Sex differences in response to discrete estradiol injections

Developmental effects of perinatal androgens render adult male rats refractory to the activation of feminine sexual behavior by estradiol (E2) and progesterone (P). Recent evidence suggested that fluctuating levels of systemic E2, which are thought to approximate the ovarian secretion under physiological conditions, may reverse this insensitivity to E2 and, particularly, to the synergistic effects of P in male rats of the Wistar strain. We examined whether this hormonal regimen would reverse this insensitivity in Sprague-Dawley rats. Gonadectomized animals received two injections of E2 (1 microgram per injection) 12 hr apart at 0900 and 2100 hr followed by P (0.5 mg) or oil, at 35 hr, and a mating behavior test, at 38 hr, subsequent to the initial E2 administration. This treatment was repeated four times at 4-day intervals. The inability of Sprague-Dawley male rats to respond to E2 and P was unaffected by this pattern of exposure to exogenous E2. Receptivity scores, lordosis quotients, and proceptivity were negligible in males, and significantly less than that displayed by females. In addition, the levels of sexual receptivity and proceptivity were facilitated by the availability of P following E2 in females, but not in males. The present findings fail to support a general hypothesis that "discontinuous" E2 stimulation, achieved by two spaced injections of this hormone, reverses developmental determinants of sex differences in responsiveness to hormones mediating female sexual behaviors.     

Sex differences in response to coalitional threat

Intergroup conflict poses a different kind of threat for men and women — a difference that can be expected to have implications for cognitive as well as behavioral processes. Participants were primed with a threat from a rival coalition vs. a control condition. Reaction times were measured on a lexical-decision task in response to ideation consistent with coalitions or with friendship/protective care. When primed for coalitional threat, men showed fast access to positive coalitional ideation (suggesting facilitation). In contrast, women showed exceptionally fast access to positive friendship/protective care ideation. Findings were interpreted as reflecting sexually dimorphic responses to coalitional threat that are consistent with differential advertising of their assets to others.     

Sex differences in response to adrenaline in white rats]

Dynamics of changes of and plasma corticosterone was studied in both male and female rats after intraperitoneal injections of adrenaline at a dose of 20 micrograms per 100 g body weight. The control rats were injected with saline. Animals were decapitated 10, 30, 60, 120, 180 and 240 min after the injections. The specific effect of adrenaline was revealed in the first 10 min of adrenaline injection. This effect was significantly increased to 30-60 min after termination of saline--induced activation of the pituitary-adrenal axis. Both saline and adrenaline caused more significant increases in corticosterone levels in female rats than in male ones. There was a significant delay in the return of corticosterone to resting levels in males compared to that in females. It is supposed that the almost two-fold difference in peak plasma corticosterone concentrations observed after stressors may be associated with increased responsiveness of the female hypothalamus with respect to adrenaline secretion.     

Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury

The myocardium generates inflammatory mediators during ischemia-reperfusion (I/R), and these mediators contribute to cardiac functional depression and apoptosis. The great majority of these data have been derived from male animals and humans. Sex has a profound effect over many inflammatory responses; however, it is unknown whether sex affects the cardiac inflammatory response to acute myocardial I/R. We hypothesized the existence of inherent sex differences in myocardial function, expression of inflammatory cytokines, and activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway after I/R. Isolated rat hearts from age-matched adult males and females were perfused (Langendorff), and myocardial contractile function was continuously recorded. After I/R, myocardium was assessed for expression of TNF-alpha, IL-1beta, and IL-6 (RT-PCR, ELISA); IL-1alpha and IL-10 mRNA (RT-PCR); and activation of p38 MAPK (Western blot). All indexes of postischemic myocardial function [left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal positive (+dP/dt) and negative (-dP/dt) values of the first derivative of pressure] were significantly improved in females compared with males. Compared with males, females had decreased myocardial TNF-alpha, IL-1beta, and IL-6 (mRNA, protein) and decreased activation of p38 MAPK pathway. These data demonstrate that hearts from age-matched adult females are relatively protected against I/R injury, possibly due to a diminished inflammatory response.     

Sex differences in the inflammatory response of primary astrocytes to lipopolysaccharide

Background

Numerous neurological and psychiatric disorders show sex differences in incidence, age of onset, symptomatology or outcome. Astrocytes, one of the glial cell types of the brain, show sex differences in number, differentiation and function. Since astrocytes are involved in the response of neural tissue to injury and inflammation, these cells may participate in the generation of sex differences in the response of the brain to pathological insults. To explore this hypothesis, we have examined whether male and female astrocytes show a different response to an inflammatory challenge and whether perinatal testosterone influences this response.

Methods

Cortical astrocyte cultures were prepared from postnatal day 1 (one day after birth) male or female CD1 mice pups. In addition, cortical astrocyte cultures were also prepared from female pups that were injected at birth with 100 μg of testosterone propionate or vehicle. Cultures were treated for 5 hours with medium containing lipopolysaccharide (LPS) or with control medium. The mRNA levels of IL6, interferon-inducible protein 10 (IP10), TNFα, IL1β, Toll-like receptor 4 (TLR4), steroidogenic acute regulatory protein and translocator protein were assessed by quantitative real-time polymerase chain reaction. Statistical significance was assessed by unpaired t-test or by one-way analysis of variance followed by the Tukey post hoc test.

Results

The mRNA levels of IL6, TNFα and IL1β after LPS treatment were significantly higher in astrocytes derived from male or androgenized females compared to astrocytes derived from control or vehicle-injected females. In contrast, IP10 mRNA levels after LPS treatment were higher in astrocytes derived from control or vehicle-injected females than in those obtained from males or androgenized females. The different response of male and female astrocytes to LPS was due neither to differences in the basal expression of the inflammatory molecules nor to differences in the expression of the LPS receptor TLR4. In contrast, the different inflammatory response was associated with increased mRNA levels of translocator protein, a key steroidogenic regulator, in female astrocytes that were treated with LPS.

Conclusions

Male and female cortical astrocytes respond differentially to an inflammatory challenge and this may be predetermined by perinatal testosterone exposure.

     

Sex differences in regional brain response to aversive pelvic visceral stimuli

To explore sex differences in the response of seven brain regions to an aversive pelvic visceral stimulus, functional magnetic resonance images were acquired from 13 healthy adults (6 women) during 15 s of cued rectal distension at two pressures: 25 mmHg (uncomfortable), and 45 mmHg (mild pain), as well as during an expectation condition (no distension). Random-effects analyses combining subject data voxelwise found 45-mmHg pressure significantly activated the insular and anterior cingulate cortices in both sexes. In men only, the left thalamus and ventral striatum were also activated. Although all activations appeared more extensive in men, no sex difference attained significance. To explore the presence of deactivations, which are generally cancelled by more numerous activations when subjects are combined for each voxel, the number of activated voxels, number of deactivated voxels, and ratio of deactivated voxels to total voxels affected were assessed via random-effects, mixed-model analyses combining subject data at the region level. Greater insula activation in men compared with women was seen during the expectation condition and during the 25-mmHg distension. Greater deactivations in women were seen in the amygdala (25-mmHg distension) and midcingulate (45-mmHg distension). Women had a significantly higher proportion of deactivated voxels than men in all four subcortical structures during 25-mmHg distension. Greater familiarity of females with physiological pelvic visceral discomfort may have enhanced brain systems that dampen arousal networks during lower levels of discomfort.     

Sex differences in immune defenses and response to parasitism in monarch butterflies

Host susceptibility and patterns of infection are predicted to differ between males and females due to sex-based tradeoffs between the demands of reproduction and costly immune defenses. In this study, we examined immune defenses and the response to experimental infection by a protozoan parasite, Ophryocystis elektroscirrha, in male and female monarch butterflies, Danaus plexippus. We quantified two measures of immunity in late instar larvae: the concentration of circulating hemocytes and mid-gut phenoloxidase activity, and also quantified final parasite loads, body size, longevity, and wing melanism of adult butterflies. Results showed that females had greater average hemocyte counts than males in the absence of infection; males, but not females, showed an increased concentration of hemocytes in the presence of infection. However, higher hemocyte concentrations in larvae were not significantly correlated with lower adult parasite loads, and mid-gut phenoloxidase activity was not significantly associated with hemocyte counts or parasite treatments. Among unparasitized females, greater hemocyte concentrations were costly in terms of reduced body size, but for parasite-treated females, hemocyte concentrations and body size were positively associated. Across all monarchs, unparasitized butterflies showed greater wing melanism (darker forewings) than parasitized monarchs. Overall, this study provides support for differential costs of immune defenses in male and female monarch butterflies, and a negative association between parasite infection and monarch wing melanism.     

Sex differences in the response of rats to drugs affecting GABAergic transmission

The administration of diazepam 1.0 mg/kg decreased the level of plasma corticosterone in female but not in male Wistar rats. Picrotoxin, another drug affecting GABAergic transmission, also brought about an increase of plasma corticosterone in both sexes. However, in order to achieve a plasma corticosterone increase of similar magnitude (more than 500%) a threefold higher dose of picrotoxin had to be given to males. When the convulsive properties of picrotoxin were tested, it became evident that the dose of picrotoxin (2.5 mg/kg) which was subconvulsive in male was almost 100% convulsive in female rats. The existing sex differences in the response of rats to drugs affecting GABAergic transmission might have possible implications in the treatment of GABA system dysfunction.     

Sex differences in the cerebral BOLD signal response to painful heat stimuli

There are limited data addressing the question of sex differences in pain-related cerebral processing. This study examined whether pain-related blood oxygenation level-dependent (BOLD) signal change measured with functional magnetic resonance imaging (fMRI) demonstrated sex differences, under conditions of equivalent pain perception. Twenty-eight healthy volunteers (17 women, 11 men) were subject to a fMRI scan while noxious heat stimuli were applied to the dorsum of the left foot. Significant BOLD signal modulation was observed in several nociceptive processing regions of interest (ROIs) in all subjects. There were no sex differences in the spatial extent of BOLD signal change for any ROI, but the signal amplitude was lower for women in most ROIs and significantly so for the primary somatosensory cortex (S1), the midanterior cingulate cortex, and the dorsolateral prefrontal cortex (DLPFC). The BOLD signal response could be positive or negative, and frequently, both polarities were observed within a single ROI. In most ROIs, women show proportionately more voxels with negative signal change than men, and this difference was statistically significant for the S1 and the DLPFC. The time course of the negative signal change was very similar to that of the positive signal change, suggesting that the latter was not "driving" the former. The location of negative and positive clusters formed distinct patterns in several of the ROIs, and these patterns suggest something other than a local "steal" phenomenon as an explanation for the negative signal changes. Sex differences in baseline cerebral blood flow may contribute to the BOLD signal differences observed in this study.     

Sex differences impact the pancreatic response to chronic immobilization stress in rats

Chronic stress has been related to multiple diseases. Inflammation is proposed strongly to link stress to stress-related diseases in different organs, such as small intestine, colon, and brain. However, stress cellular effect on the pancreatic tissue, especially the exocrine one, had received relatively little attention. This work aimed to evaluate the cellular effect of chronic immobilization stress on the pancreatic tissue function and structure along with evaluating the sex role in this type of pancreatic injury. Thirty rats were equally divided into 5 groups: control male, control female, stressed male, stressed female, and stressed female with bilateral ovariectomy. Stressed rats were exposed to immobilization for 1 h/day, 6 days/week, for 3 weeks. Rats were then decapitated for further biochemical, histological, histo-morphometric, and immunohistochemical study. The results showed that, in male and female rats, chronic immobilization stress produced hypoinsulinemia and hyperglycemia, with increasing exocrine pancreatic injury markers by increasing oxidative and inflammatory status of the pancreatic tissue, and exhibited a degenerative effect on the pancreatic tissue. However, the stress-induced pancreatic effects were more obvious in male rats and female rats with bilateral ovariectomy than that in female rats. It could be concluded that male animals were more susceptible to stress-induced pancreatic damage than females. The ovarian hormones are responsible, at least partly, for pancreatic tissue protection since the stress-induced pancreatic injury in females was exacerbated by ovariectomy. In this study, inflammatory and oxidative stress differences in both sexes could provide a plausible explanation for sex differences.     

Sex differences in the response to environmental cues regulating seasonal reproduction in birds

Although it is axiomatic that males and females differ in relation to many aspects of reproduction related to physiology, morphology and behaviour, relatively little is known about possible sex differences in the response to cues from the environment that control the timing of seasonal breeding. This review concerns the environmental regulation of seasonal reproduction in birds and how this process might differ between males and females. From an evolutionary perspective, the sexes can be expected to differ in the cues they use to time reproduction. Female reproductive fitness typically varies more as a function of fecundity selection, while male reproductive fitness varies more as a function sexual selection. Consequently, variation in the precision of the timing of egg laying is likely to have more serious fitness consequences for females than for males, while variation in the timing of recrudescence of the male testes and accompanying territory establishment and courtship are likely to have more serious fitness consequences for males. From the proximate perspective, sex differences in the control of reproduction could be regulated via the response to photoperiod or in the relative importance and action of supplementary factors (such as temperature, food supply, nesting sites and behavioural interactions) that adjust the timing of reproduction so that it is in step with local conditions. For example, there is clear evidence in several temperate zone avian species that females require both supplementary factors and long photoperiods in order for follicles to develop, while males can attain full gonadal size based on photoperiodic stimulation alone. The neuroendocrine basis of these sex differences is not well understood, though there are many candidate mechanisms in the brain as well as throughout the entire hypothalamo-pituitary-gonadal axis that might be important.     

Sex differences in the immune response to acute COVID-19 respiratory tract infection

Determine if sex differences exist in clinical characteristics and outcomes of adults hospitalized for coronavirus disease 2019 (COVID-19) in a US healthcare system. Case series study. Sequentially hospitalized adults admitted for COVID-19 at two tertiary care academic hospitals in New Orleans, LA, between 27 February and 15 July 2020. Measures included demographics, comorbidities, presenting symptoms, and laboratory results. Outcomes included intensive care unit admission (ICU), invasive mechanical ventilation (IMV), and in-hospital death. We included 776 patients (median age 60.5 years; 61.4% women, 75% non-Hispanic Black). Rates of ICU, IMV, and death were similar in both sexes. In women versus men, obesity (63.8 vs 41.6%, P < 0.0001), hypertension (77.6 vs 70.1%, P = 0.02), diabetes (38.2 vs 31.8%, P = 0.06), chronic obstructive pulmonary disease (COPD, 22.1 vs 15.1%, P = 0.015), and asthma (14.3 vs 6.9%, P = 0.001) were more prevalent. More women exhibited dyspnea (61.2 vs 53.7%, P = 0.04), fatigue (35.7 vs 28.5%, P = 0.03), and digestive symptoms (39.3 vs 32.8%, P = 0.06) than men. Obesity was associated with IMV at a lower BMI (> 35) in women, but the magnitude of the effect of morbid obesity (BMI ≥ 40) was similar in both sexes. COPD was associated with ICU (adjusted OR (aOR), 2.6; 95%CI, 1.5–4.3) and IMV (aOR, 1.8; 95%CI, 1.2–3.1) in women only. Diabetes (aOR, 2.6; 95%CI, 1.2–2.9), chronic kidney disease (aOR, 2.2; 95%CI, 1.3–5.2), elevated neutrophil-to-lymphocyte ratio (aOR, 2.5; 95%CI, 1.4–4.3), and elevated ferritin (aOR, 3.6; 95%CI, 1.7–7.3) were independent predictors of death in women only. In contrast, elevated D-dimer was an independent predictor of ICU (aOR, 7.3; 95%CI, 2.7–19.5), IMV (aOR, 6.5; 95%CI, 2.1–20.4), and death (aOR, 4.5; 95%CI, 1.2–16.4) in men only. This study highlights sex disparities in clinical determinants of severe outcomes in COVID-19 patients that may inform management and prevention strategies to ensure gender equity.     

Sex differences in endurance capacity and metabolic response to prolonged, heavy exercise

In order to test for possible sex differences in endurance capacity, groups of young, physically active women (n = 6) and men (n = 7) performed bicycle ergometer exercise at 80% and 90% of their maximal oxygen uptakes (VO2 max). The groups were matched for age and physical activity habits. At 80% VO2 max the women performed significantly longer (P less than 0.05), 53.8 +/- 12.7 min vs 36.8 +/- 12.2 min, respectively (means +/- SD). Mid-exercise and terminal respiratory exchange ratio (R) values were significantly lower in women, suggesting a later occurrence of muscle glycogen depletion as a factor in their enhanced endurance. At 90% VO2 max the endurance times were similar for men and women, 21.2 +/- 10.3 min and 22.0 +/- 5.0 min, respectively. The blood lactate levels reached in these experiments were only marginally lower (mean differences 1.5 to 2 mmol X l-1) than those obtained at VO2 max, suggesting high lactate levels as a factor in exhaustion. The changes in body weight during the 80% experiments and the degree of hemoconcentration were not significantly different between men and women.     

Sex differences in the response to influenza virus infection: modulation by stress

Influenza virus infection is a significant public health problem; however factors affecting the incidence and severity of disease have not been fully elucidated. The present study sought to examine the role of sex and stress in mediating susceptibility to an influenza viral infection in mice. Male and female mice underwent repeated cycles of restraint (RST) stress, followed by an influenza A/PR8 virus infection. Following these manipulations, levels of circulating corticosterone, lung proinflammatory cytokine gene expression and sickness behavior were examined. The data indicate sex differences in several aspects of the response to the A/PR8 virus infection. The kinetics of lung interleukin-1β mRNA expression were faster in infected males compared to females, while circulating corticosterone levels were elevated in infected females, but not in males. Anorexia and reduced saccharin consumption began earlier and symptoms were more pronounced in infected males than in females. In addition, RST modulated the response to the A/PR8 virus infection. Proinflammatory cytokine gene expression in response to infection was enhanced and sickness behavior was modulated by RST in both males and females. These data suggest that males mount more vigorous immune and behavioral responses to influenza viral infection compared to females, and stress exacerbates the response in both males and females. In conclusion, complex interactions between biological and behavioral factors are involved in mediating individual differences in health and disease. Additional studies may help uncover some of the factors contributing to the individual differences in susceptibility to influenza infection.