Effects of Sex Steroids on the Serotonin System
Primary Purpose
Gender Dysphoria
Status
Unknown status
Phase
Phase 4
Locations
Austria
Study Type
Interventional
Intervention
Testosterone
Lynestrenol
Cyproterone Acetate
Estradiol
Triptorelin acetate
Sponsored by
About this trial
This is an interventional basic science trial for Gender Dysphoria
Eligibility Criteria
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
Sites / Locations
- Department of Psychiatry and Psychotherapy, Medical University of ViennaRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
No Intervention
No Intervention
Arm Label
Female-to-Males
Male-to-Females
Female Controls
Male Controls
Arm Description
Female-to-Male Transsexuals receiving Testosterone treatment
Male-to-Female Transsexuals receiving Estradiol and Anti-androgen treatment
Female Controls receiving no intervention
Male controls receiving no intervention
Outcomes
Primary Outcome Measures
blood-to-brain clearance/trapping (K*) of [11C]AMT
[11C]AMT trapping as an estimation of brain serotonin synthesis in vivo in humans
distribution volume (DV) of [11C]harmine
distribution volume of specifically bound radioligand [11C]harmine in brain regions
Secondary Outcome Measures
white and gray matter microstructure
microstructure measured using diffusion weighted imaging
gray matter volume/density and cortical thickness
structural MRI measurements
cerebral blood flow (CBF)
cerebral blood flow measured using arterial spin labeling MRI
Scores on the Klein Sexual Orientation Grid (KSOG)
the KSOG measures sexual orientation
Scores on the Utrecht Gender Dysphoria Scale
Score for gender dysphoria
Full Information
NCT ID
NCT02715232
First Posted
March 16, 2016
Last Updated
October 12, 2018
Sponsor
Medical University of Vienna
1. Study Identification
Unique Protocol Identification Number
NCT02715232
Brief Title
Effects of Sex Steroids on the Serotonin System
Official Title
Effects of Sex Steroid Hormones on Serotonin Synthesis and Degradation Measured With PET
Study Type
Interventional
2. Study Status
Record Verification Date
October 2018
Overall Recruitment Status
Unknown status
Study Start Date
February 6, 2017 (Actual)
Primary Completion Date
December 2020 (Anticipated)
Study Completion Date
December 2020 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Medical University of Vienna
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. 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.
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:
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gender Dysphoria
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
92 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Female-to-Males
Arm Type
Experimental
Arm Description
Female-to-Male Transsexuals receiving Testosterone treatment
Arm Title
Male-to-Females
Arm Type
Experimental
Arm Description
Male-to-Female Transsexuals receiving Estradiol and Anti-androgen treatment
Arm Title
Female Controls
Arm Type
No Intervention
Arm Description
Female Controls receiving no intervention
Arm Title
Male Controls
Arm Type
No Intervention
Arm Description
Male controls receiving no intervention
Intervention Type
Drug
Intervention Name(s)
Testosterone
Intervention Description
100mg testosterone undecanoat every 8-12 weeks, or alternatively 50mg testosterone transdermally, or 50mg testosterone creme
Intervention Type
Drug
Intervention Name(s)
Lynestrenol
Intervention Description
2-3 tablets/day, if menstruation still occurs
Intervention Type
Drug
Intervention Name(s)
Cyproterone Acetate
Intervention Description
25mg daily
Intervention Type
Drug
Intervention Name(s)
Estradiol
Intervention Description
75 microgram transdermal therapeutic system twice a week, or p.o. estradiol 2x2mg/day, or estradiol gel 1,5-3mg
Intervention Type
Drug
Intervention Name(s)
Triptorelin acetate
Intervention Description
4,12mg every 4-6 weeks (powder for suspension for injection s.c. or i.m.
Primary Outcome Measure Information:
Title
blood-to-brain clearance/trapping (K*) of [11C]AMT
Description
[11C]AMT trapping as an estimation of brain serotonin synthesis in vivo in humans
Time Frame
<5 months
Title
distribution volume (DV) of [11C]harmine
Description
distribution volume of specifically bound radioligand [11C]harmine in brain regions
Time Frame
<5 months
Secondary Outcome Measure Information:
Title
white and gray matter microstructure
Description
microstructure measured using diffusion weighted imaging
Time Frame
<5 months
Title
gray matter volume/density and cortical thickness
Description
structural MRI measurements
Time Frame
<5 months
Title
cerebral blood flow (CBF)
Description
cerebral blood flow measured using arterial spin labeling MRI
Time Frame
<5 months
Title
Scores on the Klein Sexual Orientation Grid (KSOG)
Description
the KSOG measures sexual orientation
Time Frame
<5 months
Title
Scores on the Utrecht Gender Dysphoria Scale
Description
Score for gender dysphoria
Time Frame
<5 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Rupert Lanzenberger, MD
Phone
+43 40400
Ext
35760
Email
rupert.lanzenberger@meduniwien.ac.at
First Name & Middle Initial & Last Name or Official Title & Degree
Georg S Kranz, PhD
Phone
+43 40400
Ext
38250
Email
georg.kranz@meduniwien.ac.at
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rupert Lanzenberger, MD
Organizational Affiliation
Department of Psychiatry and Psychotherapy, Medical University of Vienna
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Psychiatry and Psychotherapy, Medical University of Vienna
City
Vienna
ZIP/Postal Code
1090
Country
Austria
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rupert Lanzenberger, A/Prof.
Phone
+43 40400
Ext
3825
Email
rupert.lanzenberger@meduniwien.ac.at
First Name & Middle Initial & Last Name & Degree
Rupert Lanzenberger, A/Prof. MD
12. IPD Sharing Statement
Plan to Share IPD
Yes
Citations:
PubMed Identifier
25497691
Citation
Kranz GS, Wadsak W, Kaufmann U, Savli M, Baldinger P, Gryglewski G, Haeusler D, Spies M, Mitterhauser M, Kasper S, Lanzenberger R. High-Dose Testosterone Treatment Increases Serotonin Transporter Binding in Transgender People. Biol Psychiatry. 2015 Oct 15;78(8):525-33. doi: 10.1016/j.biopsych.2014.09.010. Epub 2014 Sep 23.
Results Reference
background
PubMed Identifier
25392513
Citation
Kranz GS, Hahn A, Kaufmann U, Kublbock M, Hummer A, Ganger S, Seiger R, Winkler D, Swaab DF, Windischberger C, Kasper S, Lanzenberger R. White matter microstructure in transsexuals and controls investigated by diffusion tensor imaging. J Neurosci. 2014 Nov 12;34(46):15466-75. doi: 10.1523/JNEUROSCI.2488-14.2014.
Results Reference
background
PubMed Identifier
25217469
Citation
Hahn A, Kranz GS, Kublbock M, Kaufmann U, Ganger S, Hummer A, Seiger R, Spies M, Winkler D, Kasper S, Windischberger C, Swaab DF, Lanzenberger R. Structural Connectivity Networks of Transgender People. Cereb Cortex. 2015 Oct;25(10):3527-34. doi: 10.1093/cercor/bhu194. Epub 2014 Sep 12.
Results Reference
background
PubMed Identifier
26876303
Citation
Hahn A, Kranz GS, Sladky R, Kaufmann U, Ganger S, Hummer A, Seiger R, Spies M, Vanicek T, Winkler D, Kasper S, Windischberger C, Swaab DF, Lanzenberger R. Testosterone affects language areas of the adult human brain. Hum Brain Mapp. 2016 May;37(5):1738-48. doi: 10.1002/hbm.23133. Epub 2016 Feb 15.
Results Reference
background
PubMed Identifier
15199371
Citation
Smith LJ, Henderson JA, Abell CW, Bethea CL. Effects of ovarian steroids and raloxifene on proteins that synthesize, transport, and degrade serotonin in the raphe region of macaques. Neuropsychopharmacology. 2004 Nov;29(11):2035-45. doi: 10.1038/sj.npp.1300510.
Results Reference
background
PubMed Identifier
25205989
Citation
Aggarwal M, Puri V, Puri S. Effects of estrogen on the serotonergic system and calcitonin gene-related peptide in trigeminal ganglia of rats. Ann Neurosci. 2012 Oct;19(4):151-7. doi: 10.5214/ans.0972.7531.190403.
Results Reference
background
PubMed Identifier
22867132
Citation
Purves-Tyson TD, Handelsman DJ, Double KL, Owens SJ, Bustamante S, Weickert CS. Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra. BMC Neurosci. 2012 Aug 6;13:95. doi: 10.1186/1471-2202-13-95.
Results Reference
background
Learn more about this trial
Effects of Sex Steroids on the Serotonin System
We'll reach out to this number within 24 hrs