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In silico identification of target fetal protein(s) in the development of polycystic ovarian syndrome

Pawan Kumar1, Deepak1, Vandana Saini1, Annu1, Neelesh Yadav2, Ajit Kumar1.

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Polycystic ovarian syndrome (PCOS) is a multifactorial reproductive disorder mainly affecting ovulating women. Animal studies to date have identified hyperandrogenicity as one of the major causes of PCOS, while estrogen treatment temporarily decreases symptoms. Researchers believe that a high androgen level in a pregnant woman during pregnancy results PCOS-like symptoms in the newborn female baby, which are expressed later during reproductive age. The present work is an in silico analysis of the effect of hyperandrogenicity during fetal ovarian development. An alteration in the level of steroid hormone (androgen, estrogen, progesterone, and testosterone) reportedly affects gonadotropin-releasing hormone (GnRH) secretion and later on the development of ovarian follicles. Nuclear receptors such as DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on the X chromosome, gene 1) and steroidogenic factor-1 (SF-1) also affect the level of various sex hormones and ovary formation. Hence, the study was carried out to evaluate the effect of these steroid hormones on the promoter region of KISS1 gene and DAX1 gene apart from the effect of these steroid hormones on the binding of kisspeptin (involved in GnRH secretion) and SF1 protein (involved in DAX1 expression modulation). The study involved molecular modeling of promoter regions of KISS1 and DAX1 gene; kisspeptin and SF1 proteins, followed by molecular dockings studies of these promoter regions and proteins against steroid hormone (androgen, estrogen, progesterone, and testosterone), taken as ligand. The study reflected that both the androgen and progesterone show binding over the TATA box of the KISS1 gene, which can be inferred to possibly regulate its expression and affect GnRH secretion to imbalance hypothalamus-pituitary-gonadal axis. This alteration may further cause an abnormal luteinizing hormone: Follicle-stimulating hormone ratio that may result in abnormal steroidogenesis. The molecular docking studies of SF1 protein against DAX1 promoter region were observed to be better than binding when SF1 protein was complexed with studied steroid hormones. The observations lead to the inference that binding of steroid hormones with SF1 protein lowers the expression of DAX1 gene, as the former is essentially required for DAX1 gene expression, which may result in abnormal ovary development in a female fetus as well as abnormal sex steroids level. Thus, it may be concluded that over-secretion of sex steroids is likely to affect female fetus development and hypothalamus-pituitary-gonads axis to trigger PCOS-like symptoms.

Key words: Polycystic ovarian syndrome, Hyperandrogenism, Kisspeptin, DAX1, GnRH, SF1.

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