‘SIAMS- SIE Position statement of gender affirming hormonal treatment in transgender and non- binary people’

A. D. Fisher 1, G. Senofonte 2, C. Cocchetti 1, G. Guercio 3, V. Lingiardi 4, M. C. Meriggiola 5, M. Mosconi 6, G. Motta 7, J. Ristori 1, A. M. Speranza 4, M. Pierdominici 8, M. Maggi 9, G. Corona 10 , F. Lombardo 2

Affiliations: 1 Andrology, Women's Endocrinology and Gender Incongruence Unit, Florence University Hospital, Viale Pieraccini 6, 50139, Florence, Italy. 2 Laboratory of Seminology, Sperm Bank “Loredana Gandini,” Department of Experimental Medicine, Sapienza University of Rome, 00185 Roma, Italy. 3 Studio Legale Avv. Giovanni Guercio, Via Antonio Mordini, 14, 00195 Roma 4 Department of Dynamic and Clinical Psychology, and Health Studies, Sapienza University of Rome, Via degli Apuli 1,00185 Roma, Italy 5 Gynecology and Physiopathology of Human Reproduction, Department of Medical and Surgical Sciences (DIMEC), IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy 6 Gender Identity Development Service, Hospital S. Camillo-Forlanini, Rome, Italy 7 Division of Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy 8 Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy 9 Department of Experimental, Clinical and Biomedical Sciences, Careggi University Hospital, Viale Pieraccini 6, 50139, Florence, Italy 10 Endocrinology Unit, Medical Department, Azienda-Usl, Maggiore-Bellaria Hospital, Bologna, Italy

Corresponding Author: Francesco Lombardo [email protected]

Alessandra Fisher and Francesco Lombardo are the Coordinators of the Study Group “Disforia di Genere e Disturbi dello Sviluppo Gonadico e Genitale” of the Italian Society of Endocrinology.

Abstract

Purpose: Gender Incongruence (GI) is a marked and persistent incongruence between an individual's experienced and the assigned gender at birth. In the recent years, there has been a considerable evolution and change in attitude as regards to gender nonconforming people. Methods: According to the Italian Society of Endocrinology (SIE) and the Italian Society of Andrology and Sexual Medicine (SIAMS) rules, a team of experts on the topic has been nominated by a SIE-SIAMS Guideline Board on the basis of their recognized clinical and research expertise in the field, and coordinated by a senior author, has prepared this Position statement. Later on, the present manuscript has been submitted to the Journal of Endocrinological Investigation for the normal process of international peer reviewing after a first internal revision process made by the SIE-SIAMS Guideline Board. Results: In the present document by the SIE-SIAMS group, we propose experts opinions concerning the psychological functioning, gender affirming hormonal treatment, safety concerns, emerging issues in transgender healthcare (sexual health, fertility issues, elderly trans people), and an Italian law overview aimed to improve gender non conforming people care. Conclusion: In this Position Statement, we propose experts opinions concerning the psychological functioning of transgender people, the gender-affirming hormonal treatment (full/partial masculinization in assigned female at birth trans people, full/partial feminization and de-masculinization in assigned male at birth trans people), the emerging issues in transgender health care aimed to improve patient care. We have also included an overview of Italian law about gender affirming surgery and registry rectification.

1. Introduction

Gender Incongruence (GI) refers to a marked and persistent incongruence between an individual's experienced gender and the assigned sex at birth, according to the latest description of the International Classification of Diseases [1]. This definition encloses the whole spectrum of transgender people, including both the binary and non-binary (who identify as neither exclusively male nor female) groups. In the scientific literature, transgender people are referred also as Assigned Females at Birth (AFAB) and Assigned Males at Birth (AFAB) [2]. In recent years, there has been a considerable evolution and change in attitude as regards to gender nonconforming people. An example of the growing interest in this subject both within the scientific community as well as within public opinion, is the interest by the mass media, as demonstrated by the ever more frequent articles published and by the increasing number of television transmissions dedicated to this subject. Despite transgender identification is considered as one of the natural outcomes of one’s sexual development, to date this population is still described as psychologically more vulnerable if compared to the general one. This seems to be the consequence not only of the distress that in some cases may derive from GI itself, but also from living in a transphobic cultural background [3]. In line, increasing evidence shows that gender-affirming care is associated with improved psychological functioning and wellbeing of transgender people during the whole life spam [4, 5, 6]. However, transgender people seem to access late in gender services and to encounter a range of barriers in receiving primary health care [2]. In line, also the current healthcare situation in Italy seems not to properly meet the needs of transgender people, despite the increase in requests for support, advice and psychological and/or medical gender-affirming treatments in all age groups. For instance, in Italy, thus far hormonal treatments have been prescribed off-label and refunded only in some Regions, creating a strong discrimination between inhabitants of one region and another. Furthermore, while gender- affirming surgery (GAS) is covered by the National Health Service (NHS), accessing it actually has a cost for trans people. Based on Italian legislation (Law #164/82), access to GAS must be authorized by a court of law. Indeed, this process not only extends waiting times for surgery (e.g. by twelve months or more), but can also have a considerable cost, which represents a strong financial burden especially for a population that suffers from economic marginalization [7]. Moreover, a paucity of knowledgeable and experienced health care providers (HCP) represents a further barrier to trans healthcare in Italy [7. However, the growing international awareness about trans care needs [6], together with the commitment by European associations (i.e., European Professional Association for Transgender Health, EPATH) to promote mental, physical and social health of transgender people have started to enlighten also the Italian scenario. Indeed, recently the Italian National Institute of Health (ISS) set up a specifically dedicated Center for Gender-Specific Medicine whose mission includes the promotion of activities aimed at protecting the health of vulnerable populations such as gender minorities. In addition, the recent approval of triptorelin for puberty suppression by the Italian Medicines Agency (AIFA) ([8]), as well as the inclusion of gender-affirming hormone therapy in the list of medicines that can be dispensed entirely by the NHS [9], represent an important step to overcome the fragmentation and scarcity of trans care across Italy, although some difficulties in the applicability of these resolutions still remain in some Regions. The publication of the Guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE) is a further significant goal reached. In fact, we know how important is a proper training for HCP who have to deal with gender nonconforming people or people with gender dysphoria. A recent research (10) has revealed that, in the long term, transgender people followed by specialized services and professionals demonstrate an improved psychological functioning as compared to those followed by non-specialized personnel, as also pointed out in the Guidelines of the American Psychological Association for Psychological Practice with Transgender and Gender Nonconforming People [11]. Following these developments of the Italian scenario towards a more equal care, the aim of this paper is to provide HCP with an update on the current knowledge about transgender healthcare focusing on the Italian context. This will allow HCP to better answer the requests of transgender people that have to be highly individualized and taken care of in a multidisciplinary frame. In particular, the recommendations reported here are the result of a clinical consensus by leading Italian experts in the field with different professional backgrounds. The Position statement includes contributions written by leading experts in the field who have been dealing with the subject with commitment and dedication for many years, at the academic level and in clinical practice. These professionals are all united not only by the experience acquired over the years but also by the sensitivity they bring to the relationship with transgender people.

2. Methods

The SIE and SIAMS commissioned an expert task force to provide an updated guideline on gender-affirming hormonal therapy (GAHT) in transgender people. The authors, based on the best evidence from published literature available in PubMed, generated a series of consensus recommendations according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system [12]. The strength of recommendations and the quality of the evidence are expressed in four levels: ⊕〇〇〇 denotes “very low-quality evidence”, ⊕⊕ 〇〇 “low quality”, ⊕ ⊕⊕ 〇 “moderate quality” and ⊕ ⊕⊕⊕ “high quality”. Moreover, the number ‘1’ denotes a strong recommendation and is expressed with the phrase ‘we recommend’, whereas the number ‘2’ denotes a weaker recommendation and it is expressed with the phrase ‘we suggest’. This position statement is divided into six main sections (including Psychological functioning of transgender people, Gender-affirming hormonal treatment, Partial de-/masculinization and/or de-/feminization, Emerging issues in transgender health care, an Italian overview). The authors of this position statement, mostly SIE-SIAMS members, are actively involved in the fields of endocrinology, psychology and jurisprudence of adult trans people in Italy. According to SIE-SIAMS rules, this Position statement was prepared by a team of experts on the topic coordinated by a senior author, all nominated by a SIE-SIAMS Guideline Board on the basis of their recognized clinical and research expertise in the field. Then, the present manuscript was submitted to the Journal of Endocrinological Investigation for the normal process of international peer reviewing after having received a first internal revision process made by the SIE- SIAMS Guideline Board.

3. Psychological functioning of transgender people

Recommendation #1 We recommend considering GI individuals as a heterogeneous group of people (1 ⊕ ⊕⊕ 〇). Recommendation #2 We recommend psychologically assessing GI individuals taking their family and social background (i.e., trauma, stigmatizations) into high consideration and reading any symptoms and psychological functioning also in the light of this background (1 ⊕ ⊕⊕ 〇).

Evidence Transgender people are described as particularly vulnerable to mental health symptoms and psychological distress. A recent review screening articles published since 1980 [13] found a high lifetime frequency (53%) of DSM-Axis I mental disorders in individuals with Gender Dysphoria (GD). The most frequent disorders appear to be those of mood and anxiety, with frequencies of 42% and 27%, respectively. As the authors of another recent review [14] point out, however, firm conclusions whether the rate of psychiatric disorders is higher in transgender people than in controls cannot be reached due to the lack of well-matched controlled studies exploring psychiatric disorder. Moreover, mood and anxiety disorders, as well as clinical distress or impairment in psychological functioning can be explained both by the subjective experience of discomfort with the assigned gender at birth and by the stressful consequences of prejudice, discrimination, and victimization that persons with GI often experience. All these risk factors may contribute to mental health consequences, including increased rates of depression and suicidality [15]. To this regard, studies investigating the mental health of GD/GI people who made their transitions a long time ago, present many differences from those looking at individuals who transitioned more recently. The progress in cultural contexts and scientific community produced many changes in the levels of transphobia and discrimination over time. Furthermore, the results of hormonal treatments and surgeries were definitively less satisfying in the past, and this, in turn, affected transgender health negatively [16, 17]. Accordingly, many researches looking at GD individuals that transitioned in the 21st Century suggest that there are significant differences between current and lifetime mental disorders, highlighting that transgender people, once they are being assessed at gender specialized services, may display psychological functioning which falls in the non-clinical range [18, 19, 209, 21, 22]. As the American Psychological Association’s Guidelines for Psychological Practice With Transgender and Gender Nonconforming People [11] underline, several studies shown improved quality of life, decreased GD, and a reduction in psychopathological symptoms in the majority of transgender adults and adolescents who receive affirmative medical and psychological services in multi-disciplinary settings (i.e. psychological support, hormonal treatments, surgeries, voice therapies, etc- [22, 23, 24, 25, 26]).

3.1.2 Psychological functioning after GAHT

Recommendation #3 We recommend that all individuals wishing GAHT receive information and counselling on psychological and medical effects of treatment, in order to meet their unique psychological needs in a personalized clinical approach (1 ⊕ ⊕⊕ 〇).

Recommendation #4 We suggest that clinical psychologists monitor the psychological well-being of their clients working in collaboration with the other members of the multidisciplinary team (2 ⊕⊕ΟΟ).

Evidence Since psychological distress may be considered a reaction to the experience arising by the incongruence between the individual’s experienced gender and biological sex, GAHT could be considered an elective treatment to mitigate such incongruence. Facilitating access to care promotes high standards of health and well-being. The physical changes induced by hormone treatment are usually accompanied by an improvement in mental well-being. Two recent reviews [28, 29] support the significant improvements in mental health outcomes and psychological well-being of adults who have access to GAHT. Especially in longitudinal studies, hormone therapy is associated with less anxiety and depression, lower perceived and social distress, lower personality-related psychopathology and with higher mental health-related quality of life and self-esteem in both AMAB and AFAB transgender individuals [23, 24, 25, 27]. GI individuals undergoing GATH report lower levels of gender dysphoria, lower levels of suicidality, and higher levels of body satisfaction. In some people, hormonal treatment can help to affirm their gender identity and the person may not undergo any surgery. The reasons of this amelioration in the psychological functioning brought by hormonal therapies could be the following: (a) GAHT might mitigate the body dissatisfaction, and thus be responsible for psychological well-being; (b) hormonal treatment may help GI individuals at a social level, by reinforcing their gender affirmation with a better social recognition; (c) accessing care and receiving eligibility for hormone therapy might help in decrease the distress, offering them acceptance of their needs and requirements [28]. GI individuals who cannot access adequate specialized health care professionals or services are more exposed to stigma, violence, fear of being seen as different which in turn can lead to negative outcomes for psychological health [30]. Clinicians should consider the risks of harm to clients by not prescribing hormones when individual and/or social factors prevent them from seeking help and treatment, increasing self-medicating behaviours. Thus, for GI individuals the principle of receiving multidisciplinary, interdisciplinary, client-centred care is paramount. GI individuals should be expected to retain responsibility for their decisions and thus informed of all the options, benefits and side-effects of the available treatments, explained in a clear language, so that they can be readily understood. Professionals working in specialized services should be sensitive to any personal need of clients, and all persons with GI should have equal access to care, irrespective of ethnicity, cultural background or disability. To this regard, the role of psychologists, psychotherapists and psychiatrists, in the multidisciplinary setting of a specialized centre, should be not that of the “gatekeeper” who permits or denies the access to trans-affirmative care [31], rather it should promote in clients a better understanding of their gender identity, helping them to be clearer about their needs, in order to choose the best available options for their transitions. Moreover, as several psychological guidelines underline [32, 33], hormonal therapies can affect existing mood disorders both positively or negatively. Therefore, counselling and psychotherapy can sustain GI individuals during the various stages of treatment, helping them processing the changes both on the physical and psychological level. For instance, AMAB trans people who begin estrogen therapies may perceive and experience a broader range of emotions, whereas AFAB trans people assuming testosterone might encounter higher level of libido and higher emotional activation towards stressors [34]. Thus, mental health professionals may play a critical role in validating transgender people experiences before, during and after transitions, empowering them and increasing positive life outcomes [35, 36]. Finally, psychologists and psychotherapists should be aware of the importance of social support for GI adults and adolescents and thus assisting them in negotiating family, couple and friendship dynamics that may emerge during their transitions.

4. Gender-affirming hormonal treatment Recommendation # 5. We recommend HCP exploring together with transgender people wishing GAHT their individual needs and to offer a personalized clinical approach (1 ⊕⊕ΟΟ). Recommendation # 6 We recommend counseling transgender people against GATH self-prescriptions and use of unauthorized drugs available on the market (mainly on internet) (1 ⊕⊕ΟΟ).

The GAHT aims to reduce the action and the levels of the endogenous hormones and replace them with the sexual steroids of experienced gender, following the principles of hormone replacement therapy in hypogonadal biological male and men. The following sections specifically analyze the management of GAHT.

4.1 Full masculinization in trans AFAB people Recommendations #7 We recommend using androgens as masculinizing treatment in AFAB trans people requesting full masculinization, following the same principles of hormone replacement treatment of hypogonadal cisgender male patients (1 ⊕⊕⊕O). Recommendation #8 We suggest using testosterone (T) undecanoate or transdermal T preparations, due to pharmacokinetics differences among available T formulations (2 ⊕⊕⊕O). Recommendation # 9 We recommend adequately informing AFAB trans people on the expected effects of masculinizing hormonal treatment (1 ⊕⊕⊕O).

4.1.1. Treatment regimens Evidence Masculinizing hormonal treatment in AFAB trans people is based on T use. Different formulations are available, including parenteral injections (T esters or T undecanoate) or transdermal T, as detailed in Table 1. Desired effects can range from an androgynous presentation, to a maximum masculinization [37]. If full male characteristics are desired, serum T levels within the adult cisgender men range (320 to 1000 ng/dL, or 11.1 to 34.7 nmol/L ) should be maintained [38]. Because of their easy financial accessibility, in the recent past the most commonly prescribed androgen across Italy has been injectable short-term T esters (enanthate). However, the significant fluctuations of T levels induced by this formulation - reaching supra-physiological values soon after injection- may lead to mood swings and hematocrit increase [39, 40]. Intramuscular long-acting T undecanoate administration, as well as transdermal T formulations, result in more stable serum T levels, by mirroring the physiological male circadian rhythm. All T formulations are associated to amenorrhea by 12-18 months of hormone administration [41, 42] but transdermal formulations are associated with higher incidence of unwanted persistent vaginal bleeding in the first period of treatment if compared to long-acting intramuscular T undecanoate. According to the recent approval by AIFA of GAHT (provided free of charge to transgender people by the NHS) [9], the high cost of intramuscular long- acting T undecanoate and transdermal T is heavily subsidized, facilitating first-line use in AFAB trans people. In trans people undergoing oophorectomy, T administration must be continued to avoid impairment of cardiovascular, bone, cognitive and sexual health and to prevent the increase of mortality associated with a premature loss of hormonal support.

4.1.2. Masculinizing effects Evidence T administration results in several masculinizing effects. In the first six months, increase in facial and body hair, changes in body composition and body fat distribution, along with increased muscle mass and strength, and voice deepening [43, 44, 25] are expected. Among dermatological effects, skin oiliness, acne and –male pattern baldness - in genetically predisposed individuals- have been described [45]. Significant clitoral growth has also been reported with T [25], as well as transient increased in sexual desire and improvement in sexual well-being in the mid-term [46, 47. Suppression of menses typically occurs after one to eighteen months of T (independently from the used formulation). In those few AFAB trans people not achieving amenorrhea, a progestin (oral progestin or long-acting injectable formulations or etonogestrel subdermal implants) or gonadotropin-releasing hormone analogs (GnRHa) can be administered [38].

4.2 Full feminization and de-masculinization in AMAB trans people Recommendation #10 We recommend using estradiol in association with anti-androgen therapies in order to induce desired phenotypical effects in AMAB trans people wishing a full feminization and a full de-masculinization (1 ⊕⊕⊕O). Recommendation #11 We recommend against the use of esterified estrogens (ethinyl-estradiol, EE) and nonhuman derived estrogens (conjugated equine estrogens, CEE) (1 ⊕⊕⊕Ο). Recommendation #12 We suggest using cyproterone acetate (CPA), spironolactone or gonadotropin-releasing hormone agonists (GnRHa) as antiandrogens (2 ⊕⊕ΟΟ). Recommendation #13 We suggest against the routine use of progestins as part of feminizing hormonal treatment (2 ⊕OΟΟ). Recommendation #14 We recommend informing binary trans AMAB people on the expected effects of hormonal treatment (1⊕⊕OO).

4.2.1. Treatment regimens Evidence If maximum feminization is desired in AMAB trans people, estradiol should be associated with anti-androgens, with dosages titrated to maintain serum estradiol and T at the level for premenopausal females levels (100 to 200 pg/mL and 50 ng/dL, respectively). Nonhuman derived estrogens, such as EE or CEE, have been shown to carry a higher potential prothrombotic risk in AMAB trans people [48, 49]. Naturally human estrogens include 17beta-estradiol (E2). Oral E2 must be micronized or esterified (valerate) in tablets to improve its absorption. Transdermal preparations consist in patches or gels and are not subjected to first hepatic metabolism, avoiding an increase in prothrombotic factors. The transdermal compounds should be chosen in cases of high thromboembolic risk (i.e., >40 years of age, smoking, obesity, liver disease, diabetes mellitus with vascular complications) [38, 50, 51]. Regarding anti-androgen therapies, CPA is a progestational compound with antiandrogenic effects, acting peripherally and/or centrally. However, cases of hepatotoxicity, increased incidence of depression and hyperprolactinemia and association with the occurrence of multifocal meningiomas have been reported [52, 53, 54, 55, 56]. GnRHa could be a valuable alternative to suppress androgens levels with limited side effects [57, 58] and with some evidence of a better metabolic profile versus CPA in one comparative study recently published [59], although their high cost may limit their use [60]. Spironolactone, a pharmacologic antagonist of aldosterone, is a diuretic with anti-androgenic properties. Because of its potassium sparing effects, electrolytes should be monitored to avoid hyperkalemia. Furthermore, spironolactone use has been associated with gastrointestinal bleeding. Thus, spironolactone may be considered a valuable alternative when other options are not available.

Remarks . There are limited and low quality published studies to support a beneficial effect of progestins on breast development in AMAB trans people [61, 62, 63, 64, 65]. Available treatment options and recommended doses are reported in Table 1.

4.2.2. Feminizing and de-masculinizing effects Evidence Less than 20% of transgender women reach a Tanner breast stage 4-5 [25] and 4 out of 5 trans women either chose or considered breast augmentation after median 2 years of hormones [66]. A significative reduction in terminal facial and body hair growth – even if often not satisfying- is demonstrated during hormonal therapy [4], as well as decreased oiliness of skin [67]. Feminizing treatment has been associated with increased body fat (mainly in the gynoid regions) and a decrease in lean body mass, consistent with a more feminine body composition [68]. It is known that hormonal treatment does not modify voice frequency in transgender women [69]. Anti-androgen therapies lead to a decrease in spontaneous erections and testes volume [70. In the first 3-6 months of hormonal treatment, a transient decrease in sexual desire has been reported [71] although sexual well-being increases in the mid-term reflecting improved body image [27].

4.3 Partial de-/masculinization and/or de-/feminization Recommendation #15 . We recommend extensively discussing benefits and risks of a personalized treatment (1 ⊕⊕⊕⊕).

Evidence Non binary trans people may feel less confident to disclose to HCP their final gender-goals because of the experienced stigma of falling outside the societal binary norms. HCP are advised to provide a safe and non-judgmental environment to allow transgender people to freely express themselves outside a binary view of gender and provide the optimal care. Indeed, HCP should explore each single request and their underlying reasons. Transgender people should be informed about the lack of data regarding long-term risks of non-standardized treatment protocols. In addition, patients should be aware that biochemical thresholds necessary to obtain desired body characteristics - avoiding adverse effects of hypogonadism - have not been identified. However, personalized treatment may play a key role in improving quality of life in non-binary individuals. In order to better respond to clients’ requests, clinicians should consider hormonal and non- hormonal strategies [72].

Remarks Hormonal treatment in AMAB trans individuals wishing partial de-masculinization and/or feminization Androgen lowering therapies- such as CPA, spironolactone or GnRH analogues- can be proposed to AMAB trans individuals wishing de-masculinization with little or no feminization. However, this approach is limited by the well- established negative impact of androgen deprivation on bone mineral density [73]. For this reason, the co-administration of estrogens at lower dosages - without reaching the usual therapeutic goals for binary transgender individuals [38]- should be discussed with clients, even if there is no evidence regarding the optimal dose that allows maintenance of bone health without feminization. Other options may include non-hormonal strategies, such as permanent methods of hair reduction [74]. In some cases, AMAB trans people may request partial feminization without affecting sexual functioning. In order to preserve erectile function, only-estrogens treatment or low dosages of CPA (10 mg/daily or 25 mg on alternative days) could be proposed [72].

Hormonal treatment in AFAB trans individuals wishing partial masculinization and/or de-feminization In AFAB trans individuals desiring only partial masculinization, T could be administered at lower dosages without achieving usually recommended androgens levels [38]. The effectiveness of this approach, the possible metabolic and bone risks and the safety on genital tissues have not been yet described in literature. Furthermore, other compounds or strategies may be adopted in order to shape the effects of androgens on the body. When the desired goals include body shape changes and voice deepening, variable dosages of T treatment could be combined with 5 α-reductase inhibitors or definitive hair removal, in order to avoid male hair distribution [72, 74, 7, 76]. In this case, also surgical interventions- including chest surgery and lipofilling- can be taken into consideration. Conversely, topical minoxidil application could be considered in addition to variable dosages of T treatment in AFAB subjects requesting beard development with limited body shape changes [77]. Furthermore, AFAB trans individuals may experience high distress towards menses. When only partial masculinization is desired, low dosages of T could be unable to stop menses. For this purpose, progestins- such as medroxyprogesterone acetate (MPA) 5-10 mg/daily or depot MPA (150 mg every three months), GnRH agonists, endometrial ablation or progesterone-releasing intrauterine device represent valid options [72, 38, 78, 79].

4.3 Monitoring during hormonal treatment Recommendation #16 We recommend screening and addressing medical conditions that may worsen with gender- affirming hormonal therapies, before starting treatment (1 ⊕⊕⊕⊕). Recommendation #17 We recommend appropriate monitoring during hormonal treatment, including physical examination, blood tests and oncological screening, under the supervision of experienced endocrinologists. (1 ⊕⊕⊕⊕).

Evidence . Before starting hormonal treatment, HCP should collect accurate family and personal medical history in order to evaluate potential pre-existing health risks. Particularly, for AMAB trans people history of estrogen sensitive neoplasm, cholelithiasis, macroprolactinoma, coronary artery and/or cerebrovascular diseases represent contraindications to estrogen therapy, if not recovered [38, 65]. Moreover, history of deep vein thrombosis or pulmonary embolism should be evaluated and treated prior to the beginning of hormonal treatment. Hereditary thrombophilia should be screened (Table 2) in case of family history of thromboembolism in a close relative before the age of fifty, as suggested by AIFA for the prescription of combined oral contraceptive. Due to the limited data regarding long-term cardiovascular safety of hormonal treatment, all the modifiable risk factors (i.e. hypertension, dyslipidemia, obesity, tobacco use, sedentary lifestyle) should be managed before starting hormonal treatment [38]. Clinical and biochemical monitoring (reported in Table 2) should be periodically performed by experienced endocrinologists. Dual-energy x-ray absorptiometry (DXA) should be performed at baseline in case of anamnestic high risk of osteoporosis and thereafter after gonadectomy in case of low compliance to hormonal treatment. Routine oncological screening of all present tissues is recommended, as in cisgender individuals [38, 80].

4.4 Safety concerns Recommendation #18 We recommend informing transgender people about the possible adverse effects of GAHT (1 ⊕⊕⊕⊕). Recommendation #19 We recommend informing transgender people about the lack of short and long-term studies assessing risk profile of partial de -feminilization and/or de-masculinization treatments (1 ⊕⊕OO). Recommendation #20 We recommend maintaining sex hormones levels in the eugonadal experienced-gender range in order to avoid supra-physiological levels when it’s feasible according to patient gender identification (1 ⊕⊕OO).

Evidence Masculinizing hormonal treatment in AFAB trans people In relation to metabolic profile, masculinizing therapy results in a more atherogenic lipid profile with lowered high- density lipoprotein cholesterol and higher triglyceride and low-density lipoprotein cholesterol values [81, 82, 83, 84]. There is no evidence for an increase in short and mid-term cardiovascular adverse outcomes in trans people under T treatment. Moreover, a systematic review of the literature found that data were insufficient (due to very low–quality evidence) to allow a meaningful assessment of patient-important outcomes, such as death, stroke, myocardial infarction, or venous thromboembolism (VTE) in AFAB trans people [85]. Thromboembolic events are also rare, due to the lack of the T direct action on coagulation (instead of estrogens effects) [86]. Regarding hematocrit levels, a recent study reported an increase in the first year stabilizing afterward, within the reference range for cisgender men and rarely inducing clinically significant erythrocytosis [87]. Baseline bone mineral (BMD) levels in AFAB trans people are generally in the expected range for their pre-treatment gender [88], but adequate dose of T is essential to allow proper bone health during GAHT (especially after gonadectomy- [89, 90]).

Feminizing hormonal treatment in AMAB trans people In relation to metabolic profile, prospective studies found favorable changes in lipid parameters with increased high- density lipoprotein and decreased low-density lipoprotein concentrations in AMAB trans people [72, 91]. In a meta- analysis, only serum triglycerides were higher at 24 months without changes in other parameters [92], as a recent meta- analysis including 3,231 AMAB trans people with a follow-up range from 3 months to 41 years showed [93]. With regards to cardiovascular safety, an American cohort study showed higher rates of ischemic stroke in AMAB trans people (HR 1.9;95% CI 1.3-2.6) compared with cisgender ones [94]. In addition, myocardial infarction rates were greater among AMAB trans people than in matched cisgender women and similar to those observed among cisgender men [95]. Moreover, a recently commissioned systematic review and meta-analysis, including 3231 AMAB trans people with a follow-up range from 3 months to 41 years, did not find an increased risk of myocardial infarction, stroke or venous thrombosis, but only a significant increase in triglycerides levels [93].

VTE may be a serious complication of estrogen use. A recent metanalysis estimated the incidence rate of VTE in AMAB trans people under estrogen treatment to be 2.3 per 1000 person-years [96]. However, the risk may be overestimated, since several older studies with oral EE were included [96]. Lower baseline bone density in AMAB trans people has been reported compared with their age-matched cisgender male controls [97]. Data from prospective studies and metanalysis demonstrate that bone density improves with estrogen treatment, especially at the lumbar spine [98, 99, 100]. The fracture rate associated with feminizing hormones is unknown [65]. Sex hormones may play a role in the pathogenesis of some brain tumors. Due to its progestogenic properties, CPA administration has been associated with higher risk of meningioma in AMAB trans people than in cisgender women [101]. Considering that, CPA discontinuation after orchiectomy is suggested. A lower dosages of CPA need to be considered in case of long-term administration [102]. Moreover, estrogen treatment may promote the growth of pituitary lactotroph cells. Since a higher – although low - risk of prolactinoma has been reported in AMAB trans people [101], periodical prolactin levels monitoring is recommended. Further radiological examination should be performed only in case of persistent increase of prolactin levels despite stable or reduced estrogen levels.

5. Emerging issues in transgender health care 5.2 Sexual health Recommendation #21. We recommend HCP counselling and caring trans people regarding reproductive health, including contraceptive and sexually transmitted infections counseling. (1 ⊕⊕⊕⊕ ).

Evidence Transgender people face barriers to contraceptive access, including lack of provider knowledge about interactions between hormonal contraceptive and T use and discriminatory healthcare experiences [103]. Moreover, a recent study describes how the body dissatisfaction creates significant difficulties in engaging in sexual relations, and some of transgender people do not consider sexuality a significant part of their lives even though they technically participate in it [104]. Furthermore, misconception regarding T effects on fertility are common among AFAB trans people, with a part of them (about 15-30%) considering it as an effective method of contraception [105]. In order to be more inclusive, clinicians have to use gender-inclusive language and terminology for body-parts (such as genital instead of vulva/vagina/penis, or referring to mammary tissue as chest rather than breast tissue in AFAB trans people), processes, and procedures [106]. The contraceptive care for this population has to be patient-centered, respecting sexual behaviors and considering pregnancy risk. Unfortunately, given the lack of data on use patterns, safety, and efficacy of contraceptive methods in this population, clinicians are limited in their ability to provide evidence-based information to patients [103]. Despite the lack of guidance, interest in contraception is often present [107] and adequate counseling should be performed. Condoms are the most commonly used contraceptive [107, 108]. Regarding hormonal contraception, AFAB transgender individuals taking exogenous T for GAHT may also use exogenous estrogen and progestins for pregnancy prevention and regulation of bleeding (without further investigations, in addition to those already suggested before starting GAHT [107, 108, 109, 110, 111]. As for cisgender women, long-acting reversible contraception (LARC, in particular subdermal implants) or depot medroxyprogesterone acetate injections should be discussed first with transgender and gender non-conforming people because of their high effectiveness, few contraindications and estrogen-free content. Progesterone-only pills may be a good alternative, but they require daily assumption and present a lower contraceptive-efficacy. Even if not contraindicated, the daily usage of combined hormonal contraceptives may be a possible negative reminder of the gender assigned at birth [112]. AFAB who undertake GAHT should be informed about the possibility of ovulatory cycles and unintended pregnancy during T induced amenorrhea. Furthermore, the menstruation patterns of AFAB trans people on T therapy do not necessarily correlate with their ovulation status and reproductive potential. A 2016 survey of 197 AFAB trans people showed 16.4% of respondents were using T as their method of contraception, but pregnancy has been reported in AFAB trans people in the setting of amenorrhea or oligomenorrhea from recent T therapy [113]. The AFAB trans and non-binary people, therefore, need to understand the teratogenic effect of T on the fetus and possible degree of virilization, predominantly during the first trimester.

Remarks To our knowledge, there are no data on the pharmacological interactions between gender-affirming T use and hormonal contraception. Therefore, providers should extrapolate from what is known about T and these contraceptive methods separately and evaluate their interactions case by case. However, due to the lack of data on potential risks, side effects, and benefits specific to transgender individuals using exogenous T in combination with estrogen-containing contraceptives, it is reasonable to avoid these products unless there is a clear benefit or strong preference for the patient. Concerning sexual behaviours, transgender people should be counselled about methods that adequately protect against HIV transmission and other sexually transmitted infections. Regarding HIV transmission, providers should also involve in conversations about PrEP (pre-exposure prophylaxis) and PEP (post-exposure prophylaxis) [110]. Unfortunately, at the moment no trials of PrEP have yet been conducted among pharmacokinetic interaction in transgender people taking GAHT.

5.3 Fertility issues Recommendation #22 . We recommend that HCP adequately inform all transgender individuals seeking medical treatment about the potential impact of medical gender-affirming treatments on fertility and discuss the available fertility preservation (FP) options (1 ⊕⊕ΟΟ).

Evidence Parental desire rates reported in trans people appear relevant [114, 115, 116], although many transgender individuals still consider fertility the price to pay for transition [117]. However, a medical gender-affirming path and fertility should not be considered mutually exclusive. To this regard, the key role of HCP is to explore fertility wishes of transgender individuals seeking medical treatment and give appropriate information about the impact of GAHT and surgeries on fertility. Furthermore, HCP should be able to discuss FP options at any point of gender-affirming path. Gonadectomy leads to an irreversible loss of the reproductive potential of trans people, thus any FP strategy needs to be considered before this step. The optimal timing for FP strategies is before the start of GAHT. In post-pubertal AMAB transgender individuals, FP usually consists of cryopreservation of a sample of ejaculated semen. In case masturbation causes distress, sperm aspiration or microsurgical sperm extraction can be proposed. To date, little evidence describing the impact of GAHT on spermatogenesis is available [118, 119, 120]. Partial restoration of spermatogenesis seems to occur after GAHT cessation [120], even if the appropriate timing of suspension has not been established. During GAHT suspension, T levels increase may be accompanied by masculinizing effects that could represent a source of distress. As alternative, testicular tissue cryopreservation does not require to stop GAHT and can be performed at the time of GAS. However, for the moment this technique remains experimental. In AFAB transgender individuals, assisted reproductive techniques available for cisgender women – such as oocytes or embryos cryopreservation - can be proposed before and after the start of GAHT, even if the long-term effect of T administration remains uncertain [121, 122, 123, 124]. Both techniques require to stop GAHT and undergo controlled ovarian stimulation with transvaginal oocyte retrieval, which may be perceived as distressful [125]. In the future, ovarian tissue cryopreservation with in vitro oocyte maturation – for the moment only experimental – could represent an alternative to be performed concurrently with GAS without the need to stop GAHT.

6.4 Hormonal treatment of elderly trans people

Recommendation #23 We suggest extensively informing trans people regarding the lack of evidence about long-term GAHT safety and to discuss a possible dose-adaptation in elderly individuals (Good Clinical Practice)

Evidence Evidence regarding long-term morbidity and mortality in trans people are lacking. For this reason, to date recommendations for endocrinological management of elderly trans people reflect the experience gained through sex hormone replacement treatment in cisgender aging people [126]. This information should be shared with trans people in view of possible dosage adjustments, which may represent a source of anxiety for patients. Although evidence remain sparse, T treatment in AFAB trans people did not show harmful cardiovascular effects or significant oncological risk in the mid-term, such as to justify T interruption in elderly trans people [38]. Furthermore, due to its partial aromatization to estradiol [116], T demonstrates effectiveness in preserving bone mineral density in the mid-term [126, 129]. However, T dosages may be lowered over time - remaining in the low reference range - in case of tendency to high haematocrit or cardiac insufficiency. Due to the aromatization to estradiol, long-term T treatment may carry some concerns regarding oncological risk [126]. In fact, breast cancer has been described in AFAB trans people receiving supraphysiological doses of T or even after mastectomy [129, 130]. To date, since T cannot be definitively considered a causal factor in breast cancer development, its interruption in aging AFAB trans people is not recommended, although lower dosages can be considered. In elderly AMAB trans people estrogen interruption/reduction of dosages should be considered, due to the increased risk of stroke and thromboembolic events in post-menopausal women assuming hormonal replacement treatment [131]. On the other hand, complete discontinuation of estrogens may lead to a significant loss of bone strength. Balancing all these aspects, above the age of 50 17-β estradiol treatment may be continued in an age-appropriate dose, always changing from oral to transdermal formulations. Furthermore, considering the risk of meningiomas and thromboembolism [132, 133], long-term assumption of cyproterone acetate should be avoided. In case GAHT is requested late in life, hormonal treatment does not seem associated with disproportionately increased risks, although an extensive assessment of comorbidities and possible contraindications to hormonal treatment should be performed.

6.5 Conclusions Gender Incongruence is a non-congruence between the perceived gender and the assigned one at birth. Whenever this generates significant distress and/or social functioning problems, transgender people may start gender affirming hormone therapy. Even if international guidelines for gender affirming medical intervention already exist, the SIE-SIAMS position statement aims to focus on gender-affirming hormonal treatment (full/partial masculinization in AFAB trans people, full/partial feminization and de-masculinization in AMAB trans people), emerging issues in transgender health care and overview of Italian law about gender affirming surgery and registry rectification. For adult gender-incongruent people, the clinicians should have expertise in transgender-specific diagnostic criteria, mental health, primary care, hormone treatment, as needed by the patient.

Appendix 1 An Italian law overview 1.a Law n.164 of 1982 The procedure of gender reassignment, for those who wish to undertake it, is regulated by Law n.164/1982. According to the aforementioned law “, when it is necessary to adapt the sexual characteristics through surgical treatment, the Court authorizes it with a judgment” and, “once done the authorized treatment, orders the rectification of sex attribution” (article 3) According to this rule, therefore, the judge can issue an order for the Registry to rectify the birth certificate only after the surgical intervention has been carried out.

1.b First jurisprudence without appointment of the C.T.U. (Court expert in the subject) in the surgical interventions’ authorization phase and in the Registry’s correction phase Law 164/82, in Article 2 paragraph 4, provides the possibility (not the obligation) for the judge to appoint a technical consultant (C.T.U.) who certifies the psycho-sexual conditions of the person. Unfortunately, what was supposed to be just a “possibility”, from 1982 (year of entry into force of the law) until 1996, became the case law in use by the Italian Courts which appointed this technical consultancy without wondering whether this auxiliary activity (expensive in terms of time, embarrassment and costs) was actually “necessary”. With a petition of the writer, who pointed out that, in the presence of a certified psycho-sexual report or, better, drafted by a public hospital, there was no “need” to appoint another expert who would have done nothing but confirm what his colleagues had already certified, in 1996 the Court of Rome ruled favorably, avoiding for the first time the appointment of this expert .

1.c Case law on rectification of the Registry without the need of phalloplasty Another obstacle to be faced (again in the absolute silence of the law) was the erroneous interpretation of Law 164/1982 for people subjected to transition from female to male (FtM). The Courts in the absence of total reconstruction of the genital organs (penis and testicles) refused the registry correction. Once again the current legislation is ambiguous: art.3 paragraph 2 of the Law requires the authorized treatment to be carried out in order as to obtain the rectification of the birth certificate, but it does not clarify what this “authorized treatment” consists of. The Courts therefore for more than twenty years rejected the application substantially because the male sexual organs were not reconstructed. As a matter of fact, the problem consisted in establishing whether the rectification of the Registry was allowed after a hysterectomy with bilateral oophorectomy and mastectomy, even in the absence of a phalloplasty. The modifications of the physical sexual characteristics should represent only the tool for completing a pathway of the personality that already exists and which is the actual prerequisite for rectification. Therefore, when the Court had already ascertained the existence of a male personality (so-called psychological or behavioral sex) opposed to the biological sex and has authorized with a sentence the modification of the female sexual characteristics, this must be considered sufficient for the modification of the personal data without the full acquisition of the characteristics of the other sex (penis and testicles).

1.d Genesis of the Registry rectification without any surgery Taking in consideration that the current legislation must obey to the requirements of health protection as a constitutionally guaranteed right (Constitutional Court n.161/1985 and n.170/2014), it is therefore impossible to oblige a person to undergo surgery if it may prove to be harmful or, simply, not desired or not necessary for the achievement of the psycho- physical wellbeing and/or health of that person. The key word therefore lies in the term “necessary” indicated by the reference standards, and surgery is not, in fact, necessary, whenever the person experiences his or her body with balance and satisfaction, regardless of their physic and/or behavioral sex. The Court of Rome (October 18 1997), in a case sponsored by the writer, for the first time affirmed the principle that Law No. 164/82 does not imply surgical treatment as an indispensable prerequisite for rectification, but only provides that such intervention must be authorized, when necessary. Of the same and ultimate opinion is again the Court of Rome, with a judgment of March 22 2011 that state that “ … the person has reached such a level of integration of its genitals with its own body image that she can live satisfactorily both personally and in relationships with others"; "... this sexual identity notion therefore takes into account not only external sexual characteristics, but also psychological and social elements, so that it defines the gender as a complex data of personality …”. This milestone sentence was followed by many other Italian Courts (among which Rovereto in 2013, Siena in 2013, Messina in 2014) . Finally, the High Court on July 20, 2015 (15138/15), with a sentence considered of a measure that has been defined as of "historical" importance, declared that there is no need of surgical modification of genitals to obtain the correction of sex and name. The Supreme Court's ruling on the gender identity problem (DIG), interprets surgery not as the solution, but only as a possible aid, where necessary, for the well-being of the person. An interpretation that does not take account of this evolution, according to the Court, "ends up betraying the rationale of the law" and "the choice to undergo surgical modification of genitals can only be an expressive choice of the inviolable rights of the person, expendable only if there are superior interests to be protected". Since the current legislation does not indicate what such superior interests might be, "the public interest does not require the sacrifice of the right to the preservation of one's psycho-physical integrity". Moreover, a different interpretation would be in stark contrast to the constitutionally guaranteed principle of the impossibility of imposing on anyone any health treatment that violates human dignity, as it is unnecessary or, quite simply, unwished.

Table 1. Hormonal treatment for binary trans people available in Italy

Desired effect Hormonal compounds Mode of administration and recommended dose Masculinization Mixed T esters preparations Intramuscularly, 250 mg every 3 weeks

T enanthate Intramuscularly, 250 mg every 2-4 weeks

T undecanoate a Intramuscularly, 1000 mg every 12 weeks

T gel 1-2% Transdermal, 50 mg/day (available in dispenser pump or as single dose sachets) De-masculinization Cyproterone acetate Oral, 10-50 mg/day

Spironolactone Oral, 100–200 mg/day

GnRH agonist (leuprolide, triptorelin) Intramuscularly or subcutaneously, 3.75 mg monthly or 11.25 mg every 3 months Feminization Estradiol valerate Oral, 2–6 mg/day

Estradiol Transdermal, patch 25-100 mcg/24 h twice or once weekly

Estradiol hemihydrate Transdermal, gel 1.5-3 mg/day (available in dispenser pump or as single-dose sachets) aOne thousand milligrams initially followed by an injection at 6 weeks then at 12 weeks

Table 2 Routine clinical, laboratory and instrumental evaluations during gender-affirming hormonal treatment. Baseline First year of hormonal After the first year of treatment hormonal treatment (every 3 months (every 6-12 months) AMAB trans people Clinical evaluation (including BP Clinical evaluation Clinical evaluation and BMI) (including BP and BMI) (including BP and BMI) and hormone regimen and hormone regimen LH, FSH, total testosterone, adjustment according to adjustment according to estradiol, prolactin levels, blood patients’ requests. patients’ requests. counts, renal and liver function, lipid and glucose profile. Testosterone, estradiol Testosterone, estradiol levels, LH (every 3 (every 6-12 months) levels; Thrombophilia screening panel *. months); prolactin levels prolactin levels (every 2 (once a year). Liver years), blood counts, liver BMD in older than 60 years or in function, lipid and function, lipid and those who are not compliant with glucose profile (every 3 glucose profile (every 6-12 hormone therapy. months) months)

Serum electrolytes (every 3 Serum electrolytes (every months in spironolactone 12 months, in users) spironolactone users).

Routine cancer screening for all tissue present.

BMD evaluation after 60 years or in case of discontinuation of therapy after gonadectomy AFAB trans people Clinical evaluation (including BP Clinical evaluation Clinical evaluation and BMI) (including BP and BMI) (including BP and BMI) and hormone regimen and hormone regimen LH, FSH, total testosterone, adjustment according to adjustment according to estradiol, prolactin levels, blood patients’ requests. patients’ requests. counts, renal and liver function, lipid and glucose profile. Testosterone, estradiol Testosterone, estradiol levels, LH (every 3 (every 6-12 months) levels; BMD in older than 6 months); hematocrit, lipid hematocrit, lipid and 0 years or in those who are not and glucose profile (every 6-12 compliant with hormone therapy. glucose profile (every 3 months) months) Routine cancer screening for all tissue present.

BMD evaluation after 60 years or in case of discontinuation of therapy after gonadectomy

* to those with a personal or family history of VTE.

BP= blood pressure; BMI = body mass index, BMD= bone mineral density; PSA = prostatic specific antigen; LH=luteinizing hormone.

Compliance with ethical standards Conflict of interest All authors declare no competing interests for the present article. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent No informed consent.

References

1. Daki ć T (2020) New Perspectives on Transgender Health in the Forthcoming 11 th Revision of the International Statistical Classification of Diseases and Related Health Problems: An Overview of Gender Incongruence - Depathologization, Considerations and Recommendations for Practitioners Psychiatr Danub Summer 2020;32(2):145- 150. https://doi: 10.24869/psyd.2020.145

2 T’Sjoen G, Arcelus J, De Vries A.L.C et al (2020) European Society for Sexual Medicine Position Statement “Assessment and Hormonal Management in Adolescent and Adult Trans People, With Attention for Sexual Function and Satisfaction” J Sex Med; 7(4):570-584. doi: 10.1016/j.jsxm.2020.01.012.

3 Fisher AD, Castellini G, Ristori J et al (2016) Who has the worst attitudes toward sexual minorities? Comparison of transphobia and homophobia levels in gender dysphoric individuals, the general population and health care providers J Endocrinol Invest;40(3):263-273. https://doi: 10.1007/s40618-016-0552-3

4 Heylens G, Verroken C, De Cock S et al (2014) Effects of different steps in gender reassignment therapy on psychopathology: a prospective study of persons with a gender identity disorder J Sex Med 11(1):119-26. https://doi: 10.1111/jsm.12363

5 Fisher AD, Castellini G, Ristori J et al (2016) Cross-Sex Hormone Treatment and Psychobiological Changes in Transsexual Persons: Two-Year Follow-Up Data. J Clin Endocrinol Metab; https://doi:101:4260-4269

6. Gorin-Lazard A, Baumstarck K, Boyer L et al (2012) Is hormonal therapy associated with better quality of life in transsexuals? A cross-sectional study, J Sex Med 2012 Feb;9(2):531-41. https://doi: 10.1111/j.1743-6109.2011.02564.x.

7 Fiorilli O, Ruocco A (2019) Psychosocial issues in transgender health and barriers to healthcare Ital J Gender-Specific Med 2019;5(3):123-130 | https://doi.org/10.1723/3245.32146

8 Resolution n. 21756/ 2019, GU Serie Generale n.52/2019

9 Resolutions n. 104272/2020 and 104273/2020, GU Serie Generale n.242/2020

10 van der Miesen AIR, Steensma TD, de Vries ALC et al (2020) Psychological Functioning in Transgender Adolescents Before and After Gender-Affirmative Care Compared With Cisgender General Population Peers. J Adolesc Health; 66(6):699-704. doi: 10.1016/j.jadohealth.2019.12.018.

11 American Psychological Association (2015) Guidelines for psychological practice with transgender and gender nonconforming people. The American psychologist, 70(9), 832–864. https://doi.org/10.1037/a0039906

12 Swiglo BA, Murad MH, Schunemann HJ et al (2008) A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab 93(3):666–673. https://doi.org/10.1210/ jc.2007-1907

13 de Freitas LD, Léda-Rêgo G, Bezerra-Filho S et al (2020). Psychiatric disorders in individuals diagnosed with gender dysphoria: A systematic review. Psychiatry and clinical neurosciences, 74(2), 99–104. https://doi.org/10.1111/pcn.12947

14 Dhejne, C, Van Vlerken, R, Heylens, G et al (2016). Mental health and gender dysphoria: A review of the literature. International review of psychiatry , 28 (1), 44–57. https://doi.org/10.3109/09540261.2015.1115753

15 Clements-Nolle, K, Marx R, Katz M (2006) Attempted suicide among transgender persons: The influence of gender- based discrimination and victimization. Journal of homosexuality, 51(3), 53–69. https://doi.org/10.1300/J082v51n03_04

16 Bauer GR, Redman N, Bradley K et al (2013) Sexual health of trans men who are gay, bisexual, or who have sex with men: Results from Ontario, Canada. Int J Transgend;14:66e74 https://doi: 10.1080/15532739.2013.791650.

17 Lawrence A, Zucker K (2012) Gender identity disorders. In M. Hersen & D. Beidel (Eds.), Adult psychopathology and diagnosis, (6th ed., pp. 601–635). London: Wiley

18 Gómez-Gil E, Trilla A, Salamero M et al (2009) Sociodemographic, clinical, and psychiatric characteristics of transsexuals from Spain. Archives of sexual behavior, 38(3), 378–392.https://doi.org/10.1007/s10508-007-9307-8

19 Fisher, AD, Bandini E, Casale H et al (2013) Sociodemographic and clinical features of gender identity disorder: an Italian multicentric evaluation. The journal of sexual medicine, 10(2), 408–419. https://doi.org/10.1111/j.1743- 6109.2012.03006.x

20 Heylens G, Elaut E, Kreukels BP et al (2014) Psychiatric characteristics in transsexual individuals: multicentre study in four European countries. The British journal of psychiatry: the journal of mental science, 204(2), 151–156. https://doi.org/10.1192/bjp.bp.112.121954 210 Fisher A D, Castellini G, Bandini E et al (2014) Cross-sex hormonal treatment and body uneasiness in individuals with gender dysphoria Sex Med https://doi: 10.1111/jsm.12413 22 Bandini E, Fisher A D, Castellini G et al (2013) Gender identity disorder and eating disorders: similarities and differences in terms of body uneasiness J Sex Med Apr;10(4):1012-23. https:// doi: 10.1111/jsm.12062

23 Gorin-Lazard A, Baumstarck K, Boyer L, Maquigneau A et al (2013) Hormonal therapy is associated with better self- esteem, mood, and quality of life in transsexuals. J Nerv Ment Dis.;201 (11):996–1000 https:// doi: 10.1097/NMD.0000000000000046.

24 Oda H, Kinoshita T (2017) Efficacy of hormonal and mental treatments with MMPI in FtM individuals: cross-sectional and longitudinal studies. BMC Psychiatry. 2017;17(1):256 https:// doi: 10.1186/s12888-017-1423-y.

25 Fisher AD, Castellini G, Ristori J et al (2016) Cross-sex hormone treatment and psychobiological changes in transsexual persons: two-year follow-up data. J Clin Endocrinol Metab. 2016;101(11):4260–9 https:// doi: 10.1210/jc.2016-1276

26 Bultynck C, Pas C, Defreyne J et al (2017) 2804Self-perception of voice in transgender persons during cross-sex hormone therapy. Laryngoscope;127(12):2796-2804. https://doi: 10.1002/lary.26716.

27 Ristori J, Cocchetti C, Romani A et al (2020) Brain Sex Differences Related to Gender Identity Development: Genes or Hormones? Int J Mol Sci 2020 Mar 19;21(6):2123. https://doi: 10.3390/ijms21062123

28 Costa R, Colizzi M (2016) The effect of cross-sex hormonal treatment on gender dysphoria individuals' mental health: a systematic review. Neuropsychiatric disease and treatment, 12, 1953–1966. https://doi.org/10.2147/NDT.S95310

29 Nguyen HB, Chavez AM, Lipner E et al (2018) Gender-Affirming Hormone Use in Transgender Individuals: Impact on Behavioral Health and Cognition Curr Psychiatry Rep 2018 Oct 11;20(12):110. https://doi: 10.1007/s11920-018-0973- 0.

30 Wylie K, Knudson G, Khan SI et al (2016) Serving transgender people: clinical care considerations and service delivery models in transgender health. Lancet 23;388(10042):401-411. https://doi: 10.1016/S0140-6736(16)00682-6

31 Budge SL (2015) Psychotherapists as gatekeepers: An evidence-based case study highlighting the role and process of letter writing for transgender clients. Psychotherapy, 52(3), 287

32 Bockting WO, Knudson G, Goldberg JM (2006) Counseling and Mental Health Care for Transgender Adults and Loved Ones, International Journal of Transgenderism, 9:3-4, 35-82, https://doi:10.1300/J485v09n03_03

33 Coleman E, Bockting W, Botzer M et al (2012) Standards of care for the health of transsexual, transgender, and gender- nonconforming people, Version 7. International Journal of Transgenderism, 13(4), 165–232. https://doi:10.1080/ 15532739.2011.700873

34 Defreyne J, T'Sjoen G, Bouman WP et al (2018) Prospective Evaluation of Self-Reported Aggression in Transgender Persons.J Sex Med. 2018 May;15(5):768-776 . https://doi: 10.1016/j.jsxm.2018.03.079.

35 Bess G & Stabb S (2009) The Experiences of Transgendered Persons in Psychotherapy: Voices and Recommendations Journal of Mental Health Counseling 31(3):264-282 10.17744/mehc.31.3.f62415468l133w50

36 Rachlin K (2002) Transgender Individual's Experiences of Psychotherapy, Paper presented at the American Psychological Association 109thAnnual Convention, San Francisco, CA.

37 Defreyne J, T'Sjoen G (2019) Transmasculine Hormone Therapy, Endocrinol Metab Clin North Am. 2019 Jun;48(2):357-375. https://doi: 10.1016/j.ecl.2019.01.004

38 Hembree WC, Cohen-Kettenis PT, Gooren L et al (2017) Endocrine Treatment of Gender-Dysphoric/Gender- Incongruent Persons: An Endocrine Society* Clinical Practice Guideline. J Clin Endocrinol Metab. ; https://doi:102(11):3869–903

39 Pelusi C, Costantino A, Martelli V et al (2014) Effects of three different testosterone formulations in female-to-male transsexual persons, J Sex Med. 2014 Dec;11(12):3002-11. https:// doi: 10.1111/jsm.12698

40 Defreyne J, Vantomme B, Van Caenegem E et al (2018) Prospective evaluation of hematocrit in gender-affirming hormone treatment: results from European Network for the Investigation of Gender Incongruence Andrology; 6(3):446- 454. https://doi: 10.1111/andr.12485.

41 Gava G, Mancini I, Cerpolini S et al (2018) Testosterone undecanoate and testosterone enanthate injections are both effective and safe in transmen over 5 years of administration. Clin Endocrinol (Oxf). https://doi:;89(6):878–86.

42 Defreyne J, Vanwonterghem Y, Collet S et al (2020) Vaginal bleeding and spotting in transgender men after initiation of testosterone therapy: A prospective cohort study (ENIGI) Int J Transgend Health 2020 2020 Feb 12;21(2):163-175. https://doi: 10.1080/26895269.2020.1719951.

43 Meriggiola MC, Armillotta F, Costantino A et al (2008) Effects of Testosterone Undecanoate Administered Alone or in Combination with Letrozole or Dutasteride in Female to Male Transsexuals. J Sex Med. https://doi:5(10):2442–53.

44 Irwig MS, Childs K, Hancock AB (2016) Effects of testosterone on the transgender male voice, Andrology . 2017 Jan;5(1):107-112. https://doi: 10.1111/andr.12278

45 Wierckx K, Van de Peer F, Verhaeghe E et al (2014) Short- and long-term clinical skin effects of testosterone treatment in trans men. J Sex Med. gennaio 2014;11(1):222–9. https://doi: 10.1111/jsm.12366.

46 Ristori J, Cocchetti C, Castellini G et al (2020) Hormonal Treatment Effect on Sexual Distress in Transgender Persons: 2-Year Follow-Up Data. J Sex Med. 2020 Jan;17(1):142-151. https://doi: 10.1016/j.jsxm.2019.10.008.

47 van Dijk D, Dekker MJHJ, Conemans EB et al. (2019) Explorative Prospective Evaluation of Short-Term Subjective Effects of Hormonal Treatment in Trans People-Results from the European Network for the Investigation of Gender Incongruence;16(8):1297-1309.https://doi:10.1016/j.jsxm.2019.05.009

48 Asscheman H, Giltay EJ, Megens JAJ et al (2011) A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones. Eur J Endocrinol 2011; https://doi:164(4):635–642

49 Asscheman H, T’Sjoen G, Lemaire A et al (2014) Venous thromboembolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: a review. Andrologia. 2014;46(7):791–795 https://doi: 10.1111/and.12150

50 Hamidi O and Davidge-Pitts CJ (2019) Transfeminine Hormone Therapy. Endocrinol Metab Clin North Am. 48(2):341-355 https://doi: 10.1016/j.ecl.2019.02.001

51 Dekker H J, Wierckx K, Van Caenegem E et al (2016)A European Network for the Investigation of Gender Incongruence: Endocrine Part M J J Sex Med . 2016 Jun;13(6):994-9. https://doi: 10.1016/j.jsxm.2016.03.371

52 Kim JH, Yoo BW, Yang WJ (2014) Hepatic failure induced by cyproterone acetate: A case report and literature review. Can Urol Assoc J 2014; 8 (5-6): E458-61 https:doi: 10.5489/cuaj.1753

53 Millet N, Longworth J, Arcelus J (2016) Prevalence of anxiety symptoms and disorders in the transgender population: a systematic review of the literature. Int J Transgenderism. https://doi:18(1):27–38

54 Defreyne J, Nota N, Pereira C et al (2017) Transient elevated serum prolactin in trans women is caused by cyproterone acetate treatment. LGBT Health. 2017;4(5):328–33

55 Mancini I, Rotilio A, Coati I et al (2018) Presentation of a meningioma intranswoman after nine years of cyproterone acetate and estradiol intake: case report and literature review. Gynecol Endocrinol; 34(6):456-459. https://doi: 10.1080/09513590.2017.1395839.

56 Ter Wengel PV, Martin E, Gooren L et al (2016) Meningiomas in three male-to-female transgender subjects using oestrogens/progestogens and review of the literature. Andrologia 2016; 48:1130–7. https://doi: 10.1111/and.12550.

57 Gava G, Cerpolini S, Martelli V et al (2016) Cyproterone acetate vs leuprolide acetate in combination with transdermal oestradiol in transwomen: a comparison of safety and effectiveness. Clin Endocrinol (Oxf); 85: 239–246. . https://doi: 10.1111/cen.13050.

58 Dittrich R, Binder H, Cupisti S et al (2005) Endocrine treatment of maleto-female transsexuals using gonadotropin- releasing hormone agonist. Exp Clin Endocrinol Diabetes. https://doi;113(10):586–592

59 Gava G, Mancini I, Alvisi S et al (2020) A comparison of 5-year administration of cyproterone acetate or leuprolide acetate in combination with estradiol in transwomen, Eur J Endocrinol;183(6):561-569. https://doi: 10.1530/EJE-20- 0370.

60 Angus LM, Nolan BJ, Zajac JD et al (2020) A systematic review of antiandrogens and feminization in transgender women Clinical Endocrinology;00:1–10. https://doi: 10.1111/cen.14329 Jun 2020

61 Stevenson MO, Wixon N, Safer JD (2016) Scalp hair regrowth in hormone-treated transgender woman. Transgend Health;1(1):202–204

62 Irwig MS (2020) Is there a role for 5alpha-reductase inhibitors in transgender individuals? Andrology https://doi: 10.1111/andr.12881. Online ahead of print.

63 Prior JC (2019) Progesterone is important for transgender women’s therapy—applying evidence for the benefits of progesterone in ciswomen. J Clin Endocrinol Metab.; https://doi:104(4):1181–1186

64 Jain J, Kwan D, Forcier M (2019) Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results From a Retrospective Study. J Clin Endocrinol Metab.; https://doi:104(11):5148-5156

65 T’Sjoen G, Arcelus J, Gooren L et al (2019) Endocrinology of Transgender Medicine. Endocr Rev. 01 2019;40(1):97– 117 ; https://doi: 10.1210/er.2018-00011

66 de Blok CJM, Staphorsius AS, Wiepjes CM et al (2019) Frequency, Determinants, and Satisfaction of Breast Augmentation in Trans Women Receiving Hormone Treatment. J Sex Med;17(2):342-348 https://doi: 10.1016/j.jsxm.2019.10.021

67 Giltay EJ, Fonk JC, von Blomberg BM, et al (2000) In vivo effects of sex steroids on lymphocyte respon-siveness and immunoglobulin levels in humans. J Clin EndocrinolMetab 85,1648 – 1657 https://doi: 10.1210/jcem.85.4.6562

68 Klaver M, de Blok CJM, Wiepjes CM et al (2018) Changes in regional body fat, lean body mass and body shape in trans persons using cross-sex hormonal therapy: results from a multicenter prospective study. Eur J Endocrinol.;178(2):163–171 https://doi: 10.1530/EJE-17-0496

69 Bultynck C, Pas C, Defreyne J et al (2017) Self-perception of voice in transgender persons during cross-sex hormone therapy. Laryngoscope. 2017;127(12):2796-2804. https://doi doi: 10.1002/lary.26716.

70 Meyer III WJ, Webb A, Stuart CA et al (1986) Physical and hormonal evaluation of transsexual patients: a longitudinal study. Arch Sex Behav;15(2):121–138 https://doi: 10.1007/BF01542220.

71 Defreyne J, Elaut E, Kreukels B et al (2020) Sexual desire changes in transgender individuals upon initiation of hormone treatment: results from the Investigation of Gender Incongruence J Sex Med;17(4):812-825. https://doi: 10.1016/j.jsxm.2019.12.020.doi: 10.1016/j.jsxm.2019.12.020

72 Cocchetti C, Ristori J, Romani A (2020) Hormonal treatment strategies tailored to non-binary transgender individuals. J Clin Med 2020; 9(6):1609 https://doi: 10.3390/jcm9061609.

73 Rachner, TD, Coleman R, Hadji P et al (2018) Bone health during endocrine therapy for cancer. Lancet Diabetes Endocrinol. 2018, 6, 901–910 https://doi: 10.1016/S2213-8587(18)30047-0

74 Martin KA, Anderson RR, Chang RJ et al (2018) Evaluation and treatment of hirsutism in premenopausal women: An endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab, 103, 1233–1257 https://doi: 10.1210/jc.2018- 00241

75 Unluhizarci K, Ozel D, Tanriverdi F et al (2009) A comparison between finasteride, flutamide, and finasteride plus flutamide combination in the treatment of hirsutism. J. Endocrinol. Invest, 32, 37–40 https://doi: 10.1007/BF03345676

76 Gava G, Armillotta F, Pillastrini P et al (2021) A Randomized Double-Blind Placebo-Controlled Pilot Trial on the Effects of Testosterone Undecanoate Plus Dutasteride or Placebo on Muscle Strength, Body Composition, and Metabolic Profile in Transmen JSM:S1743-6095(20)31135-8 https://doi: 10.1016/j.jsxm.2020.12.015

77 Ingprasert S, Tanglertsampa C, Tangphianphan N (2016) Efficacy and safety of minoxidil 3% lotion for beard enhancement: A randomized, double-masked, placebo-controlled study. J. Dermatol. 2016, 43, 968–969 https://doi: 10.1111/1346-8138.13312

78 Dickersin K, Munro MG, Clark M (2007) Hysterectomy compared with endometrial ablation for dysfunctional uterine bleeding: A randomized controlled trial. OBSTET Gynecol. 2007, 110, 1279–1289 https://doi: 10.1097/01.AOG.0000292083.97478.38

79 Francis A, Jasani S, Bachmann G (2018) Contraceptive challenges and the transgender individual. Womens Midlife Health, 4, 12

80 Coleman E, Bockting W, Botzer M et al (2012) Standards of care for the health of transsexual, transgender, and gender- nonconforming people, Version 7. International Journal of Transgenderism, 13(4), 165–232. https://doi:10.1080/ 15532739.2011.700873

81 Elamin MB, Garcia MZ, Murad MH et al (2010) Effect of sex steroid use on cardiovascular risk in transsexual individuals: a systematic review and meta-analyses. Clin Endocrinol (Oxf). 2010;72(1):1–10 https://doi: 10.1111/j.1365- 2265.2009.03632.x.

82 Berra M, Armillotta, L, D'Emidio F et al (2006) Testosterone decreases adiponectin levels in female to male transsexuals. Asian J Androl;8(6):725-9. https://doi: 10.1111/j.1745-7262.2006.00204.x

83 Van Velzen DM, Paldino Al, Klaver M et al (2019) Cardiometabolic Effects of Testosterone in Transmen and Estrogen Plus Cyproterone Acetate in Transwomen, J Clin Endocrinol Metab1;104(6):1937-1947. https://doi: 10.1210/jc.2018- 02138

84 Cocchetti C, Castellini G, Iacuaniello D et al (2021) Does gender-affirming hormonal treatment affect 30-year cardiovascular risk in transgender persons? A two-year prospective European study (ENIGI) J Sex Med:S1743- 6095(21)00234-4. https://doi: 10.1016/j.jsxm.2021.01.185.

85 Maraka S, Singh Ospina N, Rodriguez-Gutierrez R et al (2017) Sex steroids and cardiovascular outcomes in transgender individuals: a systematic review and meta-analysis. J Clin Endocrinol Metab 2017;102:3914-3923 https://doi: 10.1210/jc.2017-01643

86 Getahun D, Nash R, Flanders WD et al (2018) Cross-sex hormones and acute cardiovascular events in transgender persons: a cohort study. Ann Intern Med;169:205-213 https://doi: 10.7326/M17-2785

87 Defreyne J, Vantomme B, Van Caenegem E et al (2018) Prospective evaluation of hematocrit in gender-affirming hormone treatment: results from European network for the investigation of gender incongruence. Andrology 2018;6:446- 454 https://doi: 10.1111/andr.12485

88 Van Caenegem E, Wierckx K, Taes Y et al (2015) Body composition, bone turnover, and bone mass in trans men during testosterone treatment: 1-year follow-up data from a prospective casecontrolled study (ENIGI). Eur J Endocrinol. 2015;172(2):163–171 https://doi: 10.1530/EJE-14-0586

89 Turner A, Chen TC, Barber TW et al (2004) Testosterone increases bone mineral density in female-to-male transsexuals: a case series of 15 subjects. Clin Endocrinol (Oxf);61(5):560–6 https://doi: 10.1111/j.1365- 2265.2004.02125.x

90 van Kesteren P, Lips P, Gooren LJG et al (1998) Long-term follow-up of bone mineral density and bone metabolism in transsexuals treated with cross-sex hormones. Clin Endocrinol (Oxf);48(3):347–354 https://doi: 10.1046/j.1365- 2265.1998.00396.x.

91 Elbers J M H, Giltay E J, Teerlink T et al (2003) Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects Clin Endocrinol (Oxf); 58(5):562-71. https://doi: 10.1046/j.1365-2265.2003.01753.x

92 Murad MH, Elamin MB, Garcia MZ et al (2010) Hormonal therapy and sex reassignment: a systematic review and meta-analysis of quality of life and psychosocial outcomes. Clin Endocrinol (Oxf);72(2):214–231 https://doi: 10.1111/j.1365-2265.2009.03625.x.

93 Maraka S (2016) Effect of sex steroids on lipids, venous thromboembolism, cardiovascular disease and mortality in transgender individuals: a systematic review and meta-analysis. Available at: http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2016.RE.15.FRI-136

94 Getahun D, Nash R, Flanders WD et al (2018) Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study Ann Intern Med;169(4):205-213. https://doi: 10.7326/M17-2785

95 Alzahrani T, Nguyen T, Ryan A et al (2019) Cardiovascular Disease Risk Factors and Myocardial Infarction in the Transgender Population. Circ Cardiovasc Qual Outcomes;12(4):e005597. https://doi: 10.1161/CIRCOUTCOMES.119.005597.

96 Khan J, Schmidt RL, Spittal MJ et al (2019) Venous Thrombotic Risk in Transgender Women Undergoing Estrogen Therapy: A Systematic Review and Metaanalysis. Clin Chem;65(1):57-66. https://doi: 10.1373/clinchem.2018.288316.

97 Van Caenegem E, Taes Y, Wierckx K et al (2013) Low bone mass is prevalent in male-to-female transsexual persons before the start of cross-sex hormonal therapy and gonadectomy. Bone;54(1):92–97 https://doi: 10.1016/j.bone.2013.01.039.

98 Wiepjes CM, Vlot MC, Klaver M, et al (2017) Bone mineral density increases in trans persons after 1 year of hormonal treatment: a multicenter prospective observational study. J Bone Miner Res;32:1252-1260 https://doi: 10.1002/jbmr.3102

99 Singh-Ospina N, Maraka S, Rodriguez-Gutierrez R et al (2017) Effect of Sex Steroids on the Bone Health of Transgender Individuals: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab;102:3904-3913 https://doi: 10.1210/jc.2017-01642

100 Rothman MS and Iwamoto SJ (2019) Bone Health in the Transgender Population. Clin Rev Bone Miner Metab;17(2):77-85 https://doi: 10.1007/s12018-019-09261-3

101 Nota NM, Wiepjes CM, de Blok CJM et al (2018) The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment Brain, Volume 141, Issue 7, Pages 2047–2054

102 Gil M, Oliva B, Timoner J et al (2011) Risk of meningioma among users of high doses of cyproterone acetate as compared with the general population: evidence from a populationbased cohort study. Br J Clin Pharmacol 2011; 72: 965–8 https://doi: 10.1111/j.1365-2125.2011.04031.x.

103 Gomez AM, Ð ỗ L, Ratliff A et al (2020) Contraceptive Beliefs, Needs, and Care Experiences Among Transgender and Nonbinary Young Adults. Journal of Adolescent Health 1e6 67(4):597-602. https://doi: 10.1016/j.jadohealth.2020.03.003.

104 Mirabella M, Giovanardi G, Fortunato A et al (2020) The Body I Live in. Perceptions and Meanings of Body Dissatisfaction in Young Transgender Adults: A Qualitative Study. J. Clin. Med. 9, 3733; https://doi:10.3390/jcm9113733

105 Abern L, Maguire K (2018) Contraception knowledge in transgender individuals: are we doing enough? Obstetrics & Gynecology. 131():65S, https:// doi: 10.1097/01.AOG.0000533319.47797.7e

106 Porsch LM, Dayananda I, Dean G et al (2016) An exploratory study of transgender New Yorkers’ Use of sexual health services and interest in receiving services at planned parenthood of New York city. Transgend Health;1:231e7. https:// doi: 10.1089/trgh.2016.0032

107 Bauer GR, Redman N, Bradley K et al (2013) Sexual health of trans men who are gay, bisexual, or who have sex with men: Results from Ontario, Canada. Int J Transgend;14:66e74. https:// doi: 10.1080/15532739.2013.791650

108 Reisner SL, Perkovich B, Mimiaga MJ et al (2010) A mixed methods study of the sexual health needs of New England transmen who have sex with nontransgender men. AIDS Patient Care STDS 2010; https://doi:24:501e13.

109 Tishelman AC, Sutter ME, Chen D, et al (2019) Health care provider perceptions of fertility preservation barriers and challenges with transgender patients and families: Qualitative responses to an international survey. J Assist Reprod Genet; https://doi:36:579e88.

110 Gomez AM, Wapman M et al (2017) Under (implicit) pressure: Young Black and Latina women’s perceptions of contraceptive care. Contraception;96:221e6. https://doi: 10.1016/j.contraception.2017.07.007

111 Light AD, Obedin-Maliver J, Sevelius JM et al (2014) Transgender men who experienced pregnancy after female- to-male gender transitioning. Obstet Gynecol;124:1120e7 https://doi: 10.1097/AOG.0000000000000540

112 Mancini I, Alvisi S, Gava G et al (2021) Contraception across transgender, Int J Impot Res https://doi: 10.1038/s41443-021-00412-z. Online ahead of print

113 Light A, Wang LF, Zeymo A, Gomez-Lobo V (2018) Family planning and contraception use in transgender men, Contraception; 98(4):266-269. doi: 10.1016/j.contraception.2018.06.006.

114 Auer MK, Fuss J, Nieder TO, et al. Desire to Have Children Among Transgender People in Germany: A Cross- Sectional Multi-Center Study. J Sex Med. 2018;15(5):757-767 https://doi: 10.1016/j.jsxm.2018.03.083

115 von Doussa H, Power J, Riggs D et al (2015) Imagining parenthood: the possibilities and experiences of parenthood among transgender people. Culture, Health and Sexuality;17(9):1119-1131 https:// doi: 10.1080/13691058.2015.1042919

116 Defreyne J, Van Schuylenbergh J, Motmans J et al (2020) Parental desire and fertility preservation in assigned male at birth transgender people living in Belgium. Int J Transgend Health. 8;21(1):45-57 https:// doi: 10.1080/15532739.2019.1692750.

117 T’Sjoen G, Van Caenegem E & Wierckx, K. et al (2013). Transgenderism and reproduction. Current Opinion in Endocrinology, Diabetes, and Obesity, 20(6), 575–579 https:// doi: 10.1097/01.med.0000436184.42554.b7.

118 Hamada A, Kingsberg S, Wierckx K et al (2015) Semen characteristics of transwomen referred for sperm banking before sex transition: a case series. Andrologia 2015; https://doi:47:832-8

119 Li K, Rodriguez D, Gabrielsen JS et al (2018) Sperm cryopreservation of transgender individuals: trends and findings in the past decade. Andrology;6:860-4. https:// doi: 10.1111/andr.12527

120 Adeleye AJ, Reid G, Kao CN et al (2019) Semen Parameters Among Transgender Women With a History of Hormonal Treatment. Urology 2019;124:136-41 https:// doi: 10.1016/j.urology.2018.10.005

121 Baba T, Endo T, Honnma H et al (2007) Association between polycystic ovary syndrome and female-to-male transsexuality.Hum Reprod;22(4):1011–1016 https:// doi: 10.1093/humrep/del474.

122 Spinder T, Spijkstra JJ, van den Tweel JG et al (1989) The effects of long term testosterone administration on pulsatile luteinizing hormone secretion and on ovarian histology in eugonadal female to male transsexual subjects. J Clin Endocrinol Meta;69(1):151–157 https:// doi: 10.1210/jcem-69-1-151

123 Ikeda K, Baba T, Noguchi H et al (2013) Excessive androgen exposure in female-to-male transsexual persons of reproductive age induces hyperplasia of the ovarian cortex and stroma but not polycystic ovary morphology. Hum Reprod.;28(2):453–461. https://doi: 10.1093/humrep/des385

124 Maxwell S, Noyes N, Keefe D et al (2017) Pregnancy Outcomes After Fertility Preservation in Transgender Men Obstet Gynecol;129(6):1031-1034. https://doi:10.1097/AOG.0000000000002036.

125 Armuand G, Dhejne C, Olofsson JI et al (2017) Transgender men's experiences of fertility preservation: a qualitative study. Hum Reprod;32:383-90. https://doi: 10.1093/humrep/dew323

126 Gooren LJ, T’Sjoen G et al (2018) Endocrine treatment of aging transgender people. Rev Endocr Metab Disord 2018;19:253-262. https://doi: 10.1007/s11154-018-9449-0.

127 Van Caenegem E, Taes Y, Wierckx K et al (2013) Low bone mass is prevalent in male-to-female transsexual persons before the start of cross-sex hormonal therapy and gonadectomy. Bone; 54: 92–97 https://doi: 10.1016/j.bone.2013.01.039

128 Wiepjes CM, Jm de Blok C, Staphorsius AS et al (2020) Fracture Risk in Trans Women and Trans Men Using Long- Term Gender-Affirming Hormonal Treatment: A Nationwide Cohort Study, J Bone Miner Res.;35(1):64-70. https://doi: 10.1002/jbmr.3862

129 Shao T, Grossbard ML, Klein P (2011) Breast cancer in female-tomaletranssexuals: two cases with a review of physiology and management. Clin Breast Cancer.;11(6):417–419 https://doi: 10.1016/j.clbc.2011.06.006

130 Burcombe RJ, Makris A, Pittam M et al (2003) Breast cancer after bilateral subcutaneous mastectomy in a female- to-male transsexual. Breast.;12(4):290–293. https://doi: 10.1016/s0960-9776(03)00033-x

131 Marjoribanks J, Farquhar C, Roberts H et al (2017) Longterm hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev.; https://doi.org/10.1002/14651858.CD004143.pub5.

132 Bergoglio MT, Gomez-Balaguer M, Almonacid Folch E et al (2013) Symptomatic meningioma induced by cross-sex hormone treatment in a male-to-female transsexual. Endocrinol Nutr.;60(5):264–267. https://doi: 10.1016/j.endonu.2012.07.004.

133 StegemanBH, de Bastos M, Rosendaal FR et al (2013) Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ.;347:f5298. https://doi.org/10.1136/bmj.f5298