Brain sexual differentiation and effects of cross-sex hormone therapy in transpeople: A resting-state functional magnetic resonance study.

OBJECTIVES: It is hypothesized that transpeople show sex-atypical differentiation of the brain. Various structural neuroimaging studies provide support for this notion, but little is known about the sexual differentiation of functional resting-state networks in transpeople. In this study we therefore aimed to determine whether brain functional connectivity (FC) patterns in transpeople are sex-typical or sex-atypical, before and after the start of cross-sex hormone therapy (CHT). METHODS: We acquired resting-state functional magnetic resonance data in 36 transpeople (22 with female sex assigned at birth), first during gonadal suppression, and again four months after start of CHT, and in 37 cisgender people (20 females), both sessions without any hormonal intervention. We used independent component analysis to identify the default mode network (DMN), salience network (SN), and left and right working memory network (WMN). These spatial maps were used for group comparisons. RESULTS: Within the DMN, SN, and left WMN similar FC patterns were found across groups. However, within the right WMN, cisgender males showed significantly greater FC in the right caudate nucleus than cisgender females. There was no such sex difference in FC among the transgender groups and they did not differ significantly from either of the cisgender groups. CHT (in transgender participants) and circulating sex steroids (in cisgender participants) did not affect FC. CONCLUSION: Our findings may suggest that cisgender males and females experience a dissimilar (early) differentiation of the right WMN and that such differentiation is less pronounced in transpeople.

Does polycystic ovary syndrome affect cognition? A functional magnetic resonance imaging study exploring working memory.

OBJECTIVE: To study effects of overexposure to androgens and subsequent antiandrogenic treatment on brain activity during working memory processes in women with polycystic ovary syndrome (PCOS). DESIGN: In this longitudinal study, working memory function was evaluated with the use of functional magnetic resonance imaging (MRI) in women with PCOS before and after antiandrogenic treatment. SETTING: Department of reproductive medicine, university medical center. PATIENT(S): Fourteen women with PCOS and with hyperandrogenism and 20 healthy control women without any features of PCOS or other hormonal disorders. INTERVENTION(S): Antiandrogenic hormone treatment. MAIN OUTCOME MEASURE(S): Functional MRI response during a working memory task. RESULT(S): At baseline women with PCOS showed more activation than the control group within the right superior parietal lobe and the inferior parietal lobe during task (all memory conditions). Task performance (speed and accuracy) did not differ between the groups. After antiandrogenic treatment the difference in overall brain activity between the groups disappeared and accuracy in the high memory load condition of the working memory task increased in women with PCOS. CONCLUSION(S): Women with PCOS may need additional neural resources during a working memory task compared with women without PCOS, suggesting less efficient executive functioning. This inefficiency may have effects on daily life functioning of women with PCOS. Antiandrogenic treatment appears to have a beneficial effect on this area of cognitive functioning. CLINICAL TRIAL REGISTRATION NUMBER: NTR2493.

Antimüllerian hormone levels decrease in female-to-male transsexuals using testosterone as cross-sex therapy.

OBJECTIVE: To investigate the effect of hormonal androgenic treatment on antimüllerian hormone (AMH) serum levels in female-to-male (FtM) transsexuals. Polycystic ovary syndrome (PCOS) is associated with elevated AMH levels. Some hypothesize that the high AMH level is a consequence of androgen-induced excessive development of small antral follicles. However, this role of androgens is not yet clear. DESIGN: Observational, prospective, cohort study. SETTING: Tertiary academic medical center. PATIENT(S): Twenty-two FtM transsexuals, healthy native females receiving cross-sex hormone therapy/androgenic treatment. INTERVENTION(S): Androgenic treatment with testosterone (T) and an aromatase inhibitor while endogenous hormone secretion was suppressed with the use of a GnRH agonist. MAIN OUTCOME MEASURE(S): Hormone concentrations were measured before and after androgenic treatment (administration of T and aromatase inhibitor). Measured hormones: AMH, inhibin B, T, androstenedione, DHEAS, E2, SHBG, LH, and FSH. RESULT(S): AMH concentrations were significantly lower after androgenic treatment (4.4 ± 4.4 µg/L vs. 1.4 ± 2.1 µg/L). Androgenic treatment resulted in a strong suppression of AMH secretion over a relative short period of 16 weeks. CONCLUSION(S): Our data underscore the likely important role of androgens in the dynamics of folliculogenesis. It challenges the idea that androgens induce high AMH levels, which is gaining more interest nowadays as an important particular PCOS feature. This strong decline furthermore indicates that AMH must be interpreted in the context of other reproductive endocrine conditions. CLINICAL TRIAL REGISTRATION NUMBER: NTR2493.

Sex differences in verbal fluency during adolescence: a functional magnetic resonance imaging study in gender dysphoric and control boys and girls.

INTRODUCTION: In the literature, verbal fluency (VF) is generally described as a female-favoring task. Although it is conceivable that this sex difference only evolves during adolescence or adulthood under influence of sex steroids, this has never been investigated in young adolescents. AIM: First, to assess sex differences in VF performance and regional brain activation in adolescents. Second, to determine if untreated transsexual adolescents differ from their sex of birth with regard to VF performance and regional brain activation. METHOD: Twenty-five boys, 26 girls, 8 Male-to-Female transsexual adolescents (MtFs), and 14 Female-to-Male transsexual adolescents (FtMs) were tested in a cross-sectional study, while performing a phonetic and semantic VF task within an MRI scanner. MAIN OUTCOME MEASURES: Functional MRI response during VF task. RESULTS: Boys and girls produced similar amounts of words, but the group MtFs produced significantly more words in the phonetic condition compared to control boys, girls, and FtMs. During the semantic condition, no differences were found. With regard to brain activity, control boys showed more activation in the right Rolandic operculum, a small area adjacent to Broca's area, compared to girls. No significant differences in brain activity were found comparing transsexual adolescents, although sub-threshold activation was found in the right Rolandic operculum indicating a trendwise increase in activation from control girls to FtMs to MtFs to control boys. CONCLUSIONS: The better performance of MtFs is consistent with our expectation that MtFs perform better on female-favoring tasks. Moreover, they produced more words than girls and FtMs. Even though a trendwise linear increase in brain activity between the four groups only approached significance, it may indicate differences in individuals with gender identity disorder compared to their birth sex. Although our findings should thus be interpreted with caution, they suggest a biological basis for both transgender groups performing in-between the two sexes.