ABSTRACT
Background:
Female pattern hair loss (FPHL) is the most common hair loss disorder in women. Its origin is polygenic and multifactorial. Specific genetic factors predispose androgen receptors to be particularly sensitized so that they bind to circulating androgens, even with normal circulating levels.
Objectives:
The aim of this work was to evaluate and compare the efficacy and safety of topical spironolactone versus topical minoxidil in the treatment of FPHL.
Methods:
This prospective, simple randomized, comparative study was conducted on 80 female patients with FPHL. They were divided into two groups: Group (A): was subjected to topical spironolactone 1% gel application for 6 months, twice. Group (B): was subjected to topical minoxidil 5% gel application for 6 months, twice daily. The efficacy of treatment was assessed clinically by the Ludwig scale, Global Esthetic Improvement Scale, and trichoscopy.
Results:
There was a statistically significant difference in improvement in both groups after treatment as regards: the Ludwig scale, Global Esthetic Improvement Scale, and Trichoscopy. In Group A: 10 patients had mild, 16 patients had moderate, two patients had excellent, and 12 had marked improvement. In Group B: 10 patients had mild, 14 patients had moderate, two patients had excellent, and 14 had marked improvement. Contact dermatitis, scalp irritation, and headache, which were more evident in Group B than in Group A.
Conclusions:
Both topical spironolactone and topical minoxidil were cheap, safe, and effective lines for the treatment of FPHL with minimal and tolerable side effects.
Keywords: Female pattern hair loss, topical minoxidil, topical spironolactone, treatment
INTRODUCTION
Female pattern hair loss (FPHL) is the most common hair loss disorder in women. Its origin is polygenic and multifactorial. While the role of sex hormones is clearly established in male pattern baldness, this role is less clear in women. Specific genetic factors predispose androgen receptors (ARs) to be particularly sensitized so that they bind to circulating androgens, even with normal circulating levels. FPHL is thought to be mediated by androgens since it generally manifests in postmenopausal women and may present earlier in individuals with hyperandrogenism. In the scalp, androgens exert a paradoxical effect in the dermal papillae, namely the transition from terminal hairs to vellus hairs in genetically predisposed individuals.[1]
Spironolactone is widely used in the treatment of hypertension as an aldosterone antagonist and a potassium-sparing diuretic. Its antiandrogen activity was attributed to its ability to decrease the testosterone levels and blocks the ARs in target tissues. The usual daily dose of spironolactone (50–200 mg/day) did not show serious side effects and can be considered safe for long-term therapy in FPHL. Kelidari et al.[2] reported that the usage of spironolactone as a topical treatment allows high penetration of the drug to the active site with the advantage of minimizing unwanted adverse effects of oral spironolactone.[3]
Minoxidil exerts its action through the opening of the potassium channel and increases angiogenesis around the follicles by increasing the expression of hair growth promoters such as vascular endothelial and hepatocytic growth factors. It increases hair count and weight by inducing telogen hairs to enter the anagen phase and prolonging anagen duration. Minoxidil 5% solution could produce greater growth of hair than the 2% solution in male androgenetic alopecia (AGA). Only three FDA-approved treatments for AGA available are; minoxidil, finasteride, and low-level laser therapy.[4] Hence, the aim of this work was to evaluate and compare the efficacy and safety of topical spironolactone versus topical minoxidil in the treatment of FPHL.
METHODS
This prospective, simple, randomized, comparative study was conducted on 80 female patients with FPHL. Informed written consent was obtained from each patient (informed consent to publish their pictures and share their data). It was approved by the research ethics committee approval (approval code: 34784/7/21). Inclusion criteria: Female patients with mild-to-moderate FPHL, who did not receive any treatment within at least 6 months before the start of the study. Exclusion criteria: Severe and neglected cases with FPHL, patients with renal impairment, diabetes mellitus, electrolytes imbalance, pregnant and lactating females, patients with abnormal blood pressure, adrenal insufficiency, and hormonal disturbances (such as polycystic ovary syndrome and hyperprolactinemia).
They were randomly divided into two groups: each group consisted of 40 patients as follows: Group A was subjected to topical spironolactone 1% gel application for 6 months, twice daily, an amount of 1 ml (100 units on insulin syringe) per time, mainly on the vertex with gentle massage for 2–3 min after application.
Group B was subjected to topical minoxidil forte 5% gel (manufactured by an Egyptian group of pharmaceutical industries application for 6 months, twice daily, an amount of 1 ml (100 units on insulin syringe) per time, mainly on the vertex with gentle massage for 2–3 min after application.
Complete history taking including onset, course, and duration, site of hair loss, and past and family history of FPHL. A general examination was done to exclude any systemic disease. Full dermatological examination to detect the degree of FPHL according to the Ludwig scale,[5] digital photographs, and trichoscopic pictures was taken for every patient.
Digital photographs
All patients were digitally photo-documented using an Android phone camera (OPPO F11 PRO, made in China) before treatment and at the end of the 6-month course of treatment. All photographs were taken with the same equipment, at the same lighting and location.
Materials
Minoxidil used in the study is a finished marketed product in Egypt (Minoxidil 5%). Therefore, it is essential to prepare spironolactone gel with the same additive reported by the produced company for minoxidil forte 5% gel and with the same physicochemical properties. Based on the company product brochure, the basic composition of the gel is hydroxyethyl cellulose, tween 80, and ethyl alcohol. The function of each could be expected as the following: hydroxyethyl cellulose as gel-forming substance, tween 80 as a penetration enhancer, and ethyl alcohol as a solubilizer for the minoxidil and rubefacient.
Hydroxyethyl cellulose (Isochem France lab reagent), ethanol (El Nasr pharmaceutical chemical co., Egypt), tween 80 (Alpha Chemika, India), spironolactone (specton tablet, marketed tablet produced by Cairo pharmaceutical company, Egypt). This was prepared at the Department of Pharmaceutical Technology–Faculty of Pharmacy, Tanta University.
Simulation of the quantity of the gel constituents
The amount of the gel-forming agent was estimated from the determination of the viscosity of marketed minoxidil gel. The surface tension of the marketed minoxidil gel was also measured to determine the concentration of tween 80 used. In addition, the amount of ethyl alcohol used would be dependent on the solubility of minoxidil as an active substance. Therefore, the amount of ethyl alcohol used would be in the same manner.
Preparation of hydroxyethyl cellulose gel
The required amount of hydroxyethyl cellulose was added to distilled water while stirring using (Heidolph Mechanical Stirrer, Germany) at 700 rpm till the gel was formed. An amount of tween 80 (ml) was added while stirring. Ten tablets of spironolactone, each contain 100 mg spironolactone, were ground and sieved through 75 um sieve size. The total amount of the drug was one gram. Ethyl alcohol (10 ml) was added to the grinding tablets, stirring for drug extraction and slurry formation. The alcohol slurry solution of the drug tablets was added to the previously prepared plain gel while stirring to form a homogenous gel containing 1 g spironolactone in 100 g as the weight of the product. After gel preparation, it is kept at the room temperature. Patients were advised to keep it at room temperature and to shake it well several times before use.
Assessment of therapy
Clinical assessment: (Ludwig scale)
Patients were graded according to the Ludwig scale before and after the 6-month course of treatment: Grade I: Perceptible thinning of the hair on the crown, limited in the front by a line situated 1–3 cm behind the frontal hairline. Grade II: Pronounced rarefaction of the hair on the crown within the area seen in Grade I. Grade III: Full baldness (total denudation) within the area seen in Grades I and II.[5]
The global esthetic improvement scale
Three blinded dermatologists were asked to evaluate the progress of the patients after the completion of the treatment period, through comparing the before and after digital photographs, improvement was graded according to the Global Esthetic Improvement Scale (GAIS): 0 – no improvement: if improvement was 0%. Mild improvement: 1%–25% improvement. Moderate improvement: 26%–50% improvement. Marked improvement: 51%–75% improvement. Excellent improvement: 76%–100% improvement.[6]
Patient satisfaction
Each patient was asked at the final visit about her satisfaction as follows: unsatisfied, slightly satisfied, satisfied, and very satisfied.
Trichoscopic assessment
Obtained by digital microscope (Compare View Hair Version 1.5.06, written by Prof Steven ABBot2011-13, USA) by which a computer system analyses the data. A 50-fold magnification was used for evaluating the density of hair per cm2, terminal, and vellus hairs. A 200-fold magnification was used to assess hair shaft diameters. Trichoscopic evaluations were done at 2 different points of the scalp (B and C) as follows [Figure 1]:
Figure 1.
(a) Points of trichoscopic assessement. (b) Digital trichoscope and its different lenses used in assessment
Point A: Midsagittal 9 cm behind the nasion, marking the frontal hairline (which is preserved in FPHL)
Point B: Located 2–3 cm behind the frontal hairline
Point C: Located at the vertex.
The mean value out of the last 2 (B and C) points was calculated for both hair density and hair shaft diameter at the start of the study and after 6 months of treatment; as the pathology of FPHL mainly affects the vertex.
Complications reported by the patients were documented such as headaches, itching dandruff, or any other complications. Evaluation of the patients was done before starting treatment, and then every 2 months during the 6-month duration of the course of treatment, and at the end of the course of treatment.
Statistical analysis
Data were fed to the computer and then they were analyzed using IBM SPSS software package version 20.0 (v 16; SPSS Inc., Chicago, IL, USA).
RESULTS
All clinical and demographic data of the patients are illustrated in Table 1.
Table 1.
Comparison between the two studied groups according to clinical data and Ludwig grade of patients
| Group A (n=40) | Group B (n=40) | Test of significant (U) | P | |
|---|---|---|---|---|
| Age (years) | ||||
| Minimum–maximum | 22.0–45.0 | 20.0–60.0 | 190.0 | 0.799 |
| Mean±SD | 27.25±5.53 | 31.35±12.05 | ||
| Median (IQR) | 26.0 (23.0–28.50) | 27.0 (22.0–37.50) | ||
| Duration (years) | ||||
| Minimum–maximum | 0.33–10.0 | 0.50–10.0 | 140.50 | 0.108 |
| Mean±SD | 2.57±2.19 | 3.55±2.35 | ||
| Median (IQR) | 2.0 (1.0–4.0) | 3.0 (2.0–4.50) | ||
| Family history (n) | ||||
| Positive | 36 | 40 | ||
| Negative | 4 | 0 | ||
|
| ||||
| Ludwig Scale | Group A | Group B | χ 2 | P |
|
| ||||
| Before treatment | ||||
| L1 | 0 | 0 | 0.000 | 1.000 |
| L2 | 16 | 16 | ||
| L3 | 24 | 24 | ||
| After treatment | ||||
| L1 | 10 | 12 | 0.141 | MCP=1.000 |
| L2 | 24 | 20 | ||
| L3 | 6 | 8 | ||
| MH (P0) | 28.0* (<0.001*) | 28.0* (<0.001*) | ||
*Statistically significant at P≤0.05. Group (A) - Topical spironolactone application; Group (B) - Topical minoxidil application; IQR - Interquartile range; SD - Standard deviation; U - Mann–Whitney test; P - P value for comparing between the two studied groups; Group (A) - Topical spironolactone application. Group (B) - Topical minoxidil application; χ2 - Chi-square test; MC - Monte Carlo; MH - Marginal homogeneity test; IQR - Interquartile range; SD - Standard deviation; t - Student’s t-test; P - P value for comparing between the two studied groups; P0 - P value for comparing between before and after
Assessment of therapy
According to Ludwig’s grading: As illustrated in Table 1, there was a statistically significant improvement regarding the Ludwig scale after then before treatment in both groups. There was no statistically significant difference between both groups regarding the Ludwig scale
GAIS.
According to GAIS in Group A: 10 patients (25%) showed mild improvement, 16 patients (40%) showed moderate improvement, 12 patients (30%) showed marked improvement, and two patients showed excellent improvement, while in Group B: 10 patients (25%) showed mild improvement, 14 patients (35%) showed moderate improvement, 14 patients (35%) showed marked improvement, and two patients with excellent improvement. There was no statistically significant difference between both groups regarding GAIS [Figures 2 and 3].
Figure 2.
A 26-year-old female patient with a 3-year duration with a positive family history. (a) Before treatment with topical spironolactone and (b) after 6-month treatment with marked improvement (55%) from L2 to L1
Figure 3.
A 27-year-old female patient 1st time to be diagnosed with female pattern hair loss with a positive family history. (a) Before treatment by topical minoxidil and (b) after 6 months of treatment with marked improvement (65%) from L2 to L1
Patients; satisfaction
In Group (A): 10 patients (25%) were unsatisfied, 16 patients (40%) were slightly satisfied, 2 patients (5%) were satisfied, and 12 patients (30%) were very satisfied
In group (B): 10 patients (25%) were unsatisfied, 14 patients (35%) were slightly satisfied, 2 patients (5%) were satisfied, and 14 patients (35%) were very satisfied. On comparing the two studied groups, there was no statistically significant difference regarding patients’ satisfaction.
Trichoscopic evaluation of the studied cases
There were statistically significant differences in both groups on comparing before and after treatment regarding increase in hair width, hair density, number of terminal hair, and decrease in vellus hair. There was no statistically significant difference between the two studied groups regarding hair width, hair density, number of terminal hair, and vellus hair after treatment [Table 2 and Figures 4-7].
Table 2.
Comparison between the two studied groups according to trichoscopic findings
| Trichoscopic findings | Group A (n=40) | Group B (n=40) | Test of significant | P |
|---|---|---|---|---|
| Hair width (mm) | ||||
| Before treatment | ||||
| Minimum–maximum | 0.01–0.03 | 0.01–0.03 | t=0.640 | 0.526 |
| Mean±SD | 0.02±0.0 | 0.02±0.01 | ||
| Median (IQR) | 0.02 (0.02–0.03) | 0.02 (0.02–0.02) | ||
| After treatment | ||||
| Minimum–maximum | 0.01–0.04 | 0.01–0.04 | t=0.335 | 0.739 |
| Mean±SD | 0.02±0.01 | 0.03±0.01 | ||
| Median (IQR) | 0.02 (0.02–0.03) | 0.03 (0.02–0.03) | ||
| t1 (P0) | 2.546* (0.020*) | 3.382* (0.003*) | ||
| Hair density (/cm2) | ||||
| Before treatment | ||||
| Minimum–maximum | 26.0–87.90 | 32.60–71.60 | U=180.50 | 0.602 |
| Mean±SD | 50.54±15.72 | 47.83±11.38 | ||
| Median (IQR) | 46.50 (42.30–55.95) | 43.80 (42.25–55.30) | ||
| After treatment | ||||
| Minimum–maximum | 31.50–91.40 | 39.10–95.30 | U=198.50 | 0.968 |
| Mean±SD | 61.34±17.65 | 60.64±15.57 | ||
| Median (IQR) | 55.30 (50.45–73.25) | 55.30 (50.45–66.75) | ||
| Z (P0) | 2.819* (0.005*) | 2.821* (0.005*) | ||
| Terminal hair | ||||
| Before treatment | ||||
| Minimum–maximum | 4.0–5.0 | 3.0–6.0 | U=172.50 | 0.461 |
| Mean±SD | 4.35±0.49 | 4.45±0.89 | ||
| Median (IQR) | 4.0 (4.0–5.0) | 5.0 (4.0–5.0) | ||
| After treatment | ||||
| Minimum–maximum | 3.0–10.0 | 3.0–11.0 | U=174.0 | 0.495 |
| Mean±SD | 6.90±2.31 | 7.45±2.14 | ||
| Median (IQR) | 7.50 (4.50–9.0) | 7.50 (6.0–9.0) | ||
| Z (P0) | 3.311* (0.001*) | 3.862* (<0.001*) | ||
| Vellus hair | ||||
| Before treatment | ||||
| Minimum–maximum | 6.0–16.0 | 7.0–16.0 | U=168.0 | 0.398 |
| Mean±SD | 12.80±3.0 | 12.20±2.28 | ||
| Median (IQR) | 14.0 (10.50–15.0) | 12.50 (11.0–13.0) | ||
| After treatment | ||||
| Minimum–maximum | 3.0–16.0 | 5.0–16.0 | U=162.0 | 0.314 |
| Mean±SD | 7.50±4.24 | 7.85±2.70 | ||
| Median (IQR) | 6.0 (4.0–10.0) | 7.50 (6.0–9.0) | ||
| Z (P0) | 3.531* (<0.001*) | 3.834* (<0.001*) |
*Statistically significant at P≤0.05. Group (A) - Topical spironolactone application; Group (B) - Topical minoxidil application; IQR - Interquartile range; SD - Standard deviation; t - Student’s t-test; U - Mann–Whitney test; t1 - Paired t-test; Z - Wilcoxon signed-ranks test; P - P value for comparing between the two studied groups; P0 - P value for comparing between before and after treatment
Figure 4.
(a and b) Hair density before treatment. The red dots (vellus hair) are more than the green dots (terminal hair) denoting more hair thinning. (c and d) Showing improvement after 6-month treatment with topical spironolactone indicated by the increase in green dots
Figure 7.
(a and b) Hair width before treatment. (c and d) Showing improvement after 6-month treatment with topical minoxidil
Figure 5.
(a and b) Hair width before treatment. (c and d) Showing improvement after 6-month treatment with topical spironolactone
Figure 6.
(a and b) Hair density before treatment. The red dots (vellus hair) are more than the green dots (terminal hair) denoting more hair thinning. (c and d) Showing improvement after 6-month treatment with topical minoxidil indicated by the increase in green dots
Observable side effects in both groups were as follows
Contact dermatitis, scaling, scalp irritation, and headache. All of the previous side effects were minimal and tolerable and were overcome with time and by using topical antidandruff shampoo twice weekly through the course of treatment. There was a statistically significant difference between both groups regarding contact dermatitis, scalp irritation, and headache, which were more evident in Group B than in Group A [Table 3].
Table 3.
Comparison between the two groups according to side effects
| Side effect | Group A (n=40), n (%) | Group B (n=40), n (%) | χ 2 | P |
|---|---|---|---|---|
| Contact dermatitis | 12 (30.0) | 38 (95.0) | 18.027* | <0.001* |
| Scaling | 36 (90.0) | 40 (100.0) | 2.105 | FEP=0.487 |
| Scalp irritation | 6 (15.0) | 36 (90.0) | 22.556* | <0.001* |
| Headache | 0 | 12 (30.0) | 7.059* | FEP=0.020* |
*Statistically significant at P≤0.05. Group (A) - Topical spironolactone application; Group (B): Topical minoxidil application; P: P value for comparing between the two studied groups; χ2 : Chi-square test, FE: Fisher’s exact
DISCUSSION
Spironolactone has an antiandrogen activity that was attributed to its ability to decrease testosterone levels and blocks the ARs in target tissues.[7] The usual daily dose (50–200 mg/day) did not show serious side effects and can be considered safe for long-term therapy in FPHL.[8]
Minoxidil exerts its action through the opening of the potassium channel and increases angiogenesis around the follicle by increasing the expression of hair growth promoters such as vascular endothelial and hepatocytic growth factors. It increases hair count and weight by inducing telogen hairs to enter the anagen phase and prolonging anagen duration.[9]
In the present study, we compared the effect of topical spironolactone and topical minoxidil in the treatment of FPHL. There was no statistically significant difference between both groups regarding the Ludwig scale, GAIS, patients’ satisfaction, and trichoscopic features.
In Group A (treated with topical spironolactone 1%): patients were classified between grades L2–L3 at baseline. There was a statistically significant difference regarding the Ludwig scale before and after treatment. Ten patients (25%) showed mild improvement, 16 patients (40%) showed moderate improvement, 12 patients (30%) showed marked improvement, and 2 patients showed excellent improvement.
In Group B (treated with topical minoxidil 5%): there was a statistically significant improvement regarding the Ludwig scale before than after treatment. It was found that 10 patients had mild, 14 patients had moderate, 2 patients had excellent, and 14 patients had marked improvement.
These results coincided with the result reported by Abdel-Raouf et al.,[10] who evaluated the efficacy of topical minoxidil and topical spironolactone in the treatment of FPHL, found that there was significant improvement in the group treated with topical spironolactone clinically on grading by Ludwig scale and by dermoscopy. They found that in Group I (used minoxidil gel 5%): clinical response was in 90% of the patients, four of them had excellent response, six had good response, two had fair response, and six had poor response. In Group II (used spironolactone gel 1%): clinical improvement was in 80% of the patients, five of them had excellent response, four had good response, and seven patients had poor response. In comparison between Group I and Group II, there was an insignificant difference between them.
As regarding trichoscopic findings in Group A: there was a statistically significant improvement in hair width and density after than before treatment. There was a statistically significant improvement in the number of terminal hairs after treatment. There was a statistically significant difference and reduction in the number of vellus hair after treatment.
The present results were in accordance with the result reported by Ahmed et al., 2020[11] who evaluated the efficacy of oral finasteride versus oral spironolactone in the treatment of FPHL, and showed that there was statistically significant difference and improvement in trichoscopy data after treatment with oral spironolactone. Improvement findings were: improved hair width, decreased number of vellus hair, and increased number of terminal hair.
The present study was in agreement with Ammar et al., 2022,[12] who compared the efficacy of topical minoxidil solution 5%, spironolactone solution 5%, and their combination in the treatment of AGA (in both males and females) by dermoscopy, they found that there was a statistically significant difference between (hair shaft diversity, vellus hair, and upright regrowing hair at baseline, midterm and at the end of the study treatment in Group B treated with spironolactone. In the current study, similar results were achieved with spironolactone 1%.
The present results were in agreement with the results reported by Ghonemy et al., 2021[13] that evaluated the efficacy and safety of a new 10% topical minoxidil versus 5% topical minoxidil and placebo in the treatment of AGA, there was a significant improvement in the group treated with topical minoxidil 5% clinically (by Narrwood Hamilton scale for males and Ludwig scale for females) and by dermoscopy. They reported clinical improvement in the group treated by topical minoxidil 5% by percent 90%; Eight patients showed excellent response and two patients showed good response.
As regarding trichoscopic findings in Group (B), there was a statistically significant improvement in hair width and density, the number of terminal hairs after than before treatment. There was a statistically significant decrease in the number of vellus hair after than before treatment.
The previous results were in agreement with the result reported by Hassan et al., 2022[14] who evaluated treatment with oral Vitamin D alone, topical minoxidil alone, and their combination in the treatment of FPHL both clinically and by dermoscopy, they found that there was highly significant difference in number of thin hair and single hair unit after treatment with topical minoxidil. Furthermore, found that no significant improvement as regards perifollicular pigmentation and yellow dots after treatment in the same group.
The present results were in agreement with the results reported by Ghonemy et al.,[13] they reported that significant increase in terminal hair, a significant decrease in vellus hair, decreased perifollicular pigmentation, and decreased number of single hair units.
In this study, it was found that there was no statistically significant difference between the two studied groups regarding clinical improvement and trichoscopic features after 6 months of treatment (vellus hair, terminal hair, hair width, and hair density).
Side effects in the form of contact dermatitis, scaling, scalp irritation, and headache were reported. All of the previous side effects were minimal and tolerable and were overcome with time and by using topical antidandruff shampoo twice weekly through the course of treatment. There was a statistically significant difference between both groups regarding contact dermatitis, scalp irritation, and headache, which were more evident in Group B than in Group A.
CONCLUSION
Both topical spironolactone and topical minoxidil were cheap, safe, and effective lines for the treatment of FPHL with minimal and tolerable side effects. Studies with larger sample sizes, higher concentrations, and other routes of spironolactone administration as injectable (to overcome bad compliance with topical treatment) and longer courses of treatment are recommended to fully evaluate the efficacy of topical spironolactone in FPHL treatment. Furthermore, maintenance therapy is recommended as with minoxidil to maintain the improvement achieved. Limitations: Lack of control group and topical spironolactone gel is unavailable in the marketed formula compared to other lines available for the treatment of FPHL.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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