Current management of androgenetic alopecia in men

ARTICLE

Androgenetic alopecia (AGA) is one of the dermatological conditions most commonly faced by the dermatologist or general physician. The condition affects up to 30% of men under the age of 30 and more than 50% of men over the age of 50 [1]. Despite a widespread belief that AGA is only experienced by men, it also affects women although the clinical signs are usually milder and the phenotype is different [2]. As the condition progresses, scalp hairs and their follicles become progressively miniaturized, and the terminal hair normally found on the adult scalp is replaced by vellus hairs which are shorter, finer and nonpigmented. Concomitantly, the average length of time spent by hairs in anagen (growth phase) decreases, and the proportion of hairs in telogen (resting phase) increases [3]. There is a general agreement that a genetic component to androgenetic hair loss exists, but its pattern of inheritance is not clear. A polygenic inheritance is very likely [4-7]. Our understanding of the aetiology of AGA has increased substantially in recent years with the recognition of the importance of hormonal influences, and androgens have come to be seen as key factors in the development of male pattern hair loss. This will be discussed in more detail below in the context of the pharmacological modulation of androgen metabolism as a treatment for AGA.

Until recently the absence of a truly effective treatment for AGA led to a general lack of interest in it as a clinical condition. Fortunately, the management of AGA is no longer restricted to the psychological support of the patient. Drug therapies of proven efficacy are available, and physicians should be familiar with these newer treatment modalities. Loss of hair is often trivialised but it can have profound effects on a patient's well-being and quality of life [8, 9], and patients who do not receive what they consider is adequate treatment from their physician may be driven to trying some of the many "remedies" of no or unproven efficacy that are commercially available.

In this article, the current management of AGA will be discussed in the order of methods of increasing efficacy. Most of the discussion will be devoted to drug therapies, by far the most effective available form of management.

Treatments of no proven benefit

Vitamins

Vitamin deficiencies have been implied as a cause of AGA, for which the logical cure would then be dietary vitamin supplementation. The use of biotin as a treatment for alopecia was suggested by evidence that biotin deficiency causes hair loss. Biotin, also known as vitamin H, is a water-soluble vitamin that acts as an essential cofactor for 4 different carboxylases, each of which catalyses an essential step in intermediary metabolism. Dietary biotin deficiency is most commonly the result of inadequate, often parenteral, nutrition [10], and results in a number of symptoms including alopecia and a characteristic scaly dermatitis [11]. There are also two known congenital disorders of biotin metabolism, biotinidase and holocarboxylase synthetase deficiency, both of which cause alopecia and respond to added biotin to varying degrees [12, 13]. However, these cases all involve measurable biotin deficiency. There is no evidence that the commonly observed male pattern hair loss is caused by inadequate biotin intake, or that dietary biotin supplementation can reverse AGA. The majority of articles in the literature concern the effects of congenital or acquired overt biotin deficiency. No clinical trials of biotin supplementation in AGA have been reported. Despite this, many biotin supplements and biotin-containing preparations are commercially promoted for the restoration of lost hair and qualitative improvement of damaged or weathered hair.

Other vitamin supplements are also commercially available as supplements to prevent hair loss or promote hair regrowth. However, in no case has an aetiological link with AGA been established, or improvement in the absence of overt deficiency been demonstrated in rigorous clinical trials. Most of the studies cited in the literature concern vitamin D receptor anomalies: for example, patients with the congenital condition vitamin D-dependent rickets type II also show whole body alopecia [14, 15] or the treatment of chemotherapy-induced alopecia with topical calcitriol in an animal model [16]. There are no data to suggest an influence of vitamin D on the course of AGA.

Many other substances are given orally or are sold as components of hair lotions and creams. These include zinc, amino acids, a variety of vitamins, hormones, jojoba oil, urea, wheat germ oil, and supposedly exotic herbs. Although not generally harmful, none of these substances has proven its efficacy in promoting hair growth or preventing further hair loss.

2,4-diaminopyrimidine

The substance 2,4-diaminopyrimidine (2,4-DPO) inhibits the enzyme lysylhydroxylase that is responsible for the accumulation of collagen around the hair follicle. The manufacturer of 2,4-DPO claims that perifollicular fibrosis plays an important role in the pathogenesis of AGA. However, there is no scientific evidence to substantiate this claim.

Recently, an open (not randomised, not placebo controlled) trial was published [17], in which 40 men with AGA stage III-V Hamilton Norwood applied a 1.5% 2,4-DPO solution to the scalp once daily. Thirty-three men completed the trial and the results from 29 men were evaluable. After 12 weeks of treatment with 2,4-DPO the mean anagen hair count was increased by 8.1%.

The increase in the anagen-hair-count may indicate that the progression of AGA has been inhibited. However, the open design of the study does not allow any scientifically based conclusions to be drawn. Application for only three months does not control for seasonal variations in hair shedding. In contrast to the daily application required in the study, the commercially available product containing 2,4-DPO (Dercap with Aminexil^®) is only applied three times a week for a limited period of two months. 2,4-DPO must therefore be classified as a cosmetic with unproven efficacy against AGA.

Treatments of moderate efficacy

Hair systems

Hair systems such as swatches, toupees or wigs, which may nowadays be attached semipermanently using adhesive tape, may be considered effective forms of management of AGA, even if their benefits are purely symptomatic and they do not influence the underlying cause of the alopecia.

Surgery

Surgical approaches to the treatment of hair loss have become increasingly popular. A variety of different surgical procedures have been used, including scalp reduction, flap surgery and punch grafting [18-21]. The success of hair autografts in the treatment of AGA relies on the fact that occipital hair is never affected by AGA and on the phenomenon of donor dominance. This means that control of hair growth resides within the individual follicle and thus the donated occipital hair retains its resistance to miniaturization during AGA. Today, scalp reduction and flap surgery have been replaced by micrograft hair transplantation. However, surgery is not a suitable option for younger men, as the progression of AGA may lead to further surgery being required [22].

Minoxidil

In recent years, drug therapies have become the most promising approaches to the treatment of AGA. The first pharmaceutical to be approved for AGA in both men and women was minoxidil. Minoxidil is a piperidinopyrimidine derivative that was originally developed as a systemic vasodilator for the treatment of hypertension. In about 70% of patients, however, oral administration of minoxidil also leads to hypertrichosis of the face and extremities. The mechanism by which the potassium channel opener minoxidil exerts its effect on hair growth is unclear, although some in vitro evidence suggests that it acts directly on the cells of the hair follicle [23-26] and may induce growth factors that increase vascularization around the hair papilla. One study using laser Doppler velocimetry and photopulse plethysmography showed that cutaneous blood flow increased after application of topical minoxidil [27]. Overall, the mechanisms by which minoxidil inhibits AGA are still unknown.

A number of multicentre, large scale, double-blind trials have been conducted that compared minoxidil 2% or 3% used topically to its vehicle alone [28-32]. The duration of most studies was 12 or 24 months. However, due to their design or methodology, these studies on the whole have not been as conclusive as hoped, for instance because they were open-label rather than double-blind [33], or enrolled relatively small numbers. The major potential problem of these studies lies in the methodology of hair growth and loss assessment. Most studies counted the number of hairs within a specific area on the scalp at defined time intervals. However, this method has since been criticised [34]. In some cases, subjective assessments of new hair growth were also made by the investigator and the patient.

The overall conclusion was that treatment with minoxidil 2% induces the conversion of some vellus to terminal hairs, normalises the morphology of the hair follicles, and increases the number of follicles in mid to late anagen. In patients who used topical minoxidil 2% or 3%, mean hair counts were found to have increased after 12 months, and in some patients continued to increase thereafter [30-32, 35]. Nevertheless, fewer than 5-10% of patients report dense regrowth of hair [36, 37]. Recent data using 5% minoxidil suggest that this concentration stimulates up to 45% more growth than 2% minoxidil, and may induce a more rapid response. However, the majority of those treated do not report dense regrowth.

One puzzling phenomenon in many minoxidil studies is the fact that the vehicle control alone also induced increased hair growth. A major drawback of minoxidil is the fact that it must be applied twice daily, causing inconvenience and irritation of the scalp in some patients.

Androgen modulators

The most rational approach to prevent AGA is the administration of agents that modulate the action of androgens in the scalp. This broad therapeutic approach, involving the use of systemic anti-androgens, topical estrogens, and inhibitors of the 5alpha-reductase enzyme that catalyses the conversion of testosterone to dihydrotestosterone (DHT), is based on our current understanding of the role of androgens in AGA. The classic observation by Hamilton was that castrated males do not develop AGA unless given exogenous androgens [38]. Recent evidence has demonstrated that DHT is the androgen primarily involved in the development of AGA. Male pseudohermaphrodites, who are not susceptible to AGA, are deficient in the type 2 isoenzyme of 5alpha-reductase [39], which apart from the prostate and other body sites is also strongly expressed in the inner hair root sheath [40] and the dermal hair papilla [R. Hoffmann, personal communication]. Armed with this knowledge, past and current research focuses on ways of modulating androgen metabolism.

Anti-androgens

A variety of agents may be classed as anti-androgens. Currently available anti-androgens act by blocking the binding of testosterone or DHT to the cognate receptor. Most agents with anti-androgen activity have a steroidal structure, and tend to have side effects if given to men. These include gynecomastia, erectile dysfunction and sometimes impairment of spermiogenesis. Therefore, systemic anti-androgens are not indicated for the treatment of alopecia in men.

Spironolactone is a steroid being mainly used as a diuretic and antihypertensive agent. As side effect, it causes androgen-receptor blockade and direct inhibition of testosterone production by the adrenal gland [41]. It has successfully been used to treat hirsutism in women. There has been some interest in the topical use of spironolactone in men to counter AGA. In vitro studies show that topically applied spironolactone can have potent local anti-androgenic effects [42]. However, so far no convincing clinical data have yet been presented to show the effectiveness of topical spironolactone against AGA in men.

Cyproterone acetate is another steroidal anti-androgen that effectively blocks the binding of testosterone and DHT to its receptors [43]. However, if given systemically to men, its side effects include impotence, gynecomastia and impairment of spermiogenesis.

No rigorous studies of the efficacy of topical cyproterone acetate have been carried out. In one report, a male volunteer who was treated with cyproterone acetate and minoxidil in combination experienced new hair growth but lost all the new hair when minoxidil was discontinued even though the cyproterone treatment was maintained [44].

Estrogens are indirect anti-androgens as their administration leads to an increase in the production of sex hormone binding globulin (SHBG), thereby producing a decrease in free testosterone and DHT [45]. In contrast to women, men cannot be given oral 17ß-estradiol because of side effects such as impotence and gynecomastia. Even the topical use of 17ß-estradiol may induce gynecomastia in men. In contrast, 17alpha-estradiol is said to have no biological estrogenic activity but primarily blocks 5alpha-reductase activity, at least according to the manufacturer. This implies that the topical application of 17alpha-estradiol leads to a decrease of DHT levels in the scalp, thus preventing AGA from developing. Unfortunately, there are no clinical data to support this hypothesis. However, there is a double-blind placebo controlled study on the effect of a topical 0.025% 17alpha-estradiol solution that was applied once daily by 51 men and women with AGA for a period of 6 months. In this study, there was a significant increase of hairs in anagen, hinting to an at least temporary stabilization of AGA [46]. In our clinical experience, the effects of topically applied 17alpha-estradiol solution are moderate at best.

Finasteride

At the moment, only one androgen modulator, finasteride 1 mg, has proven its efficacy against AGA and can safely be used in men. It was approved for the treatment of AGA in men by the US Food and Drug Administration (FDA) in December 1997 and since then by many other health authorities all over the world. Finasteride is a steroidal derivative that has specific inhibitory action against the type II 5alpha-reductase [47-49]. Although its structure resembles other steroid hormones, it has no demonstrable steroid action and does not bind to the androgen receptor.

Finasteride has been investigated in an animal model of AGA, the stump-tailed macaque, and in several clinical trials in humans. In preadolescent and adult macaques, oral finasteride 5 mg daily given for 6 months significantly reduced systemic levels of dihydrotestosterone (DHT), a testosterone metabolite, and also produced an increase in the mean weight of scalp hair [50]. In humans, oral finasteride 4 mg daily for 4 weeks versus placebo also significantly reduced systemic DHT, and DHT levels in the scalp, i.e. the target tissue [51]. A dose-finding study [52] led to the choice of finasteride 1 mg daily as the appropriate therapeutic dosage. A subsequent large phase III clinical trial [53] used a variety of methods of assessment: hair counts within a defined circle in the hair loss area, patient self-assessment, investigator assessment, and evaluation of standardized photographs by a panel of dermatologists. All the criteria used indicate that finasteride 1 mg per day can prevent further hair loss in more than 80% of men, and can improve appearance in 66% of men [53]. Finasteride 1 mg/d was well tolerated. Side effects such as reduction of libido or erectile dysfunction were seen in less than 2% of the men treated with the drug.

It must be emphasized that finasteride 1 mg must be taken continuously in order to maintain the beneficial effects [53]. Finasteride is contraindicated for women with AGA because by lowering systemic DHT it may cause developmental disorders of the male genitalia such as hypo- and epispadias in the developing male embryo.

CONCLUSION

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