Gender dysphoria: prejudice from childhood to adulthood, but no impact on inflammation. A cross-sectional controlled study
André Gonzales Real, Anna Martha Vaitses Fontanari, Angelo Brandelli Costa, Bianca Machado Borba Soll, Giovana Bristot, Larissa Fagundes de Oliveira, Ana Maria Kamphorst, Maiko Abel Schneider, Maria Inês Rodrigues Lobato
Abstract
Introduction
Gender dysphoria (GD) is characterized by a marked incongruence between experienced gender and one’s gender assigned at birth. Transsexual individuals present a higher prevalence of psychiatric disorders when compared to non-transsexual populations, and it has been proposed that minority stress, i.e., discrimination or prejudice, has a relevant impact on these outcomes. Transsexuals also show increased chances of having experienced maltreatment during childhood. Interleukin (IL)-1β, IL-6, IL-10 and tumor necrosis factor-alpha (TNF-α) are inflammatory cytokines that regulate our immune system. Imbalanced levels in such cytokines are linked to history of childhood maltreatment and psychiatric disorders. We compared differences in IL-1β, IL-6, IL-10 and TNF-α levels and exposure to traumatic events in childhood and adulthood in individuals with and without GD (DSM-5).
Methods
Cross-sectional controlled study comparing 34 transsexual women and 31 non-transsexual men. They underwent a thorough structured interview, assessing sociodemographic information, mood and anxiety symptoms, childhood maltreatment, explicit discrimination and suicidal ideation. Inflammatory cytokine levels (IL-1β, IL-6, IL-10 and TNF-α) were measured by multiplex immunoassay.
Results
Individuals with GD experienced more discrimination (p = 0.002) and childhood maltreatment (p = 0.046) than non-transsexual men. Higher suicidal ideation (p < 0.001) and previous suicide attempt (p = 0.001) rates were observed in transsexual women. However, no differences were observed in the levels of any cytokine.
Conclusions
These results suggest that transsexual women are more exposed to stressful events from childhood to adulthood than non-transsexual men and that GD per se does not play a role in inflammatory markers.
Keywords
References
1 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Arlington: American Psychiatric Publishing; 2013.
2 Arcelus J, Bouman WP, Van Den Noortgate W, Claes L, Witcomb G, Fernandez-Aranda F. Systematic review and meta-analysis of prevalence studies in transsexualism. Eur Psychiatry. 2015;30:807-15.
3 Corliss HL, Cochran SD, Mays VM. Reports of parental maltreatment during childhood in a United States population-based survey of homosexual, bisexual, and heterosexual adults. Child Abus Negl. 2002;26:1165-78.
4 Kersting A, Reutemann M, Gast U, Ohrmann P, Suslow T, Michael N, et al. Dissociative disorders and traumatic childhood experiences in transsexuals. J Nerv Ment Dis. 2003;191:182-9.
5 Bandini E, Fisher AD, Ricca V, Ristori J, Meriggiola MC, Jannini EA, et al. Childhood maltreatment in subjects with male-to-female gender identity disorder. Int J Impot Res. 2011;23:276-85.
6 Horwitz AV, Widom CS, Mclaughlin J, White HR. The impact of childhood abuse and neglect on adult mental health: a prospective study. J Health Soc Behav. 2001;42:184-201.
7 Perepletchikova F, Kaufman J. Emotional and behavioral sequelae of childhood maltreatment. Curr Opin Pediatr. 2010;22:610-5.
8 Dvir Y, Ford JD, Hill M, Frazier JA. Childhood maltreatment, emotional dysregulation, and psychiatric comorbidities. Harv Rev Psychiatry. 2014;149-61.
9 Pompili M, Shrivastava A, Serafini G, Innamorati M, Milelli M, Erbuto D, et al. Bereavement after the suicide of a significant other. Indian J Psychiatry. 2013;55:256-63.
10 Garofalo R, Deleon J, Osmer E, Doll M, Harper GW. Overlooked, misunderstood and at-risk: Exploring the lives and HIV risk of ethnic minority male-to-female transgender youth. J Adolesc Heal. 2006;38:230-6.
11 Vance Jr SR, Halpern-felsher BL, Rosenthal SM. Health care providers ’ comfort with and barriers to care of transgender youth. J Adolesc Heal. 2015;56:251-3.
12 Baral SD, Poteat T, Strömdahl S, Wirtz AL, Guadamuz TE, Beyrer C. Worldwide burden of HIV in transgender women: a systematic review and meta-analysis. Lancet Infect Dis. 2013;13:214-22.
13 Costa AB, Filho HT da R, Pase PF, Fontanari AMV, Catelan RF, Mueller A, et al. Healthcare needs of and access barriers for brazilian transgender and gender diverse people. J Immigr Minor Health. 2018;20:115-23.
14 Meyer IH. Minority stress and mental health in gay men. J Health Soc Behav. 1995;36:38-56.
15 Meyer IH. Prejudice, social stress, and mental health in lesbian, gay, and bisexual populations: conceptual issues and research evidence. Psychol Bull. 2003;129:674-97.
16 Hendricks ML, Testa RJ. A conceptual framework for clinical work with transgender and gender nonconforming clients: an adaptation of the minority stress model. Prof Psychol Pract J. 2012;43:460-7.
17 Wallien MSC, Swaab H, Cohen-Kettenis PT. Psychiatric comorbidity among children with gender identity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46:1307-14.
18 Gómez-Gil E, Zubiaurre-Elorza L, Esteva I, Guillamon A, Godás T, Cruz Almaraz M, et al. Hormone-treated transsexuals report less social distress, anxiety and depression. Psychoneuroendocrinology. 2012;37:662-70.
19 Hoshiai M, Matsumoto Y, Sato T, Ohnishi M, Okabe N, Kishimoto Y, et al. Psychiatric comorbidity among patients with gender identity disorder. Psychiatry Clin Neurosci. 2010;64:514-9.
20 De Vries ALC, Doreleijers TAH, Steensma TD, Cohen-Kettenis PT. Psychiatric comorbidity in gender dysphoric adolescents. J Child Psychol Psychiatry. 2011;52:1195-202.
21 Fisher AD, Bandini E, Casale H, Ferruccio N, Meriggiola MC, Gualerzi A, et al. Sociodemographic and clinical features of gender identity disorder: an italian multicentric evaluation. J Sex Med. 2013;10:408-19.
22 Auer MK, Höhne N, Bazarra-Castro MÁ, Pfister H, Fuss J, Stalla GK, et al. Psychopathological profiles in transsexuals and the challenge of their special status among the sexes. PLoS One. 2013;8:1-9.
23 Judge C, O’Donovan C, Callaghan G, Gaoatswe G, O’Shea D. Gender dysphoria - prevalence and co-morbidities in an Irish adult population. Front Endocrinol. 2014;5:1-5.
24 Dhejne C, Lichtenstein P, Boman M, Johansson ALV, Långström N, Landén M. Long-term follow-up of transsexual persons undergoing sex reassignment surgery: cohort study in Sweden. PLoS One. 2011;6:e16885.
25 Blosnich JR, Brown GR, Shipherd JC, Kauth M, Piegari RI, Bossarte RM. Prevalence of gender identity disorder and suicide risk among transgender veterans utilizing veterans health administration care. Am J Public Health. 2013;103:27-33.
26 Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatry Res. 2015;229:27-36.
27 Dinan TG. Inflammatory markers in depression. Curr Opin Psychiatry. 2009;22:32-6.
28 Miller AH. Mechanisms of cytokine-induced behavioral changes: Psychoneuroimmunology at the translational interface. Brain Behav Immun. 2009;23:149-58.
29 Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 1995;19:11-38.
30 Anisman H, Merali Z, Hayley S. Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders. Prog Neurobiol. 2008;85:1-74.
31 Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37:137-62.
32 Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A Meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446-57.
33 Haan L De, Peters B, Dingemans P, Wouters L, Linszen D. Attitudes of patients toward the first psychotic episode and the start of treatment. Schizophr Bull. 2002;28:431-42.
34 Karlovic D, Serretti A, Vrkic N, Martinac M, Marcinko D. Serum concentrations of CRP, IL-6, TNF-α and cortisol in major depressive disorder with melancholic or atypical features. Psychiatry Res. 2012;198:74-80.
35 Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J, et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015;2:1002-12.
36 Furtado M, Katzman MA. Neuroinflammatory pathways in anxiety, posttraumatic stress, and obsessive compulsive disorders. Psychiatry Res. 2015;229:37-48.
37 Quagliato LA, Nardi AE. Cytokine alterations in panic disorder: a systematic review. J Affect Disord. 2018;228:91-6.
38 Wiener CD, Moreira FP, Cardoso TA, Mondin TC, da Silva Magalhães PV, Kapczinski F, et al. Inflammatory cytokines and functional impairment in drug-free subjects with mood disorder. J Neuroimmunol. 2017;307:33-6.
39 Ganança L, Oquendo MA, Tyrka AR, Cisneros-trujillo S, Mann JJ, Sublette ME. The role of cytokines in the pathophysiology of suicidal behavior. Psychoneuroendocrinology. 2016;63:296-310.
40 Sayana P, Colpo GD, Simões LR, Giridharan VV, Teixeira AL, Quevedo J, et al. A systemic review of evidence for the role of inflammatory biomarkers in bipolar patients. J Psychiatr Res. 2017;92:160-82.
41 Audet M, Anisman H. Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses. Front Cell Neurosci. 2013;7:1-19.
42 Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci. 2007;104:1319-24.
43 Pace TWW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miller AH, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163:1630-3.
44 Tursich M, Neufeld RWJ, Frewen PA, Harricharan S, Kibler JL, Rhind SG, et al. Association of trauma exposure with proinflammatory activity: a transdiagnostic meta-analysis. Transl Psychiatry. 2014;4:413-9.
45 Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience. 2013;239:196-213.
46 Fernandes BS, Massuda R, Torres M, Camargo D, Fries GR, Gama CS, et al. Improvement of schizophrenia with electroconvulsive therapy and serum brain-derived neurotrophic factor levels: Lack of association in a pilot study. Psychiatry Clin Neurosci. 2010;64:663-5.
47 Grande I, Fries GR, Kunz M, Kapczinski F. The role of BDNF as a mediator of neuroplasticity in bipolar disorder. Psychiatry Investig. 2010;7:243-50.
48 Bennett MR, Lagopoulos J. Stress and trauma: BDNF control of dendritic-spine formation and regression. Prog Neurobiol. 2014;112:80-99.
49 Kauer-Sant’Anna M, Tramontina J, Andreazza AC, Cereser K, da Costa S, Santin A, et al. Traumatic life events in bipolar disorder: impact on BDNF levels and psychopathology. Bipolar Disord. 2007;9:128-35.
50 Boulle F, Hove DLA Van Den, Jakob SB, Rutten BP, Hamon M, Os J Van, et al. Epigenetic regulation of the BDNF gene: implications for psychiatric disorders. Mol Psychiatry. 2012;17:584-96.
51 Fernandes BS, Gama CS, Maria Ceresér K, Yatham LN, Fries GR, Colpo G, et al. Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J Psychiatr Res. 2011;45:995-1004.
52 Shaltiel G, Chen G, Manji HK. Neurotrophic signaling cascades in the pathophysiology and treatment of bipolar disorder. Curr Opin Pharmacol. 2007;7:22-6.
53 Schmidt HD, Shelton RC, Duman RS. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology. 2011;36:2375-94.
54 Mitchelmore C, Gede L. Brain derived neurotrophic factor: epigenetic regulation in psychiatric disorders. Brain Res. 2014;1586:162-72.
55 Fontanari AM, Andreazza T, Costa ÂB, Salvador J, Koff WJ, Aguiar B, et al. Serum concentrations of brain-derived neurotrophic factor in patients with gender identity disorder. J Psychiatr Res. 2013;47:1546-8.
56 Fuss J, Biedermann SV, Stalla GK, Auer MK. On the quest for a biomechanism of transsexualism: is there a role for BDNF? J Psychiatr Res. 2013;47:2015-7.
57 Fuss J, Hellweg R, Van Caenegem E, Briken P, Stalla GK, T’Sjoen G, et al. Cross-sex hormone treatment in male-to-female transsexual persons reduces serum brain-derived neurotrophic factor (BDNF). Eur Neuropsychopharmacol. 2015;25:95-9.
58 Auer MK, Hellweg R, Briken P, Stalla GK, T’Sjoen G, Fuss J. Serum brain-derived neurotrophic factor (BDNF) is not regulated by testosterone in transmen. Biol Sex Differ. 2016;7:1-6.
59 Schneider MA, Andreazza T, Martha Fontanari AV, Costa AB, da Silva DC, de Aguiar BW, et al. Serum concentrations of brain-derived neurotrophic factor in patients diagnosed with gender dysphoria undergoing sex reassignment surgery. Trends Psychiatry Psychother. 2017;39:43-7.
60 Blondeel K, de Vasconcelos S, García-Moreno C, Stephenson R, Temmerman M, Toskin I. Violence motivated by perception of sexual orientation and gender identity: a systematic review. Bull World Health Organ. 2018;96:29-41L.
61 Fontanari AMV, Rovaris DL, Costa AB, Pasley A, Cupertino RB, Soll BMB, et al. Childhood maltreatment linked with a deterioration of psychosocial outcomes in adult life for southern Brazilian transgender women. J Immigr Minor Health. 2016;1-11.
62 Müller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Müller B, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: Results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11:680-4.
63 Gabbay V, Klein RG, Guttman LE, Babb JS, Alonso CM, Nishawala M, et al. A preliminary study of cytokines in suicidal and nonsuicidal adolescents with major depression. J Child Adolesc Psychopharmacol. 2009;19:423-30.
64 Duinen MA Van, Schruers KRJ, Kenis GRL, Wauters A, Delanghe J, Griez EJL, et al. Effects of experimental panic on neuroimmunological functioning. J Psychosom Res. 2008;64:305-10.
65 Ortiz-Domínguez A, Hernández ME, Berlanga C, Gutiérrez-Mora D, Moreno J, Heinze G, et al. Immune variations in bipolar disorder: phasic differences. Bipolar Disord. 2007;9:596-602.
66 Barbosa IG, Rocha NP, Barreto R, Ferreira RA, Vinícius J, Carvalho LA, et al. Executive dysfunction in euthymic bipolar disorder patients and its association with plasma biomarkers. J Affect Disord. 2012;137:151-5.
67 Kaul M, Zheng J, Okamoto S, Gendelman HE, Lipton SA. HIV-1 infection and AIDS: Consequences for the central nervous system. Cell Death Differ. 2005;12:878-92.
68 Sheehan D V, Lecrubier Y, Sheehan KH, Weiller E, Amorim P, Janavs J, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59:22-34.
69 Amorim P. Mini International Neuropsychiatric Interview (MINI): validation of a short structured diagnostic psychiatric interview. Braz J Psychiatry. 2000;22:106-15.
70 O’Brien SM, Scully P, Fitzgerald P, Scott LV, Dinan TG. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J Psychiatr Res. 2007;41:326-31.
71 Kim Y-K, Jung H-G, Myint A-M, Kim H, Park S-H. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord. 2007;104:91-5.
72 Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 2006;21:227-31.
73 Vignola RCB, Tucci AM. Adaptation and validation of the Depression, Anxiety and Stress Scale (DASS) to Brazilian Portuguese. J Affect Disord. 2013;155:104-9.
74 Antony MM, Bieling PJ, Cox BJ, Enns MW, Swinson RP. Psychometric properties of the 42-item and 21-item versions of the Depression Anxiety Stress Scales in clinical groups and a community sample. Psychol Assess. 1998;10:176.
75 Grassi-Oliveira R, Stein LM, Pezzi JC. Translation and content validation of the Childhood Trauma Questionnaire. Rev Saude Publica. 2006;40:249-55.
76 Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, et al. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl. 2003;27:169-90.
77 Bastos JL, Reichenheim ME, Celeste RK, Faerstein E, Barros AJD, Paradies YC. Perceived discrimination south of the equator: reassessing the Brazilian Explicit Discrimination Scale. Cult Divers Ethn Minor Psychol. 2018;25:413-23.
78 Bastos JL, Faerstein E, Celeste RK, Barros AJD. Explicit discrimination and health: development and psychometric properties of an assessment instrument. Rev Saude Publica. 2012;46:269-78.
79 Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266-77.
80 Schneeberger AR, Dietl MF, Muenzenmaier KH, Huber CG, Lang UE. Stressful childhood experiences and health outcomes in sexual minority populations: a systematic review. Soc Psychiatry Psychiatr Epidemiol. 2014;49:1427-45.
81 Gehring D, Knudson G. Prevalence of childhood trauma in a clinical population of transsexual people. Int J Transgenderism. 2005;8:23-30.
82 Carballo-Diéguez A, Balan I, Dolezal C, Mello MB. Recalled sexual experiences in childhood with older partners: a study of Brazilian men who have sex with men. Arch Sex Behav. 2012;41:363-76.
83 Alejandra E, Gallo G, Neuenfeld T, Loret C, Mola D, Murray J. Gender differences in the effects of childhood maltreatment on adult depression and anxiety: a systematic review and meta-analysis. Child Abus Negl. 2018;79:107-14.
84 Drescher J. Queer diagnoses: Parallels and contrasts in the history of homosexuality, gender variance, and the Diagnostic and Statistical Manual. Arch Sex Behav. 2010;39:427-60.
85 Nemoto T, Bödeker B, Iwamoto M. Social support, exposure to violence and transphobia, and correlates of depression among male-to-female transgender women with a history of sex work. Am J Public Health. 2011;101:1980-8.
86 Essau CA, Lewinsohn PM, Olaya B, Seeley JR. Anxiety disorders in adolescents and psychosocial outcomes at age 30. J Affect Disord. 2014;163:125-32.
87 Terada S, Matsumoto Y, Sato T, Okabe N, Kishimoto Y, Uchitomi Y. Suicidal ideation among patients with gender identity disorder. J Psychiatr Res. 2011;190:159-62.
88 Clements-Nolle K, Marx R. Attempted suicide among transgender persons. J Homosex. 2006;51:53-69.
89 Perez-brumer A, Hatzenbuehler ML, Oldenburg CE, Bockting W. Individual- and structural-level risk factors for suicide attempts among transgender adults. Behav Med. 2015;41:164-71.
90 Pompili M, Gibiino S, Innamorati M, Serafini G, Del Casale A, De Risio L, et al. Prolactin and thyroid hormone levels are associated with suicide attempts in psychiatric patients. Psychiatry Res. 2012;200:389-94.
91 Bugge E, Wynn R, Mollnes TE, Reitan SK, Grønli OK. Cytokine profiles and diagnoses in elderly, hospitalized psychiatric patients. BMC Psychiatry. 2018;18:1-7.
92 White Hughto JM, Reisner SL, Pachankis JE. Transgender stigma and health: a critical review of stigma determinants, mechanisms, and interventions. Soc Sci Med. 2015;147:222-31.
93 Kedzierska K, Crowe SM. Cytokines and HIV-1: interactions and clinical implications. Antivir Chem Chemother. 2001;12:133-50.
94 Roberts L, Passmore J-AS, Williamson C, Little F, Bebell LM, Mlisana K, et al. Plasma cytokine levels during acute HIV-1 infection predict HIV disease progression. Aids. 2010;24:819-31.
95 Yuan L, Qiao L, Wei F, Yin J, Liu L, Ji Y, et al. Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China. J Neurovirol. 2015;344:1173-8.
96 Michopoulos V, Powers A, Gillespie CF, Ressler KJ, Jovanovic T. Inflammation in fear- and anxiety-based disorders: PTSD, GAD, and beyond. Neuropsychopharmacol Rev. 2017;42:254-70.
97 Valdiserri RO, Holtgrave DR, Poteat TC, Beyrer C. Unraveling health disparities among sexual and gender minorities: a commentary on the persistent impact of stigma. J Homosex. 2019;66:571-89.
98 Costa AB, Fontanari AMV, Jacinto MM, da Silva DC, Lorencetti EK, da Rosa Filho HT, et al. Population-based HIV prevalence and associated factors in male-to-female transsexuals from southern Brazil. Arch Sex Behav. 2015;44:521-4.
99 Bhatia A, Sekhon HK, Kaur G. Sex hormones and immune dimorphism. Sci World J. 2014;2014.
100 Smith JA, Das A, Butler JT, Ray SK, Banik NL. Estrogen or estrogen receptor agonist inhibits lipopolysaccharide induced microglial activation and death. Neurochem Res. 2011;36:1587-93.
101 Bianchi VE. The anti-inflammatory effects of testosterone. J Endocr Soc. 2019;3:91-107.
102 Shivers KY, Amador N, Abrams L, Hunter D, Jenab S, Quiñones-Jenab V. Estrogen alters baseline and inflammatory-induced cytokine levels independent from hypothalamic-pituitary-adrenal axis activity. Cytokine. 2015;72:121-9.
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email