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Bakhi, E. S., Roodbari, N. H., Anvari, M., & Tehrani, F. R. (2023). Prenatal kisspeptin antagonist exposure prevents polycystic ovary syndrome development in prenatally-androgenized rats in adulthood: An experimental study. International Journal of Reproductive BioMedicine (IJRM), 21(2), 99–110. https://doi.org/10.18502/ijrm.v21i2.12801
https://doi.org/10.18502/ijrm.v21i2.12801
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authors
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Elahe Sadeghian Bakhi
Elahe Sadeghian Bakhi
Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran.
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Nasim Hayati Roodbari
Nasim Hayati Roodbari
Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran.
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Morteza Anvari
Morteza Anvari
Research and Clinical Center for Infertility, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Fahimeh Ramezani Tehrani
Fahimeh Ramezani Tehrani
Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Published Date
- Mar 9, 2023
Prenatal kisspeptin antagonist exposure prevents polycystic ovary syndrome development in prenatally-androgenized rats in adulthood: An experimental study
Abstract
Background: Increased levels of kisspeptin are associated with hypothalamus-pituitary- ovary axis dysfunction. It may lead to the development of polycystic ovary syndrome (PCOS).
Objective: We aimed to investigate the effect of prenatal kisspeptin antagonist exposure on the development of PCOS in prenatally androgenized rats in adulthood.
Materials and Methods: In this experimental study, pregnant rats were injected with free testosterone (T, 5 mg/day) or T+P271 (kisspeptin antagonist) on the 20th day of the pregnancy period (n = 5 in each group), while rats in the control group received solvent. Female offspring were examined in terms of anogenital distance (AGD), anovaginal distance (AVD), vaginal opening, serum total testosterone (TT) levels, ovarian follicles, and the regularity of estrous cycles in adulthood. AGD and AVD were measured using a vernier caliper. TT levels were measured using the enzyme-linked immunosorbent assay method. Ovaries were fixed in 10% formalin, tissue processing was done by a standard protocol, and then ovaries embedded in paraffin. 5 μmthickness ovarian sections mounted on a glass slide, deparaffinized, and stained using Harris’s Hematoxylin and Eosin Y.
Results: AGD, AVD (p < 0.001), TT levels (p = 0.02), and the numbers of preantral and antral follicles (p < 0.001) in the ovaries were significantly decreased in prenatally TP271- exposed rats compared to prenatally T-exposed rats. The age of vaginal opening was early in T-P271-exposed rats compared to prenatally T-exposed rats (p < 0.001). The number of corpora lutea was significantly increased in T-P271-exposed rats (p < 0.001). No cystic follicles were observed in the ovaries of prenatally T-P271-exposed rats. Prenatally T-P271-exposed rats had regular estrous cycles compared to prenatally T-exposed rats.
Conclusion: Prenatal exposure to kisspeptin antagonist can prevent PCOS development in prenatally androgenized rats in adulthood.
Key words: Androgen, Kisspeptin antagonist, Polycystic ovary syndrome, Rat.
References
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[15] Zeydabadi Nejad S, Ramezani Tehrani F, Zadeh-Vakili A. The role of kisspeptin in female reproduction. Int J Endocrinol Metab 2017; 15: e44337.
[16] Wen L, Lin W, Li Q, Chen G, Wen J. Effect of sleeve gastrectomy on kisspeptin expression in the hypothalamus of rats with polycystic ovary syndrome. Obesity 2020; 28: 1117–1128.
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[18] Nandankar N, Negron AL, Wolfe AM, Levine JE, Radovick S. Mice with targeted deletion of ARC kisspeptin exhibit immature gametogenesis and impaired fertility. J Endocr Soc 2021; 5 (Suppl.): A543–A544.
[19] Kazemi M, McBreairty LE, Chizen DR, Pierson RA, Chilibeck PD, Zello GA. A comparison of a pulse-based diet and the therapeutic lifestyle changes diet in combination with exercise and health counselling on the cardio-metabolic risk profile in women with polycystic ovary syndrome: A randomized controlled trial. Nutrients 2018; 10: 1387.
[20] Ramezani Tehrani F, Noroozzadeh M, Zahediasl S, Piryaei A, Azizi F. Introducing a rat model of prenatal androgeninduced polycystic ovary syndrome in adulthood. Exp Physiol 2014; 99: 792–801.
[21] Sareh Z, Azita Zadeh V, Mahsa N, Razieh Bidhendi Y, Asghar G. Prenatal exposure of kisspeptin antagonist on the gonadotropin-releasing hormone (GnRH) expression in rat model of polycystic ovary syndrome. J Fertil In vitro IVF Worldw Reprod Med Genet Stem Cell Biol 2017; 5: 22– 23.
[22] Rostami Dovom M, Noroozzadeh M, Mosaffa N, Piryaei A, Zadeh-Vakili A, Aabdollahifar M-A, et al. Maternal exposure to D-galactose reduces ovarian reserve in female rat offspring later in life. Int J Endocrinol Metab 2022; 20: e123206.
[23] Paccola CC, Resende CG, Stumpp T, Miraglia SM, Cipriano I. The rat estrous cycle revisited: A quantitative and qualitative analysis. Anim Reprod 2013; 10: 677–683.
[24] Baali A, Belhsen OK, Ouazzani KC, Amenzoui K, Yahyaoui A. Age, growth and ovarian histology of Sardinella aurita (Valenciennes, 1847) in the south of Atlantic Moroccan coast. Turk J Fish Aquat Sci 2021; 21: 191–204.
[25] Filippou P, Homburg R. Is foetal hyperexposure to androgens a cause of PCOS? Hum Reprod Update 2017; 23: 421–432.
[26] Cernea M, Padmanabhan V, Goodman RL, Coolen LM, Lehman MN. Prenatal testosterone treatment leads to changes in the morphology of KNDy neurons, their inputs, and projections to GnRH cells in female sheep. Endocrinology 2015; 156: 3277–3291.
[27] Moore AM, Prescott M, Marshall CJ, Yip SH, Campbell RE. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. Proc Nati Acad Sci USA 2015; 112: 596–601.
[28] Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev 2016; 37: 467–520.
[29] Roland AV, Moenter SM. Reproductive neuroendocrine dysfunction in polycystic ovary syndrome: Insight from animal models. Front Neuroendocrinol 2014; 35: 494–511.
[30] Kauffman AS, Thackray VG, Ryan GE, Tolson KP, Glidewell- Kenney CA, Semaan SJ, et al. A novel letrozole model recapitulates both the reproductive and metabolic phenotypes of polycystic ovary syndrome in female mice. Biol Reprod 2015; 93: 69.
[31] Cardoso RC, Puttabyatappa M, Padmanabhan V. Steroidogenic versus metabolic programming of reproductive neuroendocrine, ovarian and metabolic dysfunctions. Neuroendocrinology 2015; 102: 226–237.
[32] Joksimovic Jovic J, Sretenovic J, Jovic N, Rudic J, Zivkovic V, Srejovic I, et al. Cardiovascular properties of the androgen-induced PCOS model in rats: The role of oxidative stress. Oxid Med Cell Longev 2021; 2021: 8862878.
[33] Kumariya S, Ubba V, Jha RK, Gayen JR. Autophagy in ovary and polycystic ovary syndrome: Role, dispute and future perspective. Autophagy 2021; 17: 2706–2733.
[34] Shah AB, Nivar I, Speelman DL. Elevated androstenedione in young adult but not early adolescent prenatally androgenized female rats. PloS One 2018; 13: e0196862.
[35] Szeliga A, Rudnicka E, Maciejewska-Jeske M, Kucharski M, Kostrzak A, Hajbos M, et al. Neuroendocrine determinants of polycystic ovary syndrome. Int J Environ Res Public Health 2022; 19: 3089.
[36] Dean A, Sharpe RM. Anogenital distance or digit length ratio as measures of fetal androgen exposure: Relationship to male reproductive development and its disorders. J Clin Endocrinol Metab 2013; 98: 2230–2238.
[37] Jain VG, Singal AK. Shorter anogenital distance correlates with undescended testis: A detailed genital anthropometric analysis in human newborns. Hum Reprod 2013; 28: 2343–2349.
[38] Kalamon N, Błaszczyk K, Szlaga A, Billert M, Skrzypski M, Pawlicki P, et al. Levels of the neuropeptide phoenixin- 14 and its receptor GRP173 in the hypothalamus, ovary and periovarian adipose tissue in rat model of polycystic ovary syndrome. Biochem Biophys Res Commun 2020; 528: 628–635.
[39] Ma R, Zou Y, Wang W, Zheng Q, Feng Y, Dong H, et al. Obesity management in polycystic ovary syndrome: Disparity in knowledge between obstetrician-gynecologists and reproductive endocrinologists in China. BMC Endocr Disord 2021; 21: 182.
[40] Zeng X, Xie Y-J, Liu Y-T, Long S-L, Mo Z-C. Polycystic ovarian syndrome: Correlation between hyperandrogenism, insulin resistance and obesity. Clin Chim Acta 2020; 502: 214–221.
[41] Kanasaki H, Tumurbaatar T, Oride A, Tumurgan Z, Okada H, Hara T, et al. Role of RFRP-3 in the regulation of kiss- 1 gene expression in the AVPV hypothalamic cell model mHypoA-50. Reprod Sci 2019; 26: 1249–1255.
[42] Osuka S, Iwase A, Nakahara T, Kondo M, Saito A, Nakamura T, et al. Kisspeptin in the hypothalamus of 2 rat models of polycystic ovary syndrome. Endocrinology 2017; 158: 367–377.
[43] Szeliga A, Podfigurna A, Bala G, Meczekalski B. Kisspeptin and neurokinin B analogs use in gynecological endocrinology: Where do we stand? J Endocrinol Invest 2020; 43: 555–561.
[2] Zhai Y, Pang Y. Systemic and ovarian inflammation in women with polycystic ovary syndrome. J Reprod Immunol 2022; 151: 103628.
[3] Deswal R, Nanda S, Dang AS. Association of luteinizing hormone and LH receptor gene polymorphism with susceptibility of polycystic ovary syndrome. Syst Biol Reprod Med 2019; 65: 400–408.
[4] Barber TM, Franks S. Obesity and polycystic ovary syndrome. Clin Endocrinol 2021; 95: 531–541.
[5] Abruzzese GA, Silva AF, Velazquez ME, Ferrer MJ, Motta AB. Hyperandrogenism and Polycystic ovary syndrome: Effects in pregnancy and offspring development. WIREs Mech Dis 2022; 14: e1558.
[6] Dumesic DA, Hoyos LR, Chazenbalk GD, Naik R, Padmanabhan V, Abbott DH. Mechanisms of intergenerational transmission of polycystic ovary syndrome. Reproduction 2020; 159: R1–R13.
[7] Cardoso RC, Padmanabhan V. Developmental programming of PCOS traits: Insights from the sheep. Med Sci 2019; 7: 79.
[8] Rodriguez Paris V, Bertoldo MJ. The mechanism of androgen actions in PCOS etiology. Med Sci 2019; 7: 89.
[9] Umayal B, Jayakody SN, Chandrasekharan NV, Wijesundera WS, Wijeyaratne CN. Polycystic ovary syndrome (PCOS) and kisspeptin-A Sri Lankan study. J Postgrad Med 2019; 65: 18–23.
[10] Cao Y, Li Z, Jiang W, Ling Y, Kuang H. Reproductive functions of Kisspeptin/KISS1R systems in the periphery. Reprod Biol Endocrinol 2019; 17: 1–9.
[11] Wang T, Han S, Tian W, Zhao M, Zhang H. Effects of kisspeptin on pathogenesis and energy metabolism in polycystic ovarian syndrome (PCOS). Gynecol Endocrinol 2019; 35: 807–810.
[12] Ibrahim RO, Omer SH, Fattah CN. The correlation between hormonal disturbance in PCOS women and serum level of kisspeptin. Int J Endocrinol 2020; 2020: 6237141.
[13] Albalawi FS, Daghestani MH, Daghestani MH, Eldali A, Warsy AS. rs4889 polymorphism in KISS1 gene, its effect on polycystic ovary syndrome development and anthropometric and hormonal parameters in Saudi women. J Biomed Sci 2018; 25: 50.
[14] Matsuzaki T, Tungalagsuvd A, Iwasa T, Munkhzaya M, Yanagihara R, Tokui T, et al. Kisspeptin mRNA expression is increased in the posterior hypothalamus in the rat model of polycystic ovary syndrome. Endocr J 2017; 64: 7–14.
[15] Zeydabadi Nejad S, Ramezani Tehrani F, Zadeh-Vakili A. The role of kisspeptin in female reproduction. Int J Endocrinol Metab 2017; 15: e44337.
[16] Wen L, Lin W, Li Q, Chen G, Wen J. Effect of sleeve gastrectomy on kisspeptin expression in the hypothalamus of rats with polycystic ovary syndrome. Obesity 2020; 28: 1117–1128.
[17] Esparza LA, Schafer D, Ho BS, Thackray VG, Kauffman AS. Hyperactive LH pulses and elevated kisspeptin and NKB gene expression in the arcuate nucleus of a PCOS mouse model. Endocrinology 2020; 161: bqaa 018.
[18] Nandankar N, Negron AL, Wolfe AM, Levine JE, Radovick S. Mice with targeted deletion of ARC kisspeptin exhibit immature gametogenesis and impaired fertility. J Endocr Soc 2021; 5 (Suppl.): A543–A544.
[19] Kazemi M, McBreairty LE, Chizen DR, Pierson RA, Chilibeck PD, Zello GA. A comparison of a pulse-based diet and the therapeutic lifestyle changes diet in combination with exercise and health counselling on the cardio-metabolic risk profile in women with polycystic ovary syndrome: A randomized controlled trial. Nutrients 2018; 10: 1387.
[20] Ramezani Tehrani F, Noroozzadeh M, Zahediasl S, Piryaei A, Azizi F. Introducing a rat model of prenatal androgeninduced polycystic ovary syndrome in adulthood. Exp Physiol 2014; 99: 792–801.
[21] Sareh Z, Azita Zadeh V, Mahsa N, Razieh Bidhendi Y, Asghar G. Prenatal exposure of kisspeptin antagonist on the gonadotropin-releasing hormone (GnRH) expression in rat model of polycystic ovary syndrome. J Fertil In vitro IVF Worldw Reprod Med Genet Stem Cell Biol 2017; 5: 22– 23.
[22] Rostami Dovom M, Noroozzadeh M, Mosaffa N, Piryaei A, Zadeh-Vakili A, Aabdollahifar M-A, et al. Maternal exposure to D-galactose reduces ovarian reserve in female rat offspring later in life. Int J Endocrinol Metab 2022; 20: e123206.
[23] Paccola CC, Resende CG, Stumpp T, Miraglia SM, Cipriano I. The rat estrous cycle revisited: A quantitative and qualitative analysis. Anim Reprod 2013; 10: 677–683.
[24] Baali A, Belhsen OK, Ouazzani KC, Amenzoui K, Yahyaoui A. Age, growth and ovarian histology of Sardinella aurita (Valenciennes, 1847) in the south of Atlantic Moroccan coast. Turk J Fish Aquat Sci 2021; 21: 191–204.
[25] Filippou P, Homburg R. Is foetal hyperexposure to androgens a cause of PCOS? Hum Reprod Update 2017; 23: 421–432.
[26] Cernea M, Padmanabhan V, Goodman RL, Coolen LM, Lehman MN. Prenatal testosterone treatment leads to changes in the morphology of KNDy neurons, their inputs, and projections to GnRH cells in female sheep. Endocrinology 2015; 156: 3277–3291.
[27] Moore AM, Prescott M, Marshall CJ, Yip SH, Campbell RE. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. Proc Nati Acad Sci USA 2015; 112: 596–601.
[28] Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev 2016; 37: 467–520.
[29] Roland AV, Moenter SM. Reproductive neuroendocrine dysfunction in polycystic ovary syndrome: Insight from animal models. Front Neuroendocrinol 2014; 35: 494–511.
[30] Kauffman AS, Thackray VG, Ryan GE, Tolson KP, Glidewell- Kenney CA, Semaan SJ, et al. A novel letrozole model recapitulates both the reproductive and metabolic phenotypes of polycystic ovary syndrome in female mice. Biol Reprod 2015; 93: 69.
[31] Cardoso RC, Puttabyatappa M, Padmanabhan V. Steroidogenic versus metabolic programming of reproductive neuroendocrine, ovarian and metabolic dysfunctions. Neuroendocrinology 2015; 102: 226–237.
[32] Joksimovic Jovic J, Sretenovic J, Jovic N, Rudic J, Zivkovic V, Srejovic I, et al. Cardiovascular properties of the androgen-induced PCOS model in rats: The role of oxidative stress. Oxid Med Cell Longev 2021; 2021: 8862878.
[33] Kumariya S, Ubba V, Jha RK, Gayen JR. Autophagy in ovary and polycystic ovary syndrome: Role, dispute and future perspective. Autophagy 2021; 17: 2706–2733.
[34] Shah AB, Nivar I, Speelman DL. Elevated androstenedione in young adult but not early adolescent prenatally androgenized female rats. PloS One 2018; 13: e0196862.
[35] Szeliga A, Rudnicka E, Maciejewska-Jeske M, Kucharski M, Kostrzak A, Hajbos M, et al. Neuroendocrine determinants of polycystic ovary syndrome. Int J Environ Res Public Health 2022; 19: 3089.
[36] Dean A, Sharpe RM. Anogenital distance or digit length ratio as measures of fetal androgen exposure: Relationship to male reproductive development and its disorders. J Clin Endocrinol Metab 2013; 98: 2230–2238.
[37] Jain VG, Singal AK. Shorter anogenital distance correlates with undescended testis: A detailed genital anthropometric analysis in human newborns. Hum Reprod 2013; 28: 2343–2349.
[38] Kalamon N, Błaszczyk K, Szlaga A, Billert M, Skrzypski M, Pawlicki P, et al. Levels of the neuropeptide phoenixin- 14 and its receptor GRP173 in the hypothalamus, ovary and periovarian adipose tissue in rat model of polycystic ovary syndrome. Biochem Biophys Res Commun 2020; 528: 628–635.
[39] Ma R, Zou Y, Wang W, Zheng Q, Feng Y, Dong H, et al. Obesity management in polycystic ovary syndrome: Disparity in knowledge between obstetrician-gynecologists and reproductive endocrinologists in China. BMC Endocr Disord 2021; 21: 182.
[40] Zeng X, Xie Y-J, Liu Y-T, Long S-L, Mo Z-C. Polycystic ovarian syndrome: Correlation between hyperandrogenism, insulin resistance and obesity. Clin Chim Acta 2020; 502: 214–221.
[41] Kanasaki H, Tumurbaatar T, Oride A, Tumurgan Z, Okada H, Hara T, et al. Role of RFRP-3 in the regulation of kiss- 1 gene expression in the AVPV hypothalamic cell model mHypoA-50. Reprod Sci 2019; 26: 1249–1255.
[42] Osuka S, Iwase A, Nakahara T, Kondo M, Saito A, Nakamura T, et al. Kisspeptin in the hypothalamus of 2 rat models of polycystic ovary syndrome. Endocrinology 2017; 158: 367–377.
[43] Szeliga A, Podfigurna A, Bala G, Meczekalski B. Kisspeptin and neurokinin B analogs use in gynecological endocrinology: Where do we stand? J Endocrinol Invest 2020; 43: 555–561.