Endometriosis and ovarian reserve : inflammation and prognostic markers

Abstract

Introduction: Endometriosis is a common, benign gynecological disease, associated with pelvic pain and infertility. It is generally thought to be caused by retrograde shedding of menstrual tissue with subsequent attachment to peritoneal surfaces. Endometriosis involves an altered inflammatory response and TNF seems to be an important pro-inflammatory mediator. Current medical treatment implies hormonal suppression associated with several side-effects. During treatment, pregnancy is either impossible or contra-indicated. Infertile women with endometriosis may conceive after assisted reproduction. However, during IVF, women with endometriosis often show a poor response to ovarian hyperstimulation and have lower pregnancy rate. This suggests that women with endometriosis have reduced ovarian reserve. Identifying diminished ovarian reserve is important during infertility treatment. Several factors have been proposed as markers of ovarian reserve.

Aims: To study the effects of a TNF-inhibitor on induced endometriosis and pregnancy outcome in an experimental animal model; to evaluate the significance of two markers for ovarian reserve, FSH-receptor polymorphisms and AMH, in relation to infertility, endometriosis and inflammation.

Material and methods: Endometriosis was induced in 18 female baboons and the extent of disease was measured during laparoscopy. The animals were randomized to either TNF-inhibitor (c5N, n=11) or placebo (n=7) for 25 days. The effects were evaluated by laparoscopy. 16 of the baboons received an additional 3 infusions of c5N (n=9) or placebo (n=7). Subsequently, timed mating was commenced. Pregnancy outcome was evaluated after 9 cycles. Single nucleotide polymorphisms (SNPs) at pos 680 (exon 10) in the FSH-receptor was analysed in 68 infertile women using PCR and DNA sequencing. 15 of these women had FSH-levels >10 IU/ml on cycle day 3 or after clomiphene challenge test (CCCT). AMH was measured in serum and follicular fluid from 72 women with endometriosis (n=34) and tubal factor infertility (n=38). In addition, several cytokines and growth factors were analysed in follicular fluid during IVF.

Results: Total surface area and volume of endometriotic lesions was significantly reduced in animals treated with c5N compared to placebo. The strongest effect was recorded for red lesions. No adverse effects were observed on the menstrual cycle in either group. Pregnancy rates and cycle fecundity rate (CFR) were comparable in both groups after timed mating. Women with FSH-receptor variant Serine/Serine at pos 680 had significantly higher FSH after CCCT but no differences in receptor distribution were observed. Women with endometriosis had lower AMH in serum and higher amounts of TNF in follicular fluid than women with tubal factor infertility. Women with endometriosis produced fewer small follicles and had a lower fertilization rate after IVF.

Conclusion: The results support a central role for TNF in endometriosis. Women with endometriosis seemingly have a diminished ovarian reserve, related to increased inflammatory activity. Inhibition of TNF could represent a novel principle for the treatment of this common disease. Serum levels of AMH may aid the clinician to identify poor responders among women with endometriosis prior to IVF treatment. Also, certain FSH-receptor variants may be a characteristic for a subset of infertile women.