Male pattern hair loss has been classified as an androgen-dependent hereditary disorder since the 1940s [1]. The principle of donor dominance was proposed by Orentreich [2] soon after and led to the treatment of androgenetic alopecia with hair transplants. The essential role of dihydrotestosterone (DHT) in male pattern hair loss was established through the discovery of a non-bald phenotype of individuals with a genetic deficiency of 5α-reductase [3] and also through the effectiveness of 5α-reductase inhibitors for androgenetic alopecia [4]. The discovery of two isoforms of 5α-reductase inhibitors [5,6], type I and type II 5α-reductase, has contributed further evidence to the role of DHT in male pattern baldness.

Alopecia means hair loss. The adjective androgenetic describes the two dominant aetiological factors namely genetic susceptibility and androgens.

A familial tendency to androgenetic alopecia is well recognized as is racial variation in the prevalence of balding [7,8]. Genetic factors modify the magnitude of the hair follicle response to circulating androgens. Those with a strong predisposition go bald in their teens, while those with a weak predisposition may not go bald until they are in their 60s or 70s. Fewer than 15% of men have little or no baldness by the age of 70 [9]. Osborne in 1916 [10] suggested that the baldness gene behaved in an autosomal dominant matter in men and an autosomal recessive fashion in women. Happle and Küster [11] were unable to demonstrate a bimodal distribution of phenotypes with clearly unaffected and clearly affected individuals one usually sees in autosomal dominant disorders. In contrast they observed a range of phenotypes for men and women that seem to follow a normal distribution. This, together with the finding that baldness risk increases with the number of affected family members is more consistent with polygenic inheritance. Furthermore, they noted that inherited traits due to single gene defects rarely have an incidence greater that 1:1000, whilst polygenic diseases are much more common, as is the case with androgenetic alopecia.

A polygenic inheritance is supported by an Australian study that examined the frequency of baldness in the fathers of balding men [12]. Of the fifty-four father-son relationships, 81.5% of balding sons had fathers who had cosmetically significant balding. This figure greatly exceeded the proportion expected of an autosomal dominant pattern of inheritance. The same authors also recently described an association of male pattern baldness with a polymorphism of the androgen receptor gene on the X chromosome [13]. The androgen receptor gene Stu1 restriction fragment length polymorphism [RFLP] was found in almost all (98.1%) young bald men, most older bald men (92.3%), but only in 77% of non-bald men. This polymorphism appears to be necessary for the development of androgenetic alopecia, but its presence in non bald men indicated it is not sufficient for the development of androgenetic alopecia [12]. In addition several shorter triplet repeat haplotypes were found in higher frequency in bald men than in normal controls. These RFLP’s appear to be associated with a functional variant of the androgen receptor gene that is part of the polygenic inheritance of male common baldness. Of note, the androgen receptor gene is located on the X chromosome, which is passed on from mother to a male child.

Current modeling suggests the involvement of at least 4 genes that combine to modify the age of onset, pattern of loss and rate of progression of androgenetic alopecia [7]. Other candidate genes and chromosomal regions have been examined. They include SRDA1 and SRDA5 coding for the two variants of the 5a-reductase enzymes [13], the insulin gene [14], the aromatase gene, the gene for the oestrogen receptor (ER) alpha, the non-recombinant area of the Y chromosome, and the type II insulin-like growth factor genes [7]. Thus far, no association has been found between any of the above-mentioned genetic areas and the tendency to go bald.

The effect androgens have on follicles is site specific. Under the influence of androgens during puberty, small vellus hair follicles in the pubic, axillary, beard and chest regions enlarge into large terminal hairs. The same androgens miniaturise pigmented terminal scalp hairs into non-pigmented vellus hairs, but seem to have no impact on eyebrow or occipital scalp hair [15]. There is no satisfactory explanation for these discordant events.

The demonstration that eunuchs [16], patients with androgen-insensitivity syndrome [17], and 5a-reductase deficiency [3] do not bald suggests that androgenetic alopecia is induced by activation of follicular androgen receptors by dihydrotestosterone [DHT]. In addition, patients affected by Kennedy’s disease, who have a functional abnormality of the androgen receptor gene, have a reduced risk of androgenetic alopecia [18]. Increased levels of DHT have been found in balding scalp compared to non-balding scalp [19] and androgen receptors have been demonstrated in hair follicle dermal papillae. However, the specific mechanism of the androgen effect on the hair follicle is not known.

Intrafollicular androgen over-activity may be the result of local or systemic factors. Possible local factors include an increased number of androgen receptors, functional polymorphisms of the androgen receptor, increased local production of DHT, or reduced local degradation of DHT. Possible systemic factors are increased circulating androgens providing increased substrate for the conversion to DHT, or increased systemic production of DHT at distant sites such as the prostate gland.

Dihydrotestosterone binds the androgen receptor with 5 times the avidity of testosterone and is more potent in its ability to cause downstream activation [20]. 5 α -reductase catalyses the conversion of testosterone to DHT [15]. Two 5 α -reductase isoenzymes have been characterized, based on their different pH optima [21]. Type 1 5 α -reductase is found immunohistochemically in sebaceous glands, epidermis, eccrine sweat glands, apocrine sweat glands, and hair follicles (outer root sheath, dermal papilla, matrix), as well as in the endothelial cells of small vessels and the Schwann cells of cutaneous myelinated nerves. In the skin the activity of the type 1 5α-reductase is concentrated in sebaceous glands and is significantly higher in sebaceous glands from the face and scalp compared with non acne-prone areas. Northern blot studies reveal an abundance of type 1 mRNA in neonatal foreskin keratinocytes, followed by adult facial sebocytes, and stronger expression in DP from occipital hair cells than from beard [22]. It is also found in the liver, adrenals and kidneys. Despite the wide expression pattern of type 1 enzyme, its physiological function is uncertain. The type 2 enzyme has been found by immunohistochemistry to be in the dermal papilla, the inner layer of the outer root sheath, the sebaceous ducts and proximal inner root sheath of scalp hair follicles [23]. Regional studies showed the type 2 mRNA present in beard DP, but absent from occipital scalp and axillary DP. The type 2 isoenzyme in beard DP has three times higher activity than the type 1 5α-reductase present in the occipital scalp and axillary DP. The specific activity of 5α-reductase in the hair DP exceeded those in other hair follicle compartments (connective tissue sheaths and ORS) by a factor of at least 14 in the scalp and at least 80 in the beard. The beard DP cells appeared to generate more 5α-DHT than those from non-balding scalp hair follicles; however, the individual freshly isolated intact DP was shown to possess considerably different levels of ex vivo enzyme activities [22]. It is also found in the prostate, testes, and liver. The effect of subtype specific 5 α -reductase inhibitors on serum DHT levels has been studied. Type 2 5 α -reductase accounts for about 80% of circulating DHT [20]. Androgenetic alopecia does not occur in men with a genetic deficiency of type II 5α–reductase mRNA and protein for both isoenzymes has been found in hair follicles, but this has not been universally documented. The relative contribution of circulating and locally produced DHT to activation of hair follicle androgen receptors in the balding scalp remains to be elucidated. Furthermore, the evidence for a link between levels of circulating androgens and androgenetic alopecia remains inconclusive, with very few studies finding any association [24-26].

The severity of androgenetic alopecia cannot be correlated with the presence or density of terminal hairs on the trunk and limbs. There is also no correlation with libido or masculinity as defined by sebum excretion rate, body hair density, bone, skin and muscle thickness [27]. Thus it is likely that the normal levels of systemic androgens are adequate for the maximal production of dihydrotestosterone.

Beard dermal papilla cells are known to secrete growth-inducing autocrine growth factors in response to testosterone, leading to an increase in dermal papilla size and enlargement of the hair follicle and hair cortex. This response is not seen with occipital scalp hair follicles when subjected to the same testosterone challenge [25,28]. Insulin-like growth factor-1 has been identified as a major component of secreted cytokines [29]. Similar investigations performed on dermal papilla cells from the balding scalp of the stump-tailed macaque show that testosterone inhibited the growth and proliferation of keratinocytes [30]. To date, no such work has been done on the human vertex scalp follicle. Studies examining distribution and expression of androgen receptors have shown varying results. Two studies show that androgen receptors are only found in the nuclei of dermal papilla cells [25,31]. However, another study found more extensive follicular distribution of receptors including the hair bulb [32]. Comparing different anatomical sites, there appear to be higher numbers of androgen receptors in the pubic hair follicles and beard dermal papilla cells, with occipital scalp follicles expressing lower levels [33]. Further research is required in order to reveal the seemingly paradoxical effect androgens have on different types of hair follicles.

Hair loss on the scalp progresses in an orderly and reproducible pattern, and is a function of factors intrinsic to each hair follicle. In vitro experiments have shown that the hair follicles are able to self-regulate their response to androgens by regulating the expression of 5 α-reductase and androgen receptors [33-35]. This self-regulation is postulated to produce the quantifiable difference in androgen receptor numbers [33,36] and 5 α-reductase activity [34,37] that is observed between balding and non-balding areas of the scalp. This intrinsic regulation is best demonstrated in hair transplantation experiments: occipital hairs maintain their resistance to androgenetic alopecia when transplanted to the vertex, and scalp hairs from the vertex transplanted to the forearm miniaturise at the same pace as hairs neighbouring the donor site [2].

Hair growth is cyclical. The hair cycle has 3 phases (Figure 1): anagen growth phase, catagen involutional phase and the telogen resting phase [38]. Anagen lasts for 3-5 years, catagen 2 weeks and telogen 3 months. Thus the anagen to telogen hair count is usually in the order of 12:1. Hair shedding [exogen] occurs within the telogen phase and the sub-phase of telogen that follows exogen is called the latent phase [39].

In androgenetic alopecia, the duration of anagen decreases with each cycle, whilst the length of telogen remains constant or is prolonged. This results in a reduction of the anagen to telogen ratio [7]. Balding patients often describe periods of excessive hair shedding, most noticeable whilst combing or washing. This is due to the relative increase in numbers of follicles in telogen.

As the hair growth rate remains relatively constant the duration of anagen growth determines hair length. Thus, with each successively foreshortened hair cycle, the length of each hair shaft is reduced. Ultimately, anagen duration becomes so short that the growing fails to achieve sufficient length to reach the surface of the skin, leaving an empty follicular pore.

In androgenetic alopecia, the latent phase is prolonged, reducing hair numbers, further contributing to the balding process [39].

Hair follicles consist of mesenchymal and ectodermal components. The ectodermal part consists of an invagination of epidermis into the dermis and subcutaneous fat. The hair bulb contains the hair matrix which produces the hair shaft. The mesenchymal component is the dermal papilla, a small collection of specialised fibroblasts that is totally surrounded by the hair bulb. In association with the changes in hair cycle dynamics, there is progressive, stepwise miniaturisation of the entire follicular apparatus (Figure 2). As the dermal papilla is central in the maintenance and control of hair growth, it is likely to be the target of androgen-mediated events leading to miniaturisation and hair cycle changes [40-42]. The constant geometric relationship between the dermal papilla size and the size of the hair matrix [43] suggests that the size of the dermal papilla determines the size of the hair bulb and ultimately the hair shaft produced [44].

A greater than ten fold reduction in overall cell numbers is likely to account for the decrease in hair follicular size [45]. The mechanism by which this decrease occurs is unexplained, and may be the result of either apoptotic cell death, decreased proliferation of keratinocytes [46], cell displacement with loss of cellular adhesion leading to dermal papilla fibroblasts dropping off into the dermis, or migration of dermal papilla cells into the dermal sheath associated with the outer root sheath of the hair follicle [44].

In overall volumetric terms, change in the follicular extracellular matrix is unlikely to greatly affect follicular size. However, being a potential source of biologically active molecules, small changes in its volume may have significant effects on hair follicular function [45].

Smaller follicles result in finer hairs. The caliber of hair shafts reduces from 0.08mm to less than 0.06mm. This is also followed by a reduction in pigment production. On the balding scalp, transitional indeterminate hairs represent the bridge between full-sized and miniaturised terminal hairs [47].

Traditional models of androgenetic alopecia show follicular miniaturization occurring in a stepwise fashion. This has recently been contested, and it is now believed that the transition from terminal to vellus hair occurs as an abrupt, large step process [48]. Either way the cross-sectional area of individual hair shafts remains constant throughout fully developed anagen [47], indicating that the hair follicle, and its dermal papilla, remain the same size. Therefore follicular miniaturization occurs between anagen cycles rather than within anagen.

This short window of androgen effect may also explain the lengthy delay experienced between clinical response and the commencement of therapy, as any pharmacological intervention will only have effect at the point of miniaturisation [47]. Follicular miniaturisation leaves behind stellae as dermal remnants of the full sized follicle. These stellae, also known as fibrous tracts or streamers, extend from the subcutaneous tissue up the old follicular tract to the miniaturised hair and mark the formal position of the original terminal follicle [49]. Arao-Perkins bodies may be seen with elastic stains within the follicular stellae. An Arao-Perkins body begins as a small cluster of elastic fibres in the neck of the dermal papilla. These clump in catagen and remain situated at the lowest point of origin of the follicular stellae. With the progressive shortening of anagen hair seen in androgenetic alopecia, multiple elastic clumps may be found in a stella, like the rungs of a ladder [50].

A moderate perifollicular, lymphohistiocytic infiltrate, perhaps with concentric layers of perifollicular collagen deposition, is present in some 40% of cases of androgenetic alopecia, but only 10% of normal controls [49]. Occasional eosinophils and mast cells can be seen. The cellular inflammatory changes also occur around lower follicles in some cases and occasionally involve follicular stellae. The diagnostic and prognostic significance of the degree of the inflammation is not known [49].

Hamilton estimated that 30% of men developed androgenetic alopecia by the age of 30, 50% by the age of 50 [51]. Men of Asian, Native American and African background have a decreased frequency of frontal hair loss and less extensive alopecia as compared to Caucasians [52]. In Australia a study of 1390 men between the ages of 40 and 69 was conducted to determine the prevalence and risk factors for androgenetic alopecia. The prevalence of vertex or full baldness [Figure 3] increases with age from 31% [age 40-55] to 53% [age 65-69]. A receding frontal hairline was found in 25% of men aged 40-55 and 31% aged 65-69. The factors found to be associated with baldness using unconditional logistic regression analysis were a higher weight and BMI at age 21, an early pubertal growth spurt and obesity as evidenced by waist size being in the fourth quartile at age 21 [more than 86cm] compared to men in the first quartile [78cm or less].

Androgenetic alopecia has, at various times, been associated with ischaemic heart disease [53-56]. However, most of these studies were conducted by non-dermatologists and no dermatologic expertise was included for confirmation of the accuracy of these studies. These statistically-significant, though weak, associations were discovered by epidemiological, cohort and case control studies. In general, severe early onset of androgenetic alopecia in young subjects before their 30s may have a higher risk for ischaemic heart disease. In a recent retrospective study of 22,071 American physicians, subjects who had predominantly vertex balding as opposed to frontal hair loss were shown to be at an increased incidence of myocardial infarction [57]. This pattern was especially true among men with hypertension or high cholesterol levels.

An increased incidence in benign prostatic hypertrophy has also been associated [58,59]. Prostate cancer has also been found to be positively associated with androgenetic alopecia in various studies [60,61]. A recent large scale Australian case-control study [61] found that vertex balding was associated with a 50% increase in risk of prostate cancer. No increased risk was seen for frontal balding or frontal concurrent with vertex balding. However, associations with high-grade prostate cancer were found in all patterns of androgenetic alopecia, especially significant in men aged 60-69 years.

No clear mechanistic link between these diseases has been found. High androgen levels have been postulated to cause both androgenetic alopecia as well as atherosclerosis and thrombosis, however other data has shown no association between baldness and established coronary risk factors [62]. An association and a pathophysiological mechanism for the link between androgenetic alopecia and prostate cancer also remains to be established but may involve the dual dependence of these conditions on dihydrotestosterone [63].

Topical agents should be applied to the entire area of alopecia. Systemic medications known to induce hair loss, including retinoids, cytotoxic agents and anticoagulants, should be ceased where possible. Any underlying scalp disorder such as seborrhoeic dermatitis or scalp psoriasis should be treated so that topical treatments can be more effectively applied.

Topical minoxidil and oral finasteride are the only two treatments currently approved by the Food and Drug Administration [USA] for the treatment of androgenetic alopecia. Both of these medications prevent further hair loss but are only able to partially reverse the baldness. Both require continuous use to maintain effectives. As effectiveness may take 6-12 months to become apparent, these agents should be used for at least 1 year before deciding whether to continue treatment.

Minoxidil is an antihypertensive that was found to cause hypertrichosis [70]. A topical preparation was formulated for the treatment of androgenetic alopecia. Hairs are recruited into a prolonged anagen, accompanied by enlargement of miniaturised hair follicles [71,72]. It has long been recognized that minoxidil and other potassium channel agonists (diazoxide and pinacidil) stimulate hair growth in vivo, however the specific mechanism of action is unknown. It is postulated that minoxidil sulfate, the active metabolite, opens the adenosine triphosphate (ATP) sensitive potassium channel (KATP channel) which renders the intracellular potential more negative. This negative gradient promotes depletion of intracellular calcium. In the presence of calcium, epidermal growth factor has been shown to inhibit hair follicular growth in vitro. The conversion of minoxidil to minoxidil sulfate is higher in hair follicles than in the surrounding skin and may suppress EGF-induced inhibition of growth, prolonging the anagen growth phase of hair follicles [73].

There are two topical preparations of minoxidil available: 2% and 5% solutions. Both are available over-the-counter in most countries for promoting hair growth and have been shown to be effective in increasing hair counts [74-77].

On commencing treatment, minoxidil may cause a surge in the growth of miniaturised hairs and induction of anagen from resting hair follicles. This may produce a rapid hair shedding of previous telogen hairs beginning 2-8 weeks after treatment initiation. This temporary shedding may be interpreted as a clinical indication that the minoxidil is having a beneficial effect. Regrowth is more pronounced at the vertex than in the frontal areas. The effect of minoxidil only lasts as long as the patient continues to use the preparation. Once the treatment is stopped all minoxidil dependent hairs will be shed and the overall density will return to a point determined by the natural history [76]. Patients who respond best to minoxidil typically are those who have been recently diagnosed and have a small amount of hair loss.

As minoxidil works is a non-specific promoter of hair growth, the slow miniaturisation of hair follicles induced by androgens continues in spite of treatment. Evidence for this is seen in a 120-week double-blind study [76] comparing the clipped hair weight of men treated with 5% minoxidil, 2% minoxidil and placebo and a group with no treatment. As expected, the minoxidil groups experienced a surge in hair weights at the induction of therapy. The 5% group was superior to the 2% group in terms of the initial peak in hair weights. Both were superior to placebo and no treatment groups. However, all groups [minoxidil, placebo and no treatment] showed a progressive 6% per annum decrease in hair weights during the treatment period. This would mean that patients using minoxidil as mono-therapy for androgenetic alopecia continue to bald in spite of treatment. If treatment is ceased, any positive effect on hair growth is lost in 4-6 months [76]. The role of perifollicular inflammation in the pathogenesis of androgenetic alopecia is poorly understood. However, studies in patients treated with minoxidil have demonstrated that 55% of those with microinflammation had regrowth in response to treatment compared with 77% of patients without inflammation or fibrosis [78].

Minoxidil should be used twice daily, with one milliliter spread evenly into the entire scalp. The solution should be applied before gels or hairsprays which might reduce absorption. Side effects are uncommon, with skin irritation [79] being the most frequently reported event. Dizziness and tachycardia, and contact allergic dermatitis [80] have also been reported. Side effects are more common with the 5% topical minoxidil solution rather than the 2% solution.

Finasteride is a synthetic azo-steroid that is a potent and highly selective antagonist of type II 5a-reductase. It is not an anti-androgen. Being a non-competitive antagonist, it binds irreversibly to the enzyme and inhibits the conversion of testosterone to dihydrotestosterone. Thus, while the pharmacokinetic half-life is about eight hours, the biological effect persists for much longer. The underlying principle for its use is the reduction of DHT production and thus this limits its action to scalp hair follicles.

Various studies [4,81-88] have demonstrated the beneficial effects of finasteride on reversing the pathogenesis of androgenetic alopecia with the most benefit seen for those trial patients with primarily type III vertex or type IV Hamilton/Norwood hair loss. Finasteride has been reported to slow the progression of androgenetic alopecia and to produce partial regrowth in about 2/3 of men [4]. A study measuring hair counts using macrophotographs [81] found that both total and anagen hair counts increase with treatment of finasteride. A significant increase in the anagen to telogen ratio was also achieved. This demonstrates the ability of finasteride to stimulate conversion of hair follicles into the anagen phase, possibly through reversion of the decrease in anagen phase and the increase in lag phase. A study looking at scalp biopsies [82] shows that finasteride stimulates an increase in terminal hair counts and a decrease in vellus hair counts. Other studies using hair count and hair weight as an objective measure of outcome [83,89] demonstrate that both hair count and hair weight increase, with a larger extent of increase achieved in hair weight. Factors that affect hair weight include the number of hairs, hair growth rate and hair thickness. These findings show the ability of finasteride to reverse the miniaturisation process, producing hair of greater length and thickness, and possibly with a greater growth rate.

A daily oral dose of one milligram reduces scalp DHT by 64% and serum DHT by 68% [84]. Finasteride was originally developed for the treatment of benign prostatic hyperplasia and is dosed at five milligrams daily for this condition. For the treatment of androgenetic alopecia, dose ranging studies have found no significant difference in clinical benefit between five and one milligram daily regimens [85] nor is there any significant further reduction of scalp or serum DHT levels. In practice, finasteride can be administered at either at a dose of one milligram per day, or at longer intervals.

A 5-year multinational study looking at the effect of finasteride on treatment of androgenetic alopecia found finasteride to be superior to placebo [87]. The placebo group suffered a progressive decline in hair count, losing about 26% of terminal hairs compared to baseline counts at the end of the 5-year study. In contrast, patients on finasteride have a 10% increase in hair count at the end of the first year. Hair count declined somewhat thereafter but remained above baseline throughout, remaining at 5% above the baseline hair count after 5 years of treatment. This decline rate of hair count in the finasteride group is significantly less than that of the placebo group. Taken together, there is a progressive increase in the difference between treatment and placebo group over time. This demonstrates the effects of finasteride in stimulating a substantial amount of hair regrowth, reaching its peak efficacy after one year of treatment, and slowing the progression of hair loss thereafter.

At the end of the first year, some in the placebo group were swapped onto receiving finasteride for the remaining four years. These patients demonstrated a decrease in hair count during the first year with placebo, followed by an improvement in the subsequent four years with finasteride. The improvement is similar to that of the group who received finasteride for five years throughout the study. However, mean hair count level is less than that of the patients who have taken finasteride ‘a year earlier’ at all comparable time points, with the difference being similar to the amount of hair loss sustained during the year of placebo treatment. This shows the relative benefits of early commencement of treatment with finasteride. Some of the finasteride patients were also crossed-over to receive placebo after a year of finasteride treatment. A decrease in hair count was observed twelve months later, demonstrating the reversal of the beneficial effects of treatment obtained during the first year.

Further evidence of the efficacy of finasteride in the treatment of androgenetic alopecia is seen in a randomized, double-blind, placebo-controlled twin study [88]. At month 12, all subjects in the finasteride group demonstrated an increase in hair count, while a decrease was found in 44% of the placebo group. Serum DHT levels were significantly decreased in the finasteride group, with no significant change observed in the placebo group. Global photography assessment shows significant improvement on hair growth in vertex and superior-frontal scalp in the finasteride group, with no significant differences between treatment groups observed in the temporal or anterior hairline views. This finding shows the relative effectiveness of finasteride on protecting hair loss over the vertex and superior-frontal regions of the scalp, in compare to the minimal response over the temporal and the anterior hairline regions.

Few adverse side effects were reported in the 5-year data. In the finasteride group loss of libido was reported in 1.9% and erectile dysfunction in 1.4% in the first year. The placebo groups reported these same events with frequencies of 1.3% and 0.6% respectively. These events appeared to resolve on cessation of the drug and, in some cased, with continued treatment. It has been suggested that even these figures overstate the true incidence of sexual dysfunction [90]. Of note, older men on finasteride experienced a 50% reduction in serum prostate specific antigen [PSA] levels, which could result in an underestimation of prostatic cancer risk. Previous recommendations in the urology literature state that PSA levels remain valid whilst patients are on finasteride, but the value should be doubled to correct for the finasteride effect [91-93]. Men between 18 to 41 years old are thought to have a negligible decrease in measured PSA [94]. More recent studies [95] now suggest that finasteride treatment at the 5mg/day dose affects the serum PSA concentration in a time-dependent manner and the previous method of doubling the serum PSA level in patients taking finasteride, irrespective of duration of treatment with finasteride, is no longer applicable. The doubling of the PSA value may overestimate the true risk of prostate cancer during the first 6-9 months of finasteride treatment, accurately determine the true PSA value for 1-3 years and thereafter, there may be a possible underestimation of the true PSA value.

In a recent trial 18,882 men older than 54 years with a normal digital rectal examination and a serum PSA equal to or less than 3ng/ml were randomized to finasteride 5mg daily vs placebo. There was a 25% reduction in prostate cancer prevalence in those taking finasteride [96]. However, 6.4% of the men taking finasteride developed histologically high grade cancer (Gleason score 7-10) compared with 5.1% of those on placebo. The diagnosis of high grade prostatic intraepithelial neoplasia (PIN) with or without concomitant prostate cancer was then evaluated in these subjects [97]. High grade PIN accompanied by prostate cancer was diagnosed in 144 men (3.2%) in the finasteride group vs 223 (4.6%) in the placebo group (p=0.0004). Finasteride use resulted in a decreased risk of high grade PIN, which is considered a premalignant lesion of the prostate. Finasteride use has also been suggested to significantly improve prostate cancer detection with digital rectal examination [98].

Topical finasteride has been investigated as potential variation in drug delivery. While a 0.05% of finasteride solution applied to the scalp was well absorbed and produced a 40% reduction in serum DHT, it had no effect on hair regrowth. One explanation for this observation is that inhibition of prostatic DHT production is an important factor in preventing hair loss with finasteride, ie a significant reduction in circulating DHT is required in addition to the local blockade of 5 α-reductase at the hair follicle [99].

Medical treatment should be continued indefinitely, as the benefit will not be maintained upon ceasing therapy. Up to one year of treatment may be required before any clinical response is noticeable. The monitoring of this response can be problematic. Patients inspect their hair on a daily basis and subtle changes over time may not be readily observable. Doctors are essentially reliant upon the patients’ subjective assessment of their hair density over time. Baseline photographs are helpful, but unlikely to detect changes of less than 20% in hair density. The authors make use of a camera mounted on a stereotactic device; a system that is identical to the set-up used in the phase III finasteride trials [99]. Photographs are taken of the vertex and frontal hairline at six-monthly to yearly intervals; hair densities at these time points can be readily compared. This set-up is proving to be useful in the long-term monitoring of treatment response. [figure 6 & 7] Patients are able to observe their regrowth during treatment; the photographs serve as a motivating factor, improving long-term patient compliance to medical treatment. Similar set-ups using Polaroid photographs also appear useful [100]. Finasteride is a teratogen. Male rats exposed to finasteride in utero develop hypospadius with cleft prepuce, decreased anogenital distance, reduced prostate weight and altered nipple formation [94]. As the drug is secreted in the semen and can be absorbed through the vagina during intercourse, it was originally advocated that men taking finasteride should avoid unprotected intercourse with pregnant women. In practice, the concentration of finasteride in the semen is well below the minimum effect dosage, and no recommendations regarding the use of condoms are made in the product information leaflet. To date there are no reports of adverse pregnancy outcomes among women exposed to finasteride. Finasteride has no effect on spermatogenesis or semen production [94]. With regards long term safety, finasteride has now been in use for over 10 years. Many recipients are elderly men taking 5mg per day. Very few side-effects have been observed. There is no effect of long term use on bone mineral density [101,102]. Reversible painful gynaecomastia has been reported [103] and the incidence is thought to be around 0.001%. [104]

Dutasteride inhibits both type I and type II 5α-reductase and the 0.5mg dose is approved for the treatment of benign prostatic hyperplasia. It is approximately 3 times as potent as finasteride at inhibiting type II 5α-reductase and more than 100 times more potent at inhibition of the type I isoenzyme [105]. The serum half-life of dutasteride is 4 weeks as compared with a serum half-life of 6-8 hours for finasteride. There is persistent suppression of dihydrotestosterone level after dutasteride is ceased. For this reason, patients taking dutasteride should not donate blood until at least 6 months after stopping their medication, to prevent administration to a pregnant transfusion recipient [106].

A recent phase II randomized placebo-controlled study of dutasteride versus finasteride [106] showed that 2.5mg of dutasteride was superior to 5mg finasteride in improving scalp hair growth in men between the ages of 21 and 45 years and was also able to produce hair growth earlier than finasteride. This was evidenced by target area hair counts and clinical assessment at 12 and 24 weeks. In addition, a recent randomized, double-blind, placebo-controlled study on the efficacy of dutasteride in identical twins demonstrated that dutasteride was able to significantly reduce hair loss progression in men with androgenetic alopecia [107]. Dutasteride is well tolerated and the incidence of the most common sexual side effects is low, tends to decrease over time [107] and resolves upon drug cessation.

Although human studies of combination treatment have been poorly designed, animal studies have shown an additive effect when both medications were used concurrently. Patients wishing to switch from one treatment to the other should ensure an overlap period of 3 months before discontinuing the old medication, in order to prevent excess shedding.

Oral anti-androgens (e.g. spironolactone, cyproterone acetate) have been widely used to treat women with androgenetic alopecia. However it has been contraindicated in treatment of androgenetic alopecia in males due to its systemic androgenic effects in the body, affecting libido, male sexual functions and secondary sexual characteristics development. A topical anti-androgen, fluridil has recently been rationally developed for use in male androgenetic alopecia. It is designed to be locally metabolized, not systemically resorbable, and degradable into inactive metabolites without anti-androgenic activity [108]. A double-blind, placebo-controlled study shows that patients using topical fluridil had an increase in the anagen to telogen ratio, and the maximum attainable effect is achieved within the first 90 days of daily use. No side effects on libido and sexual performances have been found. Nevertheless, a longer study is required to further investigate fluridil’s long-term safety and effectiveness in male androgenetic alopecia.

Topical ketoconazole has been reported to be effective for androgenetic alopecia [109] in case reports however placebo controlled trials have not yet been performed. It acts in both an androgen-dependent and androgen-independent manner.

Aside from the physical change and possible psychological impact, androgenetic alopecia may also lead to a loss of protection of the scalp from sunburn, cold, mechanical injury and ultraviolet light. There may be an increased incidence of actinic damage due to increased UV exposure. Patients should be advised to protect the area from UV damage by covering up or with sunscreen.

Patients who do not pursue medical treatments have various camouflage methods available to them. Spray-on scalp dye treatments, tinted powders and lotions can disguise bald scalp and give the impression of thicker hair for patients with mild androgenetic alopecia. For those with advanced disease good quality synthetic, acrylic or natural fibre wigs can be entirely imperceptible.

Scalp surgery should be reserved for those over the age of 25 years. As the predictive value of further hair loss is much lower for those men between the ages of 15 and 25 years, surgery at this early stage may give rise to an unnatural appearance later on. Scalp surgery can involve excision of bald scalp, scalp flaps as well as transplantation.

There are various scalp autograft transplantation techniques in use; typically involving the transplantation of occipital scalp hair follicles to the bald areas. A strip of full-thickness occipital scalp is harvested and under the aid of a dissecting microscope, cut down to small subunits. Minigrafts containing a cluster of hairs are transplanted into slits made with a small scalpel blade. A modified technique uses ‘follicular units’ containing between one to four hair follicles, which are inserted into smaller needle holes. Both techniques can achieve good results, but follicular unit transplantations have the advantage of being able to achieve much greater hair densities. It is preferable that surgical candidates have frontal or mid-frontal hair loss as opposed to hair loss at the vertex and their donor hair density needs to be adequate to support the surgery (i.e. > 40 follicular units/cm2). Also, thicker donor hairs are able to create better coverage compared with finer hair. Disadvantages of hair transplants are increased time and labour requirements, which translates to greater cost for the patient. Good surgeons can transplant up to 3000 units per ‘megasession’, the number of sessions required would depend on the area to be transplanted. Transplanted hairs seem to immediately go into a telogen resting phase after insertion. Thus surgical results can only be adequately assessed after no less than three months after surgery. There is always a degree of graft failure. Various reasons account for dead grafts including the skill of the surgeon, the density of graft placement, careless handling and preparation of the graft units, and desiccation of the grafts whilst awaiting insertion. These techniques have been recently reviewed in detail elsewhere [110].

Scalp reductions result in a more unnatural look with excision scars tending to be more noticeable over time. In addition, the inability to predict further hair loss over time in each patient has meant that the procedures are now uncommonly performed. Treatment with finasteride and/or topical minoxidil may complement hair transplant surgery to maintain a natural look over time.