· 1~

Strasbourg, 5 March 1993

CJ—DEIXXIII (93) 5

(Amsterdam, The Netherlands, 14 - 16 April 1993)

TRANSSEXUALISM, MEDICINE AND LAW

Memorandum

presented by

Prof. dr. L.J.G. Gooren

Internist / Endocrinologist

Free University Hospital

Amsterdam, The Netherlands

Summary

Transsexualism remains an enigmatic problem to biologists. It defies "the naturalness" of being a man or a woman. In the past century it has become clear that the differentiation process of becoming a man or a woman is a multistep process. At each step there is a biopotentiality to develop in either male or female direction. Further, each step has a window of time, a critical phase for its developmenL For times immemorial it has been assumed that the sexual differentiation process is completed with the formation of the external genitalia, which constitutes the criterion for sex assignment immediately after birth. Over the last decades it has become apparent that the formation of the external genitalia is not the final step in the process of sexual differentiation but that also the brain undergoes a sexual differentiation, which in the human occurs after birth. Through the information is not definitive there is now evidence to believe that in transsexuals the sexual differentiation process of the brain has not followed the course anticipated of the preceding criteria of sex (chrornosomal, gonadal and genital) and has become cross-sex differentiated. Sex assignment at birth by the criterion of the external genitalia is a statistically reliable prognosticator of future brain sexual differentiation. For the exceptions in whom brain sexual differentiation has not followed the path prognosticated by the nature of the external genitalia, i.e. transsexuals, the law must make provisions.

Biological aspects of transsexualism.

Most biological investigations of transsexuals have found that there are no abnormalities in chromosomal pattern, in the gonads or genitals, or in circulating, peripheral sex steroid levels that could account for the condition (Gooren, 1984). The very absence of the above-mentioned abnormalities now constitutes an element in the definition of transsexualism. If there are deviances in the above biological measures, leading to physical and psychological sexual ambiguity, the term transsexualism is no longer to be used, but rather such terms as (pseudo) hermaphroditism. The lack of any demonstrable abnormal biological parameter accessible to clinical testing could lead to the view that transsexualism is a psychological condition, a product of social learning of conditioning. However, the discovery that the same gonadal hormones which determine prenatally the morphology of the genitalia also influence the morphology and function of the brain, in a sexually dimorphic fashion, has reinforced the long-held hypothesis that sexual differentiation of the brain in transsexuals has not followed the line of sexual differentiation induced by the chromosomal pattern and subsequently by the gonadal hormones, which theoretically should explain the incongruity between the anatomical sexual differentiation of the gonads/genitals on one hand and gender identity on the other.

General biological principles of sexual differentiation.

Over the last 150 years it has become clear that sexual differentiation into male and female is a multistep process in mammals; a process that takes place in distincfly different steps. Each step is characterised by the biopotentiality to develop into a male or female direction. Further, each step has a critical period, that is that this particular step in the development can only take place in a critical phase of the development, a window of time. Once this phase has passed, the organism has reached a point of no return. In other words there is no backtracking. The process of sexual differentiation begins with the difference of the sex chromosomes established at

conception. The pattern for the male comprises an X chromosome from the mother and a Y chromosome from the father, and for the female, a Y chromosome from each parent. As far as the human is concerned, there is no evidence that the sex-specific combination of chromosomes, which is present in all cells of the body, has any direct effect on a person’s erotosexual status. It may, however, have an indirect influence by its determination of the nature of the embryonic gonadal anlage; a testis in the case of a Y chromosome, an ovary in the case of two X chromosomes. While the testis develops and becomes hormonally active approximately 8 weeks following conception, the ovary is quiescent until 16 weeks following conception. The testis starts secreting high levels of testosterone between 8 and 22 weeks following conception (Wilson et al., 1981), and this generates high levels of testosterone in the bloodstream of the male foetus. This constitutes an essential difference between the male and the female foetus. With androgens secreted in a proper amount, the foetus further differentiates as a male. In all its simplicity this rule applies across the mammalian species and irrespective of chromosomal and gonadal sex. It also applies irrespective of the source of androgens and the organ system involved. The constraints of this operative mechanism are the amount of hormone and the timing of its action, there being a critical developmental period for the induction of a specific androgenic effect. The presence (in males) or absence (in females) of testosterone leads to the differentiation of the internal genitalia from two sets of mesonephric ducts present in both sexes. There is one exception to the rule of androgens determining the fate of sexual differentiation, that is the suppression of the development of the uterus in the male foetus by a nonsteroid testicular product, Mi.illerian inhibiting factor. Both male and female external genitalia are also derived from identical anlagen, male development being mediated by the action of testosterone, though in this case, testosterone has to be converted to a different molecular form, 5-alpha-dihydrotestosterone. As far as anatomic sexual differentiation is concerned, there is now general agreement that the foregoing principles apply to human as well as most mammalian development. Less information is available on the sexual differentiation of the human brain. In lower animals evidence has accumulated that the same organising principles involved in genital differentiation apply also to sexual differentiation of the brain. Brain tissue is hormonally masculinised by the presence of testosterone or becomes feminised by the absence of such hormonal stimulation. Future mating patterns are imprinted in the brain following the above mentioned paradigm: female is the inherent pattern of development, while male development takes place only if sufficient amounts of testosterone and/or its derivative hormones are present during the critical period of sexual differentiation of the brain. The past 30 years have shown that this sexual differentiation of the brain is a robust piece of scientific information, at least in the lower mammals.

Hormonal manipulations in the critical period of development in lower mammals lead to cross-sex behaviour; in other words a rat or guinea pig with gonads and genitalia of the one sex can hormonally be manipulated as to show sexual behaviour typical of the other sex in adulthood.

In higher mammals it has been far more difficult to prove that this mechanism of hormonally determined sexual differentiation of the brain also operative, for instance in the monkey and the human.

Animal models in the study of transsexualism.

Biomedicine amply employs experimental animal models for the testing of hypotheses, and results thereof have advanced clinical medical knowledge. Even though interspecies differences

can be found, functional principles of organs and systems appear generally consistent among species. It therefore is no surprise that biomedical science resorts to animal experimentation to explore the biological underpinnings of phenomena such as transsexualism and homosexuality. Indeed, cross-sex hormonal manipulations of animals during a critically defined perinatal period can lead to cross-sex sexual behaviour postnatally; these observations have subsequently been interpreted to demonstrate the biological underpinning of this behaviour.

There are, however, a number of objections which might invalidate this extrapolation. The study of animal sexual behaviour relies almost exclusively on observation of motor behaviour patterns which are, in some species, highly sex-specific; for example, lordosis in female and mounting and insertion in male rats and guinea pigs. In the human species, there are no such highly specific masculine or feminine motor patterns of copulation (Beach, 1979). It therefore is doubtful that animal models of copulatory positioning can serve reliably as markers of overall masculinity or femininity in human beings. Biomedicine usually equates sexuality with reproductive behaviour (Money, 1981) and often refers to it as reproductive biology. In this there is a strong element of teleology (the doctrine that natural processes are shaped by a purpose and directed toward an end or goal by a driving force). From a teleological viewpoint it is only rational that an individual with male gonads and genitals would fulfil a male reproductive role and have a male sexual brain differentiation directed toward the goal of heterosexual coital activity.

Gender identity is a cognitive process that presupposes language development. Therefore, it is unlikely that parallels in animal sexology can be found (Meyer-Bahlburg, 1982). The sexual histories of transsexuals reveal that their sex acts do not necessarily reveal their gender dysphoria problem. For instance, some male-to-female transsexuals are erotically oriented towards women and some female-to-male transsexuals towards men. Observation of their sexual performance presumably would provide no clue about their gender dysphoria. It is apparently their self-experienced gender identity, contradicted by their genital morphology and secondary sex characteristics, that constitutes the problem of gender dysphoria.

Blood hormone levels and their relevance to gender identity role.

Hormones produced by the gonads influence a variety of behaviours in vertebrates in two principal ways. They act first on those parts of the prenatal brain destined to mediate sexual behaviour (i.e., organisational effect). As outlined earlier, structural and functional differences between males and females have been shown to depend on the presence (in males) or absence (in females) of testosterone (or its metabolites oestradiol and/or dihydrotestosterone) during particular phases of perinatal development (Baum, 1979; McEwen, 1983; Young, 1961). Exposure to androgen results in a male pattern of development. Absence of androgen exposure results in female development. The pivotal role of testosterone in this process of sexual differentiation has led to it being regarded as the "male" hormone. This view is further strengthened by the observation that testosterone enhances erotosexual arousal and responsiveness in males in adulthood (Davidson et al, 1982). Whereas the roles of oestrogen and progesterone for female reproduction are firmiy established, and in lower mammals, for female sexuality also (Baum, 1983), their role in erotosexual arousal and responsiveness in the human female is complex and uncertain (Sanders & Bancroft, 1982). Administration of oestrogens/progestagens to adult males

impairs sexual function. The foregoing observations have led to a dichotomy of "male" and "female" hormones.

Homosexuality and transsexualism in the male (viewed as a variant of male pseudohermaphroditism in the brain) have been associated with a deficiency of "male" hormone and an excess of "female" hormones and vice versa for the female homosexual and transsexual. With the development of techniques of hormone determination several studies testing such associations have been published. Excellent detailed reviews have been presented by MeyerBahlburg (1982, 1984) who, critical of the methodology used in many studies, concludes that peripheral sex steroids are unlikely to play a role in the etiology or phenomenology of homosexual orientation or gender dysphoria.

Hormonally induced sexual differentiation of the brain in humans.

Is the type of gonadotropin secretion a reliable indicator of the perinatal sexual differentiation of the brain in humans? Adult female animals receiving an administration of oestrogen of sufficient dosage and duration of action at a certain point in their oestrous cycle respond with an initial decline in luteinising hormone (LH) levels, followed by a subsequent rise, consequent upon a greater LH response to luteinising hormone releasing hormone (LHRH). This response has been termed oestrogen positive feedback (Young & Jaffe, 1976). The capacity for this response appears to be abolished in the male neuroendocrine system, provided it has undergone exposure to androgens (or androgen-derived oestrogens) of sufficient magnitude and duration at a critical period in foetal and/or perinatal development (D6rner, 1980).

LH levels in the eugonadal male respond to oestrogen stimulation solely with a decline; this has been termed oestrogen negative feedback. In lower mammals this sex difference in oestrogen feedback has been linked conclusively to prenatal/perinatal sex steroid exposure. It appears also to apply to primates, including man, in that adult eugonadal men display an oestrogen negative feedback effect, while adult women show an oestrogen positive feedback effect (OPFE). It appears reasonable to attribute this sex difference to a perinatal sexual differentiation of the neuroendocrine areas of the CNS involved in the secretion of LH. However, Karsch et al. (1973) demonstrated an apparent difference in the sexual differentiation of the pituitary response of LH to oestrogen stimulation between rodents and primates. After orchidectomy of male macaque monkeys this sex difference was no longer demonstrable; male monkeys then showed a qualitatively and quantitatively similar OPFE as females. This was later found to apply also to humans; in men with impaired testicular function, an OPFE effect could be evoked after oestrogen priming (Barbarmno et al., 1983). Before orchidectomy and cross-gender hormone treatment, a group of male-to-female transsexuals (Gooren, 1986a) all showed an oestrogen negative feedback effect, while after orchidectomy and oestrogen treatment these same individuals displayed an OPFE; in short, a reversal of the type of oestrogen feedback effect in the same subjects, proving that in humans the type of oestrogen feedback is not definitively and irrevocably designated perinatally. This experiment also demonstrated that in men it is not the CNS but some properties of the testis that prohibit the evocation of an OPFE. One would assume that it would be testosterone, the major testicular hormone, that would prevent the OPFE in men, but that is not the case, as was shown in monkeys (Westfahl et al., 1984) and in female-to-male transsexuals treated with testosterone (Goh et al., 1985). However, in the experiment of Gooren (1986a) testosterone had an inhibitory effect on the evocation of OPFE in ovariectomised female-to-male

transsexuals, where testosterone levels were higher than in the experiment of Goh et al. (1985). It is very likely that an as-yet unidentified testicular product prevents the occurrence of an OPFE in men. This may also solve the problems encountered by Aono et al. (1978) and Van Look et al. (1977) with the interpretation of the finding of an oestrogen negative feedback effect in subjects with androgen-insensitivity syndrome (AIS). These investigators attributed the occurrence of an oestrogen negative feedback effect in nonorchidectomised AIS subjects to a male type of neuroendocrine brain. However, Gooren (1987) demonstrated a reversal of the oestrogen feedback effect from the negative to positive following orchidectomy in an AIS subject, a finding contemporaneously reported by others (Gbretzlehner et al., 1987; Marcelli et al., 1987). Also, it has been shown that an oestrogen positive feedback effect can be evoked in foetal pituitaries (gestational ages 16-25 weeks), regardless of the sex of the foetus (Dumesic et al., 1987). This is beyond the foetal age at which, according to Dorner (1980), the sexual differentiation of that neuroendocrine function has occurred.

In primates, another impressive demonstration of the lack of the sexual differentiation of the neuroendocrine structures that regulate gonadotropin secretion has been offered by Norman and Spies (1986): Male macaque monkeys were brought to a cyclic gonadotropin secretion after orchidectomy and ovarian transplant. Women suffering from congenital adrenal hyperplasia often have high levels of circulating androgen since their own adrenals begin to function in the 12th week of gestation. Their condition can be treated successfully with glucocorticoid replacement, and they have ovulatory cycles and are reproductively successful. These observations contradict the notion that even a large prenatal excess of androgens (or androgen-derived oestrogens) would deprive these women of a later normal menstrual cycle, as would be predicted by the brain androgenisation theory proposed by Dorner (1980).

There are now also some studies on the differing endocrine regulation of the oestrogen positive effect between rodents and primates. In female monkeys LHRH priming in a fixed quantity and at a fixed rate, or even an interruption of the LHRITI priming for 48 hours, allows an oestrogen positive feedback effect to occur. This contrasts with the rat, in which the contribution of the neuroendocrine CNS seems to be more complex (for review cf. Karsch, 1987).

A report by Seyler et al. (1978) that female-to-male transsexuals displayed a more male type of oestrogen feedback could not be confirmed by others using a more rigorous endocrine methodology Wiesen & Futterweit, 1983; Gooren, 1986b).

Dorner et al. (1 983a) claimed to have found an oestrogen positive feedback in a subgroup of male-to-female transsexuals (those who were erotically oriented towards men in contrast to those erotically oriented towards women), but this could not be confirmed by others (Goodman et al., 1985; Gooren, 1986b). An increased LH response to LHRH following oestrogen exposure is the essential element in oestrogen positive feedback (Young & Jaffe, 1976). This has been ignored by most researchers testing for an oestrogen positive feedback in transsexuals and homosexuals (Dorner, 1980; Gladue et al., 1984). In the study of Gooren (1986b), the response was unequivocally negative in male-to-female transsexuals (before orchidectomy and hormone treatment) and positive in female-to-male transsexuals (before treatment); furthermore, no difference could be detected between them and controls of their genetic/gonadal/genital sex. The release of LHRH by hypothalamic neurons is regulated by a number of brain chemical substances, among which are the opiates and the catecholamines, which potentially affect the number of LHRH pulses per unit of time released by the hypothalamus.

Such differences were not detected between male-to-female transsexuals and nontranssexual men (Spijkstra et al., 1988) or between female-to-male transsexuals and non-transsexual women (Spinder et al., 1989). In these studies, conducted with a rigorous endocrine methodology, they were unable to confirm a higher prevalence of polycystic ovarian disease and/or oligo/amenorrhea, as has been reported by Futterweit et al. (1986). Neither the higher mean LH levels in transsexuals found by Kula et al. (1986) nor the different LH pulse frequency and amplitude in transsexuals found by Boyar and Aiman (1982) could be replicated in the investigations of Spijkstra et al. (1988) and Spinder et al. (1989) with larger samples of transsexuals. Also, a study with naloxone, an anti-opiate that blocks opiate action on the LHRH pulse generator, did not discriminate transsexuals from non-transsexuals (Gooren, 1984b).

Thus, on the basis of data reported in the literature and of the research of Gooren et al. we believe that the neuroendocrine regulation of LH secretion is not different between transsexuals and nontranssexuals. This is not surprising, since in primates (in contrast to lower mammals) the neuroendocrine regulation of LH secretion is not a potentially reliable indicator of the sexual differentiation of the brain.

Effects of an atypical prenatal endocrine milieu on gender identity.

What are the effects of an atypical perinatal hormonal environment (an androgen and/or oestrogen excess in women and an androgen deficiency or insentivity in men) on the development of gender identity in the human?

In view of the potential role of sex steroids on sexual differentiation of the prenatal brain in lower mammals, it is pertinent to examine the gender identity/role of subjects whose prenatal environment has been atypical for their genetic/gonadal sex: androgen/oestrogen excess in women and androgen/oestrogen deficiency or insensitivity in men. Sources of information are the so-called experiments of nature and of medicine: endocrine disorders spontaneously occurring in the human foetus or in the offspring of drug- or hormone-treated pregnant women. Some correlations have been found between an atypical prenatal environment and later gender identity/role and/or sexual orientation (for review cf. Meyer-Bahlburg, 1984).

From an endocrine viewpoint it is of note that, in comparing these studies, similarities in endocrine prenatal background may result in dissimilarities in gender identity/role and sexual orientation, and vice versa. This outcome is often not appreciated by those who directed their attention to a single endocrine factor and then linked inferentially that factor to the development of gender identity/role or sexual orientation, without comparing their data with those from clinical entities and syndromes with a similar endocrine milieu. The following syndromes must be considered:

1) The complete and partial androgen insensitivity syndrome (AIS). 46,XY subjects with this syndrome have testes as gonads and produce testosterone, but they are born with female or ambiguous external genitalia, depending on the degree of genetic expression of the disorder. In the case of the complete AIS, cases are often not identified at birth and are subsequently reared as girls on the basis of the appearance of their external genitalia. They come to the attention of the medical profession only when menarche fails to occur in their teenage years. Though their testes produce testosterone in quantities comparable to, or higher than those of normal men, as

a result of feedback insensitivity of the hypothalamo-pituitary unit, testosterone cannot exert its biological actions due to tissue androgen receptor impairment. These subjects do not lack the ability to aromatise testosterone to oestradiol in quantities sufficient for breast formation at puberty (MacDonald et al., 1979). Animal models of this syndrome demonstrate that testosterone is converted prenatally to oestradiol, which has a brain-mediated defeminising effect on later sexual behaviour (Olsen, 1979; Shapiro et al., 1980). The human foetus also is capable of converting testosterone to oestradiol, with potential effects on the sexual differentiation of the brain. Follow-up studies of AIS subjects show unambiguously that they develop a female gender identity and a sexual orientation towards men (Money et al., 1984), though Gooren and CohenKettenis (1991) have observed an exception to this rule. Very impressive is the study of Lewis and Money (1986) comparing subjects suffering from two syndromes: the AIS and the MayerRokitansky-Kuester syndrome. The latter syndrome is characterised by a partial atresia of the vagina, uterus and fallopian tubes, and thus these otherwise normally female-differentiated subjects (with 46,XX chromosomal patterns and ovaries) fail to menstruate. No differences in a range of erotosexual variables could be detected between the two syndromes. All subjects were exclusively heterosexual as women. These studies demonstrate that the androgen-derived oestrogens to which the AIS subjects are likely to have been exposed prenatally have not defeminised them, as they do in Tfm rat or Tfm mouse (Olsen, 1979; Shapiro et al., 1980).

2) Congenital adrenal hyperplasia (CAH) is a disorder in which, on the basis of an enzyme defect, the bulk of the steroid hormone production by the adrenal cortices shifts from corticosteroid to androgen. CAH subjects have a corticosteroid deficiency. This condition can, if diagnosed, be treated successfully with corticosteroid hormones. The syndrome occurs in both sexes. Early reports indicated an overriding influence of the sex of assignment and rearing of CAH girls. If CAH subjects were assigned as girls, they turned out to have a female gender identity, but their gender role behaviour might more tomboyish, with a great interest in active play and a high energy expenditure (Money & Schwartz, 1977). In a later study of CAH subjects 37% rated themselves as homosexual or bisexual (Money et al., 1984). Some CAH subjects with a 46,XX chromosomal pattern and ovaries have been assigned as boys, and they have successfully developed a male gender identity (Money & Dal~ry, 1976; Money & Norman, 1987).

These data demonstrate that exposure to an excess of androgens in prenatal/postnatal life in female CAH subjects identified as girls at birth may influence their sexual orientation, but this does not imply that they identify themselves as male. On the other hand, in female CAH subjects not identified as females due to the degree of masculinisation of their external genitalia, a male gender identity can develop following their assignment to the male sex after birth.

3) A frequently cited example of the powerful influence of testosterone on the formation of gender identity is the work of Imperato-McGinley et al. (1979), who described a pedigree of pseudohermaphrodites in an inbred population in the Dominican Republic. The subjects suffer from a deficiency in 5-alpha-reductase, the enzyme that converts testosterone to 5-alpha-dihydrotestosterone (DHT). The latter hormonal product is needed for the foetal outgrowth of the male external genitalia and for activation of the prostate and sexual hair growth at puberty. Consequently, the affected male subjects are born with a labia-like scrotum, a small, clitoris-like phallus and an urogenital sinus with a blind vaginal pouch. The genital appearance raises doubts as to their sex, resulting in an ambiguous gender assignment. At puberty their testosterone levels increase, causing phallic growth, deepening of the voice and male muscular appearance.

Imperato-McGinley et al. (1979) reported that, during the postpubertal period, 16 of a sample of 18 subjects said to have been raised as females assumed "a male gender identity", from which the authors inferred that prenatal testosterone (but apparently not 5-alpha-dihydrotestosterone) has an organising effect on the neural substrates mediating a male gender identity. This inference has met with a great deal of criticism for its reductionist approach to the complex matter of gender identity formation (Meyer-Bahlburg, 1982; Money, 1988). It is certain that the above subjects were not assigned as girls but as a locally known type of pseudohermaphrodite (guevedoce). The pubertal anatomical virilisation taking place in 5-alpha-reductase-deficient persons evokes gender identity confusion that may gradually, and with some difficulty, best be resolved by social reassignment as a male; such a person is provided with a number of psychosocial and economic assets in the prevailing societal context. This assumption has been confirmed by Herdt and Davidson (1988), who studied an identical sample in New Guinea. At best, the information from the Dominican Republic cohort can be utilised to demonstrate that a male gender identity can be formed in the absence of normal levels of DHT, which contrasts with information gathered in animal experiments that DHT given prenatally masculinises copulatory behavioural capacity in female guinea pigs, ferrets and the rhesus macaque, and that DHT in combination with oestrogen given perinatally more effectively masculinises some strains of rats than oestrogens or DHT given separately (Baum, 1979).

4) Oestrogens or oestrogenic drugs [predominantly diethylstilbestrol (DES)] and progestagens were administered to pregnant women notably in the years between 1940 and 1970. The gender identity of their offspring may provide clues to prenatal endocrine influences.

Synthetic progestagens have, dependent on their chemical formulae, an antiandrogenic or a weak androgenic biological activity. With regard to the findings in subjects prenatally exposed to oestrogens, it is of note that part of the sexual differentiation in animals is accomplished by oestrogens derived from androgens locally metabolised to oestradiol (Baum, 1979; McEwen, 1981); they have a defeminising effect. Therefore prenatal exposure of girls and boys to oestrogens is pertinent to this issue. When evaluating these results it has to be borne in mind that, in male subjects prenatally exposed to progestagens and/or oestrogens, endogenous testosterone production may have been suppressed by the progestagens/oestrogens, since these substances exert a powerful negative feedback action on the hypothalamo-pituitary axis, which is already operative in the foetus. Prenatal exposure of girls to DES or progestins has not impaired their self-identification as female (Beral & Colwell, 1981; Money & Matthews, 1982), but a higher incidence of homosexuality or bisexuality (25%) has been reported in a sample of women exposed to DES (Ehrhardt et al., 1985). In men the situation is somewhat more complex. Several follow-up studies of men prenatally exposed to DES and/or progestin have indeed found these men to display nonconformity to gender-typical behaviour (Yalom et al., 1973; Hines, 1982; Reinisch & Sanders, 1984), but a straight-line, cause-and-effect role on sexual orientation and selfidentification as male/female has not been established (Kester et aL, 1980; Meyer-Bahlburg, 1984).

Prenatal maternal stress.

It is of interest to relate the foregoing findings to the observation that in rats prenatal maternal stress causes decreased prenatal androgen secretion, with decreased brain aromatase activity and behavioural demasculinisation and feminisation (Ward & Weisz, 1980). It has been

proposed by Dorner (1 983b) that human prenatal maternal stress during the second world war in the former German Democratic Republic may have induced underexposure to androgen (and oestrogen) in the male offspring, leading to a higher prevalence of both transsexualism and homosexuality. However, this proposal could not be confirmed by Schmidt and Clement (1988) in a replication study of men born during that same period in West Germany. If indeed the maternal stress mechanism leading to lower than normal foetal androgen levels would apply to the human, the follow-up data of the DES and progestagen-exposed men contradict the notion that a lower than normal prenatal androgen milieu predisposes to transsexual gender dysphoria or homosexuality.

Morphological sex differences in the brain: Animal research.

The finding that exogenous testosterone in the prenatal or perinatal period masculinises and defeminises sexual behaviour in several species suggested that testosterone was the main factor in masculinisation and defeminisation of the mammalian brain. Subsequently, oestrogens were also shown to be capable of masculinising sexual behaviour of rodents, while nonaromatisable androgens, such as dihydrotestosterone, were generally ineffective in causing masculinisation and defeminisation. This led to the aromatisation hypothesis (McEwen et al., 1977), implicating that aromatised metabolites of androgens are essential for organisational effects on the central nervous system (CNS). More recent studies showed, however, that some aspects of CNS differentiation depend on androgen itself. Hence, in addition to a major role of aromatised steroids in sexual differentiation of the CNS, nonmetabolised androgens play a role as well. Since it is widely believed that neuromorphological sex differences underlie sex differences in neuronal function (e.g. Arnold & Gorski, 1984), the above-mentioned observations gave an impetus to research on sex differences in the morphology of the CNS, in particular the hypothalamus.

Over the past 2 decades, a large number of morphological sex differences in the CNS have been described, constituting a possible neuroanatomical basis for the observed permanent behavioural effects of androgens and oestrogens administered during development. In 1971, a sex difference was demonstrated in the structure of the medial preoptic area of the rat (Raisman & Field, 1971). Since then, a large number of morphological sex differences have been described (e.g., in the size of brain regions, in dendritic and axonal branching patterns, in the distribution of synapses and in the morphology of specific neurotransmitter systems). Many of these sex differences have been shown to depend upon the presence of sex steroids during a restricted period in development (for an extensive review, cf. De Vries et al., 1984).

In some cases, these morphological sex differences are clearly related to sexually

dimorphic functions, as in the case of the presence of the spinal motor nucleus of the bulbocavernosus in the male rat and its absence in the female rat (Breedlove & Arnold, 1980). Another example is the sexual dimorphism of some nuclei in the vocal cord control areas in the songbird brain which is related to a sex difference in singing behaviour (De Voogd, 1984).

In many cases, however, the function of a particular morphological sex difference is not clear, although the brain area in which it is found may be implicated in sexually dimorphic functions. An example is the striking sex difference in size and cell number of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in the rat as originally described by Gorski et al. in 1978. It is located in an area which is involved in gonadotropin release and which shows

a large number of morphological sex differences (for a review, cf. Gorski, 1984). Gonadal hormones were shown to determine the size of the rat SDN in the early postnatal period (Dohler et al., 1986), while a positive correlation was demonstrated between SDN volume and male copulatory behaviour (Anderson et al., 1986).

Even more puzzling are morphological sex differences which have no obvious sexually dimorphic functions. For instance, the vasopressin (VP) innervation of the male rat brain is much denser in a large number of brain areas than in females (De Vries et al., 1981). This sex difference depends on the presence of androgens in the developing male rat (De Vries et al., 1983), while in adulthood it can be manipulated by both testosterone and oestradiol (De Vries et al., 1985). The physiological significance of the central VP innervation, however, is far from clear. Hence, its striking sexual dimorphism cannot be matched at present with sexually dimorphic functions (cf. Buijs, 1987).

Morphological sex differences in the brain: Human studies.

One of the major questions in research on (morphological) sex differences in the human is whether or not animal data can reliably be extrapolated to the human. As argued above, gender identity, the recognition of the self as female or male, cannot faithfully studied in animals since in animal studies observers have to rely sexual behaviour only. Further, the eminent researcher of sexual behaviour in animals, the late Frank Beach (1979) has cautioned against a too facile extrapolation from animal to human sexology. Beach notes (1) observations of sexual behaviour in a certain animal model apply only to that species; (2) similarities in the appearance of behaviour in different species are not necessarily manifestations of the same phenomenon; (3) for human there are no exclusive masculine or feminine motor patterns of copulation. Therefore, extrapolation from animal data to the human with regard to the gender differentiation of copulatory behaviour requires caution.

The search for functional and morphological sex differences in brain function has been/is against a certain societal tide for fear that the demonstration of sex differences might be used as a scientific argument for discrimination against women. In this context it seems appropriate to quote Duberman (1991) who stated that scientific discovery merely provides insight how certain sexual patterns get formed, not whether a particular pattern is "good" or "bad"- the latter is a moral judgement reflecting cultural, not scientific imperatives.

Of late there have been well documented studies finding sex differences in the brain. Swaab & Hofman (1984) showed that the well documented sex differences in brain weight cannot be entirely accounted for by a sex difference in body height. Further analysis revealed a sexual dimorphism in relative brain size from the second year of postnatal life onward and persisting throughout life. The sexually dimorphic nucleus (SDN) of the preoptic area of the hypothalamus as first described by Gorski et al. (1978) in the rat, is still the most conspicuous morphological sex difference in the mammalian brain. The cell group is larger and contains more nerve cells with a clear cytoarchitectomic sex difference. Lesions of the SDN affect masculine sex behaviour in rats, but not severely, so that it is likely that the major function of the SDN has presently been elucidated. Swaab & Fliers (1985) have demonstrated a SDN in the preoptic area of the human hypothalamus which, judged by its localisation and cytoarchitecture, is probably homologous to the SDN in the rat (Gorski et al., 1978), but definitive proof is lacking. Morphometric analysis

of the human SDN revealed that the volume is more than twice as large in adult men compared to women and contains twice as many cells. The sex difference Swaab & fliers (1985) observed was not present in other hypothalamic nuclei. Interestingly, the magnitude of the sex difference was found not to be constant over the life span. In midpregnancy the SDN can be already be distinguished in the human foetal brain. The cell number of the SDN at term birth is not sexdimorph. During the first postnatal years there is a rapid increase in cell numbers in both boys and girls up to the age of 2-4 years. Only after this age does the human SDN become sex-differentiated. Due to a decrease in both cell numbers and volume, the SDN becomes smaller in girls than in boys in whom these parameters remain unaltered up to the age of 50 when cell numbers decline so as to become less sex-different (Swaab & Hofman, 1988)(Hofman & Swaab, 1989).

There are a number of studies reporting other sex-dimorphic nuclei. Allen et al. (1989) described two other cell groups (IINAH-2 and -3) in the preoptic anterior hypothalamus that were larger in male than in female brains. LeVay (1991) could not confirm the sex difference in INAH2, but did find a difference in INAH-3. Before these sex differences can be accepted ad definitive, immunocytochemical analysis and cell counts have to be performed. Another sex difference was described by Allen & Gorski (1990), in what they called the "darkly staining posteromedial component of the bed nucleus of the stria terminalis", an area of which the volume was 2.5 times larger in men than in women.

The suprachiasmatic nucleus is considered to be the principal component of the mammalian clock mechanism generating and coordinating a variety of hormonal, psychological and behavioural circadian rhythms (Rusak & Zucker, 1979). Its shape, but not its volume, was shown to be sex-dimorphic in human brain. The shape is more elongated in women and more spherical in men. For an extensive review of the above information the reader is referred to a recent publication of Swaab, Gooren & Hofman (1992).

Morphology of the brain and gender identity and sexual orientation.

The authors wish to stress that gender identity and sexual orientation are two different properties of a subject. A sexual orientation towards the same sex does not imply a cross-sex gender identity. And vice versa, subjects with a cross-sex gender identity may be sexually oriented to either sex (± 30% of the male-to-female transsexuals indicate a sexual orientation towards women, whereas the percentage of female-to-male transsexuals oriented towards men is lower than 10%).

The reason why gender identity and sexual orientation are both mentioned here, is that scientific reports on this subject do not always make a clear distinction.

In the study of Swaab & Hofman (1990) the authors were unable to find a difference in the volume and cell number of the sexually dimorphic nucleus between heterosexual and homosexual men. This led the authors to refute the global formulation of D&irner (1980) that male homosexuals have a female brain differentiation. But the authors did find that the suprachiasmatic nucleus (SCN) of homosexual men contained 2.1 times many cells as the SCN of a reference group of men and women. It is of note that the SCN does not display a sex difference in volume and cell number (for review: Swaab, Gooren & Hofman, 1992).

In 1991 LeVay reported that the interstitial nucleus of the anterior hypothalamus # 3 (INAH-3) was smaller in homosexual men than in heterosexual men and similar to the size found in women. LeVay limited his investigation to measurement of the size of this nucleus; before his finding can be safely accepted, cell counts have to be made (Swaab, Gooren & Hofman, 1992).

Sofar morphological data on the brains of transsexuals are extremely limited. The findings in only three male-to-female transsexuals have been reported (Swaab, Gooren & Hofman, 1992). Two of them appeared to have a large SCN with high cell numbers (resembling the pattern found in homosexual men) and a small sexually dimorphic nucleus (SDN) with low cell counts (resembling the pattern m women). The third transsexual, however, revealed exactly the opposite, i.e. a small SCN and a large SDN.

The differences between the three transsexuals could not be related to their sexual orientation; as association which could be established in this limited material, is that a large SCN and a small SDN might be related to so-called early onset transsexualism, whereas in the subject with the small SCN and the large SDN, transsexualism was of late onset. It goes without saying that the above material is too limited for definitive conclusions. Its relevance is that in these three transsexual subjects morphological differences in hypothalamic brain structure were demonstrable. Modern imaging techniques of the brain have not advanced enough to produce information on brain structures as small as the SDN and the SCN in living subjects.

Relationship between sex hormones and brain sexual differentiation.

In lower mammals (like the rat and guinea pig) the association between sex hormones and morphological and functional differences of the brain in the two sexes is straightforward. The presence of (aromatisable) androgens is a requirement for as male brain development, whereas their absence is necessary for a female brain function. Also the timing of the differentiation process is known: perinatally, that is shortly before or after birth depending on the species. The brain sexual differentiation in lower mammals occurs when the differential of the genitalia into male or female has long been completed. In the human but also in other primates the relationship between sex steroids and brain sexual differentiation is less clear. In the human only of the sexually dimorphic nucleus (SDN) and the suprachiasmatic nucleus (SCN) the developmental pattern in relation to age has been documented (Swaab & Hofman, 1988)(Swaab, Hofman & Honnebier, 1990). The SDN becomes only fully sex-dimorphic between the age of 3-4 years old, while the cell numbers of the SCN reach a peak around 13-16 months after birth to decline subsequently to adult values of about 35% of the peak values. Before puberty there are two phases in male development in which there is a clear elevation of testosterone blood levels in comparison with girls: between weeks 8-14 prenatally at the time of the formation of the genitalia and shortly after birth for a period of 60-90 days. The biological significance of the latter testosterone peak is not known in the human. Gooren & Cohen-Kettenis (1988) reported a case of a male child who lost both his testes accidentally during parturition, but nevertheless developed a male gender identity and a sexual orientation towards women, when the latter was tested at age 20. The same authors (Gooren & Cohen-Kettenis, 1991) described a male gender identity/role and a sexual orientation towards women in a 46,XY subject with the androgen insensitivity syndrome. The latter is a genetic error leading to an insensitivity of the body’s cells to the action of androgens on the basis of androgen receptor defects. Such subjects are sensitive to the action of oestrogens which have been implicated in male brain sexual differentiation but this does not fit

with the observation that almost always 46,XY subjects with the androgen insensitivity syndrome develop an unambiguous female gender identity (Money, Schwartz & Lewis, 1984). A recent report of Lish et al. (1992) showed that prenatal exposure to diethylstilbestrol did not influence childhood play and adult gender-role behaviour in study of 60 women.

By contrast morphological studies of the brain have provided evidence of a potential effect of sex steroids on the SDN. A 30-year old woman with the Prader-Willy syndrome (with a congenital LHRH deficiency and subsequent ovarian hypofunction) had a small SDN (Swaab and Hofman, 1988). Also a man affected with a 47,XXY chromosomal pattern (Klinefelter syndrome) had a small SDN, but a child that died of pituitary aplasia immediately after birth had a normal SDN for that age (Swaab, Gooren & Hofman, 1992).

Of the other reported morphological brain differences between the sexes it is not known when they become sex-differentiated, therefore it is impossible to relate them to hormonal events in the developmental process.

On balance the conclusion must be that no direct relationship between sex hormones on the one hand and sex-dimorphism of the brain on the other could be established. The relationship could be indirect in the sense that sex hormones induce certain processes which manifest themselves only several years later than the hormonal event itself, but this assumption is speculative. The finding that morphological brain differences between the two sexes develop not earlier than in the first 3-4 years after birth opens the theoretical possibility of postnatal steering mechanisms, those of a psychosocial nature not excluded.

Sex differences in brain functions. Studies in transsexuals.

It has been found in several studies that brain lateralisation, verbal ability and spatial ability vary with sex. Women tend to outperform men on verbal tasks, while men outperform women on visospatial tasks. Women also tend to be less lateralised than men (Kerns & Berenbaum, 1991; Halpern, 1986; Kimura, 1988). These sex differences are not absolute, but these properties are most adequately termed: sex-shared, threshold-different, in other words, they appear more readily in the one sex in comparison to the other. Several researchers have tried to link these relative sex differences to exposure to sex steroids prenatally and indeed some correlations have been established. Women suffering from the congenital adrenal viilising hyperplasia have prenatally been exposed to higher-than-normal androgen levels and they were found to have a better spatial ability than control women (Resnick, Berenbaum, Gottesman & Bouchard, 1986)(Reinisch, Ziemba-Davis, Sanders, 1991) while hypogonadal men who had a lower-than-normal exposure to testosterone prenatally performed worse than a control group (Hier & Crowley, 1982). Men exposed to diethylstilboestrol were less lateralised than their unexposed brothers, while exposed women were more lateralised than their unexposed sisters (Reinisch & Sanders, 1992). Geschwind & Galaburda (1985) postulated that homosexuals and transsexual males showed a higher prevalence of lefthandedness on the basis of their presumed prenatal androgen underexposure; the latter factor has, however, seriously been questioned as an etiologic moment in homosexuality (Gooren, Fliers & Courtney, 1990). Tkachuk & Zucker (1992) found no difference. Others have found that heterosexual men had higher scores than homosexual men on spatial ability (Gladue et al., 1990)(Mc Cormick & Wittelson, 1991). Others could not replicate this finding (Tuttle & Pillard, 1991).

Since the prevalence of transsexualism is rather low these studies are relatively difficult to conduct, but some results are available. Boys with gender identity problems performed significantly better on verbal than on spatial subjects of the Wechsler scales and had a relative deficit in spatial ability, but not a relative advance in verbal ability (Zucker, 1991). In an adult group of 17 male-to-female and female-to-male transsexuals no atypical Wechsler scores were found (Hunt, Carr & Hampson, 1981). La Torre, Gossman & Piper (1976), by contrast, reported that eight male-to-female transsexuals scored lower on embedded figures test than a male control group while their results were similar to those of women. In a recent study a two times elevated prevalence of lefthandedness was found in both male-to-female and female-to-male transsexuals in comparison with control groups (Orlebeke, Boomsma, Gooren Verschoor & Van den Bree, 1993); a result similar to the findings of Mc Cormick, Witelson & Kingstone (1990) in homosexuals.

In a study of Cohen- Kettenis, Doorn & Gooren (1992) 35 male-to-female and 12 female-to-male transsexuals, eligible for hormone treatment, were tested and compared to control subjects matched for age, sex and educational level. The subjects were given a dichotic listening, a two dimensional mental rotation test, a verbal memory test, a questionnaire on manual dexterity and a short questionnaire on sexual orientation and self-experienced masculinity/femininity.

Righthanded male-to-female and female-to-male transsexuals were significantly less lateralised than the control group on the dichotic listening test. On the mental rotation test, the results were in the expected direction: male-to-female transsexuals performed worse than control males while female-to-male transsexuals performed better than female controls though the differences did not reach statistical significance. Male-to-female transsexuals scored significantly better on a verbal memory test than male controls, while the reverse was true for female-to-male transsexuals. Spatial ability correlated with the scores of masculinity in the male-to-female transsexual group.

In summary: while the differences are not discriminating in an absolute sense, studies conducted in transsexuals point to brain functions different from their control groups. The relation with an abnormal prenatal endocrine milieu has been difficult to establish as an explanation for this phenomenon. As argued elsewhere (Gooren, 1990) is it questionable whether hormonal events play an important role in the establishment of gender identity. Also with regard to sex differences in brain functions and the abnormal patterns in transsexuals, other factors seem to prevail, which have as yet not been identified.

Follow-up studies in subjects with an atypical sexual differentiation process.

It has been John Money’s opus magnum to follow up individuals in whom one or more of the stages of sexual differentiation has been atypical in relation to the others. One of his conclusions was that the sex of assignment and rearing in cases of (pseudo)hermaphroditism was more accurate than any other variable as a prognosticator of the gender identity/role established by these subjects later in life. The other variables were the nature of the chromosomal sex, gonadal history, sex steroid levels and genital anatomy. With this information the discrepancy between body and gender identity/role in transsexuals becomes more comprehensible. His conclusions have often been misinterpreted to assert that the future gender identity/role of a child with a defective sexual differentiation is determined solely and exclusively by ‘non-biological’

factors such as the sex of assignment and rearing. In fact his work only demonstrated the predominance of such ‘non-biological’ factors in relation to the other (also significant) factors (Money and Ehrhardt, 1972).

Summary of biological sex differentiation and its relevance to "Transsexualism, medicine and law".

It has become clear that the differentiation process of becoming a man or a woman is a multi-step process with for each step a window of time, a critical phase. Once this phase has passed there is no backtracking. With the fusion of an ovum and a sperm, the chromosomal pattern becomes established: usually 46,XY or 46,XX, but other configurations do occur. The most well-known are 47,XXY (Klinefelter syndrome) and 45,X (Turner syndrome). The differentiation of the gonads takes place in the human foetus between 5-7 weeks of pregnancy. The indifferent, bipotential gonad becomes a testis provided the correct genetic programming is present on the short arm of the Y-chromosome. Sometimes this information has been translocated to the X-chromosome resulting in a 46,XX man with a reported frequency of about 1:20,000. A XY-chromosomal pattern may result in a development of a female with streak gonads if the ‘testis determining area’ is lacking on the Y-chromosome. When the gonads have become either testes or ovaries (or in rare cases ovotestis), the next step of the differentiation process is the formation of the internal genitalia. The foetal testis becomes endocrinologically active and secretes testosterone and Mullerian-inhibiting factor leading to involution of the ducts of Miller and formation of the male internal genitalia from the ducts of Wolff. The ovaries are endocrinologically quiescent. The ducts of Wolff regress in the absence of testosterone while in the absence of Mullerian inhibiting factor the ducts of Muller differentiate into female internal genitalia. The following step is the formation of the external genitalia, obeying to the same paradigm: male external genitalia in the presence of testosterone (provided it is metabolised to 5-alpha-dihydrotestosterone) and female external genitalia in the absence of testosterone and other androgenic hormones. There are two classical syndromes of which the errors in sexual differentiation occur in this phase: the androgen insensitivity syndrome (AIS) and the congenital viilising adrenal hyperplasia (CVAH). The essence of the AIS is that all body cells lack androgen receptors. It has only been found to occur in 46,XY subjects. These subjects have testes and produce testosterone to which their organism is insensitive. As a consequence their ducts of Wolff do not differentiate into male internal genitalia and the external genitalia are female. As a consequence these 46,XY subjects with testes are born and raised as girls. A similar clinical presentation have those 46,XY testis-bearing subjects who have an enzymatic block in the production of testosterone. In the CVAH there is an abnormal amount of androgen production of the adrenal (on the basis of an enzyme defect in the cortisol synthesis). The much higher than normal androgen production leads in an affected 46,XX foetus with ovaries to a male type of differentiation of the Wolffian ducts and of the external genitalia; in other words these 46,XX, ovary-bearing subjects are born with a penis and a scrotum and raised as boys. The above two clinical syndromes can be complete or incomplete. Apart from the two above classical syndromes there are more errors in the sexual differentiation process of the internal and external genitalia, leading to male genitalia in foetuses with a 46,XX chromosomal pattern and ovaries and to female external genitalia in foetuses with a 46,XY pattern and testes. More often ambiguity of the external genitalia is the result of a faulty sexual differentiation process of the external genitalia. The formation of the genitalia is concluded by the 16-17th week of gestation. Since times immemorial mankind has assigned its offspring to the male or female sex by the criterion of the

appearance of the external genitalia and apparently without encountering great problems. This practice infers, on the basis of a single glance, that all criteria of sexual differentiation (chromosomal pattern, nature of gonads and of internal genitalia) in their entirety are either masculine or feminine. This inference appears to be justified in the vast majority of newborns but there is no certainty that the other criteria of the sex are congruent with the appearance of the external genitalia. Abiding by the principle of assigning a newborn to the male or female sex by the criterion of the appearance of the external genitalia, this practice will inevitably produce that some subjects will be legally registered as male while their other criteria of sex (chromosomal pattern, gonads, internal genitalia) are discordant with those of the average male and vice versa will that be the case with persons registered as females.

Even more complex are the cases of newborns with ambiguous genitalia. The homespun wisdom of medically unsophisticated people confronted with such a newborn, guided them to assign the baby to the sex to which it most resembled in genital appearance. After the advent of medical technology to determine the nature of the chromosomal pattern and the gonads and internal genitalia, this practice was reconsidered. Starting with Klebs in 1876 it was assumed that microscopic examination of the gonad (testis or ovary or ovotestis) would provide a secure criterion as to the ‘true’ sex of the newborn. The introduction of techniques of chromosome determination tempted scientists to adopt a chromosomal criterion instead. It is evident that these approaches were teleological in nature, in other words they tried to read from the chromosomal pattern and the gonadal tissue what nature’s original ‘intentions’ had been with the subject involved. These medical procedures turned out to be disastrous for the subject. As can be understood from the information on sexual differentiation given above, such a procedure leads for instance to assignment to the male sex of subjects with 46,XY chromosome pattern and/or testes while this subject has female external genitalia which cannot satisfactorily be surgically reconstructed to male genitalia. It is not difficult to imagine what misery this approach must produce for the subject involved with regard to his functioning as male in all its aspects.

It has been the pioneering work of Money and Wilkins mentioned earlier, in children with ambiguous genitalia that has led to a new style of clinical decision making on sex assignment in the newborn. The decision on sex assignment is in modern medicine primarily guided by the nature of the external genitalia and/or how well they lend themselves to surgical reconstruction in conformity with the sex the newborn is to be assigned to. Preponderant in the decision is the clinically well-founded expectation of the sex role in which the newborn will genitally function best in childhood and adult life, privately as well as socially and sexually. Future fertility must be considered but is not predominant, since it may be totally at odds with the genital status (for instance in a subject that has a vulva and vagina and fertile testes).

It is clear that the above clinical practice gives high priority to the expected future genital functioning of the newborn with a substantial disregard of the nature of the chromosomal pattern and of the gonad. Most legal systems accept that in the case of newborns with ambiguous genitalia, sex assignment is executed on the basis of a medical expertise. It is evident from the above that medicine is unable to determine sex by a single criterion, like chromosomal gonadal and genital characteristics. All variables of sex are usually concordant with another, but they are capable of being discordant. For the healthy psychomedical development of a child, if not it is doomed to become a queer person, it is an exigency that it is assigned to either the male or the female sex. This assignment is usually made by parents or caretakers on the basis of the appearance of the external genitalia. The civil registration as male or female will be in agreement

with the assignment of the parents/caretakers in cases of unambiguous genitalia or with the medical expert advice in cases of genital ambiguity. Consequently, civil registration is subject to the same uncertain or arbitrary determination of sex as the medical profession is. Most legal systems have, in times that it was unknown that sexual differentiation is a stepwise process with several variables, prescribed that civil registration is to be enacted by the criterion of the appearance of the external genitalia.

Though it is, no doubt, an expedient practise doing justice to the vast majority of citizens, it must be recognised that it hinges on only one of the variables, one of the criteria of one’s sex. From the above arguments it is clear that no single criterion can, psychomedically speaking, satisfactorily define sex and therewith the most widely prevailing legal criterion of sex, that of the external genitalia, is scientifically no longer unequivocal.

Another aspect of civil registration as male or female is that it is legally bound to take place within a number of days after birth. The demonstrable sex differences in the brain become only manifest by the age of 3-4 years postnatally. In contrast to lower mammals the process of brain differentiation has no direct relationship with sex hormone action, theoretically leaving room for other agents to direct this differentiation process. Upon examination of a very limited number (three subjects) of male-to-female transsexuals post mortem, their brains showed morphological differences in comparison with non-transsexual controls. Apart from these morphological findings, also testing of brain function of transsexuals provided evidence of a cross-sex differentiation of their brains.

The implication of the above scientific insight that the sexual differentiation of the brain occurs after birth is, that assignment of a child to the male or female sex by the criterion of the external genitalia is an act of faith. In the reality of every day it is an expedient practice exercised by mankind since times immemorial. Only as few as 1:10,000 males and 1:30,000 females (Bakker, Van Kesteren, Gooren & Bezemer, 1993) (Tsoi, 1988) will later experience a contradiction between his/her gender identity/role and the actual genital morphology and other criteria of sex. Consequently, like the other variables in sexual differentiation (chromosomal pattern, gonads) the external genitalia are excellent, statistically reliable prognosticators of one’s future gender identity/role. By contrast, on the basis of this recent neuroanatomical evidence it is reasonable to require from the law that it makes provisions for those rare individuals in whom the formation of gender identity has not followed the course otherwise so reliably prognosticated by the external genitalia. Denial of this right is a negation of an important piece of scientific information on the process of sexual differentiation of the brain taking place after birth. If a strict and intransigent adherence to the criterion of the appearance of the external genitalia as directive for sex reassignment is observed, it must be realised that prenatal determinants of sexual differentiation (chromosomal pattern, gonadal characteristics, hormone production) may be at variance with the nature of the external genitalia. In other words the criterion of the external genitalia for sex reassignment is less solid, less unequivocal as it would seem to most legal experts. The validity of this criterion has been superseded by the scientific information that sexual differentiation is not a one point deterministic process, but a succession of steps concordant or disconcordant with each other. The existing law practice does justice to those newborns in whom all steps are concordant. The less fortunate citizens in whom these steps have been discordant, deserve no less.

Strasbourg, 9 March 1993

CJ-DE/XXIII (93) 4

(Amsterdam, The Netherlands, 14 - 16 April 1993)

presented by

Internist / Endocrinologist

A large majority of transsexuals have a history of trial and error to live their lives in the sex role of their biological sex. In them a battle rages between the authenticity of their cross-sex gender identity on the one hand and the physical reality of their genitalia on the other. In human existence the advent of puberty stresses the reality of belonging to one sex and not to the other. Consequently transsexuals experience puberty as an exacerbation of their gender dysphoria. Female-to-male transsexuals loath the appearance of menstrual bleedings. Male-to-female transsexuals starting their sex lives are confronted with the biological reality of male sex functions (erections, ejaculations) which are in disharmony with their gender identity. Yet they are the only sexual responses which their bodies permit as sexual outlets. Sooner or later the sense of the physical reality of the body is defeated by the greater reality and authenticity of the gender identity. Sex reassignment treatment with the culmination of sex reassignment surgery is seen as an escape route from a chronically disturbed and unrewarding existence and as the only way to improve the lot. Weary of the past, most transsexuals desire immediate solutions of their vexing, disconcerting problem. Understandably in the light of their suffering a fast reassignment procedure is often requested but it is bound to become a failure. It is essential to establish a good relationship with a therapist, preferably working in a gender team.

A good relationship has a number of ingredients. First, the transsexual must have a realistic expectation and certainty that the therapist considers his/her problem as an authentic clinical entity. Most transsexuals will only be comfortable with a therapist who views their condition as a trick, as a freak of nature rather than a development deviant from the norm for which the only way-out is a redress to the norm. It should be made explicit to the transsexual that hormonal and surgical reassignment are options the transsexual and the therapist may arrive at if indicated by their clinical case. A transsexual confronted with a therapist dismissing these options as potential outcomes of the psychotherapy program, may well move on to seek help elsewhere and embark on a tour of medical shopping or even nonmedical shopping to procure hormonal treatment through illicit channels or to find reassignment surgery in a "no questions asked" setting.

Even if a reasonable client-therapist contact is established transsexuals are often impatient in their pursuit of hormonal and even more of surgical treatment and if they believe that such help is not going to be forthcoming, they may become distrustful of the therapist. At the outset of the counselling it seems unimaginable to most transsexuals that some other candidates have changed their mind in the process of therapy or that some have regretted surgical intervention. An approach with "all options open" seems the most rewarding.

Second, the therapist and physicians involved in the treatment process should provide an accurate and realistic description of what may be expected from hormonal and surgical reassignment treatment. The concept of this somatic treatment has been well formulated by Money who states "Transsexualism is not a reversible condition judging by today’s therapeutic techniques. Nor is it a progressively deteriorative condition, but it does represent a chronic disability, requiring a patient’s life to be rehabilitated. Sex reassignment -social, hormonal, surgical and legal- is an ameliorative and rehabilitative treatment for transsexualism. It is not a cure. There cannot be a clearly formulated cure for this condition in the absence of a clearly

formulated etiology so far not discovered (Money & Ambinder, 1978). In other words: the transsexual must realise that the maximum which can be offered medically is a rehabilitative adaptation to the new sex; it is incomplete and has its shortcomings. Further, the transsexuals need to receive factual information about the somatic treatment. The male-to-female transsexual must realise that certain body characteristics (height, shape of face and jaws, hands and feet will not change following hormone administration, that an established beard will unsatisfactorily respond to hormone administration and that formation of female breast may be too little, particularly in relation to body configuration). The results of a vaginoplasty in the hands of an experienced (plastic) surgeon are satisfactory, but the neovagina is not in every sense equal to the normal female vagina.

The female-to-male transsexual may generally expect an unremarkable virilisation process with development of normal male sexual hairiness and deepening of the voice, but removal of the breasts will leave scars and phalloplasty remains an elaborate surgical procedure which provides at best the candidate with a non-erectile neophallus.

Transsexuals have often unrealistic expectations of what medicine can achieve for them in terms of bodily adaptation to the desired sex. To cite Money & Ambinder (1978) again, it is no cure, it is rehabilitation.

Undergoing sex reassignment will necessarily be a matter of losses and gains which have to be balanced. The gains are evident to the transsexual: to have a physique which no longer contradicts what one is. The farewell to the original sex role will have its price. Transsexuals will often be cut off from their families and friends though fortunately this is not always the case. New contacts with significant others have to be built up in most cases. Transsexuals must realise that this may turn out to be difficult. On the one hand transsexuals may be tempted to keep the history of a sex change secret, on the other such secrecy puts the burden on future relationships that the fact may come out one day with disastrous effects for the trust in a relationship. Job prospects may become jeopardised by the change of the sex role.

Real-life test

The clinical assessment of the transsexual is therefore a continuous process in which the clinician gets to know the client over a period of time. A clear picture should emerge of what the contents of the gender dysphoria are and whether a more permanent somatic sex change is likely to be beneficial. There should be a mutual trust. The transsexual must feel free to express doubts and difficulties with the process of a reversal of sex without endangering his/her eligibility for somatic treatment. The therapist must make an effort to offer a perspective in time of possible future steps and not keep the transsexual unnecessarily on a hold. The client who is diagnosed as gender dysphoric should be encouraged to spend time in passing in the desired sex role in a stepping-up fashion, first cross-dressing at home and in the company of trusted friends and later going public.

When these moves appear successful, the client can start living and working full-time in the new role. Characteristics of the original sex may be an impediment for crossing over to live as a member of the desired sex, but should not constitute grounds not to cross-over. Practical solutions should be found and much can be learned from the experiences of other transsexuals. With this step "the real-life test" has started.

According to Money & Ambinder (1978): " the two year real-life test allows both the patient and the physician to monitor from waking to sleeping, week by week, month by month, the experience in the new sex status as he/she habituates his/her responses to other people. Without the test of how other people react, and how he/she reacts to other people, the patient knows only his/her private convictions and fantasies of being a member of the opposite sex. Convictions and fantasies can be notoriously unreliable. They may include a covert and magical proposition, in which the reassignment operation is equated with being born again, fully accommodated, as a member of the new sex, to the gender-dimorphic expectancies and responses of other people. Such accommodation does, however require time. It should be accomplished prior to the irreversible step of surgery. Sex reassignment surgery should occupy a place in a person’s life that corresponds rehabilitatively to hysterectomy in the life of a woman, or prostatectomy in the life of a man

The objectives of "the real-life test" are manyfold. It teaches the transsexuals what it means to live as a member of the sex one reckons oneself to belong to. How do others react to it? How well is the transsexual prepared to cope with negative or even hostile reactions of the outside world, particularly when it becomes clear than one is involved in a transition from one sex to the other.

As stated above the outcome of the real life test must be open-ended. The transsexual may decide that crossing over to the other sex does not bring the anticipated relief of gender dysphoria or that the price to be paid in terms of losses may be too high. The transsexual must feel the freedom to withdraw without losing face in view of the previous pledges to undergo a sex change. The therapist must have the freedom to advise against somatic treatment on good grounds of clinical expertise that a sex change will be a disaster or that much more time is needed before "the real life test" can be considered as predictive of a reasonable success.

Most experienced clinicians agree that tampering with "the real life test" from the side of the transsexual or a too short "real life test" in a seemingly successful candidate, often lead to ill successes.

Hormone treatment may be initiated with the start of "the real life test", since, with the exception of deepening of the voice in females, the effects are largely reversible in the first months.

Surgical reassignment can only be considered after achieving a reasonably satisfactory and stable full-time adjustment in the new role for an absolute minimum of 12 months, even in the most convincing cases who, at face value, have sometimes good reasons to speed this step up, like attendance of schools and job opportunities.

Postoperative counselling must continue for some time. An intervention psychologically so heavily capitalised on, sometimes becomes a disappointment. It is not that the transsexual regrets this step but it does not bring more to the transsexual than a relief of a burden; it does not per se produce a state of blissful happiness as sometimes anticipated. Some form of support is needed to guide the transsexual through this new phase in life. Also hormone treatment must be continued for medical reasons, among others to prevent osteoporosis.

It is obvious that a sex change is not a process taking place in a vacuum. The transsexual

has roots in his family and has maybe established intimate relationships with offspring. A sex change is as much a private issue as it is an issue of the environment. Ideally family, spouses, children and friends should receive support to help them to find their position in relation to the sex change of a beloved person. In most gender clinics this important aspect receives not enough attention because of lack of funds. In the Netherlands support groups of lay people, who can call incidentally upon professionals, have proven to be supportive. In the same vein lay groups of transsexuals can play an important role in a successful sex change. They have first hand information on their "real life tests" and the problems encountered and they are living examples of what can be achieved, medically and with regard to societal integration.

Health professionals who engage in providing services to transsexuals may face challenges from their peer group. The training of psychologists and medical doctors does not include much information on this relatively rare phenomenon. Both disciplines are heir to a Cartesian tradition of a split of body and mind, the body the domain of the medical doctor and the mind the domain of the psychologist. Some psychologists and even more some psychiatrists maintain that transsexualism is a delusional belief or a deviance in gender identity development for which hormones or the surgical knife cannot possibly provide solutions. Medical doctors may be reproached that they tamper with the sexual integrity of bodies which show no pathology by accepted medical standards. Intellectually there is no way out of this conflict than to point to the intimate, inseparable relation between body and mind epitomized by transsexualism. In selected cases of transsexualism medicine has nothing better to offer than hormonal and surgical rehabilitation of the individual since there is no effective treatment for truly restoring a transsexual’s comfort with his biological sex. This does not mean that in the psychotherapeutic approach of the transsexual and "the real life test" other options than somatic treatment must not be considered or tried.

Transsexuals go through sufferings and their cry for help is convincing. They may present very good reasons why their situation is exceptional and why "the real-life test" should not strictly be adhered to in their case. It requires a long clinical experience to sympathize with them on the one hand and on the other hand to be strict with implementation of "the real-life test". It is our experience that some well-intentioned but inexperienced individual doctors honour appeals from transsexuals to prescribe hormones and to perform surgery. This carries a high risk of being premature or ill-indicated. In our view sex reassignment treatment should be laid in the hands of a gender team which should consist minimally of a psychologist/psychiatrist, endocrinologist, plastic surgeon, gynaecologist and representatives of the nursing profession. The team should meet on a regular basis and have short lines of communication. They jointly carry the responsibility for the success of the treatment. Thus the team can build up clinical experience with this relatively rare condition. They may support one another in the discipline necessary for the treatment of this gender disorder. If working in an academic setting they may do scientific research on this subject we know so little of.

It is our estimation that one team per 4-5 million people will be adequate. It constitutes a significant workload (30-40 new patients per year, while the operated patients should be hormonally followed up) but it allows clinical experience and expertise to develop and grow.

Though the principal outlines in the treatment should be decided on by the gender team, individual doctors can treat comorbidity in transsexuals. For instance psychotherapists may provide their expert help to treat psychiatric problems of transsexuals, but decisions with regard to steps and timing in the reassignment process should be made by the gender team.

Except for the sex chromosomes and gonads all bodily differences between men and women must be attributed to the action of sex hormones. Prenatally the presence of testosterone is a requirement for the formation of male genitalia, while their absence is a necessary condition for the normal development of female genitalia. The prepubertal period is hormonally relatively quiescent. The respective sex hormones activated from early puberty on, accentuate sex differences. The greater height of men, their greater ratio of muscle tissue to body fat and sexual hairiness are due to the action of androgens, while breast formation and a female body shape on the basis of fat depots around the waist and hips are effects of oestrogens and less so of progestagens. There is no known fundamental difference in sensitivity to the biological action of sex hormones on the basis of the genetic patterns of 46,XY and 46,XX.

Pivotal to sex reassignment is the acquisition to the fullest extent possible of the sex characteristics of the other sex. The attempts to induce cross-sex characteristics in transsexuals -generally normally differentiated male and female subjects in their adult years - can be subdivided in two aspects:

1) annihilation of sex characteristics of the original sex;

2) induction of sex characteristics of the sex one reckons oneself to belong to.

ad 1) Unfortunately, the annihilation of sex characteristics of the original sex is incomplete. In male-to-female transsexuals, there is no mode of treatment to revert earlier effects of androgens on the skeleton. The greater height, the shape of the jaws, the size and shape of the hands and feet, and the narrow width of the pelvis can not be redressed once they have reached their final size at the end of puberty. Conversely, the relative lower height in female-to-male transsexuals (in the Netherlands an average of 12 cm) and the broader hip configuration will not change under the influence of hormonal treatment.

ad 2) While in the majority of female-to-male transsexuals, a complete and inconspicuously masculine development can be induced with androgenic hormones, the effects of feminising hormone treatment in male-to-female transsexuals can be objectively unsatisfactory with regard to reduction of sexual hair and induction of breast development.

In male-to-female transsexuals suppression of the original sex characteristics can be obtained by compounds that exert directly or indirectly an anti-androgenic effect:

1) suppression of the gonadotropins that stimulate gonadal sex steroid production can be achieved by so-called LHRH antagonists and further by progestational compounds (medroxyprogesterone acetate, cyproterone acetate).

2) interference with the production of testosterone or its conversion to the potent metabolite 5 alpha-dihydrotestosterone (DHT) can be exercised by drugs like spironolactone and flutamide. Finasteride is a 5 alpha-reductase blocker reducing the formation of DHT. 3) drugs that interfere with the receptor binding of androgens are most widely used, like cyproterone acetate, nilutamide and the above mentioned spironolactone and flutamide.

Of all the above drugs side effects have been reported, some inherent to their action like reduction of muscle mass and haemoglobin levels. Some patients will complain of loss of energy and vitality to the degree of depression. The administration of antiandrogens can be discontinued when male body features have satisfactorily been reduced. Sexual hairiness once established is very resistant to antiandrogen therapy, so in most adult Caucasian subjects hair removal techniques are required for a successful demasculinisation process. As stated above; there is no effect on bone structures, in other words sizes of hands and feet do not decrease.

For the induction of female characteristics oestrogens are used. The other ovarian hormone progesterone and derivates are in all likelihood not significant for the feminisation process. There is a wide variety of oral, injectable and transdermal oestrogens. So far it has not been established that for the induction of feminisation a certain type of oestrogenic hormone is superior. There are a number of caveats. Some transsexuals tend to overdose themselves. Oestrogen therapy induces an increased risk of arterial, and particularly of venous thrombosis. The latter occurs more frequently in patients above 40 years. Since it is likely that oral oestrogens induce clotting factors on their passage of the liver, transdermal oestrogens are recommended for patients over 40 years. Further, ingestion of oestrogens may lead to nausea and high blood pressure and fluid retention with oedema, particularly when the dosages are high. Administration of oestrogens causes prolactin levels to rise, most of the times clinically insignificant. One case of induction of a pituitary tumour has been described (Gooren, 1989).

When a sufficient degree of feminisation has been attained, oestrogen therapy must not be discontinued. Similar to the situation in agonadal women, male-to-female transsexuals need oestrogens for the prevention of osteoporosis. Maintenance dosages are similar to those in women of the same age.

Though powerful agents, antioestrogens do not reduce female characteristics in women. By their stimulation of LH, ovarian hormone production will increase. Progestational agents in a supraphysiological dose will block pituitary LH secretion and therewith reduce ovarian hormone secretion. For the induction of male body features androgens are used, both injectable and oral and in the near future transdermal androgenic hormones. Side effects of androgens are acne, sometimes severe, increase of body weight (a ± 10% increase is normal and due to an increased body mass, but sometimes the weight gain is larger).

Androgens have an unfavourable effect on the lipid profile (more atherogenic). Also increases of blood pressure may follow.

Hormones are indispensable tools for the induction and maintenance of the characteristics of the sex the transsexual reckons hint/herself to belong to. They are relatively safe drugs in appropriate dosages. Transsexuals receive sometimes cross-sex hormones through unauthorised channels and many times overdose themselves or use inappropriate compounds, which leads to (avoidable) risks to their health.

The reader interested in cross-sex hormone therapy is referred to papers of Asscheman & Gooren (1993) and Asscheman, Gooren & Eklund (1989).

Adult men and women have distinctly different uses of their voice. It is not only the difference in pitch of the voice that accounts for this distinction but there is also a difference in intonation and resonance pattern (chest resonance versus higher use of resonance).

Androgen treatment of female-to-male transsexuals will, as a rule, lead to a lowering of the pitch of the voice so that these subjects can successfully pass as men. In male-to-female transsexuals the situation is more complicated. Their feminising hormone treatment has no effect on the vocal cords, in other words their voice keeps the original pitch. Speech therapy may produce a use of the voice that is more feminine. Resonance and intonation may be retrained as to be more feminine.

Surgical techniques to shorten the vocal cords may indeed lead to a higher pitch, but must still be considered experimental because the intonation pattern becomes restricted with a decrease in the range of the voice.

In some male-to-female transsexuals the size and shape of their noses and jaws may constitute a reminder of their male physical past. Established surgical techniques are available for the reduction in size and shape to produce a more feminine appearance.

Asscheman, H. & Gooren, L.J.G. (1993).

Hormone treatment in transsexuals. J. Psychol. & Human Sex 5 (4), 33-47. Asscheman, H. & Gooren, L.J.G. & Ekiund, P.L.E. (1989).

Gooren, L.J.G., Assies, J., Asscheman, H., De Slegte, R. & Van Kessel, H. (1988).

Money, J. & Ambinder, R. (1978).

* *

* *

* *

Strasbourg, 29 January 1993

(Amsterdam, The Netherlands, 14 - 16 April 1993)

sex reassignment surgery.

Co-report

presented by

Dr. J. Joris HAGE

Consultant Plastic Surgeon

Academic Hospital of the Free University

Amsterdam, The Netherlands

In the day to day practice of plastic surgery the indications for surgery are usually self-evident. They are removal of pathological tissue, restoration of disturbed functions, and corrections of disfiguring body features to acceptable proportions so as to improve the self-image of the patient. None of these criteria truly apply to the gross changes brought on by sex reassignment surgery, as asked for by transsexuals. Therefore, this kind of surgery has met with resistance both within and outside the medical profession, such as in legal and ethical circles. It takes a rather long period of experience with gender dysphoric subjects before one may come to believe that the patient with genuine gender dysphoria carries a discrepancy that is valid as indication for surgical sex reassignment. 1.2

The difference between physical reality of the body and gender of the mind in these patients often leads to a lack of psychological wholeness and failure to socially integrate. Driven by the persistent and unchangeable need to undo this discrepancy, transsexuals seek to adapt their bodies as optimally as possible to the sex they feel they belong to. The wish to re-enter society as a person with the physical and mental gender of their choice without being ‘spotted’ or without anyone ‘knowing’ fulfils almost all of the preoperative objectives of the transsexual and should also be the goal of surgical treatment.

For the surgeon the key issue prior to considering surgical reassignment is to establish beyond reasonable doubt that the gender dysphoria or transsexual feeling is genuine. Whether the particular patient is mentally and physically fit for surgery should be assessed preoperatively as well.

In this co-report the criteria for surgery, the possible surgical changes to meet with the private gender experience of the patient, and their physical consequences will be presented.

Prior to considering surgical reassignment the genuiness of gender dysphoria should be established. The surgeon remains responsible for any diagnosis based on which he performs surgical interventions, and he should therefore participate in diagnosing the gender dysphoria of any case he wishes to treat. However, diagnosing gender dysphoria and determining whether this warrants sex reassignment surgery is primarily the task of a behavioural scientist.

This behavioural scientist, whether psychologist or psychiatrist, should have had supervised training in this particular field of sex therapy and counselling and has to be a member of a reputable gender team, this team preferably being the same as that of the surgeon. He should know the patient in a diagnostic or therapeutic relationship for at least six months and should establish that the patient has had uninterrupted and unchangeable feelings of being in the wrong body for a period of over two years and has had a successful cross-living test over a one-year period; in other words, has undergone a reliable real-life test.³

Although not entirely similar, these preoperative requirements are in compliance with the Harry Benjamin International Gender Dysphoria Association’s Standards of Care.⁴’⁵ The Standards of Care contain criteria prerequisites for the diagnosis of gender dysphoria as accepted by the legal profession, the third party insurance payers, and the medical profession, as well as in the malpractice ‘arena’ in the United States of America.

Only when these diagnostic prerequisites are met, the rearrangement of the body towards its new sexual appearance will be performed on those subjects whose true, or most appropriate, gender has been determined to be different from their present sexual appearance. This consideration made Milton T. Edgerton, one of the principal workers in this field, remark that "in a very deep sense, these operations should be viewed as ‘sex-confirmation’ operations - and not as ‘sex-reassignment’ procedures"⁶

Before any surgical reassignment is performed, appropriate monitoring of medical conditions, as well as the effects of the hormonal treatment upon liver and other organ systems, should be accomplished. For this, the surgeon may wish to lean on the expertise of an endocrinologist. This endocrinologist is either a member of the gender team, or known by the members of the team to have substantial personal experience in this field. There is no consensus on the need of preoperative testing for possible infection by the Human Immunodeficiency Virus. Although many a surgeon doing these procedures requires a negative HIV test to -incompletely and thus falsely- appease his own fear for contamination, in our institute it is felt that even a seropositive candidate for sex reassignment surgery should not be discriminated against solely on the basis of his being HIV-positive, for his expectation of life, and particularly the quality of it, cannot be truly assessed. However, in cases where symptoms of the Auto-Immune Deficiency Syndrome have declared themselves, we tend not to intervene surgically anymore since the stress of operation may deteriorate the illness further or faster.

Distinction should be made between genital and non-genital surgical sex reassignment (Table I). Surgery of the breasts will be discussed along with the genital surgery for reasons of comprehensibility, even though in a true sense the breasts are not part of the genitalia. Genital reassignment surgery then refers to surgery of the genitalia and breasts performed for the purpose of altering the morphology in order to approximate the physical appearance of the cross sex in persons diagnosed as gender dysphoric. Non-genetical reassignment surgery includes surgical procedures of non-genital, or non-breast sites (e.g. nose, throat, chin, cheeks, hips).⁴

In genital reassignment surgery further distinction should be made between procedures performed to remove the original genitalia and those performed to construct the desired genitalia, even though some of these procedures may be performed simultaneously. The following presents reassignment surgery of the internal and external genitalia in female-to-male (F->M) transsexuals. Furthermore, the surgical possibilities for male-to-female (M->F) transsexuals will be presented. The possibilities of non-genital surgical treatment will be mentioned for each group.

-Mastectomy:

F->M transsexuals accepted for surgical reassignment usually choose breast removal to achieve a male chest configuration as their first operation. Hormonal treatment has little influence on the size of the breasts. Especially if there are large breasts, the mastectomy will enable the F->M transsexual to live as a man both in public and in private, thus facilitating the adjustment to the male life-style.

The goals of mastectomy for F->M transsexuals include the reduction of glandular and non-glandular breast tissues to obtain an aesthetic male contour of the chest wall with proper positioning of the reduced nipple-areolar complexes and, where possible, the avoidance of chest wall scars. The possible surgical techniques include adaptations from various breast reduction procedures performed in female patients as well as from gynaecomastia surgery in males.⁷’⁸ The preoperative breast size and shape, the general body habitus and the desiderata of the patients should be included in the selection of the surgical technique applied. The larger the breasts are preoperatively, the more obvious the chest wall scarring will become.

Oophoro-hysterectomy:

The resection of uterus and ovaries is not only of importance for the hormonal treatment, but -in The Netherlands- also for the legal sex change. The operation is to be performed by a gynaecologist, and may be combined with the mastectomy, or even with the urethral lengthening. Preferably the oophoro-hysterectomy is done by a vaginal -instead of an abdominal- approach to spare the abdominal flaps that may be used for phalloplasty. We ask the gynaecologist to leave the vagina intact since we use the vaginal mucosa to lengthen the urethra.⁹

-Phalloplasty

For the construction of the phallus in F->M transsexuals a variety of techniques has been suggested or used, as is true for the penile reconstruction in non-transsexual males.⁹ Functionally and cosmetically, the microsurgical free flap phalloplasty techniques lead to the best results. Ideally, phallic (re)construction should aim at (1) a one-stage (microsurgical) procedure that can be predictably reproduced, (2) creation of a competent neo-urethra to allow for voiding while standing, (3) return of both tactile and erogenous sensibility, (4) enough bulk to tolerate the insertion of a prosthetic stiffener and (5) a result that is aesthetically acceptable to the patient. We consider (6) minimal scarring or disfigurement, and (7) no functional loss in the donor area further requirements for any ideal procedure. So far, these ideal requirements have not been met by any phalloplasty technique.

Although many reports on various alleged ‘one-stage’ phalloplasty techniques have been published over the years, the term is deceiving. Genital reassignment surgery in F->M transsexuals meeting even a few of the above mentioned requirements, can seldom be achieved in one stage.

This is mainly due to the wish to create a competent neo-urethra. To construct this neo-urethra in a properly situated phallus, it is not only necessary to fit the phallus with a urinary

conduit, but also to advance the original female urinary orifice to a more anterior position. In our hospital, this advancement is accomplished by construction of a perineal, fixed part of the neo-urethra, resulting in lengthening of the urethra up to the level of the clitoris (Figure 1). Construction of this fixed perineal part is performed in a separate operation prior to the actual phalloplasty.

To provide the phallus with tactile sensibility one of the two dorsal clitoral nerves may be coapted to a cutaneous nerve in the flap used for phalloplasty. It should not be expected that this will result in erogenous phallic sensibility as well. For this reason, the second dorsal clitoral nerve is left untouched in our patients, so as not to further impair the potency for sexual stimulation of the clitoris.

The use of transplants and implants to obtain sufficient rigidity allowing for sexual penetration is difficult and often has resulted in complications and failure. Resorption, curving and fracture of autologous cartilage and bone transplants are reported, and rigid implants have a tendency to erode and extrude. Besides, a constant rigid phallus may serve as a source of embarrassment to the patient. On the other hand, hydraulic prostheses frequently show mechanical failure compared to nonhydraulic implants. For these reasons, some authorities have their patients use external devices for erection. Others fully rely on edema, scar fibrosis or congestion to give sufficient rigidity. Results of the combination in one phallus, of a neo-urethra and a stiffener, whether autologous or prosthetic, have been even more disappointing.

As an alternative for the phalloplasty techniques using pedicled or free flaps, the metaidoioplasty should be mentioned. Metaidoioplasty is defined as the surgical transformation of the clitoris to a penis, the term being derived from the Greek.’⁰ With this technique, also known as the ‘Klitorispenoid’,⁸ the clitoris is partially freed by release and resection of the ventral chordee according to the principles of hypospadias surgery. This will allow for stretching of the clitoris in such a way that its base will be moved approximately 3 cm anteriorly. If provided with a sufficiently lengthened urethra, the Klitorispenoid will act as a normal and complete penis. The clitoris becomes hypertrophic on account of the hormonal treatment. Still, metaidoioplasty, at best, provides a small phallus hardly capable of sexual penetration.

Unlike the metaidoioplasty or the use of external genital prosthesis, the phalloplasty techniques making use of free or pedicled flaps will result in scarring of the donor area. The desiderata of the patients and his body habitus should again be included in the selection of the surgical technique.

The plethora of techniques for penile construction suggests that none is ideal, and phalloplasty remains to be one of the most challenging procedures in (re)constructive surgery. meta-: prefix denoting the concept of after, or subsequent to; corresponds to the Latin ‘post’ aidoja: genitals. aidoio: archaic combining forms relating to the genitals.

plastos: formed, shaped. -plasty: suffix meaning shaping or the result thereof, as of a surgical procedure.

 -Scrotoplasty

One of the goals of genital construction in female-to-male transsexuals should be the creation of an aesthetically acceptable result. Therefore, apart from the construction of a phallus, it is necessary to give the labial region a scrotum-like appearance. The construction of an initially bifid scrotum in which testicular prostheses are implanted may be combined with the construction of the fixed perineal part of the urethra during the first session of the phalloplasty.⁹

Unlike M->F transsexuals, who may often be anxious, restless, demanding, and easily

depressed, the ‘typical’ F->M transsexual is more stable and calmer, and adjusts more easily to his male role. He is fortunate in that he can achieve a masculine appearance: male hormones produce beard growth and lowering of the voice and stimulate the development of muscle bulk, enabling him to pass for a male. Clothing covers in general more of the male body, so leg and hip shape may not attract attention. Still, the F->M transsexual may request liposuction of the hips and abdomen to minimise the female pelvic contour.

Unlike the genital surgical reassignment in F->M transsexuals, the confirmation of genitalia to gender in M->F transsexuals may be achieved in one operation.

-Mamma augmentation

In cases where the hormonal treatment has not resulted in sufficient growth of the breasts, an augmentation mammaplasty may be considered. The implantation of silicone prostheses may be done by one operative team while a second team is performing the vaginoplasty. These patients often request a ‘distinctly’ female figure.

-Orchidectomy

As is true for the uterus and ovaries in F->M transsexuals, the resection of both testes is not only of importance because of the hormonal treatment, but - in The Netherlands - also as a requirement of the legal sex change. The orchiectomy is performed in the same operation as, and immediately preceding, the actual vaginoplasty. The abdominal parts of the funiculus spermaticus and the prostate are not surgically removed.

-Vaginoplasty

The penile skin inversion technique is the method of choice for vaginoplasty. The erectile tissues of the penis are excised and the urethra is shortened to be sutured to its new perineal site." The penile skin tube is turned outside-in and brought into the neovaginal cavity that is dissected between the urethra-prostate complex anteriorly and the rectum posteriorly. This results in a skin lined vaginal cul-de-sac (Figure 2).

In cases where the penile skin is no longer available or in cases where the penile skin inversion has not led to satisfying results, a pedicled recto-sigmoid transplant may be used for vaginoplasty. By combined perineal and abdominal approach, approximately 15 cm of the colon is resected and transplanted to become the neovaginal lining. A stapler device is used to reanastomose the colon, so as to ensure its continuity.

A second alternative technique may be the use of a free split-skin graft to line the neovaginal cavity. As is true for recto-sigmoid transplantation, this method should only be applied if the penile skin will no longer suffice.

-Labia- and clitoroplasty

Part of the scrotal skin and subcutaneous tissues are used for the construction of the minor and major labia. To functionally and aesthetically imitate a clitoris the dorsal nerves of the penis are shortened, positioned at the level of the pubic symphisis, and covered by a free composite graft gathered from the tip of the penis. 8.12

-Facial surgery

Transsexuals seek to adapt their bodies as optimally as possible to their gender. Remaining male features in M->F transsexuals are most conspicious in non-covered areas like the face and neck. Correction of these features may be achieved by (1) surgical or electric depilation of the beard, (2) chemical peeling to smooth the coarse facial skin, (3) softening of sceletal contour by means of nose- jaw- orbita- and chin reduction, and by (4) augmentation of lips and zygomata.³’" These various procedures are not without complications and should not be part of the basic surgical sex reassignment treatment. However, they should be available to particular cases.

-Voice adapting surgery

In cases where logopedic treatment has not resulted in an acceptable pitch of the voice, vocal cord adapting surgery may be considered. By tightening the vocal cords the voice will attain a higher pitch. However, this kind of surgical treatment should always be combined with logopedic therapy because the use of voice, intonation, and choice of words differ according to the sex. Vocal cord surgery is usually combined with a reduction of the thyroid cartilage: the thyroid shave, If the Adam’s apple is very pronounced, thyroid shaving may be performed even in cases where no voice adapting surgery is required.

-Body contouring:

Apart from augmentation mammaplasty, hip augmentations and gluteal contour correction are body contouring procedures which are sought after by some of the M->F transsexuals. Again, we feel these should not be part of the basic surgical treatment but should be available in particular cases.

Both the mamma augmentation in M->F transsexuals and the reduction mammaplasty in F->M transsexuals are of importance to the patients in an early phase of treatment because they result in a marked change of body contour. Once these operations are performed the patients are often relieved from fear of exposure in the locker at work or from loss of identity when in social company or with their partner.

Furthermore, both the augmentation and the reduction mammaplasty are not as irrevocable as other sex changing procedures. For these reasons, mammaplasty will usually be asked for, and offered, as first operation.

Both the orchiectomy and the oophoro-hysterectomy will further prevent the patient from

physically begetting offspring. Both F->M and M->F transsexuals will become irreversibly infertile by the operations. Although the gynaecologist and plastic surgeon perform the oophoro-hysterectomy and the orchiectomy, in The Netherlands only endocrinologists and surgeons are authorised by law to certify that a transsexual has undergone sex reassignment surgery and is no longer able to procreate.

It should be noted that modern reproductive methods such as sperm storage, ovum storage, in vitro fertilisation, and use of surrogate mothers do not preclude that a transsexual procreates as a member of the original sex, even past the date of sex reassignment surgery.

Today, the cosmetic results of vaginal construction are excellent - when the surgery and postoperative treatment are properly performed. The superficial appearance of the pubic and perineal region usually will not deprive the M->F transsexual of the possibility to pass as a woman. Most neovaginas suffice to allow for sexual intercourse provided some sort of lubricant is applied. As stated, since an orchiectomy is performed and no uterus is constructed or

transplanted, the subject will not be able to physically beget offspring. Present generation operative techniques for phalloplasty include the provision of a penis that will permit the F->M transsexual micturation while standing and sometimes even satisfactory sexual intercourse. Although the surgical techniques improve, only few subjects will, in the nude, be able to pass as males on more than very superficial examination. Again, since oophoro-hysterectomy is performed and no testis will be transplanted the patient, once operated, will not be able to procreate.

Although nonsurgical treatment of transsexuality is generally believed to be enormously disappointing, the question remains whether, and how well, surgery does answer to the needs of the transsexual patient. The longterm follow up in our series is encouraging and suggests that surgeons integrated in a gender team should continue to offer sex reassignment surgery.

However, only a diagnostic process that will allow uniform screening of the many patients with gender dysphoria for those who will not be reasonably helped by surgical reassignment, high quality operations leading to uniformly aesthetic and functionally acceptable results, and careful follow-up of unselected groups of patients over a ten- to twenty-year period will eventually reveal how well surgery answers to the needs of the transsexual patient.⁶

It may be gathered from the above that counselling and treatment for gender dysphoria should be restricted to gender teams. Each such programme requires professionally strong and dedicated team members if it is to continue to help patients in a responsible and justifiable way. These teams should meet and exchange ideas and experiences on a regular basis to further move the counselling and treatment of transsexuals to a higher level.

Prior to considering surgical reassignment, the key issue for the surgeon is to establish beyond reasonable doubt that the gender dysphoria or transsexual feeling is genuine and that surgical reassignment will be beneficial. For this he will need the expertise of a reputable behavioural scientist.

To determine whether the patient is physically fit for surgery, the surgeon may lean on the expertise of an endocrinologist with substantial personal experience in the field of hormonal treatment of transsexuals.

Sex reassignment for M->F transsexuals may be completed in one operation, leading to

acceptable cosmetic and functional results provided the surgery and postoperative treatment are performed with a high degree of expertise.

Present generation operative techniques for phalloplasty in F->M transsexuals still do not meet all requirements. The term ‘one-stage phalloplasty’ is deceiving. Genital reassignment surgery in F->M transsexuals can seldom be achieved in one stage. Prior to any form of this kind of surgery, this should be made clear to the patient.

F->M and M->F transsexuals will become irreversibly infertile by the orchiectomy and the oophoro-hysterectomy usually performed on them.

Diagnosis of, and counselling and treatment for gender dysphoria should be restricted to reputable gender teams. These teams should exchange information.

during the preparation of this co-report.

Table I:

mamma augmentation orchiectomy vaginoplasty labia- and clitoroplasty

in F->M transsexuals:

mastectomy oophoro-hysterectomy phalloplasty scrotoplasty

facial surgery:

surgical depilation chemical peeling lip augmentation nose reduction jaw- and chin correction orbital rim reduction zygoma correction

Pars pendulans

C: The penile skin tube is turned outside-in and brought into the neovaginal cavity. Part of the scrotal skin is folded to construct the labia. The clitoris is imitated by a free composite graft of the tip of the penis overlying the penile neural stumps.

Resolution 1117 of the European Parliament, Tuesday 12 September 1989.  

Tuesday, 12 September 1989

I. Calls on the Commission to prepare a draft directive without delay requiring the Member States to harmonise at the highest level the payment of compensation for victims of violent crimes, regardless of the victim’s origin, and to set up offices for the advance payment of immediate aid;

2. Considers that compensation should cover, at least, loss of current and future earnings, legal expenses, medical and hospitalisation expenses and funeral expenses, pain and suffering, and, as regards dependants, loss of maintenance;

3. Calls on the Commission to include in the directive provisions requiring the payment by the Member State in which the crime was committed of expenses to witnesses required to revisit the country in order to give evidence;

4. Calls on the Member States to facilitate the implementation of administrative structures to inform the victims of their rights, especially at policy and court level, and to promote campaigns of action with that purpose;

5. Calls on the Member States to ratify the European Convention of 24 November 1983 on the compensation of victims of violent crimes and the European Convention on Mutual Assistance in Criminal Matters of 20 April 1959 and its Additional Protocol of 17 March 1978;

6. Instructs its President to forward this resolution and the report of its committee to the Commission, the Council. and the governments of the Member States.

 2. Transsexuals

Doc. A 3-16/89

having regard to Petitions Nos 16/84 and 229 87,

— having regard to the joint declaration by the European Parliament, the Council and the Commission on human rights of 27 April 1977 (OJ No C 103, 27. 4. 1977. p. 1),

— having regard to the commitment made in the preamble to the Single European Act (UJ (No L 169, 29. 6. 1987, p. I) to promote the fundamental rights recognised in the European Convention for the Protection of Human Rights and Fundamental Freedoms and the European Social Charter, notably freedom, equality and social justice,

— having regard to the European Parliament’s resolution of 29 October 1982 (OJ No C 304, 22. 11. 1982, p. 253) on legal measures to improve the protection of fundamental rights in the EC,

— having regard to its resolution on sexual discrimination at the workplace (OJ No C 104, 16. 4. 1984, p. 46),

— having regard to its resolution on violence against women (OJ No C 176, 14. 7. 1986, p. 52),

 Tuesday, 12 September 1989

— having regard to the report of the Committee on Petitions (Doc. A 3-16/89),

 A. whereas the procedure for transsexuals to change sex is still not available or regulated in all Member States of the Community, and the costs involved are not reimbursed by the health insurance institutions,

B. regretting that transsexuals everywhere are still discriminated against, marginalised and sometimes even criminalised,

C. aware that the unemployment rate among transsexuals undergoing a change of sex is between 60 and 80%,

D. whereas transsexuality is a psychological and medical problem, but also a problem of a society which is incapable of coming to terms with a change in the roles of the sexes laid down by its culture,

I. Believes that human dignity and personal rights must include the right to live according to one’s sexual identity:

2. Calls on the Member States to enact provisions on transsexuals’ right to change sex by endocrinological, plastic surgery, and cosmetic treatment, on the procedure, and banning discrimination against them:

The procedure should offer the following possibilities as a minimum:

(a) psychiatric psychotherapeutic differential diagnosis of transsexualism, by way of help with self-diagnosis,

(b) a consultation period: psychotherapeutic assistance and support: information on the change of sex: medical examinations,

(c) hormone treatment combined with a trial in every day life, i.e. living the role of the new sex for at least one year,

(d) surgery after approval by a board of experts consisting of a medical specialist, psychotherapist and, possibly, a representative nominated by the person concerned,

(e) legal recognition: change of first name: change of sex on birth certificates and identity documents.

(f) psychotherapeutic and medical aftercare:

3. Calls on the Council of Europe to enact a convention for the protection of transsexuals:

4. Calls on the Member States to ensure that the cost of psychological, endocrinological, plastic, surgical and cosmetic treatment of transsexuals is reimbursed by the health insurance institutions:

5. Calls on the Member States to grant public assistance to transsexuals who have through no fault of their own lost their jobs and/or accommodation because of their sexual adaptation:

6. Calls on the Member States to set up advice centres for transsexuals and to give financial support for self-help organisations:

7. Calls on the Member States to disseminate information on the problems of transsexuals, especially among the staff of their social services, police, frontier authorities, registration offices, military authorities and prison services:

8. Calls on the Commission and the Council to make it clear that Community directives governing the equality of men and women at the workplace also outlaw discrimination against transsexuals:

9. Calls on the Commission, the Council and the Member States to devise identity documents which would be recognised throughout the Community and in which, where applicable, the holder’s transsexuality could be indicated during the period of sexual adaptation if so requested;

10. Calls on the Council and the Member States, when harmonising the right of asylum, to recognise persecution on the grounds of transsexuality as grounds for asylum;

11. Calls on the Commission to make funds available under its aid programmes for further study of transsexuality in the medical field;

12. Calls on the Commission to urge the Member States to adopt special measures to find employment for transsexuals;

l3. Calls for the setting-up an office at the Commission to which cases of discrimination may be reported;

14. Instructs its President to forward this resolution to the Commission, the Council, the governments and parliaments of the Member States and the Council of Europe.

The Assembly,
1 Considering that transsexualism is a syndrome characterised by a dual personality, one physical, the other psychological, together with such a profound conviction of belonging to the other sex that the transsexual person is prompted to ask for the corresponding bodily "correction" to be made;

2. Considering that modern medical progress, and in particular recourse to sexual conversion surgery, enable transsexuals to be given the appearance and, to a great extent, the characteristics of the sex opposite to that which appears on their birth certificate;

3. Observing that this treatment is of a nature to bring the physical sex and the psychological sex into harmony with one another, and so give such persons a sexual identity which, moreover, constitutes a decisive feature of their personality;

4. Believing that account of the changes brought about should be taken in the transsexual’s civil status records by adding such details to the original record so as to update the data concerning sex in the birth certificate and identity papers, and by authorising a subsequent change of forename

5. Considering that a refusal of such amendment of the civil status papers exposes persons in this situation to the risk of being obliged to reveal to numerous people the reasons for the discrepancy between their physical appearance and legal status;

1. Assembly debate on 29 September 1989 (21st Sitting) (see Doc. 6100. report of the Legal Affairs Committee, Rapporteur: Mr Rodot).

Text adopted by the Assembly on 29 September 1989 (21st Sitting).

6. Noting that transsexualism raises relatively new and complex questions to which states are called upon to find answers compatible with respect for human rights;

7. Observing that, in the absence of specific rules, transsexuals are often the victims of discrimination and violation of their private life;

8. Considering, furthermore, that the legislation of many member states is seriously deficient in this area

and does not permit transsexuals, particularly those who have undergone an operation, to have civil status ~ made to take account of their appearance, external morphology, psychology and social behaviour;

9. Considering the case-law of the European Commission and Court of Human Rights;

10. Referring to the resolution which the European Parliament adopted on 12 September 1989, in which, among other things, it called on the Council of Europe to enact a convention for the protection of

transsexuals,

11. Recommends that the Committee of Ministers draw up a recommendation inviting member states to introduce legislation whereby, in the case of irreversible transsexualism:

a. the reference to the sex of the person concerned is to be rectified in the register of births and in the identity papers;

b. a change of forename is to be authorised;

c. the person’s private life is to be protected;

d. all discrimination in the enjoyment of fundamental rights and freedoms is prohibited in accordance with Article 14 of the European Convention on Human Rights.