Fertility Drugs for Ovulation Induction
Clomiphene Citrate (CC) is a weak estrogen – anti estrogen compound that comes as a scored 50 mg tablet. The primary indication for the use of CC is to induce ovulation (egg development and release) for women whose menstrual cycles are irregular. CC is also used in combination with intrauterine insemination for women with unexplained infertility. For women with irregular menses, CC may be used in combination with metformin. Generally, the initial dose is one 50 mg tablet for 5 days beginning either cycle day 3, 4 or 5. Approximately 50% of women who are going to respond to CC in terms of inducing ovulation will do so at that dose. Overall, 80% of women treated with CC to induce ovulation will respond. If ovulation does not occur at 50 mg, the dose can be increased to 100 mg and if still without ovulation, the dose can be increased to 3 tablets or 150 mg.
There is no advantage in terms of success rates to increasing the dose of CC beyond that which results in ovulation for women using it for anovulation. For women who are anovulatory, a trial of CC for 3 – 6 cycles is reasonable and if not pregnant at that point, referral to a fertility specialist is appropriate. Conception rates using CC for inducing ovulation are 15 – 20% per cycle.
For women who have fairly regular menstrual cycles and have under gone a fertility evaluation with the findings of mild to moderate male factor, suspected luteal phase deficiency, endometriosis or unexplained infertility, CC can be utilized along with intrauterine insemination (IUI) to increase the chances of conception. Conception rates for these indications are dependent on the women’s age and the motile sperm count. For women under age 35, conception rates are 11% per cycle with 25% of couples achieving a pregnancy within 3 cycles of treatment. Although this percentage rate is somewhat low, for couples who have not used any form of prevention for 2 years and have not achieved a pregnancy, spontaneous success rates (without treatment) drop to approximately 3% per cycle, suggesting a benefit for CC/IUI. For couples with unexplained infertility, CC is prescribed as 100 mg (two tablets) usually initiated on day 3 or 4 of the cycle. The majority of The Reproductive Medicine Group patients undergoing CC/IUI cycles are monitored with ultrasounds and use the trigger medication Ovidrel to induce ovulation and improve timing for the IUI procedure. CC is a relatively inexpensive medication. Risks and side effects include: hot flashes, breast tenderness, headache, moodiness/irritability and ovarian cyst formation. Ovarian cysts generally resolve spontaneously although on rare occasions could result in severe pain requiring bed rest or even hospitalization. Rarely, visual disturbances may occur which requires that the medication be discontinued. If this occurs, the CC should not be used in subsequent cycles. The risk of multiple pregnancy is increased with the use of CC with twin pregnancy occurring in 9% of pregnancies achieved with CC and triplet pregnancy in less than 1%. CC can thin the endometrial lining and/or thicken the cervical mucous. The endometrial thickness can be monitored by ultrasound evaluation during the cycle.
Letrozole is an aromatase inhibitor that is utilized to decrease the risk of breast cancer recurrence. However, it was discovered that its anti-estrogenic properties actually make it useful for fertility enhancement. Femara acts as an estrogen receptor blocker. The initial decline in estrogen stimulates the pituitary gland to secrete FSH which encourages the egg(s)/follicle(s) to develop. While letrozole works similarly to CC in terms of inducing ovulation, there are several important differences. Letrozole is cleared from the body more quickly than CC and has less negative effects on the endometrial lining and cervical mucous. Some women who fail to ovulate with CC may respond to letrozole. Letrozole comes as a 2.5 mg tablet. For fertility purposes, the usual dose is one to two tablets daily for 5 days generally beginning day 3, 4, or 5 of the cycle.
The most common side effects of letrozole include hot flashes, headaches, muscle or joint pain, fatigue, nausea or swelling of the hands/feet. Ovarian cysts can occur following letrozole use. The risk of twins is increased with the use of letrozole but is thought to be less common than with CC.
Gonadotropins (Gonal F, Follistim, Bravelle and Menopur) are medications similar to hormones produced by the pituitary gland (FSH and LH) that are used to simulate oocyte (egg) development. They are administered by injection (usually subcutaneous). These injections are usually started on day 3 of the menstrual cycle or as directed by protocol in an IVF cycle, and are continued for several days until developing oocytes are judged to be mature based on ultrasound measurement of the follicles (fluid filled cysts that contain the egg) and estradiol blood level. Daily dosages and length of time needed for adequate stimulation varies from patient to patient and from cycle to cycle, but most patients will require these injections for about 7-10 days. Gonadotropins are used in women who do not ovulate with clomiphene citrate, letrozole, or when development of multiple follicles is appropriate for unexplained infertility. All patients using gonadotropins receive a trigger injection of hCG (Ovidrel or Lupron) when monitoring reveals follicular size and estrogen levels to be appropriate.
Gonadotropin medications are excreted from the body and will leave no long lasting effects on the menstrual cycle. Subsequent cycles should return to their usual pattern prior to medication administration. Alcohol and tobacco should be avoided during a stimulation cycle. You should inform the nurse of any medications (prescription or over the counter) or herbal remedy supplements you are taking. Generally, the use of herbal medications should be discontinued. Normal activities and sexual relations may be continued during the period of ovarian stimulation during a non IVF cycle. Specific instructions are given during an IVF cycle.
Risks of gonadotropin medications for ovulation induction include hyperstimulation syndrome and multiple pregnancy. Hyperstimulation of the ovary is uncommon since estradiol levels and ovarian sonograms are used to closely monitor the stimulation cycle. Hyperstimulation of the ovaries is more likely to occur when there are a large number of follicles and the estrogen (E2) level is very high. If too many follicles develop or the blood estrogen levels are too high, the gonadotropin cycle will be cancelled to reduce the risk of hyperstimulation or high order multiple pregnancy. Symptoms of hyperstimulation include sudden weight gain (3-5 pounds or more), excessive abdominal bloating, and/or pain. If you experience any of those symptoms, or have other concerns, call the office you are seen at and ask to speak to one of the nurses. Multiple births occur in 25%-30% of patients using gonadotropins. Twins occur in about 20-25%, and triplets or more in around 5% of conceptions using gonadotropin therapy.
Human Chorionic Gonadotropin (hCG)
Human chorionic gonadotropin (hCG) is required to ripen the follicles and make ovulation occur. The hCG is available in two forms. In the first form, hCG is packaged as 10,000 international units of drug as a dry powder. This needs to be dissolved in the diluent provided before the injection can be prepared. Only 2 cc of fluid is used for dilution. The medication is given between 8:00pm – 10:00pm. In the second formulation, now used more commonly, hCG is available in premixed syringes for subcutaneous administration.