Erectile Dysfunction as an Adverse Drug Reaction

Introduction

As primary prevention for a myocardial infarction or stroke, you’ve prescribed a statin, possibly in conjunction with a fibrate, for a 50 year old male patient with one or more of the following: metabolic syndrome, type 2 diabetes, hypercholesterolemia, coronary artery disease or peripheral artery disease. In a follow-up visit, his PSA is elevated, and he complains of awakening several times each night to urinate. You prescribe finasteride. He returns several months later, worried the recession will result in his being laid off, feeling very anxious, and experiencing insomnia. After further evaluation, it’s clear he is depressed. You prescribe an SSRI.

What’s the likelihood that this patient will experience erectile dysfunction (ED) as a result of one or more of these therapies and will simply stop taking the medication(s) rather than discuss this problem with you? Unfortunately, risk for this scenario is surprisingly high.

ED remains a greatly under-reported adverse drug reaction (ADR) because male patients often are not forthcoming about, and doctors usually do not raise the issue of, sexual function. The Massachusetts Male Aging Study data showed an annual incidence of ED in men 40 – 69 years of age of 26 per 1000 men (an incidence of 12 in the 40–49-year age group and 46 in the 60–69-year age group); however, these statistics may seriously underestimate the problem.¹  Research presented at the Second Princeton Consensus Conference on Sexual Dysfunction and Cardiac Risk indicates that ED affects more than half of men >60 years.²

Since the major comorbidities of ED –diabetes, hypertension, hyperlipidemia and depression—are also key risk factors for cardiovascular disease, the question of whether the drugs used to treat these conditions might also be contributing to ED has not received much consideration, despite the fact that many of the drugs used to manage the underlying risk factors of atherosclerosis (e.g. ß-blockers, thiazide diuretics, ACE inhibitors) are well known to be risk factors for ED.³⁴⁵⁶⁷

A recent French Pharmacovigilance System Database assessment of the association between drugs and risk of ED not only confirmed a significant association for finasteride (adjusted relative odds ratio [aROR] = 14.5), fibrates (aROR = 3.6), ß-blockers (aROR = 1.5) and tricyclic antidepressants (aROR = 2.0), but revealed a surprising statistically significant association between all statins (aROR = 2.4) and ED.^{8 9}

Statin-associated ED

Given statins’ efficacy in lowering cholesterol and therefore lessening cardiovascular disease risk, an association between these drugs and increased risk for ED seems counterintuitive. However, a number of recent studies indicate the statin-to-ED connection is real.

When a group of 76 men with stable coronary artery disease, average age 64 years (range 40 to 82), were evaluated using the validated Sexual Health Inventory for Men (SHIM), 57 of the 76 (75%) had ED.  Of those with ED, 28% were on diuretics, 47% on β-blockers, but almost all, 92%, were on statins.¹⁰

As noted above, a significant association was found in the French Pharmacovigilance System Database between exposure to statins and ED. Among the total of case reports of ADRs, exposure to statins was identified in 4471 cases (4%), of which 51 reports (1.1%) concerned ED, in comparison to 431 (0.4%) cases of ED without exposure to statins. The mean delay of onset of ED after starting statins, known for 19 cases, was 62 days (median 29 days). In 56.9% of cases, recovery occurred after withdrawal of statin, and rechallenge was positive in five cases. The association with ED was statistically significant for all statins (adjusted ROR = 2.4) with adjusted relative risks for simvastatin of 2.6;  atorvastatin, 3.4; and rosuvastatin, 7.1.⁸

An earlier study involved 38 cases of impotence associated with statins in the database of the Spanish pharmacovigilance system plus 37 statin-associated cases in French pharmacovigilance system. Among the Spanish men, ED disappeared after drug withdrawal in 93% of the cases. In France, recovery was observed in 85% of cases after drug withdrawal, and in 5 cases, a positive rechallenge confirmed the ADR and recovery after cessation of statin use.⁹

How might statins promote ED?

The statin-induced decrease in cholesterol levels could negatively impact testosterone synthesis.¹¹   In vitro assays have shown that in concentrations “probably [italics added] exceeding those achieved in vivo,” simvastatin inhibits not only HMG-CoA reductase, but the 17-ketosteroid-oxidoreductase catalyzed conversion of dehydroepiandrosterone and androstenedione to androstenediol and testosterone, respectively.¹²   In support of this hypothesis, a significant decrease in free testosterone has been noted in men treated with simvastatin for hypercholesterolemia. In a study of 8 hypercholesterolemic men, free testosterone levels were determined at baseline in basal conditions and after stimulation by human Chorionic Gonadotropin, and again after 3, 6 and 12 months of treatment with simvastatin (20 mg/day). Significant reductions in free testosterone, both basal and hCG-stimulated, were observed at 6 and 12 months.¹³

In a larger study, involving 81 men, the pooled total testosterone level at baseline was 541 and 513 ng/dL in the placebo and simvastatin-treated groups, respectively, and declined to 536 ng/dL (-1.5%) and 474 ng/dL (-13.6%) after simvastatin treatment. The pooled free testosterone declined by 6.3% in the simvastatin group, while increasing 4.9% in the placebo group. Pooled bioavailable testosterone declined 10.2% in the simvastatin group, while increasing 1.4% in the placebo group.¹⁴

In addition, in familial hypercholesterolemia, the low-density lipoprotein receptor is dysfunctional, which renders the Leydig cells more dependent on ‘de novo’ synthesis of cholesterol (Leydig cells are interstitial cells in the testes that secrete testosterone when stimulated by lutenizing hormone. [Lutenizing hormone increases the activity of cholesterol desmolase, which converts cholesterol to pregnenolone, the prohormone precursor of progesterone, mineralocorticoids, glucocorticoids, androgens, including testosterone, and estrogens].) Statins have been found in small quantities in the testes, where they could inhibit this de novo synthesis of cholesterol.^{8 15}

Most recently (February 2010), the association between statin therapy and hormonal parameters was evaluated in a consecutive series of 3,484 patients (mean age 51.6 +/- 13.1 years) seeking medical care for ED at the Andrology Unit, University of Florence, Florence, Italy.  Among the patients studied, 244 (7%) patients were being treated with statins. Both total and calculated free testosterone levels were significantly lower in subjects taking statins. The use of statins was also associated with a reduced testis volume and a higher prevalence of hypogonadism-related symptoms and signs. The lower levels of total and calculated free T observed in subjects treated with statins were confirmed by comparing them with age-waist circumference and CV risk score matched controls. The researchers concluded that statin therapy might induce an overt primary hypogonadism and should be considered as a possible confounding factor for the evaluation of testosterone levels in patients with ED.¹⁶

Although ED appears, statistically, to be a rare ADR of statin therapy, the high rate of under-reporting of ED by male patients is likely to mitigate against an accurate estimate of the true prevalence of statin-related ED. Despite this, a significant literature from case reports, review articles, clinical trials and regulatory agencies has now identified statins, as well as fibrates, as a likely cause of ED.  The topic of a possible association between sexual disturbances and statins is being currently discussed at the European Medicine Agency.⁸

Exposure to statins may act as the final straw, lowering testosterone levels and producing frank ED in patients with endothelial dysfunction for whom cholesterol-lowering is neither the key—nor sufficient—means of resolving the underlying factors contributing to their risk for cardiovascular disease. (For a more complete review of this issue and discussion of agents that effectively improve cardiovascular function without increasing risk of ED, please see our earlier LMR articles “Managing Erectile Dysfunction—When Viagra Doesn’t” and the series on “Closing the Statin Gap”).

5-alpha reductase inhibitors (e.g., Finasteride) and ED

5-alpha reductase inhibitors (finasteride and dutasteride), the most commonly used drugs to treat benign prostatic hyperplasia, are associated with adverse sexual outcomes, including ED, at rates ranging from 2.1% to 38% in clinical trials. These drugs inhibit type II 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT). Of the two, dutasteride is more likely to cause ED since unlike finasteride, it inhibits both isoenzymes of 5-alpha reductase and results in near-complete suppression of serum dihydrotestosterone.¹⁸  The proposed mechanism via which the 5-alpha reductase inhibitors promote ED is decreased nitric oxide synthase activity as a result of decreased dihydrotestosterone.¹⁹

Natural agents, shown in systematic reviews to improve overall urologic symptoms of BPH including nocturia, without any increase in risk of ED, include cernilton, which is prepared from the rye-grass pollen Secale cereal,²⁰   Pygeum africanum, the extract of the African prune tree,²⁰  and Serenoa repens, the extract of the berry of the American saw palmetto, although the two most recent Cochrane Database Systematic Reviews have produced inconsistent results regarding its efficacy. Research included in the 2002 review, which included 21 randomized trials involving 3139 men, found that Serenoa repens provides mild to moderate improvement in urinary symptoms and flow measures.²¹  The 2009 review, which included 9 new trials involving 2053 additional men, found saw palmetto no more effective than placebo for treatment of the urinary symptoms of BPH.²²

SSRIs, highly likely to cause ED

Sexual dysfunction secondary to the use of antidepressants, especially SSRIs, is an adverse effect that is often underestimated, and one that, according to a number of studies, may affect from 58% to 73% of patients.^23242526 Approximately 42% of men discontinue antidepressant treatment due to its adverse sexual effects.   These present as a decrease in libido, alterations in the ability to reach orgasm/ejaculation, and ED, which appears to be related to the resulting increase in serotonin. Increased availability of serotonin results in its increased binding to and activation of the serotonin (aka 5-hydroxytryptamine) receptors 2 and 3 [the 5-HT2 and 5-HT3 receptors], which inhibit sexual desire, ejaculation, and orgasm. Thus increasing serotonin levels   promotes ED, whereas dopamine release enhances sexual function. Amineptine, a drug with an increased dopamine transmission and scant serotonin transmission, may have a more benign impact on the sexual function of depressed patients.²⁸  After substituting amineptine for SSRIs in patients with sexual dysfunction, the incidence of any type of sexual dysfunction decreased significantly from 100% (baseline) to 55.3% after 6 months. Incidence of delayed orgasm dropped to 15.8%, anorgasmia to 17.4%, and impotence to 15.8%, while the antidepressant effect that had already been achieved with the SSRI was maintained.²⁹

The best researched alternative to SSRIs, which does not increase risk of ED, is Hypericum perforatum (St. John’s Wort). Numerous randomized clinical trials, including those covered in the most recent Cochrane Database Systematic Review, confirm that Hypericum extracts are superior to placebo in patients with major depression, are similarly effective as standard antidepressants, and have fewer side effects than standard antidepressants.³⁰³¹

Conclusion

Considering the widespread use of the above drugs, especially statins, and the under-reporting of ED as an ADR, drug-associated ED may affect a large number of male patients. Fortunately, ED resulting from treatment with ß-blockers, thiazide diuretics, ACE inhibitors, fibrates, statins, finasteride, tricyclic antidepressants or SSRIs seems to be reversible in most of cases after drug withdrawal. Doctors should be aware of this potential adverse reaction when prescribing any of these drugs to their patients.

References