PubMed · 14225270
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V HINGORANI. 1964-10-16. FUNCTIONAL UTERINE BLEEDING.. https://pubmed.ncbi.nlm.nih.gov/14225270/
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The matrix metalloproteinases (MMPs) are part of an expanded family of proteins called the astacin family of zinc metalloproteinases. The MMPs, probably balanced by their tissue inhibitors of metalloproteinases (TIMPs), are essential effectors of developmental processes participating in cell migration, cell proliferation, apoptosis and tissue morphogenesis. The MMPs regulate the function of biologically active molecules as well as fulfilling an important role in endothelial cell invasion, angiogenesis and in tumor progression. The dynamic normal physiology of the human reproductive system involves almost all of the above-mentioned aspects of MMPs activity. This review presents and discusses new insights into the role of MMPs, and their TIMPs, in human endometrial cycle and ovarian function.
OBJECTIVES: To review the morphological and molecular events responsible for uterine bleeding in health and disease. METHODS: Review of pertinent literature focusing on the histology and pathophysiology of normal and abnormal uterine bleeding (AUB). RESULTS: The seat of normal menstrual bleeding is located in the upper two-thirds of the endometrial mucosa and is recognized by tissue necrosis, disruption of microvasculature, migratory leukocytes and platelet/fibrin thrombi in microvessels. The molecular events responsible for tissue and vascular breakdown are related to the release of proteolytic lysosomal enzymes of endometrial cell and inflammatory cell origin. In cases of AUB, tissue breakdown is located in the superficial layer (subsurface) of the endometrium. It is either focal (breakthrough bleeding) or diffuse (withdrawal bleeding). It is initiated by either chronic endometritis and/or microerosions or vascular fragility due to structural abnormalities of microvessels. Endometritis and microerosions occur in otherwise normal endometrium, polyps, submucosal leiomyomata, atrophy and cancer (organic causes). Primary vascular alterations are found in hyperestrogenic-type endometria, i.e. anovulatory dysfunctional uterine bleeding (DUB) and progestational-type endometrium, i.e. progestational contraceptives and combined, continuous hormonal replacement therapy (HRT) (non-organic causes). Ovulatory DUB and coagulation disorders are not appreciated histologically. These are related to impaired vasoconstriction and fibrinolysis and impaired coagulation factors, respectively. CONCLUSIONS: Histology may contribute to better understanding of the mechanisms of action that initiate, regulate and lead to AUB. Better insight may trigger in the development of therapeutic procedures that could either prevent or control vascular breakdown which results in unexpected uterine bleeding.
The cyclic growth, differentiation, and cell death of endometrium represents the most dynamic example of steroid-driven tissue turnover in human adults. Key effectors in these processes-matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs)-are regulated by ovarian steroids and, locally, by cytokines. We used reverse transcription-polymerase chain reaction to evaluate the expression of both transcriptionally regulated molecules such as estrogen receptor-alpha, progesterone receptor, and prolactin and a large array of MMPs and TIMPs (MMP-1, -2, -3, -7, -8, -9, -11, -12, -19, -26, MT1-MMP, MT2-MMP, MT3-MMP, TIMP-1, -2, -3). Altogether, three distinct patterns of MMP and two patterns of TIMP expression were detected in cycling endometrium: 1). MMPs restricted to the menstrual period (MMPs-1, -3, -8, -9, -12); 2). MMPs and TIMPs expressed throughout the cycle (MMP-2, MT1-MMP, MT2-MMP, MMP-19, TIMP-1, and TIMP-2); 3). MMPs predominantly expressed during the proliferative phase (MMP-7, MMP-11, MMP-26, and MT3-MMP); and 4). TIMP-3, which, contrary to the other TIMPs, shows significant modulations, with maximum expression during the late secretory and menstrual phases. These specific patterns of MMP expression associated with each phase of the cycle may point to specific roles in the processes of menstruation, housekeeping activities, angiogenesis, tissue growth, and extracellular matrix remodeling.