Alopecia Androgenetica 2009

Androgenetic alopecia Authors Beth G Goldstein, MD Adam O Goldstein, MD, MPH Section Editor Robert P Dellavalle, MD, PhD, MSPH Deputy Editor Abena O Ofori, MD Last literature review version 17.1: January 2009 | This topic last updated: November 18, 2008 (More) INTRODUCTION — Androgenetic alopecia is the most common type of hair loss, affecting approximately 30 to 40 percent of adult men and women [1] . The incidence is the same among men and women, although it may be camouflaged better in the latter. While it often affects women prior to the age of 40, the incidence increases around the time of menopause. Hair loss, or alopecia, is classified broadly as either scarring or nonscarring: Scarring alopecia refers to hair loss associated with fibrosis and scar tissue that replaces and often permanently destroys the hair follicle. Examples include bullous diseases, chemical alopecia, discoid lupus erythematosus, folliculitis (severe), lichen planopilaris, dissecting cellulitis, and tumors. Nonscarring alopecia refers to hair loss without permanent destruction of the hair follicle. Examples include anagen effluvium, androgenetic alopecia, chemical alopecia, folliculitis (mild), inherited disorders of the hair shaft, telogen effluvium, alopecia areata, and traumatic alopecia. All types of hair loss can be psychologically debilitating. Thus, psychologic support is essential for all patients with hair loss. This topic discusses androgenetic alopecia. The other causes of nonscarring alopecia are discussed separately. (See "Nonscarring hair loss" and see "Alopecia areata"). HAIR GROWTH CYCLE — We have all of our terminal hair follicles at birth. Growth of each of these follicles on the scalp is cyclic [2] : The growth phase, termed anagen, lasts two to three years. The involutional phase, termed catagen, lasts two to three weeks. The resting phase, termed telogen, lasts three to four months. Hair is released from the hair shaft and shed at the end of telogen, and the next cycle is initiated. Telogen hairs are characterized by a mature root sheath, or "club," at the proximal end. In the normal scalp, approximately 80 to 90 percent of follicles are growing (anagen), about 5 to 10 percent are resting (telogen), and 1 to 3 percent are undergoing involution (catagen) [3,4] . Each day up to 75 hairs in telogen are shed from the scalp and about the same number of follicles enter anagen [2] .

PATHOGENESIS — Hair "loss" in androgenetic alopecia is due to a genetically determined shortening of anagen, with subsequent production of a shorter, thinner hair shaft, a process often called follicular miniaturization. The hair growth cycle continues, but new growth becomes thinner and shorter as follicles are miniaturized. The mode of inheritance is polygenic with variable penetrance [5,6] . Miniaturization is caused by a hormonally-mediated process at the follicular level. Dihydrotestosterone binds to the androgen receptor in susceptible follicles, and the hormonereceptor complex then activates the genes responsible for the gradual transformation of large, terminal follicles to miniaturized follicles [7-10] . Young men and women with androgenetic alopecia have higher levels of 5-alpha-reductase (which converts testosterone and other androgens to dihydrotestosterone) and a higher quantity of androgen receptors, but lower levels of the enzyme cytochrome P-450 aromatase (which converts androgens such as testosterone and 4-androstenedione to the estrogens estradiol and estrone, respectively) [2] . These transformations can take place in the hair follicle itself. In addition, production rates of dihydrotestosterone are higher in men with male pattern balding than in those without [11] . Differences in the levels of androgen receptor and steroid-converting enzymes may account for the different clinical presentations of androgenetic alopecia in men and women. In one study, for example, both men and women had higher levels of receptors and 5-alphareductase in frontal hair follicles than in occipital follicles, while higher levels of aromatase were found in the latter [9] . Compared with frontal follicles in men, androgen receptor content in female frontal follicles was 40 percent lower, 5-alpha-reductase approximately three times lower, and aromatase content six times greater. A genetics study raised the possibility that variability in the androgen receptor gene may play an important role in the pathogenesis of androgenetic alopecia [12] , and two other studies found an additional association with polymorphisms on chromosome 20p11 [13,14] . CLINICAL FEATURES — Androgenetic alopecia is characterized by varying degrees of partial hair thinning primarily from the vertex and frontal areas of the scalp. It is typically more diffuse and rarely complete in women. Maintenance of the front hair line is normal, with diffuse thinning typically occurring just behind the frontal hairline or midscalp area to the vertex. The affected part is usually widened and more obvious. Hair loss usually occurs in an M-shaped pattern in the frontal hair line in men. Regression of hair in the temporal areas advances to the midscalp area as the alopecia progresses. The miniaturized hairs can be of various lengths and diameters since each follicle is in a different phase of the hair cycle; the presence of uneven lengths and texture is a classic sign of androgenetic alopecia [2] . DIAGNOSIS — The diagnosis of androgenetic alopecia is usually straightforward in men. Diffuse frontal to vertex thinning in women may provide a greater diagnostic challenge. Examine the scalp for other signs of hair disease, such as scarring or follicular plugging, which could cause permanent hair loss. Rule out other causes of diffuse hair loss, such as illness (eg,

hyper- or hypothyroidism, iron deficiency [15,16] ), medications (eg, anticoagulants, anticonvulsants, beta blockers, antidepressants, among others), or trauma. A family history of similar hair loss is suggestive of androgenetic alopecia. Although most women with androgenetic alopecia are endocrinologically normal, take a careful history and look for any signs of androgen excess in women, such as menstrual irregularities, acne, hirsutism, or other signs of virilization. Often women use techniques to hide hirsutism; it is important to ask, not just look, for excess hair growth. Given the frequency with which androgenetic alopecia occurs in women, an extensive hormonal evaluation is not necessary unless one of these signs or symptoms of androgen excess are present. Laboratory tests in women with suspected androgen excess should include total testosterone, dehydroepiandrosterone sulfate (DHEAS), and prolactin levels. (See "Evaluation of women with hirsutism"). DIFFERENTIAL DIAGNOSIS Telogen effluvium — Androgenetic alopecia in women may be so diffuse that it can be difficult to distinguish it from the diffuse hair loss of telogen effluvium. The latter is usually associated with an acute event, the results of the hair pull are positive (see "Nonscarring hair loss", section on Telogen effluvium), and a history of a precipitating event or drug is helpful. A biopsy specimen (4 to 6 mm) from an area of alopecia may be helpful to distinguish the condition (see below). Diffuse alopecia areata — Diffuse alopecia areata is usually more acute in onset than androgenetic alopecia, does not follow a classic distribution, and is associated with hair loss on other body sites. (See "Alopecia areata"). TREATMENT — Oral finasteride (Propecia) and topical solutions of minoxidil (Rogaine) are the only drugs approved by the United States Food and Drug Administration for treatment of androgenetic alopecia in men. Only minoxidil is approved in women. Pictures before initiating therapy and four months later may be helpful to document any change in appearance. Topical minoxidil — Minoxidil promotes hair growth by increasing the duration of anagen and enlarging miniaturized and suboptimal follicles; the mechanism by which this occurs is unclear [2] . Topical minoxidil is available over the counter in both 2 and 5 percent solutions and as a 5 percent foam. The 5 percent solution appears to cause somewhat more contact dermatitis than the 2 percent solution [17] , and the 5 percent foam may be somewhat less irritating [18] Use in men — Both 2 and 5 percent minoxidil have consistently demonstrated benefit in men with androgenetic alopecia compared with placebo, and the 5 percent preparation is more effective than the 2 percent solution [17,19] . In the largest controlled trial, for example, 393 men with androgenetic alopecia were randomly assigned to treatment with 5 or 2 percent topical minoxidil solution or placebo [17] . After 48 weeks of therapy, 5 percent minoxidil was significantly superior to the 2 percent solution or placebo in terms of change from baseline in nonvellus hair count (increase in count per square cm of 18.6, 12.7, and 3.9, respectively), patient rating of scalp coverage and treatment benefit, and investigator rating of scalp coverage. Treatment with 5 percent minoxidil was also associated with an earlier therapeutic

response and an improvement in the patients' psychological perceptions of hair loss. Patients treated with 5 compared with 2 percent minoxidil reported more pruritus and local irritation. Use in women — Two double-blind studies of 550 women ages 18 to 45 years with androgenetic alopecia demonstrated the efficacy of 2 percent minoxidil in women [20,21] . In one study, 13 percent of women in the minoxidil-treated group had moderate growth and 50 percent had minimal growth, compared with 6 and 33 percent, respectively, in the placebotreated group [20] . Similarly, 60 percent of women in the minoxidil group reported that they had new hair growth (20 percent moderate and 40 percent minimal) compared with 40 percent (7 percent moderate and 33 percent minimal) of patients in the placebo group. A randomized trial that compared 5 percent minoxidil, 2 percent minoxidil, and placebo in 381 women with androgenetic alopecia found that 5 percent minoxidil was significantly superior to placebo for each of the three primary endpoints (nonvellus hair count, patient assessment of hair growth/scalp coverage, and investigator assessment of hair growth/scalp coverage) [22] . Two percent minoxidil was also superior to placebo on the end points of hair count and investigator assessment, but not on the patient assessment end point. In comparing the two strengths of minoxidil, patient assessment was significantly better and there was a trend toward higher nonvellus hair counts with 5 versus 2 percent minoxidil. Dermatologic adverse events including pruritus, dermatitis, scaling, and hypertrichosis (facial hair growth), were more common with 5 percent minoxidil than with 2 percent minoxidil or placebo (14, 6, and 4 percent, respectively); hypertrichosis occurred in 4 of 153 patients receiving 5 percent minoxidil. Finasteride — Finasteride is an inhibitor of 5-alpha-reductase type II, thereby inhibiting conversion of testosterone to dihydrotestosterone [23] . Taken orally at a dose of 1 mg/day, finasteride rapidly lowers serum and scalp dihydrotestosterone levels by more than 60 percent [2] . It has no affinity for the androgen receptor and does not interfere with testosterone action nor have any steroidal effects of its own [23] . Use in men — The efficacy of finasteride for treatment of androgenetic alopecia was demonstrated in two one-year trials of 1553 men ages 18 to 41 years who were randomly assigned to oral finasteride (1 mg/day) or placebo for one-year, with blinded extension studies for a second year in 1215 of the subjects [24] . Finasteride treatment resulted in clinically significant increases in hair count and improved scalp coverage, while treatment with placebo resulted in progressive hair loss. About two-thirds of men taking finasteride had improved scalp coverage at two years; one-third had the same amount of hair as they did at the start of the study. About 1 percent of patients on finasteride lost hair. These results were confirmed in a second report [25] . Although treatment for more than two years has not been rigorously studied, the clinical impression is that scalp coverage continues to increase as the hairs recruited to grow in the first year continue to get thicker, more pigmented, and longer [2] . This impression is supported by a randomized trial that followed some men for up to 192 weeks and found that net improvements in hair weight with finasteride therapy were greater than improvements in hair count, suggesting that factors other than hair count, such as increased hair length and thickness, contribute to the beneficial effects of finasteride [26,27] .

The 1 mg dose of finasteride used to treat hair loss is much lower than the typical 5 mg dose used to treat benign prostatic hypertrophy. (See "Medical treatment of benign prostatic hyperplasia"). Side effects of the higher dose include decreased libido and ejaculatory or erectile dysfunction; these are much less common with the dose used for alopecia. In addition, the serum prostate specific antigen (PSA) may decline by as much as 50 percent in men taking even the 1 mg dose of finasteride [28] . (See "Measurement of prostate specific antigen"). When the 5 mg finasteride dose was studied for the chemoprophylaxis of prostate cancer, it reduced the overall incidence of prostate cancer but increased the risk of high grade prostate cancer [29] . It is unclear whether this has implications for the safety of 1 mg finasteride used for the long term treatment of alopecia. (See "Chemoprevention strategies in prostate cancer"). Use in women — Finasteride is contraindicated in women of reproductive potential because of concerns regarding abnormal genitalia development in the male fetus, and it is recommended that such women not even touch finasteride pills. Finasteride was used in a research study of premenopausal women with female pattern hair loss who were also receiving oral contraceptives [30] . One study that evaluated the use of finasteride in postmenopausal women with androgenetic alopecia found no evidence of benefit with finasteride compared with placebo [31] . However, in the subset of women with hair loss in the setting of hyperandrogenism, there have been reports of improvement with finasteride [32,33] . Combination and comparison with minoxidil — In a small study, finasteride 1 mg was superior to minoxidil 2 percent; this study also showed a trend toward better results with combination therapy with finasteride and minoxidil compared with finasteride alone [34] . While there are no direct head-to-head comparisons between finasteride and minoxidil 5 percent, clinical observations suggest that finasteride is easier for patients to use and thus may increase compliance with therapy, which may lead to better outcomes. Other 5-alpha-reductase inhibitors — Dutasteride, an inhibitor of both types I and II 5-alphareductase, is FDA approved for the treatment of benign prostatic hyperplasia. (See "Medical treatment of benign prostatic hyperplasia"). A randomized, placebo-controlled trial in 416 men compared a range of doses of dutasteride with finasteride 5 mg daily [35] . Hair growth showed a dose-response effect with dutasteride, and after 12 and 24 weeks of therapy, dutasteride 2.5 mg daily was more effective than finasteride. However, this is a high dose of dutasteride; the standard dose for benign prostatic hyperplasia is 0.5 mg daily. In this study, 13 percent of men treated with dutasteride 2.5 mg daily reported decreased libido. Longer term studies of safety and efficacy are needed before this high dose of dutasteride can be recommended for the treatment of hair loss in men. Dutasteride has also been tried in women [36] , however, like finasteride, it is contraindicated in women of reproductive potential.

Spironolactone — Evidence from case reports suggest that women with androgenetic alopecia who do not respond to minoxidil may benefit from the addition of spironolactone [37-39] . An observational study in women not being treated with minoxidil found that 35 of 40 women treated with spironolactone 200 mg daily had either stabilization of hair loss or hair regrowth [40] . The study found nearly identical results in 40 women treated with the antiandrogen cyproterone acetate. In women who do not response to minoxidil alone, we typically add spironolactone at a dose of 100 to 200 mg per day. Surgery — Referral to a dermatologist or plastic surgeon may be appropriate in selected patients. Available procedures include hair transplantation or flaps, and scalp reduction. Light therapy — Treatments with low-energy laser light or other lights have been marketed for androgenetic alopecia. There is not adequate evidence for the efficacy of such treatments [41] Patient education — Discourage use of hair treatments and tonics; they are unproved, often expensive, and possibly damaging to remaining hair. Minoxidil — Patients considering use of minoxidil should be advised of the following: Explain that minoxidil solution is available over-the-counter and is to be used for an indefinite time, and that it is not usually covered by insurance. Once stopped, any hair regrowth will be lost. Emphasize that minoxidil is a scalp treatment, not a hair treatment, and must be used exactly as prescribed for maximum benefit. A normal, healthy scalp is required to use this medication. Apply 1 mL twice a day to involved areas on a dry scalp. The solution can be applied by dropper or pump spray device to the scalp and spread lightly with a finger; massage is not needed. Explain that minoxidil solution must be used twice a day for at least four months before evaluating the initial response to therapy. Hair shedding usually decreases within two months of starting treatment. Hair growth may be seen within four to eight months and stabilizes at 12 to 18 months. Cosmetically significant hair growth occurs in only 30 to 40 percent of patients with vertex hair loss. The best results are obtained if the baldness pattern is present for less than five years, involves a vertex location, and is less than 10 cm in diameter. Treatment must be continued indefinitely; once discontinued, any hair maintained or regrown as a result of the medication will be lost. The most common side effects, although infrequent, are contact and irritant dermatitis [42] . Neither 5 percent nor 2 percent solution of minoxidil alters systolic or diastolic blood pressure, pulse rate, or body weight when applied daily [43] . Nevertheless, patients with a history of cardiovascular disease should be educated to watch for tachycardia, edema, or weight gain because systemic absorption can occur if the scalp skin barrier is not intact. Topical minoxidil 5 percent solution is more effective than the 2 percent solution in men; there are limited data in women that also suggest greater efficacy of 5 percent minoxidil; however, a small number of women appear to develop facial hair growth with the higher concentration solution [22] .

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Hair loss in men and women (androgenetic alopecia)"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics. SUMMARY AND RECOMMENDATIONS The diagnosis of androgenetic alopecia in men is usually straightforward. In women, if there are other signs of androgen excess, measure levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), and prolactin. (See "Evaluation of women with hirsutism"). In the absence of direct comparisons, finasteride 1 mg every day is preferable to minoxidil for treatment of androgenetic alopecia in men. Most men taking finasteride will stop losing hair, and about two-thirds of men will have increased hair coverage after two years on finasteride. Finasteride is contraindicated in women of reproductive age, and finasteride pills should not even be touched by such women; finasteride does not appear to work in postmenopausal women except perhaps in the subset of women with hyperandrogenism. Minoxidil 5 percent applied twice a day is more effective than minoxidil 2 percent in men. Even in men with vertex hair loss (where minoxidil works best), only 30 to 40 percent will have cosmetically significant hair growth. Limited data suggest that minoxidil 5 percent is more effective than minoxidil 2 percent in women with androgenetic alopecia [22] . We recommend the use of minoxidil 5 percent; however, a small number of women may develop facial hair growth with this. Women who do not respond to minoxidil may benefit from the addition of spironolactone 100 to 200 mg per day. There are limited data on combination therapy with minoxidil and finasteride [34] ; however, in men who do not respond to therapy with either agent alone, it is reasonable to try combination therapy. Hair transplantation, flaps, and scalp reduction surgery may be appropriate in selected patients. REFERENCES Olsen, EA. Androgenetic alopecia. In: Olsen, EA (Ed), Disorders of hair growth: Diagnosis and treatment, McGraw-Hill, New York 1994. p.257. Price, VH. Treatment of hair loss. N Engl J Med 1999; 341:964. Headington, JT. Telogen effluvium. New concepts and review. Arch Dermatol 1993; 129:356. Whiting, DA. Chronic telogen effluvium. Dermatol Clin 1996; 14:723. Kuster, W, Happle, R. The inheritance of common baldness: two B or not two B?. J Am Acad Dermatol 1984; 11:921. Bergfeld, WF. Androgenetic alopecia: an autosomal dominant disorder. Am J Med 1995; 98:95S. Sawaya, ME. Purification of androgen receptors in human sebocytes and hair. J Invest Dermatol 1992; 98:92S. Sawaya, ME, Shalita, AR. Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg 1998; 3:9. Sawaya, ME, Price, VH. Different levels of 5alpha-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. Sawaya, ME. Steroid chemistry and hormone controls during the hair follicle cycle. Ann N Y Acad Sci 1991; 642:376. Vierhapper, H, Nowotny, P, Maier, H, Waldhausl, W. Production rates of dihydrotestosterone in healthy men and women and in men with male pattern baldness: determination by stable isotope/dilution and mass spectrometry. J Clin Endocrinol Metab 2001; 86:5762. Hillmer, AM, Hanneken, S, Ritzmann, S, et al. Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia. Am J Hum Genet 2005; 77:140. Hillmer, AM, Brockschmidt, FF, Hanneken, S, et al. Susceptibility variants for male-pattern

baldness on chromosome 20p11. Nat Genet 2008; 40:1279. Richards, JB, Yuan, X, Geller, F, et al. Male-pattern baldness susceptibility locus at 20p11. Nat Genet 2008; 40:1282. Trost, LB, Bergfeld, WF, Calogeras, E. The diagnosis and treatment of iron deficiency and its potential relationship to hair loss. J Am Acad Dermatol 2006; 54:824. Olsen, EA. Iron deficiency and hair loss: the jury is still out. J Am Acad Dermatol 2006; 54:903. Olsen, EA, Dunlap, FE, Funicella, T, et al. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol 2002; 47:377. Olsen EA, Whiting D, Bergfeld W, et al. A multicenter, randomized, placebo-controlled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol 2007; 57:767. 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. DeVillez, RL, Jacobs, JP, Szpunar, CA, Warner, ML. Androgenetic alopecia in the female. Treatment with 2% topical minoxidil solution. Arch Dermatol 1994; 130:303. Jacobs, JP, Szpunar, CA, Warner, ML. Use of topical minoxidil therapy for androgenetic alopecia in women. Int J Dermatol 1993; 32:758. Lucky, AW, Piacquadio, DJ, Ditre, CM, et al. A randomized, placebo-controlled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss. J Am Acad Dermatol 2004; 50:541. Rittmaster, RS. Finasteride. N Engl J Med 1994; 330:120. Kaufman, KD, Olsen, EA, Whiting, D, et al. Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group. J Am Acad Dermatol 1998; 39:578. Leyden, J, Dunlap, F, Miller, B, et al. Finasteride in the treatment of men with frontal male pattern hair loss. J Am Acad Dermatol 1999; 40:930. Price, VH, Menefee, E, Sanchez, M, et al. Changes in hair weight and hair count in men with androgenetic alopecia after treatment with finasteride, 1 mg, daily. J Am Acad Dermatol 2002; 46:517. Price, VH, Menefee, E, Sanchez, M, Kaufman, KD. Changes in hair weight in men with androgenetic alopecia after treatment with finasteride (1 mg daily): threeand 4-year results. J Am Acad Dermatol 2006; 55:71. D'Amico, AV, Roehrborn, CG. Effect of 1 mg/day finasteride on concentrations of serum prostate-specific antigen in men with androgenic alopecia: a randomised controlled trial. Lancet Oncol 2007; 8:21. Thompson, IM, Goodman, PJ, Tangen, CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349:215. Iorizzo, M, Vincenzi, C, Voudouris, S, et al. Finasteride treatment of female pattern hair loss. Arch Dermatol 2006; 142:298. Price, VH, Roberts, JL, Hordinsky, M, et al. Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia. J Am Acad Dermatol 2000; 43:768. Shum, KW, Cullen, DR, Messenger, AG. Hair loss in women with hyperandrogenism: four cases responding to finasteride. J Am Acad Dermatol 2002; 47:733. Olsen, EA, Hordinsky, M, Roberts, JL, Whiting, DA. Female pattern hair loss. J Am Acad Dermatol 2002; 47:795. Khandpur, S, Suman, M, Reddy, BS. Comparative efficacy of various treatment regimens for androgenetic alopecia in men. J Dermatol 2002; 29:489. Olsen, EA, Hordinsky, M, Whiting, D, et al. The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol 2006; 55:1014. Olszewska, M, Rudnicka, L. Effective treatment of female androgenic alopecia with dutasteride. J Drugs Dermatol 2005; 4:637. Olsen, EA. My hair is thinning on the top of my head. What treatments are available for hair loss in women? Health News 2002; 8:12. Shapiro, J, Price, VH. Hair regrowth. Therapeutic agents. Dermatol Clin 1998; 16:341. Springer, K,

Brown, M, Stulberg, DL. Common hair loss disorders. Am Fam Physician 2003; 68:93. Sinclair, R, Wewerinke, M, Jolley, D. Treatment of female pattern hair loss with oral antiandrogens. Br J Dermatol 2005; 152:466. Rogers, NE, Avram, MR. Medical treatments for male and female pattern hair loss. J Am Acad Dermatol 2008; 59:547. Ebner, H, Muller, E. Allergic contact dermatitis from minoxidil. Contact Dermatitis 1995; 32:316. Rogaine extra strength for men (5 percent minoxidil topical solution): for nonprescription use. Summary volume, Pharmacia & Upjohn, Kalamazoo, MI 1997.