 Objective: According to the hypothesis regarding the stimulating effect of adenosine on increasing fibroblast growth factor-7 in dermal papilla cells and its vasorelaxant effect, we performed this study to compare the effect of topical minoxidil 5% and adenosine 0.75% on male pattern androgenic alopecia. Methods and materials: This prospective-randomized study recruited 110 male patients, who suffered from grade II-V Hamilton androgenic alopecia. Fifty-five patients received minoxidil 5% (group-1) and others received adenosine 0.75% (group-2). Later, 16 patients excluded due to allergic reactions or loss to follow-up. After 3 and 6 months of treatment, complete and relative recovery rates alongside patients\u27 satisfactory rate (faster prevention of primary hair loss and appearance of newly grown hair) were compared between groups. Results: After 3 months of treatment, relative recovery was achieved in 2.4% and 1.9% of patients in group-1 and group-2, which was not significantly different (p-value= 0.17). During 6 months, relative recovery rate did not change nighter within nor between the groups (p-value =0.99) and after 6 months none of the patients achieved complete recovery. However, the patients\u27 satisfactory rate was significantly higher in the group-2 (p-value =0.003). Conclusion: In light of the results, adenosine has no statistically superiority to minoxidil on treatment of androgenic alopecia according to the recovery rates. However, the patients were significantly more satisfied with the adenosine because of the faster prevention of hair loss and appearance of the newly grown hairs. It seems further studies with larger sample size or different drug dosages are required to clarify the findings. </span

Fariba Iraji

gholamreza askari

Gita Faghihi

manijeh Rajaee Harandi

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155ACTA DERMATOVENEROLOGICA CROATICAComparison of the Efficacy of Topical Minoxidil 5% and Adenosine 0.75% Solutions on Male Androgenetic Alopecia and Measuring Patient Satisfaction RateGita Faghihi1,2, Fariba Iraji1,2, Manijeh Rajaee Harandi2, Mohammad-Ali Nilforoushzadeh1,3, Gholamreza Askari1,3 1Skin Diseases and Leishmaniasis Research Center (Sedigheh Tahereh), 2Department of Dermatology, Isfahan University of Medical Sciences, Isfahan, 3Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, IranCorresponding author:Professor Gita Faghihi, MD, PhDDepartment of DermatologyIsfahan University of Medical SciencesIsfahan, Irang_faghihi@med.mui.ac.irReceived: March 13, 2012Accepted: March 25, 2013Acta Dermatovenerol Croat   2013;21(3):155-159                            CLINICAL ARTICLESUMMARY According to the hypothesis on the stimulating effect of adenosine on increasing fibroblast growth factor 7 in dermal papilla cells and its vasorelaxant effect, we performed this study to compare the effect of topical minoxidil 5% and adenosine 0.75% on male pattern androgenetic alopecia. This prospective-randomized study recruited 110 male patients suffering from grade II-V Hamilton androgenetic alo-pecia. Fifty-five patients received minoxidil 5% (group 1) and adenos-ine 0.75% (group 2) each. Later, 16 patients were excluded due to al-lergic reactions or loss to follow up. After 3 and 6 months of treatment, complete and relative recovery rates alongside patient satisfaction rate (faster prevention of primary hair loss and appearance of newly grown hair) were compared between the groups. After 3 months of treat-ment, relative recovery was achieved in 2.4% and 1.9% of patients in group 1 and group 2, respectively, which was not significantly different (p=0.17). During 6 months, the relative recovery rate did not change either within or between the groups (p=0.99) and after 6 months none of the patients achieved complete recovery. However, the patient sat-isfaction rate was significantly higher in group 2 (p=0.003). In the light of the results, adenosine has no statistically superiority to minoxidil in the treatment of androgenetic alopecia according to recovery rates. However, the patients were significantly more satisfied with adenosine because of faster prevention of hair loss and appearance of the newly grown hairs. It seems further studies with larger sample size or different drug dosages are required to clarify the findings.KEY woRdS: androgenetic alopecia, adenosine, minoxidil 5%InTRodUCTIonAndrogenetic alopecia (AGA) or male pattern hair loss is still the imperative cause of alopecia that revealed an obvious tendency to involve half of the population before the age of 50 years (1-5). AGA in general is a hereditary thinning of the scalp hairs by vellus transformation of the terminal hairs due to over repetition of hair growth cycles with shortened anagen phase and miniaturization of the hair follicles 156 ACTA DERMATOVENEROLOGICA CROATICA(3,6,7). Since 1942, when Hamilton first demonstrated that this polygenic inheritance process is mediated mainly by androgen (8), several studies have focused on the hair growth cycle physiology and AGA patho-physiology (2,3,5,9,10). Hair growth cycle is regulated by complex processes, which are the consequences of follicular stem cell and dermal papilla cell (DPC) interactions (9). On the other hand, frontal scalp DPCs are the main target cells of androgen action in AGA (9,10). Androgen binds to the androgen recep-tors and the complex then activates the responsible genes that control hair growth cycles. Consequently, the duration of anagen phase would be shorter and the follicles become miniaturized and produce fine, shorter and less pigmented vellus hairs that are the characteristics of AGA (2,9). In recent years, quite a lot of studies have focused on various pharmacologi-cal approaches such as minoxidil and finasteride to prevent excessive hair loss, promote hair growth and enlarge existing hairs by affecting hair growth cycle in AGA (2,4,9,11-13). Until now, a variety of different direct and indirect effects of minoxidil on hair growth cycle have been studied, such as up-regulating vas-cular endothelial growth factor (VEGF) expression through development of follicular dermal papilla cell vascularization or its direct effects on the prolifera-tion and survival of DPCs and anti-apoptotic effects on DPCs (11,14,15). Minoxidil is still in the first line of treatment of AGA; however, in recent decade and since 2001 when Li et al. (16) reported the correlation between minoxidil and adenosine, scientists have re-vealed a noticeable tendency to focus on the adenos-ine characteristics. In this study, we evaluated the ef-fect of topical minoxidil 5% and adenosine 0.75% on recovery of male pattern AGA. MATERIAlS And METhodSStudy populationThis randomized prospective study recruited 110 adult male patients who suffered from grade II to V Hamilton-Norwood clinical scale AGA (1) and were re-ferred to Hair and Skin Disease Clinic of our hospital. The study was approved by the hospital ethics com-mittee, and a written inform consent was obtained from the patients. Age under 18 years and presence of any signs and symptoms of inflammation or infec-tion on the scalp, hypersensitivity to minoxidil/ade-nosine, and history of hypertension and cardiovascu-lar diseases were considered as exclusion criteria for the study. Also, if any patient was lost to follow up or experienced allergic reaction or severe complication following treatment such as hypertrichosis or exten-sive hair loss, he was excluded from the study. A total of 110 patients were studied and randomly divided into 2 groups: 55 patients received minoxidil 5% (group 1) and another 55 patients received adenos-ine 0.75% (group 2). Later, two patients from group 1 and 14 patients from group 2 were excluded from the study due to allergic reaction to the drug or loss to follow up. So, 94 patients, i.e. 53 (56.4%) group 1 and 41 (43.6%) group 2 patients, remained in the study and were included in analysis. Formulation of the drugsMinoxidil solution was formulated by dissolving 5% minoxidil in a solution of alcohol 60% vol/vol, propylene glycol, and water and adenosine solution was formulated by dissolving 0.75% adenosine in ul-trapure water. Subjects were instructed to apply ap-proximately 1 cc of a lotion topically on the scalp (mi-noxidil 5% in group 1 and adenosine 0.75% in group 2), twice daily for 6 months.hair countingMacro-photography of scalps was performed at baseline and then at 3 and 6 months of treatment. The photographs were converted into dot maps to determine the entire thinning area and counting all visible terminal hairs at a 1-cm2 target evaluation site within thinning area of each of the four quadrants of the frontoparietal and occipitoparietal scalp. The three well-trained physicians, who were blinded to treatment, performed all evaluations. The mean rat-ings of the three investigators represented the evalu-ated factor. Recovery scoring Complete recovery following treatment was de-fined as returning hair growth in 65% to 100% of the thinning area. Relative recovery was defined as returning hair growth in 30% to 65% of the affected area. Hair growth returning in less than 30% of the thinning area was considered as no recovery or treat-ment failure. Patient satisfactionPatient satisfaction was based on the ability of the drug to prevent primary hair loss faster, stimulate growing more pigmented and thick hair with more similar characteristics of terminal hairs, and prevent hair loss recurrence following treatment discontinu-ation.ComplicationsFolliculitis, pruritus, hair loss and hair casts were considered as major complications of treatment. Faghihi et al. Acta Dermatovenerol CroatMinoxidil 5% and adenosine 0.75%  in androgenetic alopecia  2013;21(3):155-159157ACTA DERMATOVENEROLOGICA CROATICAStatistical analysis The univariate analysis of continuous variables was performed with the Student’s t test, and cat-egorical variables were compared using the χ2-test and Fisher exact test, as appropriate. For statistical analyses, SPSS version 16.0 (SPSS Inc., Chicago, IL) was used. All p values were 2-tailed. A p value of less than 0.05 was considered significant.RESUlTSThe study included 94 patients, 53 (56.4%) group 1 and 41 (43.6%) group 2 patients, mean age 30.46±6.28 years and mean androgenetic alopecia duration 6.22±5.09 years. At month 3 of treatmentNone of 94 patients experienced complete recov-ery during 3 months. Relative recovery was achieved in 2.4% of group 1 and 1.9% of group 2 patients, with no significant between-group difference (p=0.17). In the other words, 98.1% of group 1 patients and 97.6% group 2 patients had less than 30% of returning hair growth in the thinning area. At month 6 of treatmentAt the end of 6-month treatment, complete and relative recovery did not reveal changes either within or between the groups (p=0.99). Patient satisfaction rate after 6 months of treatmentThe patient satisfaction rate based on faster pre-vention of primary hair loss and appearance of newly grown hair was significantly higher in the adenosine group (group 2) (p=0.003).ComplicationsFour group 1 patients (9.8%) and two group 2 patients (3.8%) experienced mild complications dur-ing treatment. One patient in group 1 suffered from hair cast and another three patients suffered from increased hair loss. Of the two group 2 patients, one patient suffered from folliculitis and pruritus each. Details are shown in Table 1. dISCUSSIonDespite the low success rate and speculative mechanism of minoxidil in returning normal hair Characteristic Minoxidil 5% (group 1)Adenosine (group 2)Total p-value (between groups)Number of patients 41 (43.60%) 53 (56.40%) 96Age (yrs) 46.46±14.28 44.46±15.28 30.46±6.28 0.90Duration of alopecia 6.24±5.31 6.20±4.97 6.29±5.09 0.97Complications following treatment - pruritus - folliculitis - hair loss - hair cast4 (9.5%)00312 (3.8%)1 (78.95%)1 (21.05%)0011310.17Complete recovery rate - after 3 months of treatment     - after 6 months of treatment 0000-Relative recovery rate  - after 3 months of treatment  - after 6 months of treatment p-value within group1 (2.4%)1 (2.4%)1 (2.4%)1 (2.4%)1 (2.4%)1 (2.4%)2 (2.12%)2 (2.12%)2 (2.12%)0.99Patient satisfaction  - satisfied - not changed - dissatisfied13 (28.4%)22 (52.4%)6 (14.6%)37 (69.8%)16 (30.4%)00.003Data are presented as n (%) and mean ± standard deviation. Faghihi et al. Acta Dermatovenerol CroatMinoxidil 5% and adenosine 0.75%  in androgenetic alopecia  2013;21(3):155-159Table 1. Recovery rate and satisfaction among patients with androgenetic alopecia following administra-tion of topical minoxidil 5% and adenosine 0.75% 158 ACTA DERMATOVENEROLOGICA CROATICAgrowth cycle and promoting hair growth, it is still the first-line treatment for AGA. Minoxidil is an adenosine triphosphate (ATP) sensitive potassium channel open-er that demonstrated some effects on hair growth cy-cle through different mechanisms like up-regulating VEGF expression, stimulating DPC proliferation, in-creasing DPC survival and preventing DPC apoptosis and death (11,14). Expression of VEGF mRNA in DPCs varies among different phases of normal hair growth cycle, with extreme expression in anagen phase, which results in improving dermal papilla vasculariza-tion. There is strong evidence that minoxidil also has effects on improving dermal papilla vascularization by overexpression of the VEGF mRNA and resembling anagen phase alongside opening potassium chan-nels (11,15,17). However, Li et al. (16) suggest that minoxidil has no direct effect on hair growth and its effect is perhaps mediated by adenosine as activation of adenosine receptors in cultured DPCs, thus possi-bly regulating minoxidil-induced production of VEGF. Adenosine is an endogenous molecule that regulates tissue function via binding to and activating one of the four G-protein receptors, A1, A2A, A2B and A3 (18). Since the first discovery of the practical effect of ad-enosine on the cardiac function, adenosine has been investigated in many studies, which have revealed that it is able to regulate all body organ systems suf-ficiently (18-21). In this regard, Lino et al. (20) dem-onstrated that adenosine could stimulate hair growth via up-regulating fibroblast growth factor 7 (FGF-7) in DPCs. Furthermore, Oura et al. (22) confirmed the role of adenosine in stimulation of hair growth and thickening of hair shafts in hair growth cycle anagen phase and stated that adenosine is useful for treating female pattern hair loss as well as androgenetic male alopecia. Another interesting finding by Hwang et al. (21) in 2012 showed the growth of DPCs and length-ening of the anagen phase by increasing the cysteine level via fibroblast growth factors 2 and 7 in an organ culture of mouse vibrissae hair follicles.In this study, the application of adenosine 0.75% solution just once daily showed an equivalent treat-ment effect to that of 5% minoxidil applied once daily in terms of changes in total recovered area by newly grown terminal hairs. After 3 months of treat-ment, relative recovery, i.e. hair growth returning in 30% to 65% of the thinning area, was not significantly different between the groups (p=0.17). In the next 3 months, at the end of month 6, the relative recovery rate did not change either within or between the groups (p=0.99) and none of 94 patients achieved complete recovery during 6 months of treatment. De-spite no between-group difference according to re-covery rate detected by the investigator, the patient satisfaction rate was significantly higher in the ade-nosine group (p=0.003), based on faster prevention of primary hair loss and appearance of newly grown hairs. These results show that minoxidil and adenos-ine have the same effect on recovery of hair loss in AGA and there is no superiority regarding treatment of AGA by adenosine. However, according to the pa-tient satisfaction rate, adenosine is superior as the first-choice treatment for AGA due to faster preven-tion of hair loss and favorable appearance of newly grown hairs. Regardless of differences between the groups, none of the recovery rates achieved in this study was satisfactory enough. It seems to be re-lated to some reasons like insufficient application of solution by patients or inadequate dosage of mi-noxidil and adenosine administered, as in the study reported by Oura et al. (22), the patients applied 3 cc of lotions twice daily for 12 months, which is much greater dosage used over a longer treatment period. Another factor that seems to have influenced the re-sults is monotherapy. Future studies may reveal that utilizing a combination of minoxidil and adenosine just like a combination of minoxidil and finasteride can improve and return hair growth with more pig-mented, thickened, terminal hairs. On the other hand, in the present study, the patients were followed up for up to 6 months, which was a shorter period than the follow up reported from the studies that achieved better results. It could easily affect the result of the study; for instance, in the study by Oura et al. (22), hair appearance improved from 0 in month 6 to 30% in month 12 in adenosine group by dermatologist as-sessment, and from 15% in month 6 to 23% in month 12 by investigator assessment. ConClUSIon The conclusion, the present study interestingly showed that topical application of a solution with 0.75% adenosine had the same effects to minoxidil 5% in the regulation of hair growth cycle and recov-ery of hair loss. According to the patient satisfaction rate, adenosine was superior to minoxidil in the treat-ment of AGA because it could prevent hair loss faster and stimulate hair growth more desirably.References1.  Hamilton JB. Patterned loss of hair in man: types and incidence. Ann N Y Acad Sci 1951;53:708-28.2.  Price VH. Treatment of hair loss. N Engl J Med 1999;341:964-73.3.  Tsuboi R, Arano O, Nishikawa T, Yamada H, Katsu-oka K. Randomized clinical trial comparing 5% and 1% topical minoxidil for the treatment of an-Faghihi et al. Acta Dermatovenerol CroatMinoxidil 5% and adenosine 0.75%  in androgenetic alopecia  2013;21(3):155-159159ACTA DERMATOVENEROLOGICA CROATICAdrogenetic alopecia in Japanese men. J Dermatol 2009;36:437-46.4.  Otberg N, Finner AM, Shapiro J. Androgene-tic alopecia. Endocrinol Metab Clin North Am 2007;36:379-98.5.  Tosti A, Piraccini BM. Androgenetic alopecia. Int J Dermatol 1999;38:1-7.6. Inui S, Nakajima T, Itami S. Scalp dermoscopy of androgenetic alopecia in Asian people. J Der-matol 2009;36:82-5.7.  Uno H, Allegra F, Adachi K, Montagna W. Studies of common baldness of the stumptailed macaque. I. Distribution of the hair follicles. J Invest Dermatol 1967;49:288-96.8.  Hamilton J. Male hormone is prerequisite and inci-tant in common baldness. Am J Anat 1942;71:415-80.9.  Itami S. Hair follicle regeneration. Nihon Rinsho 2008;66:892-6.10. Inui S, Itami S. Molecular basis of androgenetic alopecia: from androgen to paracrine mediators through dermal papilla. J Dermatol Sci 2011;61:1-6.11. Han JH, Kwon OS, Chung JH, Cho KH, Eun HC, Kim KH. Effect of minoxidil on proliferation and apo-ptosis in dermal papilla cells of human hair fol-licle. J Dermatol Sci 2004;34:91-8.12. Zappacosta AR. Reversal of baldness in patient re-ceiving minoxidil for hypertension. N Engl J Med 1980;303:1480-1.13.  DeVillez RL. The therapeutic use of topical minoxi-dil. Dermatol Clin 1990;8:367-75.14. Headington JT. Hair follicle biology and topical minoxidil: possible mechanisms of action. Derma-tologica 1987;175(Suppl 2):19-22.15. Lachgar S, Charveron M, Gall Y, Bonafe JL. Minoxi-dil upregulates the expression of vascular en-dothelial growth factor in human hair dermal pa-pilla cells. Br J Dermatol 1998;138:407-11. 16. Li M, Marubayashi A, Nakaya Y, Fukui K, Arase S. Minoxidil-induced hair growth is mediated by adenosine in cultured dermal papilla cells: possible involvement of sulfonylurea receptor 2B as a target of minoxidil. J Invest Dermatol 2001;117:1594-600.17. Challinor-Rogers JL, McPherson GA. Potassium channel openers and other regulators of KTP chan-nels. Clin Exp Pharmacol Physiol 1994;21:583-97.18. Hasko G, Linden J, Cronstein B, Pacher P. Adeno-sine receptors: therapeutic aspects for inflamma-tory and immune diseases. Nat Rev Drug Discov 2008;7:759-70.19. Hasko G, Pacher P. A2A receptors in inflammation and injury: lessons learned from transgenic ani-mals. J Leukoc Biol 2008;83:447-55.20. Lino M, Ehama R, Nakazawa Y, Iwabuchi T, Ogo M, Tajima M, et al. Adenosine stimulates fibroblast growth factor-7 gene expression via adenosine A2b receptor signaling in dermal papilla cells. J Invest Dermatol 2007;127:1318-25.21. Hwang KA, Hwang YL, Lee MH, Kim NR, Roh SS, Lee Y, et al. Adenosine stimulates growth of der-mal papilla and lengthens the anagen phase by increasing the cysteine level via fibroblast growth factors 2 and 7 in an organ culture of mouse vi-brissae hair follicles. Int J Mol Med 2012;29(2):195-201.22. Oura H, Lino M, Nakazawa Y, Tajima M, Ideta R Nakaya Y, et al. Adenosine increases anagen hair growth and thick hairs in Japanese women with female pattern hair loss: a pilot, double-blind, randomized, placebo-controlled trial. J Dermatol 2008;35:763-7.Faghihi et al. Acta Dermatovenerol CroatMinoxidil 5% and adenosine 0.75%  in androgenetic alopecia  2013;21(3):155-159

Comparison of the efficacy of topical minoxidil 5% and adenosine 0.75% solutions on male androgenetic alopecia and measuring the patients\u27 satisfactory rate

Comparison of the efficacy of topical minoxidil 5% and adenosine 0.75% solutions on male androgenetic alopecia and measuring the patients\u27 satisfactory rate

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