A N T I B A C T E R I A L U S E B Y R U R A L A M I S H C H I L D R E Authors:
Pregnancy and Other Clinical Outcomes Using
Paul D. Silva, MD†Fertility and ReproductiveEndocrinology Center Department of Obstetrics and
Induction Agents: Results of a Prospectively
Katie M. U. Larson Fertility and ReproductiveA prospectively designed case series using metformin in women with Polycystic OvarySyndrome (PCOS) who had failed standard ovulation induction agents is presented.Metformin, which has been used to treat diabetes mellitus, is thought to improve ovulatoryfunction in PCOS by lowering insulin levels and/or inducing weight loss. Twenty-twoclomiphene-resistant, clinically obese women with PCOS were given a 3-month trial ofmetformin to bring about pregnancy. Two normal delivered pregnancies and 2 spontaneousabortions occurred. Fourteen women had baseline elevated total cholesterol (64 percent) while13 had elevated LDL (59 percent), and 6 had elevated triglycerides (27 percent). Thesefindings, similar to previous studies, indicate a strong correlation between PCOS and elevatedlipid levels. With two-thirds of the study population displaying abnormal lipid profiles, itseems that lipid screening is worthwhile in women with PCOS.Supported in part by a grant from Gundersen Lutheran MedicalFoundation
metformin is being increasingly used in North
ovulatory and anovulatory cycles. The mean number of cycles
M American infertility clinics, because of its positive failed was 5.5 (range 3-18). Twenty of the women had failed at
effect on the metabolic changes of polycystic ovary syndrome
least 150 mg of clomiphene (91 percent). Nine of the women
(PCOS). Metformin alone has been shown to induce ovulation
had failed gonadotropin cycles as well (41 percent). Three others
in 30 percent of clomiphene-resistant PCOS patients.1
had failed a short midcycle gonadotropin boost with at least one
However, a literature review shows few pregnancies, and,
cycle of clomiphene citrate (14 percent). One woman had failed
therefore, there is insufficient data to counsel PCOS patients as
gamete intrafallopian transfer (GIFT), and 1 had failed in vitro
to pregnancy prognosis with metformin. Accordingly, we report
our results with metformin in PCOS patients.
Baseline Tests MATERIALS AND METHODS
All of the women’s TSH levels were screened to ascertain
Patient Characteristics and Inclusion Criteria
that their anovulation might not be related to thyroid disease.
Twenty-two women presented with infertility and a
We did not screen for 21-hydroxylase deficiency because this is
diagnosis of PCOS. The criteria used to diagnose PCOS were
rare in our population. If the patients exhibited glactorrhea, we
anovulation with signs of androgen excess or anovulation with
tested their prolactin levels to exclude hyperprolactinemia as a
polycystic ovarian morphology on ultrasound. The mean age at
possible cause for their anovulatory infertility.
the beginning of treatment was 29 years (range 23-35). All of
Hysterosalpingograms were done to establish that the women
the women were overweight (BMI>25), and a majority of the
had open fallopian tubes, if necessary. They are done in our
women were obese (BMI> 27) (82 percent). The mean BMI for
program if there is a history of pelvic infection or prior to
the group was 36 kg/m2 (range, 25-52). Infertility was defined
gonadotropin therapy. Semen analyses were performed on the
as the inability to conceive without medical intervention for one
partners. One of the 22 men had less than 20 million sperm per
year. The average length of infertility was 5 years (range, 1-17).
milliliter, 3 had less than 40 percent sperm motility, and one
While 12 of the women had been pregnant previously, only 6
man declined a semen analysis. Serum creatinine was evaluated
to assure normal renal function; fasting insulin, fasting plasma
The subjects had all failed to have a viable pregnancy with at
glucose, and fasting lipid profiles were also performed.
least 3 cycles of clomiphene citrate. This included both
Gundersen Lutheran Medical Journal • Volume 2, Number 1, March 2003
M E T F O R M I N I N W O M E N W I T H P O LY C Y S T I C O V A R Y S Y N D R O M E Dosing of Metformin
shortly after clinical pregnancy had been established by
The women were started at 500 mg of metformin with
sonogram. One pregnancy that terminated with spontaneous
breakfast; increasing one tablet every week until they were
abortion occurred at 2 months of treatment. The other occurred
taking two tablets with breakfast and with supper, giving a
at 4 months of treatment. There were 2 normal delivered
maximum dose of 2000mg. If side effects occurred, the dose was
pregnancies. One conceived at 2 months of treatment. The
reduced to the highest level at which it was tolerated. The
patients were encouraged to use metformin for 3 months beforechanging therapy, unless they had intolerable side effects. For
purposes of the study, the length of metformin therapy was from
Ten of the patients reported side effects. The most common
the day that the first dose was taken. The patients were
was diarrhea, reported by 7 women. Four subjects experienced
encouraged to use basal body temperature charting.
diarrhea alone, 2 of whom stopped metformin. These 2 patients
Unfortunately, these were not reliably performed; therefore, a
had intolerable diarrhea even at the 500mg per day dose. The
rate of ovulation and cycle fecundity could not be calculated. A
other three experienced diarrhea plus cramps, nausea, or
pregnancy test was done as soon as pregnancy was suspected.
dizziness. One woman who experienced dizziness alone at the 1
Metformin was stopped during pregnancy. Clinical pregnancy
gram per day dose stopped metformin. Another experienced
was defined as an intrauterine gestational sac on sonogram.
clamminess, hot flashes, and faintness, and 1 experiencedvaginal itching and burning. Therefore, a total of 3 subjects
stopped metformin due to intolerable side effects. The sideeffects all resolved upon discontinuation of the drug. No
medical intervention besides stopping or reducing treatment
Fourteen women had an elevated total cholesterol (64
was necessary. The side effects of the patients who continued in
percent). Thirteen had elevated LDL (59 percent). Six had
the study were ameliorated by dose alteration.
elevated triglycerides (27 percent). Six of the women werereferred to Internal Medicine or dietary therapy for
management. Two were already receiving treatment.
Metformin has been well studied in the management of the
metabolic effects of PCOS except for fertility. Several groups
One woman had a fasting glucose level above 115 mg/dl
have studied the drug’s effect on insulin levels and glucose
(121 mg/dl).2 She was already receiving dietary therapy for her
tolerance in women with PCOS, as well as its effect on
obesity. There were 4 women whose fasting blood sugar levels
androgen levels, ovulatory function, and menstrual regularity.1,3-7
were in the range of 105-115. They were also obese and were all
Some of the studies reported favorable effects in every area. The
referred to the nutrition department for dietary care. There were
investigators who have assessed metformin’s effects on ovulation
7 women with elevated fasting insulin levels above 14 µIU/mL
and menstrual regulation have all reported positive results.1,6,7 It
(32 percent). The mean values for glucose, insulin and lipids are
is interesting that several groups that were studying metformin’s
effect on the metabolic or menstrual changes of PCOS, but notits effects on fertility, have reported pregnancies in theirsubjects.3-7 Ehrmann et al3, Diamanti-Kandarakis et al4, andMorin-Paupunen et al6 reported 1 pregnancy in 20 women, 2
pregnancies in 16 and 1 pregnancy in 31, respectively. Parameter Mean Value ± S.D. (range) Normal Values
However, these studies did not list the clinical outcomes for thepregnancies, nor the number of their patients who were
attempting pregnancy. In 2 studies by Velazquez et al5,7, more
detail is given on pregnancy outcome. The first study had 3
pregnancies in 29 women with 1 spontaneous abortion and 2
ongoing pregnancies. The second study had 4 pregnancies in 21women, which were all carried to term. None of these studies
reported whether any of their subjects had other infertility
evaluations or treatment, nor how many of the subjects wereactively seeking pregnancy. Because of this lack of information,it is difficult to determine whether metformin may have a
positive effect on fecundity in PCOS women who are actively
Four of the women became pregnant on metformin alone.
seeking pregnancy. Our study attempted to address this
They had fasting glucose levels of 104, 98, 99, and 91mg/dL.
question in at least 1 subgroup of PCOS women by assessing
Their fasting insulin levels were: 7.2, 11.0, 6.8, and 7.9
fecundity in PCOS women on metformin who had failed
µIU/mL. These values were within the normal range. Two had
clomiphene citrate with or without gonadotropins.
spontaneous abortions early in the first trimester of pregnancy
Our results seem to indicate that a 3-month trial of
metformin results in a low term pregnancy rate in PCOS
Gundersen Lutheran Medical Journal • Volume 2, Number 1, March 2003
A N T I B A C T E R I A L U S E B Y R U R A L A M I S H C H I L D R E
women who have failed standard ovulation induction. Our rate
of 2 normal delivered pregnancies in 21 women and 63.5
1. Nestler JE, Jacubowicz DJ, Evans WS, Pasquali R. Effects of metformin on
women/months of treatment is not highly encouraging.
spontaneous and clomiphene-induced ovulation in the polycystic ovary
However, to better understand how metformin may aid
syndrome. N Engl J Med 1998;338(26): 1876-80.
fecundity, larger studies with longer periods of use need to be
2. Report of the expert committee on the diagnosis and classification of diabetes
done, and more subgroups should be studied. It may be that less
mellitus. Diabetes Care 1997; 20:1183-97.
obese PCOS patients than ours (mean BMI 36 kg/m2) might
3. Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky
respond better to metformin. A randomized study with
KS. Effects of metformin on insulin secretion, insulin action, and ovarian
clomiphene citrate may be useful to test whether metformin
steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol
would be advantageous in clomiphene-naive PCOS women.
Metformin is thought to improve ovulatory function in
4. Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects
PCOS by lowering insulin levels and/or inducing weight loss.5-7
of metformin on insulin resistance and hyperandrogenism in polycystic ovary
However, only 32 percent of the women in our study had
syndrome. Eur J Endocrinol 1998;138:269-74.
elevated fasting insulin levels and only 23 percent had fasting
5. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy
glucose levels above 105. In addition, these measures were
in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance,
normal in the 4 patients who did conceive in our study. Perhaps
hyperandrogenemia, and systolic blood pressure, while facilitating normal menses
more dynamic measures of glucose or insulin may be necessary
and pregnancy. Metabolism1994;43:647-54.
to better select patients who may benefit from metformin.
6. Morin-Paupunen LC, Koivunen RM, Ruokonen A, Martikainen HK.
Our results show a high rate of lipid abnormalities in our
Metformin therapy improves the menstrual pattern with minimal endocrine and
population of women with PCOS. This data, similarly to
metabolic effects in women with polycystic ovary syndrome. Fertil Steril
previous studies, seems to indicate a strong correlation between
PCOS and elevated lipid levels.8 With two-thirds of the study
7. Velazquez EM, Acosta A, Mendoza SG. Menstrual cyclicity after metformin
population displaying abnormal lipid profiles, it seems that lipid
therapy in polycystic ovary syndrome. Obstet Gynecol 1997;90(3):392-5.
screening is worthwhile in women with PCOS.
8. Meirow D, Raz I, Yosepowitch O, Brzezinski A, Rosler A, Schenken JG, Berry
In conclusion, it seems that a 3-month trial of metformin at
EM. Dyslipidemia in polycystic ovarian syndrome: different groups, different
2g/day may offer limited success for women with PCOS who
aetologies? Human Reprod 1996;11(9):1848-53.
wish to conceive but have already failed clomiphene citrate. However, further studies will need to be reported before firm
† Address for correspondence:
conclusions may be made. At this point, screening for lipid
abnormalities in this subgroup of women with PCOS seems
Fertility and Reproductive Endocrinology Center,
Department of Obstetrics and Gynecology Gundersen Lutheran
Since acceptance of this article, a randomized study of
clomiphene citrate with metformin versus clomiphene citrate
with placebo in clomiphene-resistant women with PCOS has
been published (Kocak M et al. Fertil Steril 2002:77:101-6).
This study showed improved ovulatory and total pregnancyrates with the addition of metformin although the ultrasound-confirmed clinical pregnancy rate was not statistically improved(11 percent).
Gundersen Lutheran Medical Journal • Volume 2, Number 1, March 2003
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