Context: Transsexuals receive cross-sex hormone treatment. Its short-term use appears reasonably safe. Little is known about its long-term use. This report offers some perspectives.

Setting: The setting was a university hospital serving as the national referral center for The Netherlands (16 million people).

Patients: From the start of the gender clinic in 1975 up to 2006, 2236 male-to-female and 876 female-to-male transsexuals have received cross-sex hormone treatment. In principle, subjects are followed up lifelong.

Interventions: Male-to-female transsexuals receive treatment with the antiandrogen cyproterone acetate 100 mg/d plus estrogens (previously 100 μg ethinyl estradiol, now 2–4 mg oral estradiol valerate/d or 100 μg transdermal estradiol/d). Female-to-male transsexuals receive parenteral testosterone esters 250 mg/2 wk. After 18–36 months, surgical sex reassignment including gonadectomy follows, inducing a profound hypogonadal state.

Main Outcome Measures: Outcome measures included morbidity and mortality data and data assessing risks of osteoporosis and cardiovascular disease.

Results: Mortality was not higher than in a comparison group. Regarding morbidity, with ethinyl estradiol, there was a 6–8% incidence of venous thrombosis, which is no longer the case with use of other types of estrogens. Continuous use of cross-sex hormones is required to prevent osteoporosis. Androgen deprivation plus an estrogen milieu in male-to-female transsexuals has a larger deleterious effect on cardiovascular risk factors than inducing an androgenic milieu in female-to-male transsexuals, but there is so far no elevated cardiovascular morbidity/mortality. Low numbers of endocrine-related cancers have been observed in male-to-female transsexuals.

Conclusions: Cross-sex hormone treatment of transsexuals seems acceptably safe over the short and medium term, but solid clinical data are lacking.