PCOS is a complex lifelong disorder characterized by both endocrine and metabolic abnormalities. PCOS is defined by 3 criteria: hyperandrogenism, menstrual irregularity/anovulation, and polycystic-appearing ovaries. This diagnostic criterion, known as the Rotterdam 2004 criteria, requires two of these three for the diagnosis of the condition. In addition, many women with PCOS exhibit insulin resistance, defined as a ration of fasting glucose to insulin of less than 4.5. It is estimated that > 75% of women with PCOS are insulin resistant when measured rigorously. Obese hyperandrogenic women have a greater propensity for insulin resistance as compared with lean PCOS women. There is strong evidence to support that lifestyle changes with low-carbohydrate diet, exercise, and weight loss reduce insulin resistance.
Clomiphene citrate (Clomid) was first introduced as an agent to treat anovulatory infertility and has traditionally been a standard treatment for ovulation induction in PCOS patients for several decades. Chemically, Clomid acts as a competitive estrogen receptor antagonist and is the initial treatment of choice for most anovulatory or oligo-ovulatory infertile women, and several multicenter randomized controlled trials have upheld the use of Clomid in PCOS women. Six-month live birth rates range from 20-40%, and the multiple pregnancy rate and risk of ovarian hyperstimulation only increase significantly when gonadotropins are used in combination with Clomid. However, meta-analysis has suggested that there may be an increase in pregnancy rates with the combination of Clomid and Metformin, particularly in obese women with PCOS, compared with Clomid alone.
Metformin is a biguanide that was initially developed to treat type II diabetes, but has also been used to treat PCOS, and is considered to be an insulin sensitizer in this setting. From the start, insulin sensitizers seemed to offer a new treatment option for patients with PCOS. It is known that among PCOS women who use metformin, glucose tolerance improves or stays steady over time. Metformin may also be associated with weight loss, but results are inconsistent. Metformin has no known human teratogenic risk or embryonic lethality in humans and appears safe in humans. It is a Class-B drug. The recommended dose is 500 mg three times per day or 750 mg two times per day with meals. The most common gastrointestinal side effects such as diarrhea, abdominal diarrhea and discomfort, nausea, and vomiting are dose-related. To reduce the side effects, treatment can be started with one dose of 500 mg with the largest meal and increased gradually at 7-10 day interval if the patient tolerates the medication. Metformin may rarely induce hepatic toxicity or be complicated by lactic acidosis and is contraindicated in patients with renal, hepatic, cardiovascular problems, and sepsis.
From its initial description for management of ovulation induction in PCOS, Metformin has rapidly risen to be one of the most requested medications for management of the condition. Despite the large number of analyses completed, there are few large scale or randomized placebo-controlled trials (RTCs) using Metformin for PCOS. However a review of the largest trials of Metformin therapy in PCOS suggests that it has a limited role in reproduction. The single largest RTC of metformin in PCOS failed to show an improvement in fertility as compared with Clomid. In addition, there is no solid evidence that Metformin use early in pregnancy prevents pregnancy loss. Consequently there remains significant controversy without conclusive data on its effectiveness in PCOS.
However, a recent Cochrane review, published in 2015, analyzed all RCTs that compared Metformin treatment with placebo, or with no treatment in PCOS women undergoing IVF. A total of 9 RCTs were included. When Metformin was compared with placebo or no treatment, clinical pregnancy rates were significantly higher in the Metformin group. In addition, the risk of OHSS was significantly lower in the metformin group. However, no conclusive evidence of a benefit in live birth rates was seen.
Overall, PCOS remains the most common endocrinopathy in women of reproductive age. As such, lifestyle modifications are the best approach to modifying risks for diabetes and metformin may be considered as well. Improved insulin sensitivity with Metformin is associated with a decrease in circulating androgen levels, improved ovulation, and improved glucose tolerance. Reduction in body weight has been associated with improved pregnancy rates, and adding Metformin to Clomid likely increases pregnancy rates in obese women with PCOS, but Clomid remains the first line treatment for ovulation induction.