MMPS and TIMPS in ovarian physiology and pathophysiology

Shlomit Goldman
In: Frontiers in Bioscience · 2004 · vol. 9(1-3) , pp. 2474 · doi:10.2741/1409 · PMID:15353300 · W2075444006
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are localized in ovarian structures, with their expression correlating to follicular development, ovulation, corpus luteum formation, and regression, and altered MMP-TIMP balance is observed in PCOS.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 ⓘ

This paper reviews and experimentally characterizes where matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are localized in rodent ovaries during follicle development, ovulation, corpus luteum formation, and regression, using high-level localization of MMP-2/MMP-9 gelatinolytic activity, TIMP-1/2/3 tissue expression, and inhibitor studies in perfused rat ovaries. It reports that synthetic inhibitors of collagenases suppress ovulation, that hCG induces upregulation of MMP-19 and TIMP-1 in human follicles and also induces MMP-2 and MT1-MMP after PMSG stimulation, and that TIMP expression shows distinct cellular patterns during early luteinization. Regression of the corpus luteum is associated with increased metalloproteinase activity, while women with polycystic ovarian syndrome show a shifted MMP–TIMP balance toward greater gelatinolytic activity (higher MMP-9 and MMP-2 secretion without lower basal TIMP-1). The authors primarily infer pathology from localization and expression/inhibitor experiments, with an explicit focus on ovarian physiology and PCOS rather than other pelvic disease mechanisms. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

The matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been postulated to play a critical role in the extracellular matrix (ECM) remodeling associated with follicular development. The gelatinases were localized to the theca of developing follicles and in the stroma of the rodent ovary. Gelatinolytic activity corresponded with the localization of MMP-2 and MMP-9 around the developing follicles and at the apex of preovulatory follicles. The TIMPs-1, -2, and -3 were localized to the stroma and theca of developing follicles and correlation between MMPs and the quality of the developing follicles was found. During the process of ovulation, MMP-1 protein was found in the theca interna and externa, interstitial glands, and germinal epithelium. Synthetic inhibitor of mammalian tissue collagenases was documented to be inhibitory to ovulation in perfused rat ovaries. MMP-19 and TIMP-1 messenger RNA were localized to the granulosa and thecal-interstitial cells of large preovulatory and ovulating follicles. Both were induced and upregulated 5-10 fold by human chorionic gonadotropin (hCG). MMP-2 mRNA found in theca-interstitial cells and membrane-type (MT) 1-MMP mRNA found in granulosa and theca-interstitial cells were both induced after stimulation with pregnant mare's serum gonadotropin (PMSG). Gelatinolytic activity was observed throughout the formation of the corpus luteum. At 12 h after hCG, luteinizing granulosa cells expressed TIMP-1 and TIMP-3 mRNA. In the newly forming corpus luteum at 24 h after hCG administration, the luteal cells expressed TIMP-1, -2, and -3 mRNA with unique pattern of cellular expression for each of the TIMPs. Regression of the corpus luteum is associated with a significant increase in the activity of the metalloproteinases. In luteinized granulosa cells from women with polycystic ovarian syndrome (PCOS) the MMP-TIMP balance is shifted towards greater MMP activity. Cultured luteinized granulosa cells obtained from PCOS patients secrete higher levels of MMP-9 and MMP-2 compared to granulosa cells from normal ovulatory patients whereas the secreted basal level of TIMP-1 was similar in both types of granulosa cells. These results indicate a higher net gelatinolytic activity within the luteinizing granulosa cells of patients with PCOS. It has been shown that in sheep, diversion of normal follicles to atresia by hypophysectomy is followed by a significant increase of intrafollicular levels of MMP-2 and MMP-9 and the disappearance of connexin-43. It is therefore reasonable to speculate that MMP-9 and MMP-2 may be associated with inappropriate atresia in PCOS.

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