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Sex differences in evaluation and outcome after stress testing.

OBJECTIVE: To examine sex differences in evaluation and outcome after stress testing for coronary artery disease (CAD) in a geographically defined cohort. SUBJECTS AND METHODS: Subjects were residents of Olmsted County, Minnesota, who underwent an initial stress test between January 1, 1987, and December 31, 1990. End points included referral for coronary angiography, death, and cardiac events, defined as cardiac death, nonfatal myocardial infarction, or congestive heart failure. RESULTS: A total of 2276 men and 1270 women under went stress tests. Women were older and had more risk factors and comorbidities (P < .05). Among persons without documented CAD (86% of the cohort), the median probability of CAD was 11% (interquartile range, 5%-25%) for men and 8% (interquartile range, 2%-31%) for women (P < .001). Within 6 months after stress testing, 9% of men and 7% of women underwent coronary angiography. Among persons without documented CAD, there was no sex difference in referral for angiography when the stress test result was negative. When the test result was positive, men were more likely to be referred for angiography (adjusted odds ratio [OR] for male sex, 2.02; 95% confidence interval [CI], 1.21-3.38; P = .008). After adjusting for the predicted probability of CAD, this association was no longer detected (adjusted OR for male sex, 0.67; 95% CI, 0.26-1.73; P = .41). Among persons with documented CAD, no sex difference was noted. After a mean +/- SD follow-up of 7.6 +/- 2.7 years and among persons without documented CAD, male sex was associated with a higher adjusted risk of death (relative risk for male sex, 1.40; 95% CI, 1.05-1.86; P = .02) and cardiac events (relative risk for male sex, 1.67; 95% CI, 1.24-2.26; P < .001). Among persons with documented CAD, no sex difference in outcome was noted. CONCLUSION: These population-based data indicate that, when the diagnosis of CAD was not established, there was a greater use of angiography among men with positive stress test results, which could be attributed to the increased probability of CAD in men. In the absence of documented CAD, men fared worse than women, with an increase in the risk of death and cardiac events. Among persons with documented CAD, no sex difference in use of angiography and outcome was noted.

Adult↗

Sex differences in peripheral vascular adrenergic receptors.

Although the incidence of many vascular diseases differs in men and women, sex differences in vascular physiology have not been extensively examined in human in vivo studies. The present study compared finger blood flow responses of normal men and women with brachial artery infusions of adrenergic agonists and with other neurally and nonneurally mediated procedures. In response to phenylephrine and clonidine, men showed significant dose-related vasoconstriction while women did not. In response to isoproterenol, men showed significant dose-related vasodilation while women did not. There were no sex differences in response to intra-arterial nitroglycerin or digoxin or to reactive hyperemia, procedures that do not act through adrenergic receptors. These data show that the sensitivity and/or density of peripheral vascular adrenergic receptors is lower in women than in men. There were no sex differences in response to reflex vasoconstriction or to intra-arterial tyramine, suggesting that neurally released norepinephrine acts at alpha-adrenergic receptors that are spatially removed from those that respond to circulating catecholamines.

Adult↗

The systemizing quotient: an investigation of adults with Asperger syndrome or high-functioning autism, and normal sex differences.

Systemizing is the drive to analyse systems or construct systems. A recent model of psychological sex differences suggests that this is a major dimension in which the sexes differ, with males being more drawn to systemize than females. Currently, there are no self-report measures to assess this important dimension. A second major dimension of sex differences is empathizing (the drive to identify mental states and respond to these with an appropriate emotion). Previous studies find females score higher on empathy measures. We report a new self-report questionnaire, the Systemizing Quotient (SQ), for use with adults of normal intelligence. It contains 40 systemizing items and 20 control items. On each systemizing item, a person can score 2, 1 or 0, so the SQ has a maximum score of 80 and a minimum of zero. In Study 1, we measured the SQ of n = 278 adults (114 males, 164 females) from a general population, to test for predicted sex differences (male superiority) in systemizing. All subjects were also given the Empathy Quotient (EQ) to test if previous reports of female superiority would be replicated. In Study 2 we employed the SQ and the EQ with n = 47 adults (33 males, 14 females) with Asperger syndrome (AS) or high-functioning autism (HFA), who are predicted to be either normal or superior at systemizing, but impaired at empathizing. Their scores were compared with n = 47 matched adults from the general population in Study 1. In Study 1, as predicted, normal adult males scored significantly higher than females on the SQ and significantly lower on the EQ. In Study 2, again as predicted, adults with AS/HFA scored significantly higher on the SQ than matched controls, and significantly lower on the EQ than matched controls. The SQ reveals both a sex difference in systemizing in the general population and an unusually strong drive to systemize in AS/HFA. These results are discussed in relation to two linked theories: the 'empathizing-systemizing' (E-S) theory of sex differences and the extreme male brain (EMB) theory of autism.

Adult↗

Distribution of sex steroid hormone receptors in the avian brain: functional implications for neural sex differences and sexual behaviors.

Developmental and seasonal changes in the production of androgens, estrogens, and progestins seem to control sex-specific differentiation and seasonal changes in appetitive and consummatory sexual behaviors of birds. This results in profound sex differences in the quality (sex-specific) or quantity (sex-typical) of behaviors such as courtship, territoriality, or copulation. Steroids affect the brain by binding to intracellularly located receptors. The same brain areas express androgen, estrogen, and progesterone receptors in male and female brains. Sex differences in these genetically determined patterns occur in the size of neuron populations that intrinsically express sex steroid receptors. Further permanent sex differences are subsequent to degenerative fates of receptor expressing neuron populations during ontogeny. Transient sex differences in receptor expression appear to be due to area-specific up- and down-regulation of receptor levels, reflecting transient changes in the level of circulating steroids, changes in environmental conditions, or in the physiological status of the individuals. In particular, intrinsic sex differences in the expression pattern of sex steroid receptors and steroid-independent regulation of the expression level of these receptors in the brain are limiting mechanisms for gonad-dependent sexual development and activities.

Animals↗

Sex differences in the risk of schizophrenia: evidence from meta-analysis.

BACKGROUND: Sex differences in the risk of a particular disorder can yield important clues regarding its pathogenesis. The evidence for a sex difference in the risk of schizophrenia is inconclusive. The purpose of this study was to integrate results from the published literature and to provide a quantitative index of the male-female ratio for the incidence of schizophrenia. METHODS: The MEDLINE and PsychLIT databases were searched for English-language publications on "incidence and schizophrenia" that appeared during the period between January 1980 and September 2001. Population-based incidence studies using standard clinical diagnostic criteria were included if they reported sex-specific incidence rates. Sex-specific incidence figures were extracted directly from each study. Categorical analyses were conducted on a subset of studies that met specific methodological criteria (to minimize criterion bias, hospital bias, and age bias). Study categorization and data extraction were performed independently by 2 of us (A. A. and J.-P.S.). RESULTS: Log risk ratio meta-analysis was conducted using a random-effects model. The incidence risk ratios for men to develop schizophrenia relative to women were 1.42 (95% confidence interval [CI], 1.30-1.56) when all studies were included in the analysis (49 effect sizes), 1.31 (95% CI, 1.13-1.51) when studies that minimized selection biases were analyzed separately (23 effect sizes), and 1.39 (95% CI, 1.15-1.68) when only high-quality studies were included (11 effect sizes). The sex difference was significantly smaller in studies with sample years before 1980 than those with sample years after 1980. No significant sex differences were reported in studies from developing countries. A final analysis, limited to studies with an age cutoff of 64 years or older (16 effect sizes), yielded a mean risk ratio of 1.32 (95% CI, 1.13-1.55). CONCLUSION: This meta-analysis provides evidence for a sex difference in the risk of developing schizophrenia, as reported in the published literature from the last 2 decades.

Confidence Intervals↗

Using lod scores to detect sex differences in male-female recombination fractions.

Human recombination fraction (RF) can differ between males and females, but investigators do not always know which disease genes are located in genomic areas of large RF sex differences. Knowledge of RF sex differences contributes to our understanding of basic biology and can increase the power of a linkage study, improve gene localization, and provide clues to possible imprinting. One way to detect these differences is to use lod scores. In this study we focused on detecting RF sex differences and answered the following questions, in both phase-known and phase-unknown matings: (1) How large a sample size is needed to detect a RF sex difference? (2) What are "optimal" proportions of paternally vs. maternally informative matings? (3) Does ascertaining nonoptimal proportions of paternally or maternally informative matings lead to ascertainment bias? Our results were as follows: (1) We calculated expected lod scores (ELODs) under two different conditions: "unconstrained," allowing sex-specific RF parameters (theta(female), theta(male)); and "constrained," requiring theta(female) = theta(male). We then examined the DeltaELOD (identical with difference between maximized constrained and unconstrained ELODs) and calculated minimum sample sizes required to achieve statistically significant DeltaELODs. For large RF sex differences, samples as small as 10 to 20 fully informative matings can achieve statistical significance. We give general sample size guidelines for detecting RF differences in informative phase-known and phase-unknown matings. (2) We defined p as the proportion of paternally informative matings in the dataset; and the optimal proportion p(circ) as that value of p that maximizes DeltaELOD. We determined that, surprisingly, p(circ) does not necessarily equal (1/2), although it does fall between approximately 0.4 and 0.6 in most situations. (3) We showed that if p in a sample deviates from its optimal value, no bias is introduced (asymptotically) to the maximum likelihood estimates of theta(female) and theta(male), even though ELOD is reduced (see point 2). This fact is important because often investigators cannot control the proportions of paternally and maternally informative families. In conclusion, it is possible to reliably detect sex differences in recombination fraction.

Female↗

Risperidone treatment of outpatients with schizophrenia: no evidence of sex differences in treatment response.

OBJECTIVE: Given the renewed interest in the role of sex differences in schizophrenia, we undertook a post hoc analysis to determine whether sex differences in treatment response were present among outpatients with schizophrenia who received risperidone in an 8-week, open-label, Phase IV clinical study. METHOD: We evaluated 330 adult patients (232 men, 98 women) with a DSM-III-R diagnosis of schizophrenia for safety and 292 (206 men, 86 women) for efficacy. Antipsychotic and antiparkinsonian medications were discontinued at study entry. Treatment with risperidone was initiated at a dosage of 2 mg daily, increased to the target dosage of 6 mg daily by day 3, and maintained at 6 mg daily until day 14. The dosage was then maintained at 6 mg daily, increased or decreased by 2 mg daily each week, based on the patient's response. Risperidone treatment was given for 8 weeks; the permitted dosage range was 4 mg to 10 mg daily. RESULTS: Both male and female participants responded well to risperidone treatment; by the final assessment day, they had experienced decreases from baseline in their total Positive and Negative Syndrome Scale (PANSS) scores of 41.0% and 36.5%, respectively. Most male (77%) and female (78%) participants were considered to be PANSS responders: risperidone was effective against both the positive and negative symptoms of schizophrenia. Both sexes showed improvements over baseline in the incidence and severity of parkinsonism, dystonia, and dyskinesia. No significant (P > 0.05) sex differences in treatment response were observed for any of the efficacy outcomes or in the incidence and severity of extrapyramidal symptoms (EPS). CONCLUSIONS: In this population of outpatients with chronic schizophrenia, both men and women responded well to flexible doses of risperidone. No significant sex differences were evident either in treatment response or in neurological side effects. The absence of sex differences in response to risperidone treatment may obviate the need for a sex-based differential dosing in schizophrenia management.

Adolescent↗

Sex differences in the circadian control of hamster wheel-running activity.

The circadian pacemaker that underlies the wheel-running activity of hamsters was studied in males and females. Sex differences were found in the mechanism by which the pacemaker entrains to light-dark cycles and in the timing of activity onset. When exposed to a light-dark cycle with a period of 24.75 h (with 1 h of light/cycle), males show a greater ability to maintain entrainment than do females. This difference in the upper limit of entrainment appears due to a sex difference in the magnitude of light-induced phase shifts. A small difference in free-running period may also contribute to the sex difference in entrainment. Two weeks after castration of adults, the sex difference in entrainment is not affected, indicating that the difference does not depend on circulating gonadal steroids or on estrous cyclicity of the female. However, castration of females at an early age increases their ability to entrain, whereas long-term castration of males seems to reduce entrainment ability. During entrainment to a 24-h light-dark cycle (LD 14:10), females were found to begin their daily activity before males and before castrated females. This difference is consistent with a sex difference in the magnitude of light-induced phase shifts and in entrainment of the pacemaker. However, evidence is given that the sex difference in activity onset might also be caused by a sex difference in the relationship of locomotor activity to the pacemaker in intact males and females.

Animals↗

Sex differences in social dominance emerge late in life in a gregarious bird.

Social dominance shapes group structure and the collective behaviour of gregarious animals. Senescence, the progressive physiological deterioration associated with ageing, may influence behaviour, including social dominance, while reproductive roles may lead to different onset times or rates of senescence between the sexes. However, how ageing shapes sex differences in sociality remains poorly understood, largely due to the scarcity of long-term studies comparing male and female social behaviour. To address this gap of knowledge, we monitored dominance hierarchies during foraging in an ageing, semi-natural population of adult common waxbills (Estrilda astrild). Our study lasted 5&#x2009;years, which is more than most adult waxbills would live in the wild, to facilitate detecting effects of senescence. At the onset of the study, sex differences in dominance were negligible but became pronounced with ageing during breeding seasons. In contrast, sex differences remained weak during non-breeding seasons. Females showed stronger longitudinal and seasonal changes in dominance than males, whose dominance patterns remained more consistent across breeding and non-breeding periods. Nonetheless, social dominance also increased, on average, as the number of years until death decreased. Although sex differences in animal sociality are often thought of as largely fixed, our findings reveal a dynamic pattern in which sex differences in dominance emerge with ageing and are context-dependent, varying across breeding seasons. Overall, our results suggest that senescence and seasonal context shape sociality later in life.

behavioural ageing↗

Sex differences in the gross size of the rat neocortex.

The pervasiveness of sex differences in the size of the rat cerebral cortex was investigated in ten littermate pairs of socially housed Long-Evans hooded rats at 90 days of age. Overall, the cortex was longer and wider in male than in female rats. Sex differences were detected in most cortical regions with this sample size; the exception was the temporal cortex. While some asymmetries were found, they did not vary with the sex of the animal nor were they consistently in one direction. The contribution of the cortical layers to sex differences in cortical thickness was examined in four locations: the primary motor cortex, the forelimb area of the sensorimotor cortex and the monocular and the binocular areas of the visual cortex. The layers that showed sex differences varied among the areas but were confined to layers II-III, V and VI. Sex differences in cortical size were widespread in the adult rat but showed some regional and laminar specificity.

Animals↗

Exploring sex differences in endocannabinoid system biomarkers and their relationship with antidepressant treatment outcomes in major depressive disorder: a CAN-BIND 1 secondary analysis.

BACKGROUND: Sex differences in major depressive disorder (MDD) are well documented, but it remains unclear whether sex-related variation in peripheral endocannabinoid system (ECS)-related biomarkers is detectable in MDD. OBJECTIVES: To examine baseline sex differences in ECS-related mRNA expression, DNA methylation, and single nucleotide polymorphisms (SNPs) in MDD, and associations between baseline ECS markers and antidepressant outcomes in sex-stratified analyses. METHODS: Among 178 participants with MDD from CAN-BIND-1, all received escitalopram for 8 weeks; non-responders then received adjunctive aripiprazole from Weeks 8-16.Response was defined as &#x2265;&#x2009;50% reduction in MADRS score, and remission as MADRS&#x2009;&#x2264;&#x2009;10. ANCOVAs examined baseline sex differences and sex-stratified biomarker associations with percent MADRS reduction at Weeks 8 and 16, as well as categorical response and remission outcomes. Covariates included site, baseline MADRS, age, and ethnicity. False discovery rate correction was applied. RESULTS: Baseline sex differences in methylation were observed for CACNA1H, GABRB2, MAGL, and GABRR2, though none survived correction. No baseline sex differences in mRNA expression or SNPs were detected after correction. Lower baseline DAGLA mRNA in males was associated with greater Week 8 symptom improvement (FDR corrected). This association was not observed in females. No associations with response or remission at Weeks 8 or 16 survived correction. IMPLICATIONS: Baseline sex differences in peripheral ECS-related markers were not detected in this sample. Larger studies are needed to verify whether ECS-related biomarkers, particularly DAGLA, contribute to antidepressant outcomes in a sex-specific manner.

Humans↗

Sex differences in nociceptive withdrawal reflex and pain perception.

Experimentally induced pain often reveals sex differences, with higher pain sensitivity in females. The degree of differences has been shown to depend on the stimulation and assessment methods. Since sex differences in pain develop anywhere along the physiological and psychological components of the nociceptive system, we intended to compare the nociceptive flexion reflex (NFR) as a more physiological (spinal) aspect of pain procession to the verbal pain report of intensity and unpleasantness as the more psychological (cortical) aspect. Twenty female and twenty male healthy university students were investigated by use of nociceptive flexion reflex threshold (staircase method) after electrical stimulation of the N. suralis. Furthermore, we assessed supra-threshold reflex responses (latency, amplitude and area) by applying 10 stimuli 5 mA above reflex threshold. Following each stimulation, the subjects provided pain ratings of intensity and unpleasantness on a visual analogue scale. Females exhibited marked lower nociceptive flexion reflex thresholds than males, while the supra-threshold reflex response tailored to the individual reflex threshold did not show any significant differences. The verbal pain ratings, corrected for NFR threshold, were not found to differ significantly. The large sex differences in nociception that were present in NFR threshold but not in the pain ratings corroborate the hypothesis that spinal processes contribute substantially to sex differences in pain procession.

Adult↗

Relation of plasma triglyceride and apoB levels to insulin-mediated suppression of nonesterified fatty acids. Possible explanation for sex differences in lipoprotein pattern.

To test whether a sex difference in insulin-mediated suppression of nonesterified fatty acids (NEFAs) could account for sex differences in plasma triglyceride levels, we studied 632 normoglycemic men and women of European and South Asian descent aged 40 to 69 years. Mean fasting NEFA levels were 19% higher in women than in men. Between fasting and 2 hours after a 75-g oral glucose load, NEFA levels fell by 69% in women and 55% in men, so that mean NEFA levels at 2 hours after loading were 19% lower in women than in men. Plasma triglyceride and apolipoprotein B levels were correlated with 2-hour NEFA levels in each sex and ethnic group, and these associations were independent of glucose, insulin, and central obesity. These results are consistent with experimental studies of the effects of insulin and NEFAs on hepatic production of triglycerides and apolipoprotein B. Suppression of NEFA levels in response to insulin is greater in women than in men, and this may account for some of the sex differences in lipoprotein pattern and coronary heart disease risk.

Adult↗

Sex differences in responses to epidural steroid injection for low back pain.

UNLABELLED: Sex differences in clinical and experimental pain responses have been widely reported; however, few studies have examined sex differences in outcomes from interventional pain treatment and the predictors thereof. The aims of this study were to examine sex differences in (1) the acute pain produced by epidural steroid injections (ESIs), (2) clinical improvements in pain and pain-related psychological distress and disability after ESIs, and (3) predictors of the clinical response to ESIs. A total of 57 patients (37 menopausal women and 20 men), seen in the pain clinic of a regional medical center for ESI therapy, participated. Patients rated the painfulness of the ESI procedure itself. Also, clinical pain, depression, and disability were assessed before treatment and at 2 weeks and 2 months after the ESIs. Participants also were queried about their expectations of successful pain relief, coping strategies, and pain-related anxiety, which were examined as predictors of treatment outcome. Men reported significantly greater pain intensity and unpleasantness than women for the first injection only. All groups showed significant reductions in clinical pain, depression, and disability at 2 weeks compared to baseline, but minimal change occurred between 2 weeks and 2 months past baseline. No sex differences in the magnitude of treatment response emerged; however, specific dimensions of pain coping were associated with treatment responses in a sex-dependent manner. These findings suggest that the determinants of ESI pain and treatment outcome might differ across sex. PERSPECTIVE: Sex-related influences on pain responses have been widely reported, but few studies have explored sex-dependent predictors of treatment response. These findings indicate that pain coping was differentially associated with outcomes after ESI in women versus men.

Adaptation, Psychological↗

The role of mood states underlying sex differences in the perception and tolerance of pain.

While sex differences in pain reporting are frequently observed, the reasons underlying these differences remain unclear. The present study examined sex differences in self-report and physiological measures of pain threshold and tolerance following the administration of two laboratory pain-induction tasks. The primary study aim centered on determining whether repeated exposure to such tasks would yield sex differences in terms of pain threshold and tolerance. In addition, it was hypothesized that if such differences did exist, negative mood states might account for changes in pain ratings, threshold, and/or tolerance in subsequent exposure to noxious stimuli. Recruited from a convenience sample, 66 participants (44 female and 22 male) were exposed to both thermal and cold noxious stimuli at three separate times, while psychophysiological and self-report data were collected. Because women outnumbered men 2:1, Fisher z transformations were performed to determine whether the observed associations between mood states and pain ratings differed. We found stronger associations between fatigue and thermal-heat pain ratings for men at their first and third exposure to the pain task compared to women (z = 2.11, P < 0.05; z = 3.14, P < 0.001, respectively). Results indicated that women evidenced greater pain tolerance than men on both a behavioral and physiological level; however, they reported greater pain severity than men. Fatigue was also found to be particularly important to reports of pain severity in men and pain tolerance in response to noxious stimuli for women. Possible pathways in which mood states influenced these endpoints are discussed.

Adult↗

Sex differences in host resistance to Mycobacterium marinum infection in mice.

Sex differences were observed in host resistance to Mycobacterium marinum infection in mice. Males were found to be more susceptible than females in terms of mortality, incidence of gross skin lesions, and bacterial load in the lungs and spleen. The degree of sex differences varied from strain to strain of test mice, in the order C3H/He, A/J, and BALB/c greater than DBA/2, B10.A, and C57BL/6, on the basis of survival time and multiplication of organisms in the visceral organs. Although this ordering corresponded to the susceptibilities of both male and female mice to the organisms, much greater strain dependency was seen in males than in females. Castration caused an increase in the host resistance of males, but this effect was substantially reversed by continuous testosterone treatment. Testosterone also increased the susceptibility of female mice to this infection. These findings imply that the male sex hormone is involved in the lowered anti-M. marinum resistance of males. Although athymic mice were more susceptible than euthymic mice, a substantial degree of sex difference was also observed in the T-cell-depleted animals, indicating that natural host resistance to this infection is sex dependent. Indeed, more efficient macrophage mobilization at the site of infection was seen in females than in males. Although female T-cell transplantation improved the lowered resistance of athymic mice, there was a sex difference in bacterial growth in the lungs. This implies that sex hormones affect T-cell functions.

Animals↗

Sex differences in adrenocortical structure and function. XIII. Stereologic studies on adrenal cortex of maturing male and female hamsters.

Adrenal glands of adult male hamsters are larger and secrete more cortisol than those of females. Stereology was therefore used to study zonal and cellular aspects of development of the adrenal cortex of male and female hamsters. Adrenal glands were studied at weekly intervals from day 21 to day 77 of postnatal ontogenesis. Within this period, body weight did not differ significantly between the sexes. During development, absolute and relative adrenal weights were higher in males; their zona glomerulosa (ZG), zona fasciculata (ZF) and zona reticularis (ZR) become markedly larger than those in females. No marked changes in the volume of individual ZG cells occurred although ZF cells and ZR cells become larger in male than female animals. The total number of adrenocortical cells increased within the period studied, a greater increase being observed in ZG and ZF in males. No distinct sex difference was observed in the number of ZR cells throughout development. From day 56 of postnatal life the adrenal cortex of male hamster contained more parenchymal cells than the female gland. These results thus indicate that sex differences in hamster adrenal cortex depend upon changes in number and size of parenchymal cells.

Adrenal Cortex↗

Sex differences in right hemisphere tasks.

We tested the hypothesis that sex differences in spatial ability and emotional perception are due to sex differences in intrahemispheric organization of the right hemisphere. If the right hemisphere is differently organized by sex-primarily specialized for spatial ability in men, but primarily specialized for emotional perception in women-then there should be a negative correlation between spatial ability and emotional perception within sex, and the greatest disparity between abilities should be found in people with characteristic arousal of the right hemisphere. Undergraduate men (N = 86) and women (N = 132) completed tests of Mental Rotation, Surface Development, Profile of Nonverbal Sensitivity, Progressive Matrices, and Chimeric Faces. Although the expected pattern of sex differences was observed, there was no evidence for the hypothesized negative correlation between spatial ability and emotional perception, even after statistical control of general intelligence.

Adult↗