HAIR LOSS TREATMENTS

• ACRONYMS AND DEFINITIONS

• 5ARI - 5-alpha-reductase inhibitor
• BPH - Benign prostatic hyperplasia
• DHT - Dihydrotestosterone
• OTC - Over the counter
• PSA - Prostate specific antigen

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• OVERVIEW

• Male pattern hair loss
• Male pattern hair loss (also called androgenic or androgenetic alopecia) affects 30 - 50% of men by age 50. Age is the greatest risk factor, with vertex or full baldness occurring in 31% of males aged 40 - 55 and 53% of those aged 65 - 69. By the age of 70, more than 85% of men have some degree of balding. The condition has a strong genetic component, as studies have shown that up to 80% of balding men have fathers with significant hair loss.
• Hair loss is driven by androgens, particularly dihydrotestosterone (DHT). In hair follicles, the 5-alpha-reductase enzyme converts testosterone to DHT, which then binds androgen receptors and suppresses hair growth. The rate and extent of hair loss are determined by genetic differences in androgen receptors, which modulate the response to DHT. While androgens suppress hair growth in the scalp, they stimulate growth in other parts of the body (e.g. pubic, beard, axilla). The reason for this is not completely understood. Male pattern baldness progresses in a predictable fashion with temporal regression appearing first, vertex thinning second, and lastly, frontal balding that progresses to full baldness. [1]

• Female pattern hair loss
• Female pattern hair loss affects up to 50% of women during their lifetime. Even though it is common, it has not been studied as extensively as male baldness, and the cause is less clear. Like men, female hair follicles have DHT receptors, making androgen-induced hair loss a possibility. However, studies have not found a definitive link between testosterone levels and hair loss in women. Other possible causes include microinflammatory processes, genetic predisposition (up to 54% will have an affected family member), and environmental factors.
• Female pattern hair loss usually presents as progressive thinning over the vertex and upper parietal region, while the frontal and occipital scalp are usually spared. [2]

• Laboratories
• Female and male pattern hair loss are diagnosed clinically based on typical features. Laboratories that may be indicated in some patients include the following:
• CBC and ferritin - to rule out iron deficiency as a cause
• TSH - increased hair loss may be a sign of hypo- or hyperthyroidism
• Testosterone and DHEA-S - in women with signs of virilization

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• 5-ALPHA-REDUCTASE INHIBITORS

• Overview
• 5-alpha-reductase (5AR) converts testosterone to DHT, the primary androgen responsible for hair follicle regression. 5AR is divided into two subtypes, Type 1 5AR and Type 2 5AR. Type 1 accounts for 20 - 30% of circulating DHT and is found in different organs throughout the body, including the skin, where it is concentrated in sebaceous glands. Type 2, which is responsible for 70 - 80% of circulating DHT, is found in the prostate, liver, and hair follicles.
• Two 5AR inhibitors are currently available in the U.S., finasteride (Propecia) and dutasteride (Avodart). Dutasteride inhibits both Type 1 and Type 2 5AR, while finasteride is selective for Type 2. Finasteride reduces scalp and circulating DHT by about 65%, and dutasteride reduces serum DHT by more than 90%. Finasteride is FDA-approved to treat male pattern hair loss and benign prostatic hyperplasia (BPH); the BPH indication is for the 5 mg dose (Proscar), and the hair loss indication is for 1 mg (Propecia). Dutasteride is only approved for BPH in the U.S., but it has been approved for hair loss in other countries, including South Korea and Japan. [1,3,4]

• Efficacy in men
• Studies have consistently found that finasteride and dutasteride slow the progression of male pattern hair loss and cause partial regrowth in most men. The effects appear to be greatest for vertex and frontal balding. A review of efficacy data for each drug is provided below, along with a placebo-controlled trial that directly compared the two.

• Finasteride
• In studies, finasteride has been shown to increase average hair counts in the vertex region for up to 5 years. The earliest effect was seen after 3 months, and the peak effect occurred between 1 and 2 years. For frontal balding, finasteride has been shown to increase hair counts for up to 1 year. Temporal regression and the anterior hairline, however, have not been shown to improve in studies lasting 12 months. [3]

• Dutasteride
• Dutasteride is a more potent inhibitor of DHT than finasteride, and it also has a much longer half-life (5 weeks vs 6 hours). A handful of small studies comparing dutasteride to finasteride have found dutasteride to be superior. A 24-week placebo-controlled trial that evaluated dutasteride and finasteride in men with vertex hair loss is detailed below. [1,4,5]

• Efficacy in women
• Female hair follicles contain DHT receptors, but the association of androgens with female pattern hair loss is unclear. In studies, finasteride has not been shown to improve female hair loss. Dutasteride has not been studied extensively. [3,6]

• Sexual side effects
• 5ARI-induced sexual side effects are the subject of much debate. In studies, adverse sexual events among 5ARI-treated patients were uncommon and occurred at incidences that were only slightly higher than placebo (0 - 3%). Still, many men avoid or discontinue 5ARIs because of these perceived effects. The first table below shows the rate of sexual side effects in men with male pattern baldness who were treated with finasteride. The second table shows the effects of dutasteride in men treated for BPH. Sexual side effects from a 24-week trial that compared finasteride, dutasteride, and placebo are reported above (comparison trial).

• Nonsexual side effects
• In trials, nonsexual side effects, including breast tenderness and enlargement, were uncommon (≤ 1.1%) and occurred at rates similar to placebo [3,8]

• Contraindications / Precautions
• Pregnancy / Exposure to women - 5ARIs inhibit DHT production, which is necessary for male fetal development. 5ARIs should not be used in pregnancy or by women who can become pregnant. Women should not handle crushed or broken tablets because of the possibility of cutaneous absorption. [1,8]


• Effects on PSA testing - 5ARIs reduce serum PSA levels and can therefore interfere with prostate cancer screening. In studies, finasteride (1 mg and 5 mg dose) and dutasteride have been shown to reduce PSA levels by about 50%. To account for this, it is recommended that the measured PSA level be doubled in men taking 5ARIs. The effect of 5ARIs on PSA levels also appears to be time-dependent. In the PCPT trial that compared finasteride 5 mg to placebo for prostate cancer prevention, PSA levels were doubled during the first 3 years and then multiplied by a factor of 2.3 from year 4 and on. It may be prudent to establish a baseline PSA level before initiating 5ARIs in older men (> 45 years) and those at high risk for prostate cancer. The Free/Total PSA ratio, which is also used to detect prostate cancer, is not affected by 5ARIs. [1,3,7,8]


• High-grade prostate cancer - finasteride and dutasteride have been shown to increase the risk of high-grade prostate cancer in cancer prevention trials. In the PCPT trial, finasteride 5 mg lowered the overall risk of prostate cancer compared to placebo (18.4% vs 24.4%), but high-grade cancers (Gleason 7 - 10) were more common in the finasteride group (6.4% vs 5.1%). In the REDUCE study, dutasteride lowered the overall risk of prostate cancer (19.9% vs 24.9%), but the incidence of high-grade lesions (Gleason 8 - 10) was higher in the dutasteride group (1% vs 0.5%). The reason for these effects is not completely understood. Proposed mechanisms include the following: (1) sampling bias secondary to reduced prostate size in the 5ARI groups, (2) improved sensitivity of PSA testing in patients receiving 5ARIs, (3) 5ARIs selecting for high-grade tumors by inhibiting low-grade tumors, (4) 5ARI-induced histological changes that mimic those of high-grade disease. [1,8]


• Blood donation - 5ARIs can adversely affect a male fetus if given to pregnant females. Because of this, 5ARI-treated patients should not donate blood during therapy and for a period after stopping. Finasteride has a half-life of 6 hours, and dutasteride has a half-life of 5 weeks. Patients should wait at least 1 month after the last dose of finasteride and 6 months after dutasteride before donating blood. [8]

• Drug interactions
• CYP3A4/5 - finasteride and dutasteride are primarily metabolized by CYP3A4/5. The effects of CYP3A4/5 inhibitors and inducers on their exposure have not been studied extensively, and the manufacturers make no recommendations about dosage adjustments. [3,8]

• Dosing
• Finasteride (Propecia®)
• Dosage form: 1 mg tablet
• Dosing: 1 mg once daily
• May take without regard to food
• Effect is seen after 3 months. If drug is discontinued, reversal of effect occurs within 12 months.
• Generic available. Less than $50 for 90 tablets.


• Dutasteride (Avodart®)
• Dosage form: 0.5 mg capsule
• Dosing: 0.5 mg once daily
• May take without regard to food
• Do not open capsules
• Generic available. Less than $50 for 90 capsules.

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• TOPICAL MINOXIDIL

• Overview
• Minoxidil is a vasodilator FDA-approved in 1979 that is sometimes used to treat resistant hypertension. A notable side effect of minoxidil is hair growth, and this led to its development as a topical hair loss treatment. The mechanism by which minoxidil promotes hair growth is not entirely understood, but the prevailing theory is that it works by opening potassium channels in hair follicles, thus prolonging the anagen phase of hair growth.
• Topical minoxidil is available over the counter and is FDA-approved to treat male and female pattern hair loss. Oral minoxidil is only approved for hypertension, but it has been studied in low doses as a treatment for hair loss (see low-dose oral minoxidil). [1]

• Efficacy in men
• Topical minoxidil has been shown to improve male hair loss in studies lasting up to 30 months. The peak effect occurs at 1 year, after which hair regrowth declines but remains greater than baseline. Studies comparing minoxidil to finasteride have found that about 80% of finasteride-treated men experience improvement compared to 50% of minoxidil-treated men. In a 12-month study (N=428) that compared minoxidil to finasteride to both drugs combined, hair improvement was seen in 59%, 81%, and 94% of men, respectively. [PMID 26031764] [1,9,10]

• Efficacy in women
• A Cochrane meta-analysis that included 17 studies found that topical minoxidil was effective and safe in treating female pattern hair loss. In studies that directly compared the 2% and 5% concentrations, no difference in effect was seen. [12]

• Side effects
• Side effects of topical minoxidil include transient hair shedding in the first 2 months of therapy (up to 15%), hypertrichosis of the forehead or face (2 - 5%), contact dermatitis, and itching, which may be less common with the foam. [1,13]

• Dosage forms / Dosing
• Solution
• Minoxidil 2% solution - apply twice daily. Approved for men and women. Available OTC in generic form.
• Minoxidil 5% solution - apply twice daily. Approved for men. Available OTC in generic form.
• Foam
• Minoxidil 5% foam - apply once daily. Approved for men and women. Available OTC in generic form.

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• LOW-DOSE ORAL MINOXIDIL

• Overview
• Minoxidil is a vasodilator FDA-approved in 1979 that is sometimes used to treat resistant hypertension. A notable side effect of minoxidil is hair growth, and this led to its development as a topical hair loss treatment. The mechanism by which minoxidil promotes hair growth is not entirely understood, but the prevailing theory is that it works by opening potassium channels in hair follicles, thus prolonging the anagen phase of hair growth.
• Oral minoxidil is only FDA-approved for hypertension, but it has been studied in low doses as a treatment for male and female pattern hair loss [1]

• Efficacy in men
• Low-dose oral minoxidil has been shown to stimulate hair growth in male pattern baldness. A systematic review of low-dose trials (0.25 - 5 mg daily) encompassing 19,003 men found that objective clinical improvement was observed in 61 - 100% of subjects. [PMID 32516434] On an individual trial level, a 24-week study that followed 30 men with vertex androgenetic alopecia showed that minoxidil 5 mg daily significantly increased mean hair counts compared to baseline at 12 and 24 weeks (+26 hairs/cm², +35 hairs/cm², respectively). [PMID 32970299]

• Efficacy in women
• Small trials have found that low-dose oral minoxidil improves female pattern hair loss. A 24-week study (N=52) that compared once-daily oral minoxidil (1 mg) to the 5% topical solution found that total hair density increased by 12% in the oral group compared to 7% in the topical group. [PMID 31473295] Another 24-week study (N=36) found that minoxidil 1 mg daily improved hair counts from baseline by an average of 27 hairs/cm², while a dose of 0.25 mg once daily did not have a significant effect. [PMID 35077777]

• Side effects
• Minoxidil dosing in hypertension (≥ 10 mg) can have significant side effects and is a major reason it is not widely prescribed. Low-dose minoxidil (≤5 mg), however, has a lower risk of adverse events and has been well-tolerated in trials. Given the heterogeneity and small size of oral minoxidil trials, it's difficult to draw conclusions about the overall incidence of adverse events. Side effects from two small studies, one in men and the other in women, are described below.
• Minoxidil 5 mg once daily in men (N=30)
• Hypertrichosis occurred in 93% of patients, with the forearms, forehead, temples, and cheekbone areas being most commonly affected
• Abnormal ECG findings were observed in 6 patients (20%). Two had occasional PCVs, and 4 had new T-wave inversions, a known effect of minoxidil that occurs in up to 60% of patients at hypertensive doses.
• Pedal edema occurred in 3 patients (10%). It appeared after 1 - 2 months of treatment and resolved with salt restriction.
• Orthostatic hypotension occurred in 2 patients after the first dose and was asymptomatic
• Average blood pressure and pulse did not change significantly during the trial [14]
• Minoxidil 1 mg once daily in women (N=26)
• Hypertrichosis occurred in 27% of patients
• Pretibial edema occurred in 4% of patients
• Average heart rate at rest increased by 6.5%
• Average blood pressure did not change over time
• No hypotension-related events occurred [17]

• Contraindications / Precautions
• NOTE: The information presented here is from the minoxidil prescribing information and represents precautions seen with hypertensive doses. It is unknown if low-dose minoxidil carries the same risks.


• Pheochromocytoma - minoxidil should not be used in patients with pheochromocytoma because it may stimulate the secretion of catecholamines from the tumor through its antihypertensive action


• Fluid and salt retention - the vasodilatory effects of minoxidil can stimulate fluid and sodium retention. In two low-dose minoxidil studies, lower extremity edema was observed in 4% (1 mg) and 10% (5 mg) of patients.


• Tachycardia - minoxidil-induced vasodilation can cause reflex tachycardia. In low-dose minoxidil trials, the average heart rate was either unchanged or slightly increased.


• Hypotension - minoxidil can lower blood pressure. In two low-dose minoxidil trials (see side effects), average blood pressure did not decrease significantly.


• Cardiac chest pain (angina) - minoxidil-induced tachycardia may exacerbate angina. Concomitant beta blocker therapy can help to prevent this.


• Pericardial effusion - pericarditis and pericardial effusion, occasionally with tamponade, have been reported in 3% of minoxidil-treated patients not on dialysis. In most cases, patients had marked fluid retention from another condition (e.g. renal failure, heart failure, connective tissue disease), but in some instances, no potential cause of effusion was present. If patients develop symptoms of pericardial effusion (e.g. dyspnea, chest pain), prompt echocardiographic evaluation should be performed.


• ECG changes - up to 60% of patients treated with minoxidil have T-wave inversion on their ECG. This effect usually disappears over time or with drug discontinuation. The significance of these changes is unknown, but they have not been associated with signs of cardiac damage (e.g. chest pain, enzyme elevations).


• Lab changes
• Minoxidil-induced fluid retention can cause a transient decrease in hemoglobin and hematocrit (hemodilution). An initial fall of 7% is typical before returning to baseline values.
• Transient increases in serum creatinine (average of 6%) and BUN have been observed that return to baseline with continued treatment
• Alkaline phosphatase may increase without other signs of bone or liver disease


• Heart failure - minoxidil-induced fluid retention can worsen heart failure


• Kidney disease - minoxidil can exacerbate fluid retention in kidney disease. Start with lower doses and titrate slowly.


• Liver disease - minoxidil can exacerbate fluid retention in liver disease. Start with lower doses and titrate slowly. [18]

• Drug interactions
• Guanethidine - when minoxidil is given with guanethidine, severe orthostatic hypotension can occur. Concomitant administration is not recommended. [18]

• Dosage forms / Dosing
• Dosage forms: 2.5 mg and 10 mg tablet
• Dosing: in studies, dosing of 0.25 - 5 mg once daily has typically been used. Dosing at bedtime may help prevent orthostatic hypotension.
• Generic is available that costs less than $20/month
• Low-dose oral minoxidil patient handout

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• SPIRONOLACTONE

• Spironolactone, an aldosterone antagonist with antiandrogen properties, is sometimes used to treat female pattern hair loss. Studies examining its effects are small, of poor quality, and inconclusive. A 12-month study (N=40) that looked at the effects of spironolactone 200 mg daily found the following: 44% of women had hair regrowth, 44% had no change, and 12% continued to lose hair. [PMID 15787815]
• Available evidence does not support the use of spironolactone for female pattern hair loss [15,16,17]

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• BIBLIOGRAPHY

• 1 - PMID 25905192 - Cranwell W, Sinclair R. Male Androgenetic Alopecia. [Updated 2016 Feb 29]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.
• 2 - PMID 32832434 - Female Pattern Hair Loss-An Update, Indian Dermatol Online J (2020)
• 3 - Propecia prescribing information
• 4 - PMID 27549867 - Superiority of dutasteride over finasteride in hair regrowth and reversal of miniaturization in men with androgenetic alopecia: A randomized controlled open-label, evaluator-blinded study, Indian J Dermatol Venereol Leprol (2017)
• 5 - PMID 17110217 - The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride, J Am Acad Dermatol (2006)
• 6 - PMID - 27225981 - Interventions for female pattern hair loss, Cochrane Database Syst Rev (2016)
• 7 - PMID 17196507 - Effect of 1 mg/day finasteride on concentrations of serum prostate-specific antigen in men with androgenic alopecia: a randomised controlled trial, Lancet Oncol, (2007)
• 8 - Avodart prescribing information
• 9 - PMID - 3314717 - Topical minoxidil therapy for androgenetic alopecia. A 30-month study, Arch Dermatol (1987)
• 10 - PMID - 26031764 - Combined treatment with oral finasteride and topical minoxidil in male androgenetic alopecia: a randomized and comparative study in Chinese patients, Dermatol Ther (2015)
• 11 - PMID - 27225981 - Interventions for female pattern hair loss, Cochrane Database Syst Rev (2016)
• 12 - PMID - 15034503 - A randomized, placebo-controlled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss, J Am Acad Dermatol (2004)
• 13 - PMID - 33651080 - Diagnosis and Treatment of Nonscarring Hair Loss in Primary Care in 2021, JAMA (2021)
• 14 - PMID - 32970299 - Efficacy and Safety of Oral Minoxidil 5 mg Once Daily in the Treatment of Male Patients with Androgenetic Alopecia: An Open-Label and Global Photographic Assessment, Dermatol Ther (2020)
• 15 - PMID - 32259535 - Spironolactone for treatment of female pattern hair loss, J Am Acad Dermatol (2020)
• 16 - PMID - 29231239 - Female pattern hair loss: a pilot study investigating combination therapy with low-dose oral minoxidil and spironolactone, Int J Dermatol (2018)
• 16 - PMID - 15787815 - Treatment of female pattern hair loss with oral antiandrogens, Br J Dermatol (2005)
• 17 - PMID - 31473295 - Minoxidil 1 mg oral versus minoxidil 5% topical solution for the treatment of female-pattern hair loss: A randomized clinical trial, J Am Acad Dermatol (2020)
• 18 - Minoxidil prescribing information