9.4.18 Transsexualism

Transsexualism is the condition in which a person with apparently normal somatic sexual differentiation is convinced that he/she is actually a member of the opposite sex. It is associated with an irresistible urge to be hormonally and surgically adapted to that sex. Traditionally transsexualism has been conceptualized as a purely psychological phenomenon, but research on the brains of male-to-female transsexuals has found that the sexual differentiation of the brain—the bed nucleus of the stria terminalis (BSTC) and the hypothalamic uncinate nucleus—had followed a female pattern (1). This finding may lead to a concept of transsexualism as a form of intersex, where the sexual differentiation of the brain (which in mammals also undergoes sexual differentiation) is not consistent with the other variables of sex, such as chromosomal pattern, nature of the gonad and nature of internal/external genitalia. Thus it can be argued that transsexualism is a sexual differentiation disorder.

Sexual differentiation in mammals is a process that takes place in distinctly different steps, each with a so-called critical period, i.e. this particular step in the differentiation process can take place only during this time slot. At each step the developing organism has the bipotentiality to differentiate along male or female lines of development. In the normal male pattern of development, the as yet undifferentiated bipotential gonad becomes a testis, on the basis of the genetic information of the sex determining region on the Y chromosome. In the presence of two X chromosomes the undifferentiated gonad becomes an ovary. In both the prospective male and female fetus the ducts of Müller and Wolff are present. Under the influence of the fetal testicular hormone, mullerian inhibiting factor, the mullerian ducts regress in the male fetus while testicular testosterone directs the wolffian ducts to become the male internal genitalia. In the female fetus the ovary is endocrinologically relatively quiescent and the wolffian ducts, lacking hormonal stimulation, regress while the mullerian ducts become the female internal genitalia. From a common anlage, the genital tubercle and groove, the male fetus develops a penis and a scrotum under the influence of testicular hormones. In the female, lacking androgenic stimulation, they become the clitoris and labia.

Normally each step is contingent upon the previous one, and usually consistent with the previous one, in the sense that an XY, or alternatively, an XX chromosomal pattern predicts with a high degree of statistical accuracy the outcome of this differentiation process.

In a number of births not all the steps in the differentiation process are consistent with one another. Fetal exposure to cross-sex hormones, pathological production of androgens in the female fetus, or insensitivity to the action of androgens in the male fetus may lead to formation of external genitalia that are not consistent with the nature of the chromosomal pattern (or ‘chromosomal sex’) or of the gonad (or ‘gonadal sex’). Sometimes these syndromes are not recognized at the time of birth, and the newborn receives a sex assignment and subsequent rearing consistent with the criterion of the external genitalia (but apparently not with those of the ‘chromosomal’ or ‘gonadal sex’). A classical example is the so called androgen-insensitivity syndrome, characterized by insensitivity to the biological action of androgenic hormones. The consequence is that an XY-chromosomal, testis-bearing, and testosterone-producing fetus develops female external genitalia. Sex assignment and rearing proceed as if the child were a girl. These subjects develop the psychosexual status of a girl and later in life, of a woman, and usually enter into a marriage allowed by their legal status as female. Obviously, it would be mental cruelty to label these human beings living psychologically, socially, and legally the lives of women, wives, and mothers as male by the ‘objective’ biological criteria of their genetic or gonadal sex. Clinicians in charge of children born with ambiguous genitalia have adopted a medical policy to assign those children to the sex which carries the best prognosis for future sex-appropriate functioning. Criteria such as chromosomal sex or gonadal sex are apparently not decisive in this decision making. The inevitable conclusion must be that some of our fellow human beings live the lives of men and women while their status of manhood or womanhood is in disagreement with the genetic, gonadal and genital specifications of maleness and femaleness as formulated by biomedical science. This leaves us with the difficulty, if not impossibility, to define manhood and womanhood exclusively by biologically verifiable criteria. There is, however, a long tradition in medicine of attempting to determine the ‘true biological sex’ of subjects by trying to read ‘nature’s intentions’. In 1955, John Money formulated the status of intersexed subjects in an attempt to do justice to their actual psychosocial status of manhood or womanhood (2). He introduced the terms gender identity and gender role. Money, studying the lives of intersexed subjects, arrived at the conclusion that sex of assignment and rearing was statistically the most reliable (though not the exclusive or decisive) prognosticator of one’s future gender identity/role among other variables such as genetic information, nature of the gonad (ovary or testis), hormonal status, internal genitalia, and particularly external genitalia; the latter, understandably, play a significant role in assigning a sex to a newborn and in the (self) perception of the child as female or male.

It became Money’s conviction that to individuals the reality of gender identity/role is as solid, immutable and meaningful as is the reality of, for instance, the external genitalia. The finding that in the mammalian species the brain also undergoes sexual differentiation (see below) may lend credence to this observation. Research data indicates that gender identity/role becomes largely fixed around the age of three years, thus showing a parallel with other steps in the sexual differentiation process in that once their critical period has passed, the nature of gender identity/role cannot be reversed.

There is no conclusive evidence that transsexualism can be explained by variations in chromosomal patterns, or by gonadal, genital or hormonal anomalies (3). But it has become apparent from studies in rats, mice and other lower mammals that the brain undergoes a sexual differentiation process. In other words, sexual differentiation is not completed with the differentiation of the external genitalia, the traditional criterion labelling them as male or female. The sexual differentiation of the brain can be demonstrated neuroanatomically or in psychological function tests. In lower mammals it expresses itself in sexually dimorphic sexual behaviour (such as copulatory positions) but also in sexually dimorphic nonsexual behaviour (such as aggression, defence of territory, and caring for the young). The paradigm of this step in the sexual differentiation process of lower mammals is similar to the previous ones: in the presence of (prenatal) androgens a male brain differentiation occurs, while in the absence of androgens a female brain differentiation follows. This process has been termed the organization, the ‘wiring’ of the brain, to prepare it for future sexual/reproductive and nonsexual behaviour in agreement with the gonadal/genital status. This programming is established during the fetal period or shortly thereafter and becomes activated by the hormones of puberty.

Experimentally it has been possible to hormonally manipulate and transform this step in sexual differentiation, based on the fact that it is androgen-dependent, in lower mammals. Hormonal manipulation can induce a male copulatory pattern in a rat with a female chromosomal/gonadal/genital differentiation and vice versa.

Following exposure of the brain to androgens, male and female rat brains differ in their neuroanatomical structure (1, 3). The close parallel in the process of sexual differentiation of the gonads and genitalia between lower mammals and humans stimulated a search to see whether these male–female differences in brain anatomy/function in lower mammals could also be demonstrated in humans (3). As hypothesized, sex differences in the size and shape of certain nuclei in the hypothalamus were detected in men and women (1). One of the sexually dimorphic nuclei becomes differentiated between the ages of two to four years, not earlier (1). The BSTc only becomes sexually dimorphic in adulthood (4). The mechanism responsible for sexual differentiation of the human brain is unknown, and whether it is hormonally (co)determined or not is also unclear. From clinical observations in patients with an intersex condition or cross-sex hormone exposure during pregnancy, the a priori evidence for solely hormonal determination is not strong. Postnatal rearing is in all likelihood a significant factor in the development of gender identity/role; this is no longer irreconcilable with the existence of a biological substrate of gender identity, since one’s life history is a factor in shaping brain anatomy/function (5). If it becomes accepted that humans also undergo a differentiation of the brain as an integral part of the process of becoming a man or woman, transsexualism could be conceptualized as a sexual differentiation disorder wherein sexual differentiation of the brain has not followed the course set by the chromosomes, the gonad and the genitalia, but has crossed over to the course of development of the other sex.

Very recent research on the brains of male-to-female transsexuals demonstrated that two of the brain nuclei which are sexually dimorphic in humans, the BSTc and the hypothalamic uncinate nucleus, show all the characteristics of female differentiation (1). This finding of a biological index of female brain differentiation in male-to-female transsexuals could be a conceptual turning point in the approach to transsexualism from a number of standpoints.

Transsexualism must be distinguished from homosexuality. In erotic and sexual imagery and/or practice homosexuals are attracted to persons with the same genital morphology. A homosexual’s sexual pleasure comes from the physical functioning of his/her sexual organs (not different from heterosexuals), but homosexual sexual gratification can only be obtained in sexual encounters with a person with the same genital morphology (as opposed to heterosexuals). By contrast, transsexuals experience the physical functioning of their sex organs as estranged from themselves. Transsexuals seek a reassignment to the desired sex to the fullest extent possible. However, in recent times an increasing number of people present themselves who only want to rid themselves of the characteristics of their natal sex, without seeking reassignment to the opposite sex. Others want only partial adaptation to the opposite sex; they seek an in-between sex status (‘the lady with the penis’). There may be a social transition to the opposite sex, but sometimes this is only part time. For this category the term ‘transgenderism’ has been proposed. There are difficulties with transgenderism from a medical ethical viewpoint. Should a subject’s self-assessment of his/her gender status prevail, and must medicine provide care for those who find themselves involuntarily in an in-between gender status, and let them live in peace with that status?

Calculations of prevalence data are likely to be influenced by the prevailing social climate and provisions for medical treatment. Another factor is the definition of the condition; prevalence/incidence studies sometimes make no clear distinction between transsexuals and transgendered individuals. The prevalence of transsexualism, as assessed in the Netherlands, is 1 in 11 900 men and 1 in 30 400 women (6), and remains very stable. These figures are somewhat lower than those of Singapore but higher than those in Sweden. Incidence data in Sweden and the Netherlands show a very constant pattern over time.

The 3:1 ratio of males/females encountered in the Western world is not universal. For instance, in Serbia the ratio is close to 1:1 (7). There is no good explanation for this sex difference.

The organization involved with professional help to transsexuals, the Harry Benjamin International Gender Dysphoria Association, has drafted Standards of Care (SOC) (8). The major purpose of the SOC is to articulate this international organization’s professional consensus about the psychiatric, psychological, medical, and surgical management of gender identity disorders. Professionals may use this document to understand the framework within which they may offer assistance to those with these problems. Most professionals working in this area do so with a certain degree of isolation from mainstream medicine, and the SOC provides peer group support. It may also be of help in legal medicine to identify professional standards.

Persons with gender identity disorders, their families, and social institutions may use the SOC as a means to understand the current thinking of professionals.

In the final analysis, the aetiology of transsexualism and related expressions of gender dysphoria is unknown. There are reasonable speculations that in transsexuals the sexual differentiation of the brain is discordant with the other sex characteristics of the subject, but modern brain imaging techniques do not as yet provide diagnostic verification. The initial assessment will be based on psychodiagnostic instruments and will generally be done by a mental health professional. This should preferably be a member of a team, but local circumstances may prevent this. Two diagnostic classification systems, DSM-IV and the ICD, have spelled out diagnostic guidelines for transsexualism and related gender identity disorders. It is the task of this professional to diagnose the subject’s gender identity disorder accurately and to see whether there is any comorbid psychiatric diagnosis which may require treatment. Serious psychiatric comorbidity and adverse personal social conditions may constitute a serious impediment to a successful transition to the desired sex, but may also be the result of the difficulties the transsexual or transgendered patient finds him/herself in. These may or may not be resolved in the course of time. The main criterion for reassignment treatment is the reasonable expectation that hormonal/surgical treatment will alleviate the sufferings of gender dysphoria. If this expectation is unreal, sex reassignment should not (yet) be considered.

The patient should receive information about the treatment options and their implications. Unrealistic expectations that subjects may have, regarding the outcome of hormonal and surgical treatment for their transition to the desired sex, must be addressed. Contact with other transsexuals who are already in the process of changing over to their new sex, or who have completed this process, may be propitious in shaping a subject’s expectations of what can be achieved and what problems, personally and socially, may arise in the transition to the new sex. If there is a realistic prognosis that the subject will benefit from crossing over to the desired sex, a recommendation to a physician with endocrinological expertise can be made to provide cross-sex hormone treatment. When hormone treatment starts, or maybe even before that, the ‘real life test’ should begin. This is an extended period of full-time living as a member of the desired sex. The ‘real life test’ allows the subject and the attending professional to monitor the experience in the new sex status as s/he habituates her/his responses to other people. Without this test of how others react and how s/he reacts to others, the subject knows only his/her private convictions and fantasies of being a member of the opposite sex. Convictions and fantasies may be unreliable and may lead to magical expectations of life in the new sex. At most, sex reassignment can bring relief of gender dysphoria; there is no added bonus to sex reassignment and all human problems outside the area of gender dysphoria will remain. Embarking on the ‘real life test’ may be done in a stepwise fashion, for instance, first in a trusted environment and later also in public. However, the subject should have lived at least one full year full-time in the new sex before (irreversible) surgical reassignment can be considered. The ‘real life test’ may be prolonged if too many hurdles present themselves during this test period. During the ‘real life test’ the subject should stay in contact with a mental health professional to allow assessment of the success of the test and to discuss how to overcome problems that almost inevitably arise during this period.

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 (9, 10). Some studies on gender nonconformity in prepubertal children rather indicate that homosexuality will be the outcome (10). However, from early hormonal puberty onwards it becomes clear which children will persist in their cross-sex identity (11). If the attending mental health expert is convinced that their cross-sex gender identity has become an irreversible characteristic, the torment of (fully) developing the secondary sex characteristics at puberty of a sex they view not as their own can be spared. Similarly to the treatment of precocious puberty, depot forms of antagonists/agonists of luteinizing hormone-releasing hormone (LHRH) can be used when there are clear signs of sexual maturation to delay pubertal development until an age when a balanced and responsible decision can be made (12, 13). Less ideal are medroxy-progesterone acetate or, in boys, cyproterone acetate. Hormonal interventions in juvenile transsexuals still meet with strong reservations (14).

Fundamental to sex reassignment treatment of transsexuals is the acquisition of the sex characteristics of the other sex to the fullest extent possible (13). Secondary sex characteristics are contingent upon 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 in them, at that advanced age, a normal average degree of hormonal masculinization or feminization 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 hands, feet, jaw, and of the male pelvis) cannot be reversed. 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 original sex will be more visible than in others.

Hormonal reassignment therefore has two aims: to eliminate, as far as possible, the hormonally induced secondary sex characteristics of the original sex, and to induce those of the new sex.

To male-to-female transsexuals, elimination of sexual hair growth and induction of breast formation are essential. To attain both, an almost complete reduction of the effects of androgens is required (13). Administration of oestrogens alone will suppress gonadotropin output and, consequently, androgen production, but dual therapy with one compound suppressing androgen action and another with oestrogen action is probably more effective. Several agents are available to inhibit androgen action. In Europe the most widely used drug is cyproterone acetate (100 mg/day), a progestational compound with antiandrogenic properties. If not available, medroxyprogesterone acetate (5–10 mg/day), probably somewhat less effective, is an alternative. Nonsteroidal antiandrogens such as flutamide (50–75 mg/day) and nilutamide (150 mg/day) are also used, but they increase gonadotropin output with a rise of testosterone and oestradiol; the latter is a desirable effect in this context. Spironolactone, a diuretic with antiandrogenic properties, has similar effects. Also, LHRH agonists can be used as monthly injections. Finasteride 1 mg, now marketed for alopecia androgenica, might be considered too. There is a wide range of oestrogens to choose from. Oral ethinyloestradiol (100 mcg/day) is a potent and cheap oestrogen. However, it may cause venous thrombosis, particularly in subjects over 40 years (15), and is best avoided. Transdermal oestrogens (100 mcg 17β-oestradiol) twice a week, or oral oestradiol esters (2–4 mg), are preferred. They are, however, less potent than ethinyloestradiol. Many transsexuals favour injectable oestrogens; however, they provide high levels of circulating oestrogens with possible disadvantages and they carry a higher risk of overdosing, to which many transsexuals are inclined.

As to the effects of this dual regimen, adult male beard growth is very resilient to the described hormonal intervention and in many subjects, particularly whites, additional measures (electrolysis, photothermolysis) to eliminate facial hair are almost always necessary. Sexual hair growth on other parts of the body responds more favourably. Breast formation starts almost immediately after initiation of cross-sex hormone administration and goes through periods of growth and standstill. 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 decreased activity of the sebaceous glands which may result in dry skin or brittle nails. There is an increase in subcutaneous fat deposits, and following androgen deprivation there is a loss of approximately 4 kg of lean body mass. However, most of the time body weight increases. Testes, lacking gonadotropic stimulation, will become atrophic and may enter the inguinal canal, which may cause discomfort. After reassignment surgery, including orchidectomy, 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. Continuous oestrogen therapy is required to avoid symptoms of hormone deprivation, and most importantly, to prevent osteoporosis (13, 16).

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. Usually this can be attained with administration of parenteral testosterone enanthate or cypionate at a dose of 200–250 mg per 2 weeks or of late testosterone undecanoate 1000 mg per 12 weeks (13, 16). Occasionally menstrual bleeding does not cease upon this regimen, and addition of a progestational agent is necessary. If other types of androgens are used (oral or transdermal) addition of a progestational agent is nearly always needed. The development of sexual hair essentially follows the pattern observed in pubertal boys: first the upper lip, then chin, then cheeks, and so on. 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 after 8–10 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 kg, but the increase in body weight is usually greater (17). 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 (17). 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 (14, 16).

Cross-sex hormone administration may be associated with various side effects. In view of the needs of transsexuals, cross-sex hormone administration, provided by a knowledgeable medical expert, is an acceptably safe practice (13, 16). Mortality in male-to-female transsexuals over age 45 years may be higher than in a comparison group. Venous thrombosis and pulmonary embolism were observed in the group of male-to-female transsexuals treated with ethinyl oestradiol (incidence 2–6%). This occurred mainly in the first year of oestrogen administration and predominantly in subjects over 40 years of age. This age group, as well as subjects with risk factors, should be treated with transdermal oestrogens, which were almost never associated with venous thrombosis in the above studies.

Osteopenia or osteoporosis has been observed in subjects who stop taking cross-sex hormones or are underdosed (13, 16). Subjects with risk factors for osteoporosis should be monitored closely.

Upon high-dose oestrogen administration serum prolactin rises, sometimes associated with pituitary enlargement. This is clearly dose-related and reversible upon dose reduction. Four cases of prolactinomas following high-dose oestrogen administration have been reported in the literature (18). Although these four subjects had normal serum prolactin levels before cross-sex hormone administration, it is not known whether these subjects were more sensitive in this regard than others who used equally high doses of oestrogens and did not develop tumourous autonomous prolactin production (18).

There are three reports of male-to-female transsexuals with breast carcinomas receiving oestrogen administration (18). Though breast carcinomas are rare (self) examination of the breast 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 (18).

Three cases of prostate carcinomas in male-to-female transsexuals on oestrogen treatment have been reported (18). It is not clear whether these carcinomas were oestrogen-sensitive or whether they were present before oestrogen administration started and progressed to become hormone-independent carcinomas. Since this type of carcinoma is unexpected in this group, diagnosis may be delayed.

Two cases of ovarian carcinoma in long-term testosterone-treated female-to-male transsexuals were recently observed (18). The ovaries of female-to-male transsexuals on androgen treatment show similarities with polycystic ovaries, which may be more likely to develop malignancies. Therefore, it seems reasonable to recommend the removal of the ovaries of androgen-treated female-to-male transsexuals after a successful transition to the male role.

In male-to-female transsexuals, a neovagina is surgically constructed, usually using the penile skin for vaginal lining and scrotal skin for the labia. If breast development is judged to be insufficient, the breasts may be surgically augmented.

In female-to-male transsexuals the breasts, uterus, and ovaries are surgically removed. In rare cases the hypertrophied clitoris may serve as a phallus. In other cases a metaoidioplasty may be performed. With this technique the urethra is lengthened using an anterior vaginal wall flap to reach the tip of the phallic glans while the clitoris is partially released and stretched by resection of the ventral chordae. From the labia majora, a scrotum can be constructed in which testicular prostheses can be implanted. Free flaps removed from arms or legs can be used to construct a neophallus.

Little attention has been given to this subject, and all research has been based on self-reports. As expected, the quality of sex reassignment surgery (a functional neovagina or neophallus) plays a role. While certainly not all postoperative transsexuals are orgasmic, sexual satisfaction is greater than earlier (19)^. A hormonal factor to consider may be the androgen depletion of male-to-female transsexuals. There is increasing evidence that women need small amount of androgens to be libidinous. Female-to-male transsexuals receiving androgens generally note an increase in sexual interest. Laboratory-based research, as has been devised for sexually dysfunctional men and women, is needed to gain more insight into sexual functioning of postoperative transsexuals.

Given the irreversibility of sex reassignment surgery (and to a lesser degree of cross-sex hormone administration), it is important to gain insight into factors that spell success or a poor outcome. Prospective controlled studies specifically designed to assess outcome and its prognostic factors are difficult with this relatively rare condition, and are still lacking. There are estimates that 1–2% of transsexuals who undergo permanent transitions will have regrets (20). Some of these subjects have experienced gender dysphoria only late in adult life, but without strong manifestations in childhood; others have difficulty in transitioning to the new sex because of their appearance or limited social skills. The quality of surgical construction of the genitalia is also significant for all transsexuals.