Estrogen Loss Research Articles

Study of pruritus vulvae in geriatric age group in tertiary hospital.

According to the World Health Organization criteria, geriatric population is people above 60 years of age. In this phase of life, a woman has already gone through menopause and its associated emotional, physical, and hormonal changes. These changes are due to gradual loss of estrogen that comes with menopause which results in dramatic changes in the appearance of vulva and vagina. With age, skin of vulva becomes thin, loses elasticity, and moisture so that the patient starts feeling burning and itchy sensation. The normal acidic pH changes to basic which alters the flora and makes the person prone to other bacterial infections. Apart from infections, there are many other dermatological and nondermatological causes of vulvar itching in this age group such as eczema, contact dermatitis, lichen planus (LP), lichen sclerosus atrophicans, lichen simplex chronicus (LSC), prolapse, incontinence, and carcinoma. The aim is to diagnose the causes of pruritus vulvae in the geriatric age group to decrease the misery of these patients. We selected 40 consecutive females of age group ranging from 60 to 75 years coming to skin OPD with the complaint of pruritus of vulvar region over a period of 1 year. Clinical examination, complete blood count, fasting blood sugar, wet mount, pap smear, and skin biopsy were done in every case. Out of the forty patients who were included in this study, 17 (42.5%) were diagnosed as a case of LSC and 11 (27.5%) patients had atrophic vaginitis. Three (7.5%) patients presented with tinea. Three (7.5%) cases were clinically diagnosed as scabies. Another 2 (5%) cases were diagnosed as LP and Candida was seen in other 2 (5%) cases. 1 (2.5%) case was diagnosed as bacillary vaginosis and 1 (2.5%) patient was of lichen sclerosus. Pruritus vulvae of geriatric age group are of diverse etiology, therefore, treatment based on precise diagnosis is of prime importance.

Breastfeeding for One Month or Longer is Associated with Higher Risk of Osteoarthritis in Older Adults: NHANES 1999-2012.

Breastfeeding is associated with many health benefits to the mother but the association between osteoarthritis (OA) is not known. Menopause, a state of rapid estrogen loss, is associated with OA. To test whether lactation, another physiological state of low estrogen status, is associated with OA, a nationally representative dataset National Health and Nutrition Examination Survey (NHANES) 1999–2012 was analyzed. Information of OA diagnosis history and lactation for at least one month was self-reported by women 50 years and older that had given birth to at least one child. Women that breastfed for less than one month had a higher proportion of those that were 60 years and older, Hispanic (than non-Hispanic Black), and higher current/self-reported greatest body mass index. Women that breastfed for one month or longer had a higher proportion of those that had 3 or more children, higher poverty-income ratio, were post-menopausal and performed vigorous physical activity. Weighted percentage of OA patients was 22%, and did not differ between the two groups. However, when logistic regression was performed adjusting for multiple covariates, lactation for one month or longer was positively associated with OA. Women that breastfed for one month or longer had an adjusted odds ratio of 1.21 (95% confidence interval, 1.05–1.40) for OA compared to those that breastfed for less than one month. The results indicate that women that breastfed for at least one month have a higher risk of OA than women that delivered a child but breastfed for less than one month.

Effects of high-intensity training on cardiovascular risk factors in premenopausal and postmenopausal women

Menopause is associated with increased risk of cardiovascular disease and the causal factors have been proposed to be the loss of estrogen and the subsequent alterations of the hormonal milieu. However, which factors contribute to the deterioration of cardiometabolic health in postmenopausal women is debated as the menopausal transition is also associated with increased age and fat mass. Furthermore, indications of reduced cardiometabolic adaptations to exercise in postmenopausal women add to the adverse health profile. We sought to evaluate risk factors for type 2 diabetes and cardiovascular disease in late premenopausal and early postmenopausal women, matched by age and body composition, and investigate the effect of high-intensity training. A 3-month high-intensity aerobic training intervention, involving healthy, nonobese, late premenopausal (n= 40) and early postmenopausal (n= 39) women was conducted and anthropometrics, body composition, blood pressure, lipid profile, glucose tolerance, and maximal oxygen consumption were determined at baseline and after the intervention. At baseline, the groups matched in anthropometrics and body composition, and only differed by 4.2 years in age (mean [95% confidence limits] 49.2 [48.5-49.9] vs 53.4 [52.4-54.4] years). Time since last menstrual period for the postmenopausal women was (mean [95% confidence limits] 3.1 [2.6-3.7] years). Hormonal levels (estrogen, follicle stimulation hormone, luteinizing hormone) confirmed menopausal status. At baseline the postmenopausal women had higher total cholesterol (P < .001), low-density lipoprotein-cholesterol (P < .05), and high-density lipoprotein-cholesterol (P < .001) than the premenopausal women. The training intervention reduced body weight (P < .01), waist circumference (P < .01), and improved body composition by increasing lean body mass (P < .001) and decreasing fat mass (P < .001) similarly in both groups. Moreover, training resulted in lower diastolic blood pressure (P < .05), resting heart rate(P < .001), total cholesterol (P < .01), low-density lipoprotein-cholesterol (P< .01), total cholesterol/high-density lipoprotein-cholesterol index (P < .01), and improved plasma insulin concentration during the oral glucose tolerance test (P < .05) in both groups. Cardiovascular risk factors are similar in late premenopausal and early postmenopausal women, matched by age and body composition, with the exception that postmenopausal women have higher high- and low-density lipoprotein-cholesterol levels. A 3-month intervention of high-intensity aerobic training reduces risk factors for type 2 diabetes and cardiovascular disease to a similar extent in late premenopausal and early postmenopausal women.

Cutaneous malignant melanoma incidences analyzed worldwide by skin type over advancing age of males and females: Evidence estrogen and androgenic hair are risk factors

We previously analyzed cutaneous malignant melanoma (CMM) incidences worldwide by sex, age, and Fitzpatrick skin type over time (1955-2007) and found only European-ancestry populations have exponential increasing incidences and about a 2-log increase in the risk between the youngest age groups (0-14 and 15-29 yr). We proposed the increasing incidence over time may be from the spread of Human Papilloma Virus (HPV) found in CMM biopsies, and that the 2-log incidence increase between the youngest age groups might be from developing androgenic hair. The increasing incidence with age may be from white hairs transmitting UV radiation to follicular melanocytes. Here we analyzed CMM incidences over the advancing age of males and females of every skin type (I-VI) worldwide. We found only European-ancestry females have a linear increase in their CMM risk while males of all races have a power function increase in their risk with advancing age. We propose the gradual loss of HPV-infected androgenic follicles with advancing age of only European-ancestry females during and after menopause significantly reduces their CMM risk compared to all males who do not have significant estrogen loss and consequent loss of androgenic hair with advancing age. All other races have females with significantly lower amounts of androgenic body hair so that its loss with advancing age is not significant. These results combined with those in the literature and our previous findings showing CMM has been increasing over time, suggests estrogen synergizes HPV infection of androgenic follicular melanocytes significantly increasing the risk for getting CMM.

Mig-6 Mouse Model of Endometrial Cancer.

Endometrial cancer is a frequently occurring gynecological disorder. Estrogen-dependent endometrioid carcinoma is the most common type of gynecological cancer. One of the major pathologic phenomena of endometrial cancer is the loss of estrogen (E2) and progesterone (P4) control over uterine epithelial cell proliferation. P4 antagonizes the growth-promoting properties of E2 in the uterus. P4 prevents the development of endometrial cancer associated with unopposed E2 by blocking E2 actions. Mitogen inducible gene 6 (Mig-6, Errfi1, RALT, or gene 33) is an immediate early response gene that can be induced by various mitogens and common chronic stress stimuli. Mig-6 has been identified as an important component of P4-mediated inhibition of E2 signaling in the uterus. Decreased expression of MIG-6 is observed in human endometrial carcinomas. Transgenic mice with Mig-6 ablation in the uterus develop endometrial hyperplasia and E2-dependent endometrial cancer. Thus, MIG-6 has a tumor suppressor function in endometrial tumorigenesis. The following discussion summarizes our current knowledge of Mig-6 mouse models and their role in understanding the molecular mechanisms of endometrial tumorigenesis and in the development of therapeutic approaches for endometrial cancer.

Antipsychotic Response Worsens With Postmenopausal Duration in Women With Schizophrenia.

The loss of estrogens in the menopause may lead to increased vulnerability for psychotic relapse, poor clinical outcome, and a need for increased antipsychotic dose. However, confounders such as cumulative estrogen exposure and time since menopause have been inadequately studied. Our aim was to investigate potential variables capable of influencing antipsychotic response in a sample of postmenopausal women with schizophrenia. Sixty-four postmenopausal schizophrenic women were followed in a 12-week prospective treatment-by-clinical requirement study. Duration of reproductive years was considered an indirect measure of lifetime cumulative estrogens exposure. Psychopathological assessment included the following: Positive and Negative Syndrome Scale, Personal and Social Performance, and Clinical Global Impression-Schizophrenia Scale. Response was defined as a reduction of 30% or more of Positive and Negative Syndrome Scale total scores. Antipsychotic adherence was assessed by plasma level monitoring at 4 weeks. Regression analyses were performed to investigate the association between potential confounding factors and antipsychotic response. Forty-two participants (66%) were found to be antipsychotic responders. Time since menopause was significantly and negatively associated with overall antipsychotic response, explaining almost 42% of the variance of the model used. Smoking and cumulative estrogen exposures were associated with improvement in negative symptoms. Smoking and time since menopause were associated with improvement in excitement symptoms, and smoking was positively associated with improvement in depressive and cognitive symptoms. Time since menopause was significantly negatively associated with antipsychotic response in postmenopausal schizophrenic women, suggesting a decline in antipsychotic response after menopause. The neurobiological basis for antipsychotic response may include a role for estrogen and nicotine receptors.

Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: A sex-specific gene profiling analysis

Activation of G protein-coupled estrogen receptor (GPER) by its agonist, G1, protects the heart from stressors such as pressure-overload, ischemia, a high-salt diet, estrogen loss, and aging, in various male and female animal models. Due to nonspecific effects of G1, the exact functions of cardiac GPER cannot be concluded from studies using systemic G1 administration. Moreover, global knockdown of GPER affects glucose homeostasis, blood pressure, and many other cardiovascular-related systems, thereby confounding interpretation of its direct cardiac actions. We generated a cardiomyocyte-specific GPER knockout (KO) mouse model to specifically investigate the functions of GPER in cardiomyocytes. Compared to wild type mice, cardiomyocyte-specific GPER KO mice exhibited adverse alterations in cardiac structure and impaired systolic and diastolic function, as measured by echocardiography. Gene deletion effects on left ventricular dimensions were more profound in male KO mice compared to female KO mice. Analysis of DNA microarray data from isolated cardiomyocytes of wild type and KO mice revealed sex-based differences in gene expression profiles affecting multiple transcriptional networks. Gene Set Enrichment Analysis (GSEA) revealed that mitochondrial genes are enriched in GPER KO females, whereas inflammatory response genes are enriched in GPER KO males, compared to their wild type counterparts of the same sex. The cardiomyocyte-specific GPER KO mouse model provides us with a powerful tool to study the functions of GPER in cardiomyocytes. The gene expression profiles of the GPER KO mice provide foundational information for further study of the mechanisms underlying sex-specific cardioprotection by GPER.

Argonaute 2 Expression Correlates with a Luminal B Breast Cancer Subtype and Induces Estrogen Receptor Alpha Isoform Variation.

Estrogen receptor alpha (ERα) signaling pathways are frequently disrupted in breast cancer and contribute to disease progression. ERα signaling is multifaceted and many ERα regulators have been identified including transcription factors and growth factor pathways. More recently, microRNAs (miRNAs) are shown to deregulate ERα activity in breast carcinomas, with alterations in both ERα and miRNA expression correlating to cancer progression. In this study, we show that a high expression of Argonaute 2 (AGO2), a translation regulatory protein and mediator of miRNA function, correlates with the luminal B breast cancer subtype. We further demonstrate that a high expression of AGO2 in ERα+ tumors correlates with a poor clinical outcome. MCF-7 breast cancer cells overexpressing AGO2 (MCF7-AGO2) altered ERα downstream signaling and selective ERα variant expression. Enhanced ERα-36, a 36 kDa ERα isoform, protein and gene expression was observed in vitro. Through quantitative polymerase chain reaction (qPCR), we demonstrate decreased basal expression of the full-length ERα and progesterone receptor genes, in addition to loss of estrogen stimulated gene expression in vitro. Despite the loss, MCF-7-AGO2 cells demonstrated increased estrogen stimulated tumorigenesis in vivo. Together with our clinical findings on AGO2 expression and the luminal B subtype, we suggest that AGO2 is a regulator of altered ERα signaling in breast tumors.

Fluorosis increases the risk of postmenopausal osteoporosis by stimulating interferon γ

Estrogen deficiency in postmenopausal women frequently activates osteoclasts (OC), accelerates bone resorption, and leads to osteoporosis (OP). Previous studies have demonstrated that interferon γ (IFNγ) could increase bone resorption and may be involved in postmenopausal OP. Fluorosis also increased the risk of fractures and dental fluorosis, and fluoride may enhance osteoclast formation and induce osteoclastic bone destruction in postmenopausal women, but the underlying mechanisms are as yet unknown. Here, we show that serum fluoride and IFNγ levels are negatively correlated with bone mineral density (BMD) in postmenopausal women residing in a fluorotic area. Estrogen suppresses IFNγ, which is elevated by fluoride, playing a pivotal role in triggering bone loss in estrogen-deficient conditions. In vitro, IFNγ is inhibited by estrogen treatment and increased by fluoride in Raw264.7 cell, an osteoclast progenitor cell line. In ovariectomized (Ovx) mice, estrogen loss and IFNγ promote OC activation and subsequent bone loss in vivo. However, IFNγ deficiency prevents bone loss in Ovx mice even in fluoride conditions. Interestingly, fluoride fails to increase IFNγ expression in estrogen receptor α (ERα)-deficient conditions, but not in ERβ-deficient conditions. These findings demonstrate that fluorosis increases the bone loss in postmenopausal OP through an IFNγ-dependent mechanism. IFNγ signaling activates OC and aggravates estrogen deficiency inducing OP. Thus, stimulation of IFNγ production is a pivotal ‘‘upstream’’ mechanism by which fluoride promotes bone loss. Suppression of IFNγ levels may constitute a therapeutic approach for preventing bone loss.

The middle-aged ovariectomized marmoset (Callithrix jacchus) as a model of menopausal symptoms: Preliminary evidence

Menopausal women often suffer from hot flashes and sleep disturbances that significantly impact their quality of life. Both human and animal studies suggest that loss of estrogens during menopause contribute to these symptoms. In the female rat, both core body temperature (CBT) and sleep are sensitive to 17β-estradiol (E2) levels, but important differences between the rat and the human patterns limit the interpretation of the results. The sleep and thermoregulation of the common marmoset (Callithrix jacchus) more closely resemble human patterns. However, no study to date has examined whether E2 influences sleep and thermoregulation in this species. The main goal of the present study was to investigate the suitability of the ovariectomized (OVX) marmoset for studying two major menopausal symptoms experienced by women, sleep disturbance and thermodysregulation. Two middle-aged OVX marmosets (6years old) were implanted with a telemeter that records electroencephalograms (EEG), electromyograms (EMG), and CBT. Sleep patterns and CBT were recorded under baseline, two E2 replacement (6 and 12μg/kg/day, p.o.) conditions and two E2 withdrawal conditions. Relative to both baseline and withdrawal, high E2 replacement was associated with lower nighttime CBT. In addition, fewer nighttime arousals were observed under low E2 replacement compared to baseline. Higher delta power was observed under both E2 replacement conditions suggesting enhanced sleep quality. These preliminary results suggest that E2 modulates sleep and thermoregulation in the OVX marmoset, making it a promising model for studying menopausal symptoms.

Abstract P285: Diastolic Dysfunction After Estrogen Loss is Linked to Cardiac Chymase in WKY but Not SHR Rats

Left ventricular diastolic dysfunction (LVDD) develops in response to hypertension and estrogen (E2) loss and is consequent to heart failure in women. To understand the mechanisms underlying the development of LVDD as a result of the interaction between E2 loss and the cardiac RAS, we compared the relationships of LV tissue RAS components and E/e′ between adult SHR (n=13) and WKY (n=9) female rats after ovariectomy (OVX) or sham surgery (intact). In intact rats, E/e′ was higher in SHR vs. WKY rats (P&lt;0.05 strain effect) and after OVX, the diastolic phenotype of WKY’s mimicked that of intact SHR counterparts (Figure). While relationships between RAS enzymatic activities and E/e′ were not significant in SHRs with respect to estrogen status (data not shown), OVX-induced increases in E/e′ were significantly linked to increases in chymase gene expression and enzymatic activity in the WKY strain (Figure). These data indicate that 1) the altered diastolic function in SHR is relatively insensitive to loss of estrogen while the opposite is true in WKY rats, and 2) OVX-induced LVDD in WKY is directly related to increases in cardiac chymase activity. Further elucidation of the interplay between an activated cardiac chymase-mediated RAS metabolism and LVDD following estrogen loss in normotensive subjects is warranted.

Abstract P601: Menopausal Female Mice are Hypersensitive to Pathological Cardiac Remodeling

Prior to menopause, women are protected against cardiovascular disease (CVD) compared to age-matched men; this protection is gradually lost after menopause. Loss of estrogen is detrimental; yet, estrogen replacement as cardioprotective remains controversial. Gonadectomized rodents demonstrate benefit of estrogen replacement for CVD. Human studies that show benefit of hormone replacement therapy are challenged by studies that do not show benefit. A novel model of menopause utilizing 4-vinylcyclohexene diepoxide (VCD) induces gradual ovarian failure, preserving the “perimenopause” transitional period and androgen secreting capacity of residual ovarian tissue. We hypothesize that menopausal females are hypersensitive to CVD-induced pathological cardiac remodeling. To address this hypothesis, we instigated menopause in 2 month-old females by daily (i.p.) injections of VCD (160mg/kg, 20 consecutive days); control mice received sesame oil as vehicle. Vaginal cytology was used to monitor estrous cycles and determine when cycling ceased. Mice were considered menopausal after 15 consecutive days in persistent diestrus, non-cycling. Female mice from cycling, perimenopausal and menopausal groups received the hypertensive agent angiotensin II (Ang II, 800 ng/kg/min via alzet s.q. mini-pump, 14 days). Menopause did not impact systolic blood pressure (SBP) measured via tail cuff (control: 115.1±6.0 mmHg, n=7; menopause: 115.0±5.2 mmHg, n=10). Ang II infusion induced a significant exacerbation of hypertension (SBP) in menopausal females (156.9±4.8 mmHg; n=10) compared to Ang II controls (114.7±5.0 mmHg; n=8). This hypersensitivity to Ang II-induced hypertension was attenuated by estrogen supplementation started during perimenopause (0.1 mg, 60 day release). In addition, menopausal females demonstrated worsened pathological cardiac remodeling measured by functional (echocardiography), cellular (myocardial fibrosis) and molecular (fetal gene program) assessments. Using a novel model of menopause (VCD) combined with infusion of the hypertensive agent Ang II, we demonstrated that menopausal mice are more susceptible, or hypersensitive to pathological cardiac remodeling compared to cycling and perimenopausal mice.

Abstract P600: Activation Of GPER Ameliorates Pulmonary Hypertension In Female Rats

Introduction: Pulmonary hypertension (PH) is primarily a disease of women (female-to-male ratio 4:1) and is associated with cardiac dysfunction. Aim: The activation of GPER by its agonist G1 was evaluated in monocrotaline (MCT)-induced PH rats. Methods: Depletion of estrogen was induced by bilateral oophorectomy (OVX; n = 18) in female Wistar rats (12 wks old). Experimental groups were: SHAM or OVX that received i.p. injection of MCT (60 mg/kg) for PH induction followed by administration of vehicle or G1 (400 μg/kg/day s.c.) for 14 days (n=7 per group). Hemodynamic parameters were determined by echocardiography. The effects of G1 in the maintenance of exercise capacity was investigated using a treadmill test. Results: MCT injection and estrogen loss led to a significant decrease in pulmonary acceleration time (PAT) and an increase in RV free wall thickness and MCT-related changes were attenuated by treatment with G1 ( P &lt; 0.05; Table 1). Right ventricular systolic pressure (RVSP) was higher in MCT-injected rats and the magnitude of this increase in OVX group was significantly higher than that in SHAM group. G1 normalized RVSP in both SHAM and OVX rats (Table 1). G1 treatment reversed altered expression of SERCA2a and phospholamban proteins in the RV (Table 1). Interaction between estrogen loss and MCT also reduced treadmill time to exhaustion in PH rats ( P &lt; 0.05), and chronic administration of G1 restored the exercise capacity ( P &lt; 0.05). Conclusion: G1 reversed PH-related cardiopulmonary dysfunction and exercise intolerance in female rats, a finding that may have important implications for the ongoing clinical evaluation of new drugs for the treatment of the disease in aging females.

Abstract P283: Effects of Ovarian Estrogens on Local RAS Activity in Cardiomyocytes and Non-cardiomyocytes

The relatively low efficacy of ACE-Is in the treatment of heart failure (HF) in women after estrogen (E2) loss may be due to their inability to reach the intracellular sites at which Ang II is generated and/or the existence of cell-specific mechanisms in which ACE is not the essential processing pathway for Ang II formation. We compared the metabolic pathway for Ang II formation in freshly isolated cardiomyocytes (CMs) and non-cardiomyocytes (NCMs) extracted from hearts of gonadal-intact and ovariectomized (OVX) adult WKY and SHR rats. Circulating levels of angiotensinogen (AOGEN) were higher in WKY (958 ± 47 pg/mL) vs. SHR (SHR: 626 ± 40 pg/mL; P&lt;0.05 strain effect) and E2 loss augmented this effect in WKY (WKY OVX: 1,169 ± 66 pg/mL vs. SHR OVX: 625 ± 41 pg/mL). Correspondingly, plasma Ang II levels were higher in WKY vs. SHR (strain effect: WKY: 62 ± 6 pg/mL vs. SHR: 42 ± 9 pg/mL), independent of OVX. Chymase activity was nearly 40-fold higher in NCMs compared to CMs, and for the NCMs, activities were highest in cells from WKY vs. SHR and OVX vs. intact rats (P&lt;0.05 strain and E2 effects, respectively) (Figure). Neither strain nor gonad status influenced the lower ACE activity found in both NCMs and CMs. In contrast, ACE2 activity in CMs and NCMs was higher in cells from WKY vs. SHR (P&lt;0.05 strain effect), independent of E2 status. We conclude that NCMs from WKY and SHR express significantly higher levels of chymase, ACE, and ACE2 activities. E2 loss leads to selective changes in the activity of chymase, but not ACE, in NCMs. The significance of these novel findings is that targeted cell-specific chymase rather than ACE inhibition may have a greater benefit in the management of HF in women after menopause.

An Ecosystem to Support Traditional Clinical Investigation

See related article, pp 1011–1020 In this edition of Hypertension , Nyberg et al1 from the University of Copenhagen report that both prostacyclin- and acetylcholine-induced vasodilation are blunted in the legs of young (mean age, 54 years) postmenopausal women and subsequently improved by endurance exercise training. At first glance, this is a terrific piece of mechanistic physiology and high resolution or deep phenotyping combined with an exercise training intervention in humans. It also begins to fill an important gap in our understanding of sex differences, aging, exercise, and resistance vessel physiology and pharmacology in humans that has relevance to blood pressure regulation and hypertension. As humans, age there is a generalized decline in endothelial-mediated vasodilator function. In older men, exercise training can limit the decline in resistance vessel vasodilator function with aging.2 In older women, much less is known—the effects of exercise training on resistance vessel function have been studied minimally, and the studies on larger arteries suggest that endothelial function in older women may be less trainable than men.3 There is also speculation that the loss of estrogen at menopause contributes to potential sex differences in blood vessel trainability. In this context, the key finding of Nyberg et al1 is that the resistance vessel vasodilator responses to both prostacyclin and acetylcholine are improved by training in a relatively young group of postmenopausal women. By contrast, training had minimal effects in a group of slightly younger (mean age, 50 versus 54 …

Serum dioxin levels and neuropsychological functioning in the Seveso Women’s Health Study

INTRODUCTION: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is neurotoxic in animals but few studies have investigated its effects on the human brain. Related dioxin-like compounds have been linked to poorer cognitive function in adults, with effects more pronounced in women, perhaps due to the loss of neuro-protective estrogen in menopause. METHODS: In 2008, we measured working memory (n=459) via the Wechsler Memory Scale digit span and spatial span tests in the Seveso Women’s Health Study (SWHS), a historical cohort of women residing near Seveso, Italy in 1976, at the time of an industrial explosion which resulted in the highest known population exposure to TCDD. SWHS comprises 981 women who were 0 to 40 years in 1976, resided in the most contaminated areas, and had TCDD concentration measured in archived sera collected soon after the explosion. The associations between 1976 serum TCDD and memory scale scores were modeled with multivariate linear regression and targeted maximum likelihood estimation (tmle). RESULTS: In the 2008 study sample, the geometric mean of 1976 serum TCDD levels was 68.1 (95% confidence interval: 59.8, 77.5) ppt, lipid-adjusted. The average age was 52.3(±11.3) years, with 53% post-menopause in 2008. The proportion of women scoring below the age-scaled median on the digit span (7) and spatial span (8) tests was 44% and 41%, respectively. Adjusting for a priori confounders, a 10-fold increase in TCDD was not associated with performance on the digit span test [β=0.25 (95%CI -0.19, 0.69)], spatial span test (β=0.02 (95%CI -0.44, 0.48), nor their forward and backward components. We did not observe effect modification by menopause status in 2008. DISCUSSION: This is the first study of the exclusive effects of TCDD on cognition in women, particularly surrounding menopause. Our findings do not indicate an adverse effect of dioxin exposure on working memory function in adult women in Italy.

Estrogen receptor-α and aryl hydrocarbon receptor involvement in the actions of botanical estrogens in target cells

Botanical estrogen (BE) dietary supplements are consumed by women as substitutes for loss of endogenous estrogens at menopause. To examine the roles of estrogen receptor α (ERα) and aryl hydrocarbon receptor (AhR) and their crosstalk in the actions of BEs, we studied gene regulation and proliferation responses to four widely used BEs, genistein, daidzein, and S-equol from soy, and liquiritigen from licorice root in breast cancer and liver cells. BEs and estradiol (E2), acting through ERα, stimulated proliferation, ERα chromatin binding and target-gene expression. BEs but not E2, acting through AhR, bound to xenobiotic response element-containing chromatin sites and enhanced AhR target-gene expression (CYP1A1, CYP1B1). While E2 and TCDD acted quite selectively through their respective receptors, BEs acted via both receptors, with their AhR activity moderated by negative crosstalk through ERα. Both ERα and AhR should be considered as mediators of the biology and pharmacology of BEs.

Soy Reduces Bone Turnover Markers in Women During Early Menopause: A Randomized Controlled Trial.

Menopausal estrogen loss leads to an increased bone loss. Soy isoflavones can act as selective estrogen receptor modulators, their role in bone turnover is unclear. The primary outcome was assessing changes in plasma bone turnover markers. The secondary outcomes were assessing changes in cardiovascular risk markers including insulin resistance, blood pressure, and lipid profile. We performed a double-blind randomized parallel study in which 200 women within 2 years after the onset of their menopause were randomized to 15 g soy protein with 66 mg isoflavone (SPI) or 15 g soy protein alone (SP), daily for 6 months. There was a significant reduction in type I collagen crosslinked beta C-telopeptide (βCTX) (bone-resorption marker) with SPI supplementation (0.40 ± 0.17 versus 0.15 ± 0.09 μg/L; p < 0.01) compared to SP supplementation (0.35 ± 0.12 versus 0.35 ± 0.13 μg/L; p = 0.92) after 6 months. There was also a significant reduction in type I procollagen-N-propeptide (P1NP) (bone formation marker) with SPI supplementation (50.5 ± 25.0 versus 34.3 ± 17.6 μg/L; p < 0.01), more marked between 3 and 6 months. Following SPI there was a significant reduction in fasting glucose, fasting insulin, insulin resistance, and systolic blood pressure whereas no significant changes in these parameters was observed with SP. There were no significant changes in fasting lipid profile and diastolic blood pressure with either preparation. There was a significant increase in TSH and reduction in free thyroxine (p < 0.01) with SPI supplementation though free tri-iodothyronine was unchanged. In conclusion, soy protein with isoflavones may confer a beneficial effect on bone health, analogous to the mode of action of antiresorptive agents, albeit to a less magnitude. There was a significant improvement of cardiovascular risk markers, but a significant increase in TSH and reduction in free thyroxine after SPI supplementation indicating a detrimental effect on thyroid function. © 2016 American Society for Bone and Mineral Research.

Activation of GPR30 improves exercise capacity and skeletal muscle strength in senescent female Fischer344 × Brown Norway rats

The molecular mechanisms of muscle weakness and sarcopenia in postmenopausal women are largely unknown. To determine the effect of a new estrogen receptor, GPR30, in the maintenance of exercise capacity and skeletal muscle function in females, the selective GPR30 agonist, G1 (100 μg/kg/day), or vehicle (V, soybean oil) was administered subcutaneously daily (n = 7 per group) to ovariectomized (OVX) 27-month-old Fischer 344 × Brown Norway (F344BN) female rats. Following 8 weeks of treatment, the exercise capacity (treadmill walk time to exhaustion) was reduced in OVX vs. sham rats (5.1 ± 1.4 vs. 11.0 ± 0.9 min, P < 0.05), and chronic G1 restored exercise capacity (12.9 ± 1.2 min; P < 0.05 vs. OVX-V). Similarly, the peak twitch of electrically stimulated soleus muscles was decreased by 22% in OVX vs. sham rats (P < 0.05), and G1 attenuated this decline (P < 0.05). Western blot analysis showed that chronic G1 treatment attenuated OVX-associated decreases in heat shock protein (HSP) 90, HSP70, and HSP27 expressions. In vitro studies using the L6 myoblast cell line demonstrated that G1 increased mRNA levels of HSPs in cultured cells. Collectively, these data demonstrate that the activation of GPR30 mitigates the adverse effects of estrogen loss on exercise capacity and skeletal muscle contractile function in old F344BN rats. The protective effects of GPR30 might be through its upregulation of heat shock proteins in skeletal muscle.

Premature ovarian insufficiency: the context of long-term effects.

PurposePremature ovarian insufficiency (POI) is defined as the cessation of the ovarian function before the age of 40 years. POI aetiology may be related to iatrogenic or endogenous factors and in many cases remains unclear. The aim of this review was to characterize the long-term consequences of POI.MethodsThe available literature regarding the long-term consequences of POI from MEDLINE has been reviewed.ResultsLack of ovarian steroids synthesis has serious consequences for women’s health. The short-term effects are similar to spontaneous menopause and refer mainly to the climacteric syndrome. In a longer perspective, POI affects a variety of aspects. It obviously and drastically reduces the chances for spontaneous pregnancies. Oestrogen loss leads also to urogenital atrophy. The most common urogenital symptoms include vaginal dryness, vaginal irritation and itching. The urogenital atrophy and hypoestrogenism interferes also with sexual functioning. Patients with POI are threatened by a decrease in bone mineral density (BMD). POI women also experience psychological distress and some studies have shown an increased risk of neurodegenerating diseases. Overall, POI women have a shortened life expectancy, mainly due to cardiovascular disease. Some studies have reported a reduced risk of breast cancer in this group of patients.ConclusionsIn conclusion there are several well-characterized health risks in POI women. With every patient, an individualized approach is required to properly recognize and prevent these risks.