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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: https://doi.org/10.1136/bmj.38867.631551.55 (Published 22 June 2006) Cite this as: BMJ 2006;332:1485

Good Work, but not the end of the PCOS/Metformin Saga.

Dear Editor

Etelka Moll and colleagues should be congratulated for their hard
work in organising the randomised controlled trial comparing first-line
clomiphene treatment with combined clomiphene and metformin in infertile
women with Polycystic Ovary Syndrome (PCOS) (1). The article however does
not really address the rationale for metformin use in women with PCOS.
First-line metformin alone or combined with clomiphene in PCOS
theoretically avoids or reduces the risks of multiple pregancy (2),
ovarian hyperstimulation (3) and ovarian tumours (4), associated with
clomiphene use, (although the links between clomiphene use and ovarian
tumours are debatable (5)).

In clinical practice, similar live-birth rates (key outcome of
interest to infertile women with PCOS) with meformin use compared to
clomiphene, with a reduced exposure to a potential risk factor for ovarian
tumours, multiple pregancy and ovarian hyperstimulation would justify the
use of metformin. Moll et al’s study was not powered to measure these
variables.

With regard to the study design, it was not clear why the authors
expected combining metformin to clomiphene to lead to a 15% increase in
ovulation rates to 90% from a baseline of 75% with clomiphene alone. A
statistical test of equivalence using live birth rates as the primary
outcome measure would have been the preferable statistical test to use in
the study. Another issue requiring clarification is how the authors could
have used criteria published in 2003 in the diagnosis of PCOS for their
study, which started recruiting on 2001.

The study is however a useful addition to the ongoing debate on the
role of Metformin use in women with PCOS

Kind regards

Mr William Atiomo
Associate Professor/Consultant Gynaecologist
School of Human Development, University of Nottingham
Nottingham University Hospitals, Queens Medical Centre Campus, Nottingham
NG7 2UH

1) Etelka Moll, Patrick M M Bossuyt, Johanna C Korevaar, Cornelis B
Lambalk, Fulco van der Veen. 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;332:1485

2) Kousta E, White DM, Franks S. Modern use of clomiphene citrate in
induction of ovulation. Hum Reprod Update. 1997;3(4):359-65.

3) Balen A. Ovulation induction for polycystic ovary syndrome. Hum
Fertil (Camb). 2000;3(2):106-111.

4) Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors
in a cohort of infertile women. N Engl J Med. 1994 22;331(12):771-6.

5) Rossing MA, Tang MT, Flagg EW, Weiss LK, Wicklund KG. A case-
control study of ovarian cancer in relation to infertility and the use of
ovulation-inducing drugs.
Am J Epidemiol. 2004 ;160(11):1070-8

Competing interests:
None declared

Competing interests: No competing interests

23 June 2006
William U Atiomo
Associate Professor/Consultant Gynaecologist
School of Human Development, University of Nottingham, NG7 2UH