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Hestiantoro, A., Al Maghfira, R. N., Fathmasari, R., Febri, R. R., Joyo, E. O., Muharam, R., Pratama, G., & Bowolaksono, A. (2024). Altered expression of kisspeptin, dynorphin, and related neuropeptides in polycystic ovary syndrome: A cross-sectional study. International Journal of Reproductive BioMedicine (IJRM), 22(5), 395–404. https://doi.org/10.18502/ijrm.v22i5.16440
https://doi.org/10.18502/ijrm.v22i5.16440
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Andon Hestiantoro
Andon Hestiantoro
Reproductive Immunoendocrinology Division, Department of Obstetrics and Gynecology, Faculty of Medicine University of Indonesia/Cipto Mangunkusumo General Hospital, Jakarta, Indonesia.
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Rachellina Noor Al Maghfira
Rachellina Noor Al Maghfira
Department of Biology, Faculty of Mathematics and Natural Sciences, University of Indonesia, Depok, Indonesia.
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Ratna Fathmasari
Ratna Fathmasari
Department of Biology, Faculty of Mathematics and Natural Sciences, University of Indonesia, Depok, Indonesia.
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Ririn Rahmala Febri
Ririn Rahmala Febri
Cluster of Human Reproduction, Fertility and Family Planning, Indonesia Medical Education and Research Institute, University of Indonesia, Jakarta, Indonesia.
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Ericko Ongko Joyo
Ericko Ongko Joyo
Faculty of Medicine University of Indonesia, Jakarta, Indonesia.
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Raden Muharam
Raden Muharam
Reproductive Immunoendocrinology Division, Department of Obstetrics and Gynecology, Faculty of Medicine University of Indonesia/Cipto Mangunkusumo General Hospital, Jakarta, Indonesia.
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Gita Pratama
Gita Pratama
Reproductive Immunoendocrinology Division, Department of Obstetrics and Gynecology, Faculty of Medicine University of Indonesia/Cipto Mangunkusumo General Hospital, Jakarta, Indonesia.
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Anom Bowolaksono
Anom Bowolaksono
Cellular and Molecular Mechanisms in Biological System Research Group, Department of Biology, Faculty of Mathematics and Natural Sciences, University of Indonesia, Depok, Indonesia.
Published Date
- Jul 2, 2024
Altered expression of kisspeptin, dynorphin, and related neuropeptides in polycystic ovary syndrome: A cross-sectional study
Abstract
Background: Since kisspeptin (KISS1) in the hypothalamus is affected by the inhibitory effect of dynorphin, it raises questions about the controlled balance of these 2 neuropeptides in women with and without polycystic ovary syndrome (PCOS).
Objective: This study compares the expression levels of KISS1, dynorphin, neurokinin-B, leptin, and neuropeptide-Y in women with and without PCOS.
Materials and Methods: In this cross-sectional study, the peripheral blood samples of 20 women with PCOS and 20 women without PCOS who referred to Yamin Kencana Clinic, Cipto Mangunkusumo hospital, Jakarta, Indonesia were enrolled from August-December 2022. mRNA relative expression of genes related to the central factors associated with PCOS, such as leptin, neuropeptide-Y, KISS1, tachykinin-3, and prodynorphin (PDYN), in PCOS and non-PCOS populations were examined. Gene quantification was carried out by the quantitative polymerase chain reaction method.
Results: The KISS1/PDYN ratio was significantly higher in the PCOS group than in the control group (p = 0.02), and the PDYN was lower in the PCOS group than the control group (p < 0.001). Moreover, the positive correlation between KISS1 and the KISS1/PDYN ratio was significantly stronger in the PCOS group than in the control group (R = 0.93; p < 0.001 vs. R = 0.66, p < 0.001).
Conclusion: Our results suggest that an increased KISS1/PDYN ratio in PCOS women is related to diminished dynorphin expression. Low expression of the gene encoding dynorphin and a high KISS1/PDYN ratio is highly specific to PCOS.
Key words: Dynorphins, Kisspeptins, Neuropeptides, Polycystic ovary syndrome.
References
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[2] McCartney ChR, Campbell RE. Abnormal GnRH pulsatility in polycystic ovary syndrome: Recent insights. Curr Opin Endocr Metab Res 2020; 12: 78–84.
[3] Nagae M, Uenoyama Y, Okamoto S, Tsuchida H, Ikegami K, Goto T, et al. Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator. Proc Natl Acad Sci U S A 2021; 118: e2009156118.
[4] Chaudhary H, Patel J, Jain NK, Joshi R. The role of polymorphism in various potential genes on polycystic ovary syndrome susceptibility and pathogenesis. J Ovarian Res 2021; 14: 125.
[5] Farsimadan M, Moammadzadeh Ghosi F, Takamoli S, Vaziri H. Association analysis of KISS1 polymorphisms and haplotypes with polycystic ovary syndrome. Br J Biomed Sci 2021; 78: 201–205.
[6] Liu J, Qu T, Li Z, Yu L, Zhang S, Yuan D, et al. Serum kisspeptin levels in polycystic ovary syndrome: A meta-analysis. J Obstet Gynaecol Res 2021; 47: 2157– 2165.
[7] Dudek M, Ziarniak K, Sliwowska JH. Kisspeptin and metabolism: The brain and beyond. Front Endocrinol 2018; 9: 145.
[8] Koseci T, Kaya O, Haksoyler V, Yildirim DD, Sezer K. Investigation of the relationship between insulin resistance and neuropeptide Y levels in polycystic ovary syndrome. Marmara Med J 2019; 32: 1–6.
[9] Rodriguez Paris V, Bertoldo M. The mechanism of androgen actions in PCOS etiology. Med Sci 2019; 7: 89.
[10] Emekci Ozay O, Ozay AC, Acar B, Cagliyan E, Seçil M, Küme T. Role of kisspeptin in polycystic ovary syndrome (PCOS). Gynecol Endocrinol 2016; 32: 718–722.
[11] Chen L, Liu M, Ji J, Lin W, Shan F, Liu H. Diagnostic accuracy of peripheral blood Kisspeptin mRNA and plasma CA125 protein for detection of epithelial ovarian cancer in patients who have ever been pregnant. Neoplasma 2016; 63: 999–1006.
[12] Shahkarami K, Vousooghi N, Golab F, Mohsenzadeh A, Baharvand P, Sadat-Shirazi MS, et al. Evaluation of dynorphin and kappa-opioid receptor level in the human blood lymphocytes and plasma: Possible role as a biomarker in severe opioid use disorder. Drug Alcohol Depend 2019; 205: 107638.
[13] Kolic I, Stojkovic L, Dincic E, Jovanovic I, Stankovic A, Živkovic M. Expression of LEP, LEPR and PGC1A genes is altered in peripheral blood mononuclear cells of patients with relapsing-remitting multiple sclerosis. J Neuroimmunol 2020; 338: 577090.
[14] Chang S, Dunaif A. Diagnosis of polycystic ovary syndrome: Which criteria to use and when? Endocrinol Metab Clin North Am 2021; 50: 11–23.
[15] Lima-Oliveira G, Lippi G, Salvagno GL, Picheth G, Guidi GC. Laboratory diagnostics and quality of blood collection. J Med Biochem 2015; 34: 288–294.
[16] Ganger MT, Dietz GD, Ewing SJ. A common base method for analysis of qPCR data and the application of simple blocking in qPCR experiments. BMC Bioinformatics 2017; 18: 534.
[17] Payne SH. The utility of protein and mRNA correlation. Trends Biochem Sci 2015; 40: 1–3.
[18] Tang R, Ding X, Zhu J. Kisspeptin and polycystic ovary syndrome. Front Endocrinol 2019; 10: 298.
[19] Gorkem U, Togrul C, Arslan E, Sargin Oruc A, Buyukkayaci Duman N. Is there a role for kisspeptin in pathogenesis of polycystic ovary syndrome? Gynecol Endocrinol 2018; 34: 157–160.
[20] 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.
[21] 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.
[22] 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.
[23] Daghestani MH. Evaluation of biochemical, endocrine, and metabolic biomarkers for the early diagnosis of polycystic ovary syndrome among non-obese Saudi women. Int J Gynaecol Obstet 2018; 142: 162–169.
[24] Wahab F, Atika B, Shahab M, Behr R. Kisspeptin signalling in the physiology and pathophysiology of the urogenital system. Nat Rev Urol 2016; 13: 21–32.
[25] Uenoyama Y, Pheng V, Tsukamura H, Maeda KI. The roles of kisspeptin revisited: Inside and outside the hypothalamus. J Reprod Dev 2016; 62: 537–545.
[26] Navarro VM. Metabolic regulation of kisspeptin- the link between energy balance and reproduction. Nat Rev Endocrinol 2020; 16: 407–420.
[27] 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: 164.
[28] Ruddenklau A, Campbell RE. Neuroendocrine impairments of polycystic ovary syndrome. Endocrinology 2019; 160: 2230–2242.
[29] 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.
[30] Cernea M, Phillips R, Padmanabhan V, Coolen LM, Lehman MN. Prenatal testosterone exposure decreases colocalization of insulin receptors in kisspeptin/neurokinin b/dynorphin and agouti-related peptide neurons of the adult ewe. Eur J Neurosci 2016; 44: 2557–2568.
[2] McCartney ChR, Campbell RE. Abnormal GnRH pulsatility in polycystic ovary syndrome: Recent insights. Curr Opin Endocr Metab Res 2020; 12: 78–84.
[3] Nagae M, Uenoyama Y, Okamoto S, Tsuchida H, Ikegami K, Goto T, et al. Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator. Proc Natl Acad Sci U S A 2021; 118: e2009156118.
[4] Chaudhary H, Patel J, Jain NK, Joshi R. The role of polymorphism in various potential genes on polycystic ovary syndrome susceptibility and pathogenesis. J Ovarian Res 2021; 14: 125.
[5] Farsimadan M, Moammadzadeh Ghosi F, Takamoli S, Vaziri H. Association analysis of KISS1 polymorphisms and haplotypes with polycystic ovary syndrome. Br J Biomed Sci 2021; 78: 201–205.
[6] Liu J, Qu T, Li Z, Yu L, Zhang S, Yuan D, et al. Serum kisspeptin levels in polycystic ovary syndrome: A meta-analysis. J Obstet Gynaecol Res 2021; 47: 2157– 2165.
[7] Dudek M, Ziarniak K, Sliwowska JH. Kisspeptin and metabolism: The brain and beyond. Front Endocrinol 2018; 9: 145.
[8] Koseci T, Kaya O, Haksoyler V, Yildirim DD, Sezer K. Investigation of the relationship between insulin resistance and neuropeptide Y levels in polycystic ovary syndrome. Marmara Med J 2019; 32: 1–6.
[9] Rodriguez Paris V, Bertoldo M. The mechanism of androgen actions in PCOS etiology. Med Sci 2019; 7: 89.
[10] Emekci Ozay O, Ozay AC, Acar B, Cagliyan E, Seçil M, Küme T. Role of kisspeptin in polycystic ovary syndrome (PCOS). Gynecol Endocrinol 2016; 32: 718–722.
[11] Chen L, Liu M, Ji J, Lin W, Shan F, Liu H. Diagnostic accuracy of peripheral blood Kisspeptin mRNA and plasma CA125 protein for detection of epithelial ovarian cancer in patients who have ever been pregnant. Neoplasma 2016; 63: 999–1006.
[12] Shahkarami K, Vousooghi N, Golab F, Mohsenzadeh A, Baharvand P, Sadat-Shirazi MS, et al. Evaluation of dynorphin and kappa-opioid receptor level in the human blood lymphocytes and plasma: Possible role as a biomarker in severe opioid use disorder. Drug Alcohol Depend 2019; 205: 107638.
[13] Kolic I, Stojkovic L, Dincic E, Jovanovic I, Stankovic A, Živkovic M. Expression of LEP, LEPR and PGC1A genes is altered in peripheral blood mononuclear cells of patients with relapsing-remitting multiple sclerosis. J Neuroimmunol 2020; 338: 577090.
[14] Chang S, Dunaif A. Diagnosis of polycystic ovary syndrome: Which criteria to use and when? Endocrinol Metab Clin North Am 2021; 50: 11–23.
[15] Lima-Oliveira G, Lippi G, Salvagno GL, Picheth G, Guidi GC. Laboratory diagnostics and quality of blood collection. J Med Biochem 2015; 34: 288–294.
[16] Ganger MT, Dietz GD, Ewing SJ. A common base method for analysis of qPCR data and the application of simple blocking in qPCR experiments. BMC Bioinformatics 2017; 18: 534.
[17] Payne SH. The utility of protein and mRNA correlation. Trends Biochem Sci 2015; 40: 1–3.
[18] Tang R, Ding X, Zhu J. Kisspeptin and polycystic ovary syndrome. Front Endocrinol 2019; 10: 298.
[19] Gorkem U, Togrul C, Arslan E, Sargin Oruc A, Buyukkayaci Duman N. Is there a role for kisspeptin in pathogenesis of polycystic ovary syndrome? Gynecol Endocrinol 2018; 34: 157–160.
[20] 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.
[21] 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.
[22] 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.
[23] Daghestani MH. Evaluation of biochemical, endocrine, and metabolic biomarkers for the early diagnosis of polycystic ovary syndrome among non-obese Saudi women. Int J Gynaecol Obstet 2018; 142: 162–169.
[24] Wahab F, Atika B, Shahab M, Behr R. Kisspeptin signalling in the physiology and pathophysiology of the urogenital system. Nat Rev Urol 2016; 13: 21–32.
[25] Uenoyama Y, Pheng V, Tsukamura H, Maeda KI. The roles of kisspeptin revisited: Inside and outside the hypothalamus. J Reprod Dev 2016; 62: 537–545.
[26] Navarro VM. Metabolic regulation of kisspeptin- the link between energy balance and reproduction. Nat Rev Endocrinol 2020; 16: 407–420.
[27] 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: 164.
[28] Ruddenklau A, Campbell RE. Neuroendocrine impairments of polycystic ovary syndrome. Endocrinology 2019; 160: 2230–2242.
[29] 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.
[30] Cernea M, Phillips R, Padmanabhan V, Coolen LM, Lehman MN. Prenatal testosterone exposure decreases colocalization of insulin receptors in kisspeptin/neurokinin b/dynorphin and agouti-related peptide neurons of the adult ewe. Eur J Neurosci 2016; 44: 2557–2568.