The Emerging Role of Estrogens in Thyroid Redox Homeostasis and Carcinogenesis

Abstract

Reactive oxygen species (ROS) are the most critical class of free radicals or reactive metabolites produced by all living organisms. ROS regulate several cellular functions through redox-dependent mechanisms, including proliferation, differentiation, hormone synthesis, and stress defense response. However, ROS overproduction or lack of appropriate detoxification is harmful to cells and can be linked to the development of several diseases, such as cancer. Oxidative damage in cellular components, especially in DNA, can promote the malignant transformation that has already been described in thyroid tissue. In thyrocyte physiology, NADPH oxidase enzymes produce large amounts of ROS that are necessary for hormone biosynthesis and might contribute to the high spontaneous mutation rate found in this tissue. Thyroid cancer is the most common endocrine malignancy, and its incidence is significantly higher in women than in men. Several lines of evidence suggest the sex hormone estrogen as a risk factor for thyroid cancer development. Estrogen in turn, besides being a potent growth factor for both normal and tumor thyroid cells, regulates different mechanisms of ROS generation. Our group demonstrated that the thyroid gland of adult female rats exhibits higher hydrogen peroxide (H2O2) production and lower enzymatic antioxidant defense in comparison with male glands. In this review, we discuss the possible involvement of thyroid redox homeostasis and estrogen in the development of thyroid carcinogenesis.

Thyroid redox imbalance in adult Wistar rats that were exposed to nicotine during breastfeeding

“…Estrogen acts increasing iodide uptake, TPO activity and TG expression, and it modulates TSH level. Furthermore, estrogen also influences the thyroid gland redox status, as previously reported 17,33 . It is conceivable that the mechanisms underlying this influence involve the estrogen-regulated NOX4 and DUOX2 activity and expression.…”

“…Even though studies have demonstrated a relationship between thyroid pathologies and thyrocytes redox imbalance 15 – 17 , the interconnection between metabolic programming and oxidative stress in the thyroid is mostly unknown. Our hypothesis is that maternal exposure to nicotine during breastfeeding impact directly the redox homeostasis of the thyroid gland, impairing the thyroid hormonogenesis process in the offspring and imprinting thyroid dysfunctions later in life.…”

Mitofusin-2 modulates the epithelial to mesenchymal transition in thyroid cancer progression

“…Because high levels of ROS are produced during thyroid hormone synthesis, mitochondrial defense mechanisms against ROS are important in thyroid follicular cells. These antioxidant defense systems have been found to be inactive in thyroid cancers 4 , 5 . In Hürthle cell carcinoma, a rare type of differentiated thyroid cancer is characterized by excess mitochondria as well as defective mitochondrial oxidative phosphorylation 6 .…”

Cystathionine γ-lyase promotes estrogen-stimulated uterine artery blood flow via glutathione homeostasis

“…E 2 can inactivate vascular smooth muscle inflammatory NFκB and TNFα signaling and promote flow-mediated vasodilation [ 3 , 4 , 10 , 11 ], but E 2 stimulation of blood flow can also paradoxically increase vascular oxidative stress through dramatic effects on cellular metabolism [ [12] , [13] , [14] ]. Therefore, we tested whether E 2 perturbs crucial elements of redox homeostasis in WT and CSE KO uterine and renal arteries.…”

“…In addition to its vasodilatory role, E 2 influences redox homeostasis. E 2 attenuates pro-oxidant NFκB and TNFα pathways [ 10 , 11 ], but paradoxically increases superoxide (O 2 − ) and hydrogen peroxide (H 2 O 2 ) production [ 12 , 13 ]. In some situations, E 2 replacement therapy can exacerbate post-menopausal cardiovascular disease [ 14 ].…”