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24 April 2018 Polycystic ovary syndrome: possible involvement of androgen-induced, chemerin-mediated ovarian recruitment of monocytes/macrophages
Patricia D. A. Lima, Anne-Laure Nivet, Qi Wang, Yi-An Chen, Arthur Leader, Annie Cheung, Chii-Ruey Tzeng, Benjamin K. Tsang
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Abstract

Polycystic ovary syndrome (PCOS) is a continuum of endocrine and reproductive disorders characterized by hyperandrogenism, antral follicle growth arrest, and chronic inflammation. Macrophages play key role in inflammation, and the balance between M1 (inflammatory) and M2 (anti-inflammatory) macrophages determines physiological/pathological outcomes. Here, we investigated if hyperandrogenism increases ovarian chemerin altering the balance of M1 and M2 macrophages and the granulosa cell death. Ovarian chemerin was upregulated by 5α- dihydrotestosterone (DHT) in lean and overweight rats; while increased serum chemerin levels were only evident in overweight rats, suggesting that the serum chemerin may be reflective of a systemic response and associated with obesity, whereas increased ovarian chemerin expression is a localized response independent of the metabolic status. DHT altered follicle dynamics while increased the M1: M2 macrophages ratio in antral and pre-ovulatory follicles. While ovarian M1 macrophages expressing chemokine-like receptor 1 (CMKLR1) were increased, CMKLR1+ monocytes, which migrated toward chemerin-rich environment, were markedly decreased after 15 days of DHT. Androgen-induced granulosa cell apoptosis was dependent on the presence of macrophages. In humans, chemerin levels in follicular fluid, but not in serum, were higher in lean PCOS patients compared to BMI-matched controls and were associated with increased M1: M2 ratio. Our results support the concept that in PCOS, hyperandrogenemia increases chemerin expression while promotes CMKLR1+ monocytes recruitment and deregulates the immunological niche of ovaries. This study established a new immunological perspective in PCOS at the ovarian level. Hyperandrogenism is associated with upregulation of chemerin and macrophage unbalance in the ovaries.

Summary Sentence

Hyperandrogenism increases chemerin inducing the migration of CMKLR1+ monocytes to the ovaries where they become CMKLR1+ M1 macrophages. Macrophages induce granulosa cell apoptosis in response to the androgen.

© The Author(s) 2018. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Patricia D. A. Lima, Anne-Laure Nivet, Qi Wang, Yi-An Chen, Arthur Leader, Annie Cheung, Chii-Ruey Tzeng, and Benjamin K. Tsang "Polycystic ovary syndrome: possible involvement of androgen-induced, chemerin-mediated ovarian recruitment of monocytes/macrophages," Biology of Reproduction 99(4), 838-852, (24 April 2018). https://doi.org/10.1093/biolre/ioy096
Received: 12 November 2017; Accepted: 22 April 2018; Published: 24 April 2018
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