The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment

The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment Abstract Benign brain tumours may be hormone sensitive. To induce physical characteristics of the desired gender, transgender individuals often receive cross-sex hormone treatment, sometimes in higher doses than hypogonadal individuals. To date, long-term (side) effects of cross-sex hormone treatment are largely unknown. In the present retrospective chart study we aimed to compare the incidence of common benign brain tumours: meningiomas, pituitary adenomas (non-secretive and secretive), and vestibular schwannomas in transgender individuals receiving cross-sex hormone treatment, with those reported in general Dutch or European populations. This study was performed at the VU University Medical Centre in the Netherlands and consisted of 2555 transwomen (median age at start of cross-sex hormone treatment: 31 years, interquartile range 23–41) and 1373 transmen (median age 23 years, interquartile range 18–31) who were followed for 23 935 and 11 212 person-years, respectively. For each separate brain tumour, standardized incidence ratios with 95% confidence intervals were calculated. In transwomen (male sex assigned at birth, female gender identity), eight meningiomas, one non-secretive pituitary adenoma, nine prolactinomas, and two vestibular schwannomas occurred. The incidence of meningiomas was higher in transwomen than in a general European female population (standardized incidence ratio 4.1, 95% confidence interval 1.9–7.7) and male population (11.9, 5.5–22.7). Similar to meningiomas, prolactinomas occurred more often in transwomen compared to general Dutch females (4.3, 2.1–7.9) and males (26.5, 12.9–48.6). Noteworthy, most transwomen had received orchiectomy but still used the progestogenic anti-androgen cyproterone acetate at time of diagnosis. In transmen (female sex assigned at birth, male gender identity), two cases of somatotrophinomas were observed, which was higher than expected based on the reported incidence rate in a general European population (incidence rate females = incidence rate males; standardized incidence ratio 22.2, 3.7–73.4). Based on our results we conclude that cross-sex hormone treatment is associated with a higher risk of meningiomas and prolactinomas in transwomen, which may be linked to cyproterone acetate usage, and somatotrophinomas in transmen. Because these conditions are quite rare, performing regular screenings for such tumours (e.g. regular prolactin measurements for identifying prolactinomas) seems not necessary. transgender individuals, cross-sex hormone treatment, benign brain tumours, meningioma, pituitary Introduction Meningiomas, pituitary adenomas (non-secretive adenoma, prolactinoma, somatotrophinoma, corticotrophinoma and thyrotrophinoma), and vestibular schwannomas are the most common benign brain neoplasms (Black, 1995). Various studies have reported sex differences in the occurrence of benign brain tumours. For example, meningiomas and prolactinomas are reported to occur more frequently in females than in males (Mindermann and Wilson, 1994; Sun et al., 2015; Day et al., 2016). Hypothetically, sex hormones/sex hormone receptors could play a role in the reported sex differences (Cahill et al., 1984; Blankenstein et al., 2000; Sarkar, 2006). Therefore, administration of exogenous sex hormones may affect the risk of brain tumour development. Gender dysphoria refers to the suffering due to an incongruence between one’s sex assigned at birth and one’s experienced gender (American Psychiatric Association, 2013). In transwomen (male sex assigned at birth, female gender identity) cross-sex hormone treatment usually consists of oestrogens, often combined with anti-androgens. In transmen (female sex assigned at birth, male gender identity) cross-sex hormone treatment usually consists of testosterone only. The prevalence of individuals who experience gender incongruence and wish to obtain hormones/surgery is currently estimated at 0.2% for females and 0.6% for males (Kuyper and Wijsen, 2014). However, in recent decades an on-going increase in referrals has been observed. Although many transgender individuals receive lifelong cross-sex hormone treatment, there is still little known about the (long-term) risks of this treatment. Nevertheless, several cases of benign brain tumours in transgender individuals treated with cross-sex hormones have been reported, such as meningiomas (Gazzeri et al., 2007; Ter Wengel et al., 2016) and prolactinomas (Kovacs et al., 1994; Bunck et al., 2009; García-Malpartida et al., 2010; Cunha et al., 2015) in transwomen, and a somatotrophinoma in a transman (Roerink et al., 2014). Because of a potential increased risk of prolactinomas in transwomen, the Endocrine Society advises to regularly monitor prolactin levels during cross-sex hormone treatment (Hembree et al., 2017), although it is not known whether the incidence of prolactinomas is truly increased. There are no such advices for the detection of other benign brain tumours. In the current study we aimed to determine how often common benign brain tumours (meningiomas, pituitary adenomas, and vestibular schwannomas) develop in transgender individuals during cross-sex hormone treatment and whether the incidence of these tumours differs from that reported in general Dutch and European populations. We hypothesized that meningiomas and prolactinomas occur more often in transwomen receiving cross-sex hormone treatment than in general male populations, but that the incidence of these tumours is comparable to that of general female populations. We also hypothesized that transmen using cross-sex hormones do not have an increased risk for developing benign brain tumours. Materials and methods Subjects We performed a retrospective chart study, reviewing the medical files of all individuals who were seen for psychological, endocrine, or surgical evaluations/interventions at the gender clinic of the VU University Medical Centre between February 1972 and December 2015. Baseline and follow-up data of these 6793 individuals were entered into a cumulative database and constitute the Amsterdam Cohort Study of Gender Dysphoria (Wiepjes et al., 2018). For the current study, we only included individuals in whom cross-sex hormones had been prescribed in our centre or one of our affiliates (such as University Medical Centre Groningen), who had at least one follow-up visit at our clinic since then, and of whom a start date of cross-sex hormone treatment was known. Several participants had already used cross-sex hormones before their first visit to our hospital. To provide the most accurate estimation of the total cross-sex hormone treatment duration in these individuals, we used the actual start date of cross-sex hormones (if available). We excluded participants who had used female and male sex hormones alternately or had discontinued cross-sex hormone treatment for an extended period of time during follow-up, because of regret of their transition. Finally, we used the data of 3928 subjects: 2555 transwomen [median age at start of cross-sex hormone treatment: 31 years, interquartile range (IQR) 23–41] and 1373 transmen (median age at start of cross-sex hormone treatment: 23 years, IQR 18–31). The medical records of these subjects were screened for the occurrence of tumours during cross-sex hormone treatment, which were both clinically and radiologically suspicious for a meningioma, pituitary adenoma (secreting and non-secreting), and/or vestibular schwannoma. The ethical committee of the VU University Medical Centre approved this study. A waiver of informed consent was granted because of the retrospective study design, the large number of participants included, and the absence of a need to contact participants. Personal identification information was removed from the database to protect anonymity. Cross-sex hormone treatment In adult transwomen, cross-sex hormone treatment usually consisted of oestrogens and, if desired, anti-androgens (usually given to those who had not received an orchiectomy). Over the whole study period the most frequently prescribed anti-androgens were cyproterone acetate (CPA, 50–100 mg/day) and spironolactone (100–200 mg/day). In the past, oestrogens were mainly prescribed in the form of ethinylestradiol (50–100 μg/day), conjugated oestrogens (0.625–2.5 mg/day), oestradiol patches (50–150 µg/day), oestradiol implants (20 mg/3–6 months), or oestradiol injections (10–100 mg/month). More recently, we have mainly used oestradiol implants (20 mg/3–6 months), oral oestradiol valerate (2–4 mg/day), oestradiol patches (50–150 µg/day), and oestradiol gel (1.5 mg/day). In adult transmen, cross-sex hormone treatment usually consisted of testosterone gel (20–100 mg/day), intramuscular testosterone esters (250 mg/2–3 weeks), or oral or intramuscular testosterone undecanoate (40–160 mg/day orally or 1000 mg/10–14 weeks intramuscularly). Some transmen experiencing uterine bleeding additionally received lynesterol (5–10 mg/daily). When treatment was started at adolescence (<18 years) it usually consisted of CPA (50–100 mg/day) or triptorelin (3.75 mg/4 weeks) in transgirls, and of lynestrenol (5 mg/day) or triptorelin (3.75 mg/4weeks) in transboys. From the age of 16 this treatment was eventually combined with oestrogens (mostly oestradiol valerate, ethinylestradiol, or oestradiol hemihydrate) in transgirls and testosterone (mostly testosterone esters) in transboys. Statistical analysis Stata version 13.1 (StataCorp, College Station Texas, USA) and OpenEpi version 3.01 (www.OpenEpi.com) were used for the statistical analyses. Data of transwomen and transmen were analysed separately. Subject characteristics (age) and follow-up/treatment durations were expressed as actual numbers or as medians with range or IQR. Standardized incidence ratios (SIRs) were calculated using several steps. Firstly, the number of new cases of each separate brain tumour that occurred in transwomen and transmen (observed cases) was determined. Subsequently, the total person-time of observation in years was determined by calculating the period of time that each participant had been followed-up since start of cross-sex hormone treatment (date of last physical visit or brain tumour diagnosis minus start date of cross-sex hormone treatment). Hereafter, the expected cases, based on reported incidence rates in general Dutch or European populations (if reliable Dutch rates were not available) and the total person-time of observation, were calculated. When different incidence rates were reported for females and males, we calculated the expected cases twice, once using the incidence rate of females and once using the incidence rate of males (see Table 1 for the references used to calculate the expected cases). Finally, we performed mid-P exact tests for calculating SIRs with 95% confidence intervals (CIs) for each type of tumour. Table 1 SIRs for each separate benign brain tumour in transmen and transwomen Type of tumour  Observed cases  Expected cases  SIR (95% CI)  Expected cases  SIR (95% CI)              Using females as reference  Using males as reference  Transwomen  Meningioma  8  1.97a  4.1 (1.9–7.7)  0.67a  11.9 (5.5-22.7)  Non-secretive pituitary adenoma  1  0.13b  7.7 (0.4–37.9)  0.13b  7.7 (0.4–37.9)  Secretive pituitary adenoma                1. Prolactinoma                    Total  9  2.08c  4.3 (2.1–7.9)  0.34c  26.5 (12.9–48.6)          Symptomatic  5  2.08c  2.4 (0.9–5.3)  0.34c  14.7 (5.4–32.6)      2. Somatotrophinoma  0  0.18d  –  0.18d  –      3. Corticotrophinoma  0  0.06e  –  0.02e  –      4. Thyrotrophinoma  0  0.01f  –  0.01f  –  Vestibular schwannoma  2  0.90g  2.2 (0.4–7.3)  0.90g  2.2 (0.4–7.3)  Transmen            Meningioma  0  0.92a  –  0.32a  –  Non-secretive pituitary adenoma  0  0.06b  –  0.06b  –  Secretive pituitary adenoma                1. Prolactinoma  1  0.98c  1.02 (0.1–5.0)  0.16c  6.3 (0.3–30.8)      2. Somatotrophinoma  2  0.09d  22.2 (3.7–73.4)  0.09d  22.2 (3.7–73.4)      3. Corticotrophinoma  0  0.03e  –  0.01e  –      4. Thyrotrophinoma  0  0.00f  –  0.00f  –  Vestibular schwannoma  0  0.42g  –  0.42g  –  Type of tumour  Observed cases  Expected cases  SIR (95% CI)  Expected cases  SIR (95% CI)              Using females as reference  Using males as reference  Transwomen  Meningioma  8  1.97a  4.1 (1.9–7.7)  0.67a  11.9 (5.5-22.7)  Non-secretive pituitary adenoma  1  0.13b  7.7 (0.4–37.9)  0.13b  7.7 (0.4–37.9)  Secretive pituitary adenoma                1. Prolactinoma                    Total  9  2.08c  4.3 (2.1–7.9)  0.34c  26.5 (12.9–48.6)          Symptomatic  5  2.08c  2.4 (0.9–5.3)  0.34c  14.7 (5.4–32.6)      2. Somatotrophinoma  0  0.18d  –  0.18d  –      3. Corticotrophinoma  0  0.06e  –  0.02e  –      4. Thyrotrophinoma  0  0.01f  –  0.01f  –  Vestibular schwannoma  2  0.90g  2.2 (0.4–7.3)  0.90g  2.2 (0.4–7.3)  Transmen            Meningioma  0  0.92a  –  0.32a  –  Non-secretive pituitary adenoma  0  0.06b  –  0.06b  –  Secretive pituitary adenoma                1. Prolactinoma  1  0.98c  1.02 (0.1–5.0)  0.16c  6.3 (0.3–30.8)      2. Somatotrophinoma  2  0.09d  22.2 (3.7–73.4)  0.09d  22.2 (3.7–73.4)      3. Corticotrophinoma  0  0.03e  –  0.01e  –      4. Thyrotrophinoma  0  0.00f  –  0.00f  –  Vestibular schwannoma  0  0.42g  –  0.42g  –  Expected cases are based on incidence rates reported by: aBaldi et al. (2011); bNielsen et al. (2007); cKars et al. (2009); dHoskuldsdottir et al. (2015); eLindholm et al. (2001); fÖnnestam et al. (2013); gKleijwegt et al. (2016). Table 1 SIRs for each separate benign brain tumour in transmen and transwomen Type of tumour  Observed cases  Expected cases  SIR (95% CI)  Expected cases  SIR (95% CI)              Using females as reference  Using males as reference  Transwomen  Meningioma  8  1.97a  4.1 (1.9–7.7)  0.67a  11.9 (5.5-22.7)  Non-secretive pituitary adenoma  1  0.13b  7.7 (0.4–37.9)  0.13b  7.7 (0.4–37.9)  Secretive pituitary adenoma                1. Prolactinoma                    Total  9  2.08c  4.3 (2.1–7.9)  0.34c  26.5 (12.9–48.6)          Symptomatic  5  2.08c  2.4 (0.9–5.3)  0.34c  14.7 (5.4–32.6)      2. Somatotrophinoma  0  0.18d  –  0.18d  –      3. Corticotrophinoma  0  0.06e  –  0.02e  –      4. Thyrotrophinoma  0  0.01f  –  0.01f  –  Vestibular schwannoma  2  0.90g  2.2 (0.4–7.3)  0.90g  2.2 (0.4–7.3)  Transmen            Meningioma  0  0.92a  –  0.32a  –  Non-secretive pituitary adenoma  0  0.06b  –  0.06b  –  Secretive pituitary adenoma                1. Prolactinoma  1  0.98c  1.02 (0.1–5.0)  0.16c  6.3 (0.3–30.8)      2. Somatotrophinoma  2  0.09d  22.2 (3.7–73.4)  0.09d  22.2 (3.7–73.4)      3. Corticotrophinoma  0  0.03e  –  0.01e  –      4. Thyrotrophinoma  0  0.00f  –  0.00f  –  Vestibular schwannoma  0  0.42g  –  0.42g  –  Type of tumour  Observed cases  Expected cases  SIR (95% CI)  Expected cases  SIR (95% CI)              Using females as reference  Using males as reference  Transwomen  Meningioma  8  1.97a  4.1 (1.9–7.7)  0.67a  11.9 (5.5-22.7)  Non-secretive pituitary adenoma  1  0.13b  7.7 (0.4–37.9)  0.13b  7.7 (0.4–37.9)  Secretive pituitary adenoma                1. Prolactinoma                    Total  9  2.08c  4.3 (2.1–7.9)  0.34c  26.5 (12.9–48.6)          Symptomatic  5  2.08c  2.4 (0.9–5.3)  0.34c  14.7 (5.4–32.6)      2. Somatotrophinoma  0  0.18d  –  0.18d  –      3. Corticotrophinoma  0  0.06e  –  0.02e  –      4. Thyrotrophinoma  0  0.01f  –  0.01f  –  Vestibular schwannoma  2  0.90g  2.2 (0.4–7.3)  0.90g  2.2 (0.4–7.3)  Transmen            Meningioma  0  0.92a  –  0.32a  –  Non-secretive pituitary adenoma  0  0.06b  –  0.06b  –  Secretive pituitary adenoma                1. Prolactinoma  1  0.98c  1.02 (0.1–5.0)  0.16c  6.3 (0.3–30.8)      2. Somatotrophinoma  2  0.09d  22.2 (3.7–73.4)  0.09d  22.2 (3.7–73.4)      3. Corticotrophinoma  0  0.03e  –  0.01e  –      4. Thyrotrophinoma  0  0.00f  –  0.00f  –  Vestibular schwannoma  0  0.42g  –  0.42g  –  Expected cases are based on incidence rates reported by: aBaldi et al. (2011); bNielsen et al. (2007); cKars et al. (2009); dHoskuldsdottir et al. (2015); eLindholm et al. (2001); fÖnnestam et al. (2013); gKleijwegt et al. (2016). Results Transwomen For transwomen, the median person-time of observation was 6.22 years (range 0.01–54.77) and the total person-time of observation 23 935 years. Table 1 shows the observed and expected number of new brain tumour cases with the corresponding SIRs and 95% CIs. In total, 20 cases of new benign brain tumours were identified: eight meningiomas, one non-secretive pituitary adenoma, nine prolactinomas, and two vestibular schwannomas. As expected, no cases of somatotrophinomas, corticotrophinomas or thyrotrophinomas were found (Lindholm et al., 2001; Önnestam et al., 2013; Hoskuldsdottir et al., 2015). Also the number of observed non-secretive pituitary adenomas (n = 1; SIR 7.7, 95% CI 0.4–37.9) and vestibular schwannomas (n = 2; SIR 2.2, 95% CI 0.4–7.3) was not different from the expected number in general female and male populations (Nielsen et al., 2007; Kleijwegt et al., 2016). On the other hand, transwomen showed significantly more cases of meningiomas than could be expected based on the incidence rate of a European (French) female (SIR 4.1, 95% CI 1.9–7.7) and male (SIR 11.9, 95% CI 5.5–22.7) population (Baldi et al., 2011). In addition, more prolactinomas were identified in transwomen than in the general Dutch female (SIR 4.3, 95% CI 2.1–7.9) and male (SIR 26.5, 95% CI 12.9–48.6) population (Kars et al., 2009). However, when we included only transwomen with prolactinoma-associated symptoms at time of diagnosis in our analyses, we found an almost comparable incidence between transwomen and the general female population (SIR 2.4, 95% CI 0.9–5.3). Table 2 provides a detailed description of each separate brain tumour case in transwomen. It is of note that at time of diagnosis, most individuals (including those who have received orchiectomy) diagnosed with a meningioma or prolactinoma were still using CPA (a drug that is usually discontinued after orchiectomy). Table 2 Detailed description of each brain tumour case in transwomen Type of tumour  Age  CHT duration  CHT typea  GDX  Reason for tumour diagnostics  Management  Meningiomab              Case 1 (suprasellar located)  45 years  ±59 months  CPA 10 mg, oestradiol implant 20 mg/4 months  Yes  Vision problems  Surgery  Case 2 (multiple locations)  65 years  ±230 months  CPA 10 mg, conjugated oestrogens 1.25 mg  Yes  Vision problems  Surgery, stop CHTc  Case 3 (frontal located)  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100µg  Yes  Epileptic insults  Surgery, anti-epileptics  Case 4 (temporal located)  66 years  ±477 months  CPA 10 mg  Yes  Headache, vertigo, vibrations  Wait-and-see  Case 5 (frontobasal located)  58 years  ±75 months  CPA 50 mg, oestradiol patch 100µg  No  Diplopia, headache, hyperprolactinaemia  Wait-and-see  Case 6 (frontal located)  49 years  ±192 months  CPA 100 mg, ethinylestradiol 100 µg  Yes  Hyperprolactinaemia  Wait-and-seec  Case 7 (parietotemporal located)  59 years  ±124 months  CPA 50 mg, ethinylestradiol 100µg  Yes  Headache, tiredness  Surgery  Case 8 (parafalcine/parietotemporal located)  51 years  ±307 months  CPAd, oestradiol valerate 2 mg  Yes  Depression, apathy, delusions  Surgery  Non-secretive pituitary adenoma  Case 1 (macroadenoma)  34 years  ±35 months  CPA 50 mg, oestradiol valerate 1 mg  No  Headache, vertigo, nausea  Stop CHTc  Prolactinoma              Case 1 (microadenoma)e  52 years  ±177 months  Conjugated oestrogens 0.625 mg  Yes  Hyperprolactinaemia  Dopamine-agonist  Case 2 (microadenoma)  32 years  ±53 months  CPA 100 mg, oestradiol injection 100 mg/2weeks  Yes  Hyperprolactinaemia  Stop oestradiol  Case 3 (microadenoma)  39 years  ±172 months  CPA 100 mg, conjugated oestrogens 2.5 mg  Yes  Hypothyroidism, hyperprolactinaemia  Levothyroxine  Case 4 (microadenoma)  27 years  ±156 months  CPAd, oestradiol injectiond  No  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Case 5 (microadenoma)  46 years  ±66 months  CPA 100 mg, ethinylestradiol 100µg  No  Hyperprolactinaemia  Wait-and-see  Case 6 (microadenoma)  24 years  ±9 monthsf  CPA 100 mg  No  Hyperprolactinaemia  Dopamine-agonist  Case 7 (microadenoma)  47 years  ±91 months  CPA 100 mg, ethinylestradiol 100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 8 (microadenoma)  29 years  ±143 months  Ethinylestradiol 50-100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 9 (macroadenoma)  28 years  ±134 months  CPA 50 mg, oestradiol valerate 2 mg  Yes  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Vestibular schwannoma              Case 1  60 years  ±274 months  Tibolon 2.5 mg  Yes  Deafness, vertigo, imbalance  Wait-and-see, radiotherapy  Case 2  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100 µg  Yes  Epileptic insults  Wait-and-see, anti-epileptics  Type of tumour  Age  CHT duration  CHT typea  GDX  Reason for tumour diagnostics  Management  Meningiomab              Case 1 (suprasellar located)  45 years  ±59 months  CPA 10 mg, oestradiol implant 20 mg/4 months  Yes  Vision problems  Surgery  Case 2 (multiple locations)  65 years  ±230 months  CPA 10 mg, conjugated oestrogens 1.25 mg  Yes  Vision problems  Surgery, stop CHTc  Case 3 (frontal located)  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100µg  Yes  Epileptic insults  Surgery, anti-epileptics  Case 4 (temporal located)  66 years  ±477 months  CPA 10 mg  Yes  Headache, vertigo, vibrations  Wait-and-see  Case 5 (frontobasal located)  58 years  ±75 months  CPA 50 mg, oestradiol patch 100µg  No  Diplopia, headache, hyperprolactinaemia  Wait-and-see  Case 6 (frontal located)  49 years  ±192 months  CPA 100 mg, ethinylestradiol 100 µg  Yes  Hyperprolactinaemia  Wait-and-seec  Case 7 (parietotemporal located)  59 years  ±124 months  CPA 50 mg, ethinylestradiol 100µg  Yes  Headache, tiredness  Surgery  Case 8 (parafalcine/parietotemporal located)  51 years  ±307 months  CPAd, oestradiol valerate 2 mg  Yes  Depression, apathy, delusions  Surgery  Non-secretive pituitary adenoma  Case 1 (macroadenoma)  34 years  ±35 months  CPA 50 mg, oestradiol valerate 1 mg  No  Headache, vertigo, nausea  Stop CHTc  Prolactinoma              Case 1 (microadenoma)e  52 years  ±177 months  Conjugated oestrogens 0.625 mg  Yes  Hyperprolactinaemia  Dopamine-agonist  Case 2 (microadenoma)  32 years  ±53 months  CPA 100 mg, oestradiol injection 100 mg/2weeks  Yes  Hyperprolactinaemia  Stop oestradiol  Case 3 (microadenoma)  39 years  ±172 months  CPA 100 mg, conjugated oestrogens 2.5 mg  Yes  Hypothyroidism, hyperprolactinaemia  Levothyroxine  Case 4 (microadenoma)  27 years  ±156 months  CPAd, oestradiol injectiond  No  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Case 5 (microadenoma)  46 years  ±66 months  CPA 100 mg, ethinylestradiol 100µg  No  Hyperprolactinaemia  Wait-and-see  Case 6 (microadenoma)  24 years  ±9 monthsf  CPA 100 mg  No  Hyperprolactinaemia  Dopamine-agonist  Case 7 (microadenoma)  47 years  ±91 months  CPA 100 mg, ethinylestradiol 100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 8 (microadenoma)  29 years  ±143 months  Ethinylestradiol 50-100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 9 (macroadenoma)  28 years  ±134 months  CPA 50 mg, oestradiol valerate 2 mg  Yes  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Vestibular schwannoma              Case 1  60 years  ±274 months  Tibolon 2.5 mg  Yes  Deafness, vertigo, imbalance  Wait-and-see, radiotherapy  Case 2  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100 µg  Yes  Epileptic insults  Wait-and-see, anti-epileptics  Age, CHT duration, CHT type and GDX data are at time of diagnosis of the brain tumour. aUnless otherwise specified, the represented doses are daily doses. bThree of these meningiomas have also been reported by Ter Wengel et al. (2016). cAt request of the patient. dDose unknown. eThis case has also been reported by Bunck et al. (2009). fCHT duration was probably longer than 9 months, but the exact start date of CHT was not documented. CHT = cross-sex hormone treatment; GDX = gonadectomy. Table 2 Detailed description of each brain tumour case in transwomen Type of tumour  Age  CHT duration  CHT typea  GDX  Reason for tumour diagnostics  Management  Meningiomab              Case 1 (suprasellar located)  45 years  ±59 months  CPA 10 mg, oestradiol implant 20 mg/4 months  Yes  Vision problems  Surgery  Case 2 (multiple locations)  65 years  ±230 months  CPA 10 mg, conjugated oestrogens 1.25 mg  Yes  Vision problems  Surgery, stop CHTc  Case 3 (frontal located)  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100µg  Yes  Epileptic insults  Surgery, anti-epileptics  Case 4 (temporal located)  66 years  ±477 months  CPA 10 mg  Yes  Headache, vertigo, vibrations  Wait-and-see  Case 5 (frontobasal located)  58 years  ±75 months  CPA 50 mg, oestradiol patch 100µg  No  Diplopia, headache, hyperprolactinaemia  Wait-and-see  Case 6 (frontal located)  49 years  ±192 months  CPA 100 mg, ethinylestradiol 100 µg  Yes  Hyperprolactinaemia  Wait-and-seec  Case 7 (parietotemporal located)  59 years  ±124 months  CPA 50 mg, ethinylestradiol 100µg  Yes  Headache, tiredness  Surgery  Case 8 (parafalcine/parietotemporal located)  51 years  ±307 months  CPAd, oestradiol valerate 2 mg  Yes  Depression, apathy, delusions  Surgery  Non-secretive pituitary adenoma  Case 1 (macroadenoma)  34 years  ±35 months  CPA 50 mg, oestradiol valerate 1 mg  No  Headache, vertigo, nausea  Stop CHTc  Prolactinoma              Case 1 (microadenoma)e  52 years  ±177 months  Conjugated oestrogens 0.625 mg  Yes  Hyperprolactinaemia  Dopamine-agonist  Case 2 (microadenoma)  32 years  ±53 months  CPA 100 mg, oestradiol injection 100 mg/2weeks  Yes  Hyperprolactinaemia  Stop oestradiol  Case 3 (microadenoma)  39 years  ±172 months  CPA 100 mg, conjugated oestrogens 2.5 mg  Yes  Hypothyroidism, hyperprolactinaemia  Levothyroxine  Case 4 (microadenoma)  27 years  ±156 months  CPAd, oestradiol injectiond  No  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Case 5 (microadenoma)  46 years  ±66 months  CPA 100 mg, ethinylestradiol 100µg  No  Hyperprolactinaemia  Wait-and-see  Case 6 (microadenoma)  24 years  ±9 monthsf  CPA 100 mg  No  Hyperprolactinaemia  Dopamine-agonist  Case 7 (microadenoma)  47 years  ±91 months  CPA 100 mg, ethinylestradiol 100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 8 (microadenoma)  29 years  ±143 months  Ethinylestradiol 50-100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 9 (macroadenoma)  28 years  ±134 months  CPA 50 mg, oestradiol valerate 2 mg  Yes  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Vestibular schwannoma              Case 1  60 years  ±274 months  Tibolon 2.5 mg  Yes  Deafness, vertigo, imbalance  Wait-and-see, radiotherapy  Case 2  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100 µg  Yes  Epileptic insults  Wait-and-see, anti-epileptics  Type of tumour  Age  CHT duration  CHT typea  GDX  Reason for tumour diagnostics  Management  Meningiomab              Case 1 (suprasellar located)  45 years  ±59 months  CPA 10 mg, oestradiol implant 20 mg/4 months  Yes  Vision problems  Surgery  Case 2 (multiple locations)  65 years  ±230 months  CPA 10 mg, conjugated oestrogens 1.25 mg  Yes  Vision problems  Surgery, stop CHTc  Case 3 (frontal located)  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100µg  Yes  Epileptic insults  Surgery, anti-epileptics  Case 4 (temporal located)  66 years  ±477 months  CPA 10 mg  Yes  Headache, vertigo, vibrations  Wait-and-see  Case 5 (frontobasal located)  58 years  ±75 months  CPA 50 mg, oestradiol patch 100µg  No  Diplopia, headache, hyperprolactinaemia  Wait-and-see  Case 6 (frontal located)  49 years  ±192 months  CPA 100 mg, ethinylestradiol 100 µg  Yes  Hyperprolactinaemia  Wait-and-seec  Case 7 (parietotemporal located)  59 years  ±124 months  CPA 50 mg, ethinylestradiol 100µg  Yes  Headache, tiredness  Surgery  Case 8 (parafalcine/parietotemporal located)  51 years  ±307 months  CPAd, oestradiol valerate 2 mg  Yes  Depression, apathy, delusions  Surgery  Non-secretive pituitary adenoma  Case 1 (macroadenoma)  34 years  ±35 months  CPA 50 mg, oestradiol valerate 1 mg  No  Headache, vertigo, nausea  Stop CHTc  Prolactinoma              Case 1 (microadenoma)e  52 years  ±177 months  Conjugated oestrogens 0.625 mg  Yes  Hyperprolactinaemia  Dopamine-agonist  Case 2 (microadenoma)  32 years  ±53 months  CPA 100 mg, oestradiol injection 100 mg/2weeks  Yes  Hyperprolactinaemia  Stop oestradiol  Case 3 (microadenoma)  39 years  ±172 months  CPA 100 mg, conjugated oestrogens 2.5 mg  Yes  Hypothyroidism, hyperprolactinaemia  Levothyroxine  Case 4 (microadenoma)  27 years  ±156 months  CPAd, oestradiol injectiond  No  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Case 5 (microadenoma)  46 years  ±66 months  CPA 100 mg, ethinylestradiol 100µg  No  Hyperprolactinaemia  Wait-and-see  Case 6 (microadenoma)  24 years  ±9 monthsf  CPA 100 mg  No  Hyperprolactinaemia  Dopamine-agonist  Case 7 (microadenoma)  47 years  ±91 months  CPA 100 mg, ethinylestradiol 100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 8 (microadenoma)  29 years  ±143 months  Ethinylestradiol 50-100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 9 (macroadenoma)  28 years  ±134 months  CPA 50 mg, oestradiol valerate 2 mg  Yes  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Vestibular schwannoma              Case 1  60 years  ±274 months  Tibolon 2.5 mg  Yes  Deafness, vertigo, imbalance  Wait-and-see, radiotherapy  Case 2  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100 µg  Yes  Epileptic insults  Wait-and-see, anti-epileptics  Age, CHT duration, CHT type and GDX data are at time of diagnosis of the brain tumour. aUnless otherwise specified, the represented doses are daily doses. bThree of these meningiomas have also been reported by Ter Wengel et al. (2016). cAt request of the patient. dDose unknown. eThis case has also been reported by Bunck et al. (2009). fCHT duration was probably longer than 9 months, but the exact start date of CHT was not documented. CHT = cross-sex hormone treatment; GDX = gonadectomy. Transmen For transmen, the median person-time of observation was 4.16 years (range 0.02–41.66) and the total person-time 11 212 years. Table 1 shows the observed and expected number of new brain tumour cases with the corresponding SIRs with 95% CIs. Three cases of benign brain tumours were identified: one prolactinoma and two somatotrophinomas. The single case of prolactinoma we observed was not different from the number we expected using the incidence rates of a general Dutch female (SIR 1.02, 95% CI 0.1–5.0) and male (SIR 6.3, 95% CI 0.3–30.8) population (Kars et al., 2009). Since somatotrophinomas occur very rarely (incidence rate females = incidence rate males) (Hoskuldsdottir et al., 2015), the two observed cases of somatotrophinomas were higher than expected (SIR 22.2, 95% CI 3.7–73.4). As expected, no cases of meningiomas, non-secretive pituitary adenomas, corticotrophinomas, thyrotrophinomas, or vestibular schwannomas were found (Lindholm et al., 2001; Nielsen et al., 2007; Baldi et al., 2011; Önnestam et al., 2013; Kleijwegt et al., 2016). Table 3 provides a detailed description of each separate brain tumour case in transmen. Table 3 Detailed description of each brain tumour case in transmen Type of tumour  Age  CHT duration  Testosterone type  GDX  Reason for tumour diagnostics  Management  Prolactinoma  Case 1 (microadenoma)  42 years  ±269 months  Oral undecanoate 80 mg/day  Yes  Headache, vision problems  Dopamine-agonist  Somatotrophinoma  Case 1 (macroadenoma)  47 years  ±30 months  Unknown  Yes  Unknown  Surgery  Case 2 (macroadenoma)  31 years  ±89 months  Esters 250 mg/2 weeks  Yes  Spectacular testosterone effects  Surgery  Type of tumour  Age  CHT duration  Testosterone type  GDX  Reason for tumour diagnostics  Management  Prolactinoma  Case 1 (microadenoma)  42 years  ±269 months  Oral undecanoate 80 mg/day  Yes  Headache, vision problems  Dopamine-agonist  Somatotrophinoma  Case 1 (macroadenoma)  47 years  ±30 months  Unknown  Yes  Unknown  Surgery  Case 2 (macroadenoma)  31 years  ±89 months  Esters 250 mg/2 weeks  Yes  Spectacular testosterone effects  Surgery  Age, CHT duration, CHT type and GDX data are at time of diagnosis of the brain tumour. CHT = cross-sex hormone treatment; GDX = gonadectomy. Table 3 Detailed description of each brain tumour case in transmen Type of tumour  Age  CHT duration  Testosterone type  GDX  Reason for tumour diagnostics  Management  Prolactinoma  Case 1 (microadenoma)  42 years  ±269 months  Oral undecanoate 80 mg/day  Yes  Headache, vision problems  Dopamine-agonist  Somatotrophinoma  Case 1 (macroadenoma)  47 years  ±30 months  Unknown  Yes  Unknown  Surgery  Case 2 (macroadenoma)  31 years  ±89 months  Esters 250 mg/2 weeks  Yes  Spectacular testosterone effects  Surgery  Type of tumour  Age  CHT duration  Testosterone type  GDX  Reason for tumour diagnostics  Management  Prolactinoma  Case 1 (microadenoma)  42 years  ±269 months  Oral undecanoate 80 mg/day  Yes  Headache, vision problems  Dopamine-agonist  Somatotrophinoma  Case 1 (macroadenoma)  47 years  ±30 months  Unknown  Yes  Unknown  Surgery  Case 2 (macroadenoma)  31 years  ±89 months  Esters 250 mg/2 weeks  Yes  Spectacular testosterone effects  Surgery  Age, CHT duration, CHT type and GDX data are at time of diagnosis of the brain tumour. CHT = cross-sex hormone treatment; GDX = gonadectomy. Discussion Some benign brain tumours may be modulated by agents that affect the hormonal milieu (Cahill et al., 1984; Sarkar, 2006; Touat et al., 2014). Hypothetically, transgender individuals receiving cross-sex hormone treatment in a usually high dose, could be at higher risk for the development of benign brain tumours. In the present study we examined the occurrence of new benign brain tumour cases (meningiomas, pituitary adenomas, and vestibular schwannomas) in a cohort of 2555 transwomen and 1373 transmen receiving cross-sex hormone treatment. Transwomen Nine cases of meningiomas in transwomen have been reported in literature [see Ter Wengel et al. (2016) and Mancini et al. (2017) for a review of these cases] since the first case in 2007 (Gazzeri et al., 2007). Therefore, it is thought that meningiomas in transwomen only occur sporadically. However, in our cohort of 2555 transwomen we unexpectedly observed eight cases of meningiomas [three of these have also been reported by Ter Wengel et al. (2016)] during 23 935 person-years (calculated risk of 0.03% per person-year). This is 4.1 (95% CI 1.9–7.7) times higher than expected when using a general European (French) female population as reference and 11.9 (95% CI 5.5–22.7) times higher when using a male population as reference (Baldi et al., 2011). In line with the literature that suggests that age is an (independent) risk factor for the development of meningiomas (Wiemels et al., 2010), we found that all transwomen with meningiomas were 45 years or older at time of diagnosis. An interesting additional finding was that all transwomen (including those who have received orchiectomy) still used CPA at time of diagnosis. CPA is the most frequently used (progestogenic) anti-androgen in the Netherlands and several other European countries, and was until 2017 almost always prescribed in high doses (≥50 mg) in the year(s) prior to orchiectomy (Dekker et al., 2016). In contrast to our study, Gil et al. (2011) and Cea-Soriano et al. (2012) examined the occurrence of meningiomas in individuals using low (<50 mg or not specified) or high doses (≥50 mg) of CPA and found an association between meningioma development and CPA usage in high, but not low, doses. While Cea-Soriano et al. (2012) doubt a causal link between CPA treatment and meningioma development, Gil et al. (2011) suggest that there could be a causal relationship between CPA usage and the occurrence of meningiomas, which may be explained by the abundantly expressed progesterone receptors in human meningiomas (Blankenstein et al., 2000). Although CPA is usually discontinued after orchiectomy, as described previously, in case of hirsutism CPA is sometimes continued. Furthermore, since legal gender change in the Netherlands does not require orchiectomy any longer (Vrouenraets et al., 2016), there is an increasing number of transwomen who desire long-term anti-androgen treatment. While the actual risk of meningiomas in transwomen still seems low, the potential (dose-dependent) risk of meningioma development might make it recommendable to use as low a dose of CPA as possible in transwomen with hirsutism and to consider other types of anti-androgens in transwomen without a wish for orchiectomy. Besides meningiomas, several cases of prolactinomas (Kovacs et al., 1994; Bunck et al., 2009; García-Malpartida et al., 2010; Cunha et al., 2015) have been reported in transwomen using cross-sex hormone treatment. The Endocrine Society even recommends regular prolactin checks for transwomen receiving cross-sex hormone treatment (Hembree et al., 2017). In the current study we found nine prolactinomas in transwomen during 23 935 person-years (calculated risk of 0.04% per person-year), which is indeed more than observed in general female and male populations (Kars et al., 2009). However, it is important to note that in the study of Kars et al. (2009), to which our results were compared, all included patients probably were symptomatic (e.g. experienced galactorrhoea or headache) as they had not been regularly screened for hyperprolactinaemia like most of our participants. Four of the nine patients with a (micro)prolactinoma in our study were not symptomatic at the time of diagnosis and were noticed because of the regular prolactin checks. Without serum prolactin screenings these patients might have never been identified as almost all untreated microprolactinomas do not show any growth (Sisam et al., 1987). The other five patients experienced, in addition to hyperprolactinaemia, prolactinoma-associated symptoms at the time of diagnosis. To make our findings more comparable to those of Kars et al. (2009), we repeated our analyses with inclusion of the symptomatic transwomen only and found that their incidence of prolactinomas was higher compared to that of the general Dutch male population but almost comparable to that of the general female population. Females in the general population are not routinely screened for prolactinomas; the low incidence in transwomen seems to suggest that annual prolactin checks in transwomen are not mandatory. However, it is important to keep in mind that in contrast to ciswomen, transwomen suffering from a prolactinoma do not experience some of the prolactinoma-associated symptoms such as menstrual irregularity, which can delay the diagnosis. Similar to meningiomas, we noticed that most transwomen used CPA at time of the diagnosis of prolactinoma, which, in line with other studies, may suggest a relation between CPA usage and prolactin secretion (Defreyne et al., 2017). In addition to meningiomas and prolactinomas, one non-secreting pituitary adenoma and two vestibular schwannomas were identified. No cases of somatotrophinomas, corticotrophinomas or thyrotrophinomas were observed. These numbers were comparable to those expected (Lindholm et al., 2001; Nielsen et al., 2007; Önnestam et al., 2013; Hoskuldsdottir et al., 2015; Kleijwegt et al., 2016). Transmen In transmen, relatively few cases of benign brain tumours were observed. However, we observed two cases of somatotrophinomas during 11 212 person-years (calculated risk of 0.02% per person-year), which is relatively high in view of the incidence of this type of tumour in the general population (7.7/1 000 000 person-years) (Hoskuldsdottir et al., 2015). These two cases can be added to another recently reported case of a somatotrophinoma in a transman (Roerink et al., 2014). At time of diagnosis, at least two of the three transmen [one transman in our study and one in that of Roerink et al. (2014)] suffering from a somatotrophinoma used testosterone esters, which often induces supraphysiological testosterone levels. Interestingly, the treating physicians of these two transmen noticed that masculinization went fast. Unfortunately, little information was gathered in the other somatotrophinoma case in our study. There are also cases reported of somatotrophinomas in Klinefelter patients (who have been) treated with testosterone (Yamane et al., 1993; Fang et al., 2016), but nothing has been established about a potential relationship between testosterone therapy and (growth of) somatotrophinomas. Interestingly, it is reported that testosterone stimulates the somatotropic axis due to (local) aromatization to oestradiol (Birzniece et al., 2010). Furthermore, a recent study found that somatotrophinomas express high levels of the aromatase enzyme (Selek et al., 2015). Although an association between testosterone therapy (in high doses) and the risk of somatotrophinomas could be theoretically possible, our findings could also be coincidental. Nevertheless, it is important to stay alert and consider the presence of acromegaly in case of impressive testosterone effects, such as fast growth of bony prominences of the face (including the jaw) in a transman (Roerink et al., 2014). As expected (Lindholm et al., 2001; Nielsen et al., 2007; Kars et al., 2009; Baldi et al., 2011; Önnestam et al., 2013; Kleijwegt et al., 2016), only one prolactinoma and no meningiomas, non-secreting pituitary adenomas, corticotrophinomas, thyrotrophinomas, or vestibular schwannomas were observed. Limitations This uniquely large study provides new information about the occurrence of benign brain tumours in a large cohort of transwomen and transmen receiving cross-sex hormone treatment, but it is not without limitations. First, it is possible that our findings underestimate the actual incidence of benign brain tumours in the transpopulation because of several reasons. Our clinic provides transgender care for the nearly total population of transgender individuals in the Netherlands. However, other medical care is provided in local hospitals, and benign brain tumours, not thought to be related to sex steroids, might have been treated in local hospitals. In addition, the medical files were reviewed retrospectively, and patients suffering from serious health problems may never present in our clinic again. Second, because most transwomen included in this study have been regularly screened for hyperprolactinaemia during cross-sex hormone treatment (even when they were asymptomatic) it is difficult to compare our results to general populations whose serum prolactin is measured when a prolactinoma is suspected because of suggestive symptoms. To bypass this problem, we did additional analyses restricted to transwomen who were symptomatic (e.g. galactorrhoea or headache) at the time of diagnosis. Third, since we were not able to compose an adequate control group over the study period of 1972 to 2015, we used (sex-specific) incidence rates reported in previous Dutch or European studies to calculate the expected cases/SIRs of benign brain tumours in our study population. Different incidence rates have been reported by different studies. While we have tried to select the most reliable incidence rates as possible for comparing our data with, we cannot completely exclude the risk that the calculated SIRs deviate slightly from actual SIRs. Conclusion Considering the above-described limitations we found that cross-sex hormone treatment is associated with a higher risk of meningioma and prolactinoma development in transwomen, which may be linked to CPA usage. While it remains difficult to draw hard conclusions from the two somatotrophinoma cases observed in transmen, hypothetically there could exist a relationship between testosterone treatment (in high doses) in transmen and somatotrophinomas. Because meningiomas and prolactinomas in transwomen, and somatotrophinomas in transmen still occur sporadically, performing regular screenings (such as periodic prolactin checks for identifying prolactinomas) for these tumours in asymptomatic individuals seems not necessary. 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The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment

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© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com
ISSN
0006-8950
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1460-2156
D.O.I.
10.1093/brain/awy108
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Abstract

Abstract Benign brain tumours may be hormone sensitive. To induce physical characteristics of the desired gender, transgender individuals often receive cross-sex hormone treatment, sometimes in higher doses than hypogonadal individuals. To date, long-term (side) effects of cross-sex hormone treatment are largely unknown. In the present retrospective chart study we aimed to compare the incidence of common benign brain tumours: meningiomas, pituitary adenomas (non-secretive and secretive), and vestibular schwannomas in transgender individuals receiving cross-sex hormone treatment, with those reported in general Dutch or European populations. This study was performed at the VU University Medical Centre in the Netherlands and consisted of 2555 transwomen (median age at start of cross-sex hormone treatment: 31 years, interquartile range 23–41) and 1373 transmen (median age 23 years, interquartile range 18–31) who were followed for 23 935 and 11 212 person-years, respectively. For each separate brain tumour, standardized incidence ratios with 95% confidence intervals were calculated. In transwomen (male sex assigned at birth, female gender identity), eight meningiomas, one non-secretive pituitary adenoma, nine prolactinomas, and two vestibular schwannomas occurred. The incidence of meningiomas was higher in transwomen than in a general European female population (standardized incidence ratio 4.1, 95% confidence interval 1.9–7.7) and male population (11.9, 5.5–22.7). Similar to meningiomas, prolactinomas occurred more often in transwomen compared to general Dutch females (4.3, 2.1–7.9) and males (26.5, 12.9–48.6). Noteworthy, most transwomen had received orchiectomy but still used the progestogenic anti-androgen cyproterone acetate at time of diagnosis. In transmen (female sex assigned at birth, male gender identity), two cases of somatotrophinomas were observed, which was higher than expected based on the reported incidence rate in a general European population (incidence rate females = incidence rate males; standardized incidence ratio 22.2, 3.7–73.4). Based on our results we conclude that cross-sex hormone treatment is associated with a higher risk of meningiomas and prolactinomas in transwomen, which may be linked to cyproterone acetate usage, and somatotrophinomas in transmen. Because these conditions are quite rare, performing regular screenings for such tumours (e.g. regular prolactin measurements for identifying prolactinomas) seems not necessary. transgender individuals, cross-sex hormone treatment, benign brain tumours, meningioma, pituitary Introduction Meningiomas, pituitary adenomas (non-secretive adenoma, prolactinoma, somatotrophinoma, corticotrophinoma and thyrotrophinoma), and vestibular schwannomas are the most common benign brain neoplasms (Black, 1995). Various studies have reported sex differences in the occurrence of benign brain tumours. For example, meningiomas and prolactinomas are reported to occur more frequently in females than in males (Mindermann and Wilson, 1994; Sun et al., 2015; Day et al., 2016). Hypothetically, sex hormones/sex hormone receptors could play a role in the reported sex differences (Cahill et al., 1984; Blankenstein et al., 2000; Sarkar, 2006). Therefore, administration of exogenous sex hormones may affect the risk of brain tumour development. Gender dysphoria refers to the suffering due to an incongruence between one’s sex assigned at birth and one’s experienced gender (American Psychiatric Association, 2013). In transwomen (male sex assigned at birth, female gender identity) cross-sex hormone treatment usually consists of oestrogens, often combined with anti-androgens. In transmen (female sex assigned at birth, male gender identity) cross-sex hormone treatment usually consists of testosterone only. The prevalence of individuals who experience gender incongruence and wish to obtain hormones/surgery is currently estimated at 0.2% for females and 0.6% for males (Kuyper and Wijsen, 2014). However, in recent decades an on-going increase in referrals has been observed. Although many transgender individuals receive lifelong cross-sex hormone treatment, there is still little known about the (long-term) risks of this treatment. Nevertheless, several cases of benign brain tumours in transgender individuals treated with cross-sex hormones have been reported, such as meningiomas (Gazzeri et al., 2007; Ter Wengel et al., 2016) and prolactinomas (Kovacs et al., 1994; Bunck et al., 2009; García-Malpartida et al., 2010; Cunha et al., 2015) in transwomen, and a somatotrophinoma in a transman (Roerink et al., 2014). Because of a potential increased risk of prolactinomas in transwomen, the Endocrine Society advises to regularly monitor prolactin levels during cross-sex hormone treatment (Hembree et al., 2017), although it is not known whether the incidence of prolactinomas is truly increased. There are no such advices for the detection of other benign brain tumours. In the current study we aimed to determine how often common benign brain tumours (meningiomas, pituitary adenomas, and vestibular schwannomas) develop in transgender individuals during cross-sex hormone treatment and whether the incidence of these tumours differs from that reported in general Dutch and European populations. We hypothesized that meningiomas and prolactinomas occur more often in transwomen receiving cross-sex hormone treatment than in general male populations, but that the incidence of these tumours is comparable to that of general female populations. We also hypothesized that transmen using cross-sex hormones do not have an increased risk for developing benign brain tumours. Materials and methods Subjects We performed a retrospective chart study, reviewing the medical files of all individuals who were seen for psychological, endocrine, or surgical evaluations/interventions at the gender clinic of the VU University Medical Centre between February 1972 and December 2015. Baseline and follow-up data of these 6793 individuals were entered into a cumulative database and constitute the Amsterdam Cohort Study of Gender Dysphoria (Wiepjes et al., 2018). For the current study, we only included individuals in whom cross-sex hormones had been prescribed in our centre or one of our affiliates (such as University Medical Centre Groningen), who had at least one follow-up visit at our clinic since then, and of whom a start date of cross-sex hormone treatment was known. Several participants had already used cross-sex hormones before their first visit to our hospital. To provide the most accurate estimation of the total cross-sex hormone treatment duration in these individuals, we used the actual start date of cross-sex hormones (if available). We excluded participants who had used female and male sex hormones alternately or had discontinued cross-sex hormone treatment for an extended period of time during follow-up, because of regret of their transition. Finally, we used the data of 3928 subjects: 2555 transwomen [median age at start of cross-sex hormone treatment: 31 years, interquartile range (IQR) 23–41] and 1373 transmen (median age at start of cross-sex hormone treatment: 23 years, IQR 18–31). The medical records of these subjects were screened for the occurrence of tumours during cross-sex hormone treatment, which were both clinically and radiologically suspicious for a meningioma, pituitary adenoma (secreting and non-secreting), and/or vestibular schwannoma. The ethical committee of the VU University Medical Centre approved this study. A waiver of informed consent was granted because of the retrospective study design, the large number of participants included, and the absence of a need to contact participants. Personal identification information was removed from the database to protect anonymity. Cross-sex hormone treatment In adult transwomen, cross-sex hormone treatment usually consisted of oestrogens and, if desired, anti-androgens (usually given to those who had not received an orchiectomy). Over the whole study period the most frequently prescribed anti-androgens were cyproterone acetate (CPA, 50–100 mg/day) and spironolactone (100–200 mg/day). In the past, oestrogens were mainly prescribed in the form of ethinylestradiol (50–100 μg/day), conjugated oestrogens (0.625–2.5 mg/day), oestradiol patches (50–150 µg/day), oestradiol implants (20 mg/3–6 months), or oestradiol injections (10–100 mg/month). More recently, we have mainly used oestradiol implants (20 mg/3–6 months), oral oestradiol valerate (2–4 mg/day), oestradiol patches (50–150 µg/day), and oestradiol gel (1.5 mg/day). In adult transmen, cross-sex hormone treatment usually consisted of testosterone gel (20–100 mg/day), intramuscular testosterone esters (250 mg/2–3 weeks), or oral or intramuscular testosterone undecanoate (40–160 mg/day orally or 1000 mg/10–14 weeks intramuscularly). Some transmen experiencing uterine bleeding additionally received lynesterol (5–10 mg/daily). When treatment was started at adolescence (<18 years) it usually consisted of CPA (50–100 mg/day) or triptorelin (3.75 mg/4 weeks) in transgirls, and of lynestrenol (5 mg/day) or triptorelin (3.75 mg/4weeks) in transboys. From the age of 16 this treatment was eventually combined with oestrogens (mostly oestradiol valerate, ethinylestradiol, or oestradiol hemihydrate) in transgirls and testosterone (mostly testosterone esters) in transboys. Statistical analysis Stata version 13.1 (StataCorp, College Station Texas, USA) and OpenEpi version 3.01 (www.OpenEpi.com) were used for the statistical analyses. Data of transwomen and transmen were analysed separately. Subject characteristics (age) and follow-up/treatment durations were expressed as actual numbers or as medians with range or IQR. Standardized incidence ratios (SIRs) were calculated using several steps. Firstly, the number of new cases of each separate brain tumour that occurred in transwomen and transmen (observed cases) was determined. Subsequently, the total person-time of observation in years was determined by calculating the period of time that each participant had been followed-up since start of cross-sex hormone treatment (date of last physical visit or brain tumour diagnosis minus start date of cross-sex hormone treatment). Hereafter, the expected cases, based on reported incidence rates in general Dutch or European populations (if reliable Dutch rates were not available) and the total person-time of observation, were calculated. When different incidence rates were reported for females and males, we calculated the expected cases twice, once using the incidence rate of females and once using the incidence rate of males (see Table 1 for the references used to calculate the expected cases). Finally, we performed mid-P exact tests for calculating SIRs with 95% confidence intervals (CIs) for each type of tumour. Table 1 SIRs for each separate benign brain tumour in transmen and transwomen Type of tumour  Observed cases  Expected cases  SIR (95% CI)  Expected cases  SIR (95% CI)              Using females as reference  Using males as reference  Transwomen  Meningioma  8  1.97a  4.1 (1.9–7.7)  0.67a  11.9 (5.5-22.7)  Non-secretive pituitary adenoma  1  0.13b  7.7 (0.4–37.9)  0.13b  7.7 (0.4–37.9)  Secretive pituitary adenoma                1. Prolactinoma                    Total  9  2.08c  4.3 (2.1–7.9)  0.34c  26.5 (12.9–48.6)          Symptomatic  5  2.08c  2.4 (0.9–5.3)  0.34c  14.7 (5.4–32.6)      2. Somatotrophinoma  0  0.18d  –  0.18d  –      3. Corticotrophinoma  0  0.06e  –  0.02e  –      4. Thyrotrophinoma  0  0.01f  –  0.01f  –  Vestibular schwannoma  2  0.90g  2.2 (0.4–7.3)  0.90g  2.2 (0.4–7.3)  Transmen            Meningioma  0  0.92a  –  0.32a  –  Non-secretive pituitary adenoma  0  0.06b  –  0.06b  –  Secretive pituitary adenoma                1. Prolactinoma  1  0.98c  1.02 (0.1–5.0)  0.16c  6.3 (0.3–30.8)      2. Somatotrophinoma  2  0.09d  22.2 (3.7–73.4)  0.09d  22.2 (3.7–73.4)      3. Corticotrophinoma  0  0.03e  –  0.01e  –      4. Thyrotrophinoma  0  0.00f  –  0.00f  –  Vestibular schwannoma  0  0.42g  –  0.42g  –  Type of tumour  Observed cases  Expected cases  SIR (95% CI)  Expected cases  SIR (95% CI)              Using females as reference  Using males as reference  Transwomen  Meningioma  8  1.97a  4.1 (1.9–7.7)  0.67a  11.9 (5.5-22.7)  Non-secretive pituitary adenoma  1  0.13b  7.7 (0.4–37.9)  0.13b  7.7 (0.4–37.9)  Secretive pituitary adenoma                1. Prolactinoma                    Total  9  2.08c  4.3 (2.1–7.9)  0.34c  26.5 (12.9–48.6)          Symptomatic  5  2.08c  2.4 (0.9–5.3)  0.34c  14.7 (5.4–32.6)      2. Somatotrophinoma  0  0.18d  –  0.18d  –      3. Corticotrophinoma  0  0.06e  –  0.02e  –      4. Thyrotrophinoma  0  0.01f  –  0.01f  –  Vestibular schwannoma  2  0.90g  2.2 (0.4–7.3)  0.90g  2.2 (0.4–7.3)  Transmen            Meningioma  0  0.92a  –  0.32a  –  Non-secretive pituitary adenoma  0  0.06b  –  0.06b  –  Secretive pituitary adenoma                1. Prolactinoma  1  0.98c  1.02 (0.1–5.0)  0.16c  6.3 (0.3–30.8)      2. Somatotrophinoma  2  0.09d  22.2 (3.7–73.4)  0.09d  22.2 (3.7–73.4)      3. Corticotrophinoma  0  0.03e  –  0.01e  –      4. Thyrotrophinoma  0  0.00f  –  0.00f  –  Vestibular schwannoma  0  0.42g  –  0.42g  –  Expected cases are based on incidence rates reported by: aBaldi et al. (2011); bNielsen et al. (2007); cKars et al. (2009); dHoskuldsdottir et al. (2015); eLindholm et al. (2001); fÖnnestam et al. (2013); gKleijwegt et al. (2016). Table 1 SIRs for each separate benign brain tumour in transmen and transwomen Type of tumour  Observed cases  Expected cases  SIR (95% CI)  Expected cases  SIR (95% CI)              Using females as reference  Using males as reference  Transwomen  Meningioma  8  1.97a  4.1 (1.9–7.7)  0.67a  11.9 (5.5-22.7)  Non-secretive pituitary adenoma  1  0.13b  7.7 (0.4–37.9)  0.13b  7.7 (0.4–37.9)  Secretive pituitary adenoma                1. Prolactinoma                    Total  9  2.08c  4.3 (2.1–7.9)  0.34c  26.5 (12.9–48.6)          Symptomatic  5  2.08c  2.4 (0.9–5.3)  0.34c  14.7 (5.4–32.6)      2. Somatotrophinoma  0  0.18d  –  0.18d  –      3. Corticotrophinoma  0  0.06e  –  0.02e  –      4. Thyrotrophinoma  0  0.01f  –  0.01f  –  Vestibular schwannoma  2  0.90g  2.2 (0.4–7.3)  0.90g  2.2 (0.4–7.3)  Transmen            Meningioma  0  0.92a  –  0.32a  –  Non-secretive pituitary adenoma  0  0.06b  –  0.06b  –  Secretive pituitary adenoma                1. Prolactinoma  1  0.98c  1.02 (0.1–5.0)  0.16c  6.3 (0.3–30.8)      2. Somatotrophinoma  2  0.09d  22.2 (3.7–73.4)  0.09d  22.2 (3.7–73.4)      3. Corticotrophinoma  0  0.03e  –  0.01e  –      4. Thyrotrophinoma  0  0.00f  –  0.00f  –  Vestibular schwannoma  0  0.42g  –  0.42g  –  Type of tumour  Observed cases  Expected cases  SIR (95% CI)  Expected cases  SIR (95% CI)              Using females as reference  Using males as reference  Transwomen  Meningioma  8  1.97a  4.1 (1.9–7.7)  0.67a  11.9 (5.5-22.7)  Non-secretive pituitary adenoma  1  0.13b  7.7 (0.4–37.9)  0.13b  7.7 (0.4–37.9)  Secretive pituitary adenoma                1. Prolactinoma                    Total  9  2.08c  4.3 (2.1–7.9)  0.34c  26.5 (12.9–48.6)          Symptomatic  5  2.08c  2.4 (0.9–5.3)  0.34c  14.7 (5.4–32.6)      2. Somatotrophinoma  0  0.18d  –  0.18d  –      3. Corticotrophinoma  0  0.06e  –  0.02e  –      4. Thyrotrophinoma  0  0.01f  –  0.01f  –  Vestibular schwannoma  2  0.90g  2.2 (0.4–7.3)  0.90g  2.2 (0.4–7.3)  Transmen            Meningioma  0  0.92a  –  0.32a  –  Non-secretive pituitary adenoma  0  0.06b  –  0.06b  –  Secretive pituitary adenoma                1. Prolactinoma  1  0.98c  1.02 (0.1–5.0)  0.16c  6.3 (0.3–30.8)      2. Somatotrophinoma  2  0.09d  22.2 (3.7–73.4)  0.09d  22.2 (3.7–73.4)      3. Corticotrophinoma  0  0.03e  –  0.01e  –      4. Thyrotrophinoma  0  0.00f  –  0.00f  –  Vestibular schwannoma  0  0.42g  –  0.42g  –  Expected cases are based on incidence rates reported by: aBaldi et al. (2011); bNielsen et al. (2007); cKars et al. (2009); dHoskuldsdottir et al. (2015); eLindholm et al. (2001); fÖnnestam et al. (2013); gKleijwegt et al. (2016). Results Transwomen For transwomen, the median person-time of observation was 6.22 years (range 0.01–54.77) and the total person-time of observation 23 935 years. Table 1 shows the observed and expected number of new brain tumour cases with the corresponding SIRs and 95% CIs. In total, 20 cases of new benign brain tumours were identified: eight meningiomas, one non-secretive pituitary adenoma, nine prolactinomas, and two vestibular schwannomas. As expected, no cases of somatotrophinomas, corticotrophinomas or thyrotrophinomas were found (Lindholm et al., 2001; Önnestam et al., 2013; Hoskuldsdottir et al., 2015). Also the number of observed non-secretive pituitary adenomas (n = 1; SIR 7.7, 95% CI 0.4–37.9) and vestibular schwannomas (n = 2; SIR 2.2, 95% CI 0.4–7.3) was not different from the expected number in general female and male populations (Nielsen et al., 2007; Kleijwegt et al., 2016). On the other hand, transwomen showed significantly more cases of meningiomas than could be expected based on the incidence rate of a European (French) female (SIR 4.1, 95% CI 1.9–7.7) and male (SIR 11.9, 95% CI 5.5–22.7) population (Baldi et al., 2011). In addition, more prolactinomas were identified in transwomen than in the general Dutch female (SIR 4.3, 95% CI 2.1–7.9) and male (SIR 26.5, 95% CI 12.9–48.6) population (Kars et al., 2009). However, when we included only transwomen with prolactinoma-associated symptoms at time of diagnosis in our analyses, we found an almost comparable incidence between transwomen and the general female population (SIR 2.4, 95% CI 0.9–5.3). Table 2 provides a detailed description of each separate brain tumour case in transwomen. It is of note that at time of diagnosis, most individuals (including those who have received orchiectomy) diagnosed with a meningioma or prolactinoma were still using CPA (a drug that is usually discontinued after orchiectomy). Table 2 Detailed description of each brain tumour case in transwomen Type of tumour  Age  CHT duration  CHT typea  GDX  Reason for tumour diagnostics  Management  Meningiomab              Case 1 (suprasellar located)  45 years  ±59 months  CPA 10 mg, oestradiol implant 20 mg/4 months  Yes  Vision problems  Surgery  Case 2 (multiple locations)  65 years  ±230 months  CPA 10 mg, conjugated oestrogens 1.25 mg  Yes  Vision problems  Surgery, stop CHTc  Case 3 (frontal located)  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100µg  Yes  Epileptic insults  Surgery, anti-epileptics  Case 4 (temporal located)  66 years  ±477 months  CPA 10 mg  Yes  Headache, vertigo, vibrations  Wait-and-see  Case 5 (frontobasal located)  58 years  ±75 months  CPA 50 mg, oestradiol patch 100µg  No  Diplopia, headache, hyperprolactinaemia  Wait-and-see  Case 6 (frontal located)  49 years  ±192 months  CPA 100 mg, ethinylestradiol 100 µg  Yes  Hyperprolactinaemia  Wait-and-seec  Case 7 (parietotemporal located)  59 years  ±124 months  CPA 50 mg, ethinylestradiol 100µg  Yes  Headache, tiredness  Surgery  Case 8 (parafalcine/parietotemporal located)  51 years  ±307 months  CPAd, oestradiol valerate 2 mg  Yes  Depression, apathy, delusions  Surgery  Non-secretive pituitary adenoma  Case 1 (macroadenoma)  34 years  ±35 months  CPA 50 mg, oestradiol valerate 1 mg  No  Headache, vertigo, nausea  Stop CHTc  Prolactinoma              Case 1 (microadenoma)e  52 years  ±177 months  Conjugated oestrogens 0.625 mg  Yes  Hyperprolactinaemia  Dopamine-agonist  Case 2 (microadenoma)  32 years  ±53 months  CPA 100 mg, oestradiol injection 100 mg/2weeks  Yes  Hyperprolactinaemia  Stop oestradiol  Case 3 (microadenoma)  39 years  ±172 months  CPA 100 mg, conjugated oestrogens 2.5 mg  Yes  Hypothyroidism, hyperprolactinaemia  Levothyroxine  Case 4 (microadenoma)  27 years  ±156 months  CPAd, oestradiol injectiond  No  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Case 5 (microadenoma)  46 years  ±66 months  CPA 100 mg, ethinylestradiol 100µg  No  Hyperprolactinaemia  Wait-and-see  Case 6 (microadenoma)  24 years  ±9 monthsf  CPA 100 mg  No  Hyperprolactinaemia  Dopamine-agonist  Case 7 (microadenoma)  47 years  ±91 months  CPA 100 mg, ethinylestradiol 100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 8 (microadenoma)  29 years  ±143 months  Ethinylestradiol 50-100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 9 (macroadenoma)  28 years  ±134 months  CPA 50 mg, oestradiol valerate 2 mg  Yes  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Vestibular schwannoma              Case 1  60 years  ±274 months  Tibolon 2.5 mg  Yes  Deafness, vertigo, imbalance  Wait-and-see, radiotherapy  Case 2  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100 µg  Yes  Epileptic insults  Wait-and-see, anti-epileptics  Type of tumour  Age  CHT duration  CHT typea  GDX  Reason for tumour diagnostics  Management  Meningiomab              Case 1 (suprasellar located)  45 years  ±59 months  CPA 10 mg, oestradiol implant 20 mg/4 months  Yes  Vision problems  Surgery  Case 2 (multiple locations)  65 years  ±230 months  CPA 10 mg, conjugated oestrogens 1.25 mg  Yes  Vision problems  Surgery, stop CHTc  Case 3 (frontal located)  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100µg  Yes  Epileptic insults  Surgery, anti-epileptics  Case 4 (temporal located)  66 years  ±477 months  CPA 10 mg  Yes  Headache, vertigo, vibrations  Wait-and-see  Case 5 (frontobasal located)  58 years  ±75 months  CPA 50 mg, oestradiol patch 100µg  No  Diplopia, headache, hyperprolactinaemia  Wait-and-see  Case 6 (frontal located)  49 years  ±192 months  CPA 100 mg, ethinylestradiol 100 µg  Yes  Hyperprolactinaemia  Wait-and-seec  Case 7 (parietotemporal located)  59 years  ±124 months  CPA 50 mg, ethinylestradiol 100µg  Yes  Headache, tiredness  Surgery  Case 8 (parafalcine/parietotemporal located)  51 years  ±307 months  CPAd, oestradiol valerate 2 mg  Yes  Depression, apathy, delusions  Surgery  Non-secretive pituitary adenoma  Case 1 (macroadenoma)  34 years  ±35 months  CPA 50 mg, oestradiol valerate 1 mg  No  Headache, vertigo, nausea  Stop CHTc  Prolactinoma              Case 1 (microadenoma)e  52 years  ±177 months  Conjugated oestrogens 0.625 mg  Yes  Hyperprolactinaemia  Dopamine-agonist  Case 2 (microadenoma)  32 years  ±53 months  CPA 100 mg, oestradiol injection 100 mg/2weeks  Yes  Hyperprolactinaemia  Stop oestradiol  Case 3 (microadenoma)  39 years  ±172 months  CPA 100 mg, conjugated oestrogens 2.5 mg  Yes  Hypothyroidism, hyperprolactinaemia  Levothyroxine  Case 4 (microadenoma)  27 years  ±156 months  CPAd, oestradiol injectiond  No  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Case 5 (microadenoma)  46 years  ±66 months  CPA 100 mg, ethinylestradiol 100µg  No  Hyperprolactinaemia  Wait-and-see  Case 6 (microadenoma)  24 years  ±9 monthsf  CPA 100 mg  No  Hyperprolactinaemia  Dopamine-agonist  Case 7 (microadenoma)  47 years  ±91 months  CPA 100 mg, ethinylestradiol 100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 8 (microadenoma)  29 years  ±143 months  Ethinylestradiol 50-100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 9 (macroadenoma)  28 years  ±134 months  CPA 50 mg, oestradiol valerate 2 mg  Yes  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Vestibular schwannoma              Case 1  60 years  ±274 months  Tibolon 2.5 mg  Yes  Deafness, vertigo, imbalance  Wait-and-see, radiotherapy  Case 2  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100 µg  Yes  Epileptic insults  Wait-and-see, anti-epileptics  Age, CHT duration, CHT type and GDX data are at time of diagnosis of the brain tumour. aUnless otherwise specified, the represented doses are daily doses. bThree of these meningiomas have also been reported by Ter Wengel et al. (2016). cAt request of the patient. dDose unknown. eThis case has also been reported by Bunck et al. (2009). fCHT duration was probably longer than 9 months, but the exact start date of CHT was not documented. CHT = cross-sex hormone treatment; GDX = gonadectomy. Table 2 Detailed description of each brain tumour case in transwomen Type of tumour  Age  CHT duration  CHT typea  GDX  Reason for tumour diagnostics  Management  Meningiomab              Case 1 (suprasellar located)  45 years  ±59 months  CPA 10 mg, oestradiol implant 20 mg/4 months  Yes  Vision problems  Surgery  Case 2 (multiple locations)  65 years  ±230 months  CPA 10 mg, conjugated oestrogens 1.25 mg  Yes  Vision problems  Surgery, stop CHTc  Case 3 (frontal located)  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100µg  Yes  Epileptic insults  Surgery, anti-epileptics  Case 4 (temporal located)  66 years  ±477 months  CPA 10 mg  Yes  Headache, vertigo, vibrations  Wait-and-see  Case 5 (frontobasal located)  58 years  ±75 months  CPA 50 mg, oestradiol patch 100µg  No  Diplopia, headache, hyperprolactinaemia  Wait-and-see  Case 6 (frontal located)  49 years  ±192 months  CPA 100 mg, ethinylestradiol 100 µg  Yes  Hyperprolactinaemia  Wait-and-seec  Case 7 (parietotemporal located)  59 years  ±124 months  CPA 50 mg, ethinylestradiol 100µg  Yes  Headache, tiredness  Surgery  Case 8 (parafalcine/parietotemporal located)  51 years  ±307 months  CPAd, oestradiol valerate 2 mg  Yes  Depression, apathy, delusions  Surgery  Non-secretive pituitary adenoma  Case 1 (macroadenoma)  34 years  ±35 months  CPA 50 mg, oestradiol valerate 1 mg  No  Headache, vertigo, nausea  Stop CHTc  Prolactinoma              Case 1 (microadenoma)e  52 years  ±177 months  Conjugated oestrogens 0.625 mg  Yes  Hyperprolactinaemia  Dopamine-agonist  Case 2 (microadenoma)  32 years  ±53 months  CPA 100 mg, oestradiol injection 100 mg/2weeks  Yes  Hyperprolactinaemia  Stop oestradiol  Case 3 (microadenoma)  39 years  ±172 months  CPA 100 mg, conjugated oestrogens 2.5 mg  Yes  Hypothyroidism, hyperprolactinaemia  Levothyroxine  Case 4 (microadenoma)  27 years  ±156 months  CPAd, oestradiol injectiond  No  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Case 5 (microadenoma)  46 years  ±66 months  CPA 100 mg, ethinylestradiol 100µg  No  Hyperprolactinaemia  Wait-and-see  Case 6 (microadenoma)  24 years  ±9 monthsf  CPA 100 mg  No  Hyperprolactinaemia  Dopamine-agonist  Case 7 (microadenoma)  47 years  ±91 months  CPA 100 mg, ethinylestradiol 100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 8 (microadenoma)  29 years  ±143 months  Ethinylestradiol 50-100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 9 (macroadenoma)  28 years  ±134 months  CPA 50 mg, oestradiol valerate 2 mg  Yes  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Vestibular schwannoma              Case 1  60 years  ±274 months  Tibolon 2.5 mg  Yes  Deafness, vertigo, imbalance  Wait-and-see, radiotherapy  Case 2  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100 µg  Yes  Epileptic insults  Wait-and-see, anti-epileptics  Type of tumour  Age  CHT duration  CHT typea  GDX  Reason for tumour diagnostics  Management  Meningiomab              Case 1 (suprasellar located)  45 years  ±59 months  CPA 10 mg, oestradiol implant 20 mg/4 months  Yes  Vision problems  Surgery  Case 2 (multiple locations)  65 years  ±230 months  CPA 10 mg, conjugated oestrogens 1.25 mg  Yes  Vision problems  Surgery, stop CHTc  Case 3 (frontal located)  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100µg  Yes  Epileptic insults  Surgery, anti-epileptics  Case 4 (temporal located)  66 years  ±477 months  CPA 10 mg  Yes  Headache, vertigo, vibrations  Wait-and-see  Case 5 (frontobasal located)  58 years  ±75 months  CPA 50 mg, oestradiol patch 100µg  No  Diplopia, headache, hyperprolactinaemia  Wait-and-see  Case 6 (frontal located)  49 years  ±192 months  CPA 100 mg, ethinylestradiol 100 µg  Yes  Hyperprolactinaemia  Wait-and-seec  Case 7 (parietotemporal located)  59 years  ±124 months  CPA 50 mg, ethinylestradiol 100µg  Yes  Headache, tiredness  Surgery  Case 8 (parafalcine/parietotemporal located)  51 years  ±307 months  CPAd, oestradiol valerate 2 mg  Yes  Depression, apathy, delusions  Surgery  Non-secretive pituitary adenoma  Case 1 (macroadenoma)  34 years  ±35 months  CPA 50 mg, oestradiol valerate 1 mg  No  Headache, vertigo, nausea  Stop CHTc  Prolactinoma              Case 1 (microadenoma)e  52 years  ±177 months  Conjugated oestrogens 0.625 mg  Yes  Hyperprolactinaemia  Dopamine-agonist  Case 2 (microadenoma)  32 years  ±53 months  CPA 100 mg, oestradiol injection 100 mg/2weeks  Yes  Hyperprolactinaemia  Stop oestradiol  Case 3 (microadenoma)  39 years  ±172 months  CPA 100 mg, conjugated oestrogens 2.5 mg  Yes  Hypothyroidism, hyperprolactinaemia  Levothyroxine  Case 4 (microadenoma)  27 years  ±156 months  CPAd, oestradiol injectiond  No  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Case 5 (microadenoma)  46 years  ±66 months  CPA 100 mg, ethinylestradiol 100µg  No  Hyperprolactinaemia  Wait-and-see  Case 6 (microadenoma)  24 years  ±9 monthsf  CPA 100 mg  No  Hyperprolactinaemia  Dopamine-agonist  Case 7 (microadenoma)  47 years  ±91 months  CPA 100 mg, ethinylestradiol 100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 8 (microadenoma)  29 years  ±143 months  Ethinylestradiol 50-100µg  Yes  Galactorrhoea, hyperprolactinaemia  Wait-and-see  Case 9 (macroadenoma)  28 years  ±134 months  CPA 50 mg, oestradiol valerate 2 mg  Yes  Galactorrhoea, hyperprolactinaemia  Dopamine-agonist  Vestibular schwannoma              Case 1  60 years  ±274 months  Tibolon 2.5 mg  Yes  Deafness, vertigo, imbalance  Wait-and-see, radiotherapy  Case 2  51 years  ±130 months  CPA 20 mg/week, oestradiol patch 100 µg  Yes  Epileptic insults  Wait-and-see, anti-epileptics  Age, CHT duration, CHT type and GDX data are at time of diagnosis of the brain tumour. aUnless otherwise specified, the represented doses are daily doses. bThree of these meningiomas have also been reported by Ter Wengel et al. (2016). cAt request of the patient. dDose unknown. eThis case has also been reported by Bunck et al. (2009). fCHT duration was probably longer than 9 months, but the exact start date of CHT was not documented. CHT = cross-sex hormone treatment; GDX = gonadectomy. Transmen For transmen, the median person-time of observation was 4.16 years (range 0.02–41.66) and the total person-time 11 212 years. Table 1 shows the observed and expected number of new brain tumour cases with the corresponding SIRs with 95% CIs. Three cases of benign brain tumours were identified: one prolactinoma and two somatotrophinomas. The single case of prolactinoma we observed was not different from the number we expected using the incidence rates of a general Dutch female (SIR 1.02, 95% CI 0.1–5.0) and male (SIR 6.3, 95% CI 0.3–30.8) population (Kars et al., 2009). Since somatotrophinomas occur very rarely (incidence rate females = incidence rate males) (Hoskuldsdottir et al., 2015), the two observed cases of somatotrophinomas were higher than expected (SIR 22.2, 95% CI 3.7–73.4). As expected, no cases of meningiomas, non-secretive pituitary adenomas, corticotrophinomas, thyrotrophinomas, or vestibular schwannomas were found (Lindholm et al., 2001; Nielsen et al., 2007; Baldi et al., 2011; Önnestam et al., 2013; Kleijwegt et al., 2016). Table 3 provides a detailed description of each separate brain tumour case in transmen. Table 3 Detailed description of each brain tumour case in transmen Type of tumour  Age  CHT duration  Testosterone type  GDX  Reason for tumour diagnostics  Management  Prolactinoma  Case 1 (microadenoma)  42 years  ±269 months  Oral undecanoate 80 mg/day  Yes  Headache, vision problems  Dopamine-agonist  Somatotrophinoma  Case 1 (macroadenoma)  47 years  ±30 months  Unknown  Yes  Unknown  Surgery  Case 2 (macroadenoma)  31 years  ±89 months  Esters 250 mg/2 weeks  Yes  Spectacular testosterone effects  Surgery  Type of tumour  Age  CHT duration  Testosterone type  GDX  Reason for tumour diagnostics  Management  Prolactinoma  Case 1 (microadenoma)  42 years  ±269 months  Oral undecanoate 80 mg/day  Yes  Headache, vision problems  Dopamine-agonist  Somatotrophinoma  Case 1 (macroadenoma)  47 years  ±30 months  Unknown  Yes  Unknown  Surgery  Case 2 (macroadenoma)  31 years  ±89 months  Esters 250 mg/2 weeks  Yes  Spectacular testosterone effects  Surgery  Age, CHT duration, CHT type and GDX data are at time of diagnosis of the brain tumour. CHT = cross-sex hormone treatment; GDX = gonadectomy. Table 3 Detailed description of each brain tumour case in transmen Type of tumour  Age  CHT duration  Testosterone type  GDX  Reason for tumour diagnostics  Management  Prolactinoma  Case 1 (microadenoma)  42 years  ±269 months  Oral undecanoate 80 mg/day  Yes  Headache, vision problems  Dopamine-agonist  Somatotrophinoma  Case 1 (macroadenoma)  47 years  ±30 months  Unknown  Yes  Unknown  Surgery  Case 2 (macroadenoma)  31 years  ±89 months  Esters 250 mg/2 weeks  Yes  Spectacular testosterone effects  Surgery  Type of tumour  Age  CHT duration  Testosterone type  GDX  Reason for tumour diagnostics  Management  Prolactinoma  Case 1 (microadenoma)  42 years  ±269 months  Oral undecanoate 80 mg/day  Yes  Headache, vision problems  Dopamine-agonist  Somatotrophinoma  Case 1 (macroadenoma)  47 years  ±30 months  Unknown  Yes  Unknown  Surgery  Case 2 (macroadenoma)  31 years  ±89 months  Esters 250 mg/2 weeks  Yes  Spectacular testosterone effects  Surgery  Age, CHT duration, CHT type and GDX data are at time of diagnosis of the brain tumour. CHT = cross-sex hormone treatment; GDX = gonadectomy. Discussion Some benign brain tumours may be modulated by agents that affect the hormonal milieu (Cahill et al., 1984; Sarkar, 2006; Touat et al., 2014). Hypothetically, transgender individuals receiving cross-sex hormone treatment in a usually high dose, could be at higher risk for the development of benign brain tumours. In the present study we examined the occurrence of new benign brain tumour cases (meningiomas, pituitary adenomas, and vestibular schwannomas) in a cohort of 2555 transwomen and 1373 transmen receiving cross-sex hormone treatment. Transwomen Nine cases of meningiomas in transwomen have been reported in literature [see Ter Wengel et al. (2016) and Mancini et al. (2017) for a review of these cases] since the first case in 2007 (Gazzeri et al., 2007). Therefore, it is thought that meningiomas in transwomen only occur sporadically. However, in our cohort of 2555 transwomen we unexpectedly observed eight cases of meningiomas [three of these have also been reported by Ter Wengel et al. (2016)] during 23 935 person-years (calculated risk of 0.03% per person-year). This is 4.1 (95% CI 1.9–7.7) times higher than expected when using a general European (French) female population as reference and 11.9 (95% CI 5.5–22.7) times higher when using a male population as reference (Baldi et al., 2011). In line with the literature that suggests that age is an (independent) risk factor for the development of meningiomas (Wiemels et al., 2010), we found that all transwomen with meningiomas were 45 years or older at time of diagnosis. An interesting additional finding was that all transwomen (including those who have received orchiectomy) still used CPA at time of diagnosis. CPA is the most frequently used (progestogenic) anti-androgen in the Netherlands and several other European countries, and was until 2017 almost always prescribed in high doses (≥50 mg) in the year(s) prior to orchiectomy (Dekker et al., 2016). In contrast to our study, Gil et al. (2011) and Cea-Soriano et al. (2012) examined the occurrence of meningiomas in individuals using low (<50 mg or not specified) or high doses (≥50 mg) of CPA and found an association between meningioma development and CPA usage in high, but not low, doses. While Cea-Soriano et al. (2012) doubt a causal link between CPA treatment and meningioma development, Gil et al. (2011) suggest that there could be a causal relationship between CPA usage and the occurrence of meningiomas, which may be explained by the abundantly expressed progesterone receptors in human meningiomas (Blankenstein et al., 2000). Although CPA is usually discontinued after orchiectomy, as described previously, in case of hirsutism CPA is sometimes continued. Furthermore, since legal gender change in the Netherlands does not require orchiectomy any longer (Vrouenraets et al., 2016), there is an increasing number of transwomen who desire long-term anti-androgen treatment. While the actual risk of meningiomas in transwomen still seems low, the potential (dose-dependent) risk of meningioma development might make it recommendable to use as low a dose of CPA as possible in transwomen with hirsutism and to consider other types of anti-androgens in transwomen without a wish for orchiectomy. Besides meningiomas, several cases of prolactinomas (Kovacs et al., 1994; Bunck et al., 2009; García-Malpartida et al., 2010; Cunha et al., 2015) have been reported in transwomen using cross-sex hormone treatment. The Endocrine Society even recommends regular prolactin checks for transwomen receiving cross-sex hormone treatment (Hembree et al., 2017). In the current study we found nine prolactinomas in transwomen during 23 935 person-years (calculated risk of 0.04% per person-year), which is indeed more than observed in general female and male populations (Kars et al., 2009). However, it is important to note that in the study of Kars et al. (2009), to which our results were compared, all included patients probably were symptomatic (e.g. experienced galactorrhoea or headache) as they had not been regularly screened for hyperprolactinaemia like most of our participants. Four of the nine patients with a (micro)prolactinoma in our study were not symptomatic at the time of diagnosis and were noticed because of the regular prolactin checks. Without serum prolactin screenings these patients might have never been identified as almost all untreated microprolactinomas do not show any growth (Sisam et al., 1987). The other five patients experienced, in addition to hyperprolactinaemia, prolactinoma-associated symptoms at the time of diagnosis. To make our findings more comparable to those of Kars et al. (2009), we repeated our analyses with inclusion of the symptomatic transwomen only and found that their incidence of prolactinomas was higher compared to that of the general Dutch male population but almost comparable to that of the general female population. Females in the general population are not routinely screened for prolactinomas; the low incidence in transwomen seems to suggest that annual prolactin checks in transwomen are not mandatory. However, it is important to keep in mind that in contrast to ciswomen, transwomen suffering from a prolactinoma do not experience some of the prolactinoma-associated symptoms such as menstrual irregularity, which can delay the diagnosis. Similar to meningiomas, we noticed that most transwomen used CPA at time of the diagnosis of prolactinoma, which, in line with other studies, may suggest a relation between CPA usage and prolactin secretion (Defreyne et al., 2017). In addition to meningiomas and prolactinomas, one non-secreting pituitary adenoma and two vestibular schwannomas were identified. No cases of somatotrophinomas, corticotrophinomas or thyrotrophinomas were observed. These numbers were comparable to those expected (Lindholm et al., 2001; Nielsen et al., 2007; Önnestam et al., 2013; Hoskuldsdottir et al., 2015; Kleijwegt et al., 2016). Transmen In transmen, relatively few cases of benign brain tumours were observed. However, we observed two cases of somatotrophinomas during 11 212 person-years (calculated risk of 0.02% per person-year), which is relatively high in view of the incidence of this type of tumour in the general population (7.7/1 000 000 person-years) (Hoskuldsdottir et al., 2015). These two cases can be added to another recently reported case of a somatotrophinoma in a transman (Roerink et al., 2014). At time of diagnosis, at least two of the three transmen [one transman in our study and one in that of Roerink et al. (2014)] suffering from a somatotrophinoma used testosterone esters, which often induces supraphysiological testosterone levels. Interestingly, the treating physicians of these two transmen noticed that masculinization went fast. Unfortunately, little information was gathered in the other somatotrophinoma case in our study. There are also cases reported of somatotrophinomas in Klinefelter patients (who have been) treated with testosterone (Yamane et al., 1993; Fang et al., 2016), but nothing has been established about a potential relationship between testosterone therapy and (growth of) somatotrophinomas. Interestingly, it is reported that testosterone stimulates the somatotropic axis due to (local) aromatization to oestradiol (Birzniece et al., 2010). Furthermore, a recent study found that somatotrophinomas express high levels of the aromatase enzyme (Selek et al., 2015). Although an association between testosterone therapy (in high doses) and the risk of somatotrophinomas could be theoretically possible, our findings could also be coincidental. Nevertheless, it is important to stay alert and consider the presence of acromegaly in case of impressive testosterone effects, such as fast growth of bony prominences of the face (including the jaw) in a transman (Roerink et al., 2014). As expected (Lindholm et al., 2001; Nielsen et al., 2007; Kars et al., 2009; Baldi et al., 2011; Önnestam et al., 2013; Kleijwegt et al., 2016), only one prolactinoma and no meningiomas, non-secreting pituitary adenomas, corticotrophinomas, thyrotrophinomas, or vestibular schwannomas were observed. Limitations This uniquely large study provides new information about the occurrence of benign brain tumours in a large cohort of transwomen and transmen receiving cross-sex hormone treatment, but it is not without limitations. First, it is possible that our findings underestimate the actual incidence of benign brain tumours in the transpopulation because of several reasons. Our clinic provides transgender care for the nearly total population of transgender individuals in the Netherlands. However, other medical care is provided in local hospitals, and benign brain tumours, not thought to be related to sex steroids, might have been treated in local hospitals. In addition, the medical files were reviewed retrospectively, and patients suffering from serious health problems may never present in our clinic again. Second, because most transwomen included in this study have been regularly screened for hyperprolactinaemia during cross-sex hormone treatment (even when they were asymptomatic) it is difficult to compare our results to general populations whose serum prolactin is measured when a prolactinoma is suspected because of suggestive symptoms. To bypass this problem, we did additional analyses restricted to transwomen who were symptomatic (e.g. galactorrhoea or headache) at the time of diagnosis. Third, since we were not able to compose an adequate control group over the study period of 1972 to 2015, we used (sex-specific) incidence rates reported in previous Dutch or European studies to calculate the expected cases/SIRs of benign brain tumours in our study population. Different incidence rates have been reported by different studies. While we have tried to select the most reliable incidence rates as possible for comparing our data with, we cannot completely exclude the risk that the calculated SIRs deviate slightly from actual SIRs. Conclusion Considering the above-described limitations we found that cross-sex hormone treatment is associated with a higher risk of meningioma and prolactinoma development in transwomen, which may be linked to CPA usage. While it remains difficult to draw hard conclusions from the two somatotrophinoma cases observed in transmen, hypothetically there could exist a relationship between testosterone treatment (in high doses) in transmen and somatotrophinomas. Because meningiomas and prolactinomas in transwomen, and somatotrophinomas in transmen still occur sporadically, performing regular screenings (such as periodic prolactin checks for identifying prolactinomas) for these tumours in asymptomatic individuals seems not necessary. 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BrainOxford University Press

Published: Apr 23, 2018

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