Our main research goal is to increase our understanding of how gonadal hormones induce sex differences in the brain and behavior during fetal development but also how they further affect brain structure and functioning during puberty and later in adulthood. We use transgenic mouse models for mechanistic studies on how gonadal hormones affect brain development as well as neuroimaging techniques (functional and structural MRI) and postmortem analyses of patients with Disorders of Sexual Development (DSD) or suffering from gender dysphoria (GD) to translate and validate findings obtained in animal models.

Our transgenic mouse studies have shown that the development of the female brain actually requires estradiol during a specific prepubertal period and by consequence that the female brain does not develop by default, i.e. in the absence of any gonadal hormones, as has always been thought. This finding is very relevant to several DSD in humans, such as Turner Syndrome, but also to patients with (congenital) hypogonadotropic hypogonadism (CHH). In addition, these studies showed that there might be different time windows for the development of male- versus female-typical neural and behavioral characteristics, with male-typical sexual differentiation occurring pre- and early postnatally, and female-typical sexual differentiation primarily postnatally, both under the influence of gonadal hormones, however.  Our most recent discovery is that kisspeptin, a neuropeptide best known for triggering GnRH release and by consequence ovulation, also robustly stimulates sexual behavior in female mice. These results suggest that kisspeptin neurons represent a central hub in the neural network synchronizing sexual behavior with ovulation in female mice.

Our human studies have provided important evidence that individuals suffering from gender dysphoria (GD; strong incongruence between their natal sex and their gender identity, i.e. their experienced gender, DSM-5) have undergone an atypical sexual differentiation of the brain. By using functional magnetic resonance imaging (fMRI) we found that adolescents with GD displayed sex-atypical hypothalamic activations to the male pheromone androstadienone and thus responded like their experienced gender. Furthermore, analyses of gray matter (GM) volumes using a voxel-based morphometric approach indicated sex-atypical GM volumes in sexually dimorphic brain structures (e.g. cerebellum, hypothalamus, medial frontal cortex) in adolescents with GD. Finally, postmortem analyses of the hypothalamus indicated a female-typical expression of neurokinin B, an important modulator of GnRH release, in male-to-female transsexuals. 

Furthermore, we have shown that sex differences in brain activation and structure are most likely not directly driven by genetic sex, but rather reflect gonadal hormone exposure and in particularly androgens. We found that women with complete androgen insensitivity syndrome (CAIS), who have a 46,XY karyotype but a female phenotype due to a mutation in the androgen receptor gene, showed a female-like neural activation pattern in the parietal lobe, indicating feminization of the brain in CAIS.

Even though all these findings have pointed to an important role for gonadal hormones in the sexual differentiation of the human and rodent brain, many questions still remain on how and when the brain is sexually differentiated under the influence of gonadal hormones. It is particularly not clear whether the brain remains sensitive to gonadal hormones beyond the perinatal period and whether puberty might be an additional period of brain organization. Future studies will thus focus on the question whether gonadal hormones could still affect brain structure and function beyond the perinatal period. We are part of the COST Action (BM1105) GnRH Deficiency: elucidation of the neuroendocrine control of reproduction (www.gnrhnetwork.eu). This particular network provides access to a large cohort of patients with congenital hypogonadotropic hypogonadism.




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