Abstract
BackgroundMenstruation is the culmination of a cascade of events, triggered by the withdrawal of progesterone at the end of the menstrual cycle. Initiation of tissue destruction and endometrial shedding causes spiral arteriole constriction in the functional layer of the endometrium. Upregulation of genes involved in angiogenesis and immune cell recruitment, two processes that are essential to successful repair and remodelling of the endometrium, both thought to be induced by reduced oxygen has been reported. Evidence for stabilisation/increased expression of the transcriptional regulator hypoxia inducible factor in the human endometrium at menses has been published. The current literature debates whether hypoxia plays an essential role during menstrual repair, therefore this study aims to delineate a role for hypoxia using a sensitive detection method (the Hypoxyprobe™) in combination with an established mouse model of endometrial breakdown and repair.ResultsUsing our mouse model of menses, during which documented breakdown and synchronous repair occurs in a 24 h timeframe, in combination with the Hypoxyprobe™ detection system, oxygen tensions within the uterus were measured. Immunostaining revealed striking spatial and temporal fluctuations in hypoxia during breakdown and showed that the epithelium is also exposed to hypoxic conditions during the repair phase. Furthermore, time-dependent changes in tissue hypoxia correlated with the regulation of mRNAs encoding for the angiogenic genes vascular endothelial growth factor and stromal derived factor (Cxcl12).ConclusionsOur findings are consistent with a role for focal hypoxia during endometrial breakdown in regulating gene expression during menses. These data have implications for treatment of endometrial pathologies such as heavy menstrual bleeding.
Highlights
Menstruation is the culmination of a cascade of events, triggered by the withdrawal of progesterone at the end of the menstrual cycle
HIF1α protein and its mRNA have been identified in the human endometrium, the number of samples recovered during the menstrual phase was low with only n = 2 [5]
There is some disagreement in the literature as to whether hypoxia plays an essential role in regulation of tissue breakdown and initiation of repair during menses
Summary
Menstruation is the culmination of a cascade of events, triggered by the withdrawal of progesterone at the end of the menstrual cycle. Evidence for stabilisation/increased expression of the transcriptional regulator hypoxia inducible factor in the human endometrium at menses has been published. In women demise of the corpus luteum in the absence of pregnancy results in a rapid decline in peripheral progesterone that precipitates a cascade of molecular changes which induce myometrial contractions and vasoconstriction of the spiral arterioles of the endometrium. There is some disagreement in the literature as to whether hypoxia plays an essential role in regulation of tissue breakdown and initiation of repair during menses. In the same study, in vitro culture of endometrial stromal cells under hypoxic conditions resulted in an increase in intracellular HIF1α and VEGF [8] and together with data from Maybin et al [9] would appear to support a role for hypoxia at menses
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