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Hormonal Sex Reassignment
Louis J.G. Gooren
Netherlands.
[Abstract] Full Text [PDF]
Abstract
Hormonal Sex Reassignment
Male-to-female transsexuals
Female-to-male transsexuals
Side effects
Cardiovascular
disease
Juvenile
Gender Dysphoria
Abstract
The author reviews the relevant current
literature on the subject. He goes on to outline detailed treatment
recommendations for MTFs with estrogens and antiandrogens. He highlights side
effects and complications such as venous thrombosis, breast cancer in
individuals with a predisposing family history and the rare incidence of
prolactin producing tumors.
Similarly, a detailed review of androgen
administration in FTMs is provided describing the cessation of menstruation
and the development of a male hair pattern. Contraindication against high dose
use of sex steroids consist of serious liver, cardiovascular, cerebrovascualar,
and thromboembolic disease, marked obesity, and poorly controlled diabetes
mellitus.
Finally, the complicated medicolegal issues
of juvenile gender dysphoria are mentioned. Rather than giving heterotypical
sex steroids, the author recommends hormonal delay of the onset of puberty
until an age when a responsible decision can be made.
Hormonal Sex Reassignment
Fundamental to sex reassignment treatment of
transsexuals is the acquisition of the sex characteristics of the other sex to
the fullest extent possible. Secondary sex characteristics are contingent on
sex steroids. There is no known fundamental difference in sensitivity to the
biological action of sex steroids on the basis of genetic configurations or
gonadal status. Adult transsexuals undergoing sex reassignment have the
disadvantage that at that age a normal average degree of hormonal
masculinisation or feminisation has already taken place. Unfortunately, the
elimination of the hormonally induced sex characteristics of the original sex
is rarely complete. In male-to-female transsexuals the previous effects of
androgens on the skeleton (the average greater height, the size and shape of
hand, feet, jaws, and of the male type pelvis) cannot be reversed by hormone
treatment. Conversely, the relatively lower height of female-to-male
transsexuals compared to men and the broader hip configuration will not change
under androgen treatment. These features show a considerable overlap between
the sexes, so in some transsexuals characteristics of the natal sex will be
more visible than in others.
Hormonal reassignment has therefore two aims:
1) to eliminate, in so far as possible, the hormonally induced secondary sex
characteristics of the natal sex and 2) to induce those of the new sex.
The usual transsexual is a rather young and
healthy person and, therefore, there are rarely absolute or relative
contra-indications against cross-sex hormone administration.
Contra-indications against estrogen use are a strong family history of breast
cancer or harboring a prolactin-producing pituitary tumor, and against
androgen use severe lipid disorders with cardiovascular complications.
Contra-indications against high dose use of either sex steroid are serious
cardiovascular disease, cerebrovascular disease, thromboembolic disease,
marked obesity, poorly controlled diabetes mellitus and serious liver disease
(Futterweit).
It is recommendable to discontinue sex
steroid administration 3-4 weeks before any elective surgical intervention.
Immobilization is a trombogenic risk factor and sex steroids may aggravate the
risk of thromboembolism. Once subjects are fully mobilized again, hormone
therapy may be reinstated.
Male-to-female
transsexuals
To male-to-female transsexuals elimination of
sexual hair growth and induction of breast formation are essential (Asscheman
& Gooren, 1992; Futterweit, 1998; Schlatterer et al., 1998). To attain
both an almost complete reduction of the effects of androgens is required.
Administration of estrogens alone will suppress gonadotropin output and
therewith androgen production, but dual therapy with one compound suppressing
androgen action and an other with estrogen effect is probably more effective.
Several agents are available to inhibit androgen action. In Europe the most
widely used drug is cyproterone acetate, a progestational compound with
antiandrogenic properties. The usual starting dose is 100 mg per day. Later
when testosterone levels are effectively suppressed the dose may be reduced to
50 mg per day. If not available medroxyprogesterone acetate, 5-10 mg per day,
probably somewhat less effective, is an alternative. Nonsteroidal
antiandrogens such as flutamide and nilutamide are also used but they increase
gonadotropin output with a rise of testosterone and estradiol; the latter is a
desirable effect in this context. Spironolactone, a diuretic with
antiandrogenic properties, has similar effects. Also LHRH (ant)agonists as
monthly injections can be considered but these compounds are rarely used.
Finasteride 1 mg, now marketed for alopecia androgenica, might be tried.
Finasteride inhibits the conversion of testosterone to dihydrotestosterone,
the androgen responsible for induction of sexual hair growth. But there are as
yet no studies on the use of this drug in transsexuals, and it must be
remembered that as a single therapy they increase actually testosterone
levels. There is a wide range of estrogens to choose from. Oral
ethinylestradiol, 50-100 micrograms per day, is a potent and cheap estrogen.
It may cause venous thrombosis, particularly in subjects over 40 years of age
(13). For them and for subjects with risk factors such as thrombosis
transdermal estrogens (100 ug 17-estradiol) twice a week is an alternative. It
is, however, less potent than ethinylestradiol. Many transsexuals favor
injectable estrogens; they provide high levels of circulating estrogens with
possible disadvantages and they carry a higher risk of overdosing to which not
so few transsexuals are inclined. If an emergency occurs which would make
absence of estrogenic stimulation desirable, it is impossible to get rid of
the long-lasting effects of depot forms of injected estrogens.
As to the effects of this dual regimen: adult
male beard growth is very resilient to the described hormonal intervention.
Therefore, in Caucasian subjects extra measures to eliminate facial hair are
often necessary. Sexual hair growth on other parts of the body responds more
favorably. Breast formation starts almost immediately after initiation of
cross-sex hormone administration and goes through periods of growth and
standstill. Androgens have an inhibitory effect on breast formation and
therefore estrogens will be most effective in the absence of significant
androgen levels. After two years of hormone administration no further
development can be expected. It is quantitatively satisfactory in 40-50% of
the subjects; the remaining 50-60% judge their breast formation as
insufficient. The attained size is often disproportional to the male dimension
of the chest and height and surgical breast augmentation may be desired.
Higher age also impedes full breast formation. Androgen deprivation leads to a
decreased activity of the sebaceous glands which may result in a dry skin or
brittle nails. There is an increase in subcutaneous fat depots and following
androgen deprivation there is a loss of approximately 4 kilograms of lean body
mass. But most of the time body weight increases. Testes, lacking
gonadotrophic stimulation, will become atrophic and may enter the inguinal
canal which may cause discomfort. After reassignment surgery including
orchiectomy hormone therapy must be continued. Some subjects still experience
an increased growth of male type of sexual hair and antiandrogens appear to be
effective, though their dose may be reduced (for instance, cyproterone acetate
10 mg per day). Continuous estrogen therapy is required to avoid symptoms of
hormone deprivation and most importantly, to prevent osteoporosis (14).
Female-to-male
transsexuals
Androgen administration may decrease glandular
activity of the breasts, but it does not reduce their size. The objectives of
androgen administration are to stop menstrual activities, experienced as
improper, and to induce a male pattern of sexual hair and male physical
contours (Asscheman & Gooren, 1992; Futterweit, 1998; Schlatterer et al.,
1998). Usually this can be attained with administration of parenteral
testosterone esters in a dose of 200-250 mg per 2 weeks. Occasionally
menstrual bleeding does not cease upon this regimen and addition of a
progestational agent is necessary (medroxyprogesterone acetate 5 or 10 mg
orally). If other types of androgens are used (oral or transdermal) addition
of a progestational agent is nearly always needed. The development of sexual
hair follows essentially the pattern observed in pubertal boys: first the
upper lip, then chin then cheeks et cetera. The degree of hairiness can
usually be predicted from the degree and pattern in male members of the same
family. The same applies to the occurrence of alopecia androgenica. Deepening
of the voice occurs already after 6-10 weeks of androgen administration and is
irreversible. Androgen administration leads to a reduction of subcutaneous fat
but increases abdominal fat storage. The increase in lean body mass as a
result of the anabolic effects of androgens amounts to 4 kilograms but
increase in body weight is usually larger. Side effects are minor. In
approximately 40% acne is observed predominantly on the back as is also the
case in hypogonadal men starting androgen treatment past the age of normal
puberty (Van Kesteren et al., 1997). This can usually be remedied with
conventional anti-acne treatment. Clitoral enlargement occurs in all but to a
varying degree; in a small number of subjects the size becomes sufficient for
vaginal intercourse with a partner. Most subjects will note an increase in
libido. Ovaries show changes which are indistinguishable from polycystic
ovaries. After surgical sex reassignment including ovariectomy androgen
therapy must be continued to prevent symptoms of hormone deprivation and
osteoporosis (Van Kesteren et al., 1998). Discontinuation of cross-sex
hormones following surgical adaptation to the desired sex leads to loss of
bone mineral density. Our study showed that the serum level of luteinizing
hormone (LH) was the best predictor of loss of bone density. Higher LH as an
expression of insufficient suppression by the administered cross-sex hormones
was associated with a higher degree of loss of bone mineral density in both
reassigned sexes.
Side effects
(Cross) sex hormone administration may be
associated with various side effects. A recent review of 816 male-to-female
transsexuals and 293 female-to-male transsexuals (total exposure 10,152
patient years) showed that, in view of the needs of the transsexuals,
cross-sex hormone administration provided by a knowledgeable medical expert,
is an acceptably safe practice (Van Kesteren et al., 1997; Futterweit, 1998;
Schlatterer et al., 1998). Mortality was not higher than in a comparison
group. Venous thrombosis and pulmonary embolism were observed in the group of
male-to-female transsexuals treated with oral estrogens (incidence 2-6%). This
occurred mainly in the first year of estrogen administration and predominantly
in subjects over 40 years of age (Van Kesteren et al., 1997). This age group
and also subjects with risk factors should be treated with transdermal
estrogens which were almost never associated with venous thrombosis in the
above series.
Upon high dose estrogen administration serum
prolactin rises, sometimes associated with pituitary enlargement. This is
clearly dose-related and reversible upon dose reduction. Two cases of
prolactinomas following high dose estrogen administration have been reported
in the literature (for review: Van Kesteren et al, 1997). Though these two
subjects had normal serum prolactin levels before cross-sex hormone
administration, it is not known whether these subjects were more susceptible
in this regard than others who use equally high doses of estrogens and did not
develop tumorous autonomous prolactin production. In general when recommended
dosages of estrogens are used, there are no significant risks of inducing
pituitary tumors.
There are two reports of male-to-female
transsexuals with breast carcinomas receiving estrogen administration (for
review: Van Kesteren et al, 1997). In the above series no case was observed,
but (self)examination of the breast but must be part of the medical follow-up
of cross-sex hormone administration, following the same guidelines as exist
for other women. Anecdotally, a breast carcinoma has been observed in residual
breast tissue after mastectomy in a female-to-male transsexual.
Three cases of prostate carcinomas in
male-to-female transsexuals on estrogen treatment have been reported (for
review: Van Kesteren et al, 1997; Van Haarst et al., 1998). It is not clear
whether these carcinomas were estrogen-sensitive or whether they were present
before estrogen administration started and progressed to become
hormone-independent carcinomas. Since this type of carcinoma is unexpected in
this group, diagnosing may be delayed.
We have recently observed a case of ovarian
carcinoma in a long-term testosterone-treated female-to-male transsexual and
one case or a borderline malignant ovarian tumor in another person who
received androgens for about a year. Ovaries of female-to-male transsexuals on
androgen treatment show similarities with polycystic ovaries which are also
more likely to develop malignancies. Therefore, it seems recommendable to
remove the ovaries of androgen-treated female-to-male transsexuals after a
successful transition to the male role.
Cardiovascular
disease
Prevalence and incidence of cardiovascular
disease show a considerable sex difference; this may be due to factors such as
lifestyle, genetics, rates of aging, but traditionally hormonal differences
have received major attention, probably because they can easily be related to
laboratory variables, such as lipids, clotting/fibrinolytic factors,
vasoactive substances, insulin resistance etc. The latter variables have
emerged as cardiovascular risk factors from epidemiological studies. It
remains, however, to be established whether these isolated laboratory
variables, prove to be valid surrogate markers of cardiovascular risks. The
picture that has emerged is that estrogens are protective and/or that
androgens are deleterious for cardiovascular disease (Futterweit, 1998). In
view of the sex difference in prevalence of cardiovascular disease these
studies are, at face value, quite convincing, but only long-term prospective
studies in transsexuals using genuine clinical endpoints (cardiovascular
morbidity/mortality) can establish their reliability. In our studies of
female-to-male transsexuals receiving androgens, the effects on cardiovascular
risk factors studied over the first 12 months, were relatively benign. Maybe,
if there is a relation between androgen exposure and cardiovascular disease,
it is a result of prolonged exposure or due to indirect effects of androgens.
But in our long-term follow-up study of transsexuals (van Kesteren et al.,
1997) there were no clear indications that long-term androgens increased
cardiovascular disease incidence. Neither was there an indication that
estrogens conferred a clear protection to male-to-female transsexuals.
Juvenile Gender
Dysphoria
Adult transsexuals often recall that their
gender dysphoria started early in life, well before puberty. Children with
gender identity problems come increasingly to the attention of the
psychomedical care system. There is as yet not sufficient information whether
all children with gender nonconformity will turn out to be genuine
transsexuals later in life. Some studies on gender nonconformity in
prepubertal children rather indicate that homosexuality will be the outcome.
But if, in expert opinion, their cross-sex gender identity will not change in
long term follow-up, the torment of (fully) developing at puberty secondary
sex characteristics of a sex they view not as their own, can be spared. Depot
forms of antagonists/agonists of luteinizing hormone-releasing hormone can be
used when there are clear signs of sexual maturation to delay pubertal
development until an age that a balanced and responsible decision can be made
(Gooren & Delemarre - van de Waal, 1996). Less ideal are
medroxyprogesterone acetate or in boys cyproterone acetate.
References
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Poland D, Kemper J, Stalla GK. A follow-up study estimating the effectiveness
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Van Kesteren P, Lips P, Gooren LJG, Asscheman
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Citation: IJT
July-September 1999, 3,3, an article published on the Internet by The
International Journal of Transgenderism <http://www.symposion.com/ijt/>
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