Side effects of sex steroid therapy in more conventional categories of 
patients have been extensively reported: oral contraceptives in women of 
reproductive age,2,3 estrogen substitution in postmenopausal women,4-6 
estrogen treatment of prostatic carcinoma,7 and androgen replacement in men.8  
Reports on side effects of cross-gender hormone treatment in transsexuals have 
been few.  One study evaluating the efficacy of estrogens and androgens in 90 
transsexual patients documented only liver enzyme abnormalities and mild 
elevations of cholesterol and triglyceride levels.9  Case reports have 
described pulmonary embolism,10 cerebral thrombosis,11 myocardial 
infarction,12 prostatic metaplasia,13 and breast cancer14,15 in estrogen-
treated male-to-female transsexuals and recurrent myocardial infarction in a 
female-to-male transsexual treated with androgens.16  We report here a 
retrospective investigation into the side effects of cross gender hormone 
administration in 425 transsexuals treated between 1972 and 1986. 

   MATERIALS AND METHODS 
   The files of all patients seen in our outpatient department between 1972 
and 1986 were reviewed Diagnosis of transsexualism followed the Standards of 
Care of the Harry Benjamin Gender Dysphoria Association.17  There were files 
of 558 patients with a problem of gender dysphoria, of whom 425 were included 
in this study.  Reasons for exclusion of the others were as follows: no 
hormonal treatment (n = 71), only antiandrogen treatment (n = 6), failure to 
comply with our follow-up schedule (n = 15), no data available (n = 10), and 
treatment either not yet started or for less than six months (n = 31).  The 
population included in this analysis comprised 303 male-to-female and 122 
female-to-male transsexuals.  Our standard hormone treatment regimen in male-
to-female transsexuals consisted of 100 mg cyproterone acetate and 100 mg 
ethinylestradiol/ day orally (n = 258).  Until 1980 diethylstilbestrol (5 to 
15 mg/d) was prescribed for a few patients.  Some patients insisted on 
parenteral estrogen therapy.  They procured the estrogens outside our clinic 
and these were self-administered in a dose of 200 to 800 mg estradiol-17-
undecanoate/month in (n = 45).  Recommended dose of parenteral estrogens in 
postmenopausal women is 20 to 100 mg/m. 

   In female-to-male patients long-acting testosterone esters 250 mg im every 
2 weeks (n = 69) or testosterone undecanoate 120 to 160 mg/d orally (n = 19), 
or both, but not simultaneously (n = 34), were prescribed.  If menstrual 
activity did not cease within three months after start of the hormone 
administration, an oral progestin, lynestrol 5 mg/d, was added (n = 3). 

   The patients' ages at the start of hormone treatment ranged from 16 to 67 
years (median 32 years) in male-to-female patients and 16-54 years (median 
25.4 years) in female-to-male patients.  The duration of hormone therapy 
ranged from six months to more than 13 years (median 4.4 years in male-to-
female and 3.6 years in female-to-male patients).  In the first two years of 
treatment, patients were seen every three months and every six to nine months 
thereafter.  At each visit physical changes and complaints were recorded and a 
general physical examination was carried out.  At least once, and generally 
twice a year, blood samples were drawn for determination of liver enzymes, 
prolactin levels, and, if indicated, other laboratory parameters.  Diagnosis 
of venous thrombosis or pulmonary embolism was confirmed by phlebography or 
lung scintigraphy.  Twelve transsexuals died during this follow-up period.  
The cause of death was determined either by autopsy report or from information 
given by the patients's general practioner.  The expected mortality and 
morbidity of a comparable group of subjects were calculated from published 
reports on the incidence of mortality and similar morbidity in the general 
population aged 15 to 64 years.  The expected number of cases was adjusted for 
age (15-24, 25-39, and 40-64 years of age) and sex,18 as well as for the 
period of time the study population was on cross-gender hormone treatment. 

   RESULTS 
   The observed and the expected mortalities in male to-female transsexuals 
treated with estrogens and cyproterone acetate are shown in Table 1.  The 
total number of deaths in the treatment group represented a 2.5- to 9-fold 
increase over the general population.  The increased mortality was in 
particular due to an increase of suicides and of deaths by unknown cause.  
There may have been a connection to sex steroid treatment in the three deaths 
of unknown cause, although autopsy in two of these cases failed to demonstrate 
a hormone-related cause.  All other causes of death were within the 95% 
confidence intervals of the expected mortality.  As can be expected in a 
relatively young age group, six of the 12 deaths (95% Cl, 2.5-9.5) were not 
from natural causes. 

   A summary of all morbidity encountered and, if data were available, the 
number of expected cases in the general population, aged 15 to 64 years, is 
shown in Table 2 (male-to-female transsexuals) and Table 3 (female-to-male 
transsexuals). 

   A clinically serious side effect of estrogen treatment (45-fold increase) 
was venous thrombosis of the legs (n = 13) and/or pulmonary embolism (n = 6).  
Of the total male to-female transsexual group this occurred in 19 (6.3%) 
patients, yet was expected in only one patient.  In the 235 male-to-female 
transsexuals who underwent sex reassignment surgery 4 (1.7%) were diagnosed 
postoperatively with venous thrombosis and/or pulmonary embolism.  This low 
postoperative incidence in comparison to the total incidence of thromboembolic 
events in our patients is probably due to our policy of discontinuing all 
hormone treatment at least 4 weeks before surgery.  If thrombosis attributed 
to estrogen occurred, this happened most often during the first year of 
treatment (ten of 13 cases).  Furthermore, there was a strong association 
between age and the incidence of thrombosis: five of 237 (2.1%) patients under 
40 years of age v eight of 66 (12%) patients over 40 years (P < .05, chi-
square test).  In the cases of thrombosis that occurred postoperatively or 
following leg trauma (one severe leg contusion and one tibial fracture), this 
association with age was not significant (2.2% v 4.0%), possibly due to the 
low number of cases. 

   The two cases of myocardial infarction occurred, after several years of 
hormone treatment, in one 45- and in one 50-year-old male-to-female 
transsexual.  Both had a strong positive family history of heart disease and 
one also smoked 50 cigarettes a day. 
   

   Table 1.  Observed Mortality in 303 Male-to-Female Transsexuals Treated 
With Estrogens and Cyproterone Acetate, and Expected Mortality in the General 
Male Population 15 to 64 Years of Age (Adjusted for Age 15 to 24, 25 to 39, 
end 40 to 64 Years) 

        No. Observed    No. Expected 
        (95% Cl) 
   Suicide      3 (0.63-8.8)    0.208 
   Murder       1 (0.024-5.5)   0.022 
   Accidental drowning  2       NA 
   Unknown      3 (0.63-8.8)    0.103 
   Myocardial infarction        1 (0.024-5.5)   0.619 
   COPD 1 (0.024-5.5)   0.066 
   Pancreatitis 1 (0.024-5.5)   0.075 
   Total number of deaths       12 (6.3-20.9)   2.333 
   

   Abbreviation: NA, not available. 
   

   Table 2.  Observed Morbidity in 303 Male-to-Female Transsexuals Treated 
With Estrogens and Cyproterone Acetate and Expected Number of Cases in the 
General Male Population 15 to 64 Years of Age (Adjusted for Age 15 to 24, 25 
to 39, and 40 to 64 Years) 
   

        No. Observed    No. Expected* 
        (95% C1) 
   Venous thrombosis and/or 
   pulmonary embolism   19(11.7-29.4)   0.422 
   Postoperatively (n = 235) 4 
   After trauma 2 
   Without clear cause 13 
   Myocardial infarction 
   (one lethal) 2 (0.25-7.2)    0.61932 
   Hypertension (> 1 60/95 mmHg)        14 (7.8-23.1)   18.70827 
   Transient ischemic attack    1 (0.024-5.5)   0.54733 
   Depressive mood change       25 (16.5-36.3)  1.59134 
   Prolactin level > 1,000 mU/L 
   (n = 214)    46 (33.8-57.8)  0.10819 
   Enlarged pituitary gland (CT scan)   5 
   Elevation of liver enzymes   22 (14.4-33.3)  NA 
   Hepatitis B  6 (2.22-12.9)   0.118 
   Alcohol-related      2       NA 
   Transient    12      NA 
   Unknown      2       NA 
   Cholelithiasis (surgery)     2 (0.25-7.2)    0.42935 
   Mastitis/abscess     1 
   Hyperthyroidism      1 
   Skin rash    2 
   

   *References are given. 
   

   Table 3.  Observed Morbidity in 122 Female-to-Male Transsexuals Treated 
With Long-acting Testosterone Esters or Testosterone Undecanoete, and Expected 
Morbidity (Adjusted for Age) 
   

        No. Observed 
        (95% Cl)        No. Expected* 
   Hypertension (>160/95 mmHg) 
   all three preexistent        3 (0.51-7.1)    1.27427 
   Elevation of liver enzymes   7 (3.5-16.9)    NA 
   Alcohol-related      3 
   Transient    1 
   CMV infection        1 
   Preexistent  1 
   Unknown      1 
   Edema        2 (0.24-5.9)    NA 
   Acne 15 (10.5-29.3)  NA 
   Weight increase > 10%        21 (15.3-36)    NA 
   

   *Reference is given. 
   

   For four patients with preexistent hypertension, kept adequately under 
control through medication (<150/90 mmHg), hormonal therapy was not considered 
to be contraindicated.  Ten patients developed high blood pressure (>160/95 
mmHg) during sex steroid treatment.  With appropriate antihypertensive 
treatment we were able to manage this without discontinuing the steroids. 
   In the first six months of hormone treatment depressive mood changes were 
reported spontaneously by 25 (8.3%) male-to-female patients.  We did not 
specifically inquire into depressive symptoms nor was psychometric testing 
done of these patients.  However, before the start of treatment all patients 
were informed of the possible effects hormones could have on their mood. 

   Serum prolactin levels increased in all estrogen-treated patients.  In 46 
(21.4%) patients serum prolactin levels rose to more than 1,000 mU/L (upper 
limit for males 300 mU/L), whereas only 0.108 of 214 patients were expected 
according to published prevalence rates.19  After reduction of the estrogen 
dosage serum prolactin levels fell to only slightly elevated values in 23 
patients.  CT scanning of the pituitary with contrast enhancement was 
performed in 15 of the 23 remaining patients (eight were either lost for 
follow-up or they refused radiologic evaluation).  In five of these 15 
patients pituitary enlargement was documented.20  

   In female-to-male patients androgen treatment deepened the voice, increased 
body hair growth, and induced beard growth to a varying extent.  Shaving 
became necessary in >90% of them after one year of androgen treatment and some 
grew a full beard.  Severe acne was observed in 15 (12.3%) subjects.  Topical 
treatment for the acne was moderately effective in most patients.  All 21 
patients (17.2%) who gained more than 10% body weight were already obese 
before the start of testosterone administration.  Minor weight increase (I to 
3 kg) was common in both estrogen- and androgen-treated patients, but minor 
weight loss was also regularly documented. 

   DISCUSSION 
   This study is a retrospective and not a case-control study.  Therefore, no 
definitive conclusions about the relative risks of cross-gender hormone 
treatment can be drawn.  The conclusion of this study could have been more 
firm if a control group had been included.  It did not appear feasible to 
match our group, which was heterogeneous in age and duration of hormone 
treatment, with a control group.  In the latter group there should have been a 
similar follow-up with regular clinic visits and laboratory tests.  To 
compensate for this drawback, we compared our findings with the expected 
number of deaths and morbidity calculated from health statics, adjusted for 
age and sex, of the general population.  This approach still poses a problem 
because our group was selected in two ways: (1) in our clinical population 
serious preexistent morbidity was excluded (eg, serious cardiovascular 
disease), and (2) the patients were treated on the basis of their 
transsexualism, which might be associated with a greater proneness to some 
pathologies (eg, suicide).  How ever, these comparisons are the best available 
for clinical evaluation of cross-gender hormone treatment.  Compliance with 
the prescribed hormones was obvious from the induced physical changes and was 
not monitored in this study. 

   The increased mortality in male-to-female transsexuals compared with the 
expected mortality can be partly explained by the increased suicide rate.  
Many patients (14%, unpublished observations of our group) attempted suicide 
before the start of sex reassignment treatment.  This increased suicide rate 
confirms the notion that gender reassignment is not fully effective in 
relieving co-existent morbidity in cases of gender dysphoria.  The increased 
number of deaths by unknown cause does raise concern.  Two of these three 
deaths might have been suicide, according to friends and relatives.  The 
autopsy of one did not include toxicologic screening; thus, the assumption of 
suicide cannot be refuted.  More extensive follow-up will be necessary to 
evaluate the risk of death by unknown cause. 

   It is evident from our results that the incidence rates of venous 
thrombosis and/or pulmonary embolism (45-fold), hyperprolactinemia (400-fold), 
depressive mood changes (15-fold), and transient elevation of liver enzymes 
were increased with estrogen and/or cyproterone acetate use, whereas weight 
increase and acne were associated with androgen use. 

   In accordance with previous studies of hyperlipemic men treated with 
estrogens,2l our study shows an increased incidence of thrombosis in estrogen-
treated male-to-female transsexuals.  The observed incidence in our study of 
1,140 of 100,000 exposure years is similar to the incidence of 1,100 of 
100,000 exposure years calculated from the data of the Coronary Drug Project 
Research Group.21  In comparison, the incidence of thromboembolic disease in 
oral contraceptive users is 300 of 100,000 exposure years and in healthy men 
estimated at 30 of 100,000 exposure years.2  The magnitude of this increased 
incidence rate of thromboembolic events is worrisome and should be a stimulant 
for research for less thrombogenic hormone schedules.  Either reduction of the 
estrogen dosage to the lowest possible effective dose, similar to what has 
been shown with oral contraceptives, or another way of administering, eg, 
percutaneous estradiol with less hepatic effects, might be effective ways of 
reducing this risk.  We also found advanced age (>40 years) to be a factor 
affecting the incidence of documented venous thrombosis and pulmonary embolism 
in male to-female transsexuals using estrogens.  The latter results have also 
been reported in women using oral contraceptives.3  
  

  The connection between sex hormone levels, coronary heart disease, and 
coronary risk factors is complex.22  Epidemiologic studies suggest that 
changes in blood lipid levels similar to those that occur during estrogen 
treatment reduce the risk of coronary heart disease.23  Yet, it has been found 
that estrogens did not prevent recurrent episodes of clinical coronary heart 
disease in hyperlipemic men with previous myocardial infarction.21  
Furthermore, in prostatic cancer patients, treatment with estrogens has been 
associated with an increased incidence of cardiovascular events24 and 
mortality.25  Our follow-up study of relatively young and healthy gender 
dysphoric males has still been too short to confirm any association. 

   The effect of androgens on blood lipids (increasing total cholesterol and 
decreasing HDL-cholesterol26 has also been found in women treated with 
testosterone cypionate (100 to 800 mg/mo im) for transsexualism.9  In this 
cross-sectional study these authors reported an increase of the total 
cholesterol levels in the low (100 to 300 mg/mo) and high dosage (800 mg/mo) 
regimen (11 observations) and no increase in the medium dosage of 400 mg (30 
observations).  This last dosage is comparable to the dosage we used.  Our 
limited number of prospective observations, as yet insufficient for 
statistical analysis, shows a highly variable response.  Theoretically, the 
increased serum total cholesterol and decreased HDL-cholesterol level could 
increase the risk of coronary heart disease.  To our knowledge, only one case 
report supports this assumption, although pretreatment serum lipid levels in 
this case were not available.16  The relatively young age and the follow-up 
period of median 3.6 years in our study preclude a definite conclusion. 

   The number of cases of hypertension observed is slightly less than 
expected.  This observation is in contrast with the reported effect of oral 
contraceptives on blood pressure in women.2  Meyer et al9 also failed to find 
changes of arterial blood pressure in estrogen-treated male-to-female 
transsexuals.  This discrepancy with the findings in oral contraceptive users 
may be explained by the way blood pressure readings were made.  In their study 
and in the present study blood pressure was measured during clinic visits in 
patients who often came for the first time to a gender clinic.  Blood pressure 
readings in this setting tend to be higher because of the nervous stress 
associated with new experiences.  At follow-up visits the blood pressure 
decreases and can mask the increase caused by estrogens.  Another reason we 
did not observe more cases of hypertension in the study group may be the 
relatively high prevalence of hypertension in the Dutch male population aged 
15 to 49 years.27  This could obscure an increased incidence associated with 
estrogen and/or cyproterone acetate.  More recent studies on blood pressure in 
women taking estrogens as replacement treatment also contradict the general 
assumption that estrogen treatment is associated with an increase in blood 
pressure.  Actually, the majority of women in these studies experienced a 
decline in blood pressure.28,29  

   Temporary mood changes were spontaneously reported by a considerable number 
of male-to-female transsexual patients in the first six months of treatment 
but subsequently waned.  In particular, cyproterone acetate has been reported 
to be associated with a lack of energy and depressive mood changes.30  The 
reason for these mental changes may not only be the hormone effect but also 
the psychologic pressure of living in the new gender role.  Because depressive 
mood changes were found predominantly in the first six months of the hormone 
treatment, it is improbable that there has been an association with the three 
observed suicides: they occurred after 1.5, 4, and 8 years of hormone 
treatment. 

   If liver enzyme abnormalities were observed, patients were examined by 
hepatitis serology, ultrasonography of the liver, and follow-up of liver 
enzyme tests, in particular, if applicable after discontinuation of alcohol 
abuse.  Most persistent liver enzyme abnormalities could be attributed to 
hepatitis B and alcohol abuse.  No evidence of liver tumors, such as peliosis 
hepatis or hepatic adenoma, was observed.  Transient liver enzyme 
abnormalities, similar to those found in the present study, have also been 
observed in estrogen-treated prostatic cancer patients but did not result in 
liver damage.31  

   The other side effects of cross-gender hormone treatment were minor.  Many 
side effects were reversible with appropriate therapy or temporary 
discontinuation of hormones.  The occurrence of serious side effects (eg, the 
prevalence of thromboembolic disease of 6.3%) was, however, not rare.  In view 
of the needs of transsexuals these side effects present a difficult dilemma in 
hormonal gender reassignment.  At present no firm guidelines can be given.  
The cornerstone of the decision to prescribe cross-gender hormones remains 
with the explanation of the possible side effects to the patients and careful 
clinical judgment.  Further follow-up of this relatively young population to 
disclose long-term side effects and to elucidate the association of sex 
steroids with coronary heart disease, as well as efforts to reduce the risk of 
thromboembolic events, are required. 

   ACKNOWLEDGMENT 
   The authors thank Jos Megens for his invaluable administrative and 
organizational contributions to this study, Elisabeth Savage, MA, and Dr Keith 
Courtney for their editorial assistance, and Dr Jos Nauta for his statistical 
advice. 

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