Medications

Fertility drugs are often used alone as initial treatment to induce ovulation. If they fail as sole therapy, then they may be used with assisted reproductive procedures or artificial insemination to produce multiple eggs, a process called superovulation.

Clomiphene

Clomiphene citrate (Clomid, Serophene) is usually the first fertility drug of choice for women with infrequent periods and long cycles. Unlike more potent drugs used in superovulation, clomiphene is gentler and works by blocking estrogen, which tricks the pituitary into producing FSH and LH. This boosts follicle growth and the release of the egg. Clomiphene can be taken orally, is relatively inexpensive, and the risk for multiple births (about 5%, mostly twins) is lower than with other drugs.

Women with the best chances for success with this drug are those with the following conditions:

  • Polycystic ovaries
  • Ability to menstruate but irregular menstrual cycle

Women with poorer chances to no chances with this drug have the following conditions:

  • Infertility but with normal ovulation
  • Women with low estrogen levels
  • Premature ovarian failure (early menopause)

One or two tablets are taken each day for 5 days, usually starting 2 - 5 days after the period starts. If successful, ovulation occurs about a week after the last pill has been taken. If ovulation does not occur, then a higher dose may be given for the next cycle. If this isn't successful, treatment may be prolonged or additional drugs may be added. Experts usually do not recommend more than 6 cycles.

The drug often reduces the amount and quality of cervical mucous and may cause thinning of the uterine lining. In such cases, other hormonal drugs may be given to restore thickness. Other side effects include ovarian cysts, hot flashes, nausea, headaches, weight gain, and fatigue. There is a 5% chance of having twins with this drug, and a slightly increased risk for miscarriage.

Superovulation with Gonadotropins and GnRH Agonists

Superovulation, also called controlled ovarian stimulation, is generally used if clomiphene does not work. This approach is the direct administration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), collectively called gonadotropins. The intent is to mimic the natural process leading to ovulation and produce multiple follicles. Superovulation is generally used in conjunction with assisted reproductive technologies.

Many of the drugs used in superovulation are either taken from natural sources (menotropins) or are genetically developed:

  • The standard drugs are menotropins, which are hormones extracted from urine of postmenopausal or pregnant women. Menotropins contain high concentrations of FSH or LH. The specific drugs that are administered either in combination or as FSH.
  • Genetically developed hormones (called recombinant drugs) are proving to be very effective. These are pure hormonal drugs, and they are allowing the doctor to better tailor the regimen to the unique needs of the patient.

Human Menopausal Gonadotropins (hMG). HMG (Pergonal, Repronal, Metrodin) is a menotropin that contains both FSH and LH and is obtained from the urine of postmenopausal women. HMG must be self-administered as an injection. It is one of the potent ovulation drugs and is often used in assisted reproductive techniques. It may help stimulate fertility in women with ovarian dysfunction, endometriosis, and unexplained infertility. HMG is administered as a series of injections 2 - 3 days after the period starts. Injections are usually given for 7 - 12 days, but the time may be extended if ovulation does not occur. In such cases, an injection of human chorionic gonadotropin (hCG) may trigger ovulation.

FSH. FSH stimulates the follicles directly and may be used with hCG to produce the LH and FSH surges that trigger ovulation. FSH is typically used alone for women who have taken clomiphene and failed. Such women often have polycystic ovaries, which is characterized by high LH and low FSH levels.

Urofollitropin (Metrodin, Fertinex, Bravelle) is a menotropin extracted from the urine of postmenopausal women and has been the standard FSH drug. Recombinant follicle-stimulating hormone (Puregon, Gonal-F, Follistim) is genetically developed form of the natural FSH. Therefore it has no risk for contaminants, such as urinary proteins or traces of LH, which can occur with menotropins. (Bravelle is a highly-purified menotropin and may be as effective as recombinant FSH.)

Human Chorionic Gonadotropin (hCG). Human chorionic gonadotropin or hCG is similar to luteinizing hormone and mimics the LH surge, which is to stimulate the follicle to release the egg. Standard hCG drugs (APL, Follutein, Pregnyl, Profasi, Humegon) are derived from the urine of pregnant women. The recombinant (genetically developed) form of hCG (Ovridel) has fewer side effects at the injection site, and its quality can be better controlled than the natural drugs. It is generally used after hMG or FSH to stimulate the final maturation stages of the follicles. Ovulation, if it occurs, does so about 36 - 72 hours after administration.

GnRH Analogs (Agonists or Antagonists). Gonadotropin-releasing hormone analogs (GnRH-a) can be either GnRH agonists or antagonists. They are synthetic drugs that are similar to natural GnRH but have very different actions. While natural GnRH stimulates LH, these drugs actually prevent the LH and FSH surge that occurs right before ovulation. This action helps prevent the premature release of the eggs before they can be harvested for assisted reproductive technologies.

  • GnRH agonists include leuprolide (Lupron), nafarelin (Synarel), goserelin (Zoladex), and buserelin.
  • GnRH antagonists include ganirelix (Antagon) and cetrorelix (Cetrotide). These are newer drugs that act more quickly than GnRh agonists. They appear to pose less of a risk for treatment complications and side effects. It is not clear, however, if they offer any advantages in achieving pregnancies.

GnRH-a drugs are administered by injection or nasal spray. They increase the risk for ovarian cysts, but according to a 2000 study, they have no negative effect on pregnancy. They may increase the risk for ovarian cysts and cause menopause-like effects, including hot flashes, vaginal dryness, insomnia, and osteoporosis.

Women with endometriosis often have an especially difficult time getting pregnant. A 2006 review suggested that GnRH agonists may help women with endometriosis quadruple their chances of becoming pregnant when the drug is 3 – 6 months prior to in vitro fertilization (IVF) or intracysoplasmic sperm injection. [For more information, see In-Depth Report #74: Endometriosis.]

Complications of Superovulation

Multiple Births. Overproduction of follicles can lead to ovarian enlargement. This event increases the risk for multiple births. There is a 25% chance of multiple births (about 17% for twins and 8% for triplets and over).

Ovarian Hyperstimulation Syndrome. The most serious complication with superovulation is ovarian hyperstimulation syndrome (OHS), which is associated with the enlarged ovary (although the precise cause is unknown). This can result in dangerous fluid and electrolyte imbalances and endanger the liver and kidney. OHS is also associated with a higher risk for blood clots. In rare cases, it can be fatal. Symptoms include abdominal bloating, nausea, vomiting, and shortness of breath.

Bleeding and Rupture of Ovarian Cysts. Overproduction of follicles, if unchecked, may result in bleeding and rupture of ovarian cysts.

Cancer Concerns. There has been concern about an increased risk for ovarian and breast cancers in women taking fertility drugs, particularly clomiphene and human menopausal gonadotropins. In general, a strong body of evidence is finding no higher risk for either breast or ovarian cancer from the drugs themselves. Instead, such studies are suggesting that these cancers are caused by the same factors that contribute to the infertility itself.

Other Drugs Used or Under Investigation

Tamoxifen. Tamoxifen (Nolvadex) is a drug known as a selective estrogen-receptor modulators (SERM). It is used to prevent breast cancer in high-risk women. Studies suggest that it may equal clomiphene in its ability to induce ovulation. It may be especially useful when used along with IVF for preserving fertility in breast cancer patients. This drug is less expensive than clomiphene, but it poses some health hazards, including a risk for blood clots and uterine cancer.

Aromatase Inhibitors.Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many major body tissues. These drugs include anastrozole (Arimidex) and letrozole (Femara). These drugs are used for treating breast cancer and are being investigated for stimulating ovulation in infertile women. Although letrozole is not approved for treatment of infertility, it has become widely used for this purpose in recent years. Some experts were concerned that letrozole could increase the risk of birth defects. However, a major 2006 study indicated that letrozole does not increase risk to the fetus. The study compared the rate of birth defects among babies whose mothers conceived with letrozole and those who used clomiphene (the standard first-line fertility drug). Researchers found no differences in birth outcomes between the two groups.

Typical Regimen for Hyperstimulation and In Vitro Fertilization

Regimens to induce ovulation vary widely according to individual need. A typical procedure, involving superovulation and in vitro fertilization (IVF) may be as follows:

  • Doctors make sure that the patient is not pregnant or in the luteal phase of her menstrual cycle (the premenstrual period).
  • Injections of either hMG (which contains LH and FSH) or pure FSH are administered daily 2 - 4 days after day 1 of the next cycle. Either drug may be used.
  • After 4 - 8 days of treatment, estrogen levels are monitored. Increasing levels on the fourth day of treatment may be strong indicators of success. If estrogen levels indicate that ovaries are responding, ultrasound is then performed to detect possible overproduction of follicles. Such evaluation should then be conducted every 1 - 2 days and dosages adjusted accordingly.
  • GnRH analogs are used to prevent a premature release of LH hormone (and therefore ovulation). GnRH agonists are typically administered either early on or a few days after ovulation in the cycle previous to the one planned for IVF. This approach is referred to as the long protocol, and it serves to suppress the pituitary gland and allows time for the eggs to mature before harvesting. Other protocols using GnRH antagonists are under investigation, but to date the long protocol has the best pregnancy rates.
  • When at least three follicles have reached a diameter of 18 mm, hCG is typically administered to release the egg. It is not given if there are signs of overproduction of follicles, which suggests a risk for ovarian hyperstimulation syndrome (OHS), a dangerous complication. (One study reported that giving high doses of progesterone to high-risk women the day of hCG administration may prevent OHS.)
  • Egg retrieval may be performed about 36 hours following hCG administration, with the transfer of the embryo (the fertilized egg) back into the woman 2 - 3 days after retrieval.
  • Embryos are transferred to the uterus through a small tube. This process does not require an anesthetic, although the procedure can cause cramping.

Gentler Alternatives to Superovulation

Natural (Unstimulated) In Vitro Fertilization Cycles. An alternative to superovulation for some couples is natural IVF cycles. It allows multiple, consecutive cycles of treatment. Natural IVF is far less expensive than standard hyperstimulation methods and avoids their risks, including multiple births and ovarian hyperstimulation syndrome (OHS).

  • The process involves ultrasound and hormonal monitoring starting 5 days before the estimated ovulation day.
  • No superovulation drugs are used, such as FSH and hMG. The doctor, however, may administer an injection of hCG to stimulate the LH surge.
  • The egg retrieval timing is based on detecting LH surge.
  • A single egg is retrieved. The procedure that follows is similar to other IVF cycles.

The basic disadvantage to this approach is that the eggs may be released before there is a chance for them to be harvested. Women report far lower stress levels with this approach, however, even though it requires more treatment cycles. In one 2001 study, the live-birth rate was 32%. Not all women are appropriate candidates, however. Women should have regular menstrual cycles and infertility of unknown cause or associated with problems in the fallopian tubes. Pregnancy rates are still very low in older women.

Clomiphene. Another gentler alternative to superovulation is the use of clomiphene before IVF, which works slightly better than unstimulated IVF.