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Current Women`s Health Reviews

Editor-in-Chief

ISSN (Print): 1573-4048
ISSN (Online): 1875-6581

Systematic Review Article

Prospective Role of Leptin Receptor Gene and its Polymorphisms on the Onset of Polycystic Ovarian Syndrome

Author(s): Keerthi Vanamala and Srujana Medithi*

Volume 20, Issue 2, 2024

Published on: 10 May, 2023

Article ID: e300323215199 Pages: 14

DOI: 10.2174/1573404820666230330104046

Price: $65

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Abstract

Introduction: Leptin hormone is produced by adipose tissue and soluble leptin receptor (sOB-R) influences leptin's free bioavailability. Obese individuals have unusually elevated leptin levels. Obesity influences insulin and other hormone levels and is a key risk factor for developing polycystic ovarian syndrome (PCOS) and mutations such as rs2025804 and G2548A (rs7799039). PCOS is a hormonal condition that affects females of reproductive age primarily. Although there is no known cause of PCOS, studies have linked it to various factors, including insulin resistance, obesity, and genetics. Till now, research indicates a substantial correlation between leptin and female reproductive hormones, and PCOS. Thus, the purpose of this study is to compile the available data for a better understanding of the link between leptin and its effect on female reproductive hormones and PCOS and to determine whether the leptin receptor polymorphism (LEPR) influences the start of PCOS.

Methods: Following a review of the relevant papers, it was determined that there is an association between leptin and female reproductive hormones such as luteinizing hormone (LH), folliclestimulating hormone (FSH), estradiol (E2), progesterone, and prolactin. It was observed that Gln223Arg (Q223R/rs1137101), Pro1019Pro (A3057G), Lys109Arg (K109R/rs1147100), rs2025804, and G2548A (rs7799039) are the LEPR polymorphisms associated with PCOS. Gln223Arg is the most frequently studied variant in the LEPR gene across populations.

Results: Interestingly, different groups demonstrated varying relationships between leptin receptor polymorphisms and PCOS, particularly for Gln223Arg, which contains two alleles (G allele and A allele). The G allele was protective against PCOS in the Korean population but increased the frequency of PCOS in countries such as Bahrain, India, Iran, and Iraq. There was no significant difference between PCOS and controls with this polymorphism in places such as China, Turkey, Saudi Arabia, and Helsinki.

Conclusion: To summarize, the association between multiple leptin receptor polymorphisms and PCOS is complex and varies by research region. There hasn't been much research done on the gene polymorphism "Gln223Arg" or the other polymorphisms. While certain research findings were notable, each came with its limitations. As a result, additional interventional studies, including precise criteria in bigger and more diverse groups, are required.

Graphical Abstract

[1]
Li, L.; Lee, K.J.; Choi, B.C.; Baek, K.H. Relationship between leptin receptor and polycystic ovary syndrome. Gene, 2013, 527(1), 71-74.
[http://dx.doi.org/10.1016/j.gene.2013.05.074] [PMID: 23769971]
[2]
Kelesidis, T.; Kelesidis, I.; Chou, S.; Mantzoros, C.S. Narrative review: The role of leptin in human physiology: emerging clinical applications. Ann. Intern. Med., 2010, 152(2), 93-100.
[http://dx.doi.org/10.7326/0003-4819-152-2-201001190-00008] [PMID: 20083828]
[3]
Mitchell, M.; Armstrong, D.T.; Robker, R.L.; Norman, R.J. Adipokines: Implications for female fertility and obesity. Reproduction, 2005, 130(5), 583-597.
[http://dx.doi.org/10.1530/rep.1.00521] [PMID: 16264089]
[4]
Dallel, M.; Douma, Z.; Finan, R.R.; Hachani, F.; Letaifa, D.B.; Mahjoub, T.; Almawi, W.Y. Contrasting association of Leptin receptor polymorphisms and haplotypes with polycystic ovary syndrome in Bahraini and Tunisian women: A case–control study. Biosci. Rep., 2021, 41(1), BSR20202726.
[http://dx.doi.org/10.1042/BSR20202726] [PMID: 33245096]
[5]
Gorska, E.; Popko, K.; Stelmaszczyk-Emmel, A.; Ciepiela, O.; Kucharska, A.; Wasik, M. Leptin receptors. Eur. J. Med. Res., 2010, 15(Suppl. 2), 50-54.
[http://dx.doi.org/10.1186/2047-783X-15-S2-50] [PMID: 21147620]
[6]
Salem, A.M. Variation of leptin during menstrual cycle and its relation to the hypothalamic–pituitary–gonadal (Hpg) axis: A systematic review. Int. J. Womens Health, 2021, 13, 445-458.
[http://dx.doi.org/10.2147/IJWH.S309299] [PMID: 34007218]
[7]
Pérez-Pérez, A.; Sánchez-Jiménez, F.; Maymó, J.; Dueñas, J.L.; Varone, C.; Sánchez-Margalet, V. Role of leptin in female reproduction. Clinic. Chemist. Laborat. Medici., 2015, 53(1), 15-28.
[http://dx.doi.org/10.1515/cclm-2014-0387] [PMID: 25014521]
[8]
Pusalkar, M.; Meherji, P.; Gokral, J.; Savardekar, L.; Chinnaraj, S.; Maitra, A. Obesity and polycystic ovary syndrome: association with androgens, leptin and its genotypes. Gynecol. Endocrinol., 2010, 26(12), 874-882.
[http://dx.doi.org/10.3109/09513590.2010.487586] [PMID: 20500101]
[9]
Ashrafi Mahabadi, S.; Tafvizi, F. Reduction of soluble leptin receptor levels in women with unexplained infertility and the effect of Leptin Receptor gln223arg polymorphism on its serum level. J. Obstet. Gynecol. Cancer Res., 2020, 5(4), 149-158.
[http://dx.doi.org/10.30699/jogcr.5.4.149]
[10]
Micić, D.; Macut, D.; Popović, V.; Ŝumarac-Dumanović, M.; Kendereŝki, A.; Ĉolić, M.; Dieguez, C.; Casanueva, F.F. Leptin levels and insulin sensitivity in obese and non-obese patients with polycystic ovary syndrome. Gynecol. Endocrinol., 1997, 11(5), 315-320.
[http://dx.doi.org/10.3109/09513599709152554] [PMID: 9385530]
[11]
Rizk, A.Y.; Bedaiwy, M.A.; Al-Inany, H.G. N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate–resistant patients with polycystic ovary syndrome. Fertil. Steril., 2005, 83(2), 367-370.
[http://dx.doi.org/10.1016/j.fertnstert.2004.07.960] [PMID: 15705376]
[12]
Odle, A.K.; Akhter, N.; Syed, M.M.; Allensworth-James, M.L.; Beneš, H.; Melgar Castillo, A.I.; MacNicol, M.C.; MacNicol, A.M.; Childs, G.V. Leptin regulation of gonadotrope gonadotropin-releasing hormone receptors as a metabolic checkpoint and gateway to reproductive competence. Front. Endocrinol., 2018, 8(8), 367.
[http://dx.doi.org/10.3389/fendo.2017.00367] [PMID: 29354094]
[13]
Blüher, S.; Mantzoros, C.S. Leptin in reproduction. Curr. Opin. Endocrinol. Diabetes Obes., 2007, 14(6), 458-464.
[http://dx.doi.org/10.1097/MED.0b013e3282f1cfdc] [PMID: 17982352]
[14]
Catteau, A.; Caillon, H.; Barrière, P.; Denis, M.G.; Masson, D.; Fréour, T. Leptin and its potential interest in assisted reproduction cycles. Hum. Reprod. Update, 2016, 22(3), 320-341.
[http://dx.doi.org/10.1093/humupd/dmv057] [PMID: 26663219]
[15]
Al-Harithy, R.N.; Al-Doghaither, H.; Abualnaja, K. Correlation of leptin and sex hormones with endocrine changes in healthy Saudi women of different body weights. Ann. Saudi Med., 2006, 26(2), 110-115.
[http://dx.doi.org/10.5144/0256-4947.2006.110] [PMID: 16761447]
[16]
Ahrens, K.; Mumford, S.L.; Schliep, K.C.; Kissell, K.A.; Perkins, N.J.; Wactawski-Wende, J.; Schisterman, E.F. Serum leptin levels and reproductive function during the menstrual cycle. Am. J. Obstet. Gynecol., 2014, 210(3), 248.e1-248.e9.
[http://dx.doi.org/10.1016/j.ajog.2013.11.009] [PMID: 24215851]
[17]
Baig, M.; Azhar, A.; Rehman, R.; Syed, H.; Tariq, S.; Gazzaz, Z.J. Relationship of serum leptin and reproductive hormones in unexplained infertile and fertile females. Cureus, 2019, 11(12), e6524.
[http://dx.doi.org/10.7759/cureus.6524] [PMID: 32025443]
[18]
Baig, M.; Rehman, R.; Tariq, S.; Fatima, S.S. Serum leptin levels in polycystic ovary syndrome and its relationship with metabolic and hormonal profile in pakistani females. Int. J. Endocrinol., 2014, 2014, 132908.
[http://dx.doi.org/10.1155/2014/132908] [PMID: 25587271]
[19]
Hahn, S.; Haselhorst, U.; Quadbeck, B.; Tan, S.; Kimmig, R.; Mann, K.; Janssen, O.E. Decreased soluble leptin receptor levels in women with polycystic ovary syndrome. Eur. J. Endocrinol., 2006, 154(2), 287-294.
[http://dx.doi.org/10.1530/eje.1.02078] [PMID: 16452543]
[20]
Pirwany, I.R.; Fleming, R.; Sattar, N.; Greer, I.A.; Wallace, A.M. Circulating leptin concentrations and ovarian function in polycystic ovary syndrome. Eur. J. Endocrinol., 2001, 145(3), 289-294.
[http://dx.doi.org/10.1530/eje.0.1450289] [PMID: 11517009]
[21]
Telli, M.H.; Yildirim, M.; Noyan, V. Serum leptin levels in patients with polycystic ovary syndrome. Fertil. Steril., 2002, 77(5), 932-935.
[http://dx.doi.org/10.1016/S0015-0282(02)02995-3] [PMID: 12009346]
[22]
Chakrabarti, J. Serum leptin level in women with polycystic ovary syndrome: Correlation with adiposity, insulin, and circulating testosterone. Ann. Med. Health Sci. Res., 2013, 3(2), 191-196.
[http://dx.doi.org/10.4103/2141-9248.113660] [PMID: 23919188]
[23]
Ramanand, S.; Ramanand, J.; Jain, S.; Raparti, G.; Ghanghas, R.; Halasawadekar, N.; Patil, P.; Pawar, M. Leptin in non PCOS and PCOS women: A comparative study. Int. J. Basic Clin. Pharmacol., 2014, 3(1), 186.
[http://dx.doi.org/10.5455/2319-2003.ijbcp20140224]
[24]
El-Gharib, M.; Badawy, T. Correlation between insulin, leptin and polycystic ovary syndrome. J. Basic Clinic. Reprod. Sci., 2014, 3(1), 49.
[http://dx.doi.org/10.4103/2278-960X.129281]
[25]
Chiu, K.C.; Chu, A.; Chuang, L.M.; Saad, M.F. Association of leptin receptor polymorphism with insulin resistance. Eur. J. Endocrinol., 2004, 150(5), 725-729.
[http://dx.doi.org/10.1530/eje.0.1500725] [PMID: 15132731]
[26]
Frühbeck, G. Intracellular signalling pathways activated by leptin. Biochem. J., 2006, 393(1), 7-20.
[http://dx.doi.org/10.1042/BJ20051578] [PMID: 16336196]
[27]
Matsuda, J.; Masuzaki, H.; Miyawaki, T.; Azuma, N.; Nishimura, H.; Nishi, S.; Thompson, D.B.; Nakao, K.; Natsui, K.; Hosoda, K.; Ogawa, Y.; Matsuoka, N.; Yoshimasa, Y. Human leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or association of sequence variants with obesity. Diabetologia, 1997, 40(10), 1204-1210.
[http://dx.doi.org/10.1007/s001250050808] [PMID: 9349603]
[28]
Oksanen, L.; Tiitinen, A.; Kaprio, J.; Koistinen, H.A.; Karonen, S.; Kontula, K. No evidence for mutations of the leptin or leptin receptor genes in women with polycystic ovary syndrome. Mol. Hum. Reprod., 2000, 6(10), 873-876.
[http://dx.doi.org/10.1093/molehr/6.10.873] [PMID: 11006314]
[29]
Erel, C.T.; Cine, N.; Elter, K.; Kaleli, S.; Senturk, L.M.; Baysal, B. Leptin receptor variant in women with polycystic ovary syndrome. Fertil. Steril., 2002, 78(6), 1334-1335.
[http://dx.doi.org/10.1016/S0015-0282(02)04352-2] [PMID: 12477538]
[30]
Daghestani, M.H.; Daghestani, M.H.; Daghistani, M.H.; Bjørklund, G.; Chirumbolo, S.; Warsy, A. The influence of the rs1137101 genotypes of leptin receptor gene on the demographic and metabolic profile of normal Saudi females and those suffering from polycystic ovarian syndrome. BMC Womens Health, 2019, 19(1), 10.
[http://dx.doi.org/10.1186/s12905-018-0706-x] [PMID: 30635060]
[31]
Tu, X.; Yu, C.; Gao, M.; Zhang, Y.; Zhang, Z.; He, Y.; Yao, L.; Du, J.; Sun, Y.; Sun, Z. LEPR gene polymorphism and plasma soluble leptin receptor levels are associated with polycystic ovary syndrome in Han Chinese women. Per. Med., 2017, 14(4), 299-307.
[http://dx.doi.org/10.2217/pme-2017-0016] [PMID: 29749830]
[32]
Chen, Z.J.; Zhao, H.; He, L.; Shi, Y.; Qin, Y.; Shi, Y.; Li, Z.; You, L.; Zhao, J.; Liu, J.; Liang, X.; Zhao, X.; Zhao, J.; Sun, Y.; Zhang, B.; Jiang, H.; Zhao, D.; Bian, Y.; Gao, X.; Geng, L.; Li, Y.; Zhu, D.; Sun, X.; Xu, J.; Hao, C.; Ren, C.; Zhang, Y.; Chen, S.; Zhang, W.; Yang, A.; Yan, J.; Li, Y.; Ma, J.; Zhao, Y.; Zhao, Y. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat. Genet., 2011, 43(1), 55-59.
[http://dx.doi.org/10.1038/ng.732] [PMID: 21151128]
[33]
Sampurna, K.; Ramesh, B.; Rajesh, B.; Madhavi, S.; Parveen, S.; Bhargav, P.R.K.; Vimala Devi, N.; Gayathri, K.B. Genotype-Phenotype correlations of Leptin receptor gene in Polycystic ovarian disease (PCOS). IOSR J. Biotechnol. Biochem., 2018, 4(1), 20-27.
[http://dx.doi.org/10.9790/264X-04012027]
[34]
Rajesh, B.; Ramesh, B.; Gayathri, G.; Venkateshwara Reddy, M.; Vighnesh, D.; Rajkiran Reddy, B.; Chakrapani, B.; Bhargav, P.R.K. Genotype- phenotype correlations of TNF-[Alpha], IL-6 and leptin receptor gene polymorphisms in poly cystic ovarian syndrome. Endocrine Abstracts, 2018, 56, P528.
[http://dx.doi.org/10.1530/endoabs.56.P528]
[35]
Smaism, M.F. Assessment of leptin levels in the different genotypes and leptin receptor genes in the women with polycystic ovary syndrome and diabetes mellitus Type 2 in Iraq Population. Int. J. Pharm. Tech. Res., 2016, 9(5), 269-276.
[36]
Liang, J.; Lan, J.; Li, M.; Wang, F. Associations of Leptin Receptor and peroxisome proliferator-activated receptor gamma Polymorphisms with polycystic ovary syndrome: A meta-analysis. Ann. Nutr. Metab., 2019, 75(1), 1-8.
[http://dx.doi.org/10.1159/000500996] [PMID: 31412346]
[37]
Mendonça, H.C.; Montenegro, Junior, R.M.; Foss, M.C.; Silva de Sá, M.F.; Ferriani, R.A. Positive correlation of serum leptin with estradiol levels in patients with polycystic ovary syndrome. Braz. J. Med. Biol. Res., 2004, 37(5), 729-736.
[http://dx.doi.org/10.1590/S0100-879X2004000500015] [PMID: 15107936]
[38]
Bidzińska-Speichert, B.; Lenarcik, A.; Tworowska-Bardzińska, U.; Slezak, R.; Bednarek-Tupikowska, G.; Milewicz, A.; Krepuła, K. Pro12Ala PPAR gamma2 gene polymorphism in women with polycystic ovary syndrome. Ginekol. Pol., 2011, 82(6), 426-429.
[PMID: 21853931]
[39]
Ashrafi, M.S.; Farzaneh, T. Gln223arg Leptin Receptor Genetic Variation In Women With Unexplained Infertility And Fertile Women. J. Sabzavar Univer. Medic. Sci., 2018, 25(2), 127-134.

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