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In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.

Cyclic fluctuations in hypothalamic-pituitary-gonadal axis (HPG-axis) hormones exert powerful behavioral, structural, and functional effects through actions on the mammalian central nervous system. Yet, very little is known about how these fluctuations alter the structural nodes and information highways of the human brain. In a study of 30 naturally cycling women, we employed multidimensional diffusion and T1-weighted imaging during three estimated menstrual cycle phases (menses, ovulation, and mid-luteal) to investigate whether HPG-axis hormone concentrations co-fluctuate with alterations in white matter (WM) microstructure, cortical thickness (CT), and brain volume. Across the whole brain, 17β-estradiol and luteinizing hormone (LH) concentrations were directly proportional to diffusion anisotropy (μFA; 17β-estradiol: β1 = 0.145, highest density interval (HDI) = [0.211, 0.4]; LH: β1 = 0.111, HDI = [0.157, 0.364]), while follicle-stimulating hormone (FSH) was directly proportional to CT (β1 = 0 .162, HDI = [0.115, 0.678]). Within several individual regions, FSH and progesterone demonstrated opposing relationships with mean diffusivity (Diso) and CT. These regions mainly reside within the temporal and occipital lobes, with functional implications for the limbic and visual systems. Finally, progesterone was associated with increased tissue (β1 = 0.66, HDI = [0.607, 15.845]) and decreased cerebrospinal fluid (CSF; β1 = -0.749, HDI = [-11.604, -0.903]) volumes, with total brain volume remaining unchanged. These results are the first to report simultaneous brain-wide changes in human WM microstructure and CT coinciding with menstrual cycle-driven hormone rhythms. Effects were observed in both classically known HPG-axis receptor-dense regions (medial temporal lobe, prefrontal cortex) and in other regions located across frontal, occipital, temporal, and parietal lobes. Our results suggest that HPG-axis hormone fluctuations may have significant structural impacts across the entire brain.

IntroductionReproductive health history may contribute to cognitive aging and risk for Alzheimer's disease, but this is understudied among Hispanic/Latina women.MethodsParticipants included 2126 Hispanic/Latina postmenopausal women (44 to 75 years) from the Study of Latinos-Investigation of Neurocognitive Aging. Survey linear regressions separately modeled the associations between reproductive health measures (age at menarche, history of oral contraceptive use, number of pregnancies, number of live births, age at menopause, female hormone use at Visit 1, and reproductive span) with cognitive outcomes at Visit 2 (performance, 7-year change, and mild cognitive impairment [MCI] prevalence).ResultsYounger age at menarche, oral contraceptive use, lower pregnancies, lower live births, and older age at menopause were associated with better cognitive performance. Older age at menarche was protective against cognitive change. Hormone use was linked to lower MCI prevalence.DiscussionSeveral aspects of reproductive health appear to impact cognitive aging among Hispanic/Latina women.

Human milk (HM) contains macronutrients, micronutrients, and a multitude of other bioactive factors, which can have a long-term impact on infant growth and development. We systematically searched MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science to synthesize evidence published between 1980 and 2022 on HM components and anthropometry through 2 y of age among term-born infants. From 9992 abstracts screened, 141 articles were included and categorized based on their reporting of HM micronutrients, macronutrients, or bioactive components. Bioactives including hormones, HM oligosaccharides (HMOs), and immunomodulatory components are reported here, based on 75 articles from 69 unique studies reporting observations from 9980 dyads. Research designs, milk collection strategies, sampling times, geographic and socioeconomic settings, reporting practices, and outcomes varied considerably. Meta-analyses were not possible because data collection times and reporting were inconsistent among the studies included. Few measured infant HM intake, adjusted for confounders, precisely captured breastfeeding exclusivity, or adequately described HM collection protocols. Only 5 studies (6%) had high overall quality scores. Hormones were the most extensively examined bioactive with 46 articles (n = 6773 dyads), compared with 13 (n = 2640 dyads) for HMOs and 12 (n = 1422 dyads) for immunomodulatory components. Two studies conducted untargeted metabolomics. Leptin and adiponectin demonstrated inverse associations with infant growth, although several studies found no associations. No consistent associations were found between individual HMOs and infant growth outcomes. Among immunomodulatory components in HM, IL-6 demonstrated inverse relationships with infant growth. Current research on HM bioactives is largely inconclusive and is insufficient to address the complex composition of HM. Future research should ideally capture HM intake, use biologically relevant anthropometrics, and integrate components across categories, embracing a systems biology approach to better understand how HM components work independently and synergistically to influence infant growth.

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IntroductionInduction of lactation in a non-gestational parent has numerous potential benefits including parent-child bonding, optimal nutrition, and health benefits to the child and breast- or chest-feeding parent. For transgender women and nonbinary people on estrogen-based, gender-affirming hormone therapy, the ability to nourish their infants through production of their own milk may also be a profoundly gender-affirming experience. Two prior case studies have been published describing induced lactation in transgender women, but analysis of the nutritional quality of the milk produced has not been previously described.Main issueHere we describe the experience of a transgender woman who underwent successful induction of lactation in order to breastfeed her infant, who was gestated by her partner.ManagementThrough modification of exogenous hormone therapy, use of domperidone as a galactogogue, breast pumping, and ultimately direct breastfeeding, the participant was able to co-feed her infant for the first 4 months of life. We provide a detailed description and timeline of the medications used, laboratory and electrocardiographic measurements, results of the participant's milk analysis showing robust macronutrient content, and description of the participant's experience in her own words.ConclusionThese findings provide reassurance about the adequacy of nutrition from human milk produced by non-gestational transgender female and nonbinary parents on estrogen-based, gender-affirming hormone therapy, and support the importance of this experience on a personal level.

There are numerous bidirectional interactions between the reproductive system and the liver. Sex steroids regulate metabolic health through signaling effects in both peripheral and central metabolic tissues, including adipose tissue, liver, skeletal muscle, and brain, and have a role in the etiology of structural and functional liver diseases. Blood samples were obtained from 90 healthy women (control group) and 90 women that have hormonal changes (patients’ group). The levels of reproductive hormones (follicle stimulation hormone/FSH, luteinizing hormone/LH, estradiol/E2, progesterone/P4) were measured by using fully automated Cobas E411, whereas those of liver enzymes (alanine transaminase /ALT, aspartate aminotransferase/AST, alkaline phosphatase/ALP) were measured by using fully automated Cobas C111. Levels of copper and ceruloplasmin were measured as well. The results demonstrate a strongly significant positive correlation between the levels of FSH and ALT (r = 0.45, p = 0.0001), FSH and AST (r = 0.48, p = 0.0001), and FSH and ALP (r = 0.303, p = 0.005), LH and ALT (r = 0.301, p = 0.005), LH and AST (r = 0.34, p = 0.001), and LH and ALP (r = 0.307, p = 0.004). The reproductive hormones and liver enzymes had a strong positive correlation. The results demonstrate a correlation between estrogen and copper (r = 0.38, p = 0.0001), as well as a highly significant positive correlation between estrogen and ceruloplasmin (r = 0.43, p = 0.0001) and a positive significant correlation between progesterone and copper (r = 0.26, p = 0.01). These findings are consistent with earlier research that has found a clear link between low estrogen levels in the blood and liver disease in women. These findings imply that an abnormally low level of estrogen may render women more susceptible to developing liver damage. [ABSTRACT FROM AUTHOR]

PURPOSE: Prior studies have identified a significant relationship between internalized transphobia and poor mental health among transgender and gender-diverse (TGD) adults; however, this relationship has not been extensively examined among youth. Further, little research has sought to explore protective factors, such as identity pride, and their influence on this relationship. We examined the association between internalized transphobia and depression and anxiety symptoms among TGD youth and explored the moderating role of gender identity pride on these associations. METHODS: Participants were 315 TGD youth ages 12-20 years (mean = 16; standard deviation = 1.89) seeking gender-affirming hormone treatment at one of four major pediatric hospitals across the United States. At the time of enrollment, participants were naïve to gender-affirming hormone treatment. Participants self-reported mental health, internalized transphobia, and identity pride. Multiple regression models were used with depression and anxiety symptoms as outcomes and age, designated sex at birth, and perceived parental support included as covariates. RESULTS: Greater internalized transphobia was associated with greater depressive symptoms, and gender identity pride moderated this relationship, such that greater gender identity pride was associated with fewer depressive symptoms. Greater internalized transphobia was significantly associated with greater anxiety symptoms; no moderation effect was observed for this relationship. DISCUSSION: Gender identity pride influenced mental health symptoms for youth experiencing internalized transphobia and represents a potential key protective factor. These results support efforts to further develop, test, and implement clinical inventions to bolster identity pride for TGD youth.

Continuous body temperature is a rich source of information on hormonal status, biological rhythms, and metabolism, all of which undergo stereotyped change across adolescence. Due to the direct actions of these dynamic systems on body temperature regulation, continuous temperature may be uniquely suited to monitoring adolescent development and the impacts of exogenous reproductive hormones or peptides (e.g., hormonal contraception, puberty blockers, gender affirming hormone treatment). This mini-review outlines how traditional methods for monitoring the timing and tempo of puberty may be augmented by markers derived from continuous body temperature. These features may provide greater temporal precision, scalability, and reduce reliance on self-report, particularly in females. Continuous body temperature data can now be gathered with ease across a variety of wearable form factors, providing the opportunity to develop tools that aid in individual, parental, clinical, and researcher awareness and education.

BackgroundThere continues to be controversy regarding the simultaneous encouragement of both breastfeeding and immediate postpartum contraception.Research aimTo explore postpartum women's perspectives about breastfeeding and their breastfeeding behaviors, while using one of three different hormonally systemic contraceptive methods immediately postpartum over a 6 month period of time.MethodsThis was a retrospective, longitudinal, three group comparative, secondary analysis of a prospective cohort study (N = 471) of immediate postpartum contraception. Breastfeeding, for this study, was defined as providing any human milk to the infant. Participants who chose one of three different hormonally systemic forms of contraception immediately postpartum (a long-acting hormonal reversible contraceptive (n = 200), depot medroxyprogesterone acetate 150 mg (n = 98), or a non-hormonal method (n = 173)) were compared at hospital discharge, 6 weeks, 3 months, and 6 months postpartum. The primary outcome was any breastfeeding at 6 months. Secondary outcomes included any and exclusive breastfeeding, concerns about breastfeeding while using contraception, and reasons for breastfeeding discontinuation.ResultsThere was no significant difference in the rate of any breastfeeding between the two hormonal and the non-hormonal contraceptive groups at 6 months postpartum (long-acting hormonal 20.1%, non-hormonal 21.7%, depot medroxyprogesterone acetate 13.9%, p = .77, 0.28, respectively). The number of participants who reported stopping breastfeeding due to decreased milk supply was not significantly different between any groups at all time points (total number who discontinued at 6 months postpartum was long-acting hormonal 24.7%, non-hormonal 25.1%, depot medroxyprogesterone acetate 19.3%, p = .30).ConclusionsBreastfeeding perspectives and behavioral outcomes over the first 6 months postpartum were not influenced by participants chosen form of immediate postpartum contraception.

Sex is a significant source of heterogeneity in schizophrenia, with more negative symptoms in males and more affective symptoms and internalizing comorbidity in females. In this narrative review, we argue that there are likely sex differences in the pathophysiological mechanisms of schizophrenia-spectrum disorders (SZ) that originate during puberty and relate to the sex-specific impacts of pubertal maturation on brain development. Pubertal maturation might also trigger underlying (genetic or other) vulnerabilities in at-risk individuals, influencing brain development trajectories that contribute to the emergence of SZ. This review is the first to integrate links between pubertal development and neural development with cognitive neuroscience research in SZ to form and evaluate these hypotheses, with a focus on the frontal-striatal and frontal-limbic networks and their hypothesized contribution to negative and mood symptoms respectively. To test these hypotheses, longitudinal research with human adolescents is needed that examines the role of sex and pubertal development using large cohorts or high risk samples. We provide recommendations for such studies, which will integrate the fields of psychiatry, developmental cognitive neuroscience, and developmental endocrinology towards a more nuanced understanding of the role of pubertal factors in the hypothesized sex-specific pathophysiological mechanisms of schizophrenia.

Bitter taste receptors (Tas2rs in mice) detect bitterness, a warning signal for toxins and poisons, and are expressed in enteroendocrine cells. We tested the hypothesis that Tas2r138 and Tas2r116 mRNAs are modulated by microbiota alterations induced by a long-term high-fat diet (HFD) and antibiotics (ABX) (ampicillin and neomycin) administered in drinking water. Cecum and colon specimens and luminal contents were collected from C57BL/6 female and male mice for qRT-PCR and microbial luminal 16S sequencing. HFD with/without ABX significantly increased body weight and fat mass at 4, 6, and 8 weeks. Tas2r138 and Tas2r116 mRNAs were significantly increased in mice fed HFD for 8 weeks vs. normal diet, and this increase was prevented by ABX. There was a distinct microbiota separation in each experimental group and significant changes in the composition and diversity of microbiome in mice fed a HFD with/without ABX. Tas2r mRNA expression in HFD was associated with several genera, particularly with Akkermansia, a Gram-negative mucus-resident bacterium. These studies indicate that luminal bacterial composition is affected by sex, diet, and ABX and support a microbial dependent upregulation of Tas2rs in HFD-induced obesity, suggesting an adaptive host response to specific diet-induced dysbiosis.

BackgroundFeminizing hormonal therapy (FHT) and HIV potentially alter cardiovascular disease (CVD) risk in transgender women (TW).MethodsTW were enrolled in Los Angeles, California and Houston, Texas and frequency-matched to Multicenter AIDS Cohort Study cisgender men (CM) on age, race, substance use, and abacavir use. Biomarkers of CVD risk and inflammation were assessed via ELISA. Wilcoxon rank sum and Fisher's exact tests compared TW and CM. Multivariable linear regression assessed factors associated with biomarker concentrations.ResultsTW (HIV+ n  = 75, HIV- n  = 47) and CM (HIV+ n  = 40, HIV- n  = 40) had mean age 43-45 years; TW/CM were 90%/91% non-Hispanic Black, Hispanic, or Multiracial, 26%/53% obese, and 34%/24% current smokers; 67% of TW were on FHT. Among people with HIV (PWH), TW had higher median extracellular newly-identified receptor for advanced glycation end-products (EN-RAGE), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), soluble tumor necrosis factor receptor type (sTNFR) I/II, interleukin (IL)-8 and plasminogen activator inhibitor (PAI)-1, but lower soluble CD14, von Willebrand factor (vWF) and endothelin (ET)-1 levels than CM. Findings were similar for participants without HIV (all P

The transgender community has expressed concerns regarding drug-drug interactions between HIV-pre-exposure prophylaxis (PrEP) and gender-affirming hormones. In this study, we evaluated emtricitabine (F, FTC)/tenofovir (TFV) disoporoxil fumarate (TDF) pharmacokinetics (PK) among adolescent and young adult transgender persons receiving gender-affirming hormone therapy (GAHT). This was a prospective, observational study among transgender women (TW) and men (TM) without HIV, 15-24 years of age, receiving GAHT (estradiol with/without spironolactone, or testosterone). Participants received 1 month of directly observed daily F/TDF. Weekly convenience blood samples were collected for plasma TFV and FTC, and intracellular TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in peripheral blood mononuclear cells (PBMC) and dried blood spots (DBS). After 2-3 weeks of F/TDF dosing, intensive PK sampling was conducted. PK parameters were estimated using noncompartmental methods. Data were log-transformed and compared between TM and TW, and to historical data among cisgender adults. Plasma TFV exposures were similar between TM and TW [geometric mean ratio (GMR); confidence interval (95% CI): 1.06 (0.89-1.28)], whereas FTC plasma exposures were 21% higher in TM versus TW (95% CI: 1.07-1.38). TFV-DP in PBMC and DBS and FTC-TP in DBS did not differ between TM versus TW after controlling for creatinine clearance (CrCl), but FTC-TP in PBMC remained 46% (95% CI: 1.15-1.86) higher in TM versus TW. All PK exposures were within expected ranges based on historical studies. TM had higher FTC exposures compared with TW, but overall plasma and intracellular exposures for both drugs were within the range of historical studies, suggesting high PrEP efficacy will be retained in adolescent and young adult transgender persons. Registered at ClinicalTrials.gov (NCT03652623).

BACKGROUND: Depressive symptoms are associated with age-related cognitive impairment, but the relative risk of specific subtypes of mild cognitive impairment (MCI) conferred by depressive symptoms is unclear. The purpose of this exploratory study was to determine the longitudinal association between baseline depressive symptoms and incident cases of MCI subtypes (amnestic vs. non-amnestic) and probable dementia (PD) (Alzheimers disease, vascular, mixed) among postmenopausal women. METHODS: Depressive symptoms were assessed at study baseline using an 8-item Burnam algorithm in 7043 postmenopausal women who participated in the Womens Health Initiative Memory Study (WHIMS) and the WHIMS-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) extension study. During the median 9.4-year follow-up interval, the presence of MCI and PD was classified by a central adjudication committee. Classification of participants by MCI subtype (amnestic single and multi-domain, non-amnestic single and multi-domain) was done algorithmically based on established criteria using data from annual cognitive testing. RESULTS: At baseline, 557 women (7.9%) had clinically significant depressive symptoms based on Burnam algorithm cut-point of 0.06. Depressive symptoms at baseline were associated with an increased risk of incident amnestic MCI (hazard ratio [HR] = 1.91, 95% confidence interval [CI] 1.32-2.78, p

BackgroundRacial differences in metabolomic profiles may reflect underlying differences in social determinants of health by self-reported race and may be related to racial disparities in coronary heart disease (CHD) among women in the United States. However, the magnitude of differences in metabolomic profiles between Black and White women in the United States has not been well-described. It also remains unknown whether such differences are related to differences in CHD risk.MethodsPlasma metabolomic profiles were analyzed using liquid chromatography-tandem mass spectrometry in the WHI-OS (Women's Health Initiative-Observational Study; 138 Black and 696 White women), WHI-HT trials (WHI-Hormone Therapy; 156 Black and 1138 White women), MESA (Multi-Ethnic Study of Atherosclerosis; 114 Black and 219 White women), JHS (Jackson Heart Study; 1465 Black women with 107 incident CHD cases), and NHS (Nurses' Health Study; 2506 White women with 136 incident CHD cases). First, linear regression models were used to estimate associations between self-reported race and 472 metabolites in WHI-OS (discovery); findings were replicated in WHI-HT and validated in MESA. Second, we used elastic net regression to construct a racial difference metabolomic pattern (RDMP) representing differences in the metabolomic patterns between Black and White women in the WHI-OS; the RDMP was validated in the WHI-HT and MESA. Third, using conditional logistic regressions in the WHI (717 CHD cases and 719 matched controls), we examined associations of metabolites with large differences in levels by race and the RDMP with risk of CHD, and the results were replicated in Black women from the JHS and White women from the NHS.ResultsOf the 472 tested metabolites, levels of 259 (54.9%) metabolites, mostly lipid metabolites and amino acids, significantly differed between Black and White women in both WHI-OS and WHI-HT after adjusting for baseline characteristics, socioeconomic status, lifestyle factors, baseline health conditions, and medication use (false discovery rate

First-line CDK4/6 inhibitor ribociclib plus letrozole improves survival in the metastatic setting, but lack of accrual of African American women is a shortcoming. Predicting benefit in the early-stage setting and diverse enrollment in trials need to be priorities.1.

ObjectivesTo describe practice patterns of an integrated complex family planning-pediatric hematology oncology clinic for patients with blood disorders STUDY DESIGN: We retrospectively evaluated the outcomes of patients who had an initial consultation for blood disorders impacting menstrual bleeding in an integrated complex family planning-pediatric hematology oncology clinic from October 2015 to September 2020. We reviewed all charts to extract medical and gynecologic history, blood disorder diagnosis, hormonal treatment prior to and following initial consultation, subsequent visits to the integrated clinic, and hormonal treatment up to 24 months after initial consultation.ResultsWe saw 47 patients; their most common blood disorder diagnosis was protein defect (14 of 47, 30%). Most patients (30 of 47, 64%) were not using any hormonal treatment prior to their initial consultation. After the initial consultation, 26 (55%) elected to start, change, or discontinue hormonal treatment for abnormal menstrual bleeding, the most common treatment being combined hormonal contraception (CHC, 22 of 47, 47%), alone or as dual therapy. Over the study duration, 36 patients (77%) initiated, changed, or discontinued their hormone treatment, 22 (61%) of whom changed their treatment plan more than once. CHC usage decreased from 19 of 47 (40%) to 8 of 37 (22%) and hormonal device usage, particularly the implant, increased from 9 of 47 (19%) to 11 of 37 (30%) over the 24 months from initial consultation.ConclusionMost patients in an integrated complex family planning-pediatric hematology oncology clinic will change their menstrual bleeding hormone treatment with initial consultation, although management may require multiple changes. The most common treatment 24 months following the initial consultation was hormonal devices.ImplicationsPatients with blood disorders affecting menstrual bleeding have complex needs that could be addressed by an integrated complex family planning-pediatric hematology oncology clinic. Most patients require multiple changes in treatment to achieve adequate control of their bleeding, and patients were more likely to choose hormonal devices for management over time.

Sertoli cells (Sc) are the sole target of follicle-stimulating hormone (FSH) in the testis and attain functional maturation post-birth to significantly augment germ cell (Gc) division and differentiation at puberty. Despite having an operational microRNA (miRNA) machinery, limited information is available on miRNA-mediated regulation of Sc maturation and male fertility. We have shown before that miR-92a-3p levels decline in pubertal rat Sc. In response to FSH treatment, the expressions of FSH Receptor, Claudin11 and Klf4 were found to be elevated in pubertal rat Sc coinciding with our finding of FSH-induced decline in miR-92a-3p levels. To investigate the association of miR-92a-3p and spermatogenesis, we generated transgenic mice where such pubertal decline of miR-92a-3p was prevented by its overexpression in pubertal Sc under proximal Rhox5 promoter, which is known to be activated specifically at puberty, in Sc. Our in vivo observations provided substantial evidence that FSH-induced decline in miR-92a-3p expression during Sc maturation acts as an essential prerequisite for the pubertal onset of spermatogenesis. Elevated expression of miR-92a-3p in post-pubertal testes results into functionally compromised Sc, leading to impairment of the blood-testis barrier formation and apoptosis of pre-meiotic Gc, ultimately culminating into infertility. Collectively, our data suggest that regulation of miR-92a-3p expression is crucial for Sc-mediated induction of active spermatogenesis at puberty and regulation of male fertility.

BackgroundKlotho is a longevity and neuroprotective hormone encoded by the KLOTHO gene, and heterozygosity for the KL-VS variant confers a protective effect against neurodegenerative disease.ObjectiveTest whether klotho concentrations in serum or cerebrospinal fluid (CSF) vary as a function of KLOTHO KL-VS genotype, determine whether circulating klotho concentrations from serum and CSF differ from one another, and evaluate whether klotho levels are associated with Alzheimer's disease risk factors.MethodsCirculating klotho was measured in serum (n = 1,116) and CSF (n = 183) of cognitively intact participants (aged 62.4 ± 6.5 years; 69.5% female). KLOTHO KL-VS zygosity (non-carrier; heterozygote; homozygote) was also determined. Linear regression was used to test whether klotho hormone concentration varied as a function of KL-VS genotype, specimen source, and demographic and clinical characteristics.ResultsSerum and CSF klotho were higher in KL-VS carriers than non-carriers. Klotho concentration was higher in CSF than in serum. Females had higher serum and CSF klotho, while younger age was associated with higher klotho in CSF.ConclusionIn a cohort enriched for risk for Alzheimer's disease, heterozygotic and homozygotic carriers of the KL-VS allele, females, and younger individuals have higher circulating klotho. Fluid source, KL-VS genotype, age, and sex should be considered in analyses of circulating klotho on brain health.

BackgroundLow heart rate variability (HRV), a measure of autonomic imbalance, is associated with increased risk of coronary heart disease (CHD) and heart failure (HF). However, its relationship with HF subtypes; heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) has not been studied prior.Methods and findingsWe conducted a longitudinal study in Women's Health Initiative study cohort to investigate the association of baseline quartiles of resting heart rate (rHR) and HRV measures; SDNN (SD of normal-to-normal RR interval) and RMSSD (root mean square of successive difference of RR interval) measured by twelve-lead electrocardiogram (ECG) on enrollment, with the risk of hospitalized HF and its subtypes. Total of 28,603 post-menopausal women, predominantly non-Hispanic whites (69%), with a mean (SD) age of 62.6 (7.1) years, free of baseline CHD and HF were included. In a fully adjusted cox-proportional hazards regression model which adjusted for age, race, BMI, alcohol intake, education, physical activity, hyperlipidemia, hypertension, left ventricular hypertrophy, use of beta-blocker, calcium-channel blocker, hormone therapy, and time-varying incident CHD, the hazard ratios of lowest quartile of HRV (Q1) with HF risk were significant (Q1 SDNN compared to Q4 SDNN: 1.22, 95% CI 1.07, 1.39; Q1 RMSSD compared to Q4 RMSSD: 1.17, 95% CI 1.02, 1.33). On subgroup analysis of HF subtypes, low HRV was associated with elevated HFpEF risk (Q1 vs Q4 SDNN: 1.22, 95% CI 1.02, 1.47) but not with HFrEF (Q1 vs Q4 SDNN: 1.19, 95% CI 0.95, 1.50; Q1 RMSSD: 1.13, 95% CI 0.90, 1.43).ConclusionLow HRV is associated with elevated overall hospitalized HF risk and HFpEF risk in post-menopausal women. Whether interventions to increase HRV through healthy lifestyle changes will decrease HF risk warrants further investigation.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous endocrine-disrupting combustion by-products that have been linked to preterm birth. One possible mechanism is through disruption of placental corticotropin releasing hormone (pCRH), a key hormone implicated in parturition. As an extension of recent research identifying pCRH as a potential target of endocrine disruption, we examined maternal PAH exposure in relation to pCRH in a large, diverse sample. Participants, drawn from the CANDLE cohort, part of the ECHO-PATHWAYS Consortium, completed study visits at 16-29 weeks (V1) and 22-39 weeks (V2) gestation (n=812). Seven urinary mono-hydroxylated PAH metabolites (OH-PAHs) were measured at V1 and serum pCRH at V1 and V2. Associations between individual log-transformed OH-PAHs (as well as two summed PAH measures) and log(pCRH) concentrations across visits were estimated using mixed effects models. Minimally-adjusted models included gestational age and urinary specific gravity, while fully-adjusted models also included sociodemographic characteristics. We additionally evaluated effect modification by pregnancy complications, fetal sex, and maternal childhood trauma history. We observed associations between 2-OH-Phenanthrene (2-OH-PHEN) and rate of pCRH change that persisted in fully adjusted models (β=0.0009, 0.00006, 0.0017), however, positive associations with other metabolites (most notably 3-OH-Phenanthrene and 1-Hydroxypyrene) were attenuated after adjustment for sociodemographic characteristics. Associations tended to be stronger at V1 compared to V2 and we observed no evidence of effect modification by pregnancy complications, fetal sex, or maternal childhood trauma history. In conclusion, we observed modest evidence of association between OH-PAHs, most notably 2-OH-PHEN, and pCRH in this sample. Additional research using serial measures of PAH exposure is warranted, as is investigation of alternative mechanisms that may link PAHs and timing of birth, such as inflammatory, epigenetic, or oxidative stress pathways.

This study investigated whether men with a history of real-life aggressive, dominant behavior show increases in testosterone and cortisol levels after brief social contact with women. Furthermore, we tested the prediction that such changes in hormones would be larger than those observed previously in young male students. Sixty-seven male participants convicted of intimate partner violence (IPV) either had brief social contact with a female confederate (experimental condition) or a male confederate (control condition). We also performed meta-analyses to investigate whether IPV perpetrators' hormonal responses were larger than the typical responses of young male students in prior studies. All statistical analyses were preregistered. Change in testosterone did not differ across experimental conditions, and testosterone in the IPV perpetrators actually declined from baseline in the female confederate condition. Our meta-analysis showed that this testosterone decrease was different from the testosterone increase typically observed in young male students. The cortisol levels of IPV perpetrators did not change in response to contact with women. This result was consistent with our meta-analysis since young male students also did not experience a cortisol change in response to interactions with women. In sum, our findings provide no evidence that male IPV perpetrators exhibit larger hormone increases to brief interactions with women, although it is possible that the men in this sample did not perceive the social contact period as a courtship opportunity. These results suggest that hormone reactivity to social encounters may differ across subject populations and depend on how subjects perceive social situations within laboratory settings.

The rodent estrous cycle modulates a range of biological functions, from gene expression to behavior. The cycle is typically divided into four stages, each characterized by distinct hormone concentration profiles. Given the difficulty of repeatedly sampling plasma steroid hormones from rodents, the primary method for classifying estrous stage is by identifying vaginal epithelial cell types. However, manual classification of epithelial cell samples is time-intensive and variable, even amongst expert investigators. Here, we use a deep learning approach to achieve classification accuracy at expert level. Due to the heterogeneity and breadth of our input dataset, our deep learning approach ("EstrousNet") is highly generalizable across rodent species, stains, and subjects. The EstrousNet algorithm exploits the temporal dimension of the hormonal cycle by fitting classifications to an archetypal cycle, highlighting possible misclassifications and flagging anestrus phases (e.g., pseudopregnancy). EstrousNet allows for rapid estrous cycle staging, improving the ability of investigators to consider endocrine state in their rodent studies.

PurposeCurrent treatment guidelines for male breast cancer are guided by female-only trials despite data suggesting distinct clinicopathologic differences between sexes. We sought to evaluate whether radiation therapy (RT) after lumpectomy was associated with equivalent survival among men > 70 years of age with stage I, estrogen receptor (ER) positive tumors, as seen in women from the Cancer and Leukemia Group B (CALGB) 9343 trial.MethodsWe performed a retrospective analysis of 752 stage I, ER-positive male breast cancer patients ≥ 70 years who were treated with hormone therapy and surgery, with or without RT, from the National Cancer Database between 2004 and 2014. Patients were categorized based on surgery and RT (lumpectomy alone, lumpectomy with RT, and mastectomy alone). Multivariable Cox proportional hazards regression analysis was used to compare overall survival between treatment groups.ResultsMost patients underwent total mastectomy, with only 32.6% treated with lumpectomy. Of those who underwent lumpectomy, 72.7% received adjuvant RT. In multivariate analysis, there was no statistical difference in overall survival when comparing lumpectomy alone and lumpectomy with RT (aHR 0.72 [95% CI 0.38-1.37], p = 0.31) or when comparing lumpectomy (alone or with RT) and mastectomy (aHR 1.28 [95% CI 0.88-1.87], p = 0.20).ConclusionsIn this national sample of elderly men with ER-positive early-stage disease treated with endocrine therapy, there were no significant differences in overall survival when comparing lumpectomy alone and lumpectomy with RT, or lumpectomy (alone or with RT) and mastectomy. These results suggest that less aggressive treatment may be appropriate for a subset of male breast cancer patients.

Hyperglycemia during pregnancy and gestational diabetes mellitus (GDM) constitute an important public health problem due to their prevalence and long-term health consequences both for the mother and offspring. Results from studies in rodents and some clinical investigations suggest that meal time manipulation may be a potential lifestyle approach against conditions involving perturbations in glucose homeostasis (e.g., hyperglycemia, insulin resistance, diabetes, etc.). The purpose of this review is to summarize and critically evaluate the current literature on the role of meal timing and daily nutrient distribution on glycemic control during pregnancy. Only a small number of mostly observational studies have assessed the role of meal timing in glucose homeostasis during pregnancy. Food consumption earlier in the day and short-term fasting with adequate nutrient intake may improve glycemic control during the second and third trimester of gestation. Considering that the field of chrononutrition is still in its infancy and many questions remain unanswered, future prospective and carefully designed studies are needed to better understand the role of meal timing in metabolic homeostasis and maternal and fetal health outcomes during pregnancy.

Hormones mediate physiological and behavioral changes in adults as they transition into reproduction. In this study, we characterize the circulating levels of five key hormones involved in reproduction in rock doves (Columba livia): corticosterone, progesterone, estradiol, testosterone, and prolactin using univariate and multivariate approaches. We show similar patterns as previous studies in the overall patterns in circulating levels of these hormones, i.e., testosterone (males) and estradiol (females) high during nest-building or egg-laying, prolactin increasing at mid-incubation and peaking at hatching (both sexes), and elevated corticosterone levels in later incubation and early nestling development. In our investigation of hormone co-variation, we find a strong correlation between prolactin and corticosterone across sampling stages and similarities in earlier (early to mid-incubation) compared to later (late incubation to nestling d9) sampling stages in males and females. Finally, we utilized experimental manipulations to simulate nest loss or altered caregiving lengths to test whether external cues, internal timing, or a combination of these factors contributed most to hormone variation. Following nest loss, we found that both males and females responded to the external cue. Males generally responded quickly following nest loss by increasing circulating testosterone, but this response was muted when nest loss occurred early in reproduction. Similar treatment type, e.g., removal of eggs, clustered similarly in hormone space. These results suggest internal drivers limited male response early in reproduction to nest loss. In contrast, circulating levels of these hormones in females either did not change or decreased following nest manipulation suggesting responsiveness to external drivers, but unlike males, this result suggests that reproductive processes were decreasing.

Differences in pancreatic anatomy, size, and function exist in men and women. The anatomical differences could contribute to the increase in complications associated with pancreatic surgery in women. Although diagnostic criteria for pancreatitis are the same in men and women, major sex differences in etiology are reported. Alcohol and tobacco predominate in men, whereas idiopathic and obstructive etiologies predominate in women. Circulating levels of estrogens, progesterone, and androgens contribute significantly to overall health outcomes; premenopausal women have lower prevalence of cardiovascular and pancreatic diseases suggesting protective effects of estrogens, whereas androgens promote growth of normal and cancerous cells. Sex chromosomes and gonadal and nongonadal hormones together determine an individual's sex, which is distinct from gender or gender identity. Human pancreatic disease etiology, outcomes, and sex-specific mechanisms are largely unknown. In rodents of both sexes, glucocorticoids and estrogens from the adrenal glands influence pancreatic secretion and acinar cell zymogen granule numbers. Lack of corticotropin-releasing factor receptor 2 function, a G protein-coupled receptor whose expression is regulated by both estrogens and glucocorticoids, causes sex-specific changes in pancreatic histopathology, zymogen granule numbers, and endoplasmic reticulum ultrastructure changes in acute pancreatitis model. Here, we review existing literature on sex differences in the normal exocrine pancreas and mechanisms that operate at homeostasis and diseased states in both sexes. Finally, we review pregnancy-related pancreatic diseases and discuss the effects of sex differences on proposed treatments in pancreatic disease.

Alterations in myelin, the protective and insulating sheath surrounding axons, affect brain function, as is evident in demyelinating diseases where the loss of myelin leads to cognitive and motor dysfunction. Recent evidence suggests that changes in myelination, including both hyper- and hypo-myelination, may also play a role in numerous neurological and psychiatric diseases. Protecting myelin and promoting remyelination is thus crucial for a wide range of disorders. Oligodendrocytes (OLs) are the cells that generate myelin, and oligodendrogenesis, the creation of new OLs, continues throughout life and is necessary for myelin plasticity and remyelination. Understanding the regulation of oligodendrogenesis and myelin plasticity within disease contexts is, therefore, critical for the development of novel therapeutic targets. In our companion manuscript, we review literature demonstrating that multiple hormone classes are involved in the regulation of oligodendrogenesis under physiological conditions. The majority of hormones enhance oligodendrogenesis, increasing oligodendrocyte precursor cell differentiation and inducing maturation and myelin production in OLs. Thus, hormonal treatments present a promising route to promote remyelination. Here, we review the literature on hormonal regulation of oligodendrogenesis within the context of disorders. We focus on steroid hormones, including glucocorticoids and sex hormones, peptide hormones such as insulin-like growth factor 1, and thyroid hormones. For each hormone, we describe whether they aid in OL survival, differentiation, or remyelination, and we discuss their mechanisms of action, if known. Several of these hormones have yielded promising results in both animal models and in human conditions; however, a better understanding of hormonal effects, interactions, and their mechanisms will ultimately lead to more targeted therapeutics for myelin repair.

ObjectiveBilateral salpingo-oophorectomy (oophorectomy) is recommended to women with a germline BRCA1 or BRCA2 mutation before natural menopause to prevent ovarian and fallopian tube cancer. The adverse effects of early surgical menopause are well established. Although many of the side effects can be ameliorated by the use of hormone therapy (HT); use of HT in this group of predominantly young patients remains suboptimal. The goal of this study was to identify the frequency of HT use, as well as predictors of HT uptake in BRCA mutation carriers who underwent preventive oophorectomy before natural menopause.MethodsEligible participants were identified from a longitudinal study of BRCA mutation carriers. We included premenopausal women with no personal history of cancer who underwent oophorectomy before age 50 and who had a minimum of 2 years of follow-up. Detailed information on HT use and other important variables was collected by a research questionnaire every 2 years. Descriptive statistics were used to evaluate the use of HT in various subgroups.ResultsA total of 793 women with a BRCA1 or BRCA2 mutation were included in this analysis. The mean age at oophorectomy was 42 years (range 28-49). Sixty-one percent of the women reported using HT after oophorectomy. Factors associated with HT use included young age at surgery, a high level of education and preventive mastectomy.ConclusionsThe uptake of HT after oophorectomy in women with a BRCA1 or BRCA2 mutation varies by age, education, and surgical history. Clinician and patient awareness may lead to better utilization of HT in women who undergo oophorectomy at an early age to help mitigate the adverse effects associated with surgical menopause.

The present study examined the impact of hormonal differences between late follicular (LF) and midluteal (ML) phases on restoration of fluid balance following dehydration. Ten eumenorrheic female participants were dehydrated by 2% of their body mass through overnight fluid restriction followed by exercise-heat stress. Trials were undertaken during the LF (between Days 10 and 13 of the menstrual cycle) and ML phases (between Days 18 and 23 of the menstrual cycle) with one phase repeated to assess reliability of observations. Following dehydration, participants ingested a volume equivalent to 100% of mass loss of a commercially available sports drink in four equal volumes over 30 min. Mean serum values for steroid hormones during the ML (estradiol [E2]: 92 ± 11 pg/ml, progesterone: 19 ± 4 ng/ml) and LF (estradiol [E2]: 232 ± 64 pg/ml, progesterone: 3 ± 2 ng/ml) were significantly different between phases. Urine tests confirmed no luteinizing hormone surge evident during LF trials. There was no effect of menstrual cycle phase on cumulative urine volume during the 3-hr rehydration period (ML: 630 [197--935] ml, LF: 649 [180--845] ml) with percentage of fluid retained being 47% (33--85)% on ML and 46% (37--89)% on LF (p = .29). There was no association between the progesterone:estradiol ratio and fluid retained in either phase. Net fluid balance, urine osmolality, and thirst intensity were not different between phases. No differences in sodium (ML: -61 [-36 to -131] mmol, LF: -73 [-5 to -118] mmol; p = .45) or potassium (ML: -36 [-11 to -80] mmol, LF: -30 [-19 to -89] mmol; p = .96) balance were observed. Fluid replacement after dehydration does not appear to be affected by normal hormonal fluctuations during the menstrual cycle in eumenorrheic young women. [ABSTRACT FROM AUTHOR]

BackgroundIntrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC.MethodsWe harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases).ResultsHysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors.ConclusionsThis study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

No organ in the body is impervious to the effects of stress, and a coordinated response from all organs is essential to deal with stressors. A dysregulated stress response that fails to bring systems back to homeostasis leads to compromised function and ultimately a diseased state. The components of the corticotropin-releasing factor (CRF) family, an ancient and evolutionarily conserved stress hormone-receptor system, helps both initiate stress responses and bring systems back to homeostasis once the stressors are removed. The mammalian CRF family comprises of four known agonists, CRF and urocortins (UCN1-3), and two known G protein-coupled receptors (GPCRs), CRF1 and CRF2. Evolutionarily, precursors of CRF- and urocortin-like peptides and their receptors were involved in osmoregulation/diuretic functions, in addition to nutrient sensing. Both CRF and UCN1 peptide hormones as well as their receptors appeared after a duplication event nearly 400 million years ago. All four agonists and both CRF receptors show sex-specific changes in expression and/or function, and single nucleotide polymorphisms are associated with a plethora of human diseases. CRF receptors harbor N-terminal cleavable peptide sequences, conferring biased ligand properties. CRF receptors have the ability to heteromerize with each other as well as with other GPCRs. Taken together, CRF receptors and their agonists due to their versatile functional adaptability mediate nuanced responses and are uniquely positioned to orchestrate sex-specific signaling and function in several tissues.

BackgroundObesity is a risk factor for insulin resistance (IR) and metabolic disease.ObjectiveTo examine potential metabolic pathways linking childhood weight status to adolescent IR and metabolic risk.MethodsParticipants were 600 low- to middle-income Chilean adolescents from a cohort studied since infancy as part of an iron deficiency anemia preventive trial and follow-up study. We examined body mass index z-score at 10 y (BMIz-10y) and blood pressure, total fat, and fasting glucose, adiponectin to leptin ratio (A:L), ghrelin, and HOMA-IR at 16 y. A total count for metabolic risk factors (MRF) was calculated using the International Diabetes Federation criteria. We used path analysis to estimate pathways and model indirect effects from BMIz-10y, controlling for child age and sex and maternal body mass index (BMI).ResultsParticipants were 54% male; mean BMIz-10y of 0.53 (SD = 1.02); mean MRF of 1.3 (SD = 0.9); mean HOMA-IR of 1.8 (SD = 1.3). Path analysis showed that BMIz-10y directly and indirectly related to increased MRF via A:L and HOMA-IR. Ghrelin was not in the metabolic pathway from BMIz-10y to MRF but was related to MRF via HOMA-IR.ConclusionThese results elucidate metabolic pathways involving child weight status, IR and metabolic risk in adolescents. Childhood BMI was an indirect risk factor for adolescent cardiometabolic risk via several pathways that involved BMI, appetite hormones, markers of inflammation, and insulin resistance during adolescence. Findings illustrate the adverse effect that childhood obesity has on adolescent health outcomes, which sets precedence for health outcomes over the life course.

BackgroundMaternal milk production requires the neuropeptide oxytocin. Individual variation in oxytocin function is a compelling target for understanding low milk production, a leading cause of breastfeeding attrition. Complicating the understanding of oxytocin pathways is that vasopressin may interact with oxytocin receptors, yet little is known about the role of vasopressin in lactation.Research aimsThe aims of this study were (1) to describe maternal plasma oxytocin, vasopressin, and prolactin patterns during breastfeeding following low-risk spontaneous labor and birth in healthy first-time mothers and (2) to relate hormone patterns to maternal characteristics and breastfeeding measures.MethodsEligible women were recruited before hospital discharge. Forty-six participants enrolled and 35 attended the study visit. Participants kept a journal of breastfeeding frequency, symptoms of lactogenesis, and infant weight. Plasma samples were obtained at breastfeeding onset on Day 4-5 postpartum, and repeated after 20 min. Hormones were measured with immunoassays. Infant weight change, milk transfer, and onset of lactogenesis were also measured.ResultsBaseline oxytocin and vasopressin were inversely related to one another. Oxytocin and prolactin increased significantly across the 20-min sampling period while vasopressin decreased. Higher oxytocin was associated with higher maternal age, lower BMI, shorter active labor, physiologic labor progression, and less weight loss in the newborn. Higher vasopressin correlated with younger maternal age, higher BMI, and greater newborn weight loss.ConclusionsOxytocin and vasopressin have contrasting relationships with maternal clinical characteristics and newborn weight gain in early breastfeeding infants. Further study is needed to understand how oxytocin and vasopressin influence lactation outcomes.

Polybrominated diphenyl ethers (PBDEs) are brominated flame retardant chemicals and environmental contaminants with endocrine-disrupting properties that are associated with diabetes and metabolic syndrome in humans. However, their diabetogenic actions are not completely characterized or understood. In this study, we investigated the effects of DE-71, a commercial penta-mixture of PBDEs, on glucoregulatory parameters in a perinatal exposure model using female C57Bl/6 mice. Results from in vivo glucose and insulin tolerance tests and ex vivo analyses revealed fasting hyperglycemia, glucose intolerance, reduced sensitivity and delayed glucose clearance after insulin challenge, decreased thermogenic brown adipose tissue mass, and exaggerated hepatic endocannabinoid tone in F1 offspring exposed to 0.1 mg/kg DE-71 relative to control. DE-71 effects on F0 dams were more limited indicating that indirect exposure to developing offspring is more detrimental. Other ex vivo glycemic correlates occurred more generally in exposed F0 and F1, i.e., reduced plasma insulin and altered glucoregulatory endocrines, exaggerated sympathoadrenal activity and reduced hepatic glutamate dehydrogenase enzymatic activity. Hepatic PBDE congener analysis indicated maternal transfer of BDE-28 and -153 to F1 at a collective level of 200 ng/g lipid, in range with maximum values detected in serum of human females. Given the persistent diabetogenic phenotype, especially pronounced in female offspring after developmental exposure to environmentally relevant levels of DE-71, additional animal studies should be conducted that further characterize PBDE-induced diabetic pathophysiology and identify critical developmental time windows of susceptibility. Longitudinal human studies should also be conducted to determine the risk of long-lasting metabolic consequences after maternal transfer of PBDEs during early-life development.

Giant pandas are mono-estrus seasonal breeders, with the breeding season typically occurring in the spring. Successful fertilization is followed by an embryonic diapause, of variable length, with birth in the late summer/autumn. There is a need for additional understanding of giant panda reproductive physiology, and the development of enhanced biomarkers for impending proestrus and peak fertility. We aimed to determine the utility of non-invasive androgen measurements in the detection of both proestrus and estrus. Urine from 20 cycles (−40 days to +10 days from peak estrus) from 5 female giant pandas was analyzed for estrogen, progestogens and androgens (via testosterone and DHEA assays), and hormone concentrations were corrected against urinary specific gravity. Across proestrus, estrogens increased while progestogens and androgens decreased – at the point of entry into proestrus, androgens (as detected by the testosterone assay) decreased prior to progestogens and gave 4 days advanced warning of proestrus. At the time of peak estrus, androgens (as detected by the DHEA assay) were significantly increased at the time of the decrease in estrogen metabolites from the peak, acting as an alternative confirmatory indicator of the fertile window. This novel finding allows for enlargement of the preparative window for captive breeding and facilitates panda management within breeding programmes. Androgens allow an enhanced monitoring of giant panda estrus, not only advancing the warning of impending proestrus, but also prospectively identifying peak fertility.

Cirrhosis is associated with hormonal dysregulation, as evidenced by secondary amenorrhoea in reproductive-aged women, and feminization of cirrhotic men. Whether hormone levels vary by severity of cirrhosis in women is not known. If identified, such changes may have important clinical relevance, particularly, as low sex hormone binding globulin (SHBG) and follicle stimulating hormone (FSH) are known to promote metabolic and cardiovascular disease in women. In a cohort of post-menopausal women with chronic hepatitis C virus (HCV) infection, we compared comprehensive sex hormone levels by presence of cirrhosis, as well as across Child-Turcotte-Pugh (CTP) class. Results: There were n = 18 cirrhotic and n = 21 noncirrhotic women with a median age of 57 years (interquartile range [IQR] 53-62). Compared to noncirrhotics, cirrhotic women had higher oestradiol (11.0 vs 6.0 pg/mL, P = 0.05) and oestrone levels (32.0 vs 8.0 ng/mL, P

Alzheimer's disease (AD) begins several decades before the onset of clinical symptoms, at a time when women may still undergo reproductive cycling. Whether ovarian functions alter substrates of AD pathogenesis is unknown. Here we show that ovarian cycle stages significantly modulate AD-related alterations in neural network patterns, cognitive impairments, and pathogenic protein production in the hAPP-J20 mouse model of AD. Female hAPP mice spent more time in estrogen-dominant cycle stages and these ovarian stages worsened AD-related network dysfunction and cognitive impairments. In contrast, progesterone-dominant stages and gonadectomy attenuated these AD-related deficits. Further studies revealed a direct role for estradiol in stimulating neural network excitability and susceptibility to seizures in hAPP mice and increasing amyloid beta levels. Understanding dynamic effects of the ovarian cycle on the female nervous system in disease, including AD, is of critical importance and may differ from effects on a healthy brain. The pattern of ovarian cycle effects on disease-related networks, cognition, and pathogenic protein expression may be relevant to young women at risk for AD.

OBJECTIVE: To identify associations between circulating endocannabinoids and craving during the luteal phase of the menstrual cycle. This report is a secondary analysis of a trial registered in clinicaltrials.gov as NCT01407692. METHODS: Seventeen premenopausal women were studied during the follicular and luteal phases of their menstrual cycle. Previously we had reported fasting plasma estradiol, progesterone, leptin associations with luteal phase cravings for carbohydrate, fat, sweet-rich foods, and eating behavior. Here, we measured fasting plasma endocannabinoids (ECs) endocannabinoid-like substances (ECLs), and postprandial metabolic responses to a mixed meal challenge. Structural equation modeling was used to evaluate relationships between measured variables and cravings. RESULTS: Oleoylethanolamide (OEA) and postprandial lipids were inversely associated with craving sweet-rich foods, while progesterone was positively associated (RMSEA = 0.041, χ2 p: 0.416 i.e. hypothetical and physiological models not different). OEA, progesterone and disinhibition were positively associated with craving carbohydrates (RMSEA:

Parabens have been used as antimicrobial preservatives since the 1920s. The prevalent use of parabens increases their detection in the environment and in women's biological samples including reproductive tissues. Recent studies suggest parabens may alter endocrine function and thus female reproductive health may be affected. In this literature review, we summarize findings on parabens and female reproduction while focusing on epidemiological and rodent-based studies. The topics reviewed include paraben effects on cyclicity, pregnancy, newborn and pubertal development, reproductive hormones, and ovarian and uterine specific outcomes. Overall, the scientific literature on paraben effects on female reproduction is limited and with some conflicting results. Yet, some epidemiological and/or rodent-based experimental studies report significant findings in relation to paraben effects on cyclicity, fertility, gestation length, birth weight, postnatal development and pubertal onset, hormone levels, and hormone signaling in reproductive tissues. Future epidemiological and experimental studies are needed to better understand paraben effects on female reproduction while focusing on human related exposures including mixtures, physiologic concentrations of parabens, and multi-generational studies. [Display omitted] • Paraben exposure may impact reproductive cyclicity, fertility, and pregnancy outcomes, yet findings are often limited or inconsistent. • Limited research suggests paraben exposure may alter reproductive and thyroid hormone levels, in pregnant and non-pregnant females. • Research gaps exist in the study of paraben effects on ovarian and uterine function and pathologies. • Future research should also focus on human-relevant doses, paraben mixtures, and longer exposure durations. [ABSTRACT FROM AUTHOR]

In contrast to a large body of work concerning the effects of physiological stress reactivity on children's socioemotional functioning, far less attention has been devoted to understanding the effects of such reactivity on cognitive, including mnemonic, functioning. How well children learn and remember information under stress has implications for a range of educational, clinical, and legal outcomes. We evaluated 8-14 year olds' (N = 94, 50 female) memory for negative, neutral, and positive images. Youth had seen the images a week previously as a part of a laboratory stress task. At encoding and retrieval, and in between, youth provided saliva samples that were later assayed for cortisol, salivary α amylase (sAA), testosterone, and dehydroepiandrosterone (DHEA). Overall, higher cortisol reactivity to the lab task predicted enhanced memory for emotional but not neutral images. However, cortisol further interacted with pubertal hormones (testosterone and DHEA) to predict memory. Among girls with lower pubertal hormone levels, greater cortisol reactivity was associated with enhanced memory for negative information, whereas among boys with higher pubertal hormone levels, cortisol reactivity was associated with enhanced memory for positive information. sAA, was unrelated to memory. Overall, our findings reveal that individual differences in hormone levels associated with pubertal development have implications for our understanding of how stress-responsive biological systems directly and interactively influence cognitive outcomes. (PsycINFO Database Record

Background parenchymal enhancement (BPE) is the degree to which normal breast tissue enhances on contrast-enhanced magnetic resonance imaging (MRI). MRI-density is a volumetric measure of breast density that is highly correlated with mammographic density, an established breast cancer risk factor. Endogenous estrogen concentrations are positively associated with postmenopausal breast cancer risk and BPE has been shown to be sensitive to hormonal exposures. The objective of our study was to examine the relationship between BPE and MRI-density and serum hormone concentrations in postmenopausal women. This was a study of cancer-free postmenopausal women undergoing contrast-enhanced breast MRI (N = 118). At the time of MRI all women completed a self-administered questionnaire and blood samples were collected for hormone analyses. Serum concentrations of estrone (E1), estradiol (E2) and bioavailable E2 were examined by category of BPE and MRI-density. Compared to women with minimal BPE, those who had marked BPE had significantly higher serum concentrations of E1, E2 and bioavailable E2 (90% increase, ptrend across all categories = 0.001; 150% increase, ptrend  = 0.001; and 158% increase, ptrend  = 0.001, respectively). These associations were only affected to a minor extent by adjustment for BMI and other variables. After adjustment for BMI, no significant associations between MRI-density and serum E1, E2 and bioavailable E2 were observed. Serum estrogen concentrations were significantly positively associated with BPE. Our study provides further evidence of the hormone-sensitive nature of BPE, indicating a potential role for BPE as an imaging marker of endogenous and exogenous hormonal exposures in the breast.

In order to reduce gender dysphoria and combat stigma, transgender women often affirm their gender through social and medical transition, which may include cross-sex hormone therapy. This study examined associations between medically monitored hormone use and hormone misuse (non-prescribed hormone use including "fillers"), structural inequities (access to housing, health insurance, and income), and social network dynamics among 271 transgender women in Los Angeles. Hormone use status was coded trichotomously (hormone use, hormone misuse, no hormone use), and robust multinomial logistic regression as well as novel social network analysis was conducted to examine associations. Results demonstrated that younger, African-American/Black transgender women were most likely to engage in hormone misuse compared to transgender women who were older or non-African-American/Black. One-third of the sample reported sex work as a main source of income, and this group was more likely to misuse hormones than those with another primary source of income. Transgender women with access to stable housing and health insurance were most likely to engage in medically monitored hormone use. Social network analysis revealed that transgender women with a greater number of hormone-using network alters were most likely to misuse hormones, but that using the Internet to find transgender friends mitigated this association. Results demonstrate the multifaceted risk profile of transgender women who use and misuse hormones, including that social networks play an important role in hormone usage among transgender women.

Although individuals age and die with time, an animal species can continue indefinitely, because of its immortal germ-cell lineage. How the germline avoids transmitting damage from one generation to the next remains a fundamental question in biology. Here we identify a lysosomal switch that enhances germline proteostasis before fertilization. We find that Caenorhabditis elegans oocytes whose maturation is arrested by the absence of sperm exhibit hallmarks of proteostasis collapse, including protein aggregation. Remarkably, sperm-secreted hormones re-establish oocyte proteostasis once fertilization becomes imminent. Key to this restoration is activation of the vacuolar H+-ATPase (V-ATPase), a proton pump that acidifies lysosomes. Sperm stimulate V-ATPase activity in oocytes by signalling the degradation of GLD-1, a translational repressor that blocks V-ATPase synthesis. Activated lysosomes, in turn, promote a metabolic shift that mobilizes protein aggregates for degradation, and reset proteostasis by enveloping and clearing the aggregates. Lysosome acidification also occurs during Xenopus oocyte maturation; thus, a lysosomal switch that enhances oocyte proteostasis in anticipation of fertilization may be conserved in other species.

Parental care by fathers, although rare among mmmals, can be essential for the survival and normal development of offspring in biparental species. A growing body of research on biparental rodents has identified several developmental and experiential influences on paternal responsiveness. Some of these factors, such as pubertal maturation, interactions with pups, and cues from a pregnant mate, contribute to pronounced changes in paternal responsiveness across the course of the lifetime in individual males. Others, particularly intrauterine position during gestation and parental care received during postnatal development, can have long-term effects on paternal behavior and contribute to stable differences among individuals within a species. Focusing on five well-studied, biparental rodent species, we review the developmental and experiential factors that have been shown to influence paternal responsiveness, and consider their roles in generating both intra- and inter-individual variation. We also review hormones and neuropeptides that have been shown to modulate paternal care and discuss their potential contributions to behavioral differences within and between males. Finally, we discuss the possibility that vasopressinergic and possibly oxytocinergic signaling within the brain, modulated by gonadal steroid hormones, may represent the "final common pathway" mediating effects of developmental and experiential variables on intra- and inter-individual variation in paternal care.

Essentials Endogenous hormone levels' influence on hemostatic factor levels is not fully characterized. We tested for associations of endogenous hormone with hemostatic factor levels in postmenopause. Estrone levels were inversely associated with the natural anticoagulant, protein S antigen. Dehydroepiandrosterone sulfate levels were inversely associated with thrombin generation.SummaryBackground Oral use of exogenous estrogen/progestin alters hemostatic factor levels. The influence of endogenous hormones on these levels is incompletely characterized. Objectives Our study aimed to test whether, among postmenopausal women, high levels of estradiol (E2), estrone (E1), testosterone (T), dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), and androstenedione, and low levels of sex hormone-binding globulin (SHBG), are positively associated with measures of thrombin generation (TG), a normalized activated protein C sensitivity ratio (nAPCsr), and factor VII activity (FVIIc), and negatively associated with antithrombin activity (ATc) and total protein S antigen (PSAg). Methods This Heart and Vascular Health study cross-sectional analysis included 131 postmenopausal women without a prior venous thrombosis who were not currently using hormone therapy. Adjusted mean differences in TG, nAPCsr, FVIIc, ATc and PSAg levels associated with differences in hormone levels were estimated using multiple linear regression. We measured E2, E1, total T, DHEAS, DHEA and androstenedione levels by mass spectrometry, SHBG levels by immunoassay, and calculated the level of free T. Results One picogram per milliliter higher E1 levels were associated with 0.24% lower PSAg levels (95% Confidence Interval [CI]: -0.35, -0.12) and 1 μg mL-1 higher DHEAS levels were associated with 40.8 nm lower TG peak values (95% CI: -59.5, -22.2) and 140.7 nm×min lower TG endogenous thrombin potential (ETP) (95% CI: -212.1, -69.4). After multiple comparisons correction, there was no evidence for other associations. Conclusions As hypothesized, higher E1 levels were associated with lower levels of the natural anticoagulant PSAg. Contrary to hypotheses, higher DHEAS levels were associated with differences in TG peak and ETP that suggest less generation of thrombin.