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Metformin and Polycystic Ovary Syndrome February 2004 Welcome What is the logic behind the use of Metformin for patients with polycystic ovary syndrome and what is the evidence for its benefit? This case discusses these issues. Initial Presentation Maria is a 23 year old woman who has been diagnosed with polycystic ovary syndrome. She has typical menstrual irregularity, facial hirsutism requiring plucking every 3 days and a BMI of 28. She has a family history of type 2 diabetes in a sister and her mother. Before she commenced a combined oral contraceptive, she had the following biochemistry:
Since being on the pill her periods have been regular and her hirsutism has decreased, but she has had trouble losing weight. She has been accessing information from the Internet and is asking about the use of metformin. Consultant Comment The clinical and biochemical picture are diagnostic of the polycystic ovary syndrome (PCOS). This condition is normally associated with insulin resistance. This may rarely be due to a mutation in the insulin receptor, but is more commonly caused by abnormal phosphorylation of the insulin receptor, which impairs its function. In addition, Maria is overweight and has a strong family history of diabetes, both of which are highly suggestive of insulin resistance. Other clinical markers include a waist:hip ratio greater than 0.85, a history of gestational diabetes or a baby weighing more than 4.5 kg and acanthosis nigricans (a black or dark yellow skin pigmentation in the axillae or on the back of the neck). Insulin resistance results in increased insulin secretion (as long as the beta cell is capable of increasing its function). High circulating insulin levels are an important component in maintaining the PCOS. They are responsible for increased activity of 17 hydroxylase (an enzyme involved in testosterone production) and for increasing the number and amplitude of LH pulses (which stimulate testosterone production from the ovary). High circulating levels of insulin are also associated with an increased risk of gestational diabetes, type 2 diabetes and difficulty losing weight. There is evidence that high insulin levels may also be a cardiovascular risk factor. Hypertension, impaired endothelial function and an unfavourable lipid profile may all be caused by hyperinsulinaemia. Metformin has long been used to control blood sugar levels in type 2 diabetes. It has multiple actions, but essentially, it acts to improve the effectiveness of endogenous insulin (ie it reduces insulin resistance). The target dose for metformin is 1.5 to 2.55 gm/day. It is important to begin with a small dose (½ tablet) taken with the evening meal and slowly increase this by ½ tablet each week to the target dose. Side effects of metformin are diarrhoea, flatulence, nausea, indigestion and abdominal discomfort. Rarely, the drug causes fatal lactic acidosis, but this has mostly been reported in elderly patients, those with renal failure, or predisposing conditions (ie liver disease, poor organ perfusion). Maria is also taking the OCP which might contribute to her insulin resistance. Metformin is likely to be of benefit to her. Maria begins metformin 425 mg daily and is able to increase her dose over one month to 850 mg bd. At the same time she institutes an increase in exercise and finds that her weight decreases by 5 kg over the next 6 months. She and Alberto would like to start a family. Consultant Comment A number of studies have shown that metformin assists women with PCOS to lose weight and particularly if diet, exercise and metformin are combined. Diet (7% weight loss), exercise (150 minutes/week) and metformin are effective in reducing insulin levels, and decreasing the short term (2.8 years) risk of diabetes (1). Metformin increases the ovulation rate in women with PCOS when given alone or combined with clomiphene. In women with PCOS being treated with clomiphene to induce ovulation, the number needed to treat (NNT) with metformin to improve ovulation over placebo is 2 (Table 1). Metformin is not approved for use in pregnancy, being classified as category C by the TGA. However, small trials have suggested that metformin may reduce early pregnancy loss in women with PCOS and may reduce the risk of development of gestational diabetes (for review see 2). Maria ceases the OCP and continues metformin. Generally, Clomiphene is a more reliable therapeutic agent for ovulation induction but given her current treatment, it is reasonable to assess the effect of metformin alone in the first instance. Ovulation is established by subsequent blood tests and she becomes pregnant in her third cycle. Metformin was ceased at the time the pregnancy was diagnosed.
References 1. Diabetes Prevention Program Research Group 2. Barbieri, R. Metformin for the treatment of polycystic ovary syndrome.  PRINT THIS PAGE
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