Involvement of Pitx2, a Homeodomain Transcription Factor, in Hypothyroidism Associated Reproductive Disorders

Abstract

Hypothyroid-associated reproductive disorders have now become a striking phenomenon worldwide but the molecular mechanism behind these disorders is not fully known. Pitx2 gene encodes homeodomain transcription factor, which regulates Plod2 gene in brain tissue, transactivates gonadotropin genes in pituitary and plays a substantial role in cell growth and proliferation in different tissues. Pitx2 binds to Plod2 promoter and activates this gene in rat ovary. In this report, we show that Pitx2’s expression is markedly reduced in hypothyroid ovary as well as in ovarian granulosa cells, which is recovered with T₃-supplementation both in vitro and in vivo conditions. Reduced Pitx2 expression could decrease Plod2 expression and hence facilitate ovarian ECM degradation. We have also observed similar pattern of expression of Pitx1 and -3 in hypothyroid and T₃-supplemented ovaries. The temporal expression of Pitx2 across the estrous cycle shows that it is expressed through all the 4 phases of the cycle and reaches its maximum in the proestrus phase suggesting its possible role in ovulation followed by luteinization. The present study reveals that the reduced Pitx2 expression in hypothyroid ovary could lead to ovarian dysfunction by modulating the Pitx2-Plod2 interaction, further study will be necessary to unravel the complete regulatory mechanism of Pitx2 in ovarian function.