Sex differences in obesity and the regulation of energy homeostasis.

Obesity prevalence is generally higher in women than in men, and there is also a sex difference in body fat distribution. Sex differences in obesity can be explained in part by the influence of gonadal steroids on body composition and appetite; however, behavioural, socio-cultural and chromosomal factors may also play a role. This review, which evolved from the 2008 Stock Conference on sex differences in obesity, summarizes current research and recommendations related to hormonal and neuroendocrine influences on energy balance and fat distribution. A number of important gaps in the research are identified, including a need for more studies on chromosomal sex effects on energy balance, the role of socio-cultural (i.e. gender) factors in obesity and the potential deleterious effects of high-fat diets during pregnancy on the foetus. Furthermore, there is a paucity of clinical trials examining sex-specific approaches and outcomes of obesity treatment (lifestyle-based or pharmacological), and research is urgently needed to determine whether current weight loss programmes, largely developed and tested on women, are appropriate for men. Last, it is important that both animal and clinical research on obesity be designed and analysed in such a way that data can be separately examined in both men and women.

Sex differences: From mental rotation to object location memory, an ERP study

Sex differences in cognition have been largely investigated. The most consistent sex differences favoring females are observed in object location memory involving the left hemisphere whereas the most consistent sex differences favoring males are observed in tasks that require mental rotation involving the right hemisphere. Here we used a task involving these two abilities to see the impact of mental rotation on object location memory. To that end we used a combination of behavioral and event-related potential (ERP) electroencephalography (EEG) measures.A computer screen displayed a square frame of 4 pairs of images (a "teddy" bear, a shoe, an umbrella and a lamp) randomly arranged around a central fixation cross. After a 10-second interval for memorization, images disappeared and were replaced by a test frame with no image but a random pair of two locations marked in black. In addition, this test frame was randomly displayed either in the original orientation (0° rotation) or in the rotated one (90° clockwise - CW - or 90° counterclockwise - CCW). Preceding the test frame, an arrow indicating the presence or the absence of rotation of the frame was displayed on the screen. The task of the participants (15 females and 15 males) was to determine if two marked locations corresponded or not to a pair of identical images. Each response was followed by feedback.Findings showed no significant sex differences in the performance of the original orientation. In comparison with this position, the rotation of the frame produced an equal decrease of male and female performance. In addition, this decrease was significantly higher when the rotation of the frame was in a CCW direction. We further assessed the ERP when the arrow indicated the direction of rotation as stimulus-onset, during four time windows representing major components C1, P1, N1 and N2. Although no sex differences were observed in performance, brain activities differed according to sex. Enhanced amplitudes were found for the CCW compared to CW rotation over the right posterior areas for the P1, N1 and N2 components for men as well as for women. Major topographical differences related to sex were measured for the CW rotation condition as marked lateralized amplitude: left-hemisphere amplitude larger than right one was measured during P1 time range for men. These similar patterns prolonged from P1 to N1 for women. Early distinctions were found in interaction with sex between CCW and CW waveform amplitudes, expressing over anterior electrode sites during C1 time range (0-50 ms post-stimulus).In conclusion (i) women do not outperform men in object location memory in this study (absence of rotation condition); (ii) mental rotation, in particular the direction of rotation, influences performance on object location memory; (iii) CCW rotation is associated with activity in the right parietal hemisphere whereas the CW rotation involves the left parietal hemisphere; (iv) this last effect is less pronounced in males, which could explain why greater involvement of right parietal areas in men and of bilateral posterior areas in women is generally reported in mental rotation tasks; and (v) the early distinctions between both directions of rotation located over anterior sites could be related to sex differences in their respective involvement of control mechanisms.

Sex differences in the neurobiology of fear conditioning and extinction: a preliminary fMRI study of shared sex differences with stress-arousal circuitry.

BACKGROUND: The amygdala, hippocampus, medial prefrontal cortex (mPFC) and brain-stem subregions are implicated in fear conditioning and extinction, and are brain regions known to be sexually dimorphic. We used functional magnetic resonance imaging (fMRI) to investigate sex differences in brain activity in these regions during fear conditioning and extinction. METHODS: Subjects were 12 healthy men comparable to 12 healthy women who underwent a 2-day experiment in a 3 T MR scanner. Fear conditioning and extinction learning occurred on day 1 and extinction recall occurred on day 2. The conditioned stimuli were visual cues and the unconditioned stimulus was a mild electric shock. Skin conductance responses (SCR) were recorded throughout the experiment as an index of the conditioned response. fMRI data (blood-oxygen-level-dependent [BOLD] signal changes) were analyzed using SPM8. RESULTS: Findings showed no significant sex differences in SCR during any experimental phases. However, during fear conditioning, there were significantly greater BOLD-signal changes in the right amygdala, right rostral anterior cingulate (rACC) and dorsal anterior cingulate cortex (dACC) in women compared with men. In contrast, men showed significantly greater signal changes in bilateral rACC during extinction recall. CONCLUSIONS: These results indicate sex differences in brain activation within the fear circuitry of healthy subjects despite similar peripheral autonomic responses. Furthermore, we found that regions where sex differences were previously reported in response to stress, also exhibited sex differences during fear conditioning and extinction.

Startegy selection during exploratory behavior: sex differences, uncertainty and risk managment

This study deals with the psychological processes underlying the selection of appropriate strategy during exploratory behavior. A new device was used to assess sexual dimorphisms in spatial abilities that do not depend on spatial rotation, map reading or directional vector extraction capacities. Moreover, it makes it possible to investigate exploratory behavior as a specific response to novelty that trades off risk and reward. Risk management under uncertainty was assessed through both spontaneous searching strategies and signal detection capacities. The results of exploratory behavior, detection capacities, and decision-making strategies seem to indicate that women's exploratory behavior is based on risk-reducing behavior while men behavior does not appear to be influenced by this variable. This difference was interpreted as a difference in information processing modifying beliefs concerning the likelihood of uncertain events, and therefore influencing risk evaluation.

Sex differences in urinary levels of several biological indicators of exposure: a simulation study using a compartmental based toxicokinetic model

Toxicokinetic modeling is a useful tool to describe or predict the behavior of a chemical agent in the human or animal organism. A general model based on four compartments was developed in a previous study in order to quantify the effect of human variability on a wide range of biological exposure indicators. The aim of this study was to adapt this existing general toxicokinetic model to three organic solvents, which were methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1,-trichloroethane, and to take into account sex differences. We assessed in a previous human volunteer study the impact of sex on different biomarkers of exposure corresponding to the three organic solvents mentioned above. Results from that study suggested that not only physiological differences between men and women but also differences due to sex hormones levels could influence the toxicokinetics of the solvents. In fact the use of hormonal contraceptive had an effect on the urinary levels of several biomarkers, suggesting that exogenous sex hormones could influence CYP2E1 enzyme activity. These experimental data were used to calibrate the toxicokinetic models developed in this study. Our results showed that it was possible to use an existing general toxicokinetic model for other compounds. In fact, most of the simulation results showed good agreement with the experimental data obtained for the studied solvents, with a percentage of model predictions that lies within the 95% confidence interval varying from 44.4 to 90%. Results pointed out that for same exposure conditions, men and women can show important differences in urinary levels of biological indicators of exposure. Moreover, when running the models by simulating industrial working conditions, these differences could even be more pronounced. In conclusion, a general and simple toxicokinetic model, adapted for three well known organic solvents, allowed us to show that metabolic parameters can have an important impact on the urinary levels of the corresponding biomarkers. These observations give evidence of an interindividual variablity, an aspect that should have its place in the approaches for setting limits of occupational exposure.

Sex differences in urinary levels of several biological indicators of exposure: a human volunteer study

The aim of the study was to quantify the variability on biological indicators of exposure between men and women for three well known solvents: methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1-trichloroethane. Another purpose was to explore the effect of selected CYP2E1 polymorphisms on the toxicokinetic profile. Controlled human exposures were carried out in a 12m(3) exposure chamber for each solvent separately, during 6h and at half of the threshold limit value. The human volunteers groups were composed of ten young men and fifteen young women, including ten women using hormonal contraceptive. An analysis of variance mainly showed an effect on the urinary levels of several biomarkers of exposure among women due to the use of hormonal contraceptive, with an increase of more than 50% in metabolites concentrations and a decrease of up to 50% in unchanged substances concentrations, suggesting an increase in their metabolism rate. The results also showed a difference due to the genotype CYP2E1*6, when exposed to methyl ethyl ketone, with a tendency to increase CYP2E1 activity when volunteers were carriers of the mutant allele. Our study suggests that not only physiological differences between men and women but also differences due to sex hormones levels can have an impact on urinary concentrations of several biomarkers of exposure. The observed variability due to sex among biological exposure indices can lead to misinterpretation of biomonitoring results. This aspect should have its place in the approaches for setting limits of occupational exposure. [Authors]

Sex differences in atheroma burden and endothelial function in patients with early coronary atherosclerosis.

AIMS: Women and men have different clinical presentations and outcomes in coronary artery disease (CAD). We tested the hypothesis that sex differences may influence coronary atherosclerotic burden and coronary endothelial function before development of obstructive CAD. METHODS AND RESULTS: A total of 142 patients (53 men, 89 women; mean +/- SD age, 49.3 +/- 11.7 years) with early CAD simultaneously underwent intravascular ultrasonography and coronary endothelial function assessment. Atheroma burden in the left main and proximal left anterior descending (LAD) arteries was significantly greater in men than women (median, 23.0% vs. 14.1%, P = 0.002; median, 40.1% vs. 29.3%, P = 0.001, respectively). Atheroma eccentricity in the proximal LAD artery was significantly higher in men than women (median, 0.89 vs. 0.80, P = 0.04). The length of the coronary segments with endothelial dysfunction was significantly longer in men than women (median, 39.2 vs. 11.1 mm, P = 0.002). In contrast, maximal coronary flow reserve was significantly lower in women than men (2.80 vs. 3.30, P < 0.001). Sex was an independent predictor of atheroma burden in the left main and proximal LAD arteries (both P < 0.05) by multivariate analysis. CONCLUSION: Men have greater atheroma burden, more eccentric atheroma, and more diffuse epicardial endothelial dysfunction than women. These results suggest that men have more severe structural and functional abnormalities in epicardial coronary arteries than women, even in patients with early atherosclerosis, which may result in the higher incidence rates of CAD and ST-segment myocardial infarction in men than women.

Sex differences in hospital readmission among colorectal cancer patients.

Background: While several studies have analysed sex and socioeconomic differences in cancer incidence and mortality, sex differences in oncological health care have been seldom considered. Objective: To investigate sex based inequalities in hospital readmission among patients diagnosed with colorectal cancer. Design: Prospective cohort study. Setting: Hospital Universitary in L¿Hospitalet (Barcelona, Spain). Participants: Four hundred and three patients diagnosed with colorectal between January 1996 and December 1998 were actively followed up until 2002. Main outcome measurements and methods: Hospital readmission times related to colorectal cancer after surgical procedure. Cox proportional model with random effect (frailty) was used to estimate hazard rate ratios and 95% confidence intervals of readmission time for covariates analysed. Results: Crude hazard rate ratio of hospital readmission in men was 1.61 (95% CI 1.21 to 2.15). When other significant determinants of readmission were controlled for (including Dukes¿s stage, mortality, and Charlson¿s index) a significant risk of readmission was still present for men (hazard rate ratio: 1.52, 95% CI 1.17 to 1.96). Conclusions: In the case of colorectal cancer, women are less likely than men to be readmitted to the hospital, even after controlling for tumour characteristics, mortality, and comorbidity. New studies should investigate the role of other non-clinical variable such as differences in help seeking behaviours or structural or personal sex bias in the attention given to patients.

Sex differences in lipid and glucose kinetics after ingestion of an acute oral fructose load.

The increase in VLDL TAG concentration after ingestion of a high-fructose diet is more pronounced in men than in pre-menopausal women. We hypothesised that this may be due to a lower fructose-induced stimulation of de novo lipogenesis (DNL) in pre-menopausal women. To evaluate this hypothesis, nine healthy male and nine healthy female subjects were studied after ingestion of oral loads of fructose enriched with 13C6 fructose. Incorporation of 13C into breath CO2, plasma glucose and plasma VLDL palmitate was monitored to evaluate total fructose oxidation, gluconeogenesis and hepatic DNL, respectively. Substrate oxidation was assessed by indirect calorimetry. After 13C fructose ingestion, 44.0 (sd 3.2)% of labelled carbons were recovered in plasma glucose in males v. 41.9 (sd 2.3)% in females (NS), and 42.9 (sd 3.7)% of labelled carbons were recovered in breath CO2 in males v. 43.0 (sd 4.5)% in females (NS), indicating similar gluconeogenesis from fructose and total fructose oxidation in males and females. The area under the curve for 13C VLDL palmitate tracer-to-tracee ratio was four times lower in females (P < 0.05), indicating a lower DNL. Furthermore, lipid oxidation was significantly suppressed in males (by 16.4 (sd 5.2), P < 0.05), but it was not suppressed in females ( -1.3 (sd 4.7)%). These results support the hypothesis that females may be protected against fructose-induced hypertriglyceridaemia because of a lower stimulation of DNL and a lower suppression of lipid oxidation.

Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism.

Several observations support the hypothesis that differences in synaptic and regional cerebral plasticity between the sexes account for the high ratio of males to females in autism. First, males are more susceptible than females to perturbations in genes involved in synaptic plasticity. Second, sex-related differences in non-autistic brain structure and function are observed in highly variable regions, namely, the heteromodal associative cortices, and overlap with structural particularities and enhanced activity of perceptual associative regions in autistic individuals. Finally, functional cortical reallocations following brain lesions in non-autistic adults (for example, traumatic brain injury, multiple sclerosis) are sex-dependent. Interactions between genetic sex and hormones may therefore result in higher synaptic and consecutively regional plasticity in perceptual brain areas in males than in females. The onset of autism may largely involve mutations altering synaptic plasticity that create a plastic reaction affecting the most variable and sexually dimorphic brain regions. The sex ratio bias in autism may arise because males have a lower threshold than females for the development of this plastic reaction following a genetic or environmental event.

Personality effects and sex differences on the international affective picture system (IAPS) : a Spanish and Swiss study

The present study analyses the relationship between Anxiety and Impulsivity personality factors and emotions, by controlling for country and sex effects in a sample of Spanish and Swiss university students. Emotions were assessed through the International Affective Picture System (IAPS) of pictures (valence/arousal) using the Self-Assessment Manikin (SAM) procedure. The mixed valence/arousal groups' pictures were formed according to Tok, Koyuncu, Dural and Catikkas procedure (2010). Results showed that females scored significantly higher in Anxiety factor and men in Impulsivity factor in both countries. The effect of sex was highly significant for Anxiety (ŋ2: 0.12), but there was no significant effect of the country. Also, females obtained higher scores in the four valence/arousal pictures groups. The sex effect was particularly robust for negative valence-high arousal (ŋ2: 0.13). Impulsivity correlated with high ratings of positive valence-high arousal while Anxiety correlated with high ratings of negative valence-high arousal and with high ratings of negative valence-low arousal in both sexes, although scores were higher for females. Structural Equation Modelling confirmed these relationships. Nevertheless, Anxiety and Impulsivity explained only a small amount of the accounted variance of the self-reported valence and arousal of the pictures.

Sex differences in angiotensin II- induced hypertension

Sex differences in the development of hypertension and cardiovascular disease have been described in humans and in animal models. In this paper we will review some of our studies which have as their emphasis the examination of the role of sex differences and sex steroids in modulating the central actions of angiotensin II (ANG II) via interactions with free radicals and nitric oxide, generating pathways within brain circumventricular organs and in central sympathomodulatory systems. Our studies indicate that low-dose infusions of ANG II result in hypertension in wild-type male mice but not in intact wild-type females. Furthermore, we have demonstrated that ANG II-induced hypertension in males is blocked by central infusions of the androgen receptor antagonist, flutamide, and by central infusions of the superoxide dismutase mimetic, tempol. We have also found that, in comparison to females, males show greater levels of intracellular reactive oxygen species in circumventricular organ neurons following long-term ANG II infusions. In female mice, ovariectomy, central blockade of estrogen receptors or total knockout of estrogen a receptors augments the pressor effects of ANG II. Finally, in females but not in males, central blockade of nitric oxide synthase increases the pressor effects of ANG II. Taken together, these results suggest that sex differences and estrogen and testosterone play important roles in the development of ANG II-induced hypertension.