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Effects of Estrogen Treatment on Sexual Behavior
in Male-to-Female Transsexuals: Experimental and Clinical Observations
Marie Kwan, Ph.D.1
Judy VanMaasdam, B.A.2
Julian M. Davidson, Ph.D.1
The effects of oral estrogen treatment on sexual physiology
and behavior were examined in seven pre-surgical male-to-female
transsexuals engaged in cross-living. Subjects were studied prior
to hormone treatment during long-term hormone treatment and during
an experimental double-blind period in which the effects of their
usual hormone regimen were compared to those of placebo during
successive 4-week periods. Subjects maintained daily logs of their
spontaneous erections, sexual activity (masturbation), and feelings
throughout the study. Nocturnal penile tumescence was measured
using home monitors in order to estimate estrogen-induced changes
in erectile capacity. Erectile response to sexually arousing
stimuli (erotic films and self-generated fantasy) was also assessed
in the laboratory. Blood samples were taken at intervals for
testosterone and sex-hormone-binding globulin measurements and free
testosterone levels were calculated. Estrogen treatment inhibited
sexual activity spontaneous erections and nocturnal penile tumescence.
No significant effects on psycho-physiological response to film and
fantasy or frequency of sexual feelings were found, but the psycho-
physiological data were very variable. Testosterone levels were
suppressed by estrogen, but not to the extent that free testosterone
levels were. It appears that declining free testosterone level is
associated with inhibition of spontaneous erections (during both
sleep and waking) and of sexual activity, though the latter relation-
ship is less clear. No evidence of an effect on film or fantasy-
induced erections was obtained.
KEY WORDS: transsexuals
testosterone
sexual behavior
estrogen
nocturnal penile tumescence.
1Department of Physiology, Stanford University, Stanford,
California 94305.
2Gender Dysphoria Program, 900 Welch Road, Palo Alto,
California 94305.
INTRODUCTION
It is now well established that testosterone has multiple
stimulatory effects on sexual behavior both in male mammals
(Davidson 1977; Davidson et al., 1978) and men (Davidson et al.,
1979,1982; Skakkebaek et al., 1980). Yet much remains to be
learned about the behavioral mechanism of this action of androgen,
particularly in men, since controlled human research on this subject
is still meager (Bancroft, 1980; Davidson et al. 1982).
We recently showed that testosterone stimulates nocturnal
penile tumescence in hypogonadal men in addition to increasing
sexual activity and spontaneous erections, but erections elicited
in the laboratory during psychophysiological testing were not affected
by hypogonadism or testosterone treatment (Kwan et al., 1983). That
some types of erection might be androgen-dependent, and others not,
seems counterintuitive, and further investigation is indicated. A
different approach to these problems is to study the effects of
androgen suppression in healthy men. The availability of pre-surgical
male-to-female transsexuals undergoing hormone therapy provides an
opportunity to study the effects of estrogen simultaneously on sexual
behavior and testosterone levels in physically normal genetic males
and to test the hypothesis that estrogen's suppressive effects would
parallel testosterone inhibition. Unfortunately, uniform experimental
protocols could not be maintained across these individually variable
subjects, who are usually highly invested in their treatment regimens.
Nevertheless, we were able to gather informative experimental and
clinical data on effects of estrogen treatment in healthy men and to
compare the results with findings in a companion study of effects of
testosterone treatment on components of sexuality in hypogonadal men
(Kwan et al., 1983).
METHODS
Seven genetically male transsexual subjects (see Table I) were
recruited for long-term assessment and a double-blind crossover study
of estrogen vs. placebo. They were referred from the Gender Dysphoria
Program (directed by D. Laub, M.D.), a multidisciplinary project that
has provided diagnosis and treatment for approximately 750 transsexuals. All were living as women during a mandatory 2-3-year period
of cross-dressing and daily estrogen ingestion before qualifying for
gender change surgery. Because of the reluctance of these patients to
change or relinquish their estrogen treatments, even for a short
period, their recruitment required a long-term establishment of trust
with the investigative team. Moreover, the patients' previous oral
estrogen treatment regimen was used in the blind experiment.
Two subjects took the informed consent option of having the code
broken and returning to estrogen treatment if a subject suffered undue
disquiet while on placebo, 2 weeks (subject 1) and 3 weeks (subject 5)
after onset of placebo treatment. Since in these two cases the
estrogen was administered first, these (and the other) experiments
were blind during estrogen treatment. The subjects were seen by the
senior author at regular intervals over extended periods of time
before, during, and after the blind experimental period. Total and
free plasma testosterone levels and self-report and physiological data
on sexual behavior (see below) were obtained from the subjects
periodically, and results are reported here.
Table I. Description of Subjects' Treatments and Observation
Periods, the Total Duration of Observation for All Different Measures,
as Well as Time Elapsed from First to Last Observation and Durations
of Estrogen Treatment before Onset of Observations
NPT
(number Duration Duration
Estrogen of of obser- prior
Age treatment Logs test vation treatment
Subject (years) (mg/day) (weeks) (periodsa) (months) (months)
1 26 Premarin 9 6 11 8
(2.5)
2 23 Premarin 9 - 10 1.5
(2.5)
3 30 Premarin 9 3 11 30
(5.0)
4 25 Diethyl- 17 7 11 >18
stilbestrol
(5.0)
5 21 Premarin 14 4 13 7
(2.5)
6 53 Premarin 21 5 19 3
(2.5)
7 30 Premarin 10 7 6 2
(2.5)
a2-5 nights of observation per period.
Throughout the experimental period, and at other times (see Table
I), subjects kept daily logs and agreed to record therein all sexual
acts: coitus, masturbation, petting, orgasms, spontaneous erections
(those not generated in sex acts), and sexual feelings, by frequency
per day. Logs were brought to the laboratory each week, at which time
a brief interview was conducted and a 20-ml blood sample obtained.
The blood was separated, frozen, and subsequently tested for
testosterone level by radioimmunoassay (Frankel et al., 1975) and for
sex-hormone-binding globulin (SHBG) by the filter paper method
(Mickelson and Petra, 1974), from which estimated free testosterone
levels were calculated (Wiest et al., 1978).
Physiological Observations
Quantitative assessments of nocturnal penile tumescence (NPT) for
2-5 nights were obtained using portable home monitors. Recordings that
were technically questionable (e.g., due to strain gauge breakage) were
eliminated during blind scoring of the data. The NPT data were
evaluated in terms of (a) percentage of sleep time spent within 80% of
the maximum magnitude (MM) of increased penile circumference per
erectile episode multiplied by MM for that episode totaled over the
night (% T.MM) and (b) percentage of sleep time during which MM was
greater than 1.5 cm (% T > 1.5) Erectile responses to sexual
stimuli were measured by subjects observing erotic videotapes (or
sexually neutral television programs) and generating sexual fantasies
("imagine the most sexually arousing experience possible"), all in
complete privacy. The sequence of testing was neutral / fantasy /
neutral / film / neutral / film / neutral / film / neutral / fantasy /
neutral; each episode lasted 4 minutes. The data were analyzed to
generate two amplitude x duration measures (T.MM and T > 1.5), similar
to those derived for the NPT data.
Experimental Protocol and Analysis
Subjects volunteered to spend 2 months in a double-blind cross-
over experiment at a time of their choice within the longer series of
clinical observations. One month on the subject's usual oral estrogen
treatment was to be alternated with one month of receiving placebo.
Daily log data were collected throughout the experimental period.
Information on periods of data collection before and after the
experimental period are presented in Table I, along with other details.
Blood samples were taken two to four times times during the
experimental period and also during the other observation periods. The
decrease in testosterone level, due to negative feedback inhibition of
gonadotropin by estrogen (Santen, 1975) or its absence during placebo
administration, provided a weekly check on patient compliance.
{TGGuide Note: No figures were included with report}
Placebo Estrogen Placebo Estrogen
Fig. 1. Average weekly frequencies of spontaneous erections and
sexual acts (masturbation) during double-blind administration of
estrogen or placebo.
RESULTS
Daily Logs
Daily log data collected during the experimental treatments were
scored and expressed as weekly frequencies of spontaneous erections,
sex acts (coitus was never reported, so these were always
masturbatory), orgasms, and sexual feelings. Since sex acts were
almost always orgasmic, the data on orgasm frequency were almost
identical with those dealing with sexual acts. Placebo vs. estrogen
data were compared statistically using the paired t test. There were
no significant differences between these two conditions on any measure.
Examination of the data on erections, sexual acts, and orgasms
plotted across time, however, revealed clear-cut changes appearing
approximately 2 weeks following a change in treatment. Accordingly,
the data were reanalyzed in terms of mean weekly responses during the
3rd and 4th weeks after the onset of a change in treatment. These 2-
week periods were the last 2 weeks of each treatment; in the two cases
where the placebo was administered for less than 4 weeks, the "placebo
treatment periods" actually consisted of the first 2 weeks of Premarin
treatment in subject 1 and 1 week of placebo plus 1 week of Premarin
in subject 5. Figure 1 shows data on sexual acts and spontaneous
erections arranged in this fashion. In all subjects, estrogen had the
effect of decreasing the behavior, except for subjects 4 and 5, whose
frequency of sex acts remained at 0 and 1 per week, respectively,
during both treatment conditions. Spontaneous erection, sex act, and
orgasm frequencies were significantly lower on estrogen than placebo
(t = 3.75, p < 0.005, and t = 2.77, p < 0.025, 1-tailed, for erections
and acts respectively).
Analysis of the data on frequency of sexual feelings by either of
the two methods used above revealed no significant differences between
conditions, in part because subjects 2, 3, and 6 reported no sexual
feelings at all during the blind experiment. The subjects were
requested to state their guesses as to which treatment was which. By
2 weeks after the onset of blind treatments, all had guessed
correctly the identity of the treatment and attributed this to
noticing the return of spontaneous erections while on placebo.
Table II. Mean Total (TT) and Free (FT) Plasma Testosterone
Levels before Estrogen Treatment Was Initiated
(Baseline); during the 3rd and 4th Weeks after
Change of Treatment in the Experimental Period
(Estrogen and Placebo); and for Periods of Over
2 Months of Estrogen Treatment (Chronic Estrogen)a
Experimental Experimental Chronic
Baseline Placebo Estrogen Estrogen
TT FT TT FT TT FT TT FT
1 7.78 202 16.19 318 1.68 12 3.00 20
2 6.89 241 10.06 299 7.14 93 1.07 10
3 - - 9.81 382 7.01 126 2.75 28
4 - - 3.32 53 0.30 2 0.22 2
5 5.33 201 7.85 318 7.36 201 4.07 73
6 5.44 173 7.46 238 6.12 79 2.55 44
7 8.91 288 5.92 175 4.76 94 5.72 116
Mean 6.87 221 8.66 255 4.91 87 2.77 42
S.E. ±0.68 ±20 ±1.53 ±68 ±0.38 ±26 ±0.69 ±15
aMean values in ng/ml (TT) and pg/ml (FT) are shown. All baseline
values are means of 3 samples, and chronic estrogen of 3 or 4.
Experimental values are means of 2 samples or single ones (subjects 3,
6, 7).
Hormonal Data
Mean total and free testosterone levels are shown in Table II for
the different phases of the study: before onset of estrogen treatment
(baseline), during the experimental period, and during long-term
estrogen treatment. Placebo and estrogen treatment periods were as
defined in the previous section. During the baseline observations,
total testosterone levels were well within the normal range (3-11
ng/ml). During placebo treatment, total and free testosterone levels
were above baseline values in 4 of the 5 subjects with baseline data.
Particularly high total and/or free levels were present in subjects 1
and 2. In all 7 subjects, the levels were lower during estrogen
treatment than placebo, though only in subjects 1 and 4 did they drop
to the hypogonadal range. Even after long-term treatment, subjects 5
and 7 had total testosterone values clearly within the normal range.
In all cases, however, the percentage of decrease from placebo to
estrogen conditions was considerably greater for free testosterone
than for total testosterone. Thus, with estrogen treatment total
testosterone dropped to an average of 60 ± 13% (S.E.) of the placebo
level, while free testosterone dropped to 23 ± 9%. Subject 5 showed
the least change in total or free testosterone levels with estrogen
treatment; independent evidence confirmed inconsistent pill-taking in
this case. In all cases, testosterone levels returned to the normal
range of values for men by the third week after onset of placebo
treatment, with the DES-treated subject showing the lowest value.
Table III. Nocturnal Penile Tumescence Data during Blind
Experimental Period
Number of
% T.MM % T > 1.5 nights tested
Subject Placebo Estrogen Placebo Estrogen Placebo Estrogen
1 31.83 1.39 38.85 3.75 3 3
3 62.55 22.67 32.72 8.10 2 6
4 2.88 0.0 0.0 0.0 6 3
5 72.4 69.58 32.14 25.49 3 3
6 11.78 5.04 1.75 0.92 2 2
7 43.41 50.12 20.34 22.86 7 7
Mean 37.48 24.8 20.97 10.19
S.E ±11.21 ±11.8 ±6.81 ±4.58
Fig. 2. Relationships between free testosterone level and
nocturnal penile tumescence (% of sleep time in maximum erection x
degree of tumescence, see Methods) throughout the various periods
of observation during the study. Both measures are expressed as
percentage of the highest value for the same individual during the
study. Each of the six subjects with NPT and hormone data is
represented by a separate data point for each observation period,
which is a mean of several observations during a specific period of
study.
Nocturnal Penile Tumescence
Data on NPT (see Table III) were available for only six of the
seven subjects, since subject 2 would not use the NPT monitor. In
addition, two subjects had extremely low NPT scores. Subject 4 showed
a virtual absence of nocturnal erections, and this subject (receiving
5 mg DES) also had the lowest testosterone values of the group. Table
III shows mean NPT results during placebo and estrogen conditions for
all subjects. In light of considerable variability in the data, it
was not surprising that there was no significant difference between
the two experimental conditions, using the paired t test on either NPT
variable (p > 0.05, 1-tailed). However, the trend was clearly toward
a decline in NPT measures with estrogen; robust decreases were found
in three subjects. This was further investigated by examining NPT-
testosterone relationships both outside and within the experimental
period. Free and total testosterone mean values for all subjects in
all conditions were plotted against the concurrently collected mean
NPT data. NPT data were obtained for two to five nights during 1-week
periods, with blood sampling on days one and eight; the two
testosterone values were averaged to generate a mean testosterone
value used in the analysis.
Figure 2 shows a scattergram of the individual data on NPT vs.
free testosterone from each period of observation, and Table IV
presents mean coefficients of correlation for each individual subject.
It is clear that NPT is positively related to free testosterone levels
(though the scattergram was less impressive for total testosterone).
Individual correlation coefficients were high and positive in all
subjects except subject 7. The slopes of the regression lines
(hormone vs. NPT) were calculated for each subject, and the
significance of the slope was calculated by single-sample t test and
found to show significance for total and free testosterone.
Table IV. Individual Correlation Coefficients for the
Relationship between NPT (% T.MM) and Total
or Free Testosterone over the Various Conditions
and Significance of the Slopes of the Regression
Lines
Total Free
Subject testosterone testosterone
1 .92 .99
3 .97 .99
4 .48 .47
5 .97 .77
6 .68 .81
7 - .15 - .12
Significance, t 2.16 2.34
p (1-tailed) < 0.05 < 0.05
Table V. Psychophysiological Data: Erectile Responses to
Film and fantasy (Amplitude x Duration, T.MM)
during Experimental Period
Film Fantasy
Subject Placebo Estrogen Placebo Estrogen
1 332.5 133.0 462.0 185.0
2 752.0 918.5 384.0 586.0
3 2023.0 1045.5 722.0 0.0
4 4.0 0.0 0.0 0.0
5 553.5 757.5 488.5 686.5
6 1824.0 2159.0 815 .5 300.0
7 1278.5 838.1 750.3 356.8
Mean 966.8 835.9 517.5 302.0
S.E ±288.4 ±267.3 ±106.3 ±100.9
A similar analysis was done for self-reported data on spontaneous
erections and sexual acts. The daily log data were analyzed in blocks
of six days, three each before and after the testosterone determination
to which they were being related. Statistical significance was
obtained (p < 0.05, t = 2.04, 1-tailed) for the relationship between
free (but not total) testosterone and spontaneous erections, but not
for the relationships between total or free testosterone and sexual
acts.
Psychophysiological Data
Table V shows the psychophysiological responses to erotic film
and fantasy.
Three subjects showed an increased response to film with estrogen;
three others decreased. Four of the seven subjects showed a marked
decrease in response to fantasy during estrogen treatment, and two
a less marked decrease. One subject (4) showed essentially no
response to either stimulus. This was the same subject (receiving
DES) who was only barely responsive on the NPT test. A paired t
test revealed no significant differences between placebo and estrogen
for the film or fantasy tests (p > 0.05, 1-tailed).
DISCUSSION
This report indicates that estrogen administration to genetic
male transsexuals with intact testes reduces sexual activity, orgasms,
and spontaneous erections. Changes in these measures of sexuality
followed changes in hormone treatment by approximately 2 weeks.
Objective assessment of spontaneous erectile capacity was obtained
from periods of all-night recordings of nocturnal erections and the
quantitative analysis of the resulting data. The relationship between
free testosterone vs. NPT and self-reported spontaneous erection data
following observations made in a variety of hormonal situations
revealed a positive relationship between these variables. In each of
these situations except the experimental period, hormone levels had
reached steady-state conditions.
Though erectile responses to erotic film and fantasy were not
found to be significantly affected by estrogen, the data are too
variable to allow for reliable negative conclusions from such a small
sample. However, Bancroft et al. (1974) found no reduction in film-
induced erections in sex offenders whose testosterone levels were
suppressed by estrogen.
The data suggest that spontaneous (waking or nocturnal)
erections and sexual activity are testosterone-dependent, but this
does not necessarily reflect an overall testosterone dependence of
the intrinsic erectile mechanism. Similar (and firmer) conclusions
have arisen from the study of testosterone treatment in hypogonadal
men. Thus, Kwan et al. (1983) reported that sexual activity and NPT
responses in these subjects were clearly testosterone-dependent, but
not their responses to film and fantasy, while Bancroft and Wu (1983)
found that testosterone affected the film but not the fantasy
response. The additional conclusion from our work and that of others
(Skakkebaek et al. 1980; Luisi and Franchi, 1980; Bancroft, 1980) that
testosterone also independently stimulates libido was not reflected in
the present results on frequency of sexual feelings. However, male-
to-female transsexuals may commonly report a lack of sexual feelings
before gender surgery is performed, for reasons unrelated to libido
status.
Free testosterone was more suppressed by the estrogen treatment
than total testosterone, as a result of elevated SHBG levels and
consequent binding of testosterone. Because severe decreases in
sexual function occurred when free testosterone level was reduced,
but total testosterone was not below the normal range, and because
free but not total testosterone was related to spontaneous erections,
we tentatively conclude that the free fraction is responsible for
effects on sexuality. This is consistent with our previous finding
that the sexual decline in aging men is slightly but significantly
correlated with low free but not total testosterone level (Davidson
et al. 1983). The data provide no indication of a stimulatory effect
of estrogen on any of the aspects of sexual function studied.
However, it should be noted that the animal data showing positive
effects of estrogen on sexual behavior are mostly limited to
motivational (i.e., libido) measures (Beyer, 1979; Davidson, 1969)
and do not include reflex erectile response (Gray et al. 1980; Hart,
1979). Finally, the possibility that estrogen inhibits sexual
function directly, rather than via androgen suppression, cannot
yet be excluded.
ACKNOWLEDGMENTS
We gratefully acknowledge the help of Drs. Donald Laub and
Norman Fisk and thank Brenda Siddall for excellent technical
assistance. Special thanks are due to Dr. Jeanette Chen, who began
the work that led to this study. The antiserum for the testosterone
assay was kindly supplied by Dr. B. Caldwell.
REFERENCES
Bancroft, J. (1980). Endocrinology of sexual function. Clin.
Obstet. Gynaecol. 7: 253-281.
Bancroft, J., and Wu (1983). Changes in erectile responsiveness
during androgen replacement therapy. Arch. Sex Behav.
12: 59-66.
Bancroft, J., Tennent, T. G., Loucas, K., and Cass, J. (1974).
Control of deviant sexual behavior by drugs: Behavioral
effects of estrogens and antiandrogens. Brit. J. Psychiat.
125: 310-315.
Bever, C. (1979). Endocrine Control of Sexual Behavior. Raven
Press New York.
Davidson, J. M. (1969). Effects of estrogen on the sexual
behavior of male rats. Endocrinology 84: 1365-1372.
Davidson, J. M. (1977). Neuro-hormonal bases of male sexual
behavior. In Greep, R. O. (ed.), Reproductive Physiology
II (International Review of Physiology, Vol. 13),
University Park Press, Baltimore, Maryland, pp. 225-254.
Davidson, J. M., Gray, G. D., and Smith, E. R. (1978). Animal
models in the endocrinology of reproductive behavior. In
Alexander, N. (ed.), Animal Models for Research on
Contraception and Fertility Harper & Row, Hagerstown,
Maryland, pp. 61-81.
Davidson, J. M., Camargo, and Smith (1979). Effects of
androgen on sexual behavior in hypogonadal men. J. Clin.
Endocrinol. Metab. 48: 955-958.
Davidson, J. M., Kwan, M., and Greenleaf, W. J. (1982).
Hormonal replacement and sexuality in men. In Bancroft,
J. (ed.), Clinics in Endocrinology and Metabolism (Vol.
11) Saunders, London, pp. 599-624.
Davidson, J. M., Chen, J. J., Crapo, L., Gray, G. D.,
Greenleaf, W. J., and Catania, J. A. (1983). Hormonal
changes and sexual function in aging men. J. Clin.
Endocrinol. Metab. 57: 71-77.
Frankel, A. I., Mock, E. J., Wright, W. N., and Kamel, F.
(1975). Characterization and validation of a radioimmuno-
assay for plasma testosterone in the male rat. Steroids
25: 73.
Gray, G. D., Smith, E. R., and Davidson, J. M. (1980). Hormonal
regulation of penile erection in castrated male rats.
Physiol. Behav. 24: 463-468.
Hart, B. L. (1979). Activation of sexual reflexes of male rats
by dihydrotestosterone but not by estrogen. Physiol.
Behav. 23: 107-109.
Kwan, M., Greenleaf, W. J., Mann, J., Crapo, L., and Davidson,
J. M. (1983). The nature of androgen action on male
sexuality: A combined laboratory-self-report study on
hypogonadal men. J. Clin. Endocrinol. Metab. 57: 557.
Luisi, M., and Franchi, F. (1980). Double-blind group
comparative study of testosterone undecanoate and
mesterolone in hypogonadal male patients. J. Endocrinol.
Invest. 3: 305-308.
Mickelson, K. E., and Petra, P. H. (1974). A filter assay for
the sex steroid binding protein (SEP) of human serum.
FEBN Letters 44: 34.
Santen, R. J. (1975). Is aromatization of testosterone to
estradiol required for inhibition of LH secretion in
man? J. Clin. Invest. 56: 1555-1563.
Skakkebaek, N. E., Bancroft, L., Davidson, D. W., and Warner,
P. (1980). Androgen replacement with oral testosterone
undecanoate in hypogonadal men: A double-blind controlled
study. Clin. Endocrinol. 14: 49-61.
Wiest, W. G., Paulson, J. D., Keller, D. W., and Warren, J. C.
(1978). Free testosterone concentration in serum: A method
for determination. Amer. J. Obstet. Gynecol. 130: 321.
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