Polycystic ovary syndrome and iron overload: biochemical link and underlying mechanisms with potential novel therapeutic avenues

Abstract

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder in women with components of significant genetic predisposition and possibly multiple, but not yet clearly defined, triggers. This disorder shares several clinical features with hemochromatosis, a genetically defined inheritable disorder of iron overload, which includes insulin resistance, increased adiposity, diabetes, fatty liver, infertility, and hyperandrogenism. A notable difference between the two disorders, however, is that the clinical symptoms in PCOS appear at much younger age whereas they become evident in hemochromatosis at a much later age. Nonetheless, noticeable accumulation of excess iron in the body is a common finding in both disorders even at adolescence. Hepcidin, the iron-regulatory hormone secreted by the liver, is reduced in both disorders and consequently increases intestinal iron absorption. Recent studies have shown that gut bacteria play a critical role in the control of iron absorption in the intestine. As dysbiosis is a common finding between PCOS and hemochromatosis, changes in bacterial composition in the gut may represent another cause for iron overload in both diseases via increased iron absorption. This raises the possibility that strategies to prevent accumulation of excess iron with iron chelators and/or probiotics may have therapeutic potential in the management of polycystic ovary syndrome.

Keywords: bacterial dysbiosis; hemochromatosis; hepcidin; iron overload; polycystic ovary syndrome; probiotics.

Figure 1. Absorption of dietary iron in the proximal intestine

Abbreviations: BBM, brush-border membrane; BLM, basolateral membrane; DcytB, duodenal cytochrome B; DMT1, divalent metal transporter 1 (also called SLC11A2); SLC, solute carrier.

Figure 2. Molecular mechanisms underlying the defective granulosa cell function and cell death induced by exposure to excess iron

Abbreviations: GPX4, glutathione peroxidase 4; iNOS, inducible nitric oxide synthase; NF-κB, nuclear factor κB; NRF2, nuclear factor erythroid 2-related factor 2.

Figure 3. Modulation of intestinal iron absorption and PCOS phenotype by colonic bacteria and their metabolites

Abbreviations: AhR, aryl hydrocarbon receptor; DcytB, duodenal cytochrome B; HIF-1α, hypoxia-inducible factor-1α; NRF2, nuclear factor erythroid 2-related factor 2; PCOS, polycystic ovary syndrome; SLC, solute carrier.