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Downregulation of adiponectin system in granulosa cells and low levels of HMW adiponectin in PCOS

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

The purpose of the study was to investigate changes in adiponectin system expression in granulosa cells (GCs) and high molecular weight adiponectin levels in serum and follicular fluid (FF) of 40 women with polycystic ovary syndrome (PCOS) compared to those in 40 women with normal ovary function.

Methods

Adiponectin (Adipo), adiponectin receptor 1 (AdipoR1), and adiponectin receptor 2 (AdipoR2) messenger RNA (mRNA) expression levels were measured using quantitative real-time polymerase chain reaction (qRT-PCR). High molecular weight (HMW) adiponectin protein concentration was evaluated by ELISA method. Data were analyzed using Student’s t test and one-way ANOVA in SPSS 21 software. At oocyte retrieval, FF was aspirated and GCs were obtained from a pooled collection of FF per each patient.

Results

PCR results showed expression of adiponectin, AdipoR1, AdipoR2, follicle-stimulating hormone receptor (FSHR), and luteinizing hormone receptor (LHR) in GCs. After controlling body mass index (BMI) values, qRT-PCR demonstrated a decreased expression of adiponectin system in GCs of PCOS patients compared to those in controls (p = 0.001). There was a strong positive correlation among AdipoR1 and AdipoR2 expression and also among FSH and LH receptor expression. (Both r = 0.8, p = 0.001). There were low levels of high molecular weight adiponectin in the serum of PCOS patients with controlled ovarian hyperstimulation (30.19 ± 4.3 ng/ml) compared to the controls (48.47 ± 5.9 ng/ml) and in the FF of PCOS patients with controlled ovarian hyperstimulation (7.86 ± 1.44 ng/ml) compared to the controls (14.22 ± 2.01 ng/ml; p = 0.02).

Conclusions

Lower expression of adiponectin and its receptors in GCs might be an important manifestation in gonadotropin-stimulated PCOS patients which could influence the physiologic adiponectin roles such as interaction with insulin and LH in induction of GC gene expression.

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References

  1. Webber LJ, Stubbs SA, Stark J, Margara RA, Trew GH, Lavery SA, et al. Prolonged survival in culture of preantral follicles from polycystic ovaries. J Clin Endocrinol Metab. 2007;92(5):1975–8. doi:10.1210/jc.2006-1422.

    Article  PubMed  CAS  Google Scholar 

  2. Sartor BM, Dickey RP. Polycystic ovarian syndrome and the metabolic syndrome. Am J Med Sci. 2005;330(6):336–42.

    Article  PubMed  Google Scholar 

  3. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007;13(3):332–9. doi:10.1038/nm1557.

    Article  PubMed  CAS  Google Scholar 

  4. Takemura Y, Osuga Y, Yamauchi T, Kobayashi M, Harada M, Hirata T, et al. Expression of adiponectin receptors and its possible implication in the human endometrium. Endocrinology. 2006;147(7):3203–10.

    Article  PubMed  CAS  Google Scholar 

  5. Guerre-Millo M. Adiponectin: an update. Diabetes Metab. 2008;34(1):12–8. doi:10.1016/j.diabet.2007.08.002.

    Article  PubMed  CAS  Google Scholar 

  6. Maddineni S, Metzger S, Ocon O, Hendricks 3rd G, Ramachandran R. Adiponectin gene is expressed in multiple tissues in the chicken: food deprivation influences adiponectin messenger ribonucleic acid expression. Endocrinology. 2005;146(10):4250–6. doi:10.1210/en.2005-0254.

    Article  PubMed  CAS  Google Scholar 

  7. Chabrolle C, Tosca L, Crochet S, Tesseraud S, Dupont J. Expression of adiponectin and its receptors (AdipoR1 and AdipoR2) in chicken ovary: potential role in ovarian steroidogenesis. Domest Anim Endocrinol. 2007;33(4):480–7. doi:10.1016/j.domaniend.2006.08.002.

    Article  PubMed  CAS  Google Scholar 

  8. Chappaz E, Albornoz MS, Campos D, Che L, Palin MF, Murphy BD, et al. Adiponectin enhances in vitro development of swine embryos. Domest Anim Endocrinol. 2008;35(2):198–207. doi:10.1016/j.domaniend.2008.05.007.

    Article  PubMed  CAS  Google Scholar 

  9. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. 2005;26(3):439–51. doi:10.1210/er.2005-0005.

    Article  PubMed  CAS  Google Scholar 

  10. Michalakis KG, Segars JH. The role of adiponectin in reproduction: from polycystic ovary syndrome to assisted reproduction. Fertility and Sterility. 2010;94(6).

  11. Richards JS, Liu Z, Kawai T, Tabata K, Watanabe H, Suresh D, et al. Adiponectin and its receptors modulate granulosa cell and cumulus cell functions, fertility, and early embryo development in the mouse and human. Fertil Steril. 2012;98(2):471–9. e1.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Pierre P, Froment P, Negre D, Rame C, Barateau V, Chabrolle C et al. Role of adiponectin receptors, AdipoR1 and AdipoR2, in the steroidogenesis of the human granulosa tumor cell line, KGN. Human reproduction. 2009:dep292.

  13. Ledoux S, Campos DB, Lopes FL, Dobias-Goff M, Palin MF, Murphy BD. Adiponectin induces periovulatory changes in ovarian follicular cells. Endocrinology. 2006;147(11):5178–86. doi:10.1210/en.2006-0679.

    Article  PubMed  CAS  Google Scholar 

  14. Mao X, Kikani CK, Riojas RA, Langlais P, Wang L, Ramos FJ, et al. APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol. 2006;8(5):516–23.

    Article  PubMed  CAS  Google Scholar 

  15. Nechamen CA, Thomas RM, Cohen BD, Acevedo G, Poulikakos PI, Testa JR, et al. Human follicle-stimulating hormone (FSH) receptor interacts with the adaptor protein APPL1 in HEK 293 cells: potential involvement of the PI3K pathway in FSH signaling. Biol Reprod. 2004;71(2):629–36.

    Article  PubMed  CAS  Google Scholar 

  16. Mihm M, Evans A. Mechanisms for dominant follicle selection in monovulatory species: a comparison of morphological, endocrine and intraovarian events in cows, mares and women. Reprod Domest Anim. 2008;43(s2):48–56.

    Article  PubMed  Google Scholar 

  17. Jeppesen JV, Kristensen SG, Nielsen ME, Humaidan P, Dal Canto M, Fadini R, et al. LH-receptor gene expression in human granulosa and cumulus cells from antral and preovulatory follicles. J Clin Endocrinol Metab. 2012;97(8):E1524–31.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Yding Andersen C, Bungum L, Nyboe Andersen A, Humaidan P. Preovulatory progesterone concentration associates significantly to follicle number and LH concentration but not to pregnancy rate. Reprod biomed online. 2011;23(2):187–95.

    Article  PubMed  Google Scholar 

  19. Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update. 2005;11(4):391–410.

    Article  PubMed  CAS  Google Scholar 

  20. Voronina E, Lovasco LA, Gyuris A, Baumgartner RA, Parlow AF, Freiman RN. Ovarian granulosa cell survival and proliferation requires the gonad-selective TFIID subunit TAF4b. Dev Biol. 2007;303(2):715–26.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Jonard S, Dewailly D. The follicular excess in polycystic ovaries, due to intra‐ovarian hyperandrogenism, may be the main culprit for the follicular arrest. Hum Reprod Update. 2004;10(2):107–17.

    Article  PubMed  Google Scholar 

  22. Das M, Djahanbakhch O, Hacihanefioglu B, Saridogan E, Ikram M, Ghali L, et al. Granulosa cell survival and proliferation are altered in polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93(3):881–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Ferrero H, Delgado-Rosas F, Garcia-Pascual CM, Monterde M, Zimmermann RC, Simón C, et al. Efficiency and purity provided by the existing methods for the isolation of luteinized granulosa cells: a comparative study. Hum Reprod. 2012;27(6):1781–9.

    Article  PubMed  CAS  Google Scholar 

  24. Acosta E, Peña Ó, Naftolin F, Ávila J, Palumbo A. Angiotensin II induces apoptosis in human mural granulosa-lutein cells, but not in cumulus cells. Fertil Steril. 2009;91(5):1984–9.

    Article  PubMed  CAS  Google Scholar 

  25. Quinn M, McGregor S, Stanton J, Hessian P, Gillett W, Green D. Purification of granulosa cells from human ovarian follicular fluid using granulosa cell aggregates. Reprod Fertil Dev. 2006;18(5):501–8.

    Article  PubMed  CAS  Google Scholar 

  26. Chilvers R, Bodenburg Y, Denner L, Urban R. Development of a novel protocol for isolation and purification of human granulosa cells. J Assist Reprod Genet. 2012;29(6):547–56.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Centurione L, Giampietro F, Sancilio S, Piccirilli M, Artese L, Tiboni GM, et al. Morphometric and ultrastructural analysis of human granulosa cells after gonadotrophin-releasing hormone agonist or antagonist. Reprod biomed online. 2010;20(5):625–33.

    Article  PubMed  CAS  Google Scholar 

  28. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2< sup>− ΔΔCT</sup> method. Methods. 2001;25(4):402–8.

    Article  PubMed  CAS  Google Scholar 

  29. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3(6):1101–8.

    Article  PubMed  CAS  Google Scholar 

  30. Blüher M, Williams CJ, Klöting N, Hsi A, Ruschke K, Oberbach A, et al. Gene expression of adiponectin receptors in human visceral and subcutaneous adipose tissue is related to insulin resistance and metabolic parameters and is altered in response to physical training. Diabetes Care. 2007;30(12):3110–5.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ahima RS, Lazar MA. Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol. 2008;22(5):1023–31.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Trujillo ME, Scherer PE. Adipose tissue-derived factors: impact on health and disease. Endocr Rev. 2006;27(7):762–78.

    Article  PubMed  CAS  Google Scholar 

  33. Carmina E, Bucchieri S, Mansueto P, Rini G, Ferin M, Lobo RA. Circulating levels of adipose products and differences in fat distribution in the ovulatory and anovulatory phenotypes of polycystic ovary syndrome. Fertil Steril. 2009;91(4):1332–5.

    Article  PubMed  Google Scholar 

  34. Aroda V, Ciaraldi TP, Chang S-A, Dahan MH, Chang RJ, Henry RR. Circulating and cellular adiponectin in polycystic ovary syndrome: relationship to glucose tolerance and insulin action. Fertil Steril. 2008;89(5):1200–8.

    Article  PubMed  CAS  Google Scholar 

  35. Zhang N, Shi Y-H, Hao C-F, Gu HF, Li Y, Zhao Y-R, et al. Association of +45G15G (T/G) and +276 (G/T) polymorphisms in the ADIPOQ gene with polycystic ovary syndrome among Han Chinese women. Eur J Endocrinol. 2008;158(2):255–60.

    Article  PubMed  CAS  Google Scholar 

  36. Orio Jr F, Palomba S, Cascella T, Milan G, Mioni R, Pagano C, et al. Adiponectin levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88(6):2619–23.

    Article  PubMed  CAS  Google Scholar 

  37. Panidis D, Kourtis A, Farmakiotis D, Mouslech T, Rousso D, Koliakos G. Serum adiponectin levels in women with polycystic ovary syndrome. Hum Reprod. 2003;18(9):1790–6.

    Article  PubMed  CAS  Google Scholar 

  38. Shroff R, Kerchner A, Maifeld M, Van Beek EJ, Jagasia D, Dokras A. Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis. J Clin Endocrinol Metab. 2007;92(12):4609–14.

    Article  PubMed  CAS  Google Scholar 

  39. Barber TM, Hazell M, Christodoulides C, Golding SJ, Alvey C, Burling K, et al. Serum levels of retinol-binding protein 4 and adiponectin in women with polycystic ovary syndrome: associations with visceral fat but no evidence for fat mass-independent effects on pathogenesis in this condition. J Clin Endocrinol Metab. 2008;93(7):2859–65.

    Article  PubMed  CAS  Google Scholar 

  40. Chabrolle C, Tosca L, Rame C, Lecomte P, Royere D, Dupont J. Adiponectin increases insulin-like growth factor I-induced progesterone and estradiol secretion in human granulosa cells. Fertil Steril. 2009;92(6):1988–96. doi:10.1016/j.fertnstert.2008.09.008.

    Article  PubMed  CAS  Google Scholar 

  41. Chabrolle C, Tosca L, Dupont J. Regulation of adiponectin and its receptors in rat ovary by human chorionic gonadotrophin treatment and potential involvement of adiponectin in granulosa cell steroidogenesis. Reproduction. 2007;133(4):719–31. doi:10.1530/REP-06-0244.

    Article  PubMed  CAS  Google Scholar 

  42. Maillard V, Uzbekova S, Guignot F, Perreau C, Ramé C, Coyral-Castel S, et al. Effect of adiponectin on bovine granulosa cell steroidogenesis, oocyte maturation and embryo development. Reprod Biol Endocrinol. 2010;8(23):10.1186.

    Google Scholar 

  43. Campos DB, Palin MF, Bordignon V, Murphy BD. The ‘beneficial’ adipokines in reproduction and fertility. Int J Obes (Lond). 2008;32(2):223–31. doi:10.1038/sj.ijo.0803719.

    Article  CAS  Google Scholar 

  44. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. 2005;26(3):439–51.

    Article  PubMed  CAS  Google Scholar 

  45. Combs TP, Pajvani UB, Berg AH, Lin Y, Jelicks LA, Laplante M, et al. A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology. 2004;145(1):367–83.

    Article  PubMed  CAS  Google Scholar 

  46. Madsen EL, Rissanen A, Bruun JM, Skogstrand K, Tonstad S, Hougaard DM, et al. Weight loss larger than 10% is needed for general improvement of levels of circulating adiponectin and markers of inflammation in obese subjects: a 3-year weight loss study. Eur J Endocrinol. 2008;158(2):179–87.

    Article  PubMed  CAS  Google Scholar 

  47. Spranger J, Möhlig M, Wegewitz U, Ristow M, Pfeiffer AF, Schill T, et al. Adiponectin is independently associated with insulin sensitivity in women with polycystic ovary syndrome. Clin Endocrinol. 2004;61(6):738–46.

    Article  CAS  Google Scholar 

  48. Orio F, Palomba S, Zullo F, Colao A, Lombard G. Are serum adiponectin levels really reduced in obese women with polycystic ovary syndrome? Hum Reprod. 2004;19:215–6.

    Article  PubMed  Google Scholar 

  49. Ardawi MS, Rouzi AA. Plasma adiponectin and insulin resistance in women with polycystic ovary syndrome. Fertil Steril. 2005;83(6):1708–16. doi:10.1016/j.fertnstert.2004.11.077.

    Article  PubMed  CAS  Google Scholar 

  50. Garcia V, Orostica L, Poblete C, Rosas C, Astorga I, Romero C, et al. Endometria from obese PCOS women with hyperinsulinemia exhibit altered adiponectin signaling. Horm Metab Res. 2015. doi:10.1055/s-0035-1555806.

    Google Scholar 

  51. Schwarz PE, Towers GW, Fischer S, Govindarajalu S, Schulze J, Bornstein SR, et al. Hypoadiponectinemia is associated with progression toward type 2 diabetes and genetic variation in the ADIPOQ gene promoter. Diabetes Care. 2006;29(7):1645–50.

    Article  PubMed  CAS  Google Scholar 

  52. Jalovaara K, Santaniemi M, Timonen M, Jokelainen J, Kesäniemi YA, Ukkola O, et al. Low serum adiponectin level as a predictor of impaired glucose regulation and type 2 diabetes mellitus in a middle-aged Finnish population. Metabolism. 2008;57(8):1130–4.

    Article  PubMed  CAS  Google Scholar 

  53. Zyriax B-C, Algenstaedt P, Hess UF, Schöffauer M, Bamberger C, Boeing H, et al. Factors contributing to the risk of cardiovascular disease reflected by plasma adiponectin: data from the coronary risk factors for atherosclerosis in women (CORA) study. Atherosclerosis. 2008;200(2):403–9.

    Article  PubMed  CAS  Google Scholar 

  54. Rotterdam E, ASRM-Sponsored P. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human reprod (Oxford, England). 2004;19(1):41.

    Article  Google Scholar 

  55. Jakimiuk AJ, Weitsman SR, Navab A, Magoffin DA. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries 1. J Clin Endocrinol Metab. 2001;86(3):1318–23.

    PubMed  CAS  Google Scholar 

  56. Liu N, Ma Y, Wang S, Zhang X, Zhang Q, Zhang X, et al. Association of the genetic variants of luteinizing hormone, luteinizing hormone receptor and polycystic ovary syndrome. Reprod Biol Endocrinol. 2012;10(1):36.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  57. Catteau-Jonard S, Jamin SP, Leclerc A, Gonzalès J, Dewailly D, di Clemente N. Anti-Mullerian hormone, its receptor, FSH receptor, and androgen receptor genes are overexpressed by granulosa cells from stimulated follicles in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93(11):4456–61.

    Article  PubMed  CAS  Google Scholar 

  58. Wickham 3rd EP, Tao T, Nestler JE, McGee EA. Activation of the LH receptor up regulates the type 2 adiponectin receptor in human granulosa cells. J Assist Reprod Genet. 2013;30(7):963–8. doi:10.1007/s10815-013-0012-3.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Deepa SS, Dong LQ. APPL1: role in adiponectin signaling and beyond. Amn J Physiology-Endocrinol Metab. 2009;296(1):E22–36.

    Article  CAS  Google Scholar 

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Acknowledgments

We express our appreciation to the Research Center for Endometrium and Endometriosis and Research Center for Molecular Medicine, Hamadan University of Medical Sciences, for their technical assistance.

This work was supported by the Research and Technology Deputy of Iran University of Medical Sciences as a Ph.D. thesis (grant no. 16169).

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Authors and Affiliations

  1. Anatomy Department, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Tayebe Artimani & Mehdi Mehdizadeh

  2. Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran

    Massoud Saidijam & Nooshin Shabab

  3. Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

    Reza Aflatoonian & Mahnaz Ashrafi

  4. Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran

    Tayebe Artimani, Iraj Amiri, Mahnaz Yavangi & Sara SoleimaniAsl

  5. Department of Clinical Biochemistry, Hamadan University of Medical Sciences, Hamadan, Iran

    Jamshid Karimi

  6. Cellular and Molecular Research Center, Faculty of Advanced Technology in Medicine, Iran University of Medical Sciences, Tehran, Iran

    Mehdi Mehdizadeh

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  1. Tayebe Artimani
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  2. Massoud Saidijam
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Correspondence to Mehdi Mehdizadeh.

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This cross-sectional study was reviewed and approved by the Iran University of Medical Sciences Ethics Committee. An informed consent was obtained from each participant.

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The authors declare that they have no competing interests.

Additional information

Capsule The low expression of adiponectin and its receptors in PCOS patients could influence the oocyte quality and may lead to intrinsic oocyte abnormalities.

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Artimani, T., Saidijam, M., Aflatoonian, R. et al. Downregulation of adiponectin system in granulosa cells and low levels of HMW adiponectin in PCOS. J Assist Reprod Genet 33, 101–110 (2016). https://doi.org/10.1007/s10815-015-0620-1

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