Article in press - uncorrected proof Horm Mol Biol Clin Invest 2010;3(3):441–447 2010 by Walter de Gruyter • Berlin • New York. DOI 10.1515/HMBCI.2010.062
Antigonadotropic progestogens as contraceptive agents in women with contraindication to combined pill
Lorraine Maitrot-Mantelet, Anahid Agopian and Anne Gompel*
Introduction
Unit of Gynecological Endocrinology, Hoˆtel-Dieu Hospital, Paris Descartes University, INSERM UMRS 938, Paris, France
Progestogen at low doses, also called the progestogen only pill (POP), is the standard hormonal contraception for women who cannot use the combined estrogen contraceptive (COC) pill for vascular or metabolic reasons (1). Because of their limited tolerance and thus their limited compliance, alternatives could be profitable. In addition, some of these women develop estrogen-dependent disease which can necessitate antigonadotropic treatments. So far in most countries, only gonadotropin-releasing hormone (GnRH) agonists are used in these cases for a limited time and with possible important side effects (2). According to the World Health Organization (WHO) recommendations (3), women with a personal history of venous thrombosis, with arterial thrombosis or ischemic cardiovascular diseases, antiphospholipid antibodies (aPLs), migraines with aura are situations to contraindicate COC. Autoimmune diseases such as systemic lupus erythematosus (SLE) can also be associated with an increased risk of thrombosis but were not classified as grade 4 for contraindication (CI) in the WHO recommendations (3). Some diseases such as diabetes, hypercholesterolemia and hypertension are also associated with relative or absolute contraindications because of an increase risk in arterial events. In addition, contraindications could be due to a history of hormone-dependent cancer. In this paper, we will address the use of antigonadotropic progestogens in women with SLE/aPLs, venous thrombosis/ thrombophilia and hereditary angioedema (HAE).
Abstract Synthetic progestogens belong to different pharmacological classes and are mixed steroids. They display different properties due to their various affinities to the different steroid receptors. In addition, the dosage used can modify their side effects. Normethyltestosterone used at minimal doses, also called progestogen only pill (POP), constitute the standard recommended hormonal contraception for women with vascular and metabolic contraindications to combined pill (COC). However, POP efficacy and gynecological tolerance are limited. We have developed for more than 20 years in France the use of two pregnane derivatives as contraceptive agents in women with contraindication to COC. Chlormadinone acetate and cyproterone acetate have different antigonadotropic potencies but remain neutral on vascular risk. We have analyzed the efficacy, vascular and gynecological tolerances in 187 women with systemic lupus erythematous with or without antiphospholipids. Venous thrombosis and arterial events rates were lower than those reported in the literature. The current experience in women with thrombophilia is similar as reported in a series of 150 patients. In addition, we have also used antigonadotropic progestins in women with hereditary angioedema (HAE) types I, II or III. HAE symptoms can be induced or worsened by COC. We could demonstrate a significant improvement of the symptoms in most women with HAE under antigonadotropic progestins. Gynecological and general tolerances were satisfactory. In conclusion, antigonadotropic progestins could have clinical positive benefits as contraceptive agents in women with contraindication to COC. Keywords: antigonadotropic progestogen; deep venous thrombosis; estrogen-dependent diseases; hereditary angioedema; systemic lupus erythematous.
*Corresponding author: Anne Gompel, Gynecological Endocrinology Unit, Hotel Dieu de Paris, 1 Place du Parvis Notre-Dame, 75004 Paris, France Phone: q33-1-42348768, Fax: q33-1-43298766, E-mail: [email protected] Received October 29, 2010; accepted November 3, 2010
Progestogens in contraception: benefits and limits
Different classes and dosages of progestogens are used as contraceptives. 19 Normethyltestosterone derivatives
The 19 normethyltestosterone derivatives can be used at high doses (10 mg/day). At these dosages, they are potent antigonadotropic agents and antiestrogenic. However, they are also associated potentially with an increase in thrombosis (4) and metabolic disorders. In addition, they can display androgenicity and weight gain due to their androgenic/anabolic properties. The androgenicity can be useful, however, in some estrogen-dependent diseases which can indicate it, such as HAE (5). In this disease, danatrol is a potent treatment but norsteroids can be in some cases an efficient contraception with positive effect on the attacks (A. Gompel, personal data). Similarly in estrogen-dependent diseases, such as
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benign breast diseases and endometriosis, they can be of some help in the absence of contraindication. The 19 normethyltestosterone derivatives can also be used at lower doses (approximately 20-fold less) as POP. At these dosages, they are the referent contraception for women with metabolic and vascular risk. In a recent meta-analysis that we performed on POP and stroke (6), no increase in the risk under POP and medroxyprogesterone acetate (MPA) was reported (without distinction in some studies which have mixed ‘‘progestogen contraceptives’’). A similar meta-analysis on myocardial infarction also showed no increase in the risk with POP (manuscript submitted). However, there is not so much information in women with high vascular risk, whether venous or arterial. The major problem with POP is the poor gynecological tolerance. In a randomized controlled study for the commercialization of Ce´razette, 1300 women were randomized between norgestrel (ns331) and desogestrel minipills (ns989), discontinuation rate at 13 months was 45% in the desogestrel- and 39.5% in the norgestrel-treated women (7). In addition, in 20% of the cycles, an increase in estrogen production and a functional ovarian cyst was observed in another study (8). Implants (Norplant and Implanon) have similar limited clinical tolerance than POP (9). They offer the advantage of higher efficacy because there is no failure due to compliance (10). Mirena is an interesting contraceptive in women with menorrhagia or endometriosis. However, it can also be associated with side effects (acne, weight gain and metrorrhagia) and a small increase in functional ovarian cyst occurrence (11). We have reported dramatic hemoperitoneum in the context of a huge increase of the international normalized ratio (INR) in women treated with anticoagulants for aPLs (12). In some patients either a rupture of luteal cysts or functional cysts was observed (12). This suggests that contraceptive agents which are associated with persistent ovulation or increase in functional cysts (POP, implants, Mirena) can potentially expose the risk of complication in women with a high INR such as women with aPLs. Pregnane derivatives
The most frequently used pregnane derivatives in contraception is depo-MPA. Recently, its use was associated with a significant increase in the risk of deep venous thrombosis (DVT) (13). MPA is a synthetic progestin with relatively important glucocorticoid and androgenic activities (14). These properties can probably explain the increase in the relative risk of DVT observed in this study. Two other pregnane derivatives have been developed in France and have been used for a long time in women with vascular risks. Chlormadinone acetate (CMA) was initially used in women with renal failure and hemodialysis with a good clinical tolerance and no evidence of hypertensive effects. At the same time, we began to use it in women with SLE on the basis of neutral effect on surrogate markers (15). Subsequently, it was also used in women with contraindication to COC and particularly in women with thrombosis and SLE (16, 17). It is a progestin considered to have mild antiandro-
gen and glucocorticoid properties, but the evidence for these potencies are limited; it is devoid of any estrogen activity (18, 19). It has mild antigonadotropic effect (20). The development of the dominant follicle is antagonized but in most patients a small amount of estradiol persists. CMA is usually prescribed at 10 mg/day, 21 days/28. It can be associated with topical estrogens in the case of vaginal dryness. Cyproterone acetate (CPA) is usually prescribed for the treatment of hyperandrogenemia (21). It is a potent antigonadotropic agent and also a potent antiandrogen with moderate glucocorticoid activity and no estrogen activity (18, 19, 22). It has been shown to have a safe profile on the vascular risk markers. It is usually combined with estradiol either orally in women without specific risk in the treatment of hirsutism or transdermal in other women. It has been used for many years in France in women with SLE with satisfactory clinical tolerance (16, 23). In this regard, usually, systemic estradiol is not combined but topical estrogens can be associated (16, 17). We will thus report our experience with the use of these pregnane progestogens in women with SLE and thrombosis, particularly addressing the gynecological tolerance of these compounds.
Systemic lupus erythematous (SLE) SLE is a multisystem autoimmune estrogen sensitive disease that primarily affects women of child-bearing age (24). Systemic SLE has a female/male ratio of 2:1 before puberty and 9:1 between puberty and menopause. Its etiopathogenesis is complex and involves genetic factors and individual susceptibility to environmental factors (24). The role of estrogens in SLE activity is suggested by various arguments: estradiol enhances autoimmunity, whereas testosterone and progesterone are suppressors (24). The deleterious effect of estrogen in SLE has been well studied in experimental animal models, NZB/NZW and MRL/lpr mice (25). The severity of SLE flares can be life-threatening and the deleterious effect of pregnancy on the disease course is well established, especially in the case of kidney involvement (23). Thus, effective contraception is crucial in these patients but remains the object of debate (26). The use of ethinylestradiol containing contraceptive pills in SLE patients is controversial because estrogens can worsen the course, increasing the incidence and severity of the disease (27, 28). Furthermore, the risk of arterial and venous thrombosis is increased both in SLE patients without any hormonal therapy (29, 30) and in healthy women under COC (31–33). Two randomized controlled trials have recently challenged these negative data on COC in women with SLE. A trial by the Sanchez-Guerrero group (34) excluded patients with a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) )30, i.e., very severe lupus, and the SELENA trial (35) excluded patients with a high aPL level. In the latter study, lupus activity was low in most of the patients (mean
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SLEDAI scores3). However, in a recent study conducted in active SLE patients, the rate of flares, including one death, could lead one to remain prudent for the widespread use of COC in women with active SLE or with aPLs or unknown conditions for it (28). The poor compliance observed in some studies with POP suggests the need for other contraceptive methods. Julkunen et al., in a study of 82 women with SLE, recorded 32 cases using low dose POP and found that 78% of them discontinued POP within 18 months because of abnormal bleeding (36). The use of copper intrauterine devices (IUDs) is frequently challenged in SLE patients due to the potential risk of infection soon after insertion (37). The levonorgestrel-releasing intrauterine system which can carry a lower risk for infection (38) has been only recently easily available on the French market. It might be an interesting alternative but also has some limitations of tolerance including an increase in functional cysts compared to copper IUD (11, 39). In such specific medical conditions, pregnane progestogen (PP) seems to offer convenient alternatives. Our group recently published a cohort study reporting on our experience of the use of CMA and CPA for contraception in SLE women (40). In this prospective study, 187 consecutive premenopausal SLE women requesting contraception and willing to use hormonal contraception were followed in the Gynecology Unit of the Hoˆtel-Dieu Hospital. Patients received either CPA (50 mg tablets once daily orally for 20 days/27) or CMA (10 mg tablets daily orally for 21 days/28) for contraception. The choice between CPA and CMA was made according to the SLE disease activity level. Based on the hypothesis that a hypoestrogenic environment could have a beneficial effect on the course of SLE (24), patients received CPA within the year following a flare, if there was an increase of prednisone dose G30 mg/day or in the case of poor CMA tolerability. Patients were allocated CMA if it had been more than 1 year since last flare or in the case of poor CPA tolerability. As CPA has stronger antigonadotropic action than CMA, CMA was first prescribed in moderately active or quiescent SLE patients. We followed 187 patients during a total of 6854 months, 2942 cycles and 3912 cycles for CPA and CMA, respectively. Approximately, one-third of the patients had detectable aPLs and/or anticardiolipin antibodies (aCLs). The incidence of DVT prior to the progestogen contraception was 22.8/1000 women/year (95% confidence interval, CI: 12.5–32.04). The arterial and venous vascular tolerance appeared to be excellent in the study. The overall incidence of DVT during pregnane treatment was more than ten times less than before (40). No DVT occurred during CMA use. The incidence of macroarterial disease prior to progestogens was 10.02/1000 women/year (95% CI: 3.47–16.57). The overall incidence of macroarterial disease under PP treatment was also lower than before PP. These arterial events were one case of myocardial infarction in a 48-year-old patient with multiple risk factors (smoking, aPLs and obesity) and one case of tibial posterior arterial occlusion (40). The incidence of arterial events in our series was comparable to previous published
data (41). In addition, the incidence of lupus flares decreased significantly (p-0.00001) under progestogens. One of the major side effects of PP is breakthrough bleeding. Weight gain is also possible. In addition, owing to their mode of action, symptoms of hypoestrogenia can develop. Actually, following a systematic questionnaire collecting bleeding, hypoestrogenic symptoms and other side effects every 6 months during the consultation, tolerance in this study appeared to be rather satisfactory. Breakthrough bleeding was reported in less than 18% of the patients under CPA and 12.6% of the patients using CMA (40). Metrorrhagia led to treatment discontinuation in only one patient with CPA and seven with CMA. Only two patients discontinued because of hypoestrogenia using CPA and none with CMA. It is important to note that the contraceptive efficacy was 100% despite that we did not have enough cycles to raise a proper Pearl index. No unscheduled pregnancy occurred during the course of the study which represented a total of 6854 cycles. The PPs have both antigonadotropic activities. CPA is more potent than CMA. However, we advised the women to use a barrier contraception the first month of CPA use because of a progressive antigonadotropic activity as reported in the unpublished data contained in the file which was used for its commercialization. They both also have peripheral contraceptive effects of progestogen, by coagulation of the mucus, endometrial atrophy and decrease in the tubal motility.
Deep venous thrombosis (DVT) and progestin contraception COC use is one of the most common risk factors of DVT among young women and it is associated with an approximate 4-fold risk (31–33). The risk is influenced by many factors such as dose of ethinylestradiol, type of progestin, age and duration of use. COCs affect hemostatic variables and estrogen-sensitive liver proteins. The impact on hemostatic variables could be a disturbance between profibrinolytic and procoagulants effects. Furthermore, COCs with the highest risks of DVT are also associated with the highest levels of sex hormone-binding globulin (SHBG), and SHBG levels are positively associated with resistance to activated protein (42). A recent publication shows that use of MPA is also significantly associated with a higher risk of DVT. In this casecontrol study, the authors found that use of injectable MPA was associated with a 3.6-fold (95% CI: 1.8–7.1) increased risk of DVT compared with non-users of hormonal contraceptives (13). However, use of POP as well as implants and Mirena is not reported to be associated with an increased risk of DVT (13). The association between the use of PP and the risk of DVT has been previously evaluated in a case-control study including 204 women with a personal history of DVT/thrombophilia (43). A total of 102 women using CMA were compared to 102 controls; 44 women in the CMA group and
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58 in the control group had a personal history of thrombophilia. No difference concerning the risk of DVT recurrence was observed between the two groups. There were three DVT recurrences in the CMA group and six in the control group (RRs0.84; 0.18–3.93). In the Gynecology Unit of the Hoˆtel-Dieu Hospital, we have 20 years follow-up experience of women under PP with a personal history of venous thrombosis and/or thrombophilia. Here, we report a study of 203 women with such medical history seen in our Gynecology Department between 1990 and 2000. Among them, 150 patients received PP for more than 6 months; 17 women had taken PP for less than 6 months or were lost to follow-up; 36 patients did not receive any PP (pregnancy project, no need of contraception, menopause). Women under PP received either only CMA (ns97) or only CPA (ns21) combined with transdermal 17b-estradiol except in the case of aPL. A total of 32 patients received both CMA and CPA during the follow-up; four patients initially under CPA were switched to CMA and 10 patients initially under CMA were switched to CPA because of side effects; 18 successively received the two treatments during the follow-up, independently of side effects. These treatments were prescribed for contraception, hyperandrogenemia or estrogen-dependent diseases. The mean ("SE) duration of follow-up was 39.7"41 months under CMA (range: 6–156) and 29"31 months under CPA (range: 6–120). A total of 86 women presented 112 previous histories of DVT (Table 1). It is important to note that this population is characterized by an important amount of severe thromboembolic disease: 29 pulmonary embolisms occurred with more than one episode in four women. Another 12 women presented a previous history of portal thrombosis, five a history of cave thrombosis and five a history of cerebral venous thrombosis (Table 1). In total, 32 women had a thrombophilia (Table 1) such as mutation of Factor V Leiden (ns11), mutation of Factor II (ns7), mutation of Factor IIqV (ns4), deficiency in Pro-
tein C (ns3), deficiency in Protein S (ns5), deficiency of Antithrombin III (ns2). In total, 36 patients had detectable aPLs and/or aCLs. Oral anticoagulants were used in 53 patients (Table 1). DVT recurrences under PP
Eight DVT recurrences occurred in seven patients using PP: three DVT recurrences occurred under CPA and five under CMA. Two women received an anticoagulant therapy when recurrence occurred. The overall incidence of DVT during PP treatment was 14.6/1000 women/year (95% CI: 4.4– 24.6). The incidence of DVT recurrence in our study was comparable to incidence of DVT published in a recent prospective follow-up study of 414 patients with a first objective diagnosis of DVT (44). In this study, the overall incidence rate of DVT recurrence was 15.8/1000 individuals/years in women (95% CI: 10.9–22.1). The rate of idiopathic recurrence in women was 9.3/1000 individuals/years (95% CI: 5.4–14.9), whereas the recurrence rate of DVT among women still using hormonal contraception was 48.8 (95% CI: 24.3–87.2). Gynecological tolerability
Breakthrough bleeding was reported by 10 patients using CMA. Hypoestrogenic symptoms were recorded in six patients using CMA. Hyperandrogenemia was reported by two patients using CMA. Important weight gain was recorded in two patients using CPA. These symptoms were not severe enough to justify treatment discontinuation. In 14 women, side effects were more important and a switch from one progestogen to the other was proposed. In total, 10 patients initially under CMA were switched to CPA: six for hyperandrogenemia, three for bleeding and one for weight gain. Four patients initially under CPA switched to CMA: two for weight gain and two for swelling.
Table 1 Number of previous DVT events and number of DVT recurrences in women receiving PP for more than 6 monthsa. Patients, n Number of patients with thrombophilia, n (%) Presence of aPLs, n (%) Inherited thrombophilia, n (%) Number of patients under oral anticoagulant, n (%) Previous number of DVT events (number of women) Phlebitis only Pulmonary embolisms Portal thrombosis Cave thrombosis Cerebral venous thrombosis Number of DVT events during PP use (number of women) DVT recurrence under CPA DVT recurrence under CMA Overall incidence of DVT during PP treatment: (n/1000 women/year)
150 68 (45.3%) 36 (24%) 32 (21.3%) 53 (35.3%) 112 (86) 61 29 12 5 5 8 (7) 3 5 14.6 (95% CI: 4.4–24.6)
a The number of women with aPLs, inherited thrombophilia and oral anticoagulation, and the number of women who experienced DVT events previous and during PP use are reported in this table. DVT, deep venous thrombosis; PP, pregnane progestogen; aPLs, antiphospholipid antibodies; CMA, chlormadinone acetate; CPA, cyproterone acetate.
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Angioedema HAE is a rare disorder characterized by recurrent episodes of localized swelling without urticaria, which can involve the face, extremities or larynx (with a risk of death). Gastrointestinal tract involvement leads to recurrent episodes of severe abdominal pain with pseudo-surgical clinical presentation. The main mediator of edema is bradykinin, owing to activation of the kallikrein-kinin system (45). Two genetic forms have been described for years, both associated with C1 inhibitor (C1Inh) abnormalities: type I HAE in which there is a reduced production of C1Inh and type II HAE which involves functional deficiency (45). These two types refer to a single genetic disease. A new type of HAE has recently been reported associated with normal C1Inh. Type III HAE was initially described by Bork et al. (46), Binkley and Davis (47), and Martin et al. (48) in 2000 as recurrent angioedema without quantitative or functional C1Inh abnormalities, predominantly affecting women under oral contraceptives or during pregnancy. Later, the disease was associated with mutations in the F12 gene (gene encoding for Hageman factor) which leads to an increase in kinin production (49). Women with angioedema irrespective of the type were reported to have induction or worsening of their attacks in 60%–80% (50–52). Bork et al. (51) reporting on women with HAE observed the same frequency of women who experienced worsening of the diseases (62%–63%) using COC irrespective of their HAE type. Bouillet et al. (52) reported a retrospective analysis of 155 European women with HAE types I and II and observed an increase of attacks in 79% of women who used COC. During pregnancies, 38% of the women had more attacks, but 30% had fewer attacks. Puberty worsened the disease for 62%, and attacks were triggered by menses for 35% and by ovulation for 14% (52). The concept of three different forms according to estrogen sensitivity is now developed: the estrogen-sensitive HAE for women who worsen the attacks under COC/ pregnancy, the estrogen-dependent disease for women who have HAE only under COC or pregnancy and estrogen-independent HAE where estrogens do not alter the course of the disease (50). The estrogen dependency of the disease is known for several years and can be explained by the interaction of estrogens with the activation cascade of kallikreinkinin as reviewed elsewhere (5, 21). Factor XII has several estrogen-responsive elements in its promoter and an inhibiting factor on the closer one to the promoter which controls the activation of Factor XII (53, 54). A mutation of this region is associated by a gain-of-function of Factor XII which leads to its permanent activation and the increase in the kallikrein-kinin activation pathways. There is a rationale to use non-estrogenic contraception and antigonadotropic agents in these patients. Danazol is currently used in women with HAE types I and II because its androgen potency increase the level of C1Inh. It is usually used at 200 mg/day or three times a week as a prophylactic treatment and at this dose is not contraceptive but contraindicated in pregnancy. Moreover, it has some side effects such as hyperandrogenemia, cytolysis and increase risk of DVT. We thus advise
to use nortestosterone derivatives as first line treatment. They can display some androgenic effects and can be beneficial with fewer side effects than Danazol in some but not all patients with HAE type I (personal data). However, their efficacy has not been fully evaluated. The other antigonadotropic agents such as CMA or nomegestrol acetate can be used with clinical improvement of the disease. We have personal experience of the use of these antigonadotropic agents in a series of 27 women mostly with type III HAE. Approximately 80% of the women improved using these contraceptive agents with one-third stopping any other medication for HAE. In comparison, POP, levonorgestrel IUD and implant were less efficient than antigonadotropic progestin in alleviating the symptoms (personal data). The clinical tolerance of PP was also satisfactory, the main side effects being weight gain in 21% of the patients. Thus, interest in antigonadotropic agents is important in this severe disease and can increase well-being in these women.
Conclusion PPs offer a safe and effective contraception in women at risk for vascular disease such as SLE patients and patients with history of DVT. Antigonadotropic progestogens can constitute a powerful treatment in some estrogen-dependent diseases such as HAE and can increase well-being in women suffering from such conditions. Gynecological tolerance is in the same range as the estroprogestogen combined pill. Thus, antigonadotropic progestogens used in contraception could provide an excellent and safe alternative to COC or low dose POP contraception in particular medical conditions such as SLE, DVT and HAE.
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Antigonadotropic progestogens as contraceptive agents in women with contraindication to combined pill
Lorraine Maitrot-Mantelet, Anahid Agopian and Anne Gompel*
Introduction
Unit of Gynecological Endocrinology, Hoˆtel-Dieu Hospital, Paris Descartes University, INSERM UMRS 938, Paris, France
Progestogen at low doses, also called the progestogen only pill (POP), is the standard hormonal contraception for women who cannot use the combined estrogen contraceptive (COC) pill for vascular or metabolic reasons (1). Because of their limited tolerance and thus their limited compliance, alternatives could be profitable. In addition, some of these women develop estrogen-dependent disease which can necessitate antigonadotropic treatments. So far in most countries, only gonadotropin-releasing hormone (GnRH) agonists are used in these cases for a limited time and with possible important side effects (2). According to the World Health Organization (WHO) recommendations (3), women with a personal history of venous thrombosis, with arterial thrombosis or ischemic cardiovascular diseases, antiphospholipid antibodies (aPLs), migraines with aura are situations to contraindicate COC. Autoimmune diseases such as systemic lupus erythematosus (SLE) can also be associated with an increased risk of thrombosis but were not classified as grade 4 for contraindication (CI) in the WHO recommendations (3). Some diseases such as diabetes, hypercholesterolemia and hypertension are also associated with relative or absolute contraindications because of an increase risk in arterial events. In addition, contraindications could be due to a history of hormone-dependent cancer. In this paper, we will address the use of antigonadotropic progestogens in women with SLE/aPLs, venous thrombosis/ thrombophilia and hereditary angioedema (HAE).
Abstract Synthetic progestogens belong to different pharmacological classes and are mixed steroids. They display different properties due to their various affinities to the different steroid receptors. In addition, the dosage used can modify their side effects. Normethyltestosterone used at minimal doses, also called progestogen only pill (POP), constitute the standard recommended hormonal contraception for women with vascular and metabolic contraindications to combined pill (COC). However, POP efficacy and gynecological tolerance are limited. We have developed for more than 20 years in France the use of two pregnane derivatives as contraceptive agents in women with contraindication to COC. Chlormadinone acetate and cyproterone acetate have different antigonadotropic potencies but remain neutral on vascular risk. We have analyzed the efficacy, vascular and gynecological tolerances in 187 women with systemic lupus erythematous with or without antiphospholipids. Venous thrombosis and arterial events rates were lower than those reported in the literature. The current experience in women with thrombophilia is similar as reported in a series of 150 patients. In addition, we have also used antigonadotropic progestins in women with hereditary angioedema (HAE) types I, II or III. HAE symptoms can be induced or worsened by COC. We could demonstrate a significant improvement of the symptoms in most women with HAE under antigonadotropic progestins. Gynecological and general tolerances were satisfactory. In conclusion, antigonadotropic progestins could have clinical positive benefits as contraceptive agents in women with contraindication to COC. Keywords: antigonadotropic progestogen; deep venous thrombosis; estrogen-dependent diseases; hereditary angioedema; systemic lupus erythematous.
*Corresponding author: Anne Gompel, Gynecological Endocrinology Unit, Hotel Dieu de Paris, 1 Place du Parvis Notre-Dame, 75004 Paris, France Phone: q33-1-42348768, Fax: q33-1-43298766, E-mail: [email protected] Received October 29, 2010; accepted November 3, 2010
Progestogens in contraception: benefits and limits
Different classes and dosages of progestogens are used as contraceptives. 19 Normethyltestosterone derivatives
The 19 normethyltestosterone derivatives can be used at high doses (10 mg/day). At these dosages, they are potent antigonadotropic agents and antiestrogenic. However, they are also associated potentially with an increase in thrombosis (4) and metabolic disorders. In addition, they can display androgenicity and weight gain due to their androgenic/anabolic properties. The androgenicity can be useful, however, in some estrogen-dependent diseases which can indicate it, such as HAE (5). In this disease, danatrol is a potent treatment but norsteroids can be in some cases an efficient contraception with positive effect on the attacks (A. Gompel, personal data). Similarly in estrogen-dependent diseases, such as
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benign breast diseases and endometriosis, they can be of some help in the absence of contraindication. The 19 normethyltestosterone derivatives can also be used at lower doses (approximately 20-fold less) as POP. At these dosages, they are the referent contraception for women with metabolic and vascular risk. In a recent meta-analysis that we performed on POP and stroke (6), no increase in the risk under POP and medroxyprogesterone acetate (MPA) was reported (without distinction in some studies which have mixed ‘‘progestogen contraceptives’’). A similar meta-analysis on myocardial infarction also showed no increase in the risk with POP (manuscript submitted). However, there is not so much information in women with high vascular risk, whether venous or arterial. The major problem with POP is the poor gynecological tolerance. In a randomized controlled study for the commercialization of Ce´razette, 1300 women were randomized between norgestrel (ns331) and desogestrel minipills (ns989), discontinuation rate at 13 months was 45% in the desogestrel- and 39.5% in the norgestrel-treated women (7). In addition, in 20% of the cycles, an increase in estrogen production and a functional ovarian cyst was observed in another study (8). Implants (Norplant and Implanon) have similar limited clinical tolerance than POP (9). They offer the advantage of higher efficacy because there is no failure due to compliance (10). Mirena is an interesting contraceptive in women with menorrhagia or endometriosis. However, it can also be associated with side effects (acne, weight gain and metrorrhagia) and a small increase in functional ovarian cyst occurrence (11). We have reported dramatic hemoperitoneum in the context of a huge increase of the international normalized ratio (INR) in women treated with anticoagulants for aPLs (12). In some patients either a rupture of luteal cysts or functional cysts was observed (12). This suggests that contraceptive agents which are associated with persistent ovulation or increase in functional cysts (POP, implants, Mirena) can potentially expose the risk of complication in women with a high INR such as women with aPLs. Pregnane derivatives
The most frequently used pregnane derivatives in contraception is depo-MPA. Recently, its use was associated with a significant increase in the risk of deep venous thrombosis (DVT) (13). MPA is a synthetic progestin with relatively important glucocorticoid and androgenic activities (14). These properties can probably explain the increase in the relative risk of DVT observed in this study. Two other pregnane derivatives have been developed in France and have been used for a long time in women with vascular risks. Chlormadinone acetate (CMA) was initially used in women with renal failure and hemodialysis with a good clinical tolerance and no evidence of hypertensive effects. At the same time, we began to use it in women with SLE on the basis of neutral effect on surrogate markers (15). Subsequently, it was also used in women with contraindication to COC and particularly in women with thrombosis and SLE (16, 17). It is a progestin considered to have mild antiandro-
gen and glucocorticoid properties, but the evidence for these potencies are limited; it is devoid of any estrogen activity (18, 19). It has mild antigonadotropic effect (20). The development of the dominant follicle is antagonized but in most patients a small amount of estradiol persists. CMA is usually prescribed at 10 mg/day, 21 days/28. It can be associated with topical estrogens in the case of vaginal dryness. Cyproterone acetate (CPA) is usually prescribed for the treatment of hyperandrogenemia (21). It is a potent antigonadotropic agent and also a potent antiandrogen with moderate glucocorticoid activity and no estrogen activity (18, 19, 22). It has been shown to have a safe profile on the vascular risk markers. It is usually combined with estradiol either orally in women without specific risk in the treatment of hirsutism or transdermal in other women. It has been used for many years in France in women with SLE with satisfactory clinical tolerance (16, 23). In this regard, usually, systemic estradiol is not combined but topical estrogens can be associated (16, 17). We will thus report our experience with the use of these pregnane progestogens in women with SLE and thrombosis, particularly addressing the gynecological tolerance of these compounds.
Systemic lupus erythematous (SLE) SLE is a multisystem autoimmune estrogen sensitive disease that primarily affects women of child-bearing age (24). Systemic SLE has a female/male ratio of 2:1 before puberty and 9:1 between puberty and menopause. Its etiopathogenesis is complex and involves genetic factors and individual susceptibility to environmental factors (24). The role of estrogens in SLE activity is suggested by various arguments: estradiol enhances autoimmunity, whereas testosterone and progesterone are suppressors (24). The deleterious effect of estrogen in SLE has been well studied in experimental animal models, NZB/NZW and MRL/lpr mice (25). The severity of SLE flares can be life-threatening and the deleterious effect of pregnancy on the disease course is well established, especially in the case of kidney involvement (23). Thus, effective contraception is crucial in these patients but remains the object of debate (26). The use of ethinylestradiol containing contraceptive pills in SLE patients is controversial because estrogens can worsen the course, increasing the incidence and severity of the disease (27, 28). Furthermore, the risk of arterial and venous thrombosis is increased both in SLE patients without any hormonal therapy (29, 30) and in healthy women under COC (31–33). Two randomized controlled trials have recently challenged these negative data on COC in women with SLE. A trial by the Sanchez-Guerrero group (34) excluded patients with a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) )30, i.e., very severe lupus, and the SELENA trial (35) excluded patients with a high aPL level. In the latter study, lupus activity was low in most of the patients (mean
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SLEDAI scores3). However, in a recent study conducted in active SLE patients, the rate of flares, including one death, could lead one to remain prudent for the widespread use of COC in women with active SLE or with aPLs or unknown conditions for it (28). The poor compliance observed in some studies with POP suggests the need for other contraceptive methods. Julkunen et al., in a study of 82 women with SLE, recorded 32 cases using low dose POP and found that 78% of them discontinued POP within 18 months because of abnormal bleeding (36). The use of copper intrauterine devices (IUDs) is frequently challenged in SLE patients due to the potential risk of infection soon after insertion (37). The levonorgestrel-releasing intrauterine system which can carry a lower risk for infection (38) has been only recently easily available on the French market. It might be an interesting alternative but also has some limitations of tolerance including an increase in functional cysts compared to copper IUD (11, 39). In such specific medical conditions, pregnane progestogen (PP) seems to offer convenient alternatives. Our group recently published a cohort study reporting on our experience of the use of CMA and CPA for contraception in SLE women (40). In this prospective study, 187 consecutive premenopausal SLE women requesting contraception and willing to use hormonal contraception were followed in the Gynecology Unit of the Hoˆtel-Dieu Hospital. Patients received either CPA (50 mg tablets once daily orally for 20 days/27) or CMA (10 mg tablets daily orally for 21 days/28) for contraception. The choice between CPA and CMA was made according to the SLE disease activity level. Based on the hypothesis that a hypoestrogenic environment could have a beneficial effect on the course of SLE (24), patients received CPA within the year following a flare, if there was an increase of prednisone dose G30 mg/day or in the case of poor CMA tolerability. Patients were allocated CMA if it had been more than 1 year since last flare or in the case of poor CPA tolerability. As CPA has stronger antigonadotropic action than CMA, CMA was first prescribed in moderately active or quiescent SLE patients. We followed 187 patients during a total of 6854 months, 2942 cycles and 3912 cycles for CPA and CMA, respectively. Approximately, one-third of the patients had detectable aPLs and/or anticardiolipin antibodies (aCLs). The incidence of DVT prior to the progestogen contraception was 22.8/1000 women/year (95% confidence interval, CI: 12.5–32.04). The arterial and venous vascular tolerance appeared to be excellent in the study. The overall incidence of DVT during pregnane treatment was more than ten times less than before (40). No DVT occurred during CMA use. The incidence of macroarterial disease prior to progestogens was 10.02/1000 women/year (95% CI: 3.47–16.57). The overall incidence of macroarterial disease under PP treatment was also lower than before PP. These arterial events were one case of myocardial infarction in a 48-year-old patient with multiple risk factors (smoking, aPLs and obesity) and one case of tibial posterior arterial occlusion (40). The incidence of arterial events in our series was comparable to previous published
data (41). In addition, the incidence of lupus flares decreased significantly (p-0.00001) under progestogens. One of the major side effects of PP is breakthrough bleeding. Weight gain is also possible. In addition, owing to their mode of action, symptoms of hypoestrogenia can develop. Actually, following a systematic questionnaire collecting bleeding, hypoestrogenic symptoms and other side effects every 6 months during the consultation, tolerance in this study appeared to be rather satisfactory. Breakthrough bleeding was reported in less than 18% of the patients under CPA and 12.6% of the patients using CMA (40). Metrorrhagia led to treatment discontinuation in only one patient with CPA and seven with CMA. Only two patients discontinued because of hypoestrogenia using CPA and none with CMA. It is important to note that the contraceptive efficacy was 100% despite that we did not have enough cycles to raise a proper Pearl index. No unscheduled pregnancy occurred during the course of the study which represented a total of 6854 cycles. The PPs have both antigonadotropic activities. CPA is more potent than CMA. However, we advised the women to use a barrier contraception the first month of CPA use because of a progressive antigonadotropic activity as reported in the unpublished data contained in the file which was used for its commercialization. They both also have peripheral contraceptive effects of progestogen, by coagulation of the mucus, endometrial atrophy and decrease in the tubal motility.
Deep venous thrombosis (DVT) and progestin contraception COC use is one of the most common risk factors of DVT among young women and it is associated with an approximate 4-fold risk (31–33). The risk is influenced by many factors such as dose of ethinylestradiol, type of progestin, age and duration of use. COCs affect hemostatic variables and estrogen-sensitive liver proteins. The impact on hemostatic variables could be a disturbance between profibrinolytic and procoagulants effects. Furthermore, COCs with the highest risks of DVT are also associated with the highest levels of sex hormone-binding globulin (SHBG), and SHBG levels are positively associated with resistance to activated protein (42). A recent publication shows that use of MPA is also significantly associated with a higher risk of DVT. In this casecontrol study, the authors found that use of injectable MPA was associated with a 3.6-fold (95% CI: 1.8–7.1) increased risk of DVT compared with non-users of hormonal contraceptives (13). However, use of POP as well as implants and Mirena is not reported to be associated with an increased risk of DVT (13). The association between the use of PP and the risk of DVT has been previously evaluated in a case-control study including 204 women with a personal history of DVT/thrombophilia (43). A total of 102 women using CMA were compared to 102 controls; 44 women in the CMA group and
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58 in the control group had a personal history of thrombophilia. No difference concerning the risk of DVT recurrence was observed between the two groups. There were three DVT recurrences in the CMA group and six in the control group (RRs0.84; 0.18–3.93). In the Gynecology Unit of the Hoˆtel-Dieu Hospital, we have 20 years follow-up experience of women under PP with a personal history of venous thrombosis and/or thrombophilia. Here, we report a study of 203 women with such medical history seen in our Gynecology Department between 1990 and 2000. Among them, 150 patients received PP for more than 6 months; 17 women had taken PP for less than 6 months or were lost to follow-up; 36 patients did not receive any PP (pregnancy project, no need of contraception, menopause). Women under PP received either only CMA (ns97) or only CPA (ns21) combined with transdermal 17b-estradiol except in the case of aPL. A total of 32 patients received both CMA and CPA during the follow-up; four patients initially under CPA were switched to CMA and 10 patients initially under CMA were switched to CPA because of side effects; 18 successively received the two treatments during the follow-up, independently of side effects. These treatments were prescribed for contraception, hyperandrogenemia or estrogen-dependent diseases. The mean ("SE) duration of follow-up was 39.7"41 months under CMA (range: 6–156) and 29"31 months under CPA (range: 6–120). A total of 86 women presented 112 previous histories of DVT (Table 1). It is important to note that this population is characterized by an important amount of severe thromboembolic disease: 29 pulmonary embolisms occurred with more than one episode in four women. Another 12 women presented a previous history of portal thrombosis, five a history of cave thrombosis and five a history of cerebral venous thrombosis (Table 1). In total, 32 women had a thrombophilia (Table 1) such as mutation of Factor V Leiden (ns11), mutation of Factor II (ns7), mutation of Factor IIqV (ns4), deficiency in Pro-
tein C (ns3), deficiency in Protein S (ns5), deficiency of Antithrombin III (ns2). In total, 36 patients had detectable aPLs and/or aCLs. Oral anticoagulants were used in 53 patients (Table 1). DVT recurrences under PP
Eight DVT recurrences occurred in seven patients using PP: three DVT recurrences occurred under CPA and five under CMA. Two women received an anticoagulant therapy when recurrence occurred. The overall incidence of DVT during PP treatment was 14.6/1000 women/year (95% CI: 4.4– 24.6). The incidence of DVT recurrence in our study was comparable to incidence of DVT published in a recent prospective follow-up study of 414 patients with a first objective diagnosis of DVT (44). In this study, the overall incidence rate of DVT recurrence was 15.8/1000 individuals/years in women (95% CI: 10.9–22.1). The rate of idiopathic recurrence in women was 9.3/1000 individuals/years (95% CI: 5.4–14.9), whereas the recurrence rate of DVT among women still using hormonal contraception was 48.8 (95% CI: 24.3–87.2). Gynecological tolerability
Breakthrough bleeding was reported by 10 patients using CMA. Hypoestrogenic symptoms were recorded in six patients using CMA. Hyperandrogenemia was reported by two patients using CMA. Important weight gain was recorded in two patients using CPA. These symptoms were not severe enough to justify treatment discontinuation. In 14 women, side effects were more important and a switch from one progestogen to the other was proposed. In total, 10 patients initially under CMA were switched to CPA: six for hyperandrogenemia, three for bleeding and one for weight gain. Four patients initially under CPA switched to CMA: two for weight gain and two for swelling.
Table 1 Number of previous DVT events and number of DVT recurrences in women receiving PP for more than 6 monthsa. Patients, n Number of patients with thrombophilia, n (%) Presence of aPLs, n (%) Inherited thrombophilia, n (%) Number of patients under oral anticoagulant, n (%) Previous number of DVT events (number of women) Phlebitis only Pulmonary embolisms Portal thrombosis Cave thrombosis Cerebral venous thrombosis Number of DVT events during PP use (number of women) DVT recurrence under CPA DVT recurrence under CMA Overall incidence of DVT during PP treatment: (n/1000 women/year)
150 68 (45.3%) 36 (24%) 32 (21.3%) 53 (35.3%) 112 (86) 61 29 12 5 5 8 (7) 3 5 14.6 (95% CI: 4.4–24.6)
a The number of women with aPLs, inherited thrombophilia and oral anticoagulation, and the number of women who experienced DVT events previous and during PP use are reported in this table. DVT, deep venous thrombosis; PP, pregnane progestogen; aPLs, antiphospholipid antibodies; CMA, chlormadinone acetate; CPA, cyproterone acetate.
Article in press - uncorrected proof Maitrot-Mantelet et al.: Antigonadotropic progestogens as contraceptive agents 445
Angioedema HAE is a rare disorder characterized by recurrent episodes of localized swelling without urticaria, which can involve the face, extremities or larynx (with a risk of death). Gastrointestinal tract involvement leads to recurrent episodes of severe abdominal pain with pseudo-surgical clinical presentation. The main mediator of edema is bradykinin, owing to activation of the kallikrein-kinin system (45). Two genetic forms have been described for years, both associated with C1 inhibitor (C1Inh) abnormalities: type I HAE in which there is a reduced production of C1Inh and type II HAE which involves functional deficiency (45). These two types refer to a single genetic disease. A new type of HAE has recently been reported associated with normal C1Inh. Type III HAE was initially described by Bork et al. (46), Binkley and Davis (47), and Martin et al. (48) in 2000 as recurrent angioedema without quantitative or functional C1Inh abnormalities, predominantly affecting women under oral contraceptives or during pregnancy. Later, the disease was associated with mutations in the F12 gene (gene encoding for Hageman factor) which leads to an increase in kinin production (49). Women with angioedema irrespective of the type were reported to have induction or worsening of their attacks in 60%–80% (50–52). Bork et al. (51) reporting on women with HAE observed the same frequency of women who experienced worsening of the diseases (62%–63%) using COC irrespective of their HAE type. Bouillet et al. (52) reported a retrospective analysis of 155 European women with HAE types I and II and observed an increase of attacks in 79% of women who used COC. During pregnancies, 38% of the women had more attacks, but 30% had fewer attacks. Puberty worsened the disease for 62%, and attacks were triggered by menses for 35% and by ovulation for 14% (52). The concept of three different forms according to estrogen sensitivity is now developed: the estrogen-sensitive HAE for women who worsen the attacks under COC/ pregnancy, the estrogen-dependent disease for women who have HAE only under COC or pregnancy and estrogen-independent HAE where estrogens do not alter the course of the disease (50). The estrogen dependency of the disease is known for several years and can be explained by the interaction of estrogens with the activation cascade of kallikreinkinin as reviewed elsewhere (5, 21). Factor XII has several estrogen-responsive elements in its promoter and an inhibiting factor on the closer one to the promoter which controls the activation of Factor XII (53, 54). A mutation of this region is associated by a gain-of-function of Factor XII which leads to its permanent activation and the increase in the kallikrein-kinin activation pathways. There is a rationale to use non-estrogenic contraception and antigonadotropic agents in these patients. Danazol is currently used in women with HAE types I and II because its androgen potency increase the level of C1Inh. It is usually used at 200 mg/day or three times a week as a prophylactic treatment and at this dose is not contraceptive but contraindicated in pregnancy. Moreover, it has some side effects such as hyperandrogenemia, cytolysis and increase risk of DVT. We thus advise
to use nortestosterone derivatives as first line treatment. They can display some androgenic effects and can be beneficial with fewer side effects than Danazol in some but not all patients with HAE type I (personal data). However, their efficacy has not been fully evaluated. The other antigonadotropic agents such as CMA or nomegestrol acetate can be used with clinical improvement of the disease. We have personal experience of the use of these antigonadotropic agents in a series of 27 women mostly with type III HAE. Approximately 80% of the women improved using these contraceptive agents with one-third stopping any other medication for HAE. In comparison, POP, levonorgestrel IUD and implant were less efficient than antigonadotropic progestin in alleviating the symptoms (personal data). The clinical tolerance of PP was also satisfactory, the main side effects being weight gain in 21% of the patients. Thus, interest in antigonadotropic agents is important in this severe disease and can increase well-being in these women.
Conclusion PPs offer a safe and effective contraception in women at risk for vascular disease such as SLE patients and patients with history of DVT. Antigonadotropic progestogens can constitute a powerful treatment in some estrogen-dependent diseases such as HAE and can increase well-being in women suffering from such conditions. Gynecological tolerance is in the same range as the estroprogestogen combined pill. Thus, antigonadotropic progestogens used in contraception could provide an excellent and safe alternative to COC or low dose POP contraception in particular medical conditions such as SLE, DVT and HAE.
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