Ovarian Fibrosis: A Phenomenon of Concern

Feng Zhou, Li-Bing Shi, Song-Ying Zhang, Feng Zhou, Li-Bing Shi, Song-Ying Zhang

Abstract

Objective: Ovarian fibrosis is characterized by excessive proliferation of ovarian fibroblasts and deposition of extracellular matrix (ECM) and it is one of the principal reasons for ovarian dysfunction. This review aimed to investigate the pathogenetic mechanism of ovarian fibrosis and to clarify the relationship between ovarian diseases and fibrosis.

Data sources: We searched PubMed for English language articles published up to November 2016. The search terms included ovarian fibrosis OR fibrosis, ovarian chocolate cyst OR ovarian endometrioma, polycystic ovarian syndrome (PCOS), premature ovarian failure, ECM, matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), transforming growth factor-beta 1 (TGF-β1), connective tissue growth factor (CTGF), peroxisome proliferator-activated receptor gamma (PPAR-γ), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and combinations of these terms.

Study selection: Articles were obtained and reviewed to analyze the pathogenic mechanism of ovarian fibrosis and related ovarian diseases.

Results: Many cytokines, such as MMPs, TIMPs, TGF-β1, CTGF, PPAR-γ, VEGF, and ET-1, are involved in ovarian fibrogenesis. Ovarian fibrogenesis is associated with various ovarian diseases, including ovarian chocolate cyst, PCOS, and premature ovarian failure. One finding of particular interest is that fibrogenesis in peripheral tissues around an ovarian chocolate cyst commonly causes ovarian function diminution, and therefore, this medical problem should arouse widespread concern in clinicians worldwide.

Conclusions: Patients with ovarian fibrosis are susceptible to infertility and tend to have decreased responses to assisted fertility treatment. Thus, protection of ovarian function should be a priority for women who wish to reproduce when making therapeutic decisions about ovarian fibrosis-related diseases.

Conflict of interest statement

There are no conflicts of interest.

References

    1. Asadzadeh R, Khosravi S, Zavareh S, Ghorbanian MT, Paylakhi SH, Mohebbi SR. Vitrification affects the expression of matrix metalloproteinases and their tissue inhibitors of mouse ovarian tissue. Int J Reprod Biomed (Yazd) 2016;14:173–80.
    1. Kwak HJ, Park MJ, Cho H, Park CM, Moon SI, Lee HC, et al. Transforming growth factor-beta1 induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Sp1 in human fibrosarcoma cells. Mol Cancer Res. 2006;4:209–20. doi: 10.1158/1541-7786.MCR-05- 0140.
    1. Harlow CR, Davidson L, Burns KH, Yan C, Matzuk MM, Hillier SG. FSH and TGF-beta superfamily members regulate granulosa cell connective tissue growth factor gene expression in vitro and in vivo. Endocrinology. 2002;143:3316–25. doi: 10.1210/en.2001-211389.
    1. Zhu G, Kang L, Yang C, Zhang X, Wang M, Jiang Y. Differential expression of CTGF in pre- and post-ovulatory granulosa cells in the hen ovary is regulated by TGFß1 and gonadotrophins. Gen Comp Endocrinol. 2012;178:314–22. doi: 10.1016/j.ygcen.2012.06.018.
    1. Mason RM. Fell-Muir lecture: Connective tissue growth factor (CCN2) – A pernicious and pleiotropic player in the development of kidney fibrosis. Int J Exp Pathol. 2013;94:1–16. doi: 10.1111/j.1365-2613.2012.00845.x.
    1. Romão LF, Mendes FA, Feitosa NM, Faria JC, Coelho-Aguiar JM, de Souza JM, et al. Connective tissue growth factor (CTGF/CCN2) is negatively regulated during neuron-glioblastoma interaction. PLoS One. 2013;8:e55605. doi: 10.1371/journal.pone.0055605.
    1. Alfaro MP, Deskins DL, Wallus M, DasGupta J, Davidson JM, Nanney LB, et al. Aphysiological role for connective tissue growth factor in early wound healing. Lab Invest. 2013;93:81–95. doi: 10.1038/labinvest.2012.162.
    1. Lai KB, Sanderson JE, Yu CM. The regulatory effect of norepinephrine on connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF) expression in cultured cardiac fibroblasts. Int J Cardiol. 2013;163:183–9. doi: 10.1016/j.ijcard.2011.06.003.
    1. Lipson KE, Wong C, Teng Y, Spong S. CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. Fibrogenesis Tissue Repair. 2012;5(Suppl 1):S24. doi: 10.1186/1755-1536-5-S1-S24.
    1. Yang C, Zheng SD, Wu HJ, Chen SJ. Regulatory mechanisms of the molecular pathways in fibrosis induced by MicroRNAs. Chin Med J. 2016;129:2365–72. doi: 10.4103/0366-6999.190677.
    1. Chang JZ, Yang WH, Deng YT, Chen HM, Kuo MY. EGCG blocks TGFß1-induced CCN2 by suppressing JNK and p38 in buccal fibroblasts. Clin Oral Investig. 2013;17:455–61. doi: 10.1007/s00784-012-0713-5.
    1. Wang YX, Zhu WJ, Xie BG. Expression of PPAR-γ in adipose tissue of rats with polycystic ovary syndrome induced by DHEA. Mol Med Rep. 2014;9:889–93. doi: 10.3892/mmr.2014.1895.
    1. Mohiyiddeen L, Watson AJ, Apostolopoulos NV, Berry R, Alexandraki KI, Jude EB. Effects of low-dose metformin and rosiglitazone on biochemical, clinical, metabolic and biophysical outcomes in polycystic ovary syndrome. J Obstet Gynaecol. 2013;33:165–70. doi: 10.3109/01443615.2012.745839.
    1. Chen Q, Sun X, Chen J, Cheng L, Wang J, Wang Y, et al. Direct rosiglitazone action on steroidogenesis and proinflammatory factor production in human granulosa-lutein cells. Reprod Biol Endocrinol. 2009;7:147. doi: 10.1186/1477-7827-7-147.
    1. Wang L, Ying YF, Ouyang YL, Wang JF, Xu J. VEGF and bFGF increase survival of xenografted human ovarian tissue in an experimental rabbit model. J Assist Reprod Genet. 2013;30:1301–11. doi: 10.1007/s10815-013-0043-9.
    1. Luo J, Liang Y, Kong F, Qiu J, Liu X, Chen A, et al. Vascular endothelial growth factor promotes the activation of hepatic stellate cells in chronic schistosomiasis. Immunol Cell Biol. 2016 [Epub ahead of print] doi: 10.1038/icb.2016.109.
    1. Wermuth PJ, Li Z, Mendoza FA, Jimenez SA. Stimulation of transforming growth factor-ß1-induced endothelial-to-mesenchymal transition and tissue fibrosis by endothelin-1 (ET-1): A novel profibrotic effect of ET-1. PLoS One. 2016;11:e0161988. doi: 10.1371/journal.pone.0161988.
    1. Zhao M, Chang C, Liu Z, Chen LM, Chen Q. The level of vascular endothelial cell growth factor, nitric oxide, and endothelin-1 was correlated with ovarian volume or antral follicle counts: A potential predictor of pregnancy outcome in IVF. Growth Factors. 2010;28:299–305. doi: 10.3109/08977191003766866.
    1. Hughesdon PE. The structure of endometrial cysts of the ovary. J Obstet Gynaecol Br Emp. 1957;64:481–7.
    1. Schubert B, Canis M, Darcha C, Artonne C, Pouly JL, Déchelotte P, et al. Human ovarian tissue from cortex surrounding benign cysts: A model to study ovarian tissue cryopreservation. Hum Reprod. 2005;20:1786–92. doi: 10.1093/humrep/dei002.
    1. Donnez J, Nisolle M, Gillet N, Smets M, Bassil S, Casanas-Roux F. Large ovarian endometriomas. Hum Reprod. 1996;11:641–6.
    1. Zhang Q, Duan J, Liu X, Guo SW. Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation. Mol Cell Endocrinol. 2016;428:1–16. doi: 10.1016/j.mce.2016.03.015.
    1. Gordts S, Puttemans P, Gordts S, Brosens I. Ovarian endometrioma in the adolescent: A plea for early-stage diagnosis and full surgical treatment. Gynecol Surg. 2015;12:21–30. doi: 10.1007/s10397-014-0877-x.
    1. Kitajima M, Defrère S, Dolmans MM, Colette S, Squifflet J, Van Langendonckt A, et al. Endometriomas as a possible cause of reduced ovarian reserve in women with endometriosis. Fertil Steril. 2011;96:685–91. doi: 10.1016/j.fertnstert.2011.06.064.
    1. Opøien HK, Fedorcsak P, Polec A, Stensen MH, Åbyholm T, Tanbo T. Do endometriomas induce an inflammatory reaction in nearby follicles? Hum Reprod. 2013;28:1837–45. doi: 10.1093/humrep/det087.
    1. Velasco I, Acién P, Campos A, Acién MI, Ruiz-Maciá E. Interleukin-6 and other soluble factors in peritoneal fluid and endometriomas and their relation to pain and aromatase expression. J Reprod Immunol. 2010;84:199–205. doi: 10.1016/j.jri.2009.11.004.
    1. Smith LP, Williams CD, Doyle JO, Closshey WB, Brix WK, Pastore LM. Effect of endometrioma cyst fluid exposure on peritoneal adhesion formation in a rabbit model. Fertil Steril. 2007;87:1173–9. doi: 10.1016/j.fertnstert.2006.08.104.
    1. Hadadeh O, Barruet E, Peiretti F, Verdier M, Bernot D, Hadjal Y, et al. The plasminogen activation system modulates differently adipogenesis and myogenesis of embryonic stem cells. PLoS One. 2012;7:e49065. doi: 10.1371/journal.pone.0049065.
    1. Samarakoon R, Overstreet JM, Higgins PJ. TGF-ß signaling in tissue fibrosis: Redox controls, target genes and therapeutic opportunities. Cell Signal. 2013;25:264–8. doi: 10.1016/j.cellsig.2012.10.003.
    1. Boss EA, Massuger LF, Thomas CM, Geurts-Moespot A, van Schaik JH, Boonstra H, et al. Clinical value of components of the plasminogen activation system in ovarian cyst fluid. Anticancer Res. 2002;22:275–82.
    1. Tanaka K, Kobayashi Y, Dozono K, Shibuya H, Nishigaya Y, Momomura M, et al. Elevation of plasma D-dimer levels associated with rupture of ovarian endometriotic cysts. Taiwan J Obstet Gynecol. 2015;54:294–6. doi: 10.1016/j.tjog.2014.09.010.
    1. Yang Y, Bazhin AV, Werner J, Karakhanova S. Reactive oxygen species in the immune system. Int Rev Immunol. 2013;32:249–70. doi: 10.3109/08830185.2012.755176.
    1. Bryan N, Ahswin H, Smart N, Bayon Y, Wohlert S, Hunt JA. Reactive oxygen species (ROS) – A family of fate deciding molecules pivotal in constructive inflammation and wound healing. Eur Cell Mater. 2012;24:249–65.
    1. Jana SK, K NB, Chattopadhyay R, Chakravarty B, Chaudhury K. Upper control limit of reactive oxygen species in follicular fluid beyond which viable embryo formation is not favorable. Reprod Toxicol. 2010;29:447–51. doi: 10.1016/j.reprotox.2010.04.002.
    1. Barnes JL, Gorin Y. Myofibroblast differentiation during fibrosis: Role of NAD(P)H oxidases. Kidney Int. 2011;79:944–56. doi: 10.1038/ki.2010.516.
    1. Matsuzaki S, Schubert B. Oxidative stress status in normal ovarian cortex surrounding ovarian endometriosis. Fertil Steril. 2010;93:2431–2. doi: 10.1016/j.fertnstert.2009.08.068.
    1. Dumesic DA, Meldrum DR, Katz-Jaffe MG, Krisher RL, Schoolcraft WB. Oocyte environment: Follicular fluid and cumulus cells are critical for oocyte health. Fertil Steril. 2015;103:303–16. doi: 10.1016/j.fertnstert.2014.11.015.
    1. Prasad S, Tiwari M, Pandey AN, Shrivastav TG, Chaube SK. Impact of stress on oocyte quality and reproductive outcome. J Biomed Sci. 2016;23:36. doi: 10.1186/s12929-016-0253-4.
    1. Piomboni P, Focarelli R, Capaldo A, Stendardi A, Cappelli V, Cianci A, et al. Protein modification as oxidative stress marker in follicular fluid from women with polycystic ovary syndrome: The effect of inositol and metformin. J Assist Reprod Genet. 2014;31:1269–76. doi: 10.1007/s10815-014-0307-z.
    1. Benaglia L, Bermejo A, Somigliana E, Faulisi S, Ragni G, Fedele L, et al. In vitro fertilization outcome in women with unoperated bilateral endometriomas. Fertil Steril. 2013;99:1714–9. doi: 10.1016/j.fertnstert.2013.01.110.
    1. Rossi AC, Prefumo F. The effects of surgery for endometriosis on pregnancy outcomes following in vitro fertilization and embryo transfer: A systematic review and meta-analysis. Arch Gynecol Obstet. 2016;294:647–55. doi: 10.1007/s00404-016-4136-4.
    1. Karaman Y, Uslu H. Complications and their management in endometriosis surgery. Womens Health (Lond) 2015;11:685–92. doi: 10.2217/whe.15.55.
    1. Liu B, Guan YM, Zheng JH. Elevated serum levels of matrix metalloproteinase-2 in women with polycystic ovarian syndrome. Int J Gynaecol Obstet. 2007;96:204–5. doi: 10.1016/j.ijgo.2006.11.012.
    1. Gomes VA, Vieira CS, Jacob-Ferreira AL, Belo VA, Soares GM, Fernandes JB, et al. Imbalanced circulating matrix metalloproteinases in polycystic ovary syndrome. Mol Cell Biochem. 2011;353:251–7. doi: 10.1007/s11010-011-0793-6.
    1. Lewandowski KC, Komorowski J, O’Callaghan CJ, Tan BK, Chen J, Prelevic GM, et al. Increased circulating levels of matrix metalloproteinase-2 and -9 in women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:1173–7. doi: 10.1210/jc.2005-0648.
    1. Yang J, Zhong T, Xiao G, Chen Y, Liu J, Xia C, et al. Polymorphisms and haplotypes of the TGF-ß1 gene are associated with risk of polycystic ovary syndrome in Chinese Han women. Eur J Obstet Gynecol Reprod Biol. 2015;186:1–7. doi: 10.1016/j.ejogrb.2014.11.004.
    1. Lahav-Baratz S, Kraiem Z, Shiloh H, Koifman M, Ishai D, Dirnfeld M. Decreased expression of tissue inhibitor of matrix metalloproteinases in follicular fluid from women with polycystic ovaries compared with normally ovulating patients undergoing in vitro fertilization. Fertil Steril. 2003;79:567–71.
    1. Miao ZL, Guo L, Wang YX, Cui R, Yang N, Huang MQ, et al. The intervention effect of Rosiglitozone in ovarian fibrosis of PCOS rats. Biomed Environ Sci. 2012;25:46–52. doi: 10.3967/0895-3988.2012.01.007.
    1. Zhang X, Zhang C, Shen S, Xia Yj, Yi L, Gao Q, et al. Dehydroepiandrosterone induces ovarian and uterine hyperfibrosis in female rats. Hum Reprod. 2013;28:3074–85. doi: 10.1093/humrep/det341.
    1. Bulut G, Kurdoglu Z, Dönmez YB, Kurdoglu M, Erten R. Effects of jnk inhibitor on inflammation and fibrosis in the ovary tissue of a rat model of polycystic ovary syndrome. Int J Clin Exp Pathol. 2015;8:8774–85.
    1. Lai JB, Qiu CF, Chen CX, Chen MY, Chen J, Guan XD, et al. Inhibition of c-Jun N-terminal kinase signaling pathway alleviates lipopolysaccharide-induced acute respiratory distress syndrome in rats. Chin Med J. 2016;129:1719–24. doi: 10.4103/0366-6999.185867.
    1. Szmidt NA, Bhattacharya S, Maheshwari A. Does poor ovarian response to gonadotrophins predict early menopause?A retrospective cohort study with minimum of 10-year follow-up. Hum Fertil (Camb) 2016;19:212–9. doi: 10.1080/14647273.2016.1221149.
    1. Erbas O, Pala HG, Pala EE, Oltulu F, Aktug H, Yavasoglu A, et al. Ovarian failure in diabetic rat model: Nuclear factor-kappaB, oxidative stress, and pentraxin-3. Taiwan J Obstet Gynecol. 2014;53:498–503. doi: 10.1016/j.tjog.2013.11.008.
    1. Erbas O, Pala HG, Pala EE, Artunc Ulkumen B, Akman L, Akman T, et al. Therapeutic effect of sunitinib on diabetes mellitus related ovarian injury: An experimental rat model study. Gynecol Endocrinol. 2015;31:388–91. doi: 10.3109/09513590.2015.1005593.
    1. Hart RJ. Physiological aspects of female fertility: Role of the environment, modern lifestyle, and genetics. Physiol Rev. 2016;96:873–909. doi: 10.1152/physrev.00023.2015.
    1. Chen XY, Xia HX, Guan HY, Li B, Zhang W. Follicle loss and apoptosis in cyclophosphamide-treated mice: What's the matter?Int J Mol Sci. 2016;17 pii: E836. doi: 10.3390/ijms17060836.
    1. Gannon AM, Stämpfli MR, Foster WG. Cigarette smoke exposure elicits increased autophagy and dysregulation of mitochondrial dynamics in murine granulosa cells. Biol Reprod. 2013;88:63. doi: 10.1095/biolreprod.112.106617.
    1. Irving-Rodgers HF, Rodgers RJ. Extracellular matrix of the developing ovarian follicle. Semin Reprod Med. 2006;24:195–203. doi: 10.1055/s-2006-948549.

Source: PubMed

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