GENDER NON-CONFORMING / TRANSGENDER YOUTH: ENDOCRINE CONSIDERATIONS DISCLOSURE: I have nothing to disclose WHY STUDY GENDER?

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1 GENDER NON-CONFORMING / TRANSGENDER YOUTH: ENDOCRINE CONSIDERATIONS DISCLOSURE: I have nothing to disclose Stephen M. Rosenthal, M.D. Professor of Pediatrics University of California, San Francisco Stephen M. Rosenthal, M.D. Professor of Pediatrics University of California, San Francisco February 20, 2012 Sex-changing treatment for kids: It's on the rise By LINDSEY TANNER AP Medical Writer CHICAGO (AP) -- A small but growing number of teens and even younger children who think they were born the wrong sex are getting support from parents and from doctors who give them sex-changing treatments, according to reports in the medical journal Pediatrics. WHY STUDY GENDER? In some patients with Disorders of Sex Development (DSD) Gender Difficult to predict Partial Androgen Insensitivity Syndrome (PAIS) Incomplete 46 XY Gonadal Dysgenesis Some patients with Congenital Adrenal Hyperplasia (CAH) number Transgender Youth seeking Pubertal Suppression & Cross-Gender Rx 1

2 How Common is Transgender/ Gender Variance/ [Gender Identity Disorder (GID)]? Netherlands Prevalence Male-to-Female (MtF) Transexualism 1:11,900 Female-to-Male (FtM) Transexualism 1:30,400 North America Prevalence Estimates of prevalence less precise Numbers appear to have recently increased Children & Adolescents with GID: Toronto clinic, Zucker KJ t al. J Sex & Marital Therapy 34: , 2008 Children & Adolescents with GID: Amsterdam clinic, Pre-teen children 35 new referrals/year Adolescents 45 new referrals/year Kreukels BPC et al. European Psychiatry, 2010 Transgender Youth: Life-Threatening Behaviours N = 55 transgender youth (NYC) years MTF: 31 FTM: 24 Assessment Interviews Results N = 25 (45%): suicidal ideation N = 14 (26%): suicide attempts Grossman AH, et al. Suicide Life Threat Behav 37: ,

3 Outcomes of High Levels of Parental Pressure to Enforce Gender Conformity Health / Mental Health Concern Current Depression Attempted Suicide Illicit Drug Use Risk for HIV (Ryan, Family Acceptance Project, 2007) Outcome 5.01 times more likely* 3.90 times more likely* 3.82 times more likely* 2.12 times more likely* (n = 245) *Compared with peers from families with no or low levels of pressure to conform with gender expectations QUESTIONS TO PONDER: How is GID/ Transgender Dx d? Are there neurobiologic and/ or genetic marker(s) for GID? Should early adolescents with apparent GID undergo pubertal suppression? Who should manage these patients? Risks of treating vs. risks of not treating? DEFINITION OF TERMS: Sex Attributes that characterize biologic maleness or femaleness Gender Identity Person s fundamental sense of self as male or female Not always binary! 3

4 Transgender/ Gender Identity Disorder (GID) How is Transgender/ GID diagnosed? DIAGNOSTIC & STATISTICAL MANUAL (DSM) IV: Diagnostic Criteria for GID Gender Identity Disorder: Psychiatric Diagnosis Strong/ persistent cross-gender identification Persistent discomfort with one s sex or sense of inappropriateness in gender role of that sex No concurrent physical intersex condition Clinically significant emotional distress BIOLOGY OF GENDER Potential role of: Hormones (prenatal) Genetics Immunology (Fraternal Birth Order) Neuroanatomic structures HORMONES & GENDER Insights from: Congenital Adrenal Hyperplasia (CAH) Complete Androgen Insensitivity Syndrome (CAIS) 46 XY cloacal exstrophy Ablatio penis 2D:4D finger-length ratios 4

5 SEXUAL DIFRFERENTIATION Role of DHT & Androgen Receptor CAH 46XX Female DSD: 2 Extremes --CAH --CAIS Congenital Adrenal Hyperplasia (CAH) (CYP21A2 Deficiency) 46 XX raised Female (F) N = %: F gender identity 5.2%: M gender or gender confusion x > risk vs. control (1:30,400) No correlation with degree of genital virilization 46 XX raised Male (M) N = 33 Most Prader Stage V All assigned Male gender before CAH dx d 87.9%: M gender identity 12.1%: F gender or gender confusion Supports some role prenatal androgens in gender Dessens AB et al. Arch Sex Behav 2005 Congenital Adrenal Hyperplasia (CAH) (CYP21A2 Deficiency) N= 43 46XX Classical CAH, age 3-18 yr N= 27 sister/controls Questionnaire: Gender Identity Scores 5/43 = 11.6%: favored Male Gender Identity Gender: No correlation with: Degree of genital virilization Age of genital reconstructive surgery Some role for prenatal androgens in gender Yet, genital birth does not predict gender identity Berenbaum SA et al. J Clin Endocrinol Metab,

6 Male Gender Identity in Complete Androgen Insensitivity Syndrome (CAIS) Most girls/women with CAIS: Female Gender Identity 3 reported cases of Male Gender Identity 1 case: complete sex reassignment as adult Unambiguous female phenotype, 46XY Raised female Cross-gender behavior: age 3 yr CAIS dx d age 17 yr (1º amenorrhea) Androgen Receptor mutation: 2660delT premature Stop in codon 807 T Sjoen G et al. Arch Sex Behav 2010 Male Gender Identity in Complete Androgen Insensitivity Syndrome (CAIS) T Sjoen G et al. Arch Sex Behav 2010 Challenges concept: Normal AR pathway required for Male Gender Identity Possible explanation:? Post-zygotic mutation Brain mosaicism? Mother s DNA unavailable Neurobiologic Basis for GID? Dimorphic brain structures (human) Sexually dimorphic Cell groups in preoptic & anterior hypothalamic areas INAH-1,-2,-3 Suprachiasmatic nucleus Bed nuclues of the stria terminalis (BSTc) Anterior commissure Corpora mamillaria Cortex Sexual orientation dimorphic INAH-3 Gender dimorphic? Neurobiologic Basis for GID? Post-mortem brain study Determined # neurons in sex-dimorphic brain nucleus Central part of bed nucleus of stria terminalis (BSTc) Presumed heterosexual males (n=9) Homosexual males (n=9) Presumed heterosexual females (n=10) Male to Female transsexuals (n=6) Female to Male transsexual (n=1) Controls (n=7) Kruijver FPM et al. JCEM 85: ,

7 Neurobiologic Basis for GID?: BSTc Study Controls Sex Hormone Disorders F: Adrenal CA: Andro, Testosterone F: Post-menopausal: Estrogen F: Turner Syndrome (XO) M: Feminizing Adrenal CA: Estrogen M: Prostate CA, orchiectomy M: Prostate CA, orchiectomy, antiandrogen Rx Non-hormonally Rx d MtF Kruijver FPM et al. JCEM 85: , 2000 Neurobiologic Basis for GID? Regardless of sexual orientation, males had 2 x female # BSTc neurons MtF transsexuals: neuron # similar to females (P=0.83) FtM transsexual: neuron # in male range Hormone Rx or sex hormone level variation: no apparent influence on BSTc neuron # Kruijver FPM et al. JCEM 85: , 2000 Immunocytochemical staining (somatostatin) BSTc neurons BSTc neuron # according to sex, sexual orientation, & gender identity a, reference male b, reference female c, homosexual male d, MtF transsexual Kruijver, F. P. M. et al. J Clin Endocrinol Metab 2000;85: Kruijver, F. P. M. et al. J Clin Endocrinol Metab 2000;85: Copyright 2000 The Endocrine Society Copyright 2000 The Endocrine Society 7

8 Neurobiologic Basis for GID? N = 24 MtF adults (23-72 yr) Not-yet Rx d with cross-gender hormones N = 60 controls (30 M, 30 F) MRI Regional Gray Matter volumes Right Putamen (part of basal ganglia) Larger in Control F vs. Control M MtF: similar to control F Luders E et al. NeuroImage 46: , 2009 Anterior Hypothalamus: Evidence for Functional Gender Dimorphism Positron Emission Tomography (PET) Changes in regional blood flow Smelling of 2 odorous compounds Putative pheromones Progesterone derivative of 4,16 androstadien-3-one (AND) Human male sweat, saliva, semen Estrogen-like compound (EST) Urine of pregnant females Berglund H et al. Cerebral Cortex, 2008 Anterior Hypothalamus: Evidence for Functional Gender Dimorphism Anterior Hypothalamus activated by AND, EST in sexually dimorphic manner Females: activated by AND Males: activated by EST Study: N = 12 MtF adults Never-received hormonal Rx! N = 12 controls Results: MTFs: Ant hypothal activated by AND (F pattern) Differed from Male controls (p < 0.05), not from Female controls Berglund H et al. Cerebral Cortex,

9 What is the Natural History of Transgender/ GID in Children and Adolescents? Children & Adolescents with GID: Natural History University of Toronto N = 25 preadolescent girls with GID Initial assessment: Childhood Avg. age: 8.9 yr (range 3-12 yr) Follow-up Avg. age: 23.2 yr (range yr) Outcome 3 subjects (12 %) had persistent GID Drummond KD et al. Develop Psychol 44:34-35, 2008 Children & Adolescents with GID: Natural History Symptoms of GID in pre-pubertal children or disappear in 70-95% of cases GID persisting into early puberty: Highly persistent! Management of Adolescents with GID Current Practice: Amsterdam VU University Med Ctr Pubertal suppression with GnRH agonists (GnRHa) Tanner 2 Gender dysphoria from early childhood Gender dysphoria with pubertal onset Absence of psychiatric co-morbidity Adequate psychosocial support Demonstrated understanding of process 9

10 Management of Adolescents with GID GnRHa: Pro & Con Pro Buys Time Prevents experiencing puberty of undesired sex Fully reversible! Once puberty completed, can only be incompletely reversed e.g. Low voice, masculine facial features in MtF breasts, short stature in FtM Difficult to be passable as member of new sex Management of Adolescents with GID GnRHa: Pro & Con Con Some argue one can t definitively Dx GID in adolescence Theoretical risks of GnRHa Potential effects on bone mass, growth (may not be of concern with subsequent initiation of cross-sex hormone Rx) Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline Journal of Clinical Endocrinology & Metabolism Published on-line: June 9, 2009 Co-sponsoring Associations: European Society of Endocrinology European Society of Paediatric Endocrinology Pediatric Endocrine Society World Professional Association for Transgender Health Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline Pediatric/ Adolescent Recommendations: Dx GID made by mental health professional Physicians ensure GID patients understand consequences of hormone suppression & crosssex hormone Rx prior to Rx Suppression of pubertal hormones with GnRH agonist only after early puberty has been reached Initiate cross-sex hormone Rx at approx. 16 yr of age Defer surgery until at least 18 yr of age 10

11 Management of Adolescents with GID GnRHa: Further Thoughts Non-intervention is not a neutral option In dubio abstine may be harmful! Importance of Team Approach Need for adequate support for patients/ families Child and Adolescent Gender Center: UCSF / Community Collaborative Integrated care provided by multi-disciplinary team Mental Health Professionals Diagnostic assessment Psychotherapy/ counseling Support groups Pediatric Endocrinologists Pubertal suppression Cross-sex hormone Rx Advocacy Professionals School training: gender inclusive campuses & cultures Trainings with other organizations working with children & youth Legal & other forms of advocacy Child & Adolescent Gender Center (CAGC) UCSF / Community Collaborative Monthly CAGC Clinic at UCSF Multi-disciplinary team Appointments, information: Phone: (415) cagendercenter@gmail.com Stephen M. Rosenthal, MD (415) rosenthals@peds.ucsf.edu Child & Adolescent Gender Center Platform for Research Biology of Gender development Predicting persisters & desisters Endocrine intervention outcomes QOL assesments 11

12 Institute of Medicine (IOM) of the National Academies March 31, 2011 Acknowledgements Children s & Adolescent Gender Center Colleagues Diane Ehrensaft, PhD Psychologist/ Gender Specialist Joel Baum Director, Education & Training Gender Spectrum Ilana Sherer, MD Assistant Medical Director, CAGC Shane Snowdon Director, UCSF Center for LGBT Health & Equity Michael Baxter Director, Dimensions Clinic, SF Jamison Green, PhD Policy Analyst, UCSF CoE for Transgender Health Acknowledgements Children s & Adolescent Gender Center Colleagues Dan Karasic, MD Psychiatrist/ CAGC Steering Committee Jenifer Hastings, MD Family Practitioner, CAGC Steering Committee Dafna Wu, NP Family Practitioner, CAGC Steering Committee 12

13 Thank You! 13