When problem with ovulation is suspected, the first line of therapy is the use of oral ovulation induction agents such as clomiphene (Clomid, Serophene), and more recently, letrozole (Femara). These medications work by indirectly inducing the release of FSH from the pituitary, which in turn stimulates the development of the egg. The brain, however, still exerts a powerful selective effect on the egg development process to ensure that only 1 or 2 eggs are available per cycle.

Clomiphene or letrozole is often combined with HCG (human chorionnic gonadotropin) to optimize the ovulation process. HCG is similar in structure to LH (luteinizing hormone), which is normally secreted by the pituitary at midcycle to induce ovulation. By using HCG, ovulation can be assured. If planned IUI can performed about 1 to 2 days after HCG injection. Serum progesterone level is checked a week after HCG to confirm ovulation. The clomiphene or letrozole cycle is outlined as below:

Clomiphene (Clomid, Serophene) is a drug that has been used for more than 50 years to stimulate follicular development. Clomiphene works by blocking the estrogen receptor in the brain to trick it into thinking that the ovaries are not producing enough estrogen. The brain responds by effecting a higher release of FSH from the pituitary to stimulate the ovaries to produce eggs.

Clomiphene causes ovulation in 80% of users but gives only a 10-15% chance of pregnancy per cycle even with intrauterine insemination (IUI). Because 90% of pregnancies from clomiphene would have occurred by the fifth cycle, other treatment should be considered after 5 failed clomiphene cycles.

Because it binds to the estrogen receptor, clomiphene can interfere with the binding of estrogen to the endometrium (the lining of the uterus), which needs estrogen to grow. Thus prolonged use of  clomiphene can lead to a thin endometrium that is unable to support embryo implantation. The higher the dose, the more likely the side effect. Pregnancy rarely occurs when the endometrial thickness is less than 6 mm.

Letrozole (Femara) is a new medication that is currently being used to treat patients with breast cancer. It inhibits aromatase, an enzyme necessary for the synthesis of estrogen, which in turn can stimulate the growth of certain types of breast cancer. More recently, letrozole has been used in place of clomiphene to induce ovulation. Like clomiphene, letrozole is taken for 5 days at the beginning of the cycle to cause a drop in blood level of estrogen, which in turn will lead to release of FSH from the pituitary to stimulate the ovaries. Unlike clomiphene which can linger in the blood for weeks, letrozole disappears quickly from the body. Because it does not block estrogen binding to the endometrium, letrozole does not interfere with endometrial growth. At the present time letrozol is used as an off-label drug to treat infertility.

The side effects of letrozole is similar to those of clomiphene (hot flashes, 10% risk of multiple pregnancy).

Although it may be a superior drug to clomiphene due to its lack of side effect on the endometrium, letrozole probably will not yield pregnancy rate higher than 20%.

When oral medications fail to produce pregnancy, the next step is to use more powerful injectable medications to stimulate the ovaries to make multiple eggs.  These medications are actually concentrates of FSH and LH, hormones normally produced by the pituitary to stimulate egg development. By directly stimulating the ovaries, these medications bypass the tendency of the brain to select one follicle, thus making it possible to recruit multiple eggs.

The medications can be pure FSH (Bravelle, Follistim, or Gonal-f) or a mixture of LH and FSH (Pergonal, repronex). They are usually started on day 2 or 3 of the cycle, and usually take 7 to 10 days to produce mature follicles.

Close monitoring by multiple sonograms is required to avoid the risk of hyperstimulation and multiple gestations (30% of resultant pregnancies).

The cost of the superovulation cycle can be quite  high ($1000-$1500) while the pregnancy rate is increased only modestly (25% vs. 15% for clomiphene).

For best result superovulation should be combined with intrauterine insemination (IUI).

Patients with significant endometriosis (stage III or IV) will probably benefit more by going directly to IVF than by undergoing superovulation induction.

A typical superovulation cycle is outlined as below: