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  » Infertility  »  Metformin treatment of clomiphene resistant polycystic ovarian syndrome PCO and anovulation causing infertility

Metformin treatment of clomiphene resistant polycystic ovarian syndrome PCO and anovulation causing infertility


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 strucccctures, usually about 4-9 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 easiest and least complicated method is the use of clomiphene citrate tablets (Clomid, Serophene).

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 this medication and the majority will get pregnant as well. However, these medications are expensive and there are risks of ovarian hyperstimulation and multiple pregnancy involved. The daily injections and trips to the office for monitoring are also somewhat inconvenient for most women.

A relatively new method of inducing ovulation in women with polycystic ovarian syndrome is to use an oral medication called metformin 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 (if they prefer this approach).

We are currently offering 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 in order to
vulate and achieve pregnancy.

Use of metformin requires that we do some blood testing prior to starting the women on the medication. These tests will include fasting blood sugar, kidney function tests, liver function tests and various hormone levels. If the results are normal we can then start the metformin treatment.

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 20% 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 are only using this medication in anovulatory patients with polycystic ovarian syndrome (PCOS) and documented clomiphene failures. The women must be between ages 18-40.

Labs needed before starting:

LH, FSH, E2 (estradiol), DHEAS, T, 17-OHP, Prolactin, TSH, BUN, CR, AST, ALT, LDH

Fasting blood sugar


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.

Metformin 500mg 3 times daily.

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 patient a choice between continued weekly P4 checks and metformin/clomiphene combined therapy. If no ovulation (P4 > 7) after 8 weeks of metformin, begin CC treatment or stop metformin.

Patients are to keep menstrual calendars with all bleeding days and days of intercourse recorded.

This protocol will change over time as we get more experience with metformin and ovulation induction.