The efficacy of the combination of topical minoxidil and oral spironolactone compared with the combination of topical minoxidil and oral finasteride in women with androgenic alopecia, female and male hair loss patterns: A blinded randomized clinical trial

Androgenic alopecia (AGA) is the most common cause of hair loss in women, affecting their quality of life. The present study was conducted with the aim of comparing the combined effect of topical minoxidil and oral spironolactone with the combined effect of topical minoxidil and oral finasteride in women with AGA, female and male hair loss patterns.


| INTRODUC TI ON
Hair loss significantly affects the quality of life of patients.This complication has unimaginable effects on a person's self-confidence, interpersonal relationships, and social status. 1,2In a survey, it was found that 6% of women under 50 years and 38% of women over 70 years have some degree of hair loss. 3,4The most common cause of hair loss in women is androgenetic alopecia (AGA). 5Several factors are involved in this form of hair loss.The most important of which are genetic factors and androgens. 6,7Generally, AGA of women and men is divided into two categories: female pattern hair loss (FPHL) and male pattern hair loss (MPHL). 8FPHL is manifested by a diffuse decrease in hair density in the crown and crest area without affecting the anterior hairline, 9 and in the male pattern, the involvement is often seen in the bitemporal, frontal, mid-scalp, and vertex areas. 10,11Despite the many options in the treatment of both forms of AGA, the selection of a treatment option for each patient presents many challenges. 8pical minoxidil is one of the efficient treatments of AGA.This drug leads to a faster conversion of the telogen phase to the anagen phase by increasing DNA synthesis in the anagen bulbs and stimulating the germ cells of the telogen hair follicles. 12Spironolactone acts as an antiandrogen by inhibiting androgen production in the adrenal gland and binding to the androgen receptor in the target tissue and inhibiting its activity. 13It has been shown that the concomitant use of minoxidil and spironolactone is much more effective in the treatment of AGA by decreasing the severity of hair loss, increasing hair growth and thickness. 14,15Another medication approved for AGA is finasteride, but this is associated with various side effects.Its mechanism of action is inhibition of 5α-reductase type 2, which inhibits the production of dihydrotestosterone from testosterone. 16,17 date, no study has compared the effects of spironolactone and finasteride in FPHL and MPHL, both concomitantly.Considering the above cases, the present study was conducted with the aim of comparing the combined effect of topical minoxidil and oral spironolactone with the combined effect of topical minoxidil and oral finasteride in female and male hair loss patterns.

| Study population
This study was a single-blind, randomized clinical trial from 2021 to 2022 that enrolled 60 female patients aged 15-45 years with AGA.
Exclusion criteria were underlying diseases with an increase in androgens, thyroid disease, the presence of contraindications to the use of finasteride or spironolactone, such as pregnancy and breastfeeding, and a history of treatment for AGA in the past 2 months.

| Sample size
The used sample size determined according to following formula: where Z (1−α/2) is the critical value of the normal distribution at α/2 (this value is considered to be 1.96), Z (1−β) is the critical value of the normal distribution at β (in this study, β at a power of 80% was 0.2, and the critical value was 0.84), and p 1 and p 2 are the expected sample proportions of the two groups.In the present study, p 1 and p 2 (improvement in hair density after the intervention) were set at 70% and 35% for the spironolactone and finasteride groups, respectively, according to the expert opinion.Also, d was the effect size (p 1 −p 2 ).The sample size using the above formula was 28 cases for each group, but taking into account the probability of loss of cases to follow-up, this number increased to 30 cases for each group.

| Assessment tools
Sixty participating patients were divided into two equal groups of MPHL and FPHL based on clinical examination, and then each group was randomly divided into two groups, each receiving topical minoxidil 2% and oral spironolactone 100 mg/day and topical minoxidil 2%, and oral finasteride 5 mg/day, respectively.The duration of significant (p: 0.52), but there was a significant difference in the response to both treatments in male pattern hair loss (MPHL; p: 0.007).In terms of patient satisfaction, minoxidil-spironolactone treatment was significantly better than minoxidil-finasteride regarding hair density and severity of hair loss (p: 0.01).Finally, in terms of treatment complications, the patients in two groups did not have any serious adverse effects.

Conclusion:
The combination of minoxidil and spironolactone could be considered a more effective treatment than the combination of minoxidil and finasteride in women with AGA, FPHL, and MPHL.

| Random allocation
The two groups with female and male hair loss patterns were divided into two groups receiving minoxidil-spironolactone and minoxidilfinasteride according to the randomized list generated with the appropriate software.

| Blinding
In this study, we used a single-blinded method of blinding.The physician who assessed the treatment and the statistical specialist did not know the type of treatment given to each group.

| Statistical analysis
Continuous and categorical variables were presented with the mean ± SD and numbers (percentages), respectively.Independentsample T-tests were used to compare continuous variables, and Chi-squared or Fisher's exact tests were used to compare categorical variables.The significance level was considered less than 0.05, and SPSS version 22 software was used for statistical analysis.

| Ethical considerations
The present participants in this project were adhered to all Helsinki ethical principles (IRCT20211210053343N1).This research was approved by the Research Council with the ethics code number IR.IUMS.FMD.REC.1400.305.

| Basic characteristics
The mean age of cases in the minoxidil-spironolactone and minoxidilfinasteride groups was 32.36 ± 6.18 and 31.03 ± 5.32, respectively, and there were no significant differences between the two groups (p > 0.05).When marital status was compared, 20 (66.7%) and 24 (80%) of the cases in the minoxidil-spironolactone and minoxidilfinasteride groups were married, respectively (p > 0.05).Regarding the other baseline characteristics, there was no significant difference between the two groups at the time of inclusion in terms of Ludwig grade, Norwood-Hamilton grade, and hair loss pattern (p > 0.05), Table 1.

| Main outcomes 2 months after the treatment
treatment.The effect of treatment was excellent in 4 (13.3%) and 0 (0.0%) of the mentioned groups, respectively, but the mentioned difference was not statistically significant (p: 0.08).In both female and male hair loss patterns, the response to two different treatments was not statistically significant (p > 0.05).
Hair density was improved in 15 (50%) of patients in the minoxidil-spironolactone group and in 18 (60%) of patients in the minoxidil-finasteride group (p: 0.15), Figures 1,2.This index was the same for female and male hair loss patterns between the two interventions studied (p > 0.05).There was no statistical difference between the two groups in hair thickness and hair loss (p > 0.05).
Also, there were no statistical differences between the two groups in terms of female and male patterns of hair loss for the above indices (p > 0.05), Table 2. studied (p: 0.13).There was no statistical difference between the two groups in terms of hair thickness (p: 0.99).The mentioned index showed no statistical differences between the two treatment groups in female and male hair loss patterns (p > 0.05).

| Main outcomes 4 months after the treatment
Finally, hair loss was improved in 16 (53.3%)cases in the minoxidilspironolactone group and in 2 (6.7%) cases in the minoxidilfinasteride group (p: 0.01).Minoxidil-spironolactone treatment showed better performance in improving hair loss in the FPHL (p: 0.02), but the treatment effect was the same between the two interventions studied in the MPHL (p: 0.72), Table 3.

| Adverse effects
As for treatment complications, no serious adverse effects occurred in patients in either group.Two cases from the spironolactone group discontinued the drug due to menstrual irregularities and were excluded from the study.

| DISCUSS ION
Hair loss can vary in severity and affect people's social life; therefore, it is important to know a solution for its treatment.The present study is based on the fact that minoxidil is approved for the treatment of AGA, whereas a comparison between the efficacy of oral spironolactone and oral finasteride for female and male hair loss patterns of AGA has not yet been performed.
In our study, it was found that 4 months after treatment in MPHL, the response to treatment was excellent in more than 50% of cases in the minoxidil-spironolactone group, while it was significantly lower in the minoxidil-finasteride group.Hair density was also better in the minoxidil-spironolactone group than in the minoxidil-finasteride group for hair loss with a female appearance.The improvement in FPHL was significantly better in the minoxidil-spironolactone group, but for MPHL, the two groups were the same.Overall, our results indicate that the use of spironolactone may be more effective than finasteride in the treatment of AGA.The efficacy of minoxidilspironolactone has been demonstrated in previous studies. 14,15,18man et al. 15 found that spironolactone produced better results than finasteride in improving AGA in men and women.In addition, a group of women with AGA who received spironolactone had significantly better hair diameter.Another study has shown that spironolactone has an effective therapeutic effect on FPHL for 24 weeks. 19 our study, the combination of minoxidil and spironolactone was also found to have good results in the MPHL.Similar studies have shown that the combination of minoxidil and spironolactone was effective in the treatment of AGA. 6,18noxidil is a regulator of potassium ion channels with vasodilator effect and causes angiogenesis around hair follicles, which helps to transform hair shafts into terminal hair. 20,21On the other hand, spironolactone acts as an antiandrogen drug by binding to the aldosterone receptors in the kidney and reabsorbing potassium from the urine and reducing the production of androgens in the ovaries.With the reduction in androgen production, hair that has become thin and weak due to high secretion of these hormones becomes thick again and returns to its normal state.Therefore, the relationship between spironolactone and the treatment of hair loss is related to the role of spironolactone in reducing androgens. 8,22It was reported that spironolactone could reduce the symptoms of FPHL not only in adult women but also in a nine-year-old girl. 23anwhile, studies have shown different results regarding the efficacy of finasteride.Trüeb et al. studied the effect of finasteride at a dose of 2.5 mg/day in four women and at a dose of 5 mg/day in one patient who had previously been treated with topical minoxidil alone or with cyproterone acetate, topical estradiol, and systemic estrogens without improvement.They checked and evaluated it positively.Thus, after 6 months, all patients showed stabilization of hair loss, and four patients reported significant hair growth. 16 another study of 40 normo-androgenic patients, during 18 months of treatment with oral finasteride, it was found that taking 5 mg/day of finasteride was successful in treating hair loss in women. 17Clinical improvement with finasteride at a dose greater than 5 mg/day was also observed in normo-androgenic, pre-and postmenopausal women with FPHL. 9 In one study, finasteride was prescribed at a dose of 2.5 mg per day for 12 months while simultaneously taking an oral contraceptive containing drospirenone and ethinyl estradiol to prevent pregnancy.After 12 months, an increase in hair density was noted in 62% of patients.The values for hair density were significantly increased. 24 various studies, the dosage of finasteride was found to have an effect on the efficacy of treatment. 25,26In this study, an appropriate and effective dose of finasteride was used, and balanced dosing was observed in the groups.Previous results have confirmed the efficacy of oral finasteride; however, in our study, it was found that despite the efficacy of treatment with finasteride, the efficacy of treatment with oral spironolactone was higher.A review by Yousef et al. reported that topical spironolactone had better performance for AGA compared with topical finasteride.They stated that it should be kept in mind that topical finasteride has fewer side effects than oral finasteride. 15 the present study, the two treatment groups were close in terms of hair loss efficacy indicators at the second month, but at the fourth month after treatment initiation, the efficacy of the minoxidilspironolactone group was greater than that of the finasteride group, indicating that with longer follow-up, the efficacy of spironolactone compared with finasteride can be expected.
Of course, recent studies have found that the efficacy of spironolactone on AGA is considerable, but the provision of complementary methods such as micro-needling can increase the efficiency of treatment. 27,28It may be important to pay attention to this question in future studies.
androgenic alopecia, female pattern hair loss, oral finasteride, oral spironolactone, topical minoxidil treatment was 4 months, and follow-up examinations were performed 2 and 4 months after the start of treatment.The efficacy of the treatment was evaluated by the following criteria: determination of the degree of hair loss using the Ludwig grade for FPHL and the Norwood-Hamilton grade for MPHL, determination of physician satisfaction by clinical images using the physician global assessment score (no change, little, somewhat, good, and excellent), and determination of patient satisfaction by clinical images according to the density and thickness of the hair shafts and the extent of hair loss (worsening, no change, and improvement).

FourF I G U R E 2
months after the intervention, Ludwig grades were grades 1 and 2 in 13 (86.7%)and 12 (80.0%)cases in the minoxidil-spironolactone and the minoxidil-finasteride groups, respectively (p: 0.99).By Norwood-Hamilton grade, 12 (80%) and 11 (73.3%) of cases in the minoxidil-spironolactone and minoxidil-finasteride groups were grade 1, respectively (p: 0.99).Regarding treatment response, the drugs used were ineffective in 2 (6.7%) cases in the minoxidilspironolactone group and in 5 (16.7%) cases in the minoxidilfinasteride group.In addition, 13 (43.3%)and 16 (53%) cases in the minoxidil-spironolactone and minoxidil-finasteride groups, respectively, responded well to the treatment.The effect of treatment was excellent in 8 (56.7%) and 0 (0%) of the mentioned groups, respectively, and the mentioned difference was statistically significant (p: 0.01).The response to the treatment in the FPHL was not statistically significant (p: 0.52), but there was a significant difference in the response to both treatments in the MPHL (p: 0.007).Hair density was significantly better improved in the minoxidilspironolactone group than in the minoxidil-finasteride group (21(70.0%)and 10 (33.3%) cases, respectively, p: 0.01), Figures1,2.Minoxidil-spironolactone treatment showed better performance in improving hair density in the FPHL (p: 0.04), but the treatment effect was the same in the MPHL between the two interventions F I G U R E 1 Hair density improvement in the minoxidil-spironolactone group.A, B, and C: before the treatment, 2 months later, and 4 months later.Hair density improvement in the minoxidil-finasteride group.A, B, and C: before the treatment, 2 months later, and 4 months later.TA B L E 2 Comparing different outcomes 2 months after beginning of the interventions in two groups (n = 60).

TA B L E 3
Limitations of the current research include the size of the sample studied; another limitation is the failure of some patients to return at the right time or to be treated with other treatment methods; and the occurrence of treatment complications that led to treatment discontinuation.Comparing different outcomes 4 months after beginning of the interventions in two groups (n = 60).The bold p values indicates that they are meaningful.