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Long-Term Treatment of Transsexuals with Cross-Sex
Hormones: Extensive Personal Experience
Louis J. Gooren, Erik J. Giltay, and Mathijs C. Bunck Department of Endocrinology (L.J.G., M.C.B.), Vrije Universiteit University Medical Center, 1081 HV Amsterdam, The Netherlands; andLeiden University Medical Center (E.J.G.), Department of Psychiatry, 2333 ZA Leiden, The Netherlands 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 Neth-
erlands (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 ␮g ethinyl estradiol, now 2– 4 mg oral estradiol
valerate/d or 100 ␮g transdermal estradiol/d). Female-to-male transsexuals receive parenteral tes-
tosterone esters 250 mg/2 wk. After 18 –36 months, surgical sex reassignment including gonadec-
tomy 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 osteo-
porosis. 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. (J Clin Endocrinol Metab 93: 19 –25, 2008)
Transsexualism is the condition in which a person with ap- hormone treatment will not be addressed here, but guidelines
parently normal somatic sexual differentiation is con- provided by the World Professional Association for Transgender vinced that she or he is actually a member of the other sex. This Health (http://www.wpath.org) were followed.
conviction is accompanied by an irresistible urge to live in the The acquisition of the secondary sex characteristics of the other gender, which requires hormonal, anatomical, legal, and other gender is fundamental to sex reassignment. Acquisition of psychosocial adaptations. Since its initiation in 1975, 876 fe- these secondary sex characteristics is contingent on sex steroids.
male-to-male (F2M) and 2236 male-to-female transsexuals There is no known essential difference in sensitivity to the bio- (M2F) have received hormonal treatment. Eligibility criteria for logical action of sex steroids on the basis of genetic configura- Abbreviations: F2M, Female-to-male; HDL, high-density lipoprotein; LDL, low-density li- Copyright 2008 by The Endocrine Society doi: 10.1210/jc.2007-1809 Received August 13, 2007. Accepted October 29, 2007.
J Clin Endocrinol Metab, January 2008, 93(1):19 –25 J Clin Endocrinol Metab, January 2008, 93(1):19 –25 tions or gonadal status. The typical transsexual requesting treat- progestational drugs can be stopped. When F2M receive treat- ment is a young to middle-aged and healthy person, and ment with testosterone, part of it is aromatized to estradiol (5).
therefore, there are usually no or few absolute or relative con- When hysterectomy is delayed, there is some concern about en- traindications against cross-sex hormone administration. For suppression of androgen secretion or action, several agents areavailable. In Europe, the most widely used drug is cyproteroneacetate (usually 50 mg twice daily), a progestational compound Long-Term Treatment and Its Effect on Health
with antiandrogenic properties. If not available, medroxypro-gesterone acetate, 5–10 mg/d, is a less effective alternative. Spi- After reassignment surgery, which includes gonadectomy, hor- ronolactone (up to100 mg twice daily, if tolerated), a diuretic mone therapy must be continued. It is reasonable to assume that with antiandrogenic properties, has similar effects. Long-acting the principles of treatment are very similar to those of other GnRH inhibit gonadotropin secretion. Finasteride (5 mg/d), a subjects without their own gonadal hormonal secretion. An un- 5␣-reductase inhibitor, might also be considered. Hormone resolved question is whether in the long term all functions of sex treatment of transsexuals has been reviewed in recent years (1, 2).
steroids of a subject are adequately covered by cross-sex hor-mones and whether the administration of cross-sex hormones isappropriately safe, or at least as safe as administration of sex M2F Transsexual Treatment
steroids in a subject receiving long-term sex-appropriate sex ste-roids. There are presently no indications that there are funda- There is a wide range of estrogens from which to choose. Oral mental sex differences in sensitivity to hormone action of sex ethinyl estradiol (50 –100 ␮g/d) is a potent and inexpensive es- steroids. Nearly all hormone-related biochemical processes can trogen but may cause venous thrombosis, particularly in those be sex reversed by the administration of cross-sex hormones.
over age 40 (1, 3). It should therefore not be used in the dosage It is likely that that there is an underreporting of (serious) required by M2F (50 –100 ␮g/d). Oral 17␤-estradiol valerate, complications of cross-sex hormone therapy. Although the ini- 2– 4 mg/d, or transdermal 17␤-estradiol, 100 ␮g twice a week, tial treatment with cross-sex hormones is mainly concentrated in are the treatments of choice and are much less thrombogenic than specialized centers, complications occurring in the long term are ethinyl estradiol (3). Many transsexuals favor injectable estro- seen in general practice, and these complications are only occa- gens, because they generate high levels of circulating estrogens.
sionally reported in the scientific literature. The authors have However, they have the potential risk of overdose.
been contacted by other physicians on medical occurrences in There is no evidence that progestagens add to the feminiza- transsexuals, but these cases are often lost for follow-up and for tion process of M2F. In female reproductive endocrinology, pro- registration of (potential) complications of cross-sex hormonal gesterone prepares the uterus for conception and the breasts for treatment. The latter situation prevents a fair comparison with lactation. Some patients strongly believe that progestagens are a epidemiological data in the general population. Recently, a web necessary addition to estrogens in their feminization process. But site has been opened for reporting side effects of cross-sex hor- this is not the case, and progestagens may have side effects, such mone treatment: http://www.wpath.org/resources_transgender.
as salt/water retention leading to elevated blood pressure or ve- cfm (click under transgender information: resource links).
nous varicosis. In the large-scale study of postmenopausal hor- In 1997, we published a report on mortality/morbidity in mone use in women, the combination of estrogens and proge- transsexual subjects (7). This was a retrospective, descriptive stagens appeared to be associated with a higher incidence of study of 816 M2F and 293 F2M who had been treated with breast cancer (4) and cardiovascular disease.
cross-sex hormones for a total of 10,152 patient-years. Stan-dardized mortality and incidence ratios were calculated from thegeneral Dutch population (age- and gender-adjusted) and they F2M Transsexual Treatment
were also compared with side effects of cross-sex hormones intranssexuals reported in the literature. Mortality was not higher The goal of treatment in the F2M is to induce virilization (in- than in the general population. Venous thrombosis occurred fre- cluding a deepening of the voice), production of male-pattern quently but could be related to the use of oral ethinyl estradiol body hair growth and physical contours, and cessation of men- (3), and the incidence decreased to the incidence in the general ses. The principal hormonal treatment used to accomplish these population when its use was relinquished. The conclusion of the goals is a testosterone preparation. The most commonly used report was that in the short and midterm, cross-sex hormone preparations are injectable testosterone esters administered im in doses of 200 –250 mg every 2 wk. In some countries, testosterone Cross-sex hormone administration took off in the 1970s, so undecanoate (1000 mg) is available, and injections may be several transsexual subjects are now in their 60s, 70s, and even spaced at 10 –12 wk. Use of androgen gel or transdermal patches 80s. Another important but unresolved question is until what age can also provide good, steady-state testosterone levels. Occa- cross-sex hormone treatment must be continued. This question sionally, menstrual bleeding does not cease, and the addition of must be set against the information that has become available on a progestational agent is necessary, almost always needed when hormone replacement therapy in perimenopausal and post- transdermal or oral testosterone is used.
menopausal women (National Institutes of Health State-of-the- After ovariectomy, androgen therapy must be continued, but Science Conference Statement on management of menopause- J Clin Endocrinol Metab, January 2008, 93(1):19 –25 related symptoms). Should estrogen administration to M2F be mone administration to transsexuals on (biochemical) risk fac- discontinued for the reasons applicable to postmenopausal women? Not needing progestagens to prevent estrogen stimu-lation of uterine hyperplasia and malignancy, would M2F ben- Cardiovascular risk in M2F transsexuals
efit from continued estrogen-only administration in view of the Men with prostate cancer, treated with androgen depriva- reportedly favorable effects of estrogens on bone, the cardiovas- tion, develop an increase of fat mass with an altered lipid profile cular system, and the brain? The issue seems less pressing in F2M (13). These patients also appear to develop insulin resistance, receiving treatment with testosterone because in this group there hyperinsulinemia, and hyperglycemia (13). The risks of diabetes is no high risk of androgen-related malignancies. Transsexuals mellitus increase by 44% and mortality of cardiovascular dis- themselves are usually inclined to continue cross-sex hormone eases by 16% during a follow-up of up to 10 yr. Is there a parallel administration for fear that they would lose physical character- Several studies have been done in M2F transsexuals who re- The following will address some areas where sex hormones ceived estrogens and antiandrogens (either 100 ␮g ethinyl estra- are known to play a role and continuation/discontinuation and diol per day or transdermal 17␤-estradiol 100 ␮g twice a week, dose of hormone administration may be relevant.
with or without 100 mg cyproterone acetate). Many changes incardiovascular risk factors were found, and the results of thesestudies in M2F are summarized in Table 1.
Cross-Sex Hormones and Osteoporosis
Weight, body mass index, total body fat, and visceral fat increased during treatment in M2F (Table 1), resembling fea- Sex steroids play a pivotal role in the maintenance of the integrity tures of the metabolic syndrome. The observed changes in car- of the skeleton in both men and women. Postmenopausal women diovascular risk factors observed in transsexual patients may be and hypogonadal men have an increased risk of fractures. The primarily caused by the increase of the amount of visceral fat in risk of bone loss in subjects undergoing sex reassignment has M2F (14, 15). The increase in fat tissue may lead to an increased been well recognized in the literature (8 –11). In the longer term, hepatic triglyceride influx and a rise of plasma leptin (14).
bone mineral density is preserved during cross-sex hormone ad- High-density lipoprotein (HDL) cholesterol, its subfractions, ministration (10). Apparently, estrogens alone are capable of and triglyceride levels increased (Table 1), to a similar extent as maintaining bone mass in M2F. Conversely, testosterone ad- seen in men treated for prostate cancer (13). Total cholesterol ministration maintains bone mineral density in F2M. Part of was unaffected, and low-density lipoprotein (LDL) cholesterol testosterone is converted to estradiol, resulting in circulating es- levels decreased by 12% in M2F (14), whereas total and LDL tradiol levels well above the plasma level of estradiol critical for cholesterol levels were found to increase by 9% in men treated preserving bone mineral density in men (i.e. 40 –50 pmol/liter) for prostate cancer (13). The low estrogen state observed in these (5). In our study, there was an inverse relationship between se- men is responsible for the increases in total and LDL cholesterol.
rum LH concentrations and bone mineral density, so serum LH The latter was not observed in our transsexual patients who may serve as an indicator of the adequacy of sex steroid admin- receive, in addition to the androgen deprivation, treatment with istration (10). It is not known whether cross-sex hormone ad- estrogens. The slight decrease in LDL cholesterol seen in trans- ministration can be responsibly discontinued at a certain age sexuals was, however, accompanied by a decrease in LDL par- without inducing an unacceptable risk of osteoporosis and bone ticle size (14), another known cardiovascular risk factor. A study by another group found that administering GnRH agonists plusoral 17␤-estradiol valerate to M2F induced endocrine changessimilar to our studies but without an impairment of the lipid Cross-Sex Hormones and Cardiovascular
profile. The use of cyproterone acetate might explain the differ- ences. Indeed, a study using cyproterone acetate in prostate can-cer patients found a serious deterioration of the lipid profile.
Men have a higher incidence of cardiovascular events than The effects on insulin sensitivity encountered in our studies women of similar ages (12). There is, however, no evidence sup- were largely in the same detrimental direction (14) as in men with porting a causal relation between higher testosterone levels and prostate cancer treated with GnRH agonists (13). The deleteri- heart disease (12). There is as yet no true insight into the effects ous effects on insulin sensitivity are, therefore, likely due to an- of cross-sex hormone treatment on cardiovascular health. As can drogen deprivation. We found that insulin sensitivity (assessed be expected, cases of cardiovascular complications of transsex- by hyperinsulinemic euglycemic clamp) decreased, and this was uals have been reported in the literature, but it is not warranted accompanied by a compensatory increase in fasting plasma in- to generalize them to the whole population of transsexuals.
sulin concentration preventing hyperglycemia (Table 1) (14). En- There is as yet no true insight into the effects of cross-sex hor- dogenous glucose production (measured by isotope dilution with mone treatment on cardiovascular health. As can be expected, titrated glucose) was, however, not affected by cross-sex hor- cases of cardiovascular complications of transsexuals have been mone administration, indicating that the observed changes in reported in the literature, but it is not warranted to generalize glucose requirement during a hyperinsulinemic euglycemic them to the whole population of transsexuals. Over the past 15 clamp procedure were due to the diminished peripheral glucose yr, we have extensively investigated the effects of cross-sex hor- uptake (16), a finding that was later confirmed by Elbers et al. J Clin Endocrinol Metab, January 2008, 93(1):19 –25 TABLE 1. Changes over 4 –12 months in risk factors for cardiovascular disease in M2F transsexuals
Effect on CVD
morbidity/
Absolute change
Relative change
mortality
Tissue-type plasminogen activator antigen Plasminogen activator inhibitor-1 antigen Ϫ, No change in CVD risk; 1, increased CVD risk; 2, decreased CVD risk; CVD, cardiovascular disease; DHA, docosahexaenoic acid; LBM, lean body mass; MRI,magnetic resonance imaging; NS, no statistically significant change.
(14). We further found that blood pressure slightly increased HDL cholesterol, fasting triglycerides, total homocysteine, and during estrogen and antiandrogen treatment, and there was a C-reactive protein (Table 2). Blood pressure and arterial stiff- small detrimental effect on arterial stiffness (17).
ness, unlike in other reports, were unaffected by cross-sex hor-mone treatment (17).
Cardiovascular risk in F2M transsexuals
Hyperandrogenism in women, usually resulting from the polycystic ovarian syndrome, is associated with an unfavorable Concluding remarks on cardiovascular risk
cardiovascular risk profile. However, hyperandrogenism in Cross-sex hormone administration in M2F and F2M both polycystic ovarian syndrome is usually clustered with features of improves and impairs profiles of cardiovascular risk factors. It the metabolic syndrome (hyperinsulinemia, visceral obesity, hy- remains difficult to determine how much weight must be attrib- pertension, and dyslipidemia). It is difficult to disentangle the uted to these alterations in risk factors and whether these changes contributions that the various components of the metabolic syn- are of clinical significance. With these reservations in mind, the drome make to this unfavorable cardiovascular risk profile, overall impression is that inducing androgen deprivation and an more precisely, what the role of hyperandrogenism per se is.
estrogen milieu in M2F has a larger deleterious effect on the risk The results from studies in F2M transsexuals are summarized factors, than inducing an androgenic milieu in F2M (Tables 1 in Table 2. The observed changes in cardiovascular risk factors seen in F2M may again be secondary to the increase in weight and So far the only data available on hard clinical endpoints is the amount of visceral fat (14). Our group has shown that tes- from our study on cardiovascular morbidity and mortality in tosterone administration to F2M decreases plasma leptin (14); both M2F and F2M (7). This study reports no elevated (cardio- furthermore, a decrease in serum adiponectin concentration has vascular) morbidity and/or mortality in the cohort of transsex- been reported. We found a slight decrease of insulin sensitivity in uals treated at the Amsterdam clinic. Yet, to reduce the risk of the one of our studies (14, 16). Furthermore, increases were found in metabolic syndrome and cardiovascular disease and to increase J Clin Endocrinol Metab, January 2008, 93(1):19 –25 TABLE 2. Changes over 4 –12 months in risk factors for cardiovascular disease in F2M transsexuals
Effect on CVD
morbidity/
Absolute change
Relative change
mortality
Tissue-type plasminogen activator antigen Plasminogen activator inhibitor-1 antigen Ϫ, No change in CVD risk; 1, increased CVD risk; 2, decreased CVD risk; CVD, cardiovascular disease; DHA, docosahexaenoic acid; LBM, lean body mass; MRI,magnetic resonance imaging; NS, no statistically significant change.
life expectancy, it is important to advise transsexuals to adopt following is a summary of reports in the literature on tumors in healthy lifestyle and dietary behaviors.
The first documented hormone treatments of transsexuals started in the 1970s, and the length of time of exposure to hor-mones may have been too short for tumors to manifest them- Cross-Sex Hormones and Hormone-Dependent
selves. Therefore, the conclusion that hormone-related tumors are not highly prevalent among the transsexual population must Some cancers (of reproductive organs) are hormone related.
Hormone-dependent tumors are practically not occurring inhormonally treated F2M and seem a rare occurrence in M2F. But Lactotroph adenoma
transsexualism is a rare phenomenon (the highest estimates are Several cases of lactotroph adenoma (prolactinoma) after one in 12,000 males and one in 30,000 females) (18); if, in ad- high-dose estrogen administration have been reported in patients dition, the prevalence of hormone-dependent tumors is low, this with normal serum prolactin concentrations before therapy (7, may lead to an underestimation of tumors.
19 –21). We have recently encountered a case of development of M2F, as a rule, use higher doses of estrogens than women a pituitary microprolactinoma in a M2F, only occurring after 14 lacking production of gonadal hormones. In transsexuals, ex- yr of normal-dose estrogen treatment. Although causality has posure to estrogens is usually over a shorter period of lifetime, not been established, we recommend that serum prolactin levels because transsexuals mostly start cross-sex hormone treatment continue to be monitored in estrogen-treated M2F in the long well after puberty, although this is changing. Presently, adoles- cent transsexuals may be eligible for cross-sex hormone treat-ment. Furthermore, transsexuals beyond the ages of 50 or 60 yr Breast cancer
have a strong inclination to continue cross-sex hormones, in- There are two reports of M2F who developed breast carci- creasing their period of time of exposure to sex steroids. The nomas while receiving estrogen treatment (22, 23). Breast fibro- J Clin Endocrinol Metab, January 2008, 93(1):19 –25 adenomas in M2F receiving hormonal treatment have been ob- tenable, but there is an up-regulation of androgen receptors in served. In our series of approximately 2200 M2F, cumulative ovarian and uterine tissue in long-term treated F2M (32).
over 30 yr, until recently, no single case of breast cancer had beenobserved, but there is now one case. On the basis of the aboveinformation, one would be inclined to think that breast carci- Conclusions
nomas in M2F are rare, but it has to be kept in mind that 1800subjects, with a strong variation in estrogen exposure (from 1–25 It is now clear that sex reassignment of transsexuals benefits their yr), do not allow firm conclusions in assessing risk. Aging is a well-being, (33) although suicide rates remain high (7). Regrets factor in the development of cancer, and prolonged exposure to are rare (0.5–3.0%). Cross-sex hormone administration to estrogens may also prove to be a factor. Therefore, the discussion transsexuals is acceptably safe in the short and medium term.
as to the age at which estrogen treatment in M2F should be However, potentially adverse effects in the longer term are pres- terminated is pertinent. In any case, in addition to regular med- ently unknown. The data, although limited, of surrogate markers ical examination, breast self-examination must be part of the of cardiovascular disease and the reports of cancer in transsex- monitoring of estrogen administration, following the same uals leave room for a cautious optimism. But true insight can only guidelines that exist for other women.
come from close monitoring and thorough reporting of adverse Amazingly, breast cancer has been reported in a F2M after bilateral sc mastectomy while receiving treatment with testos-terone. This occurred in residual mammary tissue after 10 yr oftreatment with testosterone, which is partially aromatized to Acknowledgments
We thank Professor David Handelsman, ANZAC Research Institute,Sydney, Australia, for his helpful comments.
Benign prostate hyperplasia and prostate cancer
Address all correspondence and requests for reprints to: Dr. L. J.
The prostate is not removed with sex reassignment surgery.
Gooren, Department of Endocrinology, VU University Medical Center, Prostatectomy is a surgically cumbersome operation, with pos- De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands. E-mail: sible complications, such as urinary incontinence. As expected, Disclosure Statement: The authors have nothing to declare.
the prostate volume shrinks after androgen deprivation. Estro-gen exposure does not induce signs of hyperplasia or (pre)ma-lignancy (25). Two cases of benign prostate hyperplasia, requir-ing transurethral prostate resection, have been described in References
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