LBMON199 Peripheral Blood Mononuclear Cell Mitochondria Function Differs In Adolescent Transgender Males By Gnrha Use

BACKGROUND: About 2% of youth in the United States identify as transgender, meaning their gender identity differs from sex at birth. The Endocrine Society recommends gonadotropin-releasing hormone agonist (GnRHa) therapy for eligible individuals starting at Tanner 2 to halt endogenous pubertal progression, and later testosterone or estradiol treatment. Studies in animals and cisgender adults have shown that sex hormones influence whole-body metabolism and mitochondrial function, but most of the literature has focused on sex differences and the impact of menopause in females. Little is known about the impact of puberty blockade and gender-affirming hormone therapy on metabolic health in transgender youth. METHODS: For this pilot study, transgender males (TGM) aged 14-17 were recruited (n=16) with an assessment prior to initiation of testosterone therapy. Measures of metabolic health (body mass index [BMI], weight, exercise capacity via peak oxygen uptake [VO2 peak]) and hormone status (use of GnRHa, circulating sex hormone levels) were collected. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood via density-gradient centrifugation and mitochondrial function (maximal respiratory capacity [States 2, 3, 3s, 4, uncoupled] and respiratory control ratio [RCR]) was measured via high-resolution respirometry under carbohydrate (CHO) and lipid substrates. Participants were stratified by GnRHa use for analysis. RESULTS: Eight TGM were on GnRHa (average duration of use of 25.3+13.1 months). As expected, individuals taking GnRHas had significantly lower luteinizing hormone (LH; p=0. 03), follicle stimulating hormone (FSH; p<0. 01) and estradiol (p<0. 01) compared to those not on GnRHa. BMI, body weight, and VO2 peak were not different by GnRHa status. PBMC respiration differed between groups; those on GnRHa had higher ADP-stimulated State 3 respiration (p=0.11 CHO, p=0. 06 lipid) and RCR (p<0. 01 CHO, lipid) and lower basal State 4 respiration (p=0. 01 CHO, p=0. 01 lipid). Further, FSH and estradiol were negatively correlated with RCR (all p≤0. 05; Pearson's R -0.5 to -0.7), a finding consistent across both substrate experiments. CONCLUSION: TGM youth on GnRHa had higher PBMC mitochondrial RCR compared to TGM not on GnRHa. These RCR data, combined with lower basal and greater ADP-stimulated respiration likely represents either an advantageous mitochondrial profile in youth using GnRHa or a compensatory increase in response to estrogen suppression. Our correlation data suggest these differences are related to the absence of estradiol and FSH rather than metabolic outcomes traditionally thought to impact respiratory capacity. Future interventional investigations are needed to evaluate the impact of GnRHa in transgender youth and should target physiological mechanisms underlying this preliminary finding. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.