Hypoxia inducible factor (HIF-1) and endometrial remodelling: relevance to menstrual bleeding
Lead Research Organisation:
University of Edinburgh
Department Name: Edinburgh Research Office
Abstract
Menstrual disorders impose a major impact on quality of life for healthy women and are one of the four most common reasons for seeking advice from a general practitioner. Heavy menstrual bleeding (menorrhagia) is one of the commonest indications for referral to a gynaecologist. Management typically involves invasive surgery. Current medical treatment options are often associated with side effects such as unscheduled breakthrough bleeding. We still do not know why some women experience problematic menstrual bleeding. Enhancement of our understanding of the mechanism of normal menstruation will provide an opportunity to identify novel targets for potential therapeutic development. Our proposal aims to examine the cascade of events that occur in cells of the womb-lining (endometrium) and triggered by withdrawal of the hormone, progesterone (P). This occurs at the end of each monthly cycle prior to a period or as a consequence of treatment with long-acting progestogen treatment, such as the levonorgestrel- intrauterine system (LNG-IUS). As a consequence of P-withdrawal, enzymes that are involved in the manufacture of substances known as prostaglandins (PGs) are increased in cells of the endometrium. In turn, other factors in these cells are also switched on. In the context of our study we wish to study the factors that switch on production of the molecule, HIF-1alpha and as a result the end products of this cascade that orchestrate blood vessel growth and repair in the endometrium; both necessary events to prepare for the next menstrual cycle. Further if these events are disturbed abnormal menstrual bleeding is a likely consequence. We therefore will seek participation from women attending with menstrual complaints and ask to examine small samples of the endometrium from these patients for molecular and cellular studies. Information about these molecular and cellular pathways will help us identify points in the pathway which could be new targets for treatment, especially if these treatments could be delivered directly to the uterus.
Technical Summary
Menstrual disorders impose a significant impact on quality of life for women. It is essential to understand mechanisms involved in uterine bleeding if improved medical treatments are to be developed and
surgery (hysterectomy) avoided. Progesterone withdrawal is the trigger for menstruation, and is associated with increased expression and generation of potent vaso-active prostaglandins. We describe a case for the prostaglandin EP2 receptor, epidermal growth factor receptor (EGFR) and signalling pathway associated with their regulation of HIF-1alpha, as potential novel therapeutic targets (perhaps by local
administration) for menstrual bleeding disorders.
The functional role of HIF-1alpha in human endometrium is unknown; it may be critical to the regeneration phase of the menstrual cycle.
Tissue regeneration requires angiogenesis and matrix remodelling, processes clearly relevant to known HIF-1alpha target genes.
We propose to undertake a proof of concept study that will, in human endometrium, establish whether progesterone withdrawal and elevated prostaglandin synthesis and signalling initiate local events that lead to HIF-1alpha expression and downstream angiogenic gene expression (VEGF, CTGF, ET, Ang-2). This provides a coordinated mechanism for endometrial regeneration, that when dysregulated could result in heavy menstrual bleeding (menorrhagia). We aim to test these hypotheses in functional assays using human endometrial tissue explants derived from women with measured normal and heavy menstrual blood loss (MBL).
Our proposal addresses the following hypotheses:
(1) women with heavy menstrual bleeding have elevated endometrial HIF-1alpha expression compared to women with normal MBL.
(2)Endometrial tissue from women with heavy bleeding exhibits an altered vasculogenic potential compared to women with normal MBL. For this we will use a functional angiogenesis assay using endometrial tissue explants. (3) Novel agents (inhibitors of PGE2-EGFR-HIF-1 pathway) reduce angiogenesis in a functional explant assay through attenuated angiogenic gene expression and may represent new therapy for disorders of abnormal menstrual bleeding.
surgery (hysterectomy) avoided. Progesterone withdrawal is the trigger for menstruation, and is associated with increased expression and generation of potent vaso-active prostaglandins. We describe a case for the prostaglandin EP2 receptor, epidermal growth factor receptor (EGFR) and signalling pathway associated with their regulation of HIF-1alpha, as potential novel therapeutic targets (perhaps by local
administration) for menstrual bleeding disorders.
The functional role of HIF-1alpha in human endometrium is unknown; it may be critical to the regeneration phase of the menstrual cycle.
Tissue regeneration requires angiogenesis and matrix remodelling, processes clearly relevant to known HIF-1alpha target genes.
We propose to undertake a proof of concept study that will, in human endometrium, establish whether progesterone withdrawal and elevated prostaglandin synthesis and signalling initiate local events that lead to HIF-1alpha expression and downstream angiogenic gene expression (VEGF, CTGF, ET, Ang-2). This provides a coordinated mechanism for endometrial regeneration, that when dysregulated could result in heavy menstrual bleeding (menorrhagia). We aim to test these hypotheses in functional assays using human endometrial tissue explants derived from women with measured normal and heavy menstrual blood loss (MBL).
Our proposal addresses the following hypotheses:
(1) women with heavy menstrual bleeding have elevated endometrial HIF-1alpha expression compared to women with normal MBL.
(2)Endometrial tissue from women with heavy bleeding exhibits an altered vasculogenic potential compared to women with normal MBL. For this we will use a functional angiogenesis assay using endometrial tissue explants. (3) Novel agents (inhibitors of PGE2-EGFR-HIF-1 pathway) reduce angiogenesis in a functional explant assay through attenuated angiogenic gene expression and may represent new therapy for disorders of abnormal menstrual bleeding.
