal women who underwent total hysterectomy with bilateral oophorectomy., Methods: In two-phase open longitudinal prospective study we compared 28 premenopausal women and 35 healthy postmenopausal patients to evaluate the effect of transdermal estrogen treatment (TTS 50 twice-weekly) on plasma homocysteine levels after 6 and 12 months of therapy., Results: The study showed statistically relevant differences (P<0.05) in baseline plasma homocysteine concentration between the patients in premenopausal and in postmenopausal status. No difference in the plasma homocysteine levels was observed after 6 and 12 months of ERT on postmenopausal patients., Conclusions: Surgically postmenopausal women have higher plasma homocysteine concentrations than premenopausal women, but transdermal estrogen treatment for 12 months in postmenopausal women does not modify homocysteine levels.

Estrogen replacement therapy (ERT) has been found to be associated with increased cardiovascular risk in the first year after initiation of ERT. We compared the effects of oral and transdermal estradiol (E2) replacement therapy on markers of inflammation, coagulation and fibrinolysis in a randomized double-blind trial. Forty-three healthy women were randomized 6 weeks after surgically induced menopause to receive treatment with either oral or transdermal E2 over a period of 28 weeks. At baseline and after 28 weeks, levels of serum lipids and lipoproteins, and markers of coagulation, fibrinolysis and inflammation were determined. Among fibrinolytic parameters, oral E2 shortened euglobulin clot lysis time (P<0.05) and reduced tissue type plasminogen activator antigen (P=0.01) and plasminogen activator inhibitor activity (P<0.05). Among coagulation parameters, both routes of E2 replacement decreased fibrinogen levels (P=0.002 for oral and P=0.007 for transdermal E2). Oral E2 resulted in an increase in C-reactive protein (CRP) from 2.15 (0.71-4.05) to 3.41 (1.12-5.92) mg/l (P=0.04), while transdermal E2 showed no effect. Levels of serum amyloid A (SAA), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) did not change significantly after oral and transdermal E2. Oral E2 significantly improved the lipid profile, while transdermal E2 had a less pronounced effect. Both oral and transdermal E2 significantly reduced fasting glucose. Oral E2 was associated with a pro-inflammatory response, but at the same time improved fibrinolytic capacity, showed no pro-coagulatory effects, and acted beneficially on lipids and lipoproteins. There was no influence of transdermal E2 on markers of coagulation activation, fibrinolysis and inflammation, but it decreased fibrinogen levels significantly. Further studies are needed to explore the clinical relevance of these observations.

Objectives: We investigated whether the route of estrogen replacement therapy (ET) is the major determinant of C-reactive protein (CRP) in postmenopausal women., Background: Recent studies demonstrated that oral ET causes a sustained increase in CRP, implicating a proinflammatory effect. Because CRP is synthesized in the liver, we hypothesized that estrogen-induced CRP elevation is related to first-pass hepatic metabolism., Methods: In 21 postmenopausal women, we conducted a randomized, crossover, placebo-controlled study to compare the effects of transdermal versus oral ET on CRP and inflammatory cytokines. We measured CRP, interleukin (IL)-1-beta, IL-6, and tumor necrosis factor-alpha before and after eight weeks of transdermal estradiol (E(2)) (100 microg/day), oral conjugated estrogen (CEE) (0.625 mg/day), or placebo. Insulin-like growth factor-1 (IGF-1), a hepatic-derived anabolic peptide, was also measured., Results: Transdermal E(2) had no effect on CRP or IGF-1 levels. In contrast, eight weeks of oral conjugated estrogens caused a more than twofold increase in CRP and a significant reduction in IGF-1 (p < 0.01) in the same women. The magnitude of increase in CRP was inversely correlated to the decrease in IGF-1 (r = -0.49, p = 0.008). Neither transdermal E(2) nor oral CEE had any effects on the plasma concentrations of cytokines that promote CRP synthesis., Conclusions: In postmenopausal women, oral but not transdermal ET increased CRP by a first-pass hepatic effect. An increase in CRP levels is accompanied by a reduction in IGF-1, an anti-inflammatory growth factor. Because CRP is a powerful predictor of an adverse prognosis in otherwise healthy postmenopausal women, the route of administration may be an important consideration in minimizing the adverse effects of ET on cardiovascular outcomes.

Background: Cartilage normally has a slow turnover but in arthritis increased metabolism results in degradation of the tissue., Objective: To assess cartilage turnover in a sample of the general population by an assay measuring cartilage derived urinary collagen type II (CTX-II) C-telopeptide degradation products., Methods: CTX-II concentrations were measured in urine samples from 615 healthy men and women aged 20-87 years, and the influence of age, sex, menopause, hormone replacement therapy (HRT), and body mass index (BMI) was assessed., Results: CTX-II concentrations showed age dependent variations, with notable differences between men and women. Mean (SD) CTX-II concentration in postmenopausal women (220 (118) ng/mmol, n=25) was significantly higher than in an age matched group of premenopausal women (112 (79) ng/mmol, n=26, p<0.001). CTX-II concentration in women using HRT (118 (57) ng/mmol, n=50) was significantly lower than in an age and BMI matched group of women not receiving HRT (215 (99) ng/mmol, n=50, p<0.001). In subjects with a BMI >or=25 kg/m(2), CTX-II concentrations were significantly higher than in those with a BMI <25 kg/m(2) (185 (114) v 148 (91) ng/mmol, p<0.001)., Conclusions: Cartilage turnover, as assessed by measuring urinary degradation products of CTX-II varies considerably with age, and significant differences between CTX-II levels in men and women as well as in pre- and postmenopausal women are found. Further studies are required to validate the marker for assessing cartilage degradation in arthritis.

Objective: To determine the percentage of endometrial hyperplasia positive for p53 expression in both spontaneously occurring cases or following the use of unopposed estradiol., Methods: Fifty-four postmenopausal patients with endometrial hyperplasia diagnosed by endometrial biopsy and hysteroscopy were recruited to this study. Thirty-three patients had used unopposed estradiol for periods of time from 1 to 3 years. P53 expression was detected in paraffin-embedded endometrial specimens by immunohistochemical methods., Results: The percentage of endometrial hyperplasia positive for p53 expression was significantly greater in spontaneously occurring hyperplasia than in cases induced by the unopposed use of estradiol., Conclusion: Endometrial hyperplasia caused by the unopposed use of estradiol during menopause probably harbors fewer genomic errors than those cases occurring spontaneously.

Recent experimental and clinical studies suggest that estrogen may be an important factor influencing neuronal function during normal and pathological aging. Using different behavioral paradigms in rodents, estrogen replacement was shown to enhance learning and memory as well as attenuate learning deficits associated with cholinergic impairment. The goal of this study was to determine whether cognitive sensitivity to estrogen manipulations (short-term ovariectomy and chronic estrogen replacement) is affected by aging. Middle-aged and old female Fischer-344 rats were used to estimate the effects of estrogen manipulations at two different stages of reproductive aging. At middle age, when the females underwent an initial stage of reproductive aging (irregular cyclicity), ovariectomy did not significantly affect the acquisition of the T-maze active avoidance as compared with Sham rats, while estrogen replacement decreased behavioral vulnerability to scopolamine. However, when tested at more advanced stage of aging (consistent diestrus), old ovariectomized rats were more sensitive to scopolamine as compared with the control rats. Moreover, estrogen treatment at this age did not produce any protective effect against scopolamine. Contrasting findings of the effects of estrogen replacement in middle-aged and old rats suggest that the ability of estrogen to enhance the basal forebrain cholinergic function declines with age. These data indicate that aging processes may substantially modulate the mechanisms of estrogen action. A "time window" during which hormone replacement must be initiated in order to be effective could be determined in terms of the stages of reproductive senescence. This study is the first to clearly demonstrate that the cognitive effects of estrogen replacement are still preserved during the initial stages of reproductive aging (irregular cyclicity) and dramatically limited as aging progresses (cessation of proestrus).