Abstract
Endometriosis (EMs) is a common cause for female infertility, leading to the need for in vitro fertilization (IVF). In clinics, we found the operative oocyte retrieval to be more or less difficult in women with EMs. We hypothesized that EMs may be involved in the insufficient cumulus expansion that partially explained the lower oocyte retrieval in EMs-related infertile women undergoing assisted reproductive technology (ART). To explore whether the insufficient cumulus expansion exists in EMs-related infertile women and whether there is a possible relationship between the insufficient cumulus expansion and the clinical phenomenon of difficulty in oocyte retrieval. Those infertile women undergoing IVF recorded in our database between January 2013 and October 2017 were included. The expression levels of cumulus expansion–related genes (HAS2/PTGS2/PTX3/TNFAIP6) in the cumulus cells (CCs) from 19 infertile women with EMs and 24 controls were analyzed by real-time PCR. After that, 635 women with EMs-associated infertility (the EMs group) and 4634 women with male factor–associated infertility (the control group) were included in the retrospective analysis. The clinical outcomes were compared between the two groups. The relative mRNA levels of cumulus expansion–related genes were significantly decreased in the CCs from those infertile women with EMs when compared to the control group (all p < 0.05), especially the expression of PTGS2. The mean oocyte retrieval rates (proportion of obtained oocytes in punctured follicles) were (76.33 ± 2.58)% and (71.80 ± 0.58)% (p < 0.01). The mean numbers of flushing times per follicle were 1.11 ± 0.65 and 3.86 ± 1.53 (p < 0.001). The lower expression of cumulus expansion–related genes in CCs suggests the insufficient cumulus expansion in EMs-related infertile women, which partially explains a possible mechanism related to poor oocyte retrieval.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs43032-020-00410-4/MediaObjects/43032_2020_410_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs43032-020-00410-4/MediaObjects/43032_2020_410_Fig2_HTML.png)
Similar content being viewed by others
Data Availability
All data utilized and analyzed in this study are included in the published manuscript.
References
da Luz CM, da Broi MG, Donabela FC, Paro de Paz CC, Meola J, Navarro PA. PTGS2 down-regulation in cumulus cells of infertile women with endometriosis. Reprod BioMed Online. 2017;35:379–86.
Vassilopoulou L, Matalliotakis M, Zervou MI, Matalliotaki C, Spandidos DA, Matalliotakis I, et al. Endometriosis and in vitro fertilisation. Exp Ther Med. 2018;16:1043–51.
Eisenberg VH, Weil C, Chodick G. et al, Epidemiology of endometriosis: a large population-based database study from a healthcare provider with 2 million members. BJOG. 2018:55–62.
Gonzalez-Comadran M, Schwarze JE, Zegers-Hochschild F, Souza MD, Carreras R, Checa MA. The impact of endometriosis on the outcome of assisted reproductive technology. Reprod Biol Endocrinol. 2017;15:8.
Somigliana E, Vigano P, Tirelli AS, Felicetta I, Torresani E, Vignali M, et al. Use of the concomitant serum dosage of CA 125, CA 19-9 and interleukin-6 to detect the presence of endometriosis. Results from a series of reproductive age women undergoing laparoscopic surgery for benign gynaecological conditions. Hum Reprod. 2004;19:1871–6.
Ozkan S, Murk W, Arici A. Endometriosis and infertility: epidemiology and evidence-based treatments. Ann N Y Acad Sci. 2008;1127:92–100.
Garcia-Velasco JA, Somigliana E. Management of endometriomas in women requiring IVF: to touch or not to touch. Hum Reprod. 2009;24:496–501.
Chen L, Wert SE, Hendrix EM, Russell PT, Cannon M, Larsen WJ. Hyaluronic acid synthesis and gap junction endocytosis are necessary for normal expansion of the cumulus mass. Mol Reprod Dev. 1990;26:236–47.
Camaioni A, Hascall VC, Yanagishita M, Salustri A. Effects of exogenous hyaluronic acid and serum on matrix organization and stability in the mouse cumulus cell-oocyte complex. J Biol Chem. 1993;268:20473–81.
Richards JS. Ovulation: new factors that prepare the oocyte for fertilization. Mol Cell Endocrinol. 2005;234:75–9.
Tsafriri A. Ovulation as a tissue remodelling process. Proteolysis and cumulus expansion. Adv Exp Med Biol. 1995;377:121–40.
Calder MD, Caveney AN, Westhusin ME, Watson AJ. Cyclooxygenase-2 and prostaglandin E(2)(PGE(2)) receptor messenger RNAs are affected by bovine oocyte maturation time and cumulus-oocyte complex quality, and PGE(2) induces moderate expansion of the bovine cumulus in vitro. Biol Reprod. 2001;65:135–40.
Guo J, Zhang T, Guo Y, Sun T, Li H, Zhang X, et al. Oocyte stage-specific effects of MTOR determine granulosa cell fate and oocyte quality in mice. Proc Natl Acad Sci U S A. 2018;115:E5326–33.
Su YQ, Sugiura K, Wigglesworth K, O'Brien MJ, Affourtit JP, Pangas SA, et al. Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells. Development. 2008;135:111–21.
Gerard N, Robin E. Cellular and molecular mechanisms of the preovulatory follicle differenciation and ovulation: what do we know in the mare relative to other species. Theriogenology. 2019;130:163–76.
Duffy DM, Ko C, Jo M, Brannstrom M, Curry TE. Ovulation: parallels with inflammatory processes. Endocr Rev. 2019;40:369–416.
Robker RL, Hennebold JD, Russell DL. Coordination of ovulation and oocyte maturation: a good egg at the right time. Endocrinology. 2018;159:3209–18.
Shimada M, Umehara T, Hoshino Y. Roles of epidermal growth factor (EGF)-like factor in the ovulation process. Reprod Med Biol. 2016;15:201–16.
Jensen PJ, Rodeck U. Autocrine/paracrine regulation of keratinocyte urokinase plasminogen activator through the TGF-alpha/EGF receptor. J Cell Physiol. 1993;155:333–9.
Jo M, Gieske MC, Payne CE, Wheeler-Price SE, Gieske JB, Ignatius IV, et al. Development and application of a rat ovarian gene expression database. Endocrinology. 2004;145:5384–96.
Xie J, Qian L, Wang Y, Hamm-Alvarez SF, Mircheff AK. Role of the microtubule cytoskeleton in traffic of EGF through the lacrimal acinar cell endomembrane network. Exp Eye Res. 2004;78:1093–106.
Richards JS, Liu Z, Shimada M. Immune-like mechanisms in ovulation. Trends Endocrinol Metab. 2008;19:191–6.
Salustri A, Ulisse S, Yanagishita M, Hascall VC. Hyaluronic acid synthesis by mural granulosa cells and cumulus cells in vitro is selectively stimulated by a factor produced by oocytes and by transforming growth factor-beta. J Biol Chem. 1990;265:19517–23.
Salustri A, Yanagishita M, Hascall VC. Mouse oocytes regulate hyaluronic acid synthesis and mucification by FSH-stimulated cumulus cells. Dev Biol. 1990;138:26–32.
Chen L, Russell PT, Larsen WJ. Functional significance of cumulus expansion in the mouse: roles for the preovulatory synthesis of hyaluronic acid within the cumulus mass. Mol Reprod Dev. 1993;34:87–93.
Ochsner SA, Russell DL, Day AJ, Breyer RM, Richards JS. Decreased expression of tumor necrosis factor-alpha-stimulated gene 6 in cumulus cells of the cyclooxygenase-2 and EP2 null mice. Endocrinology. 2003;144:1008–19.
Russell DL, Ochsner SA, Hsieh M, Mulders S, Richards JS. Hormone-regulated expression and localization of versican in the rodent ovary. Endocrinology. 2003;144:1020–31.
Eppig JJ. Regulation of cumulus oophorus expansion by gonadotropins in vivo and in vitro. Biol Reprod. 1980;23:545–52.
Russell DL, Robker RL. Molecular mechanisms of ovulation: co-ordination through the cumulus complex. Hum Reprod Update. 2007;13:289–312.
Segi E, Haraguchi K, Sugimoto Y, Tsuji M, Tsunekawa H, Tamba S, et al. Expression of messenger RNA for prostaglandin E receptor subtypes EP4/EP2 and cyclooxygenase isozymes in mouse periovulatory follicles and oviducts during superovulation. Biol Reprod. 2003;68:804–11.
Barcelos ID, Donabella FC, Ribas CP, Meola J, Ferriani RA, de Paz CC, et al. Down-regulation of the CYP19A1 gene in cumulus cells of infertile women with endometriosis. Reprod BioMed Online. 2015;30:532–41.
Hosseini E, Mehraein F, Shahhoseini M, Karimian L, Nikmard F, Ashrafi M, et al. Epigenetic alterations of CYP19A1 gene in cumulus cells and its relevance to infertility in endometriosis. J Assist Reprod Genet. 2016;33:1105–13.
Chiappini F, Baston JI, Vaccarezza A, Singla JJ, Pontillo C, Miret N, et al. Enhanced cyclooxygenase-2 expression levels and metalloproteinase 2 and 9 activation by Hexachlorobenzene in human endometrial stromal cells. Biochem Pharmacol. 2016;109:91–104.
Zidan HE, Rezk NA, Alnemr AA, Abd El Ghany AM. COX-2 gene promoter DNA methylation status in eutopic and ectopic endometrium of Egyptian women with endometriosis. J Reprod Immunol. 2015;112:63–7.
Song SH, Jong HS, Choi HH, Inoue H, Tanabe T, Kim NK, et al. Transcriptional silencing of cyclooxygenase-2 by hyper-methylation of the 5′ CpG island in human gastric carcinoma cells. Cancer Res. 2001;61:4628–35.
Acknowledgments
The authors gratefully acknowledge the efforts of the doctors, nurses, embryologists, and the entire staff at the Clinical Reproductive Medicine Center, Nanjing, China.
Funding
This study was supported by the National Key Research and Development Program of China (2017YFC1001604, 2017YFC1001300) and the National Nature and Science Foundation of China (81730041, 81671438), and the program SKLRM-K201805. The funding bodies had no role in the design of the study, the collection, analysis, and interpretation of the data, and the writing of the manuscript.
Author information
Authors and Affiliations
Contributions
In this study, Yaoxue Yin collected data by interviewing the infertile women, performed the molecular biological analysis, and wrote the final draft of the manuscript. Yundong Mao and Li Shu participated in the initial conception of the study and the protocol. Anthony Liu modified and polished the entire manuscript. Chun Yuan helped in the statistical methods and revision of the manuscript. Yugui Cui provided the design and protocol of the research and reviewed and modified the final version of the manuscript. Jiayin Liu and Zhen Hou, as the main investigators, conceived of this project and reviewed and ensured the final version of this manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Ethics Approval and Consent to Participate
A retrospective cohort study was conducted at the Center of Clinical Reproductive Medicine, First Affiliated Hospital of NMU. This study was approved by the Research Ethics Committee of the hospital on 12 October 2012. All infertile women who met the eligibility criteria and agreed to participate in the study provided written informed consent.
Study Size
This retrospective study was referred to as clinical data analysis. In total, 5629 women were included for analysis, 635 women with a diagnosis of EMs via laparoscopic surgery, and 4634 women with male factor infertility as control. The above eligible patients who consented to participate were analyzed from January 2013 to October 2017. In addition, we also collected the CCs from 19 women in the EMs group and 24 women in the control group who underwent IVF to test the cumulus expansion–related genes in June 2019.
Consent for Publication
No applicable.
Competing Interests
The authors declare that they have no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Yin, Y., Mao, Y., Liu, A. et al. Insufficient Cumulus Expansion and Poor Oocyte Retrieval in Endometriosis-Related Infertile Women. Reprod. Sci. 28, 1412–1420 (2021). https://doi.org/10.1007/s43032-020-00410-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s43032-020-00410-4