Oral and Topical Spironolactone in Adult Female Acne: A Narrative Review Comparing Systemic and Local Approaches

Abstract

Background

Adult female acne (AFA) affects 12–45% of women over 25 years of age and is frequently resistant to conventional therapies. The antiandrogenic properties of spironolactone have positioned it as a promising non-antibiotic alternative. While oral spironolactone has been increasingly studied, its topical formulation remains comparatively underexplored, and recent evidence syntheses have generally pooled both routes of administration rather than comparing them within a framework specific to AFA.

Objective

This narrative review synthesizes and critically compares the available evidence on the efficacy, safety, and practical considerations of oral versus topical spironolactone in AFA.

Methods

A literature search was conducted in PubMed and Google Scholar on 1 September 2025, using search terms combining adult female acne with spironolactone. Original clinical studies—randomized controlled trials, observational studies, and case series—were included. Preclinical studies, non-English-language articles, and non-original data were excluded.

Results

Oral spironolactone (50–200 mg/day) consistently demonstrates significant reductions in inflammatory and non-inflammatory lesion counts and improves acne-specific quality of life. Head-to-head trials indicate comparable or superior efficacy relative to doxycycline, with longer treatment persistence than oral antibiotics. Topical spironolactone (2–5%) reduces comedones, papules, and pustules with minimal systemic absorption, suggesting a potential option for patients who are not candidates for systemic therapy. However, the evidence base for topical formulations remains limited by small sample sizes and heterogeneous study designs, and is derived largely from small mixed-sex or non-AFA cohorts and from pharmacokinetic studies in healthy volunteers; its applicability to AFA is therefore currently indirect and extrapolated.

Conclusion

Oral spironolactone is supported by robust evidence as an effective non-antibiotic option for AFA and is suitable for moderate-to-severe disease, whereas topical spironolactone appears promising but remains supported by limited and partly indirect evidence, derived largely from small and heterogeneous studies, and may be appropriate for mild-to-moderate acne or when systemic therapy is contraindicated. Because no head-to-head trial has compared the two routes, the comparison presented here is necessarily indirect. Future research should prioritize head-to-head comparisons of both routes and standardization of topical formulations.

Introduction

Acne vulgaris is a multifactorial inflammatory dermatosis of the pilosebaceous unit with a chronic course. It affects approximately 9.4% of the global population annually, primarily adolescents and young adults.¹ During childhood, acne is predominantly found in girls, while during adolescence it is more common in boys. Recently, an increased incidence in adults—with a female predominance—has been observed.²

Adult female acne (AFA) is diagnosed in women over the age of 25 and affects an estimated 12–45% of adult women.³ Persistent acne begins in adolescence and continues into adulthood, whereas late-onset acne first presents in adulthood. AFA typically presents with inflammatory papules and pustules of mild to moderate severity, with a predilection for the lower face, jawline, and neck (the U-zone).⁴ Truncal involvement is observed in more than 50% of female patients. Lesions frequently resolve with residual dyspigmentation, erythema, and scarring.⁴

The pathomechanism of AFA is strongly influenced by androgens.⁵ Elevated androgen expression and cutaneous hyperreactivity promote acne development through increased sebum synthesis, which in turn facilitates colonization by Cutibacterium acnes.^6,7 C. acnes stimulates the breakdown of triglycerides in sebum to free fatty acids, leading to hyperkeratinization and comedogenesis.^8,9 Concurrently, pro-inflammatory cytokines secreted by sebocytes under androgenic stimulation intensify the inflammatory cascade within the sebaceous gland.⁸

AFA is characterized by high rates of conventional treatment failure. Topical monotherapies, combination regimens with antibiotics or retinoids, and even oral isotretinoin frequently yield inadequate responses.^4,10,11 As a consequence, patients are often subjected to prolonged courses of antibiotic therapy.¹² Current treatment guidelines emphasize limiting oral antibiotic use and discourage antibiotic monotherapy.^13,14 Given rising antibiotic resistance, the search for effective non-antibiotic alternatives has become increasingly urgent.¹⁴

Acne significantly impairs quality of life, particularly self-esteem. The visible nature of acne lesions causes considerable emotional distress, increased anxiety, and reduced social well-being.¹⁵ Psychological distress has been reported in up to 25% of patients with severe acne.¹⁶

In this context, spironolactone has emerged as a valuable therapeutic option. Originally developed in the 1950s as a synthetic, non-selective mineralocorticoid receptor antagonist, spironolactone inhibits aldosterone binding in the distal renal tubule, resulting in potassium-sparing diuresis.^17,18 Beyond its cardiovascular and nephroprotective indications, spironolactone exerts potent antiandrogenic effects: it competitively inhibits androgen receptor binding, impairs testosterone biosynthesis via degradation of a cytochrome P450 cofactor, increases sex hormone–binding globulin (SHBG) levels, and reduces 5-alpha-reductase activity.^19,20 These properties directly counteract the hormonal drivers of AFA.

Spironolactone has been used off-label for acne since the 1980s.²¹ In addition to its systemic form, topical preparations (2–5%) have been investigated as a means of delivering antiandrogenic effects locally, with minimal systemic exposure. Recent systematic reviews and meta-analyses have addressed spironolactone in acne, and several have pooled oral and topical formulations within a single quantitative synthesis; comparatively few, however, have examined the two routes side by side in a clinically oriented framework restricted to AFA.

Until recently, hormonal treatment of acne necessarily implied systemic therapy, as no topical antiandrogen was available. This changed with the introduction of clascoterone 1% cream, the first topical androgen receptor inhibitor approved for acne vulgaris in patients aged 12 years and older. Clascoterone competes with dihydrotestosterone at the androgen receptor of sebocytes and follicular keratinocytes and is rapidly hydrolysed within the skin to cortexolone, so that clinically relevant systemic antiandrogenic effects do not occur; it is supported by Phase 3 randomized trials and by regulatory approval.²² Clascoterone thus provides proof of principle that androgen receptor blockade confined to the skin can improve acne, and it constitutes the natural comparator for topical spironolactone; this positioning is discussed in Oral Versus Topical Spironolactone: A Comparative Perspective.

The aim of this review is to summarize and critically compare the efficacy, adverse effects, and clinical utility of oral and topical spironolactone in AFA, thereby providing clinicians with an integrated perspective on both therapeutic routes.

Methods

This article is a narrative review that aims to synthesize and critically discuss the available evidence on both oral and topical spironolactone in AFA. A literature search was performed in PubMed and Google Scholar on 1 September 2025, using the following search string: (adult female acne OR acne OR women acne) AND (spironolactone). No date restrictions were applied.

Eligible studies included randomized controlled trials (RCTs), non-randomized comparative studies, observational studies, and case series evaluating spironolactone (oral or topical) in female acne patients. Preclinical and in vitro studies were excluded, as were articles without available full text, non-English-language publications, and non-original data such as reviews, commentaries, and editorials. Where multiple reports from the same institution described potentially overlapping patient populations, only the most recent publication was retained. Because robust data on topical spironolactone in adult females remain scarce, a small number of mechanistic and efficacy studies conducted in mixed-sex or male populations were also included where directly relevant to the topical route, and are identified as such in the text; one non–English-language report was retained on the basis of its English-language abstract and frequent citation. Under these criteria, systematic reviews and meta-analyses were not eligible as primary sources; those published up to the search date were nevertheless screened for additional primary studies and are discussed separately in Evidence From Meta-Analyses, so that the present review can be situated in relation to the existing quantitative evidence syntheses. The clinical studies ultimately included were published between 1984 and 2024.

Given the narrative design of this review, no formal risk-of-bias assessment or meta-analytic synthesis was performed. Studies were grouped thematically by route of administration (oral versus topical) and discussed according to key clinical parameters: efficacy endpoints, dosing regimens, comparator treatments, adverse effects, and quality-of-life outcomes.

Records retrieved from both databases were screened against the eligibility criteria by M.Ł. and A.Z., with disagreements resolved by consensus. Because Google Scholar yields less reproducible results than PubMed, its use was intended to capture additional reports and grey literature not indexed in PubMed. Data were extracted on study design, population and acne severity, sample size, intervention and comparator, dosing, treatment duration, efficacy endpoints, adverse effects, and quality-of-life outcomes. Non-English-language reports were excluded a priori to allow consistent appraisal of full texts; the single exception was retained because of its frequent citation and the sufficient quantitative data provided in its English-language abstract, while acknowledging that reliance on an abstract limits full critical appraisal.

Mechanism of Action

Spironolactone targets multiple points in the androgen–sebaceous gland axis (Figure 1). In sebocytes, testosterone is converted to the more potent dihydrotestosterone (DHT) by 5α-reductase; DHT then binds the androgen receptor (AR), triggering downstream transcription of genes involved in sebocyte proliferation and sebum production. Spironolactone competitively antagonizes the AR, thereby blocking DHT-mediated signaling²¹ (Figure 1).

Figure 1.

Mechanism of action of spironolactone within the pilosebaceous unit. Left panel: anatomy of the pilosebaceous unit, showing the sebaceous gland associated with the hair follicle within the dermis. Right panel: androgen signaling in the sebocyte and its inhibition by spironolactone. Testosterone enters the sebocyte, as indicated by the dashed arrow, and is converted by 5α-reductase to dihydrotestosterone (DHT). The androgen receptor (AR) is maintained in an inactive complex with heat shock proteins (Hsp). Upon ligand binding, Hsp dissociates from AR, enabling receptor dimerization, nuclear translocation, and transcription of androgen-responsive genes involved in sebocyte proliferation and sebum production. Spironolactone competes with DHT for the ligand-binding site of AR; the red cross denotes inhibition of DHT-mediated receptor activation. Solid arrows indicate successive steps in the signaling pathway. Through androgen receptor antagonism, spironolactone may reduce sebocyte proliferation, sebum production, follicular occlusion, microcomedone formation, Cutibacterium acnes proliferation, and the inflammatory response, ultimately decreasing acne severity. Created in BioRender.com Łyko, M (2026) https://BioRender.com/nsr2m89.

Abbreviations: AR, androgen receptor; DHT, dihydrotestosterone; Hsp, heat shock protein.

In addition to direct AR antagonism, oral spironolactone reduces circulating androgen levels through several complementary mechanisms: degradation of a cytochrome P450 cofactor required for gonadal and adrenal testosterone synthesis, elevation of SHBG with consequent reduction in free testosterone, and enhanced hepatic testosterone clearance.^19,20 The net result is decreased sebum production, reduced follicular occlusion, diminished C. acnes proliferation, and attenuation of the perifollicular inflammatory response.

Topical spironolactone exerts its effects primarily through local AR blockade within the pilosebaceous unit and inhibition of sebaceous gland activity, without appreciable systemic absorption. A crossover study in healthy male volunteers demonstrated that 5% topical spironolactone did not alter plasma testosterone, 17α-hydroxyprogesterone, or salivary testosterone levels, and its main metabolite, canrenone, was undetectable in plasma.²³ This pharmacokinetic distinction underlies the different safety and applicability profiles of the two routes of administration.

The two routes therefore engage the same molecular target in different compartments, and the distinction between them is essentially pharmacokinetic. After oral administration, spironolactone undergoes extensive first-pass metabolism to active metabolites, including canrenone, which have longer elimination half-lives than the parent compound and sustain antiandrogenic activity simultaneously at the sebaceous gland, the gonads and adrenal glands, and the liver; the systemic nature of this exposure accounts both for the reproducible clinical efficacy of oral therapy and for its dose-dependent endocrine adverse effects.^19,20 Topical application, by contrast, is intended to confine androgen receptor blockade to the pilosebaceous unit. Spironolactone is a highly lipophilic and poorly water-soluble steroid; these properties favour partition into sebum and the stratum corneum but limit the fraction of drug reaching the deeper, metabolically active portion of the sebaceous gland, so that the vehicle itself becomes a determinant of the delivered dose. The gels, creams and hydroalcoholic solutions evaluated in published trials differ in concentration, in the use of penetration enhancers and in application frequency, which is one reason why their results are difficult to compare directly. Human pharmacokinetic data for topical formulations are confined to small studies in healthy volunteers, in which systemic exposure was undetectable,²³ and it has not been established whether the clinical effect is exerted exclusively locally or in part through low-level systemic absorption below the sensitivity of the assays used. These pharmacokinetic differences, rather than any difference in molecular mechanism, underlie the divergent efficacy expectations, safety profiles and monitoring requirements of the two routes.

Efficacy of Oral Spironolactone

The therapeutic role of oral spironolactone in acne management—particularly in adult female patients—has been evaluated across several randomized controlled trials and comparative studies. The evidence consistently supports its efficacy in reducing both inflammatory and non-inflammatory lesions, improving quality of life, and offering a viable alternative to long-term oral antibiotic therapy.

Evidence from Placebo-Controlled Trials

The largest and most methodologically robust trial to date is the SAFA study by Santer et al,²⁴ a pragmatic, multicentre, phase 3, double-blind RCT conducted in England and Wales. Of 1267 women assessed for eligibility, 410 aged 18 years or older with facial acne of at least six months’ duration judged to warrant oral antibiotic treatment were randomly assigned to spironolactone (n = 201) or placebo (n = 209), and 342 were included in the primary analysis. Participants received 50 mg/day for the first six weeks, increasing to 100 mg/day if tolerated, for a total of 24 weeks, and were permitted to continue their usual topical treatment. Mean acne-specific quality of life (Acne-QoL) symptom subscale scores were comparable at baseline (spironolactone 13.2 vs placebo 12.9) and favoured spironolactone thereafter: 19.2 vs 17.8 at week 12 (adjusted between-group difference 1.27, 95% CI 0.07–2.46) and 21.2 vs 17.4 at week 24 (adjusted difference 3.45, 95% CI 2.16–4.75).^24,25 Investigator-assessed treatment success at week 12 was reached by 19% of participants given spironolactone versus 6% of those given placebo (adjusted odds ratio 5.18, 95% CI 2.18–12.28). The trial provides the strongest available evidence that spironolactone is an effective alternative to oral antibiotics for women whose acne does not respond to topical therapy. Its primary endpoint should nonetheless be interpreted with care: the point estimate at week 12 did not reach the two-point difference the trial was powered to detect, although the confidence interval included that value and the difference at week 24 clearly exceeded it.

Patiyasikunt et al²⁶ conducted a double-blind, placebo-controlled trial in 63 Thai women aged 25–45 with moderate AFA, comparing low-dose spironolactone (25 or 50 mg/day) plus topical benzoyl peroxide 2.5% with placebo plus benzoyl peroxide over 12 weeks. At week 12, both comedonal and inflammatory lesion counts decreased across all groups relative to baseline. However, the 50 mg group achieved significantly higher rates of “clear/almost clear” outcomes (75% vs 30%, p = 0.01), and a positive dose–response relationship was observed.

Earlier placebo-controlled evidence includes the crossover study by Muhlemann et al,²⁷ in which 21 women with moderate-to-severe acne received spironolactone 200 mg/day or placebo for 3-month periods. Spironolactone induced significant improvement in subjective benefit (p < 0.001), inflamed lesion count (p < 0.001), and independently evaluated photographic assessment (p < 0.02). Similarly, Goodfellow et al²⁸ demonstrated in 36 patients (19 female) that spironolactone at doses of 50–200 mg/day reduced sebum secretion in women by 80% (from 4.7 ± 1.7 to 1.0 ± 0.2 µg/cm²/min, p < 0.025), with the highest doses (150–200 mg) producing the most favorable subjective and objective outcomes.

Comparative Efficacy Against Other Systemic Therapies

Head-to-head comparisons with antibiotics have yielded encouraging results. In a multicenter, double-blind RCT, Dréno et al²⁹ compared spironolactone 150 mg/day with doxycycline 100 mg/day (both combined with topical benzoyl peroxide) in 133 women with moderate acne over 6 months. Spironolactone demonstrated superior efficacy, with an odds ratio of 2.87 at month 6 (p = 0.007), along with significant improvements in AFAST, ECLA scores, and quality of life.

A large retrospective analysis by Barbieri et al,³⁰ encompassing 4,321 women treated with spironolactone and 7,517 treated with tetracycline-class antibiotics, revealed that the mean duration of spironolactone use was significantly longer than that of antibiotics (697.8 ± 333.3 vs 604.4 ± 261 days, p < 0.001), suggesting better treatment persistence and comparable effectiveness.

Bomfim et al³¹ randomized 40 women over 25 with mild-to-moderate acne to oral spironolactone 100 mg/day or azelaic acid 15% gel for 6 months. Both groups demonstrated significant improvement in all Acne-QoL domains (self-perception, role-emotional, role-social, acne symptoms; all p < 0.001), with no significant between-group difference (p = 0.918). In a smaller comparative trial, Vaswani and Pandhi³² found that spironolactone 100 mg/day produced a significantly greater reduction in non-inflammatory and inflammatory lesions than cimetidine 1,400 mg/day over 3 months (p < 0.05).

Evidence from Meta-Analyses

Basendwh et al³³ published a systematic review and network meta-analysis including 2,006 patients from 7 studies, comparing oral spironolactone at different doses with topical clascoterone 1% twice daily. Spironolactone 200 mg was associated with a significant total lesion count reduction (SMD = −4.46, 95% CI: −5.60 to −3.32), with broadly similar magnitudes observed for 25 mg (SMD = −4.65), 50 mg (SMD = −4.88), and clascoterone (SMD = −4.18). These findings suggest that even lower oral doses may achieve clinically meaningful results. However, the very large effect sizes reported (SMD below −4) are atypical and most likely reflect between-study heterogeneity and differing outcome scales among the pooled trials; they should therefore be interpreted with caution. In addition, an indirect comparison of topical clascoterone with oral spironolactone within a network meta-analysis has limited clinical interpretability, given differences in the populations, acne severities, and efficacy endpoints of the contributing trials.

Two further quantitative syntheses have since addressed spironolactone in acne. AlEdani et al³⁴ pooled seven randomized placebo-controlled trials including 643 participants and reported a significant reduction in the acne severity index with spironolactone (mean difference −6.53; 95% CI −10.83 to −2.22; p = 0.003), no statistically significant differences in total lesion, comedone or papule counts at 4, 8 and 12 weeks, and rates of adverse events, including menstrual irregularity, comparable with placebo. Farrag et al,³⁵ in a meta-analysis of 14 studies including 1,086 patients, similarly found topical spironolactone 5% superior to placebo with respect to total lesion count and acne severity index. Both analyses pooled oral and topical formulations and were not restricted to adult women, which limits their direct applicability to AFA; their relationship to the present review is considered in Oral versus Topical Spironolactone: A Comparative Perspective. Two additional meta-analyses restricted to oral spironolactone reached concordant conclusions. Ghanem et al,³⁶ analysing 563 women from five randomized placebo-controlled trials, reported a sixfold higher likelihood of objectively assessed acne improvement with spironolactone (OR 6.59; 95% CI 3.50–12.43) without a significant excess of menstrual irregularity or breast enlargement, with trial sequential analysis confirming that the required information size had been reached. Kow et al³⁷ reported a pooled odds ratio of 2.51 for treatment success in adult women with moderate-to-severe acne compared with placebo or doxycycline.

Combination Therapy

Leelaphiwat et al³⁸ conducted a randomized trial in 18 women with polycystic ovary syndrome (PCOS), comparing ethinylestradiol 30 µg/desogestrel 150 µg plus spironolactone 25 mg/day with ethinylestradiol 35 µg/cyproterone acetate 2 mg. Both arms achieved reductions in acne severity, free androgen index, and increases in SHBG, with the spironolactone arm additionally showing a significant decrease in androstenedione levels. These data support the potential of combining low-dose spironolactone with oral contraceptives.

Summary of Oral Evidence

Taken together, the evidence from RCTs, retrospective analyses, and meta-analyses consistently supports the efficacy of oral spironolactone in AFA. The drug produces significant reductions in inflammatory and non-inflammatory lesions, improves acne-specific quality of life, and demonstrates comparable or superior effectiveness to standard systemic therapies such as doxycycline. Treatment persistence appears higher than for oral antibiotics, reflecting both clinical effectiveness and acceptable tolerability. Nevertheless, the overall strength of evidence remains moderate: many studies have small sample sizes, short follow-up periods (typically 12–24 weeks), heterogeneous dosing regimens, and variable outcome measures. Large-scale, standardized RCTs with longer follow-up remain warranted. Summary of clinical studies evaluating oral spironolactone in acne is presented in Table 1.

Table 1.

Summary of Clinical Studies Evaluating Oral Spironolactone in Acne

Author (Year)	n (% Female)	Age, Years	Comparator (Weeks)	SP Dose, mg/d	Key Efficacy Findings	Blinding
Santer et al (2023)24	410 (100)	≥ 18 (29.2)	Placebo (24)	50 → 100	Acne-QoL: 13.2→19.2 (wk 12), 21.2 (wk 24) vs 17.8/17.4 placebo	Double-blind
Patiyasikunt et al (2020)26	63 (100)	25–45	Placebo + BP 2.5% (12)	25 or 50 + BP	SP50: 75% clear vs 30% placebo (p=0.01); dose–response	Double-blind
Goodfellow et al (1984)28	36 (53)	18–38	Placebo (13)	50–200	Sebum decrease by 80% in women (p<0.025); 150–200 mg best	Double-blind
Muhlemann et al (1986)27	21 (100)	NR	Placebo, crossover (13)	200	Subjective (p<0.001), lesions (p<0.001), photo (p<0.02)	Double-blind
Dréno et al (2024)29	133 (100)	> 20 (28.6)	Doxycycline 100 + BP 5% (26)	150 + BP 5%	SP superior: OR 2.87 at mo 6 (p=0.007); improved AFAST, ECLA, QoL	Double-blind
Barbieri et al (2019)30	4321 (100)	12–40	Tetracycline antibiotics	NR	Longer drug survival: 697.8 vs 604.4 d (p<0.001)	Retrospective
Bomfim et al (2024)31	40 (100)	25–44 (32.7)	Azelaic acid 15% gel (26)	100	Both improved (all QoL p<0.001); no difference (p=0.918)	NR
Vaswani and Pandhi (1990)32	29 (100)	NR*	Cimetidine 1400 mg (12)	100	SP: greater reduction non-inflam (29.3) and inflam (9.7) (p<0.05)	NR*

Notes: Values in parentheses in the Age column denote mean age. NR, not reported; *full text not available—data extracted from the English-language abstract only, which limits complete appraisal.

Abbreviations: SP, spironolactone; BP, benzoyl peroxide; QoL, quality of life; OR, odds ratio.

Adverse Effects of Oral Spironolactone

Oral spironolactone is generally well tolerated; however, its hormonal activity gives rise to characteristic estrogen-like side effects. The most common adverse event is menstrual irregularity, attributed to the effects of spironolactone and its metabolites on endometrial estradiol and progesterone signaling.³⁹ Its incidence is estimated at 17.5–18% at doses of 50–100 mg/day,^20,40 although a large retrospective series by Grandhi and Alikhan⁴¹ reported only 1 case among 1,556 patients. Concomitant use of oral contraceptives is recommended to mitigate this effect.⁴² Breast tenderness and enlargement may also occur.⁴³ Loss of libido has been reported regardless of sex.⁴⁴

The potassium-sparing mechanism of spironolactone carries a theoretical risk of hyperkalemia. Thiede et al⁴⁵ found in a retrospective study of 618 women that this risk is primarily relevant for women over 45 years of age, whereas younger women experienced hyperkalemia significantly less frequently (16.7% in women 46–65 years vs <1% in women 18–45 years).⁴⁵ In otherwise healthy young women without renal disease or concomitant use of potassium-raising medications, routine potassium monitoring may therefore be unnecessary.⁴⁶ Additional reported side effects include watery rhinorrhea (secondary to the vasodilatory effect), urinary frequency, nausea, dizziness, and headache.^42,45

Regarding cancer risk, despite early animal data suggesting tumorigenic potential at supratherapeutic doses (up to 150-fold higher than human doses), a comprehensive meta-analysis by Bommareddy et al⁴⁷ found no statistically significant association between spironolactone use and breast cancer (RR 1.04, 95% CI: 0.86–1.22), or ovarian, bladder, kidney, stomach, or esophageal cancers. A reduced risk of prostate cancer was observed (RR 0.79, 95% CI: 0.68–0.90), at very low certainty of evidence.^48,49

From a practical standpoint, oral spironolactone is contraindicated in pregnancy because of its antiandrogenic activity and the theoretical risk of feminization of a male fetus; effective contraception should be ensured and the potential reproductive risks discussed before initiating treatment in patients of childbearing potential. It should also be avoided or used with particular caution in patients with significant renal impairment, pre-existing hyperkalemia, or Addison disease, and in those taking other agents that raise serum potassium, including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, potassium-sparing diuretics, potassium supplements, and non-steroidal anti-inflammatory drugs. In these higher-risk groups, baseline and periodic measurement of serum potassium and renal function is prudent, in contrast to otherwise healthy young women, in whom such laboratory monitoring is generally not required.

In summary, with appropriate patient selection and individualized dosing, the safety profile of oral spironolactone remains acceptable for long-term acne management. Clinicians should counsel patients about potential menstrual irregularities and breast tenderness, and consider potassium monitoring in older patients or those with renal comorbidities.

Efficacy of Topical Spironolactone

Topical spironolactone has emerged as a promising option for acne treatment, particularly in patients for whom systemic therapy is not indicated or tolerated. By acting locally within the pilosebaceous unit, it reduces follicular keratinization, comedone formation, and sebum production without appreciable systemic absorption.⁵⁰

A systematic review by Rehan et al,⁵¹ encompassing 5 clinical trials with 195 patients, demonstrated that topical spironolactone significantly reduced papules (p = 0.004), closed comedones (p < 0.05), and total lesion counts (p < 0.05) compared with placebo. At a concentration of 2%, spironolactone was superior to clindamycin in reducing comedones (p < 0.0001), papules (p < 0.0001), and pustules (p < 0.0001).

Afzali et al⁵² randomized 78 patients to 5% spironolactone gel or placebo over 6 weeks and found a significant reduction in total lesion count in the active group (p = 0.007), although the acne severity index (ASI) difference did not reach statistical significance (p = 0.052). In a single-blinded comparative study, Noaimi and Al-Saadi⁵³ treated 37 patients with 2% spironolactone solution and 31 with 1.5% clindamycin for 12 weeks. Spironolactone produced notable reductions in comedone count (from 91 ± 64.4 to 57 ± 52.9), papule count (from 5.7 ± 3.9 to 0 ± 0.3), pustule count (from 4.2 ± 3.0 to 0 ± 0), and ASI (from 60.1 ± 32.3 to 28.5 ± 26.4). The reduction in comedones was highly significant compared with clindamycin (p < 0.0001), and overall patient satisfaction was higher in the spironolactone group.

Yamamoto and Ito⁵⁴ observed a marked reduction in sebum secretion in 6 healthy males after 8 weeks of topical 5% spironolactone gel, with the effect persisting 4 weeks post-treatment; no change was observed on the untreated control side. Califano et al⁵⁵ reported complete regression of acne in 30% and improvement in 65% of patients treated with 5% spironolactone cream. A pilot study by Ayatollahi et al⁵⁰ in 15 patients confirmed that 5% spironolactone cream significantly reduced papules, open and closed comedones, and the acne global grading score at 4 and 8 weeks (p < 0.05). Attwa et al⁵⁶ similarly demonstrated reductions in total lesion count and ASI with 5% spironolactone gel in a larger cohort with mild-to-moderate acne. In interpreting these data, a distinction should be drawn between studies reporting sebum-secretion endpoints in healthy volunteers (eg, Yamamoto and Ito) and those reporting clinical lesion-count reductions in patients with acne; the former support a biological effect on sebaceous activity but do not by themselves establish clinical efficacy. Notably, several of these topical studies were conducted in healthy male volunteers or mixed-sex acne cohorts rather than in adult women, so their relevance to AFA is inferred rather than directly demonstrated.

Despite these promising results, the evidence base for topical spironolactone remains preliminary. Most studies have involved fewer than 100 participants, follow-up durations have been short, formulation concentrations range from 2% to 5%, and outcome measures are not standardized. Larger multicenter RCTs with unified protocols and longer observation periods are needed to define the optimal formulation, concentration, and treatment duration.

Adverse Effects of Topical Spironolactone

Topical spironolactone demonstrates an excellent safety profile. Ayatollahi et al⁵⁰ reported no instances of dry skin, erythema, or irritation with 5% cream and observed no systemic endocrine effects in either male or female participants. Rey et al²³ confirmed the absence of systemic antiandrogenic activity in a crossover study of healthy male volunteers: no changes in plasma testosterone, 17α-hydroxyprogesterone, or salivary testosterone were detected, and canrenone was undetectable in plasma. These findings underscore the suitability of topical spironolactone for male patients and for individuals in whom systemic hormonal modulation is contraindicated.

Noaimi and Al-Saadi⁵³ reported that only 5.7% of patients experienced pruritus and 11.4% a burning sensation during treatment with 2% spironolactone solution; none required discontinuation. These local adverse events are comparable to those observed with other topical anti-acne agents.

Importantly, Carpenter and Kemp⁵⁷ demonstrated that high concentrations of spironolactone can induce epidermal toxicity through proteolytic degradation of the XPB protein involved in DNA repair and transcription. This finding highlights the importance of adhering to clinically validated concentrations (2–5%) to avoid unwanted cytotoxic effects.

In summary, topical spironolactone at appropriate concentrations offers a safe alternative with minimal local and no detectable systemic adverse effects, making it suitable for a broader patient population than the oral formulation.

Oral versus Topical Spironolactone: A Comparative Perspective

Although oral and topical spironolactone share the same active compound and antiandrogenic mechanism, their pharmacokinetic profiles, evidence bases, and clinical roles differ substantially. Table 2 summarizes the key differences.

Table 2.

Comparison of Oral and Topical Spironolactone in Acne Treatment

Parameter	Oral Spironolactone	Topical Spironolactone
Dosing	50–200 mg/day	2–5% cream/gel/solution
Level of evidence	Randomized controlled trials (largest n = 410), meta-analyses	Small RCTs and case series (n < 100)
Efficacy target	Moderate-to-severe AFA; inflammatory and non-inflammatory lesions	Mild-to-moderate acne; comedones, papules, sebum reduction
Systemic effects	Menstrual irregularities, breast tenderness, hyperkalemia (dose-dependent)	None detected (no change in plasma hormones or canrenone)
Local adverse effects	Not applicable	Mild pruritus, burning (5–11%); no discontinuation required
Use in males	Generally avoided for acne in males (antiandrogenic/feminizing adverse effects)	Potentially safe (no systemic antiandrogenic effect)
Monitoring required	Consider K⁺ in women > 45 years	No routine laboratory monitoring expected based on available data
Regulatory status	Off-label in most countries	Off-label; no standardized formulation

Efficacy

Oral spironolactone is supported by randomized controlled trials (notably the 410-participant SAFA trial²⁴) and multiple meta-analyses demonstrating consistent reductions in both inflammatory and non-inflammatory lesions across a range of acne severities. Topical formulations have shown promising results in smaller studies,^50–56 with significant reductions in comedones, papules, and sebum secretion, but no trial has enrolled more than approximately 80 patients, and follow-up rarely exceeds 12 weeks. The level of evidence for oral therapy is therefore substantially stronger. Because no direct oral-versus-topical trials exist, relative efficacy between the two routes cannot be inferred from cross-study comparisons, particularly given differences in acne severity, efficacy endpoints, treatment duration, and study populations.

Safety

The most clinically significant advantage of topical spironolactone is its lack of appreciable systemic absorption.²³ Oral spironolactone carries dose-dependent risks of menstrual irregularities, breast tenderness, and—in older or comorbid patients—hyperkalemia, whereas topical application produces only occasional mild local reactions (pruritus, burning) without detectable endocrine effects.⁵³ This makes the topical route potentially suitable for male patients, adolescents, and women with contraindications to systemic antiandrogen therapy.

Clinical Applicability

Oral spironolactone, typically prescribed at 50–200 mg/day, is best suited for moderate-to-severe AFA, treatment-resistant cases, and patients who have failed conventional systemic therapies. Topical spironolactone (2–5%) may serve as a first-line option for mild-to-moderate acne, as an adjunct to systemic therapy, or as a maintenance treatment after oral spironolactone has been tapered. However, its off-label status and the absence of standardized commercial formulations remain practical barriers to widespread adoption.

Positioning Relative to Clascoterone

Topical spironolactone should also be considered alongside clascoterone, the first topical androgen-receptor inhibitor approved for acne (in patients aged 12 years and older in several countries). Both agents act locally on the androgen receptor within the pilosebaceous unit with negligible systemic antiandrogenic effect; however, clascoterone is supported by phase 3 randomized trials and regulatory approval, whereas topical spironolactone remains off-label and lacks a standardized formulation. Conceptually, the availability of an approved topical antiandrogen validates the rationale for local androgen-receptor blockade in acne and raises the unresolved question of whether compounded topical spironolactone offers any advantage over clascoterone, which has not been addressed in head-to-head studies.

Relation to Recent Evidence Syntheses

The present review should be read alongside the quantitative syntheses published in 2025.^34,35 Those analyses provide pooled effect estimates that a narrative review cannot generate, but they combine oral and topical formulations as a single intervention and are not restricted to adult women. This article is intended to complement rather than duplicate them, and differs in three respects: the clinical focus is restricted to AFA, the population in which hormonal therapy is most often considered; the oral and topical routes are examined side by side across efficacy, safety, formulation, monitoring requirements and practical prescribing considerations rather than pooled; and non-randomized, long-term and real-world data that fall outside the eligibility criteria of the meta-analyses are incorporated, since these are directly relevant to prescribing decisions. The contribution of this review therefore lies in clinical synthesis and contextualization rather than in the generation of new quantitative evidence.

Gaps in Evidence

No head-to-head trial has directly compared oral with topical spironolactone. The absence of standardized formulations for topical use (concentrations range from 2% to 5% across studies) further complicates comparisons. Whether oral and topical routes could be combined for synergistic benefit is an unexplored question that merits investigation.

Strength of Evidence and Limitations of Included Studies

Although a formal risk-of-bias assessment was not undertaken, a narrative appraisal of the certainty of the evidence is warranted given the range of study designs discussed. For oral spironolactone, the overall certainty can be regarded as moderate to high. It is anchored by two methodologically robust randomized controlled trials—the large, multicenter SAFA trial and the FASCE trial—and supported by additional comparative trials, a network meta-analysis, and a large real-world cohort. The principal limitations are heterogeneity in dosing (25–200 mg/day), variable and sometimes subjective efficacy endpoints, predominantly short follow-up (typically 12–24 weeks), and the implausibly large effect sizes reported in the pooled meta-analytic estimate, which warrant cautious interpretation.

For topical spironolactone, the certainty of evidence is low. The available studies are small (none enrolling more than approximately 80 patients), short in duration, and heterogeneous in formulation and concentration (2–5%), and several were conducted in healthy male volunteers or mixed-sex cohorts rather than in adult women. Outcome measures are not standardized, no formulation is commercially established, and no trial has directly compared topical with oral spironolactone. Consequently, conclusions regarding topical spironolactone in AFA remain provisional and rest partly on indirect extrapolation. More broadly, as a narrative review this article did not follow PRISMA methodology: the search was restricted to two databases and, with one stated exception, to publications available in English, and no formal risk-of-bias assessment was performed. A degree of selection bias therefore cannot be excluded.

Future Directions

Current evidence strongly supports the efficacy of spironolactone in AFA, yet several aspects require further investigation. As of 1 September 2025, a ClinicalTrials.gov search returned over 300 registered trials involving spironolactone, of which two specifically addressed AFA (search term “spironolactone AND acne”, accessed 1 September 2025).

For oral spironolactone, ongoing large-scale trials are expected to provide definitive evidence. In the United States, a randomized, double-blind, multicenter trial is comparing spironolactone (100 mg/day) with doxycycline (100 mg/day) in 400 women aged 16–40 years, assessing lesion reduction, quality of life, and treatment adherence. The French FASCE trial comparing spironolactone (150 mg/day) with doxycycline has already been completed and is discussed in Comparative Efficacy Against Other Systemic Therapies²⁹ These studies are critical for determining whether spironolactone can replace or complement conventional first-line systemic therapies.

For topical spironolactone, the priorities are different. Standardized formulations and optimal dosing strategies must be established through multicenter dose-ranging studies. Long-term safety data are needed, particularly regarding the cutaneous effects of chronic topical antiandrogenic exposure. The feasibility of combining oral and topical spironolactone—whether sequentially (oral induction followed by topical maintenance) or concomitantly—represents an intriguing but entirely unexplored therapeutic strategy.

Several cross-cutting challenges remain. The available literature is highly heterogeneous, with wide variability in study design, dosing regimens (25–200 mg/day orally; 2–5% topically), and patient populations. The off-label status of spironolactone in many countries limits clinical uptake, and concerns about safety—particularly hyperkalemia and menstrual irregularities—continue to deter some clinicians despite evidence that serious adverse events are rare in healthy young women. Clearer guidelines, practical monitoring strategies, and clinician education are needed. Finally, cost-effectiveness and accessibility—particularly of topical formulations—have rarely been addressed and should be included in future research agendas.

Conclusions

Spironolactone, in both oral and topical formulations, represents a promising non-antibiotic therapeutic option for adult female acne. Its antiandrogenic mechanism effectively targets the hormonal component of acne pathogenesis, producing significant improvements in lesion counts, sebum production, and quality of life.

Oral spironolactone (50–200 mg/day) is supported by a substantial body of evidence, including a large phase 3 RCT,²⁴ demonstrating efficacy comparable or superior to doxycycline,²⁹ with a favorable long-term safety profile in healthy young women. It is best suited for moderate-to-severe AFA and treatment-resistant cases. Topical spironolactone (2–5%) appears to be a promising and apparently well-tolerated option for mild-to-moderate acne that nonetheless requires confirmation in adequately powered, AFA-specific trials, with the key advantage of negligible systemic absorption,²³ making it potentially applicable to a wider patient population—including males and patients with contraindications to systemic antiandrogen therapy.

Recent quantitative syntheses have pooled oral and topical spironolactone across mixed populations,^34,35 whereas the present review compares the two routes within a single clinically oriented framework restricted to AFA and incorporates observational and long-term data that fall outside the eligibility criteria of those analyses. On the evidence available, the two routes appear complementary rather than competing: oral therapy provides systemic hormonal modulation with established efficacy over several months for more severe disease, while topical therapy targets the pilosebaceous unit locally with an apparently excellent safety profile, although the evidence supporting it remains limited and partly indirect. Whether these routes can be combined for additive benefit is an important question for future research.

Continued research should prioritize standardized dosing protocols, head-to-head comparisons of oral and topical formulations, long-term follow-up studies, and cost-effectiveness analyses to translate spironolactone from an off-label alternative into a mainstream component of evidence-based AFA management.

Funding Statement

The authors received no specific funding for this work.

AI Statement

The artificial intelligence tool Claude (Anthropic) was used solely to assist with language editing and manuscript organization. The scientific content, design concepts, and interpretations were developed and verified by authors.

Abbreviations

AFA, adult female acne; AR, androgen receptor; Acne-QoL, acne-specific quality of life; ASI, acne severity index; BP, benzoyl peroxide; CI, confidence interval; DHT, dihydrotestosterone; OR, odds ratio; PCOS, polycystic ovary syndrome; RCT, randomized controlled trial; RR, relative risk; SHBG, sex hormone–binding globulin; SMD, standardized mean difference.

Data Sharing Statement

Data sharing is not applicable to this article, as no new datasets were generated or analyzed. All data discussed are available in the original publications cited in the reference list.

Ethics Approval and Informed Consent

Ethics approval and informed consent were not required for this study. This article is a narrative review based exclusively on previously published literature and did not involve any new studies of human or animal subjects performed by any of the authors.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Magdalena Łyko reports Meeting/travel support from Johnson & Johnson, Medac, outside the submitted work. The authors report no other conflicts of interest in this work.