MALE PATTERN HAIR LOSS: PREVENTION RATHER THAN REGROWTH - International Journal of Dermatology 2000;39:728-731

Marcia Ramos-e-Silva, MD, PhD

Associate Professor
Sector of Dermatology and Post Graduation Course in Dermatology
HUCFF-UFRJ, Universidade Federal do Rio de Janeiro

PATHOLOGY OF MALE PATTERN HAIR LOSS

Androgen-dependent skin conditions, such as male pattern hair loss (androgenetic alopecia, AGA) and acne, are among the dermatological conditions most frequently encountered by the specialist and general physician. AGA is itself the commonest form of human alopecia, affecting more than 50% of men by the age of 50 1 and a smaller but still significant proportion of women2 over the same age range. Historically, the clinical management of AGA has been limited to the psychological support of the client, the use of cosmetics that thicken the remaining hair or make the scalp less conspicuous, hair systems (swatches, weaves and wigs), and surgical procedures including punch grafts and flap surgery. In recent years, drug therapy has increasingly become a realistic management option, as our understanding of the mechanisms of normal and pathological hair growth has pointed the way to improved treatments.

The changes that occur in the distribution of scalp hair as AGA progresses follow a course that has been well documented in both sexes,3 as have the pathophysiological changes in the scalp and scalp hair that are commonly found to occur in male pattern hair loss.1,4,5 The most important recent development in our understanding is the recognition that androgens play a central role in the development of AGA. It has been observed that castrated men do not exhibit AGA; however, if they are given exogenous androgens they will (reversibly) show signs of hair loss.6 Several recent lines of evidence implicate dihydrotestosterone (DHT), a metabolite of testosterone, as the active metabolite in AGA. The enzyme responsible for the conversion of testosterone to DHT is 5a-reductase. At least 2 isoenzymes of 5a-reductase exist; both have been cloned and their tissue distribution investigated.7,8,9 Type I, which is by far the most prominent in extracts of scalp tissue,10 and predominantly concentrated in sebaceous glands,11 is not implicated in the etiology of AGA and no cases of type I deficiency have been identified. While some studies have reported an overall increase in 5a-reductase in the bald scalp,10,12 others have showed no difference in the expression pattern of the predominant type 1 isoenzyme.13 However, recent studies have used sensitive immunohistochemical techniques to localize the differential isoenzyme distribution more precisely, and have shown that, although quantitatively outweighed by the type 1 isoenzyme, 5a-reductase type 2 is strongly expressed in the inner layer of the outer hair root sheath, and also in the inner root sheath in some parts of the hair follicle.14,15,16 Type 2 receptors are also present in the dermal papilla.17 The observation that male pseudohermaphrodites are not susceptible to AGA has been linked to the specific deficiency of type II 5a-reductase which is the basis of the disorder and which results in lower DHT levels than in controls.18,19

PSYCHOLOGY OF HAIR LOSS, PREVENTION AND REGROWTH

Hair forms a vital element of an individual's physical appearance, and changes in the hair, including its loss, can have correspondingly profound effects on interpersonal reactions20,21,22 and on self-image.23,24,25 Studies that specifically address the psychosocial impact of androgenetic alopecia in men have shown that men with visible hair loss are perceived as older, weaker and less physically attractive than their nonbalding counterparts.21,22 Not surprisingly, such adverse social stereotyping of individuals with hair loss has a considerable impact on the self image, and therefore on the quality of life, of men with AGA. Studies confirm that the negative self-perception of hair loss by others is reflected in the psychological responses of balding men to their own condition. Using standard psychological tests, men with AGA report experiencing distress about their hair loss, feeling less physically attractive and having greater body image dissatisfaction than their nonbalding peers.23,25,26

Given that many men are strongly motivated to seek help with their AGA, the treatment objectives may variously include the prevention of further hair loss, the maintenance of existing hair, the regrowth and retention of lost hair, or any combination of the three.3 In most cases, however, prevention and maintenance are the most realistic therapeutic options. In this context, it must be recognized that there is frequently a disparity between what the physician assumes are the patient's needs or requirements, and what the patient actually expects. Although there is a lack of rigorous scientific studies of men's attitudes towards regrowth of their lost hair as compared to the prevention of further hair loss, some indications are available in the literature. For example, in a study in which men with AGA completed the Hair Loss Effects Questionnaire (HLEQ), a high proportion gave responses that were directed towards a future rather than a present state: 93% worried about how much hair they would lose, 87% reported trying to estimate if they were losing more hair, and 80% tried to imagine how they would look with more hair loss.26 Cash23 has also reported that balding men who anticipated more hair loss in the future experienced significantly greater negative events and cognitive preoccupation, and were also less satisfied with their hair and overall appearance than men who anticipated minimal future hair loss.

Some anecdotal evidence, based on market research27 among 2200 men with at least some degree of hair loss, strongly supports the importance of prevention rather than regrowth to the patient. Thus when asked directly whether they were more concerned about the amount of hair they currently had (ie regrowth) or the rate at which they were losing it (ie prevention), most respondents (61%) were equally concerned about the two; of those expressing a greater concern for one or the other, two-thirds were more concerned with prevention and one third with regrowth. Although the ideal for most of the men involved in this research would clearly be a hair treatment that effected both regrowth and prevention, slightly more respondents thought that prevention (43%) rather than regrowth (34%) was essential in a hair loss treatment.

So it seems that many men are more anxious to prevent further hair loss in the future than they are to regrow the hair they have already lost. Nonetheless, physicians may incorrectly believe that the patient will only be satisfied with overt regrowth, when in fact he would be content with retaining his remaining hair. This is an important point because secondary prevention, that is the prevention of further loss, is currently a more realistic treatment goal for the physician to offer. This is demonstrated by the drug treatments that have been or are now available.

DRUG TREATMENTS: MINOXIDIL

The antihypertensive drug minoxidil was shown in the early 1980s to stimulate new hair growth, and was eventually approved as a topical treatment for AGA in men and women. Minoxidil is known to act as an opener of potassium channels, but the mechanism by which it exerts its effect on hair is unclear, since it is a vasodilator with no known antiandrogenic activity. It appears to convert vellus to terminal hairs, to normalize the hair follicular morphology and to increase the number of follicles in mid to late anagen, the growth phase of the hair cycle.28 Multicenter clinical trials have demonstrated the efficacy of minoxidil in AGA: in most patients treated with topical minoxidil 2% or 3% for 12 months mean hair counts increased, and in some patients hair counts continued to increase for some time afterwards.29,30,31,32

Topical minoxidil 2% nevertheless has only limited success and the individual response is highly variable. Recent clinical trials with topical minoxidil 5% have shown promising results: in one study, 54% of treated patients showed an increase in hair counts, compared to 29% of patients on placebo.33

However, minoxidil has not been approved for systemic use because of potentially serious side effects, notably cardiovascular, due to its antihypertensive action, and because extraneous hair growth on has occasionally been seen even with topically applied minoxidil,3 thought to be due to absorption and systemic action.

Furthermore, as discussed earlier, the majority of men appear to be more concerned with prevention of further hair loss than with regrowth: minoxidil has however not shown any preventive activity, and its ability in the long term to retain new growth against a background of genetically-associated hair loss has not been demonstrated.

DRUG TREATMENTS: MANIPULATING ANDROGEN METABOLISM TO RETARD MALE PATTERN HAIR LOSS

The most promising treatments modulate the metabolism of androgens in the scalp. Currently only one pharmaceutical is available to the physician for the treatment of men with AGA. Finasteride is a potent, specific inhibitor of the type II 5a-reductase that is responsible for the conversion of testosterone to DHT.34,35,36 Given orally, finasteride reduces DHT levels systemically and in the target tissues (ie scalp).37 In an animal model of AGA, the stump-tailed macaque, daily oral finasteride given over a period of 6 months significantly reduced circulating DHT levels and increased scalp hair weight.38 Finasteride at a dosage of 1 mg/day has recently been approved by the FDA for the treatment of male pattern hair loss in men. Its efficacy has been demonstrated in three double-blind, placebo-controlled, randomized studies.39 Men with androgenetic alopecia aged between 18 and 41 were given either oral finasteride 1mg/day or a placebo. Assessed by scalp hair counts, self-assessment by patients using a validated questionnaire, investigator assessment using a standardized 7-point rating scale of hair growth from baseline, and an independent expert review of photographs taken every 6 months, finasteride treatment was evaluated as resulting in improvement. Finasteride produced progressive increased in hair counts at 6, 12 and 24 months while placebo treatment resulted in significant hair loss. By 24 months, 72% of patients on placebo had lost hair compared to baseline, while 83% of patients on finasteride had experienced no further hair loss. Similarly, at 24 months the expert panel considered 66% of finasteride-treated patients greatly, moderately or slightly improved versus only 7% of those on placebo. There was little difference in the incidence of side effects reported by men on finasteride (4.2%) versus placebo (2.2%), which resolved after discontinuation and in many of the men who remained on drug treatment.

These results are in line with our current understanding of the effect of dihydrotestosterone on hair physiology. Although, as mentioned previously, the molecular details of the mechanism by which androgens affect hair growth are not known, it is apparent that in the androgen-sensitive scalp of genetically-susceptible individuals they cause a gradual miniaturization of the follicles and conversion of long, thick pigmented terminal hair to short, fine, unpigmented vellus hair. Prevention of the androgen-mediated miniaturization will inhibit or retard the process leading to hair loss, and in some cases result in new hair growth. Furthermore, there is demonstrable heterogeneity in 5a-reductase activity in scalp hair roots from patients with AGA40 which may account for some of the variation in response to finasteride.

CONCLUSIONS

The likelihood is that modulation of androgen metabolism will prevent further hair loss in the majority of patients, and induce hair growth in a smaller proportion, depending on the extent of their condition and their genetic background. It is vital, therefore, for the prescribing physician to bear in mind that the patient may suffer anxiety over the possible progression of hair loss in the future while being able to tolerate his present condition. For many patients, prevention of further hair loss alone will constitute acceptable management. For the physician, the important message is that the best therapeutic prospects lie in drug modalities that utilize our increased understanding of normal and pathological hair growth. Although topical minoxidil was the first effective drug to benefit some of these patients, targeting of the type 2 5a-reductase in the scalp hair follicle using oral finasteride is now a realistic option for the prevention of further hair loss in the patient with male pattern baldness.

REFERENCES
1. Hamilton JB. Patterned hair loss in man: Types and incidence. Ann NY Acad Sci. 1951;53:708-728.
2. Ludwig E. Classification of the types of androgenetic alopecia (common baldness) arising in the female sex. Br J Dermatol. 1977;97:249-256.
3. Olsen EA. Androgenetic alopecia. In: EA Olsen, ed. Disorders of Hair Growth. New York: McGraw-Hill Inc; 1994:257-283.
4. Rushton DH, Ramsay ID, Norris MJ, Gilkes JJ. Natural progression of male pattern baldness in young men. Clin Exp Dermatol. 1991;16:188-192.
5. Whiting DA. Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male androgenetic alopecia. J Am Acad Dermatol 1993;28:755-763.
6. Hamilton JB. Male hormone stimulation is prerequisite and an incitant in common baldness. Am J Anat. 1942;71:451-480.
7. Harris G, Azzolina B, Baginsky W, et al. Identification and selective inhibition of an isozyme of steroid 5a-reductase in human scalp. Proc Natl Acad Sci USA. 1992;89:10787-10791.
8. Anderson S, Bishop RW, Russel RW. Expression cloning and regulation of steroid 5a-reductase, an enzyme essential for male sexual differentiation. J Biol Chem. 1989;264:16249-16255.
9. Anderson S, Russel RW. Structural and biochemical properties of cloned and expressed human and rat steroid 5a-reductase. Proc Natl Acad Sci USA. 1990;87:3640-3633.
10. Bingham KD, Shaw DA. The metabolism of testosterone by human male scalp skin. J Endocrinol. 1873;57:111-121.
11. Thiboutot D, Harris G, Iles V, Cimis G, Gilliland K, Hagari S. Activity of the type 1 5a-reductase exhibits regional differences in isolated sebaceous glands and whole skin. J Invest Dermatol 1995;105:209-214.
12. Schweikert HU, Wilson JD. Regulation of human hair growth by steroid hormones. I. Testosterone metabolism in isolated hairs. J Clin Endocrinol Metab. 1974;38:811-819.
13. Thigpen AE, Silver RI, Guileyardo JM, et al. Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. J Clin Invest. 1993;92:903-910.
14. Russel DW, Wily EL, Whiting DA. Expression of 5a-reductase I and II in scalp skin in normal controls and in androgenetic alopecia. In: Van Neste D, Randall VA, eds. Hair Research for the Next Millenium. Amsterdam: Elsevier; 1996:339-340.
15. Bayne EB, Flanagan J, Azzolina B et al. Immunolocalization of type 1 5a-reductase in human hair follicles (abstract). J Invest Dermatol. 1997;108:651.
16. Sawaya ME, Price VH. Different levels of 5a-reductase I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia. J Invest Dermatol. 1997;109:296-300.
17. Hoffmann R, Happle R. Finasteride is the main inhibitor of 5a-reductase activity in microdissected dermal papillae of human hair follicles. Arch Dermatol Res. 1999;291:100-103.
18. Imperato-McGinley J, Guerero L, Gautier T, et al. Steroid 5a-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science. 1974;186:1213-1215.
19. Walsh PC, Madden JD, Harrod MJ, et al. Familial incomplete male pseudohermaphroditism, type 2: decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med. 1974;291:944-949.
20. Lawson ED. Hair color, personality, and the observer. Psychol Rep. 1971;28:311-312.
21. Cash TF. Losing hair, losing points? The effects of male pattern baldness on social impression formation. J Appl Soc Psychol. 1990;20:154-167.
22. Roll S, Verinis JS. Stereotypes of scalp and facial hair as measured by the semantic differential. Psychol Rep. 1971;28:975-980.
23. Cash TF. The psychological effects of androgenetic alopecia in men. J Am Acad Dermatol. 1992;26:926-931.
24. Franzoi SL, Anderson J, Frommelt S. Individual differences in men's perceptions of and reactions to thinning hair. J Soc Psychol. 1990;130:209-218.
25. Wells P, Wilmoth T, Russell RJH. Psychological correlates of hair loss in males. Br J Psychol. 1995;86:337-344.
26. Cash TF, Price VH, Savin RC. Psychological effects of androgenetic alopecia on women: comparisons with balding men and with female control subjects. J Am Acad Dermatol. 1993;29:568-575.
27. Merck Sharp and Dohme. Market research data (Segmentation Study) collected from 2200 men aged 20-26 in USA, UK, Germany, Italy and Brazil, during late 1996 and early 1997.
28. Pires FE, Fonseca MB, Ramos-e-Silva M. Minoxidil nas alopecias. F Med (BR). 1994;108:113-117.
29. Olsen EA, Weiner MS, Delong ER, Pinnell S. Topical minoxidil in early male pattern baldness. J Am Acad Dermatol. 1985;113:185-192.
30. Koperski JA, Orenberg EK, Wilkinson DI. Topical minoxidil therapy for androgenetic alopecia. A 30-month study. Arch Dermatol. 1987;123(11):1483-1487.
31. Rietschel RL, Duncan SH. Safety and efficacy of topical minoxidil in the management of androgenetic alopecia. J Am Acad Dermatol. 1987;16:677-685.
32. Savin RC. Use of topical minoxidil in the treatment of male pattern baldness. J Am Acad Dermatol. 1987;16:696-704.
33. Pharmacia & Upjohn, Kalamazoo MI. Rogaine extra strength for men (5% minoxidil topical solution) for non-prescription use. Data presented at FDA Non-Prescription Drug Advisory Committee Meeting, July 16, 1997.
34. Suddoth SL, Koronkowski MJ. Finasteride: the first 5 alpha-reductase inhibitor. Pharmacotherapy. 1993;13:309-325.
35. Spinucci G, Pasquali R. Finasteride: a new drug for the treatment of male hirsutism and androgenetic alopecia? Clin Ther. 1996;147:305-315.
36. Gormley GJ. Finasteride: a clinical review. Biomed Pharmacother. 1995;49:319-324.
37. Dallob AL, Sadick NS, Unger W, et al. The effect of finasteride, a 5a-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness. J Clin Endocrinol Metab. 1994;79:703-706.
38. Rhodes L, Harper J, Uno H, et al. The effects of finasteride (Proscar) on hair growth, hair cycle stage, and serum testosterone and dihydrotestosterone in adult male and female stumptail macaques (Macaca arctoides). J Clin Endocrinol Metab. 1994;79:991-996.
39. Kaufman KD, Olsen EA, Whiting D, et al and the Finasteride Male Pattern Hair Loss Study Group. Finasteride in the treatment of men with andogenetic alopecia. J Am Acad Dermatol. 1998;39:578-589.
40. Schmidt JA, Schweikert HU. Testosterone and epitestosterone metabolism of single hairs in 5 patients with 5 alpha-reductase deficiency. Acta Endocrinol (Copenh). 1986;113:588-592.