ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2017) 50 ECP1.2 | DOI: 10.1530/endoabs.50.ECP1.2

The role of hypoxia in the physiology and pathology of menstruation

Jacqueline Maybin1, Alison Murray1, Nikhil Hirani1, Philippa Saunders1, Peter Carmeliet2 & Hilary Critchley1

1University of Edinburgh, Edinburgh, UK; 2KU Leuven, Leuven, Belgium.

Heavy menstrual bleeding (HMB) is common and debilitating but it remains a taboo subject. Hence its cause remains undefined, resulting in non-specific hormone therapies with intolerable side effects.

Over 70 years ago it was proposed that progesterone withdrawal caused intense vasoconstriction and a transient endometrial hypoxia that resulted in menstruation. Subsequent research confirmed that inflammation initiated menses and disputed the role of hypoxia. By studying human tissue and a mouse model of ‘simulated menstruation’ we revealed that hypoxia is not necessary for endometrial breakdown but is essential for timely repair of the denuded endometrial surface to limit menstrual bleeding.

We found women with objectively measured HMB bled for two additional days versus those with normal bleeding, indicating defective endometrial repair. Hypoxia inducible factor (HIF-1) is the master regulator of the cellular response to hypoxia. Women with HMB displayed significantly reductioned endometrial HIF-1α and its downstream targets during menstruation, consistent with defective hypoxia. Prevention of endometrial hypoxia at menses and pharmacological or genetic reduction of HIF-1α in our mouse model did not prevent bleeding but significantly delayed endometrial repair. Further, we demonstrated that PHD inhibitors (HIF-1α stabilisers) significantly improved endometrial repair in our non-hypoxic menstruation model, revealing a promising, non-hormonal therapeutic strategy for women with HMB.

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