Sex differences have been well documented within hereditary angioedema (HAE) over the past several decades. Females often experience more frequent and more intense attacks compared to their male counterparts. Additionally, elevated estrogen levels—as seen in pregnancy and use of oral contraceptives—is a widely known trigger for angioedema attacks. In this review article, we will outline how estrogens’ downstream effects increase bradykinin, a potent vasodilator and key mediator of HAE. Estrogen-dependent HAE is a rare disorder that provides insight into the relationship between HAE and estrogens. Females affected by this subtype of HAE only experience attacks when under “high estrogen states,” such as during pregnancy and when taking exogenous estrogens (most commonly, oral contraceptives). This unique phenotype has been documented in individuals with an activating Factor XII mutation. Thus, based on this clear genotype-phenotype relationship, we conclude that Factor XII may be key in our understanding of estrogens’ role in HAE. Lastly, we propose that the sex differences seen in HAE be viewed as a spectrum from exacerbation to underlying genetic mutations in Factor XII.

在过去的几十年里，遗传性血管性水肿 (HAE) 中的性别差异已得到充分证明。与男性相比，女性通常会经历更频繁和更强烈的攻击。此外，雌激素水平升高（如怀孕和使用口服避孕药时所见）是众所周知的血管性水肿发作的诱因。在这篇评论文章中，我们将概述雌激素的下游作用如何增加缓激肽，一种有效的血管扩张剂和 HAE 的关键介质。雌激素依赖性 HAE 是一种罕见的疾病，可让您深入了解 HAE 和雌激素之间的关系。受这种 HAE 亚型影响的女性仅在处于“高雌激素状态”时才会出现发作，例如在怀孕期间和服用外源性雌激素（最常见的是口服避孕药）时。这种独特的表型已在具有激活因子 XII 突变的个体中得到证实。因此，基于这种明确的基因型-表型关系，我们得出结论，因子 XII 可能是我们理解雌激素在 HAE 中的作用的关键。最后，我们建议将 HAE 中的性别差异视为因子 XII 中从恶化到潜在基因突变的范围。