Dermatology: Practical and Conceptual Research | Dermatol Pract Concept 2020;10(2):e2020039 1 Dermatology Practical & Conceptual Efficacy of Topical Finasteride 0.5% vs 17α-Estradiol 0.05% in the Treatment of Postmenopausal Female Pattern Hair Loss: A Retrospective, Single-Blind Study of 119 Patients Alfredo Rossi,1 Francesca Magri,1 Andrea D’Arino,1 Flavia Pigliacelli,1 Marta Muscianese,1 Pierpaolo Leoncini,2 Gemma Caro,1 Alessandro Federico,1 Maria Caterina Fortuna,1 Marta Carlesimo1 1 Division of Dermatology, Department of Internal Medicine and Medical Specialties, Sapienza University, Rome, Italy 2 Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bambino Gesù Children’s Hospital, Rome, Italy Key words: female pattern hair loss, topical finasteride, 17α-estriadol, minoxidil Citation: Rossi A, Magri F, D’Arino A, Pigliacelli F, Muscianese M, Leoncini P, Caro G, Federico A, Fortuna MC, Carlesimo M. Efficacy of topical finasteride 0.5% vs 17α-estradiol 0.05% in the treatment of postmenopausal female pattern hair loss: a retrospective, single-blind study of 119 patients. Dermatol Pract Concept. 2020;10(2):e2020039. DOI: https://doi.org/10.5826/dpc.1002a39 Accepted: November 3, 2019; Published: April 20, 2020 Copyright: ©2020 Rossi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: None. Competing interests: The authors have no conflicts of interest to disclose. Authorship: All authors have contributed significantly to this publication. Corresponding author: Alfredo Rossi, MD, Division of Dermatology, Department of Internal Medicine and Medical Specialties, Sapienza University, viale del Policlinico 155, 00100, Rome, Italy. Email: alfredo.rossi@uniroma1.it Background and Objectives: Female pattern hair loss (FPHL) is a common form of scalp hair loss that occurs in 38% of females. Currently, minoxidil solution is the only therapy approved by the US Food and Drug Administration, but many other treatments are used, including cyproterone acetate, spironolactone, topical 17α-estradiol, and prostaglandin analogs. Systemic finasteride has been con- sidered a treatment option in women even though its teratogenic effects tend to limit its prescription. Recently, topical finasteride has been evaluated to limit the side effect profile of the drug. The objective of the present study is to compare retrospectively the efficacy of topical 0.05% 17α-estradiol solution and a 0.5% finasteride lotion in the treatment of FPHL. Patients and Methods: We enrolled 119 postmenopausal female patients. The first group comprised 69 women treated with finasteride 0.5% and minoxidil 2%. The second group included 50 women treated with 17α-estradiol 0.05% and minoxidil 2%. At baseline and at 6- and 12- to 18-month fol- low-up, global photographs were systematically taken. Three operators blind to the prescribed treat- ment evaluated photographs using a 7-point scale. One-way analysis of variance and unpaired Student t tests were performed to analyze 7-point scale scores. Results: The improvement was statistically significant from 6 months to 12-18 months, both for fin- asteride (P < 0.005) and 17α-estradiol (P < 0.05). The efficacy of topical finasteride was significantly ABSTRACT https://doi.org/10.5826/dpc.1002a39 mailto:alfredo.rossi@uniroma1.it 2 Research | Dermatol Pract Concept 2020;10(2):e2020039 The sample included 119 female patients affected by FPHL (I-II-III type of Ludwig classification) followed in our Department of Dermatology. Inclu- sion criteria and exclusion criteria for the study are summarized in Table 1. Patients undergoing treatment 1 comprised 50 female patients, topically treated with a galenic 100-mL solution containing finasteride 0.5%, minoxidil 2%, hydrocortisone butyrate 0.08%, and cyclosilicone pentamer 16% in alco- hol 96° 81.4%. Patients were between 46 and 74 years old and were observed between 2016 and 2019. Patients undergoing treatment 2 comprised 69 female patients who were prescribed a 100-mL galenic formulation containing 17α-estradiol 0.05%, minoxidil 2%, hydrocortisone butyrate 0.08%, and cyclosilicone pentamer 16% in alcohol 96° 81.87%. Patients were observed within a 10-year time range, from 2009 to 2019. The patients’ ages ranged from 45 to 79 years. All patients were instructed to apply 1 mL of the assigned topical solution every night, on the vertex and frontal mineral supplements, and prostaglandin analogs, as well as surgical therapy and light therapy [10]. The weak estrogen 17α-estradiol has been used for many years as a 0.25-mg/mL topical alter- native for the treatment of both male androgenetic alopecia and FPHL given the absence of feminizing estrogenic activity [11] and its ability to weakly inhibit 5α-reductase. The objective of the present study was to compare retrospectively the effi- cacy of a topical 0.05% 17α-estradiol solution and a 0.5% finasteride lotion in the treatment of FPHL. Methods We performed an observational retro- spective single-blind study of 119 female postmenopausal patients affected by FPHL. The purpose of this study was to evaluate and compare the efficacy of 2 different FPHL treatments: topi- cal finasteride 0.5% and minoxidil 2% lotion (treatment 1) vs 17α-estradiol 0.05% and minoxidil 2% formulation (treatment 2). Introduction Female pattern hair loss (FPHL), once known as female androgenetic alopecia, is a common form of nonscarring scalp hair loss in women occurring in 38% of women between the ages of 50 and 70 years [1,2]. It is characterized by a pro- gressive miniaturization of hair follicles especially localized in the frontal, cen- tral, and parietal regions of the scalp [3]. The pathophysiology of FPHL is still not completely clear. Even though genetic and hormonal factors are considered involved as in the more common male form [4], its link to androgen hormones is less clear as it has been shown to appear in females affected by complete androgen insensitivity syndrome [5]. The 2 drugs approved by the US Food and Drug Administration (FDA) and European Medicines Agency for the treatment of male androgenetic alopecia are topical 2% and 5% minoxidil and oral finasteride (1 mg/day) [6]. Cur- rently, minoxidil solution is the only FDA-approved therapeutic option for FPHL. Finasteride is a selective type II 5α-reductase inhibitor, the enzyme responsible for the conversion of tes- tosterone (T) to its more active form dihydrotestosterone (DHT). It has been considered a treatment option also in women even though its terato- genic effects tend to limit its prescrip- tion. Reports of its efficacy in women are contradictory, with less consistent results than in men [7,8]. Recently, top- ical formulations have been evaluated to limit the side effect profile of the drug [9]. Other commonly used therapies in FPHL are cyproterone acetate, spirono- lactone, flutamide, topical 17α-estradiol, greater than that of 17α-estradiol solution, both at the 6-month (P < 0.05) and at the 12- to 18-month follow-up (P < 0.005). In general, the highest improvement was observed after 12-18 months of treat- ment with topical finasteride therapy. Conclusions: Topical finasteride 0.5% in combination with minoxidil 2% could represent a valid therapeutic option for the treatment of postmenopausal FPHL, showing higher efficacy than topical 17α-estradiol with minoxidil 2% both at 6-month and 12- to 18-month follow-up. ABSTRACT Table 1. Inclusion and Exclusion Criteria for the Study Inclusion criteria: • Postmenopausal patients • Female pattern hair loss • Type I-II-III of Ludwig classification • No other concomitant treatments, including hormonal replacement therapy Exclusion criteria: • Concomitant treatments of the scalp • Associated systemic diseases and/or systemic therapies which could influence hair growth (such as oncological patients undergoing chemotherapy) • Concomitant scalp diseases (such as lichen planopilaris, alopecia areata, frontal fibrosing alopecia, telogen effluvium) Research | Dermatol Pract Concept 2020;10(2):e2020039 3 excluded these patients from further analyses. The following results apply only to patients who showed improve- ment following treatment (n = 112). We tested whether the 2 treatments led to improvements of different entity by comparing the mean ratings on the 7-point scale. The improvement was statistically significant from 6 months to 12-18 months, both for finasteride (P < 0.005) and 17α-estradiol (P < 0.05) galenic −1 on the 7-point scale). In the group to which treatment 2 (17α-estradiol) was prescribed, 64 out of 69 patients (92.7%) showed improvement. Four out of 69 patients worsened after 12-18 months (average rating of −1 in all cases), while 1 patient had worse scores already at 6 months (rated −2 after 6 months and −1 after 12-18 months). Given the small number of patients who showed a worsening of their con- dition following either treatment, we region. Follow-up visits occurred after 6 and 12-18 months. At the time of the diagnosis, and at each of the follow-up visits, pictures of the frontal and vertex scalp regions were systematically taken using a FotoFinder Video Dermatoscope (Medicam 800). The instrument was placed on the rotating arm of a head-po- sitioning device (Canfield Scientific), permitting a standardized photograph collection. To assess the improvement at dif- ferent time intervals, 3 operators blind to the prescribed treatment evaluated photographs of the affected areas for each patient at baseline, at 6 months, and at 12-18 months from diagnosis. For the evaluation, a 7-point improve- ment scale was used. This is a standard- ized quantitative score for measuring the hair growth and clinical response: −3 = greatly decreased, −2 = moderately decreased, −1 = slightly decreased, 0 = no change, +1 = slightly increased, +2 = moderately increased, and +3 = greatly increased. All operators rated photo- graphs for all participants at all time points, and the score was then averaged. Statistical Analyses One-way analysis of variance and unpaired Student t tests were performed using SPSS software v19 (IBM, Armonk, NY, USA) and GraphPad Prism v6 (GraphPad software, San Diego, CA, USA). Confidence interval was set to 95% assuming statistically significant P values ≤ 0.05. Results In our sample of 119 patients, hair loss improvement was observed in 112 women, while worsening was noticed in 7 patients. Specifically, in the group to which treatment 1 (topical finasteride) was prescribed, 48 out of 50 patients (96%) showed improvement, while 2 out of 50 showed an increase of hair loss after 6 months (both of these patients’ photographs had an average rating of Figure 1. Scalp photographs and trichoscopy of a patient undergoing topical treatment with finasteride lotion, at baseline (A,C) and after 6 months of therapy (B,D). Figure 2. Macroscopic and trichoscopy pictures of a patient under treatment with 17α-estra- diol topical lotion, at baseline (A,C) and after 6 months of therapy (B,D). 4 Research | Dermatol Pract Concept 2020;10(2):e2020039 formulations (Figures 1-3). More important, the efficacy of topical fin- asteride (treatment 1) was significantly greater than that of the 17α-estradiol solution (treatment 2), both at the 6-month (P < 0.05) and at the 12- to 18-month follow-up (P < 0.005) (Fig- ure 4). In general, the highest improve- ment was observed after 12-18 months of treatment with topical finasteride and minoxidil therapy (Figure 5). Discussion In our work, we compared 2 galenic formulations for the treatment of FPHL. The first 100-mL solution contained 17α-estradiol 0.05%, minoxidil 2%, hydrocortisone butyrate 0.08%, and cyclosilicone pentamer 16% in alcohol 96° 81.87%. The second 100-mL for- mulation was composed of finasteride 0.5%, minoxidil 2%, hydrocortisone butyrate 0.08%, and cyclosilicone pen- tamer 16% in alcohol 96° 81.4%. Hydrocortisone butyrate is a class II steroid that blocks the inflamma- tory process induced by lymphocytic peri-infundibular and peristhmic infil- trate [12,13]. Minoxidil is a piperidinopyrimidine derivative and its action is believed to be due to its vasodilator properties. This is realized through the opening of potas- sium channels localized on the smooth muscular cells of the peripheral artery [14]. Approved in 1979 for hyperten- sion, it is largely used as a topical prod- uct for alopecia owing to its common adverse effect of inducing hair growth. Minoxidil modifies the hair cycle, short- ening the telogen phase or prolonging the anagen phase [12]. It directly stimu- lates the dermal papilla or the follicular hair matrix cells, causing an increase of vascular endothelial growth factor and consequently angiogenesis [12,15]. Fur- thermore, it has been hypothesized that it activates the prostaglandin endoper- oxide synthetase enzyme type I, which induces hair growth [16]. Figure 3. Using the 7-point scale, the improvement was statistically significant from 6 months to 12-18 months, both for finasteride (P < 0.0027) and 17α-estradiol (P < 0.0205). EST = 17α-estradiol; FIN = finasteride; FPHL = female pattern hair loss; 0 = no change; 1 = slightly increased; 2 = moderately increased; 3 = greatly increased. Figure 4. Greater efficacy of topical finasteride than 17α-estradiol solution, both at 6 months (P < 0.0368) and at 12-18 months follow-up (P < 0.0042). EST = 17α-estradiol; FIN = finas- teride; 0 = no change; 1 = slightly increased; 2 = moderately increased; 3 = greatly increased. Figure 5. The highest improvement is observed after 12 to 18 months of treatment with topical finasteride and minoxidil therapy. Currently, minoxidil is the only FDA-approved therapeutic option for FPHL [17]. The 2% concentration was approved in 1991, and 5% minoxidil was approved in 2014 [18]. Systemic finasteride inhibits the type II 5α-reductase, which normally cat- alyzes the conversion of testosterone (T) to dihydrotestosterone (DHT), the more active form of T. Finasteride is Research | Dermatol Pract Concept 2020;10(2):e2020039 5 pausal FPHL, showing higher efficacy than topical formulation containing 17α-estradiol 0.05% in combination with minoxidil 2% and hydrocortisone butyrate 0.08%, both at 6-month and 12- to 18-month follow-up. References 1. Birch MP, Messenger JF, Messenger AG. Hair density, hair diameter and the prev- alence of female pattern hair loss. Br J Dermatol. 2001;144(2):297-304. 2. Price VH. Androgenetic alopecia in women. J Investig Dermatol Symp Proc. 2003;8(1):24-27. 3. Olsen EA. Female pattern hair loss and its relationship to permanent/cicatricial alopecia: a new perspective. J Investig Dermatol Symp Proc. 2005;10(3);217- 221. 4. Messenger AG. Hair through the female life cycle. Br J Dermatol. 2011;165( Sup- pl 3):2-6. 5. Cousen P, Messenger A. Female pat- tern hair loss in complete androgen insensitivity syndrome. Br J Dermatol. 2010;162(5):1135-1137. 6. Rossi A, Anzalone A, Fortuna MC, et al. Multi-therapies in androgenetic alopecia: review and clinical experiences. Derma- tol Ther. 2016;29(6):424-432. 7. Iorizzo M, Vincenzi C, Voudouris S, Pi- raccini BM, Tosti A. Finasteride treat- ment of female pattern hair loss. Arch Dermatol. 2006;142(3):298-302. 8. Olszewska M, Rudnicka L. Effective treatment of female androgenic alope- cia with dutasteride. J Drugs Dermatol. 2005;4(5):637-640. 9. Lee SW, Juhasz M, Mobasher P, Ekelem C, Mesinkovska NA. A systematic review of topical finasteride in the treatment of androgenetic alopecia in men and wom- en. J Drugs Dermatol. 2018;17(4):457- 463. 10. Choe SJ, Lee S, Choi J, Lee WS. Thera- peutic efficacy of a combination therapy of topical 17alpha-estradiol and topical minoxidil on female pattern hair loss: a noncomparative, retrospective evalu- ation. Ann Dermatol. 2017;29(3):276- 282. 11. Moos WH, Dykens JA, Howell N. 17α-Estradiol: a less-feminizing estrogen. Drug Dev Res. 2008;69(4):177-184. 12. Rossi A, Iorio A, Scarnò M, et al. Use of topical minoxidil, 17α-estradiol and hy- drocortisone butyrate in frontal fibrosing parable with the improvement of 17α-estradiol-treated patients at 12-18 months. Indeed, topical 17α-estradiol therapy required more time to achieve the same results of finasteride. The greater rapidity and higher effi- cacy of finasteride could be explained with 2 observations. First, finasteride induces a stronger block of type II 5α-re- ductase, if compared with the weak inhibition of 17α-estradiol. Moreover, the inhibition of type II 5α-reductase induced by finasteride could cause a T escape, which in turn stimulates the aro- matases, increasing estradiol conversion and guaranteeing an adjunctive activity similar to that of 17α-estradiol. As we have shown, both therapies produced an improvement that was already visible at 6 months and espe- cially after 12-18 months. Indeed, the treatment should be always continued for long periods to achieve better results. Concerning topical finasteride’s side effects, a systemic absorption is possi- ble, as described by Caserini et al [22]. Also, Suchonwanit et al demonstrated a lower serum level of DTH in postmeno- pausal women treated with it. Indeed, topical finasteride should be used only in postmenopausal women. A limit of our study was the absence of a control group. Another limit was the lack of hair analysis besides global photographs. We did not perform a computerized quan- titative measure (Trichoscale) because most of our female patients refused to realize a circumscribed shaved area on the scalp with tattoos. Another limit was the subjective assessment of patients, even though all observers were blind to the therapies. Regardless, the use of the 7-point scale allowed us to perform a valid statistical analysis. Conclusions Based on our results, topical finasteride 0.5% in combination with minoxidil 2% and hydrocortisone butyrate 0.08% could represent a valid therapeutic option for the treatment of postmeno- not FDA-approved for the female pop- ulation. Studies are limited and variable dosages of oral finasteride have been tested in female patients (1-5 mg/day) with conflicting results [19]. Therefore, further randomized studies are still nec- essary to determine the efficacy and optimal dosage of this drug. Moreover, systemic finasteride is associated with several side effects, especially sexual alterations, and its assumption is con- traindicated during pregnancy and breast-feeding because of the risk of feminization of the male fetus [18]. With the aim of reducing oral finas- teride side effects, a topical formulation of this drug was introduced years ago, with promising results in male patients. Recently, Suchonwanit et al [20] studied and compared for the first time the efficacy of topical 0.25% finasteride combined with 3% minoxidil solution and 3% minoxidil solution as mono- therapy in 30 FPHL postmenopausal patients. In their work, the finasteride/ minoxidil solution was significantly superior to minoxidil in improvement of hair diameter. 17α-Estradiol solutions represent another therapeutic option for FPHL. This is a stereoisomer of the female hormone 17β-estradiol, which weakly inhibits 5α-reductase. Furthermore, it suppresses the 17β-dehydrogenase, causing a reductive conversion of andro- stenedione to T, and it stimulates the aromatase, which induces the conver- sion of T to estradiol [21]. In our work, through global pho- tographs and using the 7-point rating scale, we observed that both galenic for- mulations determined a statistically sig- nificant improvement of hair loss from 6-month follow-up to 12- to 18-month follow-up. More important, 0.5% fin- asteride showed higher efficacy than 0.05% 17α-estradiol lotion, both at 6 and 12-18 months. This outcome was statistically significant. I t i s i n t e r e s t i n g t h a t f i n a s - teride-treated patients had an improve- ment at 6 months, which was com- 6 Research | Dermatol Pract Concept 2020;10(2):e2020039 of 0.25% finasteride and 3% minoxidil versus 3% minoxidil solution in female pattern hair loss: a randomized, dou- ble-blind, controlled study. Am J Clin Dermatol. 2019;20(1):147-153. 21. Kim JH, Lee SY, Lee HJ, Yoon NY, Lee WS. The efficacy and safety of 17α-es- tradiol (Ell-Cranell® alpha 0.025%) solution on female pattern hair loss: single center, open-label, non-compar- ative, phase IV study. Ann Dermatol. 2012;24(3):295-305. 22. Caserini M, Radicioni M, Leuratti C, Annoni O, Palmieri R. A novel finasteride 0.25% topical solution for androgenetic alopecia: pharmacokinetics and effects on plasma androgen levels in healthy male volunteers. Int J Clin Pharmacol Ther. 2014;52(10):842-849. mechanism affecting hair growth both in vitro and in vivo. J Invest Dermatol. 1992;98(3):315-319. 17. R o g e r s N E , Av r a m M R . M e d i c a l treatments for male and female pat- tern hair loss. J Am Acad Dermatol. 2008;59(4):547-566. 18. Fabbrocini G, Cantelli M, Masara A, Annunziata MC, Marasca C, Cacciapuoti S. Female pattern hair loss: a clinical, pathophysiologic, and therapeutic re- view. Int J Womens Dermatol. 2018;4(4): 203-211. 19. Hu AC, Chapman LW, Mesinkovska NA. The efficacy and use of finasteride in women: a systematic review. Int J Der- matol. 2019;58(7):759-776. 20. Suchonwanit P, Iamsumang W, Rojhirun- sakool S. Efficacy of topical combination alopecia. Eur J Inflamm. 2014;12(2):399- 404. 13. Whiting DA. Diagnostic and predictive value of horizontal sections of scalp bi- opsy specimens in male pattern andro- genetic alopecia. J Am Acad Dermatol. 1993;28(5 Pt 1):755-763. 14. Rossi A, Cantisani C, Melis L, Iorio A, Scali E, Calvieri S. Minoxidil use in der- matology, side effects and recent patents. Recent Pat Inflamm Allergy Drug Discov. 2012;6(2):130-136. 15. Walsh DS, Dunn CL, James WD. Im- provement in androgenetic alopecia (stage V) using topical minoxidil in a retinoid vehicle and oral finasteride. Arch Dermatol. 1995;131(12):1373-1375. 16. Buhl AE, Waldon DJ, Conrad SJ, et al. Potassium channel conductance: a