Sex hormones, autoimmunity and gender disparity in COVID-19.

The Coronavirus disease 2019 (COVID-19) pandemic has majorly contributed to massive and widespread mortality. Epidemiological data strongly indicates a sex-based disparity in COVID-19 clinical outcomes, with women having lower infection and hospitalisation rates, coupled with better prognosis and lesser mortality. This disparity may be explained by several mechanisms including differences in innate and adaptive immune responses, genetic factors, and an interplay between sex hormones and immune effectors, as well as gender-specific behaviour differences. These pathways, particularly the immunological divergence in response to viral infection, could potentially influence not only COVID-19 pathogenesis and disease course, but also the response to antiviral drugs and vaccines. Furthermore, factors that confer a protective advantage against COVID-19 may be exploited to develop therapeutic strategies to improve clinical outcomes in COVID-19.

Parkinson's disease in women: Mechanisms underlying sex differences.

Parkinson's disease is a neurodegenerative disease which is associated with different motor, cognitive and mood-related problems. Though it has been established that Parkinson's disease is less prevalent in women in comparison to men, the differences tend to diminish with the advancing age. Different genetic, hormonal, neuroendocrinal and molecular players contribute towards the differences in the Parkinson's disease pathogenesis. Furthermore, data available with respect to the therapeutic management of Parkinson's disease in females is limited; women often tend to suffer more from the side effects of the currently available drugs. The present review highlights the sex-specific differences which play a role in the manifestation of these symptoms and side effects of the currently available therapeutic strategies. We have also discussed the current and upcoming therapeutic strategies which are in the clinical trials such as adenosine 2A (A2A) receptor antagonists, estrogen replacement therapy, α-synuclein targeting vaccines and antibodies, Botulinum toxin A, Fas-associated factor-1 (FAF-1) inhibitors, thiazolidinediones, 5-HT1A receptor agonists, dopamine D1/D5 receptor agonists, Glucagon-like peptide 1 (GLP-1) analogues and certain plant based principles for the treatment of Parkinson's disease in women.

Gender-specific approach in psychiatric diseases: Because sex matters.

In both animals and human beings, males and females differ in their genetic background and hormonally driven behaviour and show sex-related differences in brain activity and response to internal and external stimuli. Gender-specific medicine has been a neglected dimension of medicine for long time, and only in the last three decades it is receiving the due scientific and clinical attention. Research has recently begun to identify factors that could provide a neurobiological basis for gender-based differences in health and disease and to point to gonadal hormones as important determinants of male-female differences. Animal studies have been of great help in understanding factors contributing to sex-dependent differences and sex hormones action. Here we review and discuss evidence provided by clinical and animal studies in the last two decades showing gender (in humans) and sex (in animals) differences in selected psychiatric disorders, namely eating disorders (anorexia nervosa, bulimia nervosa, binge eating disorder), schizophrenia, mood disorders (anxiety, depression, obsessive-compulsive disorder) and neurodevelopmental disorders (autism spectrum disorders, attention-deficit/hyperactivity disorder).

Gender Differences in Hypertension.

Hypertension is the leading risk factor for global mortality and morbidity and remains the major preventable cause of cardiovascular diseases. Gender differences in risk factors and awareness, treatment, and control of hypertension have been well established in humans. There are significant differences in epidemiology and clinical characteristic of hypertension between men and women. Moreover, gender differences are linked with several specific types of hypertension, including postmenopausal hypertension, white coat hypertension, masked hypertension, and hypertensive disorders of pregnancy. Gender differences have been implicated in the prevalence and determinants of hypertension and prehypertension whereas the control rate is similar between men and women taking antihypertensive medication. Importantly, distinct roles of the angiotensin-converting enzyme 2/Apelin signaling, sex hormone, endothelin-1, and sympathetic nervous activity contribute to sex differences in blood pressure control. This review summarizes gender differences in clinical features and determinants of hypertension and the underlying mechanisms responsible for hypertension.

Social control of spermatogenesis and steroidogenesis in cichlid fish: a comparative approach.

Social animals with hierarchical dominance systems are susceptible to changes their environment. Interactions with conspecifics can greatly affect individual's behavior and reproductive success. This review will show how social behavior modulates gonadal steroidogenesis and spermatogenesis in African and Neotropical cichlid fish with different social systems and how this modulation regulates reproductive capacity. Social behavior and aggressiveness are strongly linked to sex steroids, glucocorticoids and neuropeptides. The challenge hypothesis suggests that behavioral interactions increase androgen levels in response to social instability, but there is little evidence regarding estradiol levels. It has been recently demonstrated that in male Cichlasoma dimerus, a Neotropical cichlid fish, the challenge hypothesis could also be extended to estrogens. In C. dimerus, dominant males have higher gonadosomatic index than subordinated; the percentage of spermatocytes and spermatids is higher in subordinates, while dominants show a greater percentage of spermatozoa. In other species of African cichlids, socially suppressed subordinate males are not reproductively incompetent maintaining some activity at every level of their reproductive axis. Axis reactivation upon social ascent is similar to the initiation of puberty in mammals, as well as the reoccurrence of puberty observed in seasonally breeding animals. In conclusion, social behavior and reproductive strategies in females cichlids are still understudied, and Neotropical cichlids still constitute a group that deserves more attention, considering cichlids' diversity in mating systems, reproductive behavior and parental care. This review highlights the importance of performing further studies and additional research in these two areas, which still remain to be addressed.

An assessment of the multifactorial profile of steroid-metabolizing enzymes and steroid receptors in the eutopic endometrium during moderate to severe ovarian endometriosis.

BACKGROUND: Previous studies of expression profiles of major endometrial effectors of steroid physiology in endometriosis have yielded markedly conflicting conclusions, presumably because the relative effects of type of endometriosis, fertility history and menstrual cycle phases on the measured variables were not considered. In the present study, endometrial mRNA and protein levels of several effectors of steroid biosynthesis and action in patients with stage III-IV ovarian endometriosis (OE) with known fertility and menstrual cycle histories were compared with the levels in control endometrium to test this concept. METHODS: Endometrial samples were collected from patients without endometriosis (n = 32) or OE stages III-IV (n = 52) with known fertility and cycle histories. qRT-PCR and immunoblotting experiments were performed to measure levels of NR5A1, STAR, CYP19A1, HSD17Bs, ESRs and PGR transcripts and proteins, respectively. Tissue concentrations of steroids (P4, T, E1 and E2) were measured using ELISAs. RESULTS: The levels of expression of aromatase and ERß were lower (P < 0.0001) and 17ß-HSD1 (P < 0.0001) and PRA (P < 0.01) were higher in OE endometrium. Lower aromatase levels and higher 17ß-HSD1 levels were detected in fertile (aromatase: P < 0.05; 17ß-HSD1: P < 0.0001) and infertile (aromatase: P < 0.0001; 17ß-HSD1: P < 0.0001) OE endometrium than in the matched control tissues. Both proliferative (PP) and secretory (SP) phase OE samples expressed aromatase (P < 0.0001) and ERß (PP: P < 0.001; SP: P < 0.01) at lower levels and 17ß-HSD1 (P < 0.0001) and PRA (PP: P < 0.01; SP: P < 0.0001) at higher levels than matched controls. Higher 17ß-HSD1 (P < 0.01) and E2 (P < 0.05) levels and a lower (P < 0.01) PRB/PRA ratio was observed in infertile secretory phase OE endometrium than in control. CONCLUSIONS: We report that dysregulated expression of 17ß-HSD1 and PGR resulting in hyperestrogenism and progesterone resistance during the secretory phase of the menstrual cycle, rather than an anomaly in aromatase expression, was the hallmark of eutopic endometrium from infertile OE patients. Furthermore, the results provide proof of concept that the fertility and menstrual cycle histories exerted relatively different effects on steroid physiology in the endometrium from OE patients compared with the control subjects.

Sex Differences and Gender Diversity in Stress Responses and Allostatic Load Among Workers and LGBT People.

Measuring biological sex differences and socio-cultural gender diversity provides insights into individual variation in stress physiology and the development of "sex-specific" diseases. PURPOSE OF REVIEW: In this selective review, we summarize recent findings that assess sex and gender in relation to the stress hormone cortisol and multi-systemic physiological dysregulation called allostatic load. The focus of this research centers on workers as well as sexual and gender minorities as these populations provide unique insights into sex and gender at various levels of analysis from the micro-level to the macro-level. RECENT FINDINGS: Male/female sex, sex hormones, gender identity, gender roles, and sexual orientation are all variables that are distinctly correlated with stress physiology. Beyond identifying patterns of vulnerability to stress-related diseases, pathways towards resilience are of high priority in emerging literature. Stress scientists must account for both sex and gender in biobehavioral research. Future directions should assess macro-level constructs like institutionalized gender, occupational sex composition, and structural stigma to better understand the social determinants of health.

Assessment of endocrine-disrupting activities of alternative chemicals for bis(2-ethylhexyl)phthalate.

Plastic products are closely intertwined with modern life. Some plasticizers used in making plastics, such as phthalates, are reported to be endocrine-disrupting chemicals. Plasticizers can be released into the environment, and health risks related to plasticizer exposure have been reported. In addition, due to plastic waste that flows into the ocean, microplastics have been found in marine products, including non-biological seawater products such as sea salt. Plastics can affect the body via a variety of pathways, and therefore safer alternative chemicals are needed. Three chemicals were evaluated: acetyl tributyl citrate (ATBC), triethyl 2-acetylcitrate (ATEC), and trihexyl O-acetylacitrate (ATHC), replacing bis(2-ethylhexyl)phthalate (DEHP), a typical plasticizer. The endocrine-disrupting activities of each chemical, including estrogenic or anti-estrogenic activity (test guideline (TG) No. 455), androgenic or anti-androgenic activity (TG No. 458), steroidogenesis (TG No. 456), and estrogenic properties via a short-term screening test using the uterotrophic assay (TG No. 440), were assessed in accordance with the Organisation for Economic Co-operation and Development guidelines for chemical testing. Our results showed that DEHP, ATBC, ATEC, ATHC possess no estrogenic activity, whereas DEHP, ATBC and ATHC demonstrate anti-estrogenic activity and ATBC anti-androgenic activity. DEHP and ATHC exhibited a disruption in steroidogenesis activities. Additional tests are necessary, but our results suggest that ATEC is a good candidate plasticizer providing a suitable alternative to DEHP.

Mechanisms of sex differences in atrial fibrillation: role of hormones and differences in electrophysiology, structure, function, and remodelling.

Atrial fibrillation (AF) is the clinically most prevalent rhythm disorder with large impact on quality of life and increased risk for hospitalizations and mortality in both men and women. In recent years, knowledge regarding epidemiology, risk factors, and patho-physiological mechanisms of AF has greatly increased. Sex differences have been identified in the prevalence, clinical presentation, associated comorbidities, and therapy outcomes of AF. Although it is known that age-related prevalence of AF is lower in women than in men, women have worse and often atypical symptoms and worse quality of life as well as a higher risk for adverse events such as stroke and death associated with AF. In this review, we evaluate what is known about sex differences in AF mechanisms-covering structural, electrophysiological, and hormonal factors-and underscore areas of knowledge gaps for future studies. Increasing our understanding of mechanisms accounting for these sex differences in AF is important both for prognostic purposes and the optimization of (targeted, mechanism-based, and sex-specific) therapeutic approaches.

[Environmental Chemical Exposure and Its Effects on Infants' Reproductive Hormones].

In recent years, the birthrate has been continuously declining in Japan. The main causes of the decline are social factors. On the other hand, there is increasing evidence that many environmental chemicals show endocrine disrupting properties. Thus, we hypothesized that exposure to these chemicals would also be a causal for the fertility crisis. In this review, we examined current evidence that focused on environmental chemical exposure in utero and its association with reproductive hormones in children. We have included the findings from a prospective birth cohorts, the Hokkaido Study on Environment and Children's Health Sapporo cohort. According to the literature, environmental chemical levels in utero, such as polychlorinated biphenyl, dioxins, perfluorinated chemical substances, phthalates, and bisphenol A were somewhat associated with the levels of reproductive hormones, such as testosterone, estradiol, progesterone, inhibin B, and insulin-like factor-3 in cord blood, in early childhood and adolescence. The literature also suggests the association between exposure to these chemicals and brain-sexual differentiation or the anogenital distance, which suggests the disruption of androgen shower during the developmental stage in the fetal period. There are still knowledge gaps on whether these hormones at an early stage affect the pubertal development and reproductive functions in later life. In addition, alternative chemicals are produced after banning one type. The health effects of alternative chemicals should be evaluated. Effects of exposure to a mixture of the chemicals should also be examined in future studies. In conclusion, the prevention of environmental chemical hazards in relation to human reproductive function is important. It would be one of the countermeasures to the falling birthrate caused by fertility issues.

Sex differences in abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) is a vascular disorder with a high case fatality rate in the instance of rupture. AAA is a multifactorial disease, and the etiology is still not fully understood. AAA is more likely to occur in men, but women have a greater risk of rupture and worse prognosis. Women are reportedly protected against AAA possibly by premenopausal levels of estrogen and are, on average, diagnosed at older ages than men. Here, we review the present body of research on AAA pathophysiology in humans, animal models, and cultured cells, with an emphasis on sex differences and sex steroid hormone signaling.

Localized cyclical variations in immunoproteins in the female genital tract and the implications on the design and assessment of mucosal infection and therapies.

PROBLEM: Fluctuating hormones regulate reproductive processes in the female genital tract. Consequent changes in the local immunological environment are likely to affect cellular interaction with infectious agents and the assessment of therapies that target mucosal infections. METHOD OF STUDY: We compared Softcup and Weck-Cel sampling protocols and assessed the changes in the concentrations of 39 soluble proteins with menstrual cycle progression in the mucosal and peripheral compartments. RESULTS: We demonstrate that the mucosal immunological profile is distinct from serum with inflammatory and migratory signatures that are localized throughout the cycle. The analytes highlighted in the mucosal compartment were generally highest at the follicular phase with a tendency to fall as the cycle progressed through ovulation to the luteal phase. CONCLUSION: Our results underscore the need to consider these localized cyclical differences in studies aimed at assessing the outcome of disease and the efficacy of mucosal vaccines and other therapies.

Sex Differences in Muscle Wasting.

With aging and other muscle wasting diseases, men and women undergo similar pathological changes in skeletal muscle: increased inflammation, enhanced oxidative stress, mitochondrial dysfunction, satellite cell senescence, elevated apoptosis and proteasome activity, and suppressed protein synthesis and myocyte regeneration. Decreased food intake and physical activity also indirectly contribute to muscle wasting. Sex hormones also play important roles in maintaining skeletal muscle homeostasis. Testosterone is a potent anabolic factor promoting muscle protein synthesis and muscular regeneration. Estrogens have a protective effect on skeletal muscle by attenuating inflammation; however, the mechanisms of estrogen action in skeletal muscle are less well characterized than those of testosterone. Age- and/or disease-induced alterations in sex hormones are major contributors to muscle wasting. Hence, men and women may respond differently to catabolic conditions because of their hormonal profiles. Here we review the similarities and differences between men and women with common wasting conditions including sarcopenia and cachexia due to cancer, end-stage renal disease/chronic kidney disease, liver disease, chronic heart failure, and chronic obstructive pulmonary disease based on the literature in clinical studies. In addition, the responses in men and women to the commonly used therapeutic agents and their efficacy to improve muscle mass and function are also reviewed.

Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease.

Sex differences between women and men are often overlooked and underappreciated when studying the cardiovascular system. It has been long assumed that men and women are physiologically similar, and this notion has resulted in women being clinically evaluated and treated for cardiovascular pathophysiological complications as men. Currently, there is increased recognition of fundamental sex differences in cardiovascular function, anatomy, cell signaling, and pathophysiology. The National Institutes of Health have enacted guidelines expressly to gain knowledge about ways the sexes differ in both normal function and diseases at the various research levels (molecular, cellular, tissue, and organ system). Greater understanding of these sex differences will be used to steer future directions in the biomedical sciences and translational and clinical research. This review describes sex-based differences in the physiology and pathophysiology of the vasculature, with a special emphasis on sex steroid receptor (estrogen and androgen receptor) signaling and their potential impact on vascular function in health and diseases (e.g., atherosclerosis, hypertension, peripheral artery disease, abdominal aortic aneurysms, cerebral aneurysms, and stroke).

Sex in basic research: concepts in the cardiovascular field.

Women and men, female and male animals and cells are biologically different, and acknowledgement of this fact is critical to advancing medicine. However, incorporating concepts of sex-specific analysis in basic research is largely neglected, introducing bias into translational findings, clinical concepts and drug development. Research funding agencies recently approached these issues but implementation of policy changes in the scientific community is still limited, probably due to deficits in concepts, knowledge and proper methodology. This expert review is based on the EUGenMed project (www.eugenmed.eu) developing a roadmap for implementing sex and gender in biomedical and health research. For sake of clarity and conciseness, examples are mainly taken from the cardiovascular field that may serve as a paradigm for others, since a significant amount of knowledge how sex and oestrogen determine the manifestation of many cardiovascular diseases (CVD) has been accumulated. As main concepts for implementation of sex in basic research, the study of primary cell and animals of both sexes, the study of the influence of genetic vs. hormonal factors and the analysis of sex chromosomes and sex specific statistics in genome wide association studies (GWAS) are discussed. The review also discusses methodological issues, and analyses strength, weaknesses, opportunities and threats in implementing sex-sensitive aspects into basic research.

Sex Hormones and Sex Chromosomes Cause Sex Differences in the Development of Cardiovascular Diseases.

This review summarizes recent evidence concerning hormonal and sex chromosome effects in obesity, atherosclerosis, aneurysms, ischemia/reperfusion injury, and hypertension. Cardiovascular diseases occur and progress differently in the 2 sexes, because biological factors differing between the sexes have sex-specific protective and harmful effects. By comparing the 2 sexes directly, and breaking down sex into its component parts, one can discover sex-biasing protective mechanisms that might be targeted in the clinic. Gonadal hormones, especially estrogens and androgens, have long been found to account for some sex differences in cardiovascular diseases, and molecular mechanisms mediating these effects have recently been elucidated. More recently, the inherent sexual inequalities in effects of sex chromosome genes have also been implicated as contributors in animal models of cardiovascular diseases, especially a deleterious effect of the second X chromosome found in females but not in males. Hormonal and sex chromosome mechanisms interact in the sex-specific control of certain diseases, sometimes by opposing the action of the other.

Sex-Related Differences in GI Disorders.

Epidemiological studies indicate sex-related differences among functional gastrointestinal disorders (FGIDs) wherein females are more likely to receive a diagnosis than their male counterparts. However, the mechanism by which females exhibit an increased vulnerability for development of these pathophysiologies remains largely unknown, and therapeutic treatments are limited. The current chapter focuses on clinical research outlining our current knowledge of factors that contribute to the female predominance among FGID patients such as the menstrual cycle and sex hormones. In addition, we will discuss progress in preclinical research, including animal models, which serve as valuable tools for the investigation of the development and long term manifestation of symptoms observed within the patient population. Although much progress has been made, additional longitudinal studies in both clinical and preclinical research are necessary to identify more specific mechanisms underlying sex-related differences in FGIDs as well as targets for improved therapeutic approaches.

Reproduction impairment and endocrine disruption in female zebrafish after long-term exposure to MC-LR: A life cycle assessment.

Microcystin-LR (MC-LR) has been found to cause reproductive and developmental impairments as well as to disrupt sex hormone homeostasis of fish during acute and sub-chronic toxic experiments. However, fish in natural environments are continuously exposed to MC-LR throughout their entire life cycle as opposed to short-term exposure. Here, we tested the hypothesis that the mechanism by which MC-LR harms female fish reproduction and development within natural water bodies is through interference of the reproductive endocrine system. In the present study, zebrafish hatchlings (5 d post-fertilization) were exposed to 0, 0.3, 3 and 30 µg/L MC-LR for 90 d until reaching sexual maturity. Female zebrafish were selected, and the changes in growth and developmental indicators, ovarian ultrastructure as well as the levels of gonadal steroid hormones and vitellogenin (VTG) were examined along with the transcription of related genes in the hypothalamic-pituitary-gonadal-liver axis (HPGL-axis). The results showed for the first time, a life cycle exposure to MC-LR caused growth inhibition, decreased ovary weight and ovarian ultra-pathological lesions. Decreased ovarian testosterone levels indicated that MC-LR disrupted sex steroid hormone balance. Significantly up-regulated transcription of brain FSHß and LHß along with ovarian ERα, FSHR and LHR suggested positive feedback regulation in the HPGL-axis was induced as a compensatory mechanism for MC-LR damage. It was also noted that ovarian VTG content and hepatic ERα and VTG1 expression were all down-regulated, which might be responsible for reduced vitellus storage noted in our histological observations. Our findings indicate that a life cycle exposure to MC-LR impairs the development and reproduction of female zebrafish by disrupting the transcription of related HPGL-axis genes, suggesting that MC-LR has potential adverse effects on fish reproduction and thus population dynamics in MCs-contaminated aquatic environment.

Separate effects of sex hormones and sex chromosomes on brain structure and function revealed by high-resolution magnetic resonance imaging and spatial navigation assessment of the Four Core Genotype mouse model.

Males and females exhibit several differences in brain structure and function. To examine the basis for these sex differences, we investigated the influences of sex hormones and sex chromosomes on brain structure and function in mice. We used the Four Core Genotype (4CG) mice, which can generate both male and female mice with XX or XY sex chromosome complement, allowing the decoupling of sex chromosomes from hormonal milieu. To examine whole brain structure, high-resolution ex vivo MRI was performed, and to assess differences in cognitive function, mice were trained on a radial arm maze. Voxel-wise and volumetric analyses of MRI data uncovered a striking independence of hormonal versus chromosomal influences in 30 sexually dimorphic brain regions. For example, the bed nucleus of the stria terminalis and the parieto-temporal lobe of the cerebral cortex displayed steroid-dependence while the cerebellar cortex, corpus callosum, and olfactory bulbs were influenced by sex chromosomes. Spatial learning and memory demonstrated strict hormone-dependency with no apparent influence of sex chromosomes. Understanding the influences of chromosomes and hormones on brain structure and function is important for understanding sex differences in brain structure and function, an endeavor that has eventual implications for understanding sex biases observed in the prevalence of psychiatric disorders.