|
Hormonal Sex Reassignment
Louis J.G. Gooren
Netherlands.
[Abstract] Full Text [PDF]
Introduction
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
Asscheman H, Gooren LJG. Hormone treatment in
transsexuals. Journal of Psychology & Human Sexuality, 1992; 5:
39-54
Gooren LJG & Delemarre-van de Waal.
Memo on the feasibility of endocrine interventions in juvenile transsexuals.
Journal of Psychology & Human Sexuality 1996; 8: 69-74
Futterweit W. Therapy of transsexualism and
potential complications. Archives of Sexual Behavior 1998; 27:
209-226
Schlatterer K, Yassouiridis A, von Werder
K, Poland D, Kemper J, Stalla GK. A follow-up study estimating the
effectiveness of a cross-gender hormone substitution therapy on transsexual
patients. Archives of Sexual Behavior, 1998; 27: 475-492
Van Haarst EP, Newling DWW, Gooren LJG,
Asscheman H, Prenger. DM Metastatic prostate carcinoma in a male-to-female
transsexual. British Journal of Urology, 1998; 81: 776
Van Kesteren P, Megens JAJ, Asscheman H,
Gooren LJG. Side effects of cross-sex hormone administration in
transsexuals. Clinical Endocrinology, 1997; 47: 337-342
Van Kesteren P, Lips P, Gooren LJG,
Asscheman H, Megens J (1998) Longterm follow-up of bone mineral density in
transsexuals treated with cross-sex hormones. Clinical Endocrinology
48: 347-354
Citation:
IJT July-September 1999, 3,3, an article published on the Internet by The
International Journal of Transgenderism
<http://www.symposion.com/ijt/>
|
