Martínez-Aguilar Rocío, Rowley Bethan M, Walker Catherine, Critchley Hilary O D, Carmeliet Peter, Maybin Jacqueline A
Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, EH16 4UU, UK.
Laboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology, Leuven, 3000, Belgium.
J Clin Endocrinol Metab. 2025 Mar 17;110(4):1135-1147. doi: 10.1210/clinem/dgae630.
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 hypothezised that endometrial HIF2A is involved in premenstrual optimization 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 24 hours vs only 65% of wild-type mice. Mean MBL was 0.39 μL (±0.67) in Hif2a heterozygote mice vs 0.98 μL (±0.79) in wild-type mice. Conversely, when we increased HIF2A before menstruation, 11% reached early repair by 8 hours vs 30% of vehicle-treated mice. Mean MBL was 2.61 μL (±1.10) in mice with HIF2A stabilization and 2.24 μL (±1.14) in vehicle-treated mice. These nonsignificant 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 optimize endometrial function at menstruation.
月经过多（HMB）常见且使人虚弱，但导致月经量增加（MBL）的确切子宫内膜机制仍不明确。我们之前已确定缺氧在孕激素撤退后的子宫内膜修复中起作用。
由于已知缺氧诱导因子2α（HIF2A）会改变其他组织的血管功能，我们推测子宫内膜HIF2A参与分泌期子宫内膜功能的经前优化以限制MBL。
与月经量正常的女性相比，有客观月经过多的女性在分泌中期子宫内膜HIF2A水平更高（P = 0.0269）。在模拟月经的小鼠模型中，对HIF2A进行基因或药物操作并未显著影响子宫内膜的崩解/修复、MBL量或子宫内膜缺氧情况。然而，88%的Hif2a杂合子小鼠在24小时时达到早期完全修复，而野生型小鼠只有65%。Hif2a杂合子小鼠的平均MBL为0.39 μL（±0.67），野生型小鼠为0.98 μL（±0.79）。相反，当我们在月经前增加HIF2A时，11%的小鼠在8小时时达到早期修复，而接受载体处理的小鼠为30%。HIF2A稳定的小鼠平均MBL为2.61 μL（±1.10），接受载体处理的小鼠为2.24 μL（±1.14）。这些虽不显著但一致的趋势表明，子宫内膜HIF2A增加可能导致子宫内膜修复延迟和月经过多。
分泌期子宫内膜中HIF2A增加不太可能足以解释月经过多的表型，但限制HIF2水平可能会在月经时优化子宫内膜功能。
