Estrogen and its role in thyroid cancer.

Proliferative thyroid diseases are more prevalent in females than in males. Upon the onset of puberty, the incidence of thyroid cancer increases in females only and declines again after menopause. Estrogen is a potent growth factor both for benign and malignant thyroid cells that may explain the sex difference in the prevalence of thyroid nodules and thyroid cancer. It exerts its growth-promoting effect through a classical genomic and a non-genomic pathway, mediated via a membrane-bound estrogen receptor. This receptor is linked to the tyrosine kinase signaling pathways MAPK and PI3K. In papillary thyroid carcinomas, these pathways may be activated either by a chromosomal rearrangement of the tyrosine receptor kinase TRKA, by RET/PTC genes, or by a BRAF mutation and, in addition, in females they may be stimulated by high levels of estrogen. Furthermore, estrogen is involved in the regulation of angiogenesis and metastasis that are critical for the outcome of thyroid cancer. In contrast to other carcinomas, however, detailed knowledge on this regulation is still missing for thyroid cancer.