Evaluating 5 alpha reductase inhibitors for the treatment of male androgenic alopecia

KEYWORDS:

• Finasteride
• dutasteride
• minoxidil
• baldness
• balding

1. Introduction

Male androgenic alopecia (AGA) is a progressive, familial, patterned, age-related, psychologically distressing, hair-loss disorder characterized histologically by hair follicle miniaturization. Telogen effluvium precedes miniaturization and accentuates baldness.

The histological hallmark of AGA is miniaturization of terminal follicles into vellus follicles [1]. Miniaturization occurs at the onset of anagen and is due to reduced traffic of dermal sheath fibroblasts into the reconstituting dermal papilla. Reduced dermal papilla volume leads to a proportionate reduction in the hair matrix and the shaft diameter. Miniaturization occurs at the onset of anagen and is not stepwise, as previously thought, but can occur in a single hair cycle [2]. Miniaturized follicles produce hairs with a reduced fiber diameter [3].

Alone, androgen induced miniaturization does not produce baldness. The perception of balding is the product of both reduction in hair diameter and a reduction in hair density [4]. Selective shortening of anagen duration while telogen duration is maintained induces telogen effluvium (TE). TE ultimately reduces hair density when progressive shortening of anagen duration produces a hair so short, it does not emerge from the pore [5]. TE precedes hair follicle miniaturization and baldness; however, TE may be imperceptible in men with very short hair [6].

Some degree of balding is a universal, physiological, male secondary sexual characteristic that progresses in a highly reproducible and easily recognized pattern [3]. AGA becomes a medical problem when it is subjectively considered as excessive, premature and distressing [3]. AGA is generally perceived negatively as an unwelcome accompaniment of aging. While most men accept AGA without impairment of psychosocial functioning, some men tolerate AGA poorly and have a negative overall body image and diminished quality of life [3].

Miniaturization involves hair follicle androgen receptor (AR) activation [1]. While testosterone and DHT are both AR ligands, DHT binds five times more avidly than testosterone to the dermal papilla AR, and is the primary hormonal driver implicated in pathogenesis of AGA [1]. The 5a reductases (5AR) are a family of enzymes that catalyze steroid metabolism and convert testosterone to DHT [7].

There are three isoforms of the 5a reductase enzymes that are encoded by separate genes which differ in tissue expression and distribution [7]. In the skin, the type 1 isoform is mainly present in the sebaceous and sweat glands, and the type 2 isoform predominates in the genital skin, beard and scalp hair follicles [7]. In the follicles, it is found predominately in the outer root sheath, but not in the dermal papilla or sebaceous gland. The type 3 isoform is expressed ubiquitously throughout the dermis and epidermis and the expression of the type 3 isoform of 5 alpha reductase is much higher in the dermis than types 1 and 2 [7].

Congenital deficiencies in 5AR isoforms shed light on their physiological function. Type 1 5AR inactivated male mice have reduced bone mass and muscle strength [8]. Human males with type-2 deficiency have pseudohermaphroditism [9]. Antiandrogens feminize men and are therefore not used to treat hair loss in cis-men. Selective inhibition of type 2 5AR enzyme has the potential to reduce AR activation specifically in target organs such as the prostate gland and the hair follicle without reducing circulating testosterone, systemic androgenization or virilism [1]. The potential to reduce off-target androgen suppression made selective 5 alpha reductase inhibitor (5ARI) medications attractive therapeutic targets for use in the treatment of male AGA [3].

2. 5ARI therapies

2.1. Oral finasteride

Finasteride is a 5ARI that binds irreversibly to the type II-5a reductase enzyme, inhibiting conversion of testosterone to dihydrotestosterone (DHT). Finasteride also inhibits the type III-5a reductase isoenzyme, albeit to a lesser extent. It first received FDA approval for the treatment of male AGA in 1997. Finasteride 1 mg daily reduces scalp DHT by 64% and serum DHT by 68% [1]. Reduction in scalp DHT levels best predicts vertex scalp regrowth. In the pivotal phase 3 clinical trials, finasteride arrested AGA in ≥ 90% of men and promoted regrowth in 48% at 12 months and 66% at 48 months. Maximum regrowth is achieved at 2 years and thereafter vertex hair density gradually declines but remains above baseline at 5 years with continued treatment [1].

Reported adverse events include reduction in libido (1.9%), erectile dysfunction (1.4%), reduced volume of ejaculate (0.8%), gynecomastia, depression, anxiety and suicidal behavior [1,10]. In clinical trials, the prevalence of sexual dysfunction did not increase when the dosage of finasteride was raised from 1 to 5 mg per day [11*]. Less commonly reported, finasteride 5 mg per day can have a mild impact on semen parameters, but these effects seemed to resolve within a few weeks after ceasing the medication suggesting that discontinuation might be necessary for a male with fertility concerns [11].

In 2012, the FDA attached a warning to the product as there were persistent side effects reported increasingly. Interestingly, following this warning, there was a sharp rise in finasteride associated sexual dysfunction and neuropsychiatric side effect reporting [11]. One study found that the risk of persistent erectile dysfunction was higher in men with longer exposure to 5ARI’s [10]. However, side effects generally resolve within 3 to 6 months post-discontinuation. Finasteride is a teratogen, and its use is contraindicated in women of child-bearing potential [1].

Long-term use of finasteride 5 mg daily in men aged over 55 reduces the risk of low-grade prostate cancer by approximately 25%, but there is no reduction in the risk of high-grade prostate cancer [12]. Whether this benefit occurs in men under 55 years taking 1 mg daily is not known.

2.2. Dutasteride

Dutasteride, another 5ARi, is threefold more potent than finasteride in inhibiting the type II enzyme and >100-fold more potent in blocking the type I enzyme [1]. It received approval for the treatment of benign prostatic hyperplasia (BPH) in 2001. Dutasteride 0.5 mg daily decreases intraprostatic DHT (the main source of circulating DHT) by 99%, serum DHT by 92% and scalp DHT by 51% [7]. While the percentage reduction in scalp DHT best predicts hair regrowth, the increased risk of adverse sexual side effects with dutasteride has impeded its registration in many countries. However, it was eventually approved for male AGA only in Japan and South Korea.

In one phase 3 clinical trial, dutasteride 0.5 mg daily showed significantly higher efficacy than placebo based on subject self-assessment and by investigator and panel photographic assessment. A second phase 3 trial found that dutasteride 0.5 mg was statistically superior to finasteride 1 mg and placebo at 24 weeks [7].

Adverse sexual effects are slightly more common with dutasteride than with finasteride and include decreased libido, erectile dysfunction, decreased ejaculatory volume, testicular pain, and decreased sperm count [1]. Data on long-term safety and efficacy of dutasteride in AGA is lacking. Dutasteride is teratogenic and contraindicated in pregnancy.

2.3. Combination therapy

A single case report described an increase in vertex scalp hair regrowth when dutasteride was commenced in a patient who had received long-term finasteride treatment [7]*].

Options for men who experience or fear adverse sexual side effects of 5ARIs include topical finasteride and dutasteride mesotherapy.

2.4. Dutasteride mesotherapy

The pharmacological half-life of dutasteride is approximately 4 weeks compared to finasteride’s 6–8 hours [1]. This makes dutasteride amenable for mesotherapy at 4 weekly intervals. Dutasteride mesotherapy (DM) involves multiple intradermal micro-injections of dutasteride 0.01% solution spread across the balding scalp. Unblinded and uncontrolled case series have reported improvement in AGA, with increased hair density and hair diameter on trichoscopy and fewer adverse sexual side effects. The most commonly reported side effect is pain at the injection site [13].

2.5. Topical finasteride

A single phase-3 non-inferiority clinical trial comparing once daily application of topical finasteride 0.25% showed similar efficacy to 1 mg of oral finasteride with fewer adverse sexual side effects [14]*].

3. Expert opinion

The initial pathogenesis of AGA involves progressive shortening of anagen duration. This manifests as telogen effluvium. Subsequent hair follicle miniaturization leads to reduced hair fiber diameter. These two events combine to produce visible baldness.

5ARIs do not prolong anagen duration and do not reduce hair shedding. 5ARIs potentially arrest miniaturization and halt the progression of baldness. Finasteride and dutasteride may induce partial hair regrowth over the vertex scalp. A lesser degree of hair growth may also occur over the mid frontal scalp, but regrowth of bitemporal recession is rare. Doses of finasteride above 1 mg daily and dutasteride above 0.5 mg produce little or no additional benefit.

Visible improvement in vertex baldness generally takes 12 months, but may be apparent at 6 months. Improvement peaks at 24 months and then generally declines. 5ARIs work best when initiated early and used long-term to prevent baldness. Discontinuation leads to loss of effect and hair density returns to baseline at 6 months. Maintenance therapy is recommended for all patients.

While the risk of sexual dysfunction in the phase 3 clinical trials was low, the exact proportion of men who experience reduced libido or erectile dysfunction in a real world setting is uncertain, due to the high baseline prevalence of sexual dysfunction in the community, the natural decline in libido with advancing age, and under reporting post-marketing. Mild reduction in libido and loss of morning erections are common and may resolve spontaneously with continued treatment or can be managed with dose reduction. Discontinuation of 5ARIs usually leads to improvement in sexual function within 3 to 6 months.

Immediate and profound loss of libido within days or weeks of initiation of treatment is rare, but very distressing, especially when symptoms persist. The 5ARI should be ceased immediately and never re-prescribed.

While the quantum of vertex hair regrowth appears to be greater with dutasteride compared to finasteride, dutasteride is considered a second-line agent due to the increased risk of adverse sexual side effects. All patients should be made aware of the potential sexual and psychiatric side effects of both agents and the risk, albeit small, of persistence post discontinuation.

Dutasteride and finasteride have been combined to increase hair growth. Adjunctive treatment with minoxidil has an additive effect [1]. The primary action of minoxidil is to prolong anagen and reduce telogen effluvium. Minoxidil monotherapy is the preferred treatment for men with AGA and minimal vertex balding. Minoxidil has not been demonstrated to enlarge follicles miniaturized by AGA. Minoxidil does not produce adverse sexual side effects.

In our experience, topical finasteride and dutasteride mesotherapy are less effective, but better tolerated compared to systemic counterparts. Both come with considerable cost to the patient and are less realistic long-term options, but are popular patient requested alternatives.

Declaration of interest

S Eisman is/has been principal investigator in clinical trials for AbbVie, Arena Pharmaceuticals, Boston Pharmaceuticals, Botanix, Bristol-Myers Squibb, Dermaliq Therapeutics, Dermira, Eli Lilly and Company, Janssen, Immunic Therapeutics, Kobiolabs, Kymab, LEO Pharma, Nektar Therapeutics, Novartis, Pfizer Inc., Regeneron, Sanofi, Suzhou Connect Biopharmaceuticals, TEVA pharmaceuticals, Takeda, Tigermed and ZaiLab. She is also the Treasurer and Board Member of the Australian Hair and Wool Research Society (2019-present); has served on an Australian Advisory Alopecia Areata Board, Lebrikizumab Advisory Board for Eli Lilly, Dercos Advisory Board (L’Oreal) – and attracts a nominal fee for these. She does not receive financial remuneration directly from any other company but is employed by a clinical trial center, Sinclair Direct, Sinclair dermatology (Melbourne) and receives a salary to conduct the above trials. No payment is transferred directly from any company to Dr. Eisman except reimbursement for travel to investigator meetings. She has presented at a clinical meeting for Pfizer Inc but has not received any direct financial remuneration other than reimbursement for travel and meeting registration. She has been involved in Clinical Submissions/Papers/Posters for Pfizer, BMS and Abbvie but has not received financial remuneration.

R Sinclair is Director and Founder of Samson Medical Pty Ltd. He is on the pharmaceutical advisory board at Eli Lilly and Company, Pfizer Inc, Leo Pharmaceutical. He is on the speaker bureau at Pfizer, Abbvie, Novartis. Glaxo Smith Kline. And is principal investigator in clinical trials for AbbVie, Aerotech, Akesobio, Amgen, Arcutis, Arena, Ascend AstraZeneca, Bayer AG, Biotherapeutics Boehringer Ingelheim, Bristol Myer Squibb, Celgene, Coherus BioSciences, Connect, Demira, Eli Lilly and Company, Galderma, Glaxo Smith Kline, F. Hoffman – La Roche, Janssen, MedImmune, Merck and Co, Merck Sharpe & Dohme, Novartis, Oncobiologics, Pfizer, Principia, Regeneron, Roche, Reistone Biopharma, Samson Clinical, Sanofi-Genzyme, Sun Pharma UCB, Valeant and Zai Labs. He is Assistant Editor at the Australian journal of Dermatology. R Sinclair is Office Bearer and undertakes the following roles: President of the Australasian Hair and Wool Research Society; Vice President of the International Society of Dermatology; Vice President of The International Academy of Dermatology; Board member of the Australian Society of Dermatology research.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.