Moderator

Dr. U.S. Agarwal

Seminar Presentation Androgenetic Alopecia

Introduction

• Androgenetic alopecia is an extremely common disorder affecting both men and women.

• Incidence is generally considered to be greater in males than females, although some evidence suggests that apparent differences in incidence may be a reflection of different expression in males and females.

• Male pattern hair loss (also known as male androgenetic alopecia, male balding) is an androgen-dependent, genetically determined trait.

• Female pattern hair loss has also been termed androgenetc alopecia, in the belief that it is the same entity as in men, but the requirement for androgens is less clearcut than in men and the distribution of hair loss is generally different.

• however, in both men and women, pattern hair loss is characterized by a progressive decline in the duration of anagen, an increase in the duration of telogen, and miniaturization of scalp hair follicles, indicating a final common pathway of follicular regression.

• Pattern hair loss is a biologically normal trait.• Nevertheless, the high value our societies place on

maintaining a full head of hair means that loss of hair can have a significant adverse effect on quality of life.

• Both sexes are affected though, in general, the impairment of psychosocial well-being is more frequent and more severe in women.

Epidemiology

• Universally this is an extremely common disorder that affects roughly 50% of men and perhaps as many women older than 40 years.

• As many as 13% of premenopausal women reportedly have some evidence of androgenetic alopecia.

• Incidence increases greatly in women following menopause, and, according to some authors, it may affect 75% of women older than 65 years.

• Other than affecting patient psychologically, disorder is significant only in that it allows ultraviolet light to reach scalp and, thus, increases the amount of actinic damage.

• Incidence and severity of androgenetic alopecia tend to be highest in white men, second highest in Asians and African Americans, and lowest in Native Americans and Eskimos.

• Almost all patients have an onset prior to age 40 years, although many of patients (both male and female) show evidence of the disorder by age 30 years.

Pathophysiology

• This genetically determined disorder is progressive through the gradual conversion of terminal hairs into indeterminate hairs and finally to vellus hairs.

• Patients have a reduction in the terminal-to-vellus hair ratio• Following miniaturization of the follicles, fibrous tracts

remain.• Patients with this disorder usually have a typical distribution

of hair loss.

Normal hair cycle

• A working knowledge of the anatomy of normal hair cycle is useful in understanding the evolution of miniaturizing hairs.

• Average number of hairs in adult scalp is 100,000, of which 90% are in anagen and 10% in telogen.

• Average duration of anagen is 1000 days, of telogen 100 days, and the average daily loss of telogen hairs is 100.

• Hair follicle cycling occurs in the impermanent lower follicle between the bulb and the bulge, which is situated in the area of insertion of the arrector pili muscle into the follicle.

• Bulb comprises the hair matrix cells that surround the dermal papilla.

• Dermal papilla contains papillary mesenchymal cells, surrounded by extracellular matrix.

• It is continuous with the fibrous dermal sheath that surrounds bulb & contains mesenchymal cells similar to those in papilla.

• Anagen bulb produces the hair shaft and the inner and outer root sheaths.

• Inner root sheath molds the hair shaft in the lower follicle and is shed in isthmus region of the follicle.

• Several years of hair growth are followed by a resting phase: anagen is first succeeded by 3 weeks of catagen and ends in telogen, which lasts an average of 3 months.

• During this resting phase, the lower follicle retreats up to the level of bulge during catagen, dragging the exposed miniaturizing dermal papilla behind it.

• Stella or fibrous tract marks the ascent of the follicle.• dermal papilla shrinks to its smallest size during telogen.• With a new anagen cycle, the follicle follows the papilla down

the fibrous tract, and papilla generally enlarges once again.

• Exact controls of hair follicle cycling are still unknown.• Whether the cycle is initiated in hair follicle epithelium or in

papillary mesenchyme is controversial.• Some postulates hair cycling clocks.• Others believe that repeated cycling may be an innate

property of a follicle.• Most will agree that follicular epithelium, dermal papillae,

and dermal sheath cells all interact in follicular cycling.

• Cycling is probably driven by local signals changing the expression of cytokines, growth factors, hormones, neuropeptides, adhesion molecules and receptors.

• Regrowth of hair may well be initiated by stem cells in the bulge region.

• This is supported by the fact that the lower follicle retracts upward to the level of bulge area in telogen.

• Slow-cycling cells have been demonstrated in bulge region in murine follicles by autoradiography with thymidine labeling.

• The hypothesis is that entry into anagen occurs when stem cells in the bulge region are activated by signals from the dermal papilla.

• Daughter transient-amplifying cells form the hair bulb matrix and ultimately its differentiated cell products.

• It seems possible that cells in the hair bulb matrix have a finite proliferative potential that, once exhausted, would result in cessation of growth and entry into catagen.

• After transition from telogen to anagen I, and progression through subsequent stages into anagen VI, the complete hair follicle is regenerated.

Hormonal influences

Systemic hormonal effects• Key role of androgens in the pathogenesis of male AGA was

revealed by the observations of the American anatomist James Hamilton.

• He noted that men castrated before puberty did not develop balding unless treated with testosterone.

• A number of studies have tried to determine whether balding males have increased circulating androgens, but no differences between patients and controls have been consistently found.

• All these studies suffer from a lack of reproducibility, and although differences in mean levels have been variously detected, the substantial overlap in the absolute levels of all androgens between cases and controls demonstrates that normal male levels of androgen are sufficient to make manifest the degree of baldness determined genetically for the individual.

• for women, androgens in the normal female range are sufficient to induce early baldness in women with a strong genetic predisposition.

• In women without a strong predisposition, balding will not occur until later in life unless endogenous androgen production is increased or drugs with androgen-like activity are taken.

• Some women with even grossly abnormal levels of androgen do not develop clinically significant baldness, although such patients are generally hirsute.

Local hormonal effects

• Androgens do not affect all hairs equally.• Body hair grows, scalp hair is lost whereas the eyebrows

remain essentially unchanged at puberty.• On the scalp there is a hierarchy of sensitivity, with the most

anterior of the hairs at the temples being lost first, and subsequent hairs miniaturizing in a highly ordered fashion to produce patterned baldness.

• Similarly on the male beard, hairs first appear on the upper lip at the lateral corners and then over the rest of the face in a highly ordered fashion.

• In men, where circulating androgens are surplus to the requirements of hair follicles for maximal stimulation, local factors determine individual susceptibility and severity of baldness.

• This intrinsic regulation is best demonstrated in hair transplantation experiments;

• occipital hairs maintain their resistance to AGA when transplanted to vertex, and scalp hairs from the vertex transplanted to forearm miniaturize at same pace as hairs neighbouring the donor site.

• In females, where circulating androgens are not sufficient to maximally stimulate hair follicles, local factors still determine susceptibility, but severity is influenced by both local factors and levels of systemic hormone.

Hair cycle dynamics

• In AGA, the duration of anagen decreases with each successive cycle, whereas the length of telogen remains constant or is prolonged.

• Prolongation of telogen occurs particularly in latent phase of telogen (also known as kenogen) that follows release of club hair (exogen).

• This leads to a reduction of the anagen : telogen ratio and corresponds to periods of excessive hair shedding, most noticeable while combing or washing.

• Prolongation of latent phase increases the proportion of empty hair follicles on scalp, further contributing to balding process.

• 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 hair fails to achieve sufficient length to reach the surface of skin, leaving an empty follicular pore.

Hair follicle miniaturization

• Population density of hair follicles per unit area of scalp does not change with balding.

• Rather there is a gradual diminution in size of follicles that results from the transformation of terminal follicles into vellus-type follicles.

• Hair follicle miniaturization leads to finer hair that is often lighter in colour.

• On the balding scalp, transitional indeterminate hairs represent the bridge between full-sized and miniaturized terminal hairs.

• Although smaller follicles tend to cycle more quickly there is no absolute correlation between hair follicle size and anagen duration.

• Eyebrow, eyelash and nasal follicles are large but the hair is relatively short.

• It is likely that separate factors control the miniaturization and hair cycle changes.

• Dermal papilla is central to the maintenance and control of hair growth and is likely to be the target of androgen-mediated events leading to follicle miniaturization and hair cycle changes.

• Constant geometric relationship between the dermal papilla size and the size of the hair matrix suggests that the size of dermal papilla determines the size of hair bulb and ultimately the hair shaft produced.

• 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 through each individual anagen stage of the cycle.

• Thus, miniaturization occurs between rather than within cycles.

• Follicular miniaturization has been traditionally thought to occur in a stepwise fashion although there have been suggestions that it occurs rapidly, possibly in the space of a single hair cycle.

• 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.

Clinical aspects

• History reveals that the onset is gradual.• In both males and females there is transition from large, thick,

pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, nonpigmented vellus hairs.

• As the disorder progresses, the anagen phase shortens with the telogen phase remaining constant.

• As a result, more hairs are in the telogen phase, and patient may notice an increase in hair shedding.

• End result can be an area of total denudation.• This area varies from patient to patient and is usually most

marked at vertex.• Men present with gradual thinning in the temporal areas,

producing a reshaping of the anterior part of the hairline.• For the most part, evolution of baldness progresses according

to the Norwood/Hamilton classification of frontal and vertex thinning.

• Posterior and lateral scalp margins are relatively spared, and only affected in most advanced cases and with old age.

• Female pattern hair loss is usually a more diffuse process than male balding.

• Typically, there is a reduction in hair density involving the crown and frontal scalp with maintenance of frontal hair line.

• There may be miniaturized hairs in the frontotemporal region but deep recession of a well-demarcated hair line is uncommon.

• Unlike men, the parietal regions may also be involved.

• Female pattern hair loss may present with excessive hair shedding and loss of hair volume, before there is an obvious reduction in hair density.

• Differentiation from chronic telogen effluvium can be difficult.• In such cases, diagnosis may be established by the presence

of a high propoftion of miniaturized follicles on biopsy.

Ludwig scale for grading female pattern hair loss

• Grade I rarefaction 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) and at the sides the margin is 4–5 cm wide.• Grade II results in further rarefaction of the crown, with preservation of the fringe.• Grade III is near-complete baldness of the crown.

Pathology

Key elements of the histology of AGA are :• a reduction in terminal hairs, • an increase in secondary vellus hair with associated

angiofibrotic streamers, • a variable increase in telogen and catagen hairs, • a mild or moderate perifollicular lymphohistiocytic infiltrate,

with or without concentric layers of perifollicular collagen deposition.

• Many of these changes are best seen on horizontally sectioned scalp biopsies.

• Horizontal sections reveal numerous pseudovellus hair follicles in the papillary dermis, reflecting a miniaturization process.

• In the vast majority of cases there is no genuine reduction in the number of follicles, and follicular fibrosis is seen in less than 10% of cases.

• presence of arrector pili muscles and angiofibrotic streamers distinguishes them from true vellus hairs.

• There is a change in the ratio of terminal : vellus hairs from greater than 8 : 1 to less than 4 : 1.

Management

General principles• The diagnosis should be confirmed and the patients

approached with utmost care and sympathy.• Counseling forms an essential part, as does the balance

between realistic expectations and therapeutic limitations.• Patients should be advised to avoid hair care products likely to

damage scalp/hair.

• Patients should maintain an adequate diet, especially one with adequate protein.

• recommended daily allowance for protein is about 1 gm/kg.• Topical medications work only where the medication is

applied; therefore, the entire area at risk of hair loss (the top of the scalp) should be treated with a given topical agent.

• Treat any underlying scalp disorder such as seborrheic dermatitis or scalp psoriasis as these conditions can affect the ability to use topical treatments.

Medical treatment for men

• Currently, only finasteride 1 mg and minoxidil topical solution (2% and 5%) are FDA approved for the treatment of MPHL.

• Both drugs retard further thinning and increase scalp coverage.

• Neither drug restores all the lost hair.• Neither drug is able to reverse total baldness.• Both drugs require chronic use to maintain effectiveness.• Treatment should be used for 12 months before making a

decision about efficacy although benefit may be seen sooner.

Minoxidil topical solutions

• It increases duration of anagen and enlarges miniaturized follicles.

• As a potassium channel opener and vasodilator the drug's precise mechanism of action is unknown but appears independent of vasodilation.

• Mode of application should be explained to the patient. • One ml is applied twice daily to dry scalp, preferably using a

dropper application.• Topical minoxidil solution requires approximately 1 hour for

absorption.

• If the patient shampoos or the scalp becomes wet, e.g., from excessive sweating or rain, the medication should be re-applied.

• If gel or hair spray is used, the medication should be applied first so that absorption is not affected.

• Minoxidil increases terminal hair density in up to 30% of individuals

• Terminal hair appeared to regrow at the margins, but complete covering of the bald areas was seen in less than 10% of responders.

• There is a slight increase in benefit if the concentration is increased to 5%.

• Benefit is most pronounced in the first 6 months of therapy and thereafter is marginal.

• If treatment is stopped, clinical regression occurs within 6 months, to the state of baldness that would have existed if treatment had not been applied.

• Patients should be warned that in order to maintain any beneficial effect, applications must continue twice daily for the rest of their lives.

• Topical minoxidil solution may initially cause a telogen effluvium beginning 2-8 weeks after treatment initiation.

• This temporary shedding, resulting from the minoxidil initiated release of telogen hairs ("exogen") as anagen promotion begins, is self-limiting with continued treatment and should not be a cause for concern.

• Patients should be forewarned so that treatment is not interrupted.

• Adverse effects that are mainly dermatologic like scalp irritation, including dryness, scaling, itching, and/or redness, may occur; these are more common with the 5% topical minoxidil solution than the 2% topical minoxidil solution.

• Allergic contact dermatitis is uncommon.• Patch tests may help to sort out whether it is related to

minoxidil or propylene glycol.

Finasteride

• Finasteride is a synthetic aza-steroid that is a potent and highly selective antagonist of 5α-reductase type 2.

• It inhibits the conversion of testosterone to DHT.• A scalp biopsy study of patients with AGA found that after 12

months of finasteride treatment, terminal hair counts increase and vellus hair counts decrease, demonstrating the ability of finasteride to reverse the miniaturization process and to encourage the growth of terminal hairs.

• An oral dosage of 1 mg/day reduces scalp DHT by 64% and serum DHT by 68%

• Target area hair counts (TAHC) are generally used to assess efficacy in clinical trials of MPHL.

• TAHCs are circular target areas 1 cm to 1 inch in diameter typically at the anterior leading edge of the vertex balding area where the terminal, non-vellus, or visible hairs are counted pre and post -treatment.

• Target area hair counts increase over the first year and peak by 12 months.

• In men of age 18-41, hair counts increased 16. 9/cm2 for those on 1 mg finasteride as against 4.1/cm2 for those on placebo.

• Hair growth continues to improve for at least the first 24 months of treatment as the hairs grow longer and thicker.

• When treatment with finasteride is discontinued, any positive effect on hair growth will be lost in 12 months.

• Drug is quite safe with no known drug interactions and no effects on liver, kidney, bone marrow, or bone and no effect on spermatogenesis.

• Reversible sexually related side effects (decreased libido, erectile dysfunction, decreased ejaculate volume) are seen in about 2%.

• These side effect often resolve during continued treatment or within days to weeks after treatment is discontinued.

• Level of finasteride in semen of men taking finasteride is very low and semen from a man taking finasteride poses no risk to a pregnant woman or to her fetus.

• Reduction in prostate specific antigen (PSA) is physiologically based on the effect of decreased DHT on prostate.

• Dutasteride is a combined type 1 and 2 5α-reductase inhibitor.

• It produces a dose-dependent reduction in serum and scalp DHT levels to a greater degree than that seen with finasteride, and is more effective in stimulating hair regrowth in MPB.

• Dutasteride is currently marketed at a 0.5 mg dosage for BHP and it is not licensed for treatment of MPB.

• Sexual side effects are more common with dutasteride, and are also dose related, but appear to be reversible on cessation.

Medical treatment for FPHL

Minoxidil• Topical minoxidil has been shown to arrest hair loss or to

induce mild to moderate hair regrowth in approximately 60% of women with FPHL.

• A clinical trial comparing 5% and 2% formulations of minoxidil found a mean increase in non-vellus hair counts after 48 weeks of 18% and 14%, respectively.

• Currently, only 2% topical minoxidil solution is FDA approved for the treatment of "women with thinning hair.“

• Five percent topical minoxidil solution has been evaluated in women with FPHL and was found to be significantly more effective than placebo by both target area hair counts and subject assessment.

• There was a trend towards superior efficacy of 5% topical minoxidil solution over 2% topical minoxidil solution but this was not consistently statistically significant.

• Topical minoxidil solution works in those women with FPHL both with and without hyperandrogenism and in young and old, pre and postmenopausal women alike.

• Either 2% or 5% topical minoxidil solution appears safe to use in women with FHPL, with the only additional risk of the 5% topical minoxidil solution over the 2% topical minoxidil solution being a higher incidence of facial hypertrichosis.

• Hypertrichosis tends to occur over the cheeks and forehead as vellus, not terminal hair and disappears within 4 months of stopping the drug.

• Although this may be related to inadvertent spreading to the face after local application to the scalp, this may also be a result of hypersensitivity to low levels of systemic absorption of minoxidil.

Antiandrogens

• Oral antiandrogen therapy with cyproterone acetate, spironolactone or flutamide is widely used in the treatment of FPHL although there is a dearth of clinical trial data.

• Spironolactone is a synthetic steroid, structurally related to aldosterone, which acts by competitively blocking androgen receptors.

• It also weakly inhibits androgen biosynthesis.• Several studies have demonstrated the efficacy of

spironolactone in the treatment of hirsutism.• There are no controlled trials in FPHL. • Dosage ranges from 100 to 300 mg/day.

• Side effects are dose related and include menstrual irregularities, postmenopausal bleeding, breast tenderness or enlargement, and fatigue.

• Spironolactone has the potential to feminize a male fetus and women should not become pregnant while taking spironolactone.

• Cyproterone acetate is an androgen receptor blocker and potent progestin.

• subset analysis showed some increase in hair density in women with clinical evidence of androgen excess, suggesting that antiandrogens may be more effective in women with hyperandrogenism.

• There are no dose-ranging studies, but most practitioners use cyproterone acetate 50–100 mg/day for the first 10 days of each menstrual cycle.

• For postmenopausal women, cyproterone acetate may be used continuously, with or without oestrogens.

• Flutamide is a non-steroidal antiandrogen that acts by inhibiting androgen uptake and by inhibiting nuclear binding of androgen within the target tissue.

• One study suggested that flutamide is superior to cyproterone acetate and finasteride in the treatment of androgenetic alopecia

• In a double-blind, placebo-controlled study involving almost 100 postmenopausal women with FPHL, 1 mg finasteride was found to be no better than placebo.

• Subsequent case reports and a case series have reported benefits in both pre- and postmenopausal women, but teratogenicity remains a relative contraindication to use in premenopausal women.

Cosmetic aids

• Nonmedical approaches can provide cosmetic relief to men and women with thinning hair if medical treatments are not indicated, not effective, or not desired by the patient.

• They can also be used as adjuvant therapy.• Tinted powders, lotions, and hair sprays can all provide a

cosmetic covering of the scalp in areas of scalp hair thinning and can be useful in camouflaging it.

• Wigs, hair pieces, and hair extensions can be used to cover a thinning scalp.

• Advances in the technology of these prostheses have made their use much more acceptable.

Surgical treatment

• A variety of surgical techniques have been developed for treating pattern hair loss, of which hair transplantation is the most widely used.

• All involve redistributing terminal hair to the balding areas so the number of terminal hairs remains the same.

• In skilled hands, and with careful patient selection, good cosmetic results can be obtained.

• Surgery is the only treatment that can improve hair coverage on totally bald scalp, and quickly restore hair.

Hair transplants

• Patients over the age of 25 years are preferable.• Predictive value of future hair loss is much lower for

individuals between the ages of 15 and 25 years of age and surgery in this young group of men may result in misplaced hairlines or an unnatural appearance 20 or 30 years later.

• Young men with early hair loss already have enough hair for facial framing and will receive limited aesthetic benefit from surgery.

• Vertex baldness is a progressive process and does not become "stable with time," and therefore, hair transplantation of vertex should be approached with extreme caution, Ideal candidates are those with just frontal & mid-frontal hair loss.

• When frontal baldness is corrected, this creates the most dramatic positive change in appearance.

• Density of donor area should be adequate.• Patients with <40 follicular units/cm2 in the donor area are

considered poor candidates.• Thicker hair shafts (>60-70 microns) demonstrate better

coverage compared to finer hair.

• Women with mild female pattern alopecia are not optimal surgical candidates since differences in pre-transplanted scalp as against post-transplanted scalp are difficult to appreciate.

• Those with diffuse unpatterned alopecia are poor surgical candidates for the obvious reason that the entire scalp is suffering hair loss, thus, the donor area is of limited value as it is also susceptible to loss.

• Ideal female patients for hair transplantation are those with high-density donor hair and extensive hair loss or thinning of the frontal scalp.

• Experienced surgical teams can create significant coverage in one to two sessions with dense packing of higher number of grafts (1000-2000) being performed per session.

• Final results are usually seen 5-6 months after the procedure, and thus, timing between sessions, if needed, is usually a minimum of 6 months.

• Complications include facial edema, scalp erythema, and recipient site crusts of the scalp are common but usually resolve within 3-7 days although crusting may persist a few additional days.

Scalp reduction

• This attempts at a procedure where hair-bearing skin is brought closer together by removing the center scalp affected by the alopecia.

• It is not commonly performed currently.• There are many different designs employed in excising the

balding area.• Reductions may be performed in conjunction with hair

transplantation to the remaining bald scalp for a more optimum result.

• One has to remember that the efficacy diminishes over time due to the unpredictable progression of hair loss in any given individual.

• Excision scars become noticeable over time.• The scar may potentially widen secondary to stretching of

adjacent scalp skin.• Usually more than one scalp reduction is necessary to

effectively address a person's baldness.

Role of Platelet-rich Plasma in the Management of Androgenetic Alopecia

Int J Trichology. 2012 Oct-Dec; 4(4): 291–292

• PRP has been used in the past to prevent infection and speed up the wound healing process by reducing bleeding/swelling after surgery by the plastic-, general-, and orthopedic surgeons.

• PRP, an autologous concentration of human platelets in a small volume of plasma has a higher platelet concentration (4-7 times) above the baseline.

• It is obtained from the patient's own blood after processing in an automated centrifuge and it is injected subcutaneously into the area of alopecia

• Ubel in 2005 studied 23 patients of hair transplant after enriching the hair root grafts with PRP and without PRP.

• Two areas (2.5 cm2) each were marked on the scalp and planted with 20 grafts/cm2.

• After 1 year, the area implanted with the PRP-enriched grafts demonstrated a yield of 18.7 FU/cm2 versus 16.4 FU/cm2 of that without PRP, an increase in follicular density of 15.7%.

• Li et al. performed an in vivo study, where mice received s.c. injections of PRP, and their results were compared with control mice.

• Activated PRP increased the proliferation of dermal papilla cells• injection of mice with PRP induced faster telogen-to-anagen

transition than that was seen in control mice.

• The beneficial effects of PRP in AGA can be attributed to various platelet-derived growth factors causing improvement in the function of hair follicle and promotion of hair growth.

• It is safe, cheap, and non-allergic and it appears to be a useful adjuvant in the management of AGA.

Conclusion

• Because hair loss is so distressing, patients are willing to try just about everything.

• There are countless products that claim to regrow hair, but there is not enough rigorous science behind most of them.

• Patients often ask questions about hair care and we tell them that in most cases frequency of shampoos, shampoos themselves, hair coloring are irrelevant in the process of hair loss and that they can feel comfortable using any regular products.

• We do not suggest any specific shampoos unless there is seborrhoeic dermatitis or psoriasis present.

• There is so much quackery and we must discourage our patients from any 'miracle' treatments.

• Unfortunately, many patients have already spent great sums of money with no result.

• As our knowledge of androgenetic alopecia pathophysiology increases, novel targeted treatments will potentially be developed.

THANKS