Lim Rachel (Orcid ID: 0000-0001-7711-3095)

Wambier Carlos (Orcid ID: 0000-0002-4636-4489)

Goren Andy (Orcid ID: 0000-0002-8190-2289)

Spironolactone in Adolescent Acne Vulgaris

TITLE: SPIRONOLACTONE IN ADOLESCENT ACNE VULGARIS

Authors: Rachita Dhurat1, Deepti Shukla1, Rachel K. Lim2, Carlos G. Wambier3, Andy
Goren4.

Department of Dermatology, LTM Medical College & Hospital Sion, Mumbai, India1,
Brown University, Providence, Rhode Island, USA2, Department of Dermatology, Alpert
Medical School of Brown University, Providence, Rhode Island, USA3, Applied Biology
Inc, Irvine, California, USA4

Corresponding author: Rachel Lim, Brown University; rachel_lim@brown.edu

Acknowledgements: none

Conflict of Interest: The authors have no conflicts of interest to disclose.

Funding: none

Author Contribution Statement:

All authors
1. Have made substantial contributions to conception and design, or acquisition of
data, or analysis and interpretation of data; and
2. Been involved in drafting the manuscript or revising it critically for important
intellectual content; and
3. Given final approval of the version to be published; and
4. Agreed to be accountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work are appropriately
investigated and resolved.

Data Availability Statement:

Data sharing is not applicable to this article as no new data were created or analyzed in
this study.

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/dth.14680
This article is protected by copyright. All rights reserved.
 Spironolactone in Adolescent Acne Vulgaris

Abstract:

Acne vulgaris (AV) is the most common skin condition affecting adolescents, most likely
due to elevated androgen levels during puberty. Androgens stimulate and enlarge the
sebaceous glands and keratinocytes, resulting in increased production of sebum and
abnormal hyperproliferation of keratinocytes which lead to the formation of acne lesions.
Current standard of care for AV includes topical therapies for mild cases and antibiotics
or oral retinoids for severe cases. In recent years, spironolactone, an aldosterone
antagonist and diuretic, has been applied to the treatment of AV due to its anti-
androgen effects. Spironolactone is currently recommended in women who use oral
contraceptives, are refractory to or contraindicated for standard treatment, show clinical
signs of hyperandrogenism, or present with late-onset or persistent-recurrent AV past
the teenage years. It is not prescribed to adolescents due to potential side effects;
however, current data studying adults indicate that most side effects are mild, and that
potential associations with hyperkalemia and increased risk of cancer are not sufficiently
supported. Hence, we believe that spironolactone may be a safe and effective therapy
for adolescent AV.

Keywords: acne vulgaris, adolescent acne, spironolactone

 Spironolactone in Adolescent Acne Vulgaris

Introduction:

Acne vulgaris (AV) is the most common skin condition affecting adolescents, with

prevalence rates of 70–87%, likely due to the production of androgens during

puberty.(1) Its clinical presentation can range from mild to severe inflammatory cystic

acne occurring on the face, chest, and back. Management of acne usually includes a

combination of modalities that depends on the type of lesion; therefore, it is essential to

understand the pathogenesis of this disease prior to commencing treatment.

Pathogenesis of acne:

The pathogenesis of AV is multifactorial. Elevated androgen levels during

puberty stimulate and enlarge the sebaceous glands and keratinocytes, resulting in

increased production of sebum and abnormal hyperproliferation of keratinocytes.

Excess keratinocytes form a horny keratotic plug obstructing the pilosebaceous duct

which then becomes clogged with a combination of sebum and keratinous debris,

forming a non-visible plug referred to as a microcomedo. The microcomedo can expand

into a visible noninflammatory comedone. The excess sebum in the microcomedo

compromises the diffusible oxygen in the pilosebaceous unit (PSU), providing an

anaerobic growth medium for Propionibacterium acnes.(2) Moreover, the

overproduction of sebum provides a source of nutrients in the form of fatty acids to

bacteria rapidly multiplying within the PSU. The pathogenesis of AV is summarized in

Table 1.

Role of androgens in acne:

 Spironolactone in Adolescent Acne Vulgaris

Androgen levels in patients with acne are often higher than those in controls and

people with androgen insensitivity syndrome do not develop acne.(3) Androgens bind to

the androgen receptor expressed on the basal layer of sebaceous glands and in the

outer root sheath of keratinocytes of hair follicles. Circulating androgens are primarily

produced by the gonads and the adrenal gland, but they are also locally derived in

sebocytes from the adrenal precursor hormone dehydroepiandrosterone (DHEA)

sulfate. (4) Furthermore, Type I 5α reductase, the enzyme that catalyzes the formation

of androgens like testosterone and dihydrotestosterone, is strongly expressed in

sebaceous glands of the skin and dihydrotestosterone (DHT) produced locally by type I

5α-reductase has been shown to enhance sebum production.(5)

Role of Spironolactone in Acne:

Spironolactone blocks the androgen receptor and inhibits the binding of DHT to

nuclear and cytosolic receptors in target tissues such as the skin. Spironolactone

augments liver hydroxylase activity, decreasing 5α-reductase activity via increased

clearance of testosterone. It also increases the level of steroid hormone binding globulin

(SHBG), reducing circulating free testosterone. (6) Studies have shown that

spironolactone decreases androgen-stimulated sebocyte proliferation in vitro and

inhibits sebaceous activity in a dose-dependent fashion. (7) Due to this ability,

spironolactone has been used to treat AV. It is currently recommended in women who

experience premenstrual flares, use oral contraceptives, are refractory to standard

treatment with topical therapies, systemic antibiotics, or isotretinoin, are not candidates

for oral isotretinoin, show clinical signs of hyperandrogenism, have coexisting symptoms
 Spironolactone in Adolescent Acne Vulgaris

of premenstrual syndrome, or present with late-onset or persistent-recurrent AV past the

teenage years;however, there remains a lack of high-quality evidence on the benefits

and potential harms of spironolactone for AV, though there is highly significant

evidence, albeit low-quality, that it reduces inflamed AV lesion counts. (6,8)

Adolescent acne is associated with increased sebum production due to

excessive androgen production or hypersensitive sebaceous glands during puberty, but

there are other causes of abnormal androgen levels. (9) In women, the most common

cause of elevated androgen levels is polycystic ovary syndrome (PCOS); however,

diagnosing PCOS in adolescents is especially difficult because it is unlikely for

physicians to suspect PCOS in adolescents who have normal menstrual cycles.

Despite the potential efficacy of spironolactone as a treatment for acne, clinicians

avoid prescribing it for adolescent acne primarily due to potential adverse events.

In a long-term study of patients who received spironolactone for the treatment of acne,

the most common side effects were diuretic effects (29%), menstrual irregularities

(22%), and breast tenderness (17%).(10) Other less common side effects include

dizziness, headaches, nausea, and breast enlargement. (10) Severe side effects, such

as hyperkalemia and increased risk of cancer, are not sufficiently supported by

evidence. In a study of 974 women taking spironolactone for acne, no instances of

persistent and clinically meaningful hyperkalemia were observed. (11) However, sudden

death related to hyperkalemia can occur when spironolactone is taken with certain

drugs. In particular, trimethoprim–sulfamethoxazole, a potassium-sparing antibiotic

occasionally used to treat AV, has been established to cause severe hyperkalemia

when combined with spironolactone, which may in turn lead to sudden cardiac death.
 Spironolactone in Adolescent Acne Vulgaris

(12) Thus, routine potassium monitoring should be reserved for patients with medical

comorbidities or for those who are taking medications that may impair renal potassium

handling. An important consideration is that the side effects of spironolactone are dose

dependent and marked improvement of acne has been observed in 66% of women who

received low doses of spironolactone (50-100 mg/day). (13)

Spironolactone may also have teratogenic effects. Consequently, clinicians avoid

prescribing spironolactone to women of childbearing age. Nevertheless, there is some

uncertainty surrounding this teratogenic effect; in fact, spironolactone is approved by the

US Food and Drug Administration for treating edema in pregnant women, though it has

been classified pregnancy category C. (14) In a systematic review of cases of male

animals and humans exposed to spironolactone in utero, it was found that feminization

of exposed males in animals was observed when spironolactone was administered at

high doses (200 mg per day), and at doses less than 100 mg. In studies of humans

treated with spironolactone for renal disease, there was no evidence of offspring

feminization at doses as high as 400 mg a day. (14) Taken together, the effects of

spironolactone observed in animal and human models suggest that low dose

spironolactone may be a safe option in women of childbearing age, especially in those

who use oral contraceptives or who are not sexually active.

Prior studies have suggested that spironolactone for AV may be superior to

antibiotics while avoiding antibiotic resistance; nevertheless, antibiotics and retinoids

are more commonly prescribed for acne vulgaris than oral spironolactone. (15) It is

possible that administering spironolactone before oral antibiotics could improve

outcomes for female patients with acne, as it is similarly effective and eliminates the risk
 Spironolactone in Adolescent Acne Vulgaris

of developing antibiotic resistance(15). Current guidelines for the treatment

of acne advocate a combination of topical agents in mild to moderate cases and reserve

the use of systemic therapies for severe or refractory cases of acne. However,

adherence to these guidelines should not be interpreted as a standard of care. In

clinical practice, topical monotherapy may not be sufficient. Systemic therapy may

complement topical therapy to produce results that are satisfactory to the patient. In

fact, Lessner et al suggested that the addition of spironolactone to topical retinoid

treatment results in a superior response to retinoids alone in clearance in female adult

acne.(16) Hence, spironolactone can be used in low doses as monotherapy or

combined with standard acne therapies in adolescents to improve outcomes, though it

should also be accompanied by oral contraceptives in women of child-bearing age due

to potential risk of teratogenic effects.

In summation, we recommend the use of spironolactone for:

a) Adolescents having frequent AV breakouts

b) Adolescents requiring or on long term antibiotic therapy for AV

c) Adolescents in whom retinoid use is contraindicated or who cannot tolerate

retinoids

d) Adolescents having underlying signs of hyperandrogenism.

 Spironolactone in Adolescent Acne Vulgaris

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 Spironolactone in Adolescent Acne Vulgaris

Table 1. Summary of the four principal events in the pathogenesis of acne.

The four principal events in pathogenesis of acne are:

1) Androgen-stimulated increase in sebum production

2) Hyperkeratinisation and obstruction of sebaceous

follicles resulting from abnormal desquamation of

follicular epithelium

3) Proliferation of Propiniobacterium acne

4) Inflammation