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The Journal of Clinical Endocrinology & Metabolism 89(6):2756 –2762
Copyright © 2004 by The Endocrine Society
doi: 10.1210/jc.2003-031780
Comparison of Efficacy of Spironolactone with
Metformin in the Management of Polycystic Ovary
Syndrome: An Open-Labeled Study
M. ASHRAF GANIE, M. L. KHURANA, M. EUNICE, M. GULATI, S. N. DWIVEDI,
AND
A. C. AMMINI
Departments of Endocrinology and Metabolism (M.A.G., M.L.K., M.E., A.C.A.), Radiology (M.G.), and Biostatistics (S.N.D.),
All India Institute of Medical Sciences, New Delhi 110029, India
We compared the efficacy of spironolactone (50 mg/d) with
metformin (1000 mg/d) after random allocation in 82 adolescent and young women with polycystic ovary syndrome
(PCOS) on body mass index (BMI), waist-to-hip ratio, blood
pressure, menstrual cyclicity, hirsutism, hormonal levels, glycemia, and insulin sensitivity at baseline and at the 3rd and
6th months of treatment. Sixty-nine women who completed
the follow-up had a mean age of 22.6 ⴞ 5.0 yr and mean BMI of
26.8 ⴞ 4.0 kg/m2. The number of menstrual cycles in the spironolactone and metformin groups increased from 6.6 ⴞ 2.1
and 5.7 ⴞ 2.3 at baseline to 9.0 ⴞ 1.9 and 7.4 ⴞ 2.6 at 3rd month
and to 10.2 ⴞ 1.9 and 9.1 ⴞ 2.0/ year at the 6th month (P ⴝ
0.0037), respectively. The hirsutism score decreased from
T
HE POLYCYSTIC OVARY syndrome (PCOS), a heterogeneous disorder, is characterized by oligo-anovulation, menstrual disturbances, and androgen excess. The disorder, first described by Stein and Leventhal (1), is now
believed to be the most common hormone condition affecting
reproductive age group women (2, 3). Earlier, most of the
therapeutic modalities were devised to antagonize or decrease androgen production (ovarian wedge resection, ovarian suppression by estrogen and progesterone, LHRH analogs, or antiandrogens), because androgen excess is the most
common abnormality detected in these subjects (4 – 6). For
the last two decades many authors have shown that insulin
resistance and the consequent hyperinsulinemia is the driving factor for increased androgen production (7–12). The
insulin resistance has been demonstrated in nonobese
women even at younger ages (7, 9). This has been used as a
rationale for using insulin sensitizers such as metformin (13–
18) and thiazolidinediones (19 –21) in the management of
PCOS.
Metformin improves insulin sensitivity and various aspects of glucose homeostasis such as reduction in enteral
glucose absorption, inhibition of gluconeogenesis, and increase in glucose utilization in muscle and fat (22). In women
Abbreviations: AUC-I, Area under the curve for insulin; BMI, body
mass index; BP, blood pressure; DHEAS, dehydroepiandrosterone sulfate; FGIR, fasting glucose/insulin ratio; HOMA, homeostasis model
assessment; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; PRL, prolactin; WHR,
waist-to-hip ratio.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
12.9 ⴞ 3.2 and 12.5 ⴞ 4.9 at baseline to 10.1 ⴞ 3.1 and 11.4 ⴞ 4.1
at the 3rd month and to 8.7 ⴞ 1.9 and 10.0 ⴞ 3.3 at the 6th month,
respectively. Both groups showed improvement in glucose
tolerance and insulin sensitivity, although the metformin effect was significant in the latter. Serum LH/FSH and testosterone decreased in both groups. BMI, waist-to-hip ratio, and
blood pressure did not change with either drug. We conclude
that both drugs are effective in the management of PCOS.
Spironolactone appears better than metformin in the treatment of hirsutism, menstrual cycle frequency, and hormonal
derangements and is associated with fewer adverse events.
(J Clin Endocrinol Metab 89: 2756 –2762, 2004)
with PCOS, many authors have demonstrated the efficacy of
metformin in improving menstrual cycle pattern (13, 17, 18,
23), ovulation (24 –28), cervical scores (27), and pregnancy
outcomes (15). Although these effects are attributed to enhanced insulin sensitivity, metformin has also been shown to
directly inhibit human thecal cell androgen synthesis, suggesting an insulin-independent mechanism (29, 30). Recently
published meta-analyses including 12 controlled and 16 uncontrolled trials demonstrated a beneficial effect of metformin on menses and spontaneous or clomiphene citrateinduced ovulation (31). A subsequent systemic review of 13
randomized controlled trials also suggested a significant effect of metformin on various components of PCOS such as
fasting insulin levels, low-density lipoprotein cholesterol,
blood pressure (BP), ovulation, and pregnancy rates with
little or no effect on body mass index (BMI) and waist-to-hip
ratio (WHR). Nausea, vomiting, and other gut disturbances
were noted as major adverse effects (18, 32). Spironolactone
is a steroid chemically related to the mineralocorticoid aldosterone. The drug is primarily used as a diuretic by virtue
of its aldosterone antagonist effect. It is known to act as an
antiandrogen and also blocks androgen synthesis to an extent (33, 34). The drug has long been used in the treatment
of hyperandrogenism (primarily hirsutism) and anovulation
(35–39). Although the experience of spironolactone in PCOS
is limited, it has a good safety record when used in smaller
doses (37, 40, 41). To the best of our knowledge, there is no
study that compares the efficacy of metformin with the antiandrogen spironolactone. Here we report an open-labeled,
randomized study that compares the efficacy and safety of
spironolactone with metformin in the management of
women with PCOS.
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Ganie et al. • Spironolactone vs. Metformin in PCOS Women
Subjects and Methods
Subjects
Women attending the Endocrine and Metabolism Clinics of the All
India Institute of Medical Sciences between 2000 and 2001 and meeting
the National Institutes of Health National Institute of Child Health and
Human Development 1990 consensus conference criteria for diagnosis
of PCOS (42) were informed about the study. Of 168 women who met
the above criteria, 82 volunteered to enter the study and were asked to
give informed consent. The study was approved and conducted according to the guidelines of the Institute’s ethics committee. The inclusion
criteria used to enroll the subjects were presence of menstrual disturbances and hirsutism after ruling out disorders such as Cushing’s syndrome, nonclassical adrenal hyperplasia, thyroid dysfunction, hyperprolactinemia, and androgen-secreting tumors. Menstrual disturbances
were classified as oligo-/amenorrhea (ⱕ8 cycles/yr or menstrual interval ⱖ 35 d) and amenorrhea (absence of menses in last 6 or more
months). Modified Ferriman-Gallwey score (43) by a single observer was
used to assess the degree of hirsutism. A score of at least 8 of a total of
36 was taken as significant. This scoring system has been used previously in our population (44). The same observer, while being blind to the
previous score, did follow-up scoring. Anthropometric assessment included measurement of body weight (kg), height (cm), BMI (kg/m2),
and WHR. In addition to exclusion of the above mentioned disorders,
patients volunteering use of any hormonal preparations or drug(s)
known or suspected to affect reproductive or metabolic functions within
60 d of study entry or those having known diabetes mellitus or renal,
hepatic, or cardiac dysfunction were also excluded. All married/sexually active women were advised to use barrier contraception throughout
the study.
Study protocol
Blood samples were collected from the patients after an overnight fast
for the estimation of T4, TSH, LH, FSH, prolactin (PRL), testosterone,
J Clin Endocrinol Metab, June 2004, 89(6):2756 –2762 2757
dehydroepiandrosterone sulfate (DHEAS), cortisol (morning/evening
or overnight dexamethasone suppression test, if needed), blood counts,
electrolytes, lipids, liver, and kidney functions. Blood samples for hormonal investigations were collected from d 3–7 (early follicular phase)
in subjects with spontaneous menstrual cycles. Safety evaluation included recording of vital signs and any adverse events in addition to the
above workup. The oral glucose tolerance test (OGTT) was performed
at 0800 h after an overnight fast with 75 g anhydrous glucose dissolved
in 250 –300 ml water, and blood samples were collected before and 60
and 120 min later for plasma glucose and insulin. For insulin estimation,
samples were collected in ice and plasma was separated immediately in
cold centrifuge and stored at –20 C until the assay. For other hormones,
serum was separated at room temperature and stored in a similar manner. A single observer did transabdominal ultrasonography to demonstrate any suggestion of polycystic ovarian morphology, i.e. presence of
10 or more peripheral follicles each measuring 2– 8 mm in size with
echogenic ovarian stroma and/or increased ovarian volume (45). The
echogenic theca was considered the most specific finding. All subjects
were given a standard diet (35 kcal/kg comprising of 55– 60% carbohydrate, 20 –25% protein, and 20 –25% fat and high fiber content) and
lifestyle advice (120-min brisk walking per week) at the beginning of the
study. After baseline evaluation, eligible patients were randomized in an
open-labeled manner by a simple randomization process using computer-generated random number allocation according to CONSORT
guidelines (46). The allocation concealment was maintained until OGTT
was done. Two groups received either metformin or spironolactone with
the objective to compare the efficacy and safety of these drugs in the
management of women with PCOS. Metformin (Glyciphage, FRANCO
India Pharma Ltd., Mumbai, India) and spironolactone (Aldactone, RPG
Life Sciences Ltd., Mumbai, India) were administered orally in a dose of
500 mg and 25 mg twice a day, respectively, and followed up for 6
months. The progress of subjects during the trial is shown in the CONSORT chart (Fig. 1).
FIG. 1. CONSORT chart showing progress of subjects in both arms of the trial.
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Ganie et al. • Spironolactone vs. Metformin in PCOS Women
Laboratory analysis
Hormonal assays were done in duplicate by RIA (T4, testosterone,
DHEAS, 17-hydroxyprogesterone, cortisol, and insulin) and immunoradiometric assay (TSH, PRL, LH, and FSH). Commercial kits were
supplied by Diagnostic Products Corp. (Los Angles, CA) (cortisol, 17hydroxyprogesterone, testosterone, and insulin), Immunotech (Marseilles, France) (DHEAS), and Medicorp Inc. (Montreal, Canada) (T4,
TSH, LH, FSH, and PRL). Sensitivity, specificity, interassay, and intraassay coefficients of variation were within the prescribed limits given
in the manufacturer’s protocol. Plasma glucose was measured by glucose oxidase-peroxidase method (Nicholas-Piramal India Ltd., Mumbai,
India). Glucose tolerance was categorized according to WHO 1999 criteria (47). Insulin sensitivity was determined by homeostasis model
assessment (HOMA) [(fasting insulin in mIU/liter ⫻ fasting glucose in
mmol/liter)/22.5] (48), area under the curve for insulin (AUC-I), and
fasting glucose/insulin ratio (FGIR) (mmol/liter/mIU/liter) (49).
Statistical analysis
The results are expressed as mean ⫾ sd. For comparison of all quantitative variables, clinical, biochemical, and hormonal parameters between metformin and spironolactone groups at baseline 3rd and 6th
months, unpaired t test was used. The ANOVA for repeated measures
was used to compare the clinical, biochemical, and hormonal parameters
within each group. The Bonferroni test was used for multiple comparisons. Post hoc analysis was done, wherever necessary, to identify pairs
of observations having significantly different levels of observations.
Furthermore, to compare distribution of qualitative variables between
groups, ␹2 test was used. A P value of ⬍0.05 was taken as significant.
SPSS version 10.0 was used for statistical analysis.
Results
Baseline parameters
Of 82 subjects recruited (n ⫽ 41 in each group) between
2000 and 2001, six subjects dropped out (two in the spironolactone and four in the metformin group), four had incomplete data, and three were lost to follow-up. Sixty nine subjects completed the 6-month follow-up for the final analysis
(Fig. 1). Baseline clinical and anthropometric variables of
these subjects in the spironolactone (n ⫽ 34) and metformin
(n ⫽ 35) groups are compared in Table 1. Age, BMI, Ferriman-Gallwey score, and biochemical and hormonal profiles
were comparable in the groups (Table 2). In all, 16 of 69
subjects had impaired glucose tolerance (IGT) and nine of 69
subjects were diabetic (blood glucose levels did not warrant
pharmacological intervention) using World Health Organi-
zation 1999 criteria. Of these, four diabetic and seven IGT
subjects were in the spironolactone group. The BMI of subjects with diabetes mellitus/IGT was higher than those with
normal glucose tolerance (27.53 ⫾ 5.56 vs. 25.98 ⫾ 5.09).
Follow-up
Metformin. Menstrual cycle frequency improved significantly
with metformin, from 5.7 ⫾ 2.3 to 7.4 ⫾ 2.6 at 3 months and
to 9.1 ⫾ 2.0 cycles/yr at 6 months (P ⫽ 0.001). The cycles
regularized in the majority of subjects, although six of 35
cases persisted with oligo-/amenorrhea (Table 1). The hirsutism score decreased very gradually from 12.5 ⫾ 4.9 at
baseline to 11.4 ⫾ 4.1 and 10.0 ⫾ 3.3 at the 3rd and 6th months
of therapy, respectively (P ⫽ 0.001) (Table 1). Serum testosterone levels showed a significant decrease from a baseline
of 3.25 ⫾ 1.59 to 2.53 ⫾ 1.9 and to 1.7 ⫾ 0.86 nmol/liter after
the 3rd and 6th months (P ⫽ 0.001), respectively (Table 2 and
Fig. 2). Serum DHEAS levels also showed a significant decrease (Table 2). Insulin sensitivity (HOMA, AUC-I, and
FGIR) showed a significant decrease (Fig. 3). OGTT results
revealed no major changes except a downward trend in the
2-h glucose (Table 2). There was no significant effect on BMI,
WHR, BP, and LH levels with 6 months of metformin therapy
(Tables 1 and 2).
Spironolactone. Menstrual cycle frequency increased from
6.6 ⫾ 2.1 to 9.0 ⫾ 1.9 at 3 months and to 10.2 ⫾ 1.9 cycles/yr
at 6 months (P ⫽ 0.001) (Table 1). The menstrual irregularity
persisted in six of 34 subjects, and new cycle irregularity
developed in five of 34 subjects. The irregularity, however,
was not significant enough to cause drug withdrawal. The
hirsutism score decreased from 12.9 ⫾ 3.2 at baseline to
10.1 ⫾ 3.1 at 3 months and to 8.7 ⫾ 1.9 at 6 months of therapy
(P ⫽ 0.034) (Table 1). Serum testosterone levels showed a
significant decrease (P ⫽ 0.001) from 3.57 ⫾ 0.34 to 1.94 ⫾ 1.0
at the 3rd month and did not change much thereafter (to
1.94 ⫾ 1.00 nmol/liter at the 6th month) (Fig. 3). Serum
DHEAS levels decreased significantly, whereas LH levels
showed a nonsignificant decrease. Like metformin, OGTT
parameters and insulin sensitivity (by HOMA, AUC-I, and
FGIR) showed a decreasing trend (Table 2 and Fig. 3). Sim-
TABLE 1. Clinical parameters of the subjects before and during treatment
Metformin group (n ⫽ 35)
0 months
Age (yr)
BMI (kg/m2; normal range, 20 –25)
WHR (normal range ⬍ 0.80)
Age of menarche (yr)
No. of menstrual cycles/yr
(normal range ⱖ 8)
Hirsutism score (normal
range ⱕ 8)
Hirsutism duration (yr)
BP systolic (mm Hg; normal
range ⱕ 120)
BP diastolic (mm Hg; normal
range ⱕ 90)
22.9 ⫾ 5.3
26.5 ⫾ 5.6 (17–34)a
0.9 ⫾ 0.1
12.9 ⫾ 1.3
5.7 ⫾ 2.3
3 months
25.7 ⫾ 4.5
0.85 ⫾ 0.1
Spironolactone group (n ⫽ 34)
6 months
25.6 ⫾ 4.7
0.85 ⫾ 0.1
0 months
23.3 ⫾ 5.2
25.9 ⫾ 5.0 (18 –35)a
0.86 ⫾ 0.1
13.0 ⫾ 1.2
6.6 ⫾ 2.1
3 months
6 months
25.7 ⫾ 4.8
0.85 ⫾ 0.1
25.5 ⫾ 4.6
0.86 ⫾ 0.1
7.4 ⫾ 2.6b
9.1 ⫾ 2.0b
9.0 ⫾ 1.9b
12.5 ⫾ 4.9
11.4 ⫾ 4.1b
10.0 ⫾ 3.3b
12.9 ⫾ 3.2
10.1 ⫾ 3.1
8.7 ⫾ 1.9
4.0 ⫾ 2.5
122.9 ⫾ 14.9
118.3 ⫾ 18.8
122.2 ⫾ 14.9
4.4 ⫾ 2.7
122.7 ⫾ 8.50
123.1 ⫾ 6.4
122.9 ⫾ 14.7
81.1 ⫾ 5.0
81.2 ⫾ 6.4
79.6 ⫾ 14.3
82.9 ⫾ 4.8
80.3 ⫾ 6.8
81.4 ⫾ 5.6
Results are given as mean ⫾ SD.
a
BMI range.
b
P ⬍ 0.05 for comparison within the group.
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10.2 ⫾ 1.9b
90 ⫾ 15.6
(5 ⫾ 0.8)
135.2 ⫾ 49.5
(7.51 ⫾ 2.75)
132.8 ⫾ 48.1
(7.38 ⫾ 2.67)
11,235.71 ⫾ 4,328
18.47 ⫾ 18.93
(132.52 ⫾ 135.8)
122.61 ⫾ 14.37
(879.7 ⫾ 103.1)
84.65 ⫾ 9.69
(607.4 ⫾ 68.9)
10,926.6 ⫾ 6,855
4.0 ⫾ 4.18
7.9 ⫾ 0.74
7.83 ⫾ 5.72
3.65 ⫾ 2.37
2.72 ⫾ 0.5
83.9 ⫾ 45.8
(3.25 ⫾ 1.59)
257.9 ⫾ 122.3
(7.0 ⫾ 3.32)
91.4 ⫾ 13.1
(5.08 ⫾ 0.7)
135.7 ⫾ 36.9
(7.54 ⫾ 2.05)
122.2 ⫾ 36.5
(6.79 ⫾ 2.03)
11,960.4 ⫾ 3,208
13.29 ⫾ 17.6
(95.36 ⫾ 125.9)
79.54 ⫾ 8.5
(570.7 ⫾ 60.9)
56.35 ⫾ 6.7
(404.3 ⫾ 48.1)
6,862.14 ⫾ 4,015a
3.35 ⫾ 4.12
10.0 ⫾ 0.59a
7.22 ⫾ 5.06
4.08 ⫾ 1.92
2.21 ⫾ 0.36
72.9 ⫾ 54.8
(2.53 ⫾ 1.90)
241.7 ⫾ 110.5
(6.56 ⫾ 3.0)
3 months
Metformin group (n ⫽ 35)
95.9 ⫾ 12.9
(5.33 ⫾ 0.7)
135.4 ⫾ 33.3
(7.52 ⫾ 1.85)
115.7 ⫾ 24.7
(6.43 ⫾ 1.37)
11,927 ⫾ 3,652
14.28 ⫾ 17.5
(102.5 ⫾ 125)
55.85 ⫾ 6.09
(400.7 ⫾ 43.7)b
43.81 ⫾ 6.5b
(314.3 ⫾ 46.6)
4,990.8 ⫾ 3,132a
2.55 ⫾ 1.44a
10.83 ⫾ 0.69a
5.34 ⫾ 3.34a
6.06 ⫾ 8.38
1.38 ⫾ 0.18a
49.9 ⫾ 24.8
(1.7 ⫾ 0.86)a
225.5 ⫾ 101.3
(6.1 ⫾ 2.7)b
6 months
90.5 ⫾ 11.7
(5.03 ⫾ 0.6)
133.6 ⫾ 45.4
(7.42 ⫾ 2.52)
116.1 ⫾ 34.6
(6.45 ⫾ 1.92)
11,649.1 ⫾ 3,645
22.17 ⫾ 49.02
(159.0 ⫾ 351.7)
103.88 ⫾ 15.16
(745.3 ⫾ 108.8)
76.34 ⫾ 14.95
(547.7 ⫾ 107.3)d
9,203.2 ⫾ 8,667
5.32 ⫾ 13.12
9.1 ⫾ 0.7d
6.67 ⫾ 3.34
4.12 ⫾ 1.77
1.73 ⫾ 0.19b
55.9 ⫾ 28.8
(1.94 ⫾ 1.0)a
253.1 ⫾ 140.0
(6.87 ⫾ 3.8)
3 months
6 months
93.8 ⫾ 12.4
(5.21 ⫾ 0.7)
135.4 ⫾ 33.3
(7.52 ⫾ 1.85)
115.7 ⫾ 24.6
(6.43 ⫾ 1.37)
11,775.5 ⫾ 2,459
10.37 ⫾ 5.7
(74.4 ⫾ 40.7)
84.51 ⫾ 14.2
(606.4 ⫾ 101.9)a,d
66.97 ⫾ 14.4
(480.5 ⫾ 103.3)a,d
7,450.5 ⫾ 7,141
5.27 ⫾ 8.81c
9.7 ⫾ 0.69d
6.3 ⫾ 3.54a
4.68 ⫾ 1.70
1.29 ⫾ 0.18b
55.9 ⫾ 28.8
(1.94 ⫾ 1.0)a
229.5 ⫾ 73.7
(6.23 ⫾ 2.0)a
Spironolactone group (n ⫽ 34)
87.3 ⫾ 14.9
(4.85 ⫾ 0.8)
131.6 ⫾ 44.6
(7.31 ⫾ 2.48)
121.9 ⫾ 40.8
(6.77 ⫾ 2.27)
11,704.6 ⫾ 3,792
26.67 ⫾ 45.8
(191.4 ⫾ 328.5)
139.43 ⫾ 23.9
(1,000.4 ⫾ 171)
91.02 ⫾ 16.7
(653.1 ⫾ 119.8)
11,349.1 ⫾ 1,113
4.92 ⫾ 6.94
8.1 ⫾ 0.7
9.01 ⫾ 5.42
3.72 ⫾ 2.13
2.7 ⫾ 0.35d
102.9 ⫾ 9.8
(3.57 ⫾ 0.34)
255.3 ⫾ 101.3
(6.93 ⫾ 2.75)
0 months
Results are given as mean ⫾ SD. Conversion factors are as follows: insulin, pmol/liter ⫽ ␮U/ml ⫻ 7.175; LH and FSH, IU/liter ⫽ mIU/ml ⫻ 1; testosterone, nmol/liter ⫽ ng/dl
⫻ 0.03467; glucose, mmol/liter ⫽ mg/dl ⫻ 0.0555; DHEAS, ␮mol/liter ⫽ ␮g/dl ⫻ 0.02714. BG, Blood glucose; ref., reference.
a
P ⬍ 0.05 and b P ⬍ 0.001 for comparison within the group.
c
P ⬍ 0.05 and d P ⬍ 0.001 for comparison between metformin and spironolactone groups.
DHEAS, mg/dl (␮mol/liter) (0.81– 8.91)
AUC-I
HOMA (ref. range ⱕ 2)
FGIR (ref. range ⱕ 4.5)
LH, mIU/ml (IU/liter; ref. range ⫽ 0.5–15)
FSH, mIU/ml (IU/liter; ref. range ⫽ 0.2–10)
LH/FSH ratio (ref. range ⱕ 2)
Testosterone, ng/dl (nmol/liter; ref. range ⬍ 2.25)
Insulin 2 h, ␮U/ml (pmol/liter)
Insulin 1 h, ␮U/ml (pmol/liter)
AUC-glucose
Insulin fasting, ␮U/ml (pmol/liter, ref. range 35–145)
BG 2 h, mg/dl (mmol/liter; ref. range ⬍ 7.78)
BG 1 h, mg/dl (mmol/liter; ref. range ⬍ 7.7)
BG fasting; mg/dl (mmol/liter; ref. range ⬍ 6.1)
0 months
TABLE 2. Biochemical and hormonal parameters of the subjects before and during treatment
Ganie et al. • Spironolactone vs. Metformin in PCOS Women
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Ganie et al. • Spironolactone vs. Metformin in PCOS Women
less common with spironolactone. Polyuria (four of 34), abdominal pain (one of 34, leading to drug withdrawal), and
menstrual irregularity (nine of 34) were noted in the spironolactone group. One subject had hyperuricemia, which
persisted after drug withdrawal and was probably unrelated.
The metformin group had vomiting, nausea (four of 35),
diarrhea (eight of 35), and hyperadrenergic symptoms but
not a documented hypoglycemia (two of 35) leading to drug
withdrawal in four subjects.
Discussion
FIG. 2. Comparing the effect of spironolactone and metformin on
serum testosterone levels before and after treatment (conversion factor, nmol/liter ⫽ ng/dl ⫻ 0.03467).
FIG. 3. Comparing the effect of spironolactone and metformin on
blood glucose and plasma insulin levels before and after treatment (as
shown by AUC) (conversion factor for insulin, pmol/liter ⫽ ␮U/ml ⫻
7.175; for glucose, mmol/liter ⫽ mg/dl ⫻ 0.0555).
ilarly, there was no significant effect of spironolactone on
BMI, WHR, and blood pressure (Table 1).
Metformin vs. spironolactone. Compared with metformin, spironolactone was more effective in increasing the frequency
of menstrual cycles both at the 3rd (P ⫽ 0.006) and the 6th
month (P ⫽ 0.03), although at the cost of some menstrual
irregularity. This irregularity, however, did not affect the
patient satisfaction with this drug. There was a significant fall
in testosterone with both drugs, although the effect was rapid
(i.e. by the 3rd month) with spironolactone. The difference in
LH and testosterone disappeared by the 6th month due to an
equal but delayed effect of metformin (Table 2). Interestingly,
glucose intolerance improved by the same magnitude in both
groups (P ⫽ 0.79). At the end of the study, one diabetic and
five IGT subjects were in the metformin group compared
with no diabetic and four with IGT in the spironolactone
group. At the beginning of the study, nine IGT and five
diabetics were in the metformin group vs. seven IGT and four
diabetics in the spironolactone group. There was no statistically significant difference between the groups regarding
BMI, WHR, or blood pressure (Table 1). Adverse events were
Insulin resistance is now considered as one of the essential
components in the pathogenesis of PCOS (7–12, 22). Although the precise molecular basis of insulin resistance has
not been elucidated, the defects can occur at insulin binding,
receptor, or postreceptor levels and may be disproportionate
to the degree of obesity (11, 22, 50). The excess insulin has
been postulated to partly augment LH-stimulated androgen
secretion from the ovarian tissues and partly to increase free
androgens by decreasing circulating SHBG levels (50, 51).
Based on this mechanism, metformin has been lately in
vogue for the treatment of menstrual disturbances, hirsutism, ovulation induction, cervical scores, pregnancy outcomes, etc. in PCOS (18, 22–29, 31, 32). Spironolactone, an
antiandrogen, has been in use for the treatment of hyperandrogenism for nearly 21⁄2 decades. Its main benefit stems
from blocking androgen receptors with a minor contribution
from a decrease in androgen synthesis (33–36). Although
experience with the drug in PCOS is limited, it has a good
safety record at doses of 50 –100 mg both on a short- and a
long-term basis (37– 41).
This randomized, open-labeled study compared the efficacy and safety of these two drugs (metformin, 1000 mg
daily, and spironolactone, 50 mg daily) with diverse mechanisms of action. Sixty-nine subjects completed 6 months of
the study and were analyzed. Clinical, hormonal, and biochemical profiles of the two groups were comparable at
baseline. With metformin, the menstrual pattern regularized
in the majority of the subjects, and these findings are in
agreement with most recent clinical trials with metformin
(18, 31, 32). The hirsutism score decreased very gradually,
and the benefit was significant and appreciable by 6 months.
Kelly and Gordon (52) observed a similar improvement in
quantitative hair parameters, although the effect was noted
earlier, i.e. by the 3rd month. Serum testosterone and DHEAS
levels showed a significant decrease by the 6th month of
therapy as shown earlier (32). Although severity of glucose
tolerance abnormalities showed a positive trend, it did not
reflect in any improvement in individual OGTT parameters.
Insulin sensitivity demonstrated a significant increase with
metformin as has been demonstrated earlier (13, 15, 18, 31,
32). There was no significant effect on BMI, WHR, and blood
pressure with 6 months of metformin therapy. Most of the
studies have shown variable results on these parameters (31,
32). Most of the data on metformin available have been
generated with doses ranging from 1.5–2 g/d, which is
higher than the dose used in our study. Although the efficacy
of the drug at this dose in Western subjects has been inferior
(16, 53), we found comparable efficacy to higher doses with
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Ganie et al. • Spironolactone vs. Metformin in PCOS Women
a fewer number of adverse effects. This may be attributed to
the lower body mass of our subjects.
With spironolactone, the number of cycles per year increased with 6 months of therapy. The menstrual irregularity
persisted in six of 34 subjects, and new cycle irregularity
developed in five of 34 subjects. This drug is known to cause
such irregularity in menstrual cycles (39, 40, 54, 55), although
the irregularity was not significant enough to cause drug
withdrawal in this study. The hirsutism score decreased significantly by 6 months. Our results are similar to many studies, although the dose used was higher (38 – 40). The serum
testosterone and LH levels and LH/FSH ratio showed a
significant decrease compared with variable effects observed
earlier (36 – 40). There was no significant effect on BMI, WHR,
blood pressure, OGTT parameters, and insulin sensitivity,
although a significant fall was observed in 1- and 2-h insulin
levels. Both these drugs showed significant improvement in
menstrual cycle pattern, hirsutism score, and androgen levels, suggesting their efficacy in the treatment of PCOS. Spironolactone appears to be a better choice than metformin in
view of better efficacy on hair growth and patient acceptance;
however, metformin was superior in menstrual regularization and improving insulin sensitivity. Although spironolactone induced mild menstrual cycle irregularity as reported (37– 40), in the present study the abnormality was too
subtle to cause any patient dissatisfaction or drug withdrawal. This may be because of a smaller dose of the drug
used in the present study. However, the efficacy was comparable with earlier studies using higher doses (37–39, 54,
55). Both agents showed a similar effect on glucose tolerance
abnormalities. Of four diabetics and seven IGT subjects in the
spironolactone group at baseline, only four persisted with
IGT and none was diabetic at the end of the study. In the
metformin group at the end of 6 months, five patients persisted with IGT and one subject continued to be diabetic from
a baseline figure of nine IGT and five diabetics. This comparable benefit can be attributed to diet and lifestyle modification, which was similar in both groups. Insulin sensitivity improved in both groups, although it reached
statistical significance only in the metformin group. This is
in agreement with earlier reports (13–15, 18, 31, 32). In the
present study comparing metformin and spironolactone in
countering insulin resistance, metformin is definitely superior, but this effect did not seem to translate into commensurate clinical benefits such as a fall in androgens or alterations in blood glucose levels during this short-term study.
Instead, we observed that spironolactone ameliorated most
of the clinical features of PCOS in addition to some fall in
insulin levels. If insulin resistance was the basic pathogenic
factor, then metformin should have shown superior effects
on glucose tolerance, serum androgen levels, and hair parameters. Recent evidence that metformin causes direct inhibition of androgen synthesis by thecal cells (29, 30) lends
support to our observations that the insulin-lowering effect
of metformin probably is not the entire mechanism of the
clinical benefit of metformin in PCOS.
We conclude that both spironolactone and metformin are
effective agents in the management of various components
of PCOS. Spironolactone appears to be better than metformin
in the treatment of hirsutism and hormonal derangements of
J Clin Endocrinol Metab, June 2004, 89(6):2756 –2762 2761
PCOS and has a better patient tolerance at the dose used. The
fact that superior positive effects of metformin on insulin
sensitivity did not translate into the proportionate clinical
benefit in these PCOS subjects raises doubts about insulin
resistance as the sole pathogenetic factor.
Acknowledgments
We gratefully acknowledge Dr. Nandita Gupta for her help in insulin
estimation and Dr. Rajvir for statistical analysis.
Received October 10, 2003. Accepted February 23, 2004.
Address all correspondence and requests for reprints to: Dr. A. C.
Ammini, Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
E-mail: [email protected].
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