Elevated interleukin-6 levels in the ovarian hyper stimulation syndrome: Ovarian immunohistochemical localization of interleukin-6 signal

Abstract

Objective: To examine the production and immunolocalization of interleukin-6 (IL-6) in patients with the ovarian hyperstimulation syndrome. Methods: The study group consisted of patients with ovarian hyperstimulation syndrome (n=9) from whom serum and ascites samples were obtained. The control samples used were serum (n=10) and peritoneal (n=16) and follicular fluids (n=8) from healthy individuals. Follicular fluid (n=40) and serial serum samples were also obtained from patients undergoing menotropin stimulation for in vitro fertilization (IVF) before (n=10) and after ovulation (n=34). Interleukin-6 measurements were performed with a sensitive immunoassay and confirmed with a bioassay. Immunohistochemical localization of IL-6 was performed with a mouse monoclonal antibody in normal premenopausal (n=5) and postmenopausal ovaries (n=5), as well as with cells from stimulated follicular fluid aspirates (n=3). Results: We found significantly higher serum and ascites IL-6 levels in ovarian hyperstimulation syndrome (mean 18.8 ± 1.1 and 810.8 ± 60.7 pg/mL, respectively) compared with postovulatory serum and peritoneal fluid from normal controls (mean 4.4 ± .69 and 44.7 ± 7.5 pg/mL, respectively) (P < .001) or serum after menotropin stimulation (13.1 ± 1.1 pg/mL) (P < .001). At the time of ovulation, follicular fluid IL-6 levels (normal controls, mean 9 ± 2.1 pg/mL; menotropin stimulation, mean 10.1 ± 4 pg/mL) were higher than in preovulatory serum (normal controls, mean 4.5 ± .8 pg/mL; menotropin stimulation, mean 6.3 ± 1.4 pg/mL) (P < .001). Immunohistochemical localization of IL-6 revealed intense staining in corpora lutea and theca cells from large antral follicles and luteinized granulosa cells in follicular aspirates after menotropin stimulation. Conclusion: Interleukin-6 levels are markedly elevated in the ovarian hyperstimulation syndrome when compared with controls. The higher follicular fluid IL-6 levels seen suggest local secretion of this cytokine. Immunohistochemical correlation demonstrated IL-6 within ovarian theca cells. These findings suggest a local role for IL-6 both in normal and stimulated ovarian function. Whether IL-6 is directly responsible for the clinical manifestations of this syndrome is unclear. However, when produced in massive amounts, the pro-inflammatory effects of IL-6 may contribute to its pathogenesis and perhaps serve as a marker for the disease.