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Gonadal sex steroid hormones are well-studied modulators of reproductive physiology and behavior. Recent behavioral endocrinology research has focused on how the brain dynamically responds to - and may even produce - sex steroids, but the gonadal tissues that primarily release these hormones receive much less attention as a potential mediator of behavioral variation. This Commentary revisits mechanisms by which the reproductive hypothalamic-pituitary-gonadal (HPG) axis can be modulated specifically at the gonadal level. These mechanisms include those that may allow the gonad to be regulated independently of the HPG axis, such as receptors for non-HPG hormones, neural inputs and local production of conventional 'neuropeptides'. Here, I highlight studies that examine variation in these gonadal mechanisms in diverse taxa, with an emphasis on recent transcriptomic work. I then outline how future work can establish functional roles of gonadal mechanisms in reproductive behavior and evaluate gonad responsiveness to environmental cues. When integrated with neural mechanisms, further investigation of gonadal hormone regulation can yield new insight into the control and evolution of steroid-mediated traits, including behavior., Competing Interests: Competing interests The author declares no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Cutaneous melanoma represents the fifth tumor in terms of incidence in young adults, with a major involvement of males than females. Despite the significant changes in available effective treatments for cutaneous melanoma, there is still a proportion of patients that do not benefit long-term disease control with immune checkpoint inhibitors and/or BRAF/MEK inhibitors, and eventually develop progressive disease. In addition to the emerging biomarkers under investigation to understand resistance to treatments, recent studies resumed the role of sex hormones (estrogens, progesterone and androgens) in melanoma patients. In the last decades, the impact of sex hormones has been considered controversial in melanoma patients, but actual growing preclinical and clinical evidence underline the potential influence on melanoma cells' growth, tumor microenvironment, the immune system and consequently on the course of disease.This review will provide available insights on the role of sex hormones in melanoma pathogenesis, disease progression and response/resistance to systemic treatments. We will also offer an overview on the recent studies on the theme, describing the hormonal contribution to disease response and the interaction with targeted therapies and immune-checkpoint inhibitors in cutaneous melanoma patients, illustrating an insight into future research in this field., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Sex hormones play a pivotal role as endocrine hormones that exert profound effects on the biological characteristics and vascular function of vascular smooth muscle cells (VSMCs). By modulating intracellular signaling pathways, activating nuclear receptors, and regulating gene expression, sex hormones intricately influence the morphology, function, and physiological state of VSMCs, thereby impacting the biological properties of vascular contraction, relaxation, and growth. Increasing evidence suggests that abnormal phenotypic changes in VSMCs contribute to the initiation of vascular diseases, including atherosclerosis. Therefore, understanding the factors governing phenotypic alterations in VSMCs and elucidating the underlying mechanisms can provide crucial insights for refining interventions targeted at vascular diseases. Additionally, the varying levels of different types of sex hormones in the human body, influenced by sex and age, may also affect the phenotypic conversion of VSMCs. This review aims to explore the influence of sex hormones on the phenotypic switching of VSMCs and the development of associated vascular diseases in the human body., (© 2024. The Author(s).)

Abstract: There is increasing evidence that musculoskeletal tissues are differentially regulated by sex hormones in males and females. The influence of sex hormones, in addition to other sex-based differences such as in anatomical alignment and immune-system function, impact the prevalence and severity of disease as well as the types of injuries that affect the musculoskeletal system and the outcomes of prevention measures and treatment. Literature specifically addressing sex differences related to the musculoskeletal system is limited, underscoring the imperative for both basic and clinical research on this topic. This review highlights areas of research that have implications for bone and cartilage health, including growth and development, sports injuries, osteoarthritis, osteoporosis, and bone frailty. It is clear that important aspects of the musculoskeletal system have been understudied. Consideration of how sex hormone therapy will affect musculoskeletal tissues in prepuberty, during puberty, and in adults is vital, yet little is known. The purpose of this article is to foster awareness and interest in advancing our understanding of how sex differences influence orthopaedic practice., Competing Interests: Disclosure: Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Numbers R13AR082710, 1R01 AR072500, and K12AR084233; the Joan and Morgan Massey Foundation; and the Peter and Carrie Ullrich Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/I78 )., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: Skeletal modeling in childhood and adolescence and continuous remodeling throughout the lifespan are designed to adapt to a changing environment and resist external forces and fractures. The flux of sex steroids in men and women, beginning from fetal development and evolving through infancy, childhood, puberty, young adulthood, peri/menopause transition, and postmenopause, is critical for bone size, peak bone mass, and fracture resistance., Objective: This review will highlight how changes in sex steroids throughout the lifespan affect bone cells and the consequence of these changes on bone architecture and strength., Methods: Literature review and discussion., Results: The contributions of estrogen and testosterone on skeletal development have been difficult to study due to the reciprocal and intertwining contributions of one on the other. Although orchiectomy in men renders circulating testosterone absent, circulating estrogen also declines due to testosterone being the substrate for estradiol. The discovery of men with absent estradiol or resistance to estrogen and the study of mouse models led to the understanding that estrogen has a larger direct role in skeletal development and maintenance in men and women. The mechanistic reason for larger bone size in men is incompletely understood but related to indirect effects of testosterone on the skeleton, such as higher muscle mass leading to larger mechanical loading. Declines in sex steroids during menopause in women and androgen deprivation therapies in men have profound and negative effects on the skeleton. Therapies to prevent such bone loss are available, but how such therapies can be tailored based on bone size and architecture remains an area of investigation., Conclusion: In this review, the elegant interplay and contribution of sex steroids on bone architecture in men and women throughout the lifespan is described., Competing Interests: Disclosure The authors have no multiplicity of interest to disclose., (Published by Elsevier Inc.)

Introduction: Sexual dimorphism significantly influences cancer incidence and prognosis. Notably, females exhibit a lower risk and favorable prognosis for non-reproductive cancers compared to males, a pattern observable beyond the scope of risk behaviors such as alcohol consumption and smoking. Colorectal cancer, ranking third in global prevalence and second in mortality, disproportionately affects men. Sex steroid hormones, particularly estrogens and androgens, play crucial roles in cancer progression, considering epidemiological in vivo and in vitro, in general estrogens imparting a protective effect in females and androgens correlating with an increasing risk of colorectal cancer development., Main Body: The hormonal impact on immune response is mediated by receptor interactions, resulting in heightened inflammation, modulation of NF-kB, and fostering an environment conducive to cancer progression and metastasis. These molecules also influence the enteric nervous system, that is a pivotal in neuromodulator release and intestinal neuron stimulation, also contributes to cancer development, as evidenced by nerve infiltration into tumors. Microbiota diversity further intersects with immune, hormonal, and neural mechanisms, influencing colorectal cancer dynamics. A comprehensive understanding of hormonal influences on colorectal cancer progression, coupled with the complex interplay between immune responses, microbiota diversity and neurotransmitter imbalances, underpins the development of more targeted and effective therapies., Conclusions: Estrogens mitigate colorectal cancer risk by modulating anti-tumor immune responses, enhancing microbial diversity, and curbing the pro-tumor actions of the sympathetic and enteric nervous systems. Conversely, androgens escalate tumor growth by dampening anti-tumor immune activity, reducing microbial diversity, and facilitating the release of tumor-promoting factors by the nervous system. These findings hold significant potential for the strategic purposing of drugs to fine-tune the extensive impacts of sex hormones within the tumor microenvironment, promising advancements in colorectal cancer therapies., (© 2024. The Author(s).)

Sexual behavior is crucial for reproduction in many animals. In many vertebrates, females exhibit sexual behavior only during a brief period surrounding ovulation. Over the decades, studies have identified the roles of ovarian sex hormones, which peak in levels around the time of ovulation, and the critical brain regions involved in the regulation of female sexual behavior. Modern technical innovations have enabled a deeper understanding of the neural circuit mechanisms controlling this behavior. In this review, I summarize our current knowledge and discuss the neural circuit mechanisms by which female sexual behavior occurs in association with the ovulatory phase of their cycle., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Inoue.)

Fluctuations in sex hormones at different stages of reproductive life, such as the menopausal transition, have been suggested as players in weight regulation. Indeed, the transition from a predominantly estrogenic state to an androgenic state characteristic of the menopausal transition contributes to changes in body composition with accumulation of fat and simultaneous loss of lean mass. However, whether these changes contribute to the weight gain remains debatable. Other physiological and psychosocial factors come into play. It is therefore important to offer individualized support with the objective to minimize the risk of weight gain and associated complications., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Introduction: Hormones play a vital role in development from conception to birth and throughout the human lifespan. These periods are logically divided into fetal development, pre-pubertal growth, puberty, and adulthood. Deviations from standard physiological levels and release patterns of constituent hormones can lead to pathology affecting the normal developmental trajectory. Research is ongoing to better understand the mechanisms of these hormones and how their modulation affects development., Methods: This article focuses on recent developments in understanding the role hormones play in development. We also cover recent discoveries in signaling pathways and hormonal regulation., Results: New and continuing research into functional hormone regulation focuses on sex hormones, gonadotropic hormones, growth hormones, insulin-like growth factor, thyroid hormone, and the interconnectedness of each of these functional axes. Currently, the abundance of work focuses on fertility and correction of sex hormone levels based on an individual's condition and stage in life., Discussion: Continuing research is needed to fully understand the long-term effects of hormone modulation in growth and sexual development. The role of each hormone in parallel endocrine axes should also be more thoroughly investigated to help improve the safety and efficacy in endocrine pharmacotherapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Aref, Fat and Ray.)

Mechanisms underlying cerebrovascular stroke outcomes are poorly understood, and the effects of biological sex on cerebrovascular regulation post-stroke have yet to be fully comprehended. Here, we explore the overlapping roles of gonadal sex hormones and rho-kinase (ROCK), two important modulators of cerebrovascular tone, on the acute cerebrovascular response to photothrombotic (PT) focal ischemia in mice. Male mice were gonadectomized and female mice were ovariectomized to remove gonadal hormones, whereas control ("intact") animals received a sham surgery prior to stroke induction. Intact wild-type (WT) males showed a delayed drop in cerebral blood flow (CBF) compared with intact WT females, whereby maximal CBF drop was observed 48 h following stroke. Gonadectomy in males did not alter this response. However, ovariectomy in WT females produced a "male-like" phenotype. Intact Rock2 +/- males also showed the same phenotypic response, which was not altered by gonadectomy. Alternatively, intact Rock2 +/- females showed a significant difference in CBF values compared with intact WT females, displaying higher CBF values immediately post-stroke and showing a maximal CBF drop 48 h post-stroke. This pattern was not altered by ovariectomy. Altogether, these data illustrate sex differences in acute CBF responses to PT stroke, which seem to involve gonadal female sex hormones and ROCK2. Overall, this study provides a framework for exploring sex differences in acute CBF responses to focal ischemic stroke in mice., (Copyright © 2024 Raman-Nair et al.)

Endothelial cells are important constituents of blood vessels and play a critical role in vascular homeostasis. They do not only control the exchanges between the blood and the surrounding tissues, but are also essential in regulating blood flow, modulating immune-cell trafficking and controlling vascular growth and repair. Endothelial dysfunction leads to cardiovascular diseases and is characterized by deficiency in secretion of vasodilator molecules, elevated reactive oxygen species (ROS), expression of adhesion molecules and excretion of proinflammatory cytokines. The sex hormones, estrogens, androgens and progestogens, regulate endothelial functions. Because cardiovascular disease risk increases after menopause, it is believed that female hormones, estrogens and progestogens promote endothelial cell health and function whereas androgens, the male hormones, might be detrimental. However, as illustrated in the present review, the picture might not be that simple. In addition, sex influences endothelial cell physiology independently of sex hormones but at genetic level., Competing Interests: Declaration of competing interest The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author. Published by Elsevier B.V. All rights reserved.)

The increasing of older age group in the population determines studying of age related diseases and emergence of new investigations in this area. In Female body, entering the menopausal transition is the start of «aging» of reproductive function and linked with decreasing of sex hormons levels. A direct connection between changes of estrogen, progesterone, androgen ratios and cognitive function of women was revealed. The anatomical localization of sex hormone receptors, the mechanisms of interaction of hormones with these receptors determine the ways of implementing biological effects of steroids on the CNS. Modern theories of «healthy nerve cells» and «eu-estrogenemia» explains the role of additional criteria, such as the absence of neurological diseases history and the duration of hypoestrogenia, to the outcome of menopausal hormone therapy. Additional factors that can affect to MHT action include: the composition of hormone therapy, administration methods, regimens (cyclic, continuous), duration of treatment, history of endocrine diseases, diabetes mellitus, gynecological history (parity, menarche age, COC use), heredity. The sections present the effect of menopausal transition on the development of depression, mood changes, sleep disturbances and mental disabilities. The explanation of negative effects of menopausal hormone therapy to cognitive health is also described by modern point of view. The ambivalent opinions of researchers, the potential of new reading of the results of earlier studies, confirms the necessity of continuing study of this topic.

The interaction between endocrine and vestibular systems remains poorly documented so far, despite numerous observations in humans and animals revealing direct links between the two systems. For example, dizziness or vestibular instabilities often accompany the menstrual cycle and are highly associated with the pre-menopause period, while sex hormones, together with their specific receptors, are expressed at key places of the vestibular sensory network. Similarly, other hormones may be associated with vestibular disorders either as causal/inductive factors or as correlates of the pathology. This review was carried out according to the PRISMA method, covering the last two decades and using the MEDLINE and COCHRANE databases in order to identify studies associating the terms vestibular system and/or vestibular pathologies and hormones. Our literature search identified 646 articles, 67 of which referred directly to vestibular dysfunction associated with hormonal variations. While we noted specific hormonal profiles depending on the pathology considered, very few clinical studies attempted to establish a direct link between the expression of the vestibular syndrome and the level of circulating hormones. This review also proposes different approaches to shed new light on the link between hormones and vestibular disorders, and to improve both the diagnosis and the therapeutic management of dizzy patients.

Sex differences in exercise physiology, such as substrate metabolism and skeletal muscle fatigability, stem from inherent biological factors, including endogenous hormones and genetics. Studies investigating exercise physiology frequently include only males or do not take sex differences into consideration. Although there is still an underrepresentation of female participants in exercise research, existing studies have identified sex differences in physiological and molecular responses to exercise training. The observed sex differences in exercise physiology are underpinned by the sex chromosome complement, sex hormones and, on a molecular level, the epigenome and transcriptome. Future research in the field should aim to include both sexes, control for menstrual cycle factors, conduct large-scale and ethnically diverse studies, conduct meta-analyses to consolidate findings from various studies, leverage unique cohorts (such as post-menopausal, transgender, and those with sex chromosome abnormalities), as well as integrate tissue and cell-specific -omics data. This knowledge is essential for developing deeper insight into sex-specific physiological responses to exercise training, thus directing future exercise physiology studies and practical application., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Sex hormones, such as estrogens and androgens, regulate genomic and cellular processes that contribute to sex-specific disparities in the pathophysiology of various cancers. Sex hormones can modulate the immune signals and activities of tumor cells and tumor-associated leukocytes to support or suppress cancer progression. Therefore, hormonal differences between males and females play a crucial role in cancer immunity and in the response to therapies that exploit the intrinsic immune system to eliminate malignant cells. In this review, we summarize the impact of sex hormones in the breast cancer microenvironment, with a focus on how the hormonal environment affects tumor immunity. We also discuss the potential benefits of endocrine therapy used in combination with immunotherapy to strengthen the antitumor immune response., (©2022 American Association for Cancer Research.)

Sex steroids play an important role in regulation of the vertebrate reproductive phenotype. This is because sex steroids not only activate sexual behaviors that mediate copulation, courtship, and aggression, but they also help guide the development of neural and muscular systems that underlie these traits. Many biologists have therefore described the effects of sex steroid action on reproductive behavior as both "activational" and "organizational," respectively. Here, we focus on these phenomena from an evolutionary standpoint, highlighting that we know relatively little about the way that organizational effects evolve in the natural world to support the adaptation and diversification of reproductive behavior. We first review the evidence that such effects do in fact evolve to mediate the evolution of sexual behavior. We then introduce an emerging animal model - the foot-flagging frog, Staurois parvus - that will be useful to study how sex hormones shape neuromotor development necessary for sexual displays. The foot flag is nothing more than a waving display that males use to compete for access to female mates, and thus the neural circuits that control its production are likely laid down when limb control systems arise during the developmental transition from tadpole to frog. We provide data that highlights how sex steroids might organize foot-flagging behavior through its putative underlying mechanisms. Overall, we anticipate that future studies of foot-flagging frogs will open a powerful window from which to see how sex steroids influence the neuromotor systems to help germinate circuits that drive signaling behavior. In this way, our aim is to bring attention to the important frontier of endocrinological regulation of evolutionary developmental biology (endo-evo-devo) and its relationship to behavior., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose of Review: We seek to update readers on recent advances in our understanding of sex and gender in episodic migraine with a two part series. In part 1, we examine migraine epidemiology in the context of sex and gender, differences in symptomatology, and the influence of sex hormones on migraine pathophysiology (including CGRP). In part 2, we focus on practical clinical considerations for sex and gender in episodic migraine by addressing menstrual migraine and the controversial topic of hormone-containing therapies. We make note of data applicable to gender minority populations, when available, and summarize knowledge on gender affirming hormone therapy and migraine management in transgender individuals. Finally, we briefly address health disparities, socioeconomic considerations, and research bias., Recent Findings: Migraine is known to be more prevalent, frequent, and disabling in women. There are also differences in migraine co-morbidities and symptomatology. For instance, women are likely to experience more migraine associated symptoms such as nausea, photophobia, and phonophobia. Migraine pathophysiology is influenced by sex hormones, e.g., estrogen withdrawal as a known trigger for migraine. Other hormones such as progesterone and testosterone are less well studied. Relationships between CGRP (the target of new acute and preventive migraine treatments) and sex hormones have been established with both animal and human model studies. The natural course of migraine throughout the lifetime suggests a contribution from hormonal changes, from puberty to pregnancy to menopause/post-menopause. Treatment of menstrual migraine and the use of hormone-containing therapies remains controversial. Re-evaluation of the data reveals that stroke risk is an estrogen dose- and aura frequency-dependent phenomenon. There are limited data on episodic migraine in gender minorities. Gender affirming hormone therapy may be associated with a change in migraine and unique risks (including ischemic stroke with high dose estrogen). There are key differences in migraine epidemiology and symptomatology, thought to be driven at least in part by sex hormones which influence migraine pathophysiology and the natural course of migraine throughout the lifetime. More effective and specific treatments for menstrual migraine are needed. A careful examination of the data on estrogen and stroke risk suggests a nuanced approach to the issue of estrogen-containing contraception and hormone replacement therapy is warranted. Our understanding of sex and gender is evolving, with limited but growing research on the relationship between gender affirming therapy and migraine, and treatment considerations for transgender people with migraine., (© 2022. The Author(s).)

Biological sex impacts a wide array of molecular and cellular functions that impact organismal development and can influence disease trajectory in a variety of pathophysiological states. In nonreproductive cancers, epidemiological sex differences have been observed in a series of tumors, and recent work has identified previously unappreciated sex differences in molecular genetics and immune response. However, the extent of these sex differences in terms of drivers of tumor growth and therapeutic response is less clear. In glioblastoma (GBM), the most common primary malignant brain tumor, there is a male bias in incidence and outcome, and key genetic and epigenetic differences, as well as differences in immune response driven by immune-suppressive myeloid populations, have recently been revealed. GBM is a prototypic tumor in which cellular heterogeneity is driven by populations of therapeutically resistant cancer stem cells (CSCs) that underlie tumor growth and recurrence. There is emerging evidence that GBM CSCs may show a sex difference, with male tumor cells showing enhanced self-renewal, but how sex differences impact CSC function is not clear. In this mini-review, we focus on how sex hormones may impact CSCs in GBM and implications for other cancers with a pronounced CSC population. We also explore opportunities to leverage new models to better understand the contribution of sex hormones vs sex chromosomes to CSC function. With the rising interest in sex differences in cancer, there is an immediate need to understand the extent to which sex differences impact tumor growth, including effects on CSC function., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Enhancer RNAs (eRNAs) are non-coding RNAs, which are characterized as transcripts without protein coding functions. Increasing evidence indicates that eRNAs play important roles in gene regulation and cancer progression. Furthermore, various roles of eRNAs in sex hormone-induced signaling pathways are emerging, indicating the important roles of eRNAs in the development of sex hormone-dependent cancers. The aim of this study is to summarize the current knowledge about eRNAs in several typical sex hormone-dependent cancers, mainly involving their roles in sex hormones mediated pathways and cancer progression., Methods: We reviewed all the published articles concerning eRNAs in sex hormone-dependent cancers, and summarized the roles of eRNAs in these cancers., Results: In cancer development, elevated expression of some eRNAs could promote the progression of cancer cells. In gene regulation, eRNAs not only regulate gene activation but also participate in gene repression. Additionally, in androgen receptor signaling, eRNAs were found to play a role at cis and trans loci, and both sense and antisense strands of eRNAs are both important., Conclusion: Abnormal overexpression of eRNAs is mostly oncogenic, leading to cancer progression, and both strands of eRNAs play multiple and complex roles at cis and trans loci in sex hormones mediated pathways, which are tightly associated with sex hormone-dependent tumorigenesis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The aim of the present literature review is to describe the influence of sex hormones on the human voice in physiological conditions. As a secondary sexual organ, the larynx is affected by sex hormones and may change considerably over the lifespan. In the current review, sex hormone-related voice modifications occurring during childhood, puberty, the menstrual cycle, pregnancy and senescence are described. The roles of sex hormones (including gonadotropins, testosterone, estrogen, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone-sulfate) underlying physiological voice changes are discussed, the main differences between males and females are explained and clinical implications are taken into account., (© 2021. The Author(s).)

Urinary bladder cancer is worldwide one of the most diagnosed and costly types of cancer. One puzzle in the bladder cancer diagnosis is the disproportional relationship between genders. Males are more likely to be diagnosed with bladder cancer whereas females typically are diagnosed with more adverse disease and worse prognosis, which has led to speculation of the potential role of sex hormones and their receptors in this disease. Estrogen receptors are present in the human bladder, and their role in bladder cancer oncogenesis is increasingly becoming a focus for researchers around the world. This mini-review aims to give a brief overview of the status of female bladder cancer, and to which extend the sex hormones receptors play a role in this. A literature search was performed and included all female original studies on bladder cancer and hormone receptors. Estrogen-receptor alpha seems to be anti-oncogenic whereas estrogen-receptor beta is exhibiting its function pro-oncogenic. The receptor functions may be exercised through mRNA transcriptions and enzymes. Epidemiological studies indicate a potential increase in incidence of bladder cancer for females with earlier age at menopause, and clinical trials are investigating Tamoxifen as a potential treatment in bladder cancer. Increasing evidence supports the theory of bladder cancer development and progression as being partly hormone-dependent. This can lead to a change in conceptual background of bladder cancer etiology and development in the future. Further studies are required to more precise map the use of anti-hormonal drugs in the treatment of this cancer., (© 2021 Scandinavian Societies for Medical Microbiology and Pathology.)

Stimulant use disorder is associated with significant global health burden. Despite evidence for sex differences in the development and maintenance of stimulant use disorder, few studies have focused on mechanisms underpinning distinct trajectories in females versus males, including the effect of the ovarian sex hormones estrogen and progesterone. This review aimed to identify and synthesise the existing preclinical and clinical literature on the effect of ovarian sex hormones on stimulant consumption in females. A systematic search of peer-reviewed literature identified 1593 articles, screened using the following inclusion criteria: (1) adult female humans or animals, (2) using stimulant drugs, (3) ovarian sex hormones were administered exogenously OR were measured in a validated manner and (4) with stimulant consumption as an outcome measure. A total of 50 studies (3 clinical and 47 preclinical) met inclusion criteria. High-estrogen (low progesterone) phases of the menstrual/estrus cycle were associated with increased stimulant use in preclinical studies, while there were no clinical studies examining estrogen and stimulant consumption. Consistent preclinical evidence supported progesterone use reducing stimulant consumption, which was also identified in one clinical study. The review was limited by inconsistent data reporting across studies and different protocols across preclinical laboratory paradigms. Importantly, almost all studies examined cocaine use, with impact on methamphetamine use a significant gap in the existing evidence. Given the safety and tolerability profile of progesterone, further research is urgently needed to address this gap, to explore the potential therapeutic utility of progesterone as a treatment for stimulant use disorder., (© 2021 Society for the Study of Addiction.)

Neurodegenerative diseases cause severe impairments in cognitive and motor function. With an increasing aging population and the onset of these diseases between 50 and 70 years, the consequences are bound to be devastating. While age and longevity are the main risk factors for neurodegenerative diseases, sex is also an important risk factor. The characteristic of sex is multifaceted, encompassing sex chromosome complement, sex hormones (estrogens and androgens), and sex hormone receptors. Sex hormone receptors can induce various signaling cascades, ranging from genomic transcription to intracellular signaling pathways that are dependent on the health of the cell. Oxidative stress, associated with aging, can impact the health of the cell. Sex hormones can be neuroprotective under low oxidative stress conditions but not in high oxidative stress conditions. An understudied sex hormone receptor that can induce activation of oxidative stress signaling is the membrane androgen receptor (mAR). mAR can mediate nicotinamide adenine dinucleotide-phosphate (NADPH) oxidase (NOX)-generated oxidative stress that is associated with several neurodegenerative diseases, such as Alzheimer disease. Further complicating this is that aging can alter sex hormone signaling. Prior to menopause, women experience more estrogens than androgens. During menopause, this sex hormone profile switches in women due to the dramatic ovarian loss of 17β-estradiol with maintained ovarian androgen (testosterone, androstenedione) production. Indeed, aging men have higher estrogens than aging women due to aromatization of androgens to estrogens. Therefore, higher activation of mAR-NOX signaling could occur in menopausal women compared with aged men, mediating the observed sex differences. Understanding of these signaling cascades could provide therapeutic targets for neurodegenerative diseases., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Significant sex differences exist across cellular, tissue organization, and body system scales to serve the distinct sex-specific functions required for reproduction. They are present in all animals that reproduce sexually and have widespread impacts on normal development, aging, and disease. Observed from the moment of fertilization, sex differences are patterned by sexual differentiation, a lifelong process that involves mechanisms related to sex chromosome complement and the epigenetic and acute activational effects of sex hormones. In this mini-review, we examine evidence for sex differences in cellular responses to DNA damage, their underlying mechanisms, and how they might relate to sex differences in cancer incidence and response to DNA-damaging treatments., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Periodontitis is an inflammatory disease that affects the supporting structures of teeth. The presence of a bacterial biofilm initiates a destructive inflammatory process orchestrated by various inflammatory mediators, most notably proinflammatory cytokines, which are upregulated in the gingival crevicular fluid, leading to the formation of periodontal pockets. This represents a well-characterized microbial change during the transition from periodontal health to periodontitis; interestingly, the gestational condition increases the risk and severity of periodontal disease. Although the influence of periodontitis on pregnancy has been extensively reviewed, the relationship between pregnancy and the development/evolution of periodontitis has been little studied compared to the effect of periodontitis on adverse pregnancy outcomes. This review is aimed at summarizing the findings on the pregnancy-proinflammatory cytokine relationship and discussing its possible involvement in the development of periodontitis. We address (1) an overview of periodontal disease, (2) the immune response and possible involvement of proinflammatory cytokines in the development of periodontitis, (3) how bone tissue remodelling takes place with an emphasis on the involvement of the inflammatory response and metalloproteinases during periodontitis, and (4) the influence of hormonal profile during pregnancy on the development of periodontitis. Finally, we believe this review may be helpful for designing immunotherapies based on the stage of pregnancy to control the severity and pathology of periodontal disease., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Betsaida J. Ortiz-Sánchez et al.)

Inflammation is an integral part of defense against most infectious diseases. These pathogen-induced immune responses are in very many instances strongly influenced by host's sex. As a consequence, sexual dimorphisms were observed in susceptibility to many infectious diseases. They are pathogen dose-dependent, and their outcomes depend on pathogen and even on its species or subspecies. Sex may differentially affect pathology of various organs and its influence is modified by interaction of host's hormonal status and genotype: sex chromosomes X and Y, as well as autosomal genes. In this Mini Review we summarize the major influences of sex in human infections and subsequently focus on 22 autosomal genes/loci that modify in a sex-dependent way the response to infectious diseases in mouse models. These genes have been observed to influence susceptibility to viruses, bacteria, parasites, fungi and worms. Some sex-dependent genes/loci affect susceptibility only in females or only in males, affect both sexes, but have stronger effect in one sex; still other genes were shown to affect the disease in both sexes, but with opposite direction of effect in females and males. The understanding of mechanisms of sex-dependent differences in the course of infectious diseases may be relevant for their personalized management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lipoldová and Demant.)

Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, being frequently associated with obesity, unbalanced dietary regimens, and reduced physical activity. Despite their greater adiposity and reduced physical activity, women show a lower risk of developing NAFLD in comparison to men, likely a consequence of a sex-specific regulation of liver metabolism. In the liver, sex differences in the uptake, synthesis, oxidation, deposition, and mobilization of lipids, as well as in the regulation of inflammation, are associated with differences in NAFLD prevalence and progression between men and women. Given the major role of sex hormones in driving hepatic sexual dimorphism, this review will focus on the role of sex hormones and their signaling in the regulation of hepatic metabolism and in the molecular mechanisms triggering NAFLD development and progression.

The inclusion of women in preclinical pain studies has become more commonplace in the last decade as the National Institutes of Health (NIH) released its "Sex as a Biological Variable" mandate. Presumably, basic researchers have not had a comprehensive understanding about neuroimmune interactions in half of the population and how hormones play a role in this. To date, we have learned that sex hormones contribute to sexual differentiation of the nervous system and sex differences in behavior throughout the lifespan; however, the cycling of sex hormones does not always explain these differences. Here, we highlight recent advances in our understanding of sex differences and how hormones and immune interactions influence sensory neuron activity to contribute to physiology and pain. Neuroimmune mechanisms may be mediated by different cell types in each sex, as the actions of immune cells are sexually dimorphic. Unfortunately, the majority of studies assessing neuronal contributions to immune function have been limited to males, so it is unclear if the mechanisms are similar in females. Finally, pathways that control cellular metabolism, like nuclear receptors, have been shown to play a regulatory role both in pain and inflammation. Overall, communication between the neuroimmune and endocrine systems modulate pain signaling in a sex-dependent manner, but more research is needed to reveal nuances of these mechanisms., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mature erythrocytes are the major metabolic regulators by transporting oxygen throughout the body. However, their precursors and progenitors defined as CD71+ Erythroid Cells (CECs) exhibit a wide range of immunomodulatory properties. Here, we uncover pronounced sexual dimorphism in CECs. We found female but not male mice, both BALB/c and C57BL/6, and human females were enriched with CECs. CECs, mainly their progenitors defined as CD45+CECs expressed higher levels of reactive oxygen species (ROS), PDL-1, VISTA, Arginase II and Arginase I compared to their CD45- counterparts. Consequently, CECs by the depletion of L-arginine suppress T cell activation and proliferation. Expansion of CECs in anemic mice and also post-menstrual cycle in women can result in L-arginine depletion in different microenvironments in vivo (e.g. spleen) resulting in T cell suppression. As proof of concept, we found that anemic female mice and mice adoptively transferred with CECs from anemic mice became more susceptible to Bordetella pertussis infection. These observations highlight the role of sex and anemia-mediated immune suppression in females. Notably, enriched CD45+CECs may explain their higher immunosuppressive properties in female BALB/c mice. Finally, we observed significantly more splenic central macrophages in female mice, which can explain greater extramedullary erythropoiesis and subsequently abundance of CECs in the periphery. Thus, sex-specific differences frequency in the frequency of CECs might be imprinted by differential erythropoiesis niches and hormone-dependent manner., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mashhouri, Koleva, Huynh, Okoye, Shahbaz and Elahi.)

The present study investigated the relationship between occupational exposure to noise and whole-body vibration (WBV) with the levels of sex hormones in an automobile parts manufacturing plant. The level of workers' exposure ( n = 162) to each of the mentioned stressors was measured through standard methods, and the time-weighted average of exposure was calculated for each person. In order to determine serum sex hormones (free testosterone, luteinizing hormone, and follicle-stimulating hormone), blood samples were taken from all participants after 8-10 h of fasting between 7 and 9 am and then the blood samples were analyzed by an enzyme-linked immunosorbent assay method. In general, regarding testosterone as the main male sex hormone, only 49% of the participants were in the normal range. In a total of three sections, the lowest mean testosterone levels were observed in the third exposure group (WBV > 1.93 m/s 2 ; noise >92.69 dB) of the studied stressor; however, only the difference in testosterone levels between the three different groups of exposure to noise was statistically significant ( p = 0.001). The relationship between demographic variables and levels of noise and WBV exposure with sex hormones was not linear and only the relationship between noise exposure and testosterone levels was statistically significant ( R = -0.201, p = 0.013). According to the results of logistic regression, the WBV had the greatest effect on testosterone levels. However, according to the results of the correlation test, only the relationship between noise exposure and testosterone levels was statistically significant.

Competing Interests: None declared.

The gonadal steroids, including androgens, estrogens and progestogens, are involved in the control of body fat distribution in humans. Nevertheless, not only the size and localization of the fat depots depend on the sex steroids levels, but they can also highly affect the functioning of adipose tissue. Namely, the gonadocorticoids can directly influence insulin signaling, lipid metabolism, fatty acid uptake and adipokine production. They may also alter energy balance and glucose homeostasis in adipocytes in an indirect way, e.g., by changing the expression level of aquaglyceroporins. This work presents the recent advances in understanding the molecular mechanism of how the gonadal steroids influence the functioning of adipose tissue leading to a set of detrimental metabolic consequences. Special attention is given here to highlighting the sexual dimorphism of adipocyte functioning in terms of health and disease. Particularly, we discuss the molecular background of metabolic disturbances occurring in consequence of hormonal imbalance which is characteristic of some common endocrinopathies such as the polycystic ovary syndrome. From this perspective, we highlight the potential drug targets and the active substances which can be used in personalized sex-specific management of metabolic diseases, in accord with the patient's hormonal status.

Uric acid (UA) is the end metabolic product of purine metabolism. Early on, UA was considered to be a metabolite with a certain antioxidant capacity. As research has progressed, other properties of UA have been explored, and its association with many diseases has been found. The association between UA and kidney disease and cardiovascular disease is well established; however, there is still a paucity of reviews on the association between UA and the female reproductive system. An increasing number of epidemiological studies have shown elevated serum UA levels in patients with polycystic ovary syndrome (PCOS), endometriosis, etc. Additionally, serum UA can be used as a predictor of pregnancy complications and adverse foetal outcomes. An increasing number of animal experiments and clinical studies have revealed possible mechanisms related to the involvement of UA in certain female reproductive disorders: oxidative stress, chronic inflammation, mitochondrial dysfunction, etc. This article reviews the current mainstream mechanisms regarding the pathogenesis of UA and the role of UA in certain specific female reproductive disorders (direct involvement in the development of certain diseases or enhancement of other risk factors) in the hope of contributing to clinical prevention, diagnosis, treatment and improvement in prognosis.

The human and canine parasitic nematode Strongyloides stercoralis utilizes an XX/XO sex determination system, with parasitic females reproducing by mitotic parthenogenesis and free-living males and females reproducing sexually. However, the genes controlling S. stercoralis sex determination and male development are unknown. We observed precocious development of rhabditiform males in permissive hosts treated with corticosteroids, suggesting that steroid hormones can regulate male development. To examine differences in transcript abundance between free-living adult males and other developmental stages, we utilized RNA-Seq. We found two clusters of S. stercoralis-specific genes encoding predicted transmembrane proteins that are only expressed in free-living males. We additionally identified homologs of several genes important for sex determination in Caenorhabditis species, including mab-3, tra-1, fem-2, and sex-1, which may have similar functions. However, we identified three paralogs of gld-1; Ss-qki-1 transcripts were highly abundant in adult males, while Ss-qki-2 and Ss-qki-3 transcripts were highly abundant in adult females. We also identified paralogs of pumilio domain-containing proteins with sex-specific transcripts. Intriguingly, her-1 appears to have been lost in several parasite lineages, and we were unable to identify homologs of tra-2 outside of Caenorhabditis species. Together, our data suggest that different mechanisms control male development in S. stercoralis and Caenorhabditis species.

Chronic stress has various effects on organisms and is sex-specific. The aim of the study was to describe the expression of synapse strengthening protein, dendrin, in the spinal cord (SC) and the dependence of its expression on chronic stress and sex hormones. Thirteen-month-old female and male rats were castrated (ovariectomy [F-OVX] or orchidectomy [M-ORX]) or sham-operated (F-SH or M-SH), respectively. At age 15 months, three 10-day-sessions of sham stress (control, C) or chronic stress (S) were conducted. Dendrin expression was present in the thoracic SC segments and the dorsal root ganglia (DRG). In the SC, dendrin expression was prominent in superficial laminae of the dorsal horn and lamina X (central canal). The M-ORX-S group had the highest dendrin expression in the dorsal horn, being significantly higher than the M-ORX-C or M-SH-S groups (P < 0.05). Dendrin expression was significantly higher in the F-SH-S group than the F-SH-C group (P < 0.05), as well as in the F-SH-S than the M-SH-S (P < 0.05). Co-localization with the α-d-galactosyl-specific isolectin B4 (IB4) in central projections of the DRG neurons in the dorsal horn of the SC was 7.43 ± 3.36%, while with the calcitonin gene-related peptide (CGRP) was 8.47 ± 4.45%. Localization of dendrin was observed in soma and nuclei of neurons in the dorsal horn. Dendrin expression in pain-processing areas of the SC, the DRG neurons and their peripheral projections suggest possible roles in pain perception and modulation. Stress-induced increase in dendrin expression and its dependence on sex hormones may partially explain sex-specific pain hypersensitivity induced by stress., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Healthy functioning of the female reproductive tract (FRT) depends on balanced and dynamic regulation by hormones during the menstrual cycle, pregnancy and childbirth. The mucosal epithelial lining of different regions of the FRT-ovaries, fallopian tubes, uterus, cervix and vagina-facilitates the selective transport of gametes and successful transfer of the zygote to the uterus where it implants and pregnancy takes place. It also prevents pathogen entry. Recent developments in three-dimensional (3D) organoid systems from the FRT now provide crucial experimental models that recapitulate the cellular heterogeneity and physiological, anatomical and functional properties of the organ in vitro. In this review, we summarise the state of the art on organoids generated from different regions of the FRT. We discuss the potential applications of these powerful in vitro models to study normal physiology, fertility, infections, diseases, drug discovery and personalised medicine.

The purpose of this study was to examine the differences in neuromuscular control and mechanical properties of the ankle-stabilizing muscles between men and women, and during different phases of menstrual cycle in women. Fifteen women with regular menstrual cycles and 17 male counterparts were included in this study. Electromyographic signals were recorded from the peroneus longus (PL) and tibialis anterior (TA) muscles while performing three balance tasks. Muscle tone, stiffness, and elasticity of muscles were measured using a MyotonPRO in the resting position. Outcomes were measured twice (ovulation and early follicular phases) for women, while measurements were acquired only once for men. Significantly higher tibialis anterior-peroneus longus co-contraction (TA/PL ratio) was observed in all balance tasks in women than in men (p< 0.05); however, significant differences between phases of the menstrual cycle were noted only in the 2 most difficult tasks (p< 0.05). A similar pattern was observed in the postural sway. These results highlight the importance of sex-specific hormonal effects on neuromuscular control and mechanical properties, and as well as the differences during phases of the menstrual cycle. These insights assume significance in the context of developing neuromuscular strategies for the purpose of preventing lower extremity injuries during sports activities., Competing Interests: The author declare that they have no conflict of interest., (Thieme. All rights reserved.)

Puberty is an important phase of development when the neural circuit organization is transformed by sexual hormones, inducing sexual dimorphism in adult behavioural responses. The principal brain area responsible for the control of the receptive component of female sexual behaviour is the ventrolateral division of the ventromedial nucleus of the hypothalamus (VMHvl), which is known for its dependency on ovarian hormones. Inputs to the VMHvl originating from the medial preoptic nucleus (MPN) are responsible for conveying essential information that will trigger such behaviour. Here, we investigated the pattern of the projection of the MPN to the VMHvl in rats ovariectomized at the onset of puberty. Sprague Dawley rats were ovariectomized (OVX) at puberty and then subjected to iontophoretic injections of the neuronal anterograde tracer Phaseolus vulgaris leucoagglutinin into the MPN once they reached 90 days of age. This study analysed the connectivity pattern established between the MPN and the VMH that is involved in the neuronal circuit responsible for female sexual behaviour in control and OVX rats. The data show the changes in the organization of the connections observed in the OVX adult rats that displayed a reduced axonal length for the MPN fibres reaching the VMHvl, suggesting that peripubertal ovarian hormones are relevant to the organization of MPN connections with structures involved in the promotion of female sexual behaviour., (© 2020 Anatomical Society.)

Women have a number of specificities that differentiate them from men. In particular, the role of sex steroid hormones and the menstrual cycle (MC) significantly impact women's physiology. The literature has shown nonlinear relationships between MC, exercise, and nutritional intake. Notably, these relationships are bidirectional and less straightforward than one would suppose. For example, the theoretical implications of the MC's phases on exercise performance do not always translate into relevant practical effects. There is often a disconnect between internal measures (e.g., levels of hormone concentrations) and external performance. Furthermore, it is not entirely clear how nutritional intake varies across the MC's phases and whether these variations impact on exercise performance. Therefore, a thorough review of the existing knowledge could help in framing these complex relationships and potentially contribute to the optimization of exercise prescription and nutritional intake according to the naturally occurring phases of the MC. Throughout this review, an emerging trend is the lack of generalizability and the need to individualize interventions, since the consequences of the MC's phases and their relationships with exercise and nutritional intake seem to vary greatly from person to person. In this sense, average data are probably not relevant and could potentially be misleading.

Context: Menopause, the permanent cessation of menses, reflects oocyte depletion and loss of gonadal steroids. It is preceded by a transition state, the perimenopause, which is characterized by the gradual loss of oocytes, altered responsiveness to gonadal steroid feedback, wide hormonal fluctuations, and irregular menstrual patterns. The goal of this mini-review is to discuss the basic pathophysiology of the menopausal transition and the hormonal and nonhormonal management of clinicopathology attributed to it., Evidence Acquisition: A Medline search of epidemiologic, population-based studies, and studies of reproductive physiology was conducted. A total of 758 publications were screened., Evidence Synthesis: The reproductive hormonal milieu of the menopausal transition precipitates bothersome vasomotor symptoms, mood disruption, temporary cognitive dysfunction, genitourinary symptoms, and other disease processes that reduce the quality of life of affected women. The endocrine tumult of the menopause transition also exposes racial and socioeconomic disparities in the onset, severity, and frequency of symptoms. Hormone therapy (HT) treatment can be effective for perimenopausal symptoms but its use has been stymied by concerns about health risks observed in postmenopausal HT users who are older than 60 and/or women who have been postmenopausal for greater than 10 years., Conclusions: The menopause transition is a disruptive process that can last for over a decade and causes symptoms in a majority of women. It is important for clinicians to recognize early signs and symptoms of the transition and be prepared to offer treatment to mitigate these symptoms. Many safe and effective options, including HT, are available., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Traditionally sex hormones have been associated with reproductive and developmental processes only. Since the 1950s we know that hormones can have organizational effects on the developing brain and initiate hormonal transition periods such as puberty. However, recent evidence shows that sex hormones additionally structure the brain during important hormonal transition periods across a woman's life including short-term fluctuations during the menstrual cycle. However, a comprehensive review focusing on structural changes during all hormonal transition phases of women is still missing. Therefore, in this review structural changes across hormonal transition periods (i.e., puberty, menstrual cycle, oral contraceptive intake, pregnancy and menopause) were investigated in a structured way and correlations with sex hormones evaluated. Results show an overall reduction in grey matter and region-specific decreases in prefrontal, parietal and middle temporal areas during puberty. Across the menstrual cycle grey matter plasticity in the hippocampus, the amygdala as well as temporal and parietal regions were most consistently reported. Studies reporting on pre- and post-pregnancy measurements revealed volume reductions in midline structures as well as prefrontal and temporal cortices. During perimenopause, the decline in sex hormones was paralleled with a reduction in hippocampal and parietal cortex volume. Brain volume changes were significantly correlated with estradiol, testosterone and progesterone levels in some studies, but directionality remains inconclusive between studies. These results indicate that sex hormones play an important role in shaping women's brain structure during different transition periods and are not restricted to specific developmental periods., (© 2020 S. Karger AG, Basel.)

Several standard descriptions of the avian male and female reproductive tract have been reported, including effects of age, stage of reproductive maturity and gonadal hormone concentrations. Limited information on penguin reproductive biology and a lack of information on the African penguin (Spheniscus demersus) necessitated a detailed description of salient structural features of this species and provided an opportunity to evaluate seasonal changes in gonadal steroid hormone concentrations. Tissues from 36 males (adults and juveniles) and 29 females (adults and juveniles) were used for macro-anatomical descriptions and histology of the testes and ovaries. In addition, concentrations of gonadal steroid hormones for eight captive African penguins (four females and four males) were quantified during two breeding and one non-breeding season. The testes were asymmetrical, with the right testis having smaller dimensions compared to the left testis. Marked spermatogenic cellular associations and spermatid developmental stages were present in adult testes only during the breeding season. There was variation in the dimensions of the single ovary during follicular development related to the age and breeding status of the females. Testosterone, dihydrotestosterone, and estradiol concentrations fluctuated during the breeding and non-breeding periods, with males and females having similar steroid concentrations. The results from this study confirm that the breeding status in African penguins can be deduced based on testicular and ovarian histological structures. The results from the present study focused on African penguin reproductive biology should be considered in management strategies for the conservation of the species., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Gonadal steroids modulate growth hormone (GH) secretion and the pubertal growth spurt via undefined central pathways. GH-releasing hormone (GHRH) neurons express estrogen receptor α (ERα) and androgen receptor (AR), suggesting changing levels of gonadal steroids during puberty directly modulate the somatotropic axis. We generated mice with deletion of ERα in GHRH cells (GHRH ΔERα ), which displayed reduced body length in both sexes. Timing of puberty onset was similar in both groups, but puberty completion was delayed in GHRH ΔERα females. Lack of AR in GHRH cells (GHRH ΔAR mice) induced no changes in body length, but puberty completion was also delayed in females. Using a mouse model with two reporter genes, we observed that, while GHRH tdTom neurons minimally colocalize with Kiss1 hrGFP in prepubertal mice, ∼30% of GHRH neurons coexpressed both reporter genes in adult females, but not in males. Developmental analysis of Ghrh and Kiss1 expression suggested that a subpopulation of ERα neurons in the arcuate nucleus of female mice undergoes a shift in phenotype, from GHRH to Kiss1, during pubertal transition. Our findings demonstrate that direct actions of gonadal steroids in GHRH neurons modulate growth and puberty and indicate that GHRH/Kiss1 dual-phenotype neurons play a sex-specific role in the crosstalk between the somatotropic and gonadotropic axes during pubertal transition. SIGNIFICANCE STATEMENT Late maturing adolescents usually show delayed growth and bone age. At puberty, gonadal steroids have stimulatory effects on the activation of growth and reproductive axes, but the existence of gonadal steroid-sensitive neuronal crosstalk remains undefined. Moreover, the neural basis for the sex differences observed in the clinical arena is unknown. Lack of ERα in GHRH neurons disrupts growth in both sexes and causes pubertal delay in females. Deletion of androgen receptor in GHRH neurons only delayed female puberty. In adult females, not males, a subset of GHRH neurons shift phenotype to start producing Kiss1. Thus, direct estrogen action in GHRH/Kiss1 dual-phenotype neurons modulates growth and puberty and may orchestrate the sex differences in endocrine function observed during pubertal transition., (Copyright © 2020 the authors.)

Chronic pain occurs with greater frequency in women, with a parallel sexually dimorphic trend reported in sufferers of many autoimmune diseases. There is a need to continue examining neuro-immune-endocrine crosstalk in the context of sexual dimorphisms in chronic pain. Several phenomena in particular need to be further explored. In patients, autoantibodies to neural antigens have been associated with sensory pathway hyper-excitability, and the role of self-antigens released by damaged nerves remains to be defined. In addition, specific immune cells release pro-nociceptive cytokines that directly influence neural firing, while T lymphocytes activated by specific antigens secrete factors that either support nerve repair or exacerbate the damage. Modulating specific immune cell populations could therefore be a means to promote nerve recovery, with sex-specific outcomes. Understanding biological sex differences that maintain, or fail to maintain, neuroimmune homeostasis may inform the selection of sex-specific treatment regimens, improving chronic pain management by rebalancing neuroimmune feedback. Given the significance of interactions between nerves and immune cells in the generation and maintenance of neuropathic pain, this review focuses on sex differences and possible links with persistent autoimmune activity using sciatica as an example.

In autoimmune rheumatic diseases, oestrogens can stimulate certain immune responses (including effects on B cells and innate immunity), but can also have dose-related anti-inflammatory effects on T cells, macrophages and other immune cells. By contrast, androgens and progesterone have predominantly immunosuppressive and anti-inflammatory effects. Hormone replacement therapies and oral contraception (and also pregnancy) enhance or decrease the severity of autoimmune rheumatic diseases at a genetic or epigenetic level. Serum androgen concentrations are often low in men and in women with autoimmune rheumatic diseases, suggesting that androgen-like compounds might be a promising therapeutic approach. However, androgen-to-oestrogen conversion (known as intracrinology) is enhanced in inflamed tissues, such as those present in patients with autoimmune rheumatic diseases. In addition, it is becoming evident that the gut microbiota differs between the sexes (known as the microgenderome) and leads to sex-dependent genetic and epigenetic changes in gastrointestinal inflammation, systemic immunity and, potentially, susceptibility to autoimmune or inflammatory rheumatic diseases. Future clinical research needs to focus on the therapeutic use of androgens and progestins or their downstream signalling cascades and on new oestrogenic compounds such as tissue-selective oestrogen complex to modulate altered immune responses.

The severe form of COVID-19 has significant sex disparities, with high fatalities commonly reported among males than females. The incidence of COVID-19 has also been higher in males compared with their female counterparts. This trend could be attributed to a better responsive and robust immune system in females. Cytokine storm is one of the pathophysiological features of severe COVID-19, and it occurs as a result of over-activation of immune cells leading to severe inflammation and tissue damage. Nevertheless, it is well modulated in females compared to their male counterparts. Severe inflammation in males is reported to facilitate progression of mild to severe COVID-19. The sex hormones, estrogens and androgens which exist in varying functional levels respectively in females and males are cited as the underlying cause for the differential immune response to COVID-19. Evidence abounds that estrogen modulate the immune system to protect females from severe inflammation and for that matter severe COVID-19. On the contrary, androgen has been implicated in over-activation of immune cells, cytokine storm and the attendant severe inflammation, which perhaps predispose males to severe COVID-19. In this review efforts are made to expand understanding and explain the possible roles of the immune system, the sex hormones and the angiotensin-converting enzyme (ACE) systems in male bias to severe COVID-19. Also, this review explores possible therapeutic avenues including androgen deprivation therapy (ADT), estrogen-based therapy, and ACE inhibitors for consideration in the fight against COVID-19., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

The spotted hyaena (Crocuta crocuta) is a unique species, even amongst the Hyaenidae. Extreme clitoral development in female spotted hyaenas challenges aspects of the accepted framework of sexual differentiation and reproductive function. They lack a vulva and instead urinate, copulate and give birth through a single, long urogenital canal that traverses a clitoris superficially resembling a penis. Recent and historical evidence is reviewed to describe our changing understanding of the biology of this species. Expanding upon observations from hyaenas in nature, much has been learned from studies utilising the captive colony at the University of California, Berkeley. The steroid environment of pregnancy is shaped by placental androgen and oestrogen secretion and a late gestational increase in sex hormone binding globulin, the regulated expression and steroid-binding characteristics of which are unique within the Hyaenidae. While initial external genital development is largely free of androgenic influence, the increase in testosterone concentrations in late gestation influences foetal development. Specifically, anti-androgen (AA) treatment of pregnant females reduced the developmental influence of androgens on their foetuses, resulting in reduced androstenedione concentrations in young females and easier birth through a 'feminised' clitoris, but precluded intromission and mating by 'feminised' male offspring, and altered social interactions. Insight into the costs and benefits of androgen exposure on spotted hyaena reproductive development, endocrinology and behaviour emphasises the delicate balance that sustains reproductive success, forces a re-evaluation of how we define masculine vs feminine sexual characteristics, and motivates reflection about the representative value of model species.

Females of some species are considered sex-role reversed, meaning that they face stronger competition for mates compared to males. While much attention has been paid to behavioral and morphological patterns associated with sex-role reversal, less is known about its physiological regulation. Here, we evaluate hypotheses relating to the neuroendocrine basis of sex-role reversal. We refute the most widely tested activational hypothesis for sex differences in androgen secretion; sex-role reversed females do not have higher levels of androgens in circulation than males. However, we find some evidence that the effects of androgens may be sex-specific; circulating androgen levels correlate with some competitive phenotypes in sex-role reversed females. We also review evidence that sex-role reversed females have higher tissue-specific sensitivity to androgens than males, at least in some species and tissues. Organizational effects may explain these relationships, considering that early exposure to sex steroids can shape later sensitivity to hormones, often in sex-specific ways. Moving forward, experimental and correlative studies on the ontogeny and expression of sex-role reversal will further clarify the mechanisms that generate sex-specific behaviors and sex roles., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

Epidemiological data in COVID-19 mortality indicate that men are more prone to die of SARS-CoV-2 infection than women, but biological causes for this sexual dimorphism are unknown. We discuss the prospective behavioral and biological differences between the sexes that could be attributed to this sex-based differentiation. The female sex hormones and the immune stimulatory genes, including Toll-like receptors, interleukins, and micro-RNAs present on X-chromosome, may impart lesser infectivity and mortality of the SARS-CoV-2 in females over males. The sex hormone estrogen interacts with the renin-angiotensin-aldosterone system, one of the most critical pathways in COVID-19 infectivity, and modulates the vasomotor homeostasis. Testosterone on the contrary enhances the levels of the two most critical molecules, angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease serine-type 2 (TMPRSS2), transcriptionally and posttranslationally, thereby increasing viral load and delaying viral clearance in men as compared with women. We propose that modulating sex hormones, either by increasing estrogen or antiandrogen, may be a therapeutic option to reduce mortality from SARS-CoV-2.