FERTILITY AND STERILITY威

VOL. 77, NO. 4, APRIL 2002

Copyright ©2002 American Society for Reproductive Medicine
Published by Elsevier Science Inc.
Printed on acid-free paper in U.S.A.

Pregnancies following use of metformin

for ovulation induction in patients with
polycystic ovary syndrome
Michael J. Heard, M.D., Anita Pierce, M.D., Sandra A. Carson, M.D., and
John E. Buster, M.D.
Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Baylor
College of Medicine, Houston, Texas

Objective: To assess pregnancy outcome in anovulatory infertility patients diagnosed with polycystic ovary
syndrome (PCOS) who were treated with metformin.
Design: Case series.
Setting: Outpatient.
Patient(s): Anovulatory patients (n ⫽ 48) with a diagnosis of PCOS based on clinical, diagnostic, and
laboratory evaluations were enrolled in the study over a 15-month period.
Intervention(s): Metformin was started at 500 mg b.i.d. for 6 weeks and then increased to 500 mg t.i.d. if
no ovulation occurred. Clomiphene citrate (CC; 50 mg) was added if no ovulatory response occurred after 6
weeks.
Main Outcome Measure(s): Resumption of menses, presumptive ovulation, and pregnancy.
Result(s): Nineteen of 48 (40%) patients resumed spontaneous menses following treatment and showed
presumptive evidence of ovulation with metformin alone; 15/48 (31%) required CC (50 mg) in conjunction
with metformin therapy, and 10 of these 15 (67%) had evidence of ovulation; 20/48 (42%) conceived with a
median time to conception of 3 months, and 7 of these 20 (35%) had spontaneous abortions (SAB); 19/48
(40%) had gastrointestinal-related side effects, and 5 of 48 patients (10%) had to decrease the dosage of
metformin. Only 1 patient discontinued therapy.
Conclusion(s): Metformin alone in patients with PCOS results in a substantial number of pregnancies, with
69% (20/29) of those who ovulated conceiving in less than 6 months. (Fertil Steril威 2002;77:669 –73. ©2002
by American Society for Reproductive Medicine.)
Key Words: Metformin, polycystic ovary syndrome, infertility, ovulation induction

Received May 30, 2001;
revised and accepted
October 22, 2001.
Reprint requests: John E
Buster, M.D., Baylor
College of Medicine, 6550
Fannin S801A, Houston,
Texas 77030 (FAX: 713-
798-8231; E-mail:
jbuster@bcm.tmc.edu).
0015-0282/02/$22.00
PII S0015-0282(01)03266-6
Polycystic ovary syndrome (PCOS) is a
condition associated with chronic anovulation
and hyperandrogenemia. Considered a com-
mon cause of infertility, it affects up to 6% of
reproductive age women. Many women with
PCOS have insulin resistance with elevated
insulin levels and are predisposed to non-insu-
lin-dependent diabetes mellitus (NIDDM) and
its comorbidities (1–5). Hyperinsulinemia is
believed to play a role in the pathogenesis of
PCOS.
Meformin (Glucophage; Bristol-Myers Squibb,
Princeton, NJ) is a biguanide, antihyperglyce-
mic drug that improves tissue sensitivity to
insulin while decreasing insulin levels and in-
hibiting hepatic glucose production. When
used in patients with PCOS, metformin reduces
LH, sex hormone-binding globulin, and ovar-
ian androgens and corrects hyperinsulinemia
(6 –10). Metformin also induces the resumption
of regular menses and ovulation (10, 11). In
addition, Nestler et al. showed that the ovula-
tory response to clomiphene citrate (CC) can
be increased in obese PCOS women when used
in conjunction with metformin (12). Vander-
molen recently confirmed this finding in a ran-
domized study of PCOS patients and found that
metformin also increased the pregnancy rate in
those patients who were anovulatory and resis-
tant to CC (15).
One small series has been published to date
that has evaluated metformin alone for the
treatment of infertility (14). Except for a small,
preliminary study conducted by Vandermolen

669
et al. (15), no reports have evaluated metformin or met-
formin in conjunction with CC to improve ovulation with the
purpose of achieving pregnancy. This study is the first to
assess pregnancy outcome in a larger group of anovulatory
infertile women diagnosed with PCOS who were treated
with metformin.
MATERIALS AND METHODS
We studied infertile PCOS patients who were treated with
metformin with or without CC at Baylor College of Medi-
cine (Division of Reproductive Endocrinology and Infertil-
ity) from December 1, 1999, through February 15, 2001.
This study was approved by the institutional review board at
the Baylor College of Medicine. Diagnostic evaluations in-
cluded a hysterosalpingogram, a semen analysis, and labo-
ratory evaluations for thyroid dysfunction and hyperpro-
lactinemia. The clinical diagnosis of PCOS was based on a
history of hyperandrogenemia with menstrual irregularity
and anovulation ranging from oligomenorrhea (a bleeding
interval greater than 35 days but less than 6 months) to
secondary amenorrhea (bleeding interval 6 months or great-
er). Patients diagnosed with PCOS were considered a sub-
group of the World Health Organization (WHO) 2 classifi-
cation according to Rowe et al. (16). Patients with a history
of CC failure had been treated with at least three increasing
doses of CC and had no response to therapy. Of the 48
patients enrolled, 31 had a normal semen analysis (count
⬎20 million/mL, motility and morphology ⬎50%), 7 had
oligospermia (count ⬍20 million/mL), and 10 patients did
not have a semen analysis recorded (Table 1).
Treatment Protocol
Metformin was initially administered at 500 mg two times
daily for 6 weeks. Dosing was varied during the initial
start of therapy in order to accommodate side effects. Men-
strual calendars with basal body temperature (BBT) charts
were recorded initially. Luteinizing hormone monitoring to
time intercourse was initiated once menstrual cycles became
regular.
After 6 weeks of therapy, the patients returned to the
clinic. If the patient had resumed regular menses and was
showing an ovulatory response based on BBT charts, met-
formin was continued at 500 mg b.i.d. with follow-up over
the next 6 months. If the patient did not conceive during this
time, metformin therapy was discontinued and other thera-
pies were considered. If the patient did not respond to the
initial dose of 500 mg b.i.d., metformin was increased to 500
mg t.i.d. If there was no response in 6 more weeks, CC (50
mg per day for 5 days) was started in conjunction with
metformin for a maximum of 6 cycles. Clomiphene citrate
was administered regardless of whether there was a history
of CC failure. Patients who conceived while receiving met-
formin therapy continued to take this medication through 12
weeks of gestation.
670 Heard et al. Pregnancies with Metformin in PCOS
RESULTS
Forty-eight patients who were entered into the study took
metformin for at least 3 months unless they became pregnant
earlier. The mean age was 29.9 years (range, 20 –38), and the
body mass index (BMI) was 28.7 hg/m2 (range, 19.5– 48).
Following the treatment protocol, 19/48 (40%) resumed
spontaneous menses and showed evidence of ovulation with
metformin alone. Ten of 28 (36%) used CC (50 mg) in
conjunction with metformin therapy. The median time to
onset of spontaneous menses was 30 days after starting
metformin. Thus, 19/48 (40%) did not resume regular men-
ses or show an ovulatory response. There were no differ-
ences in the clinical characteristics of the patients (i.e., age,
parity, BMI, or the use of CC) between responders and
nonresponders; 20/48 (42%) conceived with a median time
to conception of 3 months, and 7 of these 20 (35%) patients
who became pregnant had spontaneous abortions. The preg-
nancy rate in couples with oligospermia was 2/8 (25%) and
3/9 (33%) in those with unknown semen analysis results;
19/49 (39%) had gastrointestinal-related side effects, includ-
ing diarrhea, abdominal cramping, and nausea; 5/49 (10%)
had to decrease the dosage of metformin due to side effects.
Only 1 patient discontinued therapy due to side effects. No
patients developed ovarian hyperstimulation syndrome, and
no multiple gestations were noted (see Table 1).
DISCUSSION
No sizable study to date has evaluated metformin alone
for use in patients who have PCOS who would like to get
pregnant. This is the second and largest study to date that
focuses on use of metformin in conjunction with CC to
increase the ovulatory and pregnancy rates when treating
infertility. The initial studies of the effects of metformin on
hyperinsulinemia and hyperandogenemia in PCOS revealed
spontaneous resumption of menses and several incidental
pregnancies (8, 11, 15, 17). Velazquez studied a small group
of patients who received metformin therapy (500 mg t.i.d.)
for 6 months; most of them resumed regular menses, spon-
taneously ovulated, and 19% of them became pregnant
(15, 18). Recently, Seale et al. reported three cases of preg-
nancy in PCOS patients with long-standing infertility who
were treated with metformin (14).
This case series evaluated the effect of metformin therapy
on the incidence of pregnancy in PCOS patients with a
known history of infertility. Previous studies have shown
benefit with resumption of menses and spontaneous ovula-
tion with the use of insulin-sensitizing agents. The clinical
use of metformin alone in this study population resulted in
resumption of menses and an ovulatory response in 40%.
This rate increased to 60% with the addition of a low dose of
CC (50 mg). Ovulation was determined based on urinary
midcycle LH monitoring. Median time to resumption of
menses was 30 days. These results are consistent with cur-
Vol. 77, No. 4, April 2002
FERTILITY & STERILITY威
TABLE 1

Data for 48 anovulatory patients with polycystic ovary syndrome who were treated with metformin.

Age Gravida/ BMI Metformin Resumed Time to Pregnancy outcome Clomiphene

Patient (y) Parity (hg/m2) Semen analysis HSG findings dose used normal menses Pregnancy pregnancy viable—delivered Side effects citrate used

1 32 G2,P0,A2 27.1 WNL Normal 500 b.i.d. Yes Yes 1 month None No
2 37 G1,P0,A1 37.5 WNL Normal HSG 500 b.i.d. Yes No None No
3 26 G1,P0,A1 26.1 WNL Not done 250 b.i.d. Yes Yes 2 months SAB None No
4 32 G0 19.8 Oligospermia Normal 500 b.i.d. Yes Yes 2 months Ongoing None No
5 30 G0 30.7 Oligospermia Not done 500 t.i.d. Yes No — — Diarrhea Yes
Endometrial polyp
with bilateral
6 27 G1,P0,A1 22 WNL tubal fill/spill 500 b.i.d. Yes Yes 5 months SAB Fainting No
7 30 G0 30.7 Oligospermia Not done 500 t.i.d. Yes No — — Diarrhea —
8 38 G1,P0,A1 22.2 WNL Normal HSG 500 t.i.d. Yes Yes 3 months Ongoing Nausea Yes
9 29 G1P1 31.2 WNL Not done 500 b.i.d. No No — — GI diarrhea Yes
10 32 G0 24 WNL Adhesions at L/S 500 b.i.d. Yes No — — — —
11 24 G0 41.4 WNL Not done 500 t.i.d. No No — — None Yes
12 20 G0 19.8 WNL Not done 500 t.i.d. Yes Yes 3 months Ongoing GI cramping No
13 28 G0,P0 45.2 Not done Not done 500 b.i.d. No No — — None —
14 35 G0 33.6 Not found Normal HSG 500 b.i.d. Yes No — — None No
15 31 G6,P3,A3 27.4 Not done Normal HSG 500 b.i.d. Yes Yes 1 month Biochemical None No
16 30 G0 18.6 WNL Not done 500 t.i.d. Yes Yes 3 months Viable None No
17 31 G0 20.1 WNL Not done 500 b.i.d. Yes Yes 1 month Viable Serious GI cramping/ No
cramping
18 28 G0,P0 36.2 WNL Normal HSG 500 t.i.d. Yes Yes 4 months Biochemical None No
19 30 G0,P0 29.5 WNL Normal HSG 500 t.i.d. Yes Yes 5 months Ongoing None Yes
20 32 G3,P0,A3 19.7 WNL No, but IUA noted 500 b.i.d. Yes Yes 2 months Missed abortion None No
on HSG
21 33 G0,P0 21 Done elsewhere—no Not done 500 b.i.d. Yes Yes 1 month Ongoing None No
report
22 31 G0 30.5 WNL Left tubal 500 t.i.d. No No — — None No
occlusion
23 29 G0,P0 48 Oligospermia Not done 500 b.i.d. No No — — Severe GI— Yes
discontinued 10
days later
24 28 G1,P1 21.3 WNL Not done 500 b.i.d. NA—intolerant No — — — No
25 25 G0 28.5 WNL Not done 500 t.i.d. Yes Yes 6 months Ongoing None —
26 27 G0,P0 25.4 Oligospermia Normal HSG 500 b.i.d. No No — — None Yes
27 32 G0 21 WNL Not done 500 b.i.d. No Yes 3 months Ongoing Diarrhea Yes
28 31 G0 20 Asthenospermia Normal HSG 500 b.i.d. Yes Yes 1 month Ongoing Cramping/diarrhea No
29 27 G0 25.4 Oligoasthenospermia Not done 500 t.i.d. Yes No — — None No
30 21 G0,P0 32.2 Patient One open tube/nl 500 b.i.d. No No — — Nausea/vomiting/ Yes
refused/normal UTX lightheadedness
postcoital test
671
672
Heard et al.

T A B L E 1 C o n tin u e d .
Pregnancies with Metformin in PCOS

Resumed
Age Gravida/ Metformin normal Time to Pregnancy outcome Clomid
Patient (y) Parity BMI Semen analysis HSG findings dose used menses Pregnancy pregnancy viable—delivered Side effects used

31 36 G1,P0,A1 33.5 WNL Not done 500 t.i.d. Yes No — — Lightheadedness/ No

dizziness
32 33 G1,P3 26.9 Not done Not done 500 b.i.d. Yes No — — None —
33 29 G0 26.6 WNL Not done 500 b.i.d. No No — — Lethargy No
34 36 G0 42.9 WNL Unilateral 500 b.i.d. Yes No — — Abdominal cramping —
obstruction
35 29 G3,P1,A1 23.2 Done elsewhere— Normal HSG 500 b.i.d. No Yes 11 months Ongoing None Yes
saw urologist-
no report
36 24 G1,P0,A1 37.7 WNL Normal HSG 500 b.i.d. Yes Yes 2 months Biochemical Diarrhea/vomiting Yes
37 30 G0 30.1 WNL Not done 500 b.i.d. No Yes 1 month Viable Abdominal cramping No
38 33 G2,P2 29.6 WNL Not done 500 b.i.d. No No — — None —
39 24 G2,P1,A1 29.6 Azoospermia Not done 500 b.i.d. Yes No — — None —
40 29 G2,P1,A1 37.8 WNL Not done 500 b.i.d. Yes No — — None No
41 31 G0,P0 19.5 Not done Normal HSG 500 b.i.d. No No — — None Yes
42 22 G0 25.1 WNL Not done 500 t.i.d. No No — — Abdominal cramping Yes
43 37 G6,P0,A6 36 WNL Normal HSG 500 b.i.d. Yes No — — None Yes
44 26 G1,P1 24.9 Normal Not done 500 b.i.d. Yes Yes 2 months Ongoing None No
45 36 G1,P1 21.9 WNL Not done 500 b.i.d. Yes No — — None
46 34 G1,P0,A1 24 Not done Normal HSG 500 t.i.d. Yes No — — None Yes
47 29 G0 48 Oligoasthenospermia No HSG done 500 b.i.d. No No — — None Yes
48 36 G1,P0,A1 26.2 WNL Normal HSG 500 b.i.d. Yes No — — Abdominal cramping Yes
Note: BMI ⫽ body mass index; HSG ⫽ hysterosalpingography; WNL ⫽ normal; L/S ⫽ laparoscopy; nl ⫽ normal; SAB ⫽ spontaneous abortion; GI ⫽ gastrointestinal; IUA ⫽ intrauterine adhesions; UTX
⫽ uterus.
Heard. Pregnancies with metformin in PCOS. Fertil Steril 2002.
Vol. 77, No. 4, April 2002
rently published data regarding the success of metformin on
spontaneous ovulation in PCOS (12, 15).
Metformin can cause gastrointestinal side effects that
include nausea, abdominal pain, and diarrhea; these side
effects occurred in 19/49 (39%) patients, but usually they
were self-limiting and presented in the first 2 weeks of
therapy. In order to tolerate side effects, 11% of patients had
to decrease the dose of metformin. Some of these patients
conceived while receiving lower initial doses of metformin.
Only 1 patient discontinued the therapy due to an inability to
tolerate side effects. Some variations in the treatment proto-
col included lower dosages of metformin or adding CC to
reduce side effects and maximize therapy. The average dos-
age of metformin was lower than that in other reports, but the
ovulatory response rate was still similar. The appropriate
dosage to maximize clinical benefit in PCOS patients has not
been examined closely and needs further study.
Metformin use in pregnancy has not been studied exten-
sively for the treatment of PCOS. One study that examined
metformin use in pregnancy found no significant adverse
outcomes (19). A pilot study done by Glueck et al. showed
that giving metformin in pregnancy might reduce the first-
trimester spontaneous abortion (SAB) rate (13). The patients
in this study continued to receive metformin for the first 12
weeks of pregnancy. The SAB rate was 7/20 (35%), which is
no lower than the usual SAB rate for PCOS patients. Met-
formin has been classified as a category B drug in pregnancy,
and there have been no teratogenic effects reported in animal
studies (20). Although some studies have shown a decreased
miscarriage rate during the first trimester (13), this study did
not. In addition, the use of this drug during pregnancy is not
considered standard of care and cannot be recommended in
pregnancy at this time.
In conclusion, this preliminary case series is the first to
demonstrate that use of metformin alone or with the addition
of CC (29 [60%] of 48) in patients with PCOS results in a
substantial number of pregnancies, with 20/48 (42%) of
those who ovulated achieving conception in less than 6
months of therapy. Gastrointestinal side effects limit its use.
Reproductive efficiency with metformin may be superior to
traditional therapy with CC but needs to be further tested in
comparative trials.
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