Endocrine intervention for transsexuals

Gender identity disorder, gender dysphoria, transgenderism and transsexualism are terms used to describe an individual's wish to live and be accepted as a member of the opposite sex. The condition manifests as discomfort with one's phenotypic sex and a wish to have treatment to make one's body correspond to that of the preferred sex. In transsexualism, genotype and somatic differentiation do not conform to brain programming as male or female. The persistent cross-gender identification that results transcends a desire for any cultural advantages of being the other sex. Transsexualism is distinct from sexual orientation, and transsexuals, like nontranssexuals, may be heterosexual, homosexual, bisexual or asexual (Schilder et al., 2001). All strata of society are affected by gender dysphoria (Hoenig & Kenna, 1974) and the similar prevalence of 1 in 13–15 000 males and 1 in 30–35 000 females across Western (van Kesteren et al., 1996a) and Eastern Europe, Singapore and the Indian subcontinent suggests that the influence of culture on the underlying condition is relatively small (van Kesteren, 2002). In Southeast Asia amongst the Hindu and Buddhist population, transsexual individuals often evoke relatively little concern on the part of those affected and their families as the condition is attributed to residues of a previous life as a member of the opposite sex (Stevenson, 1977). In other societies, the challenges that people with gender dysphoria face may transcend those faced by lesbian, gay and bisexual individuals, and they may be at greater risk of harassment and violence which in turn leads to an increased incidence of depression, substance abuse (Seal et al., 2001) and suicide (Lee, 2000; Lombardi et al., 2001; Schilder et al., 2001; Cochran et al., 2002). These risks are further compounded by marginalization from society (Landen & Innala, 2000) and inconsistent legislation with, variously, lack of precedents for changing the sex of birth certification, confused marital rights, criminalization of genital contact between people of the same sex and exclusion of sex reassignment surgery from health service funding and health insurance (Gordon, 1991). In this review, we discuss predisposing factors to transsexualism, and the diagnosis, assessment and hormone treatment of transsexual patients. We also discuss the risks and organ-specific effects of cross-sex hormone treatment. We will briefly summarize the current legal position of transsexuals in the UK and recommendations for the culturally competent delivery of transgender health care. Stable transsexualism in adulthood is a rare co-morbidity of a physical intersex state or genetic abnormality (Meyer et al., 1986) and its ICD10 classification specifically excludes intersex and sex chromosome conditions and serious mental disorders from the diagnosis. A proportion of XY patients who present with genital ambiguity in infancy or early childhood may subsequently become dissatisfied with their sex of rearing (Migeon et al., 2002; Wisneiwski & Migeon, 2002), but interest in intersex states within the transsexual community probably relates more to funding streams than biology and the conceptual need to have a physical condition rather than a more nebulous ‘psychological’ one. In support of the place of early biological programming (Davenport, 1986; Landen et al., 1998b; Wisniewski et al., 2000), inconsistent reports suggest that increased androgen exposure in utero and early postnatal life experienced, for example, by females with congenital adrenal hyperplasia may result not only in increased male-type posturing, interests and behaviour (Dittmann et al., 1990; Hines & Kaufman, 1994; Berenbaum, 1999) but in an increased prevalence of gender dysphoria in adulthood (Meyer-Bahlburg et al., 1996; Zucker et al., 1996; Hines, 1998). There is also some evidence that antenatal exposure to anticonvulsants, which in animal models alter steroid hormone levels, may enhance the risk of subsequent gender dysphoria in man (Dessens et al., 1999) and the suggestion, confounded to some extent by small numbers available for study and various other forms of bias, that male-to-female transsexuals have female sexually dimorphic brain characteristics (Kruijver et al., 2000). Gender dysphoria is a self-diagnosis, often supported by friends and family, with no supporting tests other than persistence of dysphoria for at least 2 years alleviated by cross-gender identification. It is amenable to hormonal and surgical palliation but is essentially an incurable condition associated in a significant proportion of cases with social isolation and a degree of mental anguish to which even the most judicious medical and surgical management may add physical discomfort and infertility. As the effects of treatment are often irreversible, the process of psychological evaluation to determine whether treatment will facilitate the patients’ comfort and integration into society or leave them still incapacitated by social phobias is far-reaching, and involves input from diverse sources such as ethicists, psychologists, speech and beauty therapists, social workers and personal shopping assistants as well as psychiatrists, nurses and various medical and surgical specialities (Monstrey et al., 2001). Ideally a clinic structure that encompasses the gamut of clinical governance mechanisms such as supervision, audit and continual professional development for staff should be available to optimize integration of these specialist areas. The objective of treatment is to rehabilitate the individual as a full member of society in their preferred gender role – the most perfect medical and surgical palliation being of no use ‘als ze achter de geraniums blijven zitten’ (if they feel compelled to stay behind the geraniums). Widely used (but not necessarily evidence-based) standards of care for patients with gender dysphoria are promulgated by ‘The Harry Benjamin International Gender Dysphoria Association’ (Benjamin, 1967; Meyer et al., 2001; internet search terms: ‘harry benjamin’). These standards of care, regarded as authoritative by providers but as restrictive by many transsexuals, involve a ‘real life’ trial lasting months or years in which the preferred gender roll is adopted in every aspect of life. If the process is perceived as excessively lengthy (i.e. beyond 1 year) there is a significant risk that unsafe practices, such as buying hormones on the street or internet, or seeking treatment from unscrupulous physicians or unskilled surgeons may be pursued (Lombardi, 2001). For many transsexuals, demonstrating that their preferred gender role improves their social and psychological function in society is the hardest part of the process, as they are particularly exposed to ridicule and discrimination before treatment produces noticeable changes. Assessment by at least two senior specialists is recommended, often involving a number of in-depth interviews over several months during which psychiatric (Levine, 1980) and psychological state, personality profile, physical and emotional development, school and employment background, adult relationships, physical health and current level of social functioning are addressed. The process is not an inevitable escalator of intervention (Levine & Lothstein, 1981) and many who enter the process do not proceed to full gender-reassignment surgery (Landen et al., 2001). Others are content to step in and out of medical management to suit their needs, and protocols to optimize care should be sufficiently flexible to incorporate this tendency in a nonpunitive manner. It is particularly important to allow young people flexibility to question their gender identity (Lombardi, 2001). Within the bounds of confidentiality, an objective view from the biological spouse, close friend or others within an intimate relationship may be sought to help disclose issues contributing to confusion or distress within the person's mind. Families of transsexual patients may also benefit from receiving counselling in their own right, as they too face difficult changes. The positive support of a partner or of older children can be invaluable, but for transsexuals who become alienated from their family in the process of revealing their sexual identity, unofficial ‘families of attachment’ that replace families of origin, should not be overlooked or ignored (Schilder et al., 2001). The recommendation that in addition to baseline cholesterol, urea and electrolytes, glucose and liver function tests, physical assessment should include a full examination of secondary sexual characteristics needs to be approached with care, as such scrutiny may be particularly traumatic for this group of patients. Aside from potentially disclosing evidence of self-treatment, which may be as much to do with delay, desperation and lack of information as a genuine desire to take matters into their own hands, clinical examination, like measurement of sex hormone levels, is unlikely to yield anything more than confirmation of biological sex. A clear explanation of the irreversible effects of hormone therapy on body habitus and formal consent is a necessary precaution. There are very few well validated efficacy data for different treatment regimens, a void that is filled, perhaps understandably, by case reports and internet autobiography which should be recognized as such and appraised with appropriate care. Recommendations in this review are derived from published sources and personal experience (RR) of managing over 3000 transsexual patients over the last 20 years. Female-to-male. For female-to-male transsexuals, the usual hormone treatment is Sustanon 250 mg intramuscularly (i.m.) every 2 weeks, or testosterone enanthate (Primoteston Depot) if the patient is sensitive to peanut (arachis) oil. Male-to-female. Optimal hormone treatment for male-to-female transsexuals is guided by the development of the desired mental changes and by the onset and maintenance of a feminized physical state that the male-to-female transsexual finds acceptable. The effects of different hormone preparations are as variable in XY females as in XX females in terms of breast development, mood changes and vasomotor stability. Treatment often requires modification depending on perceived efficacy and the patient's beliefs, which are almost invariably informed by the many excellent trans gender internet sites and local support networks (internet search terms: ‘gender trust’, ‘press for change’, ‘gires’, ‘looking glass society’, ‘renaissance transgender’, ‘mermaids’, ‘ftm’). A typical regimen is Estraderm TTS 50 or 100 (delivering 50 or 100 µg oestradiol/24 h transdermally when applied twice weekly, reduced to 50 µg/24 h postgender-reassignment surgery), oral ethinylestradiol 100–150 µg daily in divided doses (50 µg twice a day or three times a day, reducing to 50 µg daily postsurgery) or oral oestradiol valerate (Progynova) 4–6 mg daily (2 mg twice a day or three times a day, reducing to 1–2 mg postgender-reassignment surgery). Whilst well tolerated, the relatively short action of oestradiol valerate (the pharmacological equivalent of natural 17-β-oestradiol) is sometimes less effective in producing adequate feminization. As insufficient oestrogen and possibly also excessive oestrogen may be associated with vasomotor symptoms, adjustment of the dose in both directions may be In some mg daily et al., or mg daily (van Kesteren et al., is to or oral oestrogen in the addition of is to a risk of relatively little to the effects of to the further effects of the of oestrogen and and even if this is not to the psychological to do in their to there is no for or any other some male-to-female transsexuals that their is and breast by the addition of as mg twice a or the more mg of treatment gender reassignment surgery may to further body The mg daily and local are used if the is by and finds difficult to The and of the relatively young that to be for gender dysphoria, the small numbers and the inevitable lack of the between the risks of gender dysphoria (van Kesteren et al., and the risks to cross-sex hormone treatment. In a study of male-to-female transsexuals with cross-sex the to increased numbers of suicide and of times that of a et al., mood changes times more and increased to the et al., In the same androgen treatment in female-to-male transsexuals associated with and In both not clear whether persistent liver should be attributed to and abuse rather than the effects of cross-sex much of the and with appropriate therapy or of hormone treatment. In a study of male-to-female and female-to-male transsexuals with cross-sex there no in or that be attributed to cross-sex hormone treatment to an and gender (van Kesteren et al., In male-to-female transsexuals there an increased risk of suicide and and in but no or a in risks from and 2 and risks in this group to increased and increased with a in risk of and no in risk of or (van Kesteren et al., As only two in the female-to-male transsexual group from male hormone treatment in genetic females (van Kesteren et al., The most significant cross-sex hormone treatment risk relates to particularly during the of oral oestrogen treatment in male-to-female The incidence of to et al., Kesteren et al., to a incidence in the population, associated with a case from et al., & 2001). to who experience a to in risk of during current sex hormone therapy risk over the of years this a significant in risk in a much who may in addition be to the risk of surgical et al., 1996; et al., 1996; et al., 1996; et al., the cases of by Kesteren et only of the cases during rather than oral oestrogen and in this case the patient a (van Kesteren et al., treatment in risk not by other et al., particularly and the risk of by oestrogen treatment et al., The relatively and may with of use et al., 1998). The risk should also be the of gender dysphoria, and associated with sex hormone such as and the risk of treatment in a with co-morbidity is relatively for of and may be to the risk but is more to result in transsexuals being of the treatment that they and is not (van Kesteren, 2002). The recommendation that oestrogen least in oral for XX should be before surgery are at with from several specialist and as be there are no data available for risks of surgery in male-to-female transsexuals oestrogen at Male-to-female. of from male-to-female transsexuals treatment with ethinylestradiol 100 and 100 not any in or number or between transsexuals and et al., and in these suggests that oestrogen and treatment in male-to-female transsexuals may but is not associated with et al., In a study of 20 male-to-female transsexuals exposed to cross-sex hormones for oestrogen treatment 100 µg daily with 100 µg oestradiol by testosterone (van Kesteren et al., 1998). small of male-to-female transsexuals et al., and male-to-female transsexuals et al., similar that oestrogen treatment for 2 years or more or to adult male Female-to-male. A study of female-to-male transsexuals who and an of months treatment with 250 mg testosterone every 2 weeks, structure and increased with to and et al., A further small study of female-to-male transsexuals also to any effects of cross-sex hormone treatment sex hormone et al., 1998). The of oestrogen and testosterone on is not a and a study of female-to-male transsexuals 1 treatment (van Kesteren et al., of for months (van Kesteren et al., suggests that testosterone 250 mg every 2 to testosterone – – in of people is to associated with a in oestrogen lack of efficacy at the is at with the effects of more male hormone in genetic males et al., As individual changes in are variable and the numbers data on risk in the female-to-male transsexual group and further evidence to the place of measurement as a of adequate hormone (van Kesteren et al., are very much in breast months the of female sex hormone treatment in male-to-female transsexuals and for 2 years (Meyer et al., 1986; Kesteren, 2002). only of transsexuals more than a and with not beyond an A at least breast to the they desire or at least acceptable. development to be more in with body and may be to male-to-female transsexuals that they do not make too to the in that is often (van Kesteren, 2002). to to the preferred gender have & 2000), the most being of of hormones than of oestrogen treatment can be associated with (van Kesteren, 2002). There are case reports of breast in male-to-female transsexuals & but in the Kesteren et of and male-to-female In a study of male-to-female transsexuals with oestrogen and for from months to variable in but no risk of et al., The same group a more of and male-to-female transsexuals in which in to be In this increased to over in et al., in the Kesteren et al., and in to on but development not et al., in a male-to-female transsexual who in addition to the 100 µg oral ethinylestradiol daily with 100 mg intramuscularly for at least of the months of treatment et al., and a in a male-to-female transsexual who oestrogen for the previous years et al., the of and the of in genetic males during cross-sex hormone a between and in be to early et al., & data effects of in genetic males are sex hormones in most XY individuals et al., & et al., et al., 2000). for male-to-female transsexuals who may be sexually there is an that the same any other patient who risks their should be available to this group & 2000; 2001). As as in female-to-male transsexuals before the of a from the use of such is to be very The of development, extent and of in female-to-male transsexuals receiving testosterone is also at the present androgen in female-to-male transsexuals may changes to of et al., It is not whether these and associated changes are to those in in body glucose and degree of androgen or whether the risks associated with are to the other et al., 1996; As the between and the risks of and are not clear et al., recommendation for and out months the of testosterone treatment in female-to-male transsexuals (van Kesteren et al., to be at least on the of risk of cases of in male-to-female transsexuals have 1994; Kesteren et al., et al., 1998). The extent of in risk associated with female hormone treatment and androgen is of liver that be attributed to any other is in of male-to-female transsexuals with and for more than months in of these (van Kesteren et al., reports of et al., and of a liver et al., have in female-to-male transsexuals with a of male hormone no of to be a or perhaps more significant et al., and risk et al., are reduced in male-to-female transsexuals and increased in androgen female-to-male transsexuals et al., 1998). In the risk of in people with cross-sex hormones is not but available data suggest that there is not a (van Kesteren et al., treatment in female-to-male transsexuals results in the of and increased that is in many cases within months and to beyond & 2000). In male-to-female transsexuals, in and a months treatment with cross-sex hormones but not to almost but in or only very et al., 2000). male-to-female is almost invariably with hormonal treatment and on physical is effective but potentially if the and often too to be as a treatment. is more is is and more as the of and the of For and the of such as or h before treatment may be of can be with and body with or treatment of genital is also to but for this local or even a with may be A of some applied in two can excellent such as the of their (internet search terms: or of in 20 male-to-female transsexuals before and 1 cross-sex hormone treatment a significant in and and a in et al., In female-to-male transsexuals a et al., in and in with increased is et al., changes in male-to-female transsexuals, particularly increased the is often insufficient to female habitus and if the surgical intervention may be The sex in levels, with than males of body are by cross-sex hormone treatment et al., treatment produces an in in female-to-male transsexuals that during treatment and for several treatment et al., In a study of female-to-male transsexuals, and sexual increased by testosterone treatment (van et al., In male-to-female transsexuals in the same oestrogen treatment reduced and the of to and (van et al., In young oral in testosterone over affected et al., 2002). male-to-female transsexuals that oestrogen treatment is associated with a almost and there is some support for the use of as mood in and and to the action of & 2001; & 2002). hormone in may also be associated with mood & 1999) but the role of testosterone as an is less well and the less In a group of female-to-male transsexuals, of 1 the of treatment with testosterone mg every 2 weeks, Meyer et al., in androgen dose no (Meyer et al., transsexuals have full from discrimination in the In the of that transsexuals be to the gender on their birth and to The the of still to with the In the there is a legal for that the the of the of and transsexual people as being of their sex in personal of health care, from and to discrimination and of from to and (Lombardi, 2001; Schilder et al., 2001). Recommendations of to transgender health care on the transgender individual's than on and medical of their care, the of isolation and by many individuals and the daily of in a and community should be in people who have treatment for transsexualism is rare rather than relates to life such as early social and lack of support (Landen et al., of treatment and (van Kesteren et al., et al., 2001). A of a relationship or sexual abuse in childhood also to the risk that treatment will be 2002). within the transsexual community may also male-to-female transsexuals surgery to from – males for sexual et al., to the of surgical in an of male-to-female transsexuals out by for even those who of gender reassignment surgery not their to the as the rather than the of is of the desired perhaps by and of for personal 2002). with sexual in both male-to-female and female-to-male transsexuals to with cross-sex hormone treatment and gender-reassignment surgery even if sexual functioning may be & In transsexuals have persistent cross-gender any predisposing is by psychological which a trial in the gender before of hormonal treatment and The of cross-sex hormone treatment is and in male-to-female and potentially in are amenable to treatment. more evidence be gender dysphoria is to be than the which is associated with an risk of and few transsexuals treatment. the of transgender individuals and the of gender dysphoria as a diagnosis, lack of from and perhaps personal phobias may some of the medical to treatment or doses of cross-sex hormones on perceived individuals to optimize cross-sex hormone treatment and should not be to discrimination when they health care. The within some of the transgender community that the medical are not in their should be to We like to and and for