Hormonal influence: unraveling the impact of sex hormones on vascular smooth muscle cells.

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.

Influence of Sex and Gender on Musculoskeletal Conditions and How They Are Reported.

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.

Sexual dimorphism in colorectal cancer: molecular mechanisms and treatment strategies.

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.

Hormonal and circuit mechanisms controlling female sexual behavior.

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.

Hormonal Control of Bone Architecture Throughout the Lifespan: Implications for Fracture Prediction and Prevention.

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.

[Weight gain during menopause: physiology and practical implications]. / Prise de poids pendant la ménopause : physiologie et implications pratiques.

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.

La fluctuation des hormones sexuelles à différentes étapes de la vie reproductive, telles que la transition ménopausique, a été proposée comme une des composantes de la régulation de poids. Effectivement, le passage d'un état principalement œstrogénique à un état androgénique, caractéristique de la transition ménopausique, contribue à des modifications de la composition corporelle avec une accumulation de graisse et une perte simultanée de masse maigre. Cependant, la question de savoir si ces changements contribuent à une prise de poids reste discutable. L'obésité est une maladie multifactorielle et d'autres facteurs d'ordre physiologique et psychosociaux rentrent en jeu. Il est donc important d'offrir un accompagnement individualisé aux femmes concernées pour les aider à minimiser le risque de prise pondérale et des complications associées.

Recent insights into the role of hormones during development and their functional regulation.

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.

Sex-Specific Acute Cerebrovascular Responses to Photothrombotic Stroke in Mice.

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.

Función de las hormonas sexuales en la homeostasis del hueso y su papel en el desarrollo de la osteoporosis masculina: Una revisión narrativa / Role of sex hormones in bone homeostasis and their role in the development of male osteoporosis: A narrative review

El hueso es un tejido dinámico, que se encuentra en constante adaptación durante la vida de los vertebrados con el fin de alcanzar tamaño, forma, preservar la integridad estructural del esqueleto y regular la homeostasis mineral. Su desarrollo durante la infancia es determinante para alcanzar la estatura, así como la resistencia a fracturas en edad avanzada. Las hormonas sexuales juegan un papel importante en el remodelado óseo, tanto en hombres como en mujeres y las alteraciones en los perfiles hormonales pueden conducir al desarrollo de enfermedades asociadas con el metabolismo del hueso. En mujeres, la deficiencia de estrógenos durante la menopausia es una de las principales causas de osteoporosis, mientras que en hombres los andrógenos pueden influir en la salud ósea al unirse directamente a los receptores de andrógenos o indirectamente a receptores de estrógenos. En esta revisión se explora el papel y los efectos de las hormonas sexuales sobre el metabolismo óseo, las vías de señalización implicadas y los efectos que pueden conducir al desarrollo de enfermedades como la osteoporosis. (AU)

Bone is a dynamic tissue that undergoes constant adaptation throughout the life of vertebrates to achieve size, shape, preserve the structural integrity of the skeleton, and regulate mineral homeostasis. Bone growth during childhood is crucial to achieve height and resistance to fractures later in life. Sex hormones play a key role in bone remodeling in men and women alike, and changes to hormonal profiles can trigger bone metabolism-related diseases. In women, estrogen deficiency during menopause is one of the leading causes of osteoporosis, while in men, androgens can have an impact on bone health by binding directly to androgen receptors or indirectly to estrogen receptors. This review explores the role and effects of sex hormones on bone metabolism, the signaling pathways involved, and the effects that can trigger diseases such as osteoporosis. (AU)

Sex differences in vascular endothelial cells.

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.

Vestibular Disorders and Hormonal Dysregulations: State of the Art and Clinical Perspectives.

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.

[Cognitive and psychoemotional changes in menopausal transition: The possibility of medical correction].

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 «aging¼ 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 cells¼ and «eu-estrogenemia¼ 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.

Physiological and molecular sex differences in human skeletal muscle in response to exercise training.

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.

Sex Hormones in Breast Cancer Immunity.

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.

Activational vs. organizational effects of sex steroids and their role in the evolution of reproductive behavior: Looking to foot-flagging frogs and beyond.

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.

Sex and Gender Considerations in Episodic Migraine.

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.

Unexplored Functions of Sex Hormones in Glioblastoma Cancer Stem Cells.

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.

Roles of enhancer RNAs in sex hormone-dependent cancers.

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.

Gene-Specific Sex Effects on Susceptibility to Infectious Diseases.

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.