Sex-hormone-related Side Effects of Mineralocorticoid Antagonists
Non-selective MRAs
SPL is an effective MRA but can provoke undesirable sexual side effects leading to its discontinuation. This phenomenon results from non-selective binding of SPL to androgen and progesterone receptors and includes gynecomastia, breast pain, menstrual irregularities, impotence, and decreased libido. The RALES trial highlights both the frequency of sexual side effects of MRA, and its impact in impairing compliance. This study included 1663 patients with heart failure who were randomly assigned to placebo or a single daily dose of SPL (25 to 50 mg daily). Candidates were excluded if they had a serum creatinine concentration >2.5 mg/dl (221 μmol/l) or a serum K concentration >5.0 mEq/l. SPL was generally well tolerated. Gynecomastia or breast pain was reported by 10% of the men in the SPL group and 1% of the men in the placebo group (P<0.001), causing more patients in the SPL group than in the placebo group to discontinue treatment (10 vs. 1, P=0.006). SPL did not induce additional side effects in respiratory, metabolic, urinary, skin, gastrointestinal, or central nervous system compared with placebo.
Selective MRAs
EPL is a competitive antagonist of the MR and is an effective and selective MRA. In EPL, 17-α-thoacetyl group of SPL is replaced with a carbomethoxy group, conferring excellent selectivity for the MR over other steroid receptors. Thus, EPL possess an advantage over SPL because it produces few if any significant and debilitating sexual side effects.
In the EPHESUS trial, safety of EPL (25 mg per day initially, titrated to a maximum of 50 mg per day during a mean follow-up of 16 months) was evaluated in 3307 patients treated with EPL and 3301 placebo-treated patients. The overall incidence of adverse events reported with EPL (78.9%) was similar to placebo (79.5%). Adverse events occurred at a similar rate regardless of age, gender, or race. Patients discontinued treatment because of an adverse event at similar rates in either treatment group (4.4% EPL vs. 4.3% placebo), with the most common reasons for discontinuation being hyperkalemia, myocardial infarction, and abnormal renal function. The rates of sex-hormone–related adverse events as gynecomastia, mastodynia, abnormal vaginal bleeding was 0.5% in EPL and 0.6% in the placebo groups. EMPHASIS-HF trial was consistent with these results and did not demonstrate increased sex-hormone–related adverse events related to EPL therapy.