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Hereditary Angioedema with and Without C1-Inhibitor Deficiency in Postmenopausal Women

Abstract

Purpose

Most types of hereditary angioedema (HAE) are worsened by endogenous or exogenous estrogens. Conversely, androgens can improve HAE with abnormal C1-Inhibitor (C1-INH) by increasing C1-INH concentrations. Menopause is associated with an extinction of ovarian estrogenic and androgenic secretion. There is currently insufficient information on postmenopausal women with HAE. The objective of this study was to describe the activity of HAE in postmenopausal women.

Methods

This was a French retrospective, multicenter study in postmenopausal women with HAE with or without C1-INH deficiency/dysfunction. The patients were classified before and after menopause with a previously validated HAE disease severity score.

Results

We included 65 women from 13 centers in France. The mean age was 62.7± 9.2 years, and the mean time between menopause and inclusion was 12.5± 9.1 years. HAE was associated with C1-INH deficiencyin 88% (n = 57) of the patients, a mutation of factor 12 in 8% (n = 5), a mutation in plasminogen gene in one, and unknown HAE for two. The HAE course was not different after menopause in 46.1% (n = 30), improved in 38.5% (n = 25), and worsened in 15.4% (n = 10). Improvement was correlated with estrogen sensitivity of angioedema before menopause (p = 0.06 for improvement vs no effect or worsening). In addition, we observed that only ten women received treatment (transdermal or oral estradiol+ progestogen) for their menopause symptoms. Among them, only 3 experienced worsening of symptoms (2 on transdermal and 1 on oral estradiol).

Conclusion

Following menopause, most women with HAE remain stable but some worsen. Improvement was mainly observed in patients with previous estrogen sensitivity. More research is required in menopausal women with HAE to better understand how to manage climacteric symptoms.

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Abbreviations

C1-INH:

C1-Inhibitor

HAE:

Hereditary angioedema

C1-INH-HAE:

Hereditary angioedema with C1-Inhibitor deficiency/dysfunction

nC1-INH-HAE:

Hereditary angioedema with normal C1-Inhibitor

pdC1-INH:

Plasma-derived concentrate C1-Inhibitor

COC:

Estroprogestin combined (oral) contraception

POP:

Progestin-only pills

AGP:

Antigonadotropic

MHT:

Menopause hormone treatment

TTS-E2:

Transdermal estradiol

BMI:

Body mass index

TA:

Tranexamic acid

References

  1. 1.

    Cicardi M, Aberer W, Banerji A, Bas M, Bernstein JA, Bork K, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy. 2014;69:602–16.

    CAS  PubMed  Google Scholar 

  2. 2.

    Betschel S, Badiou J, Binkley K, Borici-Mazi R, Hébert J, Kanani A, et al. The International/Canadian Hereditary Angioedema Guideline. Allergy Asthma Clin Immunol Off J Can Soc Allergy Clin Immunol [Internet]. 2019 [cited 2020 Mar 30];15. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878678/.

  3. 3.

    Wu MA, Perego F, Zanichelli A, Cicardi M. Angioedema phenotypes: disease expression and classification. Clin Rev Allergy Immunol. 2016;51:162–9.

    CAS  PubMed  Google Scholar 

  4. 4.

    Zuraw BL, Bork K, Binkley KE, Banerji A, Christiansen SC, Castaldo A, et al. Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel. Allergy Asthma Proc. 2012;33(Suppl 1):S145–56.

    CAS  PubMed  Google Scholar 

  5. 5.

    Bova MC, Bafunno V, et al. Impaired control of the contact system in hereditary angioedema with normal C1-inhibitor allergy. Allergy. 2020 Jun;75(6):1394-1403. https://doi.org/10.1111/all.14160

  6. 6.

    Lopes Veronez C, Sevciovic Grumach A. Angioedema without urticaria: novel findings which must be measured in clinical setting. Curr Opin Allergy Clin Immunol. 2020 Jun;20(3):253–60.

    Google Scholar 

  7. 7.

    Banday AZ, Jindal AK, EAwat A, Singh S. An update on the genetics and pathogenesis of hereditary angioedema. Genes Dis. 2019;7(1):75–83.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Bork K, Wulff K, Steinmüller-Magin L, et al. Hereditary angioedema with a mutation in the plasminogen gene. Allergy. 2017;00:1e9.

    Google Scholar 

  9. 9.

    Bafunno V, Firinu D, D’Apolito M, et al. Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. J Allergy Clin Immunol. 2018;141:1009e1117.

    Google Scholar 

  10. 10.

    Bork K, Wulff K, Rossmann H, Steinmüller-Magin L, Braenne I, Witzke G, et al. Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin. Allergy. 2019;74:2479–81.

    PubMed  Google Scholar 

  11. 11.

    Caballero T, Farkas H, Bouillet L, et al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol. 2012;129:308–20.

    PubMed  Google Scholar 

  12. 12.

    Bouillet L, Longhurst H, Boccon-Gibod I, Bork K, Bucher C, Bygum A, et al. Disease expression in women with hereditary angioedema. Am J Obstet Gynecol. 2008;199:484.e1–4.

    Google Scholar 

  13. 13.

    Gompel A, Fain O, Boccon-Gibod I, Gobert D, Bouillet L. Exogenous hormones and hereditary angioedema. Int Immunopharmacol. 2020;78:106080.

    CAS  PubMed  Google Scholar 

  14. 14.

    Zotter Z, Csuka D, Szabó E, Czaller I, Nébenführer Z, Temesszentandrási G, et al. The influence of trigger factors on hereditary angioedema due to C1-inhibitor deficiency. Orphanet J Rare Dis. 2014;9:44.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Gelfand JA, Sherins RJ, Alling DW, Frank MM. Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med. 1976;295:1444–8.

    CAS  PubMed  Google Scholar 

  16. 16.

    Heinemann LAJ, DoMinh T, Strelow F, Gerbsch S, Schnitker J, Schneider HPG. The Menopause Rating Scale (MRS) as outcome measure for hormone treatment? A validation study. Health Qual Life Outcomes. 2004;2:67.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    MRS - Menopause Rating Scale [Internet]. [cited 2020 Apr 25]. Available from: http://www.menopause-rating-scale.info/.

  18. 18.

    Prior N, Remor E, Pérez-Fernández E, Caminoa M, Gómez-Traseira C, Gayá F, et al. Psychometric field study of hereditary angioedema quality of life questionnaire for adults: HAE-QoL. J Allergy Clin Immunol Pract. 2016;4:464–473.e4.

    PubMed  Google Scholar 

  19. 19.

    Bouillet L, Launay D, Fain O, Boccon-Gibod I, Laurent J, Martin L, et al. Hereditary angioedema with C1 inhibitor deficiency: clinical presentation and quality of life of 193 French patient. Ann Allergy Asthma Immunol. 2013;111(4):290–4.

    CAS  PubMed  Google Scholar 

  20. 20.

    Visy B, Füst G, Varga L, Szendei G, Takács E, Karádi I, et al. Sex hormones in hereditary angioneurotic oedema. Clin Endocrinol. 2004;60:508–15.

    CAS  Google Scholar 

  21. 21.

    Poortman J, Thijssen JH, de Waard F. Plasma oestrone, oestradiol and androstenedione levels in post-menopausal women: relation to body weight and height. Maturitas. 1981;3:65–71.

    CAS  PubMed  Google Scholar 

  22. 22.

    Luyer MD, Khosla S, Owen WG, Miller VM. Prospective randomized study of effects of unopposed estrogen replacement therapy on markers of coagulation and inflammation in postmenopausal women. J Clin Endocrinol Metab. 2001;86:3629–34.

    CAS  PubMed  Google Scholar 

  23. 23.

    Madsen JS, Kristensen SR, Gram J, Bladbjerg EM, Henriksen FL, Gram J, et al. Positive impact of hormone replacement therapy on the fibrinolytic system: a long-term randomized controlled study in healthy postmenopausal women. J Thromb Haemost JTH. 2003;1:1984–91.

    CAS  PubMed  Google Scholar 

  24. 24.

    Thiery M, Vermeulen A, Baele G, Deslypere JP. Effects of a very low-estrogen oral contraceptive on clotting factors, carbohydrate metabolism and plasma lipids and lipoproteins. Med Sci Res. 1987;15:1231–2.

    CAS  PubMed  Google Scholar 

  25. 25.

    Gallagher PE, Li P, Lenhart JR, Chappell MC, Brosnihan KB. Estrogen regulation of angiotensin-converting enzyme mRNA. Hypertens Dallas Tex 1979. 1999;33:323–8.

    CAS  Google Scholar 

  26. 26.

    Nogawa N, Sumino H, Ichikawa S, Kumakura H, Takayama Y, Nakamura T, et al. Effect of long-term hormone replacement therapy on angiotensin-converting enzyme activity and bradykinin in postmenopausal women with essential hypertension and normotensive postmenopausal women. Menopause N Y N. 2001;8:210–5.

    CAS  Google Scholar 

  27. 27.

    Sumino H, Ichikawa S, Ohyama Y, Nakamura T, Kanda T, Sakamoto H, et al. Effects of hormone replacement therapy on serum angiotensin-converting enzyme activity and plasma bradykinin in postmenopausal women according to angiotensin-converting enzyme-genotype. Hypertens Res Off J Jpn Soc Hypertens. 2003;26:53–8.

    CAS  Google Scholar 

  28. 28.

    McGlinchey PG, McCluskey DR. Hereditary angioedema precipitated by estrogen replacement therapy in a menopausal woman. Am J Med Sci. 2000;320:212–3.

    CAS  PubMed  Google Scholar 

  29. 29.

    Rousset-Jablonski C, Thalabard J-C, Gompel A. Tamoxifen contraindicated in women with hereditary angioedema? Ann Oncol Off J Eur Soc Med Oncol. 2009;20:1281–2.

    CAS  Google Scholar 

  30. 30.

    Ichikawa J, Sumino H, Ichikawa S, Ozaki M. Different effects of transdermal and oral hormone replacement therapy on the renin-angiotensin system, plasma bradykinin level, and blood pressure of normotensive postmenopausal women. Am J Hypertens. 2006;19:744–9.

    CAS  PubMed  Google Scholar 

  31. 31.

    Ichikawa A, Sumino H, Ogawa T, Ichikawa S, Nitta K. Effects of long-term transdermal hormone replacement therapy on the renin-angiotensin- aldosterone system, plasma bradykinin levels and blood pressure in normotensive postmenopausal women. Geriatr Gerontol Int. 2008;8:259–64.

    PubMed  Google Scholar 

  32. 32.

    Hitchcock CL, Prior JC. Oral micronized progesterone for vasomotor symptoms--a placebo-controlled randomized trial in healthy postmenopausal women. Menopause N Y N. 2012;19:886–93.

    Google Scholar 

  33. 33.

    Ott HW, Mattle V, Hadziomerovic D, Licht P, Döinghaus K, Rubbert A, et al. Treatment of hereditary angioneurotic oedema (HANE) with tibolone. Clin Endocrinol. 2007;66:180–4.

    CAS  Google Scholar 

  34. 34.

    Kloosterboer HJ. Tibolone: a steroid with a tissue-specific mode of action. J Steroid Biochem Mol Biol. 2001;76:231–8.

    CAS  PubMed  Google Scholar 

  35. 35.

    Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JV, et al. Treatment of symptoms of the menopause: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:3975–4011.

    CAS  PubMed  Google Scholar 

  36. 36.

    Del Pup L, Postruznik D, Corona G. Effect of one-month treatment with vaginal promestriene on serum estrone sulfate levels in cancer patients: a pilot study. Maturitas. 2012;72:93–4.

    PubMed  Google Scholar 

  37. 37.

    Salive ME. Multimorbidity in older adults. Epidemiol Rev. 2013;35:75–83.

    PubMed  Google Scholar 

  38. 38.

    Hager K, Setzer J, Vogl T, Voit J, Platt D. Blood coagulation factors in the elderly. Arch Gerontol Geriatr. 1989;9:277–82.

    CAS  PubMed  Google Scholar 

  39. 39.

    Pérez V, Velarde V, Acuña-Castillo C, Gómez C, Nishimura S, Sabaj V, et al. Increased kinin levels and decreased responsiveness to kinins during aging. J Gerontol A Biol Sci Med Sci. 2005;60:984–90.

    PubMed  Google Scholar 

  40. 40.

    Sierra F. Both T- and K-kininogens increase in the serum of old rats but by different mechanisms. Mech Ageing Dev. 1995;84:127–37.

    CAS  PubMed  Google Scholar 

  41. 41.

    Feng W, Xu X, Zhao G, Zhao J, Dong R, Ma B, et al. Increased age-related cardiac dysfunction in Bradykinin B2 receptor-deficient mice. J Gerontol A Biol Sci Med Sci. 2016;71:178–87.

    CAS  PubMed  Google Scholar 

  42. 42.

    Kintsurashvili E, Duka A, Ignjacev I, Pattakos G, Gavras I, Gavras H. Age-related changes of bradykinin B1 and B2 receptors in rat heart. Am J Physiol Heart Circ Physiol. 2005;289:H202–5.

    CAS  PubMed  Google Scholar 

  43. 43.

    Nurmi L, Heikkilä HM, Vapaatalo H, Kovanen PT, Lindstedt KA. Downregulation of Bradykinin type 2 receptor expression in cardiac endothelial cells during senescence. J Vasc Res. 2012;49:13–23.

    CAS  PubMed  Google Scholar 

  44. 44.

    Montgomery RR, Shaw AC. Paradoxical changes in innate immunity in aging: recent progress and new directions. J Leukoc Biol. 2015;98(6):937–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab. 2003;88:2404–11.

    CAS  PubMed  Google Scholar 

  46. 46.

    Moreau KL, Stauffer BL, Kohrt WM, Seals DR. Essential role of estrogen for improvements in vascular endothelial function with endurance exercise in postmenopausal women. J Clin Endocrinol Metab. 2013;98:4507–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006;444:847–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Kleniewski J, Czokało M. Plasma kininogen concentration: the low level in cord blood plasma and age dependence in adults. Eur J Haematol. 1991;46:257–62.

    CAS  PubMed  Google Scholar 

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Acknowledgements

Centre de Référence sur les angiœdèmes à kinines [CRéAk] includes S. Amarger, MD (CHU Estaing, Clermont Ferrand, France), C. Blanchard-Delaunay, MD (CH Niort, France), B. Coppere, MD (Hospices Civils de Lyon, CHU Edouard Herriot, Lyon, France), A. DuThanh, MD (CHU Montpellier, France), B. Floccard, MD (Hospices Civils de Lyon, CHU Edouard Herriot, Lyon, France), S. Gayet, MD (Hospital La Timone, APHM, Marseille, France), P. Y. Jeandel, MD (CHU Nice, France), L. Martin, MD PhD (CHU Angers, France), F. Pelletier, MD (CRHU Besançon, France), F. N. Raison Peyron, MD (Hospital St Eloi, Montpellier, France). Thanks to Felicity Neilson for editing the manuscript in English.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Correspondence to Anne Gompel.

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Conflict of Interest

AB: no conflict of interest, OF: Consultant arrangements for Shire/Takeda and Behring, travel and accommodation to a Congress from GSK, honorarium for a talk from Sanofi, DL: consultant arrangements, research grant and travel and accommodation from Actelion, GSK, Octapharma, Pfizer, and Shire/Takeda. LB: Consultant arrangements, research grant and travel and accommodation from Shire/Takeda, CSL Behring, Pharming, GSK, Novartis, Sanofi. I B-G: Consultant arrangements, research grant, travel and accommodation from Shire/Takeda, CSL Behring, Pharming, Biocryst, Novartis DG: Consultant arrangements for Shire/Takeda honorarium for talks for Shire/Takeda, travel and accommodation from Shire/Takeda et Pharming. G.P-B: no conflict of interest. AG: member of an advisory board for Mithra (Estetrol).

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Billebeau, A., Fain, O., Launay, D. et al. Hereditary Angioedema with and Without C1-Inhibitor Deficiency in Postmenopausal Women. J Clin Immunol 41, 163–170 (2021). https://doi.org/10.1007/s10875-020-00902-7

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Keywords

  • Hereditary angioedema
  • menopause
  • female
  • estrogen
  • androgen
  • aging