High-Dose Testosterone Treatment Increases Serotonin Transporter Binding in Transgender People

Georg S Kranz, Wolfgang Wadsak, Ulrike Kaufmann, Markus Savli, Pia Baldinger, Gregor Gryglewski, Daniela Haeusler, Marie Spies, Markus Mitterhauser, Siegfried Kasper, Rupert Lanzenberger, Georg S Kranz, Wolfgang Wadsak, Ulrike Kaufmann, Markus Savli, Pia Baldinger, Gregor Gryglewski, Daniela Haeusler, Marie Spies, Markus Mitterhauser, Siegfried Kasper, Rupert Lanzenberger

Abstract

Background: Women are two times more likely to be diagnosed with depression than men. Sex hormones modulating serotonergic transmission are proposed to partly underlie these epidemiologic findings. Here, we used the cross-sex steroid hormone treatment of transsexuals seeking sex reassignment as a model to investigate acute and chronic effects of testosterone and estradiol on serotonin reuptake transporter (SERT) binding in female-to-male and male-to-female transsexuals.

Methods: Thirty-three transsexuals underwent [(11)C]DASB positron emission tomography before start of treatment, a subset of which underwent a second scan 4 weeks and a third scan 4 months after treatment start. SERT nondisplaceable binding potential was quantified in 12 regions of interest. Treatment effects were analyzed using linear mixed models. Changes of hormone plasma levels were correlated with changes in regional SERT nondisplaceable binding potential.

Results: One and 4 months of androgen treatment in female-to-male transsexuals increased SERT binding in amygdala, caudate, putamen, and median raphe nucleus. SERT binding increases correlated with treatment-induced increases in testosterone levels, suggesting that testosterone increases SERT expression on the cell surface. Conversely, 4 months of antiandrogen and estrogen treatment in male-to-female transsexuals led to decreases in SERT binding in insula, anterior, and mid-cingulate cortex. Increases in estradiol levels correlated negatively with decreases in regional SERT binding, indicating a protective effect of estradiol against SERT loss.

Conclusions: Given the central role of the SERT in the treatment of depression and anxiety disorders, these findings may lead to new treatment modalities and expand our understanding of the mechanism of action of antidepressant treatment properties.

Trial registration: ClinicalTrials.gov NCT01065220.

Keywords: Estradiol; Hormone treatment; Positron emission tomography; Serotonin transporter; Testosterone; Transsexual.

Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Line chart showing changes in serotonin transporter (SERT) binding potential (BPND) and plasma levels of testosterone and estradiol in female-to-male and male-to-female transsexuals over the course of cross-sex steroid treatment. Depicted are means ± 95% confidence interval at positron emission tomography (PET) 1, i.e., baseline (BL), after 4 weeks (4w) of treatment at PET 2, and after 4 months (4m) of treatment at PET 3.
Figure 2
Figure 2
Scatter plots depicting associations between the change in serotonin reuptake transporter (SERT) binding potential (BP) and in plasma steroid hormones for (A) female-to-male (FtM) and (B) male-to-female (MtF) transsexuals. Scattered lines represent 95% confidence intervals. Positive associations between changes in SERT BP in amygdala, caudate, and putamen and testosterone plasma level increase within the first 4 weeks (4w) of treatment (baseline [BL] − 4w) were found in FtM transsexuals (upper row). Positive associations between changes in SERT BP in insula, mid-cingulate, and putamen and estradiol plasma level increase over the course of 4 months (4m) of treatment (BL − 4m) were found in FtM transsexuals (bottom row). PET, positron emission tomography.

References

    1. Kessler R.C. Epidemiology of women and depression. J Affect Disord. 2003;74:5–13.
    1. Bekker M.H., van Mens-Verhulst J. Anxiety disorders: Sex differences in prevalence, degree, and background, but gender-neutral treatment. Gend Med. 2007;4(suppl B):S178–S193.
    1. Smith D.J., Kyle S., Forty L., Cooper C., Walters J., Russell E., et al. Differences in depressive symptom profile between males and females. J Affect Disord. 2008;108:279–284.
    1. McGuinness T.M., Dyer J.G., Wade E.H. Gender differences in adolescent depression. J Psychosoc Nurs Ment Health Serv. 2012;50:17–20.
    1. Valentino R.J., Reyes B., Van Bockstaele E., Bangasser D. Molecular and cellular sex differences at the intersection of stress and arousal. Neuropharmacology. 2012;62:13–20.
    1. Weissman M.M., Olfson M. Depression in women: Implications for health care research. Science. 1995;269:799–801.
    1. Bennett H.A., Einarson A., Taddio A., Koren G., Einarson T.R. Prevalence of depression during pregnancy: Systematic review. Obstet Gynecol. 2004;103:698–709.
    1. Llaneza P., Garcia-Portilla M.P., Llaneza-Suarez D., Armott B., Perez-Lopez F.R. Depressive disorders and the menopause transition. Maturitas. 2012;71:120–130.
    1. Smith D.F., Jakobsen S. Molecular tools for assessing human depression by positron emission tomography. Eur Neuropsychopharmacol. 2009;19:611–628.
    1. Savitz J.B., Drevets W.C. Neuroreceptor imaging in depression. Neurobiol Dis. 2013;52:49–65.
    1. Hesselgrave N., Parsey R.V. Imaging the serotonin 1A receptor using [11C]WAY100635 in healthy controls and major depression. Philos Trans R Soc Lond B Biol Sci. 2013;368:20120004.
    1. Gryglewski G., Lanzenberger R., Kranz G.S., Cumming P. Meta-analysis of molecular imaging of serotonin transporters in major depression. J Cereb Blood Flow Metab. 2014;34:1096–1103.
    1. Cannon D.M., Klaver J.M., Klug S.A., Carlson P.J., Luckenbaugh D.A., Ichise M., Drevets W.C. Gender-specific abnormalities in the serotonin transporter system in panic disorder. Int J Neuropsychopharmacol. 2013;16:733–743.
    1. Maron E., Toru I., Hirvonen J., Tuominen L., Lumme V., Vasar V., et al. Gender differences in brain serotonin transporter availability in panic disorder. J Psychopharmacol. 2011;25:952–959.
    1. Staley J.K., Sanacora G., Tamagnan G., Maciejewski P.K., Malison R.T., Berman R.M., et al. Sex differences in diencephalon serotonin transporter availability in major depression. Biol Psychiatry. 2006;59:40–47.
    1. Ruhe H.G., Booij J., Reitsma J.B., Schene A.H. Serotonin transporter binding with [123I]beta-CIT SPECT in major depressive disorder versus controls: Effect of season and gender. Eur J Nucl Med Mol Imaging. 2009;36:841–849.
    1. Sullivan G.M., Ogden R.T., Oquendo M.A., Kumar J.S., Simpson N., Huang Y.Y., et al. Positron emission tomography quantification of serotonin-1A receptor binding in medication-free bipolar depression. Biol Psychiatry. 2009;66:223–230.
    1. Szewczyk B., Albert P.R., Burns A.M., Czesak M., Overholser J.C., Jurjus G.J., et al. Gender-specific decrease in NUDR and 5-HT1A receptor proteins in the prefrontal cortex of subjects with major depressive disorder. Int J Neuropsychopharmacol. 2009;12:155–168.
    1. Jovanovic H., Lundberg J., Karlsson P., Cerin A., Saijo T., Varrone A., et al. Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET. Neuroimage. 2008;39:1408–1419.
    1. Erritzoe D., Frokjaer V.G., Haahr M.T., Kalbitzer J., Svarer C., Holst K.K., et al. Cerebral serotonin transporter binding is inversely related to body mass index. Neuroimage. 2010;52:284–289.
    1. Moses-Kolko E.L., Price J.C., Shah N., Berga S., Sereika S.M., Fisher P.M., et al. Age, sex, and reproductive hormone effects on brain serotonin-1A and serotonin-2A receptor binding in a healthy population. Neuropsychopharmacology. 2011;36:2729–2740.
    1. Madsen K., Haahr M.T., Marner L., Keller S.H., Baare W.F., Svarer C., et al. Age and sex effects on 5-HT(4) receptors in the human brain: A [(11)C]SB207145 PET study. J Cereb Blood Flow Metab. 2011;31:1475–1481.
    1. Lothe A., Boni C., Costes N., Bouvard S., Gorwood P., Lavenne F., et al. 5-HT1A gene promoter polymorphism and [18F]MPPF binding potential in healthy subjects: A PET study. Behav Brain Funct. 2010;6:37.
    1. Kranz G.S., Hahn A., Baldinger P., Haeusler D., Philippe C., Kaufmann U., et al. Cerebral serotonin transporter asymmetry in females, males and male-to-female transsexuals measured by PET in vivo. Brain Struct Funct. 2014;219:171–183.
    1. Stein P., Savli M., Wadsak W., Mitterhauser M., Fink M., Spindelegger C., et al. The serotonin-1A receptor distribution in healthy men and women measured by PET and [carbonyl-11C]WAY-100635. Eur J Nucl Med Mol Imaging. 2008;35:2159–2168.
    1. Lanzenberger R., Mitterhauser M., Kranz G.S., Spindelegger C., Wadsak W., Stein P., et al. Progesterone level predicts serotonin-1a receptor binding in the male human brain. Neuroendocrinology. 2011;94:84–88.
    1. Moser U., Wadsak W., Spindelegger C., Mitterhauser M., Mien L.K., Bieglmayer C., et al. Hypothalamic serotonin-1A receptor binding measured by PET predicts the plasma level of dehydroepiandrosterone sulfate in healthy women. Neurosci Lett. 2010;476:161–165.
    1. Jovanovic H., Cerin A., Karlsson P., Lundberg J., Halldin C., Nordstrom A.L. A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria. Psychiatry Res. 2006;148:185–193.
    1. Jovanovic H., Karlsson P., Cerin A., Halldin C., Nordstrom A.L. 5-HT(1A) receptor and 5-HTT binding during the menstrual cycle in healthy women examined with [(11)C] WAY100635 and [(11)C] MADAM PET. Psychiatry Res. 2009;172:31–37.
    1. Rivera H.M., Oberbeck D.R., Kwon B., Houpt T.A., Eckel L.A. Estradiol increases Pet-1 and serotonin transporter mRNA in the midbrain raphe nuclei of ovariectomized rats. Brain Res. 2009;1259:51–58.
    1. Bethea C.L., Lu N.Z., Gundlah C., Streicher J.M. Diverse actions of ovarian steroids in the serotonin neural system. Front Neuroendocrinol. 2002;23:41–100.
    1. Bertrand P.P., Paranavitane U.T., Chavez C., Gogos A., Jones M., van den Buuse M. The effect of low estrogen state on serotonin transporter function in mouse hippocampus: A behavioral and electrochemical study. Brain Res. 2005;1064:10–20.
    1. Pecins-Thompson M., Brown N.A., Bethea C.L. Regulation of serotonin re-uptake transporter mRNA expression by ovarian steroids in rhesus macaques. Brain Res Mol Brain Res. 1998;53:120–129.
    1. Sumner B.E., Grant K.E., Rosie R., Hegele-Hartung C., Fritzemeier K.H., Fink G. Raloxifene blocks estradiol induction of the serotonin transporter and 5-hydroxytryptamine2A receptor in female rat brain. Neurosci Lett. 2007;417:95–99.
    1. Koldzic-Zivanovic N., Seitz P.K., Watson C.S., Cunningham K.A., Thomas M.L. Intracellular signaling involved in estrogen regulation of serotonin reuptake. Mol Cell Endocrinol. 2004;226:33–42.
    1. Austrian Government (2014): Recommendations for the Treatment of Gender Dysphoria and Transsexualism. Federal Ministry of Health. Available at: . Accessed October 14, 2014.
    1. Lanzenberger R.R., Hahn A., Windischberger C., Wadsak W., Holik A., Gerstl F., et al. Serotonin-1A receptor binding and reward-dependent activation are associated within the human dorsal raphe nucleus as revealed by PET-fMRI. Neuroimage. 2009;47:S1–S286.
    1. Lanzenberger R., Kranz G.S., Haeusler D., Akimova E., Savli M., Hahn A., et al. Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas. Neuroimage. 2012;63:874–881.
    1. Haeusler D., Mien L.K., Nics L., Ungersboeck J., Philippe C., Lanzenberger R.R., et al. Simple and rapid preparation of [11C]DASB with high quality and reliability for routine applications. Appl Radiat Isot. 2009;67:1654–1660.
    1. Innis R.B., Cunningham V.J., Delforge J., Fujita M., Gjedde A., Gunn R.N., et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27:1533–1539.
    1. Ichise M., Liow J.S., Lu J.Q., Takano A., Model K., Toyama H., et al. Linearized reference tissue parametric imaging methods: Application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab. 2003;23:1096–1112.
    1. Parsey R.V., Kent J.M., Oquendo M.A., Richards M.C., Pratap M., Cooper T.B., et al. Acute occupancy of brain serotonin transporter by sertraline as measured by [11C]DASB and positron emission tomography. Biol Psychiatry. 2006;59:821–828.
    1. Kish S.J., Furukawa Y., Chang L.J., Tong J., Ginovart N., Wilson A., et al. Regional distribution of serotonin transporter protein in postmortem human brain: Is the cerebellum a SERT-free brain region? Nucl Med Biol. 2005;32:123–128.
    1. Tzourio-Mazoyer N., Landeau B., Papathanassiou D., Crivello F., Etard O., Delcroix N., et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002;15:273–289.
    1. Kranz G.S., Hahn A., Savli M., Lanzenberger R. Challenges in the differentiation of midbrain raphe nuclei in neuroimaging research. Proc Natl Acad Sci U S A. 2012;109:E2000.
    1. Savli M., Bauer A., Mitterhauser M., Ding Y.S., Hahn A., Kroll T., et al. Normative database of the serotonergic system in healthy subjects using multi-tracer PET. Neuroimage. 2012;63:447–459.
    1. Varnas K., Halldin C., Hall H. Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum Brain Mapp. 2004;22:246–260.
    1. Osterlund M.K., Gustafsson J.A., Keller E., Hurd Y.L. Estrogen receptor beta (ERbeta) messenger ribonucleic acid (mRNA) expression within the human forebrain: Distinct distribution pattern to ERalpha mRNA. J Clin Endocrinol Metab. 2000;85:3840–3846.
    1. Osterlund M.K., Keller E., Hurd Y.L. The human forebrain has discrete estrogen receptor alpha messenger RNA expression: High levels in the amygdaloid complex. Neuroscience. 2000;95:333–342.
    1. McQueen J.K., Wilson H., Sumner B.E., Fink G. Serotonin transporter (SERT) mRNA and binding site densities in male rat brain affected by sex steroids. Brain Res Mol Brain Res. 1999;63:241–247.
    1. Phoenix C.H., Goy R.W., Gerall A.A., Young W.C. Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology. 1959;65:369–382.
    1. Meyer J.H. Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci. 2007;32:86–102.
    1. Cannon D.M., Ichise M., Rollis D., Klaver J.M., Gandhi S.K., Charney D.S., et al. Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder. Biol Psychiatry. 2007;62:870–877.
    1. Sherwin B.B., Gelfand M.M. Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol. 1985;151:153–160.
    1. Khera M. Patients with testosterone deficit syndrome and depression. Arch Esp Urol. 2013;66:729–736.
    1. Cohen L.S., Soares C.N., Poitras J.R., Prouty J., Alexander A.B., Shifren J.L. Short-term use of estradiol for depression in perimenopausal and postmenopausal women: A preliminary report. Am J Psychiatry. 2003;160:1519–1522.
    1. Bethea C.L., Reddy A.P., Robertson N., Coleman K. Effects of aromatase inhibition and androgen activity on serotonin and behavior in male macaques. Behav Neurosci. 2013;127:400–414.
    1. Gundlah C., Lu N.Z., Mirkes S.J., Bethea C.L. Estrogen receptor beta (ERbeta) mRNA and protein in serotonin neurons of macaques. Brain Res Mol Brain Res. 2001;91:14–22.
    1. Ramamoorthy S., Blakely R.D. Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science. 1999;285:763–766.
    1. Swaab D.F., Garcia-Falgueras A. Sexual differentiation of the human brain in relation to gender identity and sexual orientation. Funct Neurol. 2009;24:17–28.
    1. Rametti G., Carrillo B., Gomez-Gil E., Junque C., Segovia S., Gomez A., et al. White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study. J Psychiatr Res. 2011;45:199–204.
    1. Rametti G., Carrillo B., Gomez-Gil E., Junque C., Zubiarre-Elorza L., Segovia S., et al. The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study. J Psychiatr Res. 2011;45:949–954.
    1. Zhou J.N., Hofman M.A., Gooren L.J., Swaab D.F. A sex difference in the human brain and its relation to transsexuality. Nature. 1995;378:68–70.
    1. Luders E., Sanchez F.J., Gaser C., Toga A.W., Narr K.L., Hamilton L.S., Vilain E. Regional gray matter variation in male-to-female transsexualism. Neuroimage. 2009;46:904–907.
    1. Schoning S., Engelien A., Bauer C., Kugel H., Kersting A., Roestel C., et al. Neuroimaging differences in spatial cognition between men and male-to-female transsexuals before and during hormone therapy. J Sex Med. 2010;7:1858–1867.
    1. Simon L., Zsolt U., Fogd D., Czobor P. Dysfunctional core beliefs, perceived parenting behavior and psychopathology in gender identity disorder: A comparison of male-to-female, female-to-male transsexual and nontranssexual control subjects. J Behav Ther Exp Psychiatry. 2011;42:38–45.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner