Different Levels of 5α-Reductase Type I and II, Aromatase, and Androgen Receptor in Hair Follicles of Women and Men With Androgenetic Alopecia
Objective.—An increase in the production of 5α-dihydrotestosterone (DHT) is thought to be responsible for androgenic alopecia (AGA) in both women and men. The androgen receptor and 3 important androgen- converting enzymes, 5α-reductase (5α-R) types I and II and cytochrome P-450 aromatase (AROM) in scalp hair follicles of women and men with AGA are described.
Methods.—Scalp specimens were obtained from 12 women, age 14-33, and 12 men, age 18-30, with AGA. Nuclear, cytosol, mitochondrial, and microsomal fractions of follicles were subjected to enzymatic and androgen receptor analysis.
Results.—Total androgen receptor levels and 5α-R activity were higher in frontal hair follicles than occipital hair follicles in women and men. Total androgen receptor content was 40% lower in women than in men in both regions. Whereas women had about 40% more type I and II isoenzymes in the frontal than in the occipital areas, men had about 60% higher levels of type I and II isoenzymes in the frontal than occipital areas. Men had 3 and 3.5 times, respectively, the amount of type I and type II isoenzymes in frontal follicles than women. The level of AROM in the frontal follicles of women was about 6 times higher than in the frontal follicles of men. The AROM level in the occipital follicles of women was about 4 times higher than in the occipital follicles of men.
Conclusion.—In both sexes, androgen receptor levels are 1.5 times higher in frontal than in occipital follicles. In women, there are 40% fewer androgen receptors in frontal follicles than in men. Types I and II of 5α-R are found in the hair follicles of women and men with AGA. Whereas women with AGA have 40% higher total 5α-R levels in the frontal follicles compared with the occipital follicles, men with AGA have more than twice the levels of women and 3 times the total and type II 5α-R in their frontal versus occipital follicles. Women have 80% higher AROM levels in the frontal follicles than men. AROM may limit the amount of androgen in hair follicles of women by converting androgens to estrogens. The androgen receptor; 5α-R types I and II, and AROM enzymes are found in the outer root sheath and dermal papilla. The receptor and enzyme levels help to explain why AGA is more severe in men than in women.
► The findings in this article nicely explain the various clinical patterns of androgenetic alopecia in both men and women. They also help explain why this condition is more severe in men than in women and may provide insight into therapeutic strategies for the future treatment of hair loss.
Hair Growth Modulation by Topical Immunophilin Ligands: Induction of Anagen, Inhibition of Massive Catagen Development, and Relative Protection From Chemotherapy-induced Alopecia
Introduction.—Two potent hair growth modulatory agents are the immunosuppressive immunophilin ligands cyclosporin A and FK 506. These agents are inducers of active hair growth and are inhibitors of hair follicle regression. In previously established murine models that mimic premature hair follicle regression (catagen) or chemotherapy-induced alopecia, 2 major pathomechanisms underlying human hair loss, hair growth manipulation by topical cyclosporin A and FK 506 was explored.
Methods.—Six- to 9-week old mice in the telogen stage of the hair cycle (pink skin color) were used in the study. A total of 105 mice were divided into groups receiving 150 µL of cyclosporin A, 0.01%, 0.1% or 0.5%; FK 506, 0.01%, 0.1% or 0.5% in ethanol; or vehicle as the control. Daily recordings were taken of the back skin of all animals for up to 18 days after onset of treatment.
Results.—In the back skin of mice with all follicles in the resting stage (telogen), topical cyclosporin A and FK 506 induce active hair growth (anagen). Massive dexamethasone-induced, premature catagen development was inhibited in these mice. Relative protection from alopecia and follicle dystrophy induced by cyclophosphamide was observed with cyclosporin A and FK 506, perhaps by favoring the dystrophic anagen pathway of follicle response to chemical damage.
Conclusion.—Topical immunosuppressive immunophilin ligands can, in principle, act as potent manipulators of clinically relevant hair-cycling pathomechanisms; however, it remains to be established whether these immunosuppressive immunophilin ligands exert the same effects on human hair follicles. Investigation of the use of topical immunosuppressive immunophilin ligands in the management of human hair growth disorders is strongly encouraged.
► Hypertrichosis is a common side effect in patients treated with either cyclosporine or FK 506 (tacrolimus). Interestingly, both drugs have a profound suppressive effect on T-helper cell function; however, it is possible that their effect on the hair growth cycle is unrelated to their effect on the immune system. Although it is unlikely that these agents will ever have any clinical usefulness in treating alopecia, an understanding of how they influence the hair follicle may lead to the development of better therapeutic agents.
Hair Loss After Routine Immunizations
Introduction.—Alopecia is a known adverse effect of numerous medications, but vaccines are not usually considered a cause for this complaint. Hair loss occurred after routine vaccines in 60 patients.
Methods.—The FDA, Centers for Disease Control and Prevention, and the Vaccine Adverse Event Reporting System were reviewed for spontaneous reports of hair loss after immunization.
Results.—Sixty evaluable reports since 1984 coded for “alopecia” after immunizations were found, including 16 patients (4 definite, 12 possible or probable) with positive rechallenge (hair loss after vaccination on more than 1 occasion). Of 60 patients, 48 had received HBV. Both of the available recombinant products and the former plasma-derived products were represented. Females were predominantly affected in all age groups. Most patients recovered. Patients varied in clinical features, such as intervals from vaccination until onset and extent and reversibility of hair loss. Nine patients experienced previous medication allergies.
Conclusion.—-There is probably a very rare association between vacci-nations and alopecia. It is likely that more than one pathophysiologic mechanism is responsible. The nonrandom distributions of reports by vaccine, age, and sex could reflect biased case ascertainment. Further study is needed to define populations with consistent case detection.
► It is difficult to assess the magnitude of this problem given the almost nonexistent clinical description of the alopecia and the total absence of histologic data. Perhaps these biostatisticians should be encouraged to include a dermatologist among them the next time they study a skin problem. Given the paucity of data presented, the only conclusion one might make is that these patients either had telogen effluvium, alopecia areata, or a transient immune-mediated alopecia secondary to immunization.
Stress and Alopecia Areata: A Psychodermatologic Study
Background.—Reports have linked psychosocial stress to the onset and exacerbation of alopecia areata (AA), with linkage rates ranging from 6.7% to 96%. Little is known clinically about stress-reactive AA, and the severity of the emotional stressor and that of the AA do not correlate directly.
Methods.—Stress reactivity of AA and psychosocial measures were studied among 16 patients with AA (or alopecia totalis) and 28 patients with alopecia universalis. The patient used a 10-point scale to rate alopecia exacerbation by stress. Relationships between psychosocial stress measures and AA severity were determined, and dermatologic and psychological characteristics of patients reporting an association between stress and AA were compared with those who did not.
Results.—Stress reactivity score was correlated with psychological measures (P < 0.05). Patients with higher depression scores were more likely to be high stress reactors. Stress reactivity correlated significantly (P < 0.05) with 9 of 17 psychosocial measures. A prevalence of high stress reactivity in AA of 15.9% was found.
Conclusions.—In patients with AA, high stress reactivity was significantly associated with depression scores in the range of major depressive disorders, which may affect immune status. Patients with stress-reactive alopecia may have depressive illness, an important management consideration.
► Rare is the patient with AA who has not been told that his or her disease is caused by “nerves”! This article suggests that patients whose alopecia is stress-reactive may suffer from a depressive illness. This exemplifies the well-known “chicken or the egg” scenario: is the alopecia caused by stress or is stress caused by the alopecia? Similarly, what individual who has lost his or her hair, an important part of a person’s self-image, would not be at least a little depressed?
Children With Alopecia Areata: Psychiatric Symptomatology and Life Events
Introduction.—Approximately 60% of patients with alopecia areata (AA) are younger than 20 years of age. Although regrowth of hair occurs within a year in 95% of children with patches of hair loss, relapses are also common. Suggested causes of AA include an autoimmune process and stress, and there is a family history of the condition in 10% to 20% of cases. Children with AA were compared with a control group to examine the role of psychopathology in the disorder.
Methods.—life mean age of the 33 children (23 girls and 10 boys) with AA was 10.5 years. The duration of AA was less than 1 year in 22 and 1-3 years in 10. Also examined for the role of stressful life events only were 16 children with a mean age of 4.6 years and AA of less than 1 year’s duration. Controls were 46 children, 30 with a mean age of 10.6 years and 16 with a mean age of 4.2 years, who were seen by a pediatrician for a moderately acute ailment. All children were evaluated with 4 instruments: Child Psychiatric Interview, Children’s Depression Inventory, Children’s Manifest Anxiety Scale, and the Life Events Scale for Children; parents completed the Child Behavior Checklist (CBCL).
Results.—Compared with controls, children with AA had more psychological problems identified by the CBCL. Those with AA were more anxious or depressed, withdrawn, aggressive, and delinquent; they had more somatic problems and difficulties in social relations and attention. Although major depression was not detected, all children with A A exhibited mild or moderate symptoms of anxiety in the Child Psychiatric Interview. Children with AA had had fewer positive life events in the previous year than did controls.
Conclusion.—Alopecia areata in these young children appeared to be associated with psychiatric symptomatology and stressful life events. Compared with age-matched controls, children with AA had more psychiatric symptoms, particularly those of anxiety or depression. Girls with AA seemed to have been affected more than boys in dimensions of total problems, anxiety/depression, and internalizing/externalizing syndromes. Children with this condition should undergo psychiatric assessment.
► Clearly, severe AA can be an enormously stressful event both for the child and for the family. The psychological needs of all family members must be considered in the managment of this disease. The National Alopecia Areata Foundation can be quite helpful in providing emotional support.
Cytokines in Alopecia Areata: Contrasting Cytokine Profiles in Localized Form and Extensive Form (Alopecia Universalis)
Objective.—Although the cause and development of alopecia areata (AA) is not known, there is increasing evidence indicating involvement of cytokines in the process. If cytokines are involved in the disease process, cytokine profiles should differ between the localized and extensive forms of the disease. Serum levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-2, IL-4, and IL-6 in patients with the localized form of AA (LAA) were compared with those in patients with alopecia universalis (AU).
Methods.—Serum levels of cytokines were measured using radioimmunoassay or enzyme-linked immunosorbent assay (ELISA) kits in a blinded fashion in 7 patients with LAA, 7 patients with AU, and 7 healthy controls.
Results.—Serum levels of IL-1α and IL-4 were significantly higher in LAA patients than they were in controls, whereas serum levels of IFN-γ and IL-2 were significantly higher in AU patients than they were in controls. Serum levels of TNF-α and IL-1α were significantly elevated in LAA patients, compared with levels in AU patients, and IL-2 levels in LAA patients were significantly higher than those in AU patients. Disease duration and serum IL-1α levels were inversely related. Although immune responses in LAA and AU appear to be regulated by different patterns of cytokines, it is still unclear whether they are different manifestations of the same disorder or are totally distinct in their pathogenesis.
Conclusion.—Despite the fact that the number of patients in this study was small, and the presence of soluble cytokine receptors or cytokine- binding proteins may have affected the results of the immunoassay, the differences in cytokine profiles may be useful in distinguishing between LAA and AU patients, in predicting outcome, and in the development of new therapeutic approaches.
► This report demonstrates different cytokine profiles in localized and extensive forms of alopecia areata, suggesting the possibility that different pathogenetic mechanisms control these diseases. If these data can be confirmed, measurement of these cytokines may provide important prognostic information and may lead to new therapies.
Alopecia Areata but Not Androgenetic Alopecia is Characterized by a Restricted and Oligoclonal T-Cell Receptor-Repertoire Among Infiltrating Lymphocytes
Background.—Alopecia areata (AA) is a common disease with an unpredictable course, no specific therapy, and a major impact on quality of life. There is some evidence to suggest that it is caused by an autoimmune process, possibly mediated by T lymphocytes. A recent study found that treatment with diphencyclopropenone resulted in modification of a T- helper 1-type cytokine pattern in patients with AA, possibly causing an inhibitory effect on lesional T cells. The role of T cells in alopecia areata and their receptor repertoire were studied, using a reverse transcriptase polymerase chain reaction (PCR) technique.
Methods and Findings.—Patients with androgenetic alopecia (AD) were studied as controls. In patients with AD, PCR analysis of skin-infiltrating lymphocytes revealed products of almost all T-cell receptor (TCR) VB chains. In most cases, no amplified VB family made up as much as 10% of the total infiltrate. In contrast, very few TCR VB regions were detectable in 4 of 5 lesional AA samples. In these subjects, 3 VB chains made up more than 50% of the total infiltrate. The T-cell infiltrate in AA was oligoclonal in origin, as demonstrated by temperature gradient gel electrophoresis.
Conclusion.—In patients with AA, there is marked restriction and skewing of the TCR VB repertoire between circulating and infiltrating lymphocytes. As a result, the origin of the infiltrate is strikingly oligoclonal. This phenomenon may result from chronic stimulation by a conventional antigen, rather than from the skewing caused by skin-specific lymphocyte homing. The findings support the hypothesis that T cells play a key pathogenetic role in AA, although the signal responsible for triggering T-cell infiltration remains unknown.
► These results, which demonstrate the restricted nature of the lesional T-lymphocyte infiltrate in AA, strongly suggest that an antigen-specific T-cell response plays an important role in the pathogenesis of this disease.
Hair Follicle Structures Targeted by Antibodies in Patients With Alopecia Areata
Background.—An autoimmune reaction to hair follicles is believed to be responsible for alopecia areata. Antibodies can be detected to hair follicle antigens of 44, 47, 50, 52, 57, and/or 62 kd, and many of these are expressed only in the anagen hair follicle. These investigators further characterized the anagen hair follicle antigens in patients with alopecia areata and compared the properties of the antigens in both patients and controls.
Methods.—The study involved 10 patients (9 men and 1 woman, ages 20-56 years) and 8 controls (3 men and 5 women, ages 29-65 years). Serum samples were taken from all participants, and punch biopsy scalp specimens were obtained from all patients (2 specimens each—1 from an active site and 1 from an uninvolved site) and 5 controls (1 specimen each). Indirect immunofluorescence was used to detect antibodies to hair follicles and the structures these antibodies targeted.
Findings.—In the patient biopsy specimens, antibodies to hair follicle antigens were found in up to 90% of patient serum samples and up to 37% of control serum samples. Control biopsy specimens showed no antibody response to hair follicle antigens. However, specific antibody targets could be identified in the patient biopsy specimens, with the outer root sheath and matrix involved in almost one third of patient samples. Individual patients showed different patterns of antibody responses to different structures. Furthermore, serum samples reacted similarly to patient biopsy specimens from either the involved or the uninvolved site.
Conclusions.—Both patients and controls express antigens to hair follicles in the anagen phase, but expression patterns differ between the 2 groups. Specific hair structure antibody targets could be identified in the patient biopsy specimens. In patients, no clear homogeneous response to hair follicle antigens could be detected, however, and there was no difference in the antigenic response to involved or uninvolved sites. The authors speculate that the level of expression of the hair follicle antigens is a key determinant of the development of alopecia areata. Patients with greater antigen expression would be more likely to develop an autoimmune response and, ultimately, alopecia areata. The finding that normal subjects do not express hair follicle antigen antibodies, combined with other findings of the presence of antibodies before the onset of hair loss in mice, argue that the development of hair follicle antibodies is a primary event in the pathogenesis of alopecia areata. Nonetheless, whether the antigens are a cause of alopecia areata or a result of this disorder remains unknown.
► The hair follicle autoantibodies in alopecia areata are heterogeneous and target multipie structures in anagen hair follicles. This may reflect the expression of some yet-to-be-identified antigen(s). The level of expression of some hair follicle antigen(s) may modulate the initiation, localization, severity, and persistence of the disease. Interestingly, in this study there was no difference in the hair follicle antigen expression between involved and uninvolved areas of the scalp. This suggests that even clinically uninvolved areas in patients with alopecia areata may not be truly “normal.” On the other hand, it may also mean that these hair follicle antigens do not play a pathogenic role in causing hair loss.
Autoantibodies to Hair Follicles in C3H/HeJ Mice With Alopecia Areata- like Hair Loss
Introduction.—In a previous report, the authors described the occurrence of reversible hair loss comparable to alopecia areata (AA) in C3H/ HeJ mice. In humans, AA has been linked to antibodies to hair follicles. The antibody response to hair follicles was assessed in C3H/HeJ mice with hair loss to see if this is an appropriate animal model of AA.
Methods.—The study included 18 C3H/HeJ mice with alopecia, 12 age-matched but unaffected littermates, and 15 control mice of the same strain. Indirect immunofluorescence was performed to assess for circulating antibodies to C3H/HeJ anagen hair follicles. Immunoblotting was done to examine for antibodies against extracts of isolated C3H/HeJ and human anagen hair follicles.
Results.—All of the C3H/HeJ mice with hair loss and some of their unaffected littermates had antibodies to anagen hair follicles, compared with none of the control mice. These antibodies also were absent in mice of an unrelated strain with inflammatory skin disease and alopecia, suggesting that the hair loss per se did not cause the antibodies. The antibodies reacted with 40-60 kDa antigens, specific for hair follicles, which were present in mouse and human anagen hair follicles; these antigens also reacted with human AA antibodies. Some antibodies from C3H/HeJ mice and human patients with alopecia reacted with 44 and 46 kd antigens, which corresponded to hair follicle-specific keratins.
Conclusions.—Like humans with AA, C3H/HeJ mice with hair loss have circulating antibodies against hair follicles. These mice appear to provide an appropriate animal model for AA in humans.
► The correlation between the immunologic abnormalities present in human AA and those observed in these mice confirms that they are an appropriate model for human AA and supports the hypothesis that autoimmune responses to hair follicles play a key role in the human disease.
Topical FK506: A Potent Immunotherapy for Alopecia Areata? Studies Using the Dundee Experimental Bald Rat Model
Background.-Several different treatments,including contact sensitizers and systemic immunomodulators,have been tried for alopecia areata (AA),which is belived to be an autoimmune disease. However,no treatment has been consistently effective,and all have had side effects. FK506 is an antibiotic macrolide that, like cyclosporine A (CsA),is a specific immune cell inhibitor. The potential therapeutic efficacy of topical FK506 was studied in a rat model of AA.
Methods.-The Dundee experimental bald rat (DEBR)model of AA was used. The rats were divided into 5 treatment groups. Those in group 1 reveived 0.1 mL of 0.25% FK506 applied within a 2 x 2 cm bald area on 1 flank twice weekly for 8 weeks,for a dosage of 125 µg/cm2 of FK506 per week. The opposite flank was untreated. Animals in group 2 received 0.05 mL of 0.1% FK 506 5 times weekly on 1 flank for 8 weeks,for a dosage of 62.5 µg/cm2 of FK506 per week. In this group,the opposite flank was treated with control vehicle. Treatment for rats in group 3 was the same as for group 2, except that treatment was given twice weekly for 4 weeks— dosage in this group was 25 µg/cm2 of FK506 per week. A positive control group received CsA, 10 mg/kg/day for 8 weeks, and the fifth group was untreated. The results were assessed by regular examination and photography. Skin biopsy specimens were obtained from animals in groups 2 and 3.
Results.—Within 2-3 weeks, all rats treated with FK506 showed hair regrowth at the treated site. Hair continued to grow for 3 weeks after the end of treatment, followed by gradual hair loss. Vehicle application produced no hair growth, whereas untreated areas showed continued hair loss. Immunohistologic study of biopsy specimens from FK506-treated areas showed a marked decreases in the follicular inflammatory infiltrate. Animals treated with oral CsA had hair regrowth over their entire bodies.
Conclusions.—Topical FK506 appears to be a potentially useful treatment for humans with AA. The ability to give this agent topically would offer an important advantage over systemic CsA. More research is needed to determine whether hair growth can be achieved at lower FK506 doses than used in this study.
► Both physicians and affected patients anxiously await the results of human studies. There is certainly reason for optimism. Unlike topical cyclosporine, topical FK506 (tacrolimus) seems to be effective for the treatment of atopic dermatitis. Hopefully, topical FK506 will prove to be similarly effective in treating human AA, another situation in which topical cyclosporine has failed. Moreover, there recently has been described an assay to assess systemic concentrations of topically applied FK506, which should assist in assessing the benefit-risk ratio. One note of caution: it does not appear that topical FK506 will be a cure for AA. In the current study, after treatment was completed, rats subsequently lost their new hair growth.
Pulse Steroid Therapy for Children’s Severe Alopecia Areata?
Purpose.—Alopecia areata (AA) occurring in childhood has a poor prognosis. The cause of AA is unclear although an autoimmune disorder seems likely. Patients with severe AA are unlikely to have spontaneous remission. The results of pulse steroid therapy (PST) for children with severe AA of recent onset are reported.
Patients.—The study included 7 children, 4-15 years old, with severe, rapidly evolving AA. The duration of AA ranged from 3 to 44 weeks and involved more than 30% of the scalp. All patients received PST, consisting of IV methylprednisolone, 5 mg/kg twice a day, for 3 days. The patients were hospitalized and put on a salt-free diet during treatment. They were monitored for 1 year.
Outcomes.—There were no serious side effects of PST. By 12 months, 5 of the 7 patients had complete regrowth of hair. One patient had initial hair regrowth, followed by a relapse. Another patient, with alopecia totalis, had no response.
Conclusions.—This study reports a 71% rate of complete hair regrowth in children with severe AA treated with PST. This is a safe and promising treatment for extensive AA of recent onset in children and adolescents. It is not effective in patients with alopecia totalis or long-standing AA.
► The small size of the treatment group and the uncontrolled nature of the study make evaluation of the results quite difficult. A previous study using a single dose of 2 g methylprednisolone yielded a clinical response in only 3 of 22 patients with long-standing AA, many of whom had alopecia totalis. A later study using a protocol more similar to the one currently reported yielded more impressive results. As with most treatment regimens for AA, patients with recent onset of the disease and less extensive hair loss may respond the best.
Systemic Cyclosporine and Low-Dose Prednisone in the Treatment of Chronic Severe Alopecia Areata: A Clinical and Immunopathologic Evaluation
Introduction.—Topical cyclosporine has usually been unsuccessful in the treatment of alopecia areata (AA), but patients with chronic, severe AA have benefitted from systemic therapy. The efficacy of systemic cyclosporine was 50% in 1 series; all patients, however, experienced relapse after therapy was discontinued. A study was conducted to determine whether the addition of low-dose prednisone could increase the efficacy of cyclosporine, reduce the cyclosporine dose requirement, and achieve a lasting cyclosporine-free remission in chronic, severe AA.
Methods.—Eight patients, 5 women and 3 men ranging in age from 25 to 57 years, were enrolled in the study. All had AA affecting at least 95% of the scalp. The average duration of the disease was 7.5 years. Patients were given a regimen of cyclosporine (5 mg/kg/day) and prednisone (5 mg/day). Cyclosporine was reduced according to response and discontinued at week 24; prednisone was continued for 1 month. Efficacy was measured by direct clinical examination. Punch biopsy specimens were obtained for analysis.
Results.—Two of 8 patients had results judged cosmetically acceptable. The lowest cyclosporine dose able to produce such results was 3.5 mg/kg daily. Both responders lost their hair after the combined therapy was discontinued. Four patients experienced severe side effects, causing 3 to discontinue medications. Histopathologic examination showed no real trends in the CD4/CD8 ratio during treatment.
Conclusion.—There is experimental support for the efficacy of cyclosporine in AA, but regrowth of hair has proved temporary. The addition of low-dose prednisone to cyclosporine therapy yielded cosmetically acceptable regrowth in only 25% of patients in this study, and regrowth was not permanent. In addition, significant side effects were common.
► These results are disappointing. Clearly, more needs to be learned about the pathogenesis of AA to allow for the development of new, more effective therapies.
Quantitating Hair Loss in Women: A Critical Approach
Objective.—Some patients have dysmorphophobia, which can include imaginary hair loss. Quantitating hair loss is important to the diagnosis. Office hair loss assays are reviewed.
Methods.—The pull test (PT), daily count (DC), and wash test (WT) were administered to 234 women with unexplained hair loss. A trichogram was used for 43 patients. There were 89 with normally dense hair, 74 classified with Ludwig stage I, 37 with Ludwig stage II, 16 with Ludwig stage III, and 19 were unrecorded. The PT test was done 5 days after shampooing in 4 areas by gently pulling 50-80 hairs between 2 fingers of 1 hand and counting the loose hairs with the other hand. Daily count was performed on hairs on the pillow, comb or brush, shoulders, or shower floor for 7 days and a daily average obtained. The WT was performed 5 days after shampooing on hairs caught in a gauze pad covering the drain when the hair was washed again. A trichogram was performed on the vertex. Results were analyzed by ANOVA.
Results.—Median PT, DC, and WT hair counts were 0.6, 60.5, and 122, respectively. The telogen median was 16%. The PT, DC, and WT averages in patients with normal hair were significantly higher than they were in patients with Ludwig stage I-III hair loss. Telogen percentages did not differ significantly between groups. The WT was significantly correlated with DC and PT. The DC was significantly correlated with the PT. Telogen percentage did not correlate with any method.
Conclusion.—Hair loss tests should be noninvasive, easy, and repeatable. The PT is not a sensitive method. Telogen percentage does not correlate with hair loss. The DC is cumbersome. A standardized WT method is the best choice.
► These authors recommend the WT as the best method to quantitate hair loss in women. Nevertheless, assessment of normality, standardization of methods, and reproducibility are vital to confirm the diagnostic usefulness of any of these approaches.
Chronic Telogen Effluvium: Increased Scalp Hair Shedding in Middle- aged Women
Objective.—Acute telogen effluvium (ATE), anagen effluvium, drugs, chemicals, hypothyroidism, iron deficiency, nutritional disturbances, some systemic diseases, and renal and hepatic failure are causes of thinning hair. Chronic telogen effluvium (CTE) is a cause of generalized hair loss in middle-aged women. Chronic telogen effluvium can be confused with female androgenetic alopecia (AGA), except that it involves the entire scalp. Clinical and pathologic criteria for the diagnosis of CTE are presented.
Methods.—Two 4 mm punch scalp biopsies from thinning areas were taken from 355 CTE patients (9 males) age 13-88 years, 412 AGA patients (193 males) age 15-80 years, and 22 normal controls (9 female) age 18-70 years. Terminal and vellus-like hairs and follicular stellae were identified on histologic examination of vertical and horizontal sections, and perifollicular inflammation and fibrosis were graded as absent, mild, moderate, or severe.
Results.—In horizontal sections, the terminal: vellus-like hair ratios were 7:1 for controls, 9:1 for CTE patients, and 1.9:1 for AGA patients. Anagen and telogen percentages for these groups were 93.5% and 6.5%, 89% and 11%, and 83.2% and 16.8%, respectively. Inflammation or fibrosis was seen in 40.9% of controls, 40.3% of CTE patients, and 71.4% of AGA patients. Moderate inflammation appeared in 11% of controls and CTE patients and in 37% of AGA patients. Upper follicular inflammation: lower inflammation/fibrosis ratios were higher in AGA patients than they were in CTE patients or controls.
Conclusion.—Chronic telogen effluvium affects women in their 40s- 60s. Onset is abrupt, and shedding is persistent. The condition does not result in baldness, and sometimes thinning does not show. It may last from 6 months to 6 or 7 years, and patients may relapse seasonally. Hair loss eventually stabilizes in patients without coincident AGA.
► Chronic telogen effluvium is an important cause of hair loss in middle-aged women. Differentiation from androgenetic alopecia is critical for both prognostic and therapeutic reasons.
Postmenopausal Frontal Fibrosing Alopecia: A Frontal Variant of Lichen Planopilaris
Objective.—Lymphocyte-mediated scarring alopecia is most commonly caused by lichen planopilaris and lupus erythematosus. The course of a distinctive form of frontal fibrosing alopecia in 6 women without evidence of lichen planus at other sites is summarized, and the immunohistochemical profile of the infiltrating cells in the frontal variant is compared with findings in multifocal lichen planopilaris. A summary of data from 10 new patients is also included.
Methods.—The immunohistochemical profile of scalp biopsy specimens of 6 female patients, age 63-80 years, with frontal fibrosing alopecia was compared with findings from 6 scalp specimens of 6 women, age 24-71 years, with multifocal scarring lichen planopilaris.
Results.—The skin on the forehead in patients with frontal alopecia was pale, compared with the blotchy, sun-damaged skin on the rest of the face. Loss of hair follicles, follicular erythema, and follicular keratinization were observed. Thirteen patients had lost most or all of their eyebrows. All 16 scalp specimens showed a pattern of perifollicular fibrosis and lymphocytic inflammation characteristic of, and indistinguishable from, multifocal lichen planopilaris. Whereas lichen planopilaris results in patchy and asymmetric hair loss, these patients showed symmetric hairline recession with pale skin and loss of hair follicles, including those of the eyebrows. Nonetheless, the immunohistochemical findings in these 16 patients indicated that their condition was caused by a variant of lichen planopilaris.
Although all but 1 of the patients were postmenopausal, there was no hormonal indication for the process. Nine patients had normal androgen studies, and 8 patients were taking hormone replacement therapy.
Conclusion.—Although oral corticosteroids or chloroquine may be beneficial to these patients for a short time, there is no definitive treatment for this condition.
► The incidence of lichen planopilaris clearly has been underestimated, I see a number of women with this disorder on a regular basis. A biopsy specimen to confirm the diagnosis of scarring alopecia is important because it allows the physician to choose an appropriate therapy and to convey to the patient important prognostic information.
A Comparison Between Two Doses of Flutamide (250 mg/d and 500 mg/d) in the Treatment of Hirsutism
Introduction.—In hirsutism, some androgenic stimulus causes fine vellus hair to change into visible, thickened, terminal hair. The nonsteroidal drug flutamide is regarded as a “pure” antiandrogen because it acts only at the androgen receptor site. Three recent studies have found flutamide to be an effective treatment for hirsutism at doses of 500 or 750 mg/day. However, there have been no dose-ranging studies of flutamide, which is an expensive drug, for this indication. The authors have found encouraging results with low-dose flutamide, that is, 250 mg/day. They compared the clinical and hormonal effects of flutamide at 2 doses—250 and 500 mg/day—in women with hirsutism.
Methods.—The randomized trial included 65 women with moderate to severe hirsutism. They were assigned to receive oral flutamide in a dose of 250 or 500 mg/day for 12 months. The cause of hirsutism was polycystic ovary syndrome in 51% of women in the 250 mg/day group and in 60% of those in the 500 mg/day group. The 2 groups were otherwise similar in hirsutism scores, hormone levels, and body mass index. The results were assessed by hirsutism scores, hormone levels, and blood chemistry findings.
Results.—Six-month reductions in hirsutism scores were 65% in the 250 mg/day group and 62% in the 500 mg/day group. Twelve-month reductions were 71% and 70%, respectively . The differences were not significant, and all patients had clinically significant reductions in hirsutism. The response was similar for women with idiopathic hirsutism and those with polycystic ovary syndrome. Hormone levels during treatment were similar for the 2 groups. Patients taking the lower dose appeared to have less trouble with side effects. Oligomenorrhea developed in 30% of patients taking 500 mg/day vs. none of those taking 250 mg/day.
Conclusions.—Flutamide 250 mg/day appears to be an effective treatment for women with hirsutism. The clinical effect is the same as that of a 500 mg/day dose, with some reductions in side effects. Low-dose flutamide offers an effective, well-tolerated, economical treatment for hirsutism.
► As in a previous study of flutamide for the treatment of hirsutism,’ these authors fail to supply patient photos to document the clinical results. Unfortunately, neither did the authors supply relapse rates 1-2 years after cessation of treatment.
Gonadotrophin-releasing Hormone Agonist Therapy for Hirsutism Is as Effective as High Dose Cyproterone Acetate but Results in a Longer Remission
Background.—For patients with hirsutism, treatment with either cyproterone acetate (CPA) or gonadotropin-releasing hormone agonist (GnRHa) with “add-back” estrogen can be effective. However, the efficacy of these 2 approaches have not been adequately compared. Long-term GnRHa plus “add-back” estrogen therapy was compared with 2 regimens using CPA. The endocrine and clinical consequences of medication withdrawal were examined as well.
Methods.—Participants included 60 hyperandrogenic women with hirsutism, with a mean age of 24 years. The patients were arbitrarily assigned into 3 treatment groups. Patients in the Diane group, received CPA, 2 mg, plus 35 µg of ethinyl estradiol for 21 days/month. Patients in the CPA group, received CPA, 50 mg on days 5-15, and ethinylestradiol, 50 µg on days 5-25 each month. Patients in the GnRHa group received Decapeptyl, 3.75 mg IM every 28 days, plus conjugated estrogen, 0.625 mg on days 1-21, and medroxyprogesterone acetate, 10 mg on days 12-21. Before, during, and after treatment the patients were graded for hirsutism using the Ferriman-Gallwey-Lorenzo (FGL) index, anagen hair shaft diameters, and serum luteinizing hormone (LH) levels. After 1 year of treatment, the women were followed up for an additional year.
Results.—Hirsutism was reduced after 1 year of treatment in all 3 groups, but the results were better for the CPA and GnRHa groups than for the Diane group. Patients in the GnRHa group had the lowest serum LH and testosterone levels. In the 6 months after the end of treatment, the Diane and CPA groups showed rapid return of hirsutism, with FGL scores and hair shaft diameters returning to baseline values. Hirsutism was slower to return after GnRHa treatment; by 1 year, FGL scores and hair shaft diameters were still significantly lower than baseline. In all 3 groups, serum LH and testosterone levels returned to baseline within 6 months.
Conclusions.—For women with hyperandrogenic hirsutism, GnRHa plus add-back estrogen and high-dose CPA appear to be equally efficacious. However, the GnRHa regimen studied appears to produce a longer remission of hirsutism. Both regimens are more effective than low-dose CPA plus ethinylestradiol. The relationship between serum androgens and 5α-reductase activity warrants further study.
► In this study, hirsute hyperandrogenic women treated with GnRHa plus add-back estrogen did not have a recurrence of hirsutism until more than 1 year after withdrawal of therapy despite a rapid reappearance of their hy- perandrogenism. Similar data have been reported elsewhere. Unfortunately, no specific scoring method was used for comparing side effects between the groups. However, there were no major adverse effects noted and there were no patient dropouts. Liver enzymes remained unchanged, but lipids, lipoproteins, and coagulation parameters were not assessed. The add-back estrogen treatment in the GnRHa group was effective in preventing hot flashes. Some patients in the CPA groups complained of breast tenderness. The adverse sequelae, if any, of protracted treatment with any of these drugs is unknown.