Modern approaches to the management of gender dysphoria from endocrinologist`s viewpoint: clinical case

Introduction

Currently, the world community is paying more and more attention to the discomfort and suffering of men and women due to forced conformity to gender dimorphism. As early as 1979, when the World Professional Association for Transgender Health (WPATH) was founded, the first Standards of Care for Persons with Gender Dysphoria/Gender Incongruence were published [1]. In the following years, the terminology and its application have changed regularly, and today, the American Psychiatric Association’s classification system has enshrined the term “gender dysphoria” in the diagnosis of persons who are dissatisfied with their assigned gender. Moreover, in ICD-11, which came into effect in 2022, the World Health Organization (WHO) suggested using the term “gender incongruence” [2]. Thus, in the modern medical community, the following terms are used to describe the problem of gender dysphoria:

• - “transgender” is an umbrella term for individuals whose behavior or self-expression does not match their sex at birth;
• - “gender dysphoria”, a discomfort resulting from a discrepancy between a person's sex at birth and their gender identity;
• - “transgender male” (FtM) – a biologically female person who identifies with the male gender and wants to be a man;
• - “transgender woman” (MtF) – a biologically male person who identifies with the female gender and wants to be a woman;
• - “gender correction” – medication and/or surgery to adapt one's body to one's gender identity;
• - “transition” – the period of time required to change physical appearance, social role, and documents to the opposite relative to the biological sex [3].

In the Russian Federation, since 2018, there have been regulations in force, according to which a person wishing to undergo a sex correction procedure must obtain a conclusion from a board consisting of a psychiatrist, medical psychologist, and sexologist, confirming the diagnosis of “gender dysphoria”, which results in the possibility to change documents and conduct medical sex correction (Order of the Ministry of Health of the Russian Federation of October 23, 2017 No. 850n “Approval of the Form and Procedure for Issuing a Medical Organization Document on Sex Change”, registered in January 19, 2018 No. 49695). It should be noted that all medical gender correction procedures are paid solely from the patients’ own funds, which, in the authors’ opinion, is not entirely fair.

One of the most difficult tasks in assisting people with gender dysphoria is gender correction, which of course is multidisciplinary, and its success depends on the effective cooperation of specialists qualified in helping these patients, such as a psychiatrist, an endocrinologist, and a surgeon. Thus, in addition to direct diagnostic testing, patients will require psychotherapy or psychological counseling, hormone replacement therapy, and in some cases, surgical sex reassignment. Given that gender dysphoria may mask other conditions similar in symptomology, most clinical guidelines from professional societies, including WPATH and the Endocrinological Society, state that the diagnosis should only be made by a mental health professional with a high level of competence in using the Diagnostic and Statistical Manual of Mental Disorders (DSM-5 and ICD), and insist on a differential diagnosis of gender dysphoria/gender incongruence and other conditions similar in manifestations [1][3].

If one talks about the stages of gender correction, the first and most significant is еру confirmation of a diagnosis of gender dysphoria made by a psychiatrist. The success of the entire process of gender correction largely depends on the correctness of this stage. Only at the second stage, the patient can be referred to an endocrinologist for hormone therapy. Its goal is to decrease the level of endogenous hormones in order to weaken the clinical manifestations of secondary sex characteristics of the current biological sex, as well as to replace the desired gender with exogenous hormones [3].

Therapy regimens for FtM transgenders to stimulate masculinization are based on the principles of hormonal treatment of men with hypogonadism and may include the use of parenteral and transdermal testosterone preparations [4]. At the same time, the expected clinical changes appear later. For example, in the first 6 months of therapy, cessation of menstruation, increased hair growth in androgen-dependent areas, an increase in libido, appearance of acne, and an increase in muscle mass may be noted; while changes in the tone of voice, clitoromegaly, and in some cases baldness of the scalp may appear closer to the end of the first year of therapy [4].

The treatment regimen for MtF transgender people is more complex because progestins, GnRH agonists, and spironolactone may be required to suppress testosterone levels along with physiological doses of estrogen taken orally or transdermally, due to their pronounced antiandrogenic activity [5]. Clinical changes occurring in the first year of therapy include decreased growth of body and facial hair, decreased libido, fewer spontaneous erections, and redistribution of fat mass [5]. During the second year after the start of hormone therapy, growth and development of the breasts begin, but it should be taken into account that these changes are individual in nature [6][7].

It is important to remember that transgender people often have inflated expectations about clinical changes and their rate of progression during hormone therapy and, as a result, seek to enhance them through disruption of their hormone regimen. This approach can lead to the development of serious adverse consequences, the prevention of which is also an important task for an endocrinologist. Among the possible risks of hormone therapy are thromboembolic disease, macroprolactinoma, breast cancer, coronary heart disease, cerebrovascular disease, and cholelithiasis during estrogen therapy. At the same time, testosterone treatment can result in erythrocytosis, severe liver dysfunction, ischemic heart disease, cerebrovascular disease, arterial hypertension, and breast or uterine cancer.

To prevent adverse effects, regular monitoring of weight and blood pressure, clinical changes, and potential adverse effects in response to treatment, as well as laboratory monitoring of sex steroid hormone levels every 3 months during the first year of therapy and once or twice a year thereafter, should be performed [3].

The standard monitoring plan for transgender FtM patients includes monitoring the patient every 3 months for the first year of therapy and 1–2 times a year thereafter to assess virilization and prevent adverse events. The main laboratory parameters to be monitored include total testosterone, which should be evaluated every 3 months until male norms are reached (400–700 ng/dL), hematocrit and hemoglobin, which are determined before therapy, and then, every 3 months during the year. Blood pressure, weight, and lipid profile should also be assessed at each visit. In other words, the main monitoring issues are maintaining total testosterone levels in the physiological range for men and preventing adverse events such as erythrocytosis, sleep apnea syndrome, excessive weight gain, arterial hypertension, and lipid metabolism disorders [3].

MtF transgender women are monitored every 3 months during the first year of hormone therapy, and then, once or twice a year to assess feminization and prevent adverse events. Since estrogen overdose, due to its significant increase in plasma levels, may lead to a dramatic increase in the risk of thromboembolism, liver dysfunction, and the development of arterial hypertension, estradiol levels should not exceed values typical for young women (100–200 pg/ml). Among other parameters, special attention should be paid to total testosterone, the values of which should not exceed 50 ng/dL, and serum electrolytes, in particular, potassium when taking spironolactone, which should be evaluated once every 3 months during the first year of therapy [3]. For timely detection of possible complications, there is a study of bone mineral density at high risk of osteoporotic fractures, screening for cancer and for thrombophilia in patients with a burdened history or heredity [8].

It should be noted that up to 20% of MtF-transgender patients may have increased prolactin levels, which is probably due to the growth of lactotrophic cells of the pituitary gland and, as a result, an increase in the anterior lobe [9]. At the same time, a part of patients may take psychotropic drugs which, in turn, may also influence prolactin levels [10].

The last and most important step in treatment is surgery. It must be said that transgender people do not always choose this treatment, and in some cases, they can successfully live in their preferred gender role without genital surgery. To date, there are three categories of gender affirmation surgeries for transgender MtFs: facial feminization for more feminine features, breast augmentation, and genital reconstruction, which include bilateral orchiectomy, penectomy, and vaginoplasty. For FtM patients, surgical treatment options include breast reduction surgery, oophorectomy, hysterectomy and/or vaginectomy, phalloplasty, and metoidioplasty. Because of its highly invasive and irreversible nature, genital surgery should only be performed after hormone therapy and living in the patient's preferred gender role for at least one year. It is also important to make sure that gender dysphoria is persistent, that the patient is able to make informed decisions, and that all concomitant medical and mental health issues are compensated for [1]. According to the publications, cases of postoperative frustration in patients are most often provoked by the presence of concomitant psychiatric pathology, as well as a lack of support from others. Therefore, it is very important to try to avoid inflated expectations in the patient and timely assess the potential psychological and social risks of a failed medical intervention by providing full information about the possibilities and limitations of various treatment options [3].

Thus, the currently developed algorithms of medical care for individuals with gender dysphoria describe in detail the mechanism of gender correction, the contribution of various specialists in this process, as well as possible risks and methods of their prevention. Only careful adherence to them without violating the order of stages can lead to the successful achievement of the final result. While any deviations from these algorithms due to objective and subjective reasons entail serious life-threatening consequences.

Clinical Cases

Clinical case 1. MtF patient P., 25 years old, applied for hormone replacement therapy to correct his sex. It should be noted that the patient’s mother was present at the consultation and actively supported him and participated in the discussion of his medical history and treatment plan.

Medical history. The patient denies any mental diseases in the family. The MtF patient was an only child in the family; he was unsociable, quiet, and obedient by character. After puberty, his libido was decreased; he did not show any special interest in girls. At the age of 15, discomfort in wearing men’s clothes appeared. He started his sex life at the age of 19. The discomfort of not accepting his own sex began to increase. At the age of 21, he started to look for information about this subject on the Internet. He developed a strong desire to change his sex. At the age of 23, he turned to a psychiatrist, who conducted differential diagnostics of gender dysphoria with other conditions, having similar clinical manifestations. As a result, the medical board made the following conclusion: “Based on the anamnesis, dynamic observation, objective psychiatric status, gender identity disorder is diagnosed in the form of transsexualism (F64.0); no data for the endogenous process were found. There are no mental status contraindications to surgical sex correction and passport sex reassignment”. The MtF patient was also referred to an endocrinologist for hormone replacement therapy. At the age of 24, Androcur 25 mg per day and Estrogel 0.6 mg/g per day were prescribed to the patient, which he received for 6 months. The desired effect was not achieved during the treatment, and the levels of total testosterone (33 nmol/l) and estradiol (16.8 pg/ml) characteristic of the male gender persisted, so the patient started searching for alternative methods of sex correction via the Internet. Since there were no expected results, the patient again consulted an endocrinologist.

The objective examination revealed a male physique and excessive body weight (height – 172 cm, weight – 84 kg, body mass index – 28 kg/m²). Breathing in the lungs was vesicular, no rales. Heart tones were clear and rhythmic. Blood pressure – 120/75 mm Hg, heart rate – 74 bpm. Testicular volume was less than 10 ml. The patient also reported decreased libido and decreased spontaneous erections. Taking into account the absence of pronounced specific effects of sex correction, the ongoing hormonal replacement therapy was adjusted. Thus, the dosage of Androcur was increased to 50 mg per day, and Estrogel was replaced by Proginova 4 mg per day. It should be noted that before correcting the hormonal therapy for the MtF patient, the risks of developing complications of this treatment were assessed for the first time. Risk factors for thromboembolic disease were determined, among which only elevated BMI was identified. In addition, the target level of prolactin was identified, as well as normal ALT and AST values. According to medical care algorithms for individuals with gender dysphoria, an MtF patient follow-up plan was developed, which included visits every 3 months for 1 year to assess the efficacy and safety of hormone replacement therapy.

After 3 months, a minor redistribution of fat mass and breast growth were noted at the routine checkup. Other objective data remained unchanged. According to the MtF patient, decreased libido and decreased spontaneous erections persisted. The laboratory examination revealed a decrease in total testosterone (0.73 nmol/L). There was also an increase in estradiol (87.4 pg/ml), but the values were not within the target range for transgender women (100–200 pg/ml), so the Proginova dose was increased to 6 mg per day.

At the next examination after another 3 months, there was a marked redistribution of fat mass, and slight growth of the breasts continued. There was also a slight decrease in muscle mass and oiliness of the skin. The MtF patient reported a lack of libido and spontaneous erections. The laboratory examination revealed the same decreased level of total testosterone (0.86 nmol/L). Target values of estradiol (103.2 pg/ml) were also noted. However, the patient was dissatisfied with the available result, wanted faster development of the effects of hormone therapy, and insisted that the dosage be increased. It should be noted that the patient was already receiving Androcur and Proginova in maximum tolerated doses. This information was described to the MtF patient in great detail, as well as the possible risks of increasing the dosages of hormonal drugs.

The patient did not show up for his next visit 3 months later. Six months later, the MtF patient’s mother came to the appointment with her son’s medical records. It turned out that patient MtF himself began to correct the hormonal therapy based on the data obtained on the Internet due to his dissatisfaction with the results. Thus, he started taking medications without monitoring his hormone levels. Two months later, the MtF patient suffered a deep vein thrombosis, for which he discontinued treatment. According to the mother’s words, the patient refused further therapy due to fear for his condition after suffering a deep vein thrombosis, despite the continuing discomfort of not accepting his sex.

Clinical case 2. FtM patient P., 23 years old, applied for hormonal therapy to correct her sex.

Medical history. The patient denies any mental illness in the family. The FtM patient was an only child in the family; quiet, obedient, and moderately sociable by character. Since childhood, she spent more time in the company of boys. She felt extremely uncomfortable during puberty and felt awkward about the beginning of the menstrual cycle. From the age of 16 years old, she started wearing men’s clothes and wore a corset to hide her breasts. The patient is not sexually active. The discomfort of not accepting her gender began to increase, there was a persistent desire to change her gender to male, and at the age of 21, she went to a psychiatrist. After conducting differential diagnostics of gender dysphoria, a medical board made the following conclusion: “Based on the anamnesis, dynamic observation, objective mental status, disorder of sexual identification in the form of Transsexualism (F64.0) was diagnosed; no data for the endogenous process were found. There are no mental status contraindications to surgical sex correction and passport sex reassignment”. The FtM patient started hormone therapy with Nebido 1000 mg once every 3 months without a doctor’s prescription. After 3 months, at the age of 22 years old, without evaluation of the effectiveness of the therapy by an endocrinologist and a psychiatrist, she underwent a mastectomy with the formation of a male breast. Due to the peculiarities of the pharmacodynamic action of Nebido, in particular, the gradual decrease in the clinical effect of testosterone after injection, the FtM patient consulted an endocrinologist for the correction of hormone replacement therapy.

Objective examination showed that the patient had a male physique and excessive body weight (height – 173 cm, weight – 62 kg, body mass index – 20.7 kg/m²). Breathing in the lungs was vesicular, no rales. Heart tones were clear and rhythmic. Blood pressure – 105/70 mm Hg, heart rate – 68 bpm. There were isolated acne and hair growth on the face. There were scars on the chest from a mastectomy. According to the FtM patient, her menstrual cycle had been absent for 2 years. ALT, AST, and hematocrit were determined to assess the risks of the therapy and were found to be within normal limits. The FtM patient was prescribed Androgel 1% 5 g per day. In addition, a patient follow-up plan was developed, which included visits every 3 months for 1 year to assess the efficacy and safety of hormone replacement therapy.

After 3 months, objective data remained unchanged at the routine examination. The laboratory examination revealed a low level of total testosterone (0.73 ng/mL) and an elevated level of estradiol (126 pg/mL) for transgender men. Despite this, therapy at the previous dose was continued. At the same time, lipid metabolism parameters, ALT, AST, and hematocrit were within the target values.

At the next examination after another 3 months, a coarsening of the voice appeared. At the same time, according to the laboratory results, there was an increase in total testosterone levels (4.13 ng/ml), while estradiol levels (42 pg/ml) were within the target range for transgender men. The ongoing hormonal replacement therapy was continued unchanged.

At the next follow-up examination 3 months later, the FtM patient noted a significant change in her condition. In particular, body hair growth and muscle mass gain appeared, despite similar levels of total testosterone (4.43 ng/mL) and estradiol (47 pg/mL). Lipid metabolism indices, ALT, AST, and hematocrit remained within the target values.

At the next examination, 1 year after the start of Androgel therapy, redistribution of fat was added to the clinical effects. The FtM patient noted excellent well-being and reported that she had changed her sex in her passport. According to the laboratory examination, there was an increase in total testosterone (6.77 ng/mL) and the same level of estradiol (43 pg/mL).

Given the positive effect of the ongoing hormonal replacement therapy and the comfort of being in gender identity, surgical sex correction was recommended. Hysterectomy and oophorectomy were performed during the ongoing hormonal replacement therapy, and reconstruction of the fixed part of the urethra together with phalloplasty was also planned.

Discussion

Using the example of these clinical cases, the authors wanted to demonstrate that different results of hormone replacement therapy can be achieved depending on compliance or non-compliance with the developed algorithms of medical care for individuals with gender dysphoria. Thus, in clinical case #1, the patient received adequate hormone replacement therapy in maximum tolerated doses, which showed a positive trend. Moreover, the risks of complications were assessed before the treatment began, and the developed monitoring plan allowed the specialists to control both the clinical effect of therapy and possible side effects, which were discussed at each examination. However, due to the patient’s peculiarities, he formed opinions about possible treatment results obtained from the Internet and decided to self-correct hormone therapy. As a result, the patient developed deep vein thrombosis, therefore, all medications were discontinued, and, as a result, the achieved results were lost, despite the continuing discomfort of not accepting his sex. Thus, deviation from the algorithms of medical care for persons with gender dysphoria due to objective and subjective reasons led to serious life-threatening consequences.

At the same time, in clinical case #2, despite the untimely mastectomy performed due to the lack of evaluation of the efficacy of the ongoing treatment and the short period from the start of the drug administration, in general, the patient was prescribed adequate hormone replacement therapy and a follow-up plan was developed, which was fully adhered to. As a result, clinical and laboratory sex changes and comfort from being in her gender identity were achieved. Hysterectomy and oophorectomy were successfully performed, and further surgical sex correction was planned. Thus, compliance with the algorithms of medical care for individuals with gender dysphoria allowed the patient to obtain the desired result of treatment without significant complications. However, such patients require obligatory dynamic monitoring.

Conclusion

Gender reassignment is certainly a complex task, the success of which largely depends on a multidisciplinary team composed exclusively of qualified professionals competent in gender dysphoria. Before prescribing hormone replacement therapy, the endocrinologist needs to make sure that the patient meets the criteria for a diagnosis of gender dysphoria, to be sure that the patient's desire to change gender is justified, and that all the consequences of therapy, including possible physical changes and timing of their occurrence, are explained.

Hormone replacement therapy for FtM transgender people is based on the principles of treatment for men with hypogonadism. While endocrine therapy of MtF-transgender men includes estrogens and also drugs with anti-androgenic action, such as progestins, GnRH agonists, spironolactone, and cyproterone acetate. In addition, there should be regular clinical monitoring of physical changes and potential adverse effects in response to hormone replacement therapy. Only after clinical and laboratory effects are achieved, as well as the comfort of being in one’s gender identity, can one move on to the stage of surgical sex correction.

Thus, the currently developed algorithms of medical care for individuals with gender dysphoria describe in detail the mechanism of sex correction, the contribution of various specialists in this process, as well as possible risks and methods of their prevention. Only careful adherence to them without disrupting the sequence of steps can lead to the successful achievement of the final result; while any deviations from these algorithms due to objective and subjective reasons entail serious life-threatening consequences.