http://www.bsd-journal.com The latest research articles published by Biology of Sex Differences 2013-05-07T00:00:00Z Background: Women and men have diverse responses to many infectious diseases. These differences are amplified following menopause. However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system. Sex differences also manifest in the prevalence of gut associated inflammatory and autoimmune disorders, including Crohn’s disease, ulcerative colitis and Celiac disease. It is thus hypothesized that a baseline sex-associated difference in immune activation may predispose women to inflammation-associated disease. Methods: Peripheral blood samples and small intestinal biopsies were obtained from 34 healthy men and women. Immunophenotypic analysis of isolated lymphocytes was performed by flow cytometry. Oligonucleotide analysis was used to study the transcriptional profile in the gut mucosal microenvironment while real-time PCR analysis was utilized to identify differential gene expression in isolated CD4+ T cells. Transcriptional analysis was confirmed by protein expression levels for genes of interest using fluorescent immunohistochemistry. Data was analyzed using the GraphPad software package. Results: Women had higher levels of immune activation and inflammation-associated gene expression in gut mucosal samples. CD4+ and CD8+ T cells had a significantly higher level of immune activation-associated phenotype in peripheral blood as well as in gut associated lymphoid tissue along with higher levels of proliferating T cells. CD4+ T cells that showed upregulation of IL1β as well as the TH17 pathway-associated genes contributed a large part of the inflammatory profile. Conclusion: In this study, we demonstrated an upregulation in gene expression related to immune function in the gut microenvironment of women compared to men, in the absence of disease or pathology. Upon closer investigation, CD4+ T cell activation levels were higher in the LPLs in women than in men. Sex differences in the mucosal immune system may predispose women to inflammation-associated diseases that are exacerbated following menopause. Our study highlights the need for more detailed analysis of the effects of sex differences in immune responses at mucosal effector sites. http://www.bsd-journal.com/content/4/1/10 Sumathi Sankaran-Walters Monica Macal Irina Grishina Lauren Nagy Larissa Goulart Kathryn Coolidge Jay Li Anne Fenton Theodore Williams MaryK Miller Jason Flamm Thomas Prindiville Michael George Satya Dandekar Biology of Sex Differences 2013, null:10 2013-05-07T00:00:00Z doi:10.1186/2042-6410-4-10 /content/figures/2042-6410-4-10-toc.gif Biology of Sex Differences 2042-6410 ${item.volume} 10 2013-05-07T00:00:00Z XML Background: Anecdotal and clinical theories purport that females are more responsive to smoking cues, yet few objective, neurophysiological examinations of these theories have been conducted. The current study examines the impact of sex on brain responses to smoking cues. Methods: Fifty-one (31 males) cigarette-dependent sated smokers underwent pseudo-continuous arterial spin-labeled perfusion functional magnetic resonance imaging during exposure to visual smoking cues and non-smoking cues. Brain responses to smoking cues relative to non-smoking cues were examined within males and females separately and then compared between males and females. Cigarettes smoked per day was included in analyses as a covariate. Results: Both males and females showed increased responses to smoking cues compared to non-smoking cues with males exhibiting increased medial orbitofrontal cortex and ventral striatum/ventral pallidum responses, and females showing increased medial orbitofrontal cortex responses. Direct comparisons between male and female brain responses revealed that males showed greater bilateral hippocampal/amygdala activation to smoking cues relative to non-smoking cues. Conclusions: Males and females exhibit similar responses to smoking cues relative to non-smoking cues in a priori reward-related regions; however, direct comparisons between sexes indicate that smoking cues evoke greater bilateral hippocampal/amygdalar activation among males. Given the current literature on sex differences in smoking cue neural activity is sparse and incomplete, these results contribute to our knowledge of the neurobiological underpinnings of drug cue reactivity. http://www.bsd-journal.com/content/4/1/9 Reagan Wetherill Kimberly Young Kanchana Jagannathan Joshua Shin Charles O¿Brien Anna Rose Childress Teresa Franklin Biology of Sex Differences 2013, null:9 2013-04-29T00:00:00Z doi:10.1186/2042-6410-4-9 /content/figures/2042-6410-4-9-toc.gif Biology of Sex Differences 2042-6410 ${item.volume} 9 2013-04-29T00:00:00Z XML Depression is a common mental disorder that co-occurs in other neurological and somatic diseases. Further, sex differences exist in the prevalence rates of many of these diseases, as well as within non-disease associated depression. In this review, the case is made for needing a better recognition of the source of the symptoms of depression with respect to the sex of the individual; in that, some disease states, which includes the neuroendocrine and immune reactions to the underlying pathophysiology of the disease, may initiate depressive symptoms more often in one sex over the other. The diseases specifically addressed to make this argument are: epilepsy, Alzheimer’s disease, cancer, and cardiovascular disease. For each of these conditions, a review of the following are presented: prevalence rates of the conditions within each sex, prevalence rates of depressive symptoms within the conditions, identified relationships to gonadal hormones, and possible interactions between gonadal hormones, adrenal hormones, and immune signaling. Conclusions are drawn suggesting that an evaluation of the root causes for depressive symptoms in patients with these conditions is necessary, as the underlying mechanisms for eliciting the depressive symptoms may be qualitatively different across the four diseases discussed. This review attempts to identify and understand the mechanisms of depression associated with these diseases, in the context of the known sex differences in the disease prevalence and its age of onset. Hence, more extensive, sex-specific model systems are warranted that utilize these disease states to elicit depressive symptoms in order to create more focused, efficient, and sex-specific treatments for patients suffering from these diseases and concurrent depressive symptoms. http://www.bsd-journal.com/content/4/1/8 Christina Nemeth Constance Harrell Kevin Beck Gretchen Neigh Biology of Sex Differences 2013, null:8 2013-04-17T00:00:00Z doi:10.1186/2042-6410-4-8 /content/figures/2042-6410-4-8-toc.gif Biology of Sex Differences 2042-6410 ${item.volume} 8 2013-04-17T00:00:00Z XML Background: Saliva has been advocated as an alternative to serum or plasma for steroid monitoring. Little normative information is available concerning expected concentrations of the major reproductive steroids in saliva during pregnancy and the extended postpartum. Methods: Matched serum and saliva specimens controlled for time of day and collected less than 30 minutes apart were obtained in 28 women with normal singleton pregnancies between 32 and 38 weeks of gestation and in 43 women during the first six months postpartum. Concentrations of six steroids (estriol, estradiol, progesterone, testosterone, cortisol, dehydroepiandrosterone) were quantified in saliva by enzyme immunoassay. Results: For most of the steroids examined, concentrations in antepartum saliva showed linear increases near end of gestation, suggesting an increase in the bioavailable hormone component. Observed concentrations were in agreement with the limited data available from previous reports. Modal concentrations of the ovarian steroids were undetectable in postpartum saliva and, when detectable in individual women, approximated early follicular phase values. Only low to moderate correlations between the serum and salivary concentrations were found, suggesting that during the peripartum period saliva provides information that is not redundant to serum. Conclusions: Low correlations in the late antepartum may be due to differential rates of change in the total and bioavailable fractions of the circulating steroid in the final weeks of the third trimester as a consequence of dynamic changes in carrier proteins such as corticosteroid binding globulin. http://www.bsd-journal.com/content/4/1/7 Elizabeth Hampson Shauna-Dae Phillips Claudio Soares Meir Steiner Biology of Sex Differences 2013, null:7 2013-04-10T00:00:00Z doi:10.1186/2042-6410-4-7 /content/figures/2042-6410-4-7-toc.gif Biology of Sex Differences 2042-6410 ${item.volume} 7 2013-04-10T00:00:00Z XML Understanding the biology of sex differences is integral to personalized medicine. Cardiovascular disease and cognitive decline are two related conditions, with distinct sex differences in morbidity and clinical manifestations, response to treatments, and mortality. Although mortality from all-cause cardiovascular diseases has declined in women over the past five years, due in part to increased educational campaigns regarding the recognition of symptoms and application of treatment guidelines, the mortality in women still exceeds that of men. The physiological basis for these differences requires further research, with particular attention to two physiological conditions which are unique to women and associated with hormonal changes: pregnancy and menopause. Both conditions have the potential to impact life-long cardiovascular risk, including cerebrovascular function and cognition in women. This review draws on epidemiological, translational, clinical, and basic science studies to assess the impact of hypertensive pregnancy disorders on cardiovascular disease and cognitive function later in life, and examines the effects of post-menopausal hormone treatments on cardiovascular risk and cognition in midlife women. We suggest that hypertensive pregnancy disorders and menopause activate vascular components, i.e., vascular endothelium and blood elements, including platelets and leukocytes, to release cell-membrane derived microvesicles that are potential mediators of changes in cerebral blood flow, and may ultimately affect cognition in women as they age. Research into specific sex differences for these disease processes with attention to an individual’s sex chromosomal complement and hormonal status is important and timely. http://www.bsd-journal.com/content/4/1/6 Virginia Miller Vesna Garovic Kejal Kantarci Jill Barnes Muthuvel Jayachandran Michelle Mielke Michael Joyner Lynne Shuster Walter Rocca Biology of Sex Differences 2013, null:6 2013-03-28T00:00:00Z doi:10.1186/2042-6410-4-6 /content/figures/2042-6410-4-6-toc.gif Biology of Sex Differences 2042-6410 ${item.volume} 6 2013-03-28T00:00:00Z XML Sex differences occur in most non-communicable diseases, including metabolic diseases, hypertension, cardiovascular disease, psychiatric and neurological disorders and cancer. In many cases, the susceptibility to these diseases begins early in development. The observed differences between the sexes may result from genetic and hormonal differences and from differences in responses to and interactions with environmental factors, including infection, diet, drugs and stress. The placenta plays a key role in fetal growth and development and, as such, affects the fetal programming underlying subsequent adult health and accounts, in part for the developmental origin of health and disease (DOHaD). There is accumulating evidence to demonstrate the sex-specific relationships between diverse environmental influences on placental functions and the risk of disease later in life. As one of the few tissues easily collectable in humans, this organ may therefore be seen as an ideal system for studying how male and female placenta sense nutritional and other stresses, such as endocrine disruptors. Sex-specific regulatory pathways controlling sexually dimorphic characteristics in the various organs and the consequences of lifelong differences in sex hormone expression largely account for such responses. However, sex-specific changes in epigenetic marks are generated early after fertilization, thus before adrenal and gonad differentiation in the absence of sex hormones and in response to environmental conditions. Given the abundance of X-linked genes involved in placentogenesis, and the early unequal gene expression by the sex chromosomes between males and females, the role of X- and Y-chromosome-linked genes, and especially those involved in the peculiar placenta-specific epigenetics processes, giving rise to the unusual placenta epigenetic landscapes deserve particular attention. However, even with recent developments in this field, we still know little about the mechanisms underlying the early sex-specific epigenetic marks resulting in sex-biased gene expression of pathways and networks. As a critical messenger between the maternal environment and the fetus, the placenta may play a key role not only in buffering environmental effects transmitted by the mother but also in expressing and modulating effects due to preconceptional exposure of both the mother and the father to stressful conditions. http://www.bsd-journal.com/content/4/1/5 Anne Gabory Tessa Roseboom Tom Moore Lorna Moore Claudine Junien Biology of Sex Differences 2013, null:5 2013-03-21T00:00:00Z doi:10.1186/2042-6410-4-5 /content/figures/2042-6410-4-5-toc.gif Biology of Sex Differences 2042-6410 ${item.volume} 5 2013-03-21T00:00:00Z XML An introduction to the accompanying three papers. http://www.bsd-journal.com/content/4/1/4 Barbara Boyan Laura Tosi Richard Coutts Roger Enoka David Hart Daniel Nicolella Karen Berkley Kathleen Sluka C Kent Kwoh Mary O¿Connor Wendy Kohrt Eileen Resnick Biology of Sex Differences 2013, null:4 2013-02-04T00:00:00Z doi:10.1186/2042-6410-4-4 /content/figures/2042-6410-4-4-toc.gif Biology of Sex Differences 2042-6410 ${item.volume} 4 2013-02-04T00:00:00Z XML Young female athletes experience a higher incidence of ligament injuries than their male counterparts, females experience a higher incidence of joint hypermobility syndrome (a risk factor for osteoarthritis development), and post-menopausal females experience a higher prevalence of osteoarthritis than age-matched males. These observations indicate that fluctuating sex hormone levels in young females and loss of ovarian sex hormone production due to menopause likely contribute to observed sex differences in knee joint function and risk for loss of function. In studies of osteoarthritis, however, there is a general lack of appreciation for the heterogeneity of hormonal control in both women and men. Progress in this field is limited by the relatively few preclinical osteoarthritis models, and that most of the work with established models uses only male animals. To elucidate sex differences in osteoarthritis, it is important to examine sex hormone mechanisms in cells from knee tissues and the sexual dimorphism in the role of inflammation at the cell, tissue, and organ levels. There is a need to determine if the risk for loss of knee function and integrity in females is restricted to only the knee or if sex-specific changes in other tissues play a role. This paper discusses these gaps in knowledge and suggests remedies. http://www.bsd-journal.com/content/4/1/3 Barbara Boyan David Hart Roger Enoka Daniel Nicolella Eileen Resnick Karen Berkley Kathleen Sluka C Kwoh Laura Tosi Mary O¿Connor Richard Coutts Wendy Kohrt Biology of Sex Differences 2013, null:3 2013-02-04T00:00:00Z doi:10.1186/2042-6410-4-3 /content/figures/2042-6410-4-3-toc.gif Biology of Sex Differences 2042-6410 ${item.volume} 3 2013-02-04T00:00:00Z XML Stress-related psychiatric disorders, such as unipolar depression and post-traumatic stress disorder (PTSD), occur more frequently in women than in men. Emerging research suggests that sex differences in receptors for the stress hormones, corticotropin releasing factor (CRF) and glucocorticoids, contribute to this disparity. For example, sex differences in CRF receptor binding in the amygdala of rats may predispose females to greater anxiety following stressful events. Additionally, sex differences in CRF receptor signaling and trafficking in the locus coeruleus arousal center combine to make females more sensitive to low levels of CRF, and less adaptable to high levels. These receptor differences in females could lead to hyperarousal, a dysregulated state associated with symptoms of depression and PTSD. Similar to the sex differences observed in CRF receptors, sex differences in glucocorticoid receptor (GR) function also appear to make females more susceptible to dysregulation after a stressful event. Following hypothalamic pituitary adrenal axis activation, GRs are critical to the negative feedback process that inhibits additional glucocorticoid release. Compared to males, female rats have fewer GRs and impaired GR translocation following chronic adolescent stress, effects linked to slower glucocorticoid negative feedback. Thus, under conditions of chronic stress, attenuated negative feedback in females would result in hypercortisolemia, an endocrine state thought to cause depression. Together, these studies suggest that sex differences in stress-related receptors shift females more easily into a dysregulated state of stress reactivity, linked to the development of mood and anxiety disorders. The implications of these receptor sex differences for the development of novel pharmacotherapies are also discussed. http://www.bsd-journal.com/content/4/1/2 Debra Bangasser Biology of Sex Differences 2013, null:2 2013-01-21T00:00:00Z doi:10.1186/2042-6410-4-2 /content/figures/2042-6410-4-2-toc.gif Biology of Sex Differences 2042-6410 ${item.volume} 2 2013-01-21T00:00:00Z XML Women have a higher incidence of stress related disorders including depression and generalized anxiety disorder, and epigenetic mechanisms likely contribute to this sex difference. Evidence from preclinical research suggests that epigenetic mechanisms are responsible for both sexual dimorphism of brain regions and sensitivity of the stress response. Epigenetic modifications such as DNA methylation and histone modifications can occur transgenerationally, developmentally, or in response to environmental stimuli such as stress exposure. This review will provide an overview of the various forms of epigenetic modifications observed in the central nervous system and will explain how these mechanisms contribute to a sexually dimorphic brain. It will also discuss the ways in which epigenetic alterations coincide with, and functionally contribute to, the behavioral response to stress across the lifespan. Ultimately, this review will focus on novel research utilizing animal models to investigate sex differences in epigenetic mechanisms that influence susceptibility to stress. Exploration of this relationship reveals epigenetic mechanisms with the potential to explain sexual dimorphism in the occurrence of stress related disorders. http://www.bsd-journal.com/content/4/1/1 Georgia Hodes Biology of Sex Differences 2013, null:1 2013-01-21T00:00:00Z doi:10.1186/2042-6410-4-1 /content/figures/2042-6410-4-1-toc.gif Biology of Sex Differences 2042-6410 ${item.volume} 1 2013-01-21T00:00:00Z XML