Continuing Education Activity

The 5-alpha-reductase inhibitors (finasteride and dutasteride) are a class of medication used in the management and treatment of benign prostatic hyperplasia (BPH) and androgenic alopecia (male pattern hair loss). This activity outlines the indications, action, and contraindications for the 5-alpha reductase inhibitors as valuable agents in the management of benign prostatic hyperplasia and androgenic alopecia. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions) pertinent for members of the healthcare team in the management of patients with benign prostatic hyperplasia and related conditions.

Objectives:

• Identify the mechanism of action and administration of the 5-alpha-reductase inhibitors.
• Describe the adverse effects and contraindications of the 5-alpha-reductase inhibitors.
• Review the appropriate monitoring and toxicity of the 5-alpha-reductase inhibitors.
• Summarize some interprofessional team strategies for improving care coordination and communication to advance 5-alpha-reductase inhibitor use and improve outcomes.

Indications

The FDA currently has two approved indications for 5-alpha-reductase inhibitors. These conditions include benign prostate hyperplasia (BPH) and androgenic alopecia (male pattern hair loss). While not approved by the FDA, clinicians have used 5-alpha-reductase inhibitors in the management of hirsutism. 

Benign prostatic hyperplasia (BPH) is a condition typically seen in middle-aged and older men with increasing frequency seen with increasing age. BPH correlates with lower urinary tract symptoms that can cause significant distress, including nocturia, urinary urgency, increased frequency of urination, decreased stream caliber, straining while voiding, and a sensation of incomplete bladder emptying. The symptoms mentioned above can significantly affect the quality of life of patients suffering from BPH and can cause noteworthy changes in sleeping patterns. Several theories for the etiology of BPH exist; however, a widely accepted view is that the potent androgen, dihydrotestosterone (DHT), binds intracellular androgen receptors in the prostate leading to an increase in transcription of proteins that are responsible for increased cellular proliferation. As the gland enlarges, it can compress the prostatic urethra, producing classic symptoms as described above. Finasteride, as well as dutasteride, have both been shown to be efficacious in the treatment of BPH. Researchers have found that finasteride has reduced prostatic DHT by up to 90% and serum DHT by up to 70%. It is worth noting that these reductions in DHT were independent of dosage. Similarly, the research found that dutasteride leads to reductions of DHT by up to 99% for prostate and serum DHT. Furthermore, finasteride has elicited impressive reductions in prostatic volume, which are largely responsible for the troubling urinary symptoms that arise due to an enlarged prostate gland.[1][2][3]

Hair loss affects millions of men and women worldwide annually.  This condition has significant morbidity associated with it as a result of a change in physical appearance affecting the well-being of the patient. Androgenic alopecia or male pattern hair loss makes up a large number of these cases wherein hair loss begins over the crown of the scalp and progresses anteriorly while largely sparing the hair on the temporal and occipital portions of the head. The main culprit for this effect is the androgenic steroid dihydrotestosterone (DHT), which promotes hair miniaturization via its actions on androgen-sensitive receptors. Interestingly, the follicular response to androgens is different depending on the location of the body. In areas such as the face, androgens exert their growth effects on facial hair resulting in anabolic effects. In other areas of the body, such as the crown (or vertex) of the scalp, the opposite effect occurs, resulting in a decrease in hair growth. Although male pattern baldness is a natural phenomenon occurring with age, hair loss can lead to emotional distress, especially in younger populations. The two most common first-line treatments for male pattern hair loss include topical minoxidil and oral finasteride, with finasteride being more powerful as it targets the source of hair loss. Numerous studies have tested the efficacy of oral finasteride as an agent to combat androgenic alopecia.  These studies have revealed significant improvements in androgenic alopecia. One study found that while those receiving no treatment for androgenic alopecia demonstrated a loss of approximately 26% hair count over five years, patients receiving finasteride had a 10% increase in hair count in just one year. Another such study provided further evidence of finasteride’s efficacy in managing androgenic alopecia, with all patients demonstrating increased hair count at 12 months.[4][5][6][7][3]

Mechanism of Action

One must understand the androgenic steroid synthesis pathway to understand the mechanism of action of 5-alpha-reductase inhibitors. The gonads, and adrenal glands, to a lesser extent, produce androgens via several steps originating with the membrane substance, cholesterol. Testosterone, once formed, binds intracellular androgen receptors throughout the body, where it can exert its effects. A more potent androgen, dihydrotestosterone (DHT), arises via conversion from testosterone, which is catalyzed by the enzyme 5-alpha-reductase. While testosterone and DHT are both androgenic steroids, they have different effects throughout the body. Testosterone is largely responsible for the growth seen at puberty, increased muscle mass, and even increased hematocrit in males versus females. DHT, on the other hand, has roles in fetal differentiation of external male genitalia, male hair patterns and lack thereof, and also prostatic growth.[8][9]

Medications such as finasteride and dutasteride are 5-alpha-reductase inhibitors designed to decrease the production of DHT. The utility of these drugs lies in their ability to decrease male pattern hair loss and also prostatic growth that would otherwise be uncontrolled in androgenic alopecia and benign prostatic hyperplasia.[8]

Administration

Finasteride is available in 1 mg and 5 mg tablets. The usual dose for androgenic alopecia is 1 mg once daily, and the usual dose for BPH is 5 mg once daily. Dutasteride is available as a 0.5 mg capsule, and the usual dose for BPH is 0.5 mg once daily.

Adverse Effects

Research and clinical experience have reported adverse effects of 5-alpha-reductase inhibitors. These effects are primarily sexual and include erectile dysfunction, decreased ejaculatory volume, a decrease in libido, as well as gynecomastia.  Decreased DHT is partially responsible for these symptoms, but it is also the shunting of additional testosterone to estradiol that can result in the side effects mentioned. Orthostatic hypotension has also been documented in patients taking 5-alpha-reductase inhibitors.  Since dutasteride therapy is often in conjunction with tamsulosin, an alpha-1 blocker, orthostatic hypotension is more common and reported in up to 18% of patients. As a result, there are reports of orthostatic hypotension, symptoms of dizziness, and weakness.[2]

In rare instances, side effects have failed to resolve after treatment is discontinued. This condition is a post-finasteride syndrome, and current research is underway to understand this condition further.

It is also possible that 5-alpha-reductase inhibitors are associated with decreased fertility. Studies demonstrate that this decrease in fertility is reversible upon cessation of treatment and that patients are often still able to conceive while receiving treatment with 5-alpha-reductase inhibitors.[10]

Contraindications

5-alpha-reductase inhibitors result in a decrease in DHT.  Since DHT is an important androgen in sexual development, children and women who are pregnant or planning on getting pregnant should avoid use. The 5-alpha-reductase inhibitors should also be avoided in any persons who have had a hypersensitivity to these medications.[2]

Monitoring

There are no current guidelines in place for monitoring the 5-alpha-reductase inhibitors; however, PSA concentrations can be useful in assessing the treatment of BPH.  Since the prostate produces excess PSA in patients with BPH, decreases in prostatic volume result in a decreased PSA concentration.  It is, therefore, possible to assess the efficacy of the 5-alpha-reductase inhibitors by measuring PSA concentrations.[2][11]

Recently controversial studies have emerged suggesting an association between finasteride use and prostate cancer. The Prostate Cancer Prevention Trial studied the prevalence of prostate cancer in men over 55 receiving finasteride treatment. The study found a 25% reduction in the prevalence of prostate cancer but also an increased incidence of high-grade prostate cancer.  As a result of this study, the FDA placed a boxed warning on finasteride.[12]

Toxicity

5-alpha-reductase inhibitor toxicity has not been reported in the literature.

Enhancing Healthcare Team Outcomes

The 5-alpha-reductase inhibitors finasteride and dutasteride are effective medications in the treatment of benign prostatic hyperplasia and androgenic alopecia. Since these medications have a prolonged time before symptomatic relief is appreciated, patient education by providers is essential in maintaining adherence.  Patients receiving treatment with the 5-alpha-reductase inhibitors should be informed of potential side effects and screened for prostate cancer regularly while receiving these medications.