Higher Risk of Incident Hepatitis C Virus Coinfection Among Men Who Have Sex With Men, in Whom the HIV Genetic Bottleneck at Transmission Was Wide.

BACKGROUND: High-risk sexual behaviors have been suggested as drivers of the recent dramatic increase of sexually transmitted hepatitis C virus (HCV) among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). METHODS: We assessed the association between the genetic bottleneck of HIV at transmission and the prevalence and incidence of HCV coinfection in HIV-infected MSM from the Swiss HIV Cohort Study (SHCS). As a proxy for the width of the transmission bottleneck, we used the fraction of ambiguous nucleotides detected by genotypic resistance tests sampled during early HIV infection. We defined a broad bottleneck as a fraction of ambiguous nucleotides exceeding a previously established threshold (0.5%). RESULTS: From the SHCS, we identified 671 MSM with available results of HCV serologic tests and with an HIV genotypic resistance test performed during early HIV infection. Of those, 161 (24.0%) exhibited a broad HIV transmission bottleneck, 38 (5.7%) had at least 1 positive HCV test result, and 26 (3.9%) had an incident HCV infection. Individuals with broad HIV transmission bottlenecks exhibited a 2-fold higher odds of having ever experienced an HCV coinfection (odds ratio, 2.2 [95% confidence interval {CI}, 1.1-4.3]) and a 3-fold higher hazard of having an incident HCV infection (hazard ratio, 3.0 [95% CI, 1.4-6.6]) than individuals with narrow HIV transmission bottlenecks. CONCLUSIONS: Our results indicate that the currently occurring sexual spread of HCV is focused on MSM who are prone to exhibit broad HIV transmission bottlenecks. This is consistent with an important role of high-risk behavior and mucosal barrier impairment in the transmission of HCV among MSM.

Determinants of maternal sex steroids during the first half of pregnancy.

OBJECTIVE: To examine the associations of maternal and child characteristics with early pregnancy maternal concentrations of testosterone, androstenedione, progesterone, 17-hydroxyprogesterone, and estradiol (E2). METHODS: We analyzed these hormones among 1,343 women with singleton pregnancies who donated serum samples to the Finnish Maternity Cohort from 1986 to 2006 during the first half of pregnancy (median 11 weeks). The associations of maternal and child characteristics with hormone concentrations were investigated by correlation and multivariable regression. RESULTS: Women older than age 30 years had lower androgen and E2 but higher progesterone concentrations than women younger than that age. Multiparous women had 14% lower testosterone, 11% lower androstenedione and 17-hydroxyprogesterone, 9% lower progesterone, and 16% lower E2 concentrations compared with nulliparous women (all P<.05). Smoking mothers had 11%, 18%, and 8% higher testosterone, androstenedione, and 17-hydroxyprogesterone levels, respectively, but 10% lower progesterone compared with nonsmoking women (all P<.05). E2 concentrations were 9% higher (P<.05) among women with a female fetus compared with those with a male fetus. CONCLUSION: Parity, smoking, and, to a lesser extent, maternal age and child sex are associated with sex steroid levels during the first half of a singleton pregnancy. The effects of smoking on the maternal hormonal environment and the possible long-term deleterious consequences on the fetus deserve further evaluation. LEVEL OF EVIDENCE: II.

Sex reversal: a fountain of youth for sex chromosomes?

Nonrecombining Y chromosomes are expected to degenerate through the progressive accumulation of deleterious mutations. In lower vertebrates, however, most species display homomorphic sex chromosomes. To address this, paradox I propose a role for sex reversal, which occasionally occurs in ectotherms due to the general dependence of physiological processes on temperature. Because sex-specific recombination patterns depend on phenotypic, rather than genotypic sex, homomorphic X and Y chromosomes are expected to recombine in sex-reversed females. These rare events should generate bursts of new Y haplotypes, which will be quickly sorted out by natural or sexual selection. By counteracting Muller's ratchet, this regular purge should prevent the evolutionary decay of Y chromosomes. I review empirical data supporting this suggestion, and propose further investigations for testing it.

Biological monitoring of chemical exposure : toxicokinetic differences due to age and sex

Human biomonitoring is a widely used method in the assessment of occupational exposure to chemical substances and recommended biological limits are published periodically for interpretation and decision-making. However, it is increasingly recognized that a large variability is associated with biological monitoring, making interpretation less efficient than assumed. In order to improve the applicability of biological monitoring, specific factors responsible for this variability should be identified and their contribution quantified. Among these factors, age and sex are easily identifiable, and present knowledge about pharmaceutical chemicals suggests that they play an important role on the toxicokinetics of occupational chemical agents, and therefore on the biological monitoring results.The aim of the present research project was to assess the influence of age and sex on biological indicators corresponding to organic solvents. This has been done experimentally and by toxicokinetic computer simulation. Another purpose was to explore the effect of selected CYP2E1 polymorphisms on the toxicokinetic profile.Age differences were identified by numerical simulations using a general toxicokinetic model from a previous study which was applied to 14 chemicals, representing 21 specific biological entities, with, among others, toluene, phenol, lead and mercury. These models were runn with the modified parameters, indicating in some cases important differences due to age. The expected changes are mostly of the order of 10-20 %, but differences up to 50 % were observed in some cases. These differences appear to depend on the chemical and on the biological entity considered.Sex differences were quantified by controlled human exposures, which were carried out in a 12 m3 exposure chamber for three organic solvents separately: methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1-trichloroethane. The human volunteer groups were composed 12 of ten young men and fifteen young women, the latter subdivided into those with and without hormonal contraceptive. They were exposed during six hours at rest and at half of the threshold limit value. The kinetics of the parent compounds (organic volatiles) and their metabolite(s) were followed in blood, urine and expired air over time. Analyses of the solvent and their metabolites were performed by using headspace gas chromatography, CYP2E1 genotypes by using PCR-based RFLP methods. Experimental data were used to calibrate the toxicokinetic models developed for the three solvents. The results obtained for the different biomarkers of exposure mainly showed an effect on the urinary levels of several biomarkers among women due to the use of hormonal contraceptive, with an increase of about 50 % in the 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. Simulations showed that it is possible to use simple toxicokinetic tools in order to predict internal exposure when exposed to organic solvents. Our study suggests that not only physiological differences but also exogenous sex hormones could influence CYP2E1 enzyme activity. The variability among the urinary biological indicators levels gives evidence of an interindividual susceptibility, an aspect that should have its place in the approaches for setting limits of occupational exposure.

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.

Inbreeding load, bet hedging, and the evolution of sex-biased dispersal

Inbreeding load affects not only the average fecundity of philopatric individuals but also its variance. From bet-hedging theory, this should add further dispersal pressures to those stemming from the mere avoidance of inbreeding. Pressures on both sexes are identical under monogamy or promiscuity. Under polygyny, by contrast, the variance in reproductive output decreases with dispersal rate in females but increases in males, which should induce a female-biased dispersal. To test this prediction, we performed individual-based simulations. From our results, a female-biased dispersal indeed emerges as both polygyny and inbreeding load increase. We conclude that sex-biased dispersal may be selected for as a bet-hedging strategy.

First anal intercourse and condom use among men who have sex with men in Switzerland.

The aim of this study was to analyze the circumstances of first anal intercourse (FAI) among men who have sex with men (MSM) and to identify factors associated with condom use at this event. We conducted a cross-sectional survey among a convenience sample of MSM living in Switzerland (N = 2,200). Anonymous questionnaires were distributed using Swiss gay communication channels (newspapers, associations, websites) and gay bathhouses. We gathered data on age at FAI, age of the partner, degree of familiarity with him, place of first meeting, and sociodemographic indicators. We did not ask whether FAI was insertive, receptive, or both. Data were stratified by birth year classes (birth cohorts). The median age at FAI fell from 24.5 years among men born before 1965 to 20.0 years among those born between 1975 and 1984 (p < .001). In each birth cohort, between 20 and 30% reported a partner 10 years older or more. Of eight variables examined in multivariate analysis, two were positively associated with condom use: age of participants at FAI and low degree of familiarity between partners. Conversely, large age discrepancy between partners was negatively associated with condom use. In conclusion, our data showed that early initiation of anal intercourse and large age discrepancy were associated with risk taking: a pattern of initiation that may facilitate HIV transmission from older to younger cohorts of MSM. Since age at FAI is on the decrease, there is an urgent need to heighten awareness of prevention actions regarding sexual debut of MSM.

Early pregnancy sex steroids and maternal risk of epithelial ovarian cancer.

Well-established associations between reproductive characteristics and epithelial ovarian cancer (EOC) support an involvement of sex steroid hormones in the etiology of EOC. Limited previous studies have evaluated circulating androgens and the risk of EOC, and estrogens and progesterone have been investigated in only one of the previous studies. Furthermore, there is little data on potential heterogeneity in the association between circulating hormones and EOC by histological subgroup. Therefore, we conducted a nested case-control study within the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort to investigate the associations between circulating pre-diagnostic sex steroid concentrations and the histological subtypes of EOC. We identified 1052 EOC cases among cohort members diagnosed after recruitment (1975-2008) and before March 2011. Up to three controls were individually matched to each case (n=2694). Testosterone, androstenedione, 17-hydroxyprogesterone (17-OHP), progesterone, estradiol (E2), and sex hormone-binding globulin levels were measured in serum samples collected during the last pregnancy before EOC diagnosis. We used conditional logistic regression to estimate odds ratios (ORs) and 95% CIs. Associations between hormones and EOC differed with respect to tumor histology and invasiveness. Sex steroid concentrations were not associated with invasive serous tumors; however, doubling of testosterone and 17-OHP concentration was associated with approximately 40% increased risk of borderline serous tumors. A doubling of androgen concentrations was associated with a 50% increased risk of mucinous tumors. The risk of endometrioid tumors increased with higher E2 concentrations (OR: 1.89 (1.20-2.98)). This large prospective study in pregnant women supports a role of sex steroid hormones in the etiology of EOC arising in the ovaries.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.