Definition
Androgenetic alopecia (AGA) is also known as common baldness. It is a patterned, progressive and until recently largely irreversible loss of an excessive amount of hair from the scalp.
Epidemiology
Significant androgenetic alopecia occurs in 50% of men by the age of 50 and 50% of women by the age of 60 years, while limited androgenetic alopecia affects all men and women progressively as they age. This may manifest only as an alteration in the frontal hair line. Excessive or premature hair loss thus represents an exaggeration of a normal physiological process rather than a disease per se.
Aetiology
Prerequisites for androgenetic alopecia are a genetic predisposition and the presence of sufficient circulating androgens. Between 95% and 100% of the population possess the inherited predisposition, but far fewer develop significant alopecia due to variable gene expression.
The evidence in support of androgenetic alopecia being due to the local effects of androgen excess are listed below.
1 Androgenetic alopecia does not occur in eunuchs castrated prior to puberty, but can be induced by the administration of testosterone to those genetically predisposed. If the testosterone is discontinued the alopecia does not progress, although it does not reverse either.
2 Virilization produces androgenetic alopecia in women with a genetic predisposition combined with acne, hirsutes and menstrual irregularity.
3 Antiandrogen therapy slows the progression of androgenetic alopecia. It may also partly reverse hair miniaturization.
4 The 5a reducíase enzyme that converts testosterone into the more active dihydrotestosterone (DHT) is found in the dermal papilla cells, as are the androgen receptors that bind DHT. Two subtypes of 5a-reductase have been identified, both of which appear to be present on the scalp.
The response of hair to androgens is site specific. While vellus hair follicles on the prepubertal pubis, axilla, beard and chest react by enlarging into terminal hairs, the terminal hairs on the frontoparietal region of the scalp react to these same androgens by miniaturizing into vellus hairs. These two events are independent of each other and there is no correlation between the degree of baldness and the density of hair patterns on the trunks and limbs of males. There is no satisfactory explanation for this differential effect, nor for the reason many other hair follicles, including the occipital scalp hairs, are relatively unaffected by androgens.
Regional variation exists in distribution of subtypes of 5a-reductase, the activity of 5a-reductase and the density of androgen receptors in the dermal papillae, with greatest levels being found in the frontoparietal areas of the scalp corresponding to the areas of development of androgenetic alopecia. Very high levels are also found in the pubic region and other areas of secondary sexual hair development. The possibilities that different regional receptor subtypes or different second messenger processing of the signal account for the different effects require further investigation. 5 Orentreich demonstrated that punch grafts taken from the occiput of men with androgenetic alopecia and transferred to the frontoparietal area behave like the adjacent hairs from the donor site and maintain their resistance to androgenetic alopecia after transplantation. This implies that the interpretation of the androgen signal locally by the individual follicle is relatively more important than the amount of circulating androgen. This principle of donor dominance forms the basis for successful hair transplantation.
Men have sufficient circulating testosterone to maximally stimulate hair follicles so that all genetically predisposed men will develop androgenetic alopecia. In contrast, androgen levels in the normal female range will only induce balding in premenopausal women with a strong genetic predisposition. In women with a lesser genetic predisposition, baldness develops when androgen production is increased or drugs with androgen-like activity are taken.
Seborrhoea may be associated with common baldness, but is not a factor in the aetiology.
Pathogenesis
Three events combine to produce androgenetic alopecia:
1 progressive prolongation of the telogen phase of the hair cycle, associated with shortening of duration of anagen;
2 development of a latent phase in the hair cycle following shedding of the telogen hair;
3 follicular miniaturization that reduces the calibre of the anagen hairs produced.
The latent phase may last a number of months before anagen recommences and produces empty follicles. Scarring is not a feature of androgenetic alopecia and on biopsy there is no actual reduction in the number of follicles on the scalp. Loss of pigmentation of the hairs further diminishes their cosmetic significance. This process does not occur evenly over the scalp but follows a pattern of progression that has been described and graded by Hamilton (and later modified by Norwich) and Ludwig.
The follicular miniaturization is global affecting the papilla, the matrix and ultimately the hair shaft. Terminal hairs initially transform into indeterminate hairs and later into vellus hairs that ultimately become so short they do not reach the follicular ostium. These 'secondary' vellus follicles differ from de novo vellus follicles in that they still have the remnants of their arrector pili muscle attached to them.
Clinical features
Male pattern baldness
Hamilton described the distinctive pattern of progression of hair loss in men and graded the severity on a scale from I to VIII. Alteration of the frontal hair line with bitemporal recession occurs first and is followed by balding of the vertex. Eventually a more uniform frontal recession joins the bald areas and the entire frontoparietal region bears only inconspicuous secondary vellus hair. The posterior and lateral scalp margins are spared even in advanced cases.
Hamilton's type I describes the normal prepubertal pattern, and postpuberty this may still be seen in some women, but is rare in adult men. Progression to type II occurs in at least 96% of men. It is usually detectable clinically by the age of 17, however, many men do not notice it until their thirties. Types V to VIII occur in 60% of men over the age of 50 years and the balding progresses continuously until death.
Even before alopecia is evident, an increase in the number of terminal hairs less than 4 cm long is detectable due to the progressive curtailment of anagen, producing shorter and shorter hairs with each subsequent hair cycle. Ultimately the hairs fail to emerge from the follicular ostium and all that is seen on the surface of the skin is the pore. The hair pull test becomes positive in the affected areas as the proportion of vellus hairs increases.
Female pattern baldness
Hamilton pattern balding also occurs in women. Hamilton suggested 79% of women develop Hamilton II alopecia after puberty and 25% of women develop Hamilton V by the age of 50, after which time there is minimal progression, but the true incidence is somewhat less than this. Bitemporal recession tends to be less prominent in female's than males and is likely to go unnoticed until the late twenties.
Although male pattern alopecia occurs in women, more commonly females develop a hair loss over the crown with preservation of the frontal hair line. This pattern of alopecia was first described by Ludwig and the most useful grading scale for women bears his name.
The earliest change (Ludwig grade I) is thinning of the hair on the crown. This produces an oval area of alopecia encircled by a band of variable breadth with normal hair density. Frontally the fringe is narrow (1-3 cm) while at the sides the margin is 4-5 cm wide. Progression to Ludwig grade II results in further rarefaction of the crown with preservation of the fringe. Grade III is near complete baldness of the crown.
The relative incidence of Ludwig vs. Hamilton pattern alopecia among balding women has been determined. Ludwig pattern I - III occurred in 87% of premenopausal women while Hamilton stage II-IV occurred in 13%. Among postmenopausal women, Ludwig I - III occurred in 63% while Hamilton II-V occurred in 37%.
The presence or absence of assciated virilization of females with androgenetic alopecia cannot be inferred from the pattern of alopecia, be it Hamilton or Ludwig. More useful is the rate of development of the alopecia, its severity and any-associated evidence of androgen excess such as hirsutes, acne, menstrual irregularities and cliteromegaly. The vast majority of women do not require any investigation for virilization other than a directed history and examination. The causes and investigation of virilization have already been discussed. It is usually more relevant to direct investigations towards excluding other causes of a diffuse alopecia, especially in patients with early androgenetic alopecia when the pattern of loss is difficult to discern.
Diagnosis
The diagnosis of androgenetic alopecia is a clinical one and is based on recognizing the pattern of hair loss. A hair pull test may demonstrate loss of an increased number of telogen hairs from the frontoparietal region, but not the occiput, in keeping with the pattern of the altered trichogram. In doubtful cases analysis of the trichogram of clumps of plucked hairs from different regions of the scalp will further support the diagnosis.
In the early stages of androgenetic alopecia in a woman, the hair loss may be diffuse. In such cases a drug history, thyroid function tests and a serum ferritin estimation will be required to exclude other causes of a diffuse alopecia. While a scalp biopsy is only rarely required in a male, it may be the only way to distinguish early androgenetic alopecia in a female from chronic telogen effluvium.
Associated conditions
Premature balding also occurs in progeria and Werner's syndrome and early frontoparietal recession with greying is seen in myotonic dystrophy. Other signs of these disorders will allow a specific diagnosis. Occasionally a diffuse alopecia can coexist with androgenetic alopecia and will be suggested by a history of rapid deterioration and a positive hair pull test from all over the scalp. In such circumstances a drug history, thyroid function tests and a serum ferritin measurement are indicated.
Pathology
A scalp biopsy is helpful in difficult cases, but is not required routinely. At scanning magnification the histology shows a decreased number of terminal hair follicles, and an increased number of vellus follicles. The sebaceous glands appear large and solar elastosis may be apparent. Streamers (remnants of involuted anagen hairs) and a lymphohistiocytic inflammatory infiltrate around the hair follicle at the level of the sebaceous duct and also around the superficial dermal capillaries may be seen.
Prognosis
Androgenetic alopecia is a progressive disorder. The age of onset is variable, but always follows the onset of puberty. The rate of progression is also variable with some men taking 10 years and others 30 or more years to advance to Hamilton VI and VII. The rate of hair loss also fluctuates with periods of excessive shedding punctuated by periods of minimal loss.
The prepubertal hair density of the scalp is approximately 200 terminal hairs per cm2 and a reduction of 30% to 140 terminal hairs per cm2 is required before balding is apparent.
Once balding is obvious loss of terminal hairs (also referred to as nonvellus hairs in some studies) tends to progress at a rate of 10% per year, and total hair loss at a rate of 5%.
Until recently it was accepted dogma that the miniaturization of hairs was an irreversible process. The dramatic, but exceptional regrowth that has been documented with minoxidil has led to a reappraisal of this and motivated a large research effort into finding the key to unravel the complex series of events that will reverse androgenetic alopecia.
Treatment
The treatment of androgenetic alopecia is considered in terms of conservative therapy and wigs, medical management and surgical management.
Conservative management
Camouflage is the simplest, easiest, cheapest and most effective way of dealing with mild androgenetic alopecia. Balding becomes most noticeable when the scalp can be seen through the hair. Camouflage treatments dye the scalp the same colour as the hair, and give the illusion of thicker hair. Numerous brands are available, in pressurized spray cans in a number of different colours and they are often combined with a holding hair spray (and sunscreen). The hair is dried and styled before the dye that matches the patient's hair colour is sprayed onto the base of the hair. Although many of the newer agents are water resistant, problems may still arise in the rain if the hair gets wet and the dye runs. In addition patients should avoid touching their hair as the dye will colour their hands. Towels and pillow cases may stain, but these come out in the wash. Patients are advised to
Attachment to the scalp may be by either adhesive tape, glue or by suction. Suction attachments are made by taking a mould of the completely bald (or shaved) skull upon which a hairpiece is constructed by hand. Such wigs tend to remain well fixed to the skull and can be worn during all activities including water sports. One drawback of wigs is that they may get excessively hot in the summer.
In general the only wigs people tend to notice are the bad ones and many people require encouragement to visit a wig-maker. Excellent advice on wigs and wigmakers is usually available from patient support groups such as Hairline International in the UK, the National Alopecia Areata Foundation in the USA and the Alopecia Society in Australia. Clinicians are wise to familiarize themselves with the services local organizations offer.
Medical management
Currently available pharmacological therapy for women consists of antiandrogens and topical minoxidil. Antiandrogens may feminize males and are therefore not an appropriate remove the dye each night by shampooing and to reapply the dye each morning.
Wigs
Many men and women with diffuse alopecia prefer wigs to medical treatments or scalp surgery. Wigs can either be interwoven with existing hair or worn over the top of existing hair. Interwoven wigs tend to lift as the hair beneath grows and require adjustment every few weeks. This may add considerably to the expense.
Wigs are made from either a synthetic acrylic fibre or natural fibre. The most commonly used natural fibres are human hair, which may be Asian hair or European hair. Each has different advantages. Natural fibre wigs look better and last longer, but are more expensive. Wigs can be styled and washed and the manufacturer usually gives the recipient detailed instructions on wig care.
High-power photomicrograph of androgenetic alopecia, showing the perifollicular mononuclear cell infiltrate, therapy for balding men. Until recently the only effective pharmacological treatment for men was topical minoxidil. The recent introduction of oral finasteride has revolutionized
the treatment of male AG A.
Minoxidil
This is a vasodilator that was developed for the treatment of hypertension. Hypertrichosis mainly of the body and to a lesser extent of the scalp was noticed as a side-effect, and subsequently a topical preparation for use in androgenetic alopecia was developed.
Numerous dosing studies have been done. The minimum concentration that will increase nonvellus hair counts is 0.1 %. The minimum concentration that will produce cosmetically acceptable regrowth is 1 % and the optimal result is obtained with 2%. It remains controversial whether there is added long-term benefit from using 5%; however, a more rapid initial response may be noted. One millilitre should be applied directly to the bald area twice daily and gently massaged into the scalp. The scalp must be dry when minoxidil is applied and the hair should not be wetted for 1 hour after the application. Once daily use is not sufficient for maintenance therapy and there is no extra benefit with applications more frequently than twice daily.
If successful, after 2 months of continuous minoxidil use, hair shedding decreases; hair regrowth may be detected at 4-8 months. The hair counts usually stabilize after 12-18 months whereas control groups continue to progressively lose hair at 5% per year. Occasionally regrowth does not begin for up to 12 months and the treatment should not be abandoned due to lack of efficacy before then. Most people will get a regrowth of indeterminate hairs, but for many this is not cosmetically significant and insufficient to warrant the expense of treatment. Very occasionally there is a dramatic response with near reversion to normal, but this is unpredictable.
Patients need to be warned that in the initial stages there may be an increased amount of hair shedding due to stimulation of telogen follicles to re-enter anagen. If this occurs it is usually an indication that the patient is likely to respond well to the treatment.
Other useful prognostic factors for regrowth are the severity and the duration of the alopecia. Good prognostic factors are:
1 a brief history of balding (fewer than 5 years);
2 limited alopecia on the vertex (less than 10 cm diameter);
3 more than 100 indeterminate hairs in the treated area.
Approximately 50% of users find their hair loss stabilizes, while an additional 10% notice significant regrowth. If successful, treatment needs to be continued indefinitely because once stopped the new hairs fall out and regression to the pretreatment state occurs within 3 months.
Minoxidil has also been used together with tretinoic acid to enhance penetration, however, this combination produces greater scalp irritation and the benefits are minimal.
The side-effects of topical minoxidil include pruritus, a contact irritant dermatitis and occasionally contact allergic dermatitis can develop. Hypotension does not occur with topical treatment because there is minimal systemic absorption. Oral minoxidil has also been used, however, it appears to be no more effective than topical minoxidil. In addition the systemic side-effects make its routine use for androgenetic alopecia inappropriate.
Spironolactone
Used primarily as a potassium sparing diuretic, spironolactone is an aldosterone antagonist. It is also an antiandrogen that can be used to treat androgenetic alopecia in women. It appears to inhibit the interaction between dihydrotestos-terone and the intracellular receptor, as well as inhibiting ovarian androgen production. The dose range is 50-200 mg per day; however, the optimal dose of spironolactone is 100 mg daily. This tends to slow the progression of balding without reversing the process. Much of the data on spironolactone relates to its use in hirsutes and few trials have been conducted on its use in androgenetic alopecia. A contraceptive pill is not mandatory with this agent, but women of child-bearing age should be warned against becoming pregnant while on this medication due to the risks of feminizing a male child.
Cyproterone acetate
Systemic antiandrogen therapy with cyproterone acetate (as described for hirsutes on p. 45) decreases hair shedding but there is generally no cosmetically significant regrowth. In premenopausal women a contraceptive pill should be used with this agent. The effects are generally not noticed for 3-6 months after commencing treatment and they tend to continue only for as long as the tablets are taken. About one-third to one-half of women taking 100 mg of cyproterone acetate notice a major reduction in hair fall. Lower doses do not appear to work as effectively. The trial data presently available is limited and should be interpreted cautiously. Comparative trials, with pretreatment biopsy to exclude women with chronic telogen effluvium are required to judge the relative benefits of aldosterone and cyproterone acetate in androgenetic alopecia.
Finasteride
Finasteride, a selective inhibitor of the type 2 isoenzyme 5a reductase has been shown in clinical studies in a dose of 1 mg per day to effectively treat androgenetic alopecia in men, with minimal side-effects. Dose ranging studies have demonstrated no additional benefit from higher doses, however, side-effects are more common. Circulating levels of testosterone are minimally affected and there is no obvious feminization. Alteration of libido is seen in 1.8% of males receiving finasteride, compared to 1.3% in the placebo group and erectile dysfunction was seen in 1.3%, compared to 0.7% in the placebo group.
Preliminary trials in postmenopausal women failed to demonstrate efficacy and premenopausal women are cautioned against taking it as finasteride is a potential teratogen that may induce hypospadius or feminization of a male fetus. The amount of finasteride potentially absorbed from sperm through the vagina of a pregnant woman is too low to pose a risk to the fetus.
In the trials a number of measures of efficacy were used, however, the most persuasive was standardized macropho-tography. The macrophotography results of the phase III studies showed that after 2 years hair loss on the vertex of the scalp is arrested in one-third of patients, another one-third achieve minimal regrowth (sufficient to be detected by clinical photography) while another one-third achieve marked or moderate regrowth. Only 1% of the men who received finasteride had progression of their hair loss.
Frontal hair loss also responds to finasteride, albeit less well. Half the patients showed no further hair loss, about 40% had minimal regrowth and only 4% had moderate regrowth. No patients had marked regrowth and 5% had further progression of their frontal hair loss.
It is not possible to predict in advance which patients are more likely to respond to finasteride. Unlike minoxidil where a short duration of hair loss and limited extent are favourable prognostic features, some men with advanced hair loss were among the best responders to finasteride.
In the placebo group 33% of men had obvious progression of their hair loss, 60% remained unchanged and 7% had increased hair. This demonstrated the marked variation in the rate of progression in androgenetic alopecia and the fact that for many men hair loss progresses slowly. It also confirms that the amount of hair lost fluctuates on a week to week or month to month basis, with periods of accelerated loss punctuated by periods where the loss plateaus. During the plateau phases it is not uncommon for there to be some reversal of the hair loss which is detected as improvement using the macrophotographs.
Upon commencing finasteride, patients who have previously been aware of excessive hair shedding can expect to notice a reduction in hair shedding within 4 months. While regrowth may be noticed within 4 months this is exceptional, and only about 20% will be aware of regrowth at 12 months and about 40% at 24 months. Upon stopping the finasteride, the process continues, however, the rapid correction seen with minoxidil does not occur.
A major difficulty is effective monitoring of patient progress in the clinical setting. Without access to global photography patients with arrested progression of androgenetic alopecia and patients with minimal regrowth may be unable to determine whether the treatment is working or not, and one suspects that without the appropriate pretreatment counselling to ensure they have realistic expectations, and ongoing reassurance by their physician, a significant proportion of these men will abandon an effective treatment. Patient photography may prove to be a useful tool to enhance long-term patient compliance.
The combination of topical minoxidil with systemic antian-drogens or finasteride may be more efficacious than either used alone. Properly conducted trials to verify this clinical suspicion are awaited.
Surgical management
Androgenetic alopecia in women presents with a thinning of hair over the vertex. It rarely produces bald patches suitable for corrective surgery, and the techniques discussed here apply predominantly to men.
All surgical procedures aim to use androgen insensitive parietal and occipital hairs to cover the bald areas. Relocated hairs behave as they did prior to moving, showing little tendency to miniaturize in their new home. Numerous different techniques have been used and include those described below.
Scalp reduction surgery
This involves the excision of an ellipse of central bald skin. Tissue expanders can be used to increase the harvest, but require insertion up to 3 months prior to the procedure to give the tissue time to expand. Postoperatively some of the initial gain is ultimately lost as scalp laxity returns and the area of alopecia may enlarge due to 'stretch-back'. This technique is ideal for patches of nonprogressive scarring alopecia.
Rotation flaps
Rotation flaps, such as the Juri flap are used to swing in vas-cularized tissue to recreate the frontal hair line. Flaps have the advantage of achieving a high density of hair growth, although sometimes it is too dense and looks unnatural. In addition there is less postoperative telogen effluvium than occurs post-transplantation. One disadvantage of flaps is that they represent an uneconomical use of a restricted supply of donor tissue. Furthermore, if the patient has a large bald spot there may not be enough parietal and occipital skin available to cover the defect. The same applies if the patient returns 5 or 10 years later with progression of his androgenetic alopecia looking for a second graft. Another problem with flaps is with their orientation. Hairs grow in their original direction, and simple rotation directs hair growth posteriorly, exposing the scar and appearing unnatural. Newer techniques, such as tunnel flaps are designed to address this. Potential complications of the procedure include unsightly donor scars and flap devitalization with consequent loss of valuable donor tissue.
Hair transplantation
This takes advantage of donor dominance (the Orentreich principle), which is the tendency of transplanted hairs to maintain the growth characteristics of their original (donor) site, independent of the character of the recipient site. Thus occipital and parietal hairs from the scalp margin do not fall victim to androgenetic alopecia when placed on the crown. Punch grafting used to be the most commonly used technique. Multiple 4 mm punch biopsies are taken from the scalp margins and inserted into the bald areas. The donor sites can be individually glued, sutured or left to heal by secondary intention. The recipient site is prepared to receive the grafts by creating 3.5 mm circular holes in the bald skin with another punch biopsy. Slightly better results are achieved with smaller recipient holes, as the grafts tend to shrink after they are removed, while the recipient holes tend to enlarge slightly. Because the blood supply to the grafts is compromised if they are placed too close together, the final result may look artificial with discrete tufts of hair separated by bald areas.
This technique can be used to provide hair cover for large areas of bald scalp, the limiting factor being the availability of donor tissue. It is axiomatic that donor plugs should be taken from the hairy areas with the best prospect of retaining their hair during the patient's lifetime. The zone of androgen responsive hair is variable between individuals and may be too narrow to provide complete coverage of the defect. Often doubtful hair has to be used and for this reason balding recurs in the transplanted hair in the ensuing 5-10 years necessitating a further procedure. This possibility should be carefully explained to the patient in advance. Nevertheless many patients feel 5-10 years of hair in some areas is worth the moderate discomfort and significant expense.
The state of the art surgery for baldness is single follicle trans-plantation. This has gradually replaced punch grafting. The technique involves harvesting strips of hair bearing skin from areas likely to be less sensitive to androgenic alopecia. When harvesting the donor tissue, the surgeon must be careful to angle the incision to conform to the direction of hair growth so as to not transect follicles. The donor site is sutured and the grafts are then dissected by a technician into individual hairs using a scalpel and jeweller's forceps. These hairs are then placed obliquely into holes made with an 18-gauge hypodermic needle or slits made with a fine scalpel blade that are orientated according to the desired direction of hair growth. Three or four sessions (of 300-600 grafts) are usually required to achieve the desired hair density, producing a more gradual return of hair growth. The cost to the patient is approximately $US 5-10 per hair.
Single follicle grafts are particularly useful when treating 'early' androgenetic alopecia in men and can also be used for females with androgenetic alopecia as the grafts can be fed in between existing follicles to increase hair density. There is minimal damage to the recipient site using this technique, while punch grafting would require removal of some hair bearing scalp tissue.
However, used as the sole method of covering a large patch of alopecia, single follicle grafts are very time consuming and expensive. Some prefer to use a combination of small punch grafts and single follicle grafts, with the single hairs placed in between the punch grafts to soften the effect. Alternatively single grafts can be used to recreate the fringe, and punch grafts used for the main defect.
The best candidates for grafting are those with light, fine hair, good residual hair density over frontal regions, and minimal contrast between the colour of the hair and the skin. Orientation of the grafted hairs is important as the hairs will grow in the direction they have been inserted. Shortly after inserting the grafted hairs they undergo a telogen effluvium and it takes between 6 and 12 months before a good cosmetic result is achieved.
A detailed postoperative instruction leaflet is required so that the patient can know what to expect. Apart from early mild pruritus and scalp oedema, postoperative problems are uncommon. The major complications of grafting include hypertrophic scarring, hyperaesthesia, haematoma formation, arteriovenous fistula formation and postoperative infection.
Attempts to increase the pool of donor hairs have not yet.
Androgenetic alopecia (AGA) is also known as common baldness. It is a patterned, progressive and until recently largely irreversible loss of an excessive amount of hair from the scalp.
Epidemiology
Significant androgenetic alopecia occurs in 50% of men by the age of 50 and 50% of women by the age of 60 years, while limited androgenetic alopecia affects all men and women progressively as they age. This may manifest only as an alteration in the frontal hair line. Excessive or premature hair loss thus represents an exaggeration of a normal physiological process rather than a disease per se.
Aetiology
Prerequisites for androgenetic alopecia are a genetic predisposition and the presence of sufficient circulating androgens. Between 95% and 100% of the population possess the inherited predisposition, but far fewer develop significant alopecia due to variable gene expression.
The evidence in support of androgenetic alopecia being due to the local effects of androgen excess are listed below.
1 Androgenetic alopecia does not occur in eunuchs castrated prior to puberty, but can be induced by the administration of testosterone to those genetically predisposed. If the testosterone is discontinued the alopecia does not progress, although it does not reverse either.
2 Virilization produces androgenetic alopecia in women with a genetic predisposition combined with acne, hirsutes and menstrual irregularity.
3 Antiandrogen therapy slows the progression of androgenetic alopecia. It may also partly reverse hair miniaturization.
4 The 5a reducíase enzyme that converts testosterone into the more active dihydrotestosterone (DHT) is found in the dermal papilla cells, as are the androgen receptors that bind DHT. Two subtypes of 5a-reductase have been identified, both of which appear to be present on the scalp.
The response of hair to androgens is site specific. While vellus hair follicles on the prepubertal pubis, axilla, beard and chest react by enlarging into terminal hairs, the terminal hairs on the frontoparietal region of the scalp react to these same androgens by miniaturizing into vellus hairs. These two events are independent of each other and there is no correlation between the degree of baldness and the density of hair patterns on the trunks and limbs of males. There is no satisfactory explanation for this differential effect, nor for the reason many other hair follicles, including the occipital scalp hairs, are relatively unaffected by androgens.
Regional variation exists in distribution of subtypes of 5a-reductase, the activity of 5a-reductase and the density of androgen receptors in the dermal papillae, with greatest levels being found in the frontoparietal areas of the scalp corresponding to the areas of development of androgenetic alopecia. Very high levels are also found in the pubic region and other areas of secondary sexual hair development. The possibilities that different regional receptor subtypes or different second messenger processing of the signal account for the different effects require further investigation. 5 Orentreich demonstrated that punch grafts taken from the occiput of men with androgenetic alopecia and transferred to the frontoparietal area behave like the adjacent hairs from the donor site and maintain their resistance to androgenetic alopecia after transplantation. This implies that the interpretation of the androgen signal locally by the individual follicle is relatively more important than the amount of circulating androgen. This principle of donor dominance forms the basis for successful hair transplantation.
Men have sufficient circulating testosterone to maximally stimulate hair follicles so that all genetically predisposed men will develop androgenetic alopecia. In contrast, androgen levels in the normal female range will only induce balding in premenopausal women with a strong genetic predisposition. In women with a lesser genetic predisposition, baldness develops when androgen production is increased or drugs with androgen-like activity are taken.
Seborrhoea may be associated with common baldness, but is not a factor in the aetiology.
Pathogenesis
Three events combine to produce androgenetic alopecia:
1 progressive prolongation of the telogen phase of the hair cycle, associated with shortening of duration of anagen;
2 development of a latent phase in the hair cycle following shedding of the telogen hair;
3 follicular miniaturization that reduces the calibre of the anagen hairs produced.
The latent phase may last a number of months before anagen recommences and produces empty follicles. Scarring is not a feature of androgenetic alopecia and on biopsy there is no actual reduction in the number of follicles on the scalp. Loss of pigmentation of the hairs further diminishes their cosmetic significance. This process does not occur evenly over the scalp but follows a pattern of progression that has been described and graded by Hamilton (and later modified by Norwich) and Ludwig.
The follicular miniaturization is global affecting the papilla, the matrix and ultimately the hair shaft. Terminal hairs initially transform into indeterminate hairs and later into vellus hairs that ultimately become so short they do not reach the follicular ostium. These 'secondary' vellus follicles differ from de novo vellus follicles in that they still have the remnants of their arrector pili muscle attached to them.
Clinical features
Male pattern baldness
Hamilton described the distinctive pattern of progression of hair loss in men and graded the severity on a scale from I to VIII. Alteration of the frontal hair line with bitemporal recession occurs first and is followed by balding of the vertex. Eventually a more uniform frontal recession joins the bald areas and the entire frontoparietal region bears only inconspicuous secondary vellus hair. The posterior and lateral scalp margins are spared even in advanced cases.
Hamilton's type I describes the normal prepubertal pattern, and postpuberty this may still be seen in some women, but is rare in adult men. Progression to type II occurs in at least 96% of men. It is usually detectable clinically by the age of 17, however, many men do not notice it until their thirties. Types V to VIII occur in 60% of men over the age of 50 years and the balding progresses continuously until death.
Even before alopecia is evident, an increase in the number of terminal hairs less than 4 cm long is detectable due to the progressive curtailment of anagen, producing shorter and shorter hairs with each subsequent hair cycle. Ultimately the hairs fail to emerge from the follicular ostium and all that is seen on the surface of the skin is the pore. The hair pull test becomes positive in the affected areas as the proportion of vellus hairs increases.
Female pattern baldness
Hamilton pattern balding also occurs in women. Hamilton suggested 79% of women develop Hamilton II alopecia after puberty and 25% of women develop Hamilton V by the age of 50, after which time there is minimal progression, but the true incidence is somewhat less than this. Bitemporal recession tends to be less prominent in female's than males and is likely to go unnoticed until the late twenties.
Although male pattern alopecia occurs in women, more commonly females develop a hair loss over the crown with preservation of the frontal hair line. This pattern of alopecia was first described by Ludwig and the most useful grading scale for women bears his name.
The earliest change (Ludwig grade I) is thinning of the hair on the crown. This produces an oval area of alopecia encircled by a band of variable breadth with normal hair density. Frontally the fringe is narrow (1-3 cm) while at the sides the margin is 4-5 cm wide. Progression to Ludwig grade II results in further rarefaction of the crown with preservation of the fringe. Grade III is near complete baldness of the crown.
The relative incidence of Ludwig vs. Hamilton pattern alopecia among balding women has been determined. Ludwig pattern I - III occurred in 87% of premenopausal women while Hamilton stage II-IV occurred in 13%. Among postmenopausal women, Ludwig I - III occurred in 63% while Hamilton II-V occurred in 37%.
The presence or absence of assciated virilization of females with androgenetic alopecia cannot be inferred from the pattern of alopecia, be it Hamilton or Ludwig. More useful is the rate of development of the alopecia, its severity and any-associated evidence of androgen excess such as hirsutes, acne, menstrual irregularities and cliteromegaly. The vast majority of women do not require any investigation for virilization other than a directed history and examination. The causes and investigation of virilization have already been discussed. It is usually more relevant to direct investigations towards excluding other causes of a diffuse alopecia, especially in patients with early androgenetic alopecia when the pattern of loss is difficult to discern.
Diagnosis
The diagnosis of androgenetic alopecia is a clinical one and is based on recognizing the pattern of hair loss. A hair pull test may demonstrate loss of an increased number of telogen hairs from the frontoparietal region, but not the occiput, in keeping with the pattern of the altered trichogram. In doubtful cases analysis of the trichogram of clumps of plucked hairs from different regions of the scalp will further support the diagnosis.
In the early stages of androgenetic alopecia in a woman, the hair loss may be diffuse. In such cases a drug history, thyroid function tests and a serum ferritin estimation will be required to exclude other causes of a diffuse alopecia. While a scalp biopsy is only rarely required in a male, it may be the only way to distinguish early androgenetic alopecia in a female from chronic telogen effluvium.
Associated conditions
Premature balding also occurs in progeria and Werner's syndrome and early frontoparietal recession with greying is seen in myotonic dystrophy. Other signs of these disorders will allow a specific diagnosis. Occasionally a diffuse alopecia can coexist with androgenetic alopecia and will be suggested by a history of rapid deterioration and a positive hair pull test from all over the scalp. In such circumstances a drug history, thyroid function tests and a serum ferritin measurement are indicated.
Pathology
A scalp biopsy is helpful in difficult cases, but is not required routinely. At scanning magnification the histology shows a decreased number of terminal hair follicles, and an increased number of vellus follicles. The sebaceous glands appear large and solar elastosis may be apparent. Streamers (remnants of involuted anagen hairs) and a lymphohistiocytic inflammatory infiltrate around the hair follicle at the level of the sebaceous duct and also around the superficial dermal capillaries may be seen.
Prognosis
Androgenetic alopecia is a progressive disorder. The age of onset is variable, but always follows the onset of puberty. The rate of progression is also variable with some men taking 10 years and others 30 or more years to advance to Hamilton VI and VII. The rate of hair loss also fluctuates with periods of excessive shedding punctuated by periods of minimal loss.
The prepubertal hair density of the scalp is approximately 200 terminal hairs per cm2 and a reduction of 30% to 140 terminal hairs per cm2 is required before balding is apparent.
Once balding is obvious loss of terminal hairs (also referred to as nonvellus hairs in some studies) tends to progress at a rate of 10% per year, and total hair loss at a rate of 5%.
Until recently it was accepted dogma that the miniaturization of hairs was an irreversible process. The dramatic, but exceptional regrowth that has been documented with minoxidil has led to a reappraisal of this and motivated a large research effort into finding the key to unravel the complex series of events that will reverse androgenetic alopecia.
Treatment
The treatment of androgenetic alopecia is considered in terms of conservative therapy and wigs, medical management and surgical management.
Conservative management
Camouflage is the simplest, easiest, cheapest and most effective way of dealing with mild androgenetic alopecia. Balding becomes most noticeable when the scalp can be seen through the hair. Camouflage treatments dye the scalp the same colour as the hair, and give the illusion of thicker hair. Numerous brands are available, in pressurized spray cans in a number of different colours and they are often combined with a holding hair spray (and sunscreen). The hair is dried and styled before the dye that matches the patient's hair colour is sprayed onto the base of the hair. Although many of the newer agents are water resistant, problems may still arise in the rain if the hair gets wet and the dye runs. In addition patients should avoid touching their hair as the dye will colour their hands. Towels and pillow cases may stain, but these come out in the wash. Patients are advised to
Attachment to the scalp may be by either adhesive tape, glue or by suction. Suction attachments are made by taking a mould of the completely bald (or shaved) skull upon which a hairpiece is constructed by hand. Such wigs tend to remain well fixed to the skull and can be worn during all activities including water sports. One drawback of wigs is that they may get excessively hot in the summer.
In general the only wigs people tend to notice are the bad ones and many people require encouragement to visit a wig-maker. Excellent advice on wigs and wigmakers is usually available from patient support groups such as Hairline International in the UK, the National Alopecia Areata Foundation in the USA and the Alopecia Society in Australia. Clinicians are wise to familiarize themselves with the services local organizations offer.
Medical management
Currently available pharmacological therapy for women consists of antiandrogens and topical minoxidil. Antiandrogens may feminize males and are therefore not an appropriate remove the dye each night by shampooing and to reapply the dye each morning.
Wigs
Many men and women with diffuse alopecia prefer wigs to medical treatments or scalp surgery. Wigs can either be interwoven with existing hair or worn over the top of existing hair. Interwoven wigs tend to lift as the hair beneath grows and require adjustment every few weeks. This may add considerably to the expense.
Wigs are made from either a synthetic acrylic fibre or natural fibre. The most commonly used natural fibres are human hair, which may be Asian hair or European hair. Each has different advantages. Natural fibre wigs look better and last longer, but are more expensive. Wigs can be styled and washed and the manufacturer usually gives the recipient detailed instructions on wig care.
High-power photomicrograph of androgenetic alopecia, showing the perifollicular mononuclear cell infiltrate, therapy for balding men. Until recently the only effective pharmacological treatment for men was topical minoxidil. The recent introduction of oral finasteride has revolutionized
the treatment of male AG A.
Minoxidil
This is a vasodilator that was developed for the treatment of hypertension. Hypertrichosis mainly of the body and to a lesser extent of the scalp was noticed as a side-effect, and subsequently a topical preparation for use in androgenetic alopecia was developed.
Numerous dosing studies have been done. The minimum concentration that will increase nonvellus hair counts is 0.1 %. The minimum concentration that will produce cosmetically acceptable regrowth is 1 % and the optimal result is obtained with 2%. It remains controversial whether there is added long-term benefit from using 5%; however, a more rapid initial response may be noted. One millilitre should be applied directly to the bald area twice daily and gently massaged into the scalp. The scalp must be dry when minoxidil is applied and the hair should not be wetted for 1 hour after the application. Once daily use is not sufficient for maintenance therapy and there is no extra benefit with applications more frequently than twice daily.
If successful, after 2 months of continuous minoxidil use, hair shedding decreases; hair regrowth may be detected at 4-8 months. The hair counts usually stabilize after 12-18 months whereas control groups continue to progressively lose hair at 5% per year. Occasionally regrowth does not begin for up to 12 months and the treatment should not be abandoned due to lack of efficacy before then. Most people will get a regrowth of indeterminate hairs, but for many this is not cosmetically significant and insufficient to warrant the expense of treatment. Very occasionally there is a dramatic response with near reversion to normal, but this is unpredictable.
Patients need to be warned that in the initial stages there may be an increased amount of hair shedding due to stimulation of telogen follicles to re-enter anagen. If this occurs it is usually an indication that the patient is likely to respond well to the treatment.
Other useful prognostic factors for regrowth are the severity and the duration of the alopecia. Good prognostic factors are:
1 a brief history of balding (fewer than 5 years);
2 limited alopecia on the vertex (less than 10 cm diameter);
3 more than 100 indeterminate hairs in the treated area.
Approximately 50% of users find their hair loss stabilizes, while an additional 10% notice significant regrowth. If successful, treatment needs to be continued indefinitely because once stopped the new hairs fall out and regression to the pretreatment state occurs within 3 months.
Minoxidil has also been used together with tretinoic acid to enhance penetration, however, this combination produces greater scalp irritation and the benefits are minimal.
The side-effects of topical minoxidil include pruritus, a contact irritant dermatitis and occasionally contact allergic dermatitis can develop. Hypotension does not occur with topical treatment because there is minimal systemic absorption. Oral minoxidil has also been used, however, it appears to be no more effective than topical minoxidil. In addition the systemic side-effects make its routine use for androgenetic alopecia inappropriate.
Spironolactone
Used primarily as a potassium sparing diuretic, spironolactone is an aldosterone antagonist. It is also an antiandrogen that can be used to treat androgenetic alopecia in women. It appears to inhibit the interaction between dihydrotestos-terone and the intracellular receptor, as well as inhibiting ovarian androgen production. The dose range is 50-200 mg per day; however, the optimal dose of spironolactone is 100 mg daily. This tends to slow the progression of balding without reversing the process. Much of the data on spironolactone relates to its use in hirsutes and few trials have been conducted on its use in androgenetic alopecia. A contraceptive pill is not mandatory with this agent, but women of child-bearing age should be warned against becoming pregnant while on this medication due to the risks of feminizing a male child.
Cyproterone acetate
Systemic antiandrogen therapy with cyproterone acetate (as described for hirsutes on p. 45) decreases hair shedding but there is generally no cosmetically significant regrowth. In premenopausal women a contraceptive pill should be used with this agent. The effects are generally not noticed for 3-6 months after commencing treatment and they tend to continue only for as long as the tablets are taken. About one-third to one-half of women taking 100 mg of cyproterone acetate notice a major reduction in hair fall. Lower doses do not appear to work as effectively. The trial data presently available is limited and should be interpreted cautiously. Comparative trials, with pretreatment biopsy to exclude women with chronic telogen effluvium are required to judge the relative benefits of aldosterone and cyproterone acetate in androgenetic alopecia.
Finasteride
Finasteride, a selective inhibitor of the type 2 isoenzyme 5a reductase has been shown in clinical studies in a dose of 1 mg per day to effectively treat androgenetic alopecia in men, with minimal side-effects. Dose ranging studies have demonstrated no additional benefit from higher doses, however, side-effects are more common. Circulating levels of testosterone are minimally affected and there is no obvious feminization. Alteration of libido is seen in 1.8% of males receiving finasteride, compared to 1.3% in the placebo group and erectile dysfunction was seen in 1.3%, compared to 0.7% in the placebo group.
Preliminary trials in postmenopausal women failed to demonstrate efficacy and premenopausal women are cautioned against taking it as finasteride is a potential teratogen that may induce hypospadius or feminization of a male fetus. The amount of finasteride potentially absorbed from sperm through the vagina of a pregnant woman is too low to pose a risk to the fetus.
In the trials a number of measures of efficacy were used, however, the most persuasive was standardized macropho-tography. The macrophotography results of the phase III studies showed that after 2 years hair loss on the vertex of the scalp is arrested in one-third of patients, another one-third achieve minimal regrowth (sufficient to be detected by clinical photography) while another one-third achieve marked or moderate regrowth. Only 1% of the men who received finasteride had progression of their hair loss.
Frontal hair loss also responds to finasteride, albeit less well. Half the patients showed no further hair loss, about 40% had minimal regrowth and only 4% had moderate regrowth. No patients had marked regrowth and 5% had further progression of their frontal hair loss.
It is not possible to predict in advance which patients are more likely to respond to finasteride. Unlike minoxidil where a short duration of hair loss and limited extent are favourable prognostic features, some men with advanced hair loss were among the best responders to finasteride.
In the placebo group 33% of men had obvious progression of their hair loss, 60% remained unchanged and 7% had increased hair. This demonstrated the marked variation in the rate of progression in androgenetic alopecia and the fact that for many men hair loss progresses slowly. It also confirms that the amount of hair lost fluctuates on a week to week or month to month basis, with periods of accelerated loss punctuated by periods where the loss plateaus. During the plateau phases it is not uncommon for there to be some reversal of the hair loss which is detected as improvement using the macrophotographs.
Upon commencing finasteride, patients who have previously been aware of excessive hair shedding can expect to notice a reduction in hair shedding within 4 months. While regrowth may be noticed within 4 months this is exceptional, and only about 20% will be aware of regrowth at 12 months and about 40% at 24 months. Upon stopping the finasteride, the process continues, however, the rapid correction seen with minoxidil does not occur.
A major difficulty is effective monitoring of patient progress in the clinical setting. Without access to global photography patients with arrested progression of androgenetic alopecia and patients with minimal regrowth may be unable to determine whether the treatment is working or not, and one suspects that without the appropriate pretreatment counselling to ensure they have realistic expectations, and ongoing reassurance by their physician, a significant proportion of these men will abandon an effective treatment. Patient photography may prove to be a useful tool to enhance long-term patient compliance.
The combination of topical minoxidil with systemic antian-drogens or finasteride may be more efficacious than either used alone. Properly conducted trials to verify this clinical suspicion are awaited.
Surgical management
Androgenetic alopecia in women presents with a thinning of hair over the vertex. It rarely produces bald patches suitable for corrective surgery, and the techniques discussed here apply predominantly to men.
All surgical procedures aim to use androgen insensitive parietal and occipital hairs to cover the bald areas. Relocated hairs behave as they did prior to moving, showing little tendency to miniaturize in their new home. Numerous different techniques have been used and include those described below.
Scalp reduction surgery
This involves the excision of an ellipse of central bald skin. Tissue expanders can be used to increase the harvest, but require insertion up to 3 months prior to the procedure to give the tissue time to expand. Postoperatively some of the initial gain is ultimately lost as scalp laxity returns and the area of alopecia may enlarge due to 'stretch-back'. This technique is ideal for patches of nonprogressive scarring alopecia.
Rotation flaps
Rotation flaps, such as the Juri flap are used to swing in vas-cularized tissue to recreate the frontal hair line. Flaps have the advantage of achieving a high density of hair growth, although sometimes it is too dense and looks unnatural. In addition there is less postoperative telogen effluvium than occurs post-transplantation. One disadvantage of flaps is that they represent an uneconomical use of a restricted supply of donor tissue. Furthermore, if the patient has a large bald spot there may not be enough parietal and occipital skin available to cover the defect. The same applies if the patient returns 5 or 10 years later with progression of his androgenetic alopecia looking for a second graft. Another problem with flaps is with their orientation. Hairs grow in their original direction, and simple rotation directs hair growth posteriorly, exposing the scar and appearing unnatural. Newer techniques, such as tunnel flaps are designed to address this. Potential complications of the procedure include unsightly donor scars and flap devitalization with consequent loss of valuable donor tissue.
Hair transplantation
This takes advantage of donor dominance (the Orentreich principle), which is the tendency of transplanted hairs to maintain the growth characteristics of their original (donor) site, independent of the character of the recipient site. Thus occipital and parietal hairs from the scalp margin do not fall victim to androgenetic alopecia when placed on the crown. Punch grafting used to be the most commonly used technique. Multiple 4 mm punch biopsies are taken from the scalp margins and inserted into the bald areas. The donor sites can be individually glued, sutured or left to heal by secondary intention. The recipient site is prepared to receive the grafts by creating 3.5 mm circular holes in the bald skin with another punch biopsy. Slightly better results are achieved with smaller recipient holes, as the grafts tend to shrink after they are removed, while the recipient holes tend to enlarge slightly. Because the blood supply to the grafts is compromised if they are placed too close together, the final result may look artificial with discrete tufts of hair separated by bald areas.
This technique can be used to provide hair cover for large areas of bald scalp, the limiting factor being the availability of donor tissue. It is axiomatic that donor plugs should be taken from the hairy areas with the best prospect of retaining their hair during the patient's lifetime. The zone of androgen responsive hair is variable between individuals and may be too narrow to provide complete coverage of the defect. Often doubtful hair has to be used and for this reason balding recurs in the transplanted hair in the ensuing 5-10 years necessitating a further procedure. This possibility should be carefully explained to the patient in advance. Nevertheless many patients feel 5-10 years of hair in some areas is worth the moderate discomfort and significant expense.
The state of the art surgery for baldness is single follicle trans-plantation. This has gradually replaced punch grafting. The technique involves harvesting strips of hair bearing skin from areas likely to be less sensitive to androgenic alopecia. When harvesting the donor tissue, the surgeon must be careful to angle the incision to conform to the direction of hair growth so as to not transect follicles. The donor site is sutured and the grafts are then dissected by a technician into individual hairs using a scalpel and jeweller's forceps. These hairs are then placed obliquely into holes made with an 18-gauge hypodermic needle or slits made with a fine scalpel blade that are orientated according to the desired direction of hair growth. Three or four sessions (of 300-600 grafts) are usually required to achieve the desired hair density, producing a more gradual return of hair growth. The cost to the patient is approximately $US 5-10 per hair.
Single follicle grafts are particularly useful when treating 'early' androgenetic alopecia in men and can also be used for females with androgenetic alopecia as the grafts can be fed in between existing follicles to increase hair density. There is minimal damage to the recipient site using this technique, while punch grafting would require removal of some hair bearing scalp tissue.
However, used as the sole method of covering a large patch of alopecia, single follicle grafts are very time consuming and expensive. Some prefer to use a combination of small punch grafts and single follicle grafts, with the single hairs placed in between the punch grafts to soften the effect. Alternatively single grafts can be used to recreate the fringe, and punch grafts used for the main defect.
The best candidates for grafting are those with light, fine hair, good residual hair density over frontal regions, and minimal contrast between the colour of the hair and the skin. Orientation of the grafted hairs is important as the hairs will grow in the direction they have been inserted. Shortly after inserting the grafted hairs they undergo a telogen effluvium and it takes between 6 and 12 months before a good cosmetic result is achieved.
A detailed postoperative instruction leaflet is required so that the patient can know what to expect. Apart from early mild pruritus and scalp oedema, postoperative problems are uncommon. The major complications of grafting include hypertrophic scarring, hyperaesthesia, haematoma formation, arteriovenous fistula formation and postoperative infection.
Attempts to increase the pool of donor hairs have not yet.