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)
Before UTMB
Gender Clinic Observations
Breasts Testes Penis Testosterone
LH
FSH
treatment
(n)
(cm) (ml) (cm)
(ng/dl) (mlU/ml)
(mlU/ml)
Never treated 9
0
23.5
1.1 14.6 0.8 978
86 5.5 1.0 7.8 1.5
Prior treatments 9
5.8
2.3 19.2 2.5 13.6
0.7 1094 145 8.8 2.1 10.7 2.9
After treatment
Conjugated estrogen
1.25 mg/day 5
5.1 2.6
16.4 3.3 13.5 0.3 586 143
5.5 1.7 7.1 2.7
2.5 mg/day 12
12.4
2.5 11.9 2.2 14.4 0.7
691 121 6.8 1.1 7.3 1.3
5.0 mg/day 8
14.5 1.2
10.9 1.8 15.2 0.4
504 124 8.4 2.1 5.0 1.1
Ethinyl estradiol
0.1 mg/day 3
10.7 0.9
19.2 1.7 10.8 0.6
143 31 2.2 0.3 3.0 1.2
0.5 mg/day 20
12.9 0.9
7.7 0.8 13.5 0.7
105 20 2.4 0.4 2.2 0.3 |
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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