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The effects of AdipoRon on cytochrome P450-related gene expression, acute steroidogenic regulatory protein, and structure of ovary in polycystic ovary syndrome model

  • Reproductive physiology and disease
  • Published:
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Abstract

Purpose

One of the most common causes of infertility in adult women is polycystic ovary syndrome (PCOS) which has been identified with symptoms such as chronic hyperandrogenism, anovulation, and polycystic ovaries. Adiponectin modulates steroidogenesis and the expression of ovulation-related genes. Herein, we assessed the effect of AdipoRon (adiponectin agonist) in the PCOS model mice.

Methods

The PCOS model was induced with letrozole in the adult female mice and the animals received intraperitoneal injection of AdipoRon (5 mg/kg) for 10 days. Expression of CYP11A, CYP17A, and CYP19A genes, StAR protein, and histomorphology of the ovary were evaluated using real-time RT-PCR, western blotting, and histochemistry methods, respectively.

Results

Although administration of letrozole caused an increase in the expression of CYP11A, CYP17A, and StAR and a decrease in the CYP19A1 expression, injection of AdipoRon reversed these changes. Moreover, AdipoRon treatment resulted in an improvement of folliculogenesis and a reduction of cysts compared to the letrozole-treated mice.

Conclusion

It is likely that AdipoRon has protective effects on the PCOS through modulation of cytochrome P450-related genes and steroidogenesis but needs further study to be sure.

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Data availability

The data presented in this study are available on request from the corresponding author.

References

  1. Franks S. Polycystic ovary syndrome. N Engl J Med. 1995;333(13):853–61.

    Article  CAS  PubMed  Google Scholar 

  2. Himelein MJ, Thatcher SS. Polycystic ovary syndrome and mental health: a review. Obstet Gynecol Surv. 2006;61(11):723–32.

    Article  PubMed  Google Scholar 

  3. Goodarzi MO, et al. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011;7(4):219–31.

    Article  CAS  PubMed  Google Scholar 

  4. Rodriguez Paris V, Bertoldo MJ. The mechanism of androgen actions in PCOS etiology. Med Sci. 2019;7(9):89.

    Google Scholar 

  5. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33(6):981–1030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dewailly D, et al. Role of anti-Müllerian hormone in the pathogenesis of polycystic ovary syndrome. Front Endocrinol. 2020;11:641.

    Article  Google Scholar 

  7. Zeng X, et al. Polycystic ovarian syndrome: correlation between hyperandrogenism, insulin resistance and obesity. Clin Chim Acta. 2020;502:214–21.

    Article  CAS  PubMed  Google Scholar 

  8. Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev. 2016;37(5):467–520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wawrzkiewicz-Jałowiecka A, et al. In search of new therapeutics—molecular aspects of the PCOS pathophysiology: genetics, hormones, metabolism and beyond. Int J Mol Sci. 2020;21(19):7054.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Aghaie F, et al. The effects of exercise on expression of CYP19 and StAR mRNA in steroid-induced polycystic ovaries of female rats. Int J Fertil Steril. 2018;11(4):298.

    CAS  PubMed  Google Scholar 

  11. Esfahani M, Shabab N, Saidijam M. AdipoRon may be benefit for atherosclerosis prevention Iran. J Basic Med Sci. 2017;20(2):107.

    Google Scholar 

  12. Okada-Iwabu M, et al. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature. 2013;503(7477):493–9.

    Article  CAS  PubMed  Google Scholar 

  13. Galluzzo A, Amato MC, Giordano C. Insulin resistance and polycystic ovary syndrome. Nutr Metab Cardiovasc Dis. 2008;18(7):511–8.

    Article  PubMed  Google Scholar 

  14. Maliqueo M, et al. Continuous administration of a P450 aromatase inhibitor induces polycystic ovary syndrome with a metabolic and endocrine phenotype in female rats at adult age. Endocrinology. 2013;154(1):434–45.

    Article  CAS  PubMed  Google Scholar 

  15. Kafali H, et al. Letrozole-induced polycystic ovaries in the rat: a new model for cystic ovarian disease. Arch Med Res. 2004;35(2):103–8.

    Article  CAS  PubMed  Google Scholar 

  16. Monsef F, et al. Effects of adipose-derived stromal vascular fraction on asherman syndrome model. Acta Histochem. 2020;122(5):151556.

    Article  CAS  PubMed  Google Scholar 

  17. GohariTaban S, et al. Abnormal expressions of ADAMTS-1, ADAMTS-9 and progesterone receptors are associated with lower oocyte maturation in women with polycystic ovary syndrome. Arch Gynecol Obstet. 2019;299(1):277–86.

    Article  CAS  PubMed  Google Scholar 

  18. Azouz AA, et al. Modulation of steroidogenesis by Actaea racemosa and vitamin C combination, in letrozole induced polycystic ovarian syndrome rat model: promising activity without the risk of hepatic adverse effect. Chin Med. 2021;16(1):1–17.

    Article  Google Scholar 

  19. Abtahi-Eivari SH, et al. The effect of Galega officinalis on hormonal and metabolic profile in a rat model of polycystic ovary syndrome. Int J Women's Health Reprod Sci. 2018;6(3):276–82.

    CAS  Google Scholar 

  20. Brennan K, Huang A, Azziz R. Dehydroepiandrosterone sulfate and insulin resistance in patients with polycystic ovary syndrome. Fertil Steril. 2009;91(5):1848–52.

    Article  CAS  PubMed  Google Scholar 

  21. Goodarzi MO, Carmina E, Azziz R. DHEA, DHEAS and PCOS. J Steroid Biochem Mol Biol. 2015;145:213–25.

    Article  CAS  PubMed  Google Scholar 

  22. Guo C, et al. Transcriptional regulation of human CYP11A1 in gonads and adrenals. J Biomed Sci. 2007;14(4):509–15.

    Article  CAS  PubMed  Google Scholar 

  23. Franks S, et al. The genetic basis of polycystic ovary syndrome. Hum Reprod. 1997;12(12):2641–8.

    Article  CAS  PubMed  Google Scholar 

  24. Qin K-N, Rosenfield RL. Role of cytochrome P450c17 in polycystic ovary syndrome. Mol Cell Endocrinol. 1998;145(1-2):111–21.

    Article  CAS  PubMed  Google Scholar 

  25. Shen W, et al. Common polymorphisms in the CYP1A1 and CYP11A1 genes and polycystic ovary syndrome risk: a meta-analysis and meta-regression. Arch Gynecol Obstet. 2014;289(1):107–18.

    Article  CAS  PubMed  Google Scholar 

  26. Xu X, et al. The single nucleotide polymorphism rs743572 of CYP17A1 shows significant association with polycystic ovary syndrome: a meta-analysis. Reprod Biomed Online. 2021;43(5):941–51.

    Article  CAS  PubMed  Google Scholar 

  27. Munawar Lone N, et al. Association of the CYP17 and CYP19 gene polymorphisms in women with polycystic ovary syndrome from Punjab, Pakistan. Gynecol Endocrinol. 2021;37(5):456–61.

    Article  CAS  PubMed  Google Scholar 

  28. Marshall JC, Eagleson CA. Neuroendocrine aspects of polycystic ovary syndrome. Endocrinol Metab Clin N Am. 1999;28(2):295–324.

    Article  CAS  Google Scholar 

  29. Wickenheisser JK, et al. Differential activity of the cytochrome P450 17α-hydroxylase and steroidogenic acute regulatory protein gene promoters in normal and polycystic ovary syndrome theca cells. J Clin Endocrinol Metabol. 2000;85(6):2304–11.

    CAS  Google Scholar 

  30. Wu S, et al. Obesity-induced infertility and hyperandrogenism are corrected by deletion of the insulin receptor in the ovarian theca cell. Diabetes. 2014;63(4):1270–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jakimiuk AJ, et al. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries. J Clin Endocrinol Metabol. 2001;86(3):1318–23.

    CAS  Google Scholar 

  32. Kosova G, Urbanek M. Genetics of the polycystic ovary syndrome. Mol Cell Endocrinol. 2013;373(1-2):29–38.

    Article  CAS  PubMed  Google Scholar 

  33. Panghiyangani R, et al. CYP19A1 gene expression in patients with polycystic ovarian syndrome. J Hum Reprod Sci. 2020;13(2):100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Erickson GF. Normal regulation of ovarian androgen production. in Seminars in reproductive endocrinology. Copyright© 1993 by Thieme Medical Publishers, Inc; 1993.

    Google Scholar 

  35. Guet P, et al. Aromatase activity of human granulosa cells in vitro: effects of gonadotrophins and follicular fluid. Hum Reprod. 1999;14(5):1182–9.

    Article  CAS  PubMed  Google Scholar 

  36. Kirilovas D, et al. Granulosa cell aromatase enzyme activity: effects of follicular fluid from patients with polycystic ovary syndrome, using aromatase conversion and [11C] vorozole-binding assays. Gynecol Endocrinol. 2006;22(12):685–91.

    Article  CAS  PubMed  Google Scholar 

  37. Hogg K, et al. Enhanced thecal androgen production is prenatally programmed in an ovine model of polycystic ovary syndrome. Endocrinology. 2012;153(1):450–61.

    Article  CAS  PubMed  Google Scholar 

  38. Sanders SL, Stouffer RL. Localization of steroidogenic enzymes in macaque luteal tissue during the menstrual cycle and simulated early pregnancy: immunohistochemical evidence supporting the two-cell model for estrogen production in the primate corpus luteum. Biol Reprod. 1997;56(5):1077–87.

    Article  CAS  PubMed  Google Scholar 

  39. Kahsar-Miller MD, et al. Steroidogenic acute regulatory protein (StAR) in the ovaries of healthy women and those with polycystic ovary syndrome. Am J Obstet Gynecol. 2001;185(6):1381–7.

    Article  CAS  PubMed  Google Scholar 

  40. Waterman MR. A rising StAR: an essential role in cholesterol transport. Science. 1995;267(5205):1780–2.

    Article  CAS  PubMed  Google Scholar 

  41. Smolinska N, et al. Effect of adiponectin on the steroidogenic acute regulatory protein, P450 side chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase gene expression, progesterone and androstenedione production by the porcine uterus during early pregnancy. J Physiol Pharmacol. 2016;67:443–56.

    CAS  PubMed  Google Scholar 

  42. Comim FV, et al. Disorders of follicle development and steroidogenesis in ovaries of androgenised foetal sheep. J Endocrinol. 2015;225(1):39–46.

    Article  CAS  PubMed  Google Scholar 

  43. Li P, et al. Expression of adiponectin receptors in mouse adrenal glands and the adrenocortical Y-1 cell line: adiponectin regulates steroidogenesis. Biochem Biophys Res Commun. 2009;390(4):1208–13.

    Article  CAS  PubMed  Google Scholar 

  44. Comim FV, et al. Effects of adiponectin including reduction of androstenedione secretion and ovarian oxidative stress parameters in vivo. PLoS One. 2016;11(5):e0154453.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Sepilian V, Nagamani M. Adiponectin levels in women with polycystic ovary syndrome and severe insulin resistance. J Soc Gynecol Investig. 2005;12(2):129–34.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by the Hamadan University of Medical Sciences (9906254309).

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Correspondence to Tayebe Artimani.

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Hazrati, P., Ramezani, M., Ahmadimoghaddam, D. et al. The effects of AdipoRon on cytochrome P450-related gene expression, acute steroidogenic regulatory protein, and structure of ovary in polycystic ovary syndrome model. J Assist Reprod Genet 40, 2453–2461 (2023). https://doi.org/10.1007/s10815-023-02900-1

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  • DOI: https://doi.org/10.1007/s10815-023-02900-1

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