Efficacy and safety of oral spironolactone for female pattern hair loss in premenopausal women: a randomized, double-blind, placebo-controlled, parallel-group pilot study

Abstract

Background:

Oral spironolactone is widely used as an alternative treatment for female pattern hair loss, particularly in women of reproductive age. However, published data on its effects are still limited.

Objective:

This study aimed to evaluate the efficacy and safety of spironolactone 100 mg daily for female pattern hair loss in premenopausal women compared with placebo.

Methods:

Forty-eight women aged 21 to 45 years were randomly assigned to receive spironolactone 100 mg or matched placebo once daily for 24 weeks. Twice-daily minoxidil 3% solution was used for all to avoid untreated participants. Efficacy was assessed by changes in hair density and diameter using videodermoscopy and global photographic assessment.

Results:

After treatment, hair density and diameter increased significantly in both treatment groups (all P < 0.001). The spironolactone group showed a greater increase in changes from baseline of terminal hair counts (9.48 ± 11.25 vs 5.32 ± 6.81 hairs/cm²) and hair diameters (4.23 ± 4.58 vs 2.96 ± 2.84 μm), compared with the placebo group. However, only the P-value of terminal hair counts approached the cutoff of statistical significance (P = .063). The spironolactone group also showed greater moderate-to-marked improvement than the placebo group (38% vs 9%; P = .034). Adverse events, primarily menstrual irregularities (37.5%), were significantly higher in the spironolactone group.

Limitations:

The sample size was small.

Conclusion:

Oral spironolactone 100 mg daily for 24 weeks showed an additive effect on topical minoxidil therapy in premenopausal women with mild-to-moderate female pattern hair loss. Although it was generally well-tolerated, irregular menstruation was common.

What is known about this subject with respect to women and their families?

• Various alternative therapies have been applied for female pattern hair loss, especially in cases of dissatisfaction with standard therapy. Oral spironolactone appears to be a popular treatment modality among women of reproductive age.

• However, randomized double-blind placebo-controlled trials to assess therapeutic efficacy and safety profiles of oral spironolactone in this condition are still lacking.

What is new in this article with respect to women and their families?

• Compared with placebo, oral spironolactone 100 mg daily for 24 weeks showed synergistic effects in promoting hair growth when concomitantly used with topical minoxidil for female pattern hair loss in premenopausal women.

• Nevertheless, irregular menstruation is quite common, occurring in approximately one-third of users.

Introduction

Female pattern hair loss (FPHL) is a preferred term for androgenetic alopecia in women, as its relationship with androgens is not as well established as male androgenetic alopecia. The global prevalence of FPHL increases with advancing age and differs between races.^1,2 The onset of hair thinning ranges from postpuberty to postmenopause, with 2 main peaks in the third and fifth decades of life.^3,4 FPHL typically progresses to a more advanced stage over time, especially if left untreated.

Topical minoxidil, 2% or 5%, remains the current standard treatment for FPHL. After 6 to 12 months of use, topical minoxidil can stabilize disease progression in approximately 90% of women with FPHL and stimulate hair regrowth with a response rate of 46 to 68%.^5–7 Women with unsatisfactory outcomes are still seeking alternative therapies, including oral antiandrogens. Childbearing potential is of great concern in the use of oral antiandrogens among women owing to the risk of feminization in the male fetus. By reason of more evidence to support the use in women, spironolactone appears to be the preferred choice of oral antiandrogens for FPHL in premenopausal women.

Spironolactone is an aldosterone antagonist primarily used as a potassium-sparing diuretic to treat hypertension and heart failure. It also exerts antiandrogen activities by competitively blocking androgen receptors in target tissues and reducing androgen synthesis in the ovaries and adrenal glands.⁸ Accordingly, spironolactone has been used in dermatology for acne, hirsutism, and FPHL. The usual dose for alopecia is approximately 100 to 200 mg daily, as either monotherapy or combined therapy. Long-term use of spironolactone monotherapy at the usual doses can prevent further hair thinning in 85 to 100% and promote hair growth in 33 to 49% of women with FPHL.^9–12

Despite its favorable tolerability in FPHL, one-quarter to one-third of spironolactone-treated women experienced adverse events.^9,13,14 The common side effects reported in previous studies are menstrual irregularities, breast tenderness, and dizziness, usually presenting with mild symptoms and uncommonly requiring drug discontinuation. The risk of developing hyperkalemia, a potential side effect of spironolactone, is dependent on age and kidney function. Healthy women aged 45 years and younger are considered low risk.^13,15–17

However, published literature on therapeutic effects of spironolactone for FPHL is limited, and there is a lack of randomized controlled trials with objective measurements of efficacy outcomes. This study aimed to evaluate the efficacy and safety of oral spironolactone 100 mg daily for FPHL in premenopausal women, compared to placebo using quantitative and qualitative measures of hair regrowth. Due to the concern of gradual hair thinning in the placebo group if untreated, topical 3% minoxidil solution, the lowest strength commercially available in Thailand, was applied to all participants in the study.

Materials and methods

Study design and participants

This randomized, double-blind, placebo-controlled pilot study with 2 parallel arms was conducted at Srinakharinwirot University Skin Center in Thailand, between June 2022 and August 2023. The study protocol was approved by the Human Research Ethics Committee of Srinakharinwirot University (SWUEC-394/2021F) and prospectively registered on Thaiclinicaltrials.org (TCTR20220613005) before enrollment. The study was performed in accordance with the Declaration of Helsinki. All participants provided written informed consent before study procedures.

Premenopausal women aged 18 to 45 years with mild-to-moderate FPHL (Ludwig stages I and II) were eligible to participate. Individuals were excluded if they met any of the following criteria: history of malignancy or significant health conditions; family history of breast cancers in first-degree relatives; pregnancy or breastfeeding; inadequate contraception or use of hormonal contraceptives; allergy to spironolactone or any component in the minoxidil solution; use of oral medications for hair loss within 6 months; use of topical medications for hair loss within 3 months; history of acute hair shedding within 3 months; and low blood pressure, abnormal kidney function or electrolyte imbalances at screening.

Sample size

In the absence of previous data on hair counts using trichoscopy after spironolactone therapy for FPHL at the time of the study, a sample size of 20 per treatment arm was used to examine its effects. Considering the potential dropout rate of 20%, the total sample size was 48.

Randomization and blinding

Participants were randomly allocated to receive 1 tablet of either spironolactone 100 mg or a perfectly matched placebo once daily, in combination with a twice-daily schedule of minoxidil 3% solution, for 24 weeks. In addition to packaging and labeling study drugs, an independent assistant performed central randomization using a web-based program to generate the random schedule. Block randomization with block sizes of 2, 4, and 6 was applied at a 1:1 allocation ratio. Sited investigators and outcome assessors were concealed for treatment allocation until study completion.

Outcome assessment

The primary efficacy outcome was the change in hair density based on paired trichoscopic images. Secondary efficacy outcomes were change in hair diameter, overall clinical change based on paired global photographs evaluated by 2 assessors, and participant-rated treatment satisfaction.

Hair density and diameter were measured before and after treatment. Trichoscopic images were captured on the mid-scalp area using a handheld videodermoscope (Folliscope®, Anagen Corp., Seoul, South Korea) at 50-fold magnification, yielding an image field of 31.07 mm². Folliscope 5.0 software was used to calculate hair counts and average hair diameters. Hairs were grouped according to thickness into terminal hairs (≥60 µm) and nonterminal hairs (<60 µm; intermediate and vellus hairs). To ensure accuracy in repeated measurements, natural landmarks or semipermanent tattoos on the scalp were used as references.

Before and after global photographs were taken in frontal and vertex views, using a high-resolution DSLR camera mounted on a stereotactic device for optimized head positioning. Two board-certified dermatologists, blinded to treatment allocation, independently assessed hair changes on paired global photographs before and after treatment using a 7-point rating scale (marked, moderate, or mild deterioration; no change; mild, moderate, or marked improvement). The concordance between 2 assessors was analyzed. In cases of disagreement, the assessors’ opinions were discussed to reach a final consensus.

Participant treatment satisfaction was measured after 24 weeks of treatment using a self-assessment questionnaire with a 10-point visual analog scale (0 = not satisfied and 10 = very satisfied).

Pregnancy and adverse events were monitored throughout the study period. At each follow-up visit in 8-week intervals, plasma levels of creatinine, sodium, and potassium were regularly measured. The procedures for blood centrifugation and serum preparation were performed within 1 hour after blood collection to avoid hemolysis.

Statistical analysis

All statistical analyses were performed on an intention-to-treat basis using STATA 18 software. Baseline characteristics were compared between 2 groups using Pearson’s chi-square test, independent t-test or Wilcoxon rank sum test, as appropriate. Paired t-test or Wilcoxon signed-rank test was used to compare hair density and diameter before and after treatment. The primary outcome, change from baseline in hair density and diameter, was analyzed using linear regression with baseline values as a covariate. Global photographic assessment and adverse events were compared using chi-square or Fisher’s exact test. Interrater agreement was assessed using kappa statistics. P value <.05 was considered statistically significant.

Results

A total of 136 Thai women were screened, of which 48 were randomized. The main reasons for ineligibility were current use of hair-stimulating medications, use of hormonal contraceptives, significant health conditions, and concomitant telogen effluvium. After 24 weeks of treatment, 43 participants (90%) completed the study as 5 dropped out at the first follow-up visit. In the spironolactone group, 2 participants complained of irregular menstruation with abnormally painful periods and requested study withdrawal, while the other moved abroad. In the placebo group, 1 participant switched to using a hormonal intrauterine device for birth control, and the other was lost to follow-up (Fig. 1).

Fig. 1.

Participant disposition.

As for baseline characteristics, statistically significant differences between 2 groups were not demonstrated in either intention-to-treat or completer analyses (all P > .40; Table 1). Average adherence rates to oral and topical medications were, respectively, 94 and 93% in the spironolactone group, compared with 89 and 92% in the placebo group.

Table 1.

Demographics and baseline characteristics (ITT population)

Characteristics	Spironolactone + topical MNX (n = 24)	Placebo + topical MNX (n = 24)
Age, years
Mean (SD)	30.79 (6.22)	31.29 (7.39)
Minimum–maximum	21–45	21–43
Duration of hair loss, years
Mean (SD)	6.71 (2.94)	6.79 (3.51)
Median (IQR)	6 (5, 10)	6.5 (3.5, 10)
Minimum–maximum	1–11	2–15
Family history of AGA
Number (%)	19 (79)	22 (92)
Baseline Ludwig stage, number (%)
I	20 (83)	22 (92)
II	4 (17)	2 (8)
Baseline hair density, hairs/cm3, mean (SD)
Total hair count	99.50 (17.34)	98.92 (23.41)
Terminal hair count	42.92 (20.56)	39.79 (12.02)
Nonterminal hair count	56.58 (19.87)	59.13 (27.03)
Baseline hair diameter, μm
Mean (SD)	55.52 (7.56)	55.60 (7.63)

The intention-to-treat population included all randomized participants (N = 48). All P >.40.

AGA, androgenetic alopecia; IQR, interquartile range; ITT, intention-to-treat; MNX, minoxidil; SD, standard deviation.

Changes in hair density and diameter

Hair density and diameter after treatment are shown in Table 2. Total hair counts, terminal hair counts, and hair diameters were significantly increased in both spironolactone and placebo groups, compared to baseline (all P < .001).

Table 2.

Hair density and diameter after treatment by trichoscopy (mITT population)

Variables	Spironolactone + topical MNX (n = 21)	Placebo + topical MNX (n = 22)	P-valuea
At week 24
Hair density, hair/cm2, mean (SD)
Total hair count	109.43 (14.62)	105.41 (24.33)	.086
Terminal hair count	53.24 (18.13)	44.95 (13.28)	.063
Nonterminal hair count	56.19 (19.86)	60.45 (23.84)	.528
Hair diameter, μm	59.93 (6.94)	58.26 (6.43)	.206
Change from baseline
Hair density, hair/cm2, mean (SD)
Total hair count	8.95 (7.61)	5.64 (5.30)	.086
Terminal hair count	9.48 (11.25)	5.32 (6.81)	.063
Nonterminal hair count	−0.52 (7.24)	0.31 (4.97)	.528
Hair diameter, μm	4.23 (4.58)	2.96 (2.84)	.206

The modified intention-to-treat population included all randomized participants who completed the study (N = 43).

mITT, modified intention-to-treat; MNX, minoxidil; SD, standard deviation.

^aLinear regression P value adjusted for baseline.

Regarding changes from baseline in hair density and diameter (Fig. 2), the spironolactone group showed a greater increase in hair count and thickness after treatment. Mean increases in total hair counts and terminal hair counts were respectively 8.95 and 9.48 hairs/cm² in the spironolactone group, compared to 5.64 and 5.32 hairs/cm² in the placebo group (P = .086 for total hair counts; P = .063 for terminal hair counts). Mean increase in hair diameters was 4.23 and 2.96 μm in the spironolactone and placebo group, respectively (P = .206). Before and after trichoscopic images are displayed in Figure 3.

Fig. 2.

Changes from baseline in hair density and diameter after 24 weeks of treatment (mITT population). mITT, modified intention-to-treat.

Fig. 3.

Baseline and week 24 trichoscopic images by videodermoscopy at 50-fold magnification on the target area. (A) Trichoscopic images on the mid-scalp of a woman with female pattern hair loss who was treated with oral spironolactone 100 mg daily combined with twice-daily minoxidil 3% solution for 24 weeks. (B) Trichoscopic images on the mid-scalp of a woman with female pattern hair loss who was treated with oral placebo combined with twice-daily minoxidil 3% solution for 24 weeks.

Global photographic assessment

There was substantial agreement between 2 assessors on ratings of overall clinical changes after treatment (percentage agreement = 81.5%; kappa coefficient = 0.72). The final ratings of hair changes based on paired global photographs are displayed in Figure 4.

Fig. 4.

Panel assessment of clinical changes based on paired global photographs before and after 24 weeks of treatment (mITT population). mITT, modified intention-to-treat.

After 24 weeks of treatment, no participants in the spironolactone or placebo group experienced progressive hair thinning; however, about half of both groups expressed no changes in hair density (43% in spironolactone; 50% in placebo). Upon the degree of improvement, in the spironolactone group, 19% had mild improvement, 33% showed moderate improvement and 5% exhibited marked improvement. In the placebo group, 41% experienced mild improvement, 9% showed moderate improvement, and none achieved marked improvement (intergroup comparison, P = .092).

Clinically meaningful outcomes, defined as moderate-to-marked improvement, were significantly higher in the spironolactone group, representing 38% (8 participants), compared to 9% (2 participants) in the placebo group (P = .034). Clinical response images are shown in Figure 5.

Fig. 5.

Baseline and week 24 global photographs. (A) A woman with female pattern hair loss who was treated with oral spironolactone 100 mg daily combined with twice-daily minoxidil 3% solution for 24 weeks and rated as marked improvement. (B) A woman with female pattern hair loss who was treated with oral placebo combined with twice-daily minoxidil 3% solution for 24 weeks and rated as moderate improvement.

Participant-reported treatment satisfaction

The mean score of treatment satisfaction was 8.81 ± 1.21 in the spironolactone group and 9.09 ± 1.02 in the placebo group (P = .488).

Safety outcomes

Adverse events were significantly more pronounced in the spironolactone group, occurring in 12 participants (50%), compared to 1 participant (4%) in the placebo group (P = .001), as shown in Table 3. The most common events were related to menstruation, including shorter menstrual cycles, spotting, and dysmenorrhea. However, only menstrual irregularities showed a statistically significant difference between groups (P = .002). Most adverse events were mild in severity and no disturbances in daily life. All participants were willing to continue medication, except for 2 participants (8%) who were concerned about irregular periods and requested study termination. The participants’ periods entirely returned to normal within 3 months after discontinuing spironolactone.

Table 3.

Adverse events (safety population)

Events Number (%)	Spironolactone + topical MNX (n = 24)	Placebo + topical MNX (n = 24)
Discontinued treatment due to AEs
Menstrual irregularities	2 (8.3)	0 (0)
Participants with ≥1 AE
Menstrual irregularities	9 (37.5)a	0 (0)
Dysmenorrhea	3 (12.5)	0 (0)
Breast tenderness	1 (4.2)	0 (0)
Dizziness	2 (8.3)	0 (0)
Facial hypertrichosis	1 (4.2)	0 (0)
Scalp pruritus	0 (0)	1 (4.2)

The safety population included all randomized participants who received at least one dose of the study medication (N = 48).

AE, adverse event; MNX, minoxidil.

^aP < .05; P = .002 for menstrual irregularities.

There were no differences between groups regarding changes in blood tests during treatment. While no abnormalities in creatinine and sodium levels were detected throughout the study, mild transient hyperkalemia without any symptoms occurred in 2 participants (9.5%) in the spironolactone group and 1 participant (4.5%) in the placebo group at week 24. Serum potassium levels ranged from 5.2 to 5.3 mEq/L and were spontaneously normalized when repeated measures in all affected participants without any treatment.

Discussion

Published evidence on therapeutic effects and safety profiles of oral spironolactone for FPHL is largely gained from case reports, retrospective studies, and open-label studies.^{9–14,18–20} Moreover, the optimal dosage or dose-response study is still unavailable to date. While spironolactone monotherapy at doses below 100 mg daily for 6 to 12 months does not seem to improve hair thinning, a daily dose of 100 to 200 mg appears to help stabilize and enhance hair growth in similar response rates with additive effects when topical minoxidil is concomitantly used.^9–12,20

This randomized study adopted a double-blind design and matched placebo to determine the actual effects of spironolactone at daily dose of 100 mg for 24 weeks in women of reproductive age. The spironolactone group showed greater improvement in overall clinical changes based on global photographic assessment, particularly with respect to the degree of improvement. A significantly higher number of women in the spironolactone group achieved clinically meaningful outcomes, defined as moderate-to-marked improvement, than those in the placebo group, 38 vs 9% (P = .034). The spironolactone group also showed a greater increase in hair density and diameter after treatment; however, the P-value only approached the cutoff but did not reach statistical significance (P = .063). This might be from underpowered statistics due to an insufficient sample size or a short duration of treatment as spironolactone use for FPHL was mentioned to require a year for noticeable improvements.^9,14

Regarding response to treatment, disease stabilization was observed in all participants in this study, which is consistent with previous data on combination therapy of oral spironolactone 100 to 200 mg daily and topical minoxidil.^13,14 However, observations of hair regrowth after these combinations appear to vary among studies. Clinical improvement based on the Sinclair scale was reported in 13% of premenopausal women treated with spironolactone 200 mg daily combined with a twice-daily minoxidil 5% solution at the end of 6 months, and the improvement increased to 69.5% at the end of 12 months.¹⁴ Contrarily, another study in the same age group, examining the effect of spironolactone 100 mg daily combined with once-daily minoxidil 5% solution, revealed a high rate of clinical improvement based on physician’s global photographic assessment after 6-month therapy, accounting for 86.5%.¹³ In this study, hair regrowth was noticed in 57% at 6 months, mostly exhibiting mild-to-moderate improvement.

Although spironolactone 100 mg daily was generally well-tolerated in this study, half of the users reported at least one side effect. However, most were mild in nature and did not cause daily routine disruptions. The most common side effect was menstrual irregularities (37.5%), followed by dysmenorrhea (12.5%), and dizziness (8%). We also found that irregular menstruation was the leading cause of treatment discontinuation, occurring in about 8% of users. Similar to the previous results, menstrual irregularities are common complaints in the use of spironolactone among women of reproductive age, range from 2% to 40%.^9,11,13,14

Mild hyperkalemia with self-resolution was observed in 9.5% (2 of 21) of the spironolactone group and 4.5% (1 of 22) of the placebo group, in the absence of specimen hemolysis. Hyperkalemia was reported at a higher rate here compared to other studies in the same age group, possibly due to a relatively small population. Previous studies have indicated that healthy women aged 45 years and younger are at low risk for hyperkalemia with spironolactone use for acne and FPHL, representing 0.72% (13 of 1,802) to 1% (1 of 112) in studies on acne, and 1% (1 of 79) to 2.5% (1 of 40) in studies on FPHL.^13,16,17

Interestingly, the occurrence of hyperkalemia in healthy women receiving spironolactone for acne was documented to be equivalent to that in age-matched women who were not taking spironolactone, 0.72% (13 of 1,802) vs 0.76% (32 of 4,209).¹⁶ By contrast, women aged over 45 years are at a higher risk of developing hyperkalemia with spironolactone use for acne and FPHL, occurring in 10% (9 of 87) to 17% (2 of 12), respectively.^15,17 Impaired kidney function and borderline high potassium levels at baseline are leading risk factors for developing hyperkalemia.¹⁵

Even though combined therapies of oral spironolactone 100 to 200 mg daily and topical minoxidil for 6 to 12 months yield a very high rate of sustained disease stabilization, many women experience unchanged hair density after treatment. The unchanged rate was reported at 43% in this study and ranged from 14 to 87% in the previous studies.^13,14 As undesirable effects from spironolactone use are not unusual, it is prudent to communicate the benefits and risks in consultations.

Study limitations included a small sample size and monoethnicity, which could influence the study power and representativeness. A 6-month period of therapy was considered another limitation. Longer treatment durations and larger sample sizes are required to accurately detect treatment effects. Moreover, further studies are needed to determine the optimal dosage. Higher doses are also needed to capture treatment response, particularly in the nonresponders.

In conclusion, combining spironolactone 100 mg daily with topical minoxidil for 24 weeks showed superiority in hair regrowth, in terms of clinically meaningful outcomes, over topical minoxidil alone for the treatment of FPHL in premenopausal women. However, spironolactone-related adverse events, particularly menstrual irregularities, are quite common. Oral spironolactone 100 mg daily can be considered as an alternative treatment option for mild-to-moderate FPHL in women of reproductive age, alongside standard treatment of topical minoxidil, to enhance therapeutic efficacy.

Conflicts of interest

None.

Funding

Supported by the Faculty of Medicine, Srinakharinwirot University, under grant number 289/2565.

Study approval

Informed, written consent was received from all participants for whom photographs are present in the manuscript.

Author contributions

PW: Methodology, data collection, and writing—original draft preparation. SH: Conceptualization and data assessment. CL: Conceptualization and methodology. SK: Conceptualization, methodology, data assessment, revision of final manuscript, and supervision.

Data availability

Available from the corresponding author upon reasonable request.