Hormonal Gender Reassignment Treatment for Gender Dysphoria
Background: No data are available at present on the prevalence of gender dysphoria (trans-identity) in Germany. On the basis of estimates from the Netherlands, it can be calculated that approximately 15 000 to 25 000 persons in Germany are affected. Persons suffering from gender dysphoria often experience significant distress and have a strong desire for gender reassignment treatment.
Method: This review is based on pertinent publications retrieved by a selective search in the PubMed database employing the searching terms “transsexualism,” “transgender,” “gender incongruence,” “gender identity disorder,” “gender-affirming hormone therapy,” and “gender dysphoria.”
Results: In view of its far-reaching consequences, some of which are irreversible, hormonal gender reassignment treatment should only be initiated after meticulous individual consideration, with the approval of the treating psychiatrist/psychotherapist and after extensive information of the patient by an experienced endocrinologist. Before the treatment is begun, the patient must be extensively screened for risk factors. The contraindications include severe preexisting thromboembolic diseases (mainly if untreated), hormone-sensitive tumors, and uncontrolled preexisting chronic diseases such as arterial hypertension and epilepsy. Finding an appropriate individual solution is the main objective even if contraindications are present. Male-to-female treatment is carried out with 17β-estradiol or 17β-estradiol valerate in combination with cyproterone acetate or spironolactone as an antiandrogen, female-to-male treatment with transdermal or intramuscular testosterone preparations. The treatment must be monitored permanently with clinical and laboratory follow-up as well as with gynecological and urological early-detection screening studies. Prospective studies and a meta-analysis (based on low-level evidence) have documented an improvement in the quality of life after gender reassignment treatment. Female-to-male gender-incongruent persons often have difficulty being accepted in a gynecological practice as a male patient.
Conclusion: Further prospective studies for the quantification of the risks and benefits of hormonal treatment would be desirable. Potential interactions of the hormone preparations with other medications must always be considered.
Gender dysphoria—or gender incongruence or transsexuality–is characterized by a mismatch between the biological sex and the inner sense of gender (gender identity). A transgender woman is a biologically male person with female gender identity; correspondingly, a transgender man is a biologically female person with male gender identity. In the Netherlands, the prevalence of gender dysphoria is estimated to be 0.02–0.03% (1). For Germany, no estimates have yet been published. Based on the above figures, it can be assumed that approximately 15 000 to 25 000 people are affected. While earlier studies (1, e1, e2) reported a gender ratio of transgender women to transgender men of approximately 2 : 1, more recent studies found increasingly similar proportions (e3) or even a reversal of this ratio (2).
With the onset of puberty, transgender persons typically experience significant psychological distress (gender dysphoria) and consequently seek gender-affirming—or gender reassignment—treatment (e4). With 9% to 11% and 1.5% to 2%, the rates of suicide attempts (3) and committed suicides (4), respectively, are increased among people with gender dysphoria compared to the general population. In 2010, a meta-analysis found a decrease in mental and physical complaints as well as an increase in quality of life after the start of gender-affirming hormone therapy (GAHT) (5), but the data quality of this study was limited. However, later prospective studies confirmed these findings (6, e5). The two-year follow-up after GAHT revealed the following differences compared to the pre-treatment status:
- Decrease in depressive symptoms (Beck Depression Inventory [BDI] II scores: transgender women −1.41, p<0.001; transgender men −1.31, p<0.001)
- Reduction in body uneasiness (Body Uneasiness Test [BUT] index: transgender women −0.24, p<0.001; transgender men −0.24, p = 0.001)
- Decrease in gender dysphoria (GIDYQ AA score: transgender women −0.06, p<0.001; transgender men −0.05, p = 0.001) (6).
For persons with gender dysphoria, treatment with cross-sex hormones delivers a sense of identity. However, since gender-affirming hormone therapy has a significant effect on a person’s hormonal balance, it is associated with a risk of adverse effects which is particularly high in the event of unsupervised treatment or overdosing.
Using treatment data from a large Dutch gender identity clinic collected in the period from 1980 to 2015, Wiepjes et al. demonstrated a 20-fold increase in newly started GAHT (1). Similarly, many treatment providers in Germany have observed an increase in the number of affected persons in recent years (personal communication from colleagues of other institutes). Factors potentially contributing to this trend include growing societal acceptance and a significant increase in public attention and media coverage (e6, e7, e8, e9, e10). Nevertheless, in Germany, too, those affected do frequently not receive optimal care (7, 8, e4, e11).
The aim of this article is to provide up-to-date insights into and recommendations for gender-affirming hormone therapy (GAHT) as well as information about special aspects that should be taken into account by general practitioners and specialists involved in the care of transgender persons.
Overall, the evidence from studies on the effects and risks of GAHT—which also forms the basis of the guidelines of the Endocrine Society which were initially created under US and European co-authorship in 2009 and then updated in 2017 (9)—is weak. Most studies are retrospective data analyses, frequently based on comparatively few cases. Prospective studies are scarce. There are no randomized controlled trials and, ultimately, it is difficult to imagine that studies designed will ever be conducted, not least for ethical reasons. A German or European guideline on GAHT has not yet been created.
This review is based on a selective search of the PubMed database for original publications and review articles up to December 2019. The following search terms were used: “transsexualism”, “transgender”, “gender incongruence“, “gender identity disorder“, “gender affirming hormone therapy“, “gender dysphoria”.
Treatment with GAHT quickly causes marked and partly irreversible changes. Thus, prior to the start of treatment, it is critical to confirm the diagnosis and to ensure that a clear, written indication for GAHT is established by a psychotherapist or psychiatrist (9, 10, 11, e12). There are no strict requirements for the duration of preceding psychotherapy and, given the very different circumstances and needs of the affected individuals, any such requirement may not be helpful after all.
GAHT can be started at about age 16 years, provided a written, documented informed consent is obtained from the adolescent’s parents or guardian and the adolescent is mature enough to make this decision. In gender-dysphoric younger children and adolescents, a reversible puberty-suppressing therapy with gonadotropin-releasing hormone (GnRH) analogs can be initiated with the onset of puberty (9). In minors, confirmation of the indication by an independent second therapist should be required (9). Prior to the initiation of treatment, the patient must be informed in detail about the treatment effects, their course over time, the limitations of the treatment and potential adverse effects (9, 10).
Medical diagnostic work-up prior to treatment initiation
A comprehensive pre-treatment risk screening, including thorough medical history, family history and physical examination as well as clinical chemistry testing of relevant parameters is required to identify potential contraindications and risk factors. This screening also helps to adapt the planned treatment to a patient’s individual risk profile (Box).
Many healthcare payers require that a somatic variation of sex development is ruled out before treatment is started (e13). These differential diagnostic conditions, such as Klinefelter syndrome and complete androgen resistance syndrome, are rare and can be excluded based on the medical history, physical examination and measuring of basal hormone levels. Only in the presence of major clinical abnormalities and grossly abnormal laboratory findings, further diagnostic work-up, including chromosomal analysis, should be performed.
Pre-existing conditions, such as arterial hypertension, diabetes, dyslipidemia, and HIV, require adequate treatment. Adequately controlled, they are not considered absolute contraindications. In the presence of elevated liver enzyme levels, a pre-existing hepatic condition should be ruled out. Further diagnostic testing may be required.
GAHT is so essential for patients with gender dysphoria that priority even over contraindications can be given to this treatment on an individual basis after detailed discussion of associated risks. The decision to provide the treatment should also be broadly supported by all clinicians involved in the patient’s care. Absolute contraindications are very rare. Unsupervised self-medication is associated with high risks. Thus, instead of withholding therapeutically controlled hormone treatment in patients with contraindications, ideally an experienced endocrinologist should carefully evaluate each case individually to find a personalized solution.
Male-to-female gender dysphoria
GAHT of male-to-female transsexuals is based on the oral or transdermal administration of 17ß-estradiol or 17ß-estradiol valerate (9). Because of the significantly more unfavorable risk profile, treatment with ethinyl estradiol is obsolete (12, 13, 14). Since thromboembolic complications are more common with oral estradiol treatment (15), preference is given to the transdermal route of application if additional risk factors, such as overweight, older age and smoking, are present.
Since reducing androgen levels is another important requirement for the desired feminization of the body (16, e14), patients also receive supplementary anti-androgen therapy. Here, the standard treatment is the administration of cyproterone acetate (17). Alternatively, treatment with spironolactone may be considered. Administration of a GnRH analog is another treatment option, but the significantly higher costs of this approach need to be taken into consideration. Anti-androgen treatment is discontinued, at the latest, once orchiectomy has been performed as part of the gender-affirming surgical procedure. An additional benefit on breast development by supplemental progesterone treatment has not yet been confirmed (18, 19). There is a lack of randomized controlled trials evaluating this aspect. Given the increased risk of breast cancer and thromboembolic events associated with hormone replacement therapy in postmenopausal women (e15), additional administration of progesterone in transgender women is currently not recommended (9). Information about the medications used for GAHT and their standard dosing schedules is provided in Table 1.
Course and limitations of treatment
Table 2 gives an overview of the course of treatment over time and its limitations. GAHT cannot alter the size and shape of the male larynx and consequently the pitch of the voice. While body and facial hear growth are diminished, they usually do not stop completely; consequently, epilation treatment is required in most cases.
Adverse reactions and risks
Table 3 gives an overview of adverse reactions and risks. The development of venous thromboembolism (VTE) is a relevant risk. Older, retrospective data from the time when ethinyl estradiol (today considered obsolete) was still commonly used show a significant increase in the risk of thromboembolism with the occurrence of a VTE in 5.5% to 6.3% of ethinyl estradiol-treated patients (12, 20). With the advent of modern treatment regimens, the prevalence of VTEs has declined to about 0.6% to 2% (21, 22). To date, no studies evaluating the perioperative risk of thromboembolism have been conducted in patients receiving feminizing hormone therapy. Studies investigating this risk in postmenopausal women receiving hormone replacement therapy found heterogeneous results (e16, e17, e18). Transdermal estradiol therapy without co-administration of progestin appears to be no significant additive risk factor in this patient population. The potential negative effect of temporarily discontinuing GAHT on mind and body, the risk profile and the treatment used have to be taken into consideration when making recommendations on the perioperativen management of GAHT (23). Most treating clinicians currently recommend to discontinue the hormone therapy for two weeks prior to scheduled surgical interventions (24).
Occasionally, weight gain of 3 to 4 kg, on average, is observed (25, 26). In addition, older studies showed an increase in triglycerides (26, 27) from 76 mg/dL to 128 mg/dL, on average, (p<0.001) and in 11% of cases a maximum increase in liver enzyme levels to the 2.5-fold of the upper limit of normal (ULN) (12). When transdermal estradiol formulations are used, unfavorable changes in these laboratory parameters are significantly less common (27) or levels even decrease to the female reference range (17).
Long-term data on cardiovascular risk are scarce. However, a recent study found an increased occurrence of cerebral ischemia in transgender individuals receiving GAHT compared to age-matched women (2.4-fold risk increase) and men (1.8-fold risk increase) (28). The rate of myocardial infarction was higher compared to biological women but comparable with the rate in age-matched men (28, 29). From about age 50 years onwards, it is recommended to reduce the estradiol dose, mimicking the normal age-related hormonal changes (30). Nevertheless, it may be useful to continue treatment with a low maintenance dose beyond the statistical age of menopause to preserve bone density (31). If additional risk factors for osteoporosis are present and especially in the rare cases where GAHT is not continued after orchiectomy, e.g. because of contraindications, it is recommended to measure bone density using dual-energy X-ray absorptiometry (DXA) (9). However, the costs of DXA for this indication are not covered by German statutory health insurance funds.
While, especially in patients receiving high doses of estradiol, mild increases in prolactin levels are common and considered acceptable, relevant increases of prolactin levels >2x ULN may require an adjustment of the estradiol dose, once functional causes of hyperprolactinemia (e.g. preceding palpation of the breast) have been ruled out. If elevated levels persist, magnetic resonance imaging (MRI) of the pituitary gland should be performed since isolated cases of prolactinoma have been reported among patients receiving long-term high-dose estradiol therapy (32). In a recent Dear Doctor letter (“Rote-Hand-Brief”), a dose-dependent increase in the risk of meningioma occurrence has been described for patients treated with cyproterone acetate.
GAHT leads to testicular atrophy and over the course of treatment potentially to irreversible infertility (33). Information about theses consequences of the therapy and the options for preserving fertility (eBox) should be an integral part of the informed consent discussion.
Female-to-male gender dysphoria
Gender-affirming hormone therapy of female-to-male transsexual persons is based on testosterone administered as a transdermal gel or intramuscular depot preparation. A progestin can be added temporarily to the regimen to suppress menstruation until adequate suppression of the gonadotropic axis is achieved by testosterone (9). Progestin preparations need to be taken very regularly to ensure reliable menstrual suppression. Typically, treatment is started with a low dose taken once daily. If this is not successful, the dose can be increased to twice daily or, alternatively, a GnRH analog may be used. Further information about the preparations used and the recommended doses is presented in Table 1.
Course and limitations of treatment
Table 2 gives an overview of the course of treatment over time and its limitations.
Adverse reactions and risks
Adverse reactions and risks are listed in Table 3. Acne is the most common adverse reaction of testosterone therapy (17, 34). Depending on the severity and form of acne, topical retinoids, benzoyl peroxide, adapalene, azelaic acid, or clindamycin are used. Systemic treatment with retinoids or antibiotics is reserved for severe forms of acne (e19). Combination oral contraceptives with anti-androgenic progestin component are not suitable for the treatment of transgender men (35). In transgender men receiving retinoid treatment who are sexually active with biological men, reliable contraception has to be ensured because of the teratogenicity of the drug.
In the experience of the authors, an increase in aggressive behavior is occasionally reported. This issue should already be addressed prior to the start of treatment and regularly discussed over the course of therapy.
Because of the effect of testosterone on erythropoiesis, up to 11% to 17% of these patients develop erythrocytosis. This risk increases with increasing duration of the hormone therapy and the size of the testosterone dose, but essentially even patients with normal testosterone levels are at risk (17, 36). If side effects occur, the dose of testosterone should be reduced or the injection interval extended. Currently there is no reliable answer to the question whether erythrocytosis in transgender men increases the risk of thrombosis to an extent which is similar to that seen in patients with myeloproliferative disorders (24).
Body weight can increase by 2 kg to 4 kg on average (25, 26); however, an increase in muscle mass is also noted. While some studies indicated an unfavorable effect on lipid metabolism (increase in LDL cholesterol and decrease in HDL cholesterol) (25, 26), other studies found that blood lipid levels rather tend to align with the male reference range (17). Overall, there is some evidence indicating a somewhat increased risk of cardiovascular events (28, 29). It appears that if modern, guideline-based treatment regimens are used, relevant increases in liver enzyme levels occur significantly less frequently (17, 27) compared to the rates reported in earlier studies (12).
Testosterone therapy alone does not provide adequate contraception before gonadectomy is performed. Safe contraceptive options which can be used in combination with GAHT include barrier methods, oral progestins as well as hormone-free or progestin-releasing intrauterine devices (37). In the informed consent discussion, the issue of contraception as well as the options for preserving fertility (eBox) must be addressed.
After the initiation of treatment, a regular clinical and laboratory follow-up of the patients is required (9). During the first year, checks at three-month intervals are useful; in the long term, checks should be performed every 6 to 12 months and be continued even after the patient underwent gender-affirming surgery. It is useful to measure serum sex hormone levels to assess the required dosing and, above all, to prevent overtreatment. In transgender women, the goal should be to achieve estradiol levels in the middle of the reference range for premenopausal women (<200 pg/mL) and testosterone levels within the reference range for women (< 55 ng/dL). The development of a female breast shows marked interindividual differences, occurs mainly during the first one to two years of hormone therapy and frequently remains incomplete at puberty level. Several studies have shown that breast development does not correlate with the estradiol levels measured (17, 18, 38). Increasing the estradiol dose beyond the normal limit does not result in further growth of the breast, but increases the risk of adverse long-term effects of the hormone therapy.
In transgender men, the goal is to achieve a testosterone level within the male reference range (approx. 250–840 ng/dL). Hemoglobin and hematocrit are important markers of the effect of testosterone (17, 36) and should be regularly monitored over the course of treatment because of the risk of erythrocytosis, among others.
In addition, patients should be screened for potential adverse reactions and risks on a regular basis. During screening, patients should be asked about risk factors and possible co-medications. Furthermore, body weight, blood pressure, liver enzyme levels, lipid status, blood count, and, in patients receiving feminizing treatment, also prolactin levels should be checked (9).
Gynecological and urological care
Male-to-female gender dysphoria
In a retrospective analysis of more than 2000 transgender women receiving feminizing GAHT, a recent study from the Netherlands has shown a 46-fold increase in breast cancer risk among transgender women compared to men. However, with a standardized incidence ratio of 0.3, the incidence of breast cancer in transgender women remains below the incidence observed in biological women (39). It is recommended that transgender women attend the standard gynecological screening program (9).
Since the prostate gland is not removed during genital gender-affirming surgery but remains in situ and sporadic cases of benign prostatic hyperplasia (40) and prostate cancer (e21) have been reported in transgender women receiving hormone therapy, annual checks of prostate-specific antigen (PSA) levels and clinical examinations of the prostate gland are recommended (9).
Female-to-male gender dysphoria
Since testosterone is aromatized to estradiol, patients receiving GAHT are in principle still at risk for hormone-dependent cancers. While related data are scarce, overall hysterectomy with bilateral salpingo-oophorectomy is recommended. It is also recommended that until patients have undergone this procedure, or as an alternative if no surgery is performed, they should attend regular gynecological screening examinations (9).
Despite their importance, these screening examinations are frequently not or only irregularly attended. The psychological barrier for transgender men to undergo a gynecological examination is often high. Reports of transgender men finding it very difficult to be accepted by a gynecologist’s practice are not uncommon (7). It is critical that transgender men have access to gynecological care—even after their legal sex status has been changed and their registered gender is male.
Treatment of pre-existing chronic conditions and intercurrent diseases
Attention should be paid to a few peculiarities and potential drug interactions (Table 4).
In memory of Dr. Sophinette Becker, 1950–2019, former Head of the Sexual Medicine Outpatient Clinic of the Frankfurt University Hospital, longstanding co-publisher of the “Zeitschrift für Sexualforschung“ and co-founder of the Rhein-Main Working Group on Transidentity.
Conflict of interest
The authors declare no conflict of interest.
Manuscript received on16 January 2020, revised version accepted on 25 June 2020
Translated from the original German by Ralf Thoene, MD.
Dr. med. Gesine Meyer
Fachärztin für Innere Medizin, Endokrinologie und Diabetologie
60596 Frankfurt am Main
Cite this as:
Meyer G, Boczek U, Bojunga J:
Hormonal gender reassignment treatment for gender dysphoria.
Dtsch Arztebl Int 2020; 117: 725–32.
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