Neuropeptide Network of Polycystic Ovary Syndrome – A Review

Dheepthi      Jayamurali; Nivetha      Ravishankar; Nivedita      Manoharan; Rajeshwari      Parasuraman; Sri   Kameshwaran   Jayashankar; Sathya   Narayanan   Govindarajulu
Abstract

Background: Polycystic Ovary Syndrome (PCOS), the ubiquitous reproductive disorder, has been documented as highly prevalent (6-9%) in India. 10% of women globally are predicted to have the disease. The highly mutable endocrinopathy, with differential clinical criteria for each diagnosis of PCOS, can mask the severity of the syndrome by influencing the incidence and occurrence of PCOS.
Area Covered: When there is a solid theoretical hypothesis between the neuroendocrine origin and ovarian origin of PCOS, recent evidence supports the neuroendocrine derivation of the pathology. It is considered of neuroendocrine basis – as it controls the ovarian axis and acts as a delicate target because it possesses receptors for various gonadal hormones, neurotransmitters & neuropeptides. Can these neuroendocrine alterations, variations in central brain circuits, and neuropeptide dysregulation be the tie that would link the pathophysiology of the disorder, the occurrence of all the 1˚ and 2˚ symptoms like polycystic ovaries, hyperandrogenism, obesity, insulin resistance, etc., in PCOS?
Conclusion: This review anticipates providing a comprehensive overview of how neuropeptides such as Kisspeptin, Neurokinin B, Dynorphin A, β-Endorphin, Nesfatin, Neuropeptide Y, Phoenixin, Leptin, Ghrelin, Orexin, and Neudesin influence PCOS, the understanding of which may help to establish potential drug candidates against precise targets in these central circuits.
Keywords: Neuropeptides, polycystic ovary syndrome, kisspeptin, neurokinin B, dynorphin A, nesfatin, neudesin, neuropeptide Y, β-endorphin, phoenixin, leptin, ghrelin, orexin.
Erratum In:
Neuropeptide Network of Polycystic Ovary Syndrome – A Review
Graphical Abstract

[1]
Kabel, A. Polycystic ovarian syndrome: Insights into pathogenesis, diagnosis. Pathog. Pcos,  2016, 1(1), 1-5.

[2]
Lizneva, D.; Suturina, L.; Walker, W.; Brakta, S.; Gavrilova-Jordan, L.; Azziz, R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil. Steril.,  2016, 106(1), 6-15.
 [http://dx.doi.org/10.1016/j.fertnstert.2016.05.003] [PMID: 27233760]

[3]
Ramanand, S.; Ghongane, B.; Ramanand, J.; Patwardhan, M.; Ghanghas, R.; Jain, S. Clinical characteristics of polycystic ovary syndrome in Indian women. Indian J. Endocrinol. Metab.,  2013, 17(1), 138-145.
 [http://dx.doi.org/10.4103/2230-8210.107858] [PMID: 23776867]

[4]
Cussons, A.J.; Stuckey, B.G.A.; Watts, G.F. Cardiovascular disease in the polycystic ovary syndrome: New insights and perspectives. Atherosclerosis,  2006, 185(2), 227-239.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2005.10.007] [PMID: 16313910]

[5]
Abbott, D.H.; Barnett, D.K.; Bruns, C.M.; Dumesic, D.A. Androgen excess fetal programming of female reproduction: A developmental aetiology for polycystic ovary syndrome? Hum. Reprod. Update,  2005, 11(4), 357-374.
 [http://dx.doi.org/10.1093/humupd/dmi013] [PMID: 15941725]

[6]
Vink, J.M.; Sadrzadeh, S.; Lambalk, C.B.; Boomsma, D.I. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J. Clin. Endocrinol. Metab.,  2006, 91(6), 2100-2104.
 [http://dx.doi.org/10.1210/jc.2005-1494] [PMID: 16219714]

[7]
Indran, I.R.; Lee, B.H.; Yong, E.L. Cellular and animal studies: Insights into pathophysiology and therapy of PCOS. Best Pract Res Clin Obstet Gynaecol,  2016, 37, 12-24.
 [http://dx.doi.org/10.1016/j.bpobgyn.2016.03.006.]

[8]
Moolhuijsen, L.M.E.; Visser, J.A. AMH in PCOS: Controlling the ovary, placenta, or brain? Curr. Opin. Endocr. Metab. Res.,  2020, 12, 91-97.
 [http://dx.doi.org/10.1016/j.coemr.2020.04.006]

[9]
Medical progress polycystic ovary syndrome. Endocrinol. Metab. Clin. North Am.,  2005, 26(4), 1223-1236.

[10]
Balen, A. The pathophysiology of polycystic ovary syndrome: Trying to understand PCOS and its endocrinology. Best Pract Res Clin Obstet Gynaecol,  2004, 18(5), 685-706.
 [http://dx.doi.org/10.1016/j.bpobgyn.2004.05.004]

[11]
Kotani, M.; Detheux, M.; Vandenbogaerde, A.; Communi, D.; Vanderwinden, J.M.; Le Poul, E.; Brézillon, S.; Tyldesley, R.; Suarez-Huerta, N.; Vandeput, F.; Blanpain, C.; Schiffmann, S.N.; Vassart, G.; Parmentier, M. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J. Biol. Chem.,  2001, 276(37), 34631-34636.
 [http://dx.doi.org/10.1074/jbc.M104847200] [PMID: 11457843]

[12]
de Roux, N.; Genin, E.; Carel, J.C.; Matsuda, F.; Chaussain, J.L.; Milgrom, E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc. Natl. Acad. Sci. USA,  2003, 100(19), 10972-10976.
 [http://dx.doi.org/10.1073/pnas.1834399100] [PMID: 12944565]

[13]
Topaloglu, A.K.; Reimann, F.; Guclu, M.; Yalin, A.S.; Kotan, L.D.; Porter, K.M.; Serin, A.; Mungan, N.O.; Cook, J.R.; Ozbek, M.N.; Imamoglu, S.; Akalin, N.S.; Yuksel, B.; O’Rahilly, S.; Semple, R.K. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat. Genet.,  2009, 41(3), 354-358.
 [http://dx.doi.org/10.1038/ng.306] [PMID: 19079066]

[14]
Page, N.M. Neurokinin B and pre-eclampsia: A decade of discovery. Reprod. Biol. Endocrinol.,  2010, 8(1), 4.
 [http://dx.doi.org/10.1186/1477-7827-8-4] [PMID: 20074343]

[15]
Page, N.M.; Morrish, D.W.; Weston-Bell, N.J. Differential mRNA splicing and precursor processing of neurokinin B in neuroendocrine tissues. Peptides,  2009, 30(8), 1508-1513.
 [http://dx.doi.org/10.1016/j.peptides.2009.04.023] [PMID: 19433124]

[16]
Goldstein, A.; Tachibana, S.; Lowney, L.I.; Hunkapiller, M.; Hood, L. Dynorphin-(1-13), an extraordinarily potent opioid peptide. Proc. Natl. Acad. Sci. USA,  1979, 76(12), 6666-6670.
 [http://dx.doi.org/10.1073/pnas.76.12.6666] [PMID: 230519]

[17]
Voigt, C.; Bennett, N. Reproductive status-dependent dynorphin and neurokinin B gene expression in female Damaraland mole-rats. J. Chem. Neuroanat.,  2019, 102, 101705.
 [http://dx.doi.org/10.1016/j.jchemneu.2019.101705] [PMID: 31669432]

[18]
Garg, A.; Patel, B.; Abbara, A.; Dhillo, W.S. Treatments targeting neuroendocrine dysfunction in polycystic ovary syndrome (PCOS). Clin. Endocrinol. (Oxf.),  2022, 97(2), 156-164.
 [http://dx.doi.org/10.1111/cen.14704] [PMID: 35262967]

[19]
Moore, A.M.; Lohr, D.B.; Coolen, L.M.; Lehman, M.N. Prenatal androgen exposure alters kndy neurons and their afferent network in a model of polycystic ovarian syndrome. Endocrinology,  2021, 162(11)
 [http://dx.doi.org/10.1210/endocr/bqab158] [PMID: 34346492]

[20]
Matsuzaki, T.; Tungalagsuvd, A.; Iwasa, T.; Munkhzaya, M.; Yanagihara, R.; Tokui, T.; Yano, K.; Mayila, Y.; Kato, T.; Kuwahara, A.; Matsui, S.; Irahara, M. Kisspeptin mRNA expression is increased in the posterior hypothalamus in the rat model of polycystic ovary syndrome. Endocr. J.,  2017, 64(1), 7-14.
 [http://dx.doi.org/10.1507/endocrj.EJ16-0282] [PMID: 27665725]

[21]
Xu, G.; Zhao, X.; Li, Z.; Hu, J.; Li, X.; Li, J.; Chen, Y. Effects of electroacupuncture on the kisspeptin-gonadotropin-releasing hormone (GnRH) /luteinizing hormone (LH) neural circuit abnormalities and androgen receptor expression of kisspeptin/neurokinin B/dynorphin neurons in PCOS rats. J. Ovarian Res.,  2023, 16(1), 15.
 [http://dx.doi.org/10.1186/s13048-022-01078-x] [PMID: 36650561]

[22]
Porter, D.T.; Moore, A.M.; Cobern, J.A.; Padmanabhan, V.; Goodman, R.L.; Coolen, L.M.; Lehman, M.N. Prenatal testosterone exposure alters GABAergic synaptic inputs to GnRH and KNDy neurons in a sheep model of polycystic ovarian syndrome. Endocrinology,  2019, 160(11), 2529-2542.
 [http://dx.doi.org/10.1210/en.2019-00137] [PMID: 31415088]

[23]
Okada, H.; Kanasaki, H.; Tumurbaatar, T.; Tumurgan, Z.; Oride, A.; Kyo, S. Hyperandrogenism induces proportional changes in the expression of Kiss-1, Tac2, and DynA in hypothalamic KNDy neurons. Reprod. Biol. Endocrinol.,  2022, 20(1), 91.
 [http://dx.doi.org/10.1186/s12958-022-00963-w] [PMID: 35729637]

[24]
Gibson, A.G.; Jaime, J.; Burger, L.L.; Moenter, S.M. Prenatal androgen treatment does not alter the firing activity of hypothalamic arcuate kisspeptin neurons in female mice. eNeuro,  2021, 8(5)
 [http://dx.doi.org/10.1523/ENEURO.0306-21.2021] [PMID: 34503965]

[25]
Sun, P.; Zhang, Y.; Sun, L.; Sun, N.; Wang, J.; Ma, H. Kisspeptin regulates the proliferation and apoptosis of ovary granulosa cells in polycystic ovary syndrome by modulating the PI3K/AKT/ERK signalling pathway. BMC Womens Health,  2023, 23(1), 15.
 [http://dx.doi.org/10.1186/s12905-022-02154-6] [PMID: 36627631]

[26]
Guzelkas, I.; Orbak, Z.; Doneray, H.; Ozturk, N.; Sagsoz, N. Serum kisspeptin, leptin, neuropeptide Y, and neurokinin B levels in adolescents with polycystic ovary syndrome. J. Pediatr. Endocrinol. Metab.,  2022, 35(4), 481-487.
 [http://dx.doi.org/10.1515/jpem-2021-0487] [PMID: 35170267]

[27]
Yuan, C.; Huang, W.Q.; Guo, J.H.; Liu, X.Y.; Yang, J.Z.; Chen, J.J.; Wu, Y.; Ruan, Y.C.; Liu, J.Y.; Cui, Y.G.; Diao, F.Y.; Chan, H.C. Involvement of kisspeptin in androgen-induced hypothalamic endoplasmic reticulum stress and its rescuing effect in PCOS rats. Biochim. Biophys. Acta Mol. Basis Dis.,  2021, 1867(12), 166242.
 [http://dx.doi.org/10.1016/j.bbadis.2021.166242] [PMID: 34389474]

[28]
Osuka, S.; Iwase, A.; Nakahara, T.; Kondo, M.; Saito, A.; Bayasula; Nakamura, T.; Takikawa, S.; Goto, M.; Kotani, T.; Kikkawa, F. Kisspeptin in the hypothalamus of two rat models of polycystic ovary syndrome. Endocrinology,  2016, 158(2)
 [http://dx.doi.org/10.1210/en.2016-1333] [PMID: 27983870]

[29]
Uenoyama, Y.; Nagae, M.; Tsuchida, H.; Inoue, N.; Tsukamura, H. Role of KNDy neurons expressing kisspeptin, neurokinin B, and dynorphin A as a GnRH pulse generator controlling mammalian reproduction. Front. Endocrinol. (Lausanne),  2021, 12(724632), 724632.
 [http://dx.doi.org/10.3389/fendo.2021.724632] [PMID: 34566891]

[30]
Ruddenklau, A.; Campbell, R.E. Neuroendocrine impairments of polycystic ovary syndrome. Endocrinology,  2019, 160(10), 2230-2242.
 [http://dx.doi.org/10.1210/en.2019-00428] [PMID: 31265059]

[31]
Hughes, J.; Smith, T.W.; Kosterlitz, H.W.; Fothergill, L.A.; Morgan, B.A.; Morris, H.R. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature,  1975, 258(5536), 577-579.
 [http://dx.doi.org/10.1038/258577a0] [PMID: 1207728]

[32]
Wallach, E.E.; Seifer, D.B.; Collins, R.L. Current concepts of β-endorphin physiology in female reproductive dysfunction. Fertil. Steril.,  1990, 54(5), 757-771.
 [http://dx.doi.org/10.1016/S0015-0282(16)53928-4] [PMID: 2226908]

[33]
Eyvazzadeh, A.D.; Pennington, K.P.; Pop-Busui, R.; Sowers, M.; Zubieta, J.K.; Smith, Y.R. The role of the endogenous opioid system in polycystic ovary syndrome. Fertil. Steril.,  2009, 92(1), 1-12.
 [http://dx.doi.org/10.1016/j.fertnstert.2009.05.012] [PMID: 19560572]

[34]
Kiałka, M.; Milewicz, T.; Spałkowska, M.; Krzyczkowska-Sendrakowska, M.; Wasyl, B.; Pełka, A.; Krzysiek, J. β-endorphins plasma level is higher in lean Polycystic Ovary Syndrome (PCOS) Women. Exp. Clin. Endocrinol. Diabetes,  2016, 124(1), 55-60.
 [http://dx.doi.org/10.1055/s-0035-1564094] [PMID: 26797863]

[35]
Nappi, C.; Petraglia, F.; Cudemo, V.; Volpe, A.; Facchinetti, U.; Genazzani, AR.; Montemagno, U. Plasma beta-endorphin levels in obese and non-obese patients with polycystic ovarian disease. Eur. J. Obstet. Gynecol. Reprod. Biol.,  1989, 30(2), 151-156.
 [http://dx.doi.org/10.1016/0028-2243(89)90062-2] [PMID: 2522898]

[36]
Carmina, E.; Ditkoff, E.C.; Malizia, G.; Vijod, A.G.; Janni, A.; Lobo, R.A. Increased circulating levels of immunoreactive β-endorphin in polycystic ovary syndrome is not caused by increased pituitary secretion. Am. J. Obstet. Gynecol.,  1992, 167(6), 1819-1824.
 [http://dx.doi.org/10.1016/0002-9378(92)91781-5] [PMID: 1471704]

[37]
Zangeneh, F.; Naghizadeh, M.; Abdollahi, A.; Abedinia, N. Opioid system (β-endorphin) and stress hormones profiling in women with polycystic ovary syndrome. Annu. Res. Rev. Biol.,  2015, 5(5), 409-418.
 [http://dx.doi.org/10.9734/ARRB/2015/12932]

[38]
Stener-Victorin, E.; Lindholm, C. Immunity and β-endorphin concentrations in hypothalamus and plasma in rats with steroid-induced polycystic ovaries: Effect of low-frequency electroacupuncture. Biol. Reprod.,  2004, 70(2), 329-333.
 [http://dx.doi.org/10.1095/biolreprod.103.022368] [PMID: 14561641]

[39]
Lin, E.J.D.; Sainsbury, A.; Lee, N.J.; Boey, D.; Couzens, M.; Enriquez, R.; Slack, K.; Bland, R.; During, M.J.; Herzog, H. Combined deletion of Y1, Y2, and Y4 receptors prevents hypothalamic neuropeptide Y overexpression-induced hyper- insulinemia despite persistence of hyperphagia and obesity. Endocrinology,  2006, 147(11), 5094-5101.
 [http://dx.doi.org/10.1210/en.2006-0097] [PMID: 16873543]

[40]
Koseci, T.; Kaya, O.; Haksoyler, V.; Derici, V.D.; Sezer, K. Investigation of the relationship between insulin resistance and neuropeptide Y levels in polycystic ovary syndrome. Marmara Med. J.,  2019, 32(1), 1-6.
 [http://dx.doi.org/10.5472/marumj.500032]

[41]
Allen, Y.S.; Adrian, TE.; Allen, JM.; Tatemoto, K.; Crow, TJ.; Bloom, SR.; Polak, JM. Neuropeptide Y distribution in the rat brain. Science,  1983, 221(4613), 877-9.
 [http://dx.doi.org/10.1126/science.6136091]

[42]
Baranowska, B.; Radzikowska, M.; Wasilewska-Dziubińska, E.; Kapliński, A.; Roguski, K.; Płonowski, A. Neuropeptide Y, leptin, galanin and insulin in women with polycystic ovary syndrome. Gynecol. Endocrinol.,  1999, 13(5), 344-351.
 [http://dx.doi.org/10.3109/09513599909167578] [PMID: 10599552]

[43]
Rosenberg, S.L. The relationship between PCOS and obesity: Which comes first? Sci. J. Lander Coll. Arts Sci.,  2019, 13(1)

[44]
Parker, R.M.C.; Herzog, H. Regional distribution of Y-receptor subtype mRNAs in rat brain. Eur. J. Neurosci.,  1999, 11(4), 1431-1448.
 [http://dx.doi.org/10.1046/j.1460-9568.1999.00553.x] [PMID: 10103138]

[45]
Turi, G.F.; Liposits, Z.; Moenter, S.M.; Fekete, C.; Hrabovszky, E. Origin of neuropeptide Y-containing afferents to gonadotropin-releasing hormone neurons in male mice. Endocrinology,  2003, 144(11), 4967-4974.
 [http://dx.doi.org/10.1210/en.2003-0470] [PMID: 12960087]

[46]
Estrada, K.M.; Pompolo, S.; Morris, M.J.; Tilbrook, A.J.; Clarke, I.J. Neuropeptide Y (NPY) delays the oestrogen-induced luteinizing hormone (LH) surge in the ovariectomized ewe: Further evidence that NPY has a predominant negative effect on LH secretion in the ewe. J. Neuroendocrinol.,  2003, 15(11), 1011-1020.
 [http://dx.doi.org/10.1046/j.1365-2826.2003.01087.x] [PMID: 14622430]

[47]
Roa, J.; Herbison, A.E. Direct regulation of GnRH neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology,  2012, 153(11), 5587-5599.
 [http://dx.doi.org/10.1210/en.2012-1470] [PMID: 22948210]

[48]
Manfredi-Lozano, M.; Roa, J.; Tena-Sempere, M. Connecting metabolism and gonadal function: Novel central neuropeptide pathways involved in the metabolic control of puberty and fertility. Front. Neuroendocrinol.,  2018, 48(May), 37-49.
 [http://dx.doi.org/10.1016/j.yfrne.2017.07.008] [PMID: 28754629]

[49]
Li, Y.; Zhi, W.; Haoxu, D.; Qing, W.; Ling, C.; Ping, Y.; Dongmei, H. Effects of electroacupuncture on the expression of hypothalamic neuropeptide Y and ghrelin in pubertal rats with polycystic ovary syndrome. PLoS One,  2022, 17(6), e0259609.
 [http://dx.doi.org/10.1371/journal.pone.0259609] [PMID: 35704659]

[50]
Liu, Y.; Xu, Y.C.; Cui, Y.G.; Jiang, S.W.; Diao, F.Y.; Liu, J.Y.; Ma, X. Androgen excess increases food intake in a rat polycystic ovary syndrome model by downregulating hypothalamus insulin and leptin signaling pathways preceding weight gain. Neuroendocrinology,  2022, 112(10), 966-981.
 [http://dx.doi.org/10.1159/000521236] [PMID: 34847556]

[51]
Urata, Y.; Salehi, R.; Wyse, B.A.; Jahangiri, S.; Librach, C.L.; Tzeng, C.R.; Osuga, Y.; Tsang, B. Neuropeptide Y directly reduced apoptosis of granulosa cells, and the expression of NPY and its receptors in PCOS subjects. J. Ovarian Res.,  2023, 16(1), 182.
 [http://dx.doi.org/10.1186/s13048-023-01261-8] [PMID: 37653540]

[52]
Romualdi, D.; De Marinis, L.; Campagna, G.; Proto, C.; Lanzone, A.; Guido, M. Alteration of ghrelin–neuropeptide Y network in obese patients with polycystic ovary syndrome: Role of hyperinsulinism. Clin. Endocrinol. (Oxf.),  2008, 69(4), 562-567.
 [http://dx.doi.org/10.1111/j.1365-2265.2008.03204.x] [PMID: 18248643]

[53]
Chen, WH.; Shi, YC.; Huang, QY.; Chen, JM.; Wang, ZY.; Lin, S.; Shi, QY. Potential for NPY receptor-related therapies for polycystic ovary syndrome: An updated review. Hormones (Athens),  2023, 22(3), 441-451.
 [http://dx.doi.org/10.1007/s42000-023-00460-8]

[54]
Xu, Y.; Zhang, H.; Li, Q.; Lao, K.; Wang, Y. The role of nesfatin-1 expression in letrozole-induced polycystic ovaries in the rat. Gynecol. Endocrinol.,  2017, 33(6), 438-441.
 [http://dx.doi.org/10.1080/09513590.2017.1290068] [PMID: 28277136]

[55]
Luo, J.; Wen, F.; Qiu, D.; Wang, S. Nesfatin-1 in lipid metabolism and lipid-related diseases. Clin. Chim. Acta,  2021, 522, 23-30.
 [http://dx.doi.org/10.1016/j.cca.2021.08.005]

[56]
Aydin, S. Multi-functional peptide hormone NUCB2/nesfatin-1. Endocrine,  2013, 44(2), 312-325.
 [http://dx.doi.org/10.1007/s12020-013-9923-0] [PMID: 23526235]

[57]
Rezk, M.Y.; Elkatawy, H.A.; Fouad, R.A.; Enan, E.T.; Attia, M.A. Nesfatin-1: A potential therapeutic target in a rat model of polycystic ovary syndrome. Int J Diabetes Res,  2019, 8(1), 9-16.
 [http://dx.doi.org/10.5923/j.diabetes.20190801.03.]

[58]
Deniz, R.; Gurates, B.; Aydin, S.; Celik, H.; Sahin, İ.; Baykus, Y.; Catak, Z.; Aksoy, A.; Citil, C.; Gungor, S. Nesfatin-1 and other hormone alterations in polycystic ovary syndrome. Endocrine,  2012, 42(3), 694-699.
 [http://dx.doi.org/10.1007/s12020-012-9638-7] [PMID: 22367584]

[59]
Oh-I, S.; Shimizu, H.; Satoh, T.; Okada, S.; Adachi, S.; Inoue, K.; Eguchi, H.; Yamamoto, M.; Imaki, T.; Hashimoto, K.; Tsuchiya, T.; Monden, T.; Horiguchi, K.; Yamada, M.; Mori, M. Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature,  2006, 443(7112), 709-12.
 [http://dx.doi.org/10.1038/nature05162]

[60]
Ademoglu, E.N.; Gorar, S.; Carlıoglu, A.; Yazıcı, H.; Dellal, F.D.; Berberoglu, Z.; Akdeniz, D.; Uysal, S.; Karakurt, F. Plasma nesfatin-1 levels are increased in patients with polycystic ovary syndrome. J. Endocrinol. Invest.,  2014, 37(8), 715-719.
 [http://dx.doi.org/10.1007/s40618-014-0089-2] [PMID: 24920281]

[61]
Fatima, F.; Saxena, P.; Jain, A. Correlation of serum Nesfatin 1 level with metabolic and clinical parameters in Indian women with and without polycystic ovarian syndrome. Int. J. Reprod. Contracept. Obstet. Gynecol.,  2023, 12(2), 427-431.
 [http://dx.doi.org/10.18203/2320-1770.ijrcog20230128]

[62]
Alp, E.; Görmüş, U.; Güdücü, N.; Bozkurt, S. Nesfatin-1 levels and metabolic markers in polycystic ovary syndrome. Gynecol. Endocrinol.,  2015, 31(7), 543-547.
 [http://dx.doi.org/10.3109/09513590.2015.1024219] [PMID: 26062107]

[63]
Binnetoǧlu, E.; Erbag, G.; Gencer, M.; Turkon, H.; Asik, M.; Gunes, F.; Sen, H.; Vural, A.; Ukinc, K. Plasma levels of nesfatin-1 in patients with polycystic ovary syndrome. Endocrine Abstracts,  2014, 30(1), 201-204.
 [http://dx.doi.org/10.1530/endoabs.35.P620]

[64]
Nylander, M.; Frøssing, S.; Clausen, H.V.; Kistorp, C.; Faber, J.; Skouby, S.O. Effects of liraglutide on ovarian dysfunction in polycystic ovary syndrome: a randomized clinical trial. Reprod. Biomed. Online,  2017, 35(1), 121-127.
 [http://dx.doi.org/10.1016/j.rbmo.2017.03.023] [PMID: 28479118]

[65]
Ullah, K.; ur Rahman, T.; Wu, D.D.; Lin, X.H.; Liu, Y.; Guo, X.Y.; Leung, P.C.K.; Zhang, R.J.; Huang, H.F.; Sheng, J.Z. Phoenixin-14 concentrations are increased in association with luteinizing hormone and nesfatin-1 concentrations in women with polycystic ovary syndrome. Clin. Chim. Acta,  2017, 471, 243-247.
 [http://dx.doi.org/10.1016/j.cca.2017.06.013] [PMID: 28624500]

[66]
Kalamon, N.; Błaszczyk, K.; Szlaga, A.; Billert, M.; Skrzypski, M.; Pawlicki, P.; Górowska - Wójtowicz, E.; Kotula - Balak, M.; Błasiak, A.; Rak, A. 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(4), 628-635.
 [http://dx.doi.org/10.1016/j.bbrc.2020.05.101] [PMID: 32505354]

[67]
Obradovic, M.; Sudar-Milovanovic, E.; Soskic, S.; Essack, M.; Arya, S.; Stewart, A.J.; Gojobori, T.; Isenovic, E.R. Leptin and obesity: Role and clinical implication. Front. Endocrinol. (Lausanne),  2021, 12(May), 585887.
 [http://dx.doi.org/10.3389/fendo.2021.585887] [PMID: 34084149]

[68]
Akeel Al-hussaniy, H.; Hikmate, A.A.; Akeel, N.M. Leptin hormone and its effectiveness in reproduction, metabolism, immunity, diabetes, hopes and ambitions. J. Med. Life,  2021, 14(5), 600-605.
 [http://dx.doi.org/10.25122/jml-2021-0153] [PMID: 35027962]

[69]
Gruzdeva, O.; Borodkina, D.; Uchasova, E.; Dyleva, Y.; Barbarash, O. Leptin resistance: Underlying mechanisms and diagnosis. Diabetes Metab. Syndr. Obes.,  2019, 12, 191-198.
 [http://dx.doi.org/10.2147/DMSO.S182406] [PMID: 30774404]

[70]
Peng, Y.; Yang, H.; Song, J.; Feng, D.; Na, Z.; Jiang, H.; Meng, Y.; Shi, B.; Li, D. Elevated serum leptin levels as a predictive marker for polycystic ovary syndrome. Front. Endocrinol. (Lausanne),  2022, 13(845165), 845165.
 [http://dx.doi.org/10.3389/fendo.2022.845165] [PMID: 35355566]

[71]
Jalilian, N.; Haghnazari, L.; Rasolinia, S. Leptin and body mass index in polycystic ovary syndrome. Indian J. Endocrinol. Metab.,  2016, 20(3), 324-328.
 [http://dx.doi.org/10.4103/2230-8210.180005] [PMID: 27186548]

[72]
Gao, T.; Wu, L.; Chang, F.; Cao, G. Low circulating ghrelin levels in women with polycystic ovary syndrome: A systematic review and meta-analysis. Endocr. J.,  2016, 63(1), 93-100.
 [http://dx.doi.org/10.1507/endocrj.EJ15-0318] [PMID: 26607017]

[73]
Houjeghani, S.; Pourghassem, G.B.; Farzadi, L. Serum leptin and ghrelin levels in women with polycystic ovary syndrome: Correlation with anthropometric, metabolic, and endocrine parameters. Int. J. Fertil. Steril.,  2012, 6(2), 117-126.
 [PMID: 25493169]

[74]
Rashad, N.M.; Saraya, Y.S.; Afifi, S.A.; Ali, A.E.; Al-sayed, R.M. Impact of weight loss on plasma ghrelin level, clinical, and metabolic features of obese women with or without polycystic ovary syndrome. Middle East Fertil. Soc. J.,  2020, 24(1), 12.
 [http://dx.doi.org/10.1186/s43043-019-0006-x]

[75]
Daghestani, M.H.; Daghestani, M.H.; El-Mazny, A. Circulating ghrelin levels and the polycystic ovary syndrome: correlation with the clinical, hormonal and metabolic features. Eur. J. Obstet. Gynecol. Reprod. Biol.,  2011, 155(1), 65-68.
 [http://dx.doi.org/10.1016/j.ejogrb.2010.11.019] [PMID: 21216086]

[76]
Yilmaz, E.; Celik, O.; Celik, N.; Simsek, Y.; Celik, E.; Yildirim, E. Serum orexin-A (OXA) level decreases in polycystic ovarian syndrome. Gynecol. Endocrinol.,  2013, 29(4), 388-390.
 [http://dx.doi.org/10.3109/09513590.2012.754874] [PMID: 23350701]

[77]
Absatarova, Y.; Evseeva, Y.; Andreeva, E.; Samsonova, M. Orexin A is a new marker of insulin resistance in polycystic ovary syndrome. Endocrine Abstracts,  2024, 99, EP98.
 [http://dx.doi.org/10.1530/endoabs.99.EP98]

[78]
Kouhetsani, S.; Khazali, H.; Rajabi-Maham, H. Orexin antagonism and substance-P: Effects and interactions on polycystic ovary syndrome in the wistar rats. J. Ovarian Res.,  2023, 16(1), 89.
 [http://dx.doi.org/10.1186/s13048-023-01168-4] [PMID: 37147728]

[79]
Kimura, I.; Nakayama, Y.; Konishi, M.; Terasawa, K.; Ohta, M.; Itoh, N.; Fujimoto, M. Functions of MAPR (membrane-associated progesterone receptor) family members as heme/steroid-binding proteins. Curr Protein Pept Sci,  2012, 13(7), 687-696.
 [http://dx.doi.org/10.2174/138920312804142110.]

[80]
Rodrigues, T.B.; Ballesteros, P.; Ramirez, B.G.; Violante, I.R.; Cruz, F.; Fonseca, L.L.; Margarida, M.; Castro, C.A.; Garcia-Martin, M.L.; Cerdan, S. Kinetic properties of the redox switch/redox coupling mechanism as determined in primary cultures of cortical neurons and astrocytes from rat brain. J. Neurosci. Res.,  2007, 3253, 3244-3253.

[81]
Mifsud, W.; Bateman, A. Membrane-bound progesterone receptors contain a cytochrome b5-like ligand-binding domain. Genome Biol.,  2002, 3(12)
 [http://dx.doi.org/10.1186/gb-2002-3-12-research0068] [PMID: 12537557]

[82]
Kimura, I.; Yoshioka, M.; Konishi, M.; Miyake, A.; Itoh, N. Neudesin, a novel secreted protein with a unique primary structure and neurotrophic activity. J. Neurosci. Res.,  2005, 79(3), 287-294.
 [http://dx.doi.org/10.1002/jnr.20356] [PMID: 15605373]

[83]
Ohta, H.; Kimura, I.; Konishi, M.; Itoh, N. Neudesin as a unique secreted protein with multi-functional roles in neural functions, energy metabolism, and tumorigenesis. Front. Mol. Biosci.,  2015, 2(MAY), 24.
 [http://dx.doi.org/10.3389/fmolb.2015.00024] [PMID: 26042224]

[84]
Kruszewska, J.; Laudy-Wiaderny, H.; Kunicki, M. Review of novel potential insulin resistance biomarkers in PCOS patients—the debate is still open. Int. J. Environ. Res. Public Health,  2022, 19(4), 2099.
 [http://dx.doi.org/10.3390/ijerph19042099] [PMID: 35206286]

[85]
Yilmaz, Y.H.; Demirpence, M.; Colak, A.; Zeytinli, M.; Yasar, E.; Taylan, A. Serum neudesin levels in patients with polycystic ovary syndrome. Ginekol. Pol.,  2021, 93(7), 525-530.
 [http://dx.doi.org/10.5603/GP.a2021.0139] [PMID: 34263912]

[86]
Bozkaya, G.; Fenercioglu, O.; Demir, İ.; Guler, A.; Aslanipour, B.; Calan, M. Neudesin: a neuropeptide hormone decreased in subjects with polycystic ovary syndrome. Gynecol. Endocrinol.,  2020, 36(10), 849-853.
 [http://dx.doi.org/10.1080/09513590.2020.1751106] [PMID: 32314607]

[87]
Kir, S.F.; Baydur, S.S.; Mete, U.U.; Cumhur, C.M.; Senturk, S.; Bayoglu, T.Y.; Balik, G.; Cure, E.; Yuce, S.; Kirbas, A. Nesfatin-1 and Vitamin D levels may be associated with systolic and diastolic blood pressure values and hearth rate in polycystic ovary syndrome. Bosn J Basic Med Sci.,  2015, 15(3), 57-63.
 [http://dx.doi.org/10.17305/bjbms.2015.432] [PMID: 26295295]

[88]
Çelikkol, A.; Binay, C.; Ayçiçek, Ö.; Güzel, S. Serum neudesin levels in obese adolescents. J. Clin. Res. Pediatr. Endocrinol.,  2022, 14(1), 69-75.
 [http://dx.doi.org/10.4274/jcrpe.galenos.2021.2021.0208] [PMID: 34776708]

[89]
Tolson, K.P.; Garcia, C.; Yen, S.; Simonds, S.; Stefanidis, A.; Lawrence, A.; Smith, J.T.; Kauffman, A.S. Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. J. Clin. Invest.,  2014, 124(7), 3075-3079.
 [http://dx.doi.org/10.1172/JCI71075] [PMID: 24937427]

[90]
Witchel, S.F.; Oberfield, S.E.; Peña, A.S. Polycystic ovary syndrome: Pathophysiology, presentation, and treatment with emphasis on adolescent girls. J. Endocr. Soc.,  2019, 3(8), 1545-1573.
 [http://dx.doi.org/10.1210/js.2019-00078] [PMID: 31384717]

[91]
Mills, E.G.; Yang, L.; Abbara, A.; Dhillo, W.S.; Comninos, A.N. Current perspectives on kisspeptins role in behaviour. Front. Endocrinol. (Lausanne),  2022, 13, 928143.
 [http://dx.doi.org/10.3389/fendo.2022.928143] [PMID: 35757400]

[92]
Merkley, C.M.; Renwick, A.N.; Shuping, S.L.; Harlow, K.; Sommer, J.R.; Nestor, C.C. Undernutrition reduces kisspeptin and neurokinin B expression in castrated male sheep. Reprod. Fertil.,  2020, 1(1), 21-33.
 [http://dx.doi.org/10.1530/RAF-20-0025] [PMID: 35128420]

[93]
Mittelman-Smith, M.A.; Williams, H.; Krajewski-Hall, S.J.; McMullen, N.T.; Rance, N.E. Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature. Proc. Natl. Acad. Sci. USA,  2012, 109(48), 19846-19851.
 [http://dx.doi.org/10.1073/pnas.1211517109] [PMID: 23150555]

[94]
Szeliga, A.; Podfigurna, A.; Bala, G.; Meczekalski, B. Decreased neurokinin B as a risk factor of functional hypothalamic amenorrhea. Gynecol Endocrinol,  2023, 39(1), 2216313.
 [http://dx.doi.org/10.1080/09513590.2023.2216313]

[95]
Pilozzi, A.; Carro, C.; Huang, X. Roles of β-endorphin in stress, behavior, neuroinflammation, and brain energy metabolism. Int. J. Mol. Sci.,  2020, 22(1), 338.
 [http://dx.doi.org/10.3390/ijms22010338] [PMID: 33396962]

[96]
Wortsman, J.; Wehrenberg, W.B.; Gavin, J.R., III; Allen, J.P. Elevated levels of plasma beta-endorphin and gamma 3-melanocyte stimulating hormone in the polycystic ovary syndrome. Obstet. Gynecol.,  1984, 63(5), 630-634.
 [PMID: 6326013]

[97]
Jaschke, N.; Lunger, F.; Wildt, L.; Seeber, B. Beta endorphin in serum and follicular fluid of PCOS- and non-PCOS women. Arch. Gynecol. Obstet.,  2018, 298(1), 217-222.
 [http://dx.doi.org/10.1007/s00404-018-4793-6] [PMID: 29808249]

[98]
Guo, Z.; Li, Y. Prisoner's dilemma game model Based on historical strategy information. Sci. Rep.,  2023, 13(1), 1.
 [http://dx.doi.org/10.1038/s41598-022-26890-9] [PMID: 36593249]

[99]
Laatikainen, T.; Salminen, K.; Virtanen, T.; Apter, D. Plasma β-endorphin, β-lipotropin and corticotropin in polycystic ovarian disease. Eur. J. Obstet. Gynecol. Reprod. Biol.,  1987, 24(4), 327-333.
 [http://dx.doi.org/10.1016/0028-2243(87)90158-4] [PMID: 3034691]

[100]
Beck, B. Neuropeptide Y in normal eating and in genetic and dietary-induced obesity. Philos. Trans. R. Soc. Lond. B Biol. Sci.,  2006, 361(1471), 1159-1185.
 [http://dx.doi.org/10.1098/rstb.2006.1855] [PMID: 16874931]

[101]
Zhang, Y.; Liu, C.Y.; Chen, W.C.; Shi, Y.C.; Wang, C.M.; Lin, S.; He, H.F. Regulation of neuropeptide Y in body microenvironments and its potential application in therapies: A review. Cell Biosci.,  2021, 11(1), 151.
 [http://dx.doi.org/10.1186/s13578-021-00657-7] [PMID: 34344469]

[102]
Huang, Y.; Lin, X.; Lin, S. Neuropeptide Y and metabolism syndrome: An update on perspectives of clinical therapeutic intervention strategies. Front. Cell Dev. Biol.,  2021, 9, 695623.
 [http://dx.doi.org/10.3389/fcell.2021.695623] [PMID: 34307371]

[103]
Ayada, C.; Toru, Ü.; Korkut, Y. Nesfatin-1 and its effects on different systems. Hippokratia,  2015, 19(1), 4-10.
 [PMID: 26435639]

[104]
Angelone, T.; Filice, E.; Pasqua, T.; Amodio, N.; Galluccio, M.; Montesanti, G.; Quintieri, A.M.; Cerra, M.C. Nesfatin-1 as a novel cardiac peptide: Identification, functional characterization, and protection against ischemia/reperfusion injury. Cell. Mol. Life Sci.,  2013, 70(3), 495-509.
 [http://dx.doi.org/10.1007/s00018-012-1138-7] [PMID: 22955491]

[105]
Kratochvilova, H.; Lacinova, Z.; Klouckova, J.; Kavalkova, P.; Cinkajzlova, A.; Trachta, P.; Krizova, J.; Benes, M.; Dolezalova, K.; Fried, M.; Vlasakova, Z.; Pelikanova, T.; Spicak, J.; Mraz, M.; Haluzik, M. Neudesin in obesity and type 2 diabetes mellitus: The effect of acute fasting and weight reducing interventions. Diabetes Metab. Syndr. Obes.,  2019, 12, 423-430.
 [http://dx.doi.org/10.2147/DMSO.S193259] [PMID: 30992678]

[106]
Elkind-Hirsch, K.; Marrioneaux, O.; Bhushan, M.; Vernor, D.; Bhushan, R. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab.,  2008, 93(7), 2670-2678.
 [http://dx.doi.org/10.1210/jc.2008-0115] [PMID: 18460557]
Cite As
Protein & Peptide Letters

Neuropeptide Network of Polycystic Ovary Syndrome – A Review

Abstract

Graphical Abstract
