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Exogenous hormones and hereditary angioedema
International Immunopharmacology 78 (2020) 106080
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International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp
Exogenous hormones and hereditary angioedema a,d,⁎
b,d
Anne Gompel , Olivier Fain Laurence Bouilletc,d
c,d
T b,d
, Isabelle Boccon-Gibod , Delphine Gobert
,
a
Université Paris Descartes, Gynécologie, 123 BD Du Port Royal, 75014 Paris, France Université Pierre et Marie Curie and APHP, Service de Médecine Interne, Hôpital St Antoine, 184 rue du Faubourg Saint Antoine, 75012 Paris, France Université de Grenoble, Service de Médecine Interne, CHU de Grenoble 38043 Cedex 09, France d National Reference Centre for Angioedema (CREAK), France b c
A R T I C LE I N FO
A B S T R A C T
Keywords: Bradykinin C1 Inhibitor Factor XII Plasmin Danazol Contraception Assisted reproductive technology Menopause Breast cancer Prostate cancer
Gonadal hormones, estrogen and androgen are strongly involved in the control of the bradykinin production. Estrogen may worsen whereas androgen can be part of the long-term prophylactic treatment. In this review, we will describe the potential impact of estrogen in the pathophysiology of hereditary angioedema (HAE). Then we will review the different hormone treatments and their implication on the course of HAE in women and men: contraception, Assisted Reproductive Technology (ART), menopause, hormone dependent cancers in women and men, treatment of hyperandrogenism in women.
1. Introduction Hereditary angioedema (HAE) is a rare disease which can be life threatening and impact quality of life in most patients. Among triggers, exogenous hormone treatment by estrogens or estrogen agonists can be strongly involved, whereas attenuated androgens are part of long term prophylactic treatment of HAE with C1inhibitor (C1Inh) deficiency. Knowing the pharmacological properties for the various hormone or antihormone treatments is mandatory when to use them in patients with HAE. We will first describe the impact of estrogen on the bradykinin pathways, then how to manage contraception in those women, ART and menopause management, breast cancer hormone therapy and antiandrogen treatments in male and female. 2. Estrogen and bradykinin Bradykinin (BK) is produced from the cleavage of high-molecularweight kininogen (HMWK). The proteolysis is performed by kallikrein (KK) itself cleaved from prekallikrein (pKK) by activated factor XII (FXIIa). There is a feedback between KK and factor XII which amplifies the activation. C1Inh acts as regulating the activation of plasma contact phase and prevents abnormal BK activation [1]. There is some evidence
⁎
for an interaction with the fibrinolytic pathways namely between plasmin and the BK pathway. Plasmin at high concentration has been shown to activate FXII and in case of mutation carriers of FXII, plasmin is even more active to generate FXIIa [2]; recently it was suggested that tissue plasminogen activator (tPA) recruits FXIIa and plasma KK to generate BK. KK can also generate plasmin by direct cleavage of plasminogen or by activating urokinases, which subsequently cleave plasminogen to plasmin [3]. BK binds the kinin B2 receptor (B2R) and thereby increases vascular permeability and smooth muscle relaxation. BK is short-lived being immediately degraded into inactive products by aminopeptidase P, neutral endopeptidase (NEP), dipeptidyl peptidase IV (DPPIV) and angiotensin-converting enzyme (ACE). Estrogens can interact with most of the steps of this cascade. The effects of estrogens can be mediated by classical nuclear genomic actions or through non genomic effects at the membrane level or in the cytoplasm on various kinases [4]. The membranous effects of estradiol (E2) have been especially well described in the endothelium [5]. The membranous effects are extremely rapid when the genomic effects need transcription of several genes. Various sites of transcription activation are targets for the complex E2 and its cognate receptor. Estrogen responsive elements (ERE) are specific whereas, AP1, CREB, SP1, NFκB… can bind other complexes of steroids and their receptors.
Corresponding author at: Université Paris Descartes, Gynécologie, 123 BD Du Port Royal, 75014 Paris, France. E-mail address: [email protected] (A. Gompel).
https://doi.org/10.1016/j.intimp.2019.106080 Received 4 July 2019; Received in revised form 17 November 2019; Accepted 23 November 2019 1567-5769/ © 2019 Elsevier B.V. All rights reserved.
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derived from testosterone modified in its structure by deleting a methyl group to become progestogenic. Among the norsteroids, the first generation contained norethisterone/norethindrone derivatives used at mg/pill. The second generation pills contain norgestrel/levonorgestrel which is used at hundreds µg. The third generation is composed of three progestins, desogestrel, a prodrug converted into 3ceto-desogestrel (or etonogestrel) to be active, gestodene and norgestimate also a prodrug partially converted to norgestrel. These progestins are used at doses around a hundred µg, being more antigonadotropic than the second and first generation ones. The combination of EE with the second generation, LNG, and norgestimate are the less associated with thrombosis [25]. Other classes of progestin are also used in combination with EE. Some belongs to the pregnane group such as chlormadinone acetate and cyproterone acetate. Cyproterone acetate is also a potent antiandrogen. Thus the combination with EE generates the most estrogenic pill and as a consequence the higher risk of VTE [26]. Chlormadinone acetate is associated with EE at a rather low dose and has no androgenic potency. There is less information on VTE but its effect on hemostasis and its pharmacological profile are likely to be associated with a higher risk of VTE than second generation pills [27]. Other combinations have been developed containing a spironolactone derivative, drospirenone. Drospirenone, like spironolactone has some mild antiandrogenic and antimineralocorticoid properties. Thus the combinations of EE with it generates also more procoagulant profiles than second generation pills. The last progestin used in contraception is dienogest, in combination with E2. Dienogest a mixed pregnane and norsteroid and has some antiandrogenic properties. A Patch containing EE and norelgestromin (a metabolite of norgestimate) was associated with an increased risk of VTE 2 folds above the risk with a norgestimate containing pills [28], supported by the finding that this system provides 60% more total estrogen than oral contraceptives containing 30 µg of ethinyl estradiol and increases more the synthesis of SHBG, a marker of estrogenicity at the hepatic level [29,30]. The ring is composed of EE and etonogestrel and is less associated to activation of coagulation compared to the patch [31]. Most of women with HAE are facing aggravation of the disease if using CO. For Bork et al. [32], this aggravation occurs in about 60% of women with C1Inh deficiency or nC1Inh and in a multicentric European study on women with C1Inh deficiency, Bouillet et al.[33] reported a 80% worsening in attacks using CO. In our own series of patients, 67.4% worsened using CO [34]. But it is also meaning that 20–40% of women may tolerate a CO. We do not know the composition of pills used by these patients who tolerated CO. It is logical to use as a first line a progestin for a hormonal contraception (see next paragraph) but if a CO is considered, a second generation pill, or a pill containing E2 + nomegestrol acetate should be chosen preferentially and we advise the exclusion of a combination containing any pregnane, drospirenone or dienogest. Patch and ring should also not be used.
Estrogens were reported to decrease C1Inh levels, during pregnancy and using contraceptive pill, but there is no ERE on C1Inh promoter which does not exclude a control at the level of transcription but this has never been demonstrated [6–10]. At the opposite, FXII contains 7ERE which can contribute to activate FXII [11]. An increased level of factor XII (FXII) was reported in plasma from users of oral contraceptive in functional as well as in immunological assays as well as an increase in BK production [12]. BK mediates relaxation through the release of nitric oxide. E2 is a potent regulator for the release of NO contributing to vascular vasodilatation [13]. This effect is mediated by the E2 membrane receptor in the caveloae [14]. It was however suggested that E2 may also have a positive effect on relaxation independently from NO [15]. Most of kallikreins are regulated by steroids including androgens and estrogens [16]. Potential EREs have been reported in the proximal promoter of rat KLK1 but their functionality not studied [16]. E2 can also enhance the HMWK cleavage [17]. In addition, we demonstrated that oral E2 was associated with an increase in plasminogen [18]. And last but not least, B2R is also a potential target for E2 which increases B2R expression and function [19]. These interactions of E2 with the BK cascade are contributing to increase the production of BK and its utilization. In addition, E2 can decrease the degradation of BK by interacting with the angiotensin converting enzyme activity. It was shown in animals and humans that chronic menopause treatment inhibits angiotensin converting enzyme activity [20]. Furthermore, only oral estrogen was associated to increase in BK concentration whereas transdermal estradiol treatment was associated with a decrease in BK [21,22]. Other steroids are also potential regulators of the BK cascade but less studied. Androgens upregulate the level of C1Inh. An Androgen Responsive Element was identified in the promoter of C1Inh. This is the basis of use of attenuated androgens in patients with C1Inh deficiency. Androgens are potent regulators of kallikrein in the prostate and some breast cancer cells [16]. But there are no data on their effect on the plasma kallikrein. Progesterone/progestins are also regulators of tissue kallikreins in breast cancer cells and endometrium [16]. A potential Progesterone Responsive Element can be present in the promoter of some of the tissue kallikreins. Aminopeptidase expression was shown to be increased by progesterone in hepatocytes in one publication [23]. Exogenous hormones can be used in various conditions in men and women. Contraception is the first condition. 3. Hormonal contraception 3.1. Combined estrogen-progestin contraception (CO) The most used hormonal contraception is a combination of estrogen and progestin. They can be administered either by oral route, by vaginal ring or patch. Most of the oral pills contain ethinylestradiol (EE) which is a synthetic estrogen with potent estrogenic activity. EE has a long half-life and is accumulated in hepatic microsomes. This can probably impact the synthesis of C1Inh. Two contraceptives were developed with estradiol or an estradiol ester. These pills have the same impact (the one containing dienogest) or a better profile (the one containing nomegestrol acetate) on coagulation than a second generation pill [24]. The coagulation activation reflects the estrogenic activity at the hepatic level and could potentially makes a difference in HAE symptoms but this has not been studied… The progestin contained in combination with the estrogen can belongs to different pharmacologic groups. The composition of the pill impacts the risk of venous thrombosis (VTE) by differentially activating the coagulation and fibrinolysis. It is shown that the balance estrogen/androgen potency at the hepatic level is associated with different level of coagulation activation. The higher the estrogen potency, the lower the androgenic potency, the higher the risk of VTE. Most progestins are normethyltestosterone (norsteroids) derivatives. They all have some androgenic potencies
3.2. Progestin Progestins are non-selective steroids (Table 1). As reminded above, some are normethyl testosterone derivatives (norsteroid) and some are synthetized from 17hydroxyprogesterone (pregnane). A smaller group is constituted by the nor-pregnane (Table 1). They all by definition bind and transactivate the progesterone receptor (PR) but some of them also can bind AR, MR, GR. And most of the norsteroids (norethisterone derivatives, tibolone) have some metabolites with a weak estrogen potency. Some of the progestins are androgen receptor (AR) agonists such as the norsteroids and medroxyprogesterone acetate, some others are AR antagonists as cyproterone acetate, dienogest, drospirenone. The latter should be avoided in women with HAE whereas, progestin with androgenic potencies can be beneficial in these women. Table 1 presents the various molecules and their potencies.
2
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antigonadotropic effect does not allowed any follicular growth and thus any endogenous secretion of estrogen from the ovary, whereas at doses provided in the progestin only pill desogestrel 75 µg/day, levonorgestrel 30 µg/day or norethisterone/norethindrone 350 µg /day they can have only a partial antigonadotropic effect which opposes the preovulatory LH peak and thus can be associated with the abnormal growth of a follicle which produces high amount of estradiol. According to the molecule used and the woman (metabolization may vary), these contraceptives can be associated with normal cycles, low estrogenic environment and amenorrhea or functional cysts of the ovary with high levels of circulating E2. Desogestrel is more antigonadotropic than the two others. Close to the oral POP, the contraceptive implants avoid the problems of compliance and increase the biodisponibility and thus the contraceptive efficacy. There are two kinds of implants: one composed of levonorgestrel (Norplant®) and the other one of etonogestrel (Nexplanon®). They can also be associated with an increase in E2 plasmatic levels by the same mechanisms than described above for oral POP Drospirenone alone as a contraceptive administered orally at the dose of 4 mg/day, 24 days of active treatment and 4 days of placebo has been recently approved by FDA (June 2019). There is not any experience in women with HAE. Its mild antiandrogenic activity may potentially induced some attacks. One of the potential side effect is hyperkaliemia by its mild antimineralocorticoid activity. Progestin can also be delivered by an intra uterine device (IUD). There are at several IUDs containing levonorgestrel available. Mirena® and Liletta®, contain the highest amount of levonorgestrel (52 mg) whereas Jaydess® and Skyla® contain 13.5 mg and Kyleena® 19.2 mg of levonorgestrel. The gynecological and systemic tolerances vary from one woman to another. Functional ovarian cysts occur in 25% of cycles with Mirena® and about 10% with the low dose IUDs [35]. The predominant side effects of progestin contraception are spotting and breakthrough bleeding. Some women will put on weight. Some can have a loss of libido. Then the contraception has to be adapted to the clinical tolerance and can be modified. The same for the efficacy on HAE symptoms. We show in a study performed in women with HAE that progestin contraception was potentially of benefits on AE attacks [34]. The most antigonadotropic they are the more benefit women will get on their attacks frequency [34]. We can thus advise to use as a first line
Table 1 classification of progestogen and their potencies. Progestin
Anti Gonadot ropic
ER-
ER+
AR+
AR-
GR+
Anti-MR
P
+
+
–
–
+
+
Dydrogesterone – Pregnanes Chlormadinone Ac + Cyproterone Ac + Megestrol Ac + MPA + Medrogestone + norpregnanes Nomegestrol Ac + Promegestone + Trimegestone + Nestorone norsteroids Norethisteron* + Lynestrenol* + Norethynodrel* + Levonorgestrel + Norgestimate + 3 ceto-desogestrel + (etonogestrel) Gestodene + Tibolone metabolites Dienogest$ + Spironolactone derivative Drospirenone +
+
–
–
(+)
+ (in vitro) –
+ + + + +
– – – – –
(+) – (+) + –
– ++ – – –
+ + + ++ –
– – – – –
+ + + +
– – – –
– – – –
– – (+) –
– + – –
– – (+)
+ + (+) + + +
+ + + – – –
+ + (+) + + +
– – – – – –
– – – – – –
– – – – – –
+ +
– +
+ ++
– –
+ –
+ –
(+)
(+)
–
+
–
–
+
–
–
+
–
+
–
*Potent antiestrogen, antigonadotropic and mild androgen if used at high doses. $ mixed pregnane and norsteroid. ER: estradiol receptor, PR:progesterone receptor, AR: androgen receptor, GR:glucocorticoid receptor, MR:mineralocorticoid receptor.
3.2.1. Contraception Table 2 presents the molecules and brand names used as contraceptives or in menopause treatment. Norsteroids when used at high doses (10 mg/day) are potent antigonadotropic and androgenic whereas when used at low doses these effects are mild. At high dose, the
Table 2 names of progestogen and their principal indication (in addition to contraception and menopause treatment they can be used for menstrual cycle abnormalities). Class
Molecule
Brand name and doses
Indication doses
Progesterone
micronised Progesterone
menopause
Progesterone Isomer pregnanes
Dydrogesterone
Utrogestan® 100, 200 mg Prometrium® Duphaston® 10 mg
Medrogestone
Colprone® 5 mg
chlormadinone Ac., Medroxyprogesterone Ac. (MPA), Cyproterone Ac.
Luteran 5, 10 mg Injectable : 250 mg Oral : 2.5 mg, 5 mg 50 mg,100 mg
norpregnane
Nomegestrol Ac.
Lutenyl® 5 and 3.75 mg
norsteroides (estranes) 1st generation
Norethisterone Ac Norethisterone Norethindrone Lynestrenol Levonorgestrel
Primolut Nor®, Norluten® Norlutate® Norlutin®, Orgametril® Milligynon® Exluton®
Contraception 10 mg Menopause 5/10 mg Contraception 10 mg Menopause 5/10 mg Contraception Menopause Hirsutism/transexual Prostate cancer Contraception 5 mg Menopause 3.75 mg Contraception 10 mg, 10 mg/5mg/ 10 mg 600µg£/500µg£1
Norsteroides (gonanes) 2nd generation Norsteroide (gonane) 3rd generation Spironolactone derivative £
Menopause 10 mg
3 ceto-Desogestrel (Etonogestrel)
Microval® Norplant ® Jadelle®, Sino-implant® Cerazette® Nexplanon®
Contraception oral 30µg£, Implant 6x36 mg Contraception oral 75 µg, Implant 68 mg
Drospirenone
Slynd®
Contraception oral 4 mg*
low dose progestin contraception «POP»
1
no more available * just approved by FDA (June 2019). 3
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spironolactone, at least when starting the treatment combined with a progestin can be in some patients tolerated. The prescription of cyproterone acetate can induce attacks [37,38]. Nevertheless, under stringent evaluation, some women can tolerate it (personal experience) maybe because it provides a low estrogenic environment.
chlormadinone acetate, lynestrenol, norethisterone, norethisterone acetate at high dose, nomegestrol acetate if available or injectable MPA. For oral preparations, they can be prescribed either continuously or sequentially (20 days/27) according to the tolerance and efficacy on the attacks. Norsteroids at high doses have the same contraindications metabolic and vascular than CO. The less antigonadotropic agents are desogestrel, low dose norethisterone and levonorgestrel, the implants and levonorgestrel IUDs. In our study, 60% of women who used a POP or equivalent (implant or Mirena®) observed a benefit on their attacks whereas the proportion was above 80% with the most potent progestins [34]. As an illustration of the benefits observed with progestin, the French recommendations of HAE management propose progestin as a first line for prophylactic long term treatment in women with HAE [36]. Progestins are better tolerated than danazol, at low cost and providing a contraception in addition to their efficacy on attacks.
5. Assisted reproductive technology (ART) The aim in ART is to stimulate the ovaries by FSH in order to retrieve a high number of oocytes. This aim is obtained by initially using a GnRH agonist administered either from the middle of the previous menstrual cycle and for usually 3 weeks (long treatment) or initiate the GnRH analog at the very beginning of the menstrual cycle for a shorter period (short protocol). A stimulation by FSH is applied to induce the growth of several follicles and the ovarian induction followed by echography and estradiol levels. When several mature follicles are obtained an injection of recombinant LH is performed and the oocytes retrieval performed. According to the number of embryos obtained, some can be frozen and usually two embryos are implanted in the next two days. In case of poor responders or if a limitation in the tolerance of estrogen levels due to a specific disease like HAE, GnRH antagonists can be used to monitor the LH peak. Some groups also associate a pretreatment by CO before the stimulation. In women with HAE, prophylaxis by C1INH concentrate can be systematically used or reserved to the time of the retrieval. We would recommend to use protocols including antagonists or implantation of frozen embryos in spontaneous cycles. We report here an unpublished case of a woman with type I HAE extremely severe controlled by danazol but with frequent attacks when she stopped danazol. We performed the stimulation using danazol at 600 mg as the antigonadotropic agent and an antagonist at the time of retrieval. Then 6 embryos were frozen and two implanted after the stop of danazol in a spontaneous cycle where she received a prophylaxis by C1Inh concentrate. She delivered a healthy son in the following pregnancy. The stimulation was remarkably well tolerated under the danazol treatment. Half-life of danazol is evaluated variably in the literature between 9 and 24 h [39,40]. There is no risk of virilisation when taken at the time of conception. We thus propose that in some cases danazol could be an option as an antigonadotropic agent in those patients. A progestin is also an option.
3.2.2. Other indications of progestogens Endometriosis, endometrial hyperplasia, adenomyosis, ovarian functional cysts, mastalgia, premenstrual syndrome, functional bleeding can be indications for the use of progestins. In most cases they can be used as antigonadotropic agent, 20 days/27. In some indications however, a ten day /month treatment by progesterone/dydrogesterone is indicated and then this treatment may be insufficient in women with HAE. This has to be taken into account but if necessary for the HAE management, then there is no contraindication to use the treatment either continuously of 20/27 days/month. 3.3. GnRH agonists (Leuproreline, Triptoreline, Gosereline) 3.3.1. In women There are not considered as contraceptive but as treatment in estrogen dependent diseases. They are the most powerful antigonadotropic agents but their clinical tolerance is limited by climacteric symptoms and potential bone impact. They have no contraindication in women with HAE, and by their effect provides a very low estrogenic environment but cannot be used for long term treatment. 3.3.2. In men: Used in the treatment of prostate cancer (as well as GnRH antagonists, Degarelix) since they act as a chemical castration they can induce attacks by drastically lowering testosterone levels (see below).
6. Breast cancer and hormonotherapy 4. Treatment of hyperandrogenism Breast cancer adjuvant treatment includes a hormonotherapy for cases which are ER positive. In premenopausal women the standard hormonotherapy is tamoxifen (tam) whereas in post-menopausal women, aromatase inhibitors (AI) are the first line. GnRH agonists can be combined in premenopausal women to tamoxifen. Tam is a Selective estrogen receptor modulator. It has partial agonist and antagonist activity on ERα. Tam is developing its estrogen agonist effects in some tissues such as endometrium, liver, bone, due to the tissue specificity of co activators and corepressors. In presence of estrogen it behaves as an antagonist. We described the first case of worsening of the attacks in a postmenopausal woman treated by tam for a breast cancer [41]. Since then 2 other cases were reported, one in a woman with nC1Inh and another one with C1Inh deficiency [42]. We also have seen 2 other cases in premenopausal women treated by tam for breast cancer and in whom was added a GnRH analog, one in a woman with C1Inh deficiency and another in a woman with FXII mutation (unpublished data). Stopping the GnRH analog in these two patients was associated with an improvement of HAE symptoms. These observations highlight the fact that even a mild estrogen like tam may worsen the course of HAE, likely by its hepatic estrogen agonist impact. AI antagonize aromatization of androgens in estrogens and drastically lower estrogens levels in postmenopausal women. They are thus not contraindicated in women with HAE, since they even increase a bit the circulating levels of androgens.
The treatment of clinical hyperandrogenism, hirsutism, acnea and alopecia is usually performed by antiandrogens. To be efficient the treatment has to be antigonadotropic to counteract the ovarian androgen secretion and combined an antiandrogen acting on the hair follicle. The most efficient one is cyproterone acetate since it combines both properties, then CO predominantly estrogenic and then spironolactone which has to be associated to an antigonadotrope. Because of their sensitivity to androgens and estrogens, these treatments can worsen the course of women with HAE. Some alternatives to antiandrogen may exist: Vaniqa® a cream containing Eflronithine chlorhydrate is approved by FDA and EMEA for the treatment of facial hair. It is a non-hormonal treatment acting by antagonizing ornithine decarboxylase, an enzyme involved in the growth of hair. There is no contraindication to the use of this drug. Laser can also be proposed to women with HAE. There is no report of any concern of using this treatment in women with HAE. We should however recommend to get Icatibant available when performing the treatment. For acnea, retinoic acid is efficient and has to be combined with a contraception which can be a progestin. Topical treatments are also available without contraindication in those women. In case where the hyperandrogenism is not solved by the non-hormonal management, a prudent and low dose prescription of 4
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7. Menopause
prostate adenoma discomfort and is an inhibitor of 5α-reductase activity. All these compounds can act by decreasing testosterone activity and thus be associated with worsening of AE course. Transexual males are treated by an antiandrogen such as cyproterone acetate + estradiol up to the time of castration, and thereafter at usually lower doses. This treatment is at high risk for patients with AE.
The menopause transition period is a time of large variation in E2 and the symptoms are usually treated by progestin. This has probably to be taken in account especially in women with HAE. In post-menopausal women the ovarian secretion of estrogen disappears and usually as well the ovarian androgen secretion. Due to the impact of gonadal steroids on HAE course, one can expect that menopause could improve the symptoms. However, in a multicentric study on women with C1Inh deficiency, only 55% improved [33]. We have conducted a study in 62 postmenopausal women and find that about 50% of them improved but 15% worsened and in most of cases with severe symptoms (manuscript submitted). In addition, our study highlights the fact that only few women had a proper management of their climacteric symptoms. In fact there are several options to help those women. Progesterone and progestin can alleviate vasomotor symptoms and progesterone helps for sleep disorders [43,44]. Vaginal estrogens are not contraindicated for women with HAE. They are usually used twice a week and provide a very low systemic level of estrogen [45]. Theoretically, local vulvar or vaginal oedema could occur but so far no such report was made. In our study several women used estradiol and a progestin without worsening of their symptoms. Most but not all used a transdermal E2 treatment. As reported in the first paragraph of this review, a study suggested a decrease in BK production was observed with transdermal E2 and an increase with oral E2 [22]. This has to be certainly confirmed but we know that transdermal route does not provide a high hepatic concentration of E2 contrary to the oral route (first pass hepatic effect). Tibolone has been used with benefit in women with HAE. Tibolone is a weak norsteroid developed for the treatment of climacteric symptoms. Its metabolites have androgenic and progestogenic (Δ4isomer) and mildly estrogenic (3α- and 3β-metabolites) properties. Tibolone (Livial®) was used in 8 women premenopausal (six) and postmenopausal (two) at doses from 2.5 mg (the usual dose for climacteric symptoms) to 7 mg. All the patients improved. However, its use in premenopausal women is not to be recommended since other norsteroids are available which are more potent and validated in premenopausal women. Alternatives to hormone treatment such as serotonin-recapture inhibitors, noradrenaline recapture inhibitors, citalopram, gabapentine, clonidine can be prescribed for women who are symptomatic for their menopause and cannot tolerate hormones (for details see [46]).
9. Danazol and hormone dependent cancers In most hormone dependent cancer, the indication of androgens may be discussed. It is clear that androgen treatment is contraindicated in prostate cancer. In breast cancers, the situation is more complex. AR is present in most of breast cancer cases and variably associated to the prognosis but not routinely performed. The ER + AR /ER ratio was suggested to be an indicator of prognosis if high [47]. Triple negative BC can belong to an AR group which is resistant to chemotherapy….The AR expression can be discordant between primary tumor and metastasis [47]. It is thus unpredictable the action of an androgen in this disease, and the use of attenuated androgens has to be stringently evaluated with the oncologist. Eigty five percent of endometrial cancer are estrogen dependent. Progestogens and androgens are not contraindicated. In most of cases of ovarian cancer, the treatment includes an oophorectomy. In some cases, a conservative treatment may be indicated. Progestins are contraindicated in low grade serous cancer but can be used in all other differentiation [48]. Up to recently there were no data on androgen and ovarian cancer. A recent publication suggests that androgens could be in some cases a deleterious agent in ovarian cancer [49]. Cervical cancers are predominantly squamous cell carcinoma. This cancer is not hormone dependent. About 10% of cervical cancers are adenocarcinoma considered as estrogen dependent. There is no contraindication to danazol or progestin such as for endometrial cancer. 10. Conclusions The exquisite sensitivity to estrogens and to a low androgen environment has to be taken in account during lifetime in patients with HAE. Those patients may be exposed to clinical situation which needs the expert in charge of their management to be perfectly aware of the potential benefit/risk balance of any hormonal treatment. This review will hopefully contribute to help the choices in these situations. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors
8. Antiandrogen in male The physiological predominant hormone in men is testosterone. It was reported that men with hypogonadism have increase in their attacks whereas the androgen treatment reversed the figure [38]. Various treatments are used in men as antiandrogens: there are indicated for the treatment of prostate cancer or adenoma. Prostate cancers are treated by chemical castration using GnRH analogs (or antagonists) or surgical castration and in case of progression by antiandrogens. Several molecules of antiandrogens have been approved by FDA or /and EMEA: Abiraterone acetate (combined with prednisone), Apalutamide, Biclutamide, Cyproterone acetate (100 mg/ pill), Nilutamide, Enzalutamide, Flutamide. They are used as a second line treatment after resistance to castration in a non-metastatic or metastatic context. Finasteride (5 mg/day) and dutasteride (0.5 mg/day) are the two approved 5α-reductase inhibitors used for the treatment of prostate adenoma. Finasteride is also indicated as low dose (1 mg/day) for the treatment of alopecia in male (but some used it out of label in women with alopecia). By inhibiting the 5α-reductase activity they decrease the transformation of testosterone into dihydrotestosterone, the androgen with the highest affinity for AR. Serenoa repens (Permixion®) is also used in the treatment of
References [1] A.P. Kaplan, K. Joseph, Pathogenic mechanisms of BK mediated diseases: dysregulation of an innate inflammatory pathway, Adv. Immunol. 121 (2014) 41–89. [2] S. de Maat, J. Björkqvist, C. Suffritti, C.P. Wiesenekker, W. Nagtegaal, A. Koekman, et al., Plasmin is a natural trigger for BK production in patients with hereditary angioedema with factor XII mutations, J. Allergy Clin. Immunol. 138 (5) (2016) 1414–1423.e9. [3] F. Marceau, H. Bachelard, G.-É. Rivard, J. Hébert, Increased fibrinolysis-induced BK formation in hereditary angioedema confirmed using stored plasma and biotechnological inhibitors, BMC Res. Notes 12 (1) (2019) 291. [4] A. Nadal, M. Díaz, M.A. Valverde, The estrogen trinity: membrane, cytosolic, and nuclear effects, News Physiol Sci. Int. J. Physiol. Prod. Jointly Int. Union Physiol. Sci. Am. Physiol. Soc. 16 (2001) 251–255. [5] Guivarc’h E, Buscato M, Guihot A-L, Favre J, Vessières E, Grimaud L, et al. Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety. J. Am. Heart Assoc. 2018 Jun 29;7(13). [6] E.M. Gordon, O.D. Ratnoff, H. Saito, V.H. Donaldson, J. Pensky, P.K. Jones, Rapid fibrinolysis, augmented Hageman factor (factor XII) titers, and decreased C1 esterase inhibitor titers in women taking oral contraceptives, J. Lab. Clin. Med. 96 (5) (1980) 762–769.
5
International Immunopharmacology 78 (2020) 106080
A. Gompel, et al.
[7] E.M. Gordon, S.R. Williams, B. Frenchek, C.A. Mazur, L. Speroff, Dose-dependent effects of postmenopausal estrogen and progestin on antithrombin III and factor XII, J. Lab. Clin. Med. 111 (1) (1988) 52–56. [8] J. Jespersen, C. Kluft, Increased euglobulin fibrinolytic potential in women on oral contraceptives low in oestrogen–levels of extrinsic and intrinsic plasminogen activators, prekallikrein, factor XII, and C1-inactivator, Thromb. Haemost. 54 (2) (1985) 454–459. [9] A. Adam, A. Albert, J. Boulanger, D. Genot, A. Demoulin, J. Damas, Influence of oral contraceptives and pregnancy on constituents of the kallikrein-kininogen system in plasma, Clin. Chem. 31 (9) (1985) 1533–1536. [10] A.J. Cohen, C. Laskin, S. Tarlo, C1 esterase inhibitor in pregnancy, J. Allergy Clin. Immunol. 90 (3 Pt 1) (1992 Sep) 412–413. [11] A. Farsetti, S. Misiti, F. Citarella, A. Felici, M. Andreoli, A. Fantoni, et al., Molecular basis of estrogen regulation of Hageman factor XII gene expression, Endocrinology 136 (11) (1995) 5076–5083. [12] N.O. Hoem, S. Johannesen, G. Hauge, A.C. Rud, S. Sandem, K. Briseid, Contact activation factors in plasma from women using oral contraceptives–increased levels of factor XII, kinin-free high molecular weight kininogen and acetone-activated kallikrein, Thromb. Res. 64 (4) (1991) 427–434. [13] K. Tarhouni, A.L. Guihot, E. Vessieres, V. Procaccio, L. Grimaud, P. Abraham, et al., Estrogens are needed for the improvement in endothelium-mediated dilation induced by a chronic increase in blood flow in rat mesenteric arteries, Vasc.Pharmacol. 80 (2016) 35–42. [14] K.L. Chambliss, I.S. Yuhanna, C. Mineo, P. Liu, Z. German, T.S. Sherman, et al., Estrogen receptor alpha and endothelial nitric oxide synthase are organized into a functional signaling module in caveolae, Circ. Res. 87 (11) (2000) E44–E52. [15] M. Barton, J. Cremer, A. Mügge, 17Beta-estradiol acutely improves endotheliumdependent relaxation to BK in isolated human coronary arteries, Eur. J. Pharmacol. 362 (1) (1998) 73–76. [16] M.G. Lawrence, J. Lai, J.A. Clements, Kallikreins on steroids: structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus, Endocr. Rev. 31 (4) (2010) 407–446. [17] K. Joseph, B.G. Tholanikunnel, A.P. Kaplan, Cytokine and estrogen stimulation of endothelial cells augments activation of the prekallikrein-high molecular weight kininogen complex: Implications for hereditary angioedema, J. Allergy Clin. Immunol. 140 (1) (2017) 170–176. [18] J. Conard, A. Gompel, C. Pelissier, C. Mirabel, A. Basdevant, Fibrinogen and plasminogen modifications during oral estradiol replacement therapy, Fertil. Steril. 68 (3) (1997) 449–453. [19] P. Madeddu, C. Emanueli, Q. Song, M.V. Varoni, M.P. Demontis, V. Anania, et al., Regulation of BK B2-receptor expression by oestrogen, Br. J. Pharmacol. 121 (8) (1997) 1763–1769. [20] N. Nogawa, H. Sumino, S. Ichikawa, H. Kumakura, Y. Takayama, T. Nakamura, et al., Effect of long-term hormone replacement therapy on angiotensin-converting enzyme activity and BK in postmenopausal women with essential hypertension and normotensive postmenopausal women, Menopause N Y N. 8 (3) (2001) 210–215. [21] A. Ichikawa, H. Sumino, T. Ogawa, S. Ichikawa, K. Nitta, Effects of long-term transdermal hormone replacement therapy on the renin-angiotensin- aldosterone system, plasma BK levels and blood pressure in normotensive postmenopausal women, Geriatr Gerontol Int. 8 (4) (2008) 259–264. [22] J. Ichikawa, H. Sumino, S. Ichikawa, M. Ozaki, Different effects of transdermal and oral hormone replacement therapy on the renin-angiotensin system, plasma BK level, and blood pressure of normotensive postmenopausal women, Am. J. Hypertens. 19 (7) (2006) 744–749. [23] A.L. Cilia La Corte, A.M. Carter, A.J. Turner, P.J. Grant, N.M. Hooper, The BKdegrading aminopeptidase P is increased in women taking the oral contraceptive pill, J. Renin-Angiotensin-Aldosterone Syst. JRAAS 9 (4) (2008) 221–225. [24] I. Lete, N. Chabbert-Buffet, C. Jamin, S. Lello, P. Lobo, R.E. Nappi, et al., Haemostatic and metabolic impact of estradiol pills and drospirenone-containing ethinylestradiol pills vs. levonorgestrel-containing ethinylestradiol pills: a literature review, Eur. J. Contracept Reprod Health Care Off. J. Eur. Soc. Contracept. 20 (5) (2015) 329–343. [25] B.H. Stegeman, M. de Bastos, F.R. Rosendaal, Vlieg A van Hylckama, F.M. Helmerhorst, T. Stijnen, et al., Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis, BMJ 12 (347) (2013 Sep) f5298. [26] J. Hugon-Rodin, M.-H. Horellou, J. Conard, A. Gompel, G. Plu-Bureau, Type of Combined Contraceptives, Factor V Leiden Mutation and Risk of Venous Thromboembolism, Thromb. Haemost. 118 (5) (2018) 922–928. [27] U.H. Winkler, E. Daume, R. Sudik, C. Oberhoff, U. Bier, C. Hallmann, et al., A comparative study of the hemostatic effects of two monophasic oral contraceptives
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38] [39]
[40]
[41]
[42]
[43] [44]
[45]
[46]
[47]
[48]
[49]
6
containing 30 mu(g) ethinylestradiol and either 2 mg chlormadinone acetate or 150 mu(g) desogestrel, Eur. J. Contracept Reprod Health Care Off. J. Eur. Soc. Contracept. 4 (3) (1999) 145–154. D.D. Dore, H. Norman, J. Loughlin, J.D. Seeger, Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users, Contraception. 81 (5) (2010) 408–413. D. Devineni, D. Skee, N. Vaccaro, J. Massarella, L. Janssens, K.D. LaGuardia, et al., Pharmacokinetics and pharmacodynamics of a transdermal contraceptive patch and an oral contraceptive, J. Clin. Pharmacol. 47 (4) (2007) 497–509. M.W. van den Heuvel, A.J.M. van Bragt, A.K.M. Alnabawy, M.C.J. Kaptein, Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive, Contraception. 72 (3) (2005) 168–174. J. Hugon-Rodin, A. Gompel, G. Plu-Bureau, Epidemiology of hormonal contraceptives-related venous thromboembolism, Eur. J. Endocrinol. 171 (6) (2014) R221–R230. K. Bork, B. Fischer, G. Dewald, Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy, Am. J. Med. 114 (4) (2003) 294–298. 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(5):484.e1-4. C. Saule, I. Boccon-Gibod, O. Fain, G. Kanny, G. Plu-Bureau, L. Martin, et al., Benefits of progestin contraception in non-allergic angioedema, Clin. Exp. Allergy J. Br. Soc. Allergy Clin. Immunol. 43 (4) (2013) 475–482. Haute Autorité de Santé - KYLEENA (lévonorgestrel), dispositif intra-utérin avec progestatif. available from: https://www.has-sante.fr/portail/jcms/c_2824470/fr/ kyleena-levonorgestrel-dispositif-intra-uterin-avec-progestatif. L. Bouillet, A. Lehmann, A. Gompel, I. Boccon-Gibod, D. Launay, O. Fain, et al., [Hereditary angiœdema treatments: recommendations from the French national center for angiœdema (Bordeaux consensus 2014)], Presse Medicale Paris Fr 44 (5) (1983) 526–532. Jamin C, Intrator L, Laurent J, Lagrue G. [Cyproterone acetate is not effective in the prevention of hereditary angioneurotic edema]. Presse Medicale Paris Fr. 1983. 1985 Sep 7;14(29):1559–60. W.J. Pichler, R. Lehner, P.J. Späth, Recurrent angioedema associated with hypogonadism or anti-androgen therapy, Ann Allergy 63 (4) (1989) 301–305. W.D. Hooper, M.J. Eadie, R.G. Dickinson, Single oral dose pharmacokinetics and comparative bioavailability of danazol in humans, Biopharm. Drug Dispos. 12 (8) (1991 Nov) 577–582. K. Selinger, H.M. Hill, J.A. Anslow, D. Gash, A liquid chromatographic method for the determination of danazol in human serum, J. Pharm. Biomed. Anal. 8 (1) (1990) 79–84. C. Rousset-Jablonski, J.-C. Thalabard, A. Gompel, Tamoxifen contraindicated in women with hereditary angioedema? Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 20 (7) (2009) 1281–1282. K. Bork, K. Wulff, G. Witzke, S. Rietz, J. Hardt, Tamoxifen may cause life-threatening angioedema attacks in patients with hereditary angioedema, J. Eur. Acad Dermatol. Venereol. JEADV 31 (5) (2017) e237–e239. J.C. Prior, Progesterone for treatment of symptomatic menopausal women, Climacteric J. Int. Menopause Soc. 21 (4) (2018) 358–365. C.L. Loprinzi, R. Levitt, D. Barton, J.A. Sloan, S.R. Dakhil, D.A. Nikcevich, et al., Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: north central cancer treatment group trial N99C7, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 24 (9) (2006) 1409–1414. C.A. Stuenkel, S.R. Davis, A. Gompel, M.A. Lumsden, M.H. Murad, J.V. Pinkerton, et al., Treatment of symptoms of the menopause: an endocrine society clinical practice guideline, J. Clin. Endocrinol. Metab. 100 (11) (2015) 3975–4011. R.J. Santen, C.A. Stuenkel, S.R. Davis, J.V. Pinkerton, A. Gompel, M.A. Lumsden, Managing Menopausal Symptoms and Associated Clinical Issues in Breast Cancer Survivors, J. Clin. Endocrinol. Metab. 102 (10) (2017) 3647–3661. S. Salvi, M. Bonafè, S. Bravaccini, Androgen receptor in breast cancer: A wolf in sheep’s clothing? A lesson from prostate cancer. Semin. Cancer Biol. 2019 Apr 16; Epud Head of publication. C. Rousset-Jablonski, F. Selle, E. Adda-Herzog, F. Planchamp, L. Selleret, C. Pomel, et al., Fertility preservation, contraception and menopause hormone therapy in women treated for rare ovarian tumours: guidelines from the French national network dedicated to rare gynaecological cancers, Eur. J. Cancer Oxf. Engl. 3 (116) (1990) 35–44. T. Mizushima, H. Miyamoto, The Role of Androgen Receptor Signaling in Ovarian Cancer. Cells. 2019 Feb 19;8(2). Epud Head of publication.
Contents lists available at ScienceDirect
International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp
Exogenous hormones and hereditary angioedema a,d,⁎
b,d
Anne Gompel , Olivier Fain Laurence Bouilletc,d
c,d
T b,d
, Isabelle Boccon-Gibod , Delphine Gobert
,
a
Université Paris Descartes, Gynécologie, 123 BD Du Port Royal, 75014 Paris, France Université Pierre et Marie Curie and APHP, Service de Médecine Interne, Hôpital St Antoine, 184 rue du Faubourg Saint Antoine, 75012 Paris, France Université de Grenoble, Service de Médecine Interne, CHU de Grenoble 38043 Cedex 09, France d National Reference Centre for Angioedema (CREAK), France b c
A R T I C LE I N FO
A B S T R A C T
Keywords: Bradykinin C1 Inhibitor Factor XII Plasmin Danazol Contraception Assisted reproductive technology Menopause Breast cancer Prostate cancer
Gonadal hormones, estrogen and androgen are strongly involved in the control of the bradykinin production. Estrogen may worsen whereas androgen can be part of the long-term prophylactic treatment. In this review, we will describe the potential impact of estrogen in the pathophysiology of hereditary angioedema (HAE). Then we will review the different hormone treatments and their implication on the course of HAE in women and men: contraception, Assisted Reproductive Technology (ART), menopause, hormone dependent cancers in women and men, treatment of hyperandrogenism in women.
1. Introduction Hereditary angioedema (HAE) is a rare disease which can be life threatening and impact quality of life in most patients. Among triggers, exogenous hormone treatment by estrogens or estrogen agonists can be strongly involved, whereas attenuated androgens are part of long term prophylactic treatment of HAE with C1inhibitor (C1Inh) deficiency. Knowing the pharmacological properties for the various hormone or antihormone treatments is mandatory when to use them in patients with HAE. We will first describe the impact of estrogen on the bradykinin pathways, then how to manage contraception in those women, ART and menopause management, breast cancer hormone therapy and antiandrogen treatments in male and female. 2. Estrogen and bradykinin Bradykinin (BK) is produced from the cleavage of high-molecularweight kininogen (HMWK). The proteolysis is performed by kallikrein (KK) itself cleaved from prekallikrein (pKK) by activated factor XII (FXIIa). There is a feedback between KK and factor XII which amplifies the activation. C1Inh acts as regulating the activation of plasma contact phase and prevents abnormal BK activation [1]. There is some evidence
⁎
for an interaction with the fibrinolytic pathways namely between plasmin and the BK pathway. Plasmin at high concentration has been shown to activate FXII and in case of mutation carriers of FXII, plasmin is even more active to generate FXIIa [2]; recently it was suggested that tissue plasminogen activator (tPA) recruits FXIIa and plasma KK to generate BK. KK can also generate plasmin by direct cleavage of plasminogen or by activating urokinases, which subsequently cleave plasminogen to plasmin [3]. BK binds the kinin B2 receptor (B2R) and thereby increases vascular permeability and smooth muscle relaxation. BK is short-lived being immediately degraded into inactive products by aminopeptidase P, neutral endopeptidase (NEP), dipeptidyl peptidase IV (DPPIV) and angiotensin-converting enzyme (ACE). Estrogens can interact with most of the steps of this cascade. The effects of estrogens can be mediated by classical nuclear genomic actions or through non genomic effects at the membrane level or in the cytoplasm on various kinases [4]. The membranous effects of estradiol (E2) have been especially well described in the endothelium [5]. The membranous effects are extremely rapid when the genomic effects need transcription of several genes. Various sites of transcription activation are targets for the complex E2 and its cognate receptor. Estrogen responsive elements (ERE) are specific whereas, AP1, CREB, SP1, NFκB… can bind other complexes of steroids and their receptors.
Corresponding author at: Université Paris Descartes, Gynécologie, 123 BD Du Port Royal, 75014 Paris, France. E-mail address: [email protected] (A. Gompel).
https://doi.org/10.1016/j.intimp.2019.106080 Received 4 July 2019; Received in revised form 17 November 2019; Accepted 23 November 2019 1567-5769/ © 2019 Elsevier B.V. All rights reserved.
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derived from testosterone modified in its structure by deleting a methyl group to become progestogenic. Among the norsteroids, the first generation contained norethisterone/norethindrone derivatives used at mg/pill. The second generation pills contain norgestrel/levonorgestrel which is used at hundreds µg. The third generation is composed of three progestins, desogestrel, a prodrug converted into 3ceto-desogestrel (or etonogestrel) to be active, gestodene and norgestimate also a prodrug partially converted to norgestrel. These progestins are used at doses around a hundred µg, being more antigonadotropic than the second and first generation ones. The combination of EE with the second generation, LNG, and norgestimate are the less associated with thrombosis [25]. Other classes of progestin are also used in combination with EE. Some belongs to the pregnane group such as chlormadinone acetate and cyproterone acetate. Cyproterone acetate is also a potent antiandrogen. Thus the combination with EE generates the most estrogenic pill and as a consequence the higher risk of VTE [26]. Chlormadinone acetate is associated with EE at a rather low dose and has no androgenic potency. There is less information on VTE but its effect on hemostasis and its pharmacological profile are likely to be associated with a higher risk of VTE than second generation pills [27]. Other combinations have been developed containing a spironolactone derivative, drospirenone. Drospirenone, like spironolactone has some mild antiandrogenic and antimineralocorticoid properties. Thus the combinations of EE with it generates also more procoagulant profiles than second generation pills. The last progestin used in contraception is dienogest, in combination with E2. Dienogest a mixed pregnane and norsteroid and has some antiandrogenic properties. A Patch containing EE and norelgestromin (a metabolite of norgestimate) was associated with an increased risk of VTE 2 folds above the risk with a norgestimate containing pills [28], supported by the finding that this system provides 60% more total estrogen than oral contraceptives containing 30 µg of ethinyl estradiol and increases more the synthesis of SHBG, a marker of estrogenicity at the hepatic level [29,30]. The ring is composed of EE and etonogestrel and is less associated to activation of coagulation compared to the patch [31]. Most of women with HAE are facing aggravation of the disease if using CO. For Bork et al. [32], this aggravation occurs in about 60% of women with C1Inh deficiency or nC1Inh and in a multicentric European study on women with C1Inh deficiency, Bouillet et al.[33] reported a 80% worsening in attacks using CO. In our own series of patients, 67.4% worsened using CO [34]. But it is also meaning that 20–40% of women may tolerate a CO. We do not know the composition of pills used by these patients who tolerated CO. It is logical to use as a first line a progestin for a hormonal contraception (see next paragraph) but if a CO is considered, a second generation pill, or a pill containing E2 + nomegestrol acetate should be chosen preferentially and we advise the exclusion of a combination containing any pregnane, drospirenone or dienogest. Patch and ring should also not be used.
Estrogens were reported to decrease C1Inh levels, during pregnancy and using contraceptive pill, but there is no ERE on C1Inh promoter which does not exclude a control at the level of transcription but this has never been demonstrated [6–10]. At the opposite, FXII contains 7ERE which can contribute to activate FXII [11]. An increased level of factor XII (FXII) was reported in plasma from users of oral contraceptive in functional as well as in immunological assays as well as an increase in BK production [12]. BK mediates relaxation through the release of nitric oxide. E2 is a potent regulator for the release of NO contributing to vascular vasodilatation [13]. This effect is mediated by the E2 membrane receptor in the caveloae [14]. It was however suggested that E2 may also have a positive effect on relaxation independently from NO [15]. Most of kallikreins are regulated by steroids including androgens and estrogens [16]. Potential EREs have been reported in the proximal promoter of rat KLK1 but their functionality not studied [16]. E2 can also enhance the HMWK cleavage [17]. In addition, we demonstrated that oral E2 was associated with an increase in plasminogen [18]. And last but not least, B2R is also a potential target for E2 which increases B2R expression and function [19]. These interactions of E2 with the BK cascade are contributing to increase the production of BK and its utilization. In addition, E2 can decrease the degradation of BK by interacting with the angiotensin converting enzyme activity. It was shown in animals and humans that chronic menopause treatment inhibits angiotensin converting enzyme activity [20]. Furthermore, only oral estrogen was associated to increase in BK concentration whereas transdermal estradiol treatment was associated with a decrease in BK [21,22]. Other steroids are also potential regulators of the BK cascade but less studied. Androgens upregulate the level of C1Inh. An Androgen Responsive Element was identified in the promoter of C1Inh. This is the basis of use of attenuated androgens in patients with C1Inh deficiency. Androgens are potent regulators of kallikrein in the prostate and some breast cancer cells [16]. But there are no data on their effect on the plasma kallikrein. Progesterone/progestins are also regulators of tissue kallikreins in breast cancer cells and endometrium [16]. A potential Progesterone Responsive Element can be present in the promoter of some of the tissue kallikreins. Aminopeptidase expression was shown to be increased by progesterone in hepatocytes in one publication [23]. Exogenous hormones can be used in various conditions in men and women. Contraception is the first condition. 3. Hormonal contraception 3.1. Combined estrogen-progestin contraception (CO) The most used hormonal contraception is a combination of estrogen and progestin. They can be administered either by oral route, by vaginal ring or patch. Most of the oral pills contain ethinylestradiol (EE) which is a synthetic estrogen with potent estrogenic activity. EE has a long half-life and is accumulated in hepatic microsomes. This can probably impact the synthesis of C1Inh. Two contraceptives were developed with estradiol or an estradiol ester. These pills have the same impact (the one containing dienogest) or a better profile (the one containing nomegestrol acetate) on coagulation than a second generation pill [24]. The coagulation activation reflects the estrogenic activity at the hepatic level and could potentially makes a difference in HAE symptoms but this has not been studied… The progestin contained in combination with the estrogen can belongs to different pharmacologic groups. The composition of the pill impacts the risk of venous thrombosis (VTE) by differentially activating the coagulation and fibrinolysis. It is shown that the balance estrogen/androgen potency at the hepatic level is associated with different level of coagulation activation. The higher the estrogen potency, the lower the androgenic potency, the higher the risk of VTE. Most progestins are normethyltestosterone (norsteroids) derivatives. They all have some androgenic potencies
3.2. Progestin Progestins are non-selective steroids (Table 1). As reminded above, some are normethyl testosterone derivatives (norsteroid) and some are synthetized from 17hydroxyprogesterone (pregnane). A smaller group is constituted by the nor-pregnane (Table 1). They all by definition bind and transactivate the progesterone receptor (PR) but some of them also can bind AR, MR, GR. And most of the norsteroids (norethisterone derivatives, tibolone) have some metabolites with a weak estrogen potency. Some of the progestins are androgen receptor (AR) agonists such as the norsteroids and medroxyprogesterone acetate, some others are AR antagonists as cyproterone acetate, dienogest, drospirenone. The latter should be avoided in women with HAE whereas, progestin with androgenic potencies can be beneficial in these women. Table 1 presents the various molecules and their potencies.
2
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antigonadotropic effect does not allowed any follicular growth and thus any endogenous secretion of estrogen from the ovary, whereas at doses provided in the progestin only pill desogestrel 75 µg/day, levonorgestrel 30 µg/day or norethisterone/norethindrone 350 µg /day they can have only a partial antigonadotropic effect which opposes the preovulatory LH peak and thus can be associated with the abnormal growth of a follicle which produces high amount of estradiol. According to the molecule used and the woman (metabolization may vary), these contraceptives can be associated with normal cycles, low estrogenic environment and amenorrhea or functional cysts of the ovary with high levels of circulating E2. Desogestrel is more antigonadotropic than the two others. Close to the oral POP, the contraceptive implants avoid the problems of compliance and increase the biodisponibility and thus the contraceptive efficacy. There are two kinds of implants: one composed of levonorgestrel (Norplant®) and the other one of etonogestrel (Nexplanon®). They can also be associated with an increase in E2 plasmatic levels by the same mechanisms than described above for oral POP Drospirenone alone as a contraceptive administered orally at the dose of 4 mg/day, 24 days of active treatment and 4 days of placebo has been recently approved by FDA (June 2019). There is not any experience in women with HAE. Its mild antiandrogenic activity may potentially induced some attacks. One of the potential side effect is hyperkaliemia by its mild antimineralocorticoid activity. Progestin can also be delivered by an intra uterine device (IUD). There are at several IUDs containing levonorgestrel available. Mirena® and Liletta®, contain the highest amount of levonorgestrel (52 mg) whereas Jaydess® and Skyla® contain 13.5 mg and Kyleena® 19.2 mg of levonorgestrel. The gynecological and systemic tolerances vary from one woman to another. Functional ovarian cysts occur in 25% of cycles with Mirena® and about 10% with the low dose IUDs [35]. The predominant side effects of progestin contraception are spotting and breakthrough bleeding. Some women will put on weight. Some can have a loss of libido. Then the contraception has to be adapted to the clinical tolerance and can be modified. The same for the efficacy on HAE symptoms. We show in a study performed in women with HAE that progestin contraception was potentially of benefits on AE attacks [34]. The most antigonadotropic they are the more benefit women will get on their attacks frequency [34]. We can thus advise to use as a first line
Table 1 classification of progestogen and their potencies. Progestin
Anti Gonadot ropic
ER-
ER+
AR+
AR-
GR+
Anti-MR
P
+
+
–
–
+
+
Dydrogesterone – Pregnanes Chlormadinone Ac + Cyproterone Ac + Megestrol Ac + MPA + Medrogestone + norpregnanes Nomegestrol Ac + Promegestone + Trimegestone + Nestorone norsteroids Norethisteron* + Lynestrenol* + Norethynodrel* + Levonorgestrel + Norgestimate + 3 ceto-desogestrel + (etonogestrel) Gestodene + Tibolone metabolites Dienogest$ + Spironolactone derivative Drospirenone +
+
–
–
(+)
+ (in vitro) –
+ + + + +
– – – – –
(+) – (+) + –
– ++ – – –
+ + + ++ –
– – – – –
+ + + +
– – – –
– – – –
– – (+) –
– + – –
– – (+)
+ + (+) + + +
+ + + – – –
+ + (+) + + +
– – – – – –
– – – – – –
– – – – – –
+ +
– +
+ ++
– –
+ –
+ –
(+)
(+)
–
+
–
–
+
–
–
+
–
+
–
*Potent antiestrogen, antigonadotropic and mild androgen if used at high doses. $ mixed pregnane and norsteroid. ER: estradiol receptor, PR:progesterone receptor, AR: androgen receptor, GR:glucocorticoid receptor, MR:mineralocorticoid receptor.
3.2.1. Contraception Table 2 presents the molecules and brand names used as contraceptives or in menopause treatment. Norsteroids when used at high doses (10 mg/day) are potent antigonadotropic and androgenic whereas when used at low doses these effects are mild. At high dose, the
Table 2 names of progestogen and their principal indication (in addition to contraception and menopause treatment they can be used for menstrual cycle abnormalities). Class
Molecule
Brand name and doses
Indication doses
Progesterone
micronised Progesterone
menopause
Progesterone Isomer pregnanes
Dydrogesterone
Utrogestan® 100, 200 mg Prometrium® Duphaston® 10 mg
Medrogestone
Colprone® 5 mg
chlormadinone Ac., Medroxyprogesterone Ac. (MPA), Cyproterone Ac.
Luteran 5, 10 mg Injectable : 250 mg Oral : 2.5 mg, 5 mg 50 mg,100 mg
norpregnane
Nomegestrol Ac.
Lutenyl® 5 and 3.75 mg
norsteroides (estranes) 1st generation
Norethisterone Ac Norethisterone Norethindrone Lynestrenol Levonorgestrel
Primolut Nor®, Norluten® Norlutate® Norlutin®, Orgametril® Milligynon® Exluton®
Contraception 10 mg Menopause 5/10 mg Contraception 10 mg Menopause 5/10 mg Contraception Menopause Hirsutism/transexual Prostate cancer Contraception 5 mg Menopause 3.75 mg Contraception 10 mg, 10 mg/5mg/ 10 mg 600µg£/500µg£1
Norsteroides (gonanes) 2nd generation Norsteroide (gonane) 3rd generation Spironolactone derivative £
Menopause 10 mg
3 ceto-Desogestrel (Etonogestrel)
Microval® Norplant ® Jadelle®, Sino-implant® Cerazette® Nexplanon®
Contraception oral 30µg£, Implant 6x36 mg Contraception oral 75 µg, Implant 68 mg
Drospirenone
Slynd®
Contraception oral 4 mg*
low dose progestin contraception «POP»
1
no more available * just approved by FDA (June 2019). 3
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spironolactone, at least when starting the treatment combined with a progestin can be in some patients tolerated. The prescription of cyproterone acetate can induce attacks [37,38]. Nevertheless, under stringent evaluation, some women can tolerate it (personal experience) maybe because it provides a low estrogenic environment.
chlormadinone acetate, lynestrenol, norethisterone, norethisterone acetate at high dose, nomegestrol acetate if available or injectable MPA. For oral preparations, they can be prescribed either continuously or sequentially (20 days/27) according to the tolerance and efficacy on the attacks. Norsteroids at high doses have the same contraindications metabolic and vascular than CO. The less antigonadotropic agents are desogestrel, low dose norethisterone and levonorgestrel, the implants and levonorgestrel IUDs. In our study, 60% of women who used a POP or equivalent (implant or Mirena®) observed a benefit on their attacks whereas the proportion was above 80% with the most potent progestins [34]. As an illustration of the benefits observed with progestin, the French recommendations of HAE management propose progestin as a first line for prophylactic long term treatment in women with HAE [36]. Progestins are better tolerated than danazol, at low cost and providing a contraception in addition to their efficacy on attacks.
5. Assisted reproductive technology (ART) The aim in ART is to stimulate the ovaries by FSH in order to retrieve a high number of oocytes. This aim is obtained by initially using a GnRH agonist administered either from the middle of the previous menstrual cycle and for usually 3 weeks (long treatment) or initiate the GnRH analog at the very beginning of the menstrual cycle for a shorter period (short protocol). A stimulation by FSH is applied to induce the growth of several follicles and the ovarian induction followed by echography and estradiol levels. When several mature follicles are obtained an injection of recombinant LH is performed and the oocytes retrieval performed. According to the number of embryos obtained, some can be frozen and usually two embryos are implanted in the next two days. In case of poor responders or if a limitation in the tolerance of estrogen levels due to a specific disease like HAE, GnRH antagonists can be used to monitor the LH peak. Some groups also associate a pretreatment by CO before the stimulation. In women with HAE, prophylaxis by C1INH concentrate can be systematically used or reserved to the time of the retrieval. We would recommend to use protocols including antagonists or implantation of frozen embryos in spontaneous cycles. We report here an unpublished case of a woman with type I HAE extremely severe controlled by danazol but with frequent attacks when she stopped danazol. We performed the stimulation using danazol at 600 mg as the antigonadotropic agent and an antagonist at the time of retrieval. Then 6 embryos were frozen and two implanted after the stop of danazol in a spontaneous cycle where she received a prophylaxis by C1Inh concentrate. She delivered a healthy son in the following pregnancy. The stimulation was remarkably well tolerated under the danazol treatment. Half-life of danazol is evaluated variably in the literature between 9 and 24 h [39,40]. There is no risk of virilisation when taken at the time of conception. We thus propose that in some cases danazol could be an option as an antigonadotropic agent in those patients. A progestin is also an option.
3.2.2. Other indications of progestogens Endometriosis, endometrial hyperplasia, adenomyosis, ovarian functional cysts, mastalgia, premenstrual syndrome, functional bleeding can be indications for the use of progestins. In most cases they can be used as antigonadotropic agent, 20 days/27. In some indications however, a ten day /month treatment by progesterone/dydrogesterone is indicated and then this treatment may be insufficient in women with HAE. This has to be taken into account but if necessary for the HAE management, then there is no contraindication to use the treatment either continuously of 20/27 days/month. 3.3. GnRH agonists (Leuproreline, Triptoreline, Gosereline) 3.3.1. In women There are not considered as contraceptive but as treatment in estrogen dependent diseases. They are the most powerful antigonadotropic agents but their clinical tolerance is limited by climacteric symptoms and potential bone impact. They have no contraindication in women with HAE, and by their effect provides a very low estrogenic environment but cannot be used for long term treatment. 3.3.2. In men: Used in the treatment of prostate cancer (as well as GnRH antagonists, Degarelix) since they act as a chemical castration they can induce attacks by drastically lowering testosterone levels (see below).
6. Breast cancer and hormonotherapy 4. Treatment of hyperandrogenism Breast cancer adjuvant treatment includes a hormonotherapy for cases which are ER positive. In premenopausal women the standard hormonotherapy is tamoxifen (tam) whereas in post-menopausal women, aromatase inhibitors (AI) are the first line. GnRH agonists can be combined in premenopausal women to tamoxifen. Tam is a Selective estrogen receptor modulator. It has partial agonist and antagonist activity on ERα. Tam is developing its estrogen agonist effects in some tissues such as endometrium, liver, bone, due to the tissue specificity of co activators and corepressors. In presence of estrogen it behaves as an antagonist. We described the first case of worsening of the attacks in a postmenopausal woman treated by tam for a breast cancer [41]. Since then 2 other cases were reported, one in a woman with nC1Inh and another one with C1Inh deficiency [42]. We also have seen 2 other cases in premenopausal women treated by tam for breast cancer and in whom was added a GnRH analog, one in a woman with C1Inh deficiency and another in a woman with FXII mutation (unpublished data). Stopping the GnRH analog in these two patients was associated with an improvement of HAE symptoms. These observations highlight the fact that even a mild estrogen like tam may worsen the course of HAE, likely by its hepatic estrogen agonist impact. AI antagonize aromatization of androgens in estrogens and drastically lower estrogens levels in postmenopausal women. They are thus not contraindicated in women with HAE, since they even increase a bit the circulating levels of androgens.
The treatment of clinical hyperandrogenism, hirsutism, acnea and alopecia is usually performed by antiandrogens. To be efficient the treatment has to be antigonadotropic to counteract the ovarian androgen secretion and combined an antiandrogen acting on the hair follicle. The most efficient one is cyproterone acetate since it combines both properties, then CO predominantly estrogenic and then spironolactone which has to be associated to an antigonadotrope. Because of their sensitivity to androgens and estrogens, these treatments can worsen the course of women with HAE. Some alternatives to antiandrogen may exist: Vaniqa® a cream containing Eflronithine chlorhydrate is approved by FDA and EMEA for the treatment of facial hair. It is a non-hormonal treatment acting by antagonizing ornithine decarboxylase, an enzyme involved in the growth of hair. There is no contraindication to the use of this drug. Laser can also be proposed to women with HAE. There is no report of any concern of using this treatment in women with HAE. We should however recommend to get Icatibant available when performing the treatment. For acnea, retinoic acid is efficient and has to be combined with a contraception which can be a progestin. Topical treatments are also available without contraindication in those women. In case where the hyperandrogenism is not solved by the non-hormonal management, a prudent and low dose prescription of 4
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7. Menopause
prostate adenoma discomfort and is an inhibitor of 5α-reductase activity. All these compounds can act by decreasing testosterone activity and thus be associated with worsening of AE course. Transexual males are treated by an antiandrogen such as cyproterone acetate + estradiol up to the time of castration, and thereafter at usually lower doses. This treatment is at high risk for patients with AE.
The menopause transition period is a time of large variation in E2 and the symptoms are usually treated by progestin. This has probably to be taken in account especially in women with HAE. In post-menopausal women the ovarian secretion of estrogen disappears and usually as well the ovarian androgen secretion. Due to the impact of gonadal steroids on HAE course, one can expect that menopause could improve the symptoms. However, in a multicentric study on women with C1Inh deficiency, only 55% improved [33]. We have conducted a study in 62 postmenopausal women and find that about 50% of them improved but 15% worsened and in most of cases with severe symptoms (manuscript submitted). In addition, our study highlights the fact that only few women had a proper management of their climacteric symptoms. In fact there are several options to help those women. Progesterone and progestin can alleviate vasomotor symptoms and progesterone helps for sleep disorders [43,44]. Vaginal estrogens are not contraindicated for women with HAE. They are usually used twice a week and provide a very low systemic level of estrogen [45]. Theoretically, local vulvar or vaginal oedema could occur but so far no such report was made. In our study several women used estradiol and a progestin without worsening of their symptoms. Most but not all used a transdermal E2 treatment. As reported in the first paragraph of this review, a study suggested a decrease in BK production was observed with transdermal E2 and an increase with oral E2 [22]. This has to be certainly confirmed but we know that transdermal route does not provide a high hepatic concentration of E2 contrary to the oral route (first pass hepatic effect). Tibolone has been used with benefit in women with HAE. Tibolone is a weak norsteroid developed for the treatment of climacteric symptoms. Its metabolites have androgenic and progestogenic (Δ4isomer) and mildly estrogenic (3α- and 3β-metabolites) properties. Tibolone (Livial®) was used in 8 women premenopausal (six) and postmenopausal (two) at doses from 2.5 mg (the usual dose for climacteric symptoms) to 7 mg. All the patients improved. However, its use in premenopausal women is not to be recommended since other norsteroids are available which are more potent and validated in premenopausal women. Alternatives to hormone treatment such as serotonin-recapture inhibitors, noradrenaline recapture inhibitors, citalopram, gabapentine, clonidine can be prescribed for women who are symptomatic for their menopause and cannot tolerate hormones (for details see [46]).
9. Danazol and hormone dependent cancers In most hormone dependent cancer, the indication of androgens may be discussed. It is clear that androgen treatment is contraindicated in prostate cancer. In breast cancers, the situation is more complex. AR is present in most of breast cancer cases and variably associated to the prognosis but not routinely performed. The ER + AR /ER ratio was suggested to be an indicator of prognosis if high [47]. Triple negative BC can belong to an AR group which is resistant to chemotherapy….The AR expression can be discordant between primary tumor and metastasis [47]. It is thus unpredictable the action of an androgen in this disease, and the use of attenuated androgens has to be stringently evaluated with the oncologist. Eigty five percent of endometrial cancer are estrogen dependent. Progestogens and androgens are not contraindicated. In most of cases of ovarian cancer, the treatment includes an oophorectomy. In some cases, a conservative treatment may be indicated. Progestins are contraindicated in low grade serous cancer but can be used in all other differentiation [48]. Up to recently there were no data on androgen and ovarian cancer. A recent publication suggests that androgens could be in some cases a deleterious agent in ovarian cancer [49]. Cervical cancers are predominantly squamous cell carcinoma. This cancer is not hormone dependent. About 10% of cervical cancers are adenocarcinoma considered as estrogen dependent. There is no contraindication to danazol or progestin such as for endometrial cancer. 10. Conclusions The exquisite sensitivity to estrogens and to a low androgen environment has to be taken in account during lifetime in patients with HAE. Those patients may be exposed to clinical situation which needs the expert in charge of their management to be perfectly aware of the potential benefit/risk balance of any hormonal treatment. This review will hopefully contribute to help the choices in these situations. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors
8. Antiandrogen in male The physiological predominant hormone in men is testosterone. It was reported that men with hypogonadism have increase in their attacks whereas the androgen treatment reversed the figure [38]. Various treatments are used in men as antiandrogens: there are indicated for the treatment of prostate cancer or adenoma. Prostate cancers are treated by chemical castration using GnRH analogs (or antagonists) or surgical castration and in case of progression by antiandrogens. Several molecules of antiandrogens have been approved by FDA or /and EMEA: Abiraterone acetate (combined with prednisone), Apalutamide, Biclutamide, Cyproterone acetate (100 mg/ pill), Nilutamide, Enzalutamide, Flutamide. They are used as a second line treatment after resistance to castration in a non-metastatic or metastatic context. Finasteride (5 mg/day) and dutasteride (0.5 mg/day) are the two approved 5α-reductase inhibitors used for the treatment of prostate adenoma. Finasteride is also indicated as low dose (1 mg/day) for the treatment of alopecia in male (but some used it out of label in women with alopecia). By inhibiting the 5α-reductase activity they decrease the transformation of testosterone into dihydrotestosterone, the androgen with the highest affinity for AR. Serenoa repens (Permixion®) is also used in the treatment of
References [1] A.P. Kaplan, K. Joseph, Pathogenic mechanisms of BK mediated diseases: dysregulation of an innate inflammatory pathway, Adv. Immunol. 121 (2014) 41–89. [2] S. de Maat, J. Björkqvist, C. Suffritti, C.P. Wiesenekker, W. Nagtegaal, A. Koekman, et al., Plasmin is a natural trigger for BK production in patients with hereditary angioedema with factor XII mutations, J. Allergy Clin. Immunol. 138 (5) (2016) 1414–1423.e9. [3] F. Marceau, H. Bachelard, G.-É. Rivard, J. Hébert, Increased fibrinolysis-induced BK formation in hereditary angioedema confirmed using stored plasma and biotechnological inhibitors, BMC Res. Notes 12 (1) (2019) 291. [4] A. Nadal, M. Díaz, M.A. Valverde, The estrogen trinity: membrane, cytosolic, and nuclear effects, News Physiol Sci. Int. J. Physiol. Prod. Jointly Int. Union Physiol. Sci. Am. Physiol. Soc. 16 (2001) 251–255. [5] Guivarc’h E, Buscato M, Guihot A-L, Favre J, Vessières E, Grimaud L, et al. Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety. J. Am. Heart Assoc. 2018 Jun 29;7(13). [6] E.M. Gordon, O.D. Ratnoff, H. Saito, V.H. Donaldson, J. Pensky, P.K. Jones, Rapid fibrinolysis, augmented Hageman factor (factor XII) titers, and decreased C1 esterase inhibitor titers in women taking oral contraceptives, J. Lab. Clin. Med. 96 (5) (1980) 762–769.
5
International Immunopharmacology 78 (2020) 106080
A. Gompel, et al.
[7] E.M. Gordon, S.R. Williams, B. Frenchek, C.A. Mazur, L. Speroff, Dose-dependent effects of postmenopausal estrogen and progestin on antithrombin III and factor XII, J. Lab. Clin. Med. 111 (1) (1988) 52–56. [8] J. Jespersen, C. Kluft, Increased euglobulin fibrinolytic potential in women on oral contraceptives low in oestrogen–levels of extrinsic and intrinsic plasminogen activators, prekallikrein, factor XII, and C1-inactivator, Thromb. Haemost. 54 (2) (1985) 454–459. [9] A. Adam, A. Albert, J. Boulanger, D. Genot, A. Demoulin, J. Damas, Influence of oral contraceptives and pregnancy on constituents of the kallikrein-kininogen system in plasma, Clin. Chem. 31 (9) (1985) 1533–1536. [10] A.J. Cohen, C. Laskin, S. Tarlo, C1 esterase inhibitor in pregnancy, J. Allergy Clin. Immunol. 90 (3 Pt 1) (1992 Sep) 412–413. [11] A. Farsetti, S. Misiti, F. Citarella, A. Felici, M. Andreoli, A. Fantoni, et al., Molecular basis of estrogen regulation of Hageman factor XII gene expression, Endocrinology 136 (11) (1995) 5076–5083. [12] N.O. Hoem, S. Johannesen, G. Hauge, A.C. Rud, S. Sandem, K. Briseid, Contact activation factors in plasma from women using oral contraceptives–increased levels of factor XII, kinin-free high molecular weight kininogen and acetone-activated kallikrein, Thromb. Res. 64 (4) (1991) 427–434. [13] K. Tarhouni, A.L. Guihot, E. Vessieres, V. Procaccio, L. Grimaud, P. Abraham, et al., Estrogens are needed for the improvement in endothelium-mediated dilation induced by a chronic increase in blood flow in rat mesenteric arteries, Vasc.Pharmacol. 80 (2016) 35–42. [14] K.L. Chambliss, I.S. Yuhanna, C. Mineo, P. Liu, Z. German, T.S. Sherman, et al., Estrogen receptor alpha and endothelial nitric oxide synthase are organized into a functional signaling module in caveolae, Circ. Res. 87 (11) (2000) E44–E52. [15] M. Barton, J. Cremer, A. Mügge, 17Beta-estradiol acutely improves endotheliumdependent relaxation to BK in isolated human coronary arteries, Eur. J. Pharmacol. 362 (1) (1998) 73–76. [16] M.G. Lawrence, J. Lai, J.A. Clements, Kallikreins on steroids: structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus, Endocr. Rev. 31 (4) (2010) 407–446. [17] K. Joseph, B.G. Tholanikunnel, A.P. Kaplan, Cytokine and estrogen stimulation of endothelial cells augments activation of the prekallikrein-high molecular weight kininogen complex: Implications for hereditary angioedema, J. Allergy Clin. Immunol. 140 (1) (2017) 170–176. [18] J. Conard, A. Gompel, C. Pelissier, C. Mirabel, A. Basdevant, Fibrinogen and plasminogen modifications during oral estradiol replacement therapy, Fertil. Steril. 68 (3) (1997) 449–453. [19] P. Madeddu, C. Emanueli, Q. Song, M.V. Varoni, M.P. Demontis, V. Anania, et al., Regulation of BK B2-receptor expression by oestrogen, Br. J. Pharmacol. 121 (8) (1997) 1763–1769. [20] N. Nogawa, H. Sumino, S. Ichikawa, H. Kumakura, Y. Takayama, T. Nakamura, et al., Effect of long-term hormone replacement therapy on angiotensin-converting enzyme activity and BK in postmenopausal women with essential hypertension and normotensive postmenopausal women, Menopause N Y N. 8 (3) (2001) 210–215. [21] A. Ichikawa, H. Sumino, T. Ogawa, S. Ichikawa, K. Nitta, Effects of long-term transdermal hormone replacement therapy on the renin-angiotensin- aldosterone system, plasma BK levels and blood pressure in normotensive postmenopausal women, Geriatr Gerontol Int. 8 (4) (2008) 259–264. [22] J. Ichikawa, H. Sumino, S. Ichikawa, M. Ozaki, Different effects of transdermal and oral hormone replacement therapy on the renin-angiotensin system, plasma BK level, and blood pressure of normotensive postmenopausal women, Am. J. Hypertens. 19 (7) (2006) 744–749. [23] A.L. Cilia La Corte, A.M. Carter, A.J. Turner, P.J. Grant, N.M. Hooper, The BKdegrading aminopeptidase P is increased in women taking the oral contraceptive pill, J. Renin-Angiotensin-Aldosterone Syst. JRAAS 9 (4) (2008) 221–225. [24] I. Lete, N. Chabbert-Buffet, C. Jamin, S. Lello, P. Lobo, R.E. Nappi, et al., Haemostatic and metabolic impact of estradiol pills and drospirenone-containing ethinylestradiol pills vs. levonorgestrel-containing ethinylestradiol pills: a literature review, Eur. J. Contracept Reprod Health Care Off. J. Eur. Soc. Contracept. 20 (5) (2015) 329–343. [25] B.H. Stegeman, M. de Bastos, F.R. Rosendaal, Vlieg A van Hylckama, F.M. Helmerhorst, T. Stijnen, et al., Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis, BMJ 12 (347) (2013 Sep) f5298. [26] J. Hugon-Rodin, M.-H. Horellou, J. Conard, A. Gompel, G. Plu-Bureau, Type of Combined Contraceptives, Factor V Leiden Mutation and Risk of Venous Thromboembolism, Thromb. Haemost. 118 (5) (2018) 922–928. [27] U.H. Winkler, E. Daume, R. Sudik, C. Oberhoff, U. Bier, C. Hallmann, et al., A comparative study of the hemostatic effects of two monophasic oral contraceptives
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38] [39]
[40]
[41]
[42]
[43] [44]
[45]
[46]
[47]
[48]
[49]
6
containing 30 mu(g) ethinylestradiol and either 2 mg chlormadinone acetate or 150 mu(g) desogestrel, Eur. J. Contracept Reprod Health Care Off. J. Eur. Soc. Contracept. 4 (3) (1999) 145–154. D.D. Dore, H. Norman, J. Loughlin, J.D. Seeger, Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users, Contraception. 81 (5) (2010) 408–413. D. Devineni, D. Skee, N. Vaccaro, J. Massarella, L. Janssens, K.D. LaGuardia, et al., Pharmacokinetics and pharmacodynamics of a transdermal contraceptive patch and an oral contraceptive, J. Clin. Pharmacol. 47 (4) (2007) 497–509. M.W. van den Heuvel, A.J.M. van Bragt, A.K.M. Alnabawy, M.C.J. Kaptein, Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive, Contraception. 72 (3) (2005) 168–174. J. Hugon-Rodin, A. Gompel, G. Plu-Bureau, Epidemiology of hormonal contraceptives-related venous thromboembolism, Eur. J. Endocrinol. 171 (6) (2014) R221–R230. K. Bork, B. Fischer, G. Dewald, Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy, Am. J. Med. 114 (4) (2003) 294–298. 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(5):484.e1-4. C. Saule, I. Boccon-Gibod, O. Fain, G. Kanny, G. Plu-Bureau, L. Martin, et al., Benefits of progestin contraception in non-allergic angioedema, Clin. Exp. Allergy J. Br. Soc. Allergy Clin. Immunol. 43 (4) (2013) 475–482. Haute Autorité de Santé - KYLEENA (lévonorgestrel), dispositif intra-utérin avec progestatif. available from: https://www.has-sante.fr/portail/jcms/c_2824470/fr/ kyleena-levonorgestrel-dispositif-intra-uterin-avec-progestatif. L. Bouillet, A. Lehmann, A. Gompel, I. Boccon-Gibod, D. Launay, O. Fain, et al., [Hereditary angiœdema treatments: recommendations from the French national center for angiœdema (Bordeaux consensus 2014)], Presse Medicale Paris Fr 44 (5) (1983) 526–532. Jamin C, Intrator L, Laurent J, Lagrue G. [Cyproterone acetate is not effective in the prevention of hereditary angioneurotic edema]. Presse Medicale Paris Fr. 1983. 1985 Sep 7;14(29):1559–60. W.J. Pichler, R. Lehner, P.J. Späth, Recurrent angioedema associated with hypogonadism or anti-androgen therapy, Ann Allergy 63 (4) (1989) 301–305. W.D. Hooper, M.J. Eadie, R.G. Dickinson, Single oral dose pharmacokinetics and comparative bioavailability of danazol in humans, Biopharm. Drug Dispos. 12 (8) (1991 Nov) 577–582. K. Selinger, H.M. Hill, J.A. Anslow, D. Gash, A liquid chromatographic method for the determination of danazol in human serum, J. Pharm. Biomed. Anal. 8 (1) (1990) 79–84. C. Rousset-Jablonski, J.-C. Thalabard, A. Gompel, Tamoxifen contraindicated in women with hereditary angioedema? Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 20 (7) (2009) 1281–1282. K. Bork, K. Wulff, G. Witzke, S. Rietz, J. Hardt, Tamoxifen may cause life-threatening angioedema attacks in patients with hereditary angioedema, J. Eur. Acad Dermatol. Venereol. JEADV 31 (5) (2017) e237–e239. J.C. Prior, Progesterone for treatment of symptomatic menopausal women, Climacteric J. Int. Menopause Soc. 21 (4) (2018) 358–365. C.L. Loprinzi, R. Levitt, D. Barton, J.A. Sloan, S.R. Dakhil, D.A. Nikcevich, et al., Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: north central cancer treatment group trial N99C7, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 24 (9) (2006) 1409–1414. C.A. Stuenkel, S.R. Davis, A. Gompel, M.A. Lumsden, M.H. Murad, J.V. Pinkerton, et al., Treatment of symptoms of the menopause: an endocrine society clinical practice guideline, J. Clin. Endocrinol. Metab. 100 (11) (2015) 3975–4011. R.J. Santen, C.A. Stuenkel, S.R. Davis, J.V. Pinkerton, A. Gompel, M.A. Lumsden, Managing Menopausal Symptoms and Associated Clinical Issues in Breast Cancer Survivors, J. Clin. Endocrinol. Metab. 102 (10) (2017) 3647–3661. S. Salvi, M. Bonafè, S. Bravaccini, Androgen receptor in breast cancer: A wolf in sheep’s clothing? A lesson from prostate cancer. Semin. Cancer Biol. 2019 Apr 16; Epud Head of publication. C. Rousset-Jablonski, F. Selle, E. Adda-Herzog, F. Planchamp, L. Selleret, C. Pomel, et al., Fertility preservation, contraception and menopause hormone therapy in women treated for rare ovarian tumours: guidelines from the French national network dedicated to rare gynaecological cancers, Eur. J. Cancer Oxf. Engl. 3 (116) (1990) 35–44. T. Mizushima, H. Miyamoto, The Role of Androgen Receptor Signaling in Ovarian Cancer. Cells. 2019 Feb 19;8(2). Epud Head of publication.