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.

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).

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.

(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.

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.

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