pharmacovigilance and principle of nonmaleficence in sex Reassignment

Physicians are obliged to provide treatment that is consistent with their commitment to avoid or minimize harm (nonmaleficence) and their commitment to do good (beneficence). Therefore, if patient’s desires were contradictory to the primary aim of medicine, the doctor’s calling would require him/her to thoroughly analyze the cause of the disease and provide an adequate as well as ethical treatment rather than obediently follow patient’s requests. Yet, chemical and surgical sex reassignment is one of the areas where some physicians surrender to the desire of their patients instead of finding out what their real condition is and trying to manage it in a way the essence of medicine would require. The objective of this article was to provide specific pharmacovigilance search details for the evaluation of the current situation and the scientific background of the treatment of gender dysphoria and to analyze its conformity with one of the two main ethical principles of medicine – nonmaleficence. Literature retrieval was accessed through Medline (1979–2011) using the terms “gender dysphoria,” “replacement hormonal therapy,” and “pharmacovigilance.” The article concludes that hormonal and surgical interventions have not proven to be medically justified and could be harmful, not treating the cause, but resulting in irreversible disability. Thus, these interventions contradict the principle of nonmaleficence and goals of basic therapeutics and pharmacovigilance. They are not based on clinical trials and are lacking a thorough follow-up assessment.


Introduction
The nature of medicine is embedded in the Hippocratic Oath as a promise to use medical knowledge for the good of the patient and to refrain from harm.The Hippocratic Oath obligates a physician the end of his art to be healing -relief of pain and suffering.As professionals dedicated to healing, in the first place, they are obliged to provide treatment that is consistent with their commitment to avoid or minimize harm (nonmaleficence) and their commitment to do good (beneficence) (1).These commitments constitute the basis and serve as justification of the practice of medicine, and without them, the whole therapeutic gesture falls apart (2).Nonmaleficence refers to a health professional's duty to prevent or do no harm to patients.Nonmaleficence corresponds with the aim to avoid adverse drug reactions.Physicians and other health care professionals are called to practice in ways that are consistent with the intentions and goals of medicine and to avoid taking up the role of mere technicians who are expected to do whatever the patient desires.Therefore, if patient's desires were contradictory to the primary aim of medicine, the doctor's calling would require him/ her to thoroughly analyze the cause of the disease and provide adequate as well as ethical treatment, rather than obediently follow patient's requests.Yet, chemical and surgical sex reassignment is one of the areas where some physicians surrender to the symptoms of their patients instead of finding out what their real condition is and trying to manage it in a way the essence of medicine would require.
Transsexualism has been defined as an extreme gender dysphoria for the imitation of the gender of the opposite sex, contrary to one's genetic-biological sex at birth.Transsexualism is not a common choice, and its nature is largely unknown.Psychologically, the desire to be accepted as a member of the opposite sex cannot be regarded as the main criterion to determine human sex identity, but is rather a symptom of an underlying psychiatric problem.The majority of transsexuals progress to taking opposite-sex hormones in the long term, and many proceed to irreversible mutilative genital surgery and destruction of biological fertility for the imitation of external genitalia of the opposite sex.The current scientific data on the balance of risks and benefits of the long-term hormonal replacement therapy (HRT) have been deemed unfavorable in healthy women (3)(4)(5).For safety reasons, the replacement and supplementation of testosterone for healthy men have also been discredited.The use of opposite-sex hormones with the intention to change personal identity is not only biologically, but also medically experimental.
There is a lack of studies evaluating the effects and consequences of using sex hormones in persons with transient or long-term psychiatric conditions, disorders, and disturbances from the viewpoint of pharmacovigilance.
The objective of this article was to provide specific pharmacovigilance search details for the evaluation of the current situation and the scientific background of the gender dysphoria treatment and to analyze its conformity with one of the two main ethical principle of medicine -nonmaleficence.Considering the fact that pharmacovigilance is concerned with the detection, assessment, understanding, and prevention of adverse effects of medicinal products, the psychological effects of sex reassignment and their significance for the ethical evaluation of sex change are not the objects of the present article.

Methods and Current Data
Methods.Literature retrieval was accessed through Medline (1979-2011) using the terms gender dysphoria, replacement hormonal therapy, and pharmacovigilance, including appropriate Boolean operators "AND" and "OR." Current Data.The prevalence of transsexualism in the Netherlands is estimated to be 1:11 900 for men and 1:19 400 for women (6) and in Germany (between 1981 to 1990) between 2.1 and 2.4 per 100 000 of the adult population (7).
According to the International Statistical Classification of Diseases and Related Health Problems, transsexuality is classified among psychiatric gender identity disorders: "F.64.0 Transsexualism.A desire to live and to be accepted as a member of the opposite sex, usually accompanied by a sense of discomfort with, or inappropriateness of, one's anatomic sex, and a wish to have surgery and hormonal treatment to make one's body as congruent as possible with one's preferred sex" (8).This definition could be criticized as fallacious leading to confounded individuals demanding methods from medical caregivers and the community, which are known as harmful for healthy individuals and have unknown effects for those with psychiatric conditions.It is the underlying psychiatric disturbance (transient or long-term), which needs to be adequately addressed and treated.According to present day's scientific understanding, the use of opposite-sex hormones for the purpose of attempting to change one's sex is not only misleading in its goal, but seriously fails to meet the main criteria of the definition of the rational use of medicines.The WHO defines the rational use of medicines as when "patients receive medications appropriate to their clinical needs in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and the community" (9).The desire of a genetically and physiologically healthy man or woman to change gender cannot be accepted as a clinical need in any pathophysiological sense.
The treatment presented below is an example of a scientifically ill-grounded treatment of transsexuals (off-label use of medicines).The doses of typical estrogens for the feminization of male-to-female (M→F) transsexuals were 2 to 3 times as high as the recommended doses for the HRT in postmenopausal women (10,11); several articles have reported the lowering of testosterone with cyproterone acetate in M→F (12), which is not approved for use; GH-releasing hormone agonists have been considered by some to increase estrogen effects in persons with the risk factors of estrogens in transsexuals (13); addition of progesterone for M→F transsexual people is advocated ( 14); testosterone has often been used alone, both before and after oophorectomy, for masculinizing female-to-male (F M) transsexuals.The addition of progestin with the aim of menses cessation in case testosterone does not adequately suppress menstruations within several months of opposite sex hormone treatment has been recommended (10).GH-releasing hormone agonists have been used in adolescent transsexual people to delay puberty and to allow cross-sex hormones to be postponed until adulthood (15).
Allowing such an inappropriate use of medicines may not only be unsafe, but also encourage misleading promotion, expectations, and use (16,17).The use of opposite-sex hormones by individuals who have been legally allowed to change their personal identity and sex-identifying code is not only biologically, but also medically artificial.
Transsexualism cannot and does not bring about any change in this biogenetic attribute of a particular individual.One cannot change a human karyotype.Genetic scientists acknowledge and insist that one's sex is biologically determined and genetically imprinted by a karyotype in all nucleated cells of an individual.Science disproves a historical dogma of transsexualism theory that male and female embryos develop in an identical fashion: there are gender-related differences at the very early stages of the development of human embryos (18).

Scientific Evidence on Hormonal Replacement Therapy in Women and Men
The low rate of cardiovascular diseases before and the increased rate after menopause have led to the conviction that the female hormone estrogen is the source of cardioprotection enjoyed by premenopausal women.This has resulted in the first meaningful study of estrogen and heart disease, the Coronary Drug Project, known ironically as a study in men.It was designed to find out whether men with coronary heart disease could avoid new attacks by taking estrogen.In 1972, the high rate of coronary events was determined in the treated groups, and this caused the termination of the study and rejection of the idea to treat men with estrogens (19).
HRT containing either estrogen alone or in combination with progestin is not longer widely recommended for women.This advice takes into consideration the latest findings from the Women's Health Initiative (WHI) Trial and the Million Women Study (3,4) and has been adopted by the European Medicines Agency (EMA) (20).The WHI, the Million Women Study, and previous studies provide good evidence that the use of estrogen-only HRT increases the risk of breast cancer, endometrial cancer, and possibly ovarian cancer in a duration-dependent manner (3,4).For combined HRT, the Million Women Study has shown that there is an increase in the risk of breast cancer, which is substantially higher than that for estrogen-only products (4).HRT has been shown to increase the risk of myocardial infarction and venous thrombosis, especially in the first year of use, and of ischemic stroke (3,21).HRT may also increase the risk of dementia and has no beneficial effect on the cognitive function (5,22); it has been linked to an increase in the risk of venous thromboembolism, biliary tract surgery (23), and lung cancer (24).Women who take estrogen plus progestin may have a significant rate of urinary incontinence than women who do not take the hormones (25).
As a result, a group of experts on HRT from a number of European countries have now reassessed all the risks and benefits of HRT and concluded the following: 1) HRT for a short-term treatment of menopausal symptoms that adversely affect the quality of life remains a suitable treatment option, but the minimum effective dose should be used for the shortest period; 2) for a long-term use, i.e., for the prevention of osteoporosis or osteoporotic fractures in women with risk factors or established osteoporosis, the balance of risks and benefits is unfavorable as the first-line treatment for this indication; and 3) in healthy women without menopausal symptoms, the balance of risks and benefits is generally unfavorable and HRT is not recommended (20).
Researchers have observed a dramatic fall in breast cancer incidences that perfectly mirrors the decline in the use of HRT in women (26,27).
Recent information on increased risks associ-ated with HRT in women has aroused a concern that men receiving hormone replacement may also be vulnerable to increased health risks (28).High doses of exogenous testosterone are associated with substantial hepatotoxicity, including the development of benign and malignant neoplasms (29,30).However, few data support a causal relation between higher testosterone levels, as a risk factor for cardiovascular disease, and sudden cardiac death (30,31).The testosterone replacement therapy has been associated with the exacerbation of sleep apnea or with the development of sleep apnea suggesting that androgen replacement contributes to sleep-disordered breathing by central mechanisms (32).
A major report from the congressionally chartered Institute of Medicine concluded that if there is no proven benefit, testosterone should not be taken no matter what the risk.The American National Institute on Aging and the National Cancer Institute asked to review the issue and called for a series of small studies to determine whether testosterone could help men cope with some of the predictable effects of aging, but these studies were recommended not to include young men because they were expected to receive less benefit for the same risks (33).

Aspects of Pharmacovigilance in Attempting Sex Reassigment
There is no proven scientific background at present about the benefit of the use of opposite-sex hormones in transsexuals.No sex hormones have approved indications in their Summary of Product Characteristics for use in attempting sex reassignment, and manufacturers cannot publish such recommendations in the absence of scientific data to support such claims because of medicolegal consequences.Legal changes allowing attempts to change sex undoubtedly also increase interest in the number of interested patients (34).It should be noted that corresponding laws in the world were passed when pharmacovigilance as a concept and a medical discipline was in its infancy worldwide.Pharmacovigilance centers were only established in the majority of countries in the aftermath of the thalidomide disaster (35).Pharmacovigilance is defined as "[t]he science and activities relating to the detection, assessment, understanding and prevention of adverse effects, or of any other drug-related problems."One of the tasks of pharmacovigilance is to assess the safety implications of the use of medicinal products outside their approved indications (36).
Transsexuals tend to experience common serious adverse effects of taking opposite-sex hormones, and these adverse effects are a frequent cause for discontinuing their use (37,38).Short-term 1-year investigations of the sex reassignment outcomes of young individuals revealed that a significant portion Pharmacovigilance and Principle of Nonmaleficence in Sex Reassignment of them had to interrupt the treatment because of unfavorable adverse effects (39).Serious adverse effects of sex steroid therapy in M→F transsexuals are real and apparent.A reported 20-fold increase in venous thrombosis is one of the greatest concerns (40,41).The adverse effects of taking opposite-sex hormones in the M→F group enhanced tendencies to anger and aggression and decreased sexual arousability and cognitive spatial ability (42).Other common phenomenon is an increase in prolactin levels.The combined use of estrogen and cyproterone acetate is associated with hyperprolactinemia (77.4%) and elevation of liver enzymes (12.9%) (41,43).Hyperprolactinemia is possibly associated with an accelerated growth of prolactinomas with the feminizing therapy (15,44).Chemical castration is associated with a significant rise in the plasma levels of beta-amyloid, which is likely to be involved in the pathogenesis of Alzheimer's disease and, clinically, with increased depression and anxiety scores (45).The use of ethinylestradiol by men has been reported to induce insulin resistance (46).Breast cancer related to apocrine metaplasia in M→F transsexuals may also occur (47).Histological and DNA histogram studies of testes after the use of opposite-sex hormones, obtained at castration, revealed a pattern of maturation arrest in the absolute majority of cases, in which the diploid cell compartment occupied most of the spermatogenetic element, followed by tetraploid and monoploid cells (48).
The adverse effects of masculinizing treatments in female-to-male transsexuals are of great concern.Thorough evaluation of the risks of androgen administration to F→M transsexual people has been limited because a small population has presented at treatment centers (41); therefore, serious adverse risks may be underestimated (39).
The administration of androgens to women has been clearly associated with an increase in the tendency to aggression and has had a deteriorating effect on verbal fluency tasks (42).Testosterone may also promote atherogenicity in women (49,50) and induce insulin resistance (46).A combination of increased weight, decreased insulin sensitivity, poor lipid profile, an increase in the amount of visceral fat (51), and an increase in hematocrit has raised the concern for cardiac and thromboembolitic events.In fact, cerebral vascular accidents have been reported for individuals with supraphysiological levels of testosterone (52).Androgen use in F→M caused hyperprolactinemia in 38.5% and elevation of liver enzymes in 19.2% of cases (37).Other common findings in F→M transsexuals seem to be hyperandrogenism with polycystic ovary syndrome and adrenocortical hyperresponsiveness to adrenocorticotrophic hormones (53).Polycystic ovarian disease is a risk factor for endometrial cancer, and polycystic ovarian morphology of the ovary has been seen in greater numbers in transsexual people (52,54).After the treatment with testosterone, mild endometrial hyperplasia has been documented on the removal of the uterus (55).A case report detailed 2 transsexual patients with ovarian cancer in F→M transsexual people: long-term exposure to the increased levels of endogenous and exogenous androgens is further hypothesized to constitute an additional risk for F→M transsexuals for associated ovarian epithelial cancer (56).
The use of opposite-sex hormones, therefore, deserves first and foremost serious, responsible, and critical assessment and evaluation (57).Finally, "one must remember that chemical surgery, namely exposing the body to chemical products, is more intrusive than physical surgery" (58).

Iatrogenic Effects After Hormonal and Surgical Intervention
Transsexuality, classified and considered predominantly as a psychiatric disorder and condition, is not an indication for, nor has it been proven to benefit from, surgical intervention.The fact that psychiatric patients have actually become the object of surgical treatment was partially predetermined also by one of the darkest episodes in the history of that field of treatment, i.e., John/Joan case story, which had been misleading medical professionals for about 3 decades and eventually became an open secret in the science and literature (59).The news about the tragic outcome of this case flew round the world in May 2004 (60).
Preclinical and clinical data show that castration could be related with anxiety or "depressive-like" symptomatology due to chronic estrogen deficiency in females (61,62).In a study aimed to show differences between two groups of hysterectomized and nonhysterectomized women with a fairly long follow-up period (7.9 years), hysterectomized women showed significantly higher levels of body complaints, depression, and decreased psychological well-being (63).Loss of estrogenic and androgenic underpinnings may destabilize women with unstable psychiatric axes (62).Surgical menopause may precipitate psychiatric disorders in women with previous psychiatric disorders and may increase the risk of depression in them (64).An oophorectomy and a hormone-deficient state were associated with a definite loss of bone mass (38).Articles addressing the outcomes of such surgical intervention have provided conflicting evidence and have, in fact, shown a more negative effect in the long-term (65)(66)(67)(68).A long-term follow-up study of female transsexuals, for instance, revealed that only 59% were willing to go through the operation again (69).
The pioneers of such genitalia surgery at John Hopkins University in Baltimore terminated such an intervention program, concluding that this type of surgery offered no advantage over psychotherapy (70,71).Other study of Medicaid funding of such surgery has also supported this conclusion (72).Surgery removing both gonads and other sex organs destroys the individual's natural fertility (73), itself causing harm and loss and conferring a degree of severe disability, and would in any other case lead to medicolegal consequences.
Castration not only renders infertility and incapacity conferring the invalidity status, but also increases the risk of atherosclerosis, myocardial infarction, and stroke (74).The premature decrease in sex hormone levels is thought to be linked to a comparatively higher risk of atherosclerosis and related morbidity and a shorter lifespan (64,75).Technical advances in such surgical methods do not address or solve these fundamental problems (69).According to the US Medicare Coverage Issues Manual, transsexual surgery for sex reassignment of transsexuals is controversial.Because of the lack of well-controlled, long-term studies of safety and effectiveness of the surgical procedures and attendant therapies for transsexualism, the treatment is considered experimental.Moreover, there is a high rate of serious complications for these surgical procedures.For these reasons, transsexual surgery is not covered (76).
Sex reassignment is related to high psychiatric morbidity, suicide, and suicide attempt rates (77)(78)(79), high rates of depression, and low quality of life (77,79); sex-reassigned persons are at a higher rate of psychiatric hospitalizations.The most striking result was the high mortality rate in both M→F and F→M as compared with the general population (77).A prolonged hormonal treatment might increase the risk of malignancies ( 80), e.g., the cause-specific risk of death from neoplasms was increased about twice (77).Besides, both M→F and F→M individuals were at a higher risk of criminal convictions as compared with female controls (77).The data indicate the need of a continued psychiatric and somatic follow-up for persons after sex reassignment, because the evidence of sex reassignment is of a very low quality due to the serious methodological limitations of the published studies; most of them had been poorly designed, and the results were unsound because researchers lost track of more than half of the participants (77,78,(81)(82)(83)(84)(85).A recent meta-analysis has concluded that the data on cardiovascular outcome after cross-sex steroid use are sparse, inconclusive, and of a very low quality (83).

Concluding Remarks
Hormonal and surgical interventions have been developed on the premise that transsexualism (gender dysphoria) has been impervious to treatment by psychotherapy and has not proved to be medically justified (as recently HRT in postmenopausal women), but it could be harmful, not treating the cause, resulting in an irreversible disability.Such medical interventions only attempt to satisfy in some way the individual's wish, but do not medically address the underlying psychiatric condition.These interventions are also contrary to the principles and goals of basic therapeutics and pharmacovigilance.They are not based on clinical trials, and there is no long-term assessment.It is obvious that transsexualism pharmacotherapy does not comply with the good clinical practice requirements that are the background of pharmacovigilance.Hormone replacement therapy with opposite-sex hormones should be regarded as a "chemical surgery," a fatal factor that impels the next phase, i.e., surgical treatment.Therefore, using opposite-sex hormones in an attempt to change one's gender should be considered inconsistent with the principle of nonmaleficence because it exposes the patient to a risk of serious side effects.The demand for such services stems from the customer's perception of the goals of medicine, entrenched in the oath of medical practitioners.Thus, the treatment of gender dysphoria not only evokes a series of problems in theoretical medicine, pharmacotherapy in psychiatry and psychosociological spheres, each of them demanding a comprehensive assessment, but also raises the ethical debate.

statement of Conflict of Interest
The authors state no conflict of interest.