NDT Advance Access originally published online on October 2, 2006
Nephrology Dialysis Transplantation 2007 22(1):293; doi:10.1093/ndt/gfl500
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Eplerenone relieves spironolactone-induced painful gynaecomastia in a patient with primary aldosteronism
Email: astkar{at}med.auth.grSir,
Eplerenone is the second oral aldosterone antagonist available for the treatment of essential hypertension and congestive heart failure. Spironolactone, the first aldosterone antagonist, although effective for the above conditions, has progestational and antiandrogenic adverse effects due to its non-specific binding to various steroid receptors.
We report the case of a 54-year-old Caucasian man, who was admitted to hospital because of severe hypertension and hypokalaemia. The plasma aldosterone/plasma renin activity ratio was well above the cut-off level of 30 ng/dl/ng ml–1 h–1. The acute intravascular volume expansion with the intravenous administration of isotonic saline showed autonomous aldosterone production. The aforementioned results were considered diagnostic of primary aldosteronism. A computerized tomography scan with fine cuts (2.5–3 mm) showed bilateral adrenal gland hyperplasia. Therefore, the patient was started on spironolactone 100 mg t.d.s., and in the following days normokalaemia was restored and blood pressure was well-controlled. Two months later, the patient presented with bilateral painful gynaecomastia. We switched spironolactone to eplerenone 25 mg t.d.s., and the patient was completely relieved within 1 month, while his blood pressure remained well-controlled and serum potassium was normal.
Spironolactone is the drug of choice for the treatment of primary aldosteronism, but presents sexual side effects, such as impotence, painful gynaecomastia and menstrual disturbances in pre-menopausal women. Several mechanisms have been proposed for these side effects, such as a dose-dependent reduction of microsomal cytochrome P-450, alterations of the testosterone–estrogen ratio, a fall in plasma testosterone or a significant increase in its metabolic clearance, and the peripheral conversion of testosterone to estradiol or increased serum levels of estrone and estradiol [1]. Gynaecomastia may be quite remarkable and its occurrence is dose- and time-dependent.
Eplerenone is a highly selective aldosterone antagonist. Spironolactone is approximately 40-fold more potent than eplerenone in blocking aldosterone activation of mineralocorticoid receptor. However, the selectivity of eplerenone is significantly greater than spironolactone at androgen, progesterone and glucocorticoid receptors. Eplerenone is 370-fold less potent at blocking dihydrotestosterone-activation of androgen receptors compared with spironolactone [2].
Two large clinical studies have evaluated the efficacy and tolerability of these aldosterone antagonists. The Randomized Aldactone Evaluation Study (RALES) found that the administration of spironolactone 12.5–50 mg/day, in addition to standard therapy, substantially reduced the risk of both morbidity and mortality among patients with severe heart failure [3]. The Eplerenone Post Acute Myocardial Infarction (AMI) Heart Failure Efficacy and Survival Study (EPHESUS) showed that eplerenone 25–50 mg/day (when initiated at a mean of 7.3 days after AMI) significantly reduced all-cause mortality 30 days after randomization, in addition to conventional therapy in patients with a left ventricular ejection fraction 
40% and signs of heart failure [4]. However, there are major differences in the incidence of sexual side effects between the two studies. In the RALES study, the incidence of gynaecomastia in men was 9 and 1% (P < 0.001); breast pain was 2 and 0.1% (P < 0.006) in the spironolactone and the placebo group, respectively. On the other hand, in the EPHESUS study, the incidence of gynaecomastia in men was 0.5 and 0.6%; impotence was the same (0.9%) and breast pain in women was 0.1 and 0.3% in the eplerenone and the placebo group, respectively.
In conclusion, the use of a selective aldosterone-receptor antagonist such as eplerenone that has a lower affinity for androgen and progesterone receptors, in comparison with spironolactone, may minimize the risk of gynaecomastia and other unfavourable sexual side effects.
Conflict of interest statement. None declared.
Second Propedeutic Department of Internal Medicine
Medical School
Aristotle University of Thessaloniki
Hippokration Hospital
Thessaloniki
Greece
References
- Menard J. (2004) The 45-year story of the development of an anti-aldosterone more specific than spironolactone. Mol Cell Endocrinol 217:45–52.[CrossRef][Web of Science][Medline]
- Garthwaite SM and McMahon EG. (2004) The evolution of aldosterone antagonists. Mol Cell Endocrinol 217:27–31.[CrossRef][Web of Science][Medline]
- Pitt B, Zannad F, Remme WJ, et al. (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators. N Engl J Med 341:709–717.
[Abstract/Free Full Text] - Pitt B, Williams G, Remme W, et al. (2001) The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone post-AMI heart failure efficacy and survival study. Cardiovasc Drugs Ther 15:79–87.[CrossRef][Web of Science][Medline]
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