Efficacy of combined estrogen–progestin hormone contraception therapy for refractory coronary spastic angina in very young women

Open ArchivePublished:February 27, 2020DOI:https://doi.org/10.1016/j.jccase.2020.02.001

      Abstract

      Coronary spastic angina (CSA) in premenopausal women is rare, but has also been suggested to be associated with estrogen decline during the menstrual cycle. In this report, we describe the case of a young premenopausal patient with refractory CSA. She presented with ventricular fibrillation (VF) at the age of 15 years and was diagnosed as having CSA. She underwent implantation of an Implantable Cardioverter Defibrillator (ICD), and despite receiving systemic drug therapy at the maximum doses, she experienced a total of four appropriate ICD shocks over the subsequent six years. Based on careful history-taking, it was suspected that the angina episodes were closely related to the phase of the menstrual cycle. We started the patient on continuous combined estrogen–progestin hormone contraception therapy so as to prevent the reduction of the blood estrogen levels just prior to and during menstruation. After the start of this treatment, the patient became completely free of angina episodes. Although there are a few reports of the efficacy of hormone replacement therapy in premenopausal women with CSA, this is the first report of the efficacy of this therapy in a woman as young as 22 years old.
      <Learning objective: There are a few reports of episodes of CSA occurring in relation to the phase of the menstrual cycle in premenopausal women. It is considered to be associated with decline of the blood estrogen levels and combined estrogen plus progestin contraception therapy may be effective in such cases.>

      Keywords

      Introduction

      Although the long-term prognosis of patients with coronary spastic angina (CSA) who are responsive to medical therapy, such as with calcium channel antagonists, is good, there are some cases of refractory CSA that is resistant to standard medications and can result in sudden cardiac death, even among young patients [
      • Murakami D.
      • Negishi K.
      • Yamamoto M.
      • Tokuyama H.
      • Kobayashi N.
      • Takano M.
      • et al.
      Refractory coronary spastic angina may induce sudden cardiac death even in young patients under appropriate medication.
      ]. In our case reported herein, despite the administration of drugs at their maximal doses, angina episodes and the potentially fatal arrhythmias consequent upon them occurred repeatedly. Our search of the literature revealed no cases of CSA in women as young as our case reported herein. It has been suggested that decrease of the blood estrogen levels during certain phases of the menstrual cycle may trigger coronary spasm, and in a limited number of cases, hormone therapy has been shown to be effective [
      • Kawano H.
      • Motoyama T.
      • Ogushi M.
      • Kugiyama K.
      • Ogawa H.
      • Yasue H.
      Menstrual cyclic variation of myocardial ischemia in premenopausal women with variant angina.
      ]. Herein, we report the first case of a young woman with CSA in whom hormone contraception therapy proved effective.

      Case report

      The patient was a 22-year-old woman who presented with a history of recurrent episodes of ventricular arrhythmias due to refractory CSA. Her father had a history of CSA. She had her first menstrual period at the age of 11 years. She had no significant past medical history prior to her initial episode of ventricular fibrillation and cardiopulmonary arrest at the age of 15 years. At the time of the first episode, she presented to our hospital and was successfully resuscitated by cardiopulmonary resuscitation and defibrillation. Coronary angiography revealed no organic stenosis, but spastic coronary arteries. An acetylcholine provocation test was performed which showed subtotal occlusions with ST-segment elevation and chest pain, provoked by injection of 20 μg and 50 μg of acetylcholine into the right coronary artery (RCA) and left coronary artery (LCA), respectively (Fig. 1). She was diagnosed as having CSA based on the clinical and angiography findings. She underwent implantation of an Implantable Cardioverter Defibrillator (ICD) and was started on standard systemic drug therapy with a calcium channel blocker (benidipine, 4 mg–8 mg/day) and a coronary vasodilator (isosorbide mononitrate, 40 mg/day). There were no 12-lead ECG findings suggesting Brugada syndrome or Long QT syndrome (Fig. 2). Pilsicainide provocation test and epinephrine provocation test were also performed, but no ECG changes were observed. Despite of the optimal medical therapy for CSA, up to 16 years of age, she had received a total of four appropriate ICD shocks, during all of which ventricular tachycardia (VT) and ventricular fibrillation (VF) were documented. Systemic drug therapy was added each time, including nicorandil (20 mg/day), diltiazem (from 100 mg to 120 mg/day), and nifedipine (20 mg/day) (Fig. 3). Despite the drug administrations at their maximal pharmacological doses, the patient complained of frequent episodes of chest pain and the ICD activated again when she was 22 years old, on the second day of her menstrual period. She was transported to another hospital. Because her hemodynamic status remained unstable even after restoration of sinus rhythm, the patient received intensive care with extra-corporeal membrane oxygenation (V-V ECMO) and intra-aortic balloon pumping (IABP). Interrogation of the ICD confirmed that the patient had had three VF episodes, each of which was successfully terminated with 41 J shocks. An electrocardiogram (ECG) recorded after resuscitation showed inverted T waves in leads I, aVL and V2–V6. An emergency coronary angiography revealed spasm of the left circumflex artery (LCx), which was relieved by intracoronary administration of nitroglycerin and nicorandil. The patient was started on continuous intravenous infusion of nicorandil (4 mg/h) and given an isosorbide nitrate patch (40 mg/day). On day 7, after she was weaned from the blood circulation assist device and brain hypothermia therapy, she was transported to our hospital. Even while she was hospitalized, after the continuous intravenous infusion of nicorandil was stopped, she developed episodes of chest pain with ST depression from two days before the start of her menstruation and on day 1 of menstruation. Careful history taking revealed the relationship between her chest pain episodes and her menstrual cycle. She frequently had her angina attacks just before and during her menstruation. The blood estrogen levels were within the normal range at any menstrual phase (45.5 pg/mL in follicular phase; 42.9 pg/mL in ovulatory phase; 117.4 pg/mL in luteal phase), but it was considered that rapid decrease in estrogen level with menstruation might prevent the dilation of vascular smooth muscle. We consulted gynecologists and started her on hormone contraception therapy. After she was started on combined estrogen–progestin contraception (norethisterone acetate, 2.7 mg/2 days plus estradiol, 0.62 mg/2 days; transdermal patch) to prevent reduction of the blood estrogen levels just before and during menstruation, the patient never had any episodes of chest pain until discharge on day 38. Subsequently, she was followed up at our outpatient department for 12 months without any recurrence of the angina episodes.
      Fig. 1
      Fig. 1Coronary angiography and acetylcholine provocation test.
      (a) Control angiography of the right coronary artery (RCA).
      (b) Angiography after injection of 20 μg of acetylcholine into the RCA revealed subtotal occlusions.
      (c) Control angiography of the left coronary artery (LCA).
      (d) Angiography after intracoronary injection of 50 μg of acetylcholine into the LCA revealed spasm of the proximal portion of the left anterior descending artery and middle portion of the left circumflex artery.

      Discussion

      Existence of a relationship between the hormonal changes during the menstrual cycle and CSA has been reported previously [
      • Kawano H.
      • Motoyama T.
      • Ogushi M.
      • Kugiyama K.
      • Ogawa H.
      • Yasue H.
      Menstrual cyclic variation of myocardial ischemia in premenopausal women with variant angina.
      ]. While there have been some reports of the efficacy of hormone replacement therapy for premenopausal women with CSA, this is the first report of its efficacy in a woman as young as 22 years old.
      Vascular endothelial function decreases with age in men. On the other hand, in women, while it does not decrease until about 50 years of age, it decreases linearly thereafter, after menopause. This suggests the close involvement of the female hormones in the development of vascular endothelial dysfunction [
      • Mendelsohn E.
      • Karas H.
      The protective effects of estrogen on the cardiovascular system.
      ]. It has been reported that the number of estrogen receptors in premenopausal women with coronary disease is lower than that in healthy women [
      • Losordo D.W.
      • Kearney M.
      • Kim E.A.
      • Jekanowski J.
      • Isner J.M.
      Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women.
      ]. Atheroprotective effect of estrogen is exerted through the stimulation of endothelium-derived nitric oxide (NO) and prostacyclin production and release, superoxide scavenger and decrease in endothelin-1 activity [
      • Boulanger C.
      • Luscher T.F.
      Release of endothelin from the porcine aorta. Inhibition by endotherium-derivered nitric oxide.
      ]. Although CSA is well known to occur in postmenopausal women, few cases of CSA have been reported in premenopausal women [
      • Kawano H.
      • Motoyama T.
      • Ogushi M.
      • Kugiyama K.
      • Ogawa H.
      • Yasue H.
      Menstrual cyclic variation of myocardial ischemia in premenopausal women with variant angina.
      ,
      • Adachi Y.
      • Ikeda N.
      • Sakakura K.
      • Netsu S.
      • Ibe T.
      • Wada H.
      • et al.
      Intractable coronary spastic angina improvement after continuous combined estrogen-progestin hormonal contraception use in a premenopausal woman.
      ]. Kawano et al. determined that the frequency of CSA in 10 premenopausal women (mean age, 44.8 years) was the highest in the late luteal and menstrual phase, when the estradiol levels are at their lowest during the menstrual cycle [
      • Kawano H.
      • Motoyama T.
      • Ogushi M.
      • Kugiyama K.
      • Ogawa H.
      • Yasue H.
      Menstrual cyclic variation of myocardial ischemia in premenopausal women with variant angina.
      ]. Even in our present case, we speculated that a reduction of the blood estrogen level served as the trigger for her angina episodes. Most cases of CSA in premenopausal women are in middle-aged women, and our search of the literature revealed no report of young women like our case. Although the mechanism is unclear, we suspect that there is some abnormality in the estrogen receptors, because her blood estrogen levels are within normal range for each menstrual period. There is an interesting report [
      • Adlanmerini M.
      • Solinhac R.
      • Abot A.
      • Fabre A.
      • Raymond-Letron I.
      • Guihot A.L.
      • et al.
      Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions.
      ] that some estrogen receptors move from nucleus to the cell membrane when the 145th cysteine is lipid-modified. When mice were knocked out with the 145th cysteine, endothelial nitric oxide synthase was not activated in vascular endothelial cells. Further elucidation of the effects of estrogen receptors on vascular endothelial cells may reveal the pathogenesis of CSA in such young women. Estrogen supplementation has proven effective in improving endothelium-dependent dilation with increased NO production and release in postmenopausal women with CSA [
      • Hulley S.
      • Grady D.
      • Bush T.
      • Furberg C.
      • Herrington D.
      • Riggs B.
      • et al.
      Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/progestin Replacement Study (HERS) Research Group.
      ], whereas the usefulness of estrogen in premenopausal women remains to be determined. Adachi and colleagues reported the case of a 44-year-old woman with CSA, in whom continuous administration of combined estrogen plus progestin contraception was strikingly effective in relieving her of her chest pain episodes occurring in the late luteal and menstrual phase [
      • Adachi Y.
      • Ikeda N.
      • Sakakura K.
      • Netsu S.
      • Ibe T.
      • Wada H.
      • et al.
      Intractable coronary spastic angina improvement after continuous combined estrogen-progestin hormonal contraception use in a premenopausal woman.
      ]. According to the guidelines of hormone replacement therapy for menopausal patients [
      • The NAMS 2017 Hormone Therapy Position Statement Advisory Panel
      The 2017 hormone therapy position statement of the North American Menopause Society.
      ], combined estrogen plus progestin regimens are prefer to estrogen alone in patients who have not undergone hysterectomy, because chronic unopposed endometrial exposure to estrogen is associated with an increased risk of endometrial hyperplasia or cancer. Progesterone prevents endometrial overgrowth and it is reported that when a progestin is combined at an adequate dose with estrogen, the risk of endometrial neoplasia is not significantly higher than that in untreated women [
      • Anderson G.L.
      • Judd H.L.
      • Kaunitz A.M.
      • Barad D.H.
      • Beresford S.A.
      • Pettinger M.
      • et al.
      Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial.
      ]. However, since this is on the premise of treatment for postmenopausal women, the risk of endometrial cancer in premenopausal women with hormone therapy remains unclear. Since our patient was only 22 years old, and will be expected to remain at risk of developing angina episodes during certain phases of her menstrual cycle every month and after menopause, it may be necessary to continue her on hormone therapy for a long time. However, considering the risks of side effects, including endometrial cancer, the pros and cons of continuous long-term administration remains unclear. There have been no large clinical trials of hormonal contraceptive therapy conducted in premenopausal women with CSA, and further clinical and basic researches are warranted.

      Conflict of interest

      None of the authors have any conflicts of interests to disclose.

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