Limiting pre-menstrual endometrial Hypoxia Inducible Factor 2 Alpha may fine-tune endometrial function at menstruation.

Abstract

Heavy menstrual bleeding (HMB) is common and debilitating, but the precise endometrial mechanisms causing increased menstrual blood loss (MBL) remain undefined. We have previously identified a role for hypoxia in endometrial repair following progesterone withdrawal. As hypoxia inducible factor 2 alpha (HIF2A) is known to alter vascular function in other tissues, we hypothesised that endometrial HIF2A is involved in pre-menstrual optimisation of endometrial function during the secretory phase to limit MBL. Women with objective HMB had higher endometrial HIF2A during the mid-secretory phase when compared to those with normal MBL (p=0.0269). In a mouse model of simulated menses, genetic or pharmacological manipulation of HIF2A did not significantly affect endometrial breakdown/repair, volume of MBL or endometrial hypoxia. However, 88% of Hif2a heterozygote mice reached early-full repair by 24h versus only 65% of wild-type mice. Mean MBL was 0.39 μl (±0.67) in Hif2a heterozygote mice versus 0.98 μl (±0.79) in wild-type mice. Conversely, when we increased HIF2A pre-menstrually, 11% reached early repair at by 8h versus 30% of vehicle-treated mice. Mean MBL was 2.61 μl (±1.10) in mice with HIF2A stabilisation and 2.24 μl (±1.14) in vehicle-treated mice. These non-significant but consistent trends indicate that increased endometrial HIF2A may contribute to delayed endometrial repair and HMB. Increased HIF2A in the secretory endometrium is unlikely to be sufficient to account for the phenotype of HMB, but limitation of HIF2 levels may optimise endometrial function at menstruation.