This is a multicenter study designed to assess the effects of groundbreaking CAH therapies on a spectrum of clinical and biochemical outcomes, with a special emphasis on reproductive and sexual health. Fertility is a profound concern for individuals with CAH, given the high prevalence of gonadal dysfunction that arises from the hormonal derangements that characterize this complex disease. At our endo-ERN accredited center for rare diseases at Policlinico Umberto I, addressing these fertility issues in CAH patients represents a daily commitment. The revolution of the pharmacological management of CAH is one of the most debated topics to date. Data on the effects of novel management options for CAH on fertility are scarce, but the anecdotal improvements in sperm count and menstrual regularity reported in the latest clinical trials have significantly motivated us to design the CALLIOPE study. Thus, we aim to delve deeper into the fertility and sexual function of CAH patients, employing advanced seminal parameter evaluations, multiparametric gonadal ultrasound, and sophisticated hormonal analyses in both females and males performed by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Beyond fertility, the CALLIOPE trial aspires to provide further understanding of therapy's effects on body composition, metabolism, immune function, coagulation, and quality of life, among other factors. We will explore the immunological impact of novel CAH therapies by quantifying Peripheral Blood Mononuclear Cells (PBMCs) and analyzing transcriptomic profiles to unveil gene expression patterns and identify biomarkers that could signal therapeutic targets or disease management strategies in CAH. Moreover, seminal plasma will be used to assess the expression of adrenal miRNAs regulating steroidogenesis and metabolism. The research will be conducted at our rare disease referral center (Policlinico Umberto I, Sapienza University of Rome) in collaboration with leading centers across Italy: Modena (Università degli Studi di Modena e Reggio Emilia), Naples (Università Federico II), Rome (Ospedale Sant'Andrea) and Bologna (Alma Mater Studiorum - Università di Bologna). https://isidorilab.com/home