Table of contents

1. Introduction
2. Definitions
3. Etiology
4. Historical notes
5. Epidemiology
6. Follow-up studies
7. Procedure
8. Hormone treatment
9. Effects of hormone treatment
10. Scope and aims of the studies
11. References

Introduction

Hormonal treatment of transsexual subjects constitutes an important part of their gender reassignment. This thesis describes our observations over 13 years of the side effects and metabolic changes occurring during cross-gender hormonal treatment. The study was done at the outpatient clinic for Andrology at the Free University Hospital, Amsterdam.

The first part of the chapter provides a general introduction to the field of gender dysphoria: definition of gender dysphoria, transsexualism, clinical criteria, etiological concepts, historical notes, and epidemiology.

The second part analyzes results of gender reassignment treatment reported in the literature. The management adopted in our clinic is described and an overview of the different hormone schedules and their effects is presented. Finally the scope and the aims of the studies reported in this thesis are presented.

Definitions

Transsexualism is the condition in which a person with an apparently normal somatic sexual differentiation has the conviction that he or she is actually a member of the opposite sex. This conviction which is accompanied by a profound sense of loathing for individuals's own primary and secondary sexual characteristics, is absolute, overwhelming and unalterable (1). The sense of belonging to a particular sex, not only biologically but also psychologically and socially, is called gender identity.

Money et al. (1955) coined the term gender identity and defined it as:

the sameness, unity and persistence of one's individuality as male, female, or ambivalent, in greater or lesser degree, especially as it is experienced in self-awareness and behavior; gender identity is the private experience of gender role, and gender role is the public expression of gender identity,

while gender role is defined as:

everything that a person says and does, to indicate to others or to the self the degree that one is either male, or female, or ambivalent; it includes but is not restricted to sexual arousal and response (2).

Gender identity and gender role should not be separated for they are actually two sides of the same coin (3). Consequently, transsexualism can be defined as an incongruence between the biological sexual differentiation and the gender identity. For clinical and diagnostic purposes the criteria of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (3rd edition) are often used (DSM III, 1980 (4)).

• A. Sense of discomfort and inappropriateness about one's anatomic sex.
• B. Wish to be rid of one's own genitals and to live as a member of the other sex.
• C. The disturbance has been continuous (not limited to periods of stress) for at least two years.
• D. Absence of physical intersex or genetic abnormality.
• E. Not due to a coexistent mental disorder, such as schizophrenia.

The above criteria give rise to some comments. First, somatic intersex and all problems associated with (pseudo)hermaphroditism exclude transsexualism as a primary diagnosis. They should first be treated by procedures accepted as medically appropriate for such conditions (congenital adrenal hyperplasia or testicular feminization are such conditions).

Second, sexual orientation is not mentioned in the above criteria. Transsexualism is a gender identity problem and a person's sexual orientation is not relevant to this issue.

Third, in case of coexisting mental disorders appropriate psychiatric treatment is mandatory, but adequately treated psychiatric disorders in themselves are no contraindication for future gender reassignment. If a gender identity problem is not secondary to a mental disorder (e.g. chronic schizophrenics occasionally experience gender dysphoria), gender reassignment may even alleviate other psychiatric symptoms. From the above definition it might appear that transsexualism is a discrete entity, which can be easily diagnosed and that gender dysphoric subjects constitute a homogeneous group. Gender identity disorders encompass, however, a whole spectrum of feelings of inappropriateness of the assigned sex and therefore a more global term as gender dysphoria is appropriate. The gender identity problem may be mild; the person is aware that he is a male or that she is a female, but discomfort and a sense of inappropriateness about the assigned sex are experienced. Transsexualism can be classified as the extreme degree of gender dysphoria. Transsexuals are not only uncomfortable with their assigned sex but have the sense of belonging to the opposite sex and wish to get rid of their own genitals. Disorders of gender identity are rare (see Epidemiology); they should not be confused with the far more common phenomena of feelings of inadequacy in fulfilling the expectations associated with one's gender role. An example of the latter would be a person who perceives himself or herself as being sexually unattractive or unsuccessful by societal standards yet experiences himself or herself unambiguously as a man or a woman in accordance with his or her assigned sex.

The classification of gender dysphoria syndromes is rather unsatisfactory. DSM III-R (1987 (5)) has classified gender identity disorders as those occurring in childhood (302-60), transsexualism (302.50) and gender identity disorder of adolescence or adulthood nontranssexual type (GIDAANT 302-85). John Money proposes classification of gender crosscoding, a broader term which encompasses gender identity, gender role, and object choice or sexual orientation, according to a multi-dimensional model on the basis of the number of components involved, and of the persistence of their behavior (see table, (3)).

Table. Classification of gender crosscoding by total (all components), partial unlimited (most components, but no surgery) and partial limited (only sexual orientation), and the continuous or episodic character of the phenomena (according to Money (3)).

Continuous Episodic or
or constant alternating

Total Transsexualism Transvestophilia
(cross dressing for
erotic arousal)

Partial Gynemimesis and Transvestism
unlimited Andromimesis (cross dressing not
(desire to live as for erotic arousal)
a member of the
opposite sex but no
wish for genital
surgery)

Partial Male hemophilia/ Bisexualism
limited Female hemophilia

Both DSM III-R and Money reintroduce sexual orientation in the classification of gender dysphoria. In our view gender identity and sexual orientation are two distinct phenomena in one person. It is not the sexual orientation that troubles transsexuals, but the identity problem. All human variants of sexual orientation are observed in transsexual subjects and in our opinion sexual orientation is not one of the criteria for diagnosis and/or treatment of transsexualism. Neither the DSM III-R classification nor Money's classification is based on underlying causes since they are as yet unknown (see Etiology).

Money acknowledges the necessity of revising his classification as soon as more data have been accumulated. It is evident from the aforementioned definitions and classifications that transsexualism and transvestism/transvestophilia are different phenomena. Cross dressing is a component of both, but it is only a sign or symptom and therefore, does not constitute a diagnosis.

Etiology

The etiology of gender dysphoria is still mute. It is extremely difficult to conceptualize gender dysphoria in terms of science. Gender identity is so intimately interwoven with the self, in transsexuals and nontranssexuals alike, that it is almost impossible to figure intellectually, and even more emotionally, what genderdysphoria means.

As usual in medicine, two opposed theories have been proposed: one somatic and the other psychopathological. In view of the potent effects that sex steroids have on the somatic development and possibly also on the brain as the substrate of gender identity, it has been thought that in transsexuals, levels of sex steroids and gonadotropins are different from those in non-transsexuals. In a balanced review, Meyer-Bahlburg (1979, (6)) could refute all endocrine differences reported in the literature between heterosexuals, homosexuals and transsexuals. In an attempt to cure transsexualism, administration of sex steroids (in particular, testosterone in male-to-female transsexuals) has unfortunately been practised by some physicians. This is apparently done, on the basis of a wrong understanding of the biology of gender dysphoria, and the effects of hormones on manhood and womanhood.

Impressed with the effects that sex steroids have on adult sexual behavior in experimental animals when they are administered during the perinatal period, it has been hypothesized that parts of the brain are organized in a sex dimorphic pattern. Concepts as "defeminization" and "androgenization" of the brain have been put forward (1).

Little is known about this in humans. In humans, scientific study depends on the fortuitous occurrence of "experiments of nature", that is, human subjects with an abnormal, atypical prenatal or perinatal endocrine history. For instance, girls with congenital adrenal hyperplasia have been exposed in utero to higher than normal levels of androgens. If these subjects are identified at birth as girls with a certain degree of virilization and are provided with an adequate corticosteroid treatment, they do not develop gender dysphoria, although their gender behavior may sometimes be more boyish than that of their peers (Ehrhardt, AA (1979), cited in (6)). In lower mammals the sexual differentiation of the brain is associated with the capacity to respond with a positive feedback effect of Luteinizing Hormone (LH) tu an estrogen stimulus. This can be evoked in normal females and is absent in normal males in the eugonadal state. Dörner (7) has proposed that this estrogen feedback effect indicates the degree of differentiation into male and female of human subjects, and he claims that he has been able to confirm his theory in human homosexuals and transsexuals. Gooren (8) and also others concluded in methodologically better designed experiments that the estrogen feedback in the human is not sex dimorphic, but depends on the circulating testicular hormones. In one and the same subject both the "male" and "female" response can be evoked depending on the endocrine milieu (9).

In summary, there is as yet no scientific proof that neuroendocrine differences, which play an important role in the sexual behavior of lower mammals, can be extrapolated to human sexual behavior. The opposite theory, claiming a purely psychopathological cause of transsexualism has been assumed by others. Some psychiatrists view transsexualism as a delusional psychosis. Consequently, some transsexuals were "treated" with multiple electroshocks and antipsychotic medications (personal observations). Fortunately, this approach is rare but the belief in a purely psychic cause of transsexualism is still quite prevalent.

Regarding the origin of gender dysphoria, three different schools of thought can be distinguished. First, the psychoanalytic approach based on innate bisexuality in humans. According to Green (10), male-to-female transsexualism might result from a failure to separate the self from the mother in early boyhood. Instead of identifying with the father, the boy identifies with the mother. Lothstein (11), who, at the Case Western Reserve University (Cleveland, USA) has seen and supervised therapy of many female-to-male transsexuals, suggests that the mothers of female-to-male transsexuals lack a cohesive self, have a defective object relationship, and an opposite-gender envy and jealousy, which may all be communicated to her child. The final decisive influence is the father's role of encouraging his daughter to masculinize herself. These two psychoanalytic theories, with many variants, present a hypothesis for the phenomenon of transsexualism, but neither one has been investigated prospectively. Studies of intrafamilial relations, divorce rates, dominance of one of the parents, marital relations and many other factors have not revealed a common pattern that could account for transsexualism. Moreover, stable and harmonious intrafamilial relations do not exclude a transsexual outcome of one or more children (12).

The second school of thought is behaviorism. Gender identity development is viewed as the result of a learning process that is imposed on an undifferentiated gender matrix. Gender identity develops as the result of "imprinting" and "conditioning" processes. In gender dysphoric syndromes these processes are fallaciously acquired. Money (3) has elaborated this theory by introducing biological factors (by hormones or by the sex dimorphic brain) and the concept of a "critical period". In the respective critical periods, biological, psychodynamic and environmental factors (in particular, the parents' expectations and the way they rear their child), have an effect on the development of the gender identity. Prior and subsequent to this critical period, such an effect does not occur. He has drawn an analogy with the critical period of genital differentiation known to operate in the fetal period. Based on the result of his very extensive research, he has hypothesized that the process of gender identity formation can be compared with the process of acquiring a language (3).

The third school of thought assumes that the ultimate development of gender identity is related to the maturation of cognitive development. Around the age of eleven years gender identity becomes consolidated by formal logical operations of thought and abstract reasoning. All authors on gender identity development agree that in every child a sense of gender identity termed "core gender identity" can be found before 3 years of age. "Core gender identity" can be described as the child's recognition that he is a boy or she is a girl; it proves to be resistant to change (13). On the basis of clinical evidence, it seems tenable to assume that the foundation of transsexualism is laid before the age of 3 (3, 13). Further research of this period is needed if one wants to understand more about the origin of transsexualism.

Gender identity, a typical human attribute, is not likely to be explained exclusively by either hormones or rearing; but science is still far away from a solid theoretical model that unifies and explains the many expressions of gender dysphoria encountered in clinical medicine. However, as in other areas of clinical medicine, treatment is often provided on empirical grounds rather than on the basis of a full understanding of the etiology.

Historical notes

The differentiation of distinct syndromes of gender dysphoria only commenced 25 years ago and has not yet been completed. In the following section some historical personages who cross dressed for a variety of reasons, are described. These short notes attempt to illustrate that gender dysphoria is not a recent phenomenon of the last decades but has been part of human history.

Retrospectively, the nature of their gender uncomformity can only be conjectured. Moreover, societal standards and lifestyles have changed profoundly. Therefore interpretations in the light of present criteria will likely be erroneous. Cross dressing and living in the role of the opposite sex have been observed for centuries. Besides well-known historical personages such as Jeanne d'Arc who did not hide her womanhood, many other examples of women who joined the army or worked as sailors, pretending to be male, have been described by historians. In the 17th and 18th century this phenomenon was not rare in Western Europe, and almost 100 cases have been reported in the Netherlands alone (14). The reasons for the change of sex role were manifold and in retrospect often difficult to establish. However, some women expressed feelings during a court trial or in their autobiography, which are similar to the feelings currently expressed by female-to-male transsexuals. It is therefore very probable that some of these women would today be diagnosed as transsexual. Historically, there were also men who dressed and behaved as women. Among the most famous were the Roman emperor Calligula; King James I of England; and Edward Hyde, Lord Cornbury, Governor of New York and New Jersey. However, in these cases their behavior was episodic. Today we would probably label them as transvestites.

A similar, but very particular case, is the life story of the Chevalier D’Eon, a nobleman who served the French King Louis XV as a diplomat in Russia. The year before his appointment he spent several months in disguise, presenting himself at the Russian court as his own (non-existent) sister Lea. He became quite popular as a woman and no one ever doubted his self-assigned sex. Later, he served in England where the rumor was spread that he was in fact a woman. He refused to settle the question by submitting to a medical examination. On the royal order of Louis XVI he was obliged to dress as a woman and live a female role until his death in 1810. The autopsy bore out that he had the body of a normal male, to the great surprise of the public and the people who knew him closely. Money (15) labels him as a transvestite who gradually gave way to his female personality, without giving up completely his male identity. As hormonal and surgical gender reassignment were impossible until the thirties of this century, it was unthinkable (although probably desired at times) to change one's secondary sex characteristics.

The modern documented history of transsexualism and medical gender reassignment ("changing the body to fit the mind") started in Germany with the first recorded adult sex change operation on a Danish artist, Einar Wegener, who in 1930 became Lily Elbe (16). Not until 1953, with the story of the surgical gender reassignment of the American ex-GI George Jorgensen, who became Christine Jorgensen, did transsexualism receive worldwide publicity. Since Jorgensen's 'sex-change’, thousands of individuals have undergone gender reassignment surgery. Very slowly, medical interest in transsexualism has evolved.

For decades only individual physicians took care of transsexuals while the mainstream of the medical community considered transsexualism to be a mental disorder. In the United States of America Dr. Harry Benjamin carefully examined, treated and followed transsexuals for many years. The account of his long-term, accurately documented experience was published as "The Transsexual Phenomenon" in 1966 (17). This work contributed largely to a more understanding opinion on transsexualism. To honor him for this great contribution the worldwide Organisation of professionals who care for transsexuals has been named The Harry Benjamin International Gender Dysphoria Association.

In the Netherlands the first recorded case of surgical gender reassignment in 1959 gave rise to storm of disapproval. Following this case, a report of the Dutch Health Council (Gezondheidsraad) was published in 1965. It stated:

In view of the incertitude regarding the diagnosis and the prognosis of transsexualism, and the great risk that the effect of the surgical sex reassignment will be very different from the anticipated effect, this procedure is explicitely dissuaded. The patient and the physician should be satisfied with the results of psychotherapy and social care of those concerned. (cited from (18).

Nevertheless, some physicians continued to treat transsexual individuals with hormones and surgical gender reassignment. One of them, Dr. O.M. de Vaal, described 20 case histories in his book Man of vrouw, dilemma van de transseksuele mens ("Man or woman, dilemma of the transsexual subject") (19). He concluded that modern medical and social care (at times including surgery) should be accompanied with more research to determine the best possible outcome.

Since 1972 the Netherlands Gender Center Foundation (Stichting Nederlands Gender Centrum), co-founded by Dr. de Vaal, has provided psychological care and advice for Dutch transsexual individuals. For hormone treatment and surgical gender reassignment, transsexuals are referred to medical centers. The great majority of transsexuals has been evaluated and treated by the Gender Team (Genderwerkgroep) of the Free University Hospital Amsterdam, but several other hospitals (in Groningen, Amsterdam, Rotterdam, Arnhem, Enschede and the Hague) provide part of the surgical care or have their own gender team. The successful outcome of gender reassignment in most transsexuals and the change of societal standards have resulted in a more liberal attitude by the health authorities. In 1977 the Dutch Health Council (Gezondheidsraad) published a new report that stated:

The physical adaptation (gender reassignment) of eligible subjects with gendez problems is a therapeutic procedure with a reasonable probability of success and is an essential part of the management, that offers the greatest likelihood to alleviate their existential distress (18).

Finally, in 1985 it became possible to change the sex assignment on all legal papers, but with the restriction that the original sex assignment remains on the birth certificate and the legally reassigned sex is annexed as a correction. Consequently, all legal papers can bear the new sex assignment, but legally all obligations preceding the reassignment remain valid (e.g. parenthood or alimony) (20). Thus, in theory, all obstacles for the emancipation of transsexual subjects have been erased.

Epidemiology

Transsexualism or, more appropriately, gender dysphoria is a worldwide phenomenon, not limited to Western societies. The way gender dysphoria is expressed and integrated in the local culture, however, varies strongly. In India male-to-female transsexuals are socially institutionalized in what is partly a caste, and partly a religious cult with its own mother goddess, Bahuchara Mata. They are called hijras and they come from families of Hindu, Muslim, Christian or other faiths. A hijra typically has a history of effeminate behavior in childhood and early adolescence. When he recognizes his affinity with other hijras, he will join them. After a probation period he will be initiated and have a female name and clothing. Traditionally they do not use sex hormones for feminization, but they do practise emasculation. Penis, scrotum and testis were amputated by established hijras. They are required to earn a living, often as the keepers of public bathhouses or singers and dancers at various public festivals, and sometimes as prostitutes (21). In Burma a similar phenomenon exists in which male-to-female transsexuals are believed to be possessed by a spirit of the opposite sex. They have a function at the temples and participate in (semi)-religious ceremonies (Coleman E, Colgan P, and Gooren L, personal observations).

In Oman men who live in the female role are known as xaniths, but their role in society is between that of men and women. They retain their male names, wear clothing between that of men and women and cut their hair medium length. They can share in the social life of women, but like men, they have the right to go about in public unescorted. They also have the right to live alone, to be hired as a house servant, and to work as a prostitute (in a culture where female prostitution is prohibited) (21).

Another cultural variant of cross-gender behavior which could be considered as transsexualism (but Money (3) prefers to call it gynemimesis) is the berdache among the American Indians. The berdache commonly showed effeminate behavior as a boy. After receiving a spirital revelation while in a divine trance, he will start to dress as a woman, do female work and engage in sexual relations with a man, and sometimes live as a berdache wife with a husband. They have a special status as a shaman and healer. This phenomenon has not become extinct, but still survives as an ongoing tradition in many tribes from Alaska to Yucatan (22).

Information on female-to-male transsexualism in other cultures is not available. Also in our Western world the existence of female-to-male transsexuals is often not acknowledged, although 1 out of 3 transsexuals is female-to-male. In Eastern Europe the prevalence of female-to-male transsexualism even surpasses that of male-to-female. A possible explanation for this higher ratio of female-to-male transsexuals has been suggested by Brzek and Hubalek (23). Masculine lesbians are more likely to be labeled transsexuals in Eastern Europe. Conversely, male-to-female transsexuals are more likely to be labeled effeminate homosexuals. But one can only speculate on the causes of the divergent prevalences of transsexualism in men and women living in various countries as no systematic studies have been performed.

The prevalence of transsexualism as assessed by the number of subjects applying for gender reassignment has been estimated in a few studies. Pauly (1968, (24)) estimated the prevalence in the USA to be 1:100,000 for female-to-male transsexuals and 1:400,000 for male-to-female transsexuals. Walinder (1971, (25)) calculated the prevalence rate in Sweden for the population above 15 years of age and found 1:37,000 men and 1:103,000 women to be transsexual. Similar figures were presented by Hoenig and Kenna (1974, (26)) in a study of the Manchester region, England. In the DSM III-R (1987 (5)) an estimated prevalence of 1:30,000 for males and 1:100,000 for females has been suggested. However, the number of applicants for gender reassignment depends largely on social acceptance, legal rights and the availability of treatment. An undocumentable estimate of 30,000-60,000 USA citizens who consider themselves to be valid candidates for gender reassignment has been proposed (27).

In a recent study (28) we calculated the prevalence of transsexualism for three different periods in order to compare and to analyze whether a trend could be discerned over the last 10 years. Prevalence of male-to-female transsexualism was 1:45,000 in 1980, 1:26,000 in 1983, and 1:18,000 in 1986. Prevalence rates for female-to-male transsexuals showed a similar increase from 1:200,000 in 1980, to 1:100,000 in 1983 and to 1:54,000 in 1986. The ratio of male-to-female to female-to-male transsexualism decreased from 4:1 to 3:1. It is evident from these figures that prevalences show a substantial upward trend. The interpretation of this trend can only be speculative. The distribution over the different age groups remains almost constant. Therefore the authors assume that the increased prevalences are the result of a higher percentage of transsexuals seeking hormonal treatment over the last 7 years. Meanwhile the social climate has become increasingly more benevolent and there are no financial barriers for those desiring treatment. A true increase would probably have shown a shift towards younger age groups, the older subjects having started treatment already.

Follow-up studies

The aim and rationale of combined psychological and biological treatment is that this will result in a better outcome than either no treatment or only psychological treatment. Many follow-up studies have been published assessing the results of treatment. However, the question remains as which criteria measure a beneficial outcome. The core symptom of transsexualism is the feeling of discomfort and inappropriateness about one's anatomic sex. This implies that treatment outcome should be evaluated according to this subjective symptom. All other symptoms more or less related to transsexualism, are secondary and should not constitute primary criteria of beneficial outcome.

Nevertheless, it is to be expected that the secondary signs, e.g. work situation, social situation, and contacts with relatives and friends do improve with successful outcome of treatment. But how should the outcome be rated if no change has occurred in these secondary problems and the subjects experience solely a relief of their gender problem? This difficult assessment has resulted in different interpretations of outcome results. Pauly (1981,(29)) reviewed 14 follow-up reports, published between 1969 and 1979. He concluded that not enough specific information is given to compare these studies. In an attempt to draw conclusions he categorized outcome as satisfactory, unsatisfactory, uncertain and unknown. He also included the number of reported suicides.

male-to-female female-to-male
(n=283) (n=83)

satisfactory 202 (71.4%) 67 (80.7%)
unsatisfactory 23 (8.1%) 5 (6.0%)
uncertain 48 (17%) 11 (13.3%)
unknown 4 (1.4%)
suicide 6 (2.1%)

The conclusion of this review, a tenfold higher probability of a favorable result than an unfavorable one, has been much criticized on methodological grounds. Lothstein (1982, (30)) discussed the lack of control groups, the differences in received care, the lack of relevant data and of valid criteria for good results in the published reports. He collected data on the results of treatment in 785 transsexual subjects. Most studies showed that transsexuals themselves were satisfied with the sex reassignment treatment. However, unfavorable results were also presented. These include disappointment regarding surgical results; some subjects who still felt inappropriate in their new gender role (some of them reverted to their biological sex), and individuals who did not experience a post-operative improvement in their well-being. Based on the reviewed results, he questioned the often cited psychological improvement in 70%-80% of the gender reassigned transsexuals.

Improvement of the objective social situation is not always evident. If one assesses the result of gender reassignment only by social integration as done by Meyer and Reiter (1979,(31)), sex reassignment surgery is not superior to a "wait and see" policy. Their criteria have, however, been heavily criticized.

Recently, Kuiper (1985,(18)) reported on a follow-up study of 143 transsexuals (107 male-to-female and 36 female-to-male) in the Netherlands. Mean follow-up period was 4.2 years. More than 50% had undergone sex reassignment surgery and all others were candidates for surgery or had undergone part of the surgery (e.g. only mastectomy). All subjects reported that the feeling of incongruity between their anatomic sex and gender identity was relieved. The emotional state was rated by the subjects themselves as happy or very happy in 64.8%, reasonable in 23.2% and unhappy in 12%. Only 4.2% had doubts about their new gender role, a main complaint being uncertainty with regard to social contacts. Some degree of loneliness was experienced by 28% of all transsexuals. In the male-to-female group, 23% felt very lonely. Suicide attempts were reported before treatment in 16.3% of the female-to-male and 12.6% in the male-to-female group. After the start of treatment 2.9% of the female-to-male but 14.4% of the male-to-female transsexuals attempted suicide. Apparently, suicide attempts were largely reduced in the female-to-male group but this was not the case in the male-to-female group. The conclusions of this study were that the primary symptom of gender incongruity was alleviated and the new gender role and the physical appearance were greatly valued; however, the psychological, social and economic situation of many transsexuals was still difficult. The authors of this study recommended that psychological therapy both during and after the gender reassignment process should be provided. The findings of a German study (1987,(32)) of 80 transsexuals, of whom 32 had undergone gender reassignment surgery, showed that operated transsexual subjects fared better than those not operated. In the operated group they found an increase in social integration measurements when they compared at the time of diagnosis, before the operation and afterwards. It is remarkable that the better social integration was already evident before the operation (when a perspective was offered ?) and subsequently increased. They attributed this to the long and intensive preoperative preparation for the new gender role accomplished by means of psychotherapeutic counseling and instruction in the behavior and attitudes of the desired gender. However, the studied group was biased since 81% of the patients was steadily employed, while in most studies 40-50% unemployment has been reported.

The above follow-up studies are almost unanimously positive with respect to the effects of gender reassignment treatment. The net effect in all studies is a relief of the core symptom, namely the feeling of inappropriateness of one's anatomic sex. In some studies, concommitant with the relief of the core symptom, there was a better social integration and socioeconomic situation, but this was not the rule. Feelings of loneliness, serious psychological problems and a bad economic situation remain prevalent after gender reassignment. Our personal experience with several hundred transsexuals confirms this outcome. Therefore, gender reassignment should be considered as a part of functional rehabilitation of an individual and not as a "cure' for transsexualism.

Procedure

No statement on appropriate care for transsexualism has been officially endorsed by the medical or psychological professions. The Harry Benjamin International Gender Dysphoria Association has presented an explicit statement on the minimal requirements of appropriate care to be offered to applicants for hormonal and surgical sex reassignment (Standards of Care, (27)). The care provided by our clinic is in agreement with these Standards of Care and will be described as a three stage procedure.

* 1) The applicant for gender reassignment is referred to a psychologist or psychiatrist with experience in gender problems. Extensive information (also written) about the possibilities, the procedure, the impossibilities and the consequences of the gender reassignment is given to the patient. During interviews information is collected about motivation, wishes, family background, gender behavior and personal history. Psychological testing is also a part of this stage. A detailed medical history, physical examination and laboratory tests (sex hormones, liver enzymes and, if indicated, further tests) are performed at this stage. The psychologist discusses all results with the applicant and together they decide whether to go on with the next stage. On the basis of the information provided by the team approximately 40% of the applicants decides to give up gender reassignment. Very few of them apply elsewhere, but several individuals return, sometimes 8 to 10 years later.

* 2) The second stage is the "two year real-life diagnostic test", first proposed by Money and Ambinder (1978, (33)). Based on the principle of "self diagnosis", this test requires a gender reassignment applicant to live in the desired gender role for at least two years. At the start of this stage, cross-gender hormones are prescribed (see Hormone Treatment), and electrolysis and vocal therapy are initiated for male-to-female transsexuals. The Dutch insurance system reimburses transsexuals for both latter treatments, if recommended by a physician. During this period, the applicant is seen by a psychologist every 6 weeks to 2 months for follow-up and counseling. Every 3 months, each subject has a physical examination, and complaints and physical changes are recorded. Blood samples for liver enzymes and prolactin measurements are drawn at least once a year. Hormonal therapy is modified if indicated by complaints or unsatisfactory results.

After 18 months of hormonal therapy and living in the new gender role, each case is discussed at a team meeting before surgery is recommended. Only patients who in the new gender role experience a relief of their gender problem, are recommended for surgery. If there is still doubt concerning the successful relief of the core symptom, surgery is postponed until this condition is fulfilled.

* 3) If all above-mentioned criteria have been met, the transsexual is referred to a plastic surgeon or gynecologist. Surgery is performed in a number of hospitals. Preferably, although not always possible, surgery is carried out in a hospital closest to the subject's home, in order to have as much social support as possible. At the time of the operation, psychological help is provided by the nursing staff in cooperation with the psychologist.

Postoperatively, the majority of transsexuals declines continuation of psychological counseling by professionals. Several reasons have been put forward for this refusal. First, many transsexuals believe that after the operation the gender change process has been completed. Only later will they admit that it took an additional 2 to 5 years before the social and psychological changes were integrated into their lives, Second, psychotherapy is not reimbursed by the Dutch insurance system.

Hormone treatment

Hormonal therapy is an essential part of the treatment for transsexuals. Both the psychological adjustment (34) and physical appearance (35) are improved by hormone administration before surgery. Postoperatively, hormonal therapy is necessary to maintain the induced body changes and to prevent hot flushes, skin atrophy and osteoporosis.

Recommended schedules for hormonal therapy have been based on different criteria. Some authors recommend doses of hormones equivalent to those for hormone replacement in adults who lack gonadal function ( 17, 35). Others have used estrogen doses that suppress serum levels of testosterone to castration levels in male-to-female subjects, and testosterone doses that suppress menstrual activity in female-to-male subjects, or pharmacological doses that suppress serum LH levels to low levels (36). Comparative data on the physical changes induced by these different treatment schedules have been reported by Meyer et al. (37)

The treatment regimen prescribed by us is empirical. The goal of the treatment is to induce feminization or masculinization and to suppress the undesired characteristics of the original sex. The administration of estrogens to male-to-female transsexuals and androgens to female-to-male transsexuals effectively induces the desired changes. The estrogen doses reported to be effective in this respect range from 0.1 - 1 milligram of ethinylestradiol, 2.5 - 10 mg of conjugated estrogens, or 20 - 40 mg of depot estrogens every two to four weeks by intramuscular injection. our results in terms of breast development with 0.1 mg ethinylestradiol/daily have been satisfactory in the past. We have continued this dosage throughout the last ten years.

In agreement with this observation are the results of Meyer et al., who reported the results with different doses of ethinylestradiol. They concluded that 0.1 mg ethinylestradiol is as effective as larger doses (37).

It has been established that the optimal dose of testosterone for female-to-male transsexuals is 200 - 250 mg long-acting testosterone esters injected intramuscularly every two weeks (37). We also use an oral androgen, testosterone undecanoate (Andriol, Organon, Oss, the Netherlands) in a dose of 160 - 240 mg/day. Older types of oral androgens have been associated with hepatic dysfunctions but this has not been observed with Andriol (38). Both androgens induce masculinization but the onset and progress of effect of long-acting testosterone esters (Sustanon, Organon, Oss, the Netherlands), 250 mg, intramuscularly every two weeks, are much faster.

Suppression of secondary sex characteristics is more difficult to achieve. Some characteristics like penis length or the volume of the breasts cannot be changed by hormones (37). In male-to-female transsexuals, suppression of androgen-dependent hair growth is desired. In part this can be achieved with estrogens. We add cyproterone acetate 100 mg/day (Androcur, Schering, FGR) for its androgen receptor-blocking effect and its anti-gonadotrophic properties. The combination of ethinylestradiol and cyproterone acetate results in maximal suppression of serum testosterone levels (< 1 nmol/1) and a further reduction of hair growth stimulation by blocking the androgen receptor on the hair follicle cell. The superiority of this combined treatment over only estrogens is frequently noted by transsexuals who have used both treatments. However, this has not been compared in a double-blind study. In female-to-male transsexuals the most appreciated effect by the patient is the cessation of the menstrual activity. With long-acting testosterone esters, suppression of the menses is achieved initially in 50% of the cases and in more than 90% within 3 months of testosterone administration. With testosterone undecanoate, menstrual activity has ceased in only 50% after 3 months. If menstruation persists, treatment is either changed to long-acting testosterone esters intramuscularly or lynestrenol, a progestative agent (Orgametril, Organon, Oss, the Netherlands) 5 mg/day is added.

Effects of hormone treatment

Transsexuals often expect rapid and complete changes after the start of hormonal therapy. The induced effects of cross-gender hormones, however, are limited and appear only gradually. Before starting hormone treatment a clear discussion of the possible changes is indispensable in order to prevent unrealistic expectations. This section describes the development of breasts, the reduction of hair growth and scalp hair loss, the reduction of testicular volume and changes in body fat distribution in male-to-female transsexuals; and the deepening of the voice, increase in hair growth, muscular development, amenorrhea and clitoris growth in female-to-male transsexuals. Neither penis length in male-to-female transsexuals nor breast volume in female-to-male transsexuals are reduced by hormones. In the initial phase of estrogen therapy, subareolar nodules, which can be painful, are common. The breast size can be quantified by measuring the maximal hemi-circumference over the nipple with a flexible ruler (37). The increase in breast size evolves gradually with a mean of 10 centimeters being observed after 1 year. Thereafter, the growth slows and the maximal hemi-circumference of 10-22 centimeters is reached after 18-24 months (37) and own unpublished results). These values are several centimeters less than the hemi-circumference of the female breast which ranges from 15.0-28.0 centimeters. Moreover, the width of the male thorax is in general larger than that of the female thorax. Consequently, the proportional effect is judged as unsatisfactory by almost 50% of the male-to-female transsexuals. The majority of those unsatisfied requests surgical breast implants. In more than 50% of the male-to-female transsexuals, the estrogen-induced breast size is judged as satisfactory by the subject, obviating breast surgery. In a small number of male-to-female transsexuals, unilateral subcutaneous mastectomy was performed because of pubertal gynecomastia. The effect of estrogens on the operated side is then nil, and in an early stage a breast implant is asked for. When the breast implant is performed before the end of the first year of hormone treatment the result is often asymetrical. It is therefore recommended to postpone unilateral breast surgery until completing one year of estrogen treatment and a good estimate of the final breast volume can be made.

Reduction of androgen-dependent hair growth with ethinylestradiol and cyproterone acetate is fairly effective on the trunk and the limbs, but has only limited success in the face. The body hair does not disappear, but following suppression of androgen-dependent growth, the hair becomes less coarse and less visible, resembling the vellus hair on the female body. If hairlessness of the body is desired, only electrolysis is effective. Waxing and shaving can result in temporary hairlessness, which can be prolonged by the decrease in hair growth associated with estrogen and antiandrogen treatment. The beard hairs also become thinner and softer after several years of hormone use. Unfortunately, once the beard growth has fully developed and regular shaving is necessary, the result is cosmetically unacceptable. Only electrolysis is effective in suppressing beard growth. In a few patients who had started treatment before developing visible beard growth, electrolysis could be omitted.

After starting hormone treatment, male type scalp hair loss ceases. Regrowth of scalp hair on bald areas is, however, incomplete and of the vellus type. Hairdo, hair implants or artificial hair techniques (partial wigs) can successfully mask the masculine alopecia while hormones can at best make a minor contribution.

The testicular volume is reduced by 25% within the first year of estrogen use (37). This reduction is appreciated as a sign of progress and also makes hiding of the male genitals easier.

Spontaneous erections are suppressed within 3 months but during erotic arousal erections still occur in most patients, evidencing relative androgen-independence of the erection.

The subcutaneous fat distribution is sex steroid dependent. Males preferentially accumulate fat in the upper abdomen and females around the hips. Estrogen treatment in male-to-female transsexuals can result in a more female fat distribution, but this is not the rule. In female-to-male transsexuals testosterone administration does not reduce the female fat distribution. Skeletal differences between men and women, e.g. the broader pelvis of women, are not influenced by sex steroid treatment.

The administration of androgens in females is associated with the deepening of the voice. This effect is often seen within three months after initiating testosterone treatment. For many female-to-male transsexuals, the lower pitched voice facilitates their public appearance as a male. In male-to-female transssexuals, estrogens do not affect the pitch of the voice, and a low voice can be a great handicap. Vocal therapy is necessary to achieve a more feminine vocal range. Vocal cord surgery does not obviate the need for vocal therapy in most cases, but the resulting higher pitched voice facilitates a female public presentation.

The cessation of menstrual activity after the start of testosterone treatment has already been mentioned (see Hormone treatment). After one year of testosterone therapy an increase of body hair is always observed. The extent of increased body hair appears to depend more on the individual genetic sensitivity than on the dosage. This is illustrated by the fact that among our full-bearded female-to-male transsexuals some have used injectable testosterone esters which result in high serum testosterone levels, while others took oral testosterone undecanoate which increases serum testosterone levels to the lower male range or to even subnormal male levels. However, in cases of unacceptably little beard growth, injectable testosterone esters can sometimes accelerate beard growth to a cosmetically acceptable degree. As with breast growth the effect on beard growth appears slowly and usually it takes several years before the final result can be judged. The growth of the clitoris reaches its maximum after approximately one year. This effect also varies with individual sensitivity. According to Meyer et al.(37) length of the clitoris can range from 3,5 tot 6 centimeters.

The muscular development that can be obtained by testosterone administration depends on muscular exercise and is not a hormonal effect as such. After 3 to 6 months, an increase in muscular strength is observed by most female-to-male transsexuals. This can cause musculoskeletal pains, which in our experience are due to a strain of the tendons. A gradual increase of muscular exercises can prevent these complaints and results in increased muscular strength. Other effects of cross-gender hormones are sometimes reported. An effect that needs further evaluation is the often reported effect on mood and emotions. Although this mood effect is hard to differentiate from the psychological effects of acquiring the desired physical change, the regular occurrence of these reported changes makes a direct effect of sex hormones on the brain very plausible.

Scope and aims of the studies

The studies reported in this thesis were initiated several years ago. We were concerned about the side effects and long-term effects of cross-gender hormone treatment. The medical literature on this subject consists largely of reports that draw an analogy with oral contraceptives in women, estrogen treatment for prostatic carcinoma and clinical trials of estrogens to prevent a recurrent myocardial infarction in hyperlipemic men (see chapter 2). Furthermore, ten case histories of side effects of cross-gender hormone treatment have been published. Except for the studies of Meyer et al.(37), no other study of side effects in a large group had been published. All published reports, including ours, have been retrospective. Therefore, there is a great lack of information on effects and side effects of cross-gender hormone treatment. Although transsexualism is a rare condition, the number of subjects who receive gender reassignment treatment can be estimated to be several ten thousands worldwide. This thesis is an attempt to fill the information gap. In chapter 2 a retrospective study of the mortality and morbidity observed in hormone-treated transsexuals as observed at our clinic is reported and compared with the mortality and morbidity in the population adjusted for age and sex. The results of this study prompted us to examine in detail the prolactin levels and the pituitary enlargement in estrogen-treated male-to-female transsexuals. These results are reported in chapter 3. Osteoporosis and its relation to sex steroids is now a well-studied topic in medical research. In chapter 4 the findings of bone biopsies and parameters of bone metabolism in 23 male-to-female transsexuals treated with ethinylestradiol and cyproterone acetate are reported. In chapter 5 the observations on serum lipids during treatment in male-to-female transsexuals with ethinylestradiol only, and with the combination of ethinylestradiol and cyproterone acetate are described. In part cross-sectionally, in part longitudinally, this chapter summarizes our preliminary results which need to be further substantiated by prospective studies now in progress.

The endocrine and clinically visible effects of the new antiandrogen Anandron (Roussel, France) on sexual hair are reported in chapter 6. In a preliminary study the short-term effect on sexual hair of Anandron is compared with our clinical experiences with cyproterone acetate. Superiority of either of these antiandrogens can only be demonstrated in a double-blind comparison trial of both drugs, but this was not feasible. We were more interested, as clinicians, in the general effect of antiandrogens on hair growth rather than on determining the superiority of either drug.

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