INTRODUCTION

Alopecia is a psychologically distressing condition. Androgenetic alopecia is the most common form of alopecia which affects millions of men and women; it is an androgen-driven disorder. Androgenetic alopecia is a process wherein continuous miniaturization of sensitive hair follicles takes place. The 5 -reductase type 2 enzyme plays a central role by intrafollicular conversion of testosterone to dihydrotestosterone, and hair loss is characterized by shortening of the anagen phase and miniaturization of hair follicles which results in thinner and shorter hair. For the treatment of androgen-related disorders like androgenetic alopecia, the synthetic steroidal drug finasteride has been approved by the US Food and Drug Administration for men. 1 Saw palmetto ( Serenoa repens ), a natural drug, has been investigated for androgen-related disorders like benign prostatic hyperplasia and male pattern baldness, as it has shown the properties of inhibiting 5 -reductase enzyme. 2 Natural products have been widely advocated in hair care industry, and the search for natural remedies is being continuously prmoted.

Androgen metabolism and hair growth

As stated above, androgens are necessary to develop AGA and the androgen metabolism within target cells is of crucial importance. The literature, however, on normal and pathologic androgen metabolism (AM) is

vast, and contradictory studies are a source of additional confusion. Here, some pivotal aspects of AM which are important for hair growth are reviewed. Androgen metabolism can be divided into glandular and extraglandular production, transport, target cell metabolism and cellular response. The synthesis of androgens is complex because it occurs in several organs, each of which has its own pecularities. The androgen metabolism of adrenals and gonads and the influence of the pituitary gland are beyond the scope of this review and are described in detail elsewhere Androgen synthesis begins with cholesterol which is converted to pregnenolone. Following a-hydroxylation at the C17-position, the action of the enzyme C17-20 lyase cleaves distal carbon moieties, leaving a C-19 carbon steroid with a C-17 ketone in the distal ring. These _17-ketosteroids_ make up a group of relatively weak androgens, such as dehydroepiandrosterone (DHEA), defined by their relatively low affinity for the androgen receptor. Approximately 75% of DHEA and 95% of dehydroepiandrosterone sulphate (DHEA-S) is derived from the adrenal gland. These weak androgens can be enzymatically converted to more potent androgens such as testosterone, which is the major circulating androgen. In the hair follicle the principial pathways involved in the conversion of weak to more potent androgens are through activity of the enzymes 3b-hydroxysteroid dehydrogenase D5fi4-isomerase (3b-HSD) and 17b-hydroxysteroid dehydrogenase (17b-HSD). In most target organs testosterone can be further metabolized to DHT via the action of 5a-reductase (Fig. 1). The affinity of DHT to the androgen receptor is approximately fivefold higher than that of testosterone. Potent androgens such as testosterone or DHT can be removed by conversion to weaker androgens, or they can be metabolized via the aromatase to oestrogens, or they can be glucuronidated to form androgen conjugates that are more rapidly cleared from the circulation.

Some target tissues show enhanced AM and androgen sensitivity.21 Circulating DHEA-S may be more rapidly metabolized to DHEA via steroid sulphatase. In turn DHEA may be more rapidly converted to androstenedione if increased 3b-HSD activity is present. Androstenedione may be converted to testosterone if 17b-HSD activity is present. If target cells convert weak androgens at an accelerated pace, then there will be enhanced conversion of testosterone to DHT. Another reason for increased sensitivity of a target to androgens is believed to involve an increase in the number of androgen receptors. Only a small fraction of androgens exist as free steroids in the circulation, with an equilibrium between free androgen hormone and protein-bound androgens. The most important protein for androgen binding is sex-hormone binding globulin (SHBG). Approximately 70% of testosterone is bound to SHBG, 19% to albumin and only the remainder is unbound. Whether the bound fractions are still metabolically active is a matter of controversy, but binding of androgens to SHBG is an important factor in AM because it acts somehow as a _sink_ for circulating testosteron Like all steroid hormones, androgens exert their effects by binding to an intracellular receptor, the androgen receptor. Binding of androgens to their androgen receptor leads to conformational change of the AR-androgen complex (ARAC) which is then transported into the nucleus where it can bind to regions of DNA that have distinctive binding sites known as androgen-responsive elements (ARE). A wide variety of proteins have this ARE encoded in their DNA. In this way androgens are able to modulate the transcription of various genes, that may be activated or suppressed. In summary, the AM is highly complex and can be tuned at various points, e.g. the amount of weak androgens present for conversion to more potent

androgens, the repertoire of metabolizing enzymes present in target cells, the ratio of conversion and backconversion, the concentration of SHBG in the serum, the affinity of androgens to the androgen receptor, etc. Furthermore, most target organs differ in their repertoire of metabolizing enzymes and this repertoire is different in men and women. Moreover, many metabolizing enzymes have isoenzymes with different tissue distribution, substrate affinity and enzymatic kinetics.

The principal elements of androgen metabolism

Androgen-dependent processes are not the result of the summation of the activity of individual metabolites, but are solely due to the binding of DHT and translocation of the receptor to the nucleus. This concept has been discussed for the development of benign prostate hyperplasia22 and is most likely valid for AGA as well. Therefore DHTdependent cell functions will only be initiated or amplified if: enough weak androgens are present for conversion; more potent androgens are formed via the action of 5a-reductase; the enzymatic activity of androgen inactivating enzymes is low, e.g. aromatase; conversion of weaker steroids to DHT takes places by, e.g. 3b-HSD or oxidative 3a-HSD; functionally active androgen receptors are present in high numbers. That this simplified concept is valid is nicely illustrated by mutations of androgen metabolizing genes, where often a lack of potent androgens leads to disturbed masculinization or to intersexuality(hoffman,germany).

1. Hair-follicle cycling and signaling molecules controlling hair growth

The hair-growth cycle: The hair follicle is subject
to constant turnover in the course of perpetual cycles through various stages of proliferation (anagen ), involution (catagen ), and resting (telogen ), with regeneration in the successive hair cycle (Fig. 1). It is a major characteristic of anagen that not only the hair shaft is growing but that most epithelial hair follicle compartments undergo proliferation, with the hair matrix keratinocytes located around the dermal papilla showing the highest proliferative activity. Also, the newly formed hair shaft is pigmented by the follicle pigmentary unit (Paus and Cotsarelis, 1999). During the following catagen stage of the hair cycle, hair follicles enter a highly controlled process of involution that is characterized by a burst of programmed cell death (apoptosis) in the majority of follicular keratinocytes, termination of pigment production, substantial extracellular matrix-remodeling, and condensation of the dermal papilla (Paus and Cotsarelis, 1999). The resulting shortening of the regressing epithelial strand is associated with an upward movement of the dermal papilla within the connective tissue sheath of the follicle. In telogen the hair shaft matures into a club hair, which is held tightly in the bulbous base of the follicular epithelium, before it is eventually shed from the follicle, usually as a result of combing or washing. It is still unresolved whether shedding of the telogen hair (teloptosis) is also an active, regulated process or represents a passive event that occurs at the onset of subsequent anagen, as the new hair grows in (Paus and Cotsarelis, 1999; Pierard-Franchimont and Pierard, 2001). There are considerable variations in length of these stages depending on the body site location, with the duration of anagen determining the type of hair produced, particularly its length (Paus and Cotsarelis, 1999). On the scalp, hairs remain in anagen for a 27-year

period of time, whereas that of telogen is 100 days, leading to a ratio of anagen to telogen hairs of approximately 9:1. On average the amount of new scalp hair formation essentially matches the amount that is lost due to shedding (approximately 100/day), thereby maintaining a consistent covering. Hair growth control: The controls that underlie the hair cycle reside within the hair follicle itself, and are believed to result from changes in the intra- and perifollicular expression of specific regulatory molecules and their receptors (Paus et al., 1999). Much circumstantial evidence suggests that the dermal papilla which is composed of specialized fibroblasts located at the base of the follicle, determines hair follicle growth characteristics, especially the regulation of cell proliferation and differentiation of hair follicle matrix: without papilla fibroblasts and an intimate contact with hair matrix keratinocytes anagen cannot be sustained. Also, hair follicle morphogenesis can be induced by implanting dermal papilla cells under an appropriately receptive epithelium (Jahoda et al., 1984). Finally, it has been shown that implanting few cells of follicle dermalsheath tissue from the scalp from an adult human male is sufficient to form new dermal papillae and induce new hair follicles in the skin of a genetically unrelated female (Reynolds et al., 1999). There is substantial evidence from bioassays that cultured dermal papilla cells can secrete a number of cytokines, growth factors and other, yet unidentified bioactive molecules that influence growth in other dermal papilla cells, outer root sheath cells, keratinocytes, and endothelial cells (Stenn et al., 1996). Finally, the hair cycle is subjected to cycle modulation by numerous extrinsic influences, such as androgens (Paus, 1996). Pathobiology of AGA: AGA is characterized by progressive shortening of the duration of anagen with successive hair cycles, leading to decreased numbers of hair in anagen at any given time, and progressive

follicular miniaturization with conversion of terminal to vellus-like follicles (Paus and Cotsarelis, 1999). The result is increased shedding of short-lived telogen hairs (telogen effluvium), while the affected hair follicles produce shorter, finer hairs that cover the scalp poorly. Since AGA involves a process of premature termination of anagen associated with premature entry into catagen, it is critically important to dissect the molecular controls of the anagen catagen transformation of the hair cycle (Paus, 1996). Catagen has been suggested to occur as a consequence of decreased expression of anagen maintaining factors, such as insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF), and increased expression of cytokines promoting apoptosis, such as transforming growth factor beta 1 (TGFb 1), interleukin1alpha (IL-1a), and tumor necrosis factor alpha (TNFa). Responses to androgens are obviously also intrinsic to the individual hair follicle: not only does the response vary from stimulation to inhibition of hair growth depending on the body site, but androgen sensitivity also varies within individual areas, i.e. regression in AGA occurs in a patterned, progressive manner. Since many extrinsic hair growth-modulatory factors, such as androgens (Randall et al., 1992), apparently operate at least in part via the dermal papilla, research is currently also focused on identifying androgen-regulated factors deriving from dermal papilla cells. Of the several factors that have been suggested to play a role in hair growth, so far only insulin-like growth factor (IGF-1) has been reported as altered in vitro by androgens (Itami et al., 1995), and stem cell factor (SCF) has been found to be produced in higher amounts by androgen-dependent beard cells than in control non-balding scalp cells, presumably also in response to androgens (Hibberts et al., 1996). Since

SCF is the ligand for the cell surface receptor c-kit on melanocytes, this may also play a role for hair pigmentation.

Pathogenesis
The three key features of androgenetic alopecia pathogenesis are alteration of hair cycle dynamics, follicular miniaturisation and inflammation. Hair cycle dynamics Hair growth is cyclical. The hair cycle has three phases (Figure 1): anagen growth phase, catagen involutional phase and the telogen resting phase [33]. Anagen lasts for 35 years, catagen 2 weeks and telogen 3 months. Thus the anagen to telogen hair count is usually in the order of 12:1. Hair shedding (exogen) occurs within the telogen phase and the sub-phase of telogen that follows exogen is called the latent phase [34]. In androgenetic alopecia, the duration of anagen decreases with each cycle, whereas the length of telogen remains constant or is prolonged. This results in a reduction of the anagen to telogen ratio [1]. Balding patients often describe periods of excessive hair shedding, most noticeable while combing or washing. This is due to the relative increase in numbers of follicles in telogen. As the hair growth rate remains relatively constant the duration of anagen growth determines

hair length. Thus, with each successively foreshortened hair cycle, the length of eachhair shaft is reduced. Ultimately, anagen duration becomes so short that the growing fails to achieve sufficient length to reach the surface of the skin, leaving an empty follicular pore. In androgenetic alopecia, the latent phase is prolonged, reducing hair numbers, further contributing to the balding process [34]. Hair follicle miniaturisation Hair follicles consist of mesenchymal and ectodermal components. The ectodermal part consists of an invagination of epidermis into the dermis and subcutaneous fat. The hair bulb contains the hair matrix which produces the hair shaft. The mesenchymal component is the dermal papilla, a small collection of specialised fibroblasts that is totally surrounded by the hair bulb. In association with the changes in hair cycle dynamics, there is progressive, stepwise miniaturisation of the entire follicular apparatus (Figure 2). As the dermal papilla is central in the maintenance and control of hair growth, it is likely to be the target of androgen-mediated events leading to miniaturisation and hair cycle changes [35-37]. The constant geometric relation between the dermal papilla size and the size of the hair matrix [38] suggests that the size of the dermal papilla determines the size of the hair bulb and ultimately the hair shaft produced [39]. A greater than tenfold reduction in overall cell numbers is likely to account for the decrease in hair follicular size [40]. The mechanism by which this decrease occurs is unexplained, and may be the result of either apoptotic cell death, decreased proliferation of keratinocytes [41], cell displacement with loss of cellular adhesion leading to dermal papilla fibroblasts dropping off into the dermis, or

migration of dermal papilla cells into the dermal sheath associated with the outer root sheath of the hair follicle [39]. In overall volumetric terms, change in the follicular extracellular matrix is unlikely to greatly affect follicular size. However, being a potential source of biologically active molecules, small changes in its volume may affect hair follicular function [40]. Smaller follicles result in finer hairs. The caliber of hair shafts reduces from 0.08 mm to less than 0.06 mm. This is also followed by a reduction in pigment production. On the balding scalp, transitional indeterminate hairs are the bridge between full-sized and miniaturised terminal hairs [42]. Traditional models of androgenetic alopecia show follicular miniaturization occurring in a stepwise fashion. This has recently been contested, and it is now believed that the transition fromterminal to vellus hair occurs as anabrupt, large step process [43]. Either way the crosssectional area of individual hair shafts remains constant throughout fully developed anagen [42], indicating that the hair follicle, and its dermal papilla, remain the same size. Therefore follicular miniaturization occurs between anagen cycles rather than within anagen. This short window of androgen effect may also explain the lengthy delay experienced between clinical response and the commencement of therapy, as any pharmacological intervention will only have effect at the point of miniaturization [42]. Follicular miniaturisation leaves behind stellae as dermal remnants of the full-sized follicle. These stellae, also known as fibrous tracts or streamers, extend from the subcutaneous tissue up the old follicular tract to the miniaturised hair and mark the formal position of the original

terminal follicle [44]. Arao-Perkins bodies can be seen with elastic stains within the follicular stellae. An Arao-Perkins body begins as a small cluster of elastic fibres in the neck of the dermal papilla. These are clumped in catagen and remain situated at the lowest point of origin of the follicular stellae. With the progressive shortening of anagen hair seen in androgenetic alopecia, multiple elastic clumps can be found in a stella, like the rungs of a ladder [45]. Review Figure 2 Androgentic alopecia involves progressive, stepwise miniturization of the entire hair follicle. Vol. 1, No. 4, pp. 319327, December 2004 323

Histopathology Histological diagnosis is rarely necessary for male androgenetic alopecia. In patients where the diagnosis is equivocal, 4 mm punch biopsies are the ideal specimen, taken from the Review Figure 3 Patterns of hair loss in male androgentic alopcia. 324 Vol. 1, No. 4, pp. 319327, December 2004 vertex of the scalp. Two biopsies should be taken and one sectioned horizontally and the other vertically. Horizontal sectioning yields much information on the number and types of follicles seen, facilitating more accurate diagnosis. The prime feature found in scalp biopsies is

the reduction in the terminal anagen hair count. The apparent reduction in the number of terminal hairs is due to progressive replacement of terminal hairs with secondary pseudovellus hairs with residual angiofibrotic tracts [55]. Horizontal sections reveal numerous pseudo-vellus hair follicles in the papillary dermis reflecting a miniaturisation process. Hairs are not destroyed. The presence of arrector pili muscle and angiofibrotic streamers distinguishes them from true vellus hairs. There is a change in the ratio of terminal to vellus hairs from greater than 6:1 to less than 4:1. Also, the anagen to telogen hair ratio reduces from 12:1 to 5:1 [45]. Others features that may be seen include follicular fibrosis and perifollicular inflammation. The fibrosis can be seen in around 10% of cases. However, fibrosis is seen in a small number of normal scalp biopsies as well. The inflammation consists of a mild to moderate peri-infundibular lymphohistiocytic inflammatory infiltrate. It is present in up to twothirds of biopsies [56], but is a non-specific feature that is also found in up to one-third of normal scalp biopsies [45]. Clinical syndrome
The clinical appearance of male androgenetic alopecia is universally and instantly recognizable in most cases. The progression of the hair loss occurs in an orderly manner and has been

well documented [46,56] (Figure 4). The main relevance of hair relates to socialization. Hair is an essential part of a persons self-image and the consequences of androgenetic alopecia are predominantly psychological. Several studies show that the negative selfperception of balding patients is consistent between Western [57,58] and Asian cultures [59]. The negative effect of androgenetic alopecia is often trivialized or ignored by unaffected people [60]. However, there is evidence that Review Figure 4 The Hamilton Norwood clinical grading scale for staging male androgentic alopecia. Vol. 1, No. 4, pp. 319327, December 2004 325 perception by others compounds the psychological problems suffered by balding men. A Korean study of the perception of balding men by women and non-balding men found that their negative perception of men with androgenetic alopecia was similar to the psychosocial effects reported by the patients themselves [59].Of note a perception of bald men looking less attractive was found in more than 90% of subjects surveyed. Importantly, this view was more common in women than non-balding men. Such negative perceptions may further impair the social functioning of balding men. It is important to note however, that most affected men cope well with androgenetic alopecia, without detriment to their psychosocial function. Thus those who do seek help are likely to be in greater emotional distress and have been dissatisfied with any treatment they have received to date.

The most distressed balding men are those with more extensive hair loss, those who have very early onset and those that deem their balding as progressive, often arising from observation of their father [57]. Review _ Male androgenetic alopecia is inherited as a complex polygenic trait _ Androgens and in particular dihydrotestosterone are necessary for the development of hair loss in predisposed men _ The type 2 isoenzyme of 5a-reductase converts testosterone into dihydrotestosterone _ Oral inhibitors of 5a-reductase arrest progression of androgenetic alopecia in over 90% of men and partially reverse it in over 65% _ Hair follicle response to androgens shows regional specificity, with vertex scalp follicles miniaturizing and beard follicles enlarging _ Androgen stimulation of scalp dermal papilla cells induces TGFb and androgen stimulation of beard dermal papilla cells produces IGF-2 as a second messenger.

Minoxidil for androgenetic alopecia Early studies testing low (2-3%) strength solutions of minoxidil for the treatment of AGA were promising.46,47 A 5-year follow-up for 31 men using 2% or 3% for AGA showed that hair regrowth tended to peak at 1 year, with a slow decline in regrowth, but that nonvellus hair, beyond that seen at baseline, was maintained at 4.5 to 5 years later.48 The topical use of 2% and 5% minoxidil demonstrated statistically significant increases in hair

weights compared with placebo.49 This study was done in four groups of nine men each (5%, 2%, vehicle alone, and placebo). The increase in hair counts was less significant, suggesting that the benefit is mostly maintaining and thickening preexisting hairs. Most dermatologists agree that greater hair growth can be achieved with the 5% solution. Indeed, a randomized, placebo controlled trial comparing the efficacy of topical 5% solution with topical 2% and placebo in men demonstrated 45% more hair growth at week 48 in the 5% group compared to the 2% group.50 Another randomized, placebo controlled trial comparing the efficacy of topical 5% solution with topical 2% and placebo in women Table I. Minoxidil: proposed mechanisms of action Vasodilatory properties16,38 Angiogenic properties17 Enhanced cell proliferation and DNA synthesis24,27 Potassium channel opener39,40 Antiandrogen effects41 Suppression of collagen synthesis42,43 Immunosuppressive effects32,35,36 Table II. Timeline for FDA approval of Rogaine solutions and foam FDA approvals of Rogaine (minoxidil) solution 1979Oral formulation approved by the FDA for severe hypertension 1988FDA approval for the 2% solution, with prescription, for hair loss in men with AGA 1992FDA approval for the 2% solution for hair loss in women 1996FDA approval for the 2% solution for OTC use in men and women with AGA 1997FDA approval for the 5% solution for OTC use in men, labeled as extra strength for men 2006FDA approval for the 5% foam for OTC use in men Rogaine is a trademark of Pfizer, Inc (New York, NY). AGA, Androgenetic alopecia; FDA, US Food and Drug Administration; OTC, over the counter.

J AM ACAD DERMATOL VOLUME 59, NUMBER 4 Rogers and Avram 549 demonstrated statistically significant increased hair growth in both the 5% and 2% group over the placebo group, but not necessarily in the 5% over the 2% group.51 There was an increased occurrence of pruritus, irritation, and hypertrichosis in the 5% versus the 2% group. Recently, minoxidil was developed into a 5% foam formula. A randomized, placebo controlled trial of 5% foam showed a statistically significant increase in (1) hair counts and (2) subjective assessment over placebo during a 16-week period of twice daily usage.52 The 1% solution has recently been proven effective in treating Asian women in a randomized, placebo controlled trial, where there was a statistically significant increase in nonvellus hair counts over placebo.53

FINASTERIDE The relationship of baldness with testosterone levels was observed by Hippocrates, who noticed that young male eunuchs did not develop hair loss.100 Male pattern baldness also does not occur in men with a genetic deficiency of the second isoenzyme of 5-a reductase.101 Both types I and II of 5-a reductase convert testosterone to dihydrotestosterone (DHT). Type I predominates in the skin, including the scalp, while type II is present in hair follicles and the prostate.102 The finasteride molecule (Fig 3) works by inhibiting type II 5-a reductase. This lowers serum and scalp levels of DHT while increasing scalp levels of testosterone103 (Fig 4). Table III summarizes the effect of finasteride on scalp and serum hormone levels. These effects on scalp and serum DHT and testosterone levels were demonstrated in 17 patients who underwent scalp biopsy before and after a 28-

day treatment with either placebo or finasteride 5mg daily.104 At baseline, DHT levels were higher in balder areas of the scalp compared to areas of the scalp that had hair, but there was no difference in testosterone levels. In the bald scalp of patients receiving finasteride, the mean DHT concentration decreased from 6.4 pmol/g at baseline to 3.62 J AM ACAD DERMATOL OCTOBER 2008 552 Rogers and Avram

3. Finasteride molecule

Fig 4. The 5-a reductase enzyme inhibits the conversion of testosterone to dihydrotestosterone

pmol/g. Scalp testosterone levels increased in 6 of 8 subjects treated with finasteride. Finasteride also decreased the mean serum DHT concentration from 1.36 nmol/L at baseline to 0.46 nmol/L on day 28, but serum testosterone levels were not affected. In a much larger study, 249 patients were randomized to placebo or finasteride at doses ranging from 0.01 to 5 mg/day, in an effort to understand the lowest possible dose that could affect scalp and serum DHT levels.105 They found that after 6 weeks, doses as low as 0.2 mg/day could significantly decrease scalp DHT levels by 60% to 75%. The serum testosterone levels were not significantly affected, and in any case have little to do with the balding process. Based on this evidence, investigators next investigated the optimal dosing for AGA, assuming it to be between 0.2 and 1 mg daily. The optimal dose of finasteride for male AGA has since been identified as 1 mg/day.106,107 FDA approval for this product was obtained in 1997 under the name Propecia (Merck & Co, Inc, Whitehouse Station, NJ). According to the product information, finasteride is metabolized extensively in the liver, and should be used with caution in patients who

have known liver abnormalities. However, no drug interactions of clinical importance have been recognized. It does not appear to affect the cytochrome P450-linked drug metabolizing enzyme. Patients treated with warfarin, digoxin, theophylline,

propranolol, and antipyrine have seen no clinically meaningful interactions.108,109 DUTASTERIDE Dutasteride (Fig 7) shares important characteristics with finasteride. While finasteride inhibits type II 5-a reductase, dutasteride inhibits both types I and II 5-a reductase isoenzymes.142 There is no isolated genetic deficiency of type I 5-a reductase to assess its role in male pattern hair loss. However, there is evidence that dutasteride is three times as potent as finasteride at inhibiting type II 5-a reductase and more than 100 times as potent at inhibiting the type I enzyme.143 This suggests enhanced efficacy over the existing finasteride. Because of these increased effects on the 5-a reductase enzymes, scalp and serum levels of DHT are more affected. Dutasteride can decrease serum DHT by more than 90%,143,144 while finasteride decreases serum DHT by 70%.104 One 4-year study of men on dutasteride 0.5 mg continuously for BPH showed a near complete suppression of serum DHT, decreasing by a mean of 93% from baseline.145 In comparison with dutasteride, finasteride reportedly reduces scalp DHT by only 34%104 to 41%.146 As with finasteride, inhibition of the 5-a reductase enzyme can increase levels of testosterone locally in the scalp. However, the increased efficacy means that it can also increase testosterone levels in the serum. The 4-year study above noted that serum testosterone rose by 25% from 3951.9 pg/mL to 4767.0 pg/mL.145 Minimal dose-dependent effects

on serum testosterone have been described for finasteride. An overview of these effects is provided

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Whiting, D.A., 1993. Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia. J. Am. Acad. Dermatol. 28, 755_/763.

Enrico CarminaJANUARY 2003 Treatment of hyperandrogenic alopecia in women

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