Sexual dimorphism in thyroid cancer: evidence from preclinical studies

Thyroid cancer (TC) exhibits strong sexual dimorphism, with higher incidence rates observed in females and more aggressive behavior in males. This disparity arises from complex interactions among genetic, hormonal and environmental factors. Data from preclinical studies evidenced a crucial role of sex hormones in driving TC prevalence and/or progression in males and females. In particular, estrogens would play a pro-tumorigenic role by directly activating estrogen receptor pathways and indirectly influencing tumorigenesis through mechanisms such as oxidative stress modulation, stimulation of thyroid stem cell proliferation, and alterations in the tumor microenvironment. Instead, androgens and androgen receptor (AR) signaling would exhibit dual roles in TC. AR downregulation in thyroid tissues is associated with increased tumor progression, whereas AR overexpression has demonstrated protective effects. These include inhibition of epithelial-to-mesenchymal transition, suppression of cell proliferation, downregulation of PD-L1 expression, and suppression of oncogenic microRNAs such as miR-146b. Conversely, androgens can promote tumor aggressiveness and metastasis in certain contexts, such as through VEGFC/VEGFR-3 signaling when a specific androgen-regulated gene is overexpressed. This review is aimed at summarizing the recent evidence coming from the literature data regarding both in vitro and in vivo studies on animal models investigating the multifaceted roles of sex hormones in TC, highlighting the critical need for new prospective longitudinal studies, also in view of gender-affirming hormones therapy. Such research will enhance our understanding of hormonal influences across diverse populations and further explain the relationship between sexual dimorphism and TC pathogenesis.