Studies On Androgenetic Alopecia Distribution Among Males

The prevalence rate of Androgenetic Alopecia varies from around 23 to 87 percent depending on ethnicity and age. There is a trend of rising prevalence with age. It is a chronic condition that often begins in the late teens and early twenties for those afflicted.

The trends and distributions clearly indicate that genetics plays a major role in prevalence and manifestation of androgenetic alopecia. Studies clearly confirm that more than 60 percent of the androgenetic alopecia patients are reported to have first degree relatives having a history of balding.

Some interesting results were observed in the studies done on some large numbers of Korean men. In Korean men, the prevalence of AGA at all ages was 14.1 percent. It increased steadily with advancing age, but was lower than that of Caucasians: 2.3 percent in the third decade, 4.0 percent in the fourth decade, 10.8 percent in the fifth decade, 24.5 percent in the sixth decade, 34.3 percent in the seventh decade and 46.9 percent over 70 years.

The Type III vertex involvement on the Norwood scale was the most common type in the third decade to the seventh decade; over 70 years, type VI was most common. A 'female pattern' was observed in 11.1 percent of all cases involved.

The prevalence of androgenetic alopecia in Korean men was lower than that in Caucasians. Korean men tend to have more frontal hairline preservation and show a more 'female pattern' of hair thinning than Caucasians.

There is some evidence to support the hypothesis that male-pattern hair loss imparts an increased risk of cardiovascular disease (CVD). It would appear that men with androgenetic alopecia are more likely to develop CVD; however, there is no evidence of an increase in conventional risk factors such as blood pressure and cholesterol concentrations. Recent studies have also demonstrated an increased risk of benign prostatic hyperplasia and prostate cancer in those with male-pattern baldness; however, the molecular basis for this link is yet to be evaluated.

Embryological development of both the hair follicle and the prostate depends on mesenchymal-epithelial interaction, which is influenced by the expression of type 5 alpha-reductase enzyme. Some important studies have been done to elucidate the association between the size of the prostate gland and the prevalence and severity of AGA.

Though no significant correlation between the age of onset of AGA and the development of BPH was observed, the results have confirmed that a larger prostate is generally associated with a prevalence of AGA. It remains to be seen if long-term use of finasteride in AGA patients will prophylactically lower the incidence of BPH.

The data observed by the various studies point towards a complex mechanism of action of Androgenetic Alopecia, where a number of other factors are responsible. And many more studies are still needed to clarify the genetic pattern the disease follows, whether it is polygenic, or whether it is autosomal or sex chromosome linked.

The pathogenesis of androgenetic alopecia involves androgen-induced miniaturization of terminal hairs into vellus hairs in affected regions of the scalp. Some degree of follicular miniaturization and consequential hair loss is universal and is considered to be a physiological secondary sexual characteristic. Androgenetic alopecia only becomes a medical problem when the hair loss is excessive, premature and distressing to the patient. A number of medical treatments aimed at arresting the progression of hair loss have become available in recent years, and surgical treatments are constantly being refined. Substantial research into the biology of androgenetic alopecia has been conducted in recent years in a number of centers around the world and is continuing.

Alopecia means hair loss. The adjective androgenetic describes the two dominant etiological factors, namely genetic susceptibility and androgen hormones.

A familial tendency for androgenetic alopecia is well recognized as is racial variation in the prevalence of balding. Genetic factors modify the magnitude of the hair follicle response to circulating androgens. Those with a strong predisposition bald in their teens, while those with a limited predisposition may not bald until they are in their 60s or 70s.

Fewer than 15 percent of Caucasian men have little or no baldness by the age of 70. Osborne suggested that the baldness gene behaved in an autosomal dominant manner in men and an autosomal recessive fashion in women.

Happle and Küster 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 that there are a range of phenotypes observable 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 in androgenetic alopecia.

A polygenic inheritance is supported by an Australian study that examined the frequency of baldness in the fathers of balding men. Of the fifty-four father-son relationships, 81.5 percent of balding sons had fathers who had cosmetically significant balding. This figure greatly exceeded the proportion expected for 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. The androgen receptor gene Stu1 restriction fragment length polymorphism [RFLP] was found in almost all (98.1 percent) young bald men, most older bald men (92.3 percent), but only in 77 percent 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. In addition, several shorter triplet repeat haplotypes were found in higher frequency in bald men than in normal controls.

These RFLPs 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 is the fact that 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 four genes that combine to modify the age of onset, pattern of loss and rate of progression of androgenetic alopecia. Other candidate gene and chromosomal regions have been examined. They include SRDA1 and SRDA5 coding for the two variants of the 5a-reductase enzymes, the insulin gene, the aromatase gene, the gene for the Era estrogen receptor, the non-recombinant area of the Y chromosome, and the type II insulin-like growth factor genes. Thus far, no association has been found between any of the above-mentioned genetic areas and the tendency to go bald.

Systemic Hormonal Effects
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 enlarge into large terminal hairs. The same androgens miniaturize pigmented terminal scalp hairs into non-pigmented vellus hairs, but seem to have no impact on eyebrow or occipital scalp hair. There is no satisfactory explanation for these discordant events.

The demonstration that eunuchs, patients with androgen-insensitivity syndrome, and 5alpha-reductase deficiency do not bald suggest that androgenetic alopecia is induced by activation of follicular androgen receptors by dihydrotestosterone [DHT]. Increased levels of DHT have been found in balding scalp compared to non-balding scalp 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 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 five times the avidity of testosterone and is more potent in its ability to cause downstream activation. 5a-reductase catalyses the conversion of testosterone to DHT. Two 5a-reductase isoenzymes have been characterized, based on their different pH optima. Type 1 5a-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 5a-reductase is concentrated in sebaceous glands and is significantly higher in sebaceous glands from the face and scalp compared with nonacne-prone areas. Northern blot studies revealed that the most abundant type of 1m RNA in neonatal foreskin is keratinocytes, followed by adult facial sebocytes, and stronger expression in DP from occipital hair cells than from beard. It is also found in the liver, adrenals and kidneys.

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. 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 5a-reductase present in the occipital scalp and axillary DP. The specific activity of 5a-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 5a-DHT than those from nonbalding scalp hair follicles; however, the individual freshly isolated intact DP was shown to possess considerably different levels of ex vivo enzyme activities. It is also found in the prostate, testis, and liver. The effect of subtype specific 5a-reductase inhibitors on serum DHT levels has been studied. Type 2 5a-reductase accounts for about 80 percent circulating DHT.

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.

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. Thus, it is likely that the normal levels of systemic androgens is adequate for the maximal production of dihydrotestosterone.

Local Hormonal Effects
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. Insulin-like growth factor-1 has been identified as a major component of secreted cytokines. 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.

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. However, another study found more extensive follicular distribution of receptors including the hair bulb. 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. 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 5a-reductase and androgen receptors.

This self-regulation is postulated to produce the quantifiable difference in androgen receptor numbers and 5a-reductase activity 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 miniaturize at the same pace as hairs neighboring the donor site.

The 3 key features are alteration of hair cycle dynamics, follicular miniaturization and inflammation.

Hair Cycle Dynamics
Hair growth is cyclical. The hair cycle has 3 phases (Figure 1): anagen growth phase, catagen involutional phase and the telogen resting phase. 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.

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. 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 and further contributing to the balding process.

Hair follicle miniaturization
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 specialized fibroblasts that is totally surrounded by the hair bulb. In association with the changes in hair cycle dynamics, there is progressive, stepwise miniaturization of the entire follicular apparatus.

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 miniaturization and hair cycle changes. The constant geometric relationship between the dermal papilla size and the size of the hair matrix suggests that the size of the dermal papilla determines the size of the hair bulb and ultimately the hair shaft produced.

A greater than ten fold reduction in overall cell numbers is likely to account for the decrease in hair follicular size. The mechanism by which this decrease occurs is unexplained, and may be the result of either apoptotic cell death, decreased proliferation of keratinocytes, 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.

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.

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 miniaturized terminal hairs.

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. Either way, the cross-sectional area of individual hair shafts remains constant throughout fully developed anagen, 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 miniaturization. Follicular miniaturization 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 miniaturized hair and mark the formal position of the original terminal follicle.

Arao-Perkins bodies may be seen with elastic stains within the follicular stellae. An Arao-Perkins body begins as a small cluster of elastic fibers in the neck of the dermal papilla. Those 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.

Inflammation
A moderate perifollicular, lymphohistiocytic infiltrate, perhaps with concentric layers of perifollicular collagen deposition, is present in some 40 percent of cases of androgenetic alopecia, but only 10 percent of normal controls. 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.

The incidence of baldness in the community in areas according to the community sample
Hamilton estimated that 30 percent of men developed androgenetic alopecia by the age of 30, 50 percent by the age of 50. In Australia, a study of 1,390 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 increased with age from 31 percent [age 40-55] to 53 percent [age 65-69]. A receding frontal hairline was found in 25 percent of men aged 40-55 and 31 percent aged 65-69.

Androgenetic alopecia has been associated with ischemic heart disease in several 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 ischemic heart disease. A study found that men with higher grades of androgenetic alopecia (vertex balding) have a higher risk of developing ischemic heart disease, especially among men with hypertension or high cholesterol levels. However, most of these studies were conducted by non-dermatologists and no dermatologic expertise was included for confirmation of the accuracy of these studies.

Prostate cancer has also been found to be positively associated with androgenetic alopecia in various studies. A large scale Australian case-control study found that vertex balding was associated with a 50 percent 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. An association and a pathophysiological mechanism for the link between androgenetic alopecia and prostate cancer also remain to be established but may involve the dual dependence of these conditions on dihydrotestosterone.

Histological diagnosis is rarely necessary for male androgenetic alopecia. In patients where the diagnosis is equivocal, 4mm punch biopsies are the ideal specimen, taken from the vertex of the scalp. Two biopsies should be taken and one sectioned horizontally and the other vertically. Horizontal sectioning yields much information on the number and types of follicles seen, facilitating more accurate diagnosis.

The prime feature found in scalp biopsies is the reduction in the terminal anagen hair count. The apparent reduction in the number of terminal hairs is due to progressive replacement of terminal hairs with secondary pseudo-vellus hairs with residual angiofibrotic tracts. Horizontal sections reveal numerous pseudo-vellus hair follicles in the papillary dermis reflecting a miniaturization process. Hairs are not destroyed. The presence of arrector pili muscle and angiofibrotic streamers distinguishes them from true vellus hairs. There is a change in the ratio of terminal to vellus hairs from greater than 6:1 to less than 4:1. Also, the anagen to telogen hair ratio reduces from 12:1 to 5:1.

Other features that may also be seen include follicular fibrosis and perifollicular inflammation. The fibrosis can be seen in around 10 percent of cases. However, fibrosis may also be seen in a small number of normal scalp biopsies as well. The inflammation consists of a mild to moderate peri-infundibular lymphohistiocytic inflammatory infiltrate. It is present in up to two thirds of biopsies, but is a non-specific feature that is also found in up to one third of normal scalp biopsies.

The clinical appearance of male androgenetic alopecia is universally and instantly recognizable in most cases. The progression of hair loss occurs in an orderly manner.

The main significance of hair relates to socialization and hair is an essential part of an individual's self-image. Thus the consequences of androgenetic alopecia are predominantly psychological. Several studies show that the negative self-perception of balding patients appears to be consistent between Western and Asian cultures. The negative impact of androgenetic alopecia is often trivialized or ignored by unaffected patients. However, there is evidence that perception by others may compound the psychological problems suffered by balding men.

A Korean study of the perception of balding men by women and non-balding men found that their negative perception of men with androgenetic alopecia was similar to the psychosocial effects reported by the patients themselves. Of note is the perception of bald men looking less attractive, which was found in more than 90 percent of subjects surveyed. Importantly, this view was more common in women than non-balding men. Such negative perceptions may further impair the social functioning of balding men.

It is important to note however, that most affected men cope well with androgenetic alopecia, without significant impact on their psychosocial function. Thus, those who do seek help are likely to be in greater emotional distress and have been dissatisfied with any treatment they have received to date.

The most distressed balding men are those with more extensive hair loss, those who have very early onset and those that deem their balding as progressive, often arising from observation of their father and socially noticeable.

A number of options are available to balding men. First, as the condition is not life threatening and the morbidity is variable, a reasonable option is to have no treatment and allow the balding to progress naturally. In fact, this is what the vast majority of men elect to do. Regardless of whether or not patients pursue treatment, an adequate explanation of the pathogenesis of the disease, how common it is in the community and the various treatment options available form an important part of the support and counseling that should occur with each patient.

Medical Management
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.

Minoxidil
Minoxidil is an antihypertensive that was found to cause hypertrichosis. A topical preparation was formulated for the treatment of androgenetic alopecia. Hairs are recruited into a prolonged anagen, accompanied by enlargement of miniaturized hair follicles. 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 would promote 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.

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.

On commencing treatment, minoxidil may cause a surge in the growth of miniaturized hairs and induction of anagen from resting hair follicles. This may produce a rapid hair shedding of previous telogen hairs. This temporary shedding may be interpreted as a clinical indication that the minoxidil is having a beneficial effect. 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.

As minoxidil works as a non-specific promoter of hair growth, the slow miniaturization of hair follicles induced by androgens continues in spite of treatment. Evidence for this is seen in a 120-week double-blind study, 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.

Minoxidil should be used twice daily, with one milliliter spread evenly into the entire scalp. Side effects are uncommon, with skin irritation being the most frequently reported event. Dizziness and tachycardia, and contact allergic dermatitis have also been reported.

Finasteride
Finasteride is a synthetic azo-steroid that is a potent and highly selective antagonist of 5a-reductase type 2. 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 limiting its action on scalp hair follicles.

Various studies have demonstrated the beneficial effects of finasteride on reversing the pathogenesis of androgenetic alopecia. A study measuring hair counts using macro-photographs 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 shows that finasteride stimulates an increase in terminal hair counts and a decrease in vellus hair counts. Another study using hair count and hair weight as an objective measure of outcome demonstrates that both hair count and hair weight increases, 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 miniaturization 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 percent and serum DHT by 68 percent. Finasteride is also approved for the treatment of benign prostatic hypertrophy at a dose of five milligrams daily. Dose ranging studies have found no significant difference in clinical benefit between five and one milligram daily regimens 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. The placebo group suffered a progressive decline in hair count, losing about 26 percent of terminal hairs compared to baseline counts at the end of the 5-year study. In contrast, patients on finasteride have a 10 percent increase in hair count at the end of the first year. Hair count declined somewhat thereafter but remained above baseline throughout, remaining at 5 percent above the baseline hair count after 5 years of treatment.

This rate of decline in 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. At month 12, all subjects in the finasteride group demonstrated an increase in hair count, while a decrease was found in 44 percent 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 in 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 comparison 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 percent and erectile dysfunction in 1.4 percent in the first year. The placebo groups reported these same events with frequencies of 1.3 percent and 0.6 percent respectively. These events appeared to resolve on cessation of the drug and, in some cases, with continued treatment. It has been suggested that even these figures overstate the true incidence of sexual dysfunction. Of note, older men on finasteride experienced a 50 percent reduction in serum prostate specific antigen [PSA] levels, which could result in an underestimation of prostatic cancer risk. It has been shown in the urology literature that PSA levels remain valid whilst patients are on finasteride, but the value should be doubled to correct for the finasteride effect. Men between 18 to 41 years old have a negligible decrease in measured PSA.

Topical finasteride has been investigated as a potential variation in drug delivery. While a 0.05% finasteride solution applied to the scalp was well absorbed and produced a 40 percent 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, i.e. a significant reduction in circulating DHT is required in addition to the local blockade of 5a-reductase at the hair follicle.

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 percent 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. Photographs are taken of the vertex and frontal hairline at six-monthly to yearly intervals; hair densities at these points can be readily compared. This set-up is proving to be useful in the long-term monitoring of treatment response. 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. 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. 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 is 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. With regards to long term safety, finasteride has now been in use for over ten 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. Reversible painful gynecomastia has been reported and the incidence is thought to be around 0.001%. Work is underway to determine whether finasteride 5mg daily is protective against the future development of prostate cancer.

Future drug development - Topical anti-androgens
Oral anti-androgens (e.g. spinorolactone, cyproterone acetate) have been widely used to treat women with androgenetic alopecia. However, it has been contraindicated in the treatment of androgenetic alopecia in males due to its systemic androgenic effects on 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 antiandrogenic activity. 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.

Other 5a reductase inhibitors are in development. Dutasteride, a combined type 1 and type 2 5 a reductase inhibitor has undergone Phase 2 trials and appears to have greater efficacy in reducing circulating and tissue levels of DHT, and stimulating hair regrowth, albeit sexual side effects are more prevalent.

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

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. The disadvantages are increased time and labor requirements, which translates to greater cost for the patient.

Good surgeons can transplant up to 3,000 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.

Androgenetic alopecia is increasingly common among men as they age. Many men find it a distressing and unwelcome event and some seek treatment to prevent further hair loss and reverse the process. A number of therapeutic options are now available for these men. In addition, androgenetic alopecia may be a marker of increased risk for the development of prostate cancer, and prophylactic treatment with 5a-reductase inhibitors is currently under investigation. The hair follicle is a complex organ biologically. The changes in the hair follicles that lead to baldness have caught the interest of stem cell scientists, geneticists, developmental biologists and immunologists and hair biology has become an increasingly fruitful field of scientific endeavor.