Should men still go bald gracefully?

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metastatic breast cancer. J Am Pharm Assoc 1999; 39: 236–38. McKenzie SJ, Marks PJ, Lam T, et al. Generation and characterization of monoclonal antibodies specific for the human neu oncogene product, p185. Oncogene 1989; 4: 543–48. Hancock MC, Langton BC, Chan T, et al. A monoclonal antibody against the c-erbB-2 protein enhances the cytotoxicity of cisdiamminedichloroplatinum against human breast and ovarian tumor cell lines. Cancer Res 1991; 51: 4575–80. Harwerth IM,Wels W, Schlegel J, et al. Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth. Br J Cancer 1993; 68: 1140–45. Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu overexpressing metastatic breast cancer. J Clin Oncol 1996; 14: 737–44. Pegram MD, Lipton A, Hayes DF, et al. Phase II study of receptorenhanced chemosensitivity using recombinant humanized antip185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16: 2659–71. Norton L, Slamon D, Leyland-Jones B, et al. Overall survival (OS) advantage to simultaneous chemotherapy (CRx) plus the humanized anti-HER2 monoclonal antibody Herceptin (H) in HER2overexpressing (HER2+) metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 1999; 18: abstr 483. Nainggolan L. Are adjuvant Herceptin trials using the wrong drugs? SCRIP 1999; 2493: 21. Wisecarver JL. HER-2/neu testing comes of age. Am J Clin Pathol 1999; 111: 299–301. Jacobs TW, Gown AM,Yaziji H and Schnitt S.J. Comparison of fluorescence in situ hybridisation and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol 1999; 17: 1974–82. Jacobs TW, Gown AM,Yaziji and Schnitt S.J. Specificity of HercepTest in Determining HER-2/neu status of breast cancers using the United States Food and Drug Administration–approved scoring system. J Clin Oncol 1999; 17: 1983–87.

Should men still go bald gracefully? At the turn of the 19th century, baldness in men was thought to be due to the wearing of hats and steel helmets. It was only in 1942 that James Hamilton clearly established, in a series of experiments in which he treated castrated men with testosterone, that androgens were essential for the development of baldness. The testoterone induced or aggravated baldness.1 The converse, treatment of baldness with anti-androgens, has not been thoroughly explored in men because of unacceptable side-effects, but it is effective for alleviating baldness in women.2 The androgen effect involves the uptake of circulating testosterone by scalp hair-follicle cells, where it is converted by the enzyme steroid 5␣-reductase (5␣R) to dihydrotestosterone (DHT) (figure). DHT binds to the nuclear androgen receptor and activates androgenresponse genes. 5␣R has long been regarded as an important part of the mechanism because it provides local amplification of testosterone by converting it to DHT, which binds to the androgen receptor with greater affinity than does testosterone.3 Hair follicles in areas prone to male-pattern balding are better equipped to enhance the androgen effect than non-balding areas because they have more 5␣R and androgen receptors and less aromatase, which removes testosterone by converting the hormone to oestradiol.4 There are two forms of 5␣R, both of which exist in the human hair follicle.4 The exact molecular relation between androgens and balding remains obscure since patients with congenital absence of 5␣R type II do not become bald despite the presence of 5aR type I, and second, a woman who has no endogenous androgens has become bald.5 Finasteride, a selective inhibitor of 5␣R type II, was developed for the treatment of benign prostatic hyperplasia. It has been licensed in the USA for the

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Modulation of hair-follicle growth

Therapy

Balding

Testosterone

5␣-reductase inhibited by DHT finasteride

Growth phase Anagen (growth phase) shortened Anagen prolonged Telogen (resting phase) initiated Hypertrichosis (? mechanism)

Androgen receptor Modulation Androgens Oestrogens, minoxidil, finasteride ␤-adrenergic antagonists, retinoids, hypothyroidism Cyclosporin, phenytoin

treatment of male-pattern alopecia since 1997, and many developed countries have since done so too. Its efficacy has been reported in two large placebo-controlled studies. K D Kaufman and colleagues6 report a double-blind study of the effects of 1 mg finasteride daily in 1553 subjects. After 12 months of therapy the number of hairs at the front of the balding scalp had increased by 11% in the treated group, whereas there was a loss of 2·7% in the untreated group. Those individuals in whom treatment was continued for 24 months maintained their increased hair numbers. Not all patients responded; at 12 months, 14% of treated individuals had had an absolute reduction in hair numbers, compared with 58% of untreated men. Janet Roberts and colleagues7 did a placebo-controlled study at a higher dose of finasteride 5 mg daily, and also a placebocontrolled dose-ranging study of 0·01, 0·1, and 1 mg/day. These studies show that a maximum effect on hair counts is obtained at a daily dose of 1 mg/day. Neither study reported any serious side-effects. Despite improvements in global hair scores by investigators and independently scored photographs, not all the men were impressed by the treatment. Men were asked their views of the cosmetic value of treatment—ie, size of bald spot, appearance of hair, growth of hair, slowing of hair loss, and satisfaction with hair; most of the men who received 1 mg/day were positive about the effects, but the scores for their responses ranged from 29 to 68%, compared with 17–45% for scores from the untreated group.6 Whether the strong response in the untreated group is a placebo response or a reflection of the cyclical manner in which balding progresses,8 it dilutes the apparent effect of treatment. The data for finasteride and minoxidil9 are encouraging in that they show that balding is a reversible process. However, neither agent is capable of growing hair on a bare scalp. Finasteride seems to be more effective than minoxidil, but its place is likely to be for early balding and therapy has to be long term. For established balding, the most effective cosmetic therapy is hair autotransplantation, by an experienced surgeon, of multiple small punch grafts from the occipital region. Such surgery is expensive and 161

carries the risk of complications. There is, however, a glimmer of hope. A J Reynolds and colleagues have recently reported that hairs can be transplanted into immunologically unrelated recipients. They grafted the sheath of scalp hair follicles into non-hairy areas of an immunologically unrelated recipient and grew pigmented terminal hair shafts.10 Many men will want to use finasteride because it has been clearly shown to be able to stabilise hair loss and to produce a small reversal in the balding process. Whether it will change the natural history of hair loss or whether it will be useful in the prevention of balding is not known. Until then, men should still be encouraged to come to terms with their hair loss. Julian H Barth Department of Clinical Biochemistry and Immunology, General Infirmary at Leeds, Leeds LS1 3EX, UK 1

Hamilton JB. Male hormone stimulation is prerequisite and an incitant in common baldness. Am J Anat 1942; 71: 451–80. 2 Rushton DH, Ramsay ID. The importance of adequate serum ferritin levels during oral cyproterone acetate and ethinyl oestradiol treatment of diffuse androgen-dependent alopecia in women. Clin Endocrinol (Oxf) 1992; 36: 421–27. 3 Grino PB, Griffin JE, Wilson JD. Testosterone at high concentrations interacts with the androgen receptor similarly to dihydrotestosterone. Endocrinology 1990; 126: 1165–72. 4 Sawaya ME, Price VH. Different levels of 5a-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia. J Invest Dermatol 1997; 109: 296–300. 5 Orme S, Cullen DR, Messenger AG. Diffuse female hair loss: are androgens necessary? Br J Dermatol 1999; 141: 521–23. 6 Kaufman KD, Olsen EA, Whiting D, et al. Finasteride in the treatment of men with androgenetic alopecia. J Am Acad Dermatol 1998; 39: 578–89. 7 Roberts JL, Fiedler V, Imperato-McGinley J, et al. Clinical dose ranging studies with finasteride, a type 2 5␣-reductase inhibitor, in men with male pattern hair loss. J Am Acad Dermatol 1999; 41: 555–63. 8 Rushton DH, Ramsay ID, Norris MJ, Gilkes JJ. Natural progression of genetic hair loss in young men. Clin Exp Dermatol 1991; 16: 188–92. 9 Price VH, Menefee E, Strauss PC. Changes in hair weight and hair count in men with androgenetic alopecia, after application of 5% and 2% topical minoxidil, placebo, or no treatment. J Am Acad Dermatol 1999; 41: 717–21. 10 Reynolds AJ, Lawrence C, Cserhalmi-Friedman PB, Christiano AM, Jahoda CAB. Transgender induction of hair follicles. Nature 1999; 402: 33–34.

Progressive forms of MS: classification streamlined or consensus overturned? A common question patients ask on receiving the diagnosis of multiple sclerosis (MS) is “What type of MS do I have, doctor?”. The current classification, based on the temporal profile of the illness separating remitting and progressive forms of MS,1 is widely accepted and has prognostic significance.2–4 In studies done in large populations, a progressive course carries a substantially greater risk of disability than a relapsing remitting (RR) course, even though progression may be slow and insidious and relapses occasionally result in severe and cumulative sequelae. The classification is used as a principal inclusion criterion for clinical trials. It is zealously applied by various health-care professionals, sometimes inappropriately. On the basis of eligibility criteria used in pivotal trials of interferon beta-1b,5 administrators may split hairs to distinguish patients with relapsing MS with stepwise worsening, who may qualify in some jurisdictions to receive third-party payment for the drug, from patients with secondary progressive (SP) MS, who may not qualify. However, the classification has been complicated by the ad hoc addition of further subtypes, primarily of progressive 162

MS, such as “relapsing progressive” and “progressive relapsing”, to deal with the seemingly infinite interindividual variation in the course of the disease. Ideally, a classification system should distinguish between subgroups in terms of pathophysiology and response to therapy. In 1996, the US National Multiple Sclerosis Society proposed a reclassification of MS, based on the responses of 125 experts (58% response rate) to a survey.6 There was broad consensus on the distinction of RRMS from progressive forms of MS. Patients with relapses with cumulative sequelae were firmly placed in the RR category, although they may be difficult to distinguish from SP. However, there were problems with the classification of progressive forms of MS. Survey responders were clear about the distinction between those who had not experienced attacks of the disease (primary progressive, PP) and those who had (SP). Several lines of evidence indicate that PPMS should be regarded as a distinct entity, because it is characterised not only by lack of clinical attacks, but also by fewer lesions on magnetic- resonance imaging and less inflammation at necropsy than are the relapsing forms.7 Immunogenetic differences, primarily an excess of HLA DR4 positive individuals compared with RRMS groups, have been found by some8,9 but not all investigators. In 1997 Thompson and colleagues proposed diagnostic criteria for PPMS.10 Because patients with PPMS may have less inflammation than do those with relapsing forms of MS, many neurologists suspect that they may be less likely to respond to immunomodulatory therapies. Consequently, patients with PPMS have been excluded from most recent clinical trials of such treatments. The survey suggested that the term “relapsing progressive” MS was unclear, so the investigators advised that this term be dropped. They suggested that patients could be classified adequately by the other terms, except for rare individuals with relapses superimposed upon a progressive course, for whom the investigators introduced the term “progressive-relapsing” (PR) MS. No quantitative data were provided to prove that this new subgroup was distinct. To assess the validity of the classification of progressive forms of MS proposed by the National Multiple Sclerosis Society, Kremenchutzky and colleagues11 reclassified their London, Ontario, cohort, which has been extensively studied over the past three decades. They found that patients with PPMS and PRMS were similar in the rate at which they reached disability milestones, such as absolute requirement for a cane for walking, confinement to a wheelchair, and death; furthermore, attacks experienced by patients with PRMS were infrequent, mild, and primarily extraspinal and did not seem to influence the course of their disease. Accordingly, Kremenchutzky and colleagues suggested that the PR subgroup should be merged with PPMS. Independently, on the basis of an analysis of 83 patients with PPMS and 12 patients with PRMS from San Francisco, Andersson and colleagues12 reached similar conclusions. PPMS and PRMS presented in similar ways, mainly as progressive hemiparesis or paraparesis. Although the follow-up in their study was shorter than that in Kremenchutzsky and colleagues’ study, Andersson and colleagues also found that the interval from onset of disease to absolute need for a cane was similar in the two subgroups. Similarly, they found that attacks were

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