When and Why We Use Metformin to Help Manage Polycystic Ovary Syndrome (PCOS)

What is polycystic ovary syndrome?

Polycystic ovary syndrome (PCOS) is a common cause of infertility. Briefly, its diagnosis is based on presence of two of the following three criteria:

1. The appearance of 12 or more antral follicles (little black circles measuring 2 to 5 mm often around its periphery; looking like a necklace) in an ultrasound image of an ovary;
2. Irregular or absent menses, and
3. Symptoms of elevated male hormones in the system, such as acne, excess hair, or receding hairline.

There is a wide variation in the clinical presentation of patients with PCOS. Obesity is not a criterion for diagnosing PCOS, although many PCOS patients are obese. In obese patients with PCOS, weight loss remains the best treatment.

With weight loss, many obese PCOS patients will start getting periods, start ovulating and even conceive naturally.

What is insulin resistance (IR)?

Insulin resistance (IR) is a common hormonal imbalance in patients with PCOS. IR is generally defined as ‘‘a state (of a cell, tissue, or organism) in which a greater than normal amount of insulin is required to elicit a quantitatively normal response’’ and maintain glucose levels within the normal range.

Individuals with IR may be overtly diabetic or merely have insulin resistance detected by testing. Your physician will check your blood sugar, and sometimes, insulin levels to diagnose IR.

What is metformin?

Metformin (Glucophage) is an oral medication that is used to treat Type II diabetes. It is also used in PCOS patients to correct insulin resistance.

It comes in immediate release (500, 850 and 1,000 mg tablets) or extended release (Glucophage XR, 500, 750 and 1,000 mg tablets) form. Both are equally effective. The XR version is slowly absorbed and has fewer side effects (nausea, vomiting, diarrhea).

A rare side effect is lactic acidosis, which mainly occurs in patients with severe kidney and liver disease (your doctor will check you for these before starting metformin).

Metformin should be discontinued if you are going to need a CT scan or MRI that requires the use of an iodine-contrast agent. It can be restarted a couple of days after your scan. If you need to have an MRI or scan while being treated with metformin, make sure you tell your practitioner you are taking it.

How does metformin work?

The mechanism of action remains unclear, but it is known that metformin reduces absorption of glucose by the stomach and intestines, reduces glucose production by the liver, and increases insulin-stimulated glucose uptake.

Use of Metformin in PCOS Patients with Infertility

Does metformin by itself increase ovulation rate in women with PCOS?

Yes, it does. Many PCOS patients will start getting regular periods and start ovulating with metformin. Surprisingly, the pregnancy and live-birth rates are not better compared to placebo (dummy-pills)!

How does metformin compare with clomiphene citrate (CC, Clomid) or letrozole (Femara)?

Not well. The ovulation rate, pregnancy rate and live birth rate is lower with metformin alone when compared to CC or letrozole. These are two commonly used drugs used for ovulation induction in patients with PCOS. The pregnancy rate is best with letrozole, which is currently the drug of choice.

Can metformin be used in combination with CC or letrozole?

Yes, it can. Pretreatment with metformin for at least 3 months followed by the addition of another ovulation-inducing drug increases live-birth rate. Addition of metformin can also help in patients that are resistant to CC alone. Metformin alone does not increase the rate of multiple pregnancy.

Can metformin be used in pregnancy?

Yes, it can. It is a Category B medication (no risk in non-human studies). If metformin is stopped at the initiation of pregnancy, it does not affect the rate of miscarriage. In patients with IR, metformin will reduce the incidence of diabetes in pregnancy.

So, what does all this mean?

Here is a summary:

• Metformin alone should not be used as first-line therapy for ovulation induction in women with PCOS, since ovulation induction agents such as CC or letrozole are more effective. CC alone or letrozole alone are reasonable first-line agents for ovulation in women with PCOS.
• Combining metformin therapy with CC therapy may be beneficial in women who are resistant to CC alone.
• While metformin alone is not likely to increase live-birth rate in women seeking pregnancy in the short term, utilizing metformin in individualized cases of PCOS with the goal of improving ovulation rates over the long term may be of benefit.
• In the context of increased ovulation rate and overall improved IR on metformin, the subsequent addition of other ovulation-inducing agents may be beneficial in increasing pregnancy rates, although there is insufficient evidence of an increase in live-birth rates.

At InVia Fertility Specialists, our board certified reproductive endocrinologists are experts in treating patients with PCOS. Please call 847-884-8884 to schedule an appointment at one of our four convenient Chicagoland locations.