Cytokines in the follicular fluid of stimulated and non-stimulated human ovaries; is ovulation a suppressed inflammatory reaction?

We determined the concentrations of tumour necrosis factor (TNF)-alpha, interleukins (IL)-1 beta, -6, -8 and -1-receptor antagonist (IL-1-ra) and of oestradiol and progesterone in the follicular fluid of 111 women undergoing in-vitro fertilization (IVF) and of six women with ovarian cysts in order to elucidate mid-cycle mechanisms causing dissociation of the follicle wall and local rupture of the ovarian tissue complex. Four stimulation protocols were administered: gonadotrophin releasing hormone agonist/human menopausal gonadotrophin (GnRHa/HMG), clomiphene citrate/HMG (CC/HMG), HMG and follicle-stimulating hormone (FSH). Concentrations of TNF alpha and IL-1 beta were below 15 and 3 pg/ml respectively. IL-6 (median 4.1, 3.5-4.4 pg/ml, 95% CI) was higher after stimulation with FSH (5.6 pg/ml) than with HMG (3.2 pg/ml, P < 0.05) or GnRHa/HMG (3.7 pg/ml, P < 0.05), and after stimulation with CC/HMG (5.5 pg/ml) than with HMG (P < 0.01) or GnRHa/HMG (P < 0.001). IL-8 ranged from 32 to 1241 pg/ml (147, 117-178 pg/ml) and IL-1-ra from < 31 to > 10,000 pg/ml (156, 109-192 pg/ml). Cytokine levels did not correlate to oestradiol or progesterone concentrations. The ovarian cysts contained similar IL-8 (14-540 pg/ml) and IL-1 beta (< 30 pg/ml), but higher IL-6 (13.6-> 500 pg/ml) and lower IL-1-ra concentrations. We assume that IL-6, IL-8 and IL-1-ra are involved in peri-ovulatory cellular interactions. Thus, ovulation appears to be a cytokine-regulated process of an 'inflammation' (IL-6 and IL-8) followed by 'anti-inflammatory' reactions (IL-1-ra).