Objective: Adverse effects of long-term cross-sex hormone administration to transsexuals are not well documented. We assessed mortality rates in transsexual subjects receiving long-term cross-sex hormones. Design: A cohort study with a median follow-up of 18.5 years at a university gender clinic. Methods: Mortality data and the standardized mortality rate were compared with the general population in 966 male-to-female (MtF) and 365 female-to-male (FtM) transsexuals, who started cross-sex hormones before July 1, 1997. Follow-up was at least 1 year. MtF transsexuals received treatment with different high-dose estrogen regimens and cyproterone acetate 100 mg/day. FtM transsexuals received parenteral/oral testosterone esters or testosterone gel. After surgical sex reassignment, hormonal treatment was continued with lower doses. Results: In the MtF group, total mortality was 51% higher than in the general population, mainly from increased mortality rates due to suicide, acquired immunodeficiency syndrome, cardiovascular disease, drug abuse, and unknown cause. No increase was observed in total cancer mortality, but lung and hematological cancer mortality rates were elevated. Current, but not past ethinyl estradiol use was associated with an independent threefold increased risk of cardiovascular death. In FtM transsexuals, total mortality and cause-specific mortality were not significantly different from those of the general population. Conclusions: The increased mortality in hormone-treated MtF transsexuals was mainly due to nonhormone-related causes, but ethinyl estradiol may increase the risk of cardiovascular death. In the FtM transsexuals, use of testosterone in doses used for hypogonadal men seemed safe.
Mortality in male-to-female and female-to-male transsexuals is not increased during cross-sex hormone treatment. Transdermal oestradiol administration is recommended in male-to-female transsexuals, particularly in the population over 40 years in whom a high incidence of venous thromboembolism was observed with oral oestrogens. It seems that in view of the deep psychological needs of transsexuals to undergo sex reassignment, our treatment schedule of cross-sex hormone administration is acceptably safe.
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.
Hyperinsulinemia is a common finding in hyperandrogenic women, during pregnancy, and in women using oral contraceptives. To test whether sex hormone treatment can induce insulin resistance in healthy subjects, we studied the effects of administration of testosterone to 13 female to male and of ethinyl estradiol to 18 male to female transsexuals. Utilization and production of glucose and levels of sex steroids were measured during a three-step hyperinsulinemic-euglycemic clamp before and after 4 months of hormone administration. Females were treated with im injections of testosterone esters (250 mg/2 weeks); males were treated with ethinyl estradiol alone (0.1 mg/day, orally) or a combination of ethinyl estradiol and cyproterone acetate (100 mg/day, orally). Similar insulin levels were achieved at each of the three steps of the clamp studies before and during hormone administration. During step 1 of each clamp, with insulin levels in the physiological range, glucose utilization decreased from 3.5 +/- 1.2 to 2.6 +/- 0.9 mmol/kg lean body mass (LBM).h in women treated with testosterone esters (P < 0.001) and from 3.2 +/- 0.7 to 2.5 +/- 0.5 mmol/kg lean body mass.h in men treated with ethinyl estradiol (P < 0.001). The effects of sex steroids during steps 2 and 3 of the clamp at higher (supraphysiological) insulin levels were less clear. Endogenous glucose production (measured by isotope dilution with tritiated glucose) was not affected by hormone administration, indicating that the observed changes in glucose requirement were determined by a diminished peripheral glucose uptake. We conclude that sex hormone administration, i.e. testosterone treatment in females and ethinyl estradiol treatment in males, can induce insulin resistance in healthy subjects.
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