Characterize Sex Differences Research Articles

Sex differences in neurosteroid and hormonal responses to metyrapone in posttraumatic stress disorder.

Mechanisms contributing to sex differences in the regulation of acute stress responsivity and their effect on the increased incidence of posttraumatic stress disorder (PTSD) in women are poorly understood. The reproductive hormone, progesterone, through conversion to allopregnanolone (ALLO), suppresses the hypothalamic pituitary adrenal (HPA) axis and has potent anxiolytic effects. The potential that progesterone and allopregnanolone reactivity modulate HPA axis responses and account for sex differences in PTSD has not been previously examined. The present study examined the effects of sex and PTSD on adrenocorticotropic hormone (ACTH), progesterone, and allopregnanolone responses to metyrapone and whether progesterone and allopregnanolone reactivity could affect the ACTH response in PTSD. Healthy medication-free male and premenopausal follicular phase female participants with chronic PTSD (n = 43; 49 % female) and controls (n = 42; 50 % female) completed an overnight metyrapone challenge and ACTH, progesterone, and allopregnanolone were obtained by repeated blood sampling. The increase in ACTH response to metyrapone was higher in PTSD subjects compared to controls and in women compared to men. Contrary to our initial prediction of an inverse relationship, progesterone and allopregnanolone were positively associated with ACTH. Progesterone and allopregnanolone partially mediated the relationship between PTSD and ACTH. Our findings of increased ACTH to metyrapone in PTSD and in women may reflect heightened hypothalamic CRF hypersecretion. Progesterone and allopregnanolone partially mediated the ACTH response in PTSD. Further characterizing sex differences in these processes will advance our understanding of the pathophysiology of PTSD, and may ultimately lead to better-targeted, more effective treatment.

Sex differences in cardiovascular and subjective stress reactions: prospective evidence in a realistic military setting

Evidence points to heightened physiological arousal in response to acute stress exposure as both a prospective indicator and a core characteristic of posttraumatic stress disorder (PTSD). Because females may be at higher risk for PTSD development, it is important to evaluate sex differences in acute stress reactions. This study characterized sex differences in cardiovascular and subjective stress reactions among military survival trainees. One hundred and eighty-five military members (78% males) were studied before, during, and 24 h after stressful mock captivity. Cardiovascular (heart rate [HR], systolic blood pressure [SBP], diastolic blood pressure [DBP]) and dissociative states were measured at all three time points. Psychological impact of mock captivity was assessed during recovery. General linear modeling with repeated measures evaluated sex differences for each cardiovascular endpoint, and causal steps modeling was used to explore interrelationships among sex, cardiovascular reactions and psychological impact of mock captivity. Although females had lower SBP than males at all three time points, the difference was most pronounced at baseline and during stress. Accordingly, females showed greater residual elevation in SBP during recovery. Females had lower DBP at all three time points. In addition, females reported greater psychological impact of mock captivity than males. Exploratory causal steps modeling suggested that stress-induced HR may partially mediate the effect of sex on psychological impact of mock captivity. In conclusion, this study demonstrated sex-specific cardiovascular stress reactions in military personnel, along with greater psychological impact of stress exposure in females. This research may elucidate sex differences in PTSD development.

Sex differences in brain activation to emotional stimuli: A meta-analysis of neuroimaging studies

Substantial sex differences in emotional responses and perception have been reported in previous psychological and psychophysiological studies. For example, women have been found to respond more strongly to negative emotional stimuli, a sex difference that has been linked to an increased risk of depression and anxiety disorders. The extent to which such sex differences are reflected in corresponding differences in regional brain activation remains a largely unresolved issue, however, in part because relatively few neuroimaging studies have addressed this issue. Here, by conducting a quantitative meta-analysis of neuroimaging studies, we were able to substantially increase statistical power to detect sex differences relative to prior studies, by combining emotion studies which explicitly examined sex differences with the much larger number of studies that examined only women or men. We used an activation likelihood estimation approach to characterize sex differences in the likelihood of regional brain activation elicited by emotional stimuli relative to non-emotional stimuli. We examined sex differences separately for negative and positive emotions, in addition to examining all emotions combined. Sex differences varied markedly between negative and positive emotion studies. The majority of sex differences favoring women were observed for negative emotion, whereas the majority of the sex differences favoring men were observed for positive emotion. This valence-specificity was particularly evident for the amygdala. For negative emotion, women exhibited greater activation than men in the left amygdala, as well as in other regions including the left thalamus, hypothalamus, mammillary bodies, left caudate, and medial prefrontal cortex. In contrast, for positive emotion, men exhibited greater activation than women in the left amygdala, as well as greater activation in other regions including the bilateral inferior frontal gyrus and right fusiform gyrus. These meta-analysis findings indicate that the amygdala, a key region for emotion processing, exhibits valence-dependent sex differences in activation to emotional stimuli. The greater left amygdala response to negative emotion for women accords with previous reports that women respond more strongly to negative emotional stimuli, as well as with hypothesized links between increased neurobiological reactivity to negative emotion and increased prevalence of depression and anxiety disorders in women. The finding of greater left amygdala activation for positive emotional stimuli in men suggests that greater amygdala responses reported previously for men for specific types of positive stimuli may also extend to positive stimuli more generally. In summary, this study extends efforts to characterize sex differences in brain activation during emotion processing by providing the largest and most comprehensive quantitative meta-analysis to date, and for the first time examining sex differences as a function of positive vs. negative emotional valence. The current findings highlight the importance of considering sex as a potential factor modulating emotional processing and its underlying neural mechanisms, and more broadly, the need to consider individual differences in understanding the neurobiology of emotion.

Abstract P324: Abdominal Visceral Adiposity and Liver Fat in Relation to Sex-Related Differences in Cardiometabolic Risk Profile: The INSPIRE ME IAA Study

Objectives: Sex differences in the cardiovascular risk profile are well established. The objectives of the present analyses were 1) to characterize sex differences in visceral adiposity (VA) and estimated liver fat content assessed by computed tomography (CT) and in the cardiometabolic risk (CMR) profile in a large international multiethnic cohort; 2) to determine whether differences between men and women in CMR factors remain after controlling for VA and/or liver fat. Methods: In the International Study of Prediction of Intra-abdominal adiposity and its Relationship with cardioMEtabolic risk/Intra-Abdominal Adiposity (INSPIRE ME IAA), 297 primary care physicians, cardiologists, endocrinologists/diabetologists recruited 4504 patients from 29 countries. VA and liver attenuation (inversely correlated to liver fat) were assessed by CT. Cardiometabolic risk factors (triglyceride (TG), HDL-C, Apolipoprotein B (ApoB), HOMA, 2h-glucose (OGTT), adiponectin, C-Reactive Protein (CRP)) were assessed using standardized methods. The present cross-sectional analyses were performed in 1193 men and 1214 women free of type 2 diabetes. Results: Whereas mean BMI was similar in women and men (27.5±0.1 vs 27.5±0.1 kg/m2), men had higher waist circumference (98.1±0.4 vs 89.6±0.4 cm), higher VA (165±2 vs 131±2 cm2) and lower liver attenuation (54.9±0.3 vs 57.4±0.3 HU) (p<0.0001 for all) than women. Men displayed higher TG and HOMA but lower HDLc, CRP and adiponectin levels (p<0.001 for all) than women. In both sexes, VA and liver fat were significantly correlated positively with CMR variables: TG, HOMA and CRP and negatively with HDLc and adiponectin (p<0.05 simple regression analysis). In multiple regression analyses, VA and liver attenuation independently affected CMR variables. Sex differences in TG were eliminated after adjustment for VA or both variables simultaneously but HDLc remained higher in women even after such adjustment. HOMA was higher in women when adjusted for VA or for both variables and similar to men when adjusted for liver attenuation. Being not different between sexes before adjustment, 2h-glucose was higher in women when controlling for VA/liver fat. Adiponectin remained higher in women after all adjustments. Sex differences in CRP were magnified after adjustment for VA/liver fat and remained higher in women. Conclusion: In this large standardized international CT-imaging/cardiometabolic study, substantial sex differences in abdominal adiposity/liver fat and CMR factors were observed, with men presenting an overall more deteriorated CMR profile than women. Controlling for VA and liver fat was not sufficient to abolish sex differences in all inflammatory, insulin sensitivity or lipid factors.

Sex differences in the neural correlates of autonomic arousal: A pilot PET study

Electrophysiology, behavioral, and neuroimaging studies have revealed sex-related differences in autonomic cardiac control, as reflected in measurements of heart rate variability (HRV). Imaging studies indicate that the neurobiological correlates of autonomic nervous system (ANS) function can be investigated by measuring indices of HRV during the performance of mildly strenuous motor tasks or mildly stressful cognitive tasks. In this preliminary study, fifteen male and seven female healthy subjects underwent H 2 15O-positron emission tomography (PET) and electrocardiograph (ECG) recording while performing a handgrip motor task and an n-back task. Indices of HRV were calculated and correlated with regional cerebral blood flow (rCBF). We hypothesized that sex differences would be evident in brain regions known to participate in autonomic regulation: the anterior insula, the anterior cingulate cortex, the orbitofrontal cortex, and the amygdala. Our study found that associations between rCBF and parasympathetic indices differed significantly between female and male subjects in the amygdala. Females showed a positive correlation between rCBF and parasympathetic indices while males exhibited negative correlations. This differential correlation of amygdala rCBF and parasympathetic activity between males and females may reflect differences in parasympathetic/sympathetic balance between sexes, consistent with known sexual dimorphism in the amygdala and closely related structures such as the hypothalamus. These preliminary imaging results are consistent with earlier reports of significant correlation between brain activity and HRV, and extend these findings by demonstrating prominent sex differences in the neural control of the ANS. While the generalizability of our results was limited by the small size of the study samples, the relatively robust effect size of the differences found between groups encourages further work in larger samples to characterize sex differences in the neural correlates of autonomic arousal.

Male mice have increased thrombotic potential: Sex differences in a mouse model of venous thrombosis

Introduction Our objectives were to characterize sex differences during venous thrombosis, using the electrolytic inferior vena cava model of the disease. Materials and methods Male and female C57BL/6 mice (6-8 weeks) underwent inferior vena cava thrombosis. Time points included 6 hours, day 2, day 6, and day 14 post surgery, along with surgically naïve true controls and surgical shams. Analyses included thrombus weight, vein wall morphometrics, vein wall protein and gene expression for P-selectin, interleukin-1β, and tumor necrosis factor-α; hematology, soluble P-selectin, and plasma microparticle tissue factor activity assays. Results Male venous thrombi were significantly larger than females at days 2 (13.1 ± 1.0 vs. 6.8 ± 0.5 × 10 -3 grams, p < 0.01), 6 (10.4 ± 0.8 vs. 5.4 ± 0.5 × 10 -3 grams, p < 0.01) and 14 (6.3 ± 0.5 vs. 4.1 ± 0.3 × 10 -3 grams, p < 0.01). Both male and female mice exhibited significantly increased vein wall P-selectin at 6 hours, vs. true controls (p < 0.05). Males had increased vein wall interleukin-1β, versus females, at 6 hours (180.926 ± 24.596 vs. 60.417 ± 10.478 pg/mL, p < 0.05) and day 6 (76.966 ± 13.081 vs. 33.834 ± 4.198 pg/mL, p < 0.01). Males showed decreased tumor necrosis factor-α expression (-66 %) at 6 hours. Females had increased tumor necrosis factor-α expression at 6 hours (+ 541%) and day 6 (+ 539%). Both sexes demonstrated decreased peripheral platelets at 6 hours (p < 0.05), coinciding with thrombogenesis. Plasma P-selectin increased in both sexes, versus controls, through day 6 (p < 0.05). Conclusions Males had significantly larger venous thrombi than females. Sex differences in vascular anatomy and response to inflammation may influence thrombus formation in our mouse thrombosis model.

Sex Differences in Pulse Pressure Trends With Age Are Cross-Cultural

Sex differences in systolic and diastolic blood pressure levels and trends with age have been consistently observed in both industrialized and unindustrialized populations. However, the impact of sex on pulse pressure, an index of vascular aging, in unindustrialized populations has not been addressed. The objective of this report was to characterize sex differences in aging trends of pulse pressure within unindustrialized populations. Using PubMed and Medline, we identified 60 articles with blood pressure data from unacculturated or partially acculturated populations. Data on 27 populations from 22 articles were included for analysis, on the basis of adequate description of study design and blood pressure measurement. Blood pressure means of adult age groups were modeled by linear and polynomial regression. The pulse pressure levels of women were lower than those of men in early adulthood and higher in older ages. Women had a steeper, steady increase in pulse pressure with age than men (P<0.001), whereas men had a stronger curvilinear upswing in pulse pressure with age (P=0.006). Partially acculturated populations had higher pulse pressures than unacculturated populations. Sex had a stronger effect on pulse pressure than acculturation. Pulse pressure trajectories of unindustrialized populations were slightly attenuated compared with those seen in National Health and Nutritional Examination Surveys III and IV of the US population. A sex effect on pulse pressure trends with age prevails across unacculturated and acculturated populations. Accordingly, the biological principles of arterial aging, as expressed in pulse pressure, are the same in all humans, regardless of demography.

Sex differences in the recognition of and innate antiviral responses to Seoul virus in Norway rats

Among rodents that carry hantaviruses, more males are infected than females. Male rats also have elevated copies of Seoul virus RNA and reduced transcription of immune-related genes in the lungs than females. To further characterize sex differences in antiviral defenses and whether these differences are mediated by gonadal hormones, we examined viral RNA in the lungs, virus shedding in saliva, and antiviral defenses among male and female rats that were intact, gonadectomized neonatally, or gonadectomized in adulthood. Following inoculation with Seoul virus, high amounts viral RNA persisted longer in lungs from intact males than intact females. Removal of the gonads in males reduced the amount of viral RNA to levels comparable with intact females at 40days post-inoculation (p.i.). Intact males shed more virus in saliva than intact females 15days p.i.; removal of the gonads during either the neonatal period or in adulthood increased virus shedding in females and decreased virus shedding in males. Induction of pattern recognition receptors (PRRs; Tlr7 and Rig-I), expression of antiviral genes (Myd88, Visa, Jun, Irf7, Ifnβ, Ifnar1, Jak2, Stat3, and Mx2), and production of Mx protein was elevated in the lungs of intact females compared with intact males. Gonadectomy had more robust effects on the induction of PRRs than on downstream IFNβ or Mx2 expression. Putative androgen and estrogen response elements are present in the promoters of several of these antiviral genes, suggesting the propensity for sex steroids to directly affect dimorphic antiviral responses against Seoul virus infection.

Sex-Dependent Liver Gene Expression Is Extensive and Largely Dependent upon Signal Transducer and Activator of Transcription 5b (STAT5b): STAT5b-Dependent Activation of Male Genes and Repression of Female Genes Revealed by Microarray Analysis

Sexual dimorphism in mammalian liver contributes to sex differences in physiology, homeostasis, and steroid and foreign compound metabolism. Many sex-dependent liver genes are regulated by sex differences in pituitary GH secretion, with the transcription factor, signal transducer and activator of transcription (STAT5b), proposed to mediate signaling by the pulsatile, male plasma GH profile. Presently, a large-scale gene expression study was conducted using male and female mice, wild type and Stat5b inactivated, to characterize sex differences in liver gene expression and their dependence on STAT5b. The relative abundance of individual liver RNAs was determined for each sex-genotype combination by competitive hybridization to 23,574-feature oligonucleotide microarrays. Significant sex differences in hepatic expression were seen for 1603 mouse genes. Of 850 genes showing higher expression in males, 767 (90%) were down-regulated in STAT5b-deficient males. Moreover, of 753 genes showing female-predominant expression, 461 (61%) were up-regulated in STAT5b-deficient males. In contrast, approximately 90% of the sex-dependent genes were unaffected by STAT5b deficiency in females. Thus: 1) STAT5b is essential for sex-dependent liver gene expression, a characteristic of approximately 1600 mouse genes (4% of the genome); 2) male-predominant liver gene expression requires STAT5b, or STAT5b-dependent factors, which act in a positive manner; and 3) many female-predominant liver genes are repressed in males in a STAT5b-dependent manner. Several of the STAT5b-dependent male genes encode transcriptional repressors; these may include direct STAT5b targets that repress female-predominant genes in male liver. Several female-predominant repressors are elevated in STAT5b-deficient males; these may contribute to the major loss of male gene expression seen in the absence of STAT5b.

Generation of specific antibodies and their use to characterize sex differences in four rat P450 3A enzymes following vehicle and pregnenolone 16α-carbonitrile treatment

The purpose of this study was to identify isozyme-specific antibodies and use them to determine the expression levels of four P450 3A enzymes in the livers of vehicle- and pregnenolone 16α-carbonitrile (PCN)-treated rats of both sexes, since previous work on mRNA levels has shown considerable sexual dimorphism. Using Western blot analysis with four isozyme-specific antibodies, we show that P450 3A1, 3A2, and 3A9 were expressed in vehicle-treated adult female rats at very low levels whereas P450 3A18 was not detected. PCN treatment of females strongly induced the expression of P450 3A1 in the livers with protein product increases of 214-, 3-, and 5-fold for P450 3A1, 3A2, and 3A9, respectively, and P450 3A18 was induced to 3.7 pmol/mg protein. In contrast, all four P450 3As were detected in livers of vehicle-treated males, in the order of 3A2 ≫ 3A18 > 3A9 ≅ 3A1. The protein product increases induced by PCN treatment of male rats were 92-, 3-, 6-, and 16-fold for P450 3A1, 3A2, 3A9, and 3A18, respectively.

Morphine responses and experimental pain: Sex differences in side effects and cardiovascular responses but not analgesia

Sex differences in analgesic responses to μ opioid agonists have been reported, although the direction of these differences varies across studies. To further characterize sex differences in responses to μ opioids, the analgesic effects of intravenous morphine (0.08 mg/kg) were determined in healthy women (n = 61) and men (n = 39) by using 3 experimental pain models, heat pain, pressure pain, and ischemic pain. Each pain procedure was conducted before and after double-blind administration of both morphine and saline, which occurred on separate days in counterbalanced order. Although morphine produced significant analgesic effects for all pain stimuli, no significant sex differences in morphine analgesia emerged. However, morphine attenuated cardiovascular reactivity to the ischemic pain task in men but not women, and women reported significantly more drug-related adverse effects than men. These findings are in contrast with some recent clinical and experimental results suggesting more robust analgesic response to μ opioids among women compared to men, although the data indicate that sex differences in non-analgesic effects of morphine were present. These results suggest that sex differences in responses to morphine might depend on the pain model and/or drug dose as well as the specific end point assessed. Perspective This study examines morphine responses in women and men by using laboratory pain measures. The results indicate no sex differences in analgesia, but women reported greater side effects, and morphine attenuated cardiovascular responses more strongly among men than women. These results add to the literature regarding sex differences in response to opioids.

Sex differences in the central nervous system actions of ethanol.

For many years, researchers have avoided including females in their research because of the poorly understood influences of cycling hormones. However, we are becoming increasingly aware that sex matters, showing that it is important to conduct studies in females as well as males. This review will focus on the central nervous system (CNS) actions of alcohol (ethanol) because we have found significant sex differences in ethanol actions at the molecular as well as the behavioral level. Most recently, in our studies of ethanol dependence and withdrawal, we found that female rats displayed a shorter time for recovery from ethanol withdrawal, assessed by measuring seizure susceptibility. We now report that this finding was confirmed with a second convulsant agent. Moreover, GABAA receptor function was differentially altered in ethanol-withdrawn female compared to male rats. Studies by other investigators have reported additional significant sex differences in ethanol seeking and drinking behaviors and across several measures of ethanol dependence and withdrawal. We are gaining a better understanding of how the actions of ethanol in the CNS overlay sex differences in brain architecture and the hormonal milieu. Therefore, it is not surprising to observe sex-selective effects on cellular and behavioral outcomes from ethanol consumption. While current research is focused on characterizing sex differences in the actions of ethanol, it has not yet reached the point where we can integrate our findings into a unifying concept of how being female differentially regulates CNS responses to ethanol. This is likely a result of the complexity of ethanol actions, involving multiple neurotransmitter systems and responses covering the spectrum from drug seeking behaviors to neuropathological consequences of ethanol misuse. Regardless, the observed sex differences in ethanol withdrawal are noteworthy because they suggest that treatment of alcoholism should be managed differently in women than in men. Finally, it remains important to compare and contrast responses in males and females because recent studies of sex differences in basic physiology have made it clear that being female impacts health and disease.

Sex Differences in Left Ventricular Geometry in Aortic Stenosis: Impact on Outcome

This study of surgical aortic stenosis characterized sex differences in left ventricular (LV) geometry and outcome. We examined 92 women and 82 men who underwent echocardiography before valve replacement for aortic stenosis. Women had a smaller cavity size (LV end-diastolic diameter 48.2 +/- 7 mm in women vs 53.6 +/- 7.6 mm in men; p = 0.0001) and higher ejection fraction (59% in women vs 54% in men; p = 0.02). LV mass was greater in men than women (300.4 +/- 88 g in men vs 250.6 +/- 85.8 g in women; p = 0.0055) but when corrected for body surface area, the difference was not significant. The prevalence of LV hypertrophy was similar in both sexes (51% in women vs 49% in men; p = 0.62). The 5-year survival was 82% in women and 79% in men (p = 0. 9). Several descriptors of LV geometry differed between men and women. These differences were largely eliminated after normalizing for body surface area. No differences in surgical mortality or long-term outcome were noted.

The preoptic area/anterior hypothalamus of different strains of mice: sex differences and development

While sex differences in neural morphology in the preoptic area/anterior hypothalamus (POA/AH) have been demonstrated in many species, their existence in mice have been controversial. Given the increased use of transgenic and gene-disrupted mice, we characterized sex differences using Nissl stains, and the immunocytochemical location of estrogen receptor-α (ER-α) and galanin in the POA/AH of two widely used strains, C57BL/6 and 129SvEv, and a mixed strain (C57BL/6×129Sv); the wild-type littermates of steroidogenic factor-1 (SF-1) gene-disrupted mice. Cell grouping was not a reliable marker of sex. In adults, cells located beneath the anterior commissure (AC) were reliably larger in females than males in 129SvEv, but not in the other strains. Caudally, cells in a group medial to the medial extension of the bed nucleus of the stria terminalis (BST) were significantly larger in males than females in C57BL/6J and SF-1 gene-disrupted wild-types. Cell groups discernible by embryonic day (E) 18 were not sexually dimorphic for cell size in C57BL/6J mice at E18 or postnatal day (P) 4. The pattern of distribution of cells containing ER-α was similar among the strains, reduced in the group medial to the BST; a pattern established by P0. Galanin-containing cells and fibers were seen from E15 to adulthood ventral to the AC. Caudally, a smaller group ventromedial to the BST was found only in 129SvEv adults. Sex differences in neural morphology which develop within the POA/AH depend upon multiple factors, particularly including genetic background.

An Animal Model of Attention Deficit Disorder

The main objective of the present study was to characterize sex differences in the temporal discrimination and activity level of an animal model of attention deficit disorder (ADD) using a conjunctive 120-s variable interval 16-s differential reinforcement of low rate (VIDRL) schedule of reinforcement. The results showed that the spontaneously hypertensive (SHR) male was generally hyperactive and that the SHR female was both hyperactive and had severe time discrimination problems. The latter caused relatively fewer reinforcers to be delivered. However, even when a reinforcer was delivered, the SHR female frequently failed to collect it. When the SHR females were in diestrus, their behavior became even less efficient. The present findings with the animal model seem to be in general agreement with the behavior of ADD children when a DRL schedule is used. Most of our results were explained as due to impulsiveness, which is more pronounced in the SHR female than in the male. In addition, the SHR female had attention problems. The present study further supports the usefulness of the SHR as animal model of ADD.