CASE REPORT Intisari Sains Medis 2021, Volume 12, Number 1: 60-63 P-ISSN: 2503-3638, E-ISSN: 2089-9084 High dose and long-term use of induce gynecomastia in an elderly man with chronic heart failure: a case report

Published by Intisari Sains Medis Putu Giani Anabella Bestari Putri1*, Nurfitriani1, I Gusti Ayu Suryawati2

ABSTRACT Introduction: Gynecomastia is caused by an 40 mg once a day, Clopidogrel 75 mg once a day, imbalance of and in the male Valsartan 10 mg once a day, Bisoprolol 1.25 mg once a tissue. It can be divided into three causes, physiological, day, and Spironolactone 100 mg once a day. On physical drug-induced, and idiopathic. Spironolactone is a examination, tenderness was felt on the right breast. potassium-sparing diuretic that has known to pose an Fine-needle aspiration cytology examination of the effect and can cause gynecomastia. right breast was conducted, the finding was compatible Case Description: A 75 years old man came for with gynecomastia. a regular cardiac examination at the hospital. He Conclusion: Gynecomastia is a breast enlargement 1 General Practitioner, Bangli General Hospital, complained of tenderness and pain at his right breast in men that occurred due to hormonal imbalance and Bangli, Bali, Indonesia for the last six months and only getting worse since most often caused by the side effect of a high-dose and 2Cardiology division, Bangli General Hospital, Bangli, Bali, Indonesia the previous two weeks. He had a regular appointment long-term use of Spironolactone. Discontinuation of the with a cardiologist after diagnosed with Chronic Heart spironolactone treatment or switching to other therapy Failure Functional Class III, Suspected as Coronary is recommended. However, gynecomastia should not *Corresponding author: Artery Disease, Hypertensive Heart Disease since be used as a reason for not prescribing Spironolactone Putu Giani Anabella Bestari Putri; General January 2017. The patient regularly takes Furosemide to patients with severe heart failure. Practitioner, Bangli General Hospital, Bangli, Bali, Indonesia; [email protected] Keywords: chronic heart failure, gynecomastia, spironolactone. Cite This Article: Putri, P.G.A.B., Nurfitriani., Suryawati, I.G.A. 2021.High dose and long-term use of spironolactone induce gynecomastia in an elderly man with chronic heart failure: a case report. Intisari Sains Medis 12(1): 60-63. Received: 2021-01-24 DOI: 10.15562/ism.v12i1.972 Accepted: 2021-03-27 Published: 2021-04-01

INTRODUCTION endocrine diseases such as a testicular, class III and IV. It was also used when the adrenocortical, pituitary tumor, optimal dose of beta-blocker and ACEI or Gynecomastia is a benign condition of hyperthyroid, and non-endocrine ARB had been reached, but the patient still breast enlargement that happens to men, causes such as , stress, and renal symptomatic.4 caused by the proliferation of glandular failure.3 Around 20%-25% of new cases tissue and local fat accumulation. of gynecomastia are triggered by drugs. CASE Gynecomastia can make patients feel One of the drugs that quite often cause A 75-year-old man came to the uncomfortable, cause psychological stress, gynecomastia is spironolactone diuretic. cardiologist for routine examination with and harms self-confidence. Meanwhile, Spironolactone mainly works as an a chief complaint of pain on the right side pseudo-gynecomastia frequently occurred aldosterone antagonist. Spironolactone of his chest. The chest also felt tender and in men with , without glandular also inhibits production 1 heavy for the previous six months, and it is proliferation. Proliferation on breast in the , increases the process of getting worse for the last two weeks before tissue can occur at any age and can be of testosterone to , his routine visit to the clinic. The patient unilateral or bilateral. Gynecomastia can and binds with androgen receptors at routinely checks himself to a cardiologist occur in 36% of young adult men aged 17 some tissues. Thus, spironolactone also every month. On examination, complaints to 58 years old, and 50% can be found in works as an anti-androgenic substance.1 2 such as pain in the left chest that men age above 44 years old. Spironolactone is one of the therapies that penetrates the back, being crushed, cold Gynecomastia can happen because of must be considered for all patients with sweat were absent. The only complaint a physiological process or pathological ejection fraction less than 35% and severe was shortness of breath that exaggerated conditions such as induced by drugs, symptomatic heart failure functional

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when the patients do moderate to heavy DISCUSSION Spironolactone work as aldosterone activity. The patient usually sleeps with antagonist. Spironolactone also inhibits Gynecomastia is referred to as a condition three pillows. Urination and defecation testosterone production in the testicle, where one or both of the men’s frequency was within normal limits. This increases the process of testosterone enlarged.5 To differentiate between the true patient has been diagnosed with chronic aromatization to estradiol, and gynecomastia with pseudo-gynecomastia heart failure functional class III, coronary spironolactone also binds to the androgen or another kind of breast tumor, proper artery disease, and hypertensive heart receptor in several tissues.1 Spironolactone physical examination through inspection disease since 2017. Since then, he has inhibits the androgen receptor and prevents and palpation had to be done. In true been prescribed the following medication, the receptor from binding with testosterone Gynecomastia, the tissue will feel tender, furosemide 40 mg once a day, clopidogrel concentric around the and . 75 mg once a day, valsartan 10 mg once Meanwhile, patients with pseudo- a day, bisoprolol 1.25 mg once a day and gynecomastia do not show a consistency spironolactone 100 once mg per day. such as a tender mound and do not pose The patient appeared to be in full a strong bond with surrounding tissues.1 awareness (compos mentis) and moderate This is consistent with what was found pain from the physical examination. in this patient. From chest examination, Blood pressure was 100/80 mmHg, it was found that the right breast looked pulse frequency of 84 times per minute, slightly larger than the left breast, and on respiratory rate of 22 times per minute, palpation, it was tender. the body temperature of 37°C. The general Gynecomastia is caused by benign examination found that eye within normal hyperplasia from the glandular, fibrous, and limits, with no sign of anemia or icterus. that occurred because of the From inspection of the chest, it was found imbalance of estrogen and androgen that that the chest looks symmetric, with affects these breast tissue. Gynecomastia slight size differences of the right breast can occur because of many pathological (figure ).1 Chest auscultation revealed conditions. One of the most common vesicular breathing on both sides of lung triggering factors is drugs which affect fields. The right breast felt more tender the hormonal balance. It is estimated that from breast palpation than the left, and drugs, including spironolactone, caused the patient complained of pain when the around 10-20% of the gynecomastia.5 Figure 1. Swelling on the right breast. right breast was pressed. From extremities examination, it was warm, and no was present. From echocardiography examination, it was found that the patient had coronary heart disease, left heart hypertrophy, with an ejection fraction of 76.74%. Regarding the breast-related complaint, the patient was consulted with a surgeon. The patient did the fine-needle aspiration cytology examination. The cytology examination from the sample taken from the right breast was compatible with gynecomastia’s cells. Based on these data, the patient was diagnosed with gynecomastia induced by spironolactone. The cardiologist gives the patient furosemide 40 mg once per day, clopidogrel 75 mg once per day, valsartan 10 mg once per day, bisoprolol 1.25 mg per day, and the spironolactone treatment had to be stopped for a month. The surgeon prescribed a treatment of LanturolTM 400 once mg per day and meloxicam 15 mg once per day. Figure 2. The mechanism of spironolactone involvement in the development of gynecomastia.5

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the risk gynecomastia. However, gynecomastia’s risk should not be used as a barrier to prescribing Spironolactone to a man with severe heart failure, as it could significantly decrease the risk of morbidity and mortality.9

CONCLUSION Gynecomastia is breast enlargement in men that can make the patients feel uncomfortable and psychologically stressed. One of the most common causes Figure 3. Prevalence of gynecomastia in a double-blinded study of 79 adult men. of gynecomastia is the side effect of HCTZ = Hydrochlorothiazide.6 prolonged, high doses of spironolactone medication. Spironolactone can cause gynecomastia through several and . This substance 100 mg once per day, and he started to feel mechanisms that disrupt the balance decreases testosterone production by chest tenderness and pain in June 2019. of estradiol and testosterone level in a testicle and inhibits the 17-alpha- Another research by Chapman et al. the blood. The clinician can remind the hydroxylase and 17,20-desmolase enzyme. showed that out of 1790 participants who patient of spironolactone’s side effects Furthermore, spironolactone replaces consumed Spironolactone, gynecomastia to prevent drug usage due to their own testosterone binding with SHBG (sex occurred in 114 male participants and led will, misunderstanding, and anxiety hormone-binding globulin) and increases to discontinued use in 52 participants.8 due to side effects. Discontinuation of the metabolic cleaning of Testosterone. In a case-control study by Nuttall et spironolactone or changing to another This will escalate the estrogen level by al., among the 16 subjects studied, all therapy with a similar therapeutic increasing the peripheral testosterone subjects that received spironolactone and function such as Canreonate or conversion into estradiol (Figure 2). had complaints of swelling on the breast is recommended. Side effects This mechanism augments the level without any pain or tenderness. They also such as gynecomastia should not be used of estradiol in the blood that leads to found that the testosterone levels in their as an obstacle for giving spironolactone gynecomastia. However, the involvement blood were significantly decreased while to patients with severe heart failure, of spironolactone with gynecomastia is their blood estradiol level increased. This considering that spironolactone can heavily influenced by its dose and duration suggests that spironolactone alters the reduce morbidity and mortality risk in of use.3,5 peripheral testosterone metabolism in patients with heart failure. A previous report from the Boston some men and causes testosterone ratio Collaborative Drug Surveillance reported changes to estradiol. The gynecomastia DISCLOSURE that out of 788 patients with gynecomastia disappears after they discontinued the hospitalized, 20.8% of them had a history spironolactone.2 Current report has been previously of using Spironolactone for therapy. In this patient, the spironolactone presented in Bali Cardiology Update 2019 Among 79 gynecomastia males with treatment was stopped. He was given as a poster presentation without any prior spironolactone therapy, it was found another additional therapy by the surgeon, publication on the event. that 5.69% of these patients were on LanturolTM 400 mg per day and Meloxicam 50 mg of spironolactone twice per day, 15 mg per day. Discontinuation of ETHICAL CONSIDERATION 11.8% on 100 mg of spironolactone spironolactone treatment or replacement The authors had gained consent from the twice per day, 40.4% patients on 200 mg with other drugs with similar function patients to publish his case in an academic of spironolactone twice per day (Figure is recommended. For example, the journal without revealing any personal 3). The prevalence of gynecomastia cancreonate, one of the two spironolactone identity and solely for academic purposes. increases with the increasing dose of metabolites, shows a similar therapeutic spironolactone consumed.6 Another study effect to spironolactone but without the CONFLICT OF INTEREST in France involving 182 patients reported side effects from any other metabolite gynecomastia incidence also related to such as 17-alpha-hydroksyspironolactone, The authors stated that there is no conflict the Spironolactone dose, about 7.0% which is responsible for gynecomastia. of interest in writing this article. among the patients who consumed a 25- Eplerenone can also be used as a FUNDING 50 mg spironolactone, 16.7% for 75-100 replacement for spironolactone.5 mg, and 52.2% for 150-300 mg.7 In this Eplerenone has a lower affinity to The author is independently responsible case, the patient was known to consume androgen and receptors for this case report’s funding without spironolactone since 2017. The dose was than spironolactone, thereby minimizing

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involving sponsorship or other funding 2. Nuttall FQ, Warrier RS, Gannon MC. 7. Jeunemaitre X, Chatellier G, Kreft-Jais C, sources. Gynecomastia and drugs: a critical evaluation of Charru A, DeVries C, Plouin PF, et al. Efficacy the literature. Eur J Clin Pharmacol. 2015/04/02 and tolerance of spironolactone in essential ed. 2015;71(5):569–78. hypertension. Am J Cardiol. 1987;60(10):820–5. AUTHOR CONTRIBUTION 3. Veeregowda SH, Krishnamurthy JJ, 8. Chapman N, Dobson J, Wilson S, Dahlöf B, Krishnaswamy B, Narayana S. Spironolactone- Sever PS, Wedel H, et al. Effect of Spironolactone IGAS was responsible for the patient Induced Unilateral Gynecomastia. Int J Appl on Blood Pressure in Subjects With Resistant management and oversight of the Basic Med Res. 2018;8(1):45–7. Hypertension. Hypertension. 2007;49(4):839– pharmacotherapy of the patient. PGABP 4. Siswanto B, Hersunarti N, Erwinanto, 45. and NF were responsible for writing Nauli SE, Lubis AC, Wiryawan N, et al. 9. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne Pedoman Tatalaksana Gagal Jantung. Jakarta: A, Perez A, et al. The Effect of Spironolactone on the report and conducting follow-up Perhimpunan Dokter Spesialis Kardiovaskular; Morbidity and Mortality in Patients with Severe examinations in collaboration with IGAS. 2015. 48 p. Heart Failure. N Engl J Med. 1999;341(10):709– 5. Schab K, Prystupa A, Mulawka D, Mulawka 17. REFERENCE P. Severe gynaecomastia associated with spironolactone treatment in a patient with 1. Barros ACSD de, Sampaio M de CM. decompensated alcoholic liver cirrhosis – Case Gynecomastia: physiopathology, evaluation and report. J Pre-Clin Clin Res. 2015;9(1):92–5. treatment. Sao Paulo Med J. 2012;130(3):187– 6. Prisant LM, Chin E. Gynecomastia and 97. Hypertension. J Clin Hypertens. 2005;7(4):245– 8.

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