Adipokinesand Ghrelin Rolein Regulation of Ovarian Function in Obesity
https://doi.org/10.14341/omet12825
Abstract
There is a great worldwide trend in the incidence of obesity, which is increasing with each passing year among all populations, including women of reproductive age. Given the impressive list of diseases associated with obesity, as well as the negative inverse correlation of the severity of obesity with fertility, this problem is global not only in the social sphere, but it also becomes demographically significant.
Along with other pathogenetic mechanisms leading to persistent anovulation, an imbalance in adipokine production by adipose tissue can also serve as one of the important links in the development of reproductive dysfunction. Despite apparent interest in this topic, a large number of previously discovered adipokines are still not studied. Among adipokines, the effects of adiponectin and leptin on reproductive function are best known. Alterations in adiponectin and leptin levels can affect hypothalamic-pituitary-gonadal signaling, folliculogenesis, oogenesis and steroidogenesis. In addition, leptin is involved in the initiation of puberty, regulation of the menstrual cycle, and changes the balance between proliferation and apoptosis in ovarian cells. The leading causes of reduced fertility, infertility, and IVF failure in obese patients are mechanisms that promote the formation of chronic anovulation, delay the maturation of oocytes, reduce their quality, and/or lead to changes in endometrial susceptibility. These effects can be caused by an imbalance in the concentrations of leptin and adiponectin (leptin excess and adiponectin deficiency), lead to endometrial dysfunction, disruption of implantation and early embryogenesis. These changes, in turn, can affect just as the likelihood of spontaneous conception, so the effectiveness of assisted reproductive technologies and subsequent gestation.
Thus, the study of potential pathogenetic pathways of fertility regulation in obesity, one of which is the subject of this review, is an important area for further study.
About the Authors
A. I. AbdusalamovaRussian Federation
Albina I. Abdusalamova, MD
Saint Petersburg
O. A. Bettikher
Almazov National Medical Research Centre; The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott
Russian Federation
Ofelia A. Bettikher, MD, PhD
2В Akkuratova street, 197341, Saint Petersburg
Researcher ID: AAH-8832-2020;
Scopus Author ID: 57190122861;
eLibrary SPIN: 4398-3964
K. A. Rudenko
Russian Federation
Kseniia A. Rudenko, postgraduate student
Saint Petersburg
Researcher ID: ABC-1438-2021;
eLibrary SPIN: 3534-4785
O. A. Belyaeva
Russian Federation
Olga A. Belyaeva, MD
Saint Petersburg
A. E. Neimark
Almazov National Medical Research Centre
Russian Federation
Aleksandr E. Neimark, MD, PhD
Saint Petersburg
Researcher ID: AAT-9752-2021;
Scopus Author ID: 56651924200;
eLibrary SPIN: 6554-3217
I. E. Zazerskaya
Almazov National Medical Research Centre; The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott
Russian Federation
Irina E. Zazerskaya, MD, PhD, Professor
Saint Petersburg
Researcher ID: AAI-1309-2020;
Scopus Author ID: 55981393900;
еLibrary SPIN: 5683-6741
References
1. Dedov II, Shestakova M V., Melnichenko GA, et al. Interdisciplinary clinical practice guidelines “Management of obesity and its comorbidities.” Obesity and metabolism. 2021;18(1):5-99. (In Russ.). doi: https://doi.org/10.14341/omet12714
2. Obesity and overweight. Who.int [Internet]. 9 June 2021 [cited 13.01.2022]. Available from: http://www.who.int/mediacentre/factsheets/fs311/en/
3. Tsallagova EV, Prilepskaya VN. Obesity and women’s health: from menarche to menopause. Gynecology. 2019;21(5): 7-11. (In Russ.). doi: https://doi.org/10.26442/20795696.2019.5.190732
4. Zhu L, Zhou B, Zhu X, et al. Association Between Body Mass Index and Female Infertility in the United States: Data from National Health and Nutrition Examination Survey 2013–2018. Int J Gen Med. 2022;(15):1821-1831. doi: https://doi.org/10.2147/IJGM.S349874
5. García-Ferreyra J, Carpio J, Zambrano M, et al. Overweight and obesity significantly reduce pregnancy, implantation, and live birth rates in women undergoing In Vitro Fertilization procedures. JBRA Assist Reprod. 2021;25(3):394-402. doi: https://doi.org/10.5935/1518-0557.20200105
6. Silvestris E, de Pergola G, Rosania R, Loverro G. Obesity as disruptor of the female fertility. Reprod Biol Endocrinol. 2018;16(1):22. doi: https://doi.org/10.1186/s12958-018-0336-z
7. Maiborodina D, Antonenko M, Komisarenko Y, Stolyar V. Adipocytokines leptin and adiponeсtin as predictors of generalized periodontitis associated with obesity. Georgian Med News. 2021;(312):42-46.
8. Dubinskaya ED, Aleshkina EV, Gasparov AS, et al. Obesity and fertility. Vopr Ginekol akušerstva i Perinatol. 2018;17(6):76-84. (In Russ.). doi: https://doi.org/10.20953/1726-1678-2018-6-76-84
9. Khanna D, Rehman A. Pathophysiology of obesity. 2022 Jun 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.
10. Lainez NM, Coss D. Obesity, neuroinflammation, and reproductive function. Endocrinology. 2019;160(11):2719-2736. doi: https://doi.org/10.1210/en.2019-00487
11. McPherson RA, Pincus MR. Henry’s clinical diagnosis and management by laboratory methods, 24th Edition. Elsevier; 2021. 974 p.
12. Kurowska P, Mlyczyńska E, Dawid M, et al. Adipokines change the balance of proliferation/apoptosis in the ovarian cells of human and domestic animals: A comparative review. Anim Reprod Sci. 2021;(228):106737. doi: https://doi.org/10.1016/j.anireprosci.2021.106737
13. Barbe A, Bongrani A, Mellouk N, et al. Mechanisms of adiponectin action in fertility: an overview from gametogenesis to gestation in humans and animal models in normal and pathological conditions. Int J Mol Sci. 2019;20(7):1526. doi: https://doi.org/10.3390/ijms20071526
14. Estienne A, Brossaud A, Reverchon M, et al. Adipokines expression and effects in oocyte maturation, fertilization and early embryo development: lessons from mammals and birds. Int J Mol Sci. 2020;21(10):3581. doi: https://doi.org/10.3390/ijms21103581
15. Elagin IB, Orazov MR, Semyonov PA. Pathogenesis of impaired fertility in obese women. Difficult patient. 2020;18(1-2):36-43. (In Russ.). doi: https://doi.org/10.24411/2074-1995-2020-10007
16. Alam Q, Alam MZ, Mushtaq G, et al. Inflammatory Process in Alzheimer’s and Parkinson’s Diseases: Central Role of Cytokines. Curr Pharm Des. 2016;22(5):541-548. doi: https://doi.org/10.2174/1381612822666151125000300
17. Goldsammler M, Merhi Z, Buyuk E. Role of hormonal and inflammatory alterations in obesity-related reproductive dysfunction at the level of the hypothalamic-pituitary-ovarian axis. Reprod Biol Endocrinol. 2018;16(1):45. doi: https://doi.org/10.1186/s12958-018-0366-6
18. Nikanfar S, Oghbaei H, Rastgar Rezaei Y, et al. Role of adipokines in the ovarian function: Oogenesis and steroidogenesis. J Steroid Biochem Mol Biol. 2021;209(6):105852. doi: https://doi.org/10.1016/j.jsbmb.2021.105852
19. Bilbao MG, Di Yorio MP, Galarza RA, et al. Regulation of the ovarian oxidative status by leptin during the ovulatory process in rats. Reproduction. 2015;149(4):357-366. doi: https://doi.org/10.1530/REP-14-0536
20. Cheng L, Shi H, Jin Y, et al. Adiponectin deficiency leads to female subfertility and ovarian dysfunctions in mice. Endocrinology. 2016;157(12):4875-4887. doi: https://doi.org/10.1210/en.2015-2080
21. Merhi Z, Bazzi AA, Bonney EA, Buyuk E. Role of adiponectin in ovarian follicular development and ovarian reserve. Biomed Rep. 2019;1(1):1-5. doi: https://doi.org/10.3892/br.2019.1213
22. Chappaz E, Albornoz MS, Campos D, et al. Adiponectin enhances in vitro development of swine embryos. Domest Anim Endocrinol. 2008;35(2):198-207. doi: https://doi.org/10.1016/j.domaniend.2008.05.007
23. Gomes ET, Costa JAS, Silva DMF, et al. Effects of adiponectin during in vitro maturation of goat oocytes: MEK 1/2 pathway and gene expression pattern. Reprod Domest Anim. 2018;53(6):1323-1329. doi: https://doi.org/10.1111/rda.13251
24. Ledoux S, Campos DB, Lopes FL, et al. Adiponectin induces periovulatory changes in ovarian follicular cells. Endocrinology. 2006;147(11):5178-5186. doi: https://doi.org/10.1210/en.2006-0679
25. Comim FV, Gutierrez K, Bridi A, et al. Effects of adiponectin including reduction of androstenedione secretion and ovarian oxidative stress parameters in vivo. PLoS One. 2016;11(5):e0154453. doi: https://doi.org/10.1371/journal.pone.0154453
26. Smolinska N, Szeszko K, Dobrzyn K, et al. Transcriptomic Analysis of Porcine Endometrium during Implantation after In Vitro Stimulation by Adiponectin. Int J Mol Sci. 2019;20(6):1335. doi: https://doi.org/10.3390/ijms20061335
27. Lin K, Sun X, Wang X, et al. Circulating adipokine levels in nonobese women with polycystic ovary syndrome and in nonobese control women: A systematic review and meta-analysis. Front Endocrinol (Lausanne). 2021;11:537809. doi: https://doi.org/10.3389/fendo.2020.537809
28. Vedzizheva ER, Uspenskaya YuB, Gitel EP, Kuznetsova IV. The influence of obesity and dyslipidemia on ghrelin production in women of reproductive age. Gynecology. 2017; 19 (2): 29–33 (In Russ.).
29. Kurowska P, Mlyczyńska E, Dawid M, et al. Adipokines change the balance of proliferation/apoptosis in the ovarian cells of human and domestic animals: A comparative review. Anim Reprod Sci. 2021;228:106737. doi: https://doi.org/10.1016/j.anireprosci.2021.106737
30. Balogh O, Kowalewski MP, Reichler IM. Leptin and leptin receptor gene expression in the canine corpus luteum during diestrus, pregnancy and after aglepristone-induced luteolysis. Reprod Domest Anim. 2012;47(S6):40-42. doi: https://doi.org/10.1111/rda.12005
31. Ryzhov JR, Shpakov AO, Gzgzyan AM. Leptin role in reproductive system regulation and its perspectives in assisted reproductive technologies. Problemy Reproduktsii. 2020;26(2):53. (In Russ.). doi: https://doi.org/10.17116/repro20202602153
32. Karelina OB, Artymuk NV. leptin serum level in women with obesity do not define leptin cord blood level in their newborns. Fundamental and Clinical Medicine. 2017;2(3):21-27. (In Russ.).
33. Reshma R, Mishra SR, Thakur N, et al. Modulatory role of leptin on ovarian functions in water buffalo (Bubalus bubalis). Theriogenology. 2016;86(7):1720-1739. doi: https://doi.org/10.1016/j.theriogenology.2016.05.029
34. Bernardi O, Estienne A, Reverchon M, et al. Adipokines in metabolic and reproductive functions in birds: An overview of current knowns and unknowns. Mol Cell Endocrinol. 2021;534(2):111370. doi: https://doi.org/10.1016/j.mce.2021.111370
35. Evans MC, Lord RA, Anderson GM. Multiple Leptin Signalling Pathways in the Control of Metabolism and Fertility: A Means to Different Ends? Int J Mol Sci. 2021;22(17):9210. doi: https://doi.org/10.3390/ijms22179210
36. Peng Y, Yang H, Song J, et al. Elevated Serum Leptin Levels as a Predictive Marker for Polycystic Ovary Syndrome. Front Endocrinol (Lausanne). 2022;13(2):111370. doi: https://doi.org/10.3389/fendo.2022.845165
37. Anifandis G, Koutselini E, Stefanidis I, et al. Serum and follicular fluid leptin levels are correlated with human embryo quality. Reproduction. 2005;130(6):917-921. doi: https://doi.org/10.1530/rep.1.00705
38. Münzberg H, Morrison CD. Structure, production and signaling of leptin. Metabolism. 2015;64(1):13-23. doi: https://doi.org/10.1016/j.metabol.2014.09.010
39. Castro NP, Euclydes VV, Simões FA, et al. The Relationship between Maternal Plasma Leptin and Adiponectin Concentrations and Newborn Adiposity. Nutrients. 2017;9(3):182. doi: https://doi.org/10.3390/nu9030182
40. Patenaude J, Lacerte G, Lacroix M, et al. Associations of Maternal Leptin with Neonatal Adiposity Differ according to Pregravid Weight. Neonatology. 2017;111(4):344-352. doi: https://doi.org/10.1159/000454756
41. Estienne A, Bongrani A, Reverchon M, et al. Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models. Int J Mol Sci. 2019;20(18):4431. doi: https://doi.org/10.3390/ijms20184431
42. Cabral A, López Soto EJ, Epelbaum J, Perelló M. Is Ghrelin Synthesized in the Central Nervous System? Int J Mol Sci. 2017;18(3):638. doi: https://doi.org/10.3390/ijms18030638
43. Uriarte M, De Francesco PN, Fernández G, et al. Circulating ghrelin crosses the blood-cerebrospinal fluid barrier via growth hormone secretagogue receptor dependent and independent mechanisms. Mol Cell Endocrinol. 2021;538(2):111449. doi: https://doi.org/10.1016/j.mce.2021.111449
44. Chan JL, Bullen J, Lee JH, et al. Ghrelin levels are not regulated by recombinant leptin administration and/or three days of fasting in healthy subjects. J Clin Endocrinol Metab. 2004;89(1):335-343. doi: https://doi.org/10.1210/jc.2003-031412
45. Sun Y, Wang P, Zheng H, Smith RG. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci U S A. 2004;101(13):4679-4684. doi: https://doi.org/10.1073/pnas.0305930101
46. Schalla MA, Stengel A. The Role of the Gastric Hormones Ghrelin and Nesfatin-1 in Reproduction. Int J Mol Sci. 2021;22(20):11059. doi: https://doi.org/10.3390/ijms222011059
47. Sominsky L, Goularte JF, Andrews ZB, Spencer SJ. Acylated Ghrelin Supports the Ovarian Transcriptome and Follicles in the Mouse: Implications for Fertility. Front Endocrinol (Lausanne). 2019;9(2):111449. doi: https://doi.org/10.3389/fendo.2018.00815
48. Jang H, Na Y, Hong K, et al. Synergistic effect of melatonin and ghrelin in preventing cisplatin-induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27 Kip1 promoter in primordial follicles. J Pineal Res. 2017;63(3):e12432. doi: https://doi.org/10.1111/jpi.12432
49. Kheradmand A, Roshangar L, Taati M, Sirotkin AV. Morphometrical and intracellular changes in rat ovaries following chronic administration of ghrelin. Tissue Cell. 2009;41(5):311-317. doi: https://doi.org/10.1016/j.tice.2009.01.002
50. Luque EM, Carlini VP, Vincenti LM, et al. Effects of hexarelin (a ghrelin analogue) on fertilisation and the pre- and postnatal development of mice. Reprod Fertil Dev. 2010;22(6):926-938. doi: https://doi.org/10.1071/RD09231
51. Xu XL, Bai JH, Feng T, et al. N-octanoylated ghrelin peptide inhibits bovine oocyte meiotic resumption. Gen Comp Endocrinol. 2018;263(3):7-11. doi: https://doi.org/10.1016/j.ygcen.2018.04.016
52. Chouzouris TM, Dovolou E, Krania F, et al. Effects of ghrelin on activation of Akt1 and ERK1/2 pathways during in vitro maturation of bovine oocytes. Zygote. 2017;25(2):183-189. doi: https://doi.org/10.1017/S096719941700003X
53. Du C, Li H, Cao G, et al. Expression of the orexigenic peptide ghrelin and the type 1a growth hormone secretagogue receptor in sheep oocytes and pre-implantation embryos produced in vitro. Reprod Domest Anim. 2010;45(1):92-98. doi: https://doi.org/10.1111/j.1439-0531.2008.01259.x
54. Luque EM, Torres PJ, de Loredo N, et al. Role of ghrelin in fertilization, early embryo development, and implantation periods. Reproduction. 2014;148(2):159-167. doi: https://doi.org/10.1530/REP-14-0129
55. Wang D, Yang Y, Song Y, et al. The Effect of Ghrelin on the Maturation of Sheep Oocytes and Early Embryonic Development In Vitro. Animals (Basel). 2022;12(9):1158. doi: https://doi.org/10.3390/ani12091158
56. Li L, Ferin M, Sauer MV, Lobo RA. Serum and follicular fluid ghrelin levels negatively reflect human oocyte quality and in vitro embryo development. Fertil Steril. 2011;96(5):1116-1120. doi: https://doi.org/10.1016/j.fertnstert.2011.08.017
57. Tanaka K, Minoura H, Isobe T, et al. Ghrelin Is Involved in the Decidualization of Human Endometrial Stromal Cells. J Clin Endocrinol Metab. 2003;88(5):2335-2340. doi: https://doi.org/10.1210/jc.2002-021024
58. Martin JR, Lieber SB, McGrath J, et al. Maternal ghrelin deficiency compromises reproduction in female progeny through altered uterine developmental programming. Endocrinology. 2011;152(5):2060-2066. doi: https://doi.org/10.1210/en.2010-1485
59. Xu L, Shi Y, Gu J, et al. Association between ghrelin gene variations, body mass index, and waist-to-hip ratio in patients with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2014;122(3):144-148. doi: https://doi.org/10.1055/s-0034-1367024
60. Schöfl C, Horn R, Schill T, et al. Circulating ghrelin levels in patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(10):4607-4610. doi: https://doi.org/10.1210/jc.2002-020505
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For citations:
Abdusalamova A.I., Bettikher O.A., Rudenko K.A., Belyaeva O.A., Neimark A.E., Zazerskaya I.E. Adipokinesand Ghrelin Rolein Regulation of Ovarian Function in Obesity. Obesity and metabolism. 2022;19(3):324-331. (In Russ.) https://doi.org/10.14341/omet12825

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