An introduction to the accompanying three papers.

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.

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.

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.

Women are approximately twice as likely as men to develop posttraumatic stress disorder (PTSD) after trauma exposure. Mechanisms underlying this difference are not well understood. Although sleep is recognized to have a critical role in PTSD and physical and psychological health more generally, research into the role of sleep in PTSD sex differences has been only recent. In this article, we review both animal and human studies relevant to sex differences in sleep and PTSD with an emphasis on the roles of sex hormones. Sleep impairment including insomnia, trauma-related nightmares, and rapid-eye-movement (REM) sleep fragmentation has been observed in individuals with chronic and developing PTSD, suggesting that sleep impairment is a characteristic of PTSD and a risk factor for its development. Preliminary findings suggested sex specific patterns of sleep alterations in developing and established PTSD. Sleep maintenance impairment in the aftermath of trauma was observed in women who subsequently developed PTSD, and greater REM sleep fragmentation soon after trauma was associated with developing PTSD in both sexes. In chronic PTSD, reduced deep sleep has been found only in men, and impaired sleep initiation and maintenance with PTSD have been found in both sexes. A limited number of studies with small samples have shown that sex hormones and their fluctuations over the menstrual cycle influenced sleep as well as fear extinction, a process hypothesized to be critical to the pathogenesis of PTSD. To further elucidate the possible relationship between the sex specific patterns of PTSD-related sleep alterations and the sexually dimorphic risk for PTSD, future studies with larger samples should comprehensively examine effects of sex hormones and the menstrual cycle on sleep responses to trauma and the risk/resilience for PTSD utilizing various methodologies including fear conditioning and extinction paradigms and animal models.

The occurrence of knee osteoarthritis (OA) increases with age and is more common in women compared with men, especially after the age of 50 years. Recent work suggests that contact stress in the knee cartilage is a significant predictor of the risk for developing knee OA. Significant gaps in knowledge remain, however, as to how changes in musculoskeletal traits disturb the normal mechanical environment of the knee and contribute to sex differences in the initiation and progression of idiopathic knee OA. To illustrate this knowledge deficit, we summarize what is known about the influence of limb alignment, muscle function, and obesity on sex differences in knee OA. Observational data suggest that limb alignment can predict the development of radiographic signs of knee OA, potentially due to increased stresses and strains within the joint. However, these data do not indicate how limb alignment could contribute to sex differences in either the development or worsening of knee OA. Similarly, the strength of the knee extensor muscles is compromised in women who develop radiographic and symptomatic signs of knee OA, but the extent to which the decline in muscle function precedes the development of the disease is uncertain. Even less is known about how changes in muscle function might contribute to the worsening of knee OA. Conversely, obesity is a stronger predictor of developing knee OA symptoms in women than in men. The influence of obesity on developing knee OA symptoms is not associated with deviation in limb alignment, but BMI predicts the worsening of the symptoms only in individuals with neutral and valgus (knock-kneed) knees. It is more likely, however, that obesity modulates OA through a combination of systemic effects, particularly an increase in inflammatory cytokines, and mechanical factors within the joint. The absence of strong associations of these surrogate measures of the mechanical environment in the knee joint with sex differences in the development and progression of knee OA suggests that a more multifactorial and integrative approach in the study of this disease is needed. We identify gaps in knowledge related to mechanical influences on the sex differences in knee OA.

People with osteoarthritis (OA) can have significant pain that interferes with function and quality of life. Women with knee OA have greater pain and greater reductions in function and quality of life than men. In many cases, OA pain is directly related to sensitization and activation of nociceptors in the injured joint and correlates with the degree of joint effusion and synovial thickening. In some patients, however, the pain does not match the degree of injury and continues after removal of the nociceptors with a total joint replacement. Growth of new nociceptors, activation of nociceptors in the subchondral bone exposed after cartilage degradation, and nociceptors innervating synovium sensitized by inflammatory mediators could all augment the peripheral input to the central nervous system and result in pain. Enhanced central excitability and reduced central inhibition could lead to prolonged and enhanced pain that does not directly match the degree of injury. Psychosocial variables can influence pain and contribute to pain variability. This review explores the neural and psychosocial factors that contribute to knee OA pain with an emphasis on differences between the sexes and gaps in knowledge.

The categorization of individuals as “male” or “female” is based on chromosome complement and gonadal and genital phenotype. This combined genetic-gonadal-genitals sex, here referred to as 3G-sex, is internally consistent in ~99% of humans (i.e., one has either the “female” form at all levels, or the “male” form at all levels). About 1% of the human population is identified as “intersex” because of either having an intermediate form at one or more levels, or having the “male” form at some levels and the “female” form at other levels. These two types of “intersex” reflect the facts, respectively, that the different levels of 3G-sex are not completely dimorphic nor perfectly consistent. Using 3G-sex as a model to understand sex differences in other domains (e.g., brain, behavior) leads to the erroneous assumption that sex differences in these other domains are also highly dimorphic and highly consistent. But parallel lines of research have led to the conclusion that sex differences in the brain and in behavior, cognition, personality, and other gender characteristics are for the most part not dimorphic and not internally consistent (i.e., having one brain/gender characteristic with the “male” form is not a reliable predictor for the form of other brain/gender characteristics). Therefore although only ~1% percent of humans are 3G-“intersex”, when it comes to brain and gender, we all have an intersex gender (i.e., an array of masculine and feminine traits) and an intersex brain (a mosaic of “male” and “female” brain characteristics).

Background

Coxsackievirus B3 (CVB3) induces myocarditis, an inflammatory heart disease, which affects men more than women. Toll-like receptor (TLR) signaling has been shown to determine the severity of CVB3-induced myocarditis. No direct role for signaling through TLR2 had been shown in myocarditis although published studies show that cardiac myosin is an endogenous TLR2 ligand and stimulates pro-inflammatory cytokine expression by dendritic cells in vitro. The goal of this study is to determine which TLRs show differential expression in CVB3 infected mice corresponding to male susceptibility and female resistance in this disease.

Methods

Male and female C57Bl/6 mice were infected with 102 PFU CVB3 and killed on day 3 or 6 post infection. Hearts were evaluated for virus titer, myocardial inflammation, and TLR mRNA expression by PCR array and microarray analysis. Splenic lymphocytes only were evaluated by flow cytometry for the number of TLR+/CD3+, TLR+/CD4+, TLR+F4/80+ and TLR+/CD11c+ subpopulations and the mean fluorescence intensity to assess upregulation of TLR expression on these cells. Mice were additionally treated with PAM3CSK4 (TLR2 agonist) or ultrapure LPS (TLR4 agonist) on the same day as CVB3 infection or 3 days post infection to confirm their role in myocarditis susceptibility.

Results

Despite equivalent viral titers, male C57Bl/6 mice develop more severe myocarditis than females by day 6 after infection. Microarray analysis shows a differential expression of TLR2 at day 3 with female mice having higher levels of TLR2 gene expression compared to males. Disease severity correlates to greater TLR4 protein expression on splenic lymphocytes in male mice 3 days after infection while resistance in females correlates to preferential TLR2 expression, especially in spleen lymphocytes. Treating male mice with PAM reduced mortality from 55% in control CVB3 infected animals to 10%. Treating female mice with LPS increased mortality from 0% in control infected animals to 60%.

Conclusion

CVB3 infection causes an up-regulation of TLR2 in female and of TLR4 in male mice and this differential expression between the sexes contributes to disease resistance of females and susceptibility of males. While previous reports demonstrated a pathogenic role for TLR4 this is the first report that TLR2 is preferentially up-regulated in CVB3 infected female mice or that signaling through this TLR directly causes myocarditis resistance.

Biologic sex and gonadal hormones matter in human aging and diseases of aging such as Alzheimer’s – and the importance of studying their influences relates directly to human health. The goal of this article is to review the literature to date on sex and hormones in mouse models of Alzheimer’s disease (AD) with an exclusive focus on interpreting the relevance of findings to the human condition. To this end, we highlight advances in AD and in sex and hormone biology, discuss what these advances mean for merging the two fields, review the current mouse model literature, raise major unresolved questions, and offer a research framework that incorporates human reproductive aging for future studies aimed at translational discoveries in this important area. Unraveling human relevant pathways in sex and hormone-based biology may ultimately pave the way to novel and urgently needed treatments for AD and other neurodegenerative diseases.

Background

It remains unclear whether the increased risk of colorectal cancer (CRC) associated with obesity differs by gender, distribution of fat, tumour location and clinical (TNM) stage. The primary aim of this study was to examine these associations in 584 incident colorectal cancer cases from a Swedish prospective population-based cohort including 28098 men and women.

Methods

Seven anthropometric factors; height, weight, bodyfat percentage, hip circumference, waist circumference, BMI and waist-hip ratio (WHR) were categorized into quartiles of baseline anthropometric measurements. Relative risks of CRC, total risk as well as risk of different TNM stages, and risk of tumours located to the colon or rectum, were calculated for all cases, women and men, respectively, using multivariate Cox regression models.

Results

Obesity, as defined by all anthropometric variables, was significantly associated with an overall increased risk of CRC in both women and men. While none of the anthropometric measures was significantly associated with risk of tumour (T)-stage 1 and 2 tumours, all anthropometric variables were significantly associated with an increased risk of T-stage 3 and 4, in particular in men. In men, increasing quartiles of weight, hip, waist, BMI and WHR were significantly associated with an increased risk of lymph node positive (N1 and N2) disease, and risk of both non-metastatic (M0) and metastatic (M1) disease. In women, there were no or weak associations between obesity and risk of node-positive disease, but statistically significant associations between increased weight, bodyfat percentage, hip, BMI and M0 disease. Interestingly, there was an increased risk of colon but not rectal cancer in men, and rectal but not colon cancer in women, by increased measures of weight, hip-, waist circumference and bodyfat percentage.

Conclusions

This study is the first to show a relationship between obesity, measured as several different anthropometric factors, and an increased risk of colorectal cancer of more advanced clinical stage, in particular in men. These findings suggest that risk of CRC differs according to the method of characterising obesity, and also according to gender, location, and tumour stage.

Males and females differ widely in morphology, physiology, and behavior leading to disparities in many health outcomes, including sex biases in the prevalence of many neurodevelopmental disorders. However, with the exception of a relatively small number of genes on the Y chromosome, males and females share a common genome. Therefore, sexual differentiation must in large part be a product of the sex biased expression of this shared genetic substrate. microRNAs (miRs) are small non-coding RNAs involved in the post-transcriptional regulation of up to 70% of protein-coding genes. The ability of miRs to regulate such a vast amount of the genome with a high degree of specificity makes them perfectly poised to play a critical role in programming of the sexually dimorphic brain. This review describes those characteristics of miRs that make them particularly amenable to this task, and examines the influences of both the sex chromosome complement as well as gonadal hormones on their regulation. Exploring miRs in the context of sex differences in disease, particularly in sex-biased neurodevelopmental disorders, may provide novel insight into the pathophysiology and potential therapeutic targets in disease treatment and prevention.

Background

Cerebral cortex has a very large number of testosterone receptors, which could be a basis for sex differences in sensory functions. For example, audition has clear sex differences, which are related to serum testosterone levels. Of all major sensory systems only vision has not been examined for sex differences, which is surprising because occipital lobe (primary visual projection area) may have the highest density of testosterone receptors in the cortex. We have examined a basic visual function: spatial and temporal pattern resolution and acuity.

Methods

We tested large groups of young adults with normal vision. They were screened with a battery of standard tests that examined acuity, color vision, and stereopsis. We sampled the visual system’s contrast-sensitivity function (CSF) across the entire spatio-temporal space: 6 spatial frequencies at each of 5 temporal rates. Stimuli were gratings with sinusoidal luminance profiles generated on a special-purpose computer screen; their contrast was also sinusoidally modulated in time. We measured threshold contrasts using a criterion-free (forced-choice), adaptive psychophysical method (QUEST algorithm). Also, each individual’s acuity limit was estimated by fitting his or her data with a model and extrapolating to find the spatial frequency corresponding to 100% contrast.

Results

At a very low temporal rate, the spatial CSF was the canonical inverted-U; but for higher temporal rates, the maxima of the spatial CSFs shifted: Observers lost sensitivity at high spatial frequencies and gained sensitivity at low frequencies; also, all the maxima of the CSFs shifted by about the same amount in spatial frequency. Main effect: there was a significant (ANOVA) sex difference. Across the entire spatio-temporal domain, males were more sensitive, especially at higher spatial frequencies; similarly males had significantly better acuity at all temporal rates.

Conclusion

As with other sensory systems, there are marked sex differences in vision. The CSFs we measure are largely determined by inputs from specific sets of thalamic neurons to individual neurons in primary visual cortex. This convergence from thalamus to cortex is guided by cortex during embryogenesis. We suggest that testosterone plays a major role, leading to different connectivities in males and in females. But, for whatever reasons, we find that males have significantly greater sensitivity for fine detail and for rapidly moving stimuli. One interpretation is that this is consistent with sex roles in hunter-gatherer societies.

Background

Because cerebral cortex has a very large number of testosterone receptors, we examined the possible sex differences in color appearance of monochromatic lights across the visible spectrum. There is a history of men and women perceiving color differently. However, all of these studies deal with higher cognitive functions which may be culture-biased. We study basic visual functions, such as color appearance, without reference to any objects. We present here a detailed analysis of sex differences in primary chromatic sensations.

Methods

We tested large groups of young adults with normal vision, including spatial and temporal resolution, and stereopsis. Based on standard color-screening and anomaloscope data, we excluded all color-deficient observers. Stimuli were equi-luminant monochromatic lights across the spectrum. They were foveally-viewed flashes presented against a dark background. The elicited sensations were measured using magnitude estimation of hue and saturation. When the only permitted hue terms are red (R) yellow (Y), green (G), blue (B), alone or in combination, such hue descriptions are language-independent and the hue and saturation values can be used to derive a wide range of color-discrimination functions.

Results

There were relatively small but clear and significant, differences between males and females in the hue sensations elicited by almost the entire spectrum. Generally, males required a slightly longer wavelength to experience the same hue as did females. The spectral loci of the unique hues are not correlated with anomaloscope matches; these matches are directly determined by the spectral sensitivities of L- and M-cones (genes for these cones are on the X-chromosomes). Nor are there correlations between loci of pairs of unique hues (R, Y, G, B). Wavelength-discrimination functions derived from the scaling data show that males have a broader range of poorer discrimination in the middle of the spectrum. The precise values for all the data depend on whether Newtonian or Maxwellian optics were used, but the sex differences were the same for both optical systems.

Conclusion

As with our associated paper on spatio-temporal vision, there are marked sex differences in color vision. The color-appearances we measured are determined by inputs from thalamic neurons (LGN) to individual neurons in primary visual cortex. This convergence from LGN to cortex is guided by the cortex during embryogenesis. We hypothesize that testosterone plays a major role, somehow leading to different connectivities for males and females: color appearance requires a re-combination and re-weighting of neuronal inputs from the LGN to the cortex, which, as we show, depends on the sex of the participant.

Improvements in neuroimaging technologies, and greater access to their use, have generated a plethora of data regarding male/female differences in the developing brain. Examination of these differences may shed light on the pathophysiology of the many illnesses that differ between the sexes and ultimately lead to more effective interventions. In this review, we attempt to synthesize the anatomic magnetic resonance imaging (MRI) literature of male/female brain differences with emphasis on studies encompassing adolescence – a time of divergence in physical and behavioral characteristics. Across all ages total brain size is consistently reported to be about 10% larger in males. Structures commonly reported to be different between sexes include the caudate nucleus, amygdala, hippocampus, and cerebellum – all noted to have a relatively high density of sex steroid receptors. The direction and magnitude of reported brain differences depends on the methodology of data acquisition and analysis, whether and how the subcomponents are adjusted for the total brain volume difference, and the age of the participants in the studies. Longitudinal studies indicate regional cortical gray matter volumes follow inverted U shaped developmental trajectories with peak size occurring one to three years earlier in females. Cortical gray matter differences are modulated by androgen receptor genotyope and by circulating levels of hormones. White matter volumes increase throughout childhood and adolescence in both sexes but more rapidly in adolescent males resulting in an expanding magnitude of sex differences from childhood to adulthood.

Background

Since American Indians are predisposed to type 2 diabetes (DM2) and associated cardiovascular risk, Cherokee boys and girls (n = 917) were studied to determine whether BMI Z (body mass index Z score) is associated with the apoC-III (apolipoprotein C-III) content of HDL (high density lipoprotein), a previously reported predictor of DM2.

Methods

An ad hoc cross-sectional analysis was conducted on a previously studied cohort. Participants were grouped by gender-specific age groups (5 to 9, 10 to 14 and 15 to 19 years). ApoA-I (apolipoprotein A-I) and HDL apoC-III were assayed by electroimmunoassay. ApoC-III was measured in whole plasma, and in HDL to determine the molar proportion to apoA-I. General linear models were used to assess association.

Results

The HDL apoC-III to apoA-I molar ratio increased by BMI Z quartile in girls aged 10–14 years (p < 0.05 for linear trend, p < 0.05 for difference in BMI Z quartile IV vs. I to III) and aged 15–19 years (p < 0.05 for trend). In boys the increase by BMI Z occurred only at ages 15–19 years (p < 0.01 for trend and for quartile difference).

Conclusions

ApoC-III showed an obesity-related increase relative to apoA-I during adolescence beginning in girls aged 10 to 14 years and in boys aged 15 to 19 years. The earlier changes in girls may alter HDL’s protective properties on the β-cell and contribute to their increased risk for DM2.

Background

Recent research has suggested that oxytocin receptor gene (OXTR) variants may account for individual differences in social behavior, the effects of stress and parenting styles. Little is known, however, on a putative role of the gene in heritable temperamental traits.

Methods

We addressed effects of two common OXTR variants, rs237900 and rs237902, on personality dimensions in 99 healthy subjects using the Temperament and Character Inventory.

Results

When sex was controlled for and an OXTR genotype*sex interaction term was included in the regression model, 11% of the variance in Harm Avoidance could be explained (uncorrected p ≤ 0.01). Female carriers of the minor alleles scored highest, and a novel A217T mutation emerged in the most harm avoidant male participant.

Conclusions

Findings lend support to a modulatory effect of common OXTR variants on Harm Avoidance in healthy caucasian women and invite resequencing of the gene in anxiety phenotypes to identify more explanatory functional variation.

Background

Malignant melanoma is the most deadly form of skin cancer. Female sex is known to have a protective effect on incidence, tumour characteristics, and mortality from melanoma. However, the potentially modifying effect of sex on the prognostic significance of clinicopathological and investigative factors is generally not taken into consideration in biomarker studies. In this study, we compared the sex-specific distribution and prognostic value of established tumour characteristics and Ki67 expression in 255 cases of incident primary melanoma in a prospective, population-based cohort study.

Methods

The study included 255 incident cases of melanoma, 132 females and 123 males, in the Malmö Diet and Cancer Study. Tumours from 226 (88.6%) cases had been assembled in tissue microarrays. Clinicopathological factors and immunohistochemical Ki67 expression were assessed and correlated with disease-free survival (DFS) and overall survival (OS) using Kaplan-Meier analysis, log rank test and univariable and multivariable Cox regression analyses, stratified for gender. Effect of gender on melanoma-specific survival (MSS) after first recurrence was also analysed.

Results

Women were significantly younger at diagnosis than men (p = 0.012). The most common tumour sites were the legs in women (37.5%) and the dorsal trunk in men (37.8%). Kaplan-Meier analysis revealed that tumour location had no prognostic impact in women, but in men, location to the frontal trunk was significantly associated with a reduced DFS compared with all other locations combined and location to the dorsal trunk was significantly associated with a prolonged OS. High Ki67 expression was significantly associated with a reduced DFS and OS in men but not in women, also when adjusted for other factors. In men, but not in women, ulceration was an independent prognostic factor for both DFS and OS. MSS after first local, regional or distant recurrence was significantly shorter for men than for women.

Conclusions

The results from this study demonstrate that the prognostic value of tumour location, Ki67 expression and ulceration in melanoma differs according to gender. These findings need to be validated in future studies, as they may help improve prognostication in patients with melanoma. Moreover, our findings demonstrate that sex-stratified analyses add valuable information to biomarker studies.

Background

Infectious diseases and inflammation during pregnancy increase the offspring’s risk for behavioral disorders. However, how immune stress affects neural circuitry during development is not well known. We tested whether a prenatal immune challenge interferes with the development of social play and with neural circuits implicated in social behavior.

Methods

Pregnant rats were given intraperitoneal injections of the bacterial endotoxin lipopolysaccharide (LPS – 100 μg /kg) or saline on the 15th day of pregnancy. Offspring were tested for social play behaviors between postnatal days 26–40. Brains were harvested on postnatal day 45 and processed for arginine vasopressin (AVP) mRNA in situ hybridization.

Results

In males, LPS treatment reduced the frequency of juvenile play behavior and reduced AVP mRNA expression in the medial amygdala and bed nucleus of the stria terminalis. These effects were not found in females. LPS treatment did not change AVP mRNA expression in the suprachiasmatic nucleus, paraventricular nucleus, or supraoptic nucleus of either sex, nor did it affect the sex difference in the size of the sexually dimorphic nucleus of the preoptic area.

Conclusions

Given AVP’s central role in regulating social behavior, the sexually dimorphic effects of prenatal LPS treatment on male AVP mRNA expression may contribute to the sexually dimorphic effect of LPS on male social play and may, therefore, increase understanding of factors that contribute to sex differences in social psychopathology.

Women have more body fat than men, but in contrast to the deleterious metabolic consequences of the central obesity typical of men, the pear-shaped body fat distribution of many women is associated with lower cardiometabolic risk. To understand the mechanisms regulating adiposity and adipose tissue distribution in men and women, significant research attention has focused on comparing adipocyte morphological and metabolic properties, as well as the capacity of preadipocytes derived from different depots for proliferation and differentiation. Available evidence points to possible intrinsic, cell autonomous differences in preadipocytes and adipocytes, as well as modulatory roles for sex steroids, the microenvironment within each adipose tissue, and developmental factors. Gluteal-femoral adipose tissues of women may simply provide a safe lipid reservoir for excess energy, or they may directly regulate systemic metabolism via release of metabolic products or adipokines. We provide a brief overview of the relationship of fat distribution to metabolic health in men and women, and then focus on mechanisms underlying sex differences in adipose tissue biology.

Sexual differentiation of the nervous system occurs via the interplay of genetics, endocrinology and social experience through development. Much of the research into mechanisms of sexual differentiation has been driven by an implicit theoretical framework in which these causal factors act primarily and directly on sexually dimorphic neural populations within the central nervous system. This review will examine an alternative explanation by describing what is known about the role of peripheral structures and mechanisms (both neural and non-neural) in producing sex differences in the central nervous system. The focus of the review will be on experimental evidence obtained from studies of androgenic masculinization of the spinal nucleus of the bulbocavernosus, but other systems will also be considered.

Background

Although there appear to be no differences in muscle protein turnover in young and middle aged men and women, we have reported significant differences in the rate of muscle protein synthesis between older adult men and women. This suggests that aging may affect muscle protein turnover differently in men and women.

Methods

We measured the skeletal muscle protein fractional synthesis rate (FSR) by using stable isotope-labeled tracer methods during basal postabsorptive conditions and during a hyperaminoacidemic-hyperinsulinemic-euglycemic clamp in eight young men (25–45 y), ten young women (25–45 y), ten old men (65–85 y) and ten old women (65–85 y).

Results

The basal muscle protein FSR was not different in young and old men (0.040 ± 0.004 and 0.043 ± 0.005%·h-1, respectively) and combined insulin, glucose and amino acid infusion significantly increased the muscle protein FSR both in young (to 0.063 ± 0.006%·h-1) and old (to 0.051 ± 0.008%·h-1) men but the increase (0.023 ± 0.004 vs. 0.009 ± 0.004%·h-1, respectively) was ~60% less in the old men (P = 0.03). In contrast, the basal muscle protein FSR was ~30% greater in old than young women (0.060 ± 0.003 vs. 0.046 ± 0.004%·h-1, respectively; P < 0.05) and combined insulin, glucose and amino acid infusion significantly increased the muscle protein FSR in young (P < 0.01) but not in old women (P = 0.10) so that the FSR was not different between young and old women during the clamp (0.074 ± 0.006%·h-1 vs. 0.072 ± 0.006%·h-1, respectively).

Conclusions

There is sexual dimorphism in the age-related changes in muscle protein synthesis and thus the metabolic processes responsible for the age-related decline in muscle mass.

Background

Low endogenous testosterone levels have been shown to be a risk factor for the development of cardiovascular disease and cardiovascular benefits associated with testosterone replacement therapy are being advocated; however, the effects of endogenous testosterone levels on acute coronary vasomotor responses to androgen administration are not clear. The objective of this study was to compare the effects of acute androgen administration on in vivo coronary conductance and in vitro coronary microvascular diameter in intact and castrated male swine.

Methods

Pigs received intracoronary infusions of physiologic levels (1–100 nM) of testosterone, the metabolite 5α-dihydrotestosterone, and the epimer epitestosterone while left anterior descending coronary blood flow and mean arterial pressure were continuously monitored. Following sacrifice, coronary arterioles were isolated, cannulated, and exposed to physiologic concentrations (1–100 nM) of testosterone, 5α-dihydrotestosterone, and epitestosterone. To evaluate effects of the androgen receptor on acute androgen dilation responses, real-time PCR and immunohistochemistry for androgen receptor were performed on conduit and resistance coronary vessels.

Results

In vivo, testosterone and 5α-dihydrotestosterone produced greater increases in coronary conductance in the intact compared to the castrated males. In vitro, percent maximal dilation of microvessels was similar between intact and castrated males for testosterone and 5α-dihydrotestosterone. In both studies epitestosterone produced significant increases in conductance and microvessel diameter from baseline in the intact males. Androgen receptor mRNA expression and immunohistochemical staining were similar in intact and castrated males.

Conclusions

Acute coronary vascular responses to exogenous androgen administration are increased by endogenous testosterone, an effect unrelated to changes in androgen receptor expression.

Background

Early liver development and the transcriptional transitions during hepatogenesis are well characterized. However, gene expression changes during the late postnatal/pre-pubertal to young adulthood period are less well understood, especially with regards to sex-specific gene expression.

Methods

Microarray analysis of male and female mouse liver was carried out at 3, 4, and 8 wk of age to elucidate developmental changes in gene expression from the late postnatal/pre-pubertal period to young adulthood.

Results

A large number of sex-biased and sex-independent genes showed significant changes during this developmental period. Notably, sex-independent genes involved in cell cycle, chromosome condensation, and DNA replication were down regulated from 3 wk to 8 wk, while genes associated with metal ion binding, ion transport and kinase activity were up regulated. A majority of genes showing sex differential expression in adult liver did not display sex differences prior to puberty, at which time extensive changes in sex-specific gene expression were seen, primarily in males. Thus, in male liver, 76% of male-specific genes were up regulated and 47% of female-specific genes were down regulated from 3 to 8 wk of age, whereas in female liver 67% of sex-specific genes showed no significant change in expression. In both sexes, genes up regulated from 3 to 8 wk were significantly enriched (p < E-76) in the set of genes positively regulated by the liver transcription factor HNF4α, as determined in a liver-specific HNF4α knockout mouse model, while genes down regulated during this developmental period showed significant enrichment (p < E-65) for negative regulation by HNF4α. Significant enrichment of the developmentally regulated genes in the set of genes subject to positive and negative regulation by pituitary hormone was also observed. Five sex-specific transcriptional regulators showed sex-specific expression at 4 wk (male-specific Ihh; female-specific Cdx4, Cux2, Tox, and Trim24) and may contribute to the developmental changes that lead to global acquisition of liver sex-specificity by 8 wk of age.

Conclusions

Overall, the observed changes in gene expression during postnatal liver development reflect the deceleration of liver growth and the induction of specialized liver functions, with widespread changes in sex-specific gene expression primarily occurring in male liver.

Animals prioritize behaviors according to their physiological needs and reproductive goals, selecting a single behavioral strategy from a repertoire of possible responses to any given stimulus. Biological sex influences this decision-making process in significant ways, differentiating the responses animals choose when faced with stimuli ranging from food to conspecifics. We review here recent work in invertebrate models, including C. elegans, Drosophila, and a variety of insects, mollusks and crustaceans, that has begun to offer intriguing insights into the neural mechanisms underlying the sexual modulation of behavioral decision-making. These findings show that an animal's sex can modulate neural function in surprisingly diverse ways, much like internal physiological variables such as hunger or thirst. In the context of homeostatic behaviors such as feeding, an animal's sex and nutritional status may converge on a common physiological mechanism, the functional modulation of shared sensory circuitry, to influence decision-making. Similarly, considerable evidence suggests that decisions on whether to mate or fight with conspecifics are also mediated through sex-specific neuromodulatory control of nominally shared neural circuits. This work offers a new perspective on how sex differences in behavior emerge, in which the regulated function of shared neural circuitry plays a crucial role. Emerging evidence from vertebrates indicates that this paradigm is likely to extend to more complex nervous systems as well. As men and women differ in their susceptibility to a variety of neuropsychiatric disorders affecting shared behaviors, these findings may ultimately have important implications for human health.