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Henk Asscheman, Erik J Giltay, Jos A J Megens, W (Pim) de Ronde, Michael A A van Trotsenburg, and Louis J G Gooren


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.


A cohort study with a median follow-up of 18.5 years at a university gender clinic.


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.


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.


The increased mortality in hormone-treated MtF transsexuals was mainly due to non-hormone-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.

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Desiree Kronawitter, Louis J Gooren, Hendryk Zollver, Patricia G Oppelt, Matthias W Beckmann, Ralf Dittrich, and Andreas Mueller


It has been reported that hypoactive sexual desire disorder (HSDD) affects one-third of transsexual women (defined as postoperative male-to-female transsexuals) receiving estrogen replacement whose bioavailable androgen levels are lower than in ovulating women and comparable with those in surgically postmenopausal women. The aim of this study was to evaluate the efficacy of transdermal testosterone treatment and of oral dydrogesterone in transsexual women with HSDD receiving estrogens.


Seven transsexual women with HSDD were treated with a testosterone patch and nine transsexual women with HSDD were treated with oral dydrogesterone over 24 weeks. The primary end point was the change in the brief profile of female sexual function (B-PFSF) score. Secondary end points were changes in hormonal parameters and side effect assessments.


A significant increase in total testosterone and free testosterone levels was observed in the group receiving transdermal testosterone. At 24 weeks, there was a significant improvement in the B-PFSF score showing an improvement in sexual desire among transsexual women treated with the testosterone patch, whereas no change in the B-PFSF score was observed in transsexual women treated with oral dydrogesterone. No side effects were reported.


In this pilot study, sexual desire in transsexual women improved significantly after treatment with the testosterone patch, without noticeable side effects.

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Mathijs C M Bunck, Arno W F T Toorians, Paul Lips, and Louis J G Gooren

Objective: Cases of men with estrogen resistance and aromatase deficiency have highlighted the effects of estrogens on bone metabolism, the cardiovascular system and biochemical variables of the metabolic syndrome. In eugonadal men, administration of an aromatase inhibitor induces a substantial elevation of LH and testosterone due to the decreased negative-feedback signal of estrogen and may thwart the interpretation of results. As there is no gonad for LH to act on, no increase of serum testosterone concentration will be seen in female-to-male transssexuals. The aim of this study was to investigate the effects of estrogen deprivation on bone metabolism and vascular parameters without the interference of counter-regulatory effects as seen in eugonadal men.

Design: Thirty ovariectomized female-to-male transsexuals participated in this double-blind, randomized trial. During 3 months, subjects received the aromatase inhibitor anastrozole 1 mg/day (n = 16) or a placebo (n = 14) in addition to parenteral testosterone esters (Sustanon 250 every 2 weeks).

Results: Serum 17β-estradiol (E2) concentration fell significantly from 134.0 ± 78.8 to 77.7 ± 130.6 pmol/l compared with placebo (P < 0.01). LH and FSH levels rose without the rise of testosterone levels observed in eugonadal men. Within the placebo group, E2 remained at baseline levels. Of the endpoint variables measured (bone metabolism and vascular parameters) no significant changes were observed compared with placebo, or within the anastrozole-treated group.

Conclusions: These results may indicate that the negative effects of estrogen deprivation in men only become manifest when the concentration falls below the levels induced by our intervention with anastrozole (77 pmol/l). This assumption is supported by the observation in the anastrozole group that, although effects of the reduction of serum E2 on vascular parameters could not be demonstrated in subjects as a group, there was a correlation between individual serum E2 and several vascular parameters.

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Hilleke E Hulshoff Pol, Peggy T Cohen-Kettenis, Neeltje E M Van Haren, Jiska S Peper, Rachel G H Brans, Wiepke Cahn, Hugo G Schnack, Louis J G Gooren, and René S Kahn

Objective: Sex hormones are not only involved in the formation of reproductive organs, but also induce sexually-dimorphic brain development and organization. Cross-sex hormone administration to transsexuals provides a unique possibility to study the effects of sex steroids on brain morphology in young adulthood.

Methods: Magnetic resonance brain images were made prior to, and during, cross-sex hormone treatment to study the influence of anti-androgen + estrogen treatment on brain morphology in eight young adult male-to-female transsexual human subjects and of androgen treatment in six female-to-male transsexuals.

Results: Compared with controls, anti-androgen + estrogen treatment decreased brain volumes of male-to-female subjects towards female proportions, while androgen treatment in female-to-male subjects increased total brain and hypothalamus volumes towards male proportions.

Conclusions: The findings suggest that, throughout life, gonadal hormones remain essential for maintaining aspects of sex-specific differences in the human brain.