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: A university hospital serving as the national referral center for in 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 anti-androgen cyproterone acetate 100mg/d +estrogens (earlier 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 weeks. After 18-36 months surgical sex reassignment including gonadectomy follows inducing a profound hypogonadal state.

Main outcome measures: .Morbidity and mortality data; data assessing risks of osteoporosis and cardiovascular disease.

Results: Mortality was not higher than in a comparison group. 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 + 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.