Pigment epithelium-derived factor (PEDF) negates hyperandrogenic PCOS features

in Journal of Endocrinology
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  • 1 Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, Israel
  • 2 The TMCR Unit, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, Israel
  • 3 IVF and Infertility Unit, Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem, The Hebrew University Medical School of Jerusalem, Jerusalem, Israel

Correspondence should be addressed to I Ben-Ami: idorit@netvision.net.il

*(I Ben-Ami and R Shalgi contributed equally to this work)

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Polycystic ovary syndrome (PCOS), one of the most common female endocrine disorder, is a prevalent cause of infertility. Hyperandrogenism is a key feature in PCOS and is correlated with increased expression of VEGF and cytokines in the ovaries. We have previously shown that pigment epithelium-derived factor (PEDF), an endogenous protein, presents potent anti-angiogenic and anti-inflammatory activities in the ovary and negates the effects of cytokines and VEGF. Additionally, PEDF plays a role in both pathophysiology and treatment of ovarian-hyperstimulation syndrome (OHSS), frequently seen in PCOS patients. We established hyperandrogenic-PCOS models, both in vivo, using mice exposed prenatally to dihydrotestosterone (DHT) and, in vitro, using human primary granulosa cells (hpGCs) and human granulosa cell line (KGN). In PCOS-induced mice, the mRNA levels of I l-6, V egf and Amh were higher than those of control; yet, treatment with rPEDF decreased these levels. Moreover, treating OHSS-induced PCOS-mice with rPEDF alleviated all OHSS symptoms. Stimulation of hpGCs with DHT resulted in downregulation of PEDF mRNA expression, concomitantly with a significant increase in IL-6 and IL-8 mRNAs expression. However, co-stimulation of DHT with rPEDF attenuated the increase in cytokines expression. The anti-inflammatory effect of PEDF was found to be mediated via PPARγ pathway. Our findings suggest that rPEDF treatment may normalize the ovarian angiogenic-inflammatory imbalance, induced by PCOS-associated hyperandrogenism. Moreover, the therapeutic potency of PEDF in preventing OHSS symptomes offers a rationale for using PEDF as novel physiological treatment for PCOS sequels.

 

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  • Adams J, Liu Z, Ren YA, Wun WS, Zhou W, Kenigsberg S, Librach C, Valdes C, Gibbons W & Richards J 2016 Enhanced inflammatory transcriptome in the granulosa cells of women with polycystic ovarian syndrome. Journal of Clinical Endocrinology and Metabolism 101 34593468. (https://doi.org/10.1210/jc.2015-4275)

    • Search Google Scholar
    • Export Citation
  • Artini PG, Monti M, Fasciani A, Battaglia C, D’Ambrogio G & Genazzani AR 2002 Vascular endothelial growth factor, interleukin-6 and interleukin-2 in serum and follicular fluid of patients with ovarian hyperstimulation syndrome. European Journal of Obstetrics, Gynecology, and Reproductive Biology 101 169174. (https://doi.org/10.1016/s0301-2115(01)00568-1)

    • Search Google Scholar
    • Export Citation
  • Azziz R, Carmina E, Chen Z, Dunaif A, Laven JSE, Legro RS, Lizneva D, Natterson-Horowtiz B, Teede HJ & Yildiz BO 2016 Polycystic ovary syndrome. Nature Reviews: Disease Primers 2 16057. (https://doi.org/10.1038/nrdp.2016.57)

    • Search Google Scholar
    • Export Citation
  • Bhide P, Dilgil M, Gudi A, Shah A, Akwaa C & Homburg R 2015 Each small antral follicle in ovaries of women with polycystic ovary syndrome produces more antiMüllerian hormone than its counterpart in a normal ovary: an observational cross-sectional study. Fertility and Sterility 103 537541. (https://doi.org/10.1016/j.fertnstert.2014.10.033)

    • Search Google Scholar
    • Export Citation
  • Breckwoldt M, Selvaraj N, Aharoni D, Barash A, Segal I, Insler V & Amsterdam A 1996 Expression of Ad4-BP/cytochrome P450 side chain cleavage enzyme and induction of cell death in long-term cultures of human granulosa cells. Molecular Human Reproduction 2 391400. (https://doi.org/10.1093/molehr/2.6.391)

    • Search Google Scholar
    • Export Citation
  • Caldwell ASL, Middleton LJ, Jimenez M, Desai R, McMahon AC, Allan CM, Handelsman DJ & Walters KA 2014 Characterization of reproductive, metabolic, and endocrine features of polycystic ovary syndrome in female hyperandrogenic mouse models. Endocrinology 155 31463159. (https://doi.org/10.1210/en.2014-1196)

    • Search Google Scholar
    • Export Citation
  • Caldwell ASL, Edwards MC, Desai R, Jimenez M, Gilchrist RB, Handelsman DJ & Walters KA 2017 Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome. PNAS 114 E3334E3343. (https://doi.org/10.1073/pnas.1616467114)

    • Search Google Scholar
    • Export Citation
  • Chen Q, Sun X, Chen J, Cheng L, Wang J, Wang Y & Sun Z 2009 Direct rosiglitazone action on steroidogenesis and proinflammatory factor production in human granulosa-lutein cells. Reproductive Biology and Endocrinology 7 147. (https://doi.org/10.1186/1477-7827-7-147)

    • Search Google Scholar
    • Export Citation
  • Chuderland D, Ben-Ami I, Kaplan-Kraicer R, Grossman H, Komsky A, Satchi-Fainaro R, Eldar-Boock A, Ron-El R & Shalgi R 2013a Hormonal regulation of pigment epithelium-derived factor (PEDF) in granulosa cells. Molecular Human Reproduction 19 7281. (https://doi.org/10.1093/molehr/gas046)

    • Search Google Scholar
    • Export Citation
  • Chuderland D, Ben-Ami I, Kaplan-Kraicer R, Grossman H, Ron-El R & Shalgi R 2013b The role of pigment epithelium-derived factor in the pathophysiology and treatment of ovarian hyperstimulation syndrome in mice. Journal of Clinical Endocrinology and Metabolism 98 E258E266. (https://doi.org/10.1210/jc.2012-3037)

    • Search Google Scholar
    • Export Citation
  • Chuderland D, Ben-Ami I, Bar-Joseph H & Shalgi R 2014a Role of pigment epithelium-derived factor in the reproductive system. Reproduction 148 R53R61. (https://doi.org/10.1530/REP-14-0251)

    • Search Google Scholar
    • Export Citation
  • Chuderland D, Ben-Ami I, Friedler S, Hasky N, Ninio-Many L, Goldberg K, Bar-Joseph H, Grossman H & Shalgi R 2014b Hormonal regulation of pigment epithelium-derived factor (PEDF) expression in the endometrium. Molecular and Cellular Endocrinology 390 8592. (https://doi.org/10.1016/j.mce.2014.04.006)

    • Search Google Scholar
    • Export Citation
  • Deligeoroglou E, Vrachnis N, Athanasopoulos N, Iliodromiti Z, Sifakis S, Iliodromiti S, Siristatidis C & Creatsas G 2012 Mediators of chronic inflammation in polycystic ovarian syndrome. Gynecological Endocrinology 28 974978. (https://doi.org/10.3109/09513590.2012.683082)

    • Search Google Scholar
    • Export Citation
  • Dilaver N, Pellatt L, Jameson E, Ogunjimi M, Bano G, Homburg R, D Mason H & Rice S 2019 The regulation and signalling of anti-Müllerian hormone in human granulosa cells: relevance to polycystic ovary syndrome. Human Reproduction 34 24672479. (https://doi.org/10.1093/humrep/dez214)

    • Search Google Scholar
    • Export Citation
  • Dulka EA & Moenter SM 2017 Prepubertal development of gonadotropin-releasing hormone neuron activity is altered by sex, age, and prenatal androgen exposure. Endocrinology 158 39433953. (https://doi.org/10.1210/en.2017-00768)

    • Search Google Scholar
    • Export Citation
  • Fang Y, Lu X, Liu L, Lin X, Sun M, Fu J, Xu S & Tan Y 2016 Vascular endothelial growth factor induces antiMüllerian hormone receptor 2 overexpression in ovarian granulosa cells of in vitro fertilization/intracytoplasmic sperm injection patients. Molecular Medicine Reports 13 51575162. (https://doi.org/10.3892/mmr.2016.5173)

    • Search Google Scholar
    • Export Citation
  • Filippou P & Homburg R 2017 Is foetal hyperexposure to androgens a cause of PCOS? Human Reproduction Update 23 421432. (https://doi.org/10.1093/humupd/dmx013)

    • Search Google Scholar
    • Export Citation
  • González F, Sia CL, Bearson DM & Blair HE 2014 Hyperandrogenism induces a proinflammatory TNFα response to glucose ingestion in a receptor-dependent fashion. Journal of Clinical Endocrinology and Metabolism 99 E848E854. (https://doi.org/10.1210/jc.2013-4109)

    • Search Google Scholar
    • Export Citation
  • Goodarzi MO, Dumesic DA, Chazenbalk G & Azziz R 2011 Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nature Reviews: Endocrinology 7 219231. (https://doi.org/10.1038/nrendo.2010.217)

    • Search Google Scholar
    • Export Citation
  • Hirsch J, Johnson CL, Nelius T, Kennedy R, de Riese W & Filleur S 2011 PEDF inhibits IL8 production in prostate cancer cells through PEDF receptor/phospholipase A2 and regulation of NFκB and PPARγ. Cytokine 55 202210. (https://doi.org/10.1016/j.cyto.2011.04.010)

    • Search Google Scholar
    • Export Citation
  • Humaidan P, Quartarolo J & Papanikolaou EG 2010 Preventing ovarian hyperstimulation syndrome: guidance for the clinician. Fertility and Sterility 94 389400. (https://doi.org/10.1016/j.fertnstert.2010.03.028)

    • Search Google Scholar
    • Export Citation
  • Ishibashi Y, Matsui T, Ohta K, Tanoue R & Takeuchi M 2012 PEDF inhibits AGE-induced podocyte apoptosis via PPAR-gamma activation. Microvascular Research 85 5458. (https://doi.org/10.1016/j.mvr.2012.10.007)

    • Search Google Scholar
    • Export Citation
  • Jayasena CN & Franks S 2014 The management of patients with polycystic ovary syndrome. Nature Reviews: Endocrinology 10 624636. (https://doi.org/10.1038/nrendo.2014.102)

    • Search Google Scholar
    • Export Citation
  • Karakas SE 2017 New biomarkers for diagnosis and management of polycystic ovary syndrome. Clinica Chimica Acta: International Journal of Clinical Chemistry 471 248253. (https://doi.org/10.1016/j.cca.2017.06.009)

    • Search Google Scholar
    • Export Citation
  • Konson A, Pradeep S & Seger R 2010 Phosphomimetic mutants of pigment epithelium-derived factor with enhanced antiangiogenic activity as potent anticancer agents. Cancer Research 70 62476257. (https://doi.org/10.1158/0008-5472.CAN-10-0434)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Leo LF, McGregor C, Grivitishvili A, Barnstable CJ & Tombran-Tink J 2012 Pigment epithelium-derived factor (PEDF) peptide eye drops reduce inflammation, cell death and vascular leakage in diabetic retinopathy in Ins2(Akita) mice. Molecular Medicine 18 13871401. (https://doi.org/10.2119/molmed.2012.00008)

    • Search Google Scholar
    • Export Citation
  • Liu XY, Yang YJ, Tang CL, Wang K, Chen JJ, Teng XM, Ruan YC & Yang JZ 2019 Elevation of antiMüllerian hormone in women with polycystic ovary syndrome undergoing assisted reproduction: effect of insulin. Fertility and Sterility 111 157167. (https://doi.org/10.1016/j.fertnstert.2018.09.022)

    • Search Google Scholar
    • Export Citation
  • Ljubicic V & Jasmin BJ 2015 Metformin increases peroxisome proliferator-activated receptor γ co-activator-1α and utrophin a expression in dystrophic skeletal muscle. Muscle and Nerve 52 139142. (https://doi.org/10.1002/mus.24692)

    • Search Google Scholar
    • Export Citation
  • Marti N, Galván JA, Pandey AV, Trippel M, Tapia C, Müller M, Perren A & Flück CE 2017 Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome. Molecular and Cellular Endocrinology 441 116123. (https://doi.org/10.1016/j.mce.2016.07.029)

    • Search Google Scholar
    • Export Citation
  • Miller I, Chuderland D, Grossman H, Ron-El R, Ben-Ami I & Shalgi R 2016 The dual role of PEDF in the pathogenesis of OHSS: negating both angiogenic and inflammatory pathways. Journal of Clinical Endocrinology and Metabolism 101 46994709. (https://doi.org/10.1210/jc.2016-1744)

    • Search Google Scholar
    • Export Citation
  • Münzker J, Hofer D, Trummer C, Ulbing M, Harger A, Pieber T, Owen L, Keevil B, Brabant G, Lerchbaum E, et al. 2015 Testosterone to dihydrotestosterone ratio as a new biomarker for an adverse metabolic phenotype in the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 100 653660. (https://doi.org/10.1210/jc.2014-2523)

    • Search Google Scholar
    • Export Citation
  • Nandi A, Chen Z, Patel R & Poretsky L 2014 Polycystic ovary syndrome. Endocrinology and Metabolism Clinics of North America 43 123147. (https://doi.org/10.1016/j.ecl.2013.10.003)

    • Search Google Scholar
    • Export Citation
  • Nishi Y, Yanase T, Mu Y, Oba K, Ichino I, Saito M, Nomura M, Mukasa C, Okabe T, Goto K, et al. 2001 Establishment and characterization of a steroidogenic human granulosa-like tumor cell line, KGN, that expresses functional follicle-stimulating hormone receptor. Endocrinology 142 437445. (https://doi.org/10.1210/endo.142.1.7862)

    • Search Google Scholar
    • Export Citation
  • Orly J, Sato G & Erickson GF 1980 Serum suppresses the expression of hormonally induced functions in cultured granulosa cells. Cell 20 817827. (https://doi.org/10.1016/0092-8674(80)90328-1)

    • Search Google Scholar
    • Export Citation
  • Roland AV, Nunemaker CS, Keller SR & Moenter SM 2010 Prenatal androgen exposure programs metabolic dysfunction in female mice. Journal of Endocrinology 207 213223. (https://doi.org/10.1677/JOE-10-0217)

    • Search Google Scholar
    • Export Citation
  • Sathyapalan T, Al-Qaissi A, Kilpatrick ES, Dargham SR & Atkin SL 2018 Anti-Müllerian hormone measurement for the diagnosis of polycystic ovary syndrome. Clinical Endocrinology 88 258262. (https://doi.org/10.1111/cen.13517)

    • Search Google Scholar
    • Export Citation
  • Silber M, Miller I, Bar-Joseph H, Ben-Ami I & Shalgi R 2019 Elucidating the role of pigment epithelium-derived factor (PEDF) in metabolic PCOS models. Journal of Endocrinology 244 297308. (https://doi.org/10.1530/JOE-19-0297)

    • Search Google Scholar
    • Export Citation
  • Tal R, Seifer DB, Grazi RV & Malter HE 2014 Follicular fluid placental growth factor is increased in polycystic ovarian syndrome: correlation with ovarian stimulation. Reproductive Biology and Endocrinology 12 82. (https://doi.org/10.1186/1477-7827-12-82)

    • Search Google Scholar
    • Export Citation
  • Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ & International PCOS Network 2018 Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Human Reproduction 33 16021618. (https://doi.org/10.1093/humrep/dey256)

    • Search Google Scholar
    • Export Citation
  • Torchen LC, Idkowiak J, Fogel NR, O’Neil DM, Shackleton CHL, Arlt W & Dunaif A 2016 Evidence for increased 5α-reductase activity during early childhood in daughters of women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 101 20692075. (https://doi.org/10.1210/jc.2015-3926)

    • Search Google Scholar
    • Export Citation
  • Wang JJ, Zhang SX, Mott R, Chen Y, Knapp RR, Cao W & Ma JX 2008 Anti-inflammatory effects of pigment epithelium-derived factor in diabetic nephropathy. American Journal of Physiology: Renal Physiology 294 F1166F1173. (https://doi.org/10.1152/ajprenal.00375.2007)

    • Search Google Scholar
    • Export Citation
  • Xita N & Tsatsoulis A 2006 Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies. Journal of Clinical Endocrinology and Metabolism 91 16601666. (https://doi.org/10.1210/jc.2005-2757)

    • Search Google Scholar
    • Export Citation
  • Yamagishi S-I, Inagaki Y, Nakamura K, Abe R, Shimizu T, Yoshimura A & Imaizumi T 2004 Pigment epithelium-derived factor inhibits TNF-alpha-induced interleukin-6 expression in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. Journal of Molecular and Cellular Cardiology 37 497506. (https://doi.org/10.1016/j.yjmcc.2004.04.007)

    • Search Google Scholar
    • Export Citation
  • Yang S, Li Q, Zhong L, Song Y, Tian B, Cheng Q, Qing H, Xia W, Luo M & Mei M 2011 Serum pigment epithelium-derived factor is elevated in women with polycystic ovary syndrome and correlates with insulin resistance. Journal of Clinical Endocrinology and Metabolism 96 831836. (https://doi.org/10.1210/jc.2010-2140)

    • Search Google Scholar
    • Export Citation
  • Yki-Järvinen H 2004 Thiazolidinediones. New England Journal of Medicine 351 11061118. (https://doi.org/10.1056/NEJMra041001)

  • Yoshida T, Yamagishi Si, Nakamura K, Matsui T, Imaizumi T, Inoue H, Ueno T & Sata M 2006 Pigment epithelium-derived factor (PEDF) blocks the interleukin-6 signaling to C-reactive protein expression in Hep3B cells by suppressing Rac-1 activation. Life Sciences 79 19811987. (https://doi.org/10.1016/j.lfs.2006.06.034)

    • Search Google Scholar
    • Export Citation
  • Zhang SX, Wang JJ, Gao G, Shao C, Mott R & Ma JX 2006 Pigment epithelium-derived factor (PEDF) is an endogenous antiinflammatory factor. FASEB Journal 20 323325. (https://doi.org/10.1096/fj.05-4313fje)

    • Search Google Scholar
    • Export Citation
  • Zhang SX, Wang JJ, Dashti A, Wilson K, Zou MH, Szweda L, Ma JX & Lyons TJ 2008 Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein. Journal of Molecular Endocrinology 41 135143. (https://doi.org/10.1677/JME-08-0011)

    • Search Google Scholar
    • Export Citation