Endogenous Estradiol Levels Research Articles

Errors elicit frontoparietal theta-gamma coupling that is modulated by endogenous estradiol levels

Cognitive control-related error monitoring is intimately involved in behavioral adaptation, learning, and individual differences in a variety of psychological traits and disorders. Accumulating evidence suggests that a focus on women's health and ovarian hormones is critical to the study of such cognitive brain functions. Here we sought to identify a novel index of error monitoring using a time-frequency based phase amplitude coupling (t-f PAC) measure and examine its modulation by endogenous levels of estradiol in females. Forty-three healthy, naturally cycling young adult females completed a flanker task while continuous electroencephalogram was recorded on four occasions across the menstrual cycle. Results revealed significant error-related t-f PAC between theta phase generated in fronto-central areas and gamma amplitude generated in parietal-occipital areas. Moreover, this error-related theta-gamma coupling was enhanced by endogenous levels of estradiol both within females across the cycle as well as between females with higher levels of average circulating estradiol. While the role of frontal midline theta in error processing is well documented, this paper extends the extant literature by illustrating that error monitoring involves the coordination between multiple distributed systems with the slow midline theta activity modulating the power of gamma-band oscillatory activity in parietal regions. They further show enhancement of inter-regional coupling by endogenous estradiol levels, consistent with research indicating modulation of cognitive control neural functions by the endocrine system in females. Together, this work identifies a novel neurophysiological marker of cognitive control-related error monitoring in females that has implications for neuroscience and women's health.

The effects of hydrocortisone and yohimbine on human behavior in approach-avoidance conflicts

RationaleBalancing approach of positive and avoidance of negative stimuli is essential when faced with approach-avoidance conflicts, e.g., situations with both positive and negative outcomes. This balance is disturbed in several mental disorders, e.g., excessive avoidance in anxiety disorders, and heightened approach in substance use disorders. Since stress is assumed to impact these disorders’ etiology and maintenance, it seems crucial to understand how stress influences behavior in approach-avoidance conflicts. Indeed, some studies suggested altered approach-avoidance behavior under acute stress, but the mechanism underlying these effects is unknown.ObjectivesInvestigate how the pharmacological manipulation of major stress mediators (cortisol and noradrenaline) influences task-based approach-avoidance conflict behavior in healthy individuals.MethodsNinety-six participants (48 women, 48 men) received either 20mg hydrocortisone, 20mg yohimbine, both, or placebo before performing a task targeting foraging under predation in a fully crossed double-blind between-subject design. Moreover, we investigated effects of gender and endogenous testosterone and estradiol levels on approach-avoidance behavior.ResultsWhile biological stress markers (cortisol concentration, alpha amylase activity) indicated successful pharmacological manipulation, behavior in approach-avoidance conflicts was not affected as expected. Although yohimbine administration affected risky foraging latency under predation, we found no main effect of hydrocortisone or their interaction on behavior. In contrast, we found gender differences for almost all behavioral outcome measures, which might be explained by differences in endogenous testosterone levels.ConclusionsThe investigated major stress mediators were not sufficient to imitate previously shown stress effects on approach-avoidance conflict behavior. We discuss potential reasons for our findings and implications for future research.

Associations between cognitive function and endogenous levels of estradiol and testosterone in adults with Type 2 diabetes?

AbstractBackgroundType 2 diabetes mellitus (T2D) accelerates cognitive decline in women and men. Among older women, prior reports suggest that higher endogenous estradiol levels may further accelerate the cognitive decline associated with T2D and increase risks for cognitive impairment. Testosterone may interact directly with cognitive decline in T2D, or through its conversion to estradiol via the aromatase enzyme.MethodsEstradiol (E2) and total testosterone (TT) concentrations were determined using stored serum from 996 individuals, mean (±SD) age 69±6 and not receiving hormone therapies, collected at two times (averaging 4 years apart). Serum was collected during follow‐up years 8‐18 of the Look AHEAD cohort, a randomized controlled clinical trial of a 10‐year behavioral weight loss intervention in individuals with T2D and overweight or obesity at trial enrollment. One to four standardized assessments of attention, executive function, memory, and verbal fluency were collected during follow‐up years 8‐18. Mixed effects models were used to assess associations that E2 and TT concentrations had with current body mass index (BMI) and cognitive function.ResultsGreater current BMI was associated with higher E2 concentrations in women and men, and greater TT concentrations in women, but lower TT concentrations in men (all p<0.001). The weight loss intervention did not leave a legacy of differences in E2 and TT concentrations. E2 concentrations were not associated with cognitive function in women or men. TT concentrations were not associated with cognitive function in women, but greater TT concentrations were associated with better verbal fluency in men (p<0.001), most strongly among those carrying the APOE‐e4 allele (interaction p = 0.02). While the weight loss intervention left a legacy of relatively lower cognitive functioning among women, this was not mediated by current concentrations of E2 and TT.ConclusionsContrary to prior reports, we found no evidence that higher endogenous E2 concentrations were related to worse cognitive functioning in women with T2D. Higher TT concentrations were associated with better verbal fluency in men, but not women. The legacy of modestly lower cognitive function in women left by a 10‐year weight loss intervention was unrelated to any long‐term alterations in E2 or TT concentrations.

RF06 | PSAT152 Associations between Bone Mass, Hormone Levels and Body Composition in Postmenopausal Women

Abstract Emerging evidence suggests an association between FSH and bone mass in peri- and postmenopausal women. The aim of the present study was to assess body composition parameters and hormone levels as risk factors for low bone mass in women with recent menopause. In this cross-sectional study, we analyzed biorepository samples from 139 postmenopausal women aged 42 to 68 years with no evidence of clinical CVD. Inclusion criteria were as follows: menopause, defined as last menstrual period at least 12 months of amenorrhea and/or 6 months or more of amenorrhea plus FSH levels ≥35 mIU/mL occurring after 40 years of age, and no use of hormone therapy (HT) in the past 3 month. BMD and body composition were assessed by dual-energy X-ray absorptiometry (DXA), SHBG and FSH levels were measured in all patients. Serum estradiol levels were measured by gas chromatography/tandem mass spectrometry assay (GC/MS/MS) in a subset of 57 participants and free estrogen index (FEI) was estimated by dividing estradiol by SHBG × 100. Low bone mass was considered osteoporosis and osteopenia. The mean age was 54.33±5.30 years and median time since menopause was 4 (2 - 9) years. The mean BMI was 26.73±4.38 kg/m2 and 66% of participants were classified as overweight or obese. BMI, BMD and T-sc, lean mass index (LMI) and fat mass index (FMI) were lower, and SHBG was higher in women with FSH levels above the median values (83.6mUI/mL). FSH was inversely correlated with FEI (rho=-0.283, p=0.033) as well as with FMI (rho=-0.288, p=0.001) and LMI (rho=-0.186, p=0.029), but significance was lost after adjustment for estradiol levels (p=0.651). In the univariate linear regression analysis, FSH, FEI, time since menopause, SHBG, FMI and LMI were significant predictors to total femur bone mass, explaining 3.8%, 11.9%, 7.4%, 14.7%, 19.7% and 8.4% of variance in BMD at this site, respectively. In the multivariate model, the association of FSH, time since menopause and FMI with hip bone mass was no longer significant after inclusion of FEI in the respective model. The present results indicate that the negative association between FSH levels and femoral BMD in postmenopausal women are influenced by endogenous estradiol levels, time since menopause and fat mass. Additional studies are needed in order to further analyze whether some direct effect of FSH on bone mass may be additive to the presence of low bone mass in this population. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Low endogenous estradiol levels are associated with elevated risk of cardiovascular disease mortality in young and middle-aged men in the United States

Background and aimsEvidence for the association of total estradiol (E2) with cardiovascular disease (CVD) in young men is limited. We investigated the association of total E2 or free estradiol (FE2) and CVD mortality in a nationally representative multiracial sample of young and middle-aged men in the United States. MethodsData were from 954 men without CVD, cancer, diabetes and not on androgen therapy or taking anabolic steroids, who participated in the National Health and Nutrition Examination Survey (1988–1991), for whom E2 was measured, and were followed for mortality through to 2015. Fasting serum levels of E2 were measured using competitive electrochemiluminescence immunoassays. Free estradiol was estimated from the levels of estradiol, sex hormone binding globulin, and albumin. International Classification of Diseases codes were used to define CVD mortality. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). ResultsThe average age of participants at baseline was 35.7 ± 11.6 years, with 11% and 6% reporting Black and Hispanic race and ethnicity, respectively. During a median follow-up of 25.2 years, 40 CVD deaths were recorded. Controlling for baseline demographic and CVD risk factors, and total testosterone levels, a 1 standard deviation decrement in log E2 (HR: 2.33, 95%CI: 1.11–5.00) or FE2 (HR: 1.89, 95%CI: 1.01–3.57) was associated with elevated risk of CVD mortality. This elevated risk was largely limited to non-Hispanic White men. ConclusionsIn this study, low levels of E2 or FE2 were associated with elevated risk of CVD mortality.

Immune-hormonal imbalance in chemical cancerogenesis

The present article deals with experimental and clinical aspects of immuno-hormonal interactions in chemical carcinogenesis i.e., formation of DNA-adducts with chemical carcinogens as a trigger of tumor initiation; synthesis of specific antibodies as markers of human exposure to environmental carcinogens; immunomodulation of chemical carcinogenesis by the specific antibodies in experimental studies; interactions of antibodies against environmental carcinogens with endogenous steroid hormones in human carcinogenesis; immunological interference and inversion of immuno-hormonal interactions by the action of antibodies against environmental carcinogens; immune stimulation of tumor progression in cancer patients. It is shown that antibodies specific to estradiol and progesterone participate in regulation of serum estradiol and progesterone levels in healthy women. Excessive production of antibodies against benzo[a]pyrene is associated with impaired physiological balance between the levels of antibodies to estradiol and progesterone, thus causing disturbed physiological balance between serum estradiol and progesterone. Immuno-hormonal imbalance promotes tumor initiation, its growth and progression. The new approaches to the personalized cancer immunoprediction and immune prevention are discussed. Coordinated synthesis of antibodies against benzo[a]pyrene and estradiol seems to reflect production of DNA-adducts with genotoxic metabolic effects of these compounds manifesting as synergistic carcinogenic effects upon the target cells. Hence, simultaneously increased levels of serum antibodies against benzo[a]pyrene and estradiol in healthy people may be considered an immunological marker of high oncological risk and an reason to use of new immunoprotective tools against polycyclic aromatic hydrocarbons and phytoestrogens. However, ability of these antibodies to raise the blood serum levels of environmental carcinogens and endogenous estradiol, as shown in vitro and in vivo, excludes the opportunity for active cancer immune prevention. Usage of anticarcinogen vaccines aimed for induction of protective secretory antibodies is likely to further increase high levels of procarcinogenic serum antibodies against benzo[a]pyrene and estradiol, followed by additional enhancement of immuno-hormonal imbalance and promotion of carcinogenesis. Development of probiotics transduced with genes encoding human antibodies against environmental carcinogens may present an alternative approach to cancer immune prevention. The antibodies produced by such probiotics would bind appropriate carcinogens and prevent their invasion into the organism, thus inhibiting emergence of DNA-adducts and suppressing synthesis of specific autoantibodies that may promote carcinogenesis. The aim is to substantiate the concept of immuno-hormonal imbalance for the carcinogen-induced hormone-dependent tumors.

Associations between cognitive function and endogenous levels of estradiol and testosterone in adults with type 2 diabetes

AimsTo assess associations that endogenous estradiol and testosterone levels have with cognitive function in older adults with Type 2 diabetes mellitus (T2DM). MethodsWe use data from the Look AHEAD clinical trial of behavioral weight loss. Endogenous estradiol and total testosterone levels were determined using stored serum from 996 individuals, mean age 69 years, at two times (averaging 4 years apart) during years 8–18 of follow-up. One to four standardized assessments of attention, executive function, memory, and verbal fluency were collected during this follow-up. Mixed effects models and multiple imputation were used to assess associations that estradiol and total testosterone levels had with body mass index and cognitive function. ResultsEstradiol levels were not associated with cognitive function in either sex. Total testosterone levels were not associated with cognitive function in women, but greater total testosterone levels were associated with better verbal fluency in men (p < 0.001), most strongly among those carrying the APOE-e4 allele (interaction p = 0.02). The weight loss intervention left a legacy of relatively lower cognitive functioning among women, which was not mediated by current levels of sex hormones. ConclusionsBehavioral weight loss intervention does not affect cognitive functioning through mechanisms related to estradiol or testosterone.ClinicalTrials.gov Identifier: NCT00017953.

Chronic treatment with hormonal contraceptives alters hippocampal BDNF and histone H3 post-translational modifications but not learning and memory in female rats

Hormonal contraceptives prevent ovulation with subsequent reduction in endogenous levels of estradiol, progesterone and its neuroactive metabolite allopregnanolone. These neurosteroids modulate several brain functions, including neuronal plasticity, cognition and memory. We hypothesized that hormonal contraceptives might affect synaptic plasticity, learning and memory, as a consequence of suppressed endogenous hormones levels. Female rats were orally treated with a combination of ethinyl estradiol (EE, 0.020 mg) and levonorgestrel (LNG, 0.060 mg) once daily for four weeks. Decreased hippocampal brain-derived neurotrophic factor (BDNF) levels and altered histone H3 post-translational modifications (PTMs) were observed 14 days after discontinuation from chronic EE-LNG treatment. These effects were not accompanied by alterations in long-term plasticity at glutamatergic synapses, recognition memory in the novel object and novel place location tests, or spatial learning, memory, and behavioral flexibility in the Morris water maze test. Thus, decreased BDNF content does not affect synaptic plasticity and cognitive performance; rather it might be relevant for the occurrence of certain psychiatric symptoms, reported by some women using hormonal contraceptives. These results provide the first evidence of hippocampal epigenetic changes induced by hormonal contraceptives and complement previous studies on the neurobiological actions of hormonal contraceptives; the finding that effects of chronic EE-LNG treatment on BDNF content and histone PTMs are observed 14 days after drug discontinuation warrants further investigation to better understand the implications of such long-term consequences for women's health.

Therapeutic Options for the Management of Aromatase Inhibitor- Associated Bone Loss.

Breast cancer is the most commonly occurring cancer in women worldwide. Early breast cancer is a kind of invasive neoplasm that has not proliferated beyond the breast or the axillary lymph nodes. Current therapeutic strategies for breast cancer mainly include local therapies such as surgery or radiotherapy and systemic therapies like chemotherapy, endocrine, and targeted therapy. Nowadays, the adjuvant treatment for hormone receptor-positive early breast cancer in postmenopausal women remains the main effective systemic therapy which can improve disease- free survival and overall survival; it involves several endocrine treatment regimens, including Selective Estrogen Receptor Modulators (SERMs), Aromatase Inhibitors (AIs), or a combination of them. AIs have been shown to be more effective in preventing recurrence in postmenopausal women with early breast cancer when compared with tamoxifen, thus representing the standard of care for adjuvant endocrine therapy. Although AIs are usually well-tolerated, they can have some side effects. Apart from the appearance of arthralgias or myalgias and cardiovascular events, AI therapies, reducing already low endogenous postmenopausal estradiol levels, cause increased bone loss and increase fracture risk in postmenopausal women. The objective of this review is to evaluate the therapeutic options in the management of Aromatase Inhibitor-Associated Bone Loss (AIBL). We reviewed the current literature dealing with different therapeutic options in the treatment of AIBL. Clinical practice guidelines recommend a careful evaluation of skeletal health in all women with breast cancer before AI therapy initiation. Adequate calcium and vitamin D intake have also been suggested. Pharmacological attempts to minimize AI-related bone loss have focused on the use of antiresorptive agents, such as bisphosphonates and denosumab to protect bone integrity and reduce the risk of fractures. Furthermore, clinical trials have shown that by making the bone microenvironment less susceptible to breast cancer metastasis, these drugs are able to increase disease- free survival. AI, that are the pillar of the systemic treatment for patients with hormone receptorpositive breast cancer, are associated with different side effects, and in particular, osteoporosis and fractures. Both bisphosphonates and denosumab are able to prevent this negative effect.

The HeyL-Aromatase Axis Promotes Cancer Stem Cell Properties by Endogenous Estrogen-Induced Autophagy in Castration-Resistant Prostate Cancer.

Treatment of patients with castration-resistant prostate cancer (CRPC) remains a major clinical challenge. We previously showed that estrogenic effects contribute to CRPC progression and are primarily caused by the increased endogenous estradiol produced via highly expressed aromatase. However, the mechanism of aromatase upregulation and its role in CRPC are poorly described. In this study, we report that HeyL is aberrantly upregulated in CRPC tissues, and its expression is positively correlated with aromatase levels. HeyL overexpression increased endogenous estradiol levels and estrogen receptor-α (ERα) transcriptional activity by upregulating CYP19A1 expression, which encodes aromatase, enhancing prostate cancer stem cell (PCSC) properties in PC3 cells. Mechanistically, HeyL bound to the CYP19A1 promoter and activated its transcription. HeyL overexpression significantly promoted bicalutamide resistance in LNCaP cells, which was reversed by the aromatase inhibitor letrozole. In PC3 cells, the HeyL-aromatase axis promoted the PCSC phenotype by upregulating autophagy-related genes, while the autophagy inhibitor chloroquine (CQ) suppressed the aromatase-induced PCSC phenotype. The activated HeyL-aromatase axis promoted PCSC autophagy via ERα-mediated estrogenic effects. Taken together, our results indicated that the HeyL-aromatase axis could increase endogenous estradiol levels and activate ERα to suppress PCSC apoptosis by promoting autophagy, which enhances the understanding of how endogenous estrogenic effects influence CRPC development.

Sex-Related Predisposition to Post-Traumatic Stress Disorder Development-The Role of Neuropeptides.

Post-traumatic stress disorder (PTSD) is characterized by re-experiencing a traumatic event, avoidance, negative alterations in cognitions and mood, hyperarousal, and severe functional impairment. Women have a two times higher risk of developing PTSD than men. The neurobiological basis for the sex-specific predisposition to PTSD might be related to differences in the functions of stress-responsive systems due to the interaction between gonadal hormones and stress peptides such as corticotropin-releasing factor (CRF), orexin, oxytocin, and neuropeptide Y. Additionally, in phases where estrogens levels are low, the risk of developing or exacerbating PTSD is higher. Most studies have revealed several essential sex differences in CRF function. They include genetic factors, e.g., the CRF promoter contains estrogen response elements. Importantly, sex-related differences are responsible for different predispositions to PTSD and diverse treatment responses. Fear extinction (the process responsible for the effectiveness of behavioral therapy for PTSD) in women during periods of high endogenous estradiol levels (the primary form of estrogens) is reportedly more effective than in periods of low endogenous estradiol. In this review, we present the roles of selected neuropeptides in the sex-related predisposition to PTSD development.

Serum estradiol as a blood-based biomarker predicting hormonal treatment outcomes in women with schizophrenia

Patients diagnosed with schizophrenia display substantial heterogeneity in terms of their clinical presentations, and treatment response. Accumulating research suggests that such high diversity may reflect distinct biological subtypes with differentially affected underlying neurobiology. Novel treatments, including sex hormone estradiol treatments, provide alternative efficacious treatment avenues but also should be studied within the context of potential heterogeneity. This repeated-measures study characterised the association between hormone levels (estrogen, progesterone, testosterone, prolactin, FSH, LH, DHEA) and symptom treatment outcomes (defined by The Positive and Negative Syndrome Scale (PANSS)) across a 56-day study of 200 ug adjunctive estradiol treatment in women with schizophrenia. Group-based trajectory models was used to account for potential heterogeneity (subgroups). Receiver operating characteristic (ROC) curves were evaluated to define the predictive value of endogenous estradiol levels as a treatment-response biomarker of estradiol treatment. The results generated two subgroups; a treatment-responder group who demonstrated decreasing PANSS scores across time, and a treatment non-responder group, demonstrating stable PANSS scores across time. The treatment-responder subgroup was significantly negatively predicted by estradiol blood level (b= −2.34, SE= 1.17, p = 0.047), while FSH blood level was positively associated with the treatment non-responders (b= 7.14, SE= 2.54, p = 0.008). ROC for day 28, 56 time points yielded area under the curve of 0.52 and 0.55, respectively. Harrell’s C-statistic = 0.59. This is the first study to identify endocrine markers in blood serum predicting response to estradiol treatment in female schizophrenia patients, highlighting the existence of heterogeneity of response, indicative of molecular subtypes. Characterising the differential underlying biology of the subgroups may lead to better targeted, specific treatments in the future.(ClinicalTrials.gov Identifier: NCT00357006). https://www.clinicaltrials.gov/ct2/show/NCT00357006.

Ovarian reserve may influence the outcome of bone mineral density in patients with long-term use of dienogest.

Objective:Long-term administration of dienogest, which is known to have effect on bone mineral density, is frequently done in patients with endometriosis and adenomyosis, but a few studies focused on the bone mineral density changes after finishing the long-term therapy. This study aimed to reveal the factors that adversely affect lumbar bone mineral density.Method:Fifty-seven premenopausal women who visited our hospital were diagnosed as either endometriosis or adenomyosis, and they were treated by dienogest for more than 115 weeks (26.5 months). Based on a previous report, bone mineral density changes less than 2% was categorized as the osteopenic group (n = 30), and the others were assigned to the unchanged group (n = 27). Bone mineral density was measured at the lumbar spine using dual-energy X-ray absorptiometry. A representative ovarian reserve marker, endogenous estradiol levels, and follicle-stimulating hormone levels were measured over time and were compared between the osteopenic and unchanged groups.Result:Duration of dienogest intake was 59.5 months (osteopenic group) versus 57.5 months (unchanged group). These patients experienced ovarian surgeries in a similar frequency, but the ovarian reserve in osteopenic group was impaired as suggested by the decline of endogenous estradiol level during intake of dienogest compared to that of unchanged group (p = 0.0146). Endogenous follicle-stimulating hormone level between osteopenic group and unchanged group did not reach statistically significant difference, although the osteopenic group showed relatively higher level.Conclusion:This study might suggest that decreased ovarian reserve as judged by endogenous estradiol level is a factor that negatively affect bone mineral density, and measurement of endogenous estradiol level during intake of dienogest could have a predictive meaning of future decreased bone mineral density level.

Associations of HDL metrics with coronary artery calcium score and density among women traversing menopause

AbstractThe cardioprotective association of high-density lipoprotein cholesterol (HDL-C) may vary by menopause stage or estradiol level. We tested whether associations of comprehensive HDL metrics (HDL subclasses, phospholipid and triglyceride content, and HDL cholesterol efflux capacity [HDL-CEC]) with coronary artery calcium (CAC) score and density vary by menopause stage or estradiol level in women transitioning through menopause. Participants (N = 294; mean age [SD]: 51.3 [2.9]) had data on HDL metrics and CAC measures at one or two time points during the menopause transition. Generalized estimating equations were used for analyses. Effect modifications by menopause stage or estradiol level were tested in multivariable models. In adjusted models, menopause stage modified the associations of specific HDL metrics with CAC measures. Higher small HDL particles (HDL-P) concentrations (p-interaction = 0.008) and smaller HDL size (p-interaction = 0.02) were associated with greater odds of CAC presence in late perimenopause than in pre/early perimenopause stage. Women in the highest estradiol tertile, but not the lower tertiles, showed a protective association of small HDL-P with CAC presence (p-interaction = 0.007). Lower large HDL-P concentrations (p-interaction = 0.03) and smaller HDL size (p-interaction = 0.03) were associated with lower CAC density in late perimenopause than in postmenopause stage. Associations of HDL phospholipid and triglyceride content and HDL-CEC with CAC measures did not vary by menopause stage or estradiol level. We concluded that HDL subclasses may impact the likelihood of CAC presence and the stability of coronary plaque differently over the menopause transition. Endogenous estradiol levels may contribute to this observation.

Menopause and Brain Health: Hormonal Changes Are Only Part of the Story.

Most studies of menopause and brain aging have focused on the role of the sex steroid hormone, estradiol, as a key mechanisms contributing to cognitive and brain aging in women. An emerging literature demonstrates that beyond endogenous estradiol levels, menopausal symptoms, particularly vasomotor symptoms (VMS), are also key determinants of menopause-related changes in cognition and brain function. Critically, that literature shows the importance of using objective techniques to identify associations of VMS with memory performance, brain structure, and brain function. While self-report measures are important patient-centered outcomes in women's health research, objective measures of VMS typically relate more strongly to indices of cognitive and brain health. Currently, it is premature to make a causal claim about VMS and memory dysfunction, but initial findings raise the possibility that women with VMS might experience an improvement in cognition with VMS treatment. More generally, these findings underscore the utility of investigating female-specific risk factors for cognitive decline.

Vasomotor symptoms and lipids/lipoprotein subclass metrics in midlife women: Does level of endogenous estradiol matter? The SWAN HDL Ancillary Study

A greater frequency of vasomotor symptoms (VMSs) has been associated with higher low-density lipoprotein cholesterol (LDL-C), but the association with high-density lipoprotein cholesterol (HDL-C) remains unclear. Endogenous estradiol (E2) levels are associated with both VMS and lipid levels and thus may confound such associations. To assess the relationship of VMS frequency with HDL-C, LDL-C, and lipoprotein concentrations (HDL and LDL particles [HDL-P; LDL-P]) and lipoprotein sizes in midlife women and to evaluate whether these associations are explained by E2. Participants were from the Study of Women's Health Across the Nation (SWAN) HDL ancillary study who had both nuclear magnetic resonance (NMR) spectroscopy lipoprotein subclass metrics and self-reported frequency of VMS measured 2-5 times over the menopause transition. VMS frequency was categorized into none, 1-5days (infrequent), or ≥6days (frequent) within the past 2weeks. We evaluated 522 women [at baseline: mean age 50.3 (SD: 2.8) years; infrequent VMS: 29.8%, frequent VMS: 16.5%]. Adjusting for potential confounders except E2, frequent VMS was associated with smaller HDL size [β(SE): -0.06 (0.03); P=.04] and higher concentrations of LDL-C [β(SE): 3.58 (1.77); P=.04] and intermediate LDL-P [β(SE): 0.09 (0.05); P=.04] than no VMS. These associations were largely explained by E2, all P's>.05. Frequent VMSs were associated with smaller HDL size and higher concentrations of LDL-C and intermediate LDL-P. These associations were explained by endogenous E2. Whether treating frequent VMS with exogenous E2 could simultaneously improve lipids/lipoproteins profile should be assessed in future studies.

Sex differences in arterial wave reflection and the role of exogenous and endogenous sex hormones: results of the Berlin Aging Study II.

Arterial stiffness is tightly linked to hypertension. Sex differences in hypertension and arterial stiffness have already been established, yet the role of sex hormones is not precisely defined. This study examined age and sex differences of arterial wave reflection and associations with endogenous and exogenous sex hormones in women. Pulse wave analysis was performed with an oscillometric device in 590 male and 400 female participants of the Berlin Aging Study II. Participants have been recruited from two age-strata, 22-35 years and 60-82 years. Data on exposures and potential confounders, including medication, have been collected at baseline visit. Aumentation index (AIx) and pulse wave velocity increased with age. Mean AIx was higher in women than in men. Multivariable regression analysis showed a positive association between use of oral contraceptive pills (OCPs) and AIx controlling for confounders (age, BMI, current smoking, central blood pressure), with a significantly higher mean AIx in OCP-users compared with nonusers (mean group difference: 4.41; 95% confidence interval 1.61-7.22). Per quartile decrease in estradiol level AIx increased by 1.72 (95% confidence interval 0.43-3.00). In OCP users endogenous estradiol was largely suppressed. The findings suggest important sex differences in measures of arterial wave reflection, with a higher mean AIx observed in women compared with men. OCPs may promote the development of hypertension by increasing AIx. Suppressed endogenous estradiol levels may be responsible for this increased wave reflection due to increased vasotonus of the small and medium arteries.

Endogenous Testosterone Levels and the Risk of Incident Cardiovascular Events in Elderly Men: The MrOS Prospective Study.

ContextObservational studies show discordant links between endogenous testosterone levels and cardiovascular diseases (CVD).ObjectiveWe assessed whether sex hormones and sex hormone–binding globulin (SHBG) are associated with CVD in community-dwelling elderly men.Design, Setting and ParticipantsProspective study of incident CVD among 552 men ≥ 65 years in the MrOS Sleep Study without prevalent CVD and no testosterone therapy at baseline.OutcomesFasting serum levels of total testosterone and estradiol were measured using liquid chromatography-mass spectrometry, and SHBG by chemiluminescent substrate. The association of sex hormones and SHBG with incident coronary heart disease (CHD), cerebrovascular (stroke and transient ischemic attack) and peripheral arterial disease (PAD) events were assessed by quartile and per SD increase in proportional hazards models.ResultsAfter 7.4 years, 137 men (24.8%) had at least 1 CVD event: 90 CHD, 45 cerebrovascular and 26 PAD. The risk of incident CVD events was not associated with quartiles of baseline sex hormones or SHBG (all P ≥ 0.16). For +1 SD in total testosterone, the multivariate-adjusted hazard ratio was 1.04 (95% CI, 0.80-1.34) for CHD, 0.86 (0.60-1.25) for cerebrovascular, and 0.81 (0.52-1.26) for PAD events. When analyzed as continuous variables or comparing highest to low quartile, levels of bioavailable testosterone, total estradiol, testosterone/estradiol ratio and SHBG were not associated with CVD events.ConclusionsIn community-dwelling elderly men, endogenous levels of testosterone, estradiol, and SHBG were not associated with increased risk of CHD, cerebrovascular, or PAD events. These results are limited by the small number of events and should be explored in future studies.

LC-APCI+-MS/MS method for the analysis of ten hormones and two endocannabinoids in plasma and hair from the mice with different gut microbiota

The effect of gut microbiota on the activity of the HPA and HPG axes and ECS is a short-term or long-lasting process remains unclear in rodents. However, the extant studies focused only on its short-term effect on the HPA activity because there is lack of reliable biomarkers characterizing short-term activity of the HPG axis and ECS and long-term activities of the three endocrine systems. The endogenous levels of aldosterone (ALD), 11-dehydrocorticosterone (11-DHC), estradiol (E2), estrone (E1), androstenedione (A4), dihydrotestosterone (DHT), corticosterone (CORT), dehydroepiandrosterone (DHEA), testosterone (T), progesterone (P), N-arachidonoyl ethanoamide (AEA) and 1-arachydonoyl glycerol (1-AG) in hair and plasma are the potential long-term and short-term biomarkers of the three systems. This study aimed to develop the sensitive and selective methods for simultaneous quantitation of the twelve compounds in rodent’s hair and plasma. Then the methods were used to explore the differences in the hair levels of the twelve compounds between the mice in XZ group possibly having gut microbiota with more diversity and SPF group possibly having gut microbiota with less diversity and the inter-group differences in the plasma levels in the response to 1-h restraint stress. The methods were based on high performance liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization in positive mode. The methods were adopted for 20 mg hair and 100 μL plasma, respectively. Hair samples were incubated in methanol at 40 ℃ for 24 h, and were performed by solid phase extraction. Plasma samples were implemented by liquid-liquid extraction with ethyl acetate. The methods showed limit of quantification at 0.06–1.3 pg/mg and 0.03-0.6 ng/mL and recovery ranging between 87.7–115.1 % and 86.1–114.6 % for all compounds in rodent’s hair and plasma, and the intra-day and inter-day coefficients of variation less than 15 %, and good freeze/thaw and short-term stability. The present methods also had good reliability as demonstrated by the sex difference in the testosterone levels in hair and plasma. The inter-group comparison revealed that the mice in XZ group showed significantly higher hair levels than those in SPF group for 1-AG and most of hormones except for T and P. The non-stressed female mice in SPF showed significantly higher plasma levels than those in XZ for AEA and most of hormones except for E2, A4, DHT, T and 1-AG, but there were no inter-group differences for the stressed mice except for DHEA and 11-DHC and for the non-stressed male mice. Additionally, the stressed mice showed significantly higher corticosterone level in plasma than controls for male and female mice in XZ and male mice in SPF, but it was not true for female mice in SPF.

Dietary intake of isoflavones is associated with a lower prevalence of subclinical cardiovascular disease in postmenopausal women: cross-sectional study.

Menopause has been associated with an increased risk of cardiovascular disease. It has been shown that isoflavones protect vascular endothelial cells against induced oxidative stress injury. Therefore, the present study aimed to investigate the association between the dietary intake of isoflavones and the presence of subclinical cardiovascular disease (CVD) in postmenopausal women. Ninety-six postmenopausal women [mean (SD) age 55.2(4.9)years, body mass index (BMI) 27.2(4.6)kgm-2 ] completed the study protocol. Habitual physical activity was assessed using a digital pedometer, resting metabolic rate was measured by indirect calorimetry and dietary intake was assessed via a validated food frequency questionnaire. Subclinical CVD was defined as carotid artery intima-media thickness (C-IMT) >0.9mm and/or the presence of one or more atherosclerotic plaques in any of the studied segments. Mean (SD) C-IMT was 0.74(0.2)mm, 25% of participants were found to have atherosclerotic plaques and the prevalence of subclinical CVD was 35%. Participants with subclinical CVD were more likely to consume less selenium, magnesium, folate and isoflavones, even after adjusting for total energy intake. A multivariate-adjusted regression model showed that a BMI >27kgm-2 was associated with 90% higher risk of having ≥1 plaque and/or C-IMT >0.9mm (P=0.017). Higher oestradiol levels (P=0.004) and isoflavone intake (P=0.021) were independently associated with a lower risk of having subclinical CVD. In the present study, we observed that a higher isoflavone dietary intake was associated with a lower risk of subclinical CVD in postmenopausal women, independent of BMI and endogenous oestradiol levels.