Effects of Sex Steroids on the Serotonin System

NCT ID: NCT02715232

Last Updated: 2018-10-15

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

92 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-02-06

Study Completion Date

2020-12-31

Brief Summary

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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

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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.

Conditions

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Gender Dysphoria

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

NONE

Study Groups

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Female-to-Males

Female-to-Male Transsexuals receiving Testosterone treatment

Group Type EXPERIMENTAL

Testosterone

Intervention Type DRUG

100mg testosterone undecanoat every 8-12 weeks, or alternatively 50mg testosterone transdermally, or 50mg testosterone creme

Lynestrenol

Intervention Type DRUG

2-3 tablets/day, if menstruation still occurs

Triptorelin acetate

Intervention Type DRUG

4,12mg every 4-6 weeks (powder for suspension for injection s.c. or i.m.

Male-to-Females

Male-to-Female Transsexuals receiving Estradiol and Anti-androgen treatment

Group Type EXPERIMENTAL

Cyproterone Acetate

Intervention Type DRUG

25mg daily

Estradiol

Intervention Type DRUG

75 microgram transdermal therapeutic system twice a week, or p.o. estradiol 2x2mg/day, or estradiol gel 1,5-3mg

Triptorelin acetate

Intervention Type DRUG

4,12mg every 4-6 weeks (powder for suspension for injection s.c. or i.m.

Female Controls

Female Controls receiving no intervention

Group Type NO_INTERVENTION

No interventions assigned to this group

Male Controls

Male controls receiving no intervention

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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Testosterone

100mg testosterone undecanoat every 8-12 weeks, or alternatively 50mg testosterone transdermally, or 50mg testosterone creme

Intervention Type DRUG

Lynestrenol

2-3 tablets/day, if menstruation still occurs

Intervention Type DRUG

Cyproterone Acetate

25mg daily

Intervention Type DRUG

Estradiol

75 microgram transdermal therapeutic system twice a week, or p.o. estradiol 2x2mg/day, or estradiol gel 1,5-3mg

Intervention Type DRUG

Triptorelin acetate

4,12mg every 4-6 weeks (powder for suspension for injection s.c. or i.m.

Intervention Type DRUG

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

50 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Medical University of Vienna

OTHER

Sponsor Role lead

Responsible Party

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Rupert Lanzenberger

Assoc. Prof.

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Rupert Lanzenberger, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Psychiatry and Psychotherapy, Medical University of Vienna

Locations

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Department of Psychiatry and Psychotherapy, Medical University of Vienna

Vienna, , Austria

Site Status RECRUITING

Countries

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Austria

Central Contacts

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Rupert Lanzenberger, MD

Role: CONTACT

+43 40400 ext. 35760

Georg S Kranz, PhD

Role: CONTACT

+43 40400 ext. 38250

Facility Contacts

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Rupert Lanzenberger, A/Prof.

Role: primary

+43 40400 ext. 3825

References

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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.

Reference Type BACKGROUND
PMID: 25497691 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25392513 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25217469 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26876303 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 15199371 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25205989 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 22867132 (View on PubMed)

Klobl M, Reed MB, Handschuh P, Kaufmann U, Konadu ME, Ritter V, Spurny-Dworak B, Kranz GS, Lanzenberger R, Spies M. Gender Dysphoria and Sexual Euphoria: A Bayesian Perspective on the Influence of Gender-Affirming Hormone Therapy on Sexual Arousal. Arch Sex Behav. 2024 May;53(5):1859-1871. doi: 10.1007/s10508-023-02778-1. Epub 2024 Jan 12.

Reference Type DERIVED
PMID: 38216784 (View on PubMed)

Other Identifiers

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1.1-20150511

Identifier Type: -

Identifier Source: org_study_id

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