Introduction
Approximately 25% of infertile women have problems with ovulation. This includes the inability to produce fully matured eggs or failure to “ovulate” (release) the egg. The inability to produce and/or release eggs is called anovulation. Fertility specialists utilize a group of medications, often called “fertility drugs,” to temporarily correct ovulatory problems and increase a woman’s chance for pregnancy. Fertility drugs may also be used to correct other fertility problems or to stimulate the development of multiple eggs in certain circumstances, such as in an in vitro fertilization (IVF) cycle.
Who Needs Ovulation Medication?
Medications for inducing ovulation are used to treat women who ovulate irregularly. A diagnostic evaluation should be performed before medication is administered to stimulate ovulation. The evaluation may include basal body temperature (BBT) charting, monitoring urinary LH excretion (ovulation predictor kits), timed measurement of serum progesterone levels, timed endometrial biopsies and /or serial transvaginal ultrasound examinations. The causes of anovulation are varied but, whenever possible, treatment should be directed at correcting the underlying cause. Women might not ovulate because of polycystic ovarian syndrome (PCOS), insufficient production of LH and FSH by the pituitary, thyroid disease, prolactin excess, eating disorders, or extreme weight loss or exercise. Sometimes the cause of anovulation cannot be identified confidently.
Ovulation drugs also can be used to stimulate the ovaries to produce more than one mature follicle per cycle, which leads to the release of multiple eggs. This controlled ovarian hyperstimulation (COH), may be accomplished with either oral or injectable fertility medications. COH, combined with intrauterine insemination (IUI), is used for the treatment of several forms of infertility. The intent is to develop several mature eggs in hopes that at least one egg will be fertilized and result in pregnancy. Controlled ovarian hyperstimulation is also an important component of IVF treatment.
COMMONLY PRESCRIBED MEDICATIONS
Clomiphene Citrate (Clomid®, Serophene®)
The most commonly prescribed ovulation drug is clomiphene citrate (CC). Brand names include Clomid® and Serophene®. This drug is most often used to stimulate ovulation in women who have infrequent or absent ovulation; however, it is also used in combination with IUI as an empiric treatment for unexplained infertility, mild endometriosis, or mild male factors particularly in young couples with a short duration of infertility, and in those who are unwilling or unable to pursue more aggressive therapies.
The standard dosage is 50 - 150 milligrams (mg) of CC per day for five consecutive days. Treatment begins early in the cycle, usually on the second, third, fourth or fifth day after menstruation begins. If a woman does not have periods, a period can be induced by administering progesterone.
It is important to determine whether a given dosage of CC results in ovulation. We rely on the menstrual pattern, ovulation prediction kits, measurement of serum progesterone levels or ultrasound to monitor a patient’s response to treatment with clomiphene. If ovulation does not occur at a certain dosage, the dose of CC may be increased in subsequent cycles until ovulation is achieved. Occasionally, we may choose to add other medications to clomiphene if the drug is not successful in inducing ovulation. Women who are obese may have better success if weight is lost.
Clomiphene can affect cervical mucus, making it a barrier for sperm. Therefore, intrauterine insemination is sometimes used in conjunction with CC. Clomiphene can sometimes alter endometrial thickness, making it thin and unreceptive to implantation. Because of this effect, the lowest dose of clomiphene sufficient to induce ovulation in anovulatory women is usually used.
Treatment is recommended for at least three to six cycles for most patients. Clomiphene will induce ovulation in about 80% of properly selected patients. About 40% to 45% of couples receiving clomiphene citrate will become pregnant within six cycles. The chance of success is much less after six cycles. After that, alternatives may be considered.
Side effects of clomiphene are typically mild but common especially with higher doses. Hot flashes occur in 10% of women but usually resolve after the five days of treatment ends. Mood swings, breast tenderness, and nausea are also common. Severe headaches or visual problems, such as blurred or double vision, are uncommon, and virtually always reversible. If these side effects occur, stop the drug immediately and call our office. Women who conceive with clomiphene have approximately a 10% chance of having twins. Triplet and higher order pregnancies are rare (<1%), but may occur. There is no increased risk of miscarriage in pregnancies conceived with clomiphene therapy. Ovarian cysts, which can cause pelvic discomfort, may form as a result of the drug’s stimulation of the ovaries.
Letrozole (Femara®)
Although FDA approved for postmenopausal breast cancer, letrozole has been used successfully for ovulation induction. Typically, the pills are prescribed for five days starting on cycle day 3, 4, or 5. Studies indicate that pregnancy rates are comparable to clomiphene citrate. This drug is also effective in women who have not ovulated on clomiphene or who developed side effects which necessitated discontinuing clomiphene.
Gonadotropins (Repronex®, Menopur®, Follistim®, Gonal-f® and Bravelle®)
Gonadotropins are fertility medications that contain follicle stimulating hormone (FSH) and sometimes luteinizing hormone (LH). Gonadotropins are often used for couples who have tried clomiphene without success. They are also used to help women whose pituitary glands do not produce adequate amounts of FSH and LH. Additionally, these drugs are also used to induce development of multiple follicles for fertility treatments, such as COH-IUI and IVF.
Gonadotropin treatment involves a series of injections and careful monitoring during each treatment cycle. Use of gonadotropins may involve a certain amount of risk, expense, and inconvenience. We typically begin the gonadotropin injections on day 2 or 3 of the menstrual cycle. For non-IVF cycles, the usual starting dose is 75 to 150 units injected daily. Injections usually are administered over a period of 7 to 12 days, but may be extended if the ovaries are slow to respond. The follicle size is monitored with ultrasound, and the blood estrogen level may be measured throughout treatment. If tests indicate that the ovaries are not responding to gonadotropins, the dose may be increased. The goal is to achieve one or more mature follicles. If too many follicles develop, it may be necessary to cancel the treatment cycle rather than risk ovarian hyperstimulation syndrome (OHSS) or a high-order multiple pregnancy.
There are potential risks and complications associated with the use of gonadotropins. Even with intensive ultrasound monitoring, 30% of gonadotropin pregnancies are multiple. Although most of the multiple pregnancies are twins, there is about a 3% risk of triplets or more. Multiple pregnancies are at increased risk for poor outcomes including premature delivery. Premature delivery can cause complications for the infant including severe respiratory distress, intracranial hemorrhage, infection, cerebral palsy, and death. Some patients pregnant with triplets or more choose to undergo a procedure known as multifetal pregnancy reduction in an effort to decrease these risks.
Another serious side effect of gonadotropin therapy is ovarian hyperstimulation syndrome (OHSS), in which the ovaries become swollen and painful. In severe cases, fluid accumulates in the abdominal cavity and chest. In about one percent of gonadotropin cycles, hyperstimulation may be severe enough to require hospitalization. Careful monitoring of ovulation induction cycles with the use of ultrasound and/or measurement of serum estradiol levels, in conjunction with adjustment of gonadotropin dosage, can prevent most cases of severe OHSS.
Other potential side effects of gonadotropin treatment include breast tenderness, swelling or rash at the injection site, abdominal bloating or pain, and mood swings. The mood changes are usually less severe than with clomiphene.
Human Chorionic Gonadotropin
Human chorionic gonadotropin (hCG) is similar in chemical structure and function to LH. As such, in a manner similar to the natural LH surge, an injection of hCG can cause the dominant follicle to release its egg. The physician may use ultrasound and blood estrogen levels to determine the day on which to administer hCG. Ovulation will usually occur 36 to 48 hours after hCG is administered. hCG is routinely used to trigger ovulation when gonadotropins are used to induce ovulation. hCG may also be used to trigger ovulation when CC is used to induce ovulation, particularly when a mid-cycle LH surge cannot be reliably detected. A pregnancy test (which measures hCG in the urine or blood) may be falsely positive if performed less than 10 days after hCG is administered.