At the Centre for andrology and sexual medicine at Karolinska University Hospital about 30 genetic males (MtF) and 25 genetic females (FtM) every year start hormone replacement therapy. This hormonal treatment includes inhibition of one's own sex hormone production (down regulation of the gonadal axis) followed by treatment with testosterone or estrogen levels that are normal for the opposite sex. Seen as experimental model, this is a process that provides an opportunity to study the sex hormone dependent influences that explain differences in morbidity in men and women respectively. Furthermore, the constitutional differences distinguish them from those that are dynamically addressable through change in the hormonal milieu. The differences that are especially significant but not well known is 1) metabolic changes in the regulation of glucose homeostasis and lipid metabolism 2) regulation of vascular function and structural effects on the heart and arteries 3) regulation of skeletal muscle mass and fat tissue 4) morphological and functional effects on discrete areas of the brain.

It is well known that testosterone has a dose-response effect on body composition in men while conditions are less well known in women. Thus, it is not known how the adult woman's body responds to male levels of testosterone, and if the dose response relation is similar or different than that of men. The clinical impression is that women have less effect of androgen on muscle mass than men. Furthermore, it is not known whether the qualitative properties are comparable, i.e. muscle force/unit area. The basic hypothesis is that there are no constitutional sex differences in androgen response. If there are differences, we are looking to identify differences in gene expression. Another hypothetical regulatory mechanism is epigenetic differences which are not dynamically modifiable by androgen exposition. Difference in cardiovascular morbidity between men and women is well known, but there is considerable confusion if and how radical changes of sex hormone levels affects the function of the cardiovascular system both with acute and chronic exposure. Radical change of estrogen and testosterone levels can also affect the risk for metabolic disorders (lipid, carbohydrate and protein metabolism) which can cause hazard for both metabolic diseases such as diabetes and cardiovascular disease in the long term but also be a risk for future muscle weakness and osteoporosis. Effects on the central nervous system as a result of changes of sex hormone profile are not well known. However, we have several observations indicating that changes in sex hormone levels have visual effects (shown by MRI and PET) on distinctive features of the central nervous system.

Therefore, we will follow these patients for a year to study how the heart, blood vessels, brain, and risk factors for cardiovascular disease affected by altered sex hormone patterns and studying what happens in the muscles and fat in both the short and long term with respect to particular gene expression and epigenetic changes and link it to metabolic changes and body composition. Forty volunteers with gender dysphoria, 20 MtF and 20 FtM, are studied before the onset of sex hormone therapy, after a four-week shutdown of endogenous sex hormones and during one year of sex hormone treatment.