University Department of Obstetrics and Gynaecology, Royal Infirmary, Glasgow, G31 2ER, UK
1 To whom correspondence should be addressed: University Department of Obstetrics and Gynaecology, Level 3 Q.E. Building, Royal Infirmary, Glasgow, G31 2ER, UK. Email: gqta13{at}udcf.gla.ac.uk
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Abstract |
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Key words: license/metformin/polycystic ovary syndrome
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Background: PCOS and the use of metformin |
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The use of metformin for the management of type 2 diabetes is evidence based, but in recent years, treatment is becoming widespread in clinical practice for the treatment of PCOS-associated symptoms such as infertility, hirsutism and acne, and cycle regulation. Evidence supporting these practices is exciting, but generally based upon small patient numbers in very different environments. Particular concerns may be expressed over the use of metformin during pregnancy in women with PCOS, where little controlled evidence exists confirming its efficacy and safety (Norman et al., 2004). In the UK, metformin is recommended in the guidelines on fertility treatment published by the National Institute of Clinical Excellence (NICE, 2004), despite this being a non-licensed indication. In fact, metformin is not licensed for any of the PCOS indications. This situation means that there is no advice network for prescribing practice (starting therapy, doses, influence of other factors or treatments), and that there is an ad hoc treatment environment based on no guideline base and a shortage of contra-indication information.
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Duration of metformin treatment |
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Study design and recruitment |
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Discussion |
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Patients who receive metformin at the Glasgow Royal Infirmary are made aware that this drug is not licensed for the use in PCOS and as such remains a research tool, or they are prescribed on an individual patient basis after detailed discussion of the implications of off-label use. Although we believe metformin to be a safe drug even in prolonged use, as revealed by studies in patients with type 2 diabetes (UKPDS, 1998) or at increased risk for diabetes (Knowler et al., 2002
), we do not know of potential long-term sequelae affecting women with PCOS, who generally do not show evidence of glucose intolerance, and are generally younger than patients with glucose intolerance and type 2 diabetes. Furthermore, we cannot predict outcome and chronology of events once treatment is discontinued. This leaves all in a state of ignorance.
The widespread use of any drug in an unlicensed environment is not desirable. Whilst NICE guidelines support its use in infertility associated with clomiphene citrate, no protocol is available to assist patient selection or management issues. Furthermore, there are no guidelines for its use in other PCOS related symptoms, and metformin in PCOS is likely to remain in this situation for some time with many important issues unresolved. Few of the important questions have been answered to a satisfactory degree of certainty, and we suggest that much research remains to be carried out in this field.
To achieve a safer prescribing environment, we recommend that action be taken by the manufacturer of metformin (Merck Pharmaceuticals) to work with regulatory agencies (such as the MHRA) to extend prescribing indications for metformin, on a European base. This would aid national professional bodies to draw up guidelines for the use of metformin, and help establish the framework for future work to establish best practice. We propose that this issue be debated by practitioners within Europe to determine whether there is a consensus amongst gynaecologists and physicians, and whether and how progress can be made towards the licensing of metformin for treatment of women with PCOS.
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References |
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Glueck CJ, Goldenberg N, Wang P, Loftspring M and Sherman A (2004) Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Hum Reprod 19, 510521.
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Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA and Nathan DM (Diabetes Prevention Program Research Group) (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346, 393403.
Lord JM, Flight IH and Norman RJ (2003) Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 327, 951953.
NICE, (2004) National Callaborating Centre for Women's and Childrens Health (2004) RCOG Press (London) ISBN 1-900364-97-2 Fertility: Assessment and Treatment for People with Fertility Problems. Commissioned by the National Institute for Clinical Excellence.
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Submitted on April 16, 2004; resubmitted on May 26, 2004; accepted on August 26, 2004.
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