5 Alpha-reductase inhibitors (finasteride [propecia, proscar], dutasteride [avodart] – associated sexual dysfunction)
Content written by Irwin Goldstein, MD
The body synthesizes testosterone in response to pituitary-derived luteinizing hormone that causes the testicular cells (Leydig cells) to produce testosterone. Testosterone enters the circulation system and passes to various target tissues, such as the penis, bone, brain, proatate and skeletal muscles. Once inside the cell, testosterone is metabolized to its more active form, dihydrotestosterone (DHT), by the enzyme 5 alpha-reductase. There are two type (isoforms) of 5 alpha-reductase enzyme. Type two 5 alpha-reductase enzyme is the predominant isoform present in prostate tissue, while the type one isoform is found predominantly in skin and liver. Dihydroptestosterone has the highest affinity for the androgen receptor.
Finasteride (Proscar, Propecia) is a synthetic 4-azosteroid that competitively inhibits the conversion of testosterone to dihydrotestosterone in the cell. Finasteride is a selective inhibitor of the type 2 isoform of 5 alpha-reductase. Finasteride results in a reduction of plasma dihydrotestosterone levels by 75% to 80%.
Dutasteride (Avodart) inhibits both type 1 and type 2 isoenzymes of 5 alpha-reductase and reduces circulating dihydrotestosterone by more than 90%. Both finasteride and dutasteride cause a mild increase in plasma testosterone levels since the testosterone does not metabolize to dihydrotestosterone.
5 alpha-reductase inhibitors have been documented to have associated deleterious effects on sexual function. Sexual adverse effects of finasteride and dutasteride include erectile dysfunction, ejaculatory dysfunction, and decreased libido.
The rates of these sexual adverse effects with finasteride use are reported to vary from 2.1% to 39%. One study reported that 6 months of finasteride therapy caused erectile dysfunction in 22% of patients at 3 months and 33% at 6 months. There was also reported decreased sexual drive, increased ejaculatory disorders, and decreased overall sexual satisfaction. Another trial of finasteride found that erectile dysfunction occurred in 4.53% of those taking finasteride compared with 3.31% taking placebo (p < 0.05). In another study, 38.6% of patients treated with finasteride reported their sexual function to have deteriorated after 6 months of therapy.
Erectile dysfunction was the most common sexual adverse effect in clinical trials evaluating finasteride. The rate of erectile dysfnction in finasteride-treated groups was 15.8% compared with 6.3% in placebo in one large double-blind, placebo-controlled trial of a 2-year duration. In a study conducted by the American Urological Association guidelines committee, erectile dysfnction was the most common adverse effect, with a rate of 8% in finasteride groups with 4% in placebo.
After erectile dysfunction, the most common sexual adverse effects are ejaculatory dysfunction and decreased libido. In a study in almost 900 men, researchers evaluated the effect of two doses of finasteride (1 mg and 5 mg) and placebo, given once daily for 12 months. The rate of decreased libido, erectile dysfunction, and ejaculatory dysfunction was found to have increased in finasteride compared with placebo; however, the rate of sexual adverse effects between the two finasteride groups were not signifcantly different.
Finasteride is commonly prescribed at a lower dose (1 mg) than for prostate problems (5 mg) for the treatment of hair loss. Related studies have reported a lower occurrence of sexual adverse effects with the lower dose. In two clinical trials for alopecia, using 1 mg finasteride, sexual side effects were reported in 4.4% of patients treated with the active drug compared with 2.2% in placebo.
The sexual adverse effect pro?le of dutasteride appears to be similar to that of finasteride with regards to decreased libido, erectile dysfunction, and ejaculatory dysfunction. In 2002, the first clinical study to report on the effcacy of dutasteride found sexual adverse effects rates to be 7.3% for erectile dysfunction (4% placebo), 4.2% for decreased libido (2.1% placebo), and 2.2% for ejaculatory dysfunction (0.8% placebo). Moreover, in a direct comparative study of 1 year in duration, 1,630 patients taking dutasteride and finasteride showed comparable incidences of erectile dysfunction (7% vs. 8%, respectively), decreased libido (5% vs. 6%), and ejaculatory dysfunction (1% vs. 1%). According to the evidence, sexual adverse effects occur at similar rates regardless of which 5 alpha reductase isoform is inhibited.
The pathophysiology of 5 alpha reductase inhibitors on sexual function may be related to reduction of dihydrotestosterone levels. Nitric oxide and the enzyme, nitric oxide synthase are critically important in sexually stimulated penile erections. Dihydrotestosterone is more potent than testosterone in raising nitric oxide synthase activity. Because 5 alpha reductase inhibitors reduce serum levels of dihydrotestosterone, this effect may be responsible for erectile dysfunction by reducing levels of nitric oxide and reducing nitric oxide synthase activity in the penile erection tissues
Researchers have documented that at high doses, finasteride impaired erectile function by altering nitric oxide activity in the penis. In addition, investigators examined the effect of testosterone on penile erection. In this study, animals were divided into five groups: sham-operated controls, castrated controls, castrates treated with testosterone, castrates treated with dihydrotestosterone, and castrates treated with a combination of testosterone and a 5 alpha reductase inhibitor. 5 alpha reductase inhibitors caused both a decrease in nitric oxide activity in the erection tissue and a reduction in erectile response to electrical stimulation.
In summary, 5 alpha reductase inhibitors are used in the treatment of lower urinary tract symptoms and male pattern baldness. 5 alpha reductase inhibitors cause sexual dysfunction in a small but signifcant proportion of men who use the drug. While the rate of erectile dysfunctio in clinical trials ranges from 5% to 9%, it is often overlooked by clinicians. Erectile dysfunction can have signifcant effects on a patient’s quality of life, self-esteem, and ability to maintain intimate relationships. Further understanding of the effect of 5 alpha reductase inhibitors on the psychology of men and their partners can have profound consequences for a man’s quality of life.