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LONG-TERM TREATMENT OF TRANSSEXUALS WITH CROSS-SEX
HORMONES: EXTENSIVE PERSONAL EXPERIENCE
Louis J. Gooren1, Erik J. Giltay2, Mathijs C. Bunck1
1. Department of Endocrinology, VU University Medical Center, Amsterdam, the Netherlands
2. Leiden University Medical Center, Department of Psychiatry, Leiden, The Netherlands
Abbreviated title: Endocrine treatment of transsexuals
Word count: 3,952
Correspondence and requests for reprints to
Dr L.J. Gooren,
Dept of Endocrinology, VU University Medical Center
De Boelelaan 1118
1081 HV Amsterdam, the Netherlands
Telephone +66 89612 7650
Fax +3120 4440502
e-mail [email protected]
Disclosure summary:
The authors have nothing to declare
Key words:
transsexuals, estrogen administration, testosterone administration, long-term side-effects,
J Clin Endocrin Metab. First published ahead of print November 6, 2007 as doi:10.1210/jc.2007-1809
Copyright (C) 2007 by The Endocrine Society
2
ABSTRACT
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-tomale
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.
3
Introduction
Transsexualism is the condition in which a person with
apparently normal somatic sexual differentiation is
convinced that s/he is actually a member of the other
sex. This conviction is accompanied by an irresistible
urge to live in the other gender which requires
hormonal, anatomical, legal, and psychosocial
adaptations. Since its initiation in 1975, 876 female-tomale
(F2M) and 2236 male-to-female transsexuals
(M2F) have received hormonal treatment. Eligibility
criteria for hormone treatment will not be addressed
here but guidelines provided by WPATH
(http://www.wpath.org) were followed.
The acquisition of the secondary sex characteristics
of the other gender is fundamental to sex
reassignment. Acquisition of these secondary sex
characteristics is contingent on sex steroids. There
is no known essential difference in sensitivity to the
biological action of sex steroids on the basis of
genetic configurations or gonadal status. The
typical transsexual requesting treatment is a young
to middle-aged and healthy person and, therefore,
and there are usually no or few absolute or relative
contraindications against cross-sex hormone
administration. For suppression of androgen
secretion or action, several agents are available. In
Europe, the most widely-used drug is cyproterone
acetate (usually 50 mg twice daily), a progestational
compound with antiandrogenic properties. If not
available, medroxyprogesterone acetate, 5 to 10
mg/day, is a less effective alternative.
Spironolactone (up to100 mg twice daily, if
tolerated), a diuretic with antiandrogenic properties,
has similar effects. Long-acting gonadotrophinreleasing
hormone agonists (GnRH) inhibit
gonadotropin secretion. Finasteride (5 mg/day), a
5α-reductase inhibitor, might also be considered.
Hormone treatment of transsexuals has been
reviewed in recent years [1, 2].
Male-to-female transsexual treatment
There is a wide range of estrogens from which to
choose. Oral ethinyl estradiol (50 to 100 μg/day) is
a potent and inexpensive estrogen, but may cause
venous thrombosis, particularly in those over age
40 [1] [3]. It should therefore not be used in the
dosage required by M2F (50-100 μg/day). Oral
17β-estradiol valerate, 2 to 4 mg per day, or
transdermal 17β-estradiol, 100 μg twice a week, are
the treatments of choice, and are much less
thrombogenic than ethinyl estradiol [3]. Many
transsexuals favor injectable estrogens, as they
generate high levels of circulating estrogens.
However, they have the potential risk of overdose.
There is no evidence that progestagens add to the
feminization process of M2F. In female
reproductive endocrinology, progesterone prepares
the uterus for conception, and the breasts for
lactation. Some patients strongly believe that
progestagens are a necessary addition to estrogens
in their feminization process. But this is not the
case, and progestagens may have side effects, such
as salt/water retention leading to elevated blood
pressure or venous varicosis. In the large-scale
study of postmenopausal hormone use in women,
the combination of estrogens and progestagens
appeared to be associated with a higher incidence of
breast cancer[4] and cardiovascular disease.
Female-to-male transsexual treatment
The goal of treatment in the F2M is to induce
virilization (including a deepening of the voice),
production of male-pattern body hair growth and
physical contours, and cessation of menses. The
principal hormonal treatment used to accomplish
these goals is a testosterone preparation. The most
commonly used preparations are injectable
testosterone esters administered intramuscularly in
doses of 200 to 250 mg every two weeks. In some
countries, testosterone undecanoate (1000 mg) is
available, and injections may be spaced at 10-12
weeks . Use of androgen gel or transdermal patches
can also provide good, steady state testosterone
levels. Occasionally, menstrual bleeding does not
cease, and the addition of a progestational agent is
necessary, almost always needed when transdermal
or oral testosterone is used.
Following ovariectomy androgen therapy must be
continued but progestational drugs can be stopped.
When F2M receive treatment with testosterone, part
of it is aromatized to estradiol [5]. When
hysterectomy is delayed there is some concern
about endometrial cancer [6].
Long-term treatment and its effect on health
After reassignment surgery, which includes
gonadectomy, hormone therapy must be continued.
It is reasonable to assume that the principles of
4
treatment are very similar to those of other subjects
without own gonadal hormonal secretion. An
unresolved question is whether in the long-term all
functions of sex steroids of a subject are adequately
covered by cross-sex hormones and whether the
administration of cross-sex hormones is
appropriately safe, or at least as safe as
administration of sex steroids in a subject receiving
long-term sex-appropriate sex steroids. There are
presently no indications that there are fundamental
sex differences in sensitivity to hormone action of
sex steroids. Nearly all hormone-related
biochemical processes can be sex-reversed by the
administration of cross-sex hormones.
It is likely that that there is an underreporting of
(serious) complications of cross-sex hormone
therapy. While the initial treatment with cross-sex
hormones is mainly concentrated in specialized
centers, complications occurring in the long-term
are seen in general practice, and these
complications are only occasionally reported in the
scientific literature. The authors have been
contacted by other physicians on medical
occurrences in transsexuals, but these cases are
often lost for follow-up and for registration of
(potential) complications of cross-sex hormonal
treatment. The latter situation prevents a fair
comparison with epidemiological data in the
general population. Recently, a website has been
opened for reporting side effects of cross-sex
hormone treatment:
http://www.wpath.org/resources_transgender.cfm,
click under transgender information: resource links.
In 1997 we published a report on
mortality/morbidity in transsexual subjects [7]. This
was a retrospective, descriptive study of 816 M2F
and 293 F2M who had been treated with cross-sex
hormones for a total of 10,152 patient-years.
Standardized mortality and incidence ratios were
calculated from the general Dutch population (ageand
gender-adjusted) and they were also compared
to side effects of cross-sex hormones in
transsexuals reported in the literature. Mortality
was not higher than in the general population.
Venous thrombosis occurred frequently but could
be related to the use of oral ethinyl estradiol [3],
and the incidence decreased to the incidence in the
general population when its use was relinquished.
The conclusion of the report was that in the short
and mid-term cross-sex hormone treatment was
acceptably safe.
Cross-sex hormone administration took off in the
1970-ies so several transsexual subjects are now in
their 60-ies, 70-ies and even 80-ies. Another
important but unresolved question is until what age
cross-sex hormone treatment must be continued.
This question must be set against the information
which has become available on hormone
replacement therapy in perimenopausal and
postmenopausal women (NIH State-of-the-Science
Conference Statement on management of
menopause-related symptoms). Should estrogen
administration to M2F be discontinued for the
reasons applicable to postmenopausal women? Not
needing progestagens to prevent estrogen
stimulation of uterine hyperplasia and malignancy,
would M2F benefit from continued estrogen-only
administration in view of the reportedly favorable
effects of estrogens on bone, the cardiovascular
system and the brain? The issue seems less pressing
in F2M receiving treatment with testosterone since
in this group there is no high risk of androgenrelated
malignancies. Transsexuals themselves are
usually inclined to continue cross-sex hormone
administration for fear that they would lose
physical characteristics of the reassigned sex.
The following will address some areas where sex
hormones are known to play a role and
continuation/discontinuation and dose of hormone
administration may be relevant.
Cross-sex hormones and osteoporosis
Sex steroids play a pivotal role in the maintenance
of the integrity of the skeleton in both men and
women. Postmenopausal women and hypogonadal
men have an increased risk of fractures. The risk of
bone loss in subjects undergoing sex reassignment
has been well recognized in the literature [8-11]. In
the longer-term bone mineral density is preserved
during cross-sex hormone administration [10].
Apparently, estrogens alone are capable of
maintaining bone mass in M2F. Conversely,
testosterone administration maintains bone mineral
density in F2M. Part of testosterone is converted to
estradiol resulting in circulating estradiol levels
well above the plasma level of estradiol critical for
preserving bone mineral density in men (i.e., 40-50
pmol/L)[5]. In our study there was an inverse
relationship between serum luteinizing hormone
5
(LH) concentrations and bone mineral density, so
serum LH may serve as an indicator of the
adequacy of sex steroid administration [10]. It is
not known whether cross-sex hormone
administration can be responsibly discontinued at a
certain age without inducing an unacceptable risk
of osteoporosis and bone fractures.
Cross-sex hormones and cardiovascular disease
Men have a higher incidence of cardiovascular
events than women of similar ages[12]. There is,
however, no evidence supporting a causal relation
between higher testosterone levels and heart
disease[12]. There is as yet no true insight into the
effects of cross-sex hormone treatment on
cardiovascular health. As can be expected, cases of
cardiovascular complications of transsexuals have
been reported in the literature, but it is not
warranted to generalize them to the whole
population of transsexuals. T
the effects of cross-sex hormone administration to
transsexuals on (biochemical) risk factors of
cardiovascular disease.
Cardiovascular risk in male-to-female
transsexuals
Men with prostate cancer, treated with androgen
deprivation, develop an increase of fat mass with an
altered lipid profile [13]. These patients also appear
to develop insulin resistance, hyperinsulinemia and
hyperglycemia [13]. The risks of diabetes mellitus
increase by 44% and mortality of cardiovascular
diseases by 16% during a follow-up of up to 10
years. Is there a parallel in M2F upon androgen
deprivation?
Several studies have been done in male-to-female
transsexuals who received estrogens and
antiandrogens (either 100 μg ethinylestradiol per
day, or transdermal 17β-estradiol 100 μg twice a
week, with or without 100 mg cyproterone acetate).
Many changes in cardiovascular risk factors were
found and the results of these studies in M2F are
summarized in table 1.
Weight, body mass index, total body fat and
visceral fat increased during treatment in M2F
(Table 1) resembling features of the metabolic
syndrome. The observed changes in cardiovascular
risk factors observed in transsexual patients may be
primarily caused by the increase of the amount of
visceral fat in M2F [14, 15]. The increase in fat
tissue may lead to an increased hepatic triglyceride
influx and a rise of plasma leptin [14]).
High-density lipoprotein (HDL) cholesterol, it
subfractions and triglyceride levels increased
(Table 1), in similar extent as seen in men treated
for prostate cancer [13]. Total cholesterol was
unaffected and low-density lipoprotein (LDL)
cholesterol levels decreased by 12% in M2F [14],
whereas total and LDL cholesterol levels were
found to increase by 9% in men treated for prostate
cancer [13]. The low estrogen state observed in
these men is responsible for the increases in total
and LDL cholesterol. The latter was not observed in
our transsexual patients who receive in addition to
the androgen deprivation, treatment with estrogens.
The slight decrease in LDL cholesterol seen in
transsexuals was, however, accompanied by a
decrease in LDL particle size [14], another known
cardiovascular risk factor. A study by another
group, found that administering GnRH agonists +
oral 17β-estradiol valerate to M2F induced
endocrine changes similar to our studies, but
without an impairment of the lipid profile . The use
of cyproterone acetate might explain the
differences. Indeed, a study using cyproterone
acetate in prostate cancer patients found a serious
deterioration of the lipid profile .
The effects on insulin sensitivity encountered in our
studies were largely in the same detrimental
direction [14] as in men with prostate cancer treated
with GnRH agonists [13]. The deleterious effects
on insulin sensitivity are, therefore, likely due to
androgen deprivation. We found that insulin
sensitivity (assessed by hyperinsulinemic
euglycemic clamp) decreased, and this was
accompanied by a compensatory increase in fasting
plasma insulin concentration preventing
hyperglycemia (Table 1) [14]. Endogenous glucose
production (measured by isotope dilution with
titrated glucose) was however not affected by crosssex
hormone administration, indicating that the
observed changes in glucose requirement during an
hyperinsulinemic euglycemic clamp procedure
were due to the diminished peripheral glucose
uptake [16], a finding that was later confirmed by
Elbers et al [14]. We further found that blood
pressure slightly increased during estrogen and
antiandrogen treatment, and there was a small
detrimental effect on arterial stiffness [17].
6
Cardiovascular risk in female-to-male
transsexuals
Hyperandrogenism in women, usually resulting
from the polycystic ovarium syndrome (PCOS), is
associated with an unfavorable cardiovascular risk
profile. However, hyperandrogenism in PCOS is
usually clustered with features of the metabolic
syndrome (hyperinsulinemia, visceral obesity,
hypertension, dyslipidemia). It is difficult to
disentangle the contributions that the various
components of the metabolic syndrome make to
this unfavourable cardiovascular risk profile, more
precisely what the role of hyperandrogenism per se
is.
The results from studies in F2M transsexuals are
summarized in Table 2. The observed changes in
cardiovascular risk factors seen in F2M may again
be secondary to the increase in weight and the
amount of visceral fat [14]. Our group has shown
that testosterone administration to F2M decreases
plasma leptin [14]; further a decrease in serum
adiponectin concentration has been reported . We
found a slight decrease of insulin sensitivity in one
of our studies [14, 16]. Furthermore, increases were
found in HDL cholesterol, fasting triglycerides,
total homocysteine, and C-reactive protein (Table
2). Blood pressure and arterial stiffness, unlike in
other reports, were unaffected by cross-sex
hormone treatment [17].
Concluding remarks on cardiovascular risk
Cross-sex hormone administration in M2F and F2M
both improves and impairs profiles of
cardiovascular risk factors. It remains difficult to
determine how much weight must be attributed to
these alterations in risk factors and whether these
changes are of clinical significance. With these
reservations in mind, the overall impression is that
inducing androgen deprivation and an estrogen
milieu in M2F has a larger deleterious effect on the
risk factors, than inducing an androgenic milieu in
F2M (Tables 1 and 2).
So far the only data available on hard clinical
endpoints is from our study on cardiovascular
morbidity and mortality in both M2F and F2M [7].
This study reports no elevated (cardiovascular)
morbidity and/or mortality in the cohort of
transsexuals treated at the Amsterdam clinic. Yet,
to reduce the risk of the metabolic syndrome and
cardiovascular disease and to increase life
expectancy, it is important to advice transsexuals to
adopt healthy lifestyle and dietary behaviors.
Cross-sex hormones and hormone-dependent
tumors
Some cancers (of reproductive organs) are hormone
related. Hormone-dependent tumors are practically
not occurring in hormonally treated F2M and seem
a rare occurrence in M2F. But transsexualism is a
rare phenomenon (the highest estimates are
1;12,000 males and 1;30,000 females [18]); if, in
addition the prevalence of hormone-dependent
tumors is low, this may lead to an underestimation
of tumors.
M2F, as a rule, use higher doses of estrogens than
women lacking production of gonadal homones. In
transsexuals exposure to estrogens is usually over a
shorter period of lifetime, since transsexuals mostly
start cross-sex hormone treatment well after
puberty, though this is changing. Presently,
adolescent transsexuals may be eligible for crosssex
hormone treatment . Further, transsexuals
beyond the ages of 50 or 60 years, have a strong
inclination to continue cross-sex hormones
increasing their period of time of exposure to sex
steroids. The following is a summary of reports in
the literature on tumors in transsexuals.
The first documented hormone treatments of
transsexuals started in the 1970-ies and the length
of time of exposure to hormones may have been too
short for tumors to manifest themselves. Therefore,
the conclusion that hormone-related tumors are not
highly prevalent among the transsexual population
must be drawn with great caution.
Lactotroph adenoma
Several cases of lactotroph adenoma (prolactinoma)
following high dose estrogen administration have
been reported in patients with normal serum
prolactin concentrations before therapy[7, 19-21]).
We have recently encountered a case of
development of a pituitary microprolactinoma in a
M2F, only occurring after 14 years of normal-dosed
estrogen treatment. Though causality has not been
established, we recommend that serum prolactin
levels continue to be monitored in estrogen-treated
M2F in the long-term.
7
Breast cancer
There are two reports of M2F who developed breast
carcinomas while receiving estrogen treatment [22,
23]. Breast fibroadenomas in M2F receiving
hormonal treatment have been observed . In our
series of approximately 2200 M2F, cumulative over
30 years, until recently no single case of breast
cancer had been observed but there is now one case.
On the basis of the above information one would be
inclined to think that breast carcinomas in M2F are
rare. But it has to be kept in mind that 1800
subjects, with a strong variation in estrogen
exposure (from 1 to 25 years), do not allow firm
conclusions in assessing risk. Aging is a factor in
the development of cancer, and prolonged exposure
to estrogens may also prove to be a factor.
Therefore, the discussion as to the age at which
estrogen treatment in M2F should be terminated is
pertinent. In any case, in addition to regular medical
examination, breast self-examination must be part
of the monitoring of estrogen administration,
following the same guidelines that exist for other
women.
Amazingly, breast cancer has been reported in a
F2M after bilateral subcutaneous mastectomy while
receiving treatment with testosterone. This occurred
in residual mammary tissue after 10 years of
treatment with testosterone, which is partially
aromatized to estradiol [24].
Benign prostate hyperplasia and prostate cancer
The prostate is not removed with sex reassignment
surgery. Prostatectomy is a surgically cumbersome
operation, with possible complications, such as
urinary incontinence. As expected, the prostate
volume shrinks after androgen deprivation.
Estrogen exposure does not induce signs of
hyperplasia or (pre)malignancy [25]. Two cases of
benign prostate hyperplasia, requiring transurethral
prostate resection, have been described in subjects
who had been orchidectomized and had been
treated with estrogens-only for more than 20 years.
Another case of squamous metaplasia of the
verumontanum has been reported leading to
obstruction due to hypertrophy [26].
Three cases of prostate cancer in M2F taking
estrogen have been reported [27-29]. It is not clear
whether these cancers were estrogen-sensitive, or
whether they were present prior to beginning
estrogen administration and then subsequently dedifferentiated
to become androgen-independent.
These patients were each over 50 years of age when
they started cross-sex hormone treatment (with total
androgen ablation). Epidemiological studies have
shown that orchidectomy before age 40 prevents
the development of prostate cancer and benign
prostate hyperplasia, and the above cases do not
contradict this notion. In most clinics, screening for
the development of levels of prostate specific
antigen is not routinely done.
Ovarian cancer
Ovariectomy is recommended in F2M when they
are eligible for surgical sex reassignment, in our
clinic usually 18-24 months after start of
testosterone administration. We have observed two
cases of ovarian carcinoma in testosterone-treated
F2M, diagnosed before they underwent surgery
[30]. Another case has been reported recently [31].
The ovaries of female-to-male transsexuals taking
androgens resemble polycystic ovaries [5]. The
earlier notion that polycystic degenerated ovaries
are more prone to develop cancer appears not
tenable. But there is an upregulation of androgen
receptors in ovarian and uterine tissue in long-term
treated F2M [32].
Conclusions
It is now clear sex reassignment of transsexuals
benefits their well-being, [33] though suicide rates
remain high[7]. Regrets are rare (0.5-3.0%). Crosssex
hormone administration to transsexuals is
acceptably safe in the short and medium term.
However, potentially adverse effects in the longerterm
are presently unknown. The data, though
limited, of surrogate markers of cardiovascular
disease and the reports of cancer in transsexuals
leave room for a cautious optimism. But true
insight can only come from close monitoring and
thorough reporting of adverse effects in the
literature.
Acknowledgment
The authors thank Professor David Handlelsman,
ANZAC Research Institute, Sydney, Australia for
his helpful comments.
8
References
1. Gooren L 2005 Hormone treatment of the adult transsexual patient. Horm Res 64 Suppl 2:31-36
2. Moore E, Wisniewski A, Dobs A 2003 Endocrine treatment of transsexual people: a review of
treatment regimens, outcomes, and adverse effects. J Clin Endocrinol Metab 88:3467-3473
3. Toorians AW, Thomassen MC, Zweegman S, Magdeleyns EJ, Tans G, Gooren LJ, Rosing J
2003 Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment
in transsexual people. J Clin Endocrinol Metab 88:5723-5729
4. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ,
Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A 2003
Influence of estrogen plus progestin on breast cancer and mammography in healthy
postmenopausal women: the Women's Health Initiative Randomized Trial. Jama 289:3243-3253
5. Spinder T, Spijkstra JJ, van den Tweel JG, Burger CW, van Kessel H, Hompes PG, Gooren
LJ 1989 The effects of long term testosterone administration on pulsatile luteinizing hormone
secretion and on ovarian histology in eugonadal female to male transsexual subjects. J Clin
Endocrinol Metab 69:151-157
6. Futterweit W, Deligdisch L 1986 Histopathological effects of exogenously administered
testosterone in 19 female to male transsexuals. J Clin Endocrinol Metab 62:16-21
7. van Kesteren PJ, Asscheman H, Megens JA, Gooren LJ 1997 Mortality and morbidity in
transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 47:337-342
8. Lips P, Asscheman H, Uitewaal P, Netelenbos JC, Gooren L 1989 The effect of cross-gender
hormonal treatment on bone metabolism in male-to-female transsexuals. J Bone Miner Res 4:657-
662
9. Lips P, van Kesteren PJ, Asscheman H, Gooren LJ 1996 The effect of androgen treatment on
bone metabolism in female-to-male transsexuals. J Bone Miner Res 11:1769-1773
10. Van Kesteren P, Lips P, Gooren LJ, Asscheman H, Megens J 1998 Long-term follow-up of
bone mineral density and bone metabolism in transsexuals treated with cross-sex hormones. Clin
Endocrinol (Oxf) 48:347-354
11. Reutrakul S, Ongphiphadhanakul B, Piaseu N, Krittiyawong S, Chanprasertyothin S,
Bunnag P, Rajatanavin R 1998 The effects of oestrogen exposure on bone mass in male to female
transsexuals. Clin Endocrinol (Oxf) 49:811-814
12. Liu PY, Death AK, Handelsman DJ 2003 Androgens and cardiovascular disease. Endocr Rev
24:313-340
13. Smith RM LH, Nathan DM 2006 Insulin sensitivity during combined androgen blockade for
prostate cancer. J Clin Endocrinol Metab 91:1305-1308
14. Elbers JM, Giltay EJ, Teerlink T, Scheffer PG, Asscheman H, Seidell JC, Gooren LJ 2003
Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects.
Clin Endocrinol (Oxf) 58:562-571
15. Elbers JM, Asscheman H, Seidell JC, Gooren LJ 1999 Effects of sex steroid hormones on
regional fat depots as assessed by magnetic resonance imaging in transsexuals. Am J Physiol
276:E317-325
16. Polderman KH, Gooren LJ, Asscheman H, Bakker A, Heine RJ 1994 Induction of insulin
resistance by androgens and estrogens. J Clin Endocrinol Metab 79:265-271
17. Giltay EJ, Lambert J, Gooren LJ, Elbers JM, Steyn M, Stehouwer CD 1999 Sex steroids,
insulin, and arterial stiffness in women and Men. Hypertension 34:590-597
18. Van Kesteren PJ, Gooren LJ, Megens JA 1996 An epidemiological and demographic study of
transsexuals in The Netherlands. Arch Sex Behav 25:589-600
19. Gooren LJ, Assies J, Asscheman H, de Slegte R, van Kessel H 1988 Estrogen-induced
prolactinoma in a man. J Clin Endocrinol Metab 66:444-446
9
20. Kovacs K, Stefaneanu L, Ezzat S, Smyth HS 1994 Prolactin-producing pituitary adenoma in a
male-to-female transsexual patient with protracted estrogen administration. A morphologic study.
Archives of pathology & laboratory medicine 118:562-565
21. Serri O, Noiseux D, Robert F, Hardy J 1996 Lactotroph hyperplasia in an estrogen treated maleto-
female transsexual patient. J Clin Endocrinol Metab 81:3177-3179
22. Pritchard TJ, Pankowsky DA, Crowe JP, Abdul-Karim FW 1988 Breast cancer in a male-tofemale
transsexual. A case report. Jama 259:2278-2280
23. Ganly I, Taylor EW 1995 Breast cancer in a trans-sexual man receiving hormone replacement
therapy. The British journal of surgery 82:341
24. Burcombe RJ, Makris A, Pittam M, Finer N 2003 Breast cancer after bilateral subcutaneous
mastectomy in a female-to-male trans-sexual. Breast (Edinburgh, Scotland) 12:290-293
25. Van Kesteren P, Meinhardt W, van der Valk P, Geldof A, Megens J, Gooren L 1996 Effects of
estrogens only on the prostates of aging men. J Urol 156:1349-1353
26. Goodwin WE, Cummings RH 1984 Squamous metaplasia of the verumontanum with obstruction
due to hypertrophy: long-term effects of estrogen on the prostate in an aging male-to-female
transsexual. J Urol 131:553-554
27. Van Haarst EP, Newling DW, Gooren LJ, Asscheman H, Prenger DM 1998 Metastatic
prostatic carcinoma in a male-to-female transsexual. Br J Urol 81:776
28. Dorff TB, Shazer RL, Nepomuceno EM, Tucker SJ 2007 Successful treatment of metastatic
androgen-independent prostate carcinoma in a transsexual patient. Clinical genitourinary cancer
5:344-346
29. Thurston AV 1994 Carcinoma of the prostate in a transsexual. Br J Urol 73:217
30. Hage JJ, Dekker JJ, Karim RB, Verheijen RH, Bloemena E 2000 Ovarian cancer in female-tomale
transsexuals: report of two cases. Gynecologic oncology 76:413-415
31. Dizon DS, Tejada-Berges T, Koelliker S, Steinhoff M, Granai CO 2006 Ovarian cancer
associated with testosterone supplementation in a female-to-male transsexual patient. Gynecologic
and obstetric investigation 62:226-228
32. Chadha S, Pache TD, Huikeshoven JM, Brinkmann AO, van der Kwast TH 1994 Androgen
receptor expression in human ovarian and uterine tissue of long-term androgen-treated transsexual
women. Human pathology 25:1198-1204
33. Smith YL, Van Goozen SH, Kuiper AJ, Cohen-Kettenis PT 2005 Sex reassignment: outcomes
and predictors of treatment for adolescent and adult transsexuals. Psychological medicine 35:89-99
34. Giltay EJ, Verhoef P, Gooren LJ, Geleijnse JM, Schouten EG, Stehouwer CD 2003 Oral and
transdermal estrogens both lower plasma total homocysteine in male-to-female transsexuals.
Atherosclerosis 168:139-146
35. Giltay EJ, Hoogeveen EK, Elbers JM, Gooren LJ, Asscheman H, Stehouwer CD 1998 Effects
of sex steroids on plasma total homocysteine levels: a study in transsexual males and females. J
Clin Endocrinol Metab 83:550-553
36. Giltay EJ, Gooren LJ, Toorians AW, Katan MB, Zock PL 2004 Docosahexaenoic acid
concentrations are higher in women than in men because of estrogenic effects. Am J Clin Nutr
80:1167-1174
37. Giltay EJ, Gooren LJ, Emeis JJ, Kooistra T, Stehouwer CD 2000 Oral, but not transdermal,
administration of estrogens lowers tissue-type plasminogen activator levels in humans without
affecting endothelial synthesis. Arterioscler Thromb Vasc Biol 20:1396-1403
38. Giltay EJ, Elbers JM, Gooren LJ, Emeis JJ, Kooistra T, Asscheman H, Stehouwer CD 1998
Visceral fat accumulation is an important determinant of PAI-1 levels in young, nonobese men and
women: modulation by cross-sex hormone administration. Arterioscler Thromb Vasc Biol 18:1716-
1722
39. Elbers JM, Asscheman H, Seidell JC, Megens JA, Gooren LJ 1997 Long-term testosterone
administration increases visceral fat in female to male transsexuals. J Clin Endocrinol Metab
82:2044-2047
10
40. Giltay EJ, Gooren LJ, Emeis JJ, Kooistra T, Stehouwer CD 2000 Oral ethinyl estradiol, but not
transdermal 17beta-estradiol, increases plasma C-reactive protein levels in men. Thrombosis and
haemostasis 84:359-360
11
Table 1: Changes over 4 to 12 months in risk factors for cardiovascular disease in maleto-
female transsexuals
Refs Absolute change Relative
change
Effect on
CVD
morbidity/
mortality
Body composition:
- Weight (14, 15)
+4 kg +6% ▲
- Body mass index (14, 17,
34)
NS; +1 kg/m2 NS; +5%; +6% ▲
- Total body fat (34) +2 kg +17%; +21% ▲
- Visceral fat (14) +7 cm2 on MRI +18%; ▲
Lipid spectrum:
- Total cholesterol (14, 35) NS NS ▬
- LDL cholesterol (14, 35) NS; –0.3 mmol/L NS; –12% ▬▼
- HDL cholesterol (14, 34) +0.1;+0.2;+0.3mmol/L +10%; +15%;
+24%
▼
- VLDL cholesterol (14) NS NS ▬
- Triglycerides (17, 34) NS; +0.4; +0.7
mmol/L
NS; +34%;
+70%
▬ ▲
- Fish fatty acid (DHA) (36) +0.2 % by weight +35% ▼
Insulin sensitivity:
- Fasting glucose level (14, 17) NS NS ▬
- Fasting insulin level (14, 15,
17)
+13; +21 pmol/L +30%; +50% ▲
- Insulin sensitivity (14, 16) –150 mg glucose /
min; –0.7 mmol
glucose / kg LBM /
hour
–18%; –25%; –
33%
▲
Vascular functioning:
- Heart rate (17) +4 bpm +6% ▲
- Diastolic blood pressure (14, 17) NS; +6 mmHg NS; +8% ▬▲
- Systolic blood pressure (14, 17) NS; +7 mmHg NS; +6% ▬▲
- Distensibility coefficient (17) NS NS ▬
- Compliance coefficient (17) NS; –0.2 mm2/kPa NS;–20% ▬▼
Hemostasis / fibrinolysis:
- Activated protein C resistance (3) +0.7; +2.9 +54%; +241% ▲
- Prothrombin (3) NS; +9% NS; +9% ▬▲
- Fibrinogen (34) NS; +8.0 % NS; +7% ▬ ▲
- Tissue-type plasminogen
activator (tPA) antigen
(37, 38) NS; –4; –5 ng/ml NS; –52% ▬▼
- Plasminogen activator
inhibitor-1 (PAI-1) antigen
(37, 38) NS; –12;–17 ng/ml NS; –62%; –
65%
▬▼
Other CVD risk factors:
- Total homocysteine (34) –3 μmol/L –26%; –29% ▼
- C-reactive protein (34) NS; +0.2 mg/L NS; +20% ▬ ▲
▬ indicates no change in CVD risk; ▲ indicates an increased CVD risk; ▼ indicates a
decreased CVD risk; NS indicates no statistically significant change.
12
Table 2: Changes over 4 to 12 months in risk factors for cardiovascular disease in femaleto-
male transsexuals
Refs Absolute
change
Relative change Effect on
CVD
morbidity/
mortality
Body composition:
- Weight (14, 15) +3 kg +4% ▲
- Body mass index (14, 17,
35)
+1 kg/m2 +3%;+4%; +6% ▲
- Visceral fat (14, 15,
39)
NS;+5cm2 on
MRI
NS; +13%; ▬▲
Lipid spectrum:
- Total cholesterol (14, 35) NS NS ▬
- LDL cholesterol (14, 35) NS NS ▬
- HDL cholesterol (14, 17) –0.2;–
0.3mmol/L
–20%;–23% ▲
- VLDL cholesterol (14) NS NS ▬
- Triglycerides (17) +0.2 mmol/L +26% ▲
- Fish fatty acid (DHA) (36) –0.1%byweight –24% ▲
Insulin sensitivity:
- Fasting glucose level (14, 17) –0.1; –0.4
mmol/L
–2%; –8% ▼
- Fasting insulin level (14, 15,
17)
NS NS ▬
- Insulin sensitivity (14, 16) NS; –0.5; –0.8
mmol glucose /
kg LBM/ hour
NS;–10%;–20% ▬▲
Vascular functioning:
- Heart rate (17) NS NS ▬
- Diastolic blood pressure (14, 17) NS NS ▬
- Systolic blood pressure (14, 17) NS NS ▬
- Distensibility coefficient (17) NS NS ▬
- Compliance coefficient (17) NS NS ▬
Hemostasis / fibrinolysis:
- Activated protein C
resistance
(3) –0.7 -35% ▼
- Prothrombin (3) NS NS ▬
- Tissue-type plasminogen
activator (tPA) antigen
(38) NS NS ▬
- Plasminogen activator
inhibitor-1 (PAI-1) antigen
(38) NS NS ▬
Other CVD risk factors:
- Total homocysteine (38) +1.3 μmol/L +17% ▲
- C-reactive protein (40) +0.5 mg/L +141% ▲
▬ indicates no change in CVD risk; ▲ indicates an increased CVD risk; ▼ indicates a
decreased CVD risk; NS indicates no statistically significant change.
LONG-TERM TREATMENT OF TRANSSEXUALS WITH CROSS-SEX
HORMONES: EXTENSIVE PERSONAL EXPERIENCE
Louis J. Gooren1, Erik J. Giltay2, Mathijs C. Bunck1
1. Department of Endocrinology, VU University Medical Center, Amsterdam, the Netherlands
2. Leiden University Medical Center, Department of Psychiatry, Leiden, The Netherlands
Abbreviated title: Endocrine treatment of transsexuals
Word count: 3,952
Correspondence and requests for reprints to
Dr L.J. Gooren,
Dept of Endocrinology, VU University Medical Center
De Boelelaan 1118
1081 HV Amsterdam, the Netherlands
Telephone +66 89612 7650
Fax +3120 4440502
e-mail [email protected]
Disclosure summary:
The authors have nothing to declare
Key words:
transsexuals, estrogen administration, testosterone administration, long-term side-effects,
J Clin Endocrin Metab. First published ahead of print November 6, 2007 as doi:10.1210/jc.2007-1809
Copyright (C) 2007 by The Endocrine Society
2
ABSTRACT
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-tomale
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.
3
Introduction
Transsexualism is the condition in which a person with
apparently normal somatic sexual differentiation is
convinced that s/he is actually a member of the other
sex. This conviction is accompanied by an irresistible
urge to live in the other gender which requires
hormonal, anatomical, legal, and psychosocial
adaptations. Since its initiation in 1975, 876 female-tomale
(F2M) and 2236 male-to-female transsexuals
(M2F) have received hormonal treatment. Eligibility
criteria for hormone treatment will not be addressed
here but guidelines provided by WPATH
(http://www.wpath.org) were followed.
The acquisition of the secondary sex characteristics
of the other gender is fundamental to sex
reassignment. Acquisition of these secondary sex
characteristics is contingent on sex steroids. There
is no known essential difference in sensitivity to the
biological action of sex steroids on the basis of
genetic configurations or gonadal status. The
typical transsexual requesting treatment is a young
to middle-aged and healthy person and, therefore,
and there are usually no or few absolute or relative
contraindications against cross-sex hormone
administration. For suppression of androgen
secretion or action, several agents are available. In
Europe, the most widely-used drug is cyproterone
acetate (usually 50 mg twice daily), a progestational
compound with antiandrogenic properties. If not
available, medroxyprogesterone acetate, 5 to 10
mg/day, is a less effective alternative.
Spironolactone (up to100 mg twice daily, if
tolerated), a diuretic with antiandrogenic properties,
has similar effects. Long-acting gonadotrophinreleasing
hormone agonists (GnRH) inhibit
gonadotropin secretion. Finasteride (5 mg/day), a
5α-reductase inhibitor, might also be considered.
Hormone treatment of transsexuals has been
reviewed in recent years [1, 2].
Male-to-female transsexual treatment
There is a wide range of estrogens from which to
choose. Oral ethinyl estradiol (50 to 100 μg/day) is
a potent and inexpensive estrogen, but may cause
venous thrombosis, particularly in those over age
40 [1] [3]. It should therefore not be used in the
dosage required by M2F (50-100 μg/day). Oral
17β-estradiol valerate, 2 to 4 mg per day, or
transdermal 17β-estradiol, 100 μg twice a week, are
the treatments of choice, and are much less
thrombogenic than ethinyl estradiol [3]. Many
transsexuals favor injectable estrogens, as they
generate high levels of circulating estrogens.
However, they have the potential risk of overdose.
There is no evidence that progestagens add to the
feminization process of M2F. In female
reproductive endocrinology, progesterone prepares
the uterus for conception, and the breasts for
lactation. Some patients strongly believe that
progestagens are a necessary addition to estrogens
in their feminization process. But this is not the
case, and progestagens may have side effects, such
as salt/water retention leading to elevated blood
pressure or venous varicosis. In the large-scale
study of postmenopausal hormone use in women,
the combination of estrogens and progestagens
appeared to be associated with a higher incidence of
breast cancer[4] and cardiovascular disease.
Female-to-male transsexual treatment
The goal of treatment in the F2M is to induce
virilization (including a deepening of the voice),
production of male-pattern body hair growth and
physical contours, and cessation of menses. The
principal hormonal treatment used to accomplish
these goals is a testosterone preparation. The most
commonly used preparations are injectable
testosterone esters administered intramuscularly in
doses of 200 to 250 mg every two weeks. In some
countries, testosterone undecanoate (1000 mg) is
available, and injections may be spaced at 10-12
weeks . Use of androgen gel or transdermal patches
can also provide good, steady state testosterone
levels. Occasionally, menstrual bleeding does not
cease, and the addition of a progestational agent is
necessary, almost always needed when transdermal
or oral testosterone is used.
Following ovariectomy androgen therapy must be
continued but progestational drugs can be stopped.
When F2M receive treatment with testosterone, part
of it is aromatized to estradiol [5]. When
hysterectomy is delayed there is some concern
about endometrial cancer [6].
Long-term treatment and its effect on health
After reassignment surgery, which includes
gonadectomy, hormone therapy must be continued.
It is reasonable to assume that the principles of
4
treatment are very similar to those of other subjects
without own gonadal hormonal secretion. An
unresolved question is whether in the long-term all
functions of sex steroids of a subject are adequately
covered by cross-sex hormones and whether the
administration of cross-sex hormones is
appropriately safe, or at least as safe as
administration of sex steroids in a subject receiving
long-term sex-appropriate sex steroids. There are
presently no indications that there are fundamental
sex differences in sensitivity to hormone action of
sex steroids. Nearly all hormone-related
biochemical processes can be sex-reversed by the
administration of cross-sex hormones.
It is likely that that there is an underreporting of
(serious) complications of cross-sex hormone
therapy. While the initial treatment with cross-sex
hormones is mainly concentrated in specialized
centers, complications occurring in the long-term
are seen in general practice, and these
complications are only occasionally reported in the
scientific literature. The authors have been
contacted by other physicians on medical
occurrences in transsexuals, but these cases are
often lost for follow-up and for registration of
(potential) complications of cross-sex hormonal
treatment. The latter situation prevents a fair
comparison with epidemiological data in the
general population. Recently, a website has been
opened for reporting side effects of cross-sex
hormone treatment:
http://www.wpath.org/resources_transgender.cfm,
click under transgender information: resource links.
In 1997 we published a report on
mortality/morbidity in transsexual subjects [7]. This
was a retrospective, descriptive study of 816 M2F
and 293 F2M who had been treated with cross-sex
hormones for a total of 10,152 patient-years.
Standardized mortality and incidence ratios were
calculated from the general Dutch population (ageand
gender-adjusted) and they were also compared
to side effects of cross-sex hormones in
transsexuals reported in the literature. Mortality
was not higher than in the general population.
Venous thrombosis occurred frequently but could
be related to the use of oral ethinyl estradiol [3],
and the incidence decreased to the incidence in the
general population when its use was relinquished.
The conclusion of the report was that in the short
and mid-term cross-sex hormone treatment was
acceptably safe.
Cross-sex hormone administration took off in the
1970-ies so several transsexual subjects are now in
their 60-ies, 70-ies and even 80-ies. Another
important but unresolved question is until what age
cross-sex hormone treatment must be continued.
This question must be set against the information
which has become available on hormone
replacement therapy in perimenopausal and
postmenopausal women (NIH State-of-the-Science
Conference Statement on management of
menopause-related symptoms). Should estrogen
administration to M2F be discontinued for the
reasons applicable to postmenopausal women? Not
needing progestagens to prevent estrogen
stimulation of uterine hyperplasia and malignancy,
would M2F benefit from continued estrogen-only
administration in view of the reportedly favorable
effects of estrogens on bone, the cardiovascular
system and the brain? The issue seems less pressing
in F2M receiving treatment with testosterone since
in this group there is no high risk of androgenrelated
malignancies. Transsexuals themselves are
usually inclined to continue cross-sex hormone
administration for fear that they would lose
physical characteristics of the reassigned sex.
The following will address some areas where sex
hormones are known to play a role and
continuation/discontinuation and dose of hormone
administration may be relevant.
Cross-sex hormones and osteoporosis
Sex steroids play a pivotal role in the maintenance
of the integrity of the skeleton in both men and
women. Postmenopausal women and hypogonadal
men have an increased risk of fractures. The risk of
bone loss in subjects undergoing sex reassignment
has been well recognized in the literature [8-11]. In
the longer-term bone mineral density is preserved
during cross-sex hormone administration [10].
Apparently, estrogens alone are capable of
maintaining bone mass in M2F. Conversely,
testosterone administration maintains bone mineral
density in F2M. Part of testosterone is converted to
estradiol resulting in circulating estradiol levels
well above the plasma level of estradiol critical for
preserving bone mineral density in men (i.e., 40-50
pmol/L)[5]. In our study there was an inverse
relationship between serum luteinizing hormone
5
(LH) concentrations and bone mineral density, so
serum LH may serve as an indicator of the
adequacy of sex steroid administration [10]. It is
not known whether cross-sex hormone
administration can be responsibly discontinued at a
certain age without inducing an unacceptable risk
of osteoporosis and bone fractures.
Cross-sex hormones and cardiovascular disease
Men have a higher incidence of cardiovascular
events than women of similar ages[12]. There is,
however, no evidence supporting a causal relation
between higher testosterone levels and heart
disease[12]. There is as yet no true insight into the
effects of cross-sex hormone treatment on
cardiovascular health. As can be expected, cases of
cardiovascular complications of transsexuals have
been reported in the literature, but it is not
warranted to generalize them to the whole
population of transsexuals. T
the effects of cross-sex hormone administration to
transsexuals on (biochemical) risk factors of
cardiovascular disease.
Cardiovascular risk in male-to-female
transsexuals
Men with prostate cancer, treated with androgen
deprivation, develop an increase of fat mass with an
altered lipid profile [13]. These patients also appear
to develop insulin resistance, hyperinsulinemia and
hyperglycemia [13]. The risks of diabetes mellitus
increase by 44% and mortality of cardiovascular
diseases by 16% during a follow-up of up to 10
years. Is there a parallel in M2F upon androgen
deprivation?
Several studies have been done in male-to-female
transsexuals who received estrogens and
antiandrogens (either 100 μg ethinylestradiol per
day, or transdermal 17β-estradiol 100 μg twice a
week, with or without 100 mg cyproterone acetate).
Many changes in cardiovascular risk factors were
found and the results of these studies in M2F are
summarized in table 1.
Weight, body mass index, total body fat and
visceral fat increased during treatment in M2F
(Table 1) resembling features of the metabolic
syndrome. The observed changes in cardiovascular
risk factors observed in transsexual patients may be
primarily caused by the increase of the amount of
visceral fat in M2F [14, 15]. The increase in fat
tissue may lead to an increased hepatic triglyceride
influx and a rise of plasma leptin [14]).
High-density lipoprotein (HDL) cholesterol, it
subfractions and triglyceride levels increased
(Table 1), in similar extent as seen in men treated
for prostate cancer [13]. Total cholesterol was
unaffected and low-density lipoprotein (LDL)
cholesterol levels decreased by 12% in M2F [14],
whereas total and LDL cholesterol levels were
found to increase by 9% in men treated for prostate
cancer [13]. The low estrogen state observed in
these men is responsible for the increases in total
and LDL cholesterol. The latter was not observed in
our transsexual patients who receive in addition to
the androgen deprivation, treatment with estrogens.
The slight decrease in LDL cholesterol seen in
transsexuals was, however, accompanied by a
decrease in LDL particle size [14], another known
cardiovascular risk factor. A study by another
group, found that administering GnRH agonists +
oral 17β-estradiol valerate to M2F induced
endocrine changes similar to our studies, but
without an impairment of the lipid profile . The use
of cyproterone acetate might explain the
differences. Indeed, a study using cyproterone
acetate in prostate cancer patients found a serious
deterioration of the lipid profile .
The effects on insulin sensitivity encountered in our
studies were largely in the same detrimental
direction [14] as in men with prostate cancer treated
with GnRH agonists [13]. The deleterious effects
on insulin sensitivity are, therefore, likely due to
androgen deprivation. We found that insulin
sensitivity (assessed by hyperinsulinemic
euglycemic clamp) decreased, and this was
accompanied by a compensatory increase in fasting
plasma insulin concentration preventing
hyperglycemia (Table 1) [14]. Endogenous glucose
production (measured by isotope dilution with
titrated glucose) was however not affected by crosssex
hormone administration, indicating that the
observed changes in glucose requirement during an
hyperinsulinemic euglycemic clamp procedure
were due to the diminished peripheral glucose
uptake [16], a finding that was later confirmed by
Elbers et al [14]. We further found that blood
pressure slightly increased during estrogen and
antiandrogen treatment, and there was a small
detrimental effect on arterial stiffness [17].
6
Cardiovascular risk in female-to-male
transsexuals
Hyperandrogenism in women, usually resulting
from the polycystic ovarium syndrome (PCOS), is
associated with an unfavorable cardiovascular risk
profile. However, hyperandrogenism in PCOS is
usually clustered with features of the metabolic
syndrome (hyperinsulinemia, visceral obesity,
hypertension, dyslipidemia). It is difficult to
disentangle the contributions that the various
components of the metabolic syndrome make to
this unfavourable cardiovascular risk profile, more
precisely what the role of hyperandrogenism per se
is.
The results from studies in F2M transsexuals are
summarized in Table 2. The observed changes in
cardiovascular risk factors seen in F2M may again
be secondary to the increase in weight and the
amount of visceral fat [14]. Our group has shown
that testosterone administration to F2M decreases
plasma leptin [14]; further a decrease in serum
adiponectin concentration has been reported . We
found a slight decrease of insulin sensitivity in one
of our studies [14, 16]. Furthermore, increases were
found in HDL cholesterol, fasting triglycerides,
total homocysteine, and C-reactive protein (Table
2). Blood pressure and arterial stiffness, unlike in
other reports, were unaffected by cross-sex
hormone treatment [17].
Concluding remarks on cardiovascular risk
Cross-sex hormone administration in M2F and F2M
both improves and impairs profiles of
cardiovascular risk factors. It remains difficult to
determine how much weight must be attributed to
these alterations in risk factors and whether these
changes are of clinical significance. With these
reservations in mind, the overall impression is that
inducing androgen deprivation and an estrogen
milieu in M2F has a larger deleterious effect on the
risk factors, than inducing an androgenic milieu in
F2M (Tables 1 and 2).
So far the only data available on hard clinical
endpoints is from our study on cardiovascular
morbidity and mortality in both M2F and F2M [7].
This study reports no elevated (cardiovascular)
morbidity and/or mortality in the cohort of
transsexuals treated at the Amsterdam clinic. Yet,
to reduce the risk of the metabolic syndrome and
cardiovascular disease and to increase life
expectancy, it is important to advice transsexuals to
adopt healthy lifestyle and dietary behaviors.
Cross-sex hormones and hormone-dependent
tumors
Some cancers (of reproductive organs) are hormone
related. Hormone-dependent tumors are practically
not occurring in hormonally treated F2M and seem
a rare occurrence in M2F. But transsexualism is a
rare phenomenon (the highest estimates are
1;12,000 males and 1;30,000 females [18]); if, in
addition the prevalence of hormone-dependent
tumors is low, this may lead to an underestimation
of tumors.
M2F, as a rule, use higher doses of estrogens than
women lacking production of gonadal homones. In
transsexuals exposure to estrogens is usually over a
shorter period of lifetime, since transsexuals mostly
start cross-sex hormone treatment well after
puberty, though this is changing. Presently,
adolescent transsexuals may be eligible for crosssex
hormone treatment . Further, transsexuals
beyond the ages of 50 or 60 years, have a strong
inclination to continue cross-sex hormones
increasing their period of time of exposure to sex
steroids. The following is a summary of reports in
the literature on tumors in transsexuals.
The first documented hormone treatments of
transsexuals started in the 1970-ies and the length
of time of exposure to hormones may have been too
short for tumors to manifest themselves. Therefore,
the conclusion that hormone-related tumors are not
highly prevalent among the transsexual population
must be drawn with great caution.
Lactotroph adenoma
Several cases of lactotroph adenoma (prolactinoma)
following high dose estrogen administration have
been reported in patients with normal serum
prolactin concentrations before therapy[7, 19-21]).
We have recently encountered a case of
development of a pituitary microprolactinoma in a
M2F, only occurring after 14 years of normal-dosed
estrogen treatment. Though causality has not been
established, we recommend that serum prolactin
levels continue to be monitored in estrogen-treated
M2F in the long-term.
7
Breast cancer
There are two reports of M2F who developed breast
carcinomas while receiving estrogen treatment [22,
23]. Breast fibroadenomas in M2F receiving
hormonal treatment have been observed . In our
series of approximately 2200 M2F, cumulative over
30 years, until recently no single case of breast
cancer had been observed but there is now one case.
On the basis of the above information one would be
inclined to think that breast carcinomas in M2F are
rare. But it has to be kept in mind that 1800
subjects, with a strong variation in estrogen
exposure (from 1 to 25 years), do not allow firm
conclusions in assessing risk. Aging is a factor in
the development of cancer, and prolonged exposure
to estrogens may also prove to be a factor.
Therefore, the discussion as to the age at which
estrogen treatment in M2F should be terminated is
pertinent. In any case, in addition to regular medical
examination, breast self-examination must be part
of the monitoring of estrogen administration,
following the same guidelines that exist for other
women.
Amazingly, breast cancer has been reported in a
F2M after bilateral subcutaneous mastectomy while
receiving treatment with testosterone. This occurred
in residual mammary tissue after 10 years of
treatment with testosterone, which is partially
aromatized to estradiol [24].
Benign prostate hyperplasia and prostate cancer
The prostate is not removed with sex reassignment
surgery. Prostatectomy is a surgically cumbersome
operation, with possible complications, such as
urinary incontinence. As expected, the prostate
volume shrinks after androgen deprivation.
Estrogen exposure does not induce signs of
hyperplasia or (pre)malignancy [25]. Two cases of
benign prostate hyperplasia, requiring transurethral
prostate resection, have been described in subjects
who had been orchidectomized and had been
treated with estrogens-only for more than 20 years.
Another case of squamous metaplasia of the
verumontanum has been reported leading to
obstruction due to hypertrophy [26].
Three cases of prostate cancer in M2F taking
estrogen have been reported [27-29]. It is not clear
whether these cancers were estrogen-sensitive, or
whether they were present prior to beginning
estrogen administration and then subsequently dedifferentiated
to become androgen-independent.
These patients were each over 50 years of age when
they started cross-sex hormone treatment (with total
androgen ablation). Epidemiological studies have
shown that orchidectomy before age 40 prevents
the development of prostate cancer and benign
prostate hyperplasia, and the above cases do not
contradict this notion. In most clinics, screening for
the development of levels of prostate specific
antigen is not routinely done.
Ovarian cancer
Ovariectomy is recommended in F2M when they
are eligible for surgical sex reassignment, in our
clinic usually 18-24 months after start of
testosterone administration. We have observed two
cases of ovarian carcinoma in testosterone-treated
F2M, diagnosed before they underwent surgery
[30]. Another case has been reported recently [31].
The ovaries of female-to-male transsexuals taking
androgens resemble polycystic ovaries [5]. The
earlier notion that polycystic degenerated ovaries
are more prone to develop cancer appears not
tenable. But there is an upregulation of androgen
receptors in ovarian and uterine tissue in long-term
treated F2M [32].
Conclusions
It is now clear sex reassignment of transsexuals
benefits their well-being, [33] though suicide rates
remain high[7]. Regrets are rare (0.5-3.0%). Crosssex
hormone administration to transsexuals is
acceptably safe in the short and medium term.
However, potentially adverse effects in the longerterm
are presently unknown. The data, though
limited, of surrogate markers of cardiovascular
disease and the reports of cancer in transsexuals
leave room for a cautious optimism. But true
insight can only come from close monitoring and
thorough reporting of adverse effects in the
literature.
Acknowledgment
The authors thank Professor David Handlelsman,
ANZAC Research Institute, Sydney, Australia for
his helpful comments.
8
References
1. Gooren L 2005 Hormone treatment of the adult transsexual patient. Horm Res 64 Suppl 2:31-36
2. Moore E, Wisniewski A, Dobs A 2003 Endocrine treatment of transsexual people: a review of
treatment regimens, outcomes, and adverse effects. J Clin Endocrinol Metab 88:3467-3473
3. Toorians AW, Thomassen MC, Zweegman S, Magdeleyns EJ, Tans G, Gooren LJ, Rosing J
2003 Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment
in transsexual people. J Clin Endocrinol Metab 88:5723-5729
4. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ,
Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A 2003
Influence of estrogen plus progestin on breast cancer and mammography in healthy
postmenopausal women: the Women's Health Initiative Randomized Trial. Jama 289:3243-3253
5. Spinder T, Spijkstra JJ, van den Tweel JG, Burger CW, van Kessel H, Hompes PG, Gooren
LJ 1989 The effects of long term testosterone administration on pulsatile luteinizing hormone
secretion and on ovarian histology in eugonadal female to male transsexual subjects. J Clin
Endocrinol Metab 69:151-157
6. Futterweit W, Deligdisch L 1986 Histopathological effects of exogenously administered
testosterone in 19 female to male transsexuals. J Clin Endocrinol Metab 62:16-21
7. van Kesteren PJ, Asscheman H, Megens JA, Gooren LJ 1997 Mortality and morbidity in
transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 47:337-342
8. Lips P, Asscheman H, Uitewaal P, Netelenbos JC, Gooren L 1989 The effect of cross-gender
hormonal treatment on bone metabolism in male-to-female transsexuals. J Bone Miner Res 4:657-
662
9. Lips P, van Kesteren PJ, Asscheman H, Gooren LJ 1996 The effect of androgen treatment on
bone metabolism in female-to-male transsexuals. J Bone Miner Res 11:1769-1773
10. Van Kesteren P, Lips P, Gooren LJ, Asscheman H, Megens J 1998 Long-term follow-up of
bone mineral density and bone metabolism in transsexuals treated with cross-sex hormones. Clin
Endocrinol (Oxf) 48:347-354
11. Reutrakul S, Ongphiphadhanakul B, Piaseu N, Krittiyawong S, Chanprasertyothin S,
Bunnag P, Rajatanavin R 1998 The effects of oestrogen exposure on bone mass in male to female
transsexuals. Clin Endocrinol (Oxf) 49:811-814
12. Liu PY, Death AK, Handelsman DJ 2003 Androgens and cardiovascular disease. Endocr Rev
24:313-340
13. Smith RM LH, Nathan DM 2006 Insulin sensitivity during combined androgen blockade for
prostate cancer. J Clin Endocrinol Metab 91:1305-1308
14. Elbers JM, Giltay EJ, Teerlink T, Scheffer PG, Asscheman H, Seidell JC, Gooren LJ 2003
Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects.
Clin Endocrinol (Oxf) 58:562-571
15. Elbers JM, Asscheman H, Seidell JC, Gooren LJ 1999 Effects of sex steroid hormones on
regional fat depots as assessed by magnetic resonance imaging in transsexuals. Am J Physiol
276:E317-325
16. Polderman KH, Gooren LJ, Asscheman H, Bakker A, Heine RJ 1994 Induction of insulin
resistance by androgens and estrogens. J Clin Endocrinol Metab 79:265-271
17. Giltay EJ, Lambert J, Gooren LJ, Elbers JM, Steyn M, Stehouwer CD 1999 Sex steroids,
insulin, and arterial stiffness in women and Men. Hypertension 34:590-597
18. Van Kesteren PJ, Gooren LJ, Megens JA 1996 An epidemiological and demographic study of
transsexuals in The Netherlands. Arch Sex Behav 25:589-600
19. Gooren LJ, Assies J, Asscheman H, de Slegte R, van Kessel H 1988 Estrogen-induced
prolactinoma in a man. J Clin Endocrinol Metab 66:444-446
9
20. Kovacs K, Stefaneanu L, Ezzat S, Smyth HS 1994 Prolactin-producing pituitary adenoma in a
male-to-female transsexual patient with protracted estrogen administration. A morphologic study.
Archives of pathology & laboratory medicine 118:562-565
21. Serri O, Noiseux D, Robert F, Hardy J 1996 Lactotroph hyperplasia in an estrogen treated maleto-
female transsexual patient. J Clin Endocrinol Metab 81:3177-3179
22. Pritchard TJ, Pankowsky DA, Crowe JP, Abdul-Karim FW 1988 Breast cancer in a male-tofemale
transsexual. A case report. Jama 259:2278-2280
23. Ganly I, Taylor EW 1995 Breast cancer in a trans-sexual man receiving hormone replacement
therapy. The British journal of surgery 82:341
24. Burcombe RJ, Makris A, Pittam M, Finer N 2003 Breast cancer after bilateral subcutaneous
mastectomy in a female-to-male trans-sexual. Breast (Edinburgh, Scotland) 12:290-293
25. Van Kesteren P, Meinhardt W, van der Valk P, Geldof A, Megens J, Gooren L 1996 Effects of
estrogens only on the prostates of aging men. J Urol 156:1349-1353
26. Goodwin WE, Cummings RH 1984 Squamous metaplasia of the verumontanum with obstruction
due to hypertrophy: long-term effects of estrogen on the prostate in an aging male-to-female
transsexual. J Urol 131:553-554
27. Van Haarst EP, Newling DW, Gooren LJ, Asscheman H, Prenger DM 1998 Metastatic
prostatic carcinoma in a male-to-female transsexual. Br J Urol 81:776
28. Dorff TB, Shazer RL, Nepomuceno EM, Tucker SJ 2007 Successful treatment of metastatic
androgen-independent prostate carcinoma in a transsexual patient. Clinical genitourinary cancer
5:344-346
29. Thurston AV 1994 Carcinoma of the prostate in a transsexual. Br J Urol 73:217
30. Hage JJ, Dekker JJ, Karim RB, Verheijen RH, Bloemena E 2000 Ovarian cancer in female-tomale
transsexuals: report of two cases. Gynecologic oncology 76:413-415
31. Dizon DS, Tejada-Berges T, Koelliker S, Steinhoff M, Granai CO 2006 Ovarian cancer
associated with testosterone supplementation in a female-to-male transsexual patient. Gynecologic
and obstetric investigation 62:226-228
32. Chadha S, Pache TD, Huikeshoven JM, Brinkmann AO, van der Kwast TH 1994 Androgen
receptor expression in human ovarian and uterine tissue of long-term androgen-treated transsexual
women. Human pathology 25:1198-1204
33. Smith YL, Van Goozen SH, Kuiper AJ, Cohen-Kettenis PT 2005 Sex reassignment: outcomes
and predictors of treatment for adolescent and adult transsexuals. Psychological medicine 35:89-99
34. Giltay EJ, Verhoef P, Gooren LJ, Geleijnse JM, Schouten EG, Stehouwer CD 2003 Oral and
transdermal estrogens both lower plasma total homocysteine in male-to-female transsexuals.
Atherosclerosis 168:139-146
35. Giltay EJ, Hoogeveen EK, Elbers JM, Gooren LJ, Asscheman H, Stehouwer CD 1998 Effects
of sex steroids on plasma total homocysteine levels: a study in transsexual males and females. J
Clin Endocrinol Metab 83:550-553
36. Giltay EJ, Gooren LJ, Toorians AW, Katan MB, Zock PL 2004 Docosahexaenoic acid
concentrations are higher in women than in men because of estrogenic effects. Am J Clin Nutr
80:1167-1174
37. Giltay EJ, Gooren LJ, Emeis JJ, Kooistra T, Stehouwer CD 2000 Oral, but not transdermal,
administration of estrogens lowers tissue-type plasminogen activator levels in humans without
affecting endothelial synthesis. Arterioscler Thromb Vasc Biol 20:1396-1403
38. Giltay EJ, Elbers JM, Gooren LJ, Emeis JJ, Kooistra T, Asscheman H, Stehouwer CD 1998
Visceral fat accumulation is an important determinant of PAI-1 levels in young, nonobese men and
women: modulation by cross-sex hormone administration. Arterioscler Thromb Vasc Biol 18:1716-
1722
39. Elbers JM, Asscheman H, Seidell JC, Megens JA, Gooren LJ 1997 Long-term testosterone
administration increases visceral fat in female to male transsexuals. J Clin Endocrinol Metab
82:2044-2047
10
40. Giltay EJ, Gooren LJ, Emeis JJ, Kooistra T, Stehouwer CD 2000 Oral ethinyl estradiol, but not
transdermal 17beta-estradiol, increases plasma C-reactive protein levels in men. Thrombosis and
haemostasis 84:359-360
11
Table 1: Changes over 4 to 12 months in risk factors for cardiovascular disease in maleto-
female transsexuals
Refs Absolute change Relative
change
Effect on
CVD
morbidity/
mortality
Body composition:
- Weight (14, 15)
+4 kg +6% ▲
- Body mass index (14, 17,
34)
NS; +1 kg/m2 NS; +5%; +6% ▲
- Total body fat (34) +2 kg +17%; +21% ▲
- Visceral fat (14) +7 cm2 on MRI +18%; ▲
Lipid spectrum:
- Total cholesterol (14, 35) NS NS ▬
- LDL cholesterol (14, 35) NS; –0.3 mmol/L NS; –12% ▬▼
- HDL cholesterol (14, 34) +0.1;+0.2;+0.3mmol/L +10%; +15%;
+24%
▼
- VLDL cholesterol (14) NS NS ▬
- Triglycerides (17, 34) NS; +0.4; +0.7
mmol/L
NS; +34%;
+70%
▬ ▲
- Fish fatty acid (DHA) (36) +0.2 % by weight +35% ▼
Insulin sensitivity:
- Fasting glucose level (14, 17) NS NS ▬
- Fasting insulin level (14, 15,
17)
+13; +21 pmol/L +30%; +50% ▲
- Insulin sensitivity (14, 16) –150 mg glucose /
min; –0.7 mmol
glucose / kg LBM /
hour
–18%; –25%; –
33%
▲
Vascular functioning:
- Heart rate (17) +4 bpm +6% ▲
- Diastolic blood pressure (14, 17) NS; +6 mmHg NS; +8% ▬▲
- Systolic blood pressure (14, 17) NS; +7 mmHg NS; +6% ▬▲
- Distensibility coefficient (17) NS NS ▬
- Compliance coefficient (17) NS; –0.2 mm2/kPa NS;–20% ▬▼
Hemostasis / fibrinolysis:
- Activated protein C resistance (3) +0.7; +2.9 +54%; +241% ▲
- Prothrombin (3) NS; +9% NS; +9% ▬▲
- Fibrinogen (34) NS; +8.0 % NS; +7% ▬ ▲
- Tissue-type plasminogen
activator (tPA) antigen
(37, 38) NS; –4; –5 ng/ml NS; –52% ▬▼
- Plasminogen activator
inhibitor-1 (PAI-1) antigen
(37, 38) NS; –12;–17 ng/ml NS; –62%; –
65%
▬▼
Other CVD risk factors:
- Total homocysteine (34) –3 μmol/L –26%; –29% ▼
- C-reactive protein (34) NS; +0.2 mg/L NS; +20% ▬ ▲
▬ indicates no change in CVD risk; ▲ indicates an increased CVD risk; ▼ indicates a
decreased CVD risk; NS indicates no statistically significant change.
12
Table 2: Changes over 4 to 12 months in risk factors for cardiovascular disease in femaleto-
male transsexuals
Refs Absolute
change
Relative change Effect on
CVD
morbidity/
mortality
Body composition:
- Weight (14, 15) +3 kg +4% ▲
- Body mass index (14, 17,
35)
+1 kg/m2 +3%;+4%; +6% ▲
- Visceral fat (14, 15,
39)
NS;+5cm2 on
MRI
NS; +13%; ▬▲
Lipid spectrum:
- Total cholesterol (14, 35) NS NS ▬
- LDL cholesterol (14, 35) NS NS ▬
- HDL cholesterol (14, 17) –0.2;–
0.3mmol/L
–20%;–23% ▲
- VLDL cholesterol (14) NS NS ▬
- Triglycerides (17) +0.2 mmol/L +26% ▲
- Fish fatty acid (DHA) (36) –0.1%byweight –24% ▲
Insulin sensitivity:
- Fasting glucose level (14, 17) –0.1; –0.4
mmol/L
–2%; –8% ▼
- Fasting insulin level (14, 15,
17)
NS NS ▬
- Insulin sensitivity (14, 16) NS; –0.5; –0.8
mmol glucose /
kg LBM/ hour
NS;–10%;–20% ▬▲
Vascular functioning:
- Heart rate (17) NS NS ▬
- Diastolic blood pressure (14, 17) NS NS ▬
- Systolic blood pressure (14, 17) NS NS ▬
- Distensibility coefficient (17) NS NS ▬
- Compliance coefficient (17) NS NS ▬
Hemostasis / fibrinolysis:
- Activated protein C
resistance
(3) –0.7 -35% ▼
- Prothrombin (3) NS NS ▬
- Tissue-type plasminogen
activator (tPA) antigen
(38) NS NS ▬
- Plasminogen activator
inhibitor-1 (PAI-1) antigen
(38) NS NS ▬
Other CVD risk factors:
- Total homocysteine (38) +1.3 μmol/L +17% ▲
- C-reactive protein (40) +0.5 mg/L +141% ▲
▬ indicates no change in CVD risk; ▲ indicates an increased CVD risk; ▼ indicates a
decreased CVD risk; NS indicates no statistically significant change.
