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200 Uncommon finasteride side effects in male androgenic alopecia
Hair and Other Adnexal Structures | ABSTRACTS 198
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Dutasteride for men with androgenic alopecia unresponsive to finasteride IG Motofei1, DL Rowland2, SR Georgescu3, M Tampa3, VD Constantin1, S Paunica1, BC Baleanu4 and I Sinescu5 1 Surgery and Urology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 2 Psychology, Valparaiso University, Valparaiso, IN, 3 Dermatology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 4 Urology, Hermann-Josef KH, Kreisfreie Stadt Aachen Area, Germany and 5 Urology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania About 30% of men with androgenic alopecia have no significant improvement at six months after Finasteride administration. For this subgroup, dutasteride could represent an alternative therapy being more efficient and with reasonable adverse effects, according to some authors. Starting from this perspective, we intended to verify the dutasteride efficiency and side effects in androgenic alopecia, on unresponsive men to finasteride. From ninety-two men treated with Finasteride (1 mg/ day) for androgenic alopecia, twenty three subjects finished the treatment with no result on the target hair area, as confirmed by global photograph assessment and phototrichogram. From those 23 unresponsive men, 16 started a new treatment with dutasteride 0.5 mg/ day, being evaluated after six months again by dermatologists and urologists. In response to dutasteride, 9 subjects (56.25%) registered a significant improvement (hair density/ thickness) after six months, according to photograph and phototrichogram assessments. The other 7 subjects were appreciated as unresponsives to dutasteride, no aggravation being reported. Dutasteride adverse effects were reasonable, consisting in transient erectile dysfunction (in two responsive patients) and erectile dysfunction plus slight depressive episode (in 1 unresponsive patient). In contrast to Finasteride, dutasteride inhibits both type I and II of 5-a reductase enzyme, being able to ameliorate androgenic alopecia in some subjects who registered no improvement after finasteride administration. Dutasteride could be thus viewed as a secondary therapeutic option for androgenic alopecia, and a possible first therapeutic choice at subjects with predisposed (anticipated) finasteride side effects.
Hand preference and sexual orientation as useful elements to predict finasteride side effects in male androgenic alopecia DL Rowland1, IG Motofei2, SR Georgescu3, M Tampa3 and I Sinescu4 1 Psychology, Valparaiso University, Valparaiso, IN, 2 Surgery and Urology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 3 Dermatology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania and 4 Urology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania This study further investigated the distribution of finasteride adverse effects (according to hand preference and sexual orientation) on men treated for male androgenic alopecia, based on the existing interrelation among sexual hormones, pheromones, cognitive and sexual laterality of information processing. Finasteride 1 mg daily, human axillary pheromones, questionnaires regarding hand preference (Edinburgh Handedness Inventory) and related to sexual orientation/ behavior were used, to delineate within the brain hormonal and pheromonal neuromodulation of sexuality on 68 men with androgenic alopecia. Participants’ responses delineated four distinct groups. Group A with 12 men, involving especially the left hemibrain: sensitive to female axillary pheromones, left nostril and right visual hemifield, with left hand preference and predominantly heterosexuals (9 men). Group B (16 men) related to the right hemibrain: sensitive to male axillary pheromones, right nostril, and left visual hemifield, with right hand preference, six being homosexuals and ten heterosexuals. Group C with 11 men related to the left hemibrain: sensitive to androgens, with right hand preference and heterosexuals. Group D (29 men) related to right hemibrain: sensitive to estrogens, with left hand preference and mixed sexual orientation (17 heterosexuals and 12 homosexuals). Finasteride adverse effects were encountered especially in groups C (on 8 men) and group D (on 7 men), specifically on subjects who were either right handed heterosexuals or left handed homosexuals. In psycho-physiological terms, androgens seem to modulate only the left hemibrain, and more precisely, the left dorsal thalamic route.
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Uncommon finasteride side effects in male androgenic alopecia SR Georgescu1, S Paunica2, M Tampa1, MI Sarbu1, AM Limbau1, I Paunica2, BC Baleanu3 and IG Motofei4 1 Dermatology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 2 Periodontology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 3 Urology, Hermann-Josef KH, Kreisfreie Stadt Aachen Area, Germany and 4 Surgery and Urology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania The most common finasteride adverse effects are related to psychiatric (depression, insomnia), genitourinary (erectile dysfunction, libido, ejaculation and orgasmic disorders), endocrine (breast enlargement) and musculoskeletal (chronic fatigue) disorders. According to our data, some uncommon side effects could be not only infrequently encountered but also neglected, as presented here. One hundred and two patients with male androgenic alopecia received finasteride (1 mg daily) for at least four months or more, being monitored in respect to possible adverse effects by specialists in dermatology, parodontology, urology and general medicine. The monitoring period covered the therapeutic phase and six months extra after the treatment cessation. During therapeutic phase we registered as uncommon side effects melasma (1 patient), chronically dry/ thinning of the skin (4 patients), tinnitus (3 patients), postural hypotension (2 patients) and oral lesions (erythema, periodontal inflammation and/ or gingival hypertrophy in 9 patients). After treatment cessation two patients manifested severe depressive symptoms requiring psychiatric support and hospitalization (at two respectively four months, appreciated as post-finasteride syndrome), while one patient developed vitiligo one month later after the therapy. Uncommon and/ or severe Finasteride side effects seem to be incompletely documented, being encountered both during finasteride administration and after treatment cessation (as postfinasteride syndrome). On our sample, gingival hypertrophy and postural hypotension imposed treatment discontinuation, while the other (most oral) manifestations required a topical specific treatment.
Analysis of mice skin distribution using MALDI-MSI after subcutaneous injections of a new potent novel inhibitor of human hair growth, FOL-005 D Bonnel1, R Legouffe1, C Brunmark2, A Heron1, J Stauber1 and J Allenfall1 1 ImaBiotech, Loos, France and 2 Follicum, Lund, Sweden Undesired hair growth (hirsutism, hypertrichosis) can cause major psychological distress. Only few and often unsatisfactory therapeutic options are currently available, new treatment strategies need to be developed. As the multifunctional, immunomodulatory glycoprotein, osteopontin, is expressed by hair follicles (HFs) only during catagen phase of the hair growth cycle, we hypothesized that osteopontin-derived fragments may inhibit human hair growth. A newly generated, modified osteopontin-derived peptide (FOL-005) has been shown to highly and reproducibly induce hair growth in mice. However, in contrast to the effects in mice FOL005 strongly promoted premature HF regression (catagen) in organ-cultured human male scalp skin. Also, when injected intracutaneously into human male scalp skin transplanted onto SCID/beige mice, FOL-005 significantly decreased the number of hair shafts growing per graft compared to vehicle-treated control transplants. Moreover, FOL-005 administration potently counteracted the hair growth-promoting effects of minoxidil. The safety studies performed so far have not revealed any FOL-005 toxicity. FOL-005 is now being evaluated in a phase I clinical trial. As part of toxicological tests, using MALDI-MSI technology, the distribution of s.c. FOL-005 in mice was followed in skin for up to 24 hours. Indeed MALDI-MSI is a new advanced label free technique based on the combination of mass spectrometry imaging and histology. It provides qualitative and quantitative information about drug efficiency or toxicity. FOL-005 was found to exclusively be distributed in the treated skin after injection and the concentration was shown to decrease with time. No distribution was detected outside the skin area indicating that FOL-005 is locally degraded. These data identify only a local distribution of FOL-005 peptide and further supports clinical testing as a new treatment principle for excessive hair growth.
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MicroRNAs in the pathogenesis of male pattern baldness LM Hochfeld, T Anhalt, N Fricker, A Hofmann, MM No¨then and S Heilmann-Heimbach Institute of Human Genetics, University of Bonn, Bonn, Germany Male pattern baldness (MPB) is characterized by an androgen-dependent deregulation of hair follicle (HF) cycling (anagen shortening/premature catagen entry) which is accompanied by a miniaturization of the affected HFs. These characteristic changes are however restricted to HFs in the frontal and vertex area of the scalp whereas occipital HFs remain unaffected. So far, the biological mechanisms that underlie these differences between HF-subpopulations are still elusive. As micro(mi)RNAs have been demonstrated to be differentially expressed in androgen-sensitive vs. androgen-insensitive tissues and have been reported to play a role in hair biology, we hypothesized that miRNAs may contribute to the differing reactions of frontal (F) and occipital (O) HFs, thereby promoting the characteristic MPB phenotype. To test this hypothesis, we performed genome-wide miRNA- and mRNA-profiling in HFs from the F and O scalp of 25 healthy male donors and subsequently tested for differential miRNA expression. The analysis resulted in the identification of 42 significantly differentially expressed miRNAs (P<0.05). Target genes of these miRNAs were identified by (i) searching the miRWalk2.0 database and testing for HF expression and/or (ii) inverse correlation analysis of miRNA and mRNA expression levels. We discovered at total of 1,348 genes, that were targeted by 5 frontally up- (N¼495) and 37 frontally down-regulated miRNAs (N¼636). The pathway-based analysis of these target genes suggests that differential miRNA expression leads to frontal down-regulation of pathways that control WNT signaling and anagen initiation (mTOR, adipogenesis signaling) and frontal up-regulation of pathways that inhibit cell proliferation and promote apoptosis (ephrin-, androgen signaling). Thus, our data suggest that differential expression of miRNAs in HFs from the F and O scalp and the subsequently altered regulation of their target genes and pathways may promote the characteristic androgen-dependent changes in hair follicle cycling and cell proliferation in MPB.
Rebalance of the scalp microbiota by a multifunctional ingredient E Loing1, J Attia2, E Lamarque2 and M Borel3 1 Lucas Meyer Cosmetics- IFF, Quebec, QC, Canada, 2 Lucas Meyer Cosmetics- IFF, Toulouse, France and 3 Lucas Meyer Cosmetics- IFF, Champlan, France The recent scientific researches in microbiology and immunology have completely changed the understanding of the role of microorganisms on scalp. It also explained that treating dandruff with antifungal agents is insufficient. Major factors were pointed in the balance of scalp microbiota: sebum production providing support for Malassezia growth and Malassezia releasing irritating unsaturated fatty acids that affect the skin barrier function. In the present study, we identified a Rosebay extract designed to respect the microbiota and recovered homeostasis state of the scalp without irritating effect. Rosebay extract effect on lipid synthesis was studied in vitro using a normal human sebocyte culture and was evaluated with Nile red staining. Then, extract effect (1.5% in water) on yeast-exposed skin explants was investigated by histology, and immunostaining of hBDs and TLR2 as markers of the immune defense system. Clinical evaluation of the anti-dandruff efficacy of a shampoo containing the extract (1.5%) was performed, against placebo, on a panel of 24 volunteers with dandruff and seborrheic dermatitis. Presence of adherent and non-adherent dandruff was estimated, scalp sebum was measured and the total mass of lipids excreted by surface unit was quantified. In vitro, Rosebay extract inhibited sebum production (-43% at the concentration of 0.1%). In the yeast-exposed skin explant model, the extract induced a protection of the general morphology and the expression of hBD2, hBD3, and TLR2 was neutralized back to normal in the presence of the extract. In vivo, the extract significantly decreased the presence of adherent and non-adherent dandruff by -48% and -54% respectively at D30. Scalp sebum production was also significantly reduced by -67% at D30. Rosebay extract is an efficient anti-dandruff ingredient offering a new strategy to complete or substitute antifungal agent. The extract has proved to effectively and rapidly reduce dandruff production and sebum production in humans.
www.jidonline.org S195
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Dutasteride for men with androgenic alopecia unresponsive to finasteride IG Motofei1, DL Rowland2, SR Georgescu3, M Tampa3, VD Constantin1, S Paunica1, BC Baleanu4 and I Sinescu5 1 Surgery and Urology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 2 Psychology, Valparaiso University, Valparaiso, IN, 3 Dermatology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 4 Urology, Hermann-Josef KH, Kreisfreie Stadt Aachen Area, Germany and 5 Urology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania About 30% of men with androgenic alopecia have no significant improvement at six months after Finasteride administration. For this subgroup, dutasteride could represent an alternative therapy being more efficient and with reasonable adverse effects, according to some authors. Starting from this perspective, we intended to verify the dutasteride efficiency and side effects in androgenic alopecia, on unresponsive men to finasteride. From ninety-two men treated with Finasteride (1 mg/ day) for androgenic alopecia, twenty three subjects finished the treatment with no result on the target hair area, as confirmed by global photograph assessment and phototrichogram. From those 23 unresponsive men, 16 started a new treatment with dutasteride 0.5 mg/ day, being evaluated after six months again by dermatologists and urologists. In response to dutasteride, 9 subjects (56.25%) registered a significant improvement (hair density/ thickness) after six months, according to photograph and phototrichogram assessments. The other 7 subjects were appreciated as unresponsives to dutasteride, no aggravation being reported. Dutasteride adverse effects were reasonable, consisting in transient erectile dysfunction (in two responsive patients) and erectile dysfunction plus slight depressive episode (in 1 unresponsive patient). In contrast to Finasteride, dutasteride inhibits both type I and II of 5-a reductase enzyme, being able to ameliorate androgenic alopecia in some subjects who registered no improvement after finasteride administration. Dutasteride could be thus viewed as a secondary therapeutic option for androgenic alopecia, and a possible first therapeutic choice at subjects with predisposed (anticipated) finasteride side effects.
Hand preference and sexual orientation as useful elements to predict finasteride side effects in male androgenic alopecia DL Rowland1, IG Motofei2, SR Georgescu3, M Tampa3 and I Sinescu4 1 Psychology, Valparaiso University, Valparaiso, IN, 2 Surgery and Urology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 3 Dermatology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania and 4 Urology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania This study further investigated the distribution of finasteride adverse effects (according to hand preference and sexual orientation) on men treated for male androgenic alopecia, based on the existing interrelation among sexual hormones, pheromones, cognitive and sexual laterality of information processing. Finasteride 1 mg daily, human axillary pheromones, questionnaires regarding hand preference (Edinburgh Handedness Inventory) and related to sexual orientation/ behavior were used, to delineate within the brain hormonal and pheromonal neuromodulation of sexuality on 68 men with androgenic alopecia. Participants’ responses delineated four distinct groups. Group A with 12 men, involving especially the left hemibrain: sensitive to female axillary pheromones, left nostril and right visual hemifield, with left hand preference and predominantly heterosexuals (9 men). Group B (16 men) related to the right hemibrain: sensitive to male axillary pheromones, right nostril, and left visual hemifield, with right hand preference, six being homosexuals and ten heterosexuals. Group C with 11 men related to the left hemibrain: sensitive to androgens, with right hand preference and heterosexuals. Group D (29 men) related to right hemibrain: sensitive to estrogens, with left hand preference and mixed sexual orientation (17 heterosexuals and 12 homosexuals). Finasteride adverse effects were encountered especially in groups C (on 8 men) and group D (on 7 men), specifically on subjects who were either right handed heterosexuals or left handed homosexuals. In psycho-physiological terms, androgens seem to modulate only the left hemibrain, and more precisely, the left dorsal thalamic route.
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Uncommon finasteride side effects in male androgenic alopecia SR Georgescu1, S Paunica2, M Tampa1, MI Sarbu1, AM Limbau1, I Paunica2, BC Baleanu3 and IG Motofei4 1 Dermatology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 2 Periodontology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 3 Urology, Hermann-Josef KH, Kreisfreie Stadt Aachen Area, Germany and 4 Surgery and Urology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania The most common finasteride adverse effects are related to psychiatric (depression, insomnia), genitourinary (erectile dysfunction, libido, ejaculation and orgasmic disorders), endocrine (breast enlargement) and musculoskeletal (chronic fatigue) disorders. According to our data, some uncommon side effects could be not only infrequently encountered but also neglected, as presented here. One hundred and two patients with male androgenic alopecia received finasteride (1 mg daily) for at least four months or more, being monitored in respect to possible adverse effects by specialists in dermatology, parodontology, urology and general medicine. The monitoring period covered the therapeutic phase and six months extra after the treatment cessation. During therapeutic phase we registered as uncommon side effects melasma (1 patient), chronically dry/ thinning of the skin (4 patients), tinnitus (3 patients), postural hypotension (2 patients) and oral lesions (erythema, periodontal inflammation and/ or gingival hypertrophy in 9 patients). After treatment cessation two patients manifested severe depressive symptoms requiring psychiatric support and hospitalization (at two respectively four months, appreciated as post-finasteride syndrome), while one patient developed vitiligo one month later after the therapy. Uncommon and/ or severe Finasteride side effects seem to be incompletely documented, being encountered both during finasteride administration and after treatment cessation (as postfinasteride syndrome). On our sample, gingival hypertrophy and postural hypotension imposed treatment discontinuation, while the other (most oral) manifestations required a topical specific treatment.
Analysis of mice skin distribution using MALDI-MSI after subcutaneous injections of a new potent novel inhibitor of human hair growth, FOL-005 D Bonnel1, R Legouffe1, C Brunmark2, A Heron1, J Stauber1 and J Allenfall1 1 ImaBiotech, Loos, France and 2 Follicum, Lund, Sweden Undesired hair growth (hirsutism, hypertrichosis) can cause major psychological distress. Only few and often unsatisfactory therapeutic options are currently available, new treatment strategies need to be developed. As the multifunctional, immunomodulatory glycoprotein, osteopontin, is expressed by hair follicles (HFs) only during catagen phase of the hair growth cycle, we hypothesized that osteopontin-derived fragments may inhibit human hair growth. A newly generated, modified osteopontin-derived peptide (FOL-005) has been shown to highly and reproducibly induce hair growth in mice. However, in contrast to the effects in mice FOL005 strongly promoted premature HF regression (catagen) in organ-cultured human male scalp skin. Also, when injected intracutaneously into human male scalp skin transplanted onto SCID/beige mice, FOL-005 significantly decreased the number of hair shafts growing per graft compared to vehicle-treated control transplants. Moreover, FOL-005 administration potently counteracted the hair growth-promoting effects of minoxidil. The safety studies performed so far have not revealed any FOL-005 toxicity. FOL-005 is now being evaluated in a phase I clinical trial. As part of toxicological tests, using MALDI-MSI technology, the distribution of s.c. FOL-005 in mice was followed in skin for up to 24 hours. Indeed MALDI-MSI is a new advanced label free technique based on the combination of mass spectrometry imaging and histology. It provides qualitative and quantitative information about drug efficiency or toxicity. FOL-005 was found to exclusively be distributed in the treated skin after injection and the concentration was shown to decrease with time. No distribution was detected outside the skin area indicating that FOL-005 is locally degraded. These data identify only a local distribution of FOL-005 peptide and further supports clinical testing as a new treatment principle for excessive hair growth.
202
203
MicroRNAs in the pathogenesis of male pattern baldness LM Hochfeld, T Anhalt, N Fricker, A Hofmann, MM No¨then and S Heilmann-Heimbach Institute of Human Genetics, University of Bonn, Bonn, Germany Male pattern baldness (MPB) is characterized by an androgen-dependent deregulation of hair follicle (HF) cycling (anagen shortening/premature catagen entry) which is accompanied by a miniaturization of the affected HFs. These characteristic changes are however restricted to HFs in the frontal and vertex area of the scalp whereas occipital HFs remain unaffected. So far, the biological mechanisms that underlie these differences between HF-subpopulations are still elusive. As micro(mi)RNAs have been demonstrated to be differentially expressed in androgen-sensitive vs. androgen-insensitive tissues and have been reported to play a role in hair biology, we hypothesized that miRNAs may contribute to the differing reactions of frontal (F) and occipital (O) HFs, thereby promoting the characteristic MPB phenotype. To test this hypothesis, we performed genome-wide miRNA- and mRNA-profiling in HFs from the F and O scalp of 25 healthy male donors and subsequently tested for differential miRNA expression. The analysis resulted in the identification of 42 significantly differentially expressed miRNAs (P<0.05). Target genes of these miRNAs were identified by (i) searching the miRWalk2.0 database and testing for HF expression and/or (ii) inverse correlation analysis of miRNA and mRNA expression levels. We discovered at total of 1,348 genes, that were targeted by 5 frontally up- (N¼495) and 37 frontally down-regulated miRNAs (N¼636). The pathway-based analysis of these target genes suggests that differential miRNA expression leads to frontal down-regulation of pathways that control WNT signaling and anagen initiation (mTOR, adipogenesis signaling) and frontal up-regulation of pathways that inhibit cell proliferation and promote apoptosis (ephrin-, androgen signaling). Thus, our data suggest that differential expression of miRNAs in HFs from the F and O scalp and the subsequently altered regulation of their target genes and pathways may promote the characteristic androgen-dependent changes in hair follicle cycling and cell proliferation in MPB.
Rebalance of the scalp microbiota by a multifunctional ingredient E Loing1, J Attia2, E Lamarque2 and M Borel3 1 Lucas Meyer Cosmetics- IFF, Quebec, QC, Canada, 2 Lucas Meyer Cosmetics- IFF, Toulouse, France and 3 Lucas Meyer Cosmetics- IFF, Champlan, France The recent scientific researches in microbiology and immunology have completely changed the understanding of the role of microorganisms on scalp. It also explained that treating dandruff with antifungal agents is insufficient. Major factors were pointed in the balance of scalp microbiota: sebum production providing support for Malassezia growth and Malassezia releasing irritating unsaturated fatty acids that affect the skin barrier function. In the present study, we identified a Rosebay extract designed to respect the microbiota and recovered homeostasis state of the scalp without irritating effect. Rosebay extract effect on lipid synthesis was studied in vitro using a normal human sebocyte culture and was evaluated with Nile red staining. Then, extract effect (1.5% in water) on yeast-exposed skin explants was investigated by histology, and immunostaining of hBDs and TLR2 as markers of the immune defense system. Clinical evaluation of the anti-dandruff efficacy of a shampoo containing the extract (1.5%) was performed, against placebo, on a panel of 24 volunteers with dandruff and seborrheic dermatitis. Presence of adherent and non-adherent dandruff was estimated, scalp sebum was measured and the total mass of lipids excreted by surface unit was quantified. In vitro, Rosebay extract inhibited sebum production (-43% at the concentration of 0.1%). In the yeast-exposed skin explant model, the extract induced a protection of the general morphology and the expression of hBD2, hBD3, and TLR2 was neutralized back to normal in the presence of the extract. In vivo, the extract significantly decreased the presence of adherent and non-adherent dandruff by -48% and -54% respectively at D30. Scalp sebum production was also significantly reduced by -67% at D30. Rosebay extract is an efficient anti-dandruff ingredient offering a new strategy to complete or substitute antifungal agent. The extract has proved to effectively and rapidly reduce dandruff production and sebum production in humans.
www.jidonline.org S195