Use of Gonadotropin-Releasing Hormone agonists in Transgender and Gender Diverse Youth: A Systematic Review

Gianluca Tornese^1,2*Raffaella Di Mase³Jessica Munarin⁴Silvia Ciancia⁵Fabiana Santamaria³Daniela Fava^6,7Egidio Candela^8,9Donatella Capalbo¹⁰Carla Ungaro¹¹Nicola Improda¹²Pierluigi Diana¹³Patrizia Matarazzo⁴Laura Guazzarotti¹⁴Tommaso Toschetti¹³Vanessa Sambati¹³Gianluca Tamaro¹Giulia Bresciani¹Maria Rosaria Licenziati¹²Maria Elisabeth Street^13,15Tommaso Aversa¹⁶Maurizio Delvecchio¹⁷Maria Felicia Faienza¹⁸Lorenzo Iughetti^19,20Valeria Calcaterra^21,22Luisa De Sanctis⁴Mariacarolina Salerno¹⁰Roberto Franceschi^23*

• ¹Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste, Italy
• ²Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Friuli-Venezia Giulia, Italy
• ³Pediatric Endocrinology Unit, Department of Mother and Child, University Hospital Federico II, Naples, Italy
• ⁴Regina Margherita Children's Hospital, Pediatric Endocrinology, Department of Public Health and Pediatric Sciences, University of Turin, Turin, Italy
• ⁵Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, East Flanders, Belgium
• ⁶Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
• ⁷Pediatric Endocrinology Unit, Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
• ⁸Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ⁹Department of Medical and Surgical Sciences, Alma Mater Studiorum – Università di Bologna, Bologna, Emilia-Romagna, Italy
• ¹⁰Pediatric Endocrinology Unit, Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
• ¹¹Maternal and Child Unit, Local Health Unit, ASL Napoli 1 Centro, Naples, Italy
• ¹²Neuro-Endocrine Diseases and Obesity Unit, Department of Neurosciences, Santobono-Pausilipon Children's Hospital, Naples, Italy
• ¹³Department of Medicine and Surgery, University of Parma, Parma, Emilia-Romagna, Italy
• ¹⁴Endocrinology Unit, Pediatric Department, University of Padua, Padua, Italy
• ¹⁵Pediatric Clinic, Pietro Barilla Children's Hospital, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy
• ¹⁶Department of Human Pathology in Adulthood and Childhood Gaetano Barresi, University of Messina, Messina, Sicily, Italy
• ¹⁷Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
• ¹⁸Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "A. Moro", Bari, Italy
• ¹⁹University of Modena and Reggio Emilia, Modena, Emilia-Romagna, Italy
• ²⁰Pediatrics Unit, University Hospital of Modena, Modena, Italy
• ²¹Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy
• ²²Pediatric Department, Buzzi Children's Hospital, Milan, Italy
• ²³Department of Pediatrics, Santa Chiara Hospital of Trento, Azienda Provinciale per i Servizi Sanitari della Provincia Autonoma di Trento, Trento, Italy

Introduction: Puberty suppression using gonadotropin-releasing hormone agonists (GnRHa) is a reversible medical intervention that halts endogenous puberty, allowing transgender and gender-diverse (TGD) adolescents to avoid the development of secondary sexual characteristics that may cause psychological distress. This pause in pubertal progression provides time to explore gender identity or facilitates alignment with affirmed gender in those with an established identity. While widely used, long-term evidence on the efficacy and safety of GnRHa in this population remains limited. This systematic review aims to synthesize current data on the benefits and potential risks of GnRHa in TGD adolescents.Methods: We conducted a comprehensive literature search across PubMed, EMBASE, Cochrane Library, and other databases, covering studies published from February 2011 to February 2024.Eligible studies included adolescents under 18 with gender dysphoria or incongruence treated with GnRHa, reporting outcomes related to efficacy or side effects. Fifty-one studies met inclusion criteria, and data on physical health, mental health, bone density, fertility, and adverse events were extracted and assessed using the GRADE approach.Results: Of the 51 studies, 22 were rated as moderate to high-quality evidence. GnRHa effectively suppressed puberty and secondary sex characteristics. Effects on growth and body composition varied; bone mineral density declined during treatment, particularly in AMAB individuals. Mental health improved significantly, including reduced depression, anxiety, and suicidalityespecially when GnRHa was followed by gender-affirming hormone therapy (GAHT). Quality of life improved over time, while body dissatisfaction often persisted during suppression and improved after GAHT or surgery. No moderate-or high-quality evidence was found on fertility, sexual function, or cancer risk.Conclusion: GnRHa is effective in halting puberty and improving mental health in TGD adolescents. However, key clinical and ethical considerations-such as bone health monitoring, fertility counseling, psychological support, and informed decision-making-must guide treatment. Long-term safety remains uncertain, particularly regarding skeletal health, reproductive outcomes and cancer risk. A precision medicine approach and co-produced longitudinal studies are essential to support safe, individualized care.