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. 2026 Jan;19(1):34–40.

Overview of the Efficacy and Safety of Topical Hormonal Therapies for the Treatment of Acne Vulgaris: A Narrative Review

James Q Del Rosso 1,✉, Hilary Baldwin 2, Alison M Layton 3
PMCID: PMC12872258  PMID: 41648090

Abstract

OBJECTIVE

Although systemic hormonal therapies (spironolactone, oral contraceptives) are clinically effective for the treatment of acne vulgaris (AV) in female patients, perceived safety concerns have contributed to the growing interest in topical hormonal AV therapies.

METHODS

We searched PubMed using the terms "topical," "antiandrogen," "hormonal," "clascoterone," "spironolactone," and "acne vulgaris."

RESULTS

The majority of articles identified related to clascoterone and topical spironolactone. Clascoterone cream 1% was approved in 2020 by the US Food and Drug Administration (FDA) for patients with AV aged 12 years or older based on two Phase III randomized controlled trials (RCTs) in 1440 patients (722 randomized to clascoterone) and an open-label extension study; other evaluations included a Phase IIa pharmacokinetic study and a Phase IIb RCT. Six clinical studies—mostly small, randomized trials—reported 193 patients treated with topical spironolactone as 5% cream, 5% gel, 2% solution, and 1% nanogel, and 1 RCT evaluated topical flutamide gel in 27 patients. The efficacy and safety of topical spironolactone and flutamide are supported by limited data with some conflicting results; neither agent is approved by the FDA and both must be compounded extemporaneously with no supporting pharmacokinetic data.

LIMITATIONS

Clinical studies of topical spironolactone are limited by the small number of patients and wide range of formulations evaluated.

CONCLUSION

Available evidence supports the use of clascoterone cream 1% and suggests potential benefits and limitations of topical spironolactone in patients with AV; however, for topical spironolactone, pharmacokinetic studies and large-scale RCTs are needed to better characterize both efficacy and safety profiles.

Keywords: Acne, topical, clascoterone, spironolactone, efficacy, safety, sebum

Acne vulgaris (AV) is a chronic dermatological condition that typically presents in puberty and can persist or worsen during adulthood.1 The pathophysiology of AV begins with an androgen-mediated increase in sebum production by the sebaceous glands.2 The effects of androgens on the sebaceous glands are mediated via binding to androgen receptors within sebocytes, which increases the production of sebum and inflammatory cytokines.3-5 Systemic hormonal agents (eg, spironolactone, oral contraceptives) are often used to target the hormonal component of AV pathophysiology in female patients with AV.2

Although AV may be associated with other clinical features of hyperandrogenism (eg, polycystic ovary syndrome),6 most individuals with AV have normal circulating hormone levels,6,7 suggesting that local biosynthesis of androgens within the skin likely contributes to the condition. Consequently, there has been growing interest in topical hormonal therapies that have the potential to overcome some of the adverse effects and safety concerns associated with systemic therapies, including combined oral contraceptives. Although clascoterone cream 1% is currently the only topical antiandrogen therapy approved by the US Food and Drug Administration (FDA) for the treatment of AV,8 other topical antiandrogen formulations have also been evaluated in clinical studies, including topical spironolactone and topical flutamide.

In this article, we review the clinical landscape of topical hormonal therapies for AV and discuss potential safety and clinical considerations related to their use in clinical practice.

WHAT ROLE DO ANDROGENS PLAY IN THE PATHOPHYSIOLOGY OF ACNE?

Acne most often begins at the onset of adrenarche and initially progresses during puberty in conjunction with an increase in the production of sex hormones, particularly androgens.2,9 Although reproductive organs are the primary site of androgen synthesis, the sebaceous gland contains androgen-synthesizing enzymes that enable the local biosynthesis of androgens such as dihydrotestosterone (DHT) from androgenic precursors.10 The cutaneous effects of androgens are mediated via binding to androgen receptors expressed in the skin and sebaceous glands,11,12 thereby inducing the downstream transcription of genes that regulate sebum production.3,13 Androgen-mediated increased sebum production is a key driver of the acne pathogenesis cascade.7 Free fatty acids released from sebum triglycerides promote keratinocyte differentiation,14,15 and androgens can also modulate keratinocyte differentiation directly by stimulating the production of growth factors from dermal fibroblasts, thereby contributing to comedogenesis in AV.16 Sebum also provides a favorable environment for the growth of Cutibacterium acnes, triggering local inflammatory responses.17 Due to their significant roles in regulating sebaceous gland activity and sebum production, androgens are an important therapeutic target for the treatment of AV. Hormonal therapies used in the treatment of AV generally work by hindering the biological activity of androgens by decreasing androgen synthesis (eg, oral contraceptives) and/or blocking the activity of androgens at androgen receptors (eg, oral contraceptives, clascoterone, and spironolactone).6

WHAT ARE THE CURRENT RECOMMENDATIONS FOR THE USE OF HORMONAL THERAPIES FOR AV?

The American Academy of Dermatology recommends a multimodal topical treatment consisting of therapies targeting different aspects of acne pathogenesis for the management of AV, with systemic therapy typically added to the regimen for moderate-to-severe cases that are not adequately controlled by topical therapy alone.6 The spectrum of hormonal treatments available for patients with AV includes topical (clascoterone) and systemic (spironolactone, oral contraceptives) agents6; however, systemic hormonal agents are generally limited to use in female patients due to the potential for feminizing effects and other adverse effects in males, including gynecomastia, impotence, and decreased libido.2 Clascoterone cream 1% is a first-in-class topical antiandrogen therapy8,18 and is the only topical hormonal agent approved by the FDA for acne treatment as of 2025. Other topical antiandrogen agents, including topical spironolactone, are also under clinical evaluation and may ultimately provide additional options for targeted hormonal acne treatment (Table 1).

TABLE 1.

Summary of clinical studies evaluating topical antiandrogen therapies

CITATION STUDY DESIGN INTERVENTION (ENROLLED M/F) TREATMENT REGIMEN PATIENT CHARACTERISTICS KEY FINDINGS LIMITATIONS
Hebert et al18 RCT Clascoterone cream 1% (258/464); vehicle cream (282/436) BID, 12 weeks Moderate-to-severe facial acne (IGA score of 3 or 4) Efficacy: Statistically significant rates of treatment successa and reductions in lesion counts at Week 12 vs. vehicle (p<0.001)
Safety: TEAE frequency was similar between clascoterone and vehicle, and most were mild or moderate in severity		 Concomitant acne therapies were not used
Walton et al19 R 3% spironolactone powder finely ground (4/7); 5% spironolactone cream (7/4); 3% potassium canrenoate solution (5/4) BID, 2 months Moderately severe facial acneb; age not reported Efficacy: No statistically significant changes in sebum excretion rate following 2 months of treatment with topical spironolactone 3% powder (p>0.6) or 5% cream (p>0.1) Vehicle design limitations and solubility issues
Afzali et al20 RCT 5% spironolactone gel (8/30); placebo (6/34) BID, 6 weeks Mild-to-moderate acne; aged 11 to 30 years Efficacy: Statistically significant reductions in total lesion count in spironolactone-treated vs. placebo-treated patients following 6 weeks of treatment (p=0.007). Differences in ASI were not statistically significant between spironolactone- and placebo-treated patients at Week 6 (p=0.05) Small number of male patients evaluated, short study duration, absence of objective biometric assessments
Kelidari et al21 R Spironolactone-NLC 1% (3/27); spironolactone-ALC 5% (2/28) BID, 8 weeks Mild-to-moderate acnec; aged 8 years or older Efficacy: Both formulations led to significant reductions relative to baseline in noninflammatory lesion scores at Week 8 (both p<0.01), with significant increases in skin hydration observed with spironolactone-NLC (p=0.002) and reductions in sebum measurements with spironolactone-ALC (p=0.01) at Week 8
Safety: Dryness and itching were the most common symptoms reported in patients treated with spironolactone-NLC (2.7%) and spironolactone-ALC (15%), respectively		 Small number of male patients evaluated
Ayatollahi et al22 OL 5% spironolactone cream (5/10) BID, 8 weeks Mild-to-moderate acne; aged 18 to 35 years Efficacy: Statistically significant reductions relative to baseline in the numbers of total (p<0.05), inflammatory (p=0.004), and noninflammatory lesions (p<0.001) following 8 weeks of treatment
Safety: No adverse effects were reported during the treatment period
Skin characteristics: No statistically significant changes from baseline were observed in skin hydration, sebum index, or TEWL at Week 8 (all p>0.05)		 Small sample size, short follow-up period
Noaimi and Al-Saadi23 RB 2% spironolactone solution (9/26); 1.5% clindamycin solution (8/25) BID, 12 weeks Mild-to-moderate facial acne Efficacy: Statistically significant reductions in the number of comedones from baseline to Week 12 in spironolactone-treated (p=0.0001) but not clindamycin-treated patients (p>0.05); significant, comparable reductions in papules and pustules in both cohorts (all p=0.0001); reductions in ASI with spironolactone were statistically significantly greater vs. clindamycin (p<0.05)
Safety: Mild adverse effects reported in patients using spironolactone (itching, 5.7%; burning, 11.4%) and clindamycin (itching, 9.1%; burning, 18.2%)		 Absence of objective biometric assessments
Gharib et al24 RCT 5% spironolactone gel (3/11); 5% dapsone gel (2/12) BID, 12 weeks Mild-to-moderate acne; aged 17 to 24 years Efficacy: Therapeutic responsed was significantly greater in patients using spironolactone vs. dapsone (p=0.034); there was no significant difference between treatments in ASI (p>0.05)
Safety: Frequency of adverse effects was significantly lower in patients using spironolactone vs. dapsone (p=0.021)		 Small sample size, small number of male patients evaluated
Nassar et al25 RCT 1% flutamide gel (1/26); placebo (3/24) BID, 8 weeks Mild-to-moderate acne; aged 16 to 27 years Efficacy: Statistically significant reductions relative to baseline in the numbers of papules (p<0.05) and pustules (p<0.001) but not comedones or total lesions following 8 weeks of treatment with flutamide, with no statistically significant differences relative to baseline in lesion counts in placebo-treated patients
Safety: 12 (44.4%) patients treated with flutamide reported mild adverse effects, including scaling (7.4%), stinging (22.2%), erythema (7.4%), and dryness (25.9%), compared with 6 (22.2%) patients treated with placebo. No systemic adverse effects, including hot flashes, decreased libido, or impotence, were observed in patients treated with flutamide		 Small number of male patients evaluated
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aTreatment success was defined as an IGA score of 0 or 1 and at least a 2-point reduction in IGA score from baseline.18

bDefined as grade 1–3, assessed as described by Cunliffe and Burk, 1984.19

cDefined as a score of 1–30 on the GAGS scale.21

dTherapeutic response was calculated based on the percentage improvement in ASI from the first visit and was rated as poor, moderate, good, or excellent.24

ALC: alcohol gel; ASI: acne severity index; BID: twice daily; F: female; GAGS: Global Acne Grading System; IGA: Investigator's Global Assessment; M: male; NLC: nanolipid carrier gel; OL: open label; R: randomized; RB: rater (or investigator) blinded; RCT: randomized controlled trial; TEAE: treatment-emergent adverse event; TEWL: transepidermal water loss

WHAT CLINICAL EVIDENCE SUPPORTS THE USE OF TOPICAL HORMONAL AGENTS IN THE TREATMENT OF ACNE VULGARIS?

Clascoterone. Clascoterone cream 1% is approved for the topical treatment of acne vulgaris in patients aged 12 years or older.8 In vitro, clascoterone competes with DHT for binding to androgen receptors in the skin to prevent androgen-mediated sebum and inflammatory cytokine production;4,5 however, the precise mechanism of action of clascoterone in the treatment of AV is unknown.8 According to an interim report at 12 weeks from a recent study, casual facial sebum measurements obtained with a sebumeter decreased by approximately 27% following 12 weeks of treatment with clascoterone cream 1% in 40 patients with AV, providing new evidence for sebum reduction as a component of the mechanism of action of clascoterone for acne treatment.26 The full study will evaluate changes in sebum measurements following treatment with clascoterone cream 1% through 52 weeks.26

The pharmacokinetic properties of clascoterone were evaluated in an open-label Phase II study of 20 adult (aged 18 years or older) and 22 adolescent (12–17 years old) patients with AV. Patients applied approximately 6g of clascoterone cream 1% (or 4g in adolescents with a body surface area <1.6m2) twice daily for 2 weeks,27 up to 6 times the recommended dose of 1g twice daily in the approved product labeling.8 Clascoterone plasma concentrations reached steady-state levels by 96 hours after application, with mean maximum plasma concentrations of 4.4ng/mL and 4.6ng/mL in adolescents and adults, respectively, an approximately 1.8- to 2.1-fold increase compared with the first dose.27 In vitro, clascoterone is rapidly metabolized to the primary metabolite cortexolone, which has minimal physiological activity.28,29 Plasma concentrations of cortexolone were measured in the Phase II study and generally remained below the lower limit of quantitation (0.5ng/mL).27 Collectively, this evidence demonstrates the limited systemic exposure to clascoterone or its metabolite following topical application.27

Clascoterone cream 1% had favorable efficacy and safety in early Phase I and II studies. In a pilot comparative study evaluating clascoterone cream 1% versus placebo and tretinoin 0.05% cream for 8 weeks in 77 male patients with AV, clascoterone led to significantly greater reductions versus placebo in total lesion count (TLC; p=0.0017), inflammatory lesion count (ILC; p=0.0134), and acne severity index (ASI; p=0.009).30 Compared with tretinoin, clascoterone resulted in significantly greater reductions in ILC at Week 6 (p=0.0374), with comparable reductions in ASI and TLC at all time points evaluated.30 Clascoterone was also evaluated in a 12-week Phase IIb randomized controlled trial (RCT) in 363 patients with acne in which patients were randomized to clascoterone 0.1% twice daily (n=72), clascoterone 0.5% twice daily (n=76), clascoterone 1% once daily (n=70), clascoterone 1% twice daily (n = 70), or vehicle (n=75).31 At Week 12, clascoterone cream 1% dosed twice daily led to the highest rates of treatment success and the largest reductions from baseline in lesion counts compared with vehicle and the other treatment cohorts. The frequency of adverse events was similar in patients treated with clascoterone cream 1% twice daily (13 patients, 18.6%) and vehicle (17 patients, 22.7%), and clascoterone was well tolerated.31

The efficacy and safety of clascoterone cream 1% for the treatment of acne were evaluated in two randomized, double-blind, vehicle-controlled, Phase III trials of 1440 patients 9 years or older with moderate-to-severe facial acne vulgaris.18 The trials included 1421 patients aged 12 years or older (the approved population) with a mean age of 19.7 years, of whom 62% were female and 91% were White.8 Following 12 weeks of twice-daily treatment, patients using clascoterone cream 1% had significantly higher rates of Investigator's Global Assessment (IGA) score treatment success and larger reductions in lesion counts compared with those receiving vehicle.18 Clascoterone had a safety profile similar to the vehicle, with the most common adverse events being nasopharyngitis, headache, and oropharyngeal pain.18 The most common new or worsening local skin reactions were erythema and scaling/dryness.18 There was no clinical evidence of systemic adverse effects related to androgen suppression reported in the Phase III clinical trials.18 In an open-label long-term extension study, the efficacy and safety of clascoterone were maintained for up to 9 additional months of treatment in patients with facial AV, with a progressive increase in efficacy over time and with no new safety signals reported.32,33 Clascoterone cream 1% also led to improvement in truncal IGA score through 9 months in patients who opted to treat truncal acne.32

Recent clinical evidence also indicated that clascoterone cream 1% does not adversely affect the epidermal barrier, which is commonly observed in patients with AV34 and often exacerbated by common topical acne medications.35,36 Among 50 participants with acne-prone skin who applied clascoterone cream 1% twice daily in a randomized split-face study, the side of the face treated with clascoterone exhibited an increase in skin moisturization with no change in transepidermal water loss (TEWL), a measure of epidermal permeability, following 2 weeks of treatment compared with the untreated side of the face.37

Topical spironolactone. Spironolactone is an oral aldosterone receptor antagonist that is used off-label for treatment of AV in select female patients.6 Spironolactone inhibits androgen signaling through multiple mechanisms, including competing with testosterone and DHT for binding to androgen receptors.6,38 There is also evidence that spironolactone inhibits 5α-reductase, an enzyme responsible for converting testosterone into DHT, and increases levels of steroid hormone-binding globulin, thereby reducing the local bioavailability of testosterone and DHT.6,38 Several different topical formulations and concentrations of spironolactone have been evaluated in clinical studies for AV treatment.

An early study by Walton et al19 compared the effects of 3 topical spironolactone preparations (3% cream, 5% cream, and 3% solution containing the active spironolactone metabolite canrenone) in 31 patients with moderate-to-severe acne (Table 1), which revealed no statistically significant reductions in sebum excretion rate following 2 months of treatment with any of the preparations tested. Other measures of treatment efficacy, such as reductions in lesion counts, were not evaluated in the study. In a more recent study by Ayatollahi et al,22 treatment with a topical 5% spironolactone cream twice daily for 8 weeks in 15 patients with mild-to-moderate acne resulted in significant reductions in lesion counts and acne global grading score (p<0.05; Table 1).33 There were no adverse effects reported and no significant differences in skin hydration or TEWL before and after treatment with topical spironolactone. Additionally, spironolactone did not affect the skin sebum index,22 which is consistent with earlier results.19

Afzali et al20 evaluated the efficacy and safety of 5% spironolactone gel in a double-blind study of 78 patients with mild-to-moderate acne, of whom 38 received spironolactone and 40 received placebo. There was no statistically significant difference in ASI between patients treated with spironolactone and those treated with placebo (p>0.05); however, spironolactone did lead to significantly greater reductions in TLC versus placebo following 6 weeks of treatment (p=0.007). Adverse reactions were reported with similar frequency between the two treatment arms.

There is growing interest in using lipid nanoparticles and other novel topical delivery systems for optimized formulations of spironolactone, although few have been evaluated in clinical studies.35-39 Spironolactone-loaded nanostructured lipid carrier gel (SP-NLC) was compared with a spironolactone alcoholic gel (SP-ALC) in a randomized double-blind study of 76 patients with mild-to-moderate acne.21 After 8 weeks of treatment, both formulations resulted in statistically significant reductions versus baseline in the numbers of noninflammatory and total lesions, but there was no change in ILC or ASI. Notably, significant reductions in sebum levels were reported after 8 weeks in patients receiving SP-ALC,21 contrasting with studies evaluating spironolactone cream formulations.19,22

In a recently published comparative study,24 there was no significant difference in ASI between patients treated twice daily with 5% spironolactone gel (n=14) versus 5% dapsone gel (n=14; p>0.05) for 12 weeks. However, the overall frequency of adverse effects was significantly lower in patients treated with spironolactone (5 patients, 35.7%) versus dapsone (11 patients, 78.6%; p=0.021). In particular, itching was significantly more common following treatment with dapsone versus spironolactone (p=0.003). In another study of 73 patients with mild-to-moderate facial acne, spironolactone 2% solution had significantly greater efficacy versus 1.5% clindamycin solution for the reduction of the number of comedones and improvement in ASI.23 Mild local adverse effects (itching, burning) were reported with similar frequency in both cohorts.

In a systematic review of the 5 clinical trials described above that evaluated topical formulations of spironolactone including 5% cream, 5% gel, 2% solution, 3% powder, and 1% nanogel in a total of 195 patients, topical spironolactone led to statistically significant reductions in ASI and/or TLC in 4 of the 5 studies.43 The patients included adolescents and adults aged 11 to 40 years, most of whom were women (n=152).43 Topical spironolactone had a generally favorable safety profile with few adverse reactions reported.43 However, the systemic safety of topical spironolactone is not well characterized because clinical studies to date included few male patients. Additionally, there are no published data on the pharmacokinetic profile of topical spironolactone, and it is therefore not known how much systemic exposure occurs after topical application.

Topical flutamide. The antiandrogen actions of flutamide are mediated via competition with DHT for binding to androgen receptors in the skin.25 Systemically administered flutamide is approved for the treatment of prostate cancer but is not currently approved for acne.44 A topical formulation of flutamide was evaluated in a RCT of 54 patients with mild-to-moderate acne.25 Flutamide 1% gel twice daily for 8 weeks versus placebo resulted in significant reductions from baseline in the number of papules and pustules but not in the number of comedones or total lesions.43 Adverse effects were reported in 12 of 27 (44.4%) patients receiving flutamide gel, including scaling (7.4%), stinging (22.2%), erythema (7.4%), and dryness (25.9%). The overall frequency of adverse effects with flutamide was numerically but not statistically significantly higher than the frequency reported with placebo (22.2%).25 No systemic adverse effects (eg, decreased libido, impotence) were reported in patients using flutamide.25 However, it is not known how much systemic exposure occurs after topical application, as the study did not include pharmacokinetic assessments.

WHAT ARE THE THERAPEUTIC DIFFERENCES BETWEEN CLASCOTERONE AND TOPICAL SPIRONOLACTONE?

Although clascoterone and spironolactone have similar chemical structures with a 4-ring backbone similar to that of DHT,29,45 these compounds differ somewhat in their mechanisms of action (Figure 1) and are not considered to be substitutable with each other for clinical use.46 Whereas both clascoterone and spironolactone competitively inhibit DHT binding to androgen receptors within sebaceous glands,4,5,38 spironolactone also exhibits activity at aldosterone (ie, mineralocorticoid) receptors, by which it additionally regulates blood pressure and potassium levels.2,45 Systemically administered spironolactone is associated with an increased risk of hyperkalemia, particularly in patients with impaired renal function or those using concomitant drugs that increase potassium,45 although evidence suggests minimal risk of hyperkalemia in young, healthy patients.47,48 There are currently insufficient pharmacokinetic data to determine whether topical spironolactone is safe for use in patients for whom systemic spironolactone is contraindicated or those at elevated risk for adverse effects associated with systemic spironolactone. Additional data are needed on the safety profiles of topical spironolactone and flutamide, particularly the potential for systemic adverse reactions. Additionally, compounded topical spironolactone products prescribed to patients for acne treatment may differ from each other and from published formulations. Clinicians and patients should be informed of the potential differences between topical spironolactone products and clascoterone when considering optimal treatment options.

Figure 1.

Figure 1.

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Mechanisms of action of clascoterone and spironolactone.

ALD: aldosterone; AR: androgen receptor; DHT: dihydrotestosterone; MR: mineralocorticoid receptor

CONCLUSION

Topical hormonal therapies fulfill an important clinical need, as they can be used safely to address the hormonal pathophysiology of acne in a variety of patients, allowing healthcare professionals to tailor acne management in diverse populations. There has been substantial interest in developing topical hormonal therapies to address the androgen-driven component of acne with lower potential for systemic adverse reactions both before and after the approval of clascoterone cream 1% in 2020.8 Evaluations supporting the approval of clascoterone comprised Phase I and Phase II studies in patients with AV, including a pharmacokinetic study demonstrating limited systemic exposure following topical application,27,30,31 and two pivotal Phase III RCTs demonstrating clascoterone efficacy versus vehicle based on IGA success and lesion counts, along with favorable safety and tolerability.18 Evidence from a recent report demonstrating reductions in casual sebum production following treatment with clascoterone cream 1% further describe the mechanism of action of clascoterone.19

Spironolactone is readily available for compounding, and multiple clinical studies to date have evaluated a range of topical spironolactone formulations and concentrations including 5% cream, 5% gel, 2% solution, 3% powder, and 1% nanogel.43 Based on limited available evidence, topical spironolactone may potentially provide an effective option for topical hormonal therapy; however, given the relatively small study sizes and inconsistency of reported efficacy results among different formulations, pharmacokinetic studies and large-scale RCTs that include both female and male patients are needed to support its mainstream use in AV management. Similarly, topical flutamide may potentially provide an effective option for AV treatment, but clinical experience thus far is limited. Efficacy, safety, and other considerations (ie, patient characteristics and clinical history) should be taken into account when making decisions regarding topical hormonal treatment options for patients with AV.

ACKNOWLEDGMENTS

Manuscript preparation and editorial support were provided by Dana Lengel, PhD, of AlphaBioCom, a Red Nucleus company, and funded by Sun Pharma.

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