Physical and Hormonal Evaluation
of Transsexual Patients During Hormonal Therapy

Walter J. Meyer III, M.D.,1,2 Jordan W. Finkelstein, M.D.1,2 
Charles A. Stuart, M.D.,3 Alice Webb, M.S.W.,2 Edward R. Smith, Ph.D.,4 
Andrew F. Payer, Ph.D.,5 and Paul A. Walker, Ph.D.1,2 
   

   The optimal hormonal therapy for transsexual patients is not known.  The 
physical and hormonal characteristics of 38 noncastrate male-to-female 
transsexuals and 14 noncastrate female-to-male transsexuals have been measured 
before and/or during therapy with various forms and dosages of hormonal 
therapy.  All patients were hormonally and physically normal prior to therapy.  
Ethinyl estradiol was superior to conjugated estrogen in suppression of 
testosterone and gonadotropins but equal in effecting breast growth.  The 
changes in physical and hormonal characteristics were the same for 0.1 mg/d 
and 0.5 mg/d of ethinyl estradiol.  The female-to-male transsexuals were well 
managed with a dose of intramuscular testosterone cypionate of 400 mg/month, 
usually given 200 mg every two weeks.  The maximal clitoral length reached was 
usually 4 cm.  Higher doses of testosterone did not further increase clitoral 
length or suppression of gonadotropins; lower doses did not suppress the 
gonadotropins.  Based on the information found in this study, we recommend 0.1 
mg/d of ethinyl estradiol for the noncastrate male-to-female transsexual and 
200 mg of intramuscular testosterone cypionate every two weeks for the 
noncastrate female-to-male transsexual. 
   

   INTRODUCTION 
   Although the hormonal and physical characteristics of patients seeking 
treatment for transsexuality have been a subject of debate for more than 12 
years, the abnormalities reported have been, generally, of minor significance 
(Dorner et al., 1976; Hamilton and Chapman, 1977; Jones and Samimy, 1973; 
Meyer-Bahlburg, 1977, 1979; Migeon et al., 1968; Sipova and Starka, 1977; 
Starka et al., 1975).  The hormonal treatment of these patients before 
gonadectomy has been based on estimates derived from the physiological doses 
of hormones used for adults who lack gonadal function and require replacement 
therapy (Benjamin, 1966; Hamburger, 1969; Migeon, 1969; Money and Walker, 
1977). 
   This study compares various forms and dosages of hormonal therapy used in 
treatment of noncastrate transsexuals.  Physical changes were measured, as 
well as the concentration of hormones, in patients undergoing hormonal 
treatment.  The goal of this report is to point the way for more rational and 
standardized hormonal treatment of transsexual patients of both sexes. 

   METHODS 
   During the first 21/2 years after it was founded, the Gender Clinic at The 
University of Texas Medical Branch at Galveston evaluated 52 nongonadectomized 
transsexual patients on at least one occasion (38 male-to-female transsexuals, 
ranging in age from 16 to 62 years, and 14 female-to-male transsexuals, 
ranging from 21 to 55).  Patients with the adrenogenital syndrome, XO/XY 
mosaicism or other congenital endocrine problems were excluded from this 
study. 
   A total of 136 evaluations was done (98 for the male-to-female 
transsexuals, and 38 for the female-to-male transsexuals).  During a typical 
evaluation, the patient had a complete physical examination and an appropriate 
hormonal evaluation.  These evaluations were performed both at the time of 
initial registration with the Gender Clinic and after each interval (at least 
3 months) during which the patient had received a prescribed hormonal regimen. 
   The nine male-to-female transsexuals who had not been treated previously 
were given various dosages of conjugated estrogen as initial therapy.  Those 
who had been treated previously (for periods ranging from 1 1/2 to 16 years) 
were given either conjugated estrogen or ethinyl estradiol.  The dose of 
conjugated estrogen (usually Premarin) ranged from 1.25 to 5.0 mg/day, and the 
dosage of ethinyl estradiol from 0.1 to 0.5 mg/day. 
   The patients who were receiving ethinyl estradiol or conjugated estrogen at 
the time of their initial visit were usually continued at the same dosage, if 
it was within the above mentioned range, or were given a reduced dosage of the 
same medication.  Patients who were receiving other forms of estrogen were 
divided arbitrarily and randomly into two treatment groups: one received 
conjugated estrogen, the other ethinyl estradiol.  In addition to estrogen 
therapy, medroxyprogesterone was being taken by approximately 25% of the 
patients during the time they were studied.  For 90% of those observation 
periods, the dose was 10 mg/day; for the remainder, the dose was 20 mg/day. 
   Nine of the 14 female-to-male transsexuals had not been previously treated.  
All the female-to-male transsexuals were treated with testosterone 
cypionate(Depotestosterone), ranging in dosage from 100 mg/month to 200 
mg/week.  The testosterone cypionate was usually started at a dosage of 200 
mg/month and increased every 3 months in a stepwise fashion by decreasing the 
interval between doses of medication until luteinizing hormone (LH) and 
follicle-stimulating hormone (FSH) were suppressed into the prepubertal range. 
   

   
   1Gender Clinic and Department of Pediatrics, The University of Texas 
Medical Branch at Galveston, Galveston, Texas 77550. 
   2Gender Clinic and Departments of Psychiatry and Behavioral Sciences, The 
University of Texas Medical Branch at Galveston, Galveston, Texas 77550. 
   3Gender Clinic and Department of Internal Medicine, The University of Texas 
Medical Branch at Galveston, Galveston, Texas 77550. 
   4Gender Clinic and Department of Obstetrics and Gynecology, The University 
of Texas Medical Branch at Galveston, Galveston, Texas 77550.  
   5Gender Clinic and Department of Anatomy.  The University of Texas Medical 
Branch at Galveston, Galveston, Texas 77550.    
   

   Every 3 months, each patient received a complete physical examination, 
including measurement of genitalia and breasts.  The breasts were measured 
with a flexible steel tape measure, with the patient in a supine position.  
The maximal breast tissue hemicircumference, crossing over the middle of the 
nipple, was recorded.  The stretched clitoral or penile length, not including 
the foreskin or clitoral hood skin, was recorded in centimeters (Schonfeld, 
1943).  The testicular volumes were measured by comparing to Prader testicular 
models (Zachmann et al., 1974).  At the time of each physical examination, 
single blood samples for hormone measurement were obtained at some time 
between 9 A.M. and 5 P.M. The plasma testosterone and androstenedione were 
measured by radioimmunoassay after separation by LH-20 chromatography (Akesode 
et al., 1977).  Estradiol was measured by radioimmunoassay (Lindner et al., 
1972).  LH and FSH were also measured by radioimmunoassay compared to second 
IRP-HMG standard (Johanson et al., 1969; Raiti et al., 1969). 
   Data are reported for a given dosage of hormone medication only when at 
least two observations had been made for that dosage.  Therefore, it was 
possible to calculate a standard error of the mean (SEM) for each type of 
observation taken during the physical and hormonal examination. 
   

   Table I.  Results of Physical Examinations and Hormonal Determinations 
   in Male-to-Female Transsexuals before Gonadectomy (38 patients)
   

      a All patients received the stated dosage of medication for at least 3 
months, usually 6 months or longer.  The total of the subtotals of the 
observations from each treatment group does not equal the total number of 
patients, because some of the patients were studied while they received more 
than one dosage or type of medication.  Also, not all of the untreated 
subjects continued in the treatment program long enough to be included in a 
treatment group. 
   b Patients not receiving therapy at the time of this study.   
   

   RESULTS 
   Male-to-Female Transsexuals 
   Nine male-to-female transsexuals were evaluated before any treatment with 
hormones, either prescribed by a physician or obtained "off the street." The 
physical findings were normal: Tanner stage 5 pubic hair, testicular volume of 
15 to 25 ml (mean  SEM = 23.5  1.1 ml), no gynecomastia, and stretched penis 
length of 11 to 18 cm (mean  SEM = 14.6  0.8 cm).  Results of hormonal 
evaluation were also normal: plasma testosterone, mean  SEM = 978  86 ng/dl, 
range 558-1391 ng/dl; androstenedione, mean  SEM = 181  61 ng/dl, range 79-
289 ng/dl; LH, mean  SEM = 5.5  1.0 mlU/ml, range 1.6 11 mlU/ml; and FSH, 
mean  SEM = 7.8  1.5 mlU/ml, range 1.9-18 mlU/ml (Table I). 
   The physical examinations of the nine patients who had received hormonal 
medication previously but were not receiving it at the time of evaluation 
showed very similar physical and hormonal characteristics except they did have 
some breast enlargement (breast hemicircumference mean SEM = 5.8  2.3 cm, 
range 0-13 cm) and some reduction of testicular size - to a mean  SEM = 19.2 
 2.5 ml, range 10-30 cm3 (Table I). 
   Although many of the patients reported weight gain with estrogen therapy, 
such gains could not be verified statistically in this study.  Subjectively, 
the examiners and patients usually observed a redistribution of weight into 
the breasts and hips and away from muscle.  Table I compares the physical and 
hormonal changes induced by various dosages of either ethinyl estradiol or 
conjugated estrogen in male transsexuals who had received therapy before 
entering the study.  The breast hemicircumference increased in all patients 
who took estrogen (Table I).  Patients who had taken medication before 
entering the study had more breast development than those who had taken no 
previous medication, regardless of the dosage of conjugated estrogen taken 
during the study.  The higher the dosage of estrogen of either type, the more 
breast development occurred.  There was no plateau effect, and 0.5 mg of 
ethinyl estradiol seemed to have the same effect as 5.0 mg of conjugated 
estrogen. 
   No statistical effect could be shown on stretched penis length (mean  SEM 
= 13.7  0.7 cm) for patients receiving 0.5 mg of ethinyl estradiol or 5.0 mg 
of conjugated estrogen.  Changes in body hair were impossible to assess 
because so many patients had used electrolysis.  Testicular volume was reduced 
by approximately 50% after dosages of greater than 2.5 mg of conjugated 
estrogen or 0.1 mg of ethinyl estradiol (Table I). 
   Conjugated estrogen, even 5.0 mg/day, suppressed plasma testosterone to 
only about 50% of its original concentration, which was not consistently into 
the female range (Table I).  The concentration of LH and FSH did not decline 
significantly.  In contrast, 0.1 mg and 0.5 mg of ethinyl estradiol did 
suppress plasma testosterone into the female range and LH and FSH into the 
prepubertal range (Table I). 

(female to male section removed)
   
   DISCUSSION AND CONCLUSIONS 
   For the male-to-female transsexual patient who had not undergone 
gonadectomy, ethinyl estradiol seems to be more effective than its previously 
reported potency relative to conjugated estrogen of 1:10 to 1:40 (Cooke, 1978; 
Davey, 1976; Fotherby, 1976; Kupperman, et al., 1953).  Typically, 0.1 mg of 
ethinyl estradiol is considered to be equivalent to 2.5 mg of conjugated 
estrogen.  In our experience in treating male-to-female transsexuals, ethinyl 
estradiol in a dosage of 0.1 mg was superior to 5.0 mg of conjugated estrogen 
in suppression of testosterone and LH but was similar in promoting breast 
growth (Table I). 
   Since a dosage of 0.1 mg ethinyl estradiol is as effective as 0.5 mg in 
suppression of testosterone, the dose of 0.1 mg or less seems more desirable 
(Table I).  To see if even lower doses can be used, 0.05 mg of ethinyl 
estradiol should be tested.  Treatment periods of longer than 3 months will be 
needed to determine if the same ultimate breast hemicircumference is reached 
using these lower doses of medication. 
   The correlation between plasma testosterone and the histologic change of 
the testes is good.  Light microscopic studies have shown changes that varied 
from slight atrophy to disappearance of all recognizable Leydig cells in 
response to long-term treatment with stillbestrol (de la Balze, et al., 1954) 
and progestins (Camacho et al., 1972; Frick et al., 1976; Heller, et al., 
1959).  Payer et al. (1979) have reported similar evidence using the electron 
microscope to examine the testes.  The Leydig cells of normal untreated testes 
have very similar ultrastructural characteristics to those of testes of 
patients treated with conjugated estrogens.  In contrast, ethinyl estradiol 
results in reduced numbers of cells or dramatic cytologic alterations in 
Leydig cells, accompanied by a low plasma concentration of testosterone (Payer 
et al., 1979). 

(female to male section removed)

   This report is a cross-sectional survey of the physical and hormonal 
effects of several commonly used hormone treatment programs.  The cross-
sectional nature of the study may introduce a bias into the results.  Several 
limitations should be kept in mind.  First, few patients were studied during 
administration of more than one type of medication or of more than a one-
dosage regimen.  Second, although all patients received the given dose of 
medication for at least 3 months, many received it longer, and a few patients 
received medication for as long as 18 months.  Sometimes, the dosage was 
reduced during follow-up, but in most instances, if any change was made it was 
to increase the dosage.  Therefore, the duration of administration and the 
carry-over effect from any previous dosage schedule was not subject to 
controls.  Only a longitudinal study with matched groups of patients on each 
dosage will overcome these limitations.  Since a majority of the patients had 
no change in dosage, one cannot assume that the greater response in breast 
growth, testicular size reduction, and hormonal suppression by the higher 
doses of medication were due to the total length of treatment.  Based on the 
information brought forth by this study, the best treatment regimen seems to 
be 0.1 mg/day ethinyl estradiol (for the male-to-female transsexual before 
gonadectomy) and 200 mg of intramuscular testosterone cypionate every 2 weeks 
(for the female-to-male transsexual before gonadectomy). 

   ACKNOWLEDGMENT 
   The authors thank Marilyn A. Thompson and Judy Chadwick of the Office of 
Continuing Medical Education at The University of Texas Medical Branch for 
their expert editorial and typing assistance with this manuscript. 

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