Nuria Valdés ^1* Ana Romero ² Estrella Diego ¹ Maria Calatayud Gutierrez ³ Cristina Lamas ⁴ Marta Araujo-Castro ⁵ Cristina Alvarez-Escola ⁶ Jose Angel Diaz ⁷ Victoria Alcázar ⁸ Julia Sastre ⁹ Rosa Martínez ¹ Josep Oriola ¹⁰ Miguel Paja ¹¹ Paula Sánchez-Sobrino ¹² Isabel Salinas ¹³ José M. Recio-Córdova ^14,15 Elena Navarro ² Maria Dolores Chiara ¹⁶ Luis Castaño ¹ Anna Casterás ¹⁷

• ¹ Cruces University Hospital, Barakaldo, Spain
• ² Virgen del Rocío University Hospital, Seville, Spain
• ³ Research Institute Hospital 12 de Octubre, Madrid, Catalonia, Spain
• ⁴ Complejo Hospitalario Universitario de Albacete, Albacete, Spain
• ⁵ Ramón y Cajal University Hospital, Madrid, Madrid, Spain
• ⁶ University Hospital La Paz, La Paz, Madrid, Spain
• ⁷ Carlos III International School, University Carlos III of Madrid, Getafe, Madrid, Spain
• ⁸ Hospital Universitario Severo Ochoa, Madrid, Madrid, Spain
• ⁹ University of Toledo, Toledo, Ohio, United States
• ¹⁰ Other, bacelona, Spain
• ¹¹ Basurto Hospital, Bilbao, Basque Country, Spain
• ¹² Pontevedra University Hospital, Pontevedra, Spain
• ¹³ Department of Endocrinology and Nutrition, Hospital Germans Trias i Pujol, Badalona, Catalonia, Spain
• ¹⁴ Pontifical University of Salamanca, Salamanca, Spain
• ¹⁵ University Hospital of Salamanca, Salamanca, Spain
• ¹⁶ Health Research Institute of Asturias (ISPA), Oviedo, Spain
• ¹⁷ Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain

Introduction: Historically, Multiple Endocrine Neoplasia type 1 (MEN1)-related pituitary adenomas (PAs) were considered more aggressive and treatment-resistant than sporadic PAs. However, recent studies suggest similarities in their behavior. This study aimed to evaluate the long-term outcomes of MEN1 PAs and identify predictive factors. Methods: Nationwide multicenter retrospective cohort study of MEN1-related PAs with a minimum 1-year follow-up, collecting patient demographics, germline MEN1 pathogenic variants (PV), PA size, secretory profile, radiological characteristics, treatments, and outcomes. Results: We analyzed 84 PAs, 69%in females and 31% in males (P<0.001), diagnosed at a mean age of 35.2±14.9 years, mostly through screening (60.7%). Median follow-up was 9 years (IQR:4-16). Prolactin-secreting PAs (PRLomas) (53.5%) and microadenomas (65.5%) were most common. Dopamine agonist treatment was first line for 16 macroPRLomas and 25 microPRLomas, 60.9% of them achieved PRL normalization. There was no significant association observed with tumor size, sex, treatment duration or MEN1 PV. The risk of progression from micro-PA to invasive macro-PA was 7.2% (4/55), after a follow-up of 8 years (IQR:4-13), all of them were microPRLomas. Kaplan-Meier estimation curve showed significantly higher progression probability in microPRLomas than in other microadenomas subtypes (P=0.017) or microNFPAs (P=0.032). No differences were found between sex, age, or germline MEN1 PV. Conclusions: MEN1-related micro-PAs have a low risk of progressing to invasive macro-PAs, regardless of sex, age at diagnosis, or MEN1 germline PV. The risk is higher for microPRLomas over the long term. Therefore, long-term surveillance with reduced frequency, rather than intensive short-term monitoring, may be appropriate for patients with MEN1-related PAs.