ESPE Abstracts

Prior to menopause, it is known that women have a lower risk of cardiovascular disease (CVD) and coronary heart disease compared to age-matched men; it is reported that women have around half the CVD risk and almost a 10-year delay in first myocardial infarction event compared to men. Sex differences in serum lipids could contribute to CVD risk through driving atherosclerosis, the buildup of lipids in the sub-endothelial intimal layer of medium-sized to large arteries. We hypothesised that sex hormones influence changes in lipids and thus atherosclerosis risk after puberty. The interrelationship between sex hormones and lipids was explored in pre- and adolescent post-pubertal cis-gendered males (n = 10 and 17) and females (n = 10 and 23) and in adolescent transgender individuals under cross-sex-hormone treatment (trans-male/trans-female, n = 26/25) using NMR-based serum metabolomics assessing 149 lipid measures. Data were analysed by multiple t-tests and logistic regression. Atheroprotective high-density lipoproteins (HDL) and associated apolipoprotein(Apo)A1 were significantly increased and atherogenic very-low- and low-density lipoproteins were significantly decreased in adolescent post-pubertal cis-females compared to cis-males. Strikingly, these differences were not observed pre-puberty and were induced appropriately by cross-sex-hormone treatment in adolescent transgender individuals, supporting that sex hormones regulate lipid metabolism in vivo. Notably, only atheroprotective ApoA1 expressing lipoproteins (HDL) were universally differentially expressed between adolescent cis-males versus cis-females, cis-males versus trans-females and cis-females versus trans-males. In adolescent trans-females, ApoA1 levels correlated positively with circulating oestradiol levels and with the number of months on cross-sex-hormone treatment by linear regression. Finally, ApoA1 was not significantly altered in adolescent post-pubertal individuals with Turner syndrome (females with only one functional X sex chromosome, rather than the usual two) compared to healthy adolescent controls. Thus, oestradiol drives a dose-dependent atheroprotective lipid profile through upregulation of HDL and ApoA1, supporting a role for sex hormones in lipid metabolism; this was not affected by chromosome dosage and may help us to understand why males and females are differentially susceptible to CVD from a young age. Together, this could inform sex-specific therapeutic strategies for atherosclerosis and CVD management.