title: Altered Circulating Inflammatory Cytokines Are Associated with Anovulatory Polycystic Ovary Syndrome (PCOS) Women Resistant to Clomiphene Citrate Treatment.
abstract: BACKGROUND Polycystic ovary syndrome (PCOS) is a common gynecological disease characterized by chronic oligoanovulation, clinical/biochemical hyperandrogenism, polycystic ovaries, and insulin resistance. Accumulating evidence has shown that PCOS-related ovarian dysfunction is the main cause of anovulatory infertility. Clomiphene citrate (CC) is the first-line therapy for PCOS patients; however, approximately 15-40% PCOS patients are resistant to CC treatment. It has been demonstrated that PCOS is a chronic pro-inflammatory state, as some pro-inflammatory cytokines were elevated in the peripheral circulation of PCOS patients, but whether altered inflammatory cytokines expression in PCOS patients is associated with blunted response to CC remains unknown. MATERIAL AND METHODS We recruited 44 CC-resistant PCOS patients, along with 55 age and body mass index (BMI)-matched CC-sensitive PCOS patients. Ovulation was induced by administrating 50-100 mg/day CC on days 5 to 9 of each menstrual cycle. The cytokine profiles were detected by cytokine antibody microarrays and further validated by ELISAs. RESULTS CC-resistant patients had higher levels of high-sensitivity C-reactive protein (hsCRP) than the CC-sensitive individuals. A growth factor, angiopoietin-2, was significantly reduced [1.64 (0.93-1.95) vs. 1.08 (0.85-1.34), p<0.05], while a chemokine CXCL-16 was significantly increased (9.10±2.35 vs. 10.41±2.82, p<0.05) in CC-resistant patients compared to the CC-sensitive subjects. CXCL-16 was positively correlated with hsCRP (r=0.33, p<0.01). Logistic regression analysis showed that angiopoietin-2 and CXCL-16 are associated with CC resistance. CONCLUSIONS Circulating cytokines are disturbed in CC-resistant PCOS patients. Altered angiopoietin-2 and CXCL-16 levels might compromise the responsiveness of the ovary to CC through up-regulating angiogenesis and inflammation.
authors.affiliation: Department of Reproduction Health and Infertility, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China (mainland).|China-Canada-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China (mainland).
authors.forename: LianLian
authors.initials: L
authors.lastname: Wang
authors.affiliation: China-Canada-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China (mainland).|Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China (mainland).
authors.forename: HongBo
authors.initials: H
authors.lastname: Qi
authors.affiliation: China-Canada-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China (mainland).|College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester, United Kingdom.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Baker
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China (mainland).
authors.forename: QianNa
authors.initials: Q
authors.lastname: Zhen
authors.affiliation: Division of Medical Statistics, School of Public Health and Management, Chongqing Medical University, Chongqing, China (mainland).
authors.forename: Qing
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China (mainland).
authors.forename: Rui
authors.initials: R
authors.lastname: Shi
authors.affiliation: China-Canada-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China (mainland).|Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China (mainland).
authors.forename: Chao
authors.initials: C
authors.lastname: Tong
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China (mainland).
authors.forename: Qian
authors.initials: Q
authors.lastname: Ge
mesh_terms: D000328:Adult; D042702:Angiopoietin-2 / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000097:blood; D002996:Clomiphene / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000097:blood* / Q000188:drug therapy*; D051116:Receptors, Scavenger / Q000097:blood; D055815:Young Adult
chemical_list: D042702:Angiopoietin-2; C423727:CXCL16 protein, human; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D016207:Cytokines; D051116:Receptors, Scavenger; D002996:Clomiphene; D002097:C-Reactive Protein