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.