| | Targeting hirsutism: a new approach☆Abstract Hirsutism, the appearance of facial hair on women in a male pattern distribution, is a problem with potential medical, social, and psychological implications for millions of women. Hirsutism can reflect the presence of an underlying systemic disease, namely one that results in hyperandrogenic states, or it may seem to be idiopathic. Many methods of treatment have been used over the years, from pharmacological and surgical treatment for underlying disease to mechanical means of hair removal. We discuss hirsutism and review the clinical experience with a topical cream approved for facial hair removal, called eflornithine (Vaniqa), which acts by inhibiting new growth by an enzyme inhibition mechanism. Therapeutic trials and our clinical experience have shown promising results with this agent in diminishing unwanted facial hair in women.
Hirsutism refers to the presence of terminal hairs in a male pattern distribution in women and children. We deal in this article only with the condition as it affects women. Hair growth in a particular area of the body is determined both by hormones and by the intrinsic properties of the specific hair follicle. Before puberty, most hair follicles on the body produce fine, unpigmented hairs called vellus hairs (“peach fuzz”). At puberty, vellus hairs, under the influence of increased levels of circulating androgens, convert to terminal hairs, which are coarser and pigmented. Other hair follicles on the body, notably, the scalp, eyebrows, and eyelashes, do not require androgens for the production of terminal hairs. Thus, some degree of hair growth is expected on the face in postpubescent women, usually on the upper lip.
Almost half of American women complain of unwanted facial hair, and at least 25% of healthy young women have terminal hairs on the face, areola, or over the lower abdomen (1). Ethnic and genetic factors can further increase the likelihood that a healthy young woman will have some amount of facial hair growth, particularly women of Mediterranean, Middle Eastern, and South Asian ancestry.
Although the cosmetic concerns of hirsutism are nearly universal, it is the new appearance of facial hair in women who are postpuberty that is of most concern from a medical standpoint. An underlying disorder of androgen production, hereafter referred to as androgen-dependent hirsutism, causes approximately 70%–80% of these cases. Some 65%–85% of those cases are due to polycystic ovary syndrome (PCOS). The remainder are due to other abnormalities of the ovaries or adrenal glands, mainly congenital adrenal hyperplasia, neoplasms, and Cushing's syndrome. Exogenous androgen administration (anabolic steroids or postmenopausal hormone therapy) should also be considered.
Cases of hirsutism in which androgen levels are normal and the patient has regular ovulatory menstrual cycles, are labeled idiopathic hirsutism 2, 3. The prevalence of idiopathic hirsutism ranges from 6% of the population, in some studies, to as high as 55% in others, although the typical estimate is 6%–17% 2, 3. Idiopathic hirsutism is caused by increased sensitivity of the skin to androgens, presumably due to increased peripheral 5α-reductase enzyme activity (2), the enzyme responsible for the local conversion of testosterone (T) to its active form in hair follicles, dihydrotestosterone. Thus, two women with normal androgen levels may show entirely different patterns of hair growth if they have different 5α-reductase: the one with increased enzyme activity is far more likely to be hirsute than the one with normal enzyme activity.
In fact, one study indicates that 5α-reductase is increased not only in idiopathic hirsutism but in androgen-dependent hirsutism as well, compared to control populations (4). When skin samples from idiopathic hirsute patients and from hirsute patients with PCOS (androgen-dependent) were incubated with 14C-testosterone(T) and the radioactivity of the resulting dihydrotestosterone was determined, the conversion ratio of T to dihydrotestosterone in idiopathic and PCOS patients was 17.18% and 17.86%, respectively, compared to 4.48% in control patients (4). Thus, this enzyme plays a key pathophysiologic role in the growth of facial hair regardless of the patient's androgen profile. The investigators of this study conclude that the term idiopathic is a misnomer because hirsutism in these patients may be explained on the basis of increased follicular 5α-reductase (4).
Evaluation of hirsutism  A thorough patient history is the first step in evaluating a case of hirsutism. The clinician must first determine the baseline level of the patient's hair growth and distribution, as many “hirsute” patients may be presenting with a normal anatomic variant. This is particularly true in those patients with an ethnic or genetic predisposition for some facial hair growth. It is therefore imperative that the patient be asked whether the hairs of concern are new or have been present since childhood or puberty. New hairs appearing in the postpubescent period are more likely to be indicative of a potential underlying systemic disease. It is also important to determine the rate of the new hair growth. Slowly increasing body hair up until menopause can be normal, as can slowly developing facial hair in elderly women. Although the link between physiological changes related to menopause and hair growth has not been definitively characterized, a significant percentage of postmenopausal, mostly elderly, women exhibit an increase in visible facial hair. However, rapidly worsening hirsutism at any age—from adolescence to old age—often reflects a disorder of androgen production. Rapidly progressive hirsutism can indicate an androgen-secreting neoplasm (1). Any pattern of new weight gain, menstrual irregularities, or amenorrhea, must be evaluated for the possible presence of an endocrinological disorder such as PCOS. A thorough drug history is also indicated, as some drugs are known to cause hirsutism, including phenobarbital, phenytoin, cyclosporin, glucocorticoids, minoxidil, and postmenopausal androgen therapy. The physical examination is the next step in the evaluation of hirsutism. The amount and distribution of hair is an index of the androgen effect. Hairs on the face, areola, lower back, or lower abdomen may be normal, whereas terminal hairs on the upper back, shoulders, and upper abdomen suggest an increase in androgens. Any pattern or degree of hair growth can be seen in hirsutism; two women with identical hyperandrogenic profiles may display totally different patterns of hirsutism. Other signs of virilization seen in hyperandrogenic states should be looked for, including male pattern baldness, deepening of the voice, and clitoral enlargement. Acanthosis nigricans, the velvety thickening and hyperpigmentation of the skin seen mainly in the axillae and other body folds, is often a sign of hyperinsulinemia (as seen in PCOS, for example) (5). The physician must also be alert for signs of Cushing's syndrome. Striae, thin skin, muscle wasting, truncal obesity, or moon faces, can point to Cushing's syndrome as a possible etiology for hirsutism. Ob/gyns should test for the following to rule out pathology:
•Testosterone,
•17-α hydroxyprogesterone,
•Prolactin levels and thyroid function for evaluation of anovulation (if necessary),
•TSH screen in patients also complaining of alopecia,
•DHEAS (dihydroepiandrosterone),
•Peripheral 5α-reductase enzyme activity itself can only be tested in vitro.
•Patients with hirsutism are often more fearful of the social than the medical impact of this condition. Therefore, adequate counseling and patient education are warranted for each patient. Reassurance that her condition is likely treatable is important, although the therapeutic modalities can differ greatly. Support groups of patients with PCOS, for example, are available in some regions. Scheduling frequent follow-up visits is often helpful in comforting the patient. In particularly difficult cases, referral for psychological counseling may be necessary. Treatment options The method of treatment for facial hair depends on the individual case. If an underlying systemic disease is present, appropriate pharmacological or surgical therapy is indicated. Mechanical hair removal, such as shaving, plucking, waxing, and depilatory creams can help control hirsutism. Laser hair removal and electrolysis have also been successful in the removal of body hair (appendix). The clinician might find it useful to compile a referral list of reputable cosmeticians. After cosmetic or dermatologic treatment, combination oral estrogen–progestin therapy is first-line endocrine treatment for hirsutism. The estrogenic component, in particular, is responsible for suppression of LH and thus of serum androgen levels. It also results in lowering the fraction of free, or unbound, plasma testosterone. A product called Diane containing cyproterone acetate (an antiandrogenic steroid), distributed in Europe, but not in the United States, is effective against hirsutism. Spironolactone, finasteride, and flutamide are anti-androgen therapies that may be used as adjuncts to treatment with oral contraceptive pills. The advent of a new topical formulation, eflornithine, offers a potential breakthrough for the removal of facial hair. Eflornithine was synthesized in the 1970s as a potential anticancer drug, and is used widely in the treatment of late-stage trypanosomiasis (African sleeping sickness). The discovery that hair loss was a side effect of systemic treatment with this drug for trypanosomiasis led to the development of topical eflornithine HCl 13.9% cream (Vaniqa), granted FDA approval for removal of unwanted facial hair in July 2000 (6). Vaniqa represents the first and thus far only prescription cream clinically proven to slow the growth of unwanted facial hair in women (6). Eflornithine can be used in conjunction with other means of hair removal (appendix) or by itself. The hair spontaneously regresses or falls out, and is washed away with ordinary bathing. Eflornithine is a specific, irreversible inhibitor of the enzyme ornithine decarboxylase present in hair follicles. This enzyme is responsible for a key step in the biosynthesis of polyamines such as putrescine and spermidine (7). These polyamines are believed to have important roles in cell proliferation, and blocking them in hair follicles slows the growth of the hair. New ornithine decarboxylase is generated continually and when inhibition of this enzyme ceases, its functional activity increases (i.e., hair growth resumes). Topical eflornithine is applied twice daily to affected areas of the face. Clinical studies of topical eflornithine involved only hairs on the face and chin, and its usage should be limited to these areas (8). Percutaneous absorption of eflornithine was less than 1%, and what was absorbed was excreted unchanged in the urine (7). It is not yet known if topical eflornithine is secreted in breast milk (8). Topical eflornithine was evaluated in 596 adult women in two multicenter, randomized, double-blind, placebo-controlled therapeutic trials (7). The women had five or more terminal hairs per square centimeter in four discrete facial areas 48 hours after shaving, as determined by video image analysis (7). They all habitually removed facial hairs at least twice a week. The cream was applied twice daily for 24 weeks, followed by an 8-week no treatment period. The results of the trials were assessed by the Physician's Global Assessment scale (the clinician's subjective opinion on a four-point scale: no improvement/worse, improved, marked improvement, clear/almost clear) (9), video image analysis of hair growth (objective data), and a patient self-assessment questionnaire (the patient's subjective opinion). Patients deemed to be a clinical success were those with Physician's Global Assessments of “marked improvement” or “clear/almost clear” (7). By the eighth week, a statistically significant difference in the success rate was seen in the eflornithine group over the placebo group. After 24 weeks, 32% of patients treated with topical eflornithine were judged “clinical successes” vs. 8% of the placebo group by the Physician's Global Assessment (7). When “clinical success” and “improved” were taken together, the percentage of patients with a positive response to eflornithine at 24 weeks jumped to 58% versus 34% in the placebo group. Video image analysis showed eflornithine to be significantly superior to placebo in reducing spatial hair mass from week 2 onward (7). Self-assessment by patient questionnaire showed eflornithine to reduce overall discomfort and bother by 33% in the treated group vs. 15% in the placebo group (7). All three methods of assessment showed the benefit of eflornithine to be lost after the 8-week no-treatment phase, when hair growth returned to its pretreatment rate (7). Tests of the tolerability of topical eflornithine yielded positive results. In human dermal safety studies of this agent, repeated insult patch-test on 230 subjects resulted in erythema with edema in 38.9% of subjects treated with eflornithine HCl 13.9% cream and 4.8% of subjects treated with vehicle cream alone (10). However, the therapeutic trials reported erythema to be a side effect of topical eflornithine in <2% of patients. In these trials, the most common reported side effect was acne, at about 20%; however, the rate of acne reported in the placebo group was virtually the same (7). Burning/stinging/tingling was reported in nearly 15% of patients in the eflornithine group and in only 5% of the placebo group, making this the most common side effect specific to eflornithine vs. the placebo (7). Adverse effects of eflornithine were generally mild in nature and no serious treatment-related events occurred. There were no reports of contact sensitizing, photocontact allergic, or phototoxic properties of eflornithine. The dermal safety studies determined eflornithine to be appropriate for routine topical treatment (10). Key points
•5α-reductase is increased in both idiopathic hirsutism and androgen-dependent hirsutism and plays a key pathophysiologic role in the growth of facial hair regardless of the patient's androgen profile.
•Some 70%–80% of cases of hirsutism involve an underlying disorder of androgen production, known as androgen-dependent hirsutism.
•Evaluating a case of hirsutism requires a thorough history, determining the baseline level of hair growth and distribution, progression of new hair growth.
•Eflornithine (Vaniqa) acts by inhibiting new growth by enzyme inhibition.
•Vaniqa shows promising results as a new topical cream for facial hair removal. Conclusion Unwanted facial hair is considered a “pet beauty peeve” by more than 45% of American women (11). Clinical studies and our experience with the FDA-approved treatment, eflornithine HCl 13.9% cream (Vaniqa), give cause for optimism. This topical agent has been shown to slow and even eradicate the growth of facial hair in women, with a very favorable side effect profile. Topical eflornithine should be given serious consideration by physicians as a treatment option for patients with hirsutism.
Appendix. Shave, wax, or zap—the many means of hair removal There are many means of dealing with unwanted facial hair, some of great antiquity. Each method has both advantages and disadvantages. Shaving Removal of the hair by cutting on the skin line, with either a razor or an electric shaver. Advantages: quick, simple procedure that can be done at home at low cost. Disadvantages: Needs to be repeated frequently, possibly daily. Because hair is blunt-cut, it grows back as stubble. Waxing, plucking, coil-spring machines Pulling the hair out by its roots. Waxing is done by applying a wax, sugar, or honey-based mixture to the skin. With the hot-wax treatment the mixture cools until it hardens around the hairs, then the hardened substance is pulled off, tearing the hairs out with it. With the cold-wax treatment, the mixture is applied to the skin and a cloth strip is pressed over it. When it is pulled off, both the wax and hair remain attached to the cloth strip. Hairs can be plucked with either tweezers or thread. Devices that resemble electric shavers consist of a spring that catches the hair between its coils and pulls it out. Advantages: quick, results can last for several weeks, and hair grows back no coarser than before. Disadvantages: painful; requires either special dexterity or salon services; hair must be long enough to attach to pulling substance; skin susceptible to irritation and infection. Facial bleach Hair is not removed, but bleached to blend in with the skin. Advantages: easy to apply at home, results last several weeks. Disadvantages: can be used only for fine hairs, such as over the lip. Cannot be used on dark skin. Can cause chemical burns. Depilatories Hair is dissolved by chemicals in a cream or spray, then washed away. Advantages: Simple procedure, results last longer than shaving, but not as long as waxing. Disadvantages: unpleasant odor, can cause irritation. Herbal creams Used in conjunction with hair removal, they slow the regrowth of hair. Creams containing herbs such as sanguisorba officinalis, bloodwort root, or Burnet extract have an astringent effect, causing a slight stanching of blood flow to the hair root. Advantages: easy to apply, usually gentle on skin. Disadvantages: the retardation of hair growth is slight, and some of the creams are very expensive. Electrolysis Conduction of an electrical current by needle into the hair shaft to the bulb. Advantages: Long-lasting, often for many months, and sometimes permanent. Disadvantages: painful, as each hair must be treated individually and sometimes repeatedly; expensive on a long-term basis; must be performed by a qualified electrologist. Laser hair removal Selective phototricholysis. A light source sufficient to penetrate to the follicular bulge and the papillae is directed at the hair by probe. Advantages: Painless; long-lasting, and in some cases permanent. Disadvantages: Most costly treatment, using expensive laser equipment; repeated treatments usually necessary. Must be performed by highly trained personnel; in some areas, by physicians. Results best when contrast between skin color and hair color is greatest. Some 70% of hair is removed with light-skinned, dark-haired patients, whereas only 10% are removed in blondes. What's permanent? There is currently no means to achieve total, lifelong hair removal. As indicated, hair removal can last from less than a day to several months. Although electrolysis and laser treatments hold out the hope for greatest permanency, even waxing and plucking can, with numerous treatments, result in sufficient traumatically induced inflammation to destroy the follicle. Which cosmetic treatment is “best?” This depends on the patient's preference, budget, and tolerance of discomfort. Shaving, waxing, or other means, do not make hair grow back faster or thicker. To numb the pain of hair removal, over-the-counter creams and sprays can be recommended. EMLA, a topical cream containing lidocaine and prilocaine, can be perscribed for extreme sensitivity or extensive treatments. Folliculitis infection, which can follow any mechanical means of hair removal, is caused by staph, and should be treated promptly with oral or topical antibiotics. Folliculitis, although it seems minor, can spread quickly and even require hospitalization. For recurrent folliculitis after shaving, it is advised that the patient shave with the grain of the hair, rather than against it. References 1.
1
Rittmaster RS.
Hirsutism.
Lancet. 1997;349:191–195.
CrossRef
2.
2
Falsetti L, Gambera A, Platto C, Legrenzi L.
Management of hirsutism.
Am J Clin Dermatol. 2000;2:89–99. MEDLINE |
CrossRef
3.
3
Carmina E.
Prevalence of idiopathic hirsutism.
Eur J Endocrinol. 1998;139:421–423. MEDLINE |
CrossRef
4.
4
Serafini P, Lobo RA.
Increased 5 alpha-reductase activity in idiopathic hirsutism.
Fertil Steril. 1985;43:74–78. MEDLINE 5.
5
Fitzpatrick TB, Johnson RA, Wolff K, Suurmond D.
Color atlas and synopsis of clinical dermatology.
New York: McGraw-Hill; 2001;. 6.
6
Coyne PE.
The eflornithine story.
N Engl J Med. 2001;45:784–786. 7.
7
Barman Balfour JA, McClellan K.
Topical eflornithine.
Am J Clin Dermatol. 2001;2:197–201. MEDLINE |
CrossRef
8.
8
Bristol-Myers Squibb. Vaniqa patient information leaflet. Buffalo, NY: September 2002 9.
9
Schrode K, Huber F, Staszak J, et al. Randomized, double-blind, vehicle-controlled safety and efficacy evaluation of eflornithine 15% cream in the treatment of women with excessive facial hair [poster]. American Academy of Dermatology 58th Annual Meeting, March 10–15, 2000, San Francisco, CA 10.
10
Hickman JG, Huber F, Palmisano M.
Human dermal safety studies with eflornithine HCl cream (Vaniqa), a novel treatment for excessive facial hair.
Curr Med Res Opin. 2001;16:235–244. MEDLINE |
CrossRef
11.
11
Bristol-Myers Squibb Company. Women throughout the US are trying Vaniqa® to help manage unwanted facial hair [press release, 2003]. http://www.bms.com/news/press/data/fg_press_release_1388.html a Department of Dermatology, Tel Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Israel  Sarah Brenner, M.D., Department of Dermatology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel
☆ About 70–80% of cases of hirsutism are androgen- dependent The enzyme 5 α-reductase plays a key pathophysiologic role in the growth of facial hair regardless of the patient's androgen profile Patients with hirsutism are often more fearful of its social than its medical impact If underlying systemic disease is present, pharmacological or surgical therapy is indicated The author states that there are no financial interests related to these products. PII: S1546-2501(04)00111-2 doi:10.1016/j.sram.2004.04.010 © 2004 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. | |
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