WJ C
World Journal of Cardiology World J Cardiol 2014 December 26; 6(12): 1285-1289 ISSN 1949-8462 (online) © 2014 Baishideng Publishing Group Inc. All rights reserved.
Submit a Manuscript: http://www.wjgnet.com/esps/ Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx DOI: 10.4330/wjc.v6.i12.1285
CASE REPORT
Dangerous triplet: Polycystic ovary syndrome, oral contraceptives and Kounis syndrome Nurdan Erol, Aysu Turkmen Karaagac, Nicholas G Kounis Nurdan Erol, Siyami Ersek Thorax and Cardiovascular Surgery Training and Research Hospital, Pediatric Cardiology Clinic, 34668 Uskudar, Istanbul, Turkey Aysu Turkmen Karaagac, Kartal Kosuyolu Research and Training Hospital Pediatri, 34846 Kartal, Istanbul, Turkey Nicholas G Kounis, Department of Medical Sciences, Northwestern Greece Highest Institute of Education and Technology, 26221 Achaia, Greece Author contributions: Erol N carried out acqustion of data, interpreted the results and wrote the article; Kounis NG contributed to analysis and interpretation of data and revising the paper; Karaagac AT contributed to write the article. Correspondence to: Nurdan Erol, MD, Pediatric Cardiologist, Siyami Ersek Thorax and Cardiovascular Surgery Training and Research Hospital, Pediatric Cardiology Clinic, Tıbbiye Caddesi No:13, 34668 Uskudar, Istanbul, Turkey. [email protected] Telephone: +90-505-7588787 Fax: +90-216-5424444 Received: August 9, 2014 Revised: September 20, 2014 Accepted: October 23, 2014 Published online: December 26, 2014
Core tip: The young lady in our case has had suffered from hyperandrogenism, oligomenorrhea, polycystic ovaries and while was receiving oral contraceptives she developed intermittent angina attacks not strictly related to her medication. The angina attacks associated with increased cardiac enzymes increased high sensitivity cardiac troponin, skin itching and electrocardiographic changes suggesting of myocardial ischemia. Eosinophils were raised but the coronary arteries were normal. The angina attacks disappeared with discontinuation of contraceptives. Such angina attacks associated with such clinical setting are attributed to disease itself, to oral contraceptives and/or to Kounis hypersensitivity coronary syndrome, namely a dangerous triplet. Erol N, Karaagac AT, Kounis NG. Dangerous triplet: Polycystic ovary syndrome, oral contraceptives and Kounis syndrome. World J Cardiol 2014; 6(12): 1285-1289 Available from: URL: http://www.wjgnet.com/1949-8462/full/v6/i12/1285.htm DOI: http://dx.doi.org/10.4330/wjc.v6.i12.1285
Abstract Polycystic ovary syndrome is characterized by ovulatory dysfunction, androgen excess and polycystic ovaries and is associated with hypertension, diabetes, metabolic syndrome and cardiovascular events. Oral contraceptives constitute first-line treatment, particularly when symptomatic hyperandrogenism is present. However, these drugs are associated with cardiovascular events and hypersensitivity reactions that pose problem in differential diagnosis and therapy. We present a 14 year-old female with polycystic ovary syndrome taking oral contraceptive and suffering from recurrent coronary ischemic attacks with increased eosinophils, and troponin levels suggesting Kounis syndrome.
INTRODUCTION Polycystic ovary syndrome (PCOS) is a clinical disorder characterized by ovulatory dysfunction, androgen excess and polycystic ovaries. It is the most common endocrine disorder in the females of reproductive age, mostly presented with obesity, glucose intolerance, hyperinsulinemia, dyslipidemia and hypertension. The females with PCOS carry an increased risk of cardiovascular ischemic events independent of the obesity[1-3] with the prevalence of 4%-10%. In addition, the rate of occurrence of cardiovascular events in the 25-34-year-old female group with PCOS has been found to be 2.6%. Furthermore, therapy with combined oral contraceptives has been associated with both deep vein thrombosis and pulmonary embolism [4] as well as hypersensitivity reactions[5] that pose problems in differential diagnosis and treatment. We report a young
© 2014 Baishideng Publishing Group Inc. All rights reserved.
Key words: Contraceptives; Eosinophils; Kounis syndrome; Polycystic ovary syndrome; Troponin
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December 26, 2014|Volume 6|Issue 12|
Erol N et al . Kounis syndrome in PCOS Figure 1 Electrocardiogram during chest pain with increased troponin showing T wave inversion in lead III and flattening of T wave in lead left foot derivation in electrocardiography.
14-year-old female patient with PCOS who was exposed to the above dangerous triplet and suffered from recurrent attacks of chest pain with high troponin levels and increased eosinophils while the coronary arteries were normal.
T wave in lead left foot derivation in electrocardiography (Figure 1). Total cholesterol, triglyceride, high-dansity lipoprotein (HDL) cholesterol, low-dansity lipoprotein cholesterol and very low-dansity lipoprotein cholesterol levels were found to be 230 mg/dL, 290 mg/dL, 63 mg/dL, 108 mg/dL and 58 mg/dL, respectively. Eosinophils were also raised to 700/mm3 (normal levels up to 500/mm3). Chest radiography and echocardiography were also normal. Stress test, holter electrocardiogram and coronar y computed tomog raphy angiogram revealed no abnormality (Figure 2). The same clinical symptoms appeared while she was taking intermittently the contraceptive treatment and necessitating repeated hospital admissions, in approximately 1 or 2 mo intervals. At every hospitalization, repeated high sensitivity troponin levels and eosinophils were always elevated while the girl was feeling itchy. In view of the above findings we decided to change contraceptives to progesterone 5 mg and spironolactone 50 mg. After cessation of the oral contraceptive treatment, chest pain attacks disappeared despite taking the new medication. Biochemical tests, electrocardiogram (Figure 3), echocardiography, holter and repeated stress tests during the follow-up period of one year were all within normal limits. Cardiac enzymes and troponin returned to normal levels but eosinophils were still high (700/mm3). We did not perform skin prick tests and patch tests to oral contraceptives on ethical grounds. She was characterized as an atopic individual and was advised to refrain the previous contraceptive medication.
CASE REPORT A 14-year-old female [56 kg, 160 cm, body mass index (BMI): 21.87 kg/m2] attended the endocrinology outpatient clinic for PCOS due to hyperandrogenism, oligomenorrhea, and polycystic ovaries. She was referred to our pediatric cardiology clinic for recurrent chest pain attacks and the elevated cardiac enzymes while she was receiving intermittent contraceptive medication. In her past medical history, the prenatal and perinatal periods were uneventful. There was no consanguinity between her mother and father. There was no cardiovascular disease or any other chronic disease history in her family. Her physical growth and psychomotor development were compatible with her age. However, her thelarche and genital hair growth started at the age of 7.5 years. This was not accompanied by any menstual bleeding. The family brought her to endocrinology outpatient clinic where laboratory investigation showed high testosterone and cholesterol levels. Additional laboratory investigation for adrenal pathology revealed no abnormality. She was advised not to take any medication up to 14 years of age. At this age endocrinologists decided to put her on oral contraceptive (ethinyl estradiol + 0.03 mg drospirenone 3 mg combination) which resulted in menstrual bleeding. However, she could not use contraceptives regularly due to nausea, headache and loss of appetite. Three months later and while she was receiving intermittently the contraceptive therapy she experienced severe chest discomfort with skin itching lasting for 15 min and she was transferred to the emergency department. Serum creatine kinase muscle was 57 U/L (normal levels: 0-24) and the troponin level was 11.91 ng/mL (normal levels: 0-0.04). Her pulse was 100 beats per minute regular and electrocardiogram showed sinus rhythm, T wave inversion in lead Ⅲ and flattening of
WJC|www.wjgnet.com
DISCUSSION The diagnosis of PCOS is difficult because of the heterogeneity of the phenotype. The classical phenotype is observed in 75% of PCOS cases and cardiovascular risk factors are most frequently encountered in this group. Because several features of PCOS may be in evolution in adolescents, it was suggested recently[6] that only firm criteria should be used to make a diagnosis of PCOS during adolescence. These criteria include hyperandrogenism,
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Erol N et al . Kounis syndrome in PCOS
Figure 2 Normal computet tomography angiogram excluding thrombosis.
oligomenorrhea, and polycystic ovaries. Significant associations between PCOS and severity of cardiovascular diseases, family history of myocardial infarction as well as with elevated levels of insulin and triglycerides and lower levels of HDL-C have been reported[7]. Metabolic syndrome, type 2 diabetes, abdominal obesity and hypertension, are frequently observed in young patients with PCOS, which are factors associated with cardiovascular diseases. Our patient has had dyslipidemia with increased cholesterol and triglycerides. Oral contraceptives are used for the treatment of PCOS. Combined oral contraceptives containing drospirenone are preferred especially in the PCOS patients with hirsutism[8]. The risk of myocardial infarction and intracerebral events is 2.5% higher in the patients taking combined oral contraceptives containing low dose estrogen [9]. Our patient had no findings suggesting drug-related venous thromboembolism but she had chest discomfort associated with increased high sensitivity troponin levels and eosinophilia that suggested coronary event. Drug-related Kounis syndrome has been reported on several occasions[10]. In general, Kounis syndrome has an acute onset, but some subclinical cases have been reported[11]. Several mediators such as, cytokines and chemokines including histamine, neutral proteases, arachidonic acid products and platelet activating factor are released during the allergic episode. The same mediators are also involved in the acute coronary syndromes. Several drugs have been accused for triggering this syndrome. However, the only drug our patient took was oral contraceptive consisting of ethinyl estradiol and drospirenone. Allergy to oral contraceptive therapy has been already described on several occasions. Erythema multiforme limited to the oral mucosa was reported in
Figure 3 Normal electrocardiogram during cessation of contraceptive while the eosinophils were increased.
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Erol N et al . Kounis syndrome in PCOS
Peer review
a teenager on oral ethinyl estradiol and drospirenone therapy[5]. Acquired angioedema has been also related to patients receiving oestrogen contraceptives and is frequently associated with recurrent urticarial[12]. Allergic contact dermatitis has been reported in some occasions with transdermal therapeutic systems containing ethinyl estradiol[13]. In view of the increased eosinophils, skin itching, normal coronary angiography, electrocardiographic changes and troponin increase diagnosis of type Ⅰ variant of Kounis syndrome[14] was made and the culprit medication was discontinued. Eosinophils have emerged as a novel biomarker of risk stratification in patients who have experienced coronary artery episodes[15]. With cessation of combination of ethinyl estradiol and drospirenone and changing it to progestogen-only contraceptives, symptoms of the patient disappeared while eosinophil count was still increased denoting atopic diathesis. In women with PCOS and multiple cardiovascular risk factors the use of progestogen-only contraceptives is associated with substantially less risk of cardiovascular events but the danger is still watching for, since this drug can induce hypersensitivity reactions[16]. Kounis syndrome, polycystic ovary syndrome and oral contraceptives seem to constitute a dangerous triplet and should be always suspected in order to establish correct diagnosis, apply appropriate treatment and avoid untoward consequences.
This case report is well written and addresses common problems with diagnostics of polycystic ovary syndrome associated with cardiovascular symptomatology, oral contraceptives and drug hypersensitivity culminating in the developement of Kounis syndrome.
REFERENCES 1
2
3
4
5
COMMENTS COMMENTS
6
Case characteristics
The young lady in this case has had polycystic ovary syndrome and while was receiving oral contraceptives she developed intermittent angina attacks, increased cardiac enzymes, increased high sensitivity cardiac troponin, eosinophilia with skin itching and electrocardiographic changes suggesting of myocardial ischemia.
7
Clinical diagnosis
Myocardial ischemia associated with Kounis syndrome, polycystic ovary syndrome, oral contraceptive therapy.
Differential diagnosis
8
Laboratory diagnosis
9
Angina attacks with increased cardiac enzymes, increased high sensitivity cardiac troponin, electrocardiographic changes suggesting of myocardial ischemia and eosinophilia with normal coronary arteries in polycystic ovary syndrome are attributed to disease itself, to oral contraceptives and/or to Kounis hypersensitivityassociated coronary syndrome. Myocardial ischemia in polycystic ovary syndrome associated with oral contraceptive therapy and eosinophilia.
Imaging diagnosis
Coronary computed tomography angiogram performed upon the suspicion of thrombosis revealed normal coronary arteries.
10
Treatment
Discontinuation of contraceptive treatment and changing it to progesterone (medroxyprogesteronacetate) and spironolactone alleviated the symptomatology.
11
Related reports
Hyperandrogenism, oligomenorrhea, polycystic ovaries constitute the polycystic ovary syndrome which occasionally is associated with cardiovascular events, enhanced by hypersensitivity reaction to concomitant contraceptive medication.
12
Experiences and lessons
Patients with polycystic ovary syndrome who have to use oral contraceptives should be evaluated separately in terms of drug related cardiac events and hypersensitivity associated with Kounis syndrome.
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1288
Lo JC, Feigenbaum SL, Yang J, Pressman AR, Selby JV, Go AS. Epidemiology and adverse cardiovascular risk profile of diagnosed polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91: 1357-1363 [PMID: 16434451 DOI: 10.1210/ jc.2005-2430] Orio F, Palomba S, Spinelli L, Cascella T, Tauchmanovà L, Zullo F, Lombardi G, Colao A. The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. J Clin Endocrinol Metab 2004; 89: 3696-3701 [PMID: 15292291 DOI: 10.1210/jc.2003-032049] Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, Futterweit W, Lobo R, Norman RJ, Talbott E, Dumesic DA. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab 2010; 95: 2038-2049 [PMID: 20375205 DOI: 10.1210/jc.2009-2724] Gronich N, Lavi I, Rennert G. Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: a population-based cohort study. CMAJ 2011; 183: E1319-E1325 [PMID: 22065352 DOI: 10.1503/cmaj.110463] Jawetz RE, Elkin A, Michael L, Jawetz SA, Shin HT. Erythema multiforme limited to the oral mucosa in a teenager on oral contraceptive therapy. J Pediatr Adolesc Gynecol 2007; 20: 309-313 [PMID: 17868899 DOI: 10.1016/j.jpag.2007.02.001] Carmina E, Oberfield SE, Lobo RA. The diagnosis of polycystic ovary syndrome in adolescents. Am J Obstet Gynecol 2010; 203: 201.e1-201.e5 [PMID: 20435290 DOI: 10.1016/ j.ajog.2010.03.008] Shroff R, Kerchner A, Maifeld M, Van Beek EJ, Jagasia D, Dokras A. Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis. J Clin Endocrinol Metab 2007; 92: 4609-4614 [PMID: 17848406 DOI: 10.1210/jc.2007-1343] Guido M, Romualdi D, Giuliani M, Suriano R, Selvaggi L, Apa R, Lanzone A. Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study. J Clin Endocrinol Metab 2004; 89: 2817-2823 [PMID: 15181063 DOI: 10.1210/ jc.2003-031158] Baillargeon JP, McClish DK, Essah PA, Nestler JE. Association between the current use of low-dose oral contraceptives and cardiovascular arterial disease: a meta-analysis. J Clin Endocrinol Metab 2005; 90: 3863-3870 [PMID: 15814774 DOI: 10.1210/ jc.2004-1958] González-de-Olano D, Gandolfo-Cano M, MohedanoVicente E, González-Mancebo E, Matito A, Kounis NG, Escribano L. Kounis syndrome following the performance of skin test to amoxicillin. Int J Cardiol 2014; 174: 856-857 [PMID: 24801079 DOI: 10.1016/j.ijcard.2014.04.191] Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol 2006; 110: 7-14 [PMID: 16249041 DOI: 10.1016/j.ijcard.2005.08.007] Giard C, Nicolie B, Drouet M, Lefebvre-Lacoeuille C, Le Sellin J, Bonneau JC, Maillard H, Rénier G, Cichon S, Ponard D, Drouet C, Martin L. Angio-oedema induced by oestrogen contraceptives is mediated by bradykinin and is frequently associated with urticaria. Dermatology 2012; 225: 62-69 [PMID: 22922353 DOI: 10.1159/000340029]
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14
Koch P. Allergic contact dermatitis from estradiol and norethisterone acetate in a transdermal hormonal patch. Contact Dermatitis 2001; 44: 112-113 [PMID: 11205390 DOI: 10.1034/ j.1600-0536.2001.44020914.X] Kounis NG, Mazarakis A, Tsigkas G, Giannopoulos S, Goudevenos J. Kounis syndrome: a new twist on an old disease. Future Cardiol 2011; 7: 805-824 [PMID: 22050066 DOI: 10.2217/fca.11.63]
15
16
Kounis NG, Soufras GD, Tsigkas G, Hahalis G. White blood count and infarct size, myocardial salvage and clinical outcomes: the role of differentials. Int J Cardiovasc Imaging 2014; 30: 677-679 [PMID: 24384860 DOI: 10.1007/s10554-013-0359-7] Bernstein IL, Bernstein DI, Lummus ZL, Bernstein JA. A case of progesterone-induced anaphylaxis, cyclic urticaria/angioedema, and autoimmune dermatitis. J Womens Health (Larchmt) 2011; 20: 643-648 [PMID: 21417747 DOI: 10.1089/jwh.2010.2468] P- Reviewer: Aggarwal A, Kettering K, Lonardo F, Patanè S, Petix NR, Ueda H S- Editor: Tian YL L- Editor: A E- Editor: Wu HL
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Published by Baishideng Publishing Group Inc 8226 Regency Drive, Pleasanton, CA 94588, USA Telephone: +1-925-223-8242 Fax: +1-925-223-8243 E-mail: [email protected] Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx http://www.wjgnet.com
© 2014 Baishideng Publishing Group Inc. All rights reserved.
World Journal of Cardiology World J Cardiol 2014 December 26; 6(12): 1285-1289 ISSN 1949-8462 (online) © 2014 Baishideng Publishing Group Inc. All rights reserved.
Submit a Manuscript: http://www.wjgnet.com/esps/ Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx DOI: 10.4330/wjc.v6.i12.1285
CASE REPORT
Dangerous triplet: Polycystic ovary syndrome, oral contraceptives and Kounis syndrome Nurdan Erol, Aysu Turkmen Karaagac, Nicholas G Kounis Nurdan Erol, Siyami Ersek Thorax and Cardiovascular Surgery Training and Research Hospital, Pediatric Cardiology Clinic, 34668 Uskudar, Istanbul, Turkey Aysu Turkmen Karaagac, Kartal Kosuyolu Research and Training Hospital Pediatri, 34846 Kartal, Istanbul, Turkey Nicholas G Kounis, Department of Medical Sciences, Northwestern Greece Highest Institute of Education and Technology, 26221 Achaia, Greece Author contributions: Erol N carried out acqustion of data, interpreted the results and wrote the article; Kounis NG contributed to analysis and interpretation of data and revising the paper; Karaagac AT contributed to write the article. Correspondence to: Nurdan Erol, MD, Pediatric Cardiologist, Siyami Ersek Thorax and Cardiovascular Surgery Training and Research Hospital, Pediatric Cardiology Clinic, Tıbbiye Caddesi No:13, 34668 Uskudar, Istanbul, Turkey. [email protected] Telephone: +90-505-7588787 Fax: +90-216-5424444 Received: August 9, 2014 Revised: September 20, 2014 Accepted: October 23, 2014 Published online: December 26, 2014
Core tip: The young lady in our case has had suffered from hyperandrogenism, oligomenorrhea, polycystic ovaries and while was receiving oral contraceptives she developed intermittent angina attacks not strictly related to her medication. The angina attacks associated with increased cardiac enzymes increased high sensitivity cardiac troponin, skin itching and electrocardiographic changes suggesting of myocardial ischemia. Eosinophils were raised but the coronary arteries were normal. The angina attacks disappeared with discontinuation of contraceptives. Such angina attacks associated with such clinical setting are attributed to disease itself, to oral contraceptives and/or to Kounis hypersensitivity coronary syndrome, namely a dangerous triplet. Erol N, Karaagac AT, Kounis NG. Dangerous triplet: Polycystic ovary syndrome, oral contraceptives and Kounis syndrome. World J Cardiol 2014; 6(12): 1285-1289 Available from: URL: http://www.wjgnet.com/1949-8462/full/v6/i12/1285.htm DOI: http://dx.doi.org/10.4330/wjc.v6.i12.1285
Abstract Polycystic ovary syndrome is characterized by ovulatory dysfunction, androgen excess and polycystic ovaries and is associated with hypertension, diabetes, metabolic syndrome and cardiovascular events. Oral contraceptives constitute first-line treatment, particularly when symptomatic hyperandrogenism is present. However, these drugs are associated with cardiovascular events and hypersensitivity reactions that pose problem in differential diagnosis and therapy. We present a 14 year-old female with polycystic ovary syndrome taking oral contraceptive and suffering from recurrent coronary ischemic attacks with increased eosinophils, and troponin levels suggesting Kounis syndrome.
INTRODUCTION Polycystic ovary syndrome (PCOS) is a clinical disorder characterized by ovulatory dysfunction, androgen excess and polycystic ovaries. It is the most common endocrine disorder in the females of reproductive age, mostly presented with obesity, glucose intolerance, hyperinsulinemia, dyslipidemia and hypertension. The females with PCOS carry an increased risk of cardiovascular ischemic events independent of the obesity[1-3] with the prevalence of 4%-10%. In addition, the rate of occurrence of cardiovascular events in the 25-34-year-old female group with PCOS has been found to be 2.6%. Furthermore, therapy with combined oral contraceptives has been associated with both deep vein thrombosis and pulmonary embolism [4] as well as hypersensitivity reactions[5] that pose problems in differential diagnosis and treatment. We report a young
© 2014 Baishideng Publishing Group Inc. All rights reserved.
Key words: Contraceptives; Eosinophils; Kounis syndrome; Polycystic ovary syndrome; Troponin
WJC|www.wjgnet.com
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December 26, 2014|Volume 6|Issue 12|
Erol N et al . Kounis syndrome in PCOS Figure 1 Electrocardiogram during chest pain with increased troponin showing T wave inversion in lead III and flattening of T wave in lead left foot derivation in electrocardiography.
14-year-old female patient with PCOS who was exposed to the above dangerous triplet and suffered from recurrent attacks of chest pain with high troponin levels and increased eosinophils while the coronary arteries were normal.
T wave in lead left foot derivation in electrocardiography (Figure 1). Total cholesterol, triglyceride, high-dansity lipoprotein (HDL) cholesterol, low-dansity lipoprotein cholesterol and very low-dansity lipoprotein cholesterol levels were found to be 230 mg/dL, 290 mg/dL, 63 mg/dL, 108 mg/dL and 58 mg/dL, respectively. Eosinophils were also raised to 700/mm3 (normal levels up to 500/mm3). Chest radiography and echocardiography were also normal. Stress test, holter electrocardiogram and coronar y computed tomog raphy angiogram revealed no abnormality (Figure 2). The same clinical symptoms appeared while she was taking intermittently the contraceptive treatment and necessitating repeated hospital admissions, in approximately 1 or 2 mo intervals. At every hospitalization, repeated high sensitivity troponin levels and eosinophils were always elevated while the girl was feeling itchy. In view of the above findings we decided to change contraceptives to progesterone 5 mg and spironolactone 50 mg. After cessation of the oral contraceptive treatment, chest pain attacks disappeared despite taking the new medication. Biochemical tests, electrocardiogram (Figure 3), echocardiography, holter and repeated stress tests during the follow-up period of one year were all within normal limits. Cardiac enzymes and troponin returned to normal levels but eosinophils were still high (700/mm3). We did not perform skin prick tests and patch tests to oral contraceptives on ethical grounds. She was characterized as an atopic individual and was advised to refrain the previous contraceptive medication.
CASE REPORT A 14-year-old female [56 kg, 160 cm, body mass index (BMI): 21.87 kg/m2] attended the endocrinology outpatient clinic for PCOS due to hyperandrogenism, oligomenorrhea, and polycystic ovaries. She was referred to our pediatric cardiology clinic for recurrent chest pain attacks and the elevated cardiac enzymes while she was receiving intermittent contraceptive medication. In her past medical history, the prenatal and perinatal periods were uneventful. There was no consanguinity between her mother and father. There was no cardiovascular disease or any other chronic disease history in her family. Her physical growth and psychomotor development were compatible with her age. However, her thelarche and genital hair growth started at the age of 7.5 years. This was not accompanied by any menstual bleeding. The family brought her to endocrinology outpatient clinic where laboratory investigation showed high testosterone and cholesterol levels. Additional laboratory investigation for adrenal pathology revealed no abnormality. She was advised not to take any medication up to 14 years of age. At this age endocrinologists decided to put her on oral contraceptive (ethinyl estradiol + 0.03 mg drospirenone 3 mg combination) which resulted in menstrual bleeding. However, she could not use contraceptives regularly due to nausea, headache and loss of appetite. Three months later and while she was receiving intermittently the contraceptive therapy she experienced severe chest discomfort with skin itching lasting for 15 min and she was transferred to the emergency department. Serum creatine kinase muscle was 57 U/L (normal levels: 0-24) and the troponin level was 11.91 ng/mL (normal levels: 0-0.04). Her pulse was 100 beats per minute regular and electrocardiogram showed sinus rhythm, T wave inversion in lead Ⅲ and flattening of
WJC|www.wjgnet.com
DISCUSSION The diagnosis of PCOS is difficult because of the heterogeneity of the phenotype. The classical phenotype is observed in 75% of PCOS cases and cardiovascular risk factors are most frequently encountered in this group. Because several features of PCOS may be in evolution in adolescents, it was suggested recently[6] that only firm criteria should be used to make a diagnosis of PCOS during adolescence. These criteria include hyperandrogenism,
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Erol N et al . Kounis syndrome in PCOS
Figure 2 Normal computet tomography angiogram excluding thrombosis.
oligomenorrhea, and polycystic ovaries. Significant associations between PCOS and severity of cardiovascular diseases, family history of myocardial infarction as well as with elevated levels of insulin and triglycerides and lower levels of HDL-C have been reported[7]. Metabolic syndrome, type 2 diabetes, abdominal obesity and hypertension, are frequently observed in young patients with PCOS, which are factors associated with cardiovascular diseases. Our patient has had dyslipidemia with increased cholesterol and triglycerides. Oral contraceptives are used for the treatment of PCOS. Combined oral contraceptives containing drospirenone are preferred especially in the PCOS patients with hirsutism[8]. The risk of myocardial infarction and intracerebral events is 2.5% higher in the patients taking combined oral contraceptives containing low dose estrogen [9]. Our patient had no findings suggesting drug-related venous thromboembolism but she had chest discomfort associated with increased high sensitivity troponin levels and eosinophilia that suggested coronary event. Drug-related Kounis syndrome has been reported on several occasions[10]. In general, Kounis syndrome has an acute onset, but some subclinical cases have been reported[11]. Several mediators such as, cytokines and chemokines including histamine, neutral proteases, arachidonic acid products and platelet activating factor are released during the allergic episode. The same mediators are also involved in the acute coronary syndromes. Several drugs have been accused for triggering this syndrome. However, the only drug our patient took was oral contraceptive consisting of ethinyl estradiol and drospirenone. Allergy to oral contraceptive therapy has been already described on several occasions. Erythema multiforme limited to the oral mucosa was reported in
Figure 3 Normal electrocardiogram during cessation of contraceptive while the eosinophils were increased.
WJC|www.wjgnet.com
1287
December 26, 2014|Volume 6|Issue 12|
Erol N et al . Kounis syndrome in PCOS
Peer review
a teenager on oral ethinyl estradiol and drospirenone therapy[5]. Acquired angioedema has been also related to patients receiving oestrogen contraceptives and is frequently associated with recurrent urticarial[12]. Allergic contact dermatitis has been reported in some occasions with transdermal therapeutic systems containing ethinyl estradiol[13]. In view of the increased eosinophils, skin itching, normal coronary angiography, electrocardiographic changes and troponin increase diagnosis of type Ⅰ variant of Kounis syndrome[14] was made and the culprit medication was discontinued. Eosinophils have emerged as a novel biomarker of risk stratification in patients who have experienced coronary artery episodes[15]. With cessation of combination of ethinyl estradiol and drospirenone and changing it to progestogen-only contraceptives, symptoms of the patient disappeared while eosinophil count was still increased denoting atopic diathesis. In women with PCOS and multiple cardiovascular risk factors the use of progestogen-only contraceptives is associated with substantially less risk of cardiovascular events but the danger is still watching for, since this drug can induce hypersensitivity reactions[16]. Kounis syndrome, polycystic ovary syndrome and oral contraceptives seem to constitute a dangerous triplet and should be always suspected in order to establish correct diagnosis, apply appropriate treatment and avoid untoward consequences.
This case report is well written and addresses common problems with diagnostics of polycystic ovary syndrome associated with cardiovascular symptomatology, oral contraceptives and drug hypersensitivity culminating in the developement of Kounis syndrome.
REFERENCES 1
2
3
4
5
COMMENTS COMMENTS
6
Case characteristics
The young lady in this case has had polycystic ovary syndrome and while was receiving oral contraceptives she developed intermittent angina attacks, increased cardiac enzymes, increased high sensitivity cardiac troponin, eosinophilia with skin itching and electrocardiographic changes suggesting of myocardial ischemia.
7
Clinical diagnosis
Myocardial ischemia associated with Kounis syndrome, polycystic ovary syndrome, oral contraceptive therapy.
Differential diagnosis
8
Laboratory diagnosis
9
Angina attacks with increased cardiac enzymes, increased high sensitivity cardiac troponin, electrocardiographic changes suggesting of myocardial ischemia and eosinophilia with normal coronary arteries in polycystic ovary syndrome are attributed to disease itself, to oral contraceptives and/or to Kounis hypersensitivityassociated coronary syndrome. Myocardial ischemia in polycystic ovary syndrome associated with oral contraceptive therapy and eosinophilia.
Imaging diagnosis
Coronary computed tomography angiogram performed upon the suspicion of thrombosis revealed normal coronary arteries.
10
Treatment
Discontinuation of contraceptive treatment and changing it to progesterone (medroxyprogesteronacetate) and spironolactone alleviated the symptomatology.
11
Related reports
Hyperandrogenism, oligomenorrhea, polycystic ovaries constitute the polycystic ovary syndrome which occasionally is associated with cardiovascular events, enhanced by hypersensitivity reaction to concomitant contraceptive medication.
12
Experiences and lessons
Patients with polycystic ovary syndrome who have to use oral contraceptives should be evaluated separately in terms of drug related cardiac events and hypersensitivity associated with Kounis syndrome.
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Lo JC, Feigenbaum SL, Yang J, Pressman AR, Selby JV, Go AS. Epidemiology and adverse cardiovascular risk profile of diagnosed polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91: 1357-1363 [PMID: 16434451 DOI: 10.1210/ jc.2005-2430] Orio F, Palomba S, Spinelli L, Cascella T, Tauchmanovà L, Zullo F, Lombardi G, Colao A. The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. J Clin Endocrinol Metab 2004; 89: 3696-3701 [PMID: 15292291 DOI: 10.1210/jc.2003-032049] Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, Futterweit W, Lobo R, Norman RJ, Talbott E, Dumesic DA. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab 2010; 95: 2038-2049 [PMID: 20375205 DOI: 10.1210/jc.2009-2724] Gronich N, Lavi I, Rennert G. Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: a population-based cohort study. CMAJ 2011; 183: E1319-E1325 [PMID: 22065352 DOI: 10.1503/cmaj.110463] Jawetz RE, Elkin A, Michael L, Jawetz SA, Shin HT. Erythema multiforme limited to the oral mucosa in a teenager on oral contraceptive therapy. J Pediatr Adolesc Gynecol 2007; 20: 309-313 [PMID: 17868899 DOI: 10.1016/j.jpag.2007.02.001] Carmina E, Oberfield SE, Lobo RA. The diagnosis of polycystic ovary syndrome in adolescents. Am J Obstet Gynecol 2010; 203: 201.e1-201.e5 [PMID: 20435290 DOI: 10.1016/ j.ajog.2010.03.008] Shroff R, Kerchner A, Maifeld M, Van Beek EJ, Jagasia D, Dokras A. Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis. J Clin Endocrinol Metab 2007; 92: 4609-4614 [PMID: 17848406 DOI: 10.1210/jc.2007-1343] Guido M, Romualdi D, Giuliani M, Suriano R, Selvaggi L, Apa R, Lanzone A. Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study. J Clin Endocrinol Metab 2004; 89: 2817-2823 [PMID: 15181063 DOI: 10.1210/ jc.2003-031158] Baillargeon JP, McClish DK, Essah PA, Nestler JE. Association between the current use of low-dose oral contraceptives and cardiovascular arterial disease: a meta-analysis. J Clin Endocrinol Metab 2005; 90: 3863-3870 [PMID: 15814774 DOI: 10.1210/ jc.2004-1958] González-de-Olano D, Gandolfo-Cano M, MohedanoVicente E, González-Mancebo E, Matito A, Kounis NG, Escribano L. Kounis syndrome following the performance of skin test to amoxicillin. Int J Cardiol 2014; 174: 856-857 [PMID: 24801079 DOI: 10.1016/j.ijcard.2014.04.191] Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol 2006; 110: 7-14 [PMID: 16249041 DOI: 10.1016/j.ijcard.2005.08.007] Giard C, Nicolie B, Drouet M, Lefebvre-Lacoeuille C, Le Sellin J, Bonneau JC, Maillard H, Rénier G, Cichon S, Ponard D, Drouet C, Martin L. Angio-oedema induced by oestrogen contraceptives is mediated by bradykinin and is frequently associated with urticaria. Dermatology 2012; 225: 62-69 [PMID: 22922353 DOI: 10.1159/000340029]
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Koch P. Allergic contact dermatitis from estradiol and norethisterone acetate in a transdermal hormonal patch. Contact Dermatitis 2001; 44: 112-113 [PMID: 11205390 DOI: 10.1034/ j.1600-0536.2001.44020914.X] Kounis NG, Mazarakis A, Tsigkas G, Giannopoulos S, Goudevenos J. Kounis syndrome: a new twist on an old disease. Future Cardiol 2011; 7: 805-824 [PMID: 22050066 DOI: 10.2217/fca.11.63]
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Kounis NG, Soufras GD, Tsigkas G, Hahalis G. White blood count and infarct size, myocardial salvage and clinical outcomes: the role of differentials. Int J Cardiovasc Imaging 2014; 30: 677-679 [PMID: 24384860 DOI: 10.1007/s10554-013-0359-7] Bernstein IL, Bernstein DI, Lummus ZL, Bernstein JA. A case of progesterone-induced anaphylaxis, cyclic urticaria/angioedema, and autoimmune dermatitis. J Womens Health (Larchmt) 2011; 20: 643-648 [PMID: 21417747 DOI: 10.1089/jwh.2010.2468] P- Reviewer: Aggarwal A, Kettering K, Lonardo F, Patanè S, Petix NR, Ueda H S- Editor: Tian YL L- Editor: A E- Editor: Wu HL
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