Hormone modulation in women with Hereditary angioedema
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Hormones and Hereditary angioedema benefits and dangers Anne Gompel, Isabelle Boccon-Gibod, Laurence Bouillet, David Launay, Ludovic Martin, Aurélie DuThan, Olivier Fain, and CRéAK Disclosures: none with this talk • Research Grant CIFRE HRA-Pharma: Antiprogestin in BRCA1/2 mutation carriers • Research grant Luteron for Estetrol • Consultant Pfizer: benzedoxifene/CE • Consultant Richter: on contraceptive agents • Shire: Advisory board Firazyr France • Behring: Advisory board Berinert France • Lectures given for Bayer, Besins, Novartis, Viropharma… • Attendance to congresses: Shire, Viropharma Hormones and AE androgens estrogens antiandrogens Menstrual cycles: endogenous Progesterone estradiol androgens Pregnancy: endogenous estradiol Progesterone Contraception: exogenous Estrogens: Ethinyl-E2 estradiol Progestins PR, AR, ER, MR Non-selectivity of synthetic progestins Progesterone: PR, AR(-), MR(-) Normethyltestosterone derivatives:PR, AR(+), ER, GR± Norethisterone/norethindrone, NET acetate, Lynestrenol : AGP Etonogestrel, norgestrel : POP Pregnanes: PR, ±AR, ±GR MPA: glucocorticoid and androgen agonist Chlormadinone acetate : no AR, no GR AGP Cyproterone acetate strong anti AR, GR± AGP Norpregnane Nomegestrol acetate PR, AR? AGP Spironolactone, drospirenone PR, MR(-),AR(-) In contraception • Progestins combined with EE or E2, oral, patch or ring • Alone: • POP: low doses (µg), continuous, 1/3 normal cycles, 1/3 hypoestrogenic, 1/3 hyperestrogenic • Etonogestrel (Cerazette), Norgestrel ( Microval) • AGP=“Antigonadotropic agents”, continuous or discontinuous (21/28) • Norsteroids: Norethisterone 10 mg, Lynestrenol 10mg • Pregnanes: MPA, CMA, CPA (strong antiandrogen) • Norpregnanes: Nomac Androgens Treatments: prostate adenoma/prostate cancer antiandrogens GnRH a + antiandrogen, Estrogens In Men • Hypogonadism associated with more attacks (Pichler WJ,Ann Allergy,1989) • Aging: low testosterone • Antiandrogens: • for prostate cancers or adenoma • In transsexuals Rationale for estrogens and HAE •Clinical rationale: influence of exogenous and endogenous estrogens : puberty, menstrual cycle, OC, pregnancy and MHT • Biological rationale Interaction with the kinin formation, and metabolism Interaction with tissue kallicreins ? Interaction with RAAS, VD, NOS ? The pill and HAE • The EP Pill : • Induction or increase of attacks • in most of patients (not all) • In all HAE types • Bork et al: induction or worsening in 62-63% of patients (HAE I,II,III) ( Am J Med, 2003, JACI 2009 ) • PREHAEAT project 150 women in 8 countries (HAE I&II) • EP pill : 80% (Bouillet et al Am J Obstet Gynecol, 2008 ) Recommandations not to use OC in women with HAE (Int. Consensus Caballero et al, 2012 J Allergy Clin Immunol) in our own series of patients, among C1inh: OC first line in patients who need contraception. Antiestrogen agents? • Antigonadotropic agents: decrease estrogen production • Progestins • Different antigonadotropic activity and different androgenic potencies • GnRH agonists: stronger antigonadotropic agent, not androgenic • Danazol: androgen and antigonadotropic (full at 600mg) • SERMs:Tamoxifen, Raloxifen • Estrogen antagonists/partial agonists • Increase the release of gonadotropins (FSH/LH) • Aromatase inhibitors: inhibit estrogen production from androgens, not to be used alone before menopause 55 women with non allergic AE: 16 C1 Inh deficiency 19 N C1Inh (familial history and/or Factor XII mutation) 20 “sporadic” Progestin and non histaminic AE (Saule et al, CEA,2013) • 74.5% patients improved with progestin agents • 32% remained free of symptoms for a mean duration of 19.7 months ± 19 (range 3 to 72 months) and stopped their other medication • 89.5% of patients improved with AGP and • 61.3% with POP (p=0.013) Importance of estrogenic environment, role of progestins? Prospective/retrospective study in Women with C1-INH deficiency(types I/II) • 40 patients with C1-INH deficiency 25 AGP: Chlormadinone acetate , Nomac, Lynestrenol followed up for a mean of 30.5 ± 21 months 17 POP: Cerazette (etonogestrel), Microval, Nexplanon, Mirena (2 patients) followed up for a mean of 40 ± 25 months • Results on HAE attacks • AGP 21women with partial or total improvement (84%), full improvement in 8 (32%) women, 4 no effect But if strong stress: can escape from the buffering effect of progestins • POP 12 women with partial or total improvement (70.6%), full improvement in 4 (23.5%), 5 no effect Side effects in 5 patients with POP and 16 patients with AGP • 22 of these women had used a COC. 10 experienced aggravation or start of their attacks AOH type I - découvert à l'âge de 17 ans, premier œdème abdominal sous pilule oestroprogestative. enquête familiale: son père et grand-père paternel atteints (dg à partir du cas index) Le rapport avec la prescription d'oestroprogestatifs n'a pas été fait tout de suite, et elle a conservé la contraception pendant plusieurs années. - première grossesse en 1990, nombreuses crises œdémateuses abdominales traitées par ESTERASINE à plusieurs reprises. - contraception par stérilet, les œdèmes ont persisté. - 2ème grossesse en 1995. œdèmes ont été moins présents, cessé après quatre mois de grossesse. - stérilet, - puis la découverte d'un fibrome vers 2002 LUTENYL à petites doses d'abord, dix jours par mois, puis à doses contraceptive 21 jours par mois C'est sous cette dose de 3 semaines par mois que les œdèmes ont disparu. Depuis cinq ans :pas d'œdème Observation de Claire BLANCHARD-DELAUNAY Pregnancy (MC Taquet et al in preparation) French retrospective multicenter study: • 63 patients: 30 type I/II, 33 normal C1INH • 126 Full term pregnancies: 57 type I/II, 69 normal C1INH • 23 miscarriages • 95 pregnancies with previous attacks • • - Worsening : - improvement: 54.7% (52/95) 36.8% (32/95) • • - Stabilization : 8.4% ( 8/95) 38% worsen in PREHAEAT study, contrasting with 30% symptoms improvement • Attacks during postpartum period:12.7% (postpartum defined as 15 days) 25% of multiparous women described a different outcome for each of their pregnancies Grossesses: les questions • 3 autres études, Bouillet et al 2008, Czaller et al, 2010 et Martinez-Saguer et al 2010. • Pas de prédictivité de l’issue de la grossesse, mais pour une majorité idem(Czaller et al 2010, Bouillet et al 2008) • Quel trimestre les crises sont elles majeures? résultats contradictoires • Si fœtus atteint , sévérité des crises? Oui pour les hongrois non pour les allemands, mais taux de C1Inh plus bas si fœtus atteint. • Les femmes ayant une exacerbation menstruelle s’amélioreraient au 3ème trimestre (Czaller et al) • Celles ayant des crises déclenchées par un trauma mécanique auraient plus de crises pendant la grossesse (Czaller et al) Another clinical situation with an exquisite sensitivity to estrogen effects Adjuvant hormone therapy in women with breast cancer Four patients with IDC breast HAE Menopausal status Treatments attacks interpretation Post menopausal Tamoxifen AI Worsen No Tam=Estrogen agonist 45 y Pre menopausal Tam+aGnRH Tam alone Worsen No Agonist antagonist HAE III FXII+ Pre menopausal Tam+aGnRH Tam alone Worsen No Agonist antagonist Pre menopausal aGnRH ovariectomy Improved idem Chemical Surgical Castrations HAE I 69 y HAE I 43 y HAE III FXII35y both Types I received Danazol (Gompel et al) Four patients with IDC breast HAE Menopausal status Treatments attacks interpretation Post menopausal Tamoxifen AI Worsen No Tam=Estrogen agonist 45 y Pre menopausal Tam+aGnRH Tam alone Worsen No Agonist antagonist HAE III FXII+ Pre menopausal Tam+aGnRH Tam alone Worsen No Agonist antagonist Pre menopausal aGnRH ovariectomy Improved idem Chemical Surgical Castrations HAE I 69 y HAE I 43 y HAE III FXII35y both Types I received Danazol (Gompel et al) Four patients with IDC breast HAE Menopausal status Treatments attacks interpretation Post menopausal Tamoxifen AI Worsen No Tam=Estrogen agonist 45 y Pre menopausal Tam+aGnRH Tam alone Worsen No Agonist antagonist HAE III FXII+ Pre menopausal Tam+aGnRH Tam alone Worsen No Agonist antagonist Pre menopausal aGnRH ovariectomy Improved idem Chemical Surgical Castrations HAE I 69 y HAE I 43 y HAE III FXII35y both Types I received Danazol (Gompel et al) Four patients with IDC breast HAE Menopausal status Treatments attacks interpretation Post menopausal Tamoxifen AI Worsen No Tam=Estrogen agonist 45 y Pre menopausal Tam+aGnRH Tam alone Worsen No Agonist antagonist HAE III FXII+ Pre menopausal Tam+aGnRH Tam alone Worsen No Agonist antagonist Pre menopausal aGnRH ovariectomy Improved idem Chemical Surgical Castrations HAE I 69 y HAE I 43 y HAE III FXII35y both Types I received Danazol (Gompel et al) Four patients with IDC breast HAE Menopausal status Treatments attacks interpretation Post menopausal Tamoxifen AI Worsen No Tam=Estrogen agonist 45 y Pre menopausal Tam+aGnRH Tam alone Worsen No Agonist antagonist HAE III FXII+ Pre menopausal Tam+aGnRH Tam alone Worsen No Agonist antagonist Pre menopausal aGnRH ovariectomy Improved idem Chemical Surgical Castrations HAE I 69 y HAE I 43 y HAE III FXII35y both Types I received Danazol (Gompel et al) Rationale ER and AR in endothelial cells (Miller V et al Trends in pharmacological sciences 2007) C1-INH Endogenous and exogenous estrogens Factor XIIa Activation C1r,C1s, MASP2 activated Kallicrein Lower levels in pregnancy and under OC Sp1 on promoter, ARE higher levels in pregnancy and OC ERE on FXII, rat: E2x6 transcription activity clivage of kininogen activation C1,C2,C4 Human pancreatic/renal kallikrein gene contains ERE and PRE Estrogen increases transcription Activates HMWK clivage( under OC) High HK and LK, kallicrein levels OC and pregnancy Estrogens bradykinins Rec B2 Estrogens increase B2Rec expression (rats) E2 potentiates endothelium dependent responses to bradykinin (human coronary arteries) angioedema Kininases I,II, ACE APP degradation estrogens Increase in VD Bradykinin induced in follicular phase (Chan N et al,J Clin Endocrinol Metab 2001;86: 2499) 15 healthy volunteers studied in early menstrual phase (days 1–4) and midcycle (days10–13) P:0.0008 EMP MC Progesterone increases APP in vitro (C La Corte et al, JRAS 2008;9:221) PRE PRE HepG2 cells, which endogenously express AP-P and ACE, were cultured with 1µM P Attenuated androgens Danazol • Prophylactic long term treatments (Gelfand JA, N Engl J Med 1976, Rothbach C Am J Med 1979, Agostoni A et al, JACI 1980, Craig TJ, Allergy Asthma Proc. 2008) • In C1-INH deficiency patients: increase C1-INH levels • Side effects: Hepatic, VTE, metabolic, hyperandrogenemia (women) • Short prophylaxis? Increase level of C1INH (Gelfand JA, N Engl J Med 1976, Rothbach C Am J Med 1979, Nanda MK, Ann Allergy Asthma Immunol 2014 ) Discussion • Estrogens are acting at key points on the cascade: C1INH, FXII, ACE? • May be regulated in normal women but could decompensate the kinin cascade in women with susceptibility (not all) • Role of environment and individual susceptibilities different phenotype among families, different course during pregnancies… • Androgens mostly opposite action (C1INH+ACE) • Progesterone less studied: specific effects? • Progestin decrease endogenous estrogens • Need of more studies on hormones and kinin pathways Research topics • Estetrol (E4)in development in contraception: does not activate the endothelial NO synthase and endothelial healing and membrane-initiated steroid signalling, and antagonize E2 at the membrane level (EMBO J Arnal et al 2014) • Physiopathology • Confirm with new tools where estrogens are acting • Role of progestins? • Role of androgens On kallicrein, factor XII, B2/B1 receptors , (kinases, B rec …)SNPS? Interaction with RAAS, Tissue kallicreins • Selection of patients who could benefit • Progestins, • Tranexamic acid • other • Prospective trials Take Home messages • HAE are in most cases extremely estrogen dependent • Role of personal susceptibility, environment • We propose that progestin be used as prophylactic treatment and providing an efficient contraception • Avoid estrogen administration in susceptible women including SERMs • Avoid antiandrogens in men and women • Privilege non estrogenic alternatives when an hormone treatment is indicated Acknowledgements CRéAk D.Launay Lille Caen & Rouen Nurses TE G.Masurier N.Carrat H.Humeau I.Citerne Médecine interne Immunologie [email protected] [email protected] APHP A.Gompel, O.Fain Paris, Bondy L.Martin Angers Strasbourg Médecine interne Immunologie [email protected] Niort & Poitiers Médecine interne Pédiatrie [email protected] Bordeaux Lyon Immunologie Clinique Allergologie Expl. Fonct. Digestive [email protected] Médecine interne Immunologie [email protected] N.Raison A.Duthan Montpellier Grenoble Nice I Boccon-Gibod L.Bouillet D.Ponard Médecine interne C.Drouet [email protected] N.Monnier Marseille Médecine interne [email protected]
