Mechanisms of deregulation of ovarian follicular growth in polycystic ovarian syndrome
Patricia DA Lima1, Qi Wang1, Anne-Laure Nivet1, Arthur Leader2, Annie Cheung3, Chii-Ruey Tzeng4 and Benjamin K Tsang1*.
1. Department of Obstetrics & Gynecology and Cellular & Molecular Medicine, University of Ottawa; Chronic Disease Program, Ottawa Hospital Research Institute;
2. Ottawa Fertility Centre, Ottawa, Canada;
3. Department of Pathology, University of Hong Kong, Hong Kong, PRC;
4. Center for Reproductive Medicine and Science, Taipei Medical University Hospital, Taiwan.
Polycystic ovarian syndrome (PCOS) is a heterogeneous syndrome affecting 10% of women in reproductive age and accounts for 75% of anovulatory infertility. It is associated with hyperandrogenemia, chronic inflammation, suppressed proliferation and enhanced granulosa cell apoptosis and antral follicle growth arrest. The molecular and cellular mechanisms involved in antral follicular growth arrest in PCOS are not well understood.
As in human PCOS, female rats treated with 5α-dihydrotestosterone (DHT) exhibit elevated serum chemerin level. Although chemerin down-regulates rat ovarian estrogen synthesis, induces granulosa cell apoptosis and suppresses follicular growth in vitro, whether its action involves immuno-regulation is not clear. Immunological functions of chemerin include chemotaxis of macrophages expressing the chemerin receptor CMKLR1. Macrophages play key role in inflammation and the balance between M1 (inflammatory) and M2 (anti-inflammatory) macrophages determines physiological/pathological outcomes. We have examined the hypothesis that hyperandrogenism alters M1 and M2 macrophage balance in ovarian follicle stage-specific and chemerin-dependent manner, leading to antral follicle arrest. DHT increases early antral follicles and unhealthy large antral follicles and resulted in the absence of pre-ovulatory follicles. These responses are accompanied by increased M1 but reduced M2 and increased M1/M2 ratio in antral and pre-ovulatory follicles, transient increase in ovarian CMKLR1+M1 macrophages and decreased CMKLR1+monocytes which are localized primarily in unhealthy antral follicles and migration of mononuclear cells towards chemerin-rich environment. Apoptosis are higher in pre-ovulatory follicles and coincident with ovarian macrophage imbalance. Macrophage-rich follicles (MΦ-RF) are present in DHT-treated but not in control ovaries. DHT increases the total M1 macrophages expressing CMKLR1 in MΦ-RF and exhibiting phagocytic-like morphology. In humans, chemerin is significant higher in the follicular fluid but not in the serum from non-obese PCOS subjects. While stromal M1 macrophage frequency is not different between PCOS and non-PCOS ovaries, a lower abundance of stromal M2 macrophages is present in PCOS ovaries, resulting in higher M1/M2 ratio in PCOS. Our results suggest that hyperandrogenemia affects the immunological niche of the ovary and may be important in PCOS pathophysiology (Supported by CIHR).
Patricia DA Lima1, Qi Wang1, Anne-Laure Nivet1, Arthur Leader2, Annie Cheung3, Chii-Ruey Tzeng4 and Benjamin K Tsang1*.
1. Department of Obstetrics & Gynecology and Cellular & Molecular Medicine, University of Ottawa; Chronic Disease Program, Ottawa Hospital Research Institute;
2. Ottawa Fertility Centre, Ottawa, Canada;
3. Department of Pathology, University of Hong Kong, Hong Kong, PRC;
4. Center for Reproductive Medicine and Science, Taipei Medical University Hospital, Taiwan.
Polycystic ovarian syndrome (PCOS) is a heterogeneous syndrome affecting 10% of women in reproductive age and accounts for 75% of anovulatory infertility. It is associated with hyperandrogenemia, chronic inflammation, suppressed proliferation and enhanced granulosa cell apoptosis and antral follicle growth arrest. The molecular and cellular mechanisms involved in antral follicular growth arrest in PCOS are not well understood.
As in human PCOS, female rats treated with 5α-dihydrotestosterone (DHT) exhibit elevated serum chemerin level. Although chemerin down-regulates rat ovarian estrogen synthesis, induces granulosa cell apoptosis and suppresses follicular growth in vitro, whether its action involves immuno-regulation is not clear. Immunological functions of chemerin include chemotaxis of macrophages expressing the chemerin receptor CMKLR1. Macrophages play key role in inflammation and the balance between M1 (inflammatory) and M2 (anti-inflammatory) macrophages determines physiological/pathological outcomes. We have examined the hypothesis that hyperandrogenism alters M1 and M2 macrophage balance in ovarian follicle stage-specific and chemerin-dependent manner, leading to antral follicle arrest. DHT increases early antral follicles and unhealthy large antral follicles and resulted in the absence of pre-ovulatory follicles. These responses are accompanied by increased M1 but reduced M2 and increased M1/M2 ratio in antral and pre-ovulatory follicles, transient increase in ovarian CMKLR1+M1 macrophages and decreased CMKLR1+monocytes which are localized primarily in unhealthy antral follicles and migration of mononuclear cells towards chemerin-rich environment. Apoptosis are higher in pre-ovulatory follicles and coincident with ovarian macrophage imbalance. Macrophage-rich follicles (MΦ-RF) are present in DHT-treated but not in control ovaries. DHT increases the total M1 macrophages expressing CMKLR1 in MΦ-RF and exhibiting phagocytic-like morphology. In humans, chemerin is significant higher in the follicular fluid but not in the serum from non-obese PCOS subjects. While stromal M1 macrophage frequency is not different between PCOS and non-PCOS ovaries, a lower abundance of stromal M2 macrophages is present in PCOS ovaries, resulting in higher M1/M2 ratio in PCOS. Our results suggest that hyperandrogenemia affects the immunological niche of the ovary and may be important in PCOS pathophysiology (Supported by CIHR).