JOURNAL REPORTS
At the request of many patients, I have posted the article which inspired the creation of the Xandrox products. The investigation of azelaic acid as a topical agent for the inhibition of DHT has been very educational and exciting. The effect of azelaic acid on the skin has been confirmed by many subsequent studies and an azelaic acid cream is available by prescription for the treatment of acne.
Although smaller amounts of azelaic acid could be used to obtain inhibition of DHT if zinc were added to the solution, the combination of azelaic acid and zinc has a short shelf life. A fine precipitate begins to form within a few days. Therefore, azelaic acid is incorporated into Xandrox in a concentration that completely inhibits all DHT synthesis due to type 1 and type 2 5-alpha reductase, allowing for the average 4% absorption to the level of the dermis of azelaic acid.
It is encouraging to know that, although Xandrox has been in wide use for less than six months, we have been innundated with positive reports from patients world-wide who are observing new hair growth by using Xandrox alone. The consensus seems to be that what the Journal Articles report is true. There is very close to 100% elimination of DHT where the Xandrox is applied.
Richard Lee, M.D.
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British Journal of Dermatology (1988) 119, 627-632.
Inhibition of 5a-reductase activity in human skin by zinc and azelaic acid
D. STAMATIADIS, MARIE-CLAIRE BULTEAU-PORTOIS AND IRENE MOWSZOWICZ
Laboratoire de Biochimie B, Hopital Necker-Enfants-Malades, Paris, France
SUMMARY
The effects of zinc sulphate and azelaic acid on 5a-reductase activity in human skin were studied using an in vitro assay with 1,2[3H]-testosterone as substrate. When added at concentrations of 3 or 9 mmol/l, zinc was a potent inhibitor of 5a-reductase activity. At high concentrations, zinc could completely inhibit the enzyme activity. Azelaic acid was also a potent inhibitor of 5a-reductase; inhibition was detectable at concentrations as low as 0.2 mmol/l and was complete at 3 mmol/l. An additive effect of the two inhibitors was observed. Vitamin B6 potentiated the inhibitory effect of zinc, but not of azelaic acid, suggesting that two different mechanisms are involved. When the three substances were added together at very low concentrations which had been shown to be ineffective alone, 90% inhibition of 5a-reductase activity was obtained. If this inhibition is confirmed in vivo, zinc sulphate combined with azelaic acid could be an effective agent in the treatment of androgen related pathology of human skin.
Skin is a target tissue for androgens and as a result increased androgen activity is accompanied by a well-defined skin pathology including hyperseborrhoea, acne and hirsutism or alopecia. In skin, as in many other target tissues, the reduction of testosterone to dihydro-testosterone (DHT) by the enzyme 5a-reductase is the most important of the enzymatic processes involved in androgen activity; indeed DHT is a more potent androgen than is testosterone, due to its greater affinity for the androgen receptor. The active DHT is formed at the target cell site and the enzyme 5a-reductase, therefore, acts as an amplifier of the androgen signal.1 DHT is generally considered responsible for the stimulation of the sebaceous gland2 and increased local formation of DHT has been documented in acne3 and in hirsutism.4 Any product capable of limiting local DHT production could represent, therefore, a potential therapeutic agent. The trace element zinc has been used in dermatology from the times of the Ancient Egyptians; only more recently has it been shown to reduce sebum secretion.5 In addition it is involved in numerous enzyme systems6 and has been reported to play a regulatory role in testosterone metabolism in the human prostate gland.7 We have previously shown that zinc can inhibit, in vitro, the 5a-reductase of human skin.8 Also, topical application of azelaic acid has been reported to have beneficial effects on acne vulgaris.9 In the present study we have examined the in vitro effects of zinc and azelaic acid on testosterone metabolism and in particular, on 5a-reductase activity.
METHODS
Materials
1,2[3H]-Testosterone (specific activity 60 mCi/mmol), [14C]-testosterone (specific activity 60 mCi/mmol), [14C]-dihydrotestosterone (specific activity 58 mCi/mmol) and [14C]-delta 4-andros tenedione (specific activity 57 mCiimmol) were obtained from Amersham, France and purified on celite columns before use. [14C] androstanediols (3 delta and 3 delta Adiols) were prepared by sodium borohydrate reduction of [14C]-DHT as previously described.10 Unlabelled steroids were purchased from Sigma (St. Louis, MO, U.S.A) and crystallized in methanol before use. Stock solutions (10 mmol/l) were prepared in ethanol and stored at 4ºC. NADPH was obtained from Boehringer Mannheim, France S.A. (Meylan) and diluted in buffer before use. All solvents and reagents were of analytical grade. Zinc sulphate, azelaic acid and pyridoxine (vitamin B6) were kindly provided by the Laboratoires Bailleul.
Tissue preparation
Foreskins from normal children (2-3 months old) undergoing circumcision were obtained, with informed consent from the parents, snap frozen in liquid nitrogen and stored at - 80ºC. They were then homogenized with a Polytron homogenizer (five 10s strokes) in ice-cold Krebs-Ringer phosphate buffer (120 mmol/l NaCl, 4.8 mmol/l KCl, 2.6 mmol/l CaCl2, 1.2 mmoI/l MgSO4), pH 6.4 and used as a source of 5a-reductase.
Enzymatic assays
The assay for 5a-reductase activity in human skin homogenates has been reported previously.11 Increasing concentrations of [3H]-testosterone (9, 10, 15, 20, 30, 50, 100 and 500 mmol/l) were evaporated in glass tubes and NADPH (2.4 mmol/1) diluted in buffer was added; the reaction was initiated by the addition of an amount of homogenate corresponding to 10 mg of tissue and the volume adjusted to 1 ml with buffer. Incubations were carried out in a Dubnoff metabolic incubator at 37 C for periods of 5 to 30 min and stopped by the rapid addition of 10 ml of ethyl acetate/cyclohexane 1:1 (v/v). After addition of [14Cl-steroids to monitor recovery and unlabelled tracers for easy visualization, the steroids were extracted and evaporated to dryness. Tubes without homogenates, but containing the same amount of substrate, buffer and cofactors were always incubated in parallel to determine blank values. The metabolites were separated by thin-layer chromatography on silica gel, in chloroform/methanol 97.5:2.5 (v/v) -Testosterone and delta 4-androstenedione were visualized under UV light (240 nm) and 5a-reduced steroids using iodine vapour. Steroids were scraped from the plate and eluted in ethanol and acetone. 3 a- and 3 beta-adiols, not separated in this system, were eluted together. Samples were counted in a Packard 300 C liquid scintillation spectrometer with an efficiency of 68 % for [14C] and 30% for [3H]. After correction for recovery and deduction of blank values, 5a-reductase activity was expressed as fmol (DHT + Adiols)/h/mg of tissue.
Effect of zinc and azelaic acid on 5a-reductase activity
Zinc sulphate was added to the incubation tubes at final concentrations of 0.5, 1.5, 3.9 or 15 mmol/l diluted in 100 microl buffer, and the assay was performed as described above. Azelaic acid was added at final concentrations of 0.1, 0.2, 0.5 or 3 mmol/1 diluted in 10 microl ethanol. The same amount of ethanol was also added to the control tubes. In some experiments, pyridoxine(vitamin B6) at a final concentration of 0.025% was also added to the incubation medium. These compounds were added separately or together in various concentrations in order to determine the minimal concentrations which gave a maximal inhibitory effect.
RESULTS
Preliminary experiments have shown that incubation for 5 min gave good estimates of the initial velocity of the reaction for substrate concentrations as low as 10 nmol/l (data not shown). We have used 20 nmol/l testosterone and 5 min incubations to study the effects of zinc and azelaic acid on 5a-reductase activity.
Effect of zinc and azelaic acid On 5a-reductase activity
The effects of increasing concentrations of zinc sulphate (1.5 to 15 mmol/1) and azelaic acid (0.1 to 3 mmol/l) on 5a-reductase activity were studied separately and the results are shown in Figure I. In both cases, there was a dose-dependent inhibition of the enzyme activity; 98% inhibition was observed with 15 mmol/l ZnSO4, and with 3 mmol/l azelaic acid. When the two compounds were added together to the incubation medium at concentrations expected to give 50-60% inhibition (3 mmol/1 and 0-5 mmol/l, respectively), 95% inhibition was observed (data not shown).
Effects of vitamin B6 on zinc and azelaic acid inhibition of 5a-reductase activity
The addition of vitamin B6 (0.025%) to zinc sulphate (1.5 or 3 mmol/l) resulted in a two-fold increase in the inhibition of the enzyme activity (Fig. 2a). In contrast, vitamin B6 had no effect on 5a-reductase activity when added alone or together with azelaic acid (Fig. 2b). These results suggest that zinc and azelaic acid might inhibit 5a-reductase activity through two different mechanisms.
FIGURE I. Effect of (a) ZnS04 and (b) azelaic acid (AA) on 5a-reductase activity in human skin homogenates. Results are expressed as percentages of controls without inhibitor. Values are means ± SD (n=6) 3H-T =3H-testosterone.
FIGURE 2. Effect of vitamin B6 (VB6) on (a) zinc sulphate and (b) azelaic acid (AA) inhibition Of 5a-reductase activity in human skin homogenates. Results are expressed as percentages of controls without inhibitor. Values are means
± SD (n = 5). [3H]-T = 3H-testosterone.
Effect of simultaneous addition of zinc, azelaic and vitamin B6 at low concentrations
The additive effect of the three compounds was studied in order to determine minimal concentrations which would effectively inhibit 5a-reductase activity. From the present results, the concentrations used (0.025% vitamin B6, 0.5 mmol/l ZnSO4, and 0.1 mmol/I azelaic acid) were expected to have a minimal effect, or no effect at all, on the enzyme activity. Vitamin B6 0.025% and azelaic acid at 0.1 mmol/l had no effect on the enzyme activity while ZnS04 at 0. 5 mmol/l gave less than 30% inhibition (Fig. 3). In contrast, when all three compounds were added together at these concentrations, 90% inhibition Of 5a-reductase activity is observed (Fig. 3).
DISCUSSION
Several previous studies have established the inhibitory action of zinc on the 5a-reductase of human prostate.7, 12, 13 We have shown previously that zinc has an inhibitory effect on 5a-reductase in human skin.8 The present study confirms this effect. In addition, since topical azelaic acid has been reported to have beneficial effects in acne vulgaris,14 we studied the effects of azelaic acid on 5a-reductase activity. The results have shown that azelaic acid is a potent in vitro inhibitor of this enzyme in skin homogenates.
The use of in vitro assays to evaluate the local anti-androgenic action of potential 5a-reductase inhibitors has been reported previously in the study of the inhibitory effect of progesterone.15,16 The main interest of these studies is that they enable the distinction to be made between a local and a systemic effect of the inhibitor. They are of particular value when the inhibitor can be applied topically, as is the case with zinc and azelaic acid, and therefore is less likely to exert systemic effects.
The purpose of the present study was to investigate 5a-reductase inhibition with a view to eventual application in physiological or pathological situations. As plasma testosterone levels vary from 2 nmol/I (women) to 20 nmol/l (men), it appeared pertinent to study zinc and azelaic acid inhibition of 5a-reductase activity at this range of substrate concentrations under conditions which allow a precise measurement of enzyme kinetics.
FIGURE 3. Effect of zinc sulphate, azelaic acid (AA) and vitamin B6 (VB6) alone and in combination on 5a-reductase activity in human skin homogenates. Results are expressed as percentages of controls without inhibitor. Values are means of duplicate determinations. [3H] -T = 3H-testosterone.
We have demonstrated a very large inhibition of 5a-reductase activity in the presence of ZnSO4, at concentrations of 3 to 15 mmol/l; 98% inhibition was obtained with the highest concentration. In the human prostate, physiological concentrations of zinc are about 0.2 mmoI/I and high correlation has been found between zinc concentration and 5a-reductase activity.17 However, a biphasic effect of zinc on 5a-reductase activity in the human prostate has been reported, with potentiation at low concentrations (0.1 micro mol/l) and inhibition at higher concentrations (3 to 300 mmol/l).7 This inhibition was shown to be non-competitive relative to testosterone, but competitive relative to NADPH formation. Our preliminary studies (data not shown) seemed to indicate that zinc at low concentrations (0.5 to 3 mmol/l) competitively inhibits 5a-reductase activity while at higher concentrations (3 to 15 mmol/l) it acts as a noncompetitive inhibitor. These results suggest that zinc at different concentrations may act by different mechanisms and that this metal ion interferes with different enzymes, since it also inhibits NADP reduction.
Dicarboxylic acids containing 8 to 13 carbon atoms undergo beta-oxidation and have been shown to be potent inhibitors of oxydoreductases. It has been proposed that azelaic acid could competitively occupy the NADPH-binding site of 5a-reductase thus resulting in inhibition of the enzyme.14 In our experiments, azelaic acid was a potent inhibitor Of 5a-reductase activity. When zinc and azelaic acid were added together, the effect of these two inhibitors was additive suggesting that they may act by two different mechanisms.
Pyridoxine (vitamin B6) is known to interfere with fat metabolism in the skin and, therefore, to play a role, like the androgens, in the regulation of sebum excretion.18 It improves acne lesions in adolescents19 and is more active on topical than on systemic administration.18 This led us to examine the combined effects of vitamin B6 and zinc. Interestingly, whereas vitamin B6 alone had no effect on 5a-reductase activity of human skin it strongly potentiated the inhibitory effect on zinc. In contrast, vitamin B6 did not potentiate the inhibition of 5a-reductase by azelaic acid. This further supports the hypothesis that zinc and azelaic acid act by two different mechanisms.
When the three substances were tested together, 90%, inhibition of the enzyme was obtained at very low concentrations which barely had any effect when tested separately.
If this inhibition is confirmed in vivo, a combination of these substances could provide an effective topical treatment for androgen related pathology of human skin.
ACKNOWLEDGMENTS
This work was supported in part by a grant from the Scientific Council of the Faculty of Medicine Pitie-Salpetriere, University Paris VI, France and by Bailleul Laboratories, Paris, France.
REFERENCES
1 Mauvais-Jarvis P, Kuttenn F, Mowszowicz I. Androgen metabolism in human skin: importance of dihydrotestosterone formation in normal and abnormal target cells. In: Androgenization in Women (Molinatti G, Martini L, James VHT, eds) New York, Raven Press, 1983; 47-63.
2 Takayasu S, Adachi K. The conversion of testosterone to 17 beta-hydroxy- 5a-androstan- 3 -one dihydrotestosterone by human hair follicles. J Clin Endocrinol Metabol 1972; 34: 1098-101.
3 Sansone G, Reisner RM. Differential rates of conversion of testosterone to dihydrotestosterone in acne and in normal human skin: a possible pathogenic factor in acne. J Invest Dermatol 1971; 56: 366-72.
4 Kuttenn F, Mowszowicz I, Schaison G, Mauvais-Jarvis P. Androgen production and skin metabolism in hirsutism. J Endocrinol 1977; 75: 83-91.
5 Demetree JW, Safer LF, Artis WM. The effect of zinc on sebum secretion rate. Acta Dermatovenerol, 1980; 60: 166-9
6 Prasad AS. Clinical, endocrinological and biochemical effects of zinc deficiency. Clinics Endocrinol, Metabol 1985; 14: 567-89.
7 Leake A, Chisholm GD, Habib FK. The effect of zinc on the 5a-reduction of testosterone by the hyperplastic hurnan prostate gland. J Steroid Biochem 1984; 20: 651-5.
8 Starnatiadis D, Bulteau-Portois MC, Mowszowicz I. Effet inhibiteur du Zn sur l'activite 5a-reductase de L humaine. Potentialisation par la vitamine B6. Nouvelles Dermatol 1987; 6: 601-3.
9 Nazzaro-Porro M, Passi S, Picardo M et al. Beneficial effect of 15% azelaic acid cream on acne vulgaris. Br J Dermatol 1983; 109: 45-48.
10 Mowszowicz I, Bardin CW. In vitro androgen metabolism in mouse kidney: high 3 keto-reductase (3-hydroxysteroid dehydrogenase) activity relative to 5a-reductase. Steroids 1974; 23: 793-807.
11 Kuttenn F, Mauvais-Jarvis P. Testosterone 5a-reduction in the skin of normal subjects and of patients with abnormal sex development. Acta Endocrinol 1975; 79: 164-76.
12 Wallace AM, Grant JK. Effects of zinc on androgen metabolism in human hyperplastic prostate. Biochem Soc Trans 1975; 3: 540-2
13 Habib FK. Zinc and the steroid endocrinology of the human prostate gland..J Steroid Biochem 1978; 9: 40
14 Breathnach AS, Nazzaro-Porro M, Passi S. Azelaic acid. Br J Dermatol 1984; 111: 115-20.
15 Mauvais-Jarvis P, Kuttenn F, Baudot N. Inhibition of testosterone conversion to dihydrotestosterone in men treated percutaneously by progesterone. J Clin Endocrinol Metabol 1974; 38: 142-7.
16 Vermorken AJM, Goos CMAA, Roelofs HMJ. A method for the evaluation of the local antiandrogenic action of 5a-reductase inhibitors on human skin. Br J Dermatol 1980; 102: 695-701.
17 Sinquin J, Morfin R, Charles JF, Floch, HH. Testosterone metabolism by homogenates of human prostates with benign hyperplasia: effect of tissue concentrations of zinc, magnesium and copper. J Steroid Biochem 1982; 17: 395-400.
18 Schreiner AW, Slinger W, Hawkins VR, Vilter RW. Seborrheic dermatitis; a local metabolic defect involving pyridoxine. J Lab Clin Med 1952; 40: 121-30.
19 Jollife N, Rosenblum LA, Sawhill J. The effects of pyridoxine (vitamin B6) on persistent adolescent acne..J Invest Dermatol 1942; 5: 143-8.
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The following presentation was given during the meeting entitled "New Therapeutic Approaches to Alopecia" on Saturday, 14 February 98. Dr. Janet Roberts addresses men and women with hair loss in a concise and precise article.
Richard Lee, M.D.
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Androgenetic Alopecia in Men and Women:
An Overview of Cause and Treatment
Janet L. Roberts
Hair loss is a cause of anxiety and distress in both men and women. New understanding of the causes of androgenetic alopecia is leading to potential new medical therapies. Pathophysiology, clinical presentations, diagnosis, current and future treatments are discussed.
Janet L. Roberts, MD, is Clinical Professor of Dermatology, Oregon Health Sciences University, Portland, OR; and is in Private Practice in Portland.
Objectives
This independent study offering is designed for health care professionals who care for and educate patients regarding androgenetic alopecia. After studying the information presented in this article, the reader will be able to:
A brief review of the anatomy of hair follicles and the continuous cycles they undergo will provide the basis for describing the alterations that occur in androgenetic alopecia. The hair follicle comprises the dermal papilla which invaginates into the base of the follicle where rapidly dividing matrix cells are located (see Figure 1). Matrix cells differentiate into the hair-shaft and several specialized layers. The rich environment of the dermal papilla provides nutrients and signals for differentiation and proliferation.
Figure 1. The hair follicle comprises the highly vascular dermal papilla and the rapidly dividing matrix cells, which differentiate into the hair shaft and supporting layers.
Each hair follicle undergoes continuous cycles of growth, rest, and regrowth. The timing of these phases varies from site to site on the body. The growth cycle is called the anagen phase which lasts from 2 to 8 or more years on the scalp. This is followed by a brief transition phase called the catagen phase lasting no more than 2 to 3 weeks, progressing into the telogen (resting) phase lasting 2 to 3 months on the human scalp. The hair then immediately begins a new anagen growth phase (see Figure 2).
Figure 2. The hair cycle comprises the growth phase (anagen), the brief transition phase (catagen), and the resting phase (telogen).
Clinical Presentation of Androgenetic Alopecia
Alopecia is a general term for hair loss and requires further description. Androgenetic alopecia (AGA) is the most common cause of hair loss, presenting as loss of hair over the top (vertex) of the scalp in affected men and women. AGA is associated with normal levels of estrogens and androgens in both men and women. The term androgenetic alopecia. denotes that both a genetic predisposition and the presence of androgens are necessary to cause expression. The specific mode of inheritance is not known.
Androgenetic Alopecia in Men
In men, androgenetic alopecia, also called male pattern hair loss, is
characterized by hair loss in the frontal and vertex areas of the scalp. Several patterns
are commonly recognized and classified according to the Hamilton (Hamilton, 1942) and
Norwood classifications (Norwood, 1975). These classifications are based on the degree of
hair thinning and the affected areas of the scalp (see Figure 3). AGA in men begins
anytime after onset of puberty.
Figure 3. The Hamilton/Norwood classifications of androgenetic alopecia in men.
Androgenetic Alopecia in Women
In women, androgenetic alopecia, also called female diffuse thinning, presents with more diffuse thinning in a mosaic pattern over the vertex of the scalp. The frontal hairline is usually retained. Occasionally there is a prominent triangle of thinning behind the retained frontal fringe (see Figure 4). Part width over the vertex is widened when compared to the back of the scalp (see Figures 5 and 6). Onset is generally in late 20s to 30s. The hair loss in women is usually less dramatic than that seen in men. Originally, the decrees of thinning were divided into three categories by Ludwig (1977) (see Figure 7). More recently, Savin (1994) devised a scale based on eight categories of density and part width over the vertex of the scalp. Affected women are not virilized. Onset and exacerbation of hair loss often occurs at times of hormonal upheavals such as puberty, postpartum, use of oral contraceptives and the early postmenopausal period. See Figures 8 and 9 for comparisons of AGA in men and women.
Prevalence
Approximately 20% of Caucasian men are affected by the age of 20 with incidence increasing 10% per decade. Fifty percent of Caucasian women are affected by age 50. Racial differences are noted with more Caucasians affected than Asian and Negroid races (Olsen, 1993).
Psychosocial Aspects
Recent studies on the quality of life in men and women with AGA show that loss of scalp hair can have major psychologic effects.
Figure 7 The Ludwig Scale for androgenetic alopecia in women. Classification is based on hair density over the vertex of the scalp.
Men with AGA may feel less attractive and older than their peers leading to diminished self-esteem, stress, anxiety, depression, and social inadequacy (Cash, 1992). Women with AGA have both social and emotional concerns. They may be frustrated at the time and trouble necessary to camouflage thinning hair and the inability to style their hair as they would like. They may feel self-conscious that others will notice hair loss, embarrassment, decreased self-esteem and jealousy of other women who are blessed with bountiful scalp hair (Cash, Price. & Savin 1993; Girman, Hartmaier, Roberts, Berafeld, & Waldstriecher, 1996).
Pathophysiology of Androgenetic Alopecia
Although the clinical presentation is different in men and women. the
underlying, cellular processes causing AGA are thought to be similar. AGA is caused by
androgens in both men and women. Androgens are produced in men by the testes and adrenal
glands. ln women, androgens are produced by the ovaries and adrenal glands. Androgens
produced peripherally by endocrine-sensitive hair follicles and sebaceous glands also
contribute significantly to circulating androgens in both men and women. All men and women
with AGA have normal levels of circulating androgens.
Figure 8 Diagram of miniaturization of scalp hair. Affected hairs get smaller and finer with each cycle.
The androgen dihydrotestosterone (DHT), a potent metabolite of the androgen testosterone (T), causes a gradual, progressive shrinkage in the length and caliber of genetically programmed hair follicles. This process is called miniaturization. Miniaturization results from shortening of the anagen phase and a decrease in the size of the dermal papilla and volume of matrix cells. Consequently, each succeeding hair cycle results in production of smaller, finer hairs which contribute less to the overall appearance and density of the hair (Messenger, 1993) (see Figure 8). Increased shedding of miniaturized hairs and minor inflammation, as manifested by seborrheic dermatitis, may occur.
These biochemical events occur at the cellular level of the hair follicle. Because the dermal papilla is highly vascular, it is continuously bathed in circulating androgens. It has been demonstrated that the dermal papilla is rich in androgen receptors and is the primary target of androgen action (Choudhry et al., 1996; Randall, Thornton, Hamada, & Messenger, 1992). Cells in genetically programmed hair follicles contain the enzyme 5 alpha-reductase (5 alpha R). 5 alpha R converts T into the more potent DHT (Chen, Zouboulis, & Orfanos, 1996) (see Figure 9). 5, R is found in higher quantities in the scalp follicles of affected men and women (Sawaya & Price 1997). Androgen receptors in the cells of the dermal papilla bind with circulating DHT, forming androgen-receptor complexes. These complexes are presented to binding sites on the DNA in the cell nuclei of the dermal papilla. Modified DNA sends messages via messenger RNA to the matrix cells, creating proteins to carry out the androgen effects of miniaturization on the hair follicle (Randall et al., 1992) (see Figure 10).
Aromatase, present in the outer root sheath of the hair follicle, is another enzyme that plays an important function in androgenetic alopecia. This enzyme converts testosterone and dihydrotestosterone back into estrogens. Aromatase is approximately six times more abundant on the female frontal scalp as compared to males, and may be responsible for the less severe expression of AGA in women (Sawaya. & Price, 1997). It may also explain retention of the anterior hairline in women.
Differential Diagnosis of Androgenetic Alopecia
In general, the clinical appearance and history of AGA in men is straightforward and does not present a diagnostic challenge. Because the pattern is more ambiguous in women, several other types of hair loss may mimic AGA and should be kept in mind when evaluating patients.
Telogen effluvium. Women are especially prone to increased shedding of telogen hairs from various physical insults, a condition called telogen effluvium. Acute and chronic illnesses, abrupt hormonal changes, iron and dietary protein deficiency, and many medications can all cause an increased shift of hairs into the telogen phase. The scalp should be checked for signs of scarring alopecia including inflammation, obliteration of follicular orifices, and atrophy. At a minimum, laboratory examinations, including thyroid and iron evaluation should be obtained. Serum ferritin levels are the most helpful: desired values are 40-300 ng/ml. Women with AGA having regular menses, normal fertility, and no stigmata of virilization do not require endocrinologic evaluation.
Treatments for Androgenetic Alopecia
Surgical treatments. Surgical treatments for AGA, including hair follicle transplantation, have been increasingly refined in the past several years and are beyond the scope of this article. Readers are referred to the September 1997 issue of Dermatologic Surgery for a complete review of this subject (Stough. 1997).
Medical treatments. Medical therapy for androgenetic alopecia can be divided into the following categories: (a) nonspecific promoters of hair growth, (b) topical and systemic anti-androgens, (c) 5-reductase inhibitors.
Nonspecffic promoters of hair growth. Minoxidil is the best known drug in this category. Minoxidil is an oral medication used to treat refractory hypertension. It was noted to cause hypertrichosis (increased nonsexual hair growth). Mechanism by which it stimulates hair growth is unknown. Clinical trials have shown that a 2% solution applied topically to the scalp can stimulate hair growth in some men and women. Fewer than 5% of patients have dense regrowth while approximately 30% have moderate regrowth (Olsen, Weiner, DeLong, & Pinnell. 1985; Roberts, 1987). Continued use is required to maintain hair growth. Currently, it is the only drug FDA approved for treating AGA*. Five-percent topical minoxidil solution has proven more effective than the 2% solution in men and has been approved by the FDA for sale over-the-counter in the United States.
Anti-androgens. This term describes topical or systemic drugs which reduce production of androgens, interfere with androgen metabolism or prevent androgen activity at target sites such as endocrine-sensitive hair follicles. Because systemic anti-androgens reduce circulating testosterone, which is required for normal male sexual functioning, their use is limited to women (Shaw, 1996). Numerous topical preparations, such as estrogen, progesterone, and cyoctol have not been thoroughly tested in clinical studies (Olsen, 1993).
Spironolactone is a potassium-sparing diuretic used for treating mild hypertension. Oral spironolactone is used fairly widely for treating women with AGA although literature documentation of efficacy is sparse. Spironolactone works by decreasing adrenal and ovarian androgen production. It also competes with T and DHT for androgen receptors in the hair follicle cells. Doses in the range of 100 to 200 mg are used. Side effects can include breast tenderness and menstrual irregularities. Women using spironolactone should be protected from pregnancy and have yearly Pap smears and mammograms (Shaw, 1996).
Oral contraceptive pills (OCP) decrease
production of ovarian androgens (Shaw, 1996). The progestin component also competes with T
and DHT for androgen-receptor binding in the hair follicles. Oral contraceptive pills can
be relatively estrogenic or androgenic. Estrogenic OCPs are suggested if used for women
with AGA (see Table 1).
5 alpha-reductase inhibitors. Drugs in this class work by inhibiting the enzyme 5, R, which limits the conversion of T to DHT (Chen et al., 1996). Finasteride is the first drug in this class trials in men. Finasteride has selective activity against 5and follicular DHT levels are , R. As a result, serum significantly reduced (Dallob et al., 1994). Finasteride has no androgenic or estrogenic hormonal activity. Because testosterone levels are not significantly affected, finasteride is not considered an anti-androgen and may be safely used in men.
Summary
Androgenetic alopecia occurs frequently in both men and women. It is caused by the action of dihydrotestosterone, a potent metabolite of testosterone on endocrine-sensitive hair follicles. It can be the cause of significant social and emotional distress. Dermatologists can help educate their androgenetic alopecia patients by understanding the clinical presentation, differential diagnosis, pathophysiology, and current and future therapies related to this condition.
* Since publication of this article, Propecia has been approved by the U.S. FDA for AGA.
References
Cash, T.F., Price, V.H., & Savin, R.C. (1993). Psychological effects of androgenetic alopecia on women: Comparisons with balding men and with female control subjects. Journal of the American Academy of Dermatology 29(4), 568-575, 926-931.
Cash, T.F. (1992). The psychological effects of androgenetic alopecia in men. Journal of the American Academy of Dermatology (26), 926-931.
Chen, W., Zouboulis, Ch.C., & Orfanos, C.E. (1996). The 5-reductase system and its inhibitors. Dermatology 193, 177-184.
Choudry, R.. Hodgins. M.B., Van der Kwast, TA, Brinkmann, A.O. & Boersma, W.J.A. (1992). Localization of aridrogen receptors in human skin by immunohistochernistry: lmplications for the hormonal regulation of hair growth, sebaceous glands and sweat glands. Journal of Endocrinology, 133, 467-475.
Dallob, A.L., Sadick, N.S., Unger, W., Lipert, S., Geissler. L.A., Gregoire, S.L., Nguyen. H.H., Moore, E.C., & Tanaka, VV.K. (1994). The effect of finasteride, a 5-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness. Journal of Clinical Endocinology and Metabolism, 79(3), 703-706.
Girman, C.J., Hartmaier, S., Roberts, J., Bergfeld, :W., & Waldstreicher, J. (1996). Patient-perceived importance of negative effects of androgenetic alopecia in women. Unpublished manuscript.
Hamilton, J.13. (1942). Male hormone is a prerequisite and an incitant in common baldness. American Journal of Anatomy, 71, 451-480.
Ludwig. E. (1977). Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. British Journal of Dermatology, 97,127-254.
Messenger, A.G. (1993). The control of hair growth: An overview. Journal of Investigative Dermatology, 101. 4S-9S.
Norwood, O.T. (1975). Male pattern baldness: Classification and incidence. Southern Medical Journal, 68,13591365.
Olsen, E.A., Weiner, M.S., Delong, E.R., & Pinnell, S. (1985). Topical minoxidil in early male pattern baldness. Journal of the American Academy of Dermatology. 13,185-192.
Olsen, E.A. (1993). Androgenetic alopecia. In E.A. Olsen (Ed.), Disorders of hair growth: Diagnosis and treatment (pp. 257-283). New York: McGraw-Hill, Inc.
Randall, V.A., Thornton, M.J., Hamada, K., & Messenger, A.G. (1992). Mechanism of action in cultured dermal papilla cells derived from human hair follicles with varying responses to androgens in vivo. The Journal of Investigative Dermatology 98(6), 8691.
Roberts, J. (1987). Androgenetic alopecia: Treatment with topical minoxidil. Journal of the American Academy of Dermatology, 16(3), 705-710.
Savin, R.C. (1994). Upjohn Dermatology Division. Kalamazoo, MI: Upjohn Company.
Sawaya, M.E., & Price, V.H. (1997). Different levels of 5 alpha-reductase type I & II, aromatase, and androgen receptors in hair follicles of women and men with androgenetic alopecia. The Journal of Investigative Dermatology, 10(3), 296-300.
Shaw, J.C. (1996). Antiandrogen therapy in dermatology. International Journal of Dermatology, 35(11), 770-776.
Stough, D. (Ed.). (1997). Special issue: Hair. Dermatologic Surgery, 23(9).
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Notes from the Second Intercontinental Meeting of Hair Research Societies November 5th-7th, 1998, Washington, D.C.
It was a distinguished group of close to 400 attendees from 37 different countries that contributed to the proceedings at the Second Intercontinental Meeting of Hair Research Societies. The well-organized meeting consisted of plenary sessions, keynote lectures, poster presentations and workshops on the following subjects: the hair cycle, research methods, hair follicle pigmentation and epithelial-mesenchymal interactions. In addition, informal events during lunch or dinner were planned according to interest groups.
The plenary sessions offered the opportunity for numerous researchers to present their current work and findings and, although most of the presentations were dismayingly esoteric, it was exhilarating to realize how much basic science research is taking place into the understanding of hair growth.
There are many gems of wisdom to be gleaned from the 25 or so presentations. Many of the findings have great implications for future research and development. Here are examples:
An estradiol applied to the skin of CD-1 mice can arrest follicles in telogen and produce a profound and prolonged inhibition of hair growth whereas treatments with a pure estrogen receptor antagonist causes the hair follicle to exit telogen and enter anagen, thereby initiating hair growth. The results attest to the complexity of estrogen receptor mediated signaling in hair follicle biology.
It's conceivable that the 5 alpha-reductase inhibitors used in the treatment of hair loss in alopecia androgenetica may also favor the metabolism of testosterone to estrogens.
There is new evidence that the human hair follicle dermal tissue can induce new fibre-producing follicles when transplanted to an alternative adult skin site. There is obvious significance in the evidence that male tissue was not rejected from the female skin, suggesting that the sheath dermis is immunologically privileged.
Dermal components retain the capacity to form an active dermal papilla after prolonged periods of time (36 days) in organ culture.
Hepatocyte growth factor stimulates hair follicle growth in organ cultures and mitogenic activity of hair matrix-derived cells and the topical application of minoxidil sulfate increased the expression of some of the molecules.
The poster presentations were available for viewing during the length of the meeting and often the authors were present to discuss their findings. In total, 93 posters were displayed and the information was often interesting, if not particularly surprising or new. Here are a few summaries, which may be of interest:
Alopecia areata-like hair loss has been observed in dogs, cats, horses, cattle, non-human primates, and rodent species. As in humans, the hair loss is non-scarring and reversible. Spontaneous remission occurs in all species.
Topical minoxidil was proven effective in 36% of patients with alopecia areata after 48 weeks of therapy.
Dermal papilla cells have recently been shown to possess the characteristics of androgen target cells.
The presence of 5 alpha-reductase isoenzymes within the human dermal papilla is still unclear, because different techniques to detect these isoenzymes gave conflicting results.
Minoxidil itself is not able to induce capillary fenestrations, but that it stimulates vascular endothelial growth factor expression by anagen hair bulbs and hair papilla, and as a result indirectly increases fenestrations in follicular capillary walls.
Randomized, double-blind trials support the superior efficacy of 5% minoxidil topical solution over 2% without major safety concerns.
Hair growth is largely unaffected in psoriasis.
Interleukin-1beta has been shown to be a potent inhibitor of hair growth in vitro and may be a pivotal factor in initiation of catagen.
Potassium channel openers such as diazoxide and minoxidil may promote unwanted hair growth as a side effect. The mechanisms by which potassium channel regulators affect hair growth are unclear.
There is evidence that minoxidil may have an anti-androgenic effect on hair follicles in both the beard and scalp.
Normal scalp dermal papilla cells medium stimulated both human and rat dermal papilla suggesting that the soluble mitogenic factors were able to act across the species difference. Balding cell media had less mitogenic ability. Therefore, balding cells either secrete some growth inhibitory factor(s) or fail to produce some stimulatory factor, which may well be involved in the process of alopecia androgenetica.
Topical application of liposome-entrapped molecules has the potential to modify hair growth, prevent hair loss, and restore hair color. The targeted liposome delivery demonstrated the feasibility of hair follicle gene therapy. Future experiments will utilize small molecules, proteins, and genes entrapped in liposomes to target the hair follicle for specific hair modification.
The first keynote lecture was given by Dr. Harold Slavkin on "Toward a Molecular Understanding of Epithelial Appendage Morphogenesis: Ectodermal Dysplasia-A Case Study" and drew inspiration from the ongoing work of unraveling and analyzing the human genome and the parallel mysteries between the developing hair bud and other normal and abnormal developmental embryonic problems.
The second keynote lecture by Dr. Lawrence Pinto was entitled "Identification of the Genes Involved in Complex Biological Systems: What We Have Learned from the Genetic Molecular Analysis of Circadian Rhythms". Although technically circadian rhythms pertain to biological cycles recurring at approximately 24-hour intervals (i.e. circa diem), there is exciting research into the regulatory factors that initiate or inhibit other cyclic biological phenomenon such as the hair growth cycle on the human scalp.
Some of the most productive and exciting times were spent in informal social settings talking to erudite and learned scientists and knowing that we were on the threshold of more exciting discoveries, many of which may be directly applicable to the treatment or cure of alopecia androgenetica. In fact, there are more than 50 patent pending products that deal with hair growth promotion, anti-androgens, blockage of DHT, topical immunosuppressants, etc. Ironically, it wasn't that long ago that the patent office summarily dismissed all claims for products that 'grew hair'.
The whole field of hair research is in its infancy. Twenty years ago, the medical/scientific community didn't seriously consider the subject. In the Second Intercontinental Meeting of Hair Research Societies, new findings and new questions will prompt the search for more information and understanding of a subject that's an important part of our everyday lives. The proceedings from the meeting will be available in a future issue of the Journal of Investigative Dermatology. We'll all look forward to the Third Intercontinental Meeting of Hair Research Societies in 2001 in Tokyo. See you there.
Richard Lee, M.D.
From: ARCHIVES OF DERMATOLOGY, Vol. 131, December 1995
Improvement in Androgenetic Alopecia
(Stage V)
Using Topical Minoxidil in a Retinoid Vehicle
and Oral Finasteride.
SECTION EDITOR: JUNE K. ROBINSON, MD;
ASSISTANT SECTION EDITORS: JEROME M. GARDEN, MD, AMY S. PALLER, MD
MAJ Douglas S. Walsh, MC, USA; CPT Cary L. Dunn, MC, USA;
COL William D. James,MC,USA; Walter Reed Medical Center, Washington DC
The Cutting Edge: Challenges in Medical and Surgical Therapeutics
REPORT OF A CASE----A 32-year old healthy
white man with androgenetic alopecia (AGA) (Hamilton-Norwood Stage V) of 10 years'
duration presented for therapy. The patient desired to pursue medical treatment only.
THERAPEUTIC CHALLENGE----To optimize the opportunity for hair regrowth in a patient with advanced, extensive AGA using non-surgical intervention.
Figure 1. Pretreatment photographs reveal extensive frontoparietal
(left) and vertex (right) balding consistent with Hamilton-Norwood
stage V androgenetic alopecia.
THE SOLUTION----Following informed consent, the patient agreed to a 6- to 12-month trial of topical minoxidil in an optimized retinoid vehicle applied twice per day and 5 mg of finasteride taken orally each day. The topical solution was prepared as follows:
Minoxidil tablets were dissolved in distilled water, polyethylene glycol, and absolute ethanol (volume ratio, 20:30:50, respectively) to a final minoxidil concentration of 3.75% (grams per deciliter). Following filtration, the 3.75% minoxidil solution was combined with 0.05% tretinoin (4:1 vol/vol) for final concentrations of 3% minoxidil and 0.01% tretinoin. The preparation was stored at room temperature and protected from light.
Each application consisted of 1 ml of solution (0.03 g of minoxidil) applied to the bald scalp with gentle fingertip massage. The patient was compliant, and no side effects were observed.
Figure 1. Left, Five months following initiation of treatment with topical minoxidil
and tretinoin and oral finasteride reveals a marked increase in terminal hair density
over the parietal and vertex areas, respectively. Mild improvement is noted in the
extreme frontal area. Right, Seven months following initiation of treatment with
topical minoxidil and tretinoin and oral finasteride reveals a marked increase in
terminal hair density over the area of the vertex.
Increased terminal hair growth on the scalp was initially observed after only 3 months of therapy, especially over the area of the crown and vertex. Following 5 months of therapy, marked improvement was noted over the parietal region. Striking terminal hair growth continued in the region of the crown and vertex. After 8 months of therapy, some growth in the extreme frontal area was noted, while the crown, vertex, and parietal areas continued to increase the terminal hair density.
The patient chose to discontinue oral finasteride therapy after 8 months because his cosmetic objective had been met. The patient has continued the topical therapy with minoxidil and tretinoin for approximately 4 months with continued gradual improvement. No thinning or shedding has been observed.
After a total of 12 months of therapy, the patient's AGA has improved from stage V, pretreatment to stage III.
THE COMMENTARY----Topical minoxidil is the ONLY therapy approved for AGA by the US Food and Drug Administration.(1) Recent studies using combinations of minoxidil and the oral 5a-reductase inhibitor finasteride in the stumptailed macaque (an animal model of AGA) have proven more effective in preventing the onset and progression of alopecia than either agent used alone. (1,2) Human trials using combinations of finasteride and minoxidil to alter AGA are currently underway. (1,3)
The pathogenesis of AGA involves increased scalp follicle susceptibility to androgens. (1) Scalp follicles in AGA contain increased levels and activity of 5a-reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT). (1) DHT shortens the hair cycle and miniaturizes scalp follicles. (1) Other sites of body hair are testosterone independent and, thus, do not exhibit AGA patterns.
5a-reductase in the prostate increase levels of DHT and clinically manifests as benign prostatic hypertrophy.(3) Recently, oral finasteride was found to decrease the level of DHT in bald scalps to the level found in hairy scalps, suggesting a potential use in the therapy of AGA. (3)
Two isoenzymes of 5a-reductase occur in
humans: type 1 is predominantly found in the skin of the scalp, and type 2 is primarily
found in the prostate. Finasteride effectively inhibits type 2 5a-reductase with little
activity against type 1 5a-reductase.(3) A daily dose of 5 mg lowers serum DHT levels by
65% to 80% and prostatic DHT by 85%.(3) Because of its selective inhibition of the type 2
isoenzyme, the observed decrease in scalp DHT is puzzling. The scalp is highly
vascularized and may be influenced by decreased levels of circulating DHT.
Long term therapy with finasteride may progressively inhibit the type 1 isoenzyme, as suggested by in vitro studies showing high dose finasteride inhibition of type 1 isoenzyme.(4) Although type 1 5a-reductase is the dominant enzyme form in the scalp, the fact that AGA does not develop in men with congenital 5a-reductase deficiency (defective type 2 5a-reductase only) suggests a role for type 2 5a-reductase in AGA.(4)
It is not known if inhibition of both 5a-reductase isoenzyme types are necessary to promote hair growth. Finasteride was shown to be nearly as effective in animal models of AGA as N,N-diethyl-4-methyl-3-oxo-4-aza-5a-androstane-17B carboxamide, an inhibitor of both isoenzyme types, suggesting that inhibition of only a single isoenzyme type may be sufficient for preventing AGA.(4) Prolonged exposure to finasteride may be necessary for clinical effectiveness; 6 months of treatment is required for maximal response in benign prostatic hypertrophy, and a similar gradual response pattern may occur in AGA.
Minoxidil is an antihypertensive agent approved as a topical agent for AGA.(1) Although minoxidil dilates peripheral arterioles when taken systemically, the mechanism of stimulating hair growth is not understood. Minoxidil increases cutaneous blood flow when applied topically.(5) However, other topical vasodilators have been unsuccessful in stimulating hair growth. It is likely that minoxidil has a direct effect on hair growth, perhaps by stimulating dermal papillae or follicular hair matrix cells.(5)
Simultaneous administration of topical minoxidil with tretinoin may enhance the response of AGA to minoxidil. (6,7) Possible mechanisms include epithelial and vascular proliferation and increased minoxidil absorption through the alteration of the stratum corneum barrier. Both phenomena have been observed experimentally.(7) Indeed, cotreatment with tretinoin resulted in a threefold increase in cutaneous minoxidil absorption compared with a control vehicle without observed side effects.(7)
We were encouraged by the improvement in frontal scalp alopecia in our patient. Most studies using minoxidil alone report response primarily in the area of the vertex.(1) Although this patient underwent follow-up by subjective assessment only, the goal of improving cosmetic appearance was achieved. The efficacy and rate of improvement in this patient may have reflected the 'unopposed' action of minoxidil on hair follicles in the setting of lowered levels of DHT. The response may have also been potentiated by the administration of tretinoin, known to enhance minoxidil absorption, follicle differentiation, and dermal vessel formation.(5-7) Randomized clinical trials will determine if these agents are synergistic in the treatment of AGA.
Finasteride was introduced in 1989 and has demonstrated few adverse effects.(3) Untoward effects occur in fewer than 5% of patients and usually relate to decreased libido and impotence. Up to a 25% reduction in semen volume can be expected in some patients without any changes in sperm counts, motility, or morphologic features.(3) The dose taken for benign prostatic hypertrophy does not effect other hormones, serum lipids, or bone density.(3) Finasteride lowers serum levels of prostate-specific antigen, a laboratory test used to monitor benign prostatic hypertrophy and screen for prostate cancer, since elevated prostate-specific antigen levels occur in both benign prostatic hypertrophy and prostate cancer.
Finasteride may have value in treating acne and hirsutism.(3) Although a 5a-reductase inhibitor should have no adverse hormonal effects in women, ambiguous genitalia might develop in a male fetus exposed to this compound.(3) Finasteride is found in semen, but the levels do not appear to be sufficient to harm a male fetus.(3)
We report a case of extensive AGA in which
topical minoxidil and tretinoin and oral finasteride provided an effective combination
therapy. This regimen should be considered in those patients with mild to moderate AGA who
desire medical therapy following informed consent.
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense.
We thank Albert Szkutnik for thoughtful advice and the preparation of the minoxidil-tretinoin solution.
THE REFERENCES---
_________________________________________________________________________________________________________________
Telogen Effluvium (Including
Postnatal, Postfebrile, Postpartum,
and Heparinoid Alopecia)
Unit 2-35: TOXIC AND PHYSIOLOGIC ALOPECIA Vol. 1 Section 2: DISEASES OF HAIR
The separation of this form of diffuse hair loss as a distinct pathogenetic disorder has only been accomplished in this century. Appreciation of this condition has been dependent on the establishment of methods for qualitative and quantitative evaluation of statistically significant numbers of hairs from an individual scalp; manual epilation and low-power microscopic examination of approximately 100 hairs as introduced by Van Scott and co-workers1 has proved to be reasonably atraumatic and effective diagnostically and prognostically, particularly in telogen and anagen alopecias.
INCIDENCE
Telogen alopecia (along with male-pattern baldness) surely represents the most common type of alopecia. Postnatal and postpartum alopecias affect virtually all children and probably the majority of parturient women, although the latter may be so minimally affected as to escape clinical notice. Prevalence of postfebrile alopecia is not known, although "epidemics" have been noted, for example, during the 1918 flu epidemic.2 Telogen effluvium also follows discontinuation of oral contraceptives, which is analogous to the well-recognized postpartum shedding. Because this form of hair loss represents in effect an acceleration of a normal and disease states will tend to overlap considerably.
CLINICAL MANIFESTATIONS, CAUSE, AND PROGNOOSIS
The characteristic feature of telogen alopecia is a latent period of several weeks between the inciting event and clinical hair loss. The data of Schiff and Kern3 concerning onset of hair loss following delivery can be represented graphically to follow a reasonable facsimile of a bell-shaped curve, with about one half of 98 cases beginning at 11 to 13 weeks. This agrees well with the often-stipulated 3-month interval (the normal average duration of retention of telogen hair in the scalp), but variation from 4 to 16 weeks should be expected. Onset within a few days of pregnancy, however, suggests the possibility of a concomitant or antecedent process compounding the event.
Complaints of clinical alopecia will vary with the sensitivity of the affected woman to the process and her concern with cosmetic appearance. This may be particularly frustration to the examining physician, because true increase in rate of loss of telogen hairs may be exceedingly difficult to detect. It must be remembered that about 50 hairs are lost from the average scalp per day. If this rate is increased to 150 per day, for example, and the scalp contains 100,000 or more hairs, the amount of hair lost over an entire week will be only about 1%. If these hairs are lost from follicles distributed randomly over the scalp, clinical detection of alopecia may be impossible; yet the patient is losing hair at three times the normal rate and may be justifiably concerned. This is true of all type of telogen alopecia.
The loss of hair is sometimes partially patterned rather than randomly diffuse and tends to follow the frontal distribution typical of male baldness. This is particularly true of the normal postnatal shedding observed in virtually all infants.4 This little-studied and apparently universal phenomenon of infant development is better known to mothers than physicians. Justification for this medical lack of interest presumably is based on the temporary nature of the process and complete restitution of normal scalp hair by the end of the first year of life.
All these processes may be regarded as physiologic and consequent to premature induction of the normal hair cycle termination without apparent pathologic implication. In addition, exogenous administration or accidental ingestion of anticoagulants (heparin, heparinoids, coumarin), gold compounds, and propranolol, causes telogen effluvium. The effect is believed to be related to dose - not duration of therapy.5
Although usually secondary to therapeutic administration, accidental poisoning with warfarin can result in the same process. The clinical features are identical with the other cases of telogen alopecia, that is, a diffuse hair loss with clinical severity dependent on a rate of loss, percentage of hairs converted to telogen, and extent of passive removal by manipulations such as excessive brushing.
Telogen alopecia from medication causes diffuse hair loss or predominantly frontal shedding. The hair may not be shed until 3 months after starting the causative medication.
Some instances of alopecia cannot be related to specific physiologic or toxic events. Many observers have noted severe diffuse alopecia occurring in apparently temporal relation to severe antecedent emotional trauma.
The duration of telogen alopecia is somewhat variable, but complete restitution invariably occurs unless another pathologic process supervenes. In one series of subjects with postpartum alopecia, 56 or 98 patients returned to normal in 5 or 6 months. Apparently a few cases may persist for 1 or more years, but this is a distinct exception. It is difficult to assess reports of post-infectious alopecias persisting for years. In the usual case, assurance of complete return to normal with 1 year is entirely warranted.
The relationship of postpartum alopecia to recurrent pregnancies is of prognostic (and possibly pathogenetic) interest. Schiff and Kern stated that a new pregnancy established in the early postpartum period (prior to second menses) was not followed by alopecia.
ETIOLOGY AND PATHOGENESIS
Postpartum hair loss represents an apparent delay during the third trimester in the normal rate of anagen-telogen conversion. Those hairs that would have normally converted during this period apparently do so only after release from the hormonal alterations of pregnancy, resulting in a temporary increase in the number converted to telogen hairs during the postpartum period. This interpretation is based on the observation by Lynfield7 of an increased percentage of anagen hairs before delivery and a significant decrease (or increase in telogen) after delivery. The precise hormonal mechanism is unknown, although Lynfield cites the know influence of estrogen on prolonging the anagen stage.
The mechanism of postfebrile alopecia is unknown. Although clinical impressions would suggest that a major elevation of temperature is necessary there is no good quantitative evidence to support this supposition. Similarly, the induction of telogen alopecia by heparin and related compounds occurs by an unknown mechanism. The ability to produce telogen alopecia by purposeful prescription of known agents that in proper doses do not cause serious systemic toxicity provides unique opportunity for studies of pathogenesis. The interesting observation of an inconstant perivascular collagenous degeneration similar to that notes in alopecia areata8 and certain cicatricial alopecias9 requires additional investigation for appropriate interpretation.
DIAGNOSIS
The diagnosis of telogen alopecia, although reasonably evident from history in most cases, can be directly confirmed by identification of all shed hairs as morphologically normal telogen hairs by observation of a greatly increased number of telogen hairs (decreased anagen - telogen ratio) in the scalp, as reflected in a sample of epilated hairs. It must be emphasized, however, that even an anagen-telogen count must be interpreted with caution. A count late in the course of anagen alopecia when most growing hairs have already been lost would reveal a high proportion of telogen hairs by epilation: both experience and constant referral to the person are mandatory.
DIFFERENTIAL DIAGNOSIS
Diffuse nonpatterned alopecia will not normally be confused with any of the patchy or cicatricizing processes. In telogen effluvium the scalp skin is entirely normal, as are the hair shafts. Differentiation from (acute) anagen alopecia is generally not difficult. When all anagen hairs are severely damaged, 90% or more of the scalp hairs may be lost in a short time. Telogen alopecia by contrast rarely results in loss of more than 50% of scalp hair. Even this gross loss may be remarkably unspectacular clinically, particularly if the remaining hair is long and tends to mask the thinning. Observations of the hair roots will reveal characteristic differences in anagen or telogen alopecias. Hairs damaged in anagen will show specific morphologic dysplastic alterations. Hairs lost in telogen alopecia are morphologically normal resting hairs.
The situation may be more confusing when an agent responsible for anagen alopecia is delivered slowly rather than rapidly, as for example chronic ingestion of small amounts of a toxin. Similarly, smaller doses of a cancer chemotherapeutic agent may result in entirely reversible matrix inhibition or only a small percentage of visibly affected hairs. The magnitude of hair loss in such instances may be more similar to that in telogen alopecia than to gross loss of acute toxic anagen alopecia. Careful observation of spontaneously and manually epilated hairs should detect characteristic constrictions, breaks, or atrophic hairs in the latter instances.
Telogen alopecia resulting in male-pattern hair loss can be readily overlooked in the male; in the female it is less likely ignored. The etiology of male-pattern baldness in women is often obscure, but search for causes of underlying telogen alopecia is appropriate.
TREATMENT
There is no effective treatment for telogen alopecia. Careful explanation of cause and favorable prognosis, together with instructions to preserve as many telogen hairs in the scalp as possible by avoidance of manipulation until new growth has progressed, should be routine.
Anagen Alopecia (Toxic Effluvium)
The greater sensitivity of actively growing (anagen) hairs, in contrast to resting hair, to a variety of toxic chemical or physical agents has been appreciated for many decades. Indeed, x-ray (or thallium) epilation to rid the scalp of fungus infections was standard therapy. The development of pharmaceutical agents with known toxicity manifest primarily on rapidly proliferating tissues will produce anagen alopecia for many years to come. In addition, accidental exposure to poisons or natural products provides occasional cases.
INCIDENCE
Anagen alopecia is far less common than the telogen form, which occurs as a nearly normal physiologic event in postnatal and postpartum periods (although not necessarily clinically manifest). Since all the clear-cut anagen alopecias represent exposure to exogenous substances or events, their occurrence will be sporadic and in proportion to exposure. Accidental exposure is particularly likely to occur in children. Although one could probably demonstrate a statistical predilection for females if all ages were considered, this would almost undoubtedly reflect the relative psychologic importance of scalp hair to women and their desire to seek medical help. Obviously, the high prevalence of male baldness would correspondingly decrease clinically demonstrable anagen alopecia in the population of older men.
ETIOLOGY AND PATHOGENESIS
A large number of elements or compounds are known to affect anagen hairs, and alopecia results from exposure to toxic chemicals encountered iatrogenically, accidentally, occupationally, or in cosmetics.10,11 Anagen effluvium follows poisoning by thallium, mercury, and borates as well as treatment for anticancer medications, vitamin A, retinoids, and cantharidin, which act by cytotoxic inhibition of the highly proliferative hair matrix. Salts of lead, mercury, selenium, and arsenic are also incriminated. Methotrexate has been shown to cause a reversible atrophy of anagen hair bulb proportionate to dose,1 and the effect is impressed on the hair shaft as a progressive construction.12 Systematic investigation of x-ray- and antimetabolite-induced anagen alopecia must be credited primarily to Van Scott, 1,13 although anagen (and telogen) hair sensitivity to x-irradiation was documented as early as 1926 and the anatomic peculiarities of affected anagen hairs described in 1906. These historical aspects of x-ray alopecia are reviewed by Flesh.2 Temporary epilation after 300 R but permanent alopecia after 500 R or more has been attributed to damage to the mesodermal hair papilla with the larger doses. Graded response to doses of x-ray less than 300 R was demonstrated quantitatively by Van Scott and co-workers,1 who indicated that the number of affected (dysplastic) hairs was proportionate to dose and length of time after exposure. The morphologic alterations included diminution of diameter of the matrix, which generally progressed to severe atrophy and death of the hair root. Occasionally, a hair could be found whose matrix had recovered and was producing a new hair shaft, with the constricted area being propagated outward in advance of apparently normal hair development. This reversible effect after x-ray is distinctly uncommon, with lesser doses being reflected in smaller number of hairs affected rather than lesser degree of dysplasia. This situation may be contrasted to the effect of the antifollic acid compound methotrexate which was found to result in reversible atrophy of the hair bulb in proportion to the dose of the drug. With recovery of the hair root, the defect was propagated distally as a construction in the shaft. More severe constrictions resulted in breakage of the hair shaft, producing a characteristic and recognizable defect readily, distinguishable from the progressively atrophic root after irradiation. The rate of hair growth, if affected at all, also returned to normal. Thus the approximate date of drug effect could be calculated by dividing the distance between the hair root and the construction by the normal daily growth rate.13
Although this type of damage to the anagen hair has been frequently quoted as prototypical of anagen toxicity, in fact no exactly analogous situation has since been reported. Probably all antimitotic, antifoliative, or radiomimetic drugs are potentially capable of anagen toxicity; several have been documented.12 It would be useful if differences in types of morphologic or biochemical damage could be detected after different agents. Anagen effluvium is inducible by lithium,14 indomethacin, allopurinol, cholesterol-lowering agents, and overdosage of antithyroid medication. Although thallium is presumably no longer used therapeutically, it is a common ingredient of various insect and small animal poisons and still causes a substantial amount of human morbidity. Acute poisoning in young children is not likely to go unrecognized, since abrupt loss of hair will be accompanied by pain and anorexia, or more severe central nervous system gastrointestinal, or renal manifestations. Chronic thallotoxicosis in all age-groups may be much less obvious and may be far more common than generally realized.15 Evidence supporting the primary involvement of anagen hairs in thallium toxicity is well summarized by Flesch.2 Some investigators believe that the tapered end of a broken hair with a dark zone near the break, said to be caused by entrapped air bubbles, is characteristic (if not pathognomonic) of thallium alopecia. However, dysplastic atrophied hair roots may not be significantly different from those observed after the administration of certain cancer chemotherapeutic drugs.12 In animal experiments, thallium toxicity can be blocked by cystine or methionine. Incorporation of these amino acids is a vital part of normal hair growth and consolidation and can be modified by diet in both animals16 and humans.17 Since other sulfhydryl compounds do not block thallium toxicity, it is possible that the element interferes with normal cystine incorporation in the growing hair. An analogous process may be operative in the toxic anagen alopecia induced in humans by ingestion of the nuts of the monkeypot tree, coco de mono (Lecythis ollaria) a deciduous tree widely distributed in Central and South America. Many other plants are responsible for producing alopecia, including Stanleya, Astragalus pectinatus (locoweed), Leucaena, Melilotus (yellow sweet clover), Colchicum autumnale, Gloriosa, and Saptaceae (several Brazilian woods of this family).18 Kerdel Vegas19 had described from Venezuela an acute gastrointestinal syndrome followed by reversible hair loss. The active principle was isolated and characterized as selenocystathionine. In vitro, cytotoxicity of this compound could be blocked by (natural) l-cystine but not d-cystine or sulfhydryl compounds, a situation comparable to that reported for thallium.2 A similar syndrome of gastrointestinal symptoms and hair loss has been reported to follow the administration of synthetic d,l-selenocystine20 in humans, and hair loss among Indians has been associated with selenium poisoning.
Another naturally occurring amino acid analog, mimosine, is apparently responsible for causing hair loss in humans or some animals who ingest seeds of the shrubby tree Leucaena glauca. This species is widely established in Hawaii (where it was once planted as fodder for grazing animals) and can be found growing wild in southern Florida. Although originally said to be a substituted alanine, the compound acts as an inhibitor of tyrosine decarboxylase and tyrosinase. Only growing hairs are affected, establishing mimosine as another cause for anagen alopecia.
Several other heavy metals, including arsenic, lead, and bismuth, can cause alopecia, presumably of the anagen type. Some of these may act indirectly by induction of iron deficiency, a condition frequently reported to be associated with hair loss. These reports are largely of a testimonial nature, and it is difficult to assess accurately their importance. Certainly chronic poisoning should be considered in patients of all ages with diffuse alopecia of inapparent cause.
Alopecia as an occupational disease occurs in the synthetic rubber industry following exposure to chloroprene dimers, which are chemicals related to Vitamin A.21
Following tick bite of the scalp a patch of alopecia may develop, with its center presumably caused by direct necrotizing effect of the tick saliva and its radial spread attributed to the action of diffusing toxin.22
The high degree of metabolic and mitotic activity of the anagen hair root renders it (along with the bone marrow and gastrointestinal epithelium) unusually susceptible to competitive analogs, growth inhibitors, and metabolic poisons. It is unnecessary in most cases to assume specific clinical affinity of hair roots for a given compound. Essentially all the substances that can cause anagen hair loss can also cause severe generalized toxicity or death when larger amounts are present. Although the specific mechanisms of cytotoxicity may differ, it is the capacity to inhibit highly proliferative tissues in general that results in anagen hair loss.
CLINICAL MANIFESTATIONS
Approximately 90% of scalp hairs are in anagen; therefore, severe toxicity causes marked and extensive hair shedding.6 The hairs are atrophied and are easily extracted, or they break. Anagen hair loss occurs much earlier than telogen hair loss and is usually reversible.
The clinical features of anagen hair loss depend on the degree of toxicity evoked by the causative agent and the cycle state of the hair population in a given area. Although the male beard area represents a high population of anagen hairs, a daily shaving habit will tend to obscure hair loss in the area. Similarly, preexistent male-pattern baldness will obscure what might be severe anagen alopecia. Loss of eyebrow hair may be lessened because of the smaller proportion of eyebrow hairs in the growing phase as compared with scalp hairs. Constriction of hair shafts of anagen hairs as a result of recovery of the partly inhibited hair root will occur to varying degrees and may be so slight as to result in breakage of hairs only after moderately severe trauma. Excessive cosmetic manipulation will result in more hair loss in a person so predisposed than in one who rarely combs the hair.
The loss will occur earlier after the toxic insult than in telogen alopecia, since extremely atrophied hairs will leave the scalp with the gentlest of rubbing, whereas telogen hair roots are more likely to be retained in the scalp for several weeks. Any patterning of the hair loss in anagen alopecia will simply reflect the preexisting pattern of anagen - telogen ratio in a given area. Most acute anagen alopecias are entirely reversible, the obvious exception being those produced by high-dosage irradiation that causes extensive dermal alteration. The prognosis in diffuse hair loss of long duration associated with chronic poisoning is less clear and permanent thinning may occur.
DIAGNOSIS AND CLINICAL AND LABORATORY FINDINGS
The diagnosis is suggested by precipitous effluvium following a relevant exposure to, or intake of, a toxic agent. If the cause is not obvious, the case merits a careful history, physical examination, microscopic inspection of plucked hairs, and laboratory studies, including toxicologic investigation of blood, tissue, hair and nails, as circumstances dictate.
Any instance of diffuse nonpatterned hair loss should immediately arouse suspicion of toxic anagen alopecia. Precipitous hair loss generally indicates a specific exposure or ingestion in the recent past. Mild, chronic, progressive hair loss may not be immediately evident to the consulting physician, often to the consternation of the patient. A careful history, documented evidence of loss of hairs in excess of the normal daily number, adequate physical and general laboratory examination, and microscopic evaluation of spontaneously shed and manually epilated hairs represents the minimal effective diagnostic work-up.
There is no treatment for anagen alopecia except removal of the inciting cause. Nevertheless, establishment of a specific diagnosis is of paramount importance since complete recovery is the rule, and the patient can make decisions as to temporary scalp coverings based on the prognosis.
Morris Waisman
Robert G. Crounse
REFERENCES
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Minoxidil upregulates the expression of vascular endothelial growth factor in human hair dermal papilla cells.
Author
Lachgar S; Charveron M; Gall Y; Bonafe JL
Address
Laboratoire de Biologie Cellulaire Cutan´ee, Institut de Recherche Pierre Fabre, Facult´e de M´edecine Rangueil, Toulouse, France.
Source
Br J Dermatol, 138(3):407-11 1998 Mar
Abstract
The hair follicle dermal papilla which controls hair growth, is characterized in the anagen phase by a highly developed vascular network. We have demonstrated in a previous study that the expression of an angiogenic growth factor called vascular endothelial growth factor (VEGF) mRNA varied during the hair cycle.
VEGF mRNA is strongly expressed in dermal papilla cells (DPC) in the anagen phase, but during the catagen and telogen phases. VEGF mRNA is less strongly expressed. This involvement of VEGF during the hair cycle allowed us to determine whether VEGF mRNA expression by DPC was regulated by minoxidil.
In addition, the effect of minoxidil on VEGF protein synthesis in both cell extracts and DPC-conditioned medium, was investigated immunoenzymatically. Both VEGF mRNA and protein were significantly elevated in treated DPC compared with controls. DPC incubated with increasing minoxidil concentrations (0.2, 2, 6, 12 and 24 mumol/L) induced a dose-dependent expression of VEGF mRNA. Quantification of transcripts showed that DPC stimulated with 24 mumol/L minoxidil express six times more VEGF mRNA than controls.
Similarly, VEGF protein production increases in cell extracts and conditioned media following minoxidil stimulation. These studies strongly support the likely involvement of minoxidil in the development of dermal papilla vascularization via a stimulation of VEGF expression, and support the hypothesis that minoxidil has a physiological role in maintaining a good vascularization of hair follicles in androgenetic alopecia.
