Effects of Sex Steroids on the Serotonin System

Sponsor

Medical University of Vienna (Other)

Overall Status

Unknown status

CT.gov ID

NCT02715232

Collaborator

(none)

Enrollment

Location

Arms

45.8

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this study is to prove the modulatory influence of sex hormones on serotonergic neurotransmission by determining the enzymatic processes involved in serotonin synthesis and degradation using positron emission tomography (PET) in humans in vivo with the radiotracers [11C]AMT and [11C]harmine.

Condition or Disease	Intervention/Treatment	Phase
Gender Dysphoria	Drug: Testosterone Drug: Lynestrenol Drug: Cyproterone Acetate Drug: Estradiol Drug: Triptorelin acetate	Phase 4

Detailed Description

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 humans in vivo, the investigators showed strong influences of sex hormones on serotonergic neurotransmission via modulation of serotonergic 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:

Study design:

Single-blind, longitudinal 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. The investigators 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 structure and function, four MRI sequences will be performed in order to assess gray matter volume and cortical thickness, gray and white matter microstructure, as well as resting state functional connectivity and 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.

Pilot Study:

A pilot study without pharmacologic intervention consisting of one optional [11C]AMT PET and two [11C]harmine PET will be performed in 12 healthy controls in order to optimise PET measurement procedures.

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 steroids and will increase knowledge on the serotonergic role in shaping brain morphology, microstructure and structural/functional connectivity. 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

92 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Effects of Sex Steroid Hormones on Serotonin Synthesis and Degradation Measured With PET

Actual Study Start Date :

Feb 6, 2017

Anticipated Primary Completion Date :

Dec 1, 2020

Anticipated Study Completion Date :

Dec 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Female-to-Males Female-to-Male Transsexuals receiving Testosterone treatment	Drug: Testosterone 100mg testosterone undecanoat every 8-12 weeks, or alternatively 50mg testosterone transdermally, or 50mg testosterone creme Drug: Lynestrenol 2-3 tablets/day, if menstruation still occurs Drug: Triptorelin acetate 4,12mg every 4-6 weeks (powder for suspension for injection s.c. or i.m.
Experimental: Male-to-Females Male-to-Female Transsexuals receiving Estradiol and Anti-androgen treatment	Drug: Cyproterone Acetate 25mg daily Drug: Estradiol 75 microgram transdermal therapeutic system twice a week, or p.o. estradiol 2x2mg/day, or estradiol gel 1,5-3mg Drug: Triptorelin acetate 4,12mg every 4-6 weeks (powder for suspension for injection s.c. or i.m.
No Intervention: Female Controls Female Controls receiving no intervention
No Intervention: Male Controls Male controls receiving no intervention

Outcome Measures

Primary Outcome Measures

blood-to-brain clearance/trapping (K*) of [11C]AMT [<5 months]
[11C]AMT trapping as an estimation of brain serotonin synthesis in vivo in humans
distribution volume (DV) of [11C]harmine [<5 months]
distribution volume of specifically bound radioligand [11C]harmine in brain regions

Secondary Outcome Measures

white and gray matter microstructure [<5 months]
microstructure measured using diffusion weighted imaging
gray matter volume/density and cortical thickness [<5 months]
structural MRI measurements
cerebral blood flow (CBF) [<5 months]
cerebral blood flow measured using arterial spin labeling MRI
Scores on the Klein Sexual Orientation Grid (KSOG) [<5 months]
the KSOG measures sexual orientation
Scores on the Utrecht Gender Dysphoria Scale [<5 months]
Score for gender dysphoria

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

DSM-5 diagnosis of Gender Dysphoria (DSM-5: 302.85; ICD-10: F64.1) (for transsexuals only)
Somatic health based on history, physical examination, ECG, laboratory screening, SCID
willingness and competence to sign the informed consent form

Exclusion Criteria:

concomitant major medical or neurological illness
internal or neurologic medical histories as well as pregnancy (positive urine pregnancy test) or breastfeeding
other DSM-5 Axis-I comorbidities, determined by a structured clinical interview (SCID), especially body dysphoric disorder (DSM-5: 300.7; ICD-10: F45.22), schizophrenia spectrum and other psychotic disorders
steroid hormone treatment within 6 months prior to inclusion
treatment with psychotropic agents such as SSRIs
any implant or stainless steel graft
abnormal values in routine laboratory screening or general physical examination
current substance abuse or current or past substance related disorder
for participants who participated in an earlier neuroimaging study using ionizing radiation, the total radiation exposure dose of 20 mSv over the last 10 years must not be exceeded, as specified in the legislation on radiation protection (Allg. Strahlenschutzverordnung 2010; www.ris.bka.gv.at)
failure to comply with the study protocol or to follow the instructions of the investigating team