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Metformin (Glucophage) treatment of Clomid resistant polycystic ovarian syndrome (PCOS) and ovulation problems causing infertility
Advanced Fertility Center of Chicago
PCOS and Infertility Specialist Doctors
Gurnee & Crystal Lake, Illinois
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Background on PCOS and Ovulation Problems
Polycystic ovarian syndrome is a common cause of anovulation and infertility in women. Women with this syndrome do not ovulate (release eggs) regularly and therefore have irregular menstrual cycles. Their ovaries contain multiple small cystic structures, or antral follicles, usually about 2-9 mm in diameter. This gives the ovaries a characteristic "polycystic" (many cysts) appearance on ultrasound.
There are several possible ways to attempt ovulation induction in women with polycystic ovaries. The least complicated method is the use of Clomid tablets, also called Serophene, or clomiphene citrate. Another oral medication, letrozole, which is an aromatase inhibitor can also be tried - and is sometimes effective after Clomid has failed.
Many will be able to get pregnant using clomiphene to induce ovulation. For women that do not ovulate with clomiphene, the "traditional" next step has been to use injectable gonadotropins. About 90% of women that do not ovulate with clomiphene will ovulate with injectable medication and the majority will get pregnant if they do enough treatment cycles.
However, the injectable medications are expensive and there are risks of ovarian hyperstimulation syndrome and high order multiple pregnancy. The daily injections and trips to the office for monitoring are also inconvenient.
Use of Metformin for PCOS
A relatively new method of treating ovulation problems in women with polycystic ovarian syndrome is to use an oral medication called metformin (brand name is Glucophage) with or without clomiphene citrate.
Metformin has been used in the past as an oral agent to help control diabetes. Recently, it has been found to facilitate ovulation in some women with PCOS. Some women who do not ovulate after taking metformin will be able to ovulate when taking metformin in combination with clomiphene. Therefore using metformin would be a benefit to some women with polycystic ovarian syndrome by allowing them to potentially avoid the injectable FSH medications.
We currently give metformin treatment to women that are appropriate candidates. Unfortunately, not all women will respond to metformin and clomiphene and therefore some will still need to take the injectable FSH medications, or have in vitro fertilization in order to have a baby.
We will initially use metformin alone without clomiphene and do weekly blood tests to look for spontaneous ovulation. If the metformin does not result in ovulation we will add clomiphene to the regimen and again try to document ovulation by doing some blood tests. If the combination of metformin and clomiphene does not result in ovulation then we will terminate the treatment and the patient will need to take injectable FSH in order to ovulate and achieve pregnancy.
In up to 25% of women metformin causes side effects which may include abdominal discomfort, cramping, diarrhea and nausea. The side effects may be severe enough to make the woman want to stop the metformin treatment. We are not aware of any serious complications resulting from metformin treatment.
Another oral medication used for diabetes called Troglitazone has been associated with liver failure and death in rare cases. This has been publicized on television shows, in newspapers, etc. These problems have not been associated with the use of metformin.
How we are currently using metformin
We use metformin in many women experiencing fertility problems. Mainly it is used in women that do not ovulate with polycystic ovarian syndrome, PCOS. However, we also use it in women going through in vitro fertilization that have high antral follicle counts - in other words if their ovaries are polycystic by ultrasound evaluation.
Lab tests that are sometimes done before starting metformin:
Sample Metformin Protocol
Baseline ultrasound prior to starting metformin – follicles and lining. If lining > 5 mm – induce withdrawal bleed.
Patients need to be counseled regarding possibility of ovulation occurring and need for regular intercourse (about every 2-3 days) in order to maximize chances for pregnancy.
The most effective dose of Metformin is generally 500mg 3 times daily. We usually start metformin at one 500mg tablet per day for 1 week, then 1 tablet twice a day for a week, then start the full dose of 1 tablet 3 times a day. By gradually increasing the dose, there is a greatly reduced chance for the unpleasant side effects.
After 4 weeks of metformin, check P4 (progesterone) weekly X 4. Check a fasting blood sugar at least once.
If P4 indicates ovulation, check HCG and P4 if no menses by 12 days after elevated P4. If not pregnant, check weekly P4 levels again beginning about day 20-25 of next cycle.
If no ovulation (P4 > 7) after 4 weeks, offer the patient a choice between continued weekly P4 checks and metformin/clomiphene combined therapy. If no ovulation (P4 > 7) after 8 weeks of metformin, begin Clomid treatment or stop metformin.
Patients are to keep menstrual calendars with all bleeding days and days of intercourse recorded.
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