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

Background: Hereditary angioedema with C1-INH 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: To investigate the link between estrogen and bradykinin constituents to better understand the specific underlying triggers which 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 contraceptives (OCPs) alter plasma protein levels of bradykinin (BK), cleaved high-molecular-weight kininogen (cHK) and activated Factor XII (XIIa).Blood (plasma) was collected prior to, and 3-months after initiation of OCPs.High-molecular-weight kininogen (HK) was measured by ELISA and FXIIa and cHK were analyzed by Western blot analysis.Results: Twelve adult females, without HAE-CINH (<40 years of age), had median baseline plasma HK of 33,976 ng/ml.After 3 months of OCP therapy, the median HK increased to 38,202 ng/ml.There was also a significant increase in FXIIa protein (p<0.01) as well as an increase in cHK protein with OCP. Conclusion:This preliminary study, performed in females without HAE-C1INH, suggests that estrogen may exacerbate angioedema by increasing the production of cHK and FXIIa.