Clomiphene Citrate

Clomiphene citrate, a synthetic hormone commonly used to induce or regulate ovulation, is the most often prescribed fertility pill. Brand names for clomiphene citrate include Clomid and Serophene.

Clomiphene works indirectly to stimulate ovulation. In the presence of clomiphene, the brain sends signals to the pituitary gland to release hormones including follicle stimulating hormones (FSH). FSH circulates to the ovary where it stimulates the development of follicles — cystic structures that include an egg and surrounding estrogen-producing cells. Once follicle growth is initiated by clomiphene, the process of ovulation will usually proceed spontaneously.

The dose of clomiphene is tailored to each patient. Typically, a patient will begin clomiphene sometime between the 3rd and 7th day of her menstrual cycle. (We define cycle day 1 as the first day of heavy menstrual flow.) The medication is usually taken for 3, 4, or 5 consecutive days. Often the dose of medication will be higher during the first days of treatment.

Ovulation usually occurs between 9 and 12 days after the first clomiphene citrate pill is taken. A woman desiring to conceive should try to have relations on a regular basis during that time period. Alternatively, the ovulation may be monitored using urine kits, ultrasound or blood testing. The results of these tests can be used either to direct the couple when to have intercourse or to plan procedures such as artificial insemination.

Clomiphene has been used successfully by tens of thousands of women over the past 30 years. The drug has been shown to be reasonably safe and effective. However, certain potential adverse reactions or complications may occur.

What is the Chance of Getting Pregnant?

Not every patient who receives clomiphene will conceive. We expect that 85% of women who do not ovulate will ovulate as a result of taking clomiphene .Of these women, at least 50% will become pregnant. If a woman is already ovulating without the use of fertility drugs the chance of conceiving while taking clomiphene is about 10% per month. Careful attention to a patient’s response to clomiphene as well as other factors affecting her fertility (cervical mucus, fallopian tubes, sperm quality, etc.) will ensure the highest possible pregnancy rate. Most patients who conceive using clomiphene do so within the first four or five months of treatment.

Multiple Gestation

Clomiphene increases the incidence of multiple gestation. The incidence of twins is said to be approximately 10% for clomiphene pregnancies. The risk of triplets is about 1%. The risk of quadruplets, quintuplets, etc. is less than 1%. The number of eggs that a patient will ovulate can be to some degree predicted by counting the number of ripe follicles seen on ultrasound just before ovulation.

Risk of Miscarriage

The 20-25% risk of miscarriage associated with clomiphene is higher than the normal rate of miscarriage (15%). We attribute some increase in the rate of miscarriage to factors preexisting in women who require clomiphene that prevent fertilized eggs from developing normally. However, it is possible that clomiphene might increase the rate of miscarriage by changing the receptivity of the lining of the uterus. The condition (thickness) of the lining of the uterus can be evaluated with ultrasound just prior to ovulation.

No Increase in Birth Defects

Although an occasional medical journal report has described birth defects attributed to clomiphene, the majority of physicians utilizing this medication properly have failed to demonstrate any increase in the 3-5% rate of congenital abnormalities normally seen in our population. Clomiphene must not be taken by women who are already pregnant. Even if some menstrual-like bleeding has occurred, a woman should not take clomiphene if she suspects that she might be pregnant.

Is There a Risk of Future Cancer?

Preliminary data has raised concerns that the use of fertility drugs increases the chance that a woman will develop ovarian cancer later in her life. Some authors suggest that this risk might be higher for a woman who never becomes pregnant. Other authors suspect that the risk of future ovarian cancer might be greater in women who take many (for example, more than 12) cycles of treatment. Women with a family history of ovarian cancer may already be at greater risk for developing this disease. At the current time, scientific evidence neither proves nor disproves a relationship between clomiphene and ovarian cancer.

Side Effects

The most common side effect of clomiphene is hot flashes . Another common side effect is anxiety/irritability. This feeling of nervous tension may persist throughout the clomiphene cycle. Clomiphene may cause headaches, especially in women who experience migraine at the time of their period. Nausea and abdominal pain will rarely occur on the days that clomiphene is taken. If the clomiphene succeeds in stimulating a strong ovulation, the woman will likely experience some pain at the time of her ovulation, bloating through the second half of her cycle, and/or increased cramping at the time of her period (if she has not become pregnant).

Since clomiphene indirectly stimulates a woman’s ovaries, cysts may temporarily appear in her ovary. Rarely, these cysts may rupture or twist. Usually, they resolve spontaneously within a month. We try to examine the ovaries prior to each new clomiphene cycle.

Letrozole and Other Drugs


The latest class of fertility pills are aromatase inhibitors, drugs which temporarily prevent the body from making estrogen. In a fashion not too different from clomiphene, aromatase inhibitors initiate the release of FSH which stimulates the growth of follicles. At Main Line Fertility we use the aromatase inhibitor named letrozole (Femara).

Letrozole appears to be slightly less reliable than clomiphene for inducing ovulation. On the other hand, its advantages include less drying -up of cervical mucus, thicker development of the lining of the uterus, and a far lower chance of multiple gestation. As is the case with tamoxifen, metformin and rosiglitazone, letrozole is not certified for use as a fertility drug by the FDA (government). Doctors are free to use these drugs for off-label indications at their discretion.


Occasionally, we employ a drug called tamoxifen as an alternative to clomiphene. This medication works through the same mechanisms as clomiphene. It is not FDA approved for use as a fertility drug, but may be used for this “off-label” indication at the discretion of the physician.

Insulin Lowering Drugs

Another popular “off-label” drug usage involves medications normally prescribed to non-insulin requiring diabetics. Metformin (Glucophage) and pioglitazone (Actos)  are examples of medications that lower a woman’s insulin levels. Lowering insulin levels improves ovulation in some women with the condition known as polycystic ovarian syndrome (PCO).

Common side effects of metformin include gas and intestinal upset. Serious side effects are extremely rare. Pioglitazone has fewer common/minor side effects, but require blood test monitoring to detect liver problems. The incidence of miscarriage and, perhaps, birth defects may be reduced in PCO patients who take insulin lowering drugs.