Dermatology Online Journal

A review of hormonal therapy for female pattern (androgenic) alopecia
Noah Scheinfeld
Dermatology Online Journal 14 (3): 1

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Abstract

Female pattern hair loss (female androgenetic alopecia) is a common, but puzzling, condition in women. Approximately 10 percent of pre-menopausal women show evidence of androgenetic alopecia. Age increases the incidence and 50-75 percent of women 65 years or older suffer from this condition. Only 2 percent topical mindoxidil is approved for treating female androgenetic alopecia. Reviews suggest that anti-hormonal therapy (e.g. cyproterone acetate, spironolactone) is helpful in treating female pattern alopecia in some women who have normal hormone levels. The use of hormonal therapies is most extensively studied in post-menopausal women. Several studies have suggested that cyproterone acetate with or without ethinyl estradiol and spironolactone can ameliorate female androgenetic alopecia in women with normal hormone levels, but larger controlled studies need to be done. Flutamide was found to be more effective than spironolactone or cyproterone in one study. Testosterone conversion inhibitors have been tried in post-menopausual women with normal hormone levels to treat alopecia. No study has shown that 1 mg of finasteride effectively treats female androgenetic alopecia but doses of 2.5 and 5 mg finasteride have helped some women in a few open studies. One case report notes the utility of dutasteride after finasteride failed. The role and place of anti-androgentic agents in female androgenetic alopecia in both pre and post-menopausal women remains to be fully defined. The need for effective agents is highlighted by the paucity of effective treatments and the substantial psychosocial impact of alopecia on women.

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Introduction

Female pattern hair loss, also called female androgenetic alopecia, is a common condition, but difficult to treat and to understand. It may be easiest to refer to it asfemale alopecia, which is meant to exclude any pathologic form of alopecia. The predominant manifestation involves a diffuse reduction in vertex hair density with retention of the frontal hairline. As many as 10 percent of pre-menopausal women reportedly have some evidence of androgenetic alopecia; however, the incidence increases greatly in menopausal women. As many as 50-75 percent of women 65 years or older may be affected by androgenetic alopecia [1, 2]. The only FDA approved treatment for female androgenetic alopecia is 2 percent topical minoxidil [3].

Women with female pattern hair loss manifest a decreased hair density with a normal distribution. Other factors, including hair diameter, may affect the subjective impression of hair loss [1, 2]. The hair diameter data suggest that low hair density is not due to gradual progressive diminution in hair follicle size and that follicular miniaturization may occur within the space of a single hair cycle [1, 2].

The role of hormones is hard to define in female alopecia. Scalp hair loss can occur as a result of hyperandrogenism in women, but most women with female pattern hair loss do not demonstrate clinical or biochemical evidence of androgen excess when tested [4]. Sebum excretion is not elevated in women with female pattern hair loss and does not suggest a role of excess androgens in female alopecia [5]. There is an increase in vellus follicle numbers with increasing severity of hair loss in women with female alopecia, suggesting but not demonstrating terminal follicle miniaturization [6]. There is a lack of significant changes in scalp hair follicle density with advancing age despite all the normal hormonal changes with age [7]. Familial history of androgenetic alopecia was also strongly associated with increased incidence of androgenetic alopecia [8]. It seems that there are androgen-dependent and androgen-independent mechanisms involved in the development of female alopecia [4]. It seems state androgenetic alopecia has systemic associations such as hypertension [9]. In addition, it seems that there is a subset of women with alopecia and normal hormone levels for whom hormonal intervention may be beneficial. This review will summarize the data that might help physicians engage in a discussion with patients about the role of anti-androgens in treating their female alopecia.

Conventional wisdom

The conventional wisdom of a number of reviews of alopecia in women in the 1990s was that anti-hormonal therapy (e.g. cyproterone acetate, spironolactone) was helpful in treating female alopecia in some women with normal hormone levels. Tosti stated that in mild to moderate androgenetic alopecia in women, oral anti-androgens (cyproterone acetate, spironolactone) and/or topical minoxidil can be used with good results in many cases [10]. Similarly, Callen stated that anti-androgen therapy will result in some improvement in up to 50 percent of patients after 6 to 12 months of therapy, but in practice will usually only decrease the rate of hair loss and not result in new hair growth [11].

Cyproterone acetate

Cyproterone acetate is an antiandrogen, i.e. it suppresses the actions of testosterone (and its metabolite dihydrotestosterone) on tissues. It acts by blocking androgen receptors, which prevents androgens from binding and suppresses luteinizing hormone release (which in turn reduces testosterone levels) [12]. Cyproterone acetate has weak progestational activity. Cyproterone acetate is used in dermatology as a treatment for acne, hirsutism, and less commonly for female alopecia, conditions which in some cases have a hormonal basis. Cyproterone acetate is approved for use in the European Union but not the United States.

Cyproterone acetate is taken alone on days 1 to 10 of the menstrual cycle (conventionally, day 1 is the first day of menstruation) as a pure hormone blocker (e.g. for the treatment of polycystic ovary syndrome) or with ethinyl estradiol as part of a birth control hormone-normalizing regimen. The combination is generally used in pre-menopausal women to prevent pregnancy and because cyproterone can cause menstrual irregularities. The combined treatment is not necessary in post-menopausal women [13]. Cyproterone acetate, as stated above, is not available in the United States.

Several studies have assessed cyproterone with ethinyl estradiol as a treatment for female alopecia. Rushton studied forty Caucasian pre-menopausal women aged 18 to 47 years. He treated twenty women for a period of 12 months in a reverse sequential regimen employing cyproterone acetate (CPA, 50 mg once daily from Day 5 to Day 15) and ethinyl estradiol (30 µgrams once daily from Day 5 to Day 24 of the menstrual cycle). The other 20 women were left untreated and acted as controls [14]. Half of each group had serum ferritin concentrations above or below 40 µgrams/l. Rushton found that patients treated with cyproterone acetate and ethinyl estradiol improved over controls and experienced the greatest improvement of their alopecia when their serum ferritin was greater than 40 µgrams/l.

Minoxidil

Vexiau studied sixty-six women with female pattern alopecia randomly assigning them into two groups: 33 received two local applications (2 mL day-1) of topical minoxidil 2 percent plus combined oral contraceptive and 33 received cyproterone acetate 52 mg day-1 plus ethinyl estradiol 35 µg for 20 of every 28 days for 12 cycles [15]. Minoxidil treatment was more effective in the absence of signs of hyperandrogenism, hyperseborrhea, menstrual cycle abnormalities, and high body mass index. In other words, it worked best when there were no signs of biochemical hyperandrogenism. In contrast, cyproterone acetate treatment was more effective in situations suggestive of biochemical hyperandrogenism, when hyperandrogenism, hyperseborrhea, menstrual cycle abnormalities, and elevated body mass were present.

Spironolactone

Spironolactone is a synthetic 17-lactone drug that is a renal competitive aldosterone antagonist in a class of pharmaceuticals called potassium-sparing diuretics. Spironolactone, which possesses anti-androgenic effects, is given in doses of 100-200 mg daily, most commonly in women over the age of 30 years. It has been used effectively as a treatment of acne, hirsutism, seborrheic dermatitis, and androgenetic alopecia. The dose of spironolactone is usually slowly increased from 50 to 200 mg daily and is taken at night. It may take six or more months to see improvement in any of these conditions [13].

An analog of spironactone, drospirenone, is available in birth control pills combined with ethinyl estradiol (Yaz® and Yasmin®). Yaz® provides an oral contraceptive regimen consisting of 24 active film coated tablets, each containing 3 mg of drospirenone and 20 µg of ethinyl estradiol stabilized by betadex as a clathrate (molecular inclusion complex). Yasmin® provides an oral contraceptive regimen consisting of 21 active film coated tablets, each containing 3 mg of drospirenone and 30 µg of ethinyl estradiol. Yaz® is approved for the treatement of acne.

The use of spironolactone for female alopecia has surprisingly few sources in the peer-reviewed literature [10, 11, 16, 17, 18, 19]. In an interesting case report, Hoedemaker noted a 53-year-old woman with clinical evidence of female pattern hair loss and histological evidence of androgenetic alopecia. Using serial scalp photography he documented hair regrowth with 12 months of the oral anti-androgen, spironolactone 200 mg daily. The regrowth plateaued at 24 months, but regrowth again increased with the addition of twice daily therapy with topical minoxidil 5 percent solution [18].

Spironolactone versus Cyproterone-no difference

Because spironolactone and cyproterone are the cornerstones of anti-androgenic therapy it is unsurprising that Sinclair et al. decided to compare them for the treatment of female alopecia [19]. Sinclair studied 80 women between 12 and 79 years of age. All had female alopecia and biopsy-confirmed hair follicle miniaturization [terminal/vellus (T/V) hair ratio ≤ 4 : 1]. Sinclair photographed at baseline and again after patients had received a minimum of 12 months of oral anti-androgen therapy. Forty women received spironolactone 200 mg daily and 40 women received cyproterone acetate, either 50 mg daily or 100 mg for 10 days per month if pre-menopausal. Sinclair excluded women using topical minoxidil. Sinclair found that there was no significant difference in the results or the trend between spironolactone and cyproterone acetate and combined the results.

Sinclair [19] found that 35 (44%) women had hair regrowth, 35 (44%) had no clear change in hair density before and after treatment, and 10 (12%) experienced continuing hair loss during the treatment period. Ordinal logistic regression analysis to identify predictors of response revealed no influence of patient age, menopause status, serum ferritin, serum hormone levels, clinical stage (Ludwig) or histological parameters such as T/V ratio or fibrosis. The only significant predictor was midscalp clinical grade; higher-scale values were associated with a greater response. Sinclair concluded that 88 percent of women receiving oral anti-androgens could expect to see no progression of their female alopecia or hair growth improvement.

Flutamide

Flutamide is an oral anti-androgen drug that primarily competes with testosterone and dihydrotestosterone for binding to androgen receptors. In the past, flutamide was used to treat prostate cancer [20]. Flutamide has largely been replaced by a newer member of this class, bicalutamide, due to a better side-effect profile.

Carmina and Lobo [21] performed a randomized, unmasked trial of three treatments over a period of 12 months: 1. cyproterone acetate (50 mg) with ethinyl estradiol (EE) in a reverse sequential regimen; 2. flutamide (250 mg); 3. finasteride (5 mg) daily). The study patients included 48 hyperandrogenic women with alopecia; 36 were treated and 12 were observed without treatment. Additional controls included 30 age- and weight-matched women without alopecia utilized for the assessment of androgen levels [21]. They assessed patients using Ludwig scores for hair thinning as well as patient and investigator assessments of treatment effectiveness. The use of flutamide resulted in a reduction of 21 percent in Ludwig scores (2.3 +/- 0.2 to 1.8 +/- 0.1). The other treatments showed no statistically significant improvement. Patient and investigator assessments showed a similar trend. Because flutamide is a very potent agent that has been primarily used as a cancer drug, it is not in common use by dermatologists. It is hard to know if it will find a place in female alopecia treatment.

Testosterone conversion blockers

Although testosterone and its more potent derivative, dihydrotestosterone (DHT) play a key role in male health and the health of men's hair (in particular as it pertains to male pattern baldness), the role of testosterone is confusing in female alopecia in the presence of normal hormones [22-27]. Limited evidence exists that testosterone-blocking agents effectively treat female type alopecia. Nevertheless testosterone likely has a role in the development of some female cases of alopecia.

Finasteride is a Type 2 isoenzyme five α reductase inhibitor that prevents the conversion of testosterone to dihydrotestosterone. Dutasteride inhibits both Type 1 and Type 2 isoenzymes of five α reductase thereby preventing the conversion of testosterone to dihydrotestosterone [22-27].

It seems that DHT has more effect on the hair in male pattern baldness than testosterone but the exact relative effect has yet to be fully defined on male hair. DHT was 2.4 times more potent than testosterone at maintaining normal prostate weight and duct lumen mass, a measure of epithelial cell function. The two androgens were equipotent at preventing DNA fragmentation and expression of testosterone-repressed prostate message, two measures of apoptosis (cell death) [28]. It should be noted that the package inserts for finasteride and dutasteride both state that pregnant women should not even handle pills of these medications.

The lack of effectiveness of testosterone blockers in female alopecia has a basis in experimental observation. Vierhapper [22] measured production rates of testosterone and of dihydrotestosterone in young women (n=8, age, 23 to 40 years) with female pattern hair loss using the stable isotope dilution technique and mass spectrometry. He infused 1 alpha,2 alpha-d-testosterone and 2,3,4-13C-dihydro-testosterone for 10 hours at a dose of 2 µg/h each and analyzed blood samples that he obtained at 20-minute intervals during the last 4 hours of the observation period [22]. Vierhapper [22] noted an increased presence of normal metabolic clearance rates, production rates of testosterone with infusions of DHT and testosterone as outlined above (9.4 ± 5.0 µg/h; normal, 4.3 ± 1.9 µg/h, P<0.05). Metabolic clearance rates of dihydrotestosterone (8.0 ± 3.4 L/h; normal, 25.9 ± 12.3 L/h, P<0.002) were subnormal in all women and the production rates of dihydrotestosterone were within or below the normal range (mean, 1.6 ± 0.6 µg/h; normal, 2.9 ± 1.1 µg/h, P<0.02). Vierhapper [22] concluded that women with female pattern baldness are characterized by increased production rates of testosterone, but not of dihydrotestosterone. This suggests that 5 α reductase inhibition should be of no therapeutical value in female-pattern baldness. However, systemic production rates were assessed and influences locally at the hair follicle level could be quite different.

It seems that finasteride 1 mg does not promote improvement in female alopecia in post-menopausal women. In a 1-year, double-blind, placebo-controlled, randomized, multicenter trial with 137 post-menopausal women (41-60 years of age), finasteride did not improve hair growth [22]. Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia was found in a large study by Price [23]. Similar results were found by Whiting who assessed scalp biopsies in 94 post-menopausal women, aged 41-60 years; 44 were taking finasteride 1 mg daily and 50 were taking placebo. There was no significant difference in follicular counts between the finasteride and placebo groups after 12 months of treatment [24]. However, pre-menopausal women were not studied. It is not known if there would have been any benefit in this group.

It is possible that doses of 2.5-5mg of finasteride might succeed where 1 mg failed. Iorizzo [25] assessed thirty-seven premenopausal women with female pattern hair loss who were treated with oral finasteride, 2.5 mg/d, while taking an oral contraceptive containing drospirenone and ethinyl estradiol. Global photography, the hair density score from videodermoscopy, and a self-administered questionnaire were used to assess treatment effectiveness [25]. At the 12-month follow-up, 23 of the 37 patients were rated as improved using global photography (12 were slightly improved, 8 were moderately improved, and 3 were greatly improved). No improvement was recorded in 13 patients. One patient experienced worsening of the condition. It is unclear whether the success in this study in contrast to studies using 1mg of finasteride was due to the higher dosage of finasteride (2.5 mg instead of 1 mg) or to its combination with the oral contraceptive containing drospirenone, which has an antiandrogenic effect.

Studies of other hormonally related conditions have given results consistent with the findings of Iorizzo. Kohler noted that finasteride 5 mg improved acne (n=6) and alopecia (n=6) in 9/12 female patients with normal serum levels of free testosterone [25].

Trueb found that in 5 postmenopausal women without clinical or laboratory signs of hyperandrogenism, 2.5 or 5 mg/day of oral finasteride for the treatment of pattern hair loss resulted in improvement documented by patient and investigator assessments. The study also included a review of photographs taken at baseline and at months 6, 12 and 18 by an expert panel [27].It is possible that dutasteride, which blocks both types of testosterone receptors, might help with female pattern alopecia. Olszewska reported a 46-year-old woman with androgenetic alopecia, non-responsive to minoxidil, who initially benefited from finasteride. Although finasteride ceased to be beneficial, a change to dutasteride promoted improvement documented by clinical evaluation, trichogram, and computer dermoscopy after 6 months of therapy. Evaluator and patient considered the condition to be cured after 9 months of treatment [29].

Conclusion

Female alopecia remains a challenging condition to treat. Many hormonal effects on hair growth are yet to be defined [30]. The psychosocial impact of alopecia on women is great [31, 32]. While the relative effect of DHT and testosterone have been determined in some tissues [28], it has yet to be fully elucidated in the hair. Although a handful reports note the effectiveness of anti-androgenic agents such as spironolactone and cyproterone acetate, large double blind, randomized studies are still needed to define the utility of these agents. It seems certain that finasteride 1mg is not useful for female alopecia, at least in post-menopausal women. The role of spironolactone, cyproterone acetate, flutamide, finasteride, and dutasteride remains almost wholly undefined in pre-menopausal women as these agents can have untoward effects menstrually and reproductively. In view of the substantial psychosocial impact of female alopecia (androgenetic alopecia) in pre-menopausual women, it is clear that patients should be informed about their possible benefit and appropriate trials designed to really assess their value.

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