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Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial

BMJ 2006; 332 doi: (Published 22 June 2006) Cite this as: BMJ 2006;332:1485

Not All Faith In Metformin Lost

EDITOR-It is with understandable relief (or convenience) that meta-
analysis results published in Cochrane reviews are accepted as the final
word on the subject discussed. The study by Moll et al published in the
BMJ of 24 June1 serves as an awakening to the possibility that such
publications2,3 supporting combined metformin and clomifene treatment of
anovulatory infertility due to polycystic ovaries over clomifene
monotherapy, might not be the final step in the quest for the holy grail
of conclusive evidence based medicine, as far as ovulation induction is

Before we loose faith in metformin co-treatment however it would be
noteworthy to examine the metformin regime used in this trial. Moll et al
used metformin in doses of up to 2000mgs daily in a regime stepped up over
seven days. This resulted in 1 in 6 women in the metformin group
discontinuing treatment due to side effects. Many clinicians begin
treatment with 500 mg taken with a meal, to reduce gastrointestinal side
effects. If tolerated, the dose can be increased to 500 mg at lunch and
dinner, and then to 500 mg at breakfast, lunch, and dinner. One to two
weeks elapse between increases in dose. 3 Authors that used this regime
report lower drop out rates than Moll et al. There is a possibility
therefore that under a more conventional metformin dosage regime more
women would have continued with the combination of metformin and
clomifene, and more ovulations would have been ascertained in this group.

Moll et al are fortunate to serve a population of women with
polycystic ovaries with an average body mass index of 28. This was
significantly higher in many previous studies.3 Judging by our own
experience as well, we find the authors’ assertion that their study
participants are more representative of women with polycystic ovary
syndrome in Europe rather surprising. In any case they do not offer any
evidence to support this statement. We agree however with their belief
that ‘lean women are less likely to benefit from insulin sensitisers
because they are less insulin resistant’. The possibility therefore exists
that their study did not identify a benefit of combined metformin and
clomifene treatment because they did not study the population which would
most benefit from this combination.

There is a deviation from routine practice also in that Moll et al.
did not test for tubal patency before induction of ovulation. Although in
this research study ovulation was the primary end point it would be
interesting to know how this policy fits into the authors’ clinical
practice of trying to help as many infertile couples as possible to

As it would not be right to accept the results of the previous meta-
analysis as the end of the argument, it would be equally incorrect to
disregard all the evidence supporting metformin plus clomifene treatment
published before the findings of Moll et al. based on the trial alone.

Reference List

(1) Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van d, V. Effect of
clomifene citrate plus metformin and clomifene citrate plus placebo on
induction of ovulation in women with newly diagnosed polycystic ovary
syndrome: randomised double blind clinical trial. BMJ 2006; 332(7556):1485

(2) Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary
syndrome: systematic review and meta-analysis. BMJ 2003; 327(7421):951-

(3) Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs
(metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol)
for polycystic ovary syndrome. Cochrane Database Syst Rev

Competing interests:
None declared

Competing interests: No competing interests

30 June 2006
Spyros Papaioannou
Consultant Obstetrician and Gynaecologist
Elizabeth Payne, Olumide Ofinran and John Tzafettas
Heartlands Hospital, Bordsley Green East, Birmingham B9 5SS. UK.