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"Wiepjes, Chantal M."
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Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands
AbstractObjectiveTo investigate the incidence and characteristics of breast cancer in transgender people in the Netherlands compared with the general Dutch population.DesignRetrospective, nationwide cohort study.SettingSpecialised tertiary gender clinic in Amsterdam, the Netherlands.Participants2260 adult trans women (male sex assigned at birth, female gender identity) and 1229 adult trans men (female sex assigned at birth, male gender identity) who received gender affirming hormone treatment.Main outcome measuresIncidence and characteristics (eg, histology, hormone receptor status) of breast cancer in transgender people.ResultsThe total person time in this cohort was 33 991 years for trans women and 14 883 years for trans men. In the 2260 trans women in the cohort, 15 cases of invasive breast cancer were identified (median duration of hormone treatment 18 years, range 7-37 years). This was 46-fold higher than in cisgender men (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) but lower than in cisgender women (0.3, 0.2 to 0.4). Most tumours were of ductal origin and oestrogen and progesterone receptor positive, and 8.3% were human epidermal growth factor 2 (HER2) positive. In 1229 trans men, four cases of invasive breast cancer were identified (median duration of hormone treatment 15 years, range 2-17 years). This was lower than expected compared with cisgender women (standardised incidence ratio 0.2, 95% confidence interval 0.1 to 0.5).ConclusionsThis study showed an increased risk of breast cancer in trans women compared with cisgender men, and a lower risk in trans men compared with cisgender women. In trans women, the risk of breast cancer increased during a relatively short duration of hormone treatment and the characteristics of the breast cancer resembled a more female pattern. These results suggest that breast cancer screening guidelines for cisgender people are sufficient for transgender people using hormone treatment.
Journal Article
The effect of transdermal gender-affirming hormone therapy on markers of inflammation and hemostasis
Cardiovascular risk is increased in transgender persons using gender-affirming hormone therapy. To gain insight into the mechanism by which sex hormones affect cardiovascular risk in transgender persons, we investigated the effect of hormone therapy on markers of inflammation and hemostasis.
In this exploratory study, 48 trans women using estradiol patches plus cyproterone acetate (CPA) and 47 trans men using testosterone gel were included. They were between 18 and 50 years old and did not have a history of cardiovascular events. Measurements were performed before and after 3 and 12 months of hormone therapy.
After 12 months, in trans women, systemic and endothelial inflammatory markers decreased (hs-CRP -66%, (95% CI -76; -53), VCAM-1-12%, (95% CI -16; -8)), while platelet activation markers increased (PF-4 +17%, (95% CI 4; 32), β-thromboglobulin +13%, (95% CI 2; 24)). The coagulation marker fibrinogen increased transiently, after 3 months (+15%, (95% CI 1; 32)). In trans men, hs-CRP increased (+71%, (95% CI 19; 145)); platelet activation and coagulation markers were not altered. In both trans women and trans men, leptin and adiponectin changed towards reference values of the experienced gender.
Platelet activation and coagulation marker concentrations increased in trans women using transdermal estradiol plus CPA, but not in trans men using testosterone. Also, concentrations of inflammatory markers decreased in trans women, while hs-CRP increased in trans men. Our results indicate that hormone therapy may affect hemostasis in transgender persons, which could be an underlying mechanism explaining the increased cardiovascular risk in this population.
Journal Article
Toward a Lowest Effective Dose of Cyproterone Acetate in Trans Women: Results From the ENIGI Study
Abstract
Context
Cyproterone 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.
Objective
To assess the lowest effective dose of CPA in trans women to prevent side effects.
Methods
This 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.
Results
Using 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.
Conclusion
Compared 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.
Journal Article
Changes in Serum Testosterone and Adrenal Androgen Levels in Transgender Women With and Without Gonadectomy
BackgroundInitiating feminizing gender-affirming hormone therapy (GAHT) in transgender women causes a steep decline in serum testosterone. It is unknown if testosterone concentrations change further and whether adrenal androgen levels change during feminizing GAHT and after gonadectomy. This limits clinical decision making in transgender women with symptoms attributed to GAHT or gonadectomy.
MethodsTransgender women (n = 275) initiating estradiol and cyproterone acetate (CPA) were included at baseline, and had follow-up visits after 3 months, 12 months, and 2 to 4 years. During follow-up, 49.5% of transgender women underwent a gonadectomy. Total testosterone (TT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione (A4) were measured using liquid chromatography tandem mass spectrometry.
ResultsAfter 3 months of GAHT, mean TT, calculated free testosterone (cFT), and A4 decreased by 18.4 nmol/L (95% CI, −19.4 to −17.4, P < 0.001 [ie, −97.1%]), 383 pmol/L (95% CI, −405 to −362, P < 0.001 [ie, −98.3%]), and 1.2 nmol/L (95% CI, −1.4 to −1.0, P < 0.001 [ie, −36.5%]), respectively, and remained stable thereafter. DHEA and DHEAS decreased by 7.4 nmol/L (95% CI, −9.7 to −5.1 [ie, −28.0%]) and 1.8 µmol/L (95% CI, −2.2 to −1.4 [ie, −20.1%]), respectively, after 1 year and did not change thereafter. After gonadectomy, CPA therapy is stopped, which induced no further change in TT, cFT, DHEA, DHEAS, and A4 compared with those who did not undergo gonadectomy.
ConclusionsOur findings confirm that after an initial drop, testosterone levels in transgender women remain stable. Adrenal androgens decrease in the first year of CPA and estrogen supplementation and remain unchanged after gonadectomy. Androgens did not change after gonadectomy and cessation of CPA. Correlates with clinical symptoms remain to be elucidated.
Journal Article
The risk of psychosis for transgender individuals: a Dutch national cohort study
The stressful minority position of transgender persons may result in a high risk of psychosis. Conflicting data suggest that the observed risk depends on setting of recruitment. We assessed the relative risk of non-affective psychotic disorder (NAPD) in a large, representative cohort of transgender persons.
This cohort was composed using: data on legal sex change from the Dutch population registry and data on dispensing of cross-sex hormones (route 1), and a registry of insurance claims from mental health care including persons with a diagnosis of gender identity disorder (DSM-IV) or gender dysphoria (DSM-5) (route 2). They were matched by sex at birth, calendar year and country of birth to controls from the general population. Transgender persons (
= 5564) and controls (
= 27 820), aged 16-60 years at 1 January 2011, were followed until the first insurance claim for NAPD in 2011-2019.
The incidence rate ratio (IRR) of NAPD for transgender persons selected exclusively through route 1 (
= 3859, IRR = 2.00, 95%-CI 1.52-2.63) was increased, but significantly lower than the IRRs for those selected exclusively through route 2 (
= 694, IRR = 22.15, 95%-CI 13.91-35.28) and for those found by both routes (
= 1011, IRR = 5.17, 95%-CI 3.57-7.49;
value for differences in IRR < 0.001).
This study supports the social defeat-hypothesis of NAPD. The results also show the presence of a substantial number of transgender persons with severe psychiatric problems who have not (yet) taken steps to gender-affirmative care.
Journal Article
Prostate Cancer Incidence under Androgen Deprivation: Nationwide Cohort Study in Trans Women Receiving Hormone Treatment
Abstract
Context
Trans women (male sex assigned at birth, female gender identity) mostly use antiandrogens combined with estrogens and can subsequently undergo vaginoplasty including orchiectomy. Because the prostate remains in situ after this procedure, trans women are still at risk for prostate cancer.
Objective
To assess the incidence of prostate cancer in trans women using hormone treatment.
Design
In this nationwide retrospective cohort study, data of participants were linked to the Dutch national pathology database and to Statistics Netherlands to obtain data on prostate cancer diagnosis and mortality.
Setting
Gender identity clinic.
Participants
Trans women who visited our clinic between 1972 and 2016 and received hormone treatment were included.
Main Outcome Measures
Standardized incidence ratios (SIRs) were calculated using the number of observed prostate cancer cases in our cohort and the number of expected cases based on age-specific incidence numbers from the Netherlands Comprehensive Cancer Organization.
Results
The study population consisted of 2281 trans women with a median follow-up time of 14 years (interquartile range 7-24), and a total follow-up time of 37 117 years. Six prostate cancer cases were identified after a median 17 years of hormone treatment. This resulted in a lower prostate cancer risk in trans women than in Dutch reference males (SIR 0.20, 95% confidence interval 0.08-0.42).
Conclusions
Trans women receiving androgen deprivation therapy and estrogens have a substantially lower risk for prostate cancer than the general male population. Our results support the hypothesis that androgen deprivation has a preventive effect on the initiation and development of prostate cancer.
Journal Article
Sustained Breast Development and Breast Anthropometric Changes in 3 Years of Gender-Affirming Hormone Treatment
Abstract
Context
Breast development is important for most trans women. An important limitation of current breast development measurement methods is that these do not allow for 3D volume analyses.
Objectives
To examine breast development and change in anthropometry during the first 3 years of gender-affirming hormone treatment using 3D imaging. Associations with clinical or laboratory parameters and satisfaction with the gained breast development were also studied.
Design
Prospective cohort study.
Setting
Specialized tertiary gender identity clinic in Amsterdam, the Netherlands.
Participants
Participants were 69 adult trans women with a median age of 26 years (interquartile range, 21-38).
Interventions
Gender-affirming hormone treatment.
Main Outcome Measures
Volumetric and anthropometric breast development and satisfaction.
Results
Breast volume increased by 72 cc (95% confidence interval [CI], 48-97) to 100 cc (standard deviation 48). This resulted in a cup-size
Journal Article
A comparative study of 3D measuring methods for monitoring breast volume changes
Three-dimensional (3D) imaging techniques are promising new tools for measuring breast volume, for example in gender-affirming therapy. Transgender individuals can be treated with gender-affirming hormone therapy (GAHT). A robust method for monitoring breast volume changes is critical to be able to study the effects of feminizing GAHT. The primary aim of this study was to compare the accuracy of three 3D devices (Vectra XT, Artec LEO and iPhone XR) for measuring modest breast volume differences using a mannequin. The secondary aim of this study was to evaluate these methods in several performance domains. We used reference prostheses of increasing volumes and compared the volumes using GOM-inspect software. For Vectra XT 3D images, manufacturer-provided software was used to calculate volumes as well. The scanning methods were ranked based on their performance in a total of five categories: volume estimations, costs, user-friendliness, test subject-friendliness and technical aspects. The 3D models analyzed with GOM-inspect showed relative mean estimate differences from the actual volumes of 9.1% for the Vectra XT, 7.3% for the Artec LEO and 14% for the iPhone XR. For the Vectra XT models analyzed with the built-in software this was 6.2%. Root mean squared errors (RMSE) calculated based on the GOM-inspect volume analyses showed mean RMSEs of 2.27, 2.54 and 8.93 for the Vectra XT, Artec LEO and iPhone XR, respectively. The Vectra software had a mean RMSE of 3.00. In the combined performance ranking, the Vectra XT had the most favorable ranking, followed by the Artec LEO and the iPhone XR. The Vectra XT and Artec LEO are the preferred scanners to monitor breast development due to the combination of higher accuracy and overall performance. The current study shows that 3D techniques can be used to adequately measure modest breast volume differences and therefore will be useful to study for example breast changes in transgender individuals using feminizing GAHT. These observations may also be relevant in other fields of 3D imaging research.
Journal Article
Variations in Volume: Breast Size in Trans Women in Relation to Timing of Testosterone Suppression
Breast development is an important outcome for trans women receiving gender-affirming hormone therapy (GAHT). Limited breast development has been reported, possibly because of testosterone exposure during puberty. The impact of puberty suppression (PS) on breast development is unclear.
To investigate the impact of PS and timing of PS prior to GAHT on breast volume and satisfaction.
In a cross-sectional study at a tertiary gender identity clinic, 60 trans women (aged 17-57 years) after 4.5 ± 1.7 years of GAHT were included, of whom 23 initiated PS early in puberty (Tanner stage G2-3), 17 late in puberty (Tanner stage G4-5), and 20 started GAHT in adulthood without prior PS. Breast volume was measured with a 3D scanner and breast satisfaction measured with a questionnaire. Comparisons of breast volumes were adjusted for fat percentage.
Median breast volume was 115 mL (IQR, 68; 203), ie, bra cup size < A. Breast volume was 47 mL (95% CI, -9; 104) larger in the late PS group compared to early PS but this difference was only 4 mL (95% CI, -67; 75) after correction for fat percentage. Breast volume in the adult group was comparable to the early and late PS groups (adult vs early PS 27 mL [95% CI, -28; 83] and adult vs late PS -20 mL [95% CI, -80; 40]). In total, 68% of subjects were satisfied with breast size (57% of early PS, 76% of late PS, and 70% of adult group).
Early start of PS was not associated with larger breast volume, suggesting that pubertal testosterone exposure does not affect breast volume after subsequent GAHT. Despite limited breast size, most trans women were satisfied with their breast development.
Journal Article