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

Irit Miller, Hadas Bar-Joseph, Luba Nemerovsky, Ido Ben-Ami*, Ruth Shalgi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 Il-6, Vegf 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.

Original languageEnglish
Pages (from-to)291-300
Number of pages10
JournalJournal of Endocrinology
Volume245
Issue number2
DOIs
StatePublished - May 2020

Funding

FundersFunder number
Department of Endocrinology and Diabetes Mellitus
Dr Leo Mintz Research Fund in Obstetrics and Gynecology, Sackler Faculty of Medicine, Tel Aviv University
School of Medicine, Fukuoka University
Tel Aviv Israel
Israel Science Foundation1934/13
Tel Aviv University
Sackler Faculty of Medicine, Tel-Aviv University

    Keywords

    • Inflammation
    • OHSS
    • PCOS
    • PEDF

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