The effect of estrogen-containing birth control pills on the constituents of bradykinin expression in plasma

J Allergy Clin Immunol Glob. 2024 Feb 12;3(2):100226. doi: 10.1016/j.jacig.2024.100226. eCollection 2024 May.


Background: Hereditary angioedema with C1-inhibitor deficiency (HAE-C1INH) is a rare autosomal disorder presenting with recurrent angioedema. Estrogen-containing medications trigger angioedema in some patients, and conversely, progesterone may decrease attack frequency. The mechanism by which estrogen may exacerbate angioedema in HAE-C1INH is not well characterized.

Objective: Our aim was to investigate the link between estrogen and bradykinin constituents to better understand the specific underlying triggers that may exacerbate angioedema in patients with HAE-C1INH.

Methods: As estrogen is contraindicated for patients with HAE-C1INH, females without a history of angioedema were recruited to evaluate whether estrogen-containing oral contraceptive pills (OCPs) alter plasma protein levels of bradykinin, cleaved high-molecular-weight kininogen (cHK), and activated factor XII (FXIIa). Blood (plasma) was collected before initiation of OCP administration and 3 months thereafter. High-molecular-weight kininogen (HK) was measured by ELISA and FXIIa and cHK were analyzed by Western blot analysis.

Results: A total of 12 adult females without HAE-CINH (aged <40 years) had a median baseline plasma HK level of 33,976 ng/mL. After 3 months of OCP therapy, their median HK level increased to 38,202 ng/mL. With OCPs, there was also a significant increase in level of FXIIa protein (P <.01), as well as an increase in cHK protein level.

Conclusion: This preliminary study, performed in females without HAE-C1INH, suggests that estrogen may exacerbate angioedema by increasing the production of cHK and FXIIa.

Keywords: Hereditary angioedema; bradykinin; estrogen; kininogen; oral contraceptives.