IDEA Group Consensus Statement on Medical Management of Adult Gender Incongruent Individuals Seeking Gender Affirmation as Male

Abstract

Gender-affirming hormone therapy (GAHT) is the most frequent treatment offered to gender-incongruent individuals, which reduces dysphoria. The goal of therapy among gender-incongruent individuals seeking gender affirmation as male is to change their secondary sex characteristics to affect masculine physical appearances. GAHT greatly improves mental health and quality of life among gender incongruent individuals. India-specific guideline for appropriate care for gender-incongruent individuals is almost absent. This document is intended to assist endocrinologists and other healthcare professionals interested in gender incongruity for individuals seeking gender affirmation as male. A safe and effective GAHT regimen aims to effect masculinising physical features without adverse effects. In this document, we offer suggestions based on an in-depth review of national and international guidelines, recently available evidence and collegial meetings with expert Indian clinicians working in this field. Clinicians represented in our expert panel have developed expertise due to the volume of gender incongruent individuals they manage. This consensus statement provides protocols for the hormone prescribing physicians relating to diagnosis, baseline evaluation and counselling, prescription planning for masculinising hormone therapy, choice of therapy, targets for monitoring masculinising hormone therapy, clinical and biochemical monitoring, recommending sex affirmation surgery and peri-operative hormone therapy. The recommendations made in this document are not rigid guidelines, and the hormone-prescribing physicians are encouraged to modify the suggested protocol to address emerging issues.

INTRODUCTION

Gender incongruence describes a condition where an individual’s gender identity differs from the gender assigned at birth. In many individuals, gender incongruence leads to clinically significant distress (gender dysphoria) related to a strong desire to conform with another gender, which may include a desire to change primary and/or secondary sex characteristics. Gender-affirming care includes social transitioning, hormone therapy and affirming surgeries.^[1] Limited data exist on testosterone therapy and surgical outcome in transgender men from India.^[2] Several medical professional organisations have issued guidelines to guide healthcare providers in caring for gender incongruent individuals.^[1] They suggest that decisions regarding social transition, hormone therapy and affirming surgeries should be made in conjunction with an experienced mental healthcare professional (MHP), and the management and monitoring of gender incongruent individuals should be made by a multidisciplinary team. In this model of multidisciplinary care, endocrinologists and hormone-prescribing physicians play an important role. Apart from inducing physical changes, hormone therapy itself is an affirmation of gender identity. Following the National Legal Services Authority of India (NALSA) judgement in April 2014 by the Supreme Court of India (which recognised the right of every citizen to self-determine their gender), more and more individuals are seeking gender-affirming therapy across the country. Despite this historic judgement, delayed presentation and delayed consultation are common in India due to a lack of social, family, and health awareness support.^[3] Moreover, there is a paucity of published data from India on the management of transgender individuals and a lack of India-specific guidance for treating clinicians who are involved in the care of gender-incongruent persons. We have already published a consensus statement on gender-affirming hormone therapy (GAHT) of adult gender incongruent individuals seeking gender affirmation as female to assist endocrinologists and hormone-prescribing physicians whose adult gender incongruent client is seeking gender affirmation as female.^[4] The current document is intended to assist endocrinologists and hormone-prescribing physicians whose adult gender-incongruent client is seeking gender affirmation as male in a supportive, non-judgmental and inclusive clinical environment.

MATERIALS AND METHODS

This consensus statement is based on guidelines published by internationally and nationally recognised professional bodies [like The Endocrine Society,^[1] World Professional Association for Transgender Health^[5] (WPATH), Sappho Good Practice Guide^[6]] plus expert opinion of a core group of professionals. The expert group suggested the following recommendations:

Recommendation 1: Diagnosis

Evidence: Gender incongruence is no longer classified as a mental health disease in the International Classification of Disease-11 (ICD-11) and is classified under sexual health.^[7] The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria [DSM-5 302.85 (F64.9)] are conventionally used for the diagnosis.^[8] DSM-5 diagnostic criteria have been endorsed by the Endocrine Society (2017), the WPATH (2012) and the Sappho Good Practice Guideline for diagnosing gender incongruence/dysphoria.^[1,5,6]

Consensus: The expert group recommends the usage of DSM 5 as diagnostic criteria for the diagnosis of gender incongruence in adults [Annexure 1].

ANNEXURE 1

Evidence: The diagnosis of gender incongruence should be established by a trained MHP in line with the DSM-5 criteria. This has been highlighted by the Endocrine Society^[1] and the WPATH guidelines_.^[5] In Annexure 1, the diagnostic criteria for Gender Incongruent Adults, as recommended by the DSM-5, are summarised.^[8] It is also worthwhile to note that not all gender incongruent or gender-diverse people experience dysphoria, and not all gender incongruent individuals cross-dress. Crossdressing, a traditionally important step of social transition, has lost its significance as dressing in a gender-ambiguous or gender-fluid manner has gone mainstream and is not the preserve of gender-incongruent persons. A multidisciplinary approach is required, and the diagnosis is best established by an MHP.^[1] A distinction must be made between gender incongruence/dysphoria and other conditions that may have an overlapping presentation, e.g., body dysmorphic disorder. Other underlying psychiatric disorders must also be assessed and excluded. However, the current trend suggests that the diagnosis is patient initiated (some are confident in affirming their gender identity with clear treatment goals), and treatment can be started by any clinician with appropriate knowledge.^[9]

The diagnosis of gender incongruence is challenging in a pre-pubertal child or adolescent and is beyond the scope of this document, which focuses on adults with gender incongruence.

Consensus: The hormone-prescribing physician should seek help from MHP to confirm the diagnosis and exclude other underlying psychiatric comorbidities.

Recommendation 2: Baseline Evaluation and Counseling

Evidence: The Endocrine Society recommends that GAHT should be offered only to individuals after they have attained the age of consent.^[1] The Indian legal system recognises the age of consent as 18 years and Above.^[10] The Sappho Good Practice Guide to gender transition recognises 18 years as the appropriate age to provide consent,^[6] and the expert group endorses the same. This contrasts with the recommendations of the Endocrine Society (US)^[1] or the WPATH guidelines,^[5] where the age of consent is 16 years. The gender-incongruent person requires a detailed mental health/psychological evaluation by an MHP or clinical psychologist.^[11] This includes an assessment of the capacity to give consent and a history of dressing in the confirmation of the appropriate gender for at least three months.

A detailed medical evaluation is recommended, including the documentation of secondary sexual characteristics. A routine pre-treatment laboratory evaluation includes a hemogram, fasting plasma glucose, lipid profile, renal, liver functions, and thyroid profile to exclude the presence of medical conditions that may increase the complications associated with GAHT and/or are likely to be exacerbated by it. The circulating levels of sex hormones do not seem to differ in persons with or without gender incongruence.^[12] However, an assessment of physical examination and baseline sex hormone levels helps exclude previously undiagnosed disorders of sex differentiation, the prevalence of which may be higher in this population. Additional tests, including lymphocyte karyotyping and bone mineral density, may be recommended where required. This recommendation is in congruence with the Endocrine Society^[1] and WPATH guidelines.^[5]

Initiation of GAHT requires the documentation of informed consent in a language the subject can understand and comprehend.^[13] The consent should mention that the subject understands the benefits and limitations of GAHT, the onset and time course of the expected physical changes, and the possible known and unknown risks associated with masculinising medical therapy.^[13] Counselling should also extend to sharing information about the need to maintain a healthy lifestyle, use of appropriate contraception, the need for regular medical evaluation to evaluate response to treatment and emergence of possible adverse events, and the need for adequate treatment of other medical conditions such as overweight/obesity, hypertension, diabetes, etc.

GAHT can cause infertility.^[5] The cumulative dose and duration of exogenous testosterone therapy that causes permanent infertility are not known. The initial evaluation and counselling should include a discussion about the effects of treatment, especially surgical (mastectomy, salpingo-oophorectomy, and hysterectomy), on future fertility and needs to be clearly explained. It is important to appraise the patient about the irreversibility of such surgical treatment and to discuss the option of cryopreservation of oocytes or embryos.^[9] The potential cost implications and resource limitations of the cryopreservation of both oocytes and embryos should also be discussed.

Consensus: The expert group recommends the following checklist before the initiation of GAHT:

1. Confirmation of the attainment of the age of consent (above the age of 18 years)
2. Confirmation preferably from one MHP [Annexure 2] or from one Registered Clinical Psychologist [Annexure 3] to confirm persistent gender incongruence and to exclude other confounding mental health disorders
3. Confirmation that the patient can understand the consequences and possible risks associated with masculinising medical therapy and is capable of taking hormones in a responsible manner [Annexure 4]
4. Affidavit affirming the name and the preferred gender (optional)
5. Documented dressing in confirmation of the appropriate gender (real-life experience) for at least three months duration is preferable but not mandatory
6. Physical examination: Height, weight, blood pressure, and examination of breasts, & genitalia (with due consent) needs to be done for all
7. Laboratory investigation: basic investigations must be done for all, and some additional tests may be carried out where needed
8. In resource-limited setting: complete blood count including hematocrit, fasting plasma glucose, lipid profile, serum creatinine, liver function test, thyroid functions (in the presence of goitre or family history), and serum estradiol, total testosterone, follicle-stimulating hormone (FSH), luteinising hormone (LH), and viral serology (hepatitis B surface antigen, anti-hepatitis C antibody, & human immunodeficiency virus)
9. Additional tests: HbA1c (if there is suspicion of dysglycemia or diabetes), lymphocyte karyotyping (if there is suspicion of disorders of sex development), Venereal Disease Research Laboratories test (if there is a history of high-risk behaviour), and bone mineral density (BMD) with dual-energy X-ray absorptiometry (if there are risk factors for osteoporosis).
10. Informed consent for GAHT and counselling regarding the possible effects along with risks and benefits of long-term GAHT [Annexure 4]
11. Counselling for the adoption of a healthy lifestyle with regard to body weight and substance abuse (especially tobacco use)
12. Control of other health issues if coexisting (like hypertension and diabetes)
13. Counselling for the option of cryopreservation of oocytes and embryos
14. Counselling against self-medication.

ANNEXURE 2

ANNEXURE 3

ANNEXURE 4

Recommendation 3: Regimen for Masculinising Hormonal Intervention

Evidence: The gender-affirming hormonal therapy is tailored to meet the patient’s desired goal while weighing the risk-to-benefit ratio based on the existing comorbidities. Testosterone is the principal hormone used to induce virilisation and appears safe.^[14] Different testosterone formulations are available in different parts of the globe. The following preparations are available in India [Table 1].

Table 1: Testosterone preparations for masculinising hormonal intervention

The most commonly used formulations available in India are those that are administered via the intramuscular route. Testosterone enanthate and cypionate are usually administered weekly, but the dosing interval can be extended to every 10–14 days. Intramuscular injections are more painful than subcutaneous injections and are difficult to self-administer. Subcutaneous injections of testosterone enanthate and cypionate are reported as effective, safe, and well-accepted alternatives.^[15,16] Testosterone undecanoate is a long-acting testosterone that can be administered every 12 weeks. It is approved by the US Food and Drug Administration (FDA) for treating male hypogonadism and has been used off-label to treat transgender men.^[14] Testosterone undecanoate in the oral formulation is also available in India. There is limited but reassuring information on the relative safety and efficacy of oral preparations. Transdermal options are also good alternatives for some patients and provide a smoother serum testosterone profile. One-year follow-up data with transdermal testosterone vs testosterone undecanoate injection and testosterone enanthate injection is available. All the preparations produce comparable anthropometric, metabolic, and biochemical changes at the end of one year of use.^[17]

Testosterone gel once daily is applied on the shoulder, starting with 25% of the full dose (25 mg) per day and slowly titrated over the next few months to reach the full dose. Testosterone gel (1.62%), one packet (containing 20.25 mg) or testosterone gel (1%), half packet of 50 mg sachet is applied to clean, dry, intact skin once a day (usually in the morning). The rest half of the sachet may be used the next day if stored in a cool dark place away from sunlight. Testosterone gel may be applied on the abdomen or thighs also. However, transdermal testosterone may potentially cause virilisation of the partner or the children because of direct contact between the site of gel application and the partner or the child. The partner and children should avoid contact with unwashed or unclothed application sites in transmen using the testosterone gel.^[18]

Testosterone therapy is usually initiated with half the anticipated dose needed to adequately virilise and can gradually be titrated to reach the target serum level. Early effects of testosterone on achieving virilisation are dose-dependent, but within six months of initiation of therapy, no difference was seen between lower and higher doses of testosterone therapy. While higher doses may achieve virilisation sooner, the long-term effects of lower doses are similar, with the advantage of a lower risk of adverse events.^[19] Slow-release implantable testosterone pellets are approved by FDA for long-acting androgenic effects but are not available in India.^[20]

Pregnancy lactation and a history of breast or other estrogen-dependent cancers are absolute contraindications for testosterone therapy. There is a black box warning for both injectable and oral preparations of testosterone about malignant hypertension. Sleep apnoea, polycythemia with hematocrits of 55% or more, unstable coronary artery disease, and heart failure NYHA Grade III and IV are relative contraindications for testosterone therapy.^[1,5] In situations where adverse effects are a concern, transdermal preparations without peaks and troughs might be preferable.

Consensus:

1. Testosterone therapy in adults seeking GAHT as males can be administered via intramuscular, subcutaneous or transdermal route.
2. The starting dose of such GAHT with testosterone is usually half of the full replacement dose, and it is then gradually titrated to a full dose over a period of 3–6 months.
3. Once adequate virilisation has been attained, a lower dose (50% of the full replacement dose) may be continued to maintain masculinising characteristics.

Recommendation 4: Therapy to Stop Menstrual Bleeding

Evidence: Testosterone therapy usually results in cessation of menstrual bleeding, and the response may be seen within 1–12 months of its initiation.^[14] This depends on the dose of testosterone, route of administration, frequency of administration, duration of therapy, and the presence or absence of other structural abnormalities. Transdermal or oral testosterone undecanoate, associated with lower testosterone levels than injectable testosterone, often fails to stop menstrual bleeding.^[21]

If vaginal bleeding does not stop within three months after initiation of testosterone therapy, serum testosterone and gonadotropin (LH) level should be measured. The dose of testosterone should be adjusted to achieve the target range of testosterone.^[21,22] Transmen who continued to have cycles with male testosterone levels and suppressed gonadotropin are diagnosed as having abnormal uterine bleeding (AUB), needing further evaluation and treatment. AUB in transgender men should be evaluated similarly to cis women. It may occur due to uterine structural pathology (endometrial polyp, adenomyosis, leiomyomata, endometrial hyperplasia, and malignancy) or non-structural causes (pregnancy, coagulopathy and ovulatory dysfunction).^[23] AUB should be evaluated by a gynaecologist with pelvic imaging and endometrial biopsy if indicated.^[21]

In the absence of any pathology, adding a progestational agent (oral lynestrenol 5–10 mg daily or medroxyprogesterone 5–10 mg daily) might help in case of persistent menses with testosterone levels in the target range.^[14] Gonadotropin-releasing hormone (GnRH) analogues or depot medroxyprogesterone may also be used to stop menses.^[1,14] However, routine administration of progestogens to all transmen at the initiation of testosterone therapy is not necessary.^[22] Genital surgery, in the form of hysterectomy and/or salpingo-oophorectomy, is often necessary to alleviate gender dysphoria in transmen.^[5] The surgical procedures permanently address the issue of persistent menstrual bleeding. In case gender-affirming surgeries are not favoured by the transgender person, intrauterine progestational devices,^[24] aromatase inhibitors,^[23] or endometrial ablation^[1] can be considered. However, our experience and published data on using intrauterine progestational devices^[22] and aromatase inhibitors^[23] among transmen is limited.

Consensus:

1. Consider switching from transdermal or oral testosterone to injectable testosterone if the menstrual bleeding does not stop within three months of initiation of testosterone therapy.
2. Serum testosterone levels should be monitored. If the testosterone is not in the target range, the dose and frequency of injectable testosterone can be increased to achieve the cessation of menstruation.
3. Addition of a progestational agent (oral lynestrenol 5–10 mg daily or medroxyprogesterone 5–10 mg daily or depot medroxyprogesterone 150 mg intramuscular every three months) or GnRH analogues may be considered to stop menstrual bleeding if it continues despite adequate testosterone therapy.
4. Gender-affirming surgical procedures may be advised (hysterectomy and/or oophorectomy) to the transmen who fulfil the criteria for gender-affirming surgery. Endometrial ablation may be advised for those who do not prefer hysterectomy or invasive surgery.

Recommendation 5: Duration of Masculinising Hormone Therapy

Evidence: Individuals on GAHT need health care support throughout their lives; ideally, testosterone therapy should continue throughout their life span. The duration of testosterone therapy often depends on patient preference. Some patients prefer to continue testosterone for a few years until adequate masculinisation is achieved and stop after 3–5 years. Withdrawal of testosterone will lead to regression of masculinising features such as reduction in muscle mass, body hair and libido. There is no defined upper age limit in transmen when hormone therapy is absolutely contraindicated. Long-term testosterone administration in transmen appears safe and may be continued in old age with little risk regarding cardiovascular disease and cancer.^[25] However, testosterone may be continued into old age along with monitoring for cardiovascular/metabolic disease and malignancies of both the biological sex and the affirmed sex. Testosterone therapy showed positive benefits in sexual function, vitality, bone health, and anaemia; partial benefit in physical function, no benefit in cognition; and a negative effect in the exploratory cardiovascular trial in older cis-gender men over 65 years with unequivocal hypogonadism.^[26] The rise of hematocrit is often associated with testosterone replacement in older men.^[27] Hence, it would be preferable to use the lowest possible dose of testosterone that is adequate to maintain masculinisation and optimal bone health.^[5]

Consensus:

1. Testosterone therapy should be stopped if there is a serious adverse effect
2. Testosterone therapy may be continued for life if desired by the individual, keeping in mind the possible adverse consequences of long-term therapy related to cardiovascular disease and incidences of malignancies.
3. Lowest possible dose of testosterone adequate to maintain masculinisation should be used in older individuals.

Recommendation 6: Risks of Hormonal Interventions

Evidence: Common adverse events noticed on masculinising hormone therapy are the following:

Polycythemia-erythrocytosis occurs commonly (24.0%) in trans men using testosterone.^[28] Haemoglobin and hematocrit levels should be compared with the male reference interval, measured at baseline and every three months for the first year, and then biannually. The target hematocrit levels are between 0.50 and 0.54 L/L.^[28] Weight gain, smoking, the presence of chronic lung disease and sleep apnea contributes to the development of polycythemia.^[28] If the haematocrit level is >0.54, exclude alternative causes (e.g. smoking, chronic lung disease)^[1,28] and consider decreasing the testosterone dose or increasing the dosing interval. Changing to a more frequent injection schedule (maintaining the same total amount of testosterone over time) or transdermal preparations (which minimise the peak-to-trough fluctuations in circulating testosterone levels) may reduce the risk of polycythemia. Testosterone undecanoate, the long-acting injectable preparation, is associated with a higher possibility of polycythemia. Phlebotomy may be an appropriate short-term solution depending on the level of elevation.^[1,28]

Cardiovascular disease: Androgens represent a potential causative link with sex differences in cardiovascular disease. Worsening of cardiovascular risk factors (increase in hematocrit, decrease in high-density lipoprotein cholesterol, increase in triglycerides, increase in low-density lipoprotein cholesterol, increase in systolic blood pressure and a decrease in adiponectin and leptin) is commonly observed with androgen therapy.^[14] Despite the worsening of these risk factors, short-term testosterone treatment showed no increase in the incidence of cardiovascular events.^[14] On the other hand, transgender men on GAHT were associated with a more than two-fold increase in the rate of myocardial infarction compared with cisgender men and a four-fold increase compared to cisgender women in another cross-sectional observational study.^[29] The cardiovascular effects of long-term testosterone treatment are unknown due to the paucity of data. However, it is advisable to assess the cardiovascular risk of each individual periodically. Transgender men with androgen-excess polycystic ovary syndrome receiving androgen therapy may represent a more vulnerable population. Hyperandrogenism from both endogenous and exogenous sources may additively increase risk in the female cardiovascular system.^[30] High-risk (uncontrolled diabetes, uncontrolled dyslipidemia, or unstable coronary artery disease) transgender men should be informed of the risks. If testosterone therapy is desired, it should be continued with concurrent conventional management of the metabolic and cardiovascular disease.

Liver dysfunction-long term use of many synthetic androgens is capable of causing liver injury. Four distinct forms of liver injury have been observed: transient elevation of liver enzymes, acute cholestatic syndrome, chronic vascular injury (peliosis hepatis) and hepatic neoplasm. The alkylated test (methyltestosterone, methandrostenolone, oxymetholone, fluoxymesterone, stanozolol, norethandrolone, oxandrolone etc.), which are older preparations, are mostly linked with these adverse events.^[31] Newer esterified preparations (testosterone cypionate, enanthate and propionate) are much safer and serious hepatic toxicity is not anticipated.^[1,31]

Transmasculine persons may manifest mild-to-moderate increases in liver enzymes following testosterone initiation. But the incidence of liver injury is found to be low.^[32] The elevation in liver enzymes is usually mild and reversible on temporary discontinuation of testosterone therapy.^[33] Serious hepato-toxicity is uncommon with the currently used testosterone preparations; hence frequent liver enzymes screening is not recommended.^[32,34] However, alcohol abuse, obesity, known liver disease, or concomitant use of other medications with potential hepatotoxicity may increase the risk of liver injury. Therefore, annual monitoring of liver enzymes is suggested.

Obstructive sleep apnea (OSA): The concern that testosterone supplementation may cause or worsen OSA has arisen primarily from observational data.^[35] However, it is unclear whether the increase in OSA in transgender men is due to the addition of testosterone or the suppression of estrogen and/or progesterone.^[35] While hormone therapy is unlikely to change the actual shape of the airways, hormonal treatment can increase the fat deposition in the pharynx and tongue, leading to the narrowing of the upper airway. Therefore, transmen receiving GAHT should be counselled about the potential risk of OSA. The STOP BANG questionnaire should be used to screen for OSA in transgender men.^[36] If OSA is suspected, a detailed evaluation and management are needed per standards of care. Sleep apnea is a relative contraindication for testosterone therapy.

Pulmonary oil micro-embolism (POME): Testosterone undecanoate, the long-acting injectable preparation, is associated with the risk of pulmonary oil embolus.^[14] However, POME is rare and usually resolves within 30 minutes without medical intervention.^[37] It is advisable for the patient to remain under observation for at least 30 minutes after the injection to watch for symptoms such as cough.

Weight gain: Weight gain with testosterone therapy in transmen may be a cause for concern. However, there is conflicting evidence regarding the effect of testosterone on adipogenesis. Testosterone, rather, has been shown to decrease body fat and increase lean body mass. Body weight steadily increases from the beginning of testosterone therapy, and weight gain ≥5 kg may occur in almost 30% of transmasculine individuals following 1–2 years of hormone therapy.^[38]

Acne: Almost all transmen experience an increase in acne on the face and back after about 1–6 months of testosterone therapy. Acne peaks at six months of testosterone usage and gradually improves over time. Maintaining physiologic testosterone levels and avoiding excessive peaks associated with prolonged injection dosing intervals may help minimise acne.^[39]

Androgenic alopecia: Hair loss may begin soon after beginning hormone therapy and depends on genetic factors, dose, and duration of therapy. Almost one-third transmen develop moderate to severe androgenetic alopecia with long-term testosterone therapy.^[39] Patients should be counselled about the risk, unpredictable nature, extent, and time course of alopecia.

Consensus:

1. In patients on GAHT, hematocrit should be monitored at baseline, every three months for a year, and six months thereafter.
2. In patients where hematocrit rises, the dose of testosterone should be reduced, or the patient switched to a transdermal formulation. Phlebotomy may be considered to maintain the hematocrit below 0.54 L/L.
3. All transmen should be advised to adhere to a healthy lifestyle, including the cessation of tobacco consumption in any form.
4. Transmen on GAHT should be evaluated for cardiometabolic risk factors every six months, and these should be managed as per current standards of care.
5. Liver function tests are to be monitored annually.
6. STOP BANG questionnaire may be used to screen for OSA. New onset OSA is a relative contraindication of testosterone therapy.
7. Patients should be counselled about the risk of weight gain, acne, and androgenic alopecia with testosterone therapy.

Recommendation 7: Clinical and Biochemical Monitoring

Evidence: The long-term consequences of testosterone therapy are uncertain.^[34] There is a lack of information on the long-term effects of hormone therapy; therefore, the best strategies for surveillance remain unclear. Clinical monitoring should focus on the assessment of the degree of masculinisation and the possible appearance of adverse effects from long-term testosterone therapy. Patients with additional underlying comorbidities need frequent monitoring. Tele-consultation platforms provide an opportunity for remote monitoring of individuals who live in geographically remote or resource-limited areas in cases where physical monitoring is not possible.^[1]

A. Clinical evaluation: This should include a thorough physical examination emphasising weight, blood pressure, breast regression, facial hair growth and phallic enlargement. The physical changes expected to occur after initiating testosterone therapy, and the expected timelines are summarised in [Table 2]. These changes are highly variable and depend on the dose, route and duration of testosterone therapy.^[1]

B. Biochemical monitoring: Testosterone: Total testosterone levels should be measured every three months until they are in the target range and then 1–2 times per year thereafter.^[24] Total testosterone level should be maintained in the normal male physiological range (300–1000 ng/dl). High-dose testosterone therapy should be avoided as sustained supra-physiologic levels increase the risk of adverse reactions.^[1] For those individuals receiving testosterone enanthate/cypionate injections, mid-cycle levels are a good guide to therapeutic efficacy, and the target level is 400–700 mg/dl.^[1] For those receiving long-acting testosterone undecanoate, the value just before the next injection is a better guide, and the target level is more than 400 mg/dl.^[1] For those receiving transdermal testosterone, measurement should be done after one week of daily application (sample drawn at least 2 h after last application).^[1,24]

Table 2: Effects of testosterone therapy with expected timelines

Estradiol: Serum estradiol level is positively correlated with the severity of vaginal bleeding and spotting.^[22] Estradiol level may be measured during the first six months of testosterone treatment or until the cessation of menses for six months. Estradiol level should be in the cis-gender male physiological range (<50 ng/dl).^[24] There is a concern for undesirable estrogenic effects of exogenous testosterone. Aromatisation of administered exogenous testosterone leads to supra-physiologic serum estradiol levels with a risk of gynecomastia in males.^[40] Despite the paucity of objective data, there is a possible need for estrogen-lowering strategies adjunct to testosterone therapy in transgender men. However, there is no evidence for the management of elevated estradiol levels in medically treated transgender men.^[41] Further, the Endocrine Society guideline does not suggest routine measurement and monitoring of estradiol.^[1,9]

Consensus:

1. This expert committee suggests clinical and biochemical monitoring every three months for the first year and then once or twice per year to monitor for adequate masculinisation and any adverse reactions
2. Weight, blood pressure, breast regression, facial hair growth and phallic size should be monitored in every visit
3. Serum testosterone level should be measured every three months until the levels are in the range of 300–1000 ng/dl
4. Serum testosterone level should be measured between injections for those receiving parental testosterone enanthate and/or cypionate. Serum testosterone levels should be measured before the next injection for those receiving parental testosterone undecanoate. Serum testosterone level should be measured any time after one week of continuous application for those receiving transdermal testosterone
5. Routine monitoring of estradiol is not recommended.

C. Cancer screening Evidence: There is limited data on cancer risk in transgender men. Mortality data also remains scarce, but mortality in transmen seems to be similar to cis-gender women.^[14] In the absence of large-scale studies, it is difficult to have clear recommendations on the appropriate frequency and type of cancer screening protocols. Over-screening and under-screening can both have deleterious consequences. Moreover, some transmen may find it emotionally and physically challenging to undergo screening for ‘female’ cancers.^[5] The prevalence of hormone-dependent tumours is low, and not many hormone-dependent tumours have been reported in androgen-treated transmen.^[42] However, the use of abnormally high and off-label doses of androgen may have a potential impact on the development of future malignancies. In the absence of a specific cancer screening protocol for transgender persons, recommendations for the general population by National Comprehensive Cancer Network (https://www.nccn.org) can be followed.

Breast cancer: Testosterone is partially aromatised to estradiol; hence transmen receiving testosterone therapy may have clinically meaningful levels of circulating estrogens. Evidence for elevated estradiol levels in medically treated transgender men is limited.^[41] Breast cancer has been reported even in the postoperative residual mammary tissue following mastectomy in transmen on long-term GAHT.^[42] However, the incidence of reported breast cancer among transgender men is very low.^[14] Annual clinical examination of breast or residual sub- and periareolar tissue (if mastectomy has been done) is recommended for transmen between the age of 25 and 39 years, followed by annual mammography from age 40 years onwards.

Cervical cancer: Cervical cancer screening among transgender men is not required after a total hysterectomy with removal of the cervix. Screening for cervical cancer is indicated if cervical tissue is present. Annual Pap smear plus human papillomavirus (HPV) test (called “co-testing”) is the preferred approach because of the strong association between HPV infection and cervical cancer. Testing for HPV DNA should be done with the Hybrid Capture test, approved by the US FDA.^[43]

Endometrial cancer: Most patients are likely to undergo hysterectomy with oophorectomy, mitigating the need for screening for endometrial cancer. Testosterone is aromatised to estradiol, and the increased plasma level can be expected to produce biological effects in gender-affirming testosterone-treated transmen. Therefore, endometrial cancer remains a risk in transmen whose uterus has not been surgically removed.^[42] Ultrasonography and endometrial biopsy should be done to screen for endometrial cancer in persons who present with vaginal bleeding.

Ovarian cancer: Ovarian cancer screening among transgender men is not needed after total hysterectomy with salpingo-oopherectomy. But ovarian carcinoma can occur in testosterone-treated transmen before gender-affirming surgery.^[42] However, there is no reliable screening test for ovarian cancer in those with ovaries in situ. Screening with transvaginal ultrasound (TVS) and serum cancer antigen 125 (CA125) levels has not shown any mortality benefit^[44] and is not recommended.

Consensus:

1. Routine cancer screening of breasts should be performed irrespective of whether or not gender-affirming mastectomy has been done, as per existing cancer screening guidelines for the general population.

2. Routine screening for cervical, endometrial and ovarian cancer is not needed after total hysterectomy with removal of cervix and ovaries

3. Screening for cervical, endometrial and ovarian cancer should be done in accordance with the existing guidelines in those who have not undergone hysterectomy and salpingo-oophorectomy.

D. Bone health: Sex hormones have an important role in bone growth and maintenance. While BMD is likely comparable to cis women before initiation of testosterone therapy, there is a risk of increased bone loss following ovariectomy, especially if testosterone therapy is discontinued.^[45] It is reassuring that testosterone therapy, due to the aromatisation of testosterone to estradiol, preserves bone density in transgender men following ovariectomy. There is limited data on osteoporotic fractures in transgender men receiving adequate testosterone substitution.^[14] However, bone loss has been described in transgender men after ovariectomy, who are not adherent to or discontinue testosterone therapy or when the testosterone dose is inadequate.^[14] Adequate dosing of testosterone is therefore necessary for maintaining adequate bone density. LH may be a good indicator of the adequacy of testosterone supplementation required to maintain optimal bone health.^[45] It is, therefore, important to ensure optimal calcium and vitamin D intake and adequate testosterone therapy following ovariectomy. Patients with any interruption in testosterone therapy should be screened for bone loss and managed accordingly.

Consensus:

1. Routine screening for osteoporosis is not recommended before ovariectomy or after ovariectomy in individuals receiving adequate testosterone doses
2. Patients who have undergone ovariectomy and have discontinued testosterone therapy for one year or longer should be screened for osteoporosis using DEXA.

Recommendation 8: Recommending gender-affirming surgery

A detailed discussion on gender-affirming surgery (GAS) is outside the scope of this presentation.

Evidence: GAS in female-to-male transition includes gender-affirming mastectomy, gender-affirming genital surgeries (hysterectomy/salpingo-oophorectomy, metoidioplasty, phalloplasty, vaginectomy, scrotoplasty, and implantation of erection and/or testicular prostheses), and non-genital surgical interventions (facial and body contouring surgeries). Gender-affirming genital surgeries directly affect fertility, but others do not.^[5]

Gender-affirming mastectomy is a sought-after procedure in gender dysphoria which does not affect fertility. It can be done anytime if associated with persistent, well-documented dysphoria, even before hormone therapy.^[5] However, it may be prudent to wait for 1–2 years before proceeding with genital surgery. Achieving an aesthetic and gender-congruent chest is a unique challenge. The procedure includes the removal of all breast tissue while highlighting the definition of the pectoralis muscle, creating an appropriately sized and positioned nipple-areola complex, obliterating the inframammary fold, and minimising the noticeability of scars.^[46]

Persistent, well-documented gender dysphoria and continuous hormone therapy for 12 months are two important prerequisites for gender-affirming genital surgeries to ensure that the surgery is appropriate and indicated.^[5] These surgeries affect fertility. The removal of the uterus and ovaries is optional and must be discussed, as the long-term outcomes of the removal of ovaries are currently unknown. Keeping the uterus and ovaries avoids a surgical procedure and a pubic scar but may be a source of dysphoria for transgender men. Moreover, the long-term effects of androgens on the uterus and ovaries remain uncertain. Furthermore, hysterectomy and oophorectomy are conventional parts of the GAS.^[47] There is no recommendation for a specific route of hysterectomy, but minimally invasive surgeries should be preferred. Transgender men should be counselled about definitive infertility resulting from hysterectomy and oophorectomy and be given the option of cryopreservation of the oocytes or embryos.^[9] The chances of successful pregnancies after cryopreservation may be low, which needs to be discussed.

Total penile reconstruction is a multistage and difficult, and expensive procedure associated with a wide range of potential complications. The ideal aim is to allow micturition in a standing position and create the ability of penetrative intercourse with full sensation. There is no single best surgical approach for phalloplasty. The use of a radial free forearm flap is the gold standard and can provide functional, aesthetic, and psychosocial benefits. The secondary procedures may include glansplasty, scrotoplasty, and insertion of penile and testicular prostheses.^[48]

Consensus

1. Gender-affirming surgery should only be done after the age of 18 years with due informed consent
2. Both the MHP and the hormone-prescribing physician should agree that gender-affirming surgeries are medically needed and will improve the well-being of the individual
3. Any significant mental health concerns need to be managed adequately before planning gender-affirming surgeries
4. A detailed discussion about various surgical techniques, their pros and cons and realistic expectations from the surgical procedure should be undertaken before any surgical intervention
5. Before undergoing gender-affirming genital surgery, a transman must have lived in the male gender role for at least 12 months and presented as a male across all settings daily. The individual should have received at least 12 months of masculinising hormone therapy unless there is a medical contraindication for testosterone. The individual should be satisfied with the hormonal effects of medical treatment and be comfortable in the social role of a male.
6. Gender-affirming mastectomy may be performed before the initiation of hormone therapy.
7. The individual should be informed about infertility as a consequence of gender-affirming genital surgeries, and should be discussed cryopreservation of the oocytes or embryos.

Recommendation 9: Pre and Postoperative Hormone Therapy

Evidence: Preoperative risk assessment: Testosterone therapy may have undesirable side effects such as polycythemia, liver dysfunction, hyperglycemia, weight gain and sleep apnea, which may potentially increase perioperative risk.^[49,50] There is conflicting evidence with regard to cardiovascular risk.^[15,27] A detailed preoperative assessment should include evaluating these factors.

Preoperative testosterone therapy: Potentially elevated risk of venous thromboembolism and the subsequent risk of pulmonary embolism, myocardial infarction, and stroke is the primary concern relevant to surgical care.^[50] Aromatisation of testosterone to estradiol may potentially increase the risk of thromboembolism. However, there is no evidence for elevated estradiol levels in androgen-treated transgender men and no evidence to demonstrate an association between perioperative testosterone use and venous thromboembolism after surgery in transmen.^[41,50] Therefore, there is no need to discontinue testosterone before surgery.^[50,51]

Postoperative testosterone therapy:

Transmen, who undergo gonadectomy, will require long-term testosterone replacement under the supervision of a hormone-prescribing physician.^[1] They should be counselled about the importance of long-term follow-up and continuation of testosterone therapy. Discontinuation of testosterone therapy in the perioperative period is associated with negative physical and emotional effects and should be resumed in the immediate postoperative period.

Consensus

1. Cardiovascular risk, polycythemia, liver dysfunction, hyperglycemia, obesity and sleep apnea should be evaluated and appropriately addressed before surgery
2. There is no need to discontinue testosterone treatment before surgery. But in the presence of polycythemia, liver dysfunction or other adverse effects related to testosterone, the therapy should be optimised before surgery.
3. Testosterone therapy should be continued post-operatively at doses used in the preoperative period.

CONCLUSION

The current information comes mostly from West European and American studies. The main shortcoming of scientific literature concerns the data regarding the long-term safety of GAHT in transmen, especially the cardiovascular, cerebrovascular, oncological and fracrisks risk. Further research in this field is vital to enhance our understanding of the healthcare need of this population. Indian healthcare professionals face challenges in providing optimal care for the transgender population due to a lack of education on the topic and almost an absence of training among the providers in India. We hope that this document, prepared by a group of endocrinologists with extensive experience in the management of transgender persons, will help streamline the clinical care of gender incongruent individuals across India. Transgender health care needs to be included in national conferences of all involved specialities, which will help redesign gender-affirming care in India. Lastly, clinicians must listen to the voices of transgender people and recognise and respect the internal diversity within the gender-incongruent community.

Financial support and sponsorship

This consensus is prepared with financial assistance from Integrated Diabetes and Endocrine Academy, Kolkata.

Conflicts of interest

There are no conflicts of interest.