CIC Edizioni Internazionali. Finasteride for androgenetic alopecia and side effects. Review. Introduction

Transcription

1 Review Finasteride for androgenetic alopecia and side effects Alfredo Rossi 1 Marta Carlesimo 2 Giulia Pranteda 1 Maria Caterina Fortuna 1 Cristina Maxia 1 Elisabetta Scali 1 Martina Gerardi 1 Stefano Calvieri 1 Elena Mari 1 1 Department of Internal Medicine and Medical Specialties Dermatology Clinic, Sapienza University of Rome, Italy 2 Dermatology Sapienza, University of Rome, II School, Italy Address for correspondence: Elena Mari Department of Internal Medicine and Medical Specialities Dermatology Clinic Sapienza University of Rome, I School Viale del Policlinico, Rome, Italy elenamari4@virgilio.it Summary Finasteride, a 5-alpha reductase inhibitor, widely used in the medical management of male pattern hairloss, has been reported to cause various side effects, related to sexual dysfunction, gynecomastia, breast cancer, depression, ocular dysfunction and metabolic effects. Even though the etiopathogenesis is not yet completely understood, it has been noted that while many of the side effects are directly related to the drug, the others may not be at all. They are usually minimal or reversible, but may alterate the patient s quality of life or even reduce compliance to treatment. Press reports, internet sites, and misinformation by alternative medicine practitioners, have contributed to an incorrect portrayal of the drug, and led to patients psychological apprehension. In this review, we have attempted to make a critical analysis of the available literature by examining data from various clinical studies, concerning the side effects of finasteride in treating AGA. KEY WORDS: androgenetic alopecia; finasteride; side effects. Introduction Androgenetic alopecia (AGA) in men is characterized by progressive miniaturization of hair follicles and shortening of anagen phase in the vertex, anterior/ mid, frontal, and temporal regions of scalp. AGA is hereditary and androgen-dependent: androgen-dependent processes are predominantly due to the binding of dihydrotestosterone (DHT) to the androgen receptor (AR). The DHT, converted from testosterone (T) by 5-alpha reductase (5AR), is mainly responsible for the changes previously described in hair follicle and in fact predisposed scalps exhibit high levels of DHT, and increased expression of AR (1). The purpose of this data collection process and the results presented in the literature therein, is to determine and describe all the side effects induced by finasteride. Methods AGA, finasteride and side effects A 1 mg daily dose of finasteride administered over a period of 6 months to 1 year, can help improve hair count and thickness by binding irreversibly to 5AR and inhibiting conversion of testosterone to DHT. The highest plasmatic concentration is present after 2 hours and pharmacological half-life is about 6-8 hours (2,3). Finasteride does not alter the link between DHT and its receptor, and has neither affinity to the androgen receptor nor similsteroid activity. Administration of a 1 mg daily dose reduces concentration of scalp DHT and serum DHT by 64% and 68% respectively (4,5). Finasteride is well tolerated as side effects are extremely rare and even when they occur due to increased oestrogen levels, caused by partial conversion of testosterone in estradiol, through the aromatase enzyme, these are easily reversible after suspension of the drug. The increased oestrogen levels can lead to problems like water retention, adiposity, gynecomastia and increased risk of breast cancer infection, while low levels of DHT can lead to sexual dysfunction (reduced libido, reduction in amount of ejaculated semen and erection problems). Depression, ocular symptoms, alterations in lipid metabolism and increased cardiovascular risk, have also occasionally been reported. The case studies are not always collected in a complete and unique systematic review, but are often described separately in individual case reports, in which only sexual dysfunction related side effects are considered and reported. Clinical Dermatology 2013; 1 (4):

2 A. Rossi et al. Sexual dysfunction Since its approval for AGA by FDA, there has not been any large scale study report on a bigger population (6). The most recent and only review that took into consideration the efficacy of finasteride therapy and sexual disorders in AGA was published in 2010 by Mella. It included controlled randomized trials, but did not completely consider the incidence of global sexual disturbances, infact, not all the clinical trials considered, reported a precise incidence of global sexual disturbance. Based on the 12 clinical trials, grouped by Mella, finasteride increased hair count while increasing sexual dysfunction risk, however, due to imprecisions in the data, this could not be determined with certainley (7). We also took into consideration other manuscripts (not reported by Mella), that reported the incidence of global sexual disturbances and other side effects in patients treated with finasteride 1 mg (Tab. 1). Kaufman and Leyden reported 4,2% and 2% respectively of adverse effects incidence in patients treated with finasteride 1mg, with regression of symptoms (8,9). McClellan reported an incidence of 3,8% of sexual dysfunction, that disappeared after suspension of therapy (10). In 2001 Tosti reported the presence of sexual dysfunctions in 0.5% of patients treated with finasteride 1 mg, but he made no reference to their reversibility (11). However, 3 years later his team asked 186 patients with AGA to complete a questionnaire regarding erectile function domain before (IIEF-5) (at baseline) and 4 to 6 months after beginning finasteride treatment. This investigation found that the patients sexual functions remained stable during treatment (12). Whiting reported a slightly higher proportion of finasteride-treated patients (8.7%) compared to placebo-treated patients (5.1%) who experienced a drug-related sexual adverse experience (13). Olsen reported a higher incidence of drug-related sexual adverse experiences in finasteride-treated patients than in placebo-treated patients (14). Rossi et al. described an incidence of 5.9%, but the reversibility was not reported (1). Irwig et al. (15) reported findings after conducting standardized interviews with healthy men aged years, who reported onset of sexually related side effects associated with the temporal use of finasteride in which symptoms persisted for at least three months after suspension of use. Limitations to the study included the small number of patients, recall bias of before finasteride data, and no serum hormone analysis. In 2012 efficacy and safety of oral finasteride 1 mg was examined on AGA of 3177 Japanese men (16). Incidence of adverse reactions was 0.7%. Reduction of DHT, induced by finasteride, can lead to decreased ejaculatory volume. The exact role of androgen in penile erection needs to be fully elucidated; penile erection is mainly under the control of the parasympathetic nervous system. Androgens are integral to maintain the structural integrity of the penile dorsal and cavernosal nerves, the smooth muscle, connective tissue of the corpus cavernosum, and the ignalling pathway in the penis, playing a role in erection disorders. Thus, androgen deficiency, induced by inhibition of 5AR may contribute to erectile dysfunction (17). Any drug, which interferes with the action of androgens, is therefore assumed, to induce impotence. The role of nocebo effect in the causation of ED due to finasteride was also investigated. Nocebo effect refers to an adverse effect that results from the psychological awareness of the possibility of the side effects, but it is not a direct result of the specific pharmacological action of the drug. In many studies patients who developed sexual related side effects had been informed about these in advance, and the fact that these effects were usually completely reversible 5 days after drug suspension, confirms that nocebo effect has an influence in the causation of side effects and suggests the role of psychological factors too (18). By altering sexual performance, a primary requirement of the whole male virility, finasteride can influence mood and consequently the psychological sphere, suggesting a deep relationship between the sexual and emotional field. Yamazaky conducted a study in order to underline the fact that finasteride treatment can improve patients quality of life (QOL). The highly sensitive VAS and DLQI tests, used in the patients evaluation, found that finasteride indeed improved their QOL (19). Recently Ricci (20) reported the first case of successful full-term pregnancy and live birth in two couples, after long-term use of finasteride. This suggests that finasteride, even after several years, does not prevent normal conception and confirms the reversibility of the side effects. The most frequent sexual dysfunctions are erectile dysfunction (ED) ( %) followed by ejaculatory dysfunction ( %) and loss of libido ( %) (21). Gynecomastia From June 1992, when finasteride (Proscar) was approved for the treatment of prostatic hyperplasia, to February 1995, the Food and Drug Administration (FDA) received reports of gynecomastia in 214 men (ages, 47 to 90 years; median, 71) who were taking the drug in the United States. Gynecomastia has been the most frequently reported adverse effect of this drug, with an onset ranging from 14 days to 2 and a half years (median, 180 days) after the initiation of therapy. Most of the men were taking the recommended daily dose of 5 mg, about 30% had unilateral gynecomastia, 25% had bilateral involvement and for 45% the side or sides involved were not specified. Wilton and Pearce reported 0.4% of incidence after one year of treatment for benign prostatic hypertrophy (mean age 69 years), with no reference of reversibility (22). Ginecomastia, however, was not reported originally as a side effect in the large trial of finasteride 1 mg/day as a treatment for AGA, (8) and it was averred that there was no evidence that this dose caused breast tenderness or enlargement (10). Nevertheless, several reports have described gynecomastia as a side effect of finasteride even in lower doses (Tab. 2). Two men in whom gynecomastia developed during finasteride therapy were subsequently found to have pri- 198 Clinical Dermatology 2013; 1 (4):

3 Finasteride for androgenetic alopecia and side effects Table 1 - Summary of study characteristics of finasteride reporting sexual adverse events. Source Study/Center Duration Diagnosis Age Drug (N=) Placebo (N=) Incidence of Incidence of Reversibility of (year) Sexual dysfunction Sexual dysfunction side effects in Placebo 1998 Kaufman Multicenter 1+1 AGA ,2% 2,2% Resolved after suspension of therapy 1999 McClellan Review 2 AGA ,8% 2,1% Resolved after suspension of therapy 1999 Leyden Multicenter 1+1 AGA % Resolved during therapy 2001 Tosti Observational 8 months AGA ,5% study 2003 Whiting Multicenter 2 AGA ,7% 5,1% Not reported 2004 Tosti Multicenter 4-6 months AGA No significant change Resolved After suspension 2006 Olsen Multicenter 1+1 AGA Higher incidence (I anno) compared with placebo Not reported (II anno) (finasteride) (finasteride) 65(placebo) 60(placebo) (II anno) 2011 Rossi Observational 10 AGA ,9% Not reported study 2011 Irwig Observational AGA % low libido Mean duration 40 study 92% erectile months (standardized dysfunction 20% persistent interview) 92% decreased over 6 years arousal 69% problems with orgasm 2012 Sato Observational 3 AGA ,7% (all side effects) Not reported study Clinical Dermatology 2013; 1 (4):

4 A. Rossi et al. Table 2 - Summary of study characteristics of finasteride reporting gynecomastia. Side effects Author Diagnosis Drug (N=) Period of onset Incidence Reversibility of side effects Gynecomastia Wilton and Prostatic Variable 0,4% Not reported Pearce 1996 hypertrophy Green 1996 Prostatic Data reported Ranging from 14 days to 214 patients. Two of these 80 % had partial or complete remission hypertrophy from the FDA 2 ½ years developed after a primary after discontinuation in the USA intraductal breast carcinoma McClellan AGA 1879 There is no evidence that 1999 finasteride 1 mg/day causes breast tenderness or enlargement Wide and AGA 1 case Two months after 1 case report Resolved 4 weeks after stopping Sinclaire 2000 report finasteride initiation finasteride Ferrando and AGA 4 case -Two months after 4 case reports -Ten months after finasteride suspension Grimalt 2002 reports -finasteride initiation -Two months after finasteride suspension -Six months after -Three months after finasteride -finasteride initiation -suspension -Three months after -Not reported -finasteride initiation -One year after finasteride -initiation Thompson Prostatic 426 Variable 4,5% Not reported 2003 hypertrophy Finasteride 5mg Schmutz and AGA 4 case -Two months after 4 case reports -Two months after finasteride suspension Barband 2004 reports -finasteride initiation -Two months after finasteride suspension -Six months after -Three months after finasteride -finasteride initiation -suspension -Three months after -Not reported -finasteride initiation -One month after -finasteride initiation Ramot and AGA 2 case -Four months after 2 case reports -Ten months after finasteride suspension Czarnowicki reports -finasteride initiation -Two months after finasteride suspension, Two months after -but after 6 months a slight residual -finasteride initiation -swelling was present Mansouri and AGA 2 case -Seven months after 2 case reports -Four months after finasteride suspension Farshi 2009 reports -finasteride initiation -Three months after finasteride -Twenty days after -suspension, but breast enlargement -finasteride initiation -remained 200 Clinical Dermatology 2013; 1 (4):

5 Finasteride for androgenetic alopecia and side effects mary intaductal breast carcinoma (23). McClellan (10) reported that there was no evidence that finasteride 1 mg/day caused breast tenderness or enlargement, confirming Merck Research Laboratorie s data, where incidence of breast tenderness occurred as often as it did in placebo- treated patients (0.4%). Wade and Sinclair reported a case of reversible painful gynecomastia induced by finasteride (1 mg/day) (24). Other four cases of gynecomastia with low doses of finasteride were described by Ferrando and Grimalt (25) and Schmutz and Barbaud (26). In his study Thompson described the side effects, reported by patients on finasteride 5 mg treatment (27). Ramot and Czarnowicki (28) reported two cases of gynecomastia, one of which bilateral and caused by finasteride. Ramot and Czarnowicki (28) reported two cases of gynecomastia, one of which bilateral and caused by finasteride. Mansouri and Farshi (29) reported other two cases, one of which had aroused after 7 months of therapy and did not disappear. The process through which finasteride induces gynecomastia is not completely understood. Theoretically, finasteride could cause gynecomastia by reducing dihydrotestosterone in serum, shifting metabolism of T toward estradiol and altering the estrogen to androgen ratio. Breast cancer Male breast cancer is a rare disease with an incidence in the general population of 1/ man- years (30). Shenoy (31) made a review, summarizing the possible risk of breast carcinoma in males with long term usage of finasteride in the Modern Humanities Research Association (MHRA). From 1992 to 2009, there have been 50 worldwide case reports of male breast cancer in benign prostatic hypertrophy in patients treated with finasteride 5 mg. Twenty-seven cases occurred after finasteride treatment for a minimum of 1 year. Only 3 cases of male breast cancer in patients, treated with 1 mg, were reported. Anyway, due to inadequate information and the relatively short tumour onset times, the possible association between male breast cancer and finasteride cannot be completely justified (32). However, inhibition of DHT production alters the oestrogen-to-androgen ratio and may also increase the risk of gynecomastia and male breast cancer, especially in men with constitutional increased estradiol levels or reduced T levels. Ocular disorders The first case of cataract induced by finasteride 1mg, was reported by Chou (33), who observed for 3 months, the decreasing vision in both eyes of a 43- year-old man, that had discontinued the drug. Wong (34) presented the case of a man, who had been using finasteride for AGA for 4 years and was complaining of progressive bilateral blurring of vision and had developed bilateral anterior subcapsular cataracts and features of intraoperative floppy-iris syndrome. Several other drugs are known to be associated with cataract formation, but cataracts induced by most other drugs do not usually regress even when the drug is stopped. In this case, the patient received cataract extraction soon after initial presentation, so Wong was unable to tell whether stopping finasteride would have reversed the cataract formation (34). Depression Babak and Rahimi enrolled 128 men who had been subjected to finasteride (1 mg/day) for AGA, (35) in order to evaluate depressed mood and anxiety using Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS). Participants completed BDI and HADS questionnaires before beginning treatment and two months after. Treatment increased both depression scores significantly. Dihydroprogesterone (DHP), produced from progesterone by 5AR, is further converted to allopregnanolone, that is a modulator of gamma amino butyric acid type A receptor (GABA-A) and has anti-convulsant, anaesthetic and anxiolytic effects (36). Changes in levels of allopregnanolone could be considered a cause of depressive disorders (36). Barrett-Connor et al. showed that BDI scores were inversely associated with bioavailable testosterone and DHT levels, suggesting that high serum DHT levels, is inversely associated with depression (37). In agreement with Babak and Rahimi, Altomare (38) reported the case of 19 patients who developed a mood disturbance during treatment with finasteride, 1 mg/day. Depression was associated to marked anxiety in some cases, developed after 9-19 weeks of treatment and resolved after suspension of therapy. In the study Donald Rogers published, about all the drugs that could induce depression, finasteride was mentioned (39). Irwig assessed depressive symptoms and suicidal thoughts in former users of finasteride, who developed persistent sexual side effects despite the discontinuation of finasteride (40). Clinicians and potential users of finasteride should be aware of the potential risk of depressive symptoms and suicidal thoughts. This is why all patients/candidates should complete a BDI-II test, before starting finasteride therapy for AGA. Moreover, depression could have an influence on the onset of side effects (nocebo effect). Metabolic effects Recent studies showed that DHT could play a role in the metabolism of visceral fat. Duskova analysed the relationship between assumption of the drug in the treatment of AGA and improvement of some characteristics of metabolic syndrome, often associated to this condition. Twelve men affected by AGA, who had been undergoing finasteride 1mg/day therapy for 12 months were examined, monitoring hormonal and lipid profile after 4, 8 and 12 months of treatment. Results showed a reduction of DHT and an increase of testosterone and androstenedione. As far as metabolic profile is concerned, they found an early increase of total cholesterol, LDL and HDL, that tended to stabilize with pursuance of therapy, as well as a significant reduction of glycosylated hemoglobin and insulin resistance (41). Clinical Dermatology 2013; 1 (4):

6 A. Rossi et al. Over the past few decades, various Authors have investigated the relationship between male AGA and cardiovascular involvement. Cotton (42) and Hirrso (43) reported an increase in cardiovascular risk. Ellis (44) did not find any association. Lotufo (45) showed an association between severity of baldness and coronary artery disease. This fact could be justified, as reported in the given literature, by the presence of 5AR and DHT receptors on blood vessels, inducing a proliferation of vessel smooth-muscle cells. Moreover patients affected by AGA present an increase in sensitivity to andogens not only in the scalp, but also in the vessels, promoting atheroma development (46). Management of the reactions In conclusion, finasteride is the safest available drug for treatment of AGA as has been documented by several studies. It s side effects are reversible and have even been known to disappear after suspension of therapy in many patients, although some persistent cases were described in the given literature. Obviously this is not possible for breast cancer or cataract, therefore, in order to reduce risk of side effects, it is important to study the patient s personal and family history and in some men even carryout laboratory and instrumental examinations, before and during the finasteride therapy. Patients should also complete IIEF-5 and BDI-II, which should then be evaluated by physicians, before and during the therapy. If a side effect appears, the therapy should be suspended immediately and not just reduced as is suggested in the given literature (10). As far as we are concerned the efficacy of the minor dosage should first be demonstrated and besides the minor dosage could probably lead to the same side effects. To the best of our knowledge this is the first review that has critically analysed and examined all the possible side effects potentially induced by finasteride 1 mg. Nevertheless, in order to demonstrate the existence of a direct relationship between finasteride and the side effects listed above, it is necessary to carryout large scale randomized and controlled trials on patients, with the help of laboratory examinations and standardized questionnaires like IIEF-5 and BDI-II, during the therapy and after the suspension of the drug. References 1. Rossi A, Cantisani C, Scarnò M, Trucchia A, et al. Finasteride, 1 mg daily administration on male androgenetic alopecia in different age groups: 10- year follow-up. Dermatol Ther 2011; 24(4): Abe M, Ito Y, Oyunzu L, Oki-Fujino T, Yamada S. Pharmacologically Relevant Receptor Binding Characteristics and 5-α-Reductase Inhibitory Activity of Free Fatty Acids Contained in Saw Palmetto Extract. Biol Pharm Bul 2009; 32(4): Schweiger ES, Boychenko O, Bernstein RM. Update on the pathogenesis, genetics and medical treatment of patterned hair loss. J Drugs Dermatol 2010; 9(11): Rajput RJ. Controversy: is there a role for adjuvants in the management of male pattern hair loss? J Cutan Aesthet Surg 2010; 3(2): Stout SM, Stumpf JL. Finasteride treatment of hair loss in women. Ann Pharmacother 2010; 44(6): Kawashima M, Hayashi N, Igarashi A, Kitahara H, et al. Finasteride in the treatment of Japanese men with male pattern hair loss. Eur J Dermatol 2004; 14(4): Mella JM, Perret MC, Manzotti M, Catalano HN, Guyatt G. Efficacy and safety of finasteride therapy for androgenetic alopecia: a systematic review. Arch Dermatol 2010; 146(10): Kaufman KD, Olsen EA, Whiting D, Savin R, et al. Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group. J Am Acad Dermatol 1998; 39(4 Pt 1): Leyden J, Dunlap F, Miller B, Winters P, et al. Finasteride in the treatment of men with frontal male pattern hair loss. J Am Acad Dermatol 1999; 40: McClellan KJ, Markham A. Finasteride: A review of its use in male pattern hair loss. Drugs 1999; 57: Tosti A, Piraccini BM, Soli M. Evaluation of sexual function in subjects taking finasteride for the treatment of androgenetic alopecia. J Eur Acad Dermatol Venereol 2001; 15: Tosti A, Pazzaglia M, Soli M, Rossi A, et al. Evaluation of Sexual Function With an International Index of Erectile Function in Subjects Taking Finasteride for Androgenetic Alopecia. Arch Dermatol 2004; 140: Whiting DA, Olsen EA, Savin R, Halper L, Rodgers A, Wang L, Hustad C, et al. Efficacy and tolerability of finasteride 1 mg in men aged 41 to 60 years with male pattern hair loss. Eur J Dermatol 2003; 13(2): Olsen EA, Whiting DA, Savin R, Rodgers A, et al. Global photographic assessment of men aged 18 to 60 years with male pattern hair loss receiving finasteride 1 mg or placebo. Male Pattern Hair Loss Study Group. J Am Acad Dermatol 2012; 67(3): Irwig MS, Kolukula S. Persistent sexual side effects of finasteride for male pattern hair loss. J Sex Med 2011; 8(6): Sato A, Takeda A. Evaluation of efficacy and safety finasteride 1 mg in 3177 japanese men with androgenetic alopecia. J Dermatol 2012; 39: Traish AM, Hassani J, Guay AT, Zitmann M, Hansen ML. Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients. J Sex Med 2011; 8(3): Hahn RA. The nocebo phenomenon: concept, evidence, and implications for public health. Prev Med 1997; 26(5 ): Yamazaki M, Miyakura T, Uchiyama M, Hobo A, et al. Oral finasteride improved the quality of life of 202 Clinical Dermatology 2013; 1 (4):

7 Finasteride for androgenetic alopecia and side effects androgenetic alopecia patients. J Dermatol 2011; 38(8): Ricci G, Martinelli M, Luppi S, Lo Bello L, et al. Finasteride and fertility: case report and review of the literature. J Drugs Dermatol 2012; 11(12): Mysore V. Finasteride and sexual side effects. Indian Dermatol Online J 2012; 3(1): Wilton L, Pearce G, Edet E, Freemantle S, et al. The safety of finasteride used in benign prostatic hypertrophy: A non-interventional observational cohort study in patients. Br J Urol 1996; 78: Green L, Wysowski DK, Fourcroy JL. Gynecomastia and breast cancer during finasteride therapy. N Engl J Med 1996:12; 335(11): Wade MS, Sinclair RD. Reversible painful gynaecomastia induced by low dose finasteride (1 mg/day). Australas J Dermatol 2000; 41(1): Ferrando J, Grimalt R, Alsina M, Bulla F, Manasievska E. Unilateral gynecomastia induced by treatment with 1 mg of oral finasteride. Arch Dermatol 2002; 138(4): Schmutz JL, Barbaud A, Trechot P. Finasteride (Propecia) and gynaecomastia: 4 new cases. Ann Dermatol Venereol 2004; 131(6-7 Pt 1): Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, et al. The influence of finasteride on the development of prostate cancer. N Eng J Med 2003; 349: Ramot Y, Czarnowicki T, Zlotogorski A. Finasteride induced Gynecomastia: Case report and Review of the literature. Int J Trichology 2009; 1(1): Mansouri P, Farshi S, Safar F. Finasteride-induced gynecomastia. Indian J Dermatol Venereol Leprol 2009; 75(3): Lee SC, Ellis RJ. Male breast cancer during finasteride therapy. J Natl Cancer Inst 2004; 96: Shenoy NK, Prabhakar SM. Finasteride and male breast cancer: does the mhra report show a link? Cutan Aesthet Surg 2010; 3(2): Post-marketing reports of male breast cancer, UK MHRA Assessment, April Chou SY, Kao SC, Hsu WM. Propecia-associated bilateral cataract. Clin Experiment Ophtalmol 2004; 32(1): Wong AC, Mak ST. Finasteride-associated cataract and intraoperative floppy-iris syndrome. J Cataract Refract Surg 2011; 37(7): Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A. Finasteride induced depression: a prospective study. BMC Clin Pharmacol 2006; 6: Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol 1995; 7: Barrett-Connor E, Von Mühlen DG, Kritz-Silverstein D. Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study. J Clin Endocrinol Metab 1999; 84: Altomare G, Capella GL. Depression circumstantially related to the administration of finasteride for androgenetic alopecia. J Dermatol 2002; 29(10): Rogers D, Pies R. General Medical Drugs Associated with Depression. Psychiatry (Edgmont) 2008; 5(12): Irwig MS. Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. J Clin Psychiatry. 2012; 73(9): Duskova M, Hill M, Starka L. Changes of metabolic profile in men treated for androgenetic alopecia with 1 mg finasteride. Endocr Regul 2010; 44(1): Cotton SG, Nixon JM, Carpenter RG, Evans DW. Factors discriminating men with coronary heart disease from healthy controls. Br Heart J 1972; 34: Hirsso P, Rajala U, Hiltunen L, Jokelainen J, Keinanen-Kiukaanniemi S, Nayha S. Obesity and low-grade inflammation among young Finnish men with early-onset alopecia. Dermatology 2007; 214: Ellis JS, Stebbing M, Harrap SB. Male pattern baldness is not associated with established cardiovascular risk factors in the general population. Clin Sci (Colch) 2001; 100: Lotufo PA, Chae CU, Ajani UA, Hennekens CH, Manson JE. Male pattern baldness and coronary heart disease: the physician s health study. Arch Intern Med 2000; 160: Fujimoto R, Morimoto I, Morita E, Sugimoto H, Ito Y, Eto S. Androgen receptors, 5 alfa-reductase activity and androgen-dependent proliferation of vascular smooth muscle cells. J Steroid Biochem Mol Biol 1994; 50: Clinical Dermatology 2013; 1 (4):