Comparative Efficacy of Topical Finasteride (0.25%) in Combination with Minoxidil (5%) Against 5% Minoxidil or 0.25% Finasteride Alone in Male Androgenetic Alopecia: A Pilot, Randomized Open-Label Study

ABSTRACT

Background:

Androgenetic alopecia (AGA) is the most common cause of hair loss in males which remains a therapeutic challenge.

Objectives:

To compare the efficacy of topical 5% minoxidil and 0.25% finasteride combination (MNF) over 5% minoxidil (MNX) or 0.25% finasteride (FNS) alone by assessing hair count, physician assessment score (PAS), and patient satisfaction score (PSS).

Materials and Methods:

Pilot randomized open-label study where 60 male patients with AGA ≥ III grade were randomized into three treatment groups and evaluated over 24 weeks. Improvement in hair count was assessed manually using dermoscopy. Global photographs were used to assess PAS. Side effects were evaluated using relevant laboratory investigations.

Results:

At the 12^th and 24^th week, all three groups showed significant improvement in total hair density as compared to baseline (P < 0.001). None of the groups was superior to the other (P > 0.05) at the 12^th week but at 24^th week, MNF was comparatively superior (P < 0.02). At the 12^th week and 24^th week, all three groups showed significant improvement in terminal hair density as compared to baseline (P < 0.001). In the 12^th week, MNF was comparatively superior (P = 0.028) and at the 24^th week, MNF was comparatively superior (P < 0.02). PAS and PSS were significantly better with MNF and MNX compared to FNS (P < 0.004). Side effects such as scaling and itching were reported with MNF and MNX.

Conclusion:

Topical minoxidil 5% and finasteride 0.25% had an overall better efficacy compared to monotherapy without significant side effects.

INTRODUCTION

Androgenetic alopecia (AGA), also known as pattern alopecia, is said to be the most common cause of hair loss in both men and women. The prevalence of AGA in the Indian male population aged <30 years is 30% and in males aged between 30 and 50 years is 58%.[1,2,3] Several genes, androgens and environmental factors play an important role in pathogenesis.[1,2,4] The diagnosis is mainly clinical using the Modified Norwood Hamilton classification in males.[4,5]

The ratio of the terminal to vellus hair becomes <4:1 in AGA causing a substantial reduction in the hair diameter.[6] This leads to stepwise miniaturization of hair which is thought to be mainly driven by androgens.[7,8,9] Testosterone is converted to the more potent form, Dihydrotestosterone (DHT) by the enzyme 5α reductase. The balding scalp is found to have raised levels of DHT, 5α reductase and elevated expression of androgen receptors.[2,10,11,12] Either paternal or maternal family history of pattern baldness may be present, but it cannot be ruled out in the absence of family history.[3]

The two drugs that have been approved so far by the U. S Food and Drug Administration (FDA) for treating AGA in males are as follows:

Topical minoxidil

Studies have been conducted to evaluate the efficacy and side effects of varying concentrations of minoxidil[8,9] and 5% minoxidil was seen to be superior to 2% and 10% formulations. Various side effects reported in these studies include pruritus, dermatitis, loss of hair, scalp scaling, dryness of hair, and headache.

Oral finasteride, 1 mg/day

Various studies have reported rare sexual side effects and a recent entity known as postfinasteride syndrome with the use of oral finasteride which includes features such as loss of libido, ejaculatory disorders, gynecomastia, muscular atrophy, cognitive impairment, and suicidal ideation.[7,13,14,15,16,17] However, the significance of these adverse effects is debatable.

Similar adverse effects have not been reported with the use of topical finasteride. The efficacy of topical finasteride of varying concentrations and formulations has been evaluated. Although 0.1% finasteride has been extensively evaluated, it is not available as a monotherapy agent commercially and is only available as a combination solution with minoxidil. 0.25% finasteride solution has been evaluated in a few studies as monotherapy as well as in combination with a lower concentration of 3% minoxidil and it was reported to be effective.[4,18] In a recent systematic review, it has been seen that topical FNS 0.25% solution is the most efficacious concentration and its use has not resulted in the report of serious side effects.[4,19,20,21]

Studies have also postulated that the combination of topical finasteride and minoxidil has a synergistic effect and is more effective than monotherapy with either drug.[18,19,20,22,23,24]

The commercially available combination solutions have a concentration of 5% minoxidil and 0.1% finasteride.

To the best of our knowledge, ours was the first study where a higher concentration of 0.25% finasteride has been used both as monotherapy and in combination with 5% minoxidil and its efficacy and safety profile were evaluated over a 6-month period in terms of improvement in total and terminal hair count and improvement in physician scores based on global photographs. Data are lacking about the efficacy and safety of 0.25% finasteride solution and through our study we hope to bridge the gap in our knowledge regarding this booming treatment option for AGA.

MATERIALS AND METHODS

Ethical concerns

Prior to participating, written informed consent was taken from all the subjects. Institutional review board approvals of the protocols and consent were obtained on October 28, 2019. The study period extended from November 2019 to October 2021. The trial was registered with the Clinical Trial Registry of India (Trial no. CTRI/2020/05/025390). The first patient was recruited on May 29, 2020.

Study design and subjects

This was a single-center, randomized, 3-arm, open-label pilot study conducted over a 2-year period in the outpatient department of the hospital associated with Lady Hardinge Medical College. We evaluated and compared the efficacy of three treatment regimens – topical minoxidil 5% solution (MNX), topical finasteride 0.25% solution (FNS), and a combination of topical 5% minoxidil and 0.25% finasteride solution (MNF).

A clinical diagnosis of AGA was made and 60 male patients in the age group of 18-40 years with ≥ grade III AGA (Modified Norwood Hamilton classification) were included in the study. The following exclusion criteria were applied – use of topical or systemic drugs to promote hair growth in the past 6 months, scalp seborrhea, elevated levels of serum prostate-specific antigen, thyroid dysfunction, Vitamin D deficiency, and use of drugs such as antihypertensives, antiepileptics, cytotoxic drugs, systemic corticosteroids and vasodilators.

Variable block size randomization (2, 4, or 6) using a computer-generated sequence was done by a person not involved in the study to allocate the study subjects to the three respective groups. For allocation concealment, sealed opaque envelopes containing group codes were prepared. Envelopes were sequentially numbered and kept in order according to their serial number. The envelope was opened at the time of randomization and the patient was allocated to the respective group. All the subjects were instructed to maintain the same hairstyle throughout the study period.

Study drug application and clinical assessments

Topical solutions of MNF, MNX, and FNS were prepared using propylene glycol and 75% ethyl alcohol in the pharmacology department of our institute. Solutions were dispensed in identical opaque 100 ml bottles and were provided to the patients at every visit.

Subjects were instructed to apply 1 ml of the prescribed solution twice daily to the scalp. Subjects were evaluated at baseline, 12^th and 24^th week. Three areas of the scalp were identified as frontal, frontotemporal and vertex. A target area of 1 cm² was selected in each of these areas for the serial assessment and its uniformity was maintained by recording its distance from fixed bony landmarks. Total hair count per cm² and number of terminal hair per cm² was calculated manually using a dermoscope.

Global photographs were taken at baseline, 12^th and 24^th week and a 5-point scale of Physician Assessment Score (PAS) was used for evaluating the photographs by an unblinded independent observer where improvement was scored as + 3 excellent, +2 moderate, +1 mild, 0 none, and -1 deterioration. Patients graded their satisfaction according to the Patient Satisfaction Score (PSS) using a linear analog scale where the response was graded as good (7-10), moderate (4-6), and poor (0-3).

Statistical methodology

Our study hypothesis was that combination therapy with minoxidil and finasteride were more effective than monotherapy in AGA and we tested this single hypothesis with an expected rate of false discovery of 5%. Our primary objective was to compare the efficacy of MNF, MNX, and FNS in terms of improvement in total hair count per cm² and terminal hair count per cm² over a 6-month period. The secondary objectives included assessment of PAS, PSS, and the side effect profile.

Since ours was a pilot study, the sample size was calculated from previous studies with similar but not the same comparison groups.[25] Our primary outcome measures included the proportion of patients with PAS ≥ +2 and comparative improvement in mean change in total hair and terminal hair density from baseline at the 24^th week. Our secondary outcome measures included comparison of vellus hair count, PSS, and proportion of patients experiencing side effects in the three groups.

The continuous variables were expressed as mean ± standard deviation and median according the distribution of values. The categorical variables were expressed as frequencies and percentages and were analyzed using the Chi-square test. Analysis of variance, Kruskal Wallis, and Fischer's exact tests were used wherever applicable. Tukey's test for post hoc analysis was used. Paired Student's t-test and Wilcoxon signed-rank test were used wherever applicable. Statistical significance was assumed at a P < 0.05.

RESULTS

Subject demographics

Sixty male subjects were randomized and evaluated for efficacy (n = 20 in each group). There were no drop-outs. Maximum subjects (50%) belonged to the age group of 18-25 years. The duration of the disease ranged from 6 months to 15 years and most subjects (78.33%) had a duration of ≤5 years. Sixty-eight percent of patients had a family history of AGA in first-degree relatives. Most subjects (50%) presented with early Grade 3 AGA and 100% subjects had involvement in frontotemporal area. There was no statistically significant difference between the three groups in terms of the above parameters [Table 1].

Table 1.

Summary of demographic characteristics of the three treatment groups

Demographic characteristics	FNS (n=20)	MNX (n=20)	MNF (n=20)	Total (n=60)
Age (years)
Mean	27.1	25.6	26	26.23
Range	19-36	18-37	18-35	18-37
Duration (years)
Mean	3.85	2.97	3.75	3.52
Range	1-15	0.5-8	1-10	0.5-15
Family history, n (%)
Present	14 (70)	13 (65)	14 (70)	41 (68)
Absent	6 (30)	7 (35)	6 (30)	19 (32)
Grade of AGA, n (%)
3	11 (55)	8 (40)	11 (55)	30 (50)
4	5 (25)	5 (25)	4 (20)	14 (23)
5	3 (15)	5 (25)	4 (20)	12 (20)
6	1 (5)	2 (10)	1 (5)	4 (7)
Area of scalp involved, n (%)
Frontal	11 (55)	16 (80)	9 (45)	34 (57)
Fronto-temporal	20 (100)	20 (100)	20 (100)	60 (100)
Vertex	13 (65)	14 (70)	14 (70)	41 (68)

FNS - Finasteride; MNX - Minoxidil; AGA - Androgenetic alopecia; MNF - Minoxidil plus finasteride

Efficacy assessment

Results demonstrated that a combination of topical minoxidil 5% and finasteride 0.25% solution was more effective when compared to monotherapy in male AGA.

1. Total hair density/cm²: at the 12^th and 24^th week, all three groups showed significant improvement in total hair density as compared to baseline (P < 0.001). None of the groups was superior to the other (P > 0.05) at the 12^th week but at the 24^th week, MNF was comparatively superior (P < 0.02) [Table 2 and Figure 1]

2. Terminal hair density/cm² – at the 12^th week and 24^th week, all three groups showed significant improvement in terminal hair density as compared to baseline (P < 0.001). At the 12^th week, MNF was comparatively superior (P = 0.028) and at 24^th week, MNF was comparatively superior (P < 0.02)[Table 3 and Figure 2]

3. PAS – MNF and MNX showed significantly better scores as compared to FNS (P = 0.0003) [Table 4]

4. PSS – MNF and MNX showed significantly better scores compared to FNS (P = 0.001, 0.004) [Table 4].

Table 2.

Mean increase in total hair density/cm2 from baseline to 24^th week with intergroup comparison in different areas of the scalp

	FNS (n=20)	MNX (n=20)	MNF (n=20)
Frontal	7.85±1.10	9.25±1.33	10.05±1.82
Fronto-temporal	7.45±1.35	7.25±1.58	9.05±2.43
Vertex	6.75±2.04	6.8±2.06	7.3±2.53
Post hoc analysis (P)	Frontal	Fronto-temporal	Vertex
MNF versus MNX	0.2	0.008	0.69
MNF versus FNS	0.001	0.022	0.56
MNX versus FNS	0.01	0.89	0.6

FNS - Finasteride; MNX - Minoxidil; MNF - Minoxidil plus finasteride

Figure 1.

(a) Mean change in total hair density/cm² over the frontal area in the three groups between baseline, 12^th and 24^th weeks (b) Mean change in total hair density/cm² over the frontotemporal area in the three groups between baseline, 12^th and 24^th weeks (c) Mean change in total hair density/cm² over the vertex area in the three groups between baseline, 12^th and 24^th weeks

Table 3.

Mean increase in terminal hair density/cm2 from baseline to 24^th week with intergroup comparison in different areas of the scalp

	FNS (n=20)	MNX (n=20)	MNF (n=20)
Frontal	9.35±1.46	8.45±1.87	11.2±2.23
Fronto-temporal	7.9±0.96	9.7±2.10	8.55±1.60
Vertex	7.75±2.31	8.35±2.49	10.0±3.11
Post hoc analysis (P)	Frontal	Fronto-temporal	Vertex
MNF versus MNX	0.001	0.07	0.13
MNF versus FNS	0.001	0.002	0.02
MNX versus FNS	0.89	0.42	0.73

FNS - Finasteride; MNX - Minoxidil; MNF - Minoxidil plus finasteride

Figure 2.

(a) Mean change in terminal hair density/cm² over the frontal area in the three groups between baseline, 12^th and 24^th weeks (b) Mean change in terminal hair density/cm² over the frontotemporal area in the three groups between baseline, 12^th and 24^th weeks (c) Mean change in terminal hair density/cm² over the vertex area in the three groups between baseline, 12^th and 24^th weeks

Table 4.

Summary of secondary efficacy endpoints at the 24^th week as compared to baseline

Efficacy endpoints	FNS (n=20)	MNX (n=20)	MNF (n=20)	P
PAS at 24th week, n (%)
+3	3 (15)	12 (60)	15 (75)	0.0003
+2	17 (85)	8 (40)	5 (25)	0.0003
+1	-	-	-
0	-	-	-
−1	-	-	-
Mean PSS at 24th week	5.7±0.95	6.85±1.27	7±1.51	0.002
Serum PSA (ng/ml)
Baseline	1.15	0.53	1.16
24th week	1.15	0.54	1.13	0.5

PAS - Physician assessment score; PSS - Patient satisfaction score; PSA - Prostate-specific antigen; FNS - Finasteride; MNX - Minoxidil; MNF - Minoxidil plus finasteride

In addition, the effect of demographic factors on outcome was also studied. Better improvement in total hair density was seen in the age group of 18-25 years and in subjects who had a disease duration of ≤5 years. An increase in total hair density was also seen to be higher in those with early grades of AGA. Patients with a positive family history of AGA showed better response [Table 5].

Table 5.

Summary of effect of demographic characteristics on mean change in total hair density between baseline and 24^th week (hair/cm²)

Demographic characteristics	FNS (n=20)	MNX (n=20)	MNF (n=20)	Total (n=60)
Age (years)
18-25	7.58	7.85	8.93	8.12
26-30	7.49	7.72	8.74	7.98
31-40	6.88	7.33	8.33	7.51
Age of onset (years)
≤20	7	8.44	8	7.81
>20	7.46	7.47	9.06	7.99
Disease duration (years)
≤5	7.73	7.78	8.91	8.14
>5	6.44	7.66	8.33	7.37
Family history
Yes	7.63	7.73	9.02	8.12
No	6.8	7.83	8.37	7.66
Grade of AGA
3	7.48	8.37	9.87	8.57
4	7.86	7.6	7.75	7.73
5	5.77	7.53	7.33	6.87
6	5.33	6.66	7	6.33

AGA - Androgenetic alopecia; FNS - Finasteride; MNX - Minoxidil; MNF - Minoxidil plus finasteride

Safety assessment

Both local and systemic side effects were evaluated in all subjects at the 12^th and 24^th weeks. Fifteen (25%) subjects from MNF and MNX groups experienced scaling, increased hair loss, dryness, itching, and headache during the first 12 weeks. Seven of these subjects continued to experience itching and dryness during the next 12 weeks. However, it did not affect the compliance nor caused any subject to drop out of the study. None of the subjects from the FNS group experienced any local side effects. For evaluating systemic side effects, liver function test, kidney function test, and serum prostate-specific antigen were carried out at the baseline and 24^th week. All the tests remained within the normal range without any significant difference. None of the patients reported any sexual side effects.

DISCUSSION

AGA is the most common cause of progressive hair loss leading to baldness with studies demonstrating a gradual increase in incidence with age.[3] Various treatment options have been tried in AGA with differing rates of success. Apart from the FDA-approved minoxidil solution and oral finasteride, other options include oral dutasteride and invasive procedures such as platelet-rich plasma therapy and hair transplantation. Various supplements containing natural DHT inhibitors, iron, vitamins, and trace elements are seen to have an adjunctive role.[26]

Various studies have reported sexual side effects in differing frequencies with the use of oral finasteride. The most frequently reported complaints include ejaculatory dysfunction, erectile dysfunction, and loss of libido.[7,13,14,15,16] Few case reports have shown finasteride to cause changes in sperm DNA, function, and motility which improved after stopping the drug.[27,28] However, in most of the studies conducted so far, no such side effects have been reported with topical finasteride.[4,19,20]

Among all the treatment options, a topical solution of minoxidil and finasteride remains a popular choice because of its efficacy and it is also cost effective for the patient. In this pilot study, a topical combination of 5% minoxidil and 0.25% finasteride showed efficacy over monotherapy with twice daily application over a 6-month period without any significant side effects [Figures 3 and 4]. Using a higher concentration of finasteride than what is available commercially did not seem to have any effect on serum levels of prostate-specific antigen and nor were there reports of any local or sexual side effects. Monotherapy with topical finasteride was seen to show an improvement only during the first 12 weeks after which the improvement plateaued. Whereas, monotherapy with topical minoxidil was seen to cause increased hair loss in the first few weeks and the improvement was appreciated only after 12 weeks. Combining finasteride with minoxidil showed a sustained improvement throughout the 24-week study period without the initial phase of hair loss. Certain demographic factors such as younger age, shorter disease duration, and early grade of AGA were seen to have a better treatment response. It was not possible to comment upon the clinical significance of better outcomes in patients with a positive family history due to the limited sample size.

Figure 3.

(a) Global photograph at baseline –MNF (b) Global photograph at the 24^th week –MNF

Figure 4.

(a) Dermoscopy at baseline – MNF (b) Dermoscopy at the 24^th week – MNF

Our study was limited by its small sample size, lack of placebo group, and lack of long-term follow-up data. We have not compared the combination solution of 5% minoxidil and 0.25% finasteride against the commercially available combination solution of 5% minoxidil and 0.1% finasteride. We recommend large multicentric studies to establish the efficacy and safety of topical 0.25% finasteride in the long term, as due to feasibility issues, serum levels of DHT were not evaluated in our study to look for systemic absorption.

CONCLUSION

Topical application of 5% minoxidil and 0.25% finasteride solution twice daily demonstrated better efficacy when compared to monotherapy in terms of improvement in total hair density and terminal hair count. No significant side effects were reported. Recommendations for increasing the concentration of finasteride will need comparative studies of this solution against the commercially available formulation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.