markable association between ovarian dysfunction and ache since it implies that ache may not be simply a primary skin disorder but, in certain instances, a symptom of a systemic disease. Although in the study which we reported the patients indeed were selected on the basis of unresponsiveness to routine dermatologic therapy, Dr. Holshuh's perception that we might have felt that all patients with acne could benefit from an appropriate endocrine evaluation is probably correct. Since publication of this paper, we surveyed an unselected group of patients with varying severity of acne and also found a significant incidence of hyperandrogenism and ovarian dysfunction. Dr. Holshuh wonders what prompted us to conduct endocrine investigations in the 39% of patients who did not complain of "menstrual irregularities." These patients were investigated as a part of the study design, where the hypothesis tested was that a majority of patients with acne that does not respond to routine dermatologic therapy might have elevated androgen levels and ovarian dysfunction. The data obtained support this hypothesis. Dr. Holshuh is concerned about the "extensive laboratory studies," and their cost-effectiveness, that may need to be conducted in patients of this nature. Acutally, only minimal laboratory investigations need to be conducted in most instances, i.e., determination of plasma testosterone levels. Indeed, this was the only laboratory test performed in the subjects reported in our paper. For routine cases, the cost may vary between $25 and $40, depending on the laboratory. Obviously, in certain selected instances more sophisticated and more extensive studies are in order. In addition, a clinical evaluation of the ovulatory function is also indicated in these patients. This can be achieved simply by means of a basal body temperature chart (no cost to the patient) and office evaluation of cervical changes. Dr. Holshuh states that it is not made clear in the article what the dermatologist is to do once abnormal laboratory data are obtained and asks what therapy the authors propose for these patients. First, it was not the purpose of this paper to address the question of therapy of acne. Furthermore, no data on therapy were provided. However, we have demonstrated in other publications (e.g., Am J Obstet Gynecol 133:133, 1979; Fertil Steril 32:408, 1980) that therapy of patients with hyperandrogenism and ovulatory dysfunction with low dose of prednisone results in suppression of the elevated androgen levels and improvement of ovarian function in the majority of cases. It is of interest to note that in many of these patients suppression of the androgen levels also results in clearing of acne, when present. In patients in whom the androgen levels are not suppressible by pred-
Journal of the American Academy of Dermatology
nisone therapy, neither is the ovulatory function improved nor the acne cleared. It appears that acne is almost like a "red flag" which should alert the physician of the possibility of an underlying endocrine disorder. If observed in young women whose ovulatory function is only mildly affected, suppression of the excessive androgen levels may prevent the evolution of a mild ovulatory dysfunction into a major ovarian disorder associated with a polycystic condition, various forms of severe dysfunctional uterine bleeding, amenorrhea, infertility, etc. Dr. Holshuh expresses the concern of whether "a, female patient with acne would be better served by an initial visit to an endocrinologist or to a dermatologist." This is a purely academic concern. Undoubtedly, in the 1980s a patient with a complaint of acne will automatically see or be referred to a dermatologist first. Finally, Dr. Holshuh makes a "tongue-in-cheek" comment at the end of the letter that "perhaps the most significant point of this article is found when reading between the lines, as it appears that none of the authors are members of the American Academy o f Dermatology." This is simply not true. One of the authors is a member of the American Academy of D e r m a t o l o g y , the American Society for Dermatologic Surgery, the International Society for Dermatology, the Texas Dermatological Society, and the Houston Dermatological Society. We would like to assure Dr. Holshuh that our studies were conducted and this paper written with no other but the primary concern for the betterment of patient care and acquisition of new knowledge. Emil Steinberger, M.D. The University of Texas Health Science Center at Houston 6431 Fannin P.O. Box 20708 Houston, TX 77025
Topical minoxidil in alopecia areata To the Editor: Minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide) is a peripheral vasodilator now used in the United States to control severe hypertension in patients resistant to conventional treatment. The drug is chemically unrelated to other available peripheral vasodilators such as hydralazine and diazoxide. It is gaining attention in dermatology because it produces hypertrichosis in virtually all patients who receive standard therapeutic systemic dosing of the drug.l'2 This "universal" side ef-
Volume 5 Number 2 August, 1981
fect of hypertrichosis has stimulated some researchers in dermatology to consider it a possible topical agent for male pattern alopecia, z.4 We are reporting the application of topical minoxidil to recalcitrant alopecia areata unresponsive to conventional treatments. Methodology. A 1% topical minoxidil lotion was prepared by triturating thirty 10-mg commercially available tablets (Loniten, The Upjohn Co.) to a fine powder, followed by addition of 3 ml propylene glycol and 6 ml distilled water and dilution to 30 ml with 95% ethanol. The resulting unfiltered preparation contains tablet filler and binder particles that precipitate. The patients were instructed about the nature of sediment and to shake well before using. The final vehicle concentration was approximately 70% ethanol, 20% water, and 10% propylene glycol. The patient instructions were to apply thinly and evenly twice daily (every 12 hours), using a glass rod applicator, to specified areas of hair loss. The evening application was allowed to dry and to be followed by a thin layer of white petrolatum for overnight occlusion. Case 1, A 42-year-old woman sought treatment 4 years previously for rapid-onset alopecia totalis. No response to therapeutic trials of topical and intradermal corticosteroids was obtained. Subsequently, she was sensitized to dinitrochlorobenzene (DNCB), and topical DNCB applications to specified areas of hair loss were instituted. She experienced hair regrowth over the entire scalp which lasted only a few months. Despite maintenance DNCB therapy, all of the hair around the entire scalp margin was again shed. She discontinued all treatment and was lost to follow-up for approximately 1 year, when in February, 1980, she returned for further treatment of these same areas of persistent hair loss. Topical minoxidil was begun on the frontal and right temporal areas of the scalp margin. Local hair regrowth was observed in the area of application within 4 to 6 weeks. In April, 1980, she began applying minoxidil to the left temporal scalp margin also, and local hair regrowth was noted within 6 weeks. She finished her supply of minoxidil in June, 1980, and did not return for follow-up until September, at which time continued hair regrowth at sites of application was observed. Case 2. A 13-year-old girl sought treatment for the first time at the age of 8 for the rapid onset of alopecia universalis. Topical corticosteroid applications to the scalp produced no hair regrowth, She was sensitized to DNCB, and topical DNCB therapy of the scalp was instituted. Hair regrowth occurred over most of the scalp except for the parietal areas. Despite continued use of DNCB, rapid loss of most of the scalp hair was
observed approximately 2~ years after start of therapy, She had been free of treatment for 1 year, when in March, 1980, minoxidil lotion was applied daily to the entire scalp. Within 5 weeks, active regrowth of hair was found at treated sites. As of December, 1980, while treatment continued, normal hair was found over all areas of the scalp except the parietal areas, where a dense growth of short, fine hair existed. Case 3. A 19-year-old young woman sought treatment for widespread alopecia areata present since the age of 5 years. DNCB was applied to the left temporal area (3-cm-~area) daily from August, 1979, to October, 1979, with resultant hair growth at the site of application. DNCB was discontinued in October, 1979, when the patient stated a preference not to use it. Topical minoxidil therapy was applied to the fight parietal area from December, 1979, to March, 1980. No response to treatment occurred, and minoxfdil was discontinued. Cutaneous or systemic side effects were not detected in any of these patients, and all patients appeared to have good compliance with their minoxidil treatments. Pharmacology. In humans, minoxidil is absorbed from the gastrointestinal tract, resulting in maximum blood levels in the first hour. The serum half-life is approximately 4 hours. Volume of distribution is apparently four times the total body water volume, with distribution to unknown tissues and compartments. The parent drug is extensively metabolized in humans (approximately 90%) primarily by conjugation. Some converted polar metabolites identified to date are reported to reduce blood pressure (BP), but less than minoxidil itself. Minoxidil and identified metabolites are excreted primarily by the kidney. Minoxidil is minimally protein-bound in plasma, and renal clearance corresponds to glomerular filtration rate. Minoxidil and known metabolites are hemodialyzable. Since metabolism accounts for its clearance from plasma, decreased or absent renal function does not apparently affect its pharmacologic activity. Side effects. In addition to the high incidence of hypertrichosis with systemic minoxidil, other cutaneous side effects include pigmentation and "coarsening" of facial features. More serious systemic side effects are fluid retention, tachycardia, nausea, fatigue, dyspnea, and gynecomastia.~,2,z'6 To date, there have been no reported cutaneous or systemic side effects from topical minoxidil. A dermatologic description of the hypertrichosis produced by systemic minoxidil was lacking until Burton and Marshall 4 described and reviewed it in 1979. Previous descriptions had included the temples and forehead as some of the regional sites of hair growth,
Journal of the American Academy of Dermatology
not suggesting a mechanism of androgenic stimulation. The true incidence and accurate descriptions of hypertrichosis are probably inadequately reported in the literature since most investigators have been nondermatologists. A calcium thioglycolate standard depilatory has been effective in managing the hypertrichosis 7 H a i r regrowth. Although other peripheral vasodilators (such as diazoxide) are said to increase cutaneous blood flow and may produce hypertrichosis, it appears that minoxidil most significantly enhances cutaneous blood flow. At a dose of 1 mg/kg intravenously in dogs, blood flow increases 62.5% in the skin (0.8 m m / m i n / g m tissue control vs 1.3 m m / m i n / g m tissue with minoxidil). 8 Minoxidil does not reduce the blood pressure of normotensive individuals. The mechanism of minoxidil-induced hypertrichosis is unknown. Burton et aP also described diazoxide hypertrichosis. Burton and his associates postulated increased cutaneous perfusion as the possible mechanism for hypertrichosis with potent peripheral vasodilators. Localized hypertrichosis has been suspected to be associated with increased cutaneous blood flow in some cutaneous inflammatory conditions, as well as in association with arteriovenous aneurysms, t0,11 Earhart et al 7 evaluated a possible systemic androgen effect by finding normal plasma testosterone and normal excretion of urinary hydroxysteroids and ketosteroids in patients treated with oral minoxidil. Local changes in dihydrotestosterone or the reductase enzyme have not been reported. Cutaneous receptor effects have not been reported.
Virginia C. Weiss, M.D. Dennis P. West, M.S. Catherine E. Mueller, B.S. Department of Dermatology, Abraham Lincoln School of Medicine, and the Department of Pharmacy Practice, College of Pharmacy University of [Uinois at the Medical Center P.O. Box 6998 Chicago, [L 60680
REFERENCES 1. Dargie HJ, Dollery CT, Daniel J: Minoxidil in resistant hypertension. Lancet 2:515-518, 1977. 2. Devine BL, Fife R, Trust PM: Minoxidil for severe hypertension after failure of other hypotensive drugs. Br Med J 2:667-669, 1977. 3. Zappacosta AR: Reversal of baldness in patient receiving
4. 5. 6. 7. 8. 9. 10. 1i.
minoxidil for hypertension. N Engl J Med 303:14801481, 1980. Burton JL, Marshall A: Hypertrichosis due to minoxidil. Br J Dermatol 101:593-595, 1979. Mehta PK, Bashir M, Shansky RM, Sakharam DM, Dunea G: Severe hypertension--treatment with minoxidil. JAMA 233:249-252, 1975. Jacomb RG, Brunnberg FJ: The use of minoxidiI in the treatment of severe essential hypertension--a report on 100 patients. Clin Sci 51:579S-581S, 1976. Earhart RN, Ball J, Nuss DD, Aeling JL: Minoxidilinduced hypertrichosis--treatment with calcium thloglycolate depilatory. South Med J 70:442-443, 1977. Humphrey SJ, Wilson E, Zins GR: Whole body tissue blood flow in conscious dogs treated with minoxidil. Fed Proc 33:583, 1974. Burton JL, Schutt WH, Caldwell IW: Hypertrichosis due to diazoxide. Br J Dermatol 93:707-711, 1975. Ressmann AC, Butterworth T: Localized acquired hypertriehosis. Arch Dermatol Syph 65:458-463, 1952, Rook A: In Rook A, Wilkinson DS, Ebling FJG, editors: Textbook of dermatology, ed. 2. Oxford, 1972, Blackwell Scientific Publications, vol 2, p. 1580.
Nail growth revisited To the Editor: A smattering of genetics permits any reader to know that "one cannot conceive of a normal nail atop an anomalous ungual phalanx. ,,1 The best example can be given by the Coffin-Siris syndrome, which includes absence of the nails of the fifth fingers and toes and absent terminal phalanges of the fifth fingers and toes. There is just one possible exception in the literature concerning a normal nail growing above an absent phalanx: Ohya's case, reported by Kikuchi et al, 2 which presented an ectopic nail "attached to the skin on the palmar aspect of the right t h u m b . . . It had a free margin, a nail plate, and a lunula." Alas! no mention of any proximal nail fold and the excellent photograph of the patient's condition, published in a famous French textbook, fails to reveal it. z
Robert Baran, M.D. Le Grand Palais 42, Rue des Serbes 06400 Cannes, France
REFERENCES 1. Kelikian H: Congenital deformities of the hand and the forearm. Philadelphia, 1974, W. B. Saunders Co., p. 210. 2. Kikuchi I, Ono T, Ogata K: Ectopic nail. Case reports. Plast Reconstr Surg 61:781-783, 1978. 3. Milian G: Nouvelle pratique dermatologique. Paris, 1936, Masson & Cie, vol 7, p. 320.