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Molecular regulation of polycystic ovary syndrome: altered gene expression levels in mouse models pretreatment and post-treatment

Published online by Cambridge University Press:  03 November 2021

P. Tulay*
Affiliation:
Near East University, Faculty of Medicine, Department of Medical Genetics, Nicosia, Cyprus Near East University, DESAM Research Institute, Nicosia, Cyprus
T. Onal
Affiliation:
Manisa Celal Bayar University, Faculty Medicine, Department of Histology and Embryology, Manisa, Turkey
S. Vatansever
Affiliation:
Near East University, DESAM Research Institute, Nicosia, Cyprus Manisa Celal Bayar University, Faculty Medicine, Department of Histology and Embryology, Manisa, Turkey
*
Author for correspondence: Pinar Tulay. Near East University, Faculty of Medicine, Department of Medical Genetics, Near East University, DESAM Institute, Nicosia, Cyprus, Near East Boulevard, Nicosia North, Cyprus. E-mail: pinar.tulay@neu.edu.tr

Summary

Polycystic ovary syndrome (PCOS) is a complex disorder and genetic factors are believed to play a role. The main aim was to investigate expression levels of genes involved in PI3K/AKT signalling pathway pretreatment and post-treatment. Mouse models of PCOS were generated. Group one included control mice with no polycystic ovaries (n = 4), Group 2 included a PCOS mouse model (n = 8), Group 3 included PCOS mice treated with clomiphene citrate (n = 7) and Group 4 included PCOS mice treated with clomiphene citrate, metformin and pioglitazone (n = 8). Histochemical analyses were performed. Total RNA was extracted and cDNA was synthesized. Irs, Akt1 and Akt2, mTor and Pdpk1 gene expression levels were evaluated by RT-PCR amplification. In Group 1, cortex and medulla were evaluated as normal; in Group 2, ovarian cortex was composed of immature oocytes and cystic follicles with atretic follicles. In Groups 3 and 4, follicles were in the process of normal follicle differentiation. The expression levels of Akt1 and Pi3k were significantly different (P < 0.0001) between Groups 1 and 2. The significant differences in expression levels of Pi3k and Akt1 were also observed between the Group 1 and both Groups 3 and 4 (P < 0.0001). Furthermore, significant variations of the expression levels of mTor between Groups 1 and 4 were observed. The extrapolation of results of this study may imply that follicular development may be regulated by molecular pathways involving Pi3k, Akt1 and mTor expression. Therefore, genes in the PI3K/AKT pathway may have a direct regulatory role in the development of PCOS.

Type
Research Article
Copyright
© The Author(s), 2021. Published by Cambridge University Press

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References

Attia, GR, Rainey, WE and Carr, BR (2001). Metformin directly inhibits androgen production in human thecal cells. Fertil Steril 76, 517–24.CrossRefGoogle ScholarPubMed
Brewer, C, Acharya, S, Thake, F, Tang, T and Balen, A (2010). Effect of metformin taken in the “fresh” in vitro fertilization/intracytoplasmic sperm injection cycle upon subsequent frozen embryo replacement in women with polycystic ovary syndrome. Hum Fertil 13, 134–42.CrossRefGoogle ScholarPubMed
Brown, C, LaRocca, J, Pietruska, J, Ota, M, Anderson, L, Smith, SD, Weston, P, Rasoulpour, T and Hixon, ML (2010). Subfertility caused by altered follicular development and oocyte growth in female mice lacking PKB alpha/Akt1 . Biol Reprod 82, 246–56.CrossRefGoogle ScholarPubMed
Cho, H, Mu, J, Kim, JK, Thorvaldsen, JL, Chu, Q, Crenshaw, EB, Kaestner, KH, Bartolomei, MS, Shulman, GI and Birnbaum, MJ (2001). Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBbeta). Science 292(5522), 1728–31.CrossRefGoogle Scholar
De Leo, V, Musacchio, MC, Cappelli, V, Massaro, MG, Morgante, G and Petraglia, F(2016). Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol 14, 38.Google ScholarPubMed
Farini, D, La Sala, G, Tedesco, M and De Felici, M (2007). Chemoattractant action and molecular signaling pathways of Kit ligand on mouse primordial germ cells. Dev Biol 306, 572–83.CrossRefGoogle ScholarPubMed
Foretz, M, Guigas, B, Bertrand, L, Pollak, M and Viollet, B (2014). Metformin: From mechanisms of action to therapies. Cell Metab 20, 953–66.CrossRefGoogle ScholarPubMed
Gu, Y, Runyan, C, Shoemaker, A, Surani, MA and Wylie, C (2011). Membrane- bound steel factor maintains a high local concentration for mouse primordial germ cell motility, and defines the region of their migration. PLoS One 6, e25984.CrossRefGoogle ScholarPubMed
Jakubowicz, DJ, Seppälä, M, Jakubowicz, S, Rodriguez-Armas, O, Rivas-Santiago, A, Koistinen, H, Koistinen, R and Nestler, JE (2001). Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab 86, 1126–33.Google ScholarPubMed
Kauffman, AS, Thackray, VG, Ryan, GE, Tolson, KP, Glidewell-Kenney, CA, Semaan, SJ, Poling, MC, Iwata, N, Breen, KM, Duleba, AJ, Stener-Victorin, E, Shimasaki, S, Webster, NJ and Mellon, PL (2015). A novel letrozole model recapitulates both the reproductive and metabolic phenotypes of polycystic ovary syndrome in female mice. Biol Reprod 93, 69.CrossRefGoogle ScholarPubMed
Lee, SE, Sun, SC, Choi, HY, Uhm, SJ and Kim, NH (2012). mTOR is required for asymmetric division through small GTPases in mouse oocytes. Mol Reprod Dev 79, 356–66.CrossRefGoogle ScholarPubMed
Li, X, Guo, YR, Lin, JF, Feng, Y, Billig, H and Shao, R (2014). Combination of Diane-35 and metformin to treat early endometrial carcinoma in PCOS women with insulin resistance. J Cancer 5, 173–81.CrossRefGoogle ScholarPubMed
Makker, A, Goel, MM and Mahdi, AA(2014). PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: An update. J Mol Endocrinol 53, R10318.CrossRefGoogle ScholarPubMed
Manning, BD and Cantley, LC(2007). AKT/PKB signaling: navigating downstream. Cell 129, 1261–74.CrossRefGoogle ScholarPubMed
Markholt, S, Grøndahl, ML, Ernst, EH, Andersen, CY, Ernst, E and Lykke-Hartmann, K (2012). Global gene analysis of oocytes from early stages in human folliculogenesis shows high expression of novel genes in reproduction. Mol Hum Reprod 18, 96110.CrossRefGoogle ScholarPubMed
McLaughlin, M, Patrizio, P, Kayisli, U, Luk, J, Thomson, TC, Anderson, RA, Telfer, EE and Johnson, J (2011). mTOR kinase inhibition results in oocyte loss characterized by empty follicles in human ovarian cortical strips cultured in vitro . Fertil Steril 96, 1154–9.e1.CrossRefGoogle ScholarPubMed
Memmott, RM, Mercado, JR, Maier, CR, Kawabata, S, Fox, SD and Dennis, PA(2010). Metformin prevents tobacco carcinogen–induced lung tumorigenesis. Cancer Prev Res 3, 1066–76.CrossRefGoogle ScholarPubMed
Moran, LJ, Hutchison, SK, Norman, RJ and Teede, HJ (2011). Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2, CD007506.Google Scholar
Naderpoor, N, Shorakae, S, de Courten, B, Misso, ML, Moran, LJ and Teede, HJ (2015). Metformin and lifestyle modification in polycystic ovary syndrome: Systematic review and meta-analysis. Hum Reprod Update 21, 560–74.CrossRefGoogle ScholarPubMed
Nestler, JE (2008). Metformin for the treatment of the polycystic ovary syndrome. New Engl J Med 358, 4754.CrossRefGoogle ScholarPubMed
Palomba, S, Russo, T, Orio, F, Falbo, A, Manguso, F, Cascella, T, Tolino, A, Carmina, E, Colao, A and Zullo, F (2006). Uterine effects of metformin administration in anovulatory women with polycystic ovary syndrome. Hum Reprod 21, 457–65.CrossRefGoogle ScholarPubMed
Pernicova, I and Korbonits, M (2014). Metformin–mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 10, 143–56.CrossRefGoogle ScholarPubMed
Reddy, P, Liu, L, Adhikari, D, Jagarlamudi, K, Rajareddy, S, Shen, Y, Du, C, Tang, W, Hämäläinen, T, Peng, SL, Lan, ZJ, Cooney, AJ, Huhtaniemi, I and Liu, K (2008). Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science 319(5863), 611–3.CrossRefGoogle ScholarPubMed
Reddy, P, Adhikari, D, Zheng, W, Liang, S, Hämäläinen, T, Tohonen, V, Ogawa, W, Noda, T, Volarevic, S, Huhtaniemi, I and Liu, K (2009). PDK1 signaling in oocytes controls reproductive aging and lifespan by manipulating the survival of primordial follicles. Hum Mol Genet 18, 2813–24.CrossRefGoogle ScholarPubMed
Schultze, SM, Jensen, J, Hemmings, BA, Tschopp, O and Niessen, M (2011). Promiscuous affairs of PKB/AKT isoforms in metabolism. Arch Physiol Biochem 117, 70–7.CrossRefGoogle ScholarPubMed
Sivalingam, VN, Myers, J, Nicholas, S, Balen, AH and Crosbie, EJ(2014). Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications. Hum Reprod Update 20, 853–68.CrossRefGoogle ScholarPubMed
Tulay, P, Naja, RP, Cascales-Roman, O, Doshi, A, Serhal, P and SenGupta, SB (2015). Investigation of microRNA expression and DNA repair gene transcripts in human oocytes and blastocysts. J Assist Reprod Genet 32, 1757–64.CrossRefGoogle ScholarPubMed
Umayal, B, Chandrasekharan, NV, Wijesundera, WSS and Wijeyaratne, CN (2018) Polycystic ovary syndrome: genetic contributions from the hypothalamic-pituitary-gonadal axis. Int Arch Endocrinol Clin Res 4, 013.Google Scholar
Untergasser, A, Cutcutache, I, Koressaar, T, Ye, J, Faircloth, BC, Remm, M and Rozen, SG (2012). Primer3—new capabilities and interfaces. Nucl Acid Res 40, e115.CrossRefGoogle ScholarPubMed
Vanhaesebroeck, B, Guillermet-Guibert, J, Graupera, M and Bilanges, B (2010). The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 11, 329–41.CrossRefGoogle ScholarPubMed
Wullschleger, S, Loewith, R and Hall, MN (2006). TOR signaling in growth and metabolism. Cell 124, 471–84.CrossRefGoogle ScholarPubMed