Aesth. Plast. Surg. 30:689 694, 2006
DOI: 10.1007/s00266-006-0081-0

Original Articles

Anti-androgenic Therapy Using Oral Spironolactone for Acne Vulgaris in Asians

Katsujiro Sato, M.D,1 Daisuke Matsumoto, M.D,1 Fumiko Iizuka, M.D,1 Emiko Aiba-Kojima, M.D,1
Asami Watanabe-Ono, M.D,2 Hirotaka Suga, M.D,1 Keita Inoue, M.D,1 Koichi Gonda, M.D,1 andKotaro Yoshimura, M.D1
1

Department of Plastic Surgery, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Ritz Medical Clinic, Meguro Toho Building 4F, 3-1-7, Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan

2

Abstract.
Background: Few studies have addressed anti-androgenic
therapy using oral spironolactone for acne in Asians.
Obtaining this race-speciﬁc information is important because Westerners and Asians respond diﬀerently to hormone therapy. This study aimed to examine the eﬃcacy andsafety of oral spironolactone used to treat acne in Asians.
Methods: Spironolactone (initial dose, 200 mg/day) was
administered orally to 139 Japanese patients (116 females
and 23 males) with acne. Serum laboratory data, including
various hormones and electrolytes, were examined for 25 of
the subjects.
Results: Most of the female patients who completed the 20week regimen exhibited excellent improvement (evaluatedby a photographic grading scale), although some discontinued treatment because of menstrual disturbances orother reasons. The treatment was less eﬃcacious for the
males than for the females, and because gynecomastia
developed in three male patients, spironolactone treatment
for males was stopped. Examination of the serum of 25
patients did not identify any toxicity associated with thetreatment. Drug eruptions and edema in the lower
extremities were each seen in three patients.
Conclusion: Oral spironolactone is eﬀective and safe for thetreatment of acne in Asian females, and can be a good
option for severe, recurring, and widespread types of thecondition.
Key words: Acne vulgaris—Anti-androgenic therapy—
Contraceptive—Hormonal therapy—Oral spironolactone—Testosterone

Correspondence to K. Yoshimura M.D; email: yoshimura@cosmetic-medicine.jp

The treatment of acne in postadolescent females often
fails [4,17]. Some patients experience severe andchronic acne, whereas others have widespread acne
eruptions in locations such as the chest and back.
When chronic or recurrent acne is not adequately
controlled, inﬂammation, scars, or postinﬂammatory
hyperpigmentation may disﬁgure the appearance ofthe patient.
Acne treatment can be divided into two approaches: (1) antisymptomatic treatment such as theuse of chemical peeling, lasers, and antibiotics [20]),and (2) inhibitory treatment such as the use of oral
retinoids or anti-androgen therapies (retinoids also
have symptomatic eﬀects). Systemic treatments areespecially needed for severe or chronic acne, andcases in which symptoms are widespread.
Hormonal anti-androgenic treatments can inhibit
sebum production and acne formation in postadolescent females, but they also can induce side eﬀects
such as menstrual irregularity. Cyproterone acetate,a synthetic progestin, was the ﬁrst steroidal antiandrogen used widely used in the treatment ofadvanced prostatic carcinoma and severe acne.
However, the drug is potentially carcinogenic, andlong-term use can induce severe hepatocellular dysfunction [5,11]. Consequently, the sale of the agent
was discontinued in Japan in 1999. The drug still is
widely used alone or in combination with ethinyl
estradiol, a contraceptive (e.g., Diane-35), for severe
acne in many Western countries.
Flutamide is a nonsteroidal competitive antiandrogenic agent available for the treatment of
prostate cancer, benign prostatic hyperplasia, andhirsutism. Despite its proven eﬃcacy, the use ofthis agent is restricted because of its reported
hepatotoxicity [19]. In addition, ﬂutamide-induced

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Anti-androgenic Therapy Using Oral Spironolactone

Table 1. Overall inﬂammatory acne severity scale
GradeDeﬁnition

1
2
3
4

Clear, no inﬂammatory lesions
One or two inﬂammatory lesions
Three to ﬁve inﬂammatory lesions
Six to nine inﬂammatory lesions over a wide
area of the face
Moderate number of inﬂammatory lesions,some large, over a wide area of the face,with increasing erythema
Papules and pustules with larger inﬂamed
lesions over much of the face, withpronounced erythema
Large papules and pustules with pronounced
erythema involving most of the faceFig. 1. Oral spironolactone administration protocol.

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hepatotoxicity reportedly occurs more frequently
among Asians than among Caucasians [16]. For thisreason, monthly liver function testing is required
when it is used in Japan.
Spironolactone, a well-known diuretic agent, hasbeen used for more than 20 years as an antagonist of
androgens in the treatment of acne and hirsutism[8,9]. Several randomized studies have evaluated its
eﬃcacy for the treatment of hirsutism [2,6,15,18].
Serious adverse drug-related events and discontinuation of therapy have been uncommon in spironolactone therapy [14], although gynecomastia [12] andmenstrual irregularities frequently accompany highdose use. Other side eﬀects such as lethargy, fatigue,dizziness, and headache also have been reported [7–9,13].
Hormonal actions, serum hormone levels, and side
eﬀects of hormonal agents diﬀer frequently among
races and populations. For the Asian population,
spironolactone appears to be the safest of thethree aforementioned anti-androgenic agents. This
study was performed to assess the therapeutic value
and side eﬀects of oral spironolactone in Japanesepatients.

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Patients and Methods
Spironolactone was administered orally to 139 Japanese patients (116 females and 23 males; ages, 15 46
years; mean, 26 ± 6.8 years) with acne at the Ritz
Medical Clinic. Informed consent approved by the
local institutional review board was obtained fromeach patient or legal guardian. No other therapies foracne were permitted for the duration of the study.
A 20-week course of therapy was administered.
The initial dose was 200 mg/day for the ﬁrst 8 weeks.
After the initial period, the doses were progressively
lowered by 50 mg every 4 weeks (Fig. 1).
The eﬀectiveness of the treatment was evaluatedfor 64 patients (all females) who completed the
20-week regimen. A digital camera was used to takeclinical photographs before, during, and after treatment. Two experienced plastic surgeons who did not
perform the treatment evaluated acne severity byexamining the photos. Overall acne severity wasassessed using a modiﬁed version of a scale published by Allen and Smith [1] (Table 1). Clinical

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Table 2. Global response to treatment scale
Description

Improvement

Excellent

Improved 3 or more grades or showed noinﬂammatory lesions
Improved 1 or 2 grades
No change or worsened condition

Good
Poor

improvement was graded using a 3-point scale (Table 2). A posttreatment improvement of three ormore grades of acne severity was considered ‘‘excellent.’’ We also ranked patients who showed noinﬂammatory lesions as ‘‘excellent.’’
To ﬁnd related adverse events, we tested the bloodof 25 patients, collected before and after treatment.
We examined serum levels of alanine transferase(ALT), aspartate transferase (AST), blood urea
nitrogen (BUN), creatinine (Cr), sodium (Na+),
potassium (K+), chlorine (Cl)), luteinizing hormone(LH), dehydroepiandrostenedione sulfate (DHEAS),
sex hormone binding globulin (SHBG), total testosterone, and free testosterone. Not all the blood
tests were performed for all the patients because of
insuﬃcient blood collected.
Statistical Analysis
Data were calculated as mean ± standard error. The
nonparametric Mann Whitney U test was used tocompare clinical and hormonal data before and after
treatment.
Results
All 64 female patients who completed the 20-weektreatment regimen exhibited clinical improvement,with 34 patients (53.1%) evaluated as excellent

K. Sato et al.

Fig. 2. A 27-year-old female with acne vulgaris from thejawline to the neck who did not improve with repeatedalpha hydroxy acid (AHA) peeling and oral antibiotics. (A)Before treatment. (B) After 20 weeks of oral spironolactone(excellent results, fewer inﬂammatory spots).

(Figs. 2, 3, and 4) and 30 patients (46.9%) assessed as
good. During the study, 52 of the 116 female patients
dropped out for various reasons such as menstrualirregularities or reluctance to make repeated visits tothe clinic, although most patients who completed theregimen also experienced menstrual irregularities.
We administered spironolactone to 23 male patients, but discontinued treatment for males whengynecomastia developed in 3 males (13%) after 4 to 8
weeks of treatment. All three of these male patientswere between 19 and 21 years of age.
In terms of side eﬀects and complications,approximately 80% of 116 female patients experienced menstrual irregularities. Five patients had no
menstrual bleeding during the ﬁrst 3 months oftreatment, and four had severe menstrual irregularities. These nine patients were given an intramuscular
injection of estrogen (estradiol benzoate 10 mg) andprogesterone(hydroxyprogesterone
caproate
125 mg) to induce menstrual bleeding.
Other side eﬀects reported previously with spironolactone treatment such as lethargy, fatigue, dizziness, and headache were not observed in this trial.
Changes in urinary frequency were observed occasionally (at a rate less than 10%), but these changes
did not seem to reduce patient quality of life. Otherside eﬀects that occurred in only a few patients included drug-induced red papules (in 3 of 139 patients)and edema in the lower extremities (also in 3

691

Fig. 3. A 31-year-old female with acne vulgaris andseborrheic dermatitis on the whole face. (A) Before treatment. (B) After 4 months of oral spironolactone (excellent
results). Sebum discharge was markedly reduced, andseborrheic dermatitis and acne both improved.

patients). We analyzed changes in serum hormones,
laboratory data, and blood levels of electrolytes
resulting from oral spironolactone treatment in 25
patients (Fig. 5).
Unexpectedly, only two and four patients had hightotal (>0.6 ng/dl) and free (>1.5 pg/dl) testosterone
levels before treatment, respectively. All the caseswith high testosterone showed decreased total andfree testosterone levels after treatment. On the other
hand, 4 of 7 patients with low total testosterone level(<0.2 ng/dl) and 12 of 14 patients with low freetestosterone level (<1.0 pg/dl) showed increased total
and free testosterone levels after treatment, respectively. Thus, patients with high total or free testosterone levels tended to have lower levels after
treatment, whereas total or free testosterone levels
tended to rise with treatment for patients with low
initial levels.
The values of LH, DHEAS, and SHBG for all thepatients were within normal limits except for one caseeach. Indices of liver functions (ALT and AST) andthose of kidney functions (BUN and Cr) were notaﬀected by oral spironolactone. Unexpectedly, Na+
and K+ levels also were not aﬀected signiﬁcantly by
this urinary agent. Only Cl) showed a signiﬁcantdecrease (p < 0.05) with treatment. However, almost
all values were within normal limits.

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Fig. 4. A 28-year-old female with acne vulgaris and severe
sebum discharge. (A) Before treatment. (B) After 4 monthsof oral spironolactone (excellent results).

Discussion
Because acne almost always recurs, the key to successful management is to provide both preventive andcurative treatment. Our results show that oral spironolactone is very eﬀective for treating acne in Japanese females without serious side eﬀects other than
menstrual irregularities.
Although we observed no signiﬁcant abnormalities
in the pretreatment levels of serum and free testosterone in Japanese patients with severe acne, all thefemale patients in our study exhibited clinicalimprovement after 2 to 4 months of oral spironolactone monotherapy. Thus, our results strongly
suggest that androgen signals aﬀect acne in almost all
patients, but factors other than serum hormonallevels may have a critical inﬂuence on sebum production and subsequent new acne formation. Oralcontraceptives can reduce gonadotropins such asluteinizing hormone, with consequent reduction of
testosterone production and serum levels of testosterone, but they cannot block androgen signals at thelevel of the androgen receptors (some progestins can,but much less selectively for the androgen receptor
than for the progesterone receptor). Thus, this difference may be the reason why some acne patients do
not respond to oral contraceptive treatments. These
results also suggest that oral spironolactone may bebetter for treatment of acne than for use as oral
contraceptives.

Anti-androgenic Therapy Using Oral Spironolactone

Acne occasionally recurred several months after
the administration of oral spironolactone had ended.
Gradually decreasing the spironolactone dosage canhelp prevent rebound and recurrence of acne after
treatment. Several patients who dropped out of thestudy and discontinued spironolactone without
tapering the dose had an immediate recurrence ofacne formation.
Some patients who also suﬀered from concurrent
seborrheic dermatitis on their faces also showed
improvement after administration of oral spironolactone. This eﬀect probably results from the inhibitory action of spironolactone on sebum production
by blockage of androgen signals at the receptor level.
Indeed, almost all patients reported reduced sebum
discharge as soon as 2 weeks after starting treatment.
The mechanism by which oral spironolactone
causes menstrual irregularities is not clearly understood. After the start of administration, the serum
levels of testosterone or dehydrotestosterone may beacutely elevated because androgen receptors arecompetitively blocked by the drug. The excessive
testosterone could then be transformed into estradiol,which can induce endometrial hyperplasia and menstrual irregularities. Gynecomastia may be induced inmales for the same reason [12]. Because the threemale patients with gynecomastia in this study were
between 19 and 22 years of age, males in this age
range may be the most susceptible to the conversion
from testosterone to estradiol due to the high serum
level of testosterone during this period. This study
shows that male patients do not tolerate oral spironolactone well, so other therapeutic agents such asoral isoretinoin [3,10] must be considered for theirtreatment.
Most of the females in our trial were satisﬁed with
their clinical results despite the menstrual irregularities because they had experienced recurrent acne for along time and had lived stressful lives caused by
disﬁgurement. For 9 of 64 patients (14%), a combined
injection of estrogen and progesterone was performed
to induce normal menstruation, which usually wasobserved within 10 to 14 days after the injection.
Concurrent administration of contraceptives can be
useful for preventing possible pregnancy during thetreatment and may stabilize the menstrual periods.
Other side eﬀects such as itching and allergic
eruptions occurred in only a few patients. We observed no abnormal blood levels of electrolytes orlaboratory values for ALT, AST, BUN, Cr, Na+, orK+ after administration of the oral spironolactone
series. Only Cl) showed a signiﬁcant, but minor,
decrease.
In summary, this study demonstrated that oral
spironolactone is quite eﬀective for acne in Asianfemales, and that this therapy is a good option,
especially for recurrent, severe, resistant, or widespread types of the condition, although it frequently
induces menstrual irregularities. Oral spironolactone
has been used extensively as a diuretic, and its safety

K. Sato et al.

693

Fig. 5. Blood test results before and after administration of oral spironolactone. (A) Total testosterone. (B) Free testosterone.
(C) Luteinizing hormone (LH). (D) Dehydroepiandrostenedione sulfate (DHEAS). (E) Sex hormone binding globulin(SHBG). (F) Alanine transferase (ALT). (G) Aspartate transferase (AST). (H) Blood urea nitrogen (BUN). (I) Creatinine(Cr). (J) Sodium (Na+). (K) Potassium (K+). (L) Chlorine (Cl-). Increases or decreases of more than 10% from initial values
are shown as blue and red lines, respectively. Free testosterone increased signiﬁcantly (p < 0.05) and Cl- decreased signiﬁcantly (p < 0.05) with pretreatment, although almost all values were within normal limits. The LH, DHEAS, SHBG, ALT,
AST, BUN, Cr, Na+, and K+ values did not change signiﬁcantly with treatment.

has been established for Asian people, in contrast to
two other hormonal agonists used in acne therapy(cyproterone acetate and ﬂutamide) that cause liver
dysfunction in Asians. Menstrual irregularities arecommon as a side eﬀect, but a compensatory hormonal injection is available to induce menstrual regularity. Spironolactone may be regarded as animportant alternative when conventional antibiotics
such as doxycyclin and oral isotretinoin do not work.
It cannot be administered to male patients because of
a potential risk of inducing gynecomastia.

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