5α-Reductase Inhibitors (2024)

Continuing Education Activity

5α-reductase inhibitors (5-ARIs), including finasteride and dutasteride, are approved by the U.S. Food and Drug Administration for treating benign prostatic hyperplasia and androgenic alopecia. These medications inhibit the enzyme 5α-reductase, reducing the conversion of testosterone into dihydrotestosterone, a hormone implicated in prostate enlargement and hair loss. This educational activitydiscusses the indications, mechanism of action, potential adverse events, and contraindications associated with 5-ARIs. The activity also covers off-label uses, appropriate dosing recommendations, and monitoring strategies to mitigate drug interactions and ensure patient safety.

A significant focus is placed on the influence of 5-ARIs on prostate-specific antigen levels and the requisite prostate cancer screening protocols before initiating therapy. Through this activity, healthcare professionals gainknowledge vitalfor optimizing treatment outcomes for patients with conditions like benign prostatic hyperplasia, prostatic bleeding, and alopecia. The goal is to equip healthcare providers with the necessary knowledge to manage these conditions while adhering to safety protocols effectively.

Objectives:

Identify appropriate indications for 5α-reductase inhibitors, such as finasteride and dutasteride, in managing benign prostatic hyperplasia and androgenic alopecia.
Implement standardized protocols for monitoring prostate-specific antigen levels and conducting prostate cancer screening before prescribing 5α-reductase inhibitors.
Apply appropriate dosing recommendations for finasteride and dutasteride based on the indications and patient characteristics.
Implement strategieswith healthcare team members to coordinate comprehensive care for patients receiving 5-ARIs by addressing urological and dermatological concerns.

Access free multiple choice questions on this topic.

Indications

5α-reductase inhibitors (5-ARIs), specifically finasteride and dutasteride, are medications approved by the U.S. Food and Drug Administration (FDA) for treating 2 conditions: benign prostatic hyperplasia (BPH) and androgenic alopecia (male pattern hair loss).[1][2]

FDA-Approved Indications

Benign Prostatic Hyperplasia

BPHis typically seen in older men, and its frequency increases with 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, intermittency, and a sensation of incomplete bladder emptying.[3]

The symptoms mentioned above can significantly affect the quality of life of patientswith BPH and can causesevere disruptions in sleeping patterns.Several theories for the etiology of BPH exist. One widely accepted view involves the androgen dihydrotestosterone (DHT) binding to intracellular androgen receptors in the prostate, leading to increased transcription of proteins responsible for increased cellular proliferation.[3]DHT isa hormone that contributes to prostate growth and hair loss. As the gland enlarges, it can compress the prostatic urethra, producing the symptoms described above.

Both finasteride and dutasteride haveproven effectivefor treating BPH. Finasteride reduces prostatic DHT by over 90% and serum DHT by up to 70%; these reductions were dosage-independent.[1][4]Furthermore, finasteride significantly reduces prostatic volume, which contributes to distressing urinary symptoms.[2][5][6]Similarly, dutasteride reduces DHT by up to 99% in both the prostate and the serum.These reductions in prostatic DHT levels significantly decrease serum prostate-specific antigen (PSA) levels by 50% and reduce prostate volume by approximately 25% over time.[3][7]The majority of PSA reduction occurs within the first 3 months of treatment, while prostate reduction typically takes about 6 months to achieve maximal effect. However,this may require up to a year.[1][7]

The 50% reduction in PSA levels must be considered when screening for prostate cancer in men who are taking 5-ARIs.[8]Forinstance, if a patient has been on 5-ARIs for 6 months or longer, his PSA level should be doubled for comparative and risk assessment purposes. All patients should be screenedfor prostate cancer before initiating treatment with 5-ARIs.[8]

BPH is clinically monitored using a symptom score, such as the one published by the American Urological Association (AUA). Symptom scores above 10 points usually indicate further therapy. Patients withsmaller prostatesdisplay better responses to α-blocker medications. In contrast, patients with larger prostates tend to benefit more from 5-ARIs, although this response may take longer to manifest.In clinical practice, many patients with BPH are initially prescribed α-blockers for immediate symptom relief, with 5-ARIs added for larger prostates or when α-blockers become ineffective.[3][9]

Additionally, 5-ARIs are effective in reducing prostatic bleeding and are oftenadministered topatients undergoing transurethral prostate surgery for this purpose.[1][10][11][12][13][14][15]Although the exact mechanism remains unclear, it is believed to involve a reduction in microvascular density.[12][13][14]The medication should be initiated at least2 weeks before surgery to minimize operative and postoperative bleeding.[15]

Androgenic Alopecia

Androgenic alopecia, commonly known as male-pattern hair loss, affects millions of men and women globally, affecting approximately 50% of men and potentially an equal number of women aged 40 or older. Additionally, alopecia is reported in up to 13% of premenopausal women to some degree. This condition is associated with significant morbidity, as changes in physical appearance can profoundly affect the patient's well-being.Androgenic alopecia contributes to a substantial portion of these cases. Hair loss typically begins at the crown of the scalp and advances anteriorly, while the temporal and occipital portions of the head are often spared.[16] This effect is attributed to DHT, which promotes hair miniaturization by interacting with androgen-sensitive receptors.[16]

The follicular response to androgens varies depending on the body's location. For instance, in areas such as the face, androgens stimulate the growth of facial hair, producing anabolic effects. Conversely, the opposite effect occurs in regions such as the scalp's crown (or vertex), leading to diminished hair growth. While male pattern baldness is a natural phenomenon associated with aging, hair loss can evoke emotional distress, particularly among younger populations.

The2 most common first-line FDA-approved treatments for male pattern hair loss are topical minoxidil and oral finasteride, with finasteride generally considered more effective.[17]Although thesemedications are effective, they are not cures, as any benefits gained from the treatment are typically lostafter discontinuing them. Hair shedding and loss usually begin around 2 weeks after finasteride discontinuation, with all newly regrown hair being lost within a year.

Numerous studies have tested the efficacy of oral finasteridein treating androgenic alopecia, revealing a significant improvement in the condition. However, it may take up to 12 months to achieve maximal effect.

A study found that while individuals receiving no treatment for androgenic alopecia experienced a 26% loss in hair count over 5 years, patients treated with finasteride showed a 10% increase within 12 months.[2][16][18][19][20][21]

Another study provided evidence of finasteride's effectiveness in managing androgenic alopecia, with all patients demonstrating increased hair count after 12 months of treatment.[2][6][16][18][19][20][21]

Finasteride reduces hair loss in approximately 88% of men and aids in regrowing hair in about 66% of cases. Studies indicate that oral finasteride is more effective than topical minoxidil.[17]Additionally, combining oral finasteride with topical minoxidil yields superior results to either therapy alone.[22][23][24][22][24]The combination of topical finasteride and minoxidil has also shown greater efficacy than monotherapy, but it is not FDA-approved in the U.S.[23]

In a comparative study of treatment outcomes, the percentage of men who showed improvement in hair loss after a year of continuous therapy were:[24]

Topical minoxidil (5%): 59%
Finasteride oral 1 mg: 80.5%
Combination topical minoxidil and oral finasteride: 94.1%

Off-Label Uses

Topical finasteride has shown comparable efficacy to the oral formulation but lacks FDA approval for this indication.[25][26][27]Conversely, oral minoxidil is FDA-approved in the United States for severe hypertensionand is often prescribed off-label for hair loss treatment, where it demonstrates effectiveness.[28]

Dutasteride lacks FDA approval for treating hair loss but is commonly prescribed off-label for alopecia.[29]Comparativestudies indicate that dutasteride is as effective as (and possibly superior to) finasteride in treating hair loss.[29][30][31][32]Only topical minoxidil and oral finasteride have been approved by the FDA for male hair loss treatment in the United States.[6][16][33][34]

Mechanism of Action

The gonads, and to a lesser extent, the adrenal glands, produce androgens through aprocess beginning with cholesterol. Once formed, testosterone binds to intracellular androgen receptors throughout the body to exert its effects.DHT binds to the androgen receptor in the cell's cytoplasm, initiating a pathway that alters nuclear gene expression.[43][44]

DHT, a more potent androgen, is formed from testosterone by the isoenzymes of 5α-reductase (types 1 and 2), primarily found in the scalp and prostate cells. While testosterone and DHT are androgenic steroids, they exert slightly different effects throughout the body. Testosterone is largely responsible for growth during puberty, increased muscle mass, and elevated hematocrit levels in males.[45] In contrast, DHT is crucial in the fetal differentiation of external male genitalia, male hair patterns, and prostatic growth.[43][45][46]

Finasteride and dutasteride are 5-ARIs designed to decrease the intracellular production of DHT.[47]Althoughthese drugs are competitive inhibitors of 5α-reductase, finasteride selectively inhibits the type 2 isoenzyme, whereas dutasteride blocks both type 1 and 2 isoenzymes.[47]Asignificant clinical difference between these2 medications does not exist.[47]The only clinically significant pharmacological difference is their half-life: 6 to 8 hours for finasteride and 4 to 5 weeks for dutasteride.[6][48][49]

These drugsare prescribedtoreduce male pattern hair loss in androgenic alopecia as well as prostatic growth and size in BPH.[45]A recent meta-analysis demonstrated that oral 5-ARIs are more effective than minoxidil or newer treatment modalities like botulinum toxin, microneedling, and photobiomodulation formanaging androgenetic alopecia.[50]

Administration

Available Dosage Forms and Strengths:Finasteride is available in 1 mg and 5 mg tablets.Dutasteride is available in 0.5 mg capsules.

Adult Dosage:The standard daily dosage of finasteride is 1 mg for androgenic alopecia and 5 mg for BPH. The standard dosage of dutasteride is 0.5 mg once daily.

Adverse Effects

The reported adverse effects of 5-ARIs are primarily sexual and include erectile dysfunction, reduced ejacul*tory volume, decreased libido, and gynecomastia. These symptoms are believed to be caused by reduced DHT levels and the shunting of testosterone to estradiol.

Drug-Drug Interactions

Finasteride and dutasteride inhibit 5α-reductase, which converts testosterone to DHT, increasing serum testosterone levels. Excess testosterone is then converted into estradiol by aromatase, which can result in gynecomastia. Orthostatic hypotension has also been documented in patients taking 5-ARIs. As dutasteride is often taken with tamsulosin, an α-1 blocker, reports of orthostatic hypotension, dizziness, and weakness have been documented.[6]

In rare instances, adverse effects have persisted even after discontinuing treatment. This condition is known as post-finasteride syndrome, and ongoing research aims to deepen our understanding of this disorder. Additionally, 5-ARIs may be associated withreduced fertility. However, this effect is reversible upon cessation of treatment, and patients often maintain the ability to conceive while taking 5-ARIs.[51]Notably, α-blockers, frequently prescribed alongside 5-ARIs, can interfere with ejacul*tion.[52][53]

Post-finasteride syndrome encompasses a range of adverse effects linked to the discontinuation of finasteride or dutasteride. These adverse effects may persist and involve ongoing mental, neurological, physical, or sexual dysfunction. Almost all cases include sexual dysfunction, with reports also indicating increased anxiety, depression, and suicidal ideations among men who cease 5-ARI therapy. Currently, treatment for this disorder does not exist.[54][55][56][57][58]

Contraindications

5-ARIscause reduced levels of DHT, a critical androgen in sexual development. Therefore, children and pregnant or intending-to-be-pregnant women should refrain from using these drugs.[59]Additionally, individuals with a known hypersensitivity reaction to these drugs should avoid their use.[6]

Monitoring

Guidelines for monitoring responses to 5-ARIs do not exist. However, PSA concentrations can be valuable in evaluating the treatment of BPH. As the prostate typically produces elevated PSA in patients with BPH, reductions in prostatic volume lead to decreased PSA concentrations. The efficacy of 5-ARIs can be evaluated by measuring PSA concentrations.[6][60]

Several controversial studies have emerged suggesting a potential association between finasteride use and prostate cancer. Notably, the Prostate Cancer Prevention Trial investigated the prevalence of prostate cancer in men 55 or older on finasteride therapy. While this trial reported a 25% reduction in prostate cancer prevalence, it also noted an increased incidence of high-grade prostate cancer.[61]As a result, the FDA issued a boxed warning for finasteride in response to these findings.[62]However, subsequent studies have contradicted this, reporting no actual increased risk of prostate cancer in patients taking finasteride or dutasteride.[63][64][65][66]

For patients who have been on these drugs for 6 months or longer, measured PSA levels should be doubled to account for the effect of 5-ARIs.[3][7]

Toxicity

Reports of toxicity related to 5-ARIs have not been documented.

Enhancing Healthcare Team Outcomes

The 5α-reductase inhibitors (finasteride and dutasteride) are effective treatments for both BPH and androgenic alopecia. Given the longer duration of symptom relief, patient education by nurses, pharmacists, and physicians is crucial to ensure adherence. Patients should be thoroughly informed about potential adverse effects and screened for prostate cancer before starting these medications.

Review Questions

References

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: Disclosure: Blake Salisbury declares no relevant financial relationships with ineligible companies.
: Disclosure: Stephen Leslie declares no relevant financial relationships with ineligible companies.
: Disclosure: Prasanna Tadi declares no relevant financial relationships with ineligible companies.