European Network For The Investigation Of Gender Incongruence Research Articles

OR31-06 Gender-Affirming Hormone Therapy Affects Serum Cystatin C-based eGFR In Transgender Individuals

Abstract Disclosure: S.A. van Eeghen: None. C. Wiepjes: None. N. Nokoff: None. P. Bjornstad: None. M. Den Heijer: None. D. van Raalte: None. Background: Previous studies in transgender individuals have shown that masculinizing (testosterone) hormone therapy increases and feminizing (estradiol combined with anti-androgen) hormone therapy decreases serum creatinine. Translating this into estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, eGFR increases in transwomen and decreases in transmen during gender-affirming hormone therapy (GAHT). However, serum creatinine is significantly correlated with lean body mass (LBM), which also changes during GAHT, with transmen gaining and transwomen loosing muscle mass. Thus changes in creatinine-derived eGFR during hormone therapy may not reflect true changes in GFR. Another manner to estimate GFR, which is not affected by body composition, is by measuring plasma cystatin C concentrations. Therefore, we studied the effects of GAHT on serum cystatin C, a sex-independent marker for GFR. Methods: In this prospective, observational sub study of the European Network for the Investigation of Gender Incongruence (ENIGI), serum cystatin C was measured in 266 transwomen and 285 transmen before and at 12 months of GAHT. Transwomen received feminizing hormone therapy, consisting of oral (n= 122) or transdermal administration (n= 144) of estrogen in combination with the oral anti-androgen cyproteroneacetate. Transmen received masculinizing hormone therapy, which consisted of intramuscular (n= 144) or transdermal (n= 141) administration of testosterone. Serum cystatin C-based eGFR was calculated according to the full-age-spectrum equation (FAScysC; mL/min/1.73m2). Linear regression was used to assess the means. Results: In transwomen (baseline characteristics; median age 29 (IQR 23-43) years; median BMI 22.9 (IQR 20.8-26.4) kg/m2; creatinine 78.6 ± 9.9 μmol/L; creatinine-based CKD-EPI eGFR 110 ± 14 mL/min/1.73m2), cystatin C decreased by 0.07 (95% CI, 0.05 to 0.09) mg/L; from 0.94 ± 0.17 mg/L before GAHT to 0.87 ± 0.15 mg/L during GAHT. This corresponds with an increase in FAScysC of 7 (95% CI, 5 to 9) mL/min/1.73m2; from 93 ± 17 to 100 ± 18 mL/min/1.73m2. On the contrary, in transmen (baseline characteristics; median age 22 (IQR 20-28) years; median BMI 24.7 (IQR 21.4-30.1) kg/m2; creatinine 66.8 ± 9.3 μmol/L; creatinine-based CKD-EPI eGFR 110 ± 15 mL/min/1.73m2) cystatin C increased by 0.05 (95% CI, 0.03 to 0.07) mg/L; from 0.89 ± 0.17 mg/L before GAHT to 0.95 ± 0.16 mg/L during 12 months of GAHT. This is consistent with a decrease in FASCysC of 6 (95% CI, 4 to 8) mL/min/1.73m2; from 101 ± 19 to 94 ± 15 mL/min/1.73m2. Conclusions: In this large-sized cohort of transgender individuals, cystatin C-based eGFR increased with feminizing hormone therapy and decreased with masculinizing hormone therapy, indicating true biological effects of sex hormones on kidney physiology, which warrants further investigation. Presentation: Sunday, June 18, 2023

Cystatin C-Based eGFR Changes during Gender-Affirming Hormone Therapy in Transgender Individuals.

Men with CKD tend to experience a faster eGFR decline than women, potentially because of sex hormones. Limited research exists regarding the effect of gender-affirming hormone therapy (GAHT) on kidney function. Furthermore, monitoring kidney function during GAHT is challenging because serum creatinine is confounded by body composition. To investigate the relationship between sex hormones and kidney function, we studied the changes of serum creatinine and serum cystatin C, a filtration marker less affected by sex, during 1 year of GAHT. As part of the European Network for the Investigation of Gender Incongruence study, we measured serum creatinine and serum cystatin C in 260 transgender women and 285 transgender men before and 12 months after initiating GAHT. Transgender women received estradiol plus cyproterone acetate, while transgender men received testosterone. Cystatin C-based eGFR was calculated using the full-age-spectrum equation. In transgender women, cystatin C decreased by 0.069 mg/L (95% confidence interval [CI], 0.049 to 0.089), corresponding with a 7 ml/min per 1.73 m 2 increase in eGFR. In transgender men, cystatin C increased by 0.052 mg/L (95% CI, 0.031 to 0.072), corresponding with a 6 ml/min per 1.73 m 2 decrease in eGFR. Creatinine concentrations decreased (-0.065 mg/dl; 95% CI, -0.076 to -0.054) in transgender women and increased (+0.131 mg/dl; 95% CI, 0.119 to 0.142) in transgender men. Changes in creatinine-based eGFR varied substantially depending on the sex used in the equation. In this cohort of transgender individuals, cystatin C-based eGFR increased with estradiol and antiandrogen therapy and decreased with testosterone therapy.

The ENIGI (European Network for the Investigation of Gender Incongruence) Study: Overview of Acquired Endocrine Knowledge and Future Perspectives.

Literature on the efficacy and safety of gender-affirming hormonal treatment (GAHT) in transgender people is limited. For this reason, in 2010 the European Network for the Investigation of Gender Incongruence (ENIGI) study was born. The aim of this review is to summarize evidence emerging from this prospective multicentric study and to identify future perspectives. GAHT was effective in inducing desired body changes in both trans AMAB and AFAB people (assigned male and female at birth, respectively). Evidence from the ENIGI study confirmed the overall safety of GAHT in the short/mid-term. In trans AMAB people, an increase in prolactin levels was demonstrated, whereas the most common side effects in trans AFAB people were acne development, erythrocytosis, and unfavorable changes in lipid profile. The main future perspectives should include the evaluation of the efficacy and safety of non-standardized hormonal treatment in non-binary trans people. Furthermore, long-term safety data on mortality rates, oncological risk, and cardiovascular, cerebrovascular and thromboembolic events are lacking. With this aim, we decided to extend the observation of the ENIGI study to 10 years in order to study all these aspects in depth and to answer these questions.

Pleasure please! Sexual pleasure and influencing factors in transgender persons: An ENIGI follow-up study

Background: While the importance of sexual pleasure for physical and mental health becomes increasingly evident, research on sexual pleasure in transgender persons is lacking. Recently, the first version of the Amsterdam Sexual Pleasure Index (ASPI Vol. 0.1) was validated in cisgender persons. This questionnaire aims to assess the tendency to experience sexual pleasure independent of gender, sexual orientation or anatomy. Aim: The aims of this study were threefold. First, to perform exploratory scale validation analyses of the ASPI in transgender persons. Secondly, to compare transgender sexual pleasure scores to reference data in cisgender persons. Finally, to identify factors that are associated with sexual pleasure. Methods: In a follow-up study conducted within the European Network for the Investigation of Gender Incongruence (ENIGI), online questionnaires were distributed to persons who had a first clinical contact at gender clinics in Amsterdam, Ghent or Hamburg four to six years earlier. Internal consistency of the ASPI was assessed by calculating McDonald’s omega (ωt). ASPI scores were compared to scores from the cisgender population using a one sample t-test, and linear regressions were conducted to study associations with clinical characteristics, psychological wellbeing, body satisfaction and self-reported happiness. Results: In total, 325 persons filled out the ASPI. The ASPI showed excellent internal consistency (ωt, all: 0.97; transfeminine: 0.97, transmasculine: 0.97). Compared to data from cisgender persons, transgender participants had significantly lower total ASPI scores (i.e., lower sexual pleasure; transgender vs. cisgender, mean(SD): 4.13(0.94) vs. 4.71(0.61)). Lower age, current happiness and genital body satisfaction were associated with a higher tendency to experience sexual pleasure. Conclusion & discussion: The ASPI can be used to assess the tendency to experience sexual pleasure and associated factors in transgender persons. Future studies are needed to understand interplaying biopsychosocial factors that promote sexual pleasure and hence transgender sexual health and wellbeing.

Experienced barriers of care within European treatment seeking transgender individuals: A multicenter ENIGI follow-up study

Objectives: To evaluate the experienced barriers of care for treatment-seeking trans individuals (TSTG) in three large European clinics. Methods: An online follow-up questionnaire was filled out by 307 TSTG individuals as part of the research protocol of the European Network for the Investigation of Gender Incongruence (ENIGI). Data was collected during follow-up in 2017/2018, around 5 years after participants had their initial clinical appointments in Ghent (Belgium), Amsterdam (the Netherlands), or Hamburg (Germany). Background characteristics, country, treatment characteristics and mental health were analyzed in relation to experienced barriers of care (EBOC, measured though agreement with statements). Results: The majority of participants reported various EBOC, oftentimes more than one. The most-frequently reported EBOCs pertained to the lack of family and friends’ support (28.7%, n = 88) and travel time and costs (27.7%, n = 85), whereas around one-fifth felt hindered by treatment protocols. Also, a significant share expressed the feeling that they had to convince their provider they needed care and/or express their wish in such way to increase their likelihood of receiving care. A higher number of EBOCs reported was associated with more mental health problems, lower income and female gender. Conclusions: A substantial number of TSTG individuals within three European health care systems experiences EBOCs. EBOCs relate to both personal and systemic characteristics. These findings can help health care providers and centers to improve care. More research must be done to better understand the diversity among TSTG individuals and the corresponding barriers experienced. Supplemental data for this article is available online at https://doi.org/10.1080/26895269.2021.1964409

Toward a Lowest Effective Dose of Cyproterone Acetate in Trans Women: Results From the ENIGI Study.

ContextCyproterone acetate (CPA) is a competitive inhibitor of the androgen receptor and exerts negative hypothalamic feedback. It is often used in combination with estrogens in trans women to achieve feminization. However, CPA has been associated with side effects such as changes in liver enzyme concentrations and increases in prolactin concentrations. The question is whether the testosterone-lowering effect, as well as these side effects, are dose dependent.ObjectiveTo assess the lowest effective dose of CPA in trans women to prevent side effects.MethodsThis longitudinal study, conducted at gender identity centers in Amsterdam, Ghent, and Florence, is part of the European Network for the Investigation of Gender Incongruence (ENIGI), a multicenter prospective cohort study. Participants were trans women (n = 882) using estrogens only or in combination with 10, 25, 50, or 100 mg CPA daily. The primary outcome measure was the concentration of testosterone at 3 and/or 12 months of hormone therapy.ResultsUsing estrogens only (without CPA) led to testosterone concentrations of 5.5 nmol/L (standard error of the mean [SEM] 0.3). All doses of CPA resulted in testosterone concentrations below the predefined threshold of suppression of 2 nmol/L (10 mg, 0.9 nmol/L, SEM 0.7; 25 mg, 0.9 nmol/L, SEM 0.1; 50mg, 1.1 nmol/L, SEM 0.1; 100 mg, 0.9 nmol/L, SEM 0.7). Higher prolactin and lower high-density lipoprotein concentrations were observed with increasing doses of CPA. No differences in liver enzyme concentrations were found between the doses.ConclusionCompared with higher doses of CPA, a daily dose of 10 mg is equally effective in lowering testosterone concentrations in trans women, while showing fewer side effects.

Sexual orientation in transgender individuals: results from the longitudinal ENIGI study.

Transgender people and their next-of-kin may request information on sexual orientation and preferred partners during hormonal affirming process. Although previous research on sexual orientation in transgender people is extensive, this literature may already be outdated and/or the methodology of studies assessing sexual orientation may fall short. This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Gender role and preferred partner in sexual fantasies, sexual orientation and gender of current sexual partner were assessed at baseline (initiation of HT) and every follow-up visit. Data from 469 transgender women (TW) and 433 transgender men (TM) were analyzed cross-sectionally and prospectively. At baseline, more than half reported having no partner (35% of TW, 47% of TM). After 12 months, more than half reported having a partner (59% of TW, 56% of TM), with no changes between one and three years of HT. The majority of TM preferred a female partner, TW preferred male and female partners. The sexual identity of their partner matched their sexual orientation in >80%. Sexual orientation did not change over time. We did not observe associations with serum levels of sex steroids or gender-affirming surgery (chest or genital surgery). Sexual orientation did not change during hormonal transition and was not associated with sex steroids or surgery. Also, preferences matched the partner's sexual identity. We do not assume that changing serum levels of sex steroids is directly associated with changes in partner choice. The number of people with a current partner increased, possibly due to the indirect effects of gender-affirming care.

Positive and Negative Affect Changes during Gender-Affirming Hormonal Treatment: Results from the European Network for the Investigation of Gender Incongruence (ENIGI).

Improving transgender people’s quality of life (QoL) is the most important goal of gender-affirming care. Prospective changes in affect can influence QoL. We aim to assess the impact of initiating gender-affirming hormonal treatment (HT) on affect. In the European Network for the Investigation of Gender Incongruence (ENIGI) study, we prospectively collected data of 873 participants (451 transwomen (TW) and 422 transmen (TM)). At baseline, psychological questionnaires including the Positive and Negative Affect Schedule (PANAS) were administered. The PANAS, levels of sex steroids and physical changes were registered at each follow-up visit during a 3-year follow-up period, starting at the initiation of hormonal therapy. Data were analyzed cross-sectionally and prospectively. Over the first three months, we observed a decline in positive affect (PA) in both TM and TW. Thereafter, PA reached a steady state in TW, whereas in TM there was also a second decline at 18 months. In both TM and TW there was no persisting difference comparing baseline to the 36-months results. Concerning negative affect (NA), we observed a decline during the first year in TM, which sustained during the second year and was not different anymore at 36 months compared to baseline. In TW though, we did not find any change of NA during the entire follow-up. Even if some of these results show significant differences, they should be considered with caution, since there was no control group and the absolute differences are small. No association between affect and the level of sex steroids was observed. Baseline QoL and psychological burden are related to affect independently from gender but are not necessarily good predictors of the evolution of one’s affect during the gender-affirming process. Further research is necessary to investigate these preliminary results.

Characterisation of testicular function and spermatogenesis in transgender women.

Does gender-affirming treatment prevent full spermatogenesis in transgender women (TW)? Adequate hormonal therapy (HT) leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. Gender-affirming treatment in transgender individuals may involve gender-affirming HT. The effects on spermatogenesis in TW remain unclear. In order to add information from a referral centre for transgender care, we wish to compare results of earlier studies with our population of TW who received a standard hormone treatment. This was a prospective cohort study part of the European Network for the Investigation of Gender Incongruence (ENIGI), conducted between 15 February 2010 and 30 September 2015. There were 162 TW were included in the ENIGI study at the Ghent University Hospital in Belgium. Participants are included in ENIGI when they first start HT, and follow-up visits occur over the next 3 years. The study included 97 TW who initiated HT with cyproterone acetate (CPA) plus oestrogens and proceeded with gonadectomy at the Ghent University Hospital. Testicular tissue retrieved during gonadectomy was processed and stained for four different germ cell markers by the Biology of the Testis lab at the Vrije Universiteit Brussel. Subsequent immunohistochemical staining was performed for melanoma-associated antigen A4 (MAGE-A4, marker for spermatogonia and early spermatocytes), boule homologue, RNA-binding protein (BOLL, marker for secondary spermatocytes and round spermatids), cAMP-responsive element modulator (CREM, marker for round spermatids) and acrosin (marker for acrosome visualization). Serum levels of sex steroids were measured prior to surgery. Suppressed testosterone levels (<50 ng/dl) were found in 92% of the participants prior to surgery. The mean time between initiation of HT and surgery was 685 days. In 88% (85/97) of the sections, MAGE-A4 staining was positive. Further staining could not reveal complete spermatogenesis in any participant. Testicular function of the participants prior to initiation of HT was not assessed, although all participants presented with cisgender male serum testosterone values before initiation of HT. The current study only reports on people using CPA at a fixed dose and may therefore not be applicable to all TW. HT leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. Serum testosterone levels are associated with the sperm maturation rate. It is important to discuss sperm preservation before the start of hormone therapy. If serum testosterone levels remain higher, spermatogenesis may still occur. D.V.S. is a post-doctoral fellow of the Fonds Wetenschappelijk Onderzoek (FWO; 12M2819N). Processing of the testis specimens was funded by the Biology of The Testes (BITE) research group (Department of Reproduction, Genetics and Regenerative medicine at Vrije Universiteit Brussel (VUB)). There are no competing interests. N/A.

Vaginal bleeding and spotting in transgender men after initiation of testosterone therapy: A prospective cohort study (ENIGI)

Previous studies have cross-sectionally described amenorrhea in cohorts of transgender men on intramuscular or subcutaneous testosterone injections. It remains uncertain which testosterone preparations most effectively suppress vaginal bleeding and when amenorrhea occurs after testosterone initiation.To investigate the clinical effects of various testosterone preparations on vaginal bleeding and spotting in transgender men.This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Data on the persistence and intensity of vaginal bleeding and spotting, serum sex steroid levels and body composition were prospectively and cross-sectionally assessed in 267 transgender men during a three-year follow-up period, starting at the initiation of various testosterone preparations.After three months of testosterone, 17.9% of transgender men reported persistent vaginal bleeding and 26.8% reported spotting. The percentages reporting vaginal bleeding and spotting decreased over the first year of testosterone (bleeding 4.7% and spotting 6.9% at 12 months, respectively), with no participants reporting vaginal bleeding or spotting after 18 months of testosterone. Factors associated with vaginal bleeding or spotting included lower serum testosterone levels and being on testosterone gel as compared to injections (e.g., esters or undecanoate preparations). If vaginal bleeding persisted, starting progestogens at three months resulted in a decrease in the intensity of vaginal bleeding and spotting.Transgender men and hormone-prescribing providers can be reassured that vaginal bleeding and spotting usually stop within three months after testosterone initiation. If not, serum testosterone levels should be measured and testosterone dose adjusted to achieve serum testosterone levels in the physiologic male range. Adding a progestin can be considered after three to six months if bleeding persists. Providers should be aware that cessation of bleeding can be more difficult to achieve in transgender men with lower serum testosterone levels or those on testosterone gel.

P-06-13 Factors Other than Sex Steroid Levels Contribute to Sexual Desire in Transgender Women

The European Network for the Investigation of Gender Incongruence (ENIGI) investigated sexual desire scores in transgender women (TW). The prospective increase in sexual desire appears to be higher after gonadectomy. The contribution of serum steroid levels to sexual desire in transgender people are insufficiently explored. The current study assesses the role of testosterone (T), DHEAS, SHBG, free T before and after orchiectomy in TW. This prospective cohort study was part of the ENIGI study. Sex steroids, the Sexual Desire Inventory (SDI) questionnaire and self-rated sexual desire were assessed at baseline and each follow-up visit. Gender affirming hormones were initiated at baseline: estrogens (orally or transdermally) and anti-androgens (cyproterone acetate 25-50mg/day). After orchiectomy the anti-androgen were stopped. Data from 118 TW with ≥1 year of follow-up at the Ghent site were analyzed prospectively. Subgroup analyses were performed in TW who underwent orchiectomy (group A, n=85) versus TW who didn't (group B, n=33), at baseline, pre-operatively versus month 12 and post-operatively versus month 24.

SAT-745 Lower Serum Estradiol Levels in Assigned Female at Birth Transgender People with Initiation of Testosterone Therapy: Results from the European Network for the Investigation of Gender Incongruence (ENIGI)

Introduction: Aromatization of exogenous testosterone might result in increased estradiol levels. Concerns have been raised about undesired estrogenic effects in assigned female at birth (AFAB) transgender people. How serum estradiol levels change after initiation of testosterone therapy and if these levels should be monitored, remains unclear. Methods: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Serum levels of sex steroids were assessed in 746 AFAB transgender people during a three-year follow-up period, starting at the initiation of hormone treatment. Results: Estradiol levels decreased from median [P25-P75] 45.5[24.0-102.2]pg/mL to 36.5[25.0-46.2]pg/mL over three years (P<0.001), a change was already noticeable during the first three months (mean - 17.1 pg/mL, 95% CI -23.8 - -10.6, P<0.001). Serum estradiol levels were lower in people without endogenous estradiol production (contraceptive users or post gonadectomy) at baseline and after three months, compared to people with endogenous estradiol production. Using long acting testosterone undecanoate injections resulted in a more prominent decrease in serum estradiol values over twelve months, compared to short acting mixed testosterone esters (P<0.001) or testosterone gel (P=0.001). Changes in serum estradiol were positively correlated to changes in LH (ρ = 0.107, P<0.001) and negatively correlated to changes in FSH levels (ρ=-0.167, P<0.001) and body mass index (ρ=-0.082, P<0.001). Conclusion: Testosterone administration in AFAB transgender people results in decreasing serum estradiol levels. Although an underlying mechanism for the observed decrease in serum estradiol levels remains difficult to fathom, our results suggest that testosterone administration suppresses endogenous estradiol production. The exception found in people without endogenous estradiol production may be attributed to aromatization of exogenous testosterone.

OR27-05 Sexual Desire Changes in Transgender Individuals upon Initiation of Hormone Treatment; Results from the Longitudinal ENIGI Study

Introduction: Several steps in the transitioning process may affect sexual desire in transgender people. This is often underexposed by those providing gender affirming care. Testosterone therapy in transgender men (TM) generally leads to increasing frequency of desire, masturbation, sexual fantasies and arousal. Studies in transgender women (TW) are inconclusive: some report an increase in the prevalence of hypoactive sexual desire after initiation of hormone therapy, whereas others have shown a positive impact of hormonal therapy on sexual quality of life. The current study prospectively assesses sexual desire during the first three years of hormonal therapy (HT) in transgender people. Methods: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Sexual desire was prospectively assessed in 766 participants (401 TW, 364 TM) by Sexual Desire Inventory (SDI) during a three-year follow-up period, starting at the initiation of hormone treatment (HT). SDI scores were analyzed as total, dyadic and solitary SDI scores. At baseline, psychological questionnaires were administered. Sex steroids were measured at each follow-up visit. Data were analyzed cross-sectionally and prospectively. Results: In TW, total, dyadic and solitary SDI scores decreased during the first three months of HT. However, after 36 months, total and dyadic SDI scores were higher than baseline scores. Solitary scores after 36 months were comparable to baseline scores. In TM, total, dyadic and solitary SDI scores increased over the first three months, remaining stable thereafter. However, total and dyadic SDI scores after thirty-six months were comparable to baseline scores, whereas solitary scores remained higher than baseline. Factors associated with a prospective increase in SDI scores included having undergone gonadectomy, no longer experiencing vaginal bleedings (in TM) or higher gender dysphoria levels at baseline (in TM only). Factors associated with higher cross-sectional SDI scores included being in a relationship, undergoing gonadectomy, no longer experiencing vaginal bleedings (TM), lower gender dysphoria scores (TW only) and lower body dysphoria scores (TW only). Conclusion: Gender affirming hormonal therapy induces short-term changes in sexual desire in transgender people. Over a longer period of time, a net increase in dyadic sexual desire in TW receiving feminizing HT was observed. Sexual desire scores comparable to baseline in TM receiving virilizing HT were found. We observed no correlation between sexual desire and absolute serum testosterone levels. However, other factors, including undergoing gonadectomy, persistence of vaginal bleedings (in TM) and psychological factors may influence sexual desire in transgender people.

Vaginal bleeding and spotting in transgender men after initiation of testosterone therapy: A prospective cohort study (ENIGI)

Background: Previous studies have cross-sectionally described amenorrhea in cohorts of transgender men on intramuscular or subcutaneous testosterone injections. It remains uncertain which testosterone preparations most effectively suppress vaginal bleeding and when amenorrhea occurs after testosterone initiation.Aim:To investigate the clinical effects of various testosterone preparations on vaginal bleeding and spotting in transgender men.Methods: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Data on the persistence and intensity of vaginal bleeding and spotting, serum sex steroid levels and body composition were prospectively and cross-sectionally assessed in 267 transgender men during a three-year follow-up period, starting at the initiation of various testosterone preparations.Results: After three months of testosterone, 17.9% of transgender men reported persistent vaginal bleeding and 26.8% reported spotting. The percentages reporting vaginal bleeding and spotting decreased over the first year of testosterone (bleeding 4.7% and spotting 6.9% at 12 months, respectively), with no participants reporting vaginal bleeding or spotting after 18 months of testosterone. Factors associated with vaginal bleeding or spotting included lower serum testosterone levels and being on testosterone gel as compared to injections (e.g., esters or undecanoate preparations). If vaginal bleeding persisted, starting progestogens at three months resulted in a decrease in the intensity of vaginal bleeding and spotting.Discussion: Transgender men and hormone-prescribing providers can be reassured that vaginal bleeding and spotting usually stop within three months after testosterone initiation. If not, serum testosterone levels should be measured and testosterone dose adjusted to achieve serum testosterone levels in the physiologic male range. Adding a progestin can be considered after three to six months if bleeding persists. Providers should be aware that cessation of bleeding can be more difficult to achieve in transgender men with lower serum testosterone levels or those on testosterone gel.

Effects of Gender-Affirming Hormone Therapy on Insulin Sensitivity and Incretin Responses in Transgender People.

The long-term influences of sex hormone administration on insulin sensitivity and incretin hormones are controversial. We investigated these effects in 35 transgender men (TM) and 55 transgender women (TW) from the European Network for the Investigation of Gender Incongruence (ENIGI) study. Before and after 1 year of gender-affirming hormone therapy, body composition and oral glucose tolerance tests (OGTTs) were evaluated. In TM, body weight (2.8 ± 1.0 kg; P < 0.01), fat-free mass (FFM) (3.1 ± 0.9 kg; P < 0.01), and waist-to-hip ratio (-0.03 ± 0.01; P < 0.01) increased. Fasting insulin (-1.4 ± 0.8 mU/L; P = 0.08) and HOMA of insulin resistance (HOMA-IR) (2.2 ± 0.3 vs. 1.8 ± 0.2; P = 0.06) tended to decrease, whereas fasting glucose (-1.6 ± 1.6 mg/dL), glucose-dependent insulinotropic polypeptide (GIP) (-1.8 ± 1.0 pmol/L), and glucagon-like peptide 1 (GLP-1) (-0.2 ± 1.1 pmol/L) were statistically unchanged. Post-OGTT areas under the curve (AUCs) for GIP (2,068 ± 1,134 vs. 2,645 ± 1,248 [pmol/L] × min; P < 0.01) and GLP-1 (2,352 ± 796 vs. 2,712 ± 1,015 [pmol/L] × min; P < 0.01) increased. In TW, body weight tended to increase (1.4 ± 0.8 kg; P = 0.07) with decreasing FFM (-2.3 ± 0.4 kg; P < 0.01) and waist-to-hip ratio (-0.03 ± 0.01; P < 0.01). Insulin (3.4 ± 0.8 mU/L; P < 0.01) and HOMA-IR (1.7 ± 0.1 vs. 2.4 ± 0.2; P < 0.01) rose, fasting GIP (-1.4 ± 0.8 pmol/L; P < 0.01) and AUC GIP dropped (2,524 ± 178 vs. 1,911 ± 162 [pmol/L] × min; P < 0.01), but fasting glucose (-0.3 ± 1.4 mg/dL), GLP-1 (1.3 ± 0.8 pmol/L), and AUC GLP-1 (2,956 ± 180 vs. 2,864 ± 93 [pmol/L] × min) remained unchanged. In this cohort of transgender persons, insulin sensitivity but also post-OGTT incretin responses tend to increase with masculinization and to decrease with feminization.

PO-01-023 Sexual desire in transgender persons in relation with gender affirming hormone treatment. Results from ENIGI, a large multicenter prospective cohort study in transgender people

Several steps in the transitioning process may affect sexual desire, including hormone therapy and gender affirming surgery. Testosterone therapy in transgender men (TM) generally leads to increased sexual desire, masturbation, sexual fantasies and arousal. Studies in transgender women (TW) are often inconclusive. This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Upon first clinical contact, psychological questionnaires were completed. Sexual desire was prospectively assessed in 766 participants (401 TW, 364 TM) by the Sexual Desire Inventory (SDI) during a three-year follow-up period, starting at the initiation of hormone treatment (HT). Sex steroids were measured at each visit. Data were analyzed cross-sectionally and prospectively. Baseline SDI scores were comparable in TW and TM (P=0.342). In TW, SDI scores decreased from 39.0 [23.0 – 54.5] (baseline) to 33.0 [16.3 – 49.8] (12 months) (-4.77, P<0.001), returning to scores comparable to baseline after 18 months (P=0.114). After 36 months, SDI scores were higher than baseline scores (51.5 [39.5 – 61.0], P=0.003). In TM, total SDI scores increased from 40.0 [17.0 – 52.0] at baseline to 55.0 [40.5 – 67.0] (+14.61, P<0.001) after 12 months, remaining stable over the following year and returning to scores comparable to baseline scores (58.0 [23.0 – 62.0], P=0.250) after 36 months. People with a partner (P<0.001) and TW with lower levels of self-reported gender dysphoria (Utrecht Gender Dysphoria Scale) (ρ=0.336, P=0.002) reported higher SDI scores. Prospective SDI scores were not influenced by prospective changes in serum levels of sex steroids in TM and TW. Lower baseline levels of gender dysphoria (Utrecht Gender Dysphoria Scale) correlated to a higher prospective increase in SDI scores in TM after 12 months of HT (ρ=-0.355, P<0.001).

PS-01-001 Is anger intensity related to serum testosterone levels and/or exogenous testosterone therapy? Results from ENIGI, a large multicenter prospective cohort study in transgender people

Anger is a state of emotions ranging from irritation to intense rage. Aggression is the externalization of anger through destructive/punitive behavior. The World Professional Association for Transgender Health (WPATH) Standards of Care, Edition 7 (SOC7) guidelines warn about aggression in transgender men (TM) on testosterone treatment. As aggression is often initiated by feelings of anger, we aimed to assess whether anger intensity increases in TM and decreases in transgender women (TW) after initiation of hormone therapy, and to identify predictors for anger intensity in transgender people. This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Upon first clinical contact, psychological questionnaires were administered. Anger intensity was prospectively assessed in 898 participants (440 TM, 468 TW) by the STAXI-2 (State-Trait Anger Expression Inventory-2) State Anger (S-Anger) during a three-year follow-up period, starting at the initiation of hormone treatment. Sex steroids were measured at each follow-up visit. Data were analyzed cross-sectional and prospectively.

HP-02-001 The relation between sexual dysfunction and sexual pleasure in transgender individuals: results from the ENIGI follow-up study

Recently, research attention for the sexual life of individuals with Gender Dysphoria (GD, also referred to as transgender individuals), is increasing. Research has shown that the prevalence rates of sexual dysfunction (including the experience of distress) in transgender persons having received Gender Confirming Interventions (GCI) were higher compared to the general population. However, less is known on the impact of having one or more sexual dysfunctions on sexual pleasure. Further, it is possible that this relationship differs between individuals in different treatment trajectories (e.g. no medical treatment versus only hormone treatment versus hormone treatment and genital surgery), and also between individuals with fulfilled and continuing treatment intentions. This study is part of the ENIGI (European Network for the Investigation of Gender Incongruence) follow-up study. An online survey was presented to transgender persons four to six years after first clinical contact in the gender clinics of Amsterdam, Ghent or Hamburg. The participants filled in the Amsterdam Sexual Pleasure Index (ASPI) (Werner, Gaasterland, van Lunsen & Laan, in press), a recently developed questionnaire to measure sexual pleasure, and answered a broad range of questions about sexual dysfunctions (including the distress criteria). 560 individuals participated; 523 individuals filled out data on sexual functioning.

No correlation between serum testosterone levels and state-level anger intensity in transgender people: Results from the European Network for the Investigation of Gender Incongruence

IntroductionAnger is a state of emotions ranging from irritation to intense rage. Aggression implies externalizing anger through destructive/punitive behaviour. The World Professional Association for Transgender Health (WPATH) Standards of Care, Edition 7 (SOC7) guidelines warn about aggression in transgender men (TM) on testosterone treatment. We aimed to assess whether anger intensity increases in TM and decreases in transgender women (TW) after initiation of gender affirming hormone therapy and to identify predictors for anger intensity in transgender people. MethodsThis prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Anger intensity was prospectively assessed in 898 participants (440 TM, 468 TW) by STAXI-2 (State-Trait Anger Expression Inventory-2) State Anger (S-Anger) during a three-year follow-up period, starting at the initiation of hormone treatment. Data were analysed cross-sectionally and prospectively. ResultsThere was no change in STAXI-2 S-Anger scores. At three, twelve and thirty-six months of gender affirming hormone therapy, STAXI-2 S-Anger scores were not correlated to serum testosterone levels, although there was a correlation with various psychological measures after three and twelve months. TM experiencing menstrual spotting after three months had higher STAXI-2 S-Anger scores compared to those without (median 26.5 [18.0–29.8] versus 15.0 [15.0–17.0], P = 0.020).Changes in STAXI-2 S-Anger scores were not correlated to changes in serum testosterone levels after three, twelve and thirty-six months in TM or TW. ConclusionsState-level anger intensity is associated with psychological and/or psychiatric vulnerability, but not exogenous testosterone therapy or serum testosterone levels in transgender people.

Treatment Experiences and Social Support in Individuals with Gender Incongruence/Gender Dysphoria - A ENIGI 5 Year Follow-Up Study in Three European Countries

Gender Dysphoria (GD) refers to a distress resulting from an incongruence between the individual's sex characteristics and the experience of their gender (Gender Incongruence, GI). The interaction between medical treatment of GI/GD and social support in the long-term has not been investigated sufficiently so far. Using an online questionnaire, the present study investigated n=117 individuals with GI/GD assigned male and n=52 assigned female at birth that had been referred to one of the specialized clinics of the European Network for the Investigation of Gender Incongruence (ENIGI) in Belgium, the Netherlands, and Germany.They filled out a questionnaire at 2 time points within a follow-up time of 4 to 6 years after clinical entry (between 2007 and 2009). Two hierarchical regression analyses explored the effects of the sex assigned at birth, the treatment progress and social support on mental distress and satisfaction with life at follow-up in the sample. A female sex assigned at birth and higher degrees of social support significantly predicted the reduction in mental distress at follow-up. An advanced stage of the individual treatment and higher social support significantly predicted an increase in overall satisfaction with life. The results illustrate the importance of social support with regard to the outcome of medical treatment of GI/GD.