Skip to main content

Advertisement

SpringerLink
Log in

High Estrogen States in Hereditary Angioedema: a Spectrum

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

HAE:

Hereditary angioedema

HMWK:

High molecular–weight kininogen

C1INH:

C1 esterase inhibitor

ARB:

Angiotensin receptor blockers

TXA:

Tranexamic acid

References

  1. Abdulkarim A, Craig T (2020) Hereditary angioedema. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482266/

  2. Bernstein J (2018) Severity of hereditary angioedema, prevalence, and diagnostic considerations. Am J Manag Care. 24(14 Suppl):S292-S298. https://pubmed.ncbi.nlm.nih.gov/30132643/ PMID: 30132643.

  3. Nedelea I, Deleanu D (2019) Isolated angioedema: an overview of clinical features and etiology. Exp Ther Med. 17(2):1068–1072. https://doi.org/10.3892/etm.2018.6982. Epub 2018 Nov 16. PMID: 30679975; PMCID: PMC6327642.

  4. Binkley K (2010) Factor XII mutations, estrogen-dependent inherited angioedema, and related conditions. All Asth Clin Immun 6:16. https://doi.org/10.1186/1710-1492-6-16

    Article  CAS  Google Scholar 

  5. Misra L, Khurmi N, Terrence L (2016) Angioedema: classification, management and emerging therapies for the perioperative physician. Indian J Anaesth 60(8):534–541. https://doi.org/10.4103/0019-5049.187776.PMID:27601734;PMCID:PMC4989802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu J, Qin J, Borodovsky A et al (2019) An investigational RNAi therapeutic targeting factor XII (ALN-F12) for the treatment of hereditary angioedema. RNA. 25(2):255–263. https://rnajournal.cshlp.org/content/early/2018/11/21/rna.068916.118

  7. Sharma J, JindalA BA et al (2021) Pathophysiology of hereditary angioedema (HAE) beyond the SERPING1 Gene. Clinic Rev Allerg Immunol. https://doi.org/10.1007/s12016-021-08835-8

    Article  Google Scholar 

  8. Gompel A, Fain O, Boccon-Gibod I et al (2020) Exogenous hormones and hereditary angioedema Int Immunopharmacol 78 https://doi.org/10.1016/j.intimp.2019.106080

  9. Nilsson S, Makela S, Treuter E et al (2001) Mechanisms of estrogen action. Physiol Rev 81(4):1535–1565. https://doi.org/10.1152/physrev.2001.81.4.1535 (PMID: 11581496)

    Article  CAS  PubMed  Google Scholar 

  10. Sherman B, Korenman S (1974) Measurement of serum LH, FSH, estradiol and progesterone in disorders of the human menstrual cycle: the inadequate luteal phase. J Clin Endocrinol Metab 39(1):145–149. https://doi.org/10.1210/jcem-39-1-145

    Article  CAS  PubMed  Google Scholar 

  11. Baird D, Glasier A (1993) Hormonal contraception. N Engl J Med 328(21):1543–1549. https://doi.org/10.1056/NEJM199305273282108 (PMID: 8479492)

    Article  CAS  PubMed  Google Scholar 

  12. Klein K, Rosenfield R, Santen R et al (2018) Estrogen replacement in turner syndrome: literature review and practical considerations. J Clin Endocrinol Metab 103(5):1790–1803. https://doi.org/10.1210/jc.2017-02183

    Article  PubMed  Google Scholar 

  13. Angele M, Pratschke S, Hubbard W et al (2014) Gender differences in sepsis: cardiovascular and immunological aspects. Virulence 5(1):12–19. https://doi.org/10.4161/viru.26982

    Article  PubMed  Google Scholar 

  14. Oh W (2002) The evolving role of estrogen therapy in prostate cancer. Clin Prostate Cancer 1(2):81–89. https://doi.org/10.3816/cgc.2002.n.009 (PMID: 15046698)

    Article  CAS  PubMed  Google Scholar 

  15. Banerji A, Riedl M (2016) Managing the female patient with hereditary angioedema. Womens Health 12(3):351–361. https://doi.org/10.2217/whe.16.6

    Article  CAS  Google Scholar 

  16. Zeerleder S, Levi M (2016) Hereditary and acquired C1-inhibitor-dependent angioedema: From pathophysiology to treatment. Ann Med 48(4):256–267. https://doi.org/10.3109/07853890.2016.1162909

    Article  CAS  PubMed  Google Scholar 

  17. Alharbi F, Kholod A, Souverein P et al (2017) The impact of age and sex on the reporting of cough and angioedema with renin-angiotensin system inhibitors: a case/noncase study in VigiBase. Fundam Clin Pharmacol 31(6):676–684. https://doi.org/10.1111/fcp.12313

    Article  CAS  PubMed  Google Scholar 

  18. Toh S, Reichman M, Houstoun M et al (2012) Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med 172(20):1582–1589. https://doi.org/10.1001/2013.jamainternmed.34

    Article  CAS  PubMed  Google Scholar 

  19. Miller D, Oliveria S, Berlowitz D et al (2008) Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors. Hypertension 51(6):1624–1630. https://doi.org/10.1161/HYPERTENSIONAHA.108.110270

    Article  CAS  PubMed  Google Scholar 

  20. Steiner U, Weber-Chrysochoou C, Helbling A et al (2016) Hereditary angioedema due to C1 - inhibitor deficiency in switzerland: clinical characteristics and therapeutic modalities within a cohort study. Orphanet J Rare Dis 11:43. https://doi.org/10.1186/s13023-016-0423-1

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bouillet L, Longhurst H, Boccon-Gibod I et al (2008) Disease expression in women with hereditary angioedema. Obstet Gynecol 199(5):484.e1–4. https://doi.org/10.1016/j.ajog.2008.04.034 (Epub 2008 Jun 13 PMID: 18554570)

    Article  Google Scholar 

  22. Cichon S, Martin L, Hennies H et al (2006) Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet. 79(6):1098–104. https://doi.org/10.1086/509899. Epub 2006 Oct 18. PMID: 17186468; PMCID: PMC1698720.

  23. Feray S, Fain O, Kayem G et al (2018) Repeated attacks of type III hereditary angioedema with factor XII mutation during pregnancy. Int J Obstet Anesth 36:114–118. https://doi.org/10.1016/j.ijoa.2018.07.003 (Epub 2018 Aug 2 PMID: 30131260)

    Article  CAS  PubMed  Google Scholar 

  24. Hentges F, Hilger C, Kohnen M et al (2009) Angioedema and estrogen-dependent angioedema with activation of the contact system J Allergy Clin Immunol 262–4 https://doi.org/10.1016/j.jaci.2008.10.056 PMID: 19130939

  25. Deroux A, Boccon-Gibod I, Fain O et al (2016) Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French national center of reference for angioedema. Clin Exp Immunol 185(3):332–337. https://doi.org/10.1111/cei.12820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Wright State Physicians Health Center, Department of Pharmacology & Toxicology, 725 University Blvd, Fairborn, OH, USA

    Maansi Kulkarni, Jeffrey B. Travers & Craig Rohan

  2. Department of Dermatology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA

    Jeffrey B. Travers & Craig Rohan

  3. Department of Dayton Veterans Administration Medical Center, Dayton, OH, USA

    Jeffrey B. Travers

Authors
  1. Maansi Kulkarni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey B. Travers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Craig Rohan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Craig Rohan.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kulkarni, M., Travers, J.B. & Rohan, C. High Estrogen States in Hereditary Angioedema: a Spectrum. Clinic Rev Allerg Immunol 60, 396–403 (2021). https://doi.org/10.1007/s12016-021-08863-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-021-08863-4

Keywords

Search

Navigation