Matrix Metalloproteinases 2 and 9 and their Tissue Inhibitors in the Follicular Fluid of Patients with Polycystic Ovaries Undergoing In Vitro Fertilisation

The present study was undertaken to investigate the levels of matrix metalloproteinase (MMP)-2, MMP-9 and their tissue inhibitors (TIMP-2 and TIMP-1, respectively) in the follicular fluid of 39 patients with polycystic ovary syndrome (PCOS) and compare them with the levels found in 56 age- and weight-matched normally ovulating women, all undergoing in vitro fertilisation (IVF) treatment. Significantly higher levels of MMP-2 and MMP-9 (p=0.02 and p<0.001, respectively) as well as TIMP-2 and TIMP-1 (p=0.006 and p<0.001, respectively) were found in the PCOS group compared to controls. Women who achieved pregnancy had higher TIMP-1 levels compared to the non- pregnant ones in the control group (p=0.01). In conclusion, women with PCOS exhibited significantly increased gelatinolytic activity compared with controls of similar age and body mass index, thus indicating a more intense extracellular matrix remodelling in this group of patients during IVF treatment due to multiple follicular development and cyst formation. During reproductive life, human ovarian tissue is subjected to a continuous and extensive remodelling process in relation to follicular growth, ovulation and atresia. Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that are involved in extracellular matrix (ECM) remodelling during ovarian follicular growth and ovulation. Their activity is regulated at different levels by complex mechanisms including specific interactions with tissue inhibitors of metalloproteinases (TIMPs) which represent a family of polypeptides that bind to MMPs and inhibit their activity. In particular, TIMP-1 regulates the activity of MMP- 9 and TIMP-2 inhibits MMP-2 (1). Despite the fact that the production of MMPs and TIMPs as well as their mechanisms of action in human ovaries are not fully understood yet, their presence in the follicular microenvironment is important for the subsequent follicular development. Deficient follicular growth and/or ovulation have been correlated with the presence of low levels of MMPs in follicular fluid (2). Gelatinases seem to have an important role in the stabilisation of the ECM, an important process at the initiation of pregnancy (3). By definition, the polycystic ovary syndrome (PCOS) implies the presence of multiple cystic follicles together with many other morphologic changes in the ovaries, which results in a continuous and increased remodelling of the ovarian stroma. Increased serum concentrations of MMP-2 and MMP-9 have been reported in women with PCOS (4). This study was based on the hypothesis that since tissue remodelling in polycystic ovaries is more intense than in normal ovaries, some differences in the activity of these parameters are expected between the two groups. Therefore, the study was designed to detect the levels of MMP-2, MMP-9 and their tissue inhibitors (TIMP-2 and TIMP-1, respectively) in the follicular fluid of PCOS patients undergoing controlled ovarian stimulation and compare them with the levels found in normally ovulating women under in vitro fertilisation (IVF) treatment.