Ovulation and Ovulation-Inducing Fertility Medications for Treating Infertility in Women
Ovulation is the monthly process whereby the female reproductive system produces a mature egg. During ovulation, the brain's pituitary gland releases two hormones: follicle stimulating hormone (FSH) and luteinizing hormone (LH). Together, these hormones are known as gonadotropins. FSH acts as a 'messenger' sent by the pituitary gland to stimulate the development of follicles in the ovaries, each of which will contain one egg. LH is responsible for triggering the release of the egg (ovulation).
During the first half of the menstrual cycle, the ovarian follicles produce the hormone estradiol, which stimulates the growth of the uterine lining (endometrium) and the production of the watery 'raw egg white' cervical mucus that functions to help the sperm as it swims up through the uterus to the fallopian tubes. After approximately two weeks, the pituitary releases a surge of LH hormone, triggering ovulation. At this stage, the follicle, now known as the corpus luteum, begins to produce the hormone progesterone, which serves to thicken the uterine lining to prepare for possible pregnancy. Two weeks after ovulation, if a pregnancy has not occurred, the corpus luteum stops progesterone production, the endometrium sloughs off and menstrual bleeding occurs.
Ovulation-Inducing Fertility Drugs
Any number of conditions can hamper the body's ability to ovulate effectively. One of the primary ways to address this challenge is with medications that stimulate the ovarian follicles to produce multiple eggs in one cycle. The two most common fertility medications used to promote ovulation include Clomiphene Citrate (Clomid or Serophene) and Gonadotropins (Follistim, Menopur, Bravelle and Gonal-F).
Clomiphene is a synthetic chemical, taken orally, that binds to estrogen receptors in the brain and causes pituitary FSH levels to rise (see below). Gonadotropins are identical to human protein hormones FSH and LH and, given by injection, bypass the pituitary gland and directly stimulate the ovaries.
Clomiphene Citrate treatment
Clomiphene is a long trusted oral medication relied upon for its safety, effectiveness and relatively low cost. Clomiphene is used to treat absent or irregular menstrual cycles (ovulation induction), to address a condition called luteal phase defect by increasing progesterone secretion during the second half of the cycle and to make menstrual cycle lengths more predictable, thus improving the timing of intercourse or artificial insemination. Clomiphene may also be used to enhance ovulation in women who are already ovulating (ovulation augmentation).
Clomiphene Citrate for ovulation induction
Clomiphene used in conjunction with a medication called Provera may be effective in initiating menstruation and ovulation in women who have no menstrual cycle:
- Treatment begins with a 5-7 day course of Provera, taken orally.
- Two to three days after Provera is completed, a menstrual period should begin.
- On the 3rd, 4th or 5th day of menstrual flow, a course of clomiphene is started.
- A clomiphene citrate 50 mg tablet is taken orally for 5 days.
- On day 11 or 12 of the menstrual cycle, ultrasound monitoring is conducted to determine if an ovarian follicle or follicles have developed. Also at this time, patients are asked to use an ovulation predictor kit to test their urine for a surge in LH (luteinizing hormone) indicating that eggs have matured and ovulation is imminent. If no LH surge is detected, ovulation itself may be triggered with an injection of the medication hCG (Ovidrel), which will cause the release of the mature egg(s) from the follicle(s).
- Natural intercourse or insemination is timed to ovulation.
- If ovulation has been assisted by an hCG injection, a form of the hormone progesterone is given via vaginal tablets or gel. The progesterone hormone serves to support the endometrial (uterine) lining and prepare it for the fertilized egg.
- Two weeks after ovulation, patients are asked to take a home pregnancy (urine) test. If the test is positive, a blood test will be performed to confirm results.
If ovulation doesn't occur during this initial clomiphene dosage, another course of provera will be prescribed and the dose of clomiphene increased until ovulation occurs. It may be possible to begin another clomiphene cycle immediately or, if residual cysts are present on the ovarian follicles, a 'rest' cycle may be advised before resuming treatment.
If ovulation cannot be induced even with a higher dose of clomiphene, this form of treatment will be discontinued, and ovulation induction may be attempted again using a different form of fertility drug (letrozole or gonadotropins).
Clomiphene Citrate for Ovulation Augmentation
In women that menstruate regularly on their own, clomiphene may be used to help the ovaries to produce more than one mature egg. This is sometimes referred to as "superovulation." The process is as follows:
- On Day 3 of the menstrual period, a course of clomiphene is begun. Starting clomiphene early in the cycle helps with the recruitment of more than one mature egg.
- Typically, two clomiphene citrate 50-mg tablets are taken orally for 5 days, from cycle day 3 to cycle day 7.
- On day 11 or 12 of the menstrual cycle, ultrasound monitoring is conducted to determine if an ovarian follicle or follicles have developed. The ultrasound helps to determine how many mature eggs are forming within their follicles. In order for ovulation induction to be successful, 2-3 follicles should be visible at this point (with just one follicle, we would not be significantly enhancing a woman's chances to become pregnant). When an ovarian follicle matures, it produces the hormone estrogen, which causes the lining to thicken in preparation for an implanting embryo. Ultrasound monitoring at this stage also serves to measure the endometrial (uterine) lining and to make sure the clomiphene itself is not having any adverse effects on the endometrium (see Clomiphene side effects, below),
- At this stage, patients are also asked to use an ovulation predictor kit to test for a surge in LH hormone, indicating imminent ovulation. In most cases, patients are given an injection of hCG (human chorionic gonadotropin) also known as Ovidrel. This hormone initiates the release of the egg (ovulation) and the development of the corpus luteum, which will help the body to produce progesterone. Ovulation usually occurs approximately 38-44 hours after the hCG injection.
- After ovulation, a form of the hormone progesterone is given via vaginal tablets or gel in order to support the endometrial (uterine) lining and prepare it for the fertilized egg.
- Patients are asked to take a home pregnancy test (urine test) two weeks after ovulation. If the home test is positive, a blood test will be performed to confirm the results.
If the clomiphene cycle did not produce sufficient egg follicles, it may be possible to begin another cycle immediately; or, if residual cysts are present on the ovarian follicles, a rest cycle may be advised before resuming treatment.
Clomiphene Citrate side effects
Ovulation predictor kits detecting the LH surge may demonstrate false positive results if testing begins near the time of clomiphene citrate administration. If patients start ovulation predictor kit testing on cycle day 9 or earlier, there is a high probability of obtaining a false positive result. For that reason, we recommend caution in testing too soon.
If a patient is not pregnant and menses occurs, the same dose of clomiphene is given after a normal pelvic sonogram. We usually recommend up to 6 cycles for ovulation induction patients and up to 3 or 4 for ovulation augmentation patients.
Possible side effects of Clomiphene include:
- Flushing (extremely common)
- Ovulation pain and increased sensitivity –also called "mittelschmerz"
- Blurry vision, double vision or 'traces,' (a complication which may cause treatment to be discontinued)
- Moodiness (requiring discontinuation in severe cases)
- Breast tenderness
- Vaginal dryness
- Clomiphene can sometimes decrease cervical mucus production, which may make it impossible for the sperm to swim through the cervix into the uterus. To get around this potential problem, intrauterine insemination (IUI) may be advised so that cervical mucus may be bypassed altogether.
- In approximately 20% of patients clomiphene may negatively impact estrogen production, which in turn prevents the uterine lining from thickening at the necessary time. If the lining is too thin, the embryo cannot implant successfully. This side effect tends to occur with repeated use or with higher doses of medication. Endometrial thinning will stop once clomiphene treatment concludes. An alternative therapy often recommended in these situations is a medication called Letrozole, which has a milder effect on the hormonal system. Letrozole temporarily lowers estrogen levels, prompting the pituitary gland to increase FSH and LH production and promote ovulation. (While letrozole is not yet FDA-approved for ovulation induction, widely conducted studies indicate that there is no detriment to this treatment option.)
- Less than 5% of women may experience an exaggerated response to treatment, known as ovarian hyperstimulation syndrome. This condition is rare in clomiphene treatment, and more common with use of gonadotropin medications. Ovarian hyperstimulation syndrome is marked by abdominal bloating, nausea and diarrhea, and in more severe cases, symptoms including shortness of breath, difficulty with urination and chest pain. Adjustments can be made for those who hyperstimulate by decreasing medication and shortening the treatment cycle. In 1% of cases, severe hyperstimulation may require intervention with intravenous fluids or removal of abdominal fluid so that fertility treatment may continue. The symptoms of hyperstimulation begin about a week after ovulation. Mild cases last about a week and usually respond to hydration and careful monitoring. In general, ovarian hyperstimulation is highly unlikely, given careful monitoring of follicle development.
- Multiple pregnancy may be a risk with clomiphene treatment. The incidence of twins is increased to 5%; multiple births higher than twins are rare (1-2%). If an ultrasound scan reveals 3 or more mature follicles (eggs) indicating that a high multiple pregnancy is possible, patients may be advised to consider whether or not they would undergo embryo reduction, should a triplet pregnancy occur. If this procedure is not desired, or if multiple pregnancies would pose a physical or emotional challenge, patients may be recommended to forego attempts to conceive during this cycle.
Clomiphene citrate treatment success rates
Of women who are anovulatory (unable to produce an egg each month), approximately 70% will ovulate when treated with clomiphene; and conception rates consistent with a patient's age should be achieved. Women less than 35 can achieve pregnancy rates of 20-25% per month as long as there are no other significant factors present. Older patients may not achieve these rates as their declining egg quality will become a factor. We stress that success rates are highly individual and depend on a number of factors. The best thing to do is have a thorough discussion with one's RE physician to gain a better understanding of the likelihood of success with this or any treatment plan.
There are alternate fertility treatments for those who do not become pregnant with clomiphene therapy. If 3-6 full clomiphene cycles do not result in a pregnancy, other methods of ovulation induction can be recommended. For older patients, gonadotropins and intrauterine insemination may be recommended. For younger patients, in whom the risk of multiple gestations may be too high with gonadotropins and IUI, In Vitro Fertilization may be the next best step that will be recommended.