Federica Barbagallo ¹ David Bosoni ² Valeria Perone ^3,4* Laura Cucinella ^4,5* Davide De Alberti ^6* Rossella Cannarella ^1,7 Aldo E. Calogero ¹ Rossella E. Nappi ^4,5*

• ¹ Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
• ² Department of Obstetrics and Gynecology, Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
• ³ Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
• ⁴ Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation,, Pavia, Lombardy, Italy
• ⁵ Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Lombardy, Italy
• ⁶ Department of Obstetrics and Gynecology, Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo,, Alessandria, Italy
• ⁷ Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, United States

Functional hypothalamic amenorrhea (FHA) is a common cause of amenorrhea and chronic anovulation in adolescent girls and young women, diagnosed after excluding other organic causes. It is commonly associated with calorie restriction, excessive physical exercise, and psychosocial stress. These stressors alter the pulsatile secretion of gonadotropin-releasing hormone, leading to a chronic condition of hypoestrogenism and significant health consequences. Recent evidence has highlighted a genetic predisposition to FHA that could explain interindividual variability in stress response. Indeed, not all women experience FHA in response to stress. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism have been identified in women with FHA, suggesting that these mutations may contribute to an increased susceptibility of women to the trigger of stress exposure. FHA appears today as a complex disease resulting from the combination of genetic predisposition, environmental factors, and epigenetic changes. Furthermore, the genetic background of FHA allows for the hypothesis of a male counterpart. Despite the paucity of data, preliminary findings indicate that an equivalent condition of FHA exists in men, warranting further investigation. This narrative review aims to summarize the recent genetic evidence contributing to the pathophysiology of FHA and to raise awareness on a possible male counterpart.