Effects of sex hormones on serotonin synthesis and degradation

Background Sex hormones such as estradiol and testosterone modulate human brain structure and function and are tightly connected to neuropsychiatric disorders such as depression and anxiety disorders. Using molecular imaging in living humans, we showed strong influences of sex hormones on the expression of serotonergic key elements such as serotonin receptors and transporters. Although animal studies also indicate strong modulatory influences on serotonin synthesis and degradation, human data on this potential effect are absent. Objectives of the study The aim of this study is to prove the modulatory influence of sex hormones on serotonergic signaling by determining the processes involved in serotonin synthesis and degradation using positron emission tomography (PET) in humans in vivo with the radiotracers [11C]AMT and [11C]harmine. Study design In this study transsexuals will undergo four PET and two magnetic resonance imaging (MRI) measurements: 1. One [11C]AMT PET, one [11C]harmine PET and one MRI measurement before start of treatment, 2. One [11C]AMT PET, one [11C]harmine PET and one MRI measurement after 4 months of treatment. We propose an overall study duration of 36 months. Materials and Methods: PET measurements will be performed on a GE Advance PET scanner. To examine the interdependence between serotonin activity and brain morphology and function, four MRI sequences will be performed in order to investigate brain structure and function, as well as cerebral blood flow. MRI measurements will be done on a 3 Tesla scanner with high spatial and temporal resolution. Study population 20 healthy female-to-male (FtM), 20 healthy male-to-female (MtF) transsexuals (aged 18-50) who are free of hormone-medication at baseline; 40 healthy controls, matched for sex, age and education level. Relevance and implications of the study This will be the first imaging study to investigate the effects of high-dose, long-term opposite-sex steroid hormones on serotonin synthesis and degradation in the living human brain using PET. The study will lead to the establishment of a comprehensive theory of serotonergic modulation by sex hormones and will increase our knowledge on the serotonergic role in shaping brain morphology and brain function. Results will provide essential data for a better understanding of neural sex differences associated with differences in hormonal states in humans and will elucidate neurobiological correlates of the known gender difference in the prevalence of neuropsychiatric disorders, thus contributing to the development of personalized treatment, the reduction of personal suffering and the reduction of costs and occupational disability.

Sex hormones such as estradiol and testosterone are known to be involved in multiple functions of the brain which is reflected in sex-specific differences in certain cognitive skills, brain development and the frequency of several neuropsychiatric conditions such as depression, anxiety disorders or neurodegenerative diseases. Despite remarkable scientific efforts that have been made over the last decades to shed light on the mechanisms that drive these sex specific differences, the patterns of how sex hormones interact with neurotransmitters such as serotonin are still not fully understood. Studying the effects of sex hormones on the brain under naturalistic conditions is impeded by hormonal fluctuations in all sexes. Therefore, transgender individuals receiving long-term gender-affirming hormone therapy (GHT) were enrolled into this study to investigate how sex hormones influence the human brain. More specifically, diverse neuroimaging methods such as positron emission tomography (PET) and various magnetic resonance imaging (MRI) techniques (e.g., structural MRI, functional MRI and MR spectroscopy) were applied to examine serotonin degradation, brain structure and function as well as the level of other neurotransmitters (such as gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter, and glutamate, the main excitatory neurotransmitter) before and after GHT over a median time period of 4.5 months in transgender individuals. Additionally, non-transgender participants were recruited. They underwent two PET scans and two MRI sessions in a longitudinal design, however, without receiving any type of therapy between the imaging sessions. We found that testosterone treatment resulted in reductions of monoamine oxidase A (MAO-A) expression in selected brain regions. MAO-A is centrally involved in the degradation of serotonin and represents a key target for certain antidepressants. Moreover, we found that both testosterone as well as estrogen treatment led to microstructural as well as volumetric changes in multiple regions of the brain. Interestingly, in selected brain areas, both testosterone and estrogen induced similar structural changes. In addition, magnetic resonance spectroscopy data revealed testosterone-induced neuroplastic changes of the hippocampus, a brain region that is closely linked to memory functions. Additionally, elevated GABA levels in the female compared to the male insula were found. The insula is centrally involved in interoception (which is defined as the ability to sense internal body sensations). The present study has further revealed changes in the connectivity patterns between the insula and other brain regions after long-term estrogen administration as part of the GHT protocol. Functional MRI data acquired in the course of this study has further revealed that sexual arousal in transgender subjects might change throughout GHT. In summary, the present research has revealed a significant impact of GHT on brain structure and function, partly reflected in behavioral data, providing valuable knowledge on how exogenously administered sex hormones interact with diverse neurotransmitter systems.