The effects of cross-sex hormone treatment - in the dosages used in this study - in healthy, nonobese, young transsexual subjects do not show unequivocally that female sex steroids, given in large amounts to male subjects, have beneficial effects on cardiovascular profile and that high dose testosterone administration to female subjects is detrimental with respect to cardiovascular risk.

We investigated prospectively the effect of sex steroids on regional fat depots and thigh muscle mass in adult transsexuals. Ethinyl estradiol in combination with cyproterone acetate, a progestational antiandrogen, was given to 20 male-to-female (M-F) transsexuals, and parenteral testosterone esters were given to 17 female-to-male (F-M) transsexuals. Before and after 12 mo of cross-sex hormone administration, several anthropometric measurements (weight, skinfolds, body circumferences, and bioimpedance) were performed, and transverse magnetic resonance images were obtained at the level of the abdomen, hip, and thigh to quantify fat depots (subcutaneous and visceral) and muscle areas. We observed that treatment with ethinyl estradiol in M-F transsexuals induced a significant increase in all subcutaneous fat depots, with a lesser but proportional and significant increase in the visceral fat depot and a decrease in thigh muscle area. Testosterone administration in F-M transsexuals markedly increased thigh muscle area, reduced subcutaneous fat deposition at all levels measured, but slightly increased the visceral fat area. We conclude that sex steroid hormones are important determinants of the sex-specific localization of body fat.

The amount of intraabdominal (visceral) fat is an important determinant of disturbances in lipid and glucose metabolism. Cross-sectional studies in women have found associations between high androgen levels and visceral fat accumulation. The causal relation between these phenomena is unknown. We, therefore, studied prospectively the effect of testosterone administration on body fat distribution in 10 young, nonobese, female to male transsexuals undergoing sex reassignment. Before, after 1 yr, and after 3 yr of testosterone administration, magnetic resonance images were obtained at the level of the abdomen, hip, and thigh to quantify both sc and visceral fat depots. After 1 yr of testosterone administration, sc fat depots at all levels showed significant reductions compared to baseline measurements. The mean visceral fat area did not change significantly, but subjects who gained weight in the first year after testosterone administration showed an increase in visceral fat. After 3 yr of testosterone administration, sc fat depots were no longer significantly lower compared to pretreatment measurements, but the mean visceral fat depot had increased significantly by 13 cm2 (95% confidence interval, 4-22 cm2), a relative increase of 47% (95% confidence interval, 8-91%) from baseline. The increase in visceral fat was most pronounced in those subjects who had gained weight. We conclude that long term testosterone administration in young, nonobese, female subjects increases the amount of visceral fat. In addition, an increase in weight in this hyperandrogenic state leads to a preferential storage of fat in the visceral depot.

Large artery stiffening could contribute to the development of cardiovascular disease. The aim of this study was to investigate associations between arterial stiffness and diameter with insulin sensitivity and body composition in healthy men and women. In healthy, young (< 41 years old), non-obese (BMI < 27 kg/m2) men (n = 17) and women (n = 17), we measured the arterial diameter, the distension, the distensibility coefficient and the compliance coefficient of the elastic common carotid and muscular femoral arteries with a non-invasive ultrasonographic method. We also assessed glucose uptake (by a euglycaemic hyperinsulinaemic clamp technique), total body fat and lean body mass (by bioelectrical impedance analysis) and abdominal subcutaneous and visceral fat area (by magnetic resonance imaging). In women, but not in men, the distension and distensibility and compliance coefficients of the femoral artery were negatively associated with insulin concentrations (beta = -0.62, p = 0.008; beta = -0.65, p = 0.005 and beta = -0.59, p = 0.01), and positively with glucose uptake (beta = 0.59, p = 0.02; beta = 0.68, p = 0.005 and beta = 0.54, p = 0.04). Associations with glucose uptake were independent of the mean arterial pressure and body composition. In men and women, arterial compliance was positively associated with fat mass variables, which were mediated by a strong association between the femoral artery diameter and lean body mass (beta = 0.80, p < 0.001) and between the common carotid artery diameter and visceral fat area (beta = 0.56, p = 0.001). We found an independent association between insulin resistance and arterial stiffness, which was more pronounced in women than in men.

Women have higher circulating leptin levels than men. This sex difference is not simply explained by differences in the amount of body fat and is possibly influenced by their different sex steroid milieus. This prompted us to study prospectively the effects of cross-sex steroid hormones on serum leptin levels in 17 male to female transsexuals and 15 female to male transsexuals. Male to female transsexuals were treated with 100 micrograms ethinyl estradiol and 100 mg cyproterone acetate (antiandrogen) daily, and female to male transsexuals received testosterone esters (250 mg/2 weeks, im). Before and after 4 and 12 months of cross-sex hormone treatment, serum leptin levels and measures of body fatness were assessed. Before treatment, female subjects had higher serum leptin levels than male subjects independently of the amount of body fat (P < 0.01). Cross-sex hormone administration induced a reversal of the sex difference in serum leptin levels. Estrogen treatment in combination with antiandrogens in male subjects increased median serum leptin levels from 1.9 ng/mL before treatment to 4.8 ng/mL after 4 months and 5.5 ng/mL after 12 months of treatment (P < 0.0001). Testosterone administration in female subjects decreased median serum leptin levels from 5.6 to 2.6 ng/mL after 4 months and to 2.5 ng/mL after 12 months (P < 0.0001). Analysis of covariance revealed that the changes in serum leptin levels were independent of changes in body fatness in both groups (P < 0.01). In conclusion, these results indicate that sex steroid hormones, in particular testosterone, play an important role in the regulation of serum leptin levels. The prevailing sex steroid milieu, not genetic sex, is a significant determinant of the sex difference in serum leptin levels.