Endocrine intervention for transsexuals

Abstract

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 necessary. In some centres, spironolactone 100–300 mg daily (Prior et al., 1989) or cyproterone acetate 50–100 mg daily (van Kesteren et al., 1997) is routinely added to transdermal or oral oestrogen treatment, whilst in others, the addition of cyproterone is thought to confer a risk of idiosyncratic severe hepatotoxicity while adding relatively little to the antiandrogenic effects of oestrogens alone. Many patients, however, seem to appreciate the further feminizing effects of the combination of oestrogen and cyproterone acetate and will, even if this is not observed objectively, surrender to the psychological compulsion to do everything in their power to feminize. Although there is no absolute requirement for cyproterone or any other progestogenic drug, some male-to-female transsexuals find that their libido is maintained and breast growth augmented by the addition of dydrogesterone (such as Duphaston 10 mg twice a day) or the slightly more virilizing medroxyprogesterone acetate (Provera 5–10 mg daily). Continuation of cyproterone treatment after gender reassignment surgery may continue to discourage further body hair growth. The 5-α reductase inhibitor finasteride 2·5–5 mg orally daily and local minoxidil solution 2–5% (Regaine) are occasionally used if the person is distressed by scalp hair loss and finds hair pieces difficult to tolerate. The low intrinsic morbidity and mortality of the relatively young population that tend to be treated for gender dysphoria, the comparatively small numbers studied and the inevitable lack of placebo controlled, prospective trials, complicates the distinction between the risks of gender dysphoria itself (van Kesteren et al., 1997; Kenagy, 2002) and the risks attributable to cross-sex hormone treatment. In a retrospective study of 303 male-to-female transsexuals treated with cross-sex hormones, the death rate due to increased numbers of suicide and death of unknown cause was five times that of a reference population (Asscheman et al., 1989). Depressive mood changes were 15 times more common and thromboembolic events were increased 45-fold compared to the general population (Asscheman et al., 1989). In the same study, androgen treatment in 122 female-to-male transsexuals was associated with weight increase and acne. In both groups it was not clear whether persistent liver enzyme abnormalities should be attributed to hepatitis B and alcohol abuse rather than the effects of cross-sex steroids. However, much of the morbidity was minor and reversible with appropriate therapy or temporary discontinuation of hormone treatment. In a retrospective, descriptive study of 816 male-to-female and 293 female-to-male transsexuals treated with cross-sex hormones, there was no increase in mortality overall or mortality that could be attributed to cross-sex hormone treatment compared to an age and gender adjusted general Dutch population (van Kesteren et al., 1997). In male-to-female transsexuals there was an increased risk of suicide and HIV infection (a ninefold and sixfold increase in risk, respectively: n= 13) but no change or a slight reduction in risks from malignancies (risk halved: n= 7), myocardial infarction [standardized mortality ratio (SMR) 0·7: n= 6], chronic obstructive pulmonary disease and pancreatitis (SMR 0·8: n= 2 and 1, respectively). Morbidity risks in this group relate to hepatitis B (44-fold increased risk: n= 12) and cholelithiasis (14-fold increased risk: n= 8), with a possible increase in risk of stroke (1·7-fold increase: n= 6) and no detected change in risk of prostatic carcinoma, hypertension or myocardial infarction (van Kesteren et al., 1997). As only two deaths were observed in the female-to-male transsexual group (n = 293), relative mortality from male hormone treatment in genetic females (van Kesteren et al., 1997). 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 (Asscheman et al., Kesteren et al., 1997) to a incidence in the general population, associated with a case rate from pulmonary et al., 1997; & 2001). to who experience a to increase in risk of during current sex hormone therapy risk over the age of years this a significant in absolute risk in a much population who may in addition be to the risk of surgical et al., 1996; et al., 1996; et al., 1996; et al., 1997). the cases of by Kesteren et only of the cases during transdermal rather than oral oestrogen and in this case the patient a while oestrogens orally (van Kesteren et al., 1997). treatment in risk not by other et al., 1997). particularly and increase the risk of by oestrogen treatment et al., The absolute risk, however, relatively low and may with of use et al., 1998). The risk should also be the of treated gender dysphoria, and morbidity associated with sex hormone such as and the risk of treatment in a population with low 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 groups 1997) and as be there are no data available for thromboembolic risks of surgery in male-to-female transsexuals oestrogen at Male-to-female. of from male-to-female transsexuals age treatment with ethinylestradiol 100 and cyproterone acetate 100 not any in or number or between transsexuals and et al., 1989). and in these suggests that oestrogen and treatment in male-to-female transsexuals may but is not associated with loss et al., 1989). In a study of 20 male-to-female transsexuals exposed to cross-sex hormones for oestrogen treatment 100 µg daily with cyproterone acetate 100 µg oestradiol cyproterone after loss by testosterone (van Kesteren et al., 1998). small of male-to-female transsexuals et al., and 10 male-to-female transsexuals et al., similar that oestrogen treatment for 2 years or more or compared to adult male Female-to-male. A study of 15 female-to-male transsexuals age who and after an of months treatment with 250 mg testosterone every 2 weeks, structure and increased with low compared to and et al., A further small study of 10 female-to-male transsexuals also to any effects of cross-sex hormone treatment after sex hormone reduction et al., 1998). The of oestrogen reduction and testosterone on is not a and a study of female-to-male transsexuals after 1 treatment (van Kesteren et al., of were for months (van Kesteren et al., suggests that testosterone 250 mg every 2 to testosterone – – in of people is to loss associated with a in oestrogen lack of efficacy at the is at with the effects of more male hormone in genetic males et al., 1997). As individual changes in are variable and the numbers studied 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 after 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 B and with not beyond an A at least breast to the they desire or at least find acceptable. development to be more in with body and it may be to male-to-female transsexuals that they do not make too to the in weight that is often (van Kesteren, 2002). to to the preferred gender have & 2000), the most common being of of hormones than of oestrogen treatment can be associated with (van Kesteren, 2002). There are case reports of breast in treated male-to-female transsexuals & but in the Kesteren et of 816 and treated male-to-female In a study of male-to-female transsexuals treated with oestrogen and cyproterone for from months to variable in but no risk of was et al., The same group a more of and male-to-female transsexuals in which in were thought to be In this population increased to over in (Asscheman et al., in the Kesteren et al., and in 15 five were to on but development was not (Asscheman 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 10 months of treatment et al., and a in a male-to-female transsexual who oestrogen for the previous years et al., the of 1997) and the of in genetic males during cross-sex hormone a between oestrogens and in be to early (Asscheman et al., & data effects of oestrogens in genetic males are sex hormones in most XY individual

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