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Middle East Fertility Society Journal
Middle East Fertility Society
ISSN: 1110-5690
Vol. 13, Num. 1, 2008, pp. 22-27
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Middle East Fertility Society Journal, Vol.
13, No. 1, 2008, pp. 22-27
DEBATE
The
current role of metformin in the management of infertility
Dr. Bassam Elhelw, FRCOG, MFFP
Consultant in Obstetrics
& Gynecology, Middle East Fertility Center, Cairo, Egypt
Code Number: mf08006
The
polycystic ovary syndrome (PCOS) is characterized by chronic anovulation and
hyperandrogenism and affects approximately 5-10% of women of reproductive age (1-3).
PCOS is the most prevalent endocrinopathy in women and by far the most common
cause of anovulatory infertility (4).
Insulin
resistance with compensatory hyperinsulinaemia is a prominent feature of the
syndrome and appears to have a pathophysiologic role in the hyperandrogenism of
the disorder for both lean and obese women with PCOS (5). Hyperinsulinaemia
results in increased ovarian androgen biosynthesis in vivo and in vitro (6, 7)
and decreased sex hormone-binding globulin (SHBG) synthesis (8). Collectively,
these two actions of insulin increase circulating levels of free testosterone.
Further, the increase in intraovarian androgens most likely contributes to
anovulation. In this manner, hyperinsulinemia may play a causal role in the two
key features of PCOS: androgen excess and chronic oligo- or anovulation.
The
association of insulin resistance contributing to anovulation in PCOS has led
to the promising therapy of insulin-sensitizing drugs to restore ovulation and
enhance pregnancy. Of the insulin-sensitizing drugs, metformin has been the one
studied most widely and has the most reassuring safety profile (9).
Troglitazone (Thiazolidinedione) was withdrawn by the US Food and Drug
Administration (FDA) in 1999 due to reports of liver toxicity and is no longer
commercially available.
Metformin
(biguanide) enhances insulin sensitivity in both the liver, where it inhibits
hepatic glucose production, and the peripheral tissue, where it increases
glucose uptake and utilization into muscle tissue. By increasing insulin
sensitivity, metformin reduces insulin resistance, insulin secretion and
hyperinsulinaemia (10).
Metformin as first line treatment in PCOS
The first randomized, placebo-controlled
trial evaluating the use of metformin for ovulation induction in PCOS was
conducted by Nestler and colleagues in 1998 (11). They randomized 61 obese
women with PCOS to either metformin 500 mg or placebo three times daily for 35
days. If spontaneous ovulation did not occur, subjects were entered into the
second phase of the study where they were given clomiphene 50 mg daily for 5
days while continuing to take metformin or placebo for another 30 days. During
the first phase of the study, where metformin was compared with placebo, 12 of
the 35 women (34%) on metformin ovulated spontaneously compared with only one of
the 26 women (4%) in the placebo group (p<0.001).In the second phase of the
study, 19 of 21 women (90%) on the combination of metformin and clomiphene
ovulated compared with only two of 25 women (8%) who received placebo and
clomiphene (p<0.001). Notably, the rate of ovulation was higher in the women
who received metformin for 7 weeks than in those in the placebo group who
underwent a single cycle of induction with clomiphene at the 50 mg dose (34%
vs. 8%, respectively). Since then, several other studies have corroborated the
above findings.
In 2003,
the Cochrane Library published a systematic review of the use of metformin in PCOS
(12). It included randomized controlled trials that compared insulin
sensitizing drugs with placebo, no treatment, or an ovulation-induction agent
such as clomiphene or gonadotropin. A total of 13 trials were included for
analysis (11, 13-24). In almost all studies, metformin showed a favorable
effect on ovulation rates. Metformin treatment resulted in spontaneous
ovulation in 46% of women, compared with a 24% ovulation rate with placebo.
Clinical pregnancy rate also increased by 2.8-fold with metformin treatment,
but this was not statistically significant, probably because of the small
number of subjects in these studies and the fact that pregnancy was not a
defined outcome measure. One should not neglect that the majority of these
studies were short-term in nature and therefore were biased against showing a
beneficial effect with metformin, since recent studies suggest that it may take
3-6 months for metformin to exert an optimal improvement in ovulation in PCOS.
Recently, two
double-blinded randomized controlled trials in which metformin was directly
compared with CC as first-line treatment in 509 infertile women with PCOS were
published (25, 26). The pooled clinical pregnancy rate after six months of
treatment was significantly lower after metformin (27).
Metformin as co-treatment in combination with CC
Seven
randomized controlled trials compared CC plus metformin with CC in 985
infertile women with PCOS (14, 28-33). There was a significantly higher
clinical pregnancy rate in the metformin plus CC group. However, there was
significant heterogeneity in treatment effect across the trials.
Metformin in CC-resistant women
A randomized
clinical trial in which metformin was compared with placebo in 18 infertile
women with CC-resistant PCOS was reported by Ng et al. in 2001. In this small
number of women there was no evidence of a difference in clinical pregnancy or
live birth rate (34).
Five
randomized controlled trials in which CC plus metformin was compared with CC
alone in 210 infertile women with CC-resistant PCOS (35-39).
Collectively,
these studies showed that metformin plus CC led to a significantly higher
clinical pregnancy rate than CC alone. Live birth rate was also in favor of
metformin plus CC compared with the CC group.
Metformin versus laparoscopic ovarian drilling
Palomba et al. 2004 reported a randomized trial in which metformin
treatment was compared with laparoscopic ovarian drilling (LOD). There was no
difference in clinical pregnancy rate. Live birth rate however was higher in
the metformin group (40).
In 2006,
Kocak and Ustun published a randomized trial including 42 PCOS patients in
which they compared LOD followed by metformin or LOD alone. There were no
significant differences in clinical pregnancy rate or live birth rate between
both groups (41).
Metformin and gonadotrophins
In 2003
George et al., published a randomized clinical trial where they compared
metformin plus CC with gonadotrophins in 60 CC-resistant women. There was no
difference in clinical pregnancy rate between the two groups. They did not
report on live birthrate, multiple pregnancy rate or OHSS (42).
In four randomized controlled trials, FSH plus
metformin was compared with FSH alone in 154 infertile women with PCOS (24, 25,
43, 44). The clinical pregnancy rate was significantly higher in the FSH plus
metformin group compared with FSH only group. However, a difference in live
birth rate could not be proven. Although metformin led to less multiple
pregnancies, there was no evidence of a difference in OHSS.
Metformin use in IVF
Four trials
studied the effect of metformin during ovarian hyperstimulation in IVF/ICSI in
283 women with PCOS (45-48).
In the first study, reasons for IVF treatment were not specified,
patients number was (8 versus 9), the authors concluded that co-administration
of metformin is therefore likely to increase the number of oocytes collected
after ovarian stimulation in insulin-resistant women with PCOS but is unlikely
to reduce the requirement for FSH. (45).
In the
second study by Kjotrod et al. (n=37versus36), women received IVF or ICSI
because of other fertility problems like tubal pathology, endometriosis or male
subfertility. The results showed that pre-treatment with metformin prior to
conventional IVF/ICSI in women with PCOS does not improve stimulation or
clinical outcome (46).
In the third study, women with PCOS in whom conventional therapy had not
lead to pregnancy, were included (n = 53 versus 55), they concluded that
Metformin does not lead to any improvement in IVF/ICSI outcomes among patients
with PCOS (47).
In the
fourth study, reasons for IVF were failure of conventional therapy and other
fertility problems, (n = 51 versus 47); 4 patients entered twice (48). the
authors concluded that short-term co-treatment with metformin for patients with
PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation
but significantly improves the pregnancy outcome and reduces the risk of OHSS.
Combining
the results of these trials did not show a significant difference between the
women treated with metformin or placebo Live birth rate was reported in two
studies (46, 48). There was no evidence of a significant difference between the
two groups. Pooling the data of the two trials that reported multiple pregnancy
gave no evidence of a significant difference between the two groups on multiple
pregnancy rate (46, 48). OHSS was reported in all studies. When combining the
results, there was a significant reduced risk in favor of metformin (27).
There is no evidence for better live birth rates when metformin is used
during ovarian hyperstimulation in IVF. This is based on two studies with a
limited number of patients and with heterogenous populations of women, as in
one study a mix of women after failed ovulation induction and with other
indications was included, while in the other studies only women with other
fertility problems were included. In IVF addition of metformin may however,
reduce the risk of OHSS.
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