Addition of progesterone to feminizing gender-affirming hormone therapy in transgender individuals for breast development: a randomized controlled trial.

BACKGROUND: Feminizing gender-affirming hormone therapy (GAHT) for transgender individuals traditionally includes estradiol and androgen deprivation. Research has demonstrated that breast size as a result of GAHT in transgender women is often limited. Therefore, transgender women often choose to undergo breast augmentation surgery. Progesterone is important for breast development in cisgender women during puberty. A potential role for progesterone in breast development in transgender women has not been investigated in a randomized controlled experimental set-up. The primary objective of this study is to explore the effects on breast volume of addition of oral progesterone to GAHT with estradiol in transgender women after vaginoplasty or orchiectomy. Secondary objectives include assessment of safety, satisfaction, mood, sleep and sexual pleasure. METHODS: This is a non-blinded, non-placebo, randomized controlled trial using a factorial design in adult transgender individuals assigned male sex at birth who have undergone GAHT for at least one year and underwent vaginoplasty or orchiectomy. The study design allows for rapid assessment of potential synergistic effects of various dose combinations of estradiol and progesterone on breast volume change: Ninety participants will be randomized into six groups of 15 subjects each, receiving either the baseline dose of estradiol, the baseline dose of estradiol and progesterone 200 mg daily, the baseline dose of estradiol and progesterone 400 mg daily, twice the baseline dose of estradiol, twice the baseline dose of estradiol and progesterone 200 mg daily or twice the baseline dose of estradiol and progesterone 400 mg daily, all for a duration of 12 months. The main study parameters include changes in breast volume as determined by 3D measurements. Participants will be followed-up with laboratory testing including serum progesterone concentrations as well as surveys for satisfaction, mood, sleep quality and sexual pleasure. DISCUSSION: This study will indicate whether progesterone is safe and of additional value with regard to breast volume change in transgender individuals receiving feminizing GAHT. The results of this study will be useful for innovation of feminizing GAHT. TRIAL REGISTRATION: WHO International Clinical Trials Registry Platform: EUCTR2020-001952-16-NL; date of registration: 12 December 2020 https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2020-001952-16-NL .

'The medical world is very good at cis people, but trans is a specialisation'. Experiences of transgender and non-binary people with accessing primary sexual and reproductive healthcare services in the Netherlands.

Transgender and non-binary (TNB) people are at increased risk of adverse sexual and reproductive health (SRH) outcomes compared to cisgender people. With this qualitative study, we investigated the experiences of TNB people with access to primary SRH care in the Netherlands. We conducted semi-structured, explorative interviews with fourteen TNB individuals. Data were analysed using thematic analysis. We identified three themes: 'navigating cisgender assumptions', 'depending on your healthcare provider' and 'access requires labour'. In primary SRH care, respondents felt that healthcare providers made incorrect assumptions about their care needs which required respondents to actively disclose their gender identity or medical history. However, some respondents felt disclosure also exposed them to clinical bias, or reduced them to a medical category 'transgender' that their healthcare providers perceived to require specialised knowledge. In this context, respondents felt the onus was on them to ensure their SRH care needs were met. Using the concept of trans erasure, we highlight how TNB people are put at risk of adverse SRH outcomes. Creating equitable care access requires not only that providers are educated on TNB health needs and their own cisnormativity, but also an ongoing, critical reflection on the use of gender- and sex-based categories in medicine.

Alterations in the inferior fronto-occipital fasciculus - a specific neural correlate of gender incongruence?

BACKGROUND: Increasing numbers of adolescents seek help for gender-identity questions. Consequently, requests for medical treatments, such as puberty suppression, are growing. However, studies investigating the neurobiological substrate of gender incongruence (when birth-assigned sex and gender identity do not align) are scarce, and knowledge about the effects of puberty suppression on the developing brain of transgender youth is limited. METHODS: Here we cross-sectionally investigated sex and gender differences in regional fractional anisotropy (FA) as measured by diffusion MR imaging, and the impact of puberty on alterations in the white-matter organization of 35 treatment-naive prepubertal children and 41 adolescents with gender incongruence, receiving puberty suppression. The transgender groups were compared with 79 age-matched, treatment-naive cisgender (when sex and gender align) peers. RESULTS: We found that transgender adolescents had lower FA in the bilateral inferior fronto-occipital fasciculus (IFOF), forceps major and corpus callosum than cisgender peers. In addition, average FA values of the right IFOF correlated negatively with adolescents' cumulative dosage of puberty suppressants received. Of note, prepubertal children also showed significant FA group differences in, again, the right IFOF and left cortico-spinal tract, but with the reverse pattern (transgender > cisgender) than was seen in adolescents. CONCLUSIONS: Importantly, our results of lower FA (indexing less longitudinal organization, fiber coherence, and myelination) in the IFOF of gender-incongruent adolescents replicate prior findings in transgender adults, suggesting a salient neural correlate of gender incongruence. Findings highlight the complexity with which (pubertal) sex hormones impact white-matter development and add important insight into the neurobiological substrate associated with gender incongruence.

Transgender health content in medical education: a theory-guided systematic review of current training practices and implementation barriers & facilitators.

Health disparities faced by transgender people are partly explained by barriers to trans-inclusive healthcare, which in turn are linked to a lack of transgender health education in medical school curricula. We carried out a theory-driven systematic review with the aim to (1) provide an overview of key characteristics of training initiatives and pedagogical features, and (2) analyze barriers and facilitators to implementing this training in medical education. We used queer theory to contextualize our findings. We searched the PubMed/Ovid MEDLINE database (October 2009 to December 2021) for original studies that reported on transgender content within medical schools and residency programs (N = 46). We performed a thematic analysis to identify training characteristics, pedagogical features, barriers and facilitators. Most training consisted of single-session interventions, with varying modes of delivery. Most interventions were facilitated by instructors with a range of professional experience and half covered general LGBT+-content. Thematic analysis highlighted barriers including lack of educational materials, lack of faculty expertise, time/costs constraints, and challenges in recruiting and compensating transgender guest speakers. Facilitators included scaffolding learning throughout the curriculum, drawing on expertise of transgender people and engaging learners in skills-based training. Sustainable implementation of transgender-health objectives in medical education faces persistent institutional barriers. These barriers are rooted in normative biases inherent to biomedical knowledge production, and an understanding of categories of sex and gender as uncomplicated. Medical schools should facilitate trans-inclusive educational strategies to combat transgender-health inequities, which should include a critical stance toward binary conceptualizations of sex and gender throughout the curriculum.

Long-Term Gender-Affirming Hormone Therapy and Cognitive Functioning in Older Transgender Women Compared With Cisgender Women and Men.

BACKGROUND: Long-term gender-affirming hormone therapy (GHT) in older transgender individuals could have beneficial effects on cognitive functioning. Cardiovascular risk factors and psychological factors are known determinants of cognition. Despite the rising number of older transgender individuals, only few studies have examined cognitive functioning in this population. AIM: We aimed to assess differences in cognitive functioning between transgender women, and non-transgender (cisgender) women and men, and investigated the contribution of cardiovascular risk factors and psychological factors on these differences. METHODS: In this study, 37 transgender women (age range 55 to 69) receiving GHT for at least ten years (range 10.2 to 41.6) were examined, and their cognitive functioning was compared to an age and education level matched cohort consisting of 222 cisgender women and men from the Longitudinal Aging Study Amsterdam. Linear regression analyses were performed. OUTCOMES: Cognitive functioning was assessed by neuropsychological tests including Mini-Mental State Examination (MMSE), Category Fluency animals, Letter Fluency D, 15-Word test (15WT) immediate and delayed recall. Additionally, cardiovascular risk factors and psychological factors such as cardiovascular disease, hypertension, antihypertensive use, statin use, diabetes mellitus, overweight, smoking, alcohol consumption, psychopharmaceutical use, anxiety and depression symptoms were collected. RESULTS: Transgender women had higher MMSE scores compared with cisgender women (+0.9, 95% CI 0.4 to 1.5), and cisgender men (+1.1, 95% CI 0.4 to 1.8). On all other tests transgender women performed similar to cisgender men. Transgender women performed at a lower level than cisgender women on 15WT immediate recall, -5.5, 95% CI -7.6 to -3.4, and 15WT delayed recall, -2.7, 95% CI -3.7 to -1.7, and equal to cisgender women on Fluency animals and Fluency D. Cardiovascular and psychological factors (i.e., cardiovascular disease and depression symptoms) partly explained differences on MMSE score between transgender women and cisgender-control groups. CLINICAL IMPLICATIONS: The results of this study do not indicate a need for tailored hormone treatment strategies for older transgender women, based on cognitive aspects after long-term GHT. STRENGTHS & LIMITATIONS: As one of the first studies, this study compared older transgender women to a large cohort of cisgender men and women regarding cognitive functioning and took into account numerous potential influencing factors. Limitations include difference in test procedures and the cross-sectional design of the study. CONCLUSION: Cognitive differences between transgender women and cisgender women and men were small, albeit significant. This may suggest that long-term GHT effects on cognitive functioning in older transgender women are minimal. van Heesewijk JO, Dreijerink KMA, Wiepjes CM, et al. Long-Term Gender-Affirming Hormone Therapy and Cognitive Functioning in Older Transgender Women Compared With Cisgender Women and Men. J Sex Med 2021;18:1434-1443.

Postnatal Effects of Sex Hormones on Click-Evoked Otoacoustic Emissions: A Study of Adolescents with Gender Dysphoria.

Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds, generated by the inner ear in response to click-stimuli. A sex difference in emission strength is observed in neonates and adults, with weaker CEOAE amplitudes in males. These differences are assumed to originate from testosterone influences during prenatal male sexual differentiation and to remain stable throughout life. However, recent studies suggested activational, postnatal effects of sex hormones on CEOAEs. Adolescents diagnosed with gender dysphoria (GD) may receive gonadotropin-releasing hormone analogs (GnRHa) in order to suppress endogenous sex hormones and, therefore, pubertal maturation, followed by cross-sex hormone (CSH) treatment. Using a cross-sectional design, we examined whether hormonal interventions in adolescents diagnosed with GD (62 trans boys, assigned female at birth, self-identifying as male; 43 trans girls, assigned male at birth, self-identifying as female), affected their CEOAEs compared to age- and sex-matched controls (44 boys, 37 girls). Sex-typical differences in CEOAE amplitude were observed among cisgender controls and treatment-naïve trans boys but not in other groups with GD. Treatment-naïve trans girls tended to have more female-typical CEOAEs, suggesting hypomasculinized early sexual differentiation, in support of a prominent hypothesis on the etiology of GD. In line with the predicted suppressive effects of androgens, trans boys receiving CSH treatment, i.e., testosterone plus GnRHa, showed significantly weaker right-ear CEOAEs compared with control girls. A similar trend was seen in trans boys treated with GnRHa only. Unexpectedly, trans girls showed CEOAE masculinization with addition of estradiol. Our findings show that CEOAEs may not be used as an unequivocal measure of prenatal androgen exposure as they can be modulated postnatally by sex hormones, in the form of hormonal treatment.