EC Gynaecology

Research Article Volume 13 Issue 5 - 2024

The Significance of Amphiregulin and Insulin-Like Growth Factor II in Follicular Fluid: Implications for Infertility and Oocyte Quality

Kljajic Marija1*, Ney Jasmin1, Wagenpfeil Gudrun2, Baus Simona1, Abu Halima Masood3, Solomayer Erich-Franz1 and Kasoha Mariz1

1Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, Homburg, Saar, Germany

2Institute of Medical Biometry, Epidemiology and Medical Informatics, Saarland University, Homburg, Saar, Germany

3Institute of Human Genetics, Saarland University, Homburg, Saar, Germany

*Corresponding Author: Kljajic Marija, Department of Gynecology, Obstetrics and Reproductive Medicine, University Medical School of Saarland, Homburg, Saar, Germany.
Received: April 12, 2024; Published: April 23, 2024



The presented study explores the importance of amphiregulin and insulin-like growth factor II concentrations within a follicular fluid, and their relationship with gene expression in mural granulosa cells, particularly in the context of infertility. The investigation specifically targets polycystic ovary syndrome and considers patients' body mass index, as well as the impact of those proteins on oocyte quality.

A total of thirty-three women were recruited at the University Clinic of Saarland Fertility Centre (Homburg, Germany). Follicular fluid aspiration involved single/individual aspiration of follicles, enabling a 1:1 correlation with retrieved oocytes. In total 108 follicular fluid and mural granulosa cell samples were analyzed.

Amphiregulin and insulin-like grown factor II levels were determined via enzyme-linked immunosorbent assay. Expression of amphiregulin and insulin-like grown factor II was analyzed by StepOnePlus™ real-time PCR system using TaqMan fast advanced master mix assays. Results reveal that the concentration of amphiregulin and insulin-like grown factor II in follicular fluid statistically differs between healthy and infertile patients. Additionally, the results reveal that infertility diagnosis, especially polycystic ovary syndrome, affects amphiregulin concentration in follicles.

The concentration of amphiregulin in the follicular fluid significantly differs between patients based on body mass index. What is more, some findings such as the correlation between patients' body mass index and amphiregulin expression as well as between amphiregulin concentration and oocyte quality are entirely new.

In conclusion, by recognizing and highlighting the relationship between amphiregulin and infertility as well as oocyte quality, we contribute to the growing body of knowledge on reproductive biology and potentially pave the way for targeted interventions or treatments aimed at optimizing oocyte quality and enhancing fertility outcomes. This research underscores the importance of non-invasive biomarkers in optimizing assisted reproductive techniques.

  1. "ESHRE-European Society of Human Reproduction and Embryology. ART Fact Sheet" (2014).
  2. Carson Sandra Ann and Amanda N Kallen. “Diagnosis and Management of Infertility: A Review”. JAMA1 (2021): 65-76.
  3. Macut Djuro., et al. “Insulin and the polycystic ovary syndrome”. Diabetes Research and Clinical Practice 130 (2017): 163-170.
  4. Nandi Anindita., et al. “Polycystic ovary syndrome”. Endocrinology and Metabolism Clinics of North America1 (2014): 123-147.
  5. Bloom Michael S., et al. “Adiposity is associated with anovulation independent of serum free testosterone: A prospective cohort study”. Paediatric and Perinatal Epidemiology2 (2021): 174-183.
  6. Ambekar Aditi S., et al. “Proteomics of follicular fluid from women with polycystic ovary syndrome suggests molecular defects in follicular development”. The Journal of Clinical Endocrinology and Metabolism2 (2015): 744-753.
  7. Gorry Anwen., et al. “Infertility in polycystic ovary syndrome: focus on low-dose gonadotropin treatment”. Endocrine 1 (2006): 27-33.
  8. Liu Yang., et al. “Luteinizing hormone stimulates the expression of amphiregulin in human theca cells”. Journal of Ovarian Research1 (2022): 129.
  9. Richani Dulama and Robert B Gilchrist. “The epidermal growth factor network: role in oocyte growth, maturation and developmental competence”. Human Reproduction Update1 (2018): 1-14.
  10. Harris RC., et al. "EGF Receptor Ligands". Experimental Cell Research1 (2003): 2-13.
  11. Schneider Marlon R and Eckhard Wolf. “The epidermal growth factor receptor and its ligands in female reproduction: insights from rodent models”. Cytokine and Growth Factor Reviews2 (2008): 173-181.
  12. Zamah AM., et al. “Human oocyte maturation is dependent on LH-stimulated accumulation of the epidermal growth factor-like growth factor, amphiregulin”. Human Reproduction (Oxford, England)10 (2010): 2569-2578.
  13. Inoue Yoshihito., et al. “Amphiregulin is much more abundantly expressed than transforming growth factor-alpha and epidermal growth factor in human follicular fluid obtained from patients undergoing in vitro fertilization-embryo transfer”. Fertility and Sterility4 (2009): 1035-1041.
  14. Huang Ying., et al. “Altered amphiregulin expression induced by diverse luteinizing hormone receptor reactivity in granulosa cells affects IVF outcomes”. Reproductive Biomedicine Online6 (2015): 593-601.
  15. Wang Huarong., et al. “HDAC3 maintains oocyte meiosis arrest by repressing amphiregulin expression before the LH surge”. Nature Communications1 (2019): 5719.
  16. Livak KJ and Schmittgen TD. "Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method”. Methods4 (2001): 402-408.
  17. World Health Organization. "WHO Fact Sheet” (2020).
  18. Chandra Anjani., et al. “Infertility and impaired fecundity in the United States, 1982-2010: data from the National Survey of Family Growth”. National Health Statistics Reports 67 (2013): 1-18, 1 p following 19.
  19. Walker Matthew H and Kyle J Tobler. “Female Infertility”. StatPearls, StatPearls Publishing (2022).
  20. Liu Nana., et al. “Comparison of follicular fluid amphiregulin and EGF concentrations in patients undergoing IVF with different stimulation protocols”. Endocrine 3 (2012): 708-716.
  21. Vahratian Anjel and Yolanda R Smith. “Should access to fertility-related services be conditional on body mass index?”. Human Reproduction (Oxford, England)7 (2009): 1532-1537.
  22. Supramaniam Prasanna Raj., et al. “The correlation between raised body mass index and assisted reproductive treatment outcomes: a systematic review and meta-analysis of the evidence”. Reproductive Health 1 (2018): 34.
  23. Valckx S D M., et al. “BMI-related metabolic composition of the follicular fluid of women undergoing assisted reproductive treatment and the consequences for oocyte and embryo quality”. Human Reproduction (Oxford, England)12 (2012): 3531-3539.
  24. Ruebel Meghan L., et al. “Obesity modulates inflammation and lipid metabolism oocyte gene expression: a single-cell transcriptome perspective”. The Journal of Clinical Endocrinology and Metabolism6 (2017): 2029-2038.
  25. Gonzalez Macarena B., et al. “Inflammatory markers in human follicular fluid correlate with lipid levels and Body Mass Index”. Journal of Reproductive Immunology 130 (2018): 25-29.
  26. Broughton Darcy E and Kelle H Moley. “Obesity and female infertility: potential mediators of obesity's impact”. Fertility and Sterility4 (2017): 840-847.
  27. Cruickshank J K., et al. “Epidemiology of the insulin-like growth factor system in three ethnic groups”. American Journal of Epidemiology6 (2001): 504-513.
  28. Akiyama Masato., et al. “Genome-wide association study identifies 112 new loci for body mass index in the Japanese population”. Nature Genetics10 (2017): 1458-1467.
  29. Xia Qianghua and Struan F A Grant. “The genetics of human obesity”. Annals of the New York Academy of Sciences1 (2013): 178-190.
  30. Butler Merlin G., et al. “Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction”. Journal of Assisted Reproduction and Genetics4 (2015): 495-508.
  31. O'Dell S D., et al. “Apal polymorphism in insulin-like growth factor II (IGF2) gene and weight in middle-aged males”. International Journal of Obesity and Related Metabolic Disorders: Journal of the International Association for the Study of Obesity 9 (1997): 822-825.
  32. Roth S M., et al. “IGF2 genotype and obesity in men and women across the adult age span”. International Journal of Obesity and Related Metabolic Disorders Journal of the International Association for the Study of Obesity4 (2002): 585-587.
  33. Dinsdale Natalie L and Bernard J Crespi. “Endometriosis and polycystic ovary syndrome are diametric disorders”. Evolutionary Applications7 (2021): 1693-1715.
  34. Zhang, Yan., et al. “Follicular metabolic changes and effects on oocyte quality in polycystic ovary syndrome patients”. Oncotarget 46 (2017): 80472-80480.
  35. Chen Xiaojiao., et al. “Metabolic alterations associated with polycystic ovary syndrome: A UPLC Q-Exactive based metabolomic study”. Clinica Chimica Acta; International Journal of Clinical Chemistry 502 (2020): 280-286.
  36. Giudice LC. “Insulin-like growth factor family in Graafian follicle development and function”. Journal of the Society for Gynecologic Investigation1 (2001): S26-S29.
  37. Thierry van Dessel H J., et al. “Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome”. The Journal of Clinical Endocrinology and Metabolism9 (1999): 3030-3035.
  38. Zhong Gang and Biheng Chen. “Serum and follicular fluid levels of IGF-II, IGF-binding protein-4 and pregnancy-associated plasma protein-A in controlled ovarian hyperstimulation cycle between polycystic ovarian syndrome (PCOS) and non-PCOS women”. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology2 (2011): 86-90.
  39. Cara J F. “Insulin-like growth factors, insulin-like growth factor binding proteins and ovarian androgen production”. Hormone Research1-2 (1994): 49-54.
  40. Homburg R., et al. “The role of insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-1) in the pathogenesis of polycystic ovary syndrome”. Human Reproduction (Oxford, England) 10 (1992): 1379-1383.
  41. Khan Muhammad Jaseem., et al. “Genetic basis of polycystic ovary syndrome (PCOS): Current perspectives”. The Application of Clinical Genetics 12 (2019): 249-260.
  42. Kwon Hwang., et al. “mRNA expression pattern of insulin-like growth factor components of granulosa cells and cumulus cells in women with and without polycystic ovary syndrome according to oocyte maturity”. Fertility and Sterility6 (2010): 2417-2420.
  43. Kaur Surleen., et al. “Differential gene expression in granulosa cells from polycystic ovary syndrome patients with and without insulin resistance: identification of susceptibility gene sets through network analysis”. The Journal of Clinical Endocrinology and Metabolism10 (2012): E2016-E2021.
  44. Haouzi D., et al. “Altered gene expression profile in cumulus cells of mature MII oocytes from patients with polycystic ovary syndrome”. Human Reproduction (Oxford, England)12 (2012): 3523-3530.
  45. Ben-Ami I., et al. “In vitro maturation of human germinal vesicle-stage oocytes: role of epidermal growth factor-like growth factors in the culture medium”. Human Reproduction (Oxford, England)1 (2011): 76-81.
  46. Feuerstein P., et al. “Gene expression in human cumulus cells: one approach to oocyte competence”. Human Reproduction (Oxford, England) 12 (2007): 3069-3077.
  47. Kaya Aysenur., et al. “Follicular fluid concentrations of IGF-I, IGF-II, IGFBP-3, VEGF, AMH, and inhibin-B in women undergoing controlled ovarian hyperstimulation using GnRH agonist or GnRH antagonist”. European Journal of Obstetrics, Gynecology, and Reproductive Biology2 (2012): 167-171.

Kljajic Marija., et al. "The Significance of Amphiregulin and Insulin-Like Growth Factor II in Follicular Fluid: Implications for Infertility and Oocyte Quality". EC Gynaecology 13.5 (2024): 01-17.