GENDER NON-CONFORMING / TRANSGENDER YOUTH: CURRENT CONCEPTS, MANAGEMENT, & BARRIERS TO CARE

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1 GENDER NON-CONFORMING / TRANSGENDER YOUTH: CURRENT CONCEPTS, MANAGEMENT, & BARRIERS TO CARE Stephen M. Rosenthal, M.D. Professor of Pediatrics Em. Program Director, Pediatric Endocrinology Medical Director, Child & Adolescent Gender Center University of California, San Francisco Stephen.Rosenthal@ucsf.edu

2 DISCLOSURE I have been a consultant to AbbVie in October, 2016 All Rx to be discussed: Off-label for Gender Dysphoric Youth Stephen M. Rosenthal, M.D. Professor of Pediatrics Em. Program Director, Pediatric Endocrinology Medical Director, Child & Adolescent Gender Center University of California, San Francisco

3 DEFINITION OF TERMS: Sex Physical attributes that characterize biologic maleness or femaleness (i.e. Genitalia) Gender Identity Person s fundamental sense of self as male or female Not always binary!

4 DEFINITION OF TERMS: Transgender Transient or persistent identification with gender different from natal (or assigned ) gender» gender that is assumed based on physical sex characteristics present at birth

5 DEFINITION OF TERMS: Gender Identity Often confused with sexual identity/orientation People of any gender can have any sexual orientation

6 Gender Identity Disorder (DSM IV, 2000) Gender Dysphoria (GD) in Children (DSM 5, 2013) Marked incongruence between one s experienced/expressed gender and assigned gender of at least 6 months duration. Transgender identity, itself, is not a pathology Concern: Gender Dysphoria significant emotional distress that may be associated with a transgender identity American Psychiatric Association, 2013

7 How Common is Transgender? Prevalence: Adults (Boston) Survey: N = 28,176 Results»Self-identified as Transgender»N = 131»0.5% Conron KJ et al. Am J Public Health, 2012

8 How Common is Transgender? Prevalence in Youth Not yet known Our clinical program: > 425 patients (1 st pt 2009) 8-10 new referrals / month

9 Transgender Adolescents/ Young Adults: Mental Health Concerns N = 360 (Boston) 180 transgender, 180 cisgender Age: yr (Avg yr) Results: 2-3 x Risk (all p < 0.05) Depression Anxiety Disorder Suicidal Ideation Suicide attempt Self-harm without lethal intent Reisner SL et al., J Adolesc Health 56: , 2015

10 IMPACT OF PARENTAL SUPPORT FOR TRANSGENDER YOUTH Figure 1. Proportion of trans youth age years inontario experiencing positive health and life conditions, by level of parental support Parent(s) very supportive 72 Satisfied with life* VG/excellent physical health VG/excellent mental health* Parent(s) somewhat to not at all supportive High self esteem* 58 Intent to parent * = statistically significant difference (p < 0.05) Adequate housing* Adequate food N = 84 Youth Travers R et al. Children s Aid Society of Toronto & Delisle Youth Services, 2012

11 IMPACT OF PARENTAL SUPPORT FOR TRANSGENDER YOUTH Figure2. Proportion of trans youthage years in Ontario experiencing negative health and life conditions, by level of parental support Parent(s) very supportive Parent(s) somewhat to not at all supportive 23 Depressive symptoms* Considered suicide, past yr 4 57 Suicide attempt, past yr* N = 84 Youth * = statistically significant difference (p < 0.05) Travers R et al. Children s Aid Society of Toronto & Delisle Youth Services, 2012

12 QUESTIONS TO PONDER: Are there neuro-biologic and/ or genetic marker(s) for Transgender? How should such patients be managed?

13 GENDER IDENTITY Complex interplay Biologic Environmental Cultural factors

14 EVIDENCE FOR BIOLOGIC UNDERPINNINGS OF GENDER IDENTITY Insights from: Genetics Hormones Brain Not a litmus test of Transgender Not to pathologize! Goal: Understanding Acceptance, QOL

15 TRANSGENDER: ROLE OF GENETICS? Twin Studies (Heylens G et al. J Sex Med 9: , 2012) Concordance for Gender Dysphoria Comprehensive literature review N = 23 monozygotic (8 F, 15 M) twin pairs N = 21 same-sex dizygotic (5 F, 16 M) twin pairs N = 7 opposite sex twin pairs Results: Concordance for Gender Dysphoria Monozygotic Twin pairs: 39.1% Same-sex dizygotic twin pairs: 0% (p = vs. MZ twins) Opposite sex twin pairs: 0% Studies of individual candidate genes: inconsistent

16 HORMONES & GENDER IDENTITY Most transgender individuals do not have a Disorder of Sex Development (DSD) Studies in patients with DSD Informed our understanding of gender identity development Role of prenatal/ (postnatal) androgens

17 HORMONES & GENDER IDENTITY Insights from: Congenital Adrenal Hyperplasia (CAH) Variety of other hormonal, nonhormonal DSDs (46XY) 5 α-reductase-2 deficiency 17 β-hsd-3 deficiency Complete Androgen Insensitivity Cloacal exstrophy

18 SEXUAL DIFFERENTIATION Role of DHT & Androgen Receptor DSD: 2 Extremes --CAH (46XX) --Cloacal Exstrophy (46XY)

19 CAH 46XX Female

20 Congenital Adrenal Hyperplasia (CAH) (CYP21A2 Deficiency) 46 XX raised Female (F) N = 250»94.8 %: F gender identity»5.2%: M gender or gender dysphoria»10-20 x risk vs. control»no correlation with degree of genital virilization Supports some role of prenatal androgens in gender identity development Dessens AB et al. Arch Sex Behav 2005

21 Congenital Adrenal Hyperplasia (CAH) (CYP21A2 Deficiency) Youth with CAH from U.K. (4 11 yr) N = 43 Girls (37 SW, 6 SV); 38 Boys (35 SW, 3 SV) N = Controls: Age-matched relatives: 41 F, 31 M Measures: Gender Identity 2 parent reports (GIQC, CIC) 1 Child self-report (GIIC) Results 12.8% girls with CAH (vs. 0% in CAH boys, controls)» Cross-gender identification» Independent of gender role behavior ( factor analysis ) Supports some role of prenatal androgens in gender identity development Potential limitations: Selection bias; cohort effects Pasterski V et al. Arch Sex Behav, 2015

22 Cloacal Exstrophy N = 16 46XY Males 14 underwent neonatal sex reassignment to female Follow-up: age 5-16 yr Study Parent questionnaires Subjects stated Gender Identity Outcome 8/14 declared Male Gender»4/8 before knowing birth status 2/16 raised as male stayed male Supports some role of prenatal androgens in gender development Reiner WG et al. N Engl J Med 350: , 2004

23 Neurobiologic Basis for Transgender? Dimorphic brain structures (human) Sexually dimorphic Cell groups preoptic & anterior hypothalamic areas»inah-1,-2,-3 Suprachiasmatic nucleus Bed nucleus of the stria terminalis (BSTc) Anterior commissure Right putamen Sexual orientation dimorphic INAH-3 Gender dimorphic?

24 Neurobiologic Basis for Transgender? Numerous Gray, White matter studies Sexually dimorphic structures more closely aligned with gender identity than with physical sex Seen even before cross-sex hormones are given Luders E et al. NeuroImage 46: , 2009 Rametti G et al. J Psychiatric Research 45: , 2011 Hoekzema E. et al. Psychoneuroendocrinology, 2015

25 Sex beyond the genitalia: The human brain mosaic MRI Multiple data sets (4): 1400 human brains Assess degree of internal consistency Voxel-based morphometry (VBM) Focused on areas which show largest sex differences (least overlap between M, F) Principal finding: Variability more prevalent than internal consistency Joel D et al. PNAS, November 30, 2015

26 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

27 Anterior Hypothalamus: Evidence for Functional Gender Dimorphism Anterior Hypothalamus activated by AND, EST in sexually dimorphic manner in adults Females: activated by AND Males: activated by EST Study: N = 12 MTF adults»never-received hormonal Rx! N = 24 controls (12 M, 12 F) 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, 2008

28 Neurobiologic Basis for Transgender? Adolescents with Gender Dysphoria N = 38 adolescents with GD (21 FTM, 17 MTF) Blockers only (GnRH agonist) N = 41 adolescent controls (21 F, 20 M) f MRI Hypothalamic activation in response to odorous steroid: Androstadienone»Present in sweat, semen Changes in activation over time»6 on/off cycles over 3.6 min Burke SM. et al. Frontiers in Endocrinology, 2014

29 Neurobiologic Basis for Transgender? Adolescents with Gender Dysphoria Burke SM. et al. Frontiers in Endocrinology, 2014

30 Neurobiologic Basis for Transgender? Adolescents with Gender Dysphoria Burke SM. et al. Frontiers in Endocrinology, 2014

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32 Transgender Youth What we know Gaps in knowledge Priorities for research

33 Children & Adolescents with GD: Natural History Symptoms of Gender Dysphoria in pre-pubertal children or disappear in 70-95% of cases Gender Dysphoria persisting into early puberty: Likely transgender as adult!

34 Childhood Gender Dysphoria: Predictors of Persistence Persisters vs. Desisters : > Intensity of Gender Dysphoria > Likelihood of Childhood social transition (natal boys, in particular) Persisters: Believed they were the other sex Desisters: wished they were the other sex Steensma TD et al. J Am Acad Child & Adolesc Psychiatry 52: , 2013

35 Mental Health of Children Who Have Socially Transitioned Subjects Prepubescent children, national sample N = 73 (22 Natal F, 51 Natal M), age 3-12 yr (Avg 7.7 yr +/- 2.2) Controls: Non-transgender: age, gender-matched N = 73, community controls N = 49, sibs of transgender participants Study Parents completed anxiety, depression measures NIH PROMIS Parent Proxy Report Scales Results No Depression vs. controls Slight Anxiety; not clinically significant Anxiety, depression vs. non-socially-transitioned transgender children in earlier reports Olson KR et al. Pediatrics 137:e , 2016

36 Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline Pediatric/ Adolescent Recommendations: Dx GD made by mental health professional Medical providers ensure 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 about age of 16 yr Defer surgery until at least 18 yr of age Hembree WC et al. J Clin Endocrinol Metab 94: , 2009

37 Dutch protocol : 6 yr Follow-Up N= 55 (22 MTF, 33 FTM) Protocol Puberty blockers (Avg yr at start of Rx) Cross Sex Hormones (CSH) (Avg yr at start of Rx) Gender Reassignment Surgery (Avg. age 20.7 yr) Mental Health Outcomes 1 yr pre-blockers, T 0 for CSH, 1 yr post-surgery Results Gender Dysphoria: Resolved Psychological functioning: Generally improved Well being > vs. same age young adults from general population No patients reported regret at any phase of protocol De Vries ALC et al. Pediatrics, 2014

38 GnRH Agonists in Gender Dysphoric Youth: Potential Adverse Effects Bone mass, growth? Ameliorated with subsequent initiation of cross-sex hormone Rx Brain Fertility

39 Dutch Protocol : 6 yr Follow-Up Bone Mineral Density: Lumbar Spine Klink D et al. JCEM, 2015

40 Dutch Protocol : Bone Mineral Density: 6 yr Follow-Up Potential study limitations: Relatively small N (34: 15 MTF, 19 FTM)? Relatively low hormone dosage during initial CSH Rx No data on other factors influencing bone mass Dietary calcium intake Vitamin D levels Weight-bearing exercise Klink D et al. JCEM, 2015

41 GnRH Agonists & Brain Effects in Gender Dysphoric Youth Does GnRHa effect Executive Functioning? Working memory Reasoning Problem solving Planning and execution Pre-frontal activation Significant development during puberty Study MTF (N = 18): Rx d (8), 1.6 +/- 1 (SD) yr FTM (N = 22): Rx d (12), 1.6 +/- 1 (SD) yr Results No detrimental effect on Executive functioning Staphorsius AS et al. Psychoneuroendocrinology 56: , 2015

42 GnRH Agonists & Fertility in Gender Dysphoric Youth Blocking puberty at Tanner 2 Compromised oocyte maturation Compromised spermatogenesis Parental dilemmas Preservation of fertility: desired option

43 Fertility Strategies: In Vitro Spermatogenesis Neonatal mouse testes: cryopreserved Cultured on agarose gel Full in vitro spermatogenesis Micro-insemination with sperm 8 offspring Grew normally Produced progeny upon natural mating Yokonishi T et al. Nature Communications, 2014

44 Fertility Strategies: Oocyte Maturation In Vitro Maturation from primordial follicles achieved in mice (2003) Still being studied in humans In Vivo: Gonadotropin stimulation? 2 sex characteristics? Risk aneuploidy

45 Gaps in Knowledge & Priorities for Research Pre-pubertal, gender non-conforming youth: Limited data on predicting persisters Need for long-term outcomes studies of early social transition Early & Late Pubertal Youth: No data with blockers in pt < 12 yr No data with cross-sex hormones in pt < 16 yr No RCTs (likely not feasible or ethical) Need for prospective, long-term outcomes studies of medical interventions to optimize care

46 R01HD (08/01/ /30/2020): National Institutes of Health (NIH) The Impact of Early Medical Treatment of Transgender Youth Multi-Center Network Benioff Children s Hospital/ UCSF Children s Hospital LA/ USC Lurie Children s Hospital Chicago/ Northwestern Boston Children s Hospital/ Harvard

47 Transgender Youth: Barriers to Care Limited access to Rx Off-label Expensive Often denied by insurance companies Limited access to care Relatively few clinical programs Lack of training Prejudice/ misunderstanding

48 Acknowledgements Children s & Adolescent Gender Center (CAGC) Colleagues Diane Ehrensaft, PhD»Psychologist/ Gender Specialist»Mental Health Director, CAGC Joel Baum, MS»Director, Education & Training, Gender Spectrum»Director of Education & Advocacy, CAGC Asaf Orr, JD»Legal Director, CAGC Ilana Sherer, MD»Assistant Medical Director, CAGC Stanley R. Vance, Jr, MD»Fellow, Adolescent and Young Adult Medicine Meredith Russell, NP Molly Koren, LCSW

49 Thank You!