Impact of sex hormones on development and progression in NEN: a new therapeutic target?

Abstract

Neuroendocrine neoplasms (NEN) are a rare and heterogeneous group of malignancies with rising incidence, requiring multidisciplinary and personalized management. Sex is emerging as a crucial factor in NEN development and progression. Genetic, epigenetic, and hormonal mechanisms have been proposed as potential contributors influencing treatment response and prognosis, but an in-depth analysis of the role of sex hormones and their receptors in NEN is still lacking. This review aims to analyze the impact of sex hormones and their receptors in sporadic NEN to provide potential therapeutic targets in the context of precision medicine. An overview of current preclinical and clinical evidence focused on different primary NEN, including gastroenteropancreatic, lung, prostate, and medullary thyroid cancers, focusing on estrogen, progesterone, and androgen receptors, has been made to clarify their role in NEN. Variable and conflicting results emerged across different primaries. Progesterone receptors appear to play a pivotal role in pancreatic and lung NEN, while estrogen receptors are more frequently involved in small intestine NEN and medullary thyroid carcinoma, suggesting a possible role in metastatic spread. Further studies are required to increase knowledge of the underlying mechanism of sex differences in NEN to define potential therapeutic targets for personalized care.

Keywords: androgen receptor; estrogen receptor; neuroendocrine neoplasm; progesterone receptor; risk factor; sex difference; sex hormones.