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Opioids are the most prescribed drugs for the alleviation of pain. Both clinical and preclinical studies have reported strong evidence for sex-related divergence regarding opioid analgesia. There is an increasing amount of evidence indicating that gonadal hormones regulate the analgesic efficacy of opioids. This review presents an overview of the importance of gonadal steroids in modulating opioid analgesic responsiveness and focuses on elaborating what is currently known regarding the underlyingmechanism. We sought to identify the link between gonadal hormones and the effect of oipiod antinociception.

An important aspect of the neuromodulatory and neuroprotective actions exerted by neuroactive steroids is that they are sex-specific, as determined by the sexually dimorphic levels of these molecules in plasma and the nervous tissue. Thus, the identification of the factors that generate the sex-dimorphic levels of neuroactive steroids may be crucial from a neuroprotectant perspective. The main driver for sex determination in mammals is the SRY gene and the subsequent presence of a specific gonad: testes for males and ovaries for females, thus producing hormonal compounds, primarily androgens and estrogens, respectively. Nowadays, it is well established that despite the relevance of gonads, other factors control sexual features, and, among them, sex chromosome complement is highly relevant. In this study, neuroactive steroids were evaluated by liquid chromatography-tandem mass spectrometry in the hypothalamus, the hippocampus, and plasma of the four core genotype mouse model, to determine the relative contribution of sex chromosome complement and gonads in determining their sex dimorphic levels. The data obtained reveal that although gonads are the main contributing factor for sex differences in neuroactive steroid levels, the levels of some neuroactive steroids, including testosterone, are also influenced in brain and plasma by tissue-specific actions of sex chromosomes. The data presented here adds a new piece to the puzzle of steroid level regulation, which may be useful in designing sex-specific neuroprotective approaches to pathological conditions affecting the nervous system., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Gonadal hormone deprivation (GHD) and decline such as menopause and bilateral oophorectomy are associated with an increased risk of neurodegeneration. Yet, hormone therapies (HTs) show varying efficacy, influenced by factors such as sex, drug type, and timing of treatment relative to hormone decline. We hypothesize that the molecular environment of the brain undergoes a transition following GHD, impacting the effectiveness of HTs. Using a GHD model in mice treated with Tibolone, we conducted proteomic analysis and identified a reprogrammed response to Tibolone, a compound that stimulates estrogenic, progestogenic, and androgenic pathways. Through a comprehensive network pharmacological workflow, we identified a reprogrammed response to Tibolone, particularly within "Pathways of Neurodegeneration", as well as interconnected pathways including "cellular respiration", "carbon metabolism", and "cellular homeostasis". Analysis revealed 23 proteins whose Tibolone response depended on GHD and/or sex, implicating critical processes like oxidative phosphorylation and calcium signalling. Our findings suggest the therapeutic efficacy of HTs may depend on these variables, suggesting a need for greater precision medicine considerations whilst highlighting the need to uncover underlying mechanisms., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The socially monogamous prairie vole (Microtus ochrogaster) and promiscuous meadow vole (Microtus pennsylvanicus) are closely related, but only prairie voles display long-lasting pair bonds, biparental care, and selective aggression towards unfamiliar individuals after pair bonding. These social behaviors in mammals are largely mediated by steroid hormone signaling in the social behavior network (SBN) of the brain. Hormone receptors are reproducible markers of sex differences that can provide more information than anatomy alone and can even be at odds with anatomical dimorphisms. We reasoned that behaviors associated with social monogamy in prairie voles may emerge in part from unique expression patterns of steroid hormone receptors in this species, and that these expression patterns would be more similar across males and females in prairie than in meadow voles or the laboratory mouse. To obtain insight into steroid hormone signaling in the developing prairie vole brain, we assessed expression of estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), and androgen receptor (Ar) within the SBN, using in situ hybridization at postnatal day 14 in mice, meadow, and prairie voles. We found species-specific patterns of hormone receptor expression in the hippocampus and ventromedial hypothalamus, as well as species differences in the sex bias of these markers in the principal nucleus of the bed nucleus of the stria terminalis. These findings suggest the observed differences in gonadal hormone receptor expression may underlie species differences in the display of social behaviors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Epigenetic alterations such as dysregulation of miRNAs have been reported to play important roles in interactions between genetic and environmental factors. In this study, we tested the hypothesis that induction of lung inflammation by inhaled allergens triggers a sex-specific miRNA regulation that is dependent on chromosome complement and hormonal milieu. We challenged the four core genotypes (FCGs) model through intranasal sensitization with a house dust mite (HDM) solution (or PBS as a control) for 5 wk. The FCG model allows four combinations of gonads and sex chromosomes: 1 ) XX mice with ovaries (XXF), 2 ) XY mice with testes (XYM), 3 ) XX mice with testes (XXM), and 4 ) XY mice with ovaries (XYF). Following the challenge ( n = 5-7/group), we assessed the expression of 84 inflammatory miRNAs in lung tissue using a PCR array and cytokine levels in bronchoalveolar lavage fluid (BAL) by a multiplex protein assay ( n = 4-7 animals/group). Our results showed higher levels of the chemokine KC (an Il-8 homolog) and IL-7 in BAL from XYF mice challenged with HDM. In addition, IL-17A was significantly higher in BAL from both XXF and XYF mice. A three-way interaction among treatment, gonads, and sex chromosome revealed 60 of 64 miRNAs that differed in expression depending on genotype; XXF, XXM, XYF, and XYM mice had 45, 32, 4, and 52 differentially expressed miRNAs, respectively. Regulatory networks of miRNAs identified in this study were implicated in pathways associated with asthma. Female gonadal hormonal effects may alter miRNA expression and contribute to the higher susceptibility of females to asthma. NEW & NOTEWORTHY miRNAs play important roles in regulating gene and environmental interactions. However, their role in mediating sex differences in allergic responses and lung diseases has not been elucidated. Our study used a targeted omics approach to characterize the contributions of gonadal hormones and chromosomal components to lung responses to an allergen challenge. Our results point to the influence of sex hormones in miRNA expression and proinflammatory markers in allergic airway inflammation.

There is a strong male bias in the prevalence of many neurodevelopmental disorders such as autism spectrum disorder. However, the mechanisms underlying this sex bias remain elusive. Infection during the perinatal period is associated with an increased risk of neurodevelopmental disorder development. Here, we used a mouse model of early-life immune activation that reliably induces deficits in social behaviors only in males. We demonstrate that male-biased alterations in social behavior are dependent upon microglial immune signaling and are coupled to alterations in mitochondrial morphology, gene expression, and function specifically within microglia, the innate immune cells of the brain. Additionally, we show that this behavioral and microglial mitochondrial vulnerability to early-life immune activation is programmed by the male-typical perinatal gonadal hormone surge. These findings demonstrate that social behavior in males over the lifespan are regulated by microglia-specific mechanisms that are shaped by events that occur in early development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The insulin-like androgenic gland hormone gene (IAG), primarily expressed in the androgenic gland (AG), plays a crucial role in controlling male sex differentiation and maintaining male secondary sexual characteristics in decapods. In this study, we investigated the mRNA and microRNA expression profiles of male Procambarus clarkii to understand the transcriptomic regulatory mechanism of IAG after the injection of an efficient siRNA (GsiRNA) designed based on IAG. The results revealed that several differentially expressed genes were enriched in reproduction-related pathways, such as the wnt signaling pathway, MAPK signaling pathway, and GnRH signaling pathway. In the testis (Te), the injection of GsiRNA led to the up-regulation of many ovary-related genes and down-regulation of testis-related genes. Moreover, the brain (Br) and abdominal nerve cord (AN) appeared to be involved in the regulation of IAG, with numerous differentially expressed genes found in Br and AN. Notably, the expression of five neuropeptide genes, Crustacean hyperglycemic hormone, pigment-dispersing hormone, red pigment concentrating hormone precursor, corazonin, and gonadotropin-releasing hormone II receptor isoform X1 in Br/AN, was significantly changed. Additionally, three ovary-related miRNAs (miR-263a, miR-263b, miR-133) highly expressed in Te/AG showed significant up-regulation after GsiRNA injection. Furthermore, the long-term interference of GsiRNA was found to inhibit the development of male external sexual characteristics during the juvenile stage and delay it during the adult stage. This research provides valuable insights into the molecular regulatory mechanism and function of IAG in P. clarkii., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Statins have been shown to cause diverse male reproductive function impairment, and in some cases, orchialgia. Therefore, the current study investigated the possible mechanisms through which statins may alter male reproductive parameters. Thirty adult male Wistar rats (200-250 g) were divided into three groups. The animals were orally administered rosuvastatin (50 mg/kg), simvastatin (50 mg/kg), or 0.5% carboxy methyl cellulose (control), for a 30-day period. Spermatozoa were retrieved from the caudal epididymis for sperm analysis. The testis was used for all biochemical assays and immunofluorescent localization of biomarkers of interest. Rosuvastatin-treated animals presented with a significant decrease in sperm concentration when compared to both the control and simvastatin groups ( p < 0.005). While no significant difference was observed between the simvastatin and the control group. The Sertoli cells, Leydig cells and whole testicular tissue homogenate expressed transcripts of solute carrier organic anion transporters ( SLCO1B1 and SLCO1B3 ). There was a significant decrease in the testicular protein expression of the luteinizing hormone receptor, follicle stimulating hormone receptor, and transient receptor potential vanilloid 1 in the rosuvastatin and simvastatin-treated animals compared to the control. The expression of SLCO1B1 , SLCO1B2 , and SLCO1B3 in the different spermatogenic cells portray that un-bio transformed statin can be transported into the testicular microenvironment, which can subsequently alter the regulation of the gonadal hormone receptors, dysregulate pain-inflammatory biomarkers, and consequently impair sperm concentration.

For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones to the generation of sex differences in the developing brain and the expression of sex-specific physiological and behavioral phenotypes in adulthood. However, it was not until recent years that the role of sex chromosomes in the matter started to be seriously explored and unveiled beyond gonadal determination. Now we know that the divergent evolutionary process suffered by X and Y chromosomes has determined that they now encode mostly dissimilar genetic information and are subject to different epigenetic regulations, characteristics that together contribute to generate sex differences between XX and XY cells/individuals from the zygote throughout life. Here we will review and discuss relevant data showing how particular X- and Y-linked genes and epigenetic mechanisms controlling their expression and inheritance are involved, along with or independently of gonadal hormones, in the generation of sex differences in the brain.

Understanding sex differences in physiology and disease requires the identification of the molecular agents that cause phenotypic sex differences. Two groups of such agents are genes located on the sex chromosomes, and gonadal hormones. The former have coherent linkage to chromosomes that form differently in the two sexes under the influence of genomic forces that are not related to reproductive function, whereas the latter have a direct or indirect relationship to reproduction. Evidence published in the past 5 years supports the identification of several agents of sexual differentiation encoded by the X chromosome in mice, including Kdm5c, Kdm6a, Ogt and Xist. These X chromosome agents have wide pleiotropic effects, potentially influencing sex differences in many different tissues, a characteristic shared with the gonadal hormones. The identification of X chromosome agents of sexual differentiation will facilitate understanding of complex intersecting gene pathways underlying sex differences in disease., (© 2022. Springer Nature Limited.)

Gonadal hormone deficiency is associated with the development of depression, but what mediates this association is unclear. To test the possibility that it reflects neuroimmune and neuroinflammatory processes, we analyzed how gonadal hormone deficiency and replacement affect microglial activation and inflammatory response during the development of depressive symptomatology in gonadectomized male mice. Testosterone level and the ratio of testosterone to estradiol in the serum and brain tissue of mice exposed to 3-35 days of chronic unpredictable stress were much lower than in control animals. Gonadal hormone sustained deficiency in gonadectomized mice and subsequent led to acute inflammation at day 7 following castration. Activating microglia in mice exposed to 7 days of castration subsequently suppressed the proliferation of microglia, such that their numbers in hippocampus and cortex were lower than the numbers in sham-operated mice after 30 days of castration. Here, we showed that gonadal hormone deficiency induces Traf6-mediated microglia activation, a type of inflammatory mediator. Microglia treated in this way for long time showed down-regulation of activation markers, abnormal morphology and depressive-like behaviors. Restoration and maintenance of a fixed ratio of testosterone to estradiol significantly suppressed microglial activation, neuronal necroptosis, dramatically inducing hippocampal neurogenesis and reducing depressive behaviors via the suppression of Traf6/TAK1 pathway. These findings suggest that activated or immunoreactive microglia contribute to gonadal hormone deficiency-induced depression, as well as testosterone and estradiol exert synergistic anti-depressant effects via suppressing microglial activaton in gonadectomized male mice, possibly through Traf6 signaling., (Copyright © 2022. Published by Elsevier Ltd.)

Sex is a key risk factor for many types of cardiovascular disease. It is imperative to understand the mechanisms underlying sex differences to devise optimal preventive and therapeutic approaches for all individuals. Both biological sex (determined by sex chromosomes and gonadal hormones) and gender (social and cultural behaviors associated with femininity or masculinity) influence differences between men and women in disease susceptibility and pathology. Here, we focus on the application of experimental mouse models that elucidate the influence of 2 components of biological sex-sex chromosome complement (XX or XY) and gonad type (ovaries or testes). These models have revealed that in addition to well-known effects of gonadal hormones, sex chromosome complement influences cardiovascular risk factors, such as plasma cholesterol levels and adiposity, as well as the development of atherosclerosis and pulmonary hypertension. One mechanism by which sex chromosome dosage influences cardiometabolic traits is through sex-biased expression of X chromosome genes that escape X inactivation. These include chromatin-modifying enzymes that regulate gene expression throughout the genome. The identification of factors that determine sex-biased gene expression and cardiometabolic traits will expand our mechanistic understanding of cardiovascular disease processes and provide insight into sex differences that remain throughout the lifespan as gonadal hormone levels alter with age.

Sex differences in physiology and disease in mammals result from the effects of three classes of factors that are inherently unequal in males and females: reversible (activational) effects of gonadal hormones, permanent (organizational) effects of gonadal hormones, and cell-autonomous effects of sex chromosomes, as well as genes driven by these classes of factors. Often, these factors act together to cause sex differences in specific phenotypes, but the relative contribution of each and the interactions among them remain unclear. Here, we used the four core genotypes (FCG) mouse model with or without hormone replacement to distinguish the effects of each class of sex-biasing factors on transcriptome regulation in liver and adipose tissues. We found that the activational hormone levels have the strongest influence on gene expression, followed by the organizational gonadal sex effect, and last, sex chromosomal effect, along with interactions among the three factors. Tissue specificity was prominent, with a major impact of estradiol on adipose tissue gene regulation and of testosterone on the liver transcriptome. The networks affected by the three sex-biasing factors include development, immunity and metabolism, and tissue-specific regulators were identified for these networks. Furthermore, the genes affected by individual sex-biasing factors and interactions among factors are associated with human disease traits such as coronary artery disease, diabetes, and inflammatory bowel disease. Our study offers a tissue-specific account of the individual and interactive contributions of major sex-biasing factors to gene regulation that have broad impact on systemic metabolic, endocrine, and immune functions., (© 2022 Blencowe et al.; Published by Cold Spring Harbor Laboratory Press.)

Previous investigations have revealed that lipopolysaccharide (LPS) endotoxin from certain Gram-negative bacteria could adversely affect the reproductive system of female animals. However, it is unknown whether LPS endotoxin of Mannheimia haemolytica serotype A2, the principal causative bacteria that cause pneumonic mannheimiosis in small ruminants, may also induce similar insidious effects. Therefore, this study aimed to investigate the effects of M. haemolytica serotype A2 and its LPS endotoxin on the responses of female gonadal hormones (progesterone and oestrogen), pro-inflammatory cytokines (interleukin-1β, interleukin-6), acute-phase proteins (haptoglobin and serum amyloid A) and cellular changes via histopathology study of female reproductive organs of the treatment does. Twelve clinically healthy, non-pregnant, crossbred does were randomly allocated into three equal groups. Group 1 was administered intranasally with 2 ml of sterile phosphate-buffered saline (PBS) and served as a negative control group. Group 2 was challenged intranasally with 2 ml of bacterial inoculum containing 10 9 colony-forming units (CFU)/ml of M. haemolytica serotype A2, while Group 3 was challenged intravenously with 2 ml of LPS endotoxin extracted from 10 9  CFU/ml of M. haemolytica serotype A2. Following that, blood samples were collected serially at pre-determined intervals for serological analyses. All does were euthanised 60 days post-challenges, and tissue samples from the ovaries, oviducts, uterine horns, uterine body, cervix and vagina were collected for histopathological study. The serological result revealed a significant increase (p < 0.05) in the mean concentrations of progesterone, oestrogen, interleukin-1β, interleukin-6, haptoglobin and serum amyloid A for both challenged groups. Histopathologically, all reproductive organs (except the cervix and vagina) from both challenged groups displayed significant cellular alterations (p < 0.05) characterised by haemorrhage and congestion, necrosis and degeneration, inflammatory cell infiltration and oedema. This study provides new information that elucidates the potential role of pneumonic mannheimiosis in the pathogenesis of female infertility amongst small ruminants., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

What Is Known and Objective: Metformin was found to reduce elevated gonadotropin levels. The aim of the present study was to determine whether metformin modulates the impact of discontinuation of testosterone therapy on hypothalamic-pituitary-gonadal axis activity and sexual function in men with low testosterone levels., Methods: The study included 28 men with late-onset hypogonadism (defined according to the criteria of the European Male Aging Study group) receiving testosterone undecanoate (120 mg in three equal doses), 12 of whom had been treated with oral metformin (1.7-3 g daily). Both testosterone and metformin had been administered for at least six months before enrolment. In all patients, testosterone replacement required to be discontinued. The control group included 16 testosterone- and metformin-treated men with late-onset hypogonadism who during the entire study period continued their treatment. Glucose homeostasis markers, as well as plasma levels of insulin, gonadotropins, testosterone, calculated bioavailable testosterone, dehydroepiandrosterone-sulphate, oestradiol, thyrotropin, free thyroxine, prolactin, insulin-growth factor-1 and cortisol were measured at the beginning of the study and four months later. Moreover, at the beginning and the end of the study, all enrolled patients completed a questionnaire assessing their sexual functioning (IIEF-15)., Results and Discussion: Discontinuation of testosterone therapy resulted in a decrease in total testosterone and bioavailable testosterone (by 42% and 45% in metformin-treated patients, and by 52% and 54% in metformin-naïve patients), as well as impaired all aspects of male sexual function. Changes in bioavailable testosterone, as well as in erectile function, orgasmic function and sexual desire were less pronounced if subjects received metformin. Only in metformin-naïve men, follow-up FSH and LH levels were higher than at baseline (by 75% and 62%). Moreover, discontinuation of testosterone therapy in metformin-naïve men increased glycated haemoglobin, as well as worsened insulin sensitivity. There were no differences between baseline and follow-up levels of the remaining hormones. In metformin-naïve subjects, the increase in gonadotropin levels correlated with the changes in testosterone levels and insulin sensitivity. No effect on glucose homeostasis markers, hormone levels and sexual functioning was observed in the control group., What Is New and Conclusion: The obtained results suggest that metformin treatment mitigates the unfavourable effect of discontinuation of testosterone treatment on hypothalamic-pituitary-testicular axis activity and sexual function in men with late-onset hypogonadism., (© 2021 John Wiley & Sons Ltd.)

Hypobaric hypoxia is a stressful condition known to decrease fertility both in humans and animals. However, the mechanism by which the hypothalamus-pituitary-gonad axis is altered remains unknown. The aim of the present study was to analyze the effects of chronic intermittent and continuous exposure to hypoxia on hypothalamic-pituitary-gonadal axis regulation in male rats. Thirty adult male Wistar rats were assigned to one of the following three groups: control group; chronic intermittent hypoxia: subjected to 600 mbar for 18 h/d five days a week; and chronic continuous hypoxia: subjected to 600 mbar for 23.5 hours/day seven days a week, for 30 days. Plasma luteinizing hormone and testosterone concentration, hypothalamic GnRh , Kiss1 and Rfrp3 mRNA levels and PGE 2 content were determined. Levels of Rfrp3 , a negative regulator of GnRH and LH release, were higher in intermittently exposed animals than in controls. Levels of Kiss1, a neuropeptide that stimulates the release of GnRH only increased in animals exposed to continuous hypoxia. Plasma luteinizing hormone and testosterone concentrations and body weight were lower in rats subjected to intermittent hypoxia as compared to the remaining groups. GnRh mRNA levels as well as PGE 2 content remained unchanged in all groups. Taken together, results suggest that besides the well documented direct effects of hypoxia on the testes, infertility observed in male rats exposed to hypoxia may also be due to overexpression of negative regulators of GnRH and luteinizing hormone release. Intermittent, rather than continuous, to hypoxia exposure would seem to be more detrimental to fertility., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s). Published by IMR Press.)

The main mechanisms underlying sexually dimorphic outcomes in neonatal lung injury are unknown. We tested the hypothesis that hormone- or sex chromosome-mediated mechanisms interact with hyperoxia exposure to impact injury and repair in the neonatal lung. To distinguish sex differences caused by gonadal hormones versus sex chromosome complement (XX versus XY), we used the Four Core Genotypes (FCG) mice and exposed them to hyperoxia (95% FiO2, P1-P4: saccular stage) or room air. This model generates XX and XY mice that each have either testes (with Sry, XXM, or XYM) or ovaries (without Sry, XXF, or XYF). Lung alveolarization and vascular development were more severely impacted in XYM and XYF compared with XXF and XXM mice. Cell cycle-related pathways were enriched in the gonadal or chromosomal females, while muscle-related pathways were enriched in the gonadal males, and immune-response-related pathways were enriched in chromosomal males. Female gene signatures showed a negative correlation with human patients who developed bronchopulmonary dysplasia (BPD) or needed oxygen therapy at 28 days. These results demonstrate that chromosomal sex - and not gonadal sex - impacted the response to neonatal hyperoxia exposure. The female sex chromosomal complement was protective and could mediate sex-specific differences in the neonatal lung injury.

Diseases and aging-associated alterations of the nervous system often show sex-specific characteristics. Glial cells play a major role in the endogenous homeostatic response of neural tissue, and sex differences in the glial transcriptome and function have been described. Therefore, the possible role of these cells in the generation of sex differences in pathological alterations of the nervous system is reviewed here. Studies have shown that glia react to pathological insults with sex-specific neuroprotective and regenerative effects. At least three factors determine this sex-specific response of glia: sex chromosome genes, gonadal hormones and neuroactive steroid hormone metabolites. The sex chromosome complement determines differences in the transcriptional responses in glia after brain injury, while gonadal hormones and their metabolites activate sex-specific neuroprotective mechanisms in these cells. Since the sex-specific neuroprotective and regenerative activity of glial cells causes sex differences in the pathological alterations of the nervous system, glia may represent a relevant target for sex-specific therapeutic interventions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chronic stress is encountered in our everyday life and is thought to contribute to a number of diseases. Many of these stress-related disorders display a sex bias. Because glucocorticoid hormones are the main biological mediator of chronic stress, researchers have been interested in understanding the sexual dimorphism in glucocorticoid stress response to better explain the sex bias in stress-related diseases. Although not yet demonstrated for glucocorticoid regulation, sex chromosomes do influence sex-specific biology as soon as conception. Then a transient rise in testosterone start to shape the male brain during the prenatal period differently to the female brain. These organizational effects are completed just before puberty. The cerebral regions implicated in glucocorticoid regulation at rest and after stress are thereby impacted in a sex-specific manner. After puberty, the high levels of all gonadal hormones will interact with glucocorticoid hormones in specific crosstalk through their respective nuclear receptors. In addition, stress occurring early in life, in particular during the prenatal period and in adolescence will prime in the long-term glucocorticoid stress response through epigenetic mechanisms, again in a sex-specific manner. Altogether, various molecular mechanisms explain sex-specific glucocorticoid stress responses that do not exclude important gender effects in humans.

The serotonin transporter (5-HTT) is a key molecule of serotoninergic neurotransmission and target of many anxiolytics and antidepressants. In humans, 5-HTT gene variants resulting in lower expression levels are associated with behavioral traits of anxiety. Furthermore, functional magnetic resonance imaging (fMRI) studies reported increased cerebral blood flow (CBF) during resting state (RS) and amygdala hyperreactivity. 5-HTT deficient mice as an established animal model for anxiety disorders seem to be well suited for investigating amygdala (re-)activity in an fMRI study. We investigated wildtype (5-HTT+/+), heterozygous (5-HTT+/-), and homozygous 5-HTT-knockout mice (5-HTT-/-) of both sexes in an ultra-high-field 17.6 Tesla magnetic resonance scanner. CBF was measured with continuous arterial spin labeling during RS, stimulation state (SS; with odor of rats as aversive stimulus), and post-stimulation state (PS). Subsequently, post mortem c-Fos immunohistochemistry elucidated neural activation on cellular level. The results showed that in reaction to the aversive odor CBF in total brain and amygdala of all mice significantly increased. In male 5-HTT+/+ mice amygdala RS CBF levels were found to be significantly lower than in 5-HTT+/- mice. From RS to SS 5-HTT+/+ amygdala perfusion significantly increased compared to both 5-HTT+/- and 5-HTT-/- mice. Perfusion level changes of male mice correlated with the density of c-Fos-immunoreactive cells in the amygdaloid nuclei. In female mice the perfusion was not modulated by the 5-Htt-genotype, but by estrous cycle stages. We conclude that amygdala reactivity is modulated by the 5-Htt genotype in males. In females, gonadal hormones have an impact which might have obscured genotype effects. Furthermore, our results demonstrate experimental support for the tonic model of 5-HTTLPR function., Competing Interests: The authors have declared that no competing interests exist.

Clarias gariepinus juveniles were exposed to environmentally relevant concentrations of 0 (control), 2.5, 25, 250 and 500 μg L -1 atrazine in a quality-controlled 28-day laboratory procedure. Findings revealed a significant decrease in the levels of follicle-stimulating hormone, luteinizing hormone and prolactin relative to control (p < 0.05). Atrazine reduced the levels of testosterone while increasing the concentration of progesterone. Histologically, the control and treatments presented three stages of oocyte maturation: the chromatin nucleolar oocyte stage, early perinucleolar oocyte stage and the vitellogenic oocyte stage. However, in the ovaries of the treatment group with the lowest treatment concentration (2.5 μg L -1 ), atretic oocytes with broken membranes invaded many of the dead ova and empty spaces. In other treatments (25, 250 and 500 μg L -1 ), interfollicular spaces, vacuolation in oocyte formation, and dissolution of oocyte walls were observed. Disruption of the yolk vesicle and clumping of the cytoplasm in maturing oocytes was observed only at the highest atrazine concentration (500 μg L -1 ). Gross alterations in ovarian histoarchitecture and reproductive hormone levels observed in this study showed interference with oogenesis which may result in reduced egg viability and fecundity in fish with ecological implications in water bodies exposed to atrazine even at reduced concentrations.

Energy availability (EA) is defined as the amount of dietary energy available to sustain physiological function after subtracting the energetic cost of exercise. Insufficient EA due to increased exercise, reduced energy intake, or a combination of both, is a potent disruptor of the endocrine milieu. As such, EA is conceived as a key etiological factor underlying a plethora of physiological dysregulations described in the female athlete triad, its male counterpart and the Relative Energy Deficiency in Sport models. Originally developed upon female-specific physiological responses, this concept has recently been extended to males, where experimental evidence is limited. The majority of data for all these models are from cross-sectional or observational studies where hypothesized chronic low energy availability (LEA) is linked to physiological maladaptation. However, the body of evidence determining causal effects of LEA on endocrine, and physiological function through prospective studies manipulating EA is comparatively small, with interventions typically lasting ≤ 5 days. Extending laboratory-based findings to the field requires recognition of the strengths and limitations of current knowledge. To aid this, this review will: (1) provide a brief historical overview of the origin of the concept in mammalian ecology through its evolution of algebraic calculations used in humans today, (2) Outline key differences from the 'energy balance' concept, (3) summarise and critically evaluate the effects of LEA on tissues/systems for which we now have evidence, namely: hormonal milieu, reproductive system endocrinology, bone metabolism and skeletal muscle; and finally (4) provide perspectives and suggestions for research upon identified knowledge gaps.

Current food supply is a major driver of timing of breeding in income-breeding animals, likely because increased net energy balance directly increases reproductive hormones and advances breeding. In capital breeders, increased net energy balance increases energy reserves, which eventually leads to improved reproductive readiness and earlier breeding. To test the hypothesis that phenology of income-breeding birds is independent of energy reserves, we conducted an experiment on food-supplemented ("fed") and control female black-legged kittiwakes (Rissa tridactyla). We temporarily increased energy costs (via weight handicap) in a 2 × 2 design (fed/unfed; handicapped/unhandicapped) during the pre-laying period and observed movement via GPS-accelerometry. We measured body mass, baseline hormones (corticosterone; luteinising hormone) before and after handicap manipulation, and conducted a gonadotropin-releasing hormone challenge. Females from all treatment groups foraged in similar areas, implying that individuals could adjust time spent foraging, but had low flexibility to adjust foraging distance. Consistent with the idea that income breeders do not accumulate reserves in response to increased food supply, fed birds remained within an energy ceiling by reducing time foraging instead of increasing energy reserves. Moreover, body mass remained constant until the onset of follicle development 20 days prior to laying regardless of feeding or handicap, implying that females were using a 'lean and fit' approach to body mass rather than accumulating lipid reserves for breeding. Increased food supply advanced endocrine and laying phenology and altered interactions between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis, but higher energy costs (handicap) had little effect. Consistent with our hypothesis, increased food supply (but not net energy balance) advanced endocrine and laying phenology in income-breeding birds without any impact on energy reserves., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The levels of the gonadal hormones estradiol and progesterone vary throughout the menstrual cycle thereby affecting cognition, emotion, mood, and social behaviour. However, how these hormones modulate the balance of neural excitation and inhibition, which crucially regulate processing and plasticity, is not fully understood. We here used paired-pulse stimulation to investigate in healthy humans the action of low and high estradiol and progesterone on intracortical inhibition in somatosensory (SI) and visual cortex (V1). We found that paired-pulse suppression in both SI and VI depended on estradiol. During high estradiol levels, paired-pulse suppression was significantly reduced. No comparable effects were found for progesterone, presumably due to a confounding effect of estradiol. Also, no hormone level-depending effects were observed for single-pulse evoked SEPs (somatosensory evoked potentials) and VEPs (visual evoked potentials) indicating a specific hormonal action on intracortical processing. The results demonstrate that estradiol globally modulates the balance of excitation and inhibition of SI and VI cortex.

Objective: To study whether markers of prenatal exposure to reproductive hormones are related to Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, polycystic ovary syndrome (PCOS), and endometriosis., Design: Case-control study. Comparison of sex hormone-related external genital and digital characteristics in cases and controls., Setting: University hospital., Patient(s): We enrolled 172 women in four groups-women with MKRH, women with PCOS, women with endometriosis, and controls (43 in each group)., Intervention(s): Measurement of two anthropometric biomarkers: anogenital distance and digit ratio., Main Outcome Measure(s): Anogenital distance was measured from the anus to the anterior clitoral surface (AGDac) and from the anus to the posterior fourchette (AGDaf). For the digit ratio we used a direct, as well as a computer-assisted graphic measurement to measure the length of the second and fourth digit., Result(s): After adjustment for body mass index and age, AGDac was the shortest in endometriosis and the longest in PCOS groups, with a mean difference of 10 mm (95% confidence interval 3.1-16.8). AGDaf but not AGDac measures were found to be significantly larger in the MRKH group, with a mean difference compared with controls of 2.6 mm (95% confidence interval 0.1-5.2). The digit ratio was not significantly different between the groups., Conclusion(s): In this study we did find limited evidence for androgen exposure during the development of MRKH. This is compatible with the hypothesis that the uterovaginal agenesis may have been the result of temporary prenatal exposure to altered gonadal hormone concentrations. For endometriosis and PCOS we confirm previously observed associations for anogenital distance reflecting possible estrogen-based and androgen-based intrauterine origins, respectively., Dutch Trial Registration Number: NTR7492., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The hypothalamic-pituitary axis exert a major control over endocrine and exocrine testicular functions. The hypothalamic-pituitary axis corresponds to a cascade with the Gonadotropin Releasing Hormone secreted by the hypothalamus, which stimulates the synthesis and the release of Luteinizing Hormone (LH) and Follicle Stimulating Hormone by the gonadotropic cells of the anterior pituitary. The LH signaling pathway controls the steroidogenic activity of the Leydig cells via the activation of the luteinizing hormone/choriogonadotropin receptor. In order to avoid a runaway system, sex steroids exert a negative feedback within hypothalamus and pituitary. Testicular steroidogenesis is locally controlled within Leydig cells. The present work reviews some local regulations of steroidogenesis within the Leydig cells focusing mainly on the roles of the Farnesoid-X-Receptor-alpha and its interactions with several orphan members of the nuclear receptor superfamily. Further studies are required to reinforce our knowledge of the regulation of testicular endocrine function, which is necessary to ensure a better understanding of fertility disorders and then proposed an adequate treatment of the diseases., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Information regarding the possible influence of immunosuppressive drugs on male sexual function and reproductive outcomes is scarce. Men diagnosed with immune-mediated diseases and a wish to become a father represent an important neglected population since they lack vital information to make balanced decisions about their treatment., Objective and Rationale: The aim of this research was to systematically review the literature for the influence of paternal immunosuppressive drug use on many aspects of male sexual health, such as sexual function, fertility, pregnancy outcomes and offspring health outcomes., Search Methods: A systematic literature search was performed in the bibliographic databases: Embase (via Elsevier embase.com), MEDLINE ALL via Ovid, Cochrane Central Register of Trials (via Wiley) and Web of Science Core Collection. Additionally, Google Scholar and the Clinical trial registries of Europe and the USA were searched. The databases were searched from inception until 31 August 2019. The searches combined keywords regarding male sexual function and fertility, pregnancy outcomes and offspring health with a list of immunosuppressive drugs. Studies were included if they were published in English and if they included original data on male human exposure to immunosuppressive drugs. A meta-analysis was not possible to perform due to the heterogeneity of the data., Outcomes: A total of 5867 references were identified, amongst which we identified 161 articles fulfilling the eligibility criteria. Amongst these articles, 50 included pregnancy and offspring outcomes and 130 included sexual health outcomes. Except for large Scandinavian cohorts, most of the identified articles included a small number of participants. While a clear negative effect on sperm quality was evident for sulfasalazine and cyclophosphamide, a dubious effect was identified for colchicine, methotrexate and sirolimus. In three articles, exposure to tumour necrosis factor-α inhibitors in patients diagnosed with ankylosing spondylitis resulted in improved sperm quality. The information regarding pregnancy and offspring outcomes was scant but no large negative effect associated with paternal immunosuppressive drug exposure was reported., Wider Implications: Evidence regarding the safety of immunosuppressive drugs in men with a wish to become a father is inconclusive. The lack of standardisation on how to evaluate and report male sexual function, fertility and reproduction as study outcomes in men exposed to immunosuppressive drugs is an important contributor to this result. Future research on this topic is needed and should be preferably done using standardised methods., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Aging is associated with a decline in sex hormones, variable between sexes, that has an impact on many different body systems and might contribute to age-related disease progression. We aimed to characterize the sex differences in gut microbiota, and to explore the impact of depletion of gonadal hormones, alone or combined with postnatal overfeeding, in rats. Many of the differences in the gut microbiota between sexes persisted after gonadectomy, but removal of gonadal hormones shaped several gut microbiota features towards a more deleterious profile, the effect being greater in females than in males, mainly when animals were concurrently overfed. Moreover, we identified several intestinal miRNAs as potential mediators of the impact of changes in gut microbiota on host organism physiology. Our study points out that gonadal hormones contribute to defining sex-dependent differences of gut microbiota, and discloses a potential role of gonadal hormones in shaping gut microbiota, as consequence of the interaction between sex and nutrition. Our data suggest that the changes in gut microbiota, observed in conditions of sex hormone decline, as those caused by ageing in men and menopause in women, might exert different effects on the host organism, which are putatively mediated by gut microbiota-intestinal miRNA cross-talk.

Males as compared to females display increased impulsivity and inefficient inhibitory control and are more frequently diagnosed with disorders characterized by impulsivity. We previously demonstrated male rats make more impulsive action responses (i.e. premature responding) than females on the 5-choice serial reaction time task (5-CSRTT). Furthermore, pre-pubertal male rats make more impulsive choice responses (i.e. choosing an immediate small reward over a delayed larger reward) than females on a delayed-based reward T-maze task. The goal of the current work was to determine if gonadal hormones impact sex differences in impulsivity in adult rats. In an initial experiment, male and female rats underwent sham surgeries or were gonadectomized either pre-pubertally or during adulthood and tested on the 5-CSRTT in adulthood. Males displayed more impulsive action responses than females regardless of hormone status. In a second experiment, females received testosterone or vehicle injections on postnatal days 1 and 2. Males received vehicle injections. All rats were gonadectomized prior to puberty and tested on the 5-CSRTT in adulthood. Females treated neonatally with testosterone and control males made more impulsive action responses than control females. In another set of experiments, manipulation of gonadal hormones led to no differences in performance on the delayed-based reward T-maze task in males and females. Results indicate that no sex difference is apparent in impulsive choice on a delayed-base reward task in adult rats. They also reveal that adult sex differences on a task of impulsive action is mediated by organizational effects of gonadal hormones acting during the neonatal period and not impacted by hormones acting during puberty or adulthood., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ovarian hormones, including 17β-estradiol, are implicated in numerous physiological processes, including sleep. Beginning at puberty, girls report more sleep complaints than boys, which is maintained throughout the reproductive life stage. Sleep problems are exacerbated during the menopausal transition, evidenced by greater risk for sleep disorders. There is emerging evidence that menopause-associated hormone loss contributes to this elevated risk, but age is also an important factor. The extent to which menopause-associated sleep disturbance persists into postmenopause above and beyond the effects of age remains unknown. Untreated sleep disturbances have important implications for cognitive health, as they are emerging as risk factors for dementia. Given that sleep loss impairs memory, an important knowledge gap concerns the role played by menopause-associated hormone loss in exacerbating sleep disturbance and, ultimately, cognitive function in aging women. In this review, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining the sleep-wake cycle in younger and middle-aged females, with evidence implicating 17β-estradiol in supporting the memory-promoting effects of sleep. Sleep physiology is briefly reviewed before turning to behavioral and neural evidence from young females linking 17β-estradiol to sleep-wake cycle maintenance. Implications of menopause-associated 17β-estradiol loss is also reviewed before discussing how ovarian hormones may support the memory-promoting effects of sleep, and why menopause may exacerbate pathological aging via effects on sleep. While still in its infancy, this research area offers a new sex-based perspective on aging research, with a focus on a modifiable risk factor for pathological aging., (© Endocrine Society 2020.)

In humans, sex differences in mood disorders emerge during adolescence, with prevalence rates being consistently higher in females than males. It has been hypothesised that exposure to endogenous ovarian hormones during adolescence enhances the susceptibility of females to mood disorders from this stage of life onwards. However, experimental evidence in favour of this hypothesis is lacking. In the present study, we examined the long-term effects of suppressing adolescent gonadal hormone levels in a group of female Lister-hooded rats via administration of a gonadotrophin-releasing hormone antagonist (Antide; administered on postnatal day [PND] 28 and 42) compared to control females and males (n = 14 per group). We predicted that, in adulthood, Antide-treated female rats would exhibit more male-like behaviour than control females in novel environments (elevated-plus maze, open field and light-dark box), in response to novel objects and novel social partners, and in an acoustic startle task. Progesterone and luteinising hormone assays (which were conducted on blood samples collected on PND 55/56 and 69/70) confirmed that the hypothalamic-pituitary-gonadal axis was temporarily suppressed by Antide treatment. In addition, Antide-treated females were found to exhibit a modest pubertal delay, as measured by vaginal opening, which was comparable in length to the pubertal delay that has been induced by adolescent exposure to alcohol or stress in previous studies of female rats. However, Antide-treated females did not substantially differ from control females on any of the behavioural tests, despite the evidence for predicted sex differences in some measures. Following the acoustic startle response task, all subjects were culled and perfused, and c-Fos staining was conducted in the medial and basolateral amygdala, with the results showing no significant differences in cell counts between the groups. These findings suggest that ovarian hormone exposure during adolescence does not have long-term effects on anxiety-related responses in female rats., (© 2020 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

RNA interference (RNAi), which employs double-strand RNA (dsRNA) or small interference RNA (siRNA), is a popular reverse genetic manipulation tool to study gene function. Presently, there is few reports on the implementation of RNAi on the insulin-like androgenic gland gene (IAG) in red swamp crayfish Procambarus clarkii. In this study, the effective sequence of siRNA and optimal injection dose were determined, and the effects of RNAi using dsRNA, siRNA, and long-term RNAi were investigated. The results showed that the doses of 0.5 and 1 µg/g of body weight of IAG-siRNA3 produced significantly better inhibition than 0.1 µg/g. qPCR assays showed that both dsRNA and siRNA silenced the IAG expression in five tissues (brain, ventral nerve cord, androgenic gland, testis, and vas deferens) in adult P. clarkii, with the effectiveness decreasing over time, inhibiting the production of spermatid. dsRNA exhibited a longer interference effect than siRNA in adults. For long-term interference (P. clarkii juveniles were injected 7 times with 1 µg/g of body weight of IAG-dsRNA), and found that the secondary sexual characteristics of juveniles were affected, while the control group developed normally. The results of this study could lay the foundation for crayfish sex reversal with IAG RNAi, and provide the reference for those studies in which the technique of RNAi was used., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Physical exercise and body muscle/fat mass are known to affect the endocrine system, puberty onset and reproductive health. However, the potential effects of irisin, an adipo-myokine and exercise-induced hormone, have not yet been fully elucidated on reproductive maturation. Therefore, the present study aimed to determine the effects of irisin administration on pubertal maturation and reproductive system in female and male rats. Daily i.p. injection of irisin (100 ng/kg; from postnatal day 21 for about 10 weeks) delayed the ages at the vaginal opening (as an external index of puberty onset) and first estrus. Furthermore, continuous administration of irisin to female rats caused a significant decrease in serum follicle-stimulating hormone levels and an increase in serum luteinizing hormone and 17β-estradiol levels, as well as causing histopathological changes in the ovarian tissue. On the contrary, irisin administration to male rats did not modify the timing of puberty, as estimated by age at preputial separation. However, chronic exposure to irisin produced significant increases in serum luteinizing hormone and testosterone levels and also sperm concentration and seminiferous tubule diameter in male rats. In conclusion, irisin exposure has different effects on both pubertal maturation and reproductive system in female and male rats. The present findings reveal that chronic irisin exposure may lead to disorders in the female reproductive system and may have androgenic potential on the hypothalamic-pituitary-gonadal axis in males.

Acute ischemic stroke (AIS) is a devastating neurological condition with a lack of neuroprotective therapeutic options, despite the reperfusion modalities thrombolysis and thrombectomy. Post-ischemic brain damage is aggravated by an excessive inflammatory cascade involving the activation and regulation of the pro-inflammatory cytokines IL-1β and IL-18 by inflammasomes. However, the role of AIM2 and NLRC4 inflammasomes and the influence of the neuroprotective steroids 17β-estradiol (E2) and progesterone (P) on their regulation after ischemic stroke have not yet been conclusively elucidated. To address the latter, we subjected a total of 65 rats to 1 h of transient Middle Cerebral Artery occlusion (tMCAO) followed by a reperfusion period of 72 h. Moreover, we evaluated the expression and regulation of AIM2 and NLRC4 in glial single-cell cultures (astroglia and microglia) after oxygen-glucose deprivation (OGD). The administration of E2 and P decreased both infarct sizes and neurological impairments after cerebral ischemia in rats. We detected a time-dependent elevation of gene and protein levels (Western Blot/immunohistochemistry) of the AIM2 and NLRC4 inflammasomes in the post-ischemic brains. E2 or P selectively mitigated the stroke-induced increase of AIM2 and NLRC4. While both inflammasomes seemed to be exclusively abundant in neurons under physiological and ischemic conditions in vivo, single-cell cultures of cortical astrocytes and microglia equally expressed both inflammasomes. In line with the in vivo data, E and P selectively reduced AIM2 and NLRC4 in primary cortical astrocytes and microglial cells after OGD. In conclusion, the post-ischemic elevation of AIM2 and NLRC4 and their down-regulation by E2 and P may shed more light on the anti-inflammatory effects of both gonadal hormones after stroke.

Giant freshwater prawns ( Macrobrachium rosenbergii ) are commonly found throughout the world. The size of the male giant freshwater prawn is much larger than that of the female. Therefore, understanding the molecular mechanism that underlies the sexual differentiation of M. rosenbergii is of both commercial and scientific importance. Insulin-like androgenic gland hormone (IAG) plays a key role in the differentiation of sex in M. rosenbergii . Although IAG has been investigated, the regulatory relationship between IAG and its binding protein partner, the insulin-like androgenic gland hormone-binding protein (IAGBP), has not been studied in M. rosenbergii . Here, we cloned and characterized the IAGBP from M. rosenbergii ( Mr-IAGBP ) for the very first time. Transcriptomic analysis showed that Mr-IAGBP mRNA was detected in a wide array of tissues with the highest expression found in the androgenic gland. The importance of IAG in male development was further demonstrated by an increase in IAG transcripts during the development of the androgenic gland and Mr-IAG was only highly transcribed in the androgenic gland of M. rosenbergii . Interestingly, we found that the Mr-IAG gene expression started during the 20th-day larva after hatching stage (LH20), followed (20th-day post-larval stage, PL20) by a gradual elevation of Mr-IAGBP levels. The levels of both genes peaked at the adult stage. The relationship between Mr - IAGBP and Mr - IAG was further analyzed using RNA interference. The injection of Mr-IAGBP double-stranded RNA (dsRNA) significantly reduced the transcription of Mr-IAG , while the amount of Mr-IAGBP mRNA and the translation of IAGBP protein was significantly reduced by the injection of Mr - IAG dsRNA. These results revealed that IAGBP is involved in IAG signaling. Furthermore, our data supports the hypothesis that (IAG and IAGBP)-IAG receptor signaling schemes exist in M. rosenbergii . Our results will provide important information for the further study of determining the sex of M. rosenbergii .

The endocrine system plays an essential role in communication between various organs of the body to maintain homeostasis. Both substance use disorders (SUDs) and non-substance abuse disrupt this system and lead to hormonal dysregulations. Here, we focus on the comparison between the function of the endocrine system in gambling disorders and alcohol addiction to understand the commonalities and differences in their neurobiological and psychological underpinnings. We review human research to compare findings on gambling addiction and alcohol dependence pertaining to the dynamic interplay between testosterone and cortisol. Understanding and classifying similarities in hormonal responses between behavioural addiction and SUDs may facilitate development of treatments and therapeutic interventions across different types of addictive disorders, while describing differences may shed light on therapeutic interventions for specific disorders. Although research on gambling addiction is in its infancy, such evaluation may still have a positive effect for addiction research, thereby stimulating discovery of "crossover" pharmacotherapies with benefits for both SUDs and nonsubstance addictions., Competing Interests: Declaration of Competing Interest All authors have no conflicts of interest to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The aim of this survey is to explore the possible effects of unsupported and supported copper nanoparticles (CuNPs) of different morphologies on basic ovarian cell functions. For this purpose, we have compared the activity of unsupported spherical, triangular, and hexagonal CuNPs, as well as of spherical CuNPs supported on titania, zeolite Y and activated charcoal (0, 1, 10, or 100 ng/mL) on cultured porcine ovarian granulosa cells. Cell viability, proliferation (accumulation of proliferating cell nuclear antigen, PCNA), apoptosis (accumulation of Bcl-2-associated X protein, bax) and release of steroid hormones progesterone, testosterone, and 17 β -estradiol have been analyzed by the Trypan blue test, quantitative immunocytochemistry, and ELISA, respectively. Cell viability decreased after treatment with hexagonal CuNPs, whilst all the other CuNPs increased it. Unsupported spherical and hexagonal CuNPs, and spherical CuNPs/titania reduced PCNA accumulation; in contrast, an increase was noted for unsupported triangular CuNPs and CuNPs/zeolite Y. Bax accumulation was not affected by hexagonal CuNPs, whereas CuNPs/zeolite Y promoted it and all the other CuNPs depleted it. The release of all steroid hormones was inhibited by CuNPs/titanium dioxide and stimulated by CuNPs/charcoal, whilst CuNPs/zeolite Y promoted the testosterone and 17 β -estradiol output, but not that of progesterone. These results demonstrate the direct, mainly stimulatory, impact of CuNPs on basic ovarian cell functions. The character of the CuNPs' action depends on their shape and support. Therefore, CuNPs with appropriate chemical modification could be potentially useful for the control of reproductive processes and treatment of reproductive disorders.

Sex is an essential biological variable that significantly impacts multiple aspects of neural functioning in both the healthy and diseased brain. Sex differences in brain structure and function are organized early in development during the critical period of sexual differentiation. While decades of research establish gonadal hormones as the primary modulators of this process, new research has revealed a critical, and perhaps underappreciated, role of the neuroimmune system in sex-specific brain development. The immune and endocrine systems are tightly intertwined and share processes and effector molecules that influence the nervous system. Thus, a natural question is whether endocrine-immune crosstalk contributes to sexual differentiation of the brain. In this mini-review, we first provide a conceptual framework by classifying the major categories of neural sex differences and review the concept of sexual differentiation of the brain, a process occurring early in development and largely controlled by steroid hormones. Next, we describe developmental sex differences in the neuroimmune system, which may represent targets or mediators of the sexual differentiation process. We then discuss the overwhelming evidence in support of crosstalk between the neuroendocrine and immune systems and highlight recent examples that shape sex differences in the brain. Finally, we review how early life events can perturb sex-specific neurodevelopment via aberrant immune activation., (© Endocrine Society 2020.)

To investigate the degree of association between levels of sex hormones and anthropometric indices in male population. A cross-sectional survey was conducted between July 2014 and July, 2016, in a men's health polyclinic in Taiwan. Body mass index, waist circumference, waist-to-height ratio (WHtR), and conicity index were tested. Serum total testosterone, free testosterone, and dehydroepiandrosterone sulfate (DHEA-S) were measured. Decreased testosterone levels were correlated with the four indices ( r  = -0.09 to -0.27, p  < 0.01). In hypogonadism group, DHEA-S deficiency was associated with older age, higher anthropometric indices, and chronic illness. The areas under the receiver operating characteristic curves of hypogonadism and DHEA-S deficiency by the four anthropometric indices ranged from 52.5% to 65.9%. Logistic regression analysis revealed that obesity, defined by the four indices, was associated with increased risk of hypogonadism. Moreover, obesity was also associated with increased risk and DHEA-S deficiency. Anthropometric indices analyzed are associated with lower testosterone and DEAH-S deficiency. A WHtR of 0.5 is suggested to be a simple and reliable indicator of hypogonadism and DHEA-S deficiency.

Adolescence is characterized by rapid brain development in white matter (WM) that is attributed in part to surges in gonadal hormones. To date, however, there have been few longitudinal investigations relating changes in gonadal hormones and WM development in adolescents. We acquired diffusion-weighted MRI to estimate mean fractional anisotropy (FA) from 10 WM tracts and salivary testosterone from 51 females and 29 males (ages 9-14 years) who were matched on pubertal stage and followed, on average, for 2 years. We tested whether interactions between sex and changes in testosterone levels significantly explained changes in FA. We found positive associations between changes in testosterone and changes in FA within the corpus callosum, cingulum cingulate, and corticospinal tract in females (all ps<0.05, corrected) and non-significant associations in males. We also collected salivary estradiol from females and found that increases in estradiol were associated with increases in FA in the left uncinate fasciculus (p = 0.04, uncorrected); however, this effect was no longer significant after accounting for changes in testosterone. Our findings indicate there are sex differences in how changes in testosterone relate to changes in WM microstructure of tracts that support impulse control and emotion regulation across the pubertal transition., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The present study investigated neuroanatomically localised changes in de novo DNA methyltransferase expression in the female Siberian hamster (Phodopus sungorus). The objectives were to identify the neuroendocrine substrates that exhibit rhythmic Dnmt3a and Dnmt3b expression across the oestrous cycle and also examine the role of ovarian steroids. Hypothalamic Dnmt3a expression was observed to significantly increase during the transition from pro-oestrous to oestrous. A single bolus injection of diethylstilbestrol and progesterone was sufficient to increase Dnmt3a cell numbers and Dnmt3b immunoreactive intensity in the suprachiasmatic nucleus. In vitro analyses using an embryonic rodent cell line revealed that diethylstilbestrol was sufficient to induce Dnmt3b expression. Up-regulating DNA methylation in vitro reduced the expression of vasoactive intestinal polypeptide, Vip, and the circadian clock gene, Bmal1. Together, these data indicate that ovarian steroids drive de novo DNA methyltransferase expression in the mammalian suprachiasmatic nucleus and increased methylation may regulate genes involved in the circadian timing of oestrous: Vip and Bmal1. Overall, epigenetically mediated neuroendocrine reproductive events may reflect an evolutionarily ancient process involved in the timing of female fertility., (© 2019 British Society for Neuroendocrinology.)

In both sexes, estrogen is one of the most essential hormones for maintaining bone integrity. Also, especially in men, androgen has beneficial effects on bone independent of estrogen. However, estrogen replacement therapy for postmenopausal women increases the risk of developing breast cancer and endometrial cancer, and androgen replacement therapy for partial androgen deficiency of the aging male increases the risk of developing prostate cancer. Various mechanisms have been proposed on the effects of gonadal hormones on bone, such as effects through cytokines including IL-6 and effects on the OPG/RANKL ratio. In addition, large amounts of new information deriving from high-throughput gene expression analysis raise the possibility of multiple other effects on bone cells. Both estrogen and androgen exert their effects via the estrogen receptor (ER) or the androgen receptor (AR), which belongs to the nuclear receptor superfamily. Compounds such as selective estrogen receptor modulators (SERMs) and selective androgen receptor modulators (SARMs) also bind ER and AR, respectively. However, SERMs and SARMs alter the ER or AR structure differently from estrogen or androgen, resulting in other downstream gene responses. As a result they can exert favorable effects on bone while suppressing the undesirable actions of estrogen and androgen. Elucidation of ER and AR ligand-specific and tissue-specific gene regulation mechanisms will also provide information on the signal transduction mechanisms of other nuclear receptors and will be valuable for the development of new therapeutic agents.

Sex-related differences in pain and opioids has been the focus of many researches. It is demonstrated that women experience greater clinical pain, lower pain threshold and tolerance, more sensitivity and distress to experimentally induced pain compared to men. Sex differences in response to opioid treatment revealed inconsistent results. However, the etiology of these disparities is not fully elucidated. It is, therefore, conceivable now that this literature merits to be revisited comprehensively. Possible multifaceted factors seem to be associated. These include neuroanatomical, hormonal, neuroimmunological, psychological, social and cultural aspects and comorbidities. This review aims at providing an overview of the substantial literature documenting the sex differences in pain and analgesic response to opioids from animal and human studies within the context of the modulatory effects of the aforementioned factors. A detailed and critical discussion of the cellular and molecular signaling pathways underlying the modulatory actions of gonadal hormones in the sexual dimorphism in pain processing and opioid analgesia is extensively presented. It is indicated that sexual dimorphic activation of certain brain regions contributes to differential pain sensitivity between females and males. Plausible crosstalk between sex hormones and neuroimmunological signaling pertinent to toll-like and purinergic receptors is uncovered as causal cues underlying sexually dimorphic pain and opioid analgesia. Conceivably, a thorough understanding of these factors may aid in sex-related advancement in pain therapeutic management., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The present study aimed to evaluate the protective role of Selenium (Se) (0.1 ppm) on the male reproductive system of the catfish Clarias gariepinus exposed to sublethal doses of Mercury (Hg) (0.04 and 0.12 ppm) for 30 days. Indicators of seminal and gonadal hormone disruption (testosterone, estradiol and 11 keto testosterone), antioxidants (total antioxidant capacity (TAO), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)), oxidative stress biomarkers (lipid peroxidation (LPO), percentage of DNA fragmentation, carbonylated proteins (CP) and nitric oxide (NO)) and histopathological alterations in testicles of Clarias gariepinus were determined. The exposure to Hg resulted in a high accumulation of residues of this metal in testicular tissues. The results showed a significant decrease in sperm count, activity and motility and in all gonadal hormones in Hg exposed groups. Hg exposure also induced a decline in TAO, SOD, CAT and GPx, whereas LPO, DNA fragmentation, CP and NO significantly increased in testicles of C. gariepinus respect to the control group. Although exposure to Se did not reduce the degree of mercury bioconcentration in the testicles, the sperm quality parameters were recovered. Moreover, TAO levels and GPx activity significantly increased after fish exposure to Se, whereas CP levels decreased. LPO, NO, CAT and SOD were also partially normalized when compared with the groups exposed to only Hg. In conclusion, the results showed that Hg, even in the small doses is capable to induce reproductive toxicity in the male catfish. Se exposure partially restored the values of biochemical parameters and sperm quality in Hg-treated fish suggesting protective effects against Hg reproductive toxicity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Triptolide (TP), a major active ingredient of Tripterygium wilfordii, exerts potent immunosuppressive effects in the treatment of rheumatoid arthritis but is not widely used in clinical practice due to its multiorgan toxicity, particularly hepatotoxicity, nephrotoxicity, and reproductive toxicity. An LC-MS/MS approach was employed to explore the endocrine-disrupting effects of TP. The endocrine-disrupting effects of various concentrations (0-100 nM) of TP for 48 hour were firstly investigated using an in vitro model (H295R cell line). It was found that TP did not decrease cell viability. The transcriptional levels of steroidogenic enzymes in H295R cells were assessed by quantificational real-time polymerase chain reaction. The possible adrenal and endocrine effects of oral administration of TP (0, 50, and 500 μg/kg) for 28 days on both normal and collagen-induced arthritis (CIA) rats were also explored. The serum and adrenal tissue hormone levels (corticosterone and progesterone) and adrenal histopathology were analyzed, with the results that TP significantly decreased the level of cortisol in H295R cells and the level of plasma corticosterone in both normal and CIA rats. Histological alterations in adrenal cortex were observed at the dose of 500 μg/kg. Exposure to TP for 48 hour had an obvious inhibitory effect on the messenger RNA transcript levels of HSD3B2, CYP21A2, CYP17A1, and CYP11B1, which is essential for the synthesis of corticosteroids. In a word, TP leads to the disorder of corticosteroid synthesis and secretion, and corticosteroid may be a potential biomarker for the treatment of multiorgan toxicity of TP., (© 2019 Wiley Periodicals, Inc.)

Sex differences in the brain and behavior are produced by the perinatal action of testosterone, which is converted into estradiol by the enzyme aromatase in the brain. Although magnetic resonance imaging (MRI) has been widely used in humans to study these differences, the use of animal models, where hormonal status can be properly manipulated, is necessary to explore the mechanisms involved. We used sheep, a recognized model in the field of neuroendocrinology, to assess brain morphological and functional sex differences and their regulation by adult gonadal hormones. To this end, we performed voxel-based morphometry and a resting-state functional MRI approach to assess sex differences in gonadally intact animals. We demonstrated significant sex differences in gray matter concentration (GMC) at the level of the gonadotropic axis, i.e., not only within the hypothalamus and pituitary but also within the hippocampus and the amygdala of intact animals. We then performed the same analysis one month after gonadectomy and found that some of these differences were reduced, especially in the hypothalamus and amygdala. By contrast, we found few differences in the organization of the functional connectome between males and females either before or after gonadectomy. As a whole, our study identifies brain regions that are sexually dimorphic in the sheep brain at the resolution of the MRI and highlights the role of gonadal hormones in the maintenance of these differences., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Naturally occurring alterations in estradiol influence food intake in females. However, how motivational responses to food cues are affected by the estrous cycle or ovarian hormones is unknown. In addition, while individual susceptibility to obesity is accompanied by enhanced incentive motivational responses to food cues and increased NAc intrinsic excitability in males, studies in females are absent. Therefore, we examined basal differences in intrinsic NAc excitability of obesity-prone vs. obesity-resistant females and determined how conditioned approach (a measure of cue-triggered motivation), food intake, and motivation for food vary with the cycle in naturally cycling female obesity-prone, obesity-resistant, and outbred Sprague-Dawley rats. Finally, we used ovariectomy followed by hormone treatment to determine the role of ovarian hormones in cue-triggered motivation in selectively-bred and outbred female rats. We found that intrinsic excitability of NAc MSNs and conditioned approach are enhanced in female obesity-prone vs. obesity-resistant rats. These effects were driven by greater MSN excitability and conditioned approach behavior during metestrus/diestrus vs. proestrus/estrus in obesity-prone but not obesity-resistant rats, despite similar regulation of food intake and food motivation by the cycle in these groups. Furthermore, estradiol and progesterone treatment reduced conditioned approach behavior in obesity-prone and outbred Sprague-Dawley females. To our knowledge, these data are the first to demonstrate cycle- and hormone-dependent effects on the motivational response to a food cue, and the only studies to date to determine how individual susceptibility to obesity influences NAc excitability, cue-triggered food-seeking, and differences in the regulation of these neurobehavioral responses by the estrous cycle., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

In this review, we describe the sex differences in prevalence, onset, symptom profiles, and disease outcome that are evident in schizophrenia, bipolar disorder, and post-traumatic stress disorder. Women with schizophrenia tend to exhibit less disease impairment than men. By contrast, women with post-traumatic stress disorder are more affected than men. The most likely candidates to explain these sex differences are gonadal hormones. This review details the clinical evidence that oestradiol and progesterone are dysregulated in these psychiatric disorders. Notably, existing data on oestradiol, and to a lesser extent, progesterone, suggest that low levels of these hormones may increase the risk of disease development and worsen symptom severity. We argue that future studies require a more inclusive, considered analysis of gonadal steroid hormones and the intricacies of the interactions between them, with methodological rigour applied, to enhance our understanding of the roles of steroid hormones in psychiatric disorders. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc., (© 2019 The British Pharmacological Society.)

Purpose of Review: To examine the potential role of ovarian hormones in biological vulnerability to borderline personality disorder (BPD). The review focuses primarily on research examining the menstrual cycle as a source of short-term lability of BPD symptom expression, while discussing the currently understudied possibility of ovarian hormone influence in the developmental course of BPD., Findings: Several patterns of menstrual cycle effects on BPD symptoms and relevant features in non-clinical samples have been observed in empirical studies. Most symptoms demonstrated patterns consistent with perimenstrual exacerbation; however, timing varied between high and low arousal symptoms, potentially reflecting differing mechanisms. Symptoms are typically lowest around ovulation, with an exception for proactive aggression and some forms of impulsive behaviors. Preliminary evidence suggests ovarian hormones may exert strong effects on BPD symptom expression, and further research is warranted examining mechanisms and developing interventions. Recommendations for researchers and clinicians working with BPD are provided.

Prior studies suggest that levels of ovarian hormones may affect learning and memory in rats, including studies of fear conditioning and extinction. We previously showed that female rats show reduced retention of extinction compared to males when measuring fear-potentiated startle, but not when measuring freezing behavior. One commonly reported observation in studies of freezing behavior is that rats with increased levels of estradiol during extinction learning show better retention of extinction than rats given extinction training when levels of estradiol are low. Here, we tested the hypothesis that fear extinction retention in a fear-potentiated startle paradigm in females is influenced by levels gonadal hormones, which we had not accounted for in our original report. We used the fear-potentiated startle paradigm to test if extinction learning was affected by estrous phase, ovariectomy, or acute systemic injections of estradiol in ovariectomized rats. We report that neither the expression nor extinction of fear-potentiated startle differed in rats given extinction training in proestrus compared to those in metestrus. Removal of the ovaries had no effect on fear acquisition or extinction learning as assessed by fear-potentiated startle. Finally, systemic injections of estradiol given to ovariectomized rats before extinction training had no effect on the expression of fear or the retention of extinction. Our findings suggest that the effect of female gonadal hormones on fear conditioning and extinction may depend on the measure of fear employed or by the parameters used to study fear learning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).