Rashmi Hospital

Centre for Minimally Invasive Surgery & Maternity

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Basics about Infertility ] Intrauterine Insemination ] Polycystic Ovarian Syndrome [PCOS] ] Ovarian Drilling for PCOS ] [ Ovulation Induction ]

Ovulation Induction

Ovulation induction medications, often referred to as fertility drugs, are used to stimulate the follicles in your ovaries resulting in the production of multiple eggs in one cycle. The medications also control the time that you release the eggs, or ovulate, so sexual intercourse, intrauterine inseminations, and in vitro fertilization procedures can be scheduled at the most likely time to achieve pregnancy.

There are risks associated with the use of ovulation induction medications including an increase in the chance for high order multiple births and the development of ovarian cysts. A rare side effect that can occur is ovarian hyperstimulation syndrome (OHSS); symptoms include severe pain in the pelvis, abdomen and chest, nausea, vomiting, bloating, weight gain and difficulty breathing.

The medications most commonly used in fertility treatment are clomiphene citrate, gonadotropins, Metformin and Parlodel.

Clomiphene Citrate (Siphene) - This medication comes in a tablet form and is used for women who have infrequent periods or long menstrual cycles. Common side effects include headaches, blurred vision and hot flashes.

Gonadotropins - This is an injectable medication that is used to induce the release of the egg once the follicles are developed and the eggs are mature. Side effects may include abdominal distention/discomfort, bloating sensation, mood swings, fatigue or restlessness. In most cases, the side effects are relieved by follicular aspiration.

Glucophage (Metformin) - Metformin is given to patients as an insulin lowering medication. Most commonly used in PCOS patients, the medication has been shown to reverse the endocrine abnormalities seen with polycystic ovary syndrome within two or three months. The use of Metformin can result in decreased hair loss, diminished facial and body hair growth, normalization of elevated blood pressure, regulation of menses, weight loss and normal fertility.

Bromocryptine - Bromocryptine is a medication used to lower prolactin levels. It will also reduce pituitary tumor size, should one be present. An oral medication taken with meals, Bromocryptine has few side effects and is relatively inexpensive.

There are different levels of ovulation induction commonly used to treat infertility related to ovulation disorders, male factor or unknown causes. One method of treatment involves clomiphene citrate taken in pill form for 5 days at the beginning of a cycle. For women whose only infertility problem is anovulation, up to 80% of patients will ovulate using this medication and 50% of those will conceive . Clomiphene may be combined with intrauterine insemination to boost the success of the medication by placing the sperm and egg in closer proximity to each other.

The more aggressive level of ovulation induction is called superovulation. This treatment uses gonadotropins or sometimes a combination of clomiphene and gonadotropins to stimulate the production of multiple eggs. Patients undergoing superovulation must be closely monitored by blood tests and ultrasounds. Monitoring ensures that the patient does not hyperstimulate and also helps the physician administer the correct dosage of medication so that only a few follicles develop. This is a critical step to keeping the multiple pregnancy rates low. At the end of the superovulation treatment process, a low dose HCG (human chorionic gonadotropin) may be prescribed to stimulate ovulation. Ovulation will occur between 24-36 hours after HCG. The patient is instructed to either have intercourse during this time or to come in for an intrauterine insemination. Depending on the cause of infertility, the success rate per superovulation treatment cycle is approximately 10-20% based on the woman's age.

Clomiphene & Letrozole

Both clomiphene citrate and letrozole are medications used to treat infertile women who have an ovulation problem. These medications work by helping your pituitary gland (located at the base of the brain) improve the stimulation of developing follicles (eggs) in the ovaries. Neither clomiphene citrate nor letrozole may help a woman become more fertile if she is already ovulating normally. For that reason, these medications are most often prescribed to those patients who have been found to have an abnormality with their cycle.

Clomiphene is often referred to as the "fertility pill". Letrozole is very similar to clomiphene in the way it works. However, letrozole is quickly cleared from the body. It only works for the cycle in which it is taken and is less likely to adversely affect the uterine lining and cervical mucous. With clomiphene, one may experience effects 6-8 weeks after stopping the medication. Both medications are prescribed for five days each cycle, usually beginning on day three and continuing through day seven. The usual initial dose for clomiphene is 50 mg, one tablet daily. The number of tablets can be increased to as many as four daily, if a lesser dosage does not result in ovulation. Rarely are more than two tablets required. Clomiphene should be repeated each cycle until pregnancy occurs, or your doctor discontinues it. The usual dosage of letrozole is 2.5 mg., one tablet each day.

Of all women treated with clomiphene, or letrozole, 60% to 80% will ovulate normally. However, only half of those patients who ovulate will become pregnant. It is not known why only half of the women who apparently ovulate with clomiphene or letrozole therapy become pregnant. It is suspected that factors other than inadequate ovulation may be contributing to the fertility problem. Therefore, if you are not pregnant after three or four cycles, additional testing such as hysterosalpingogram or laparoscopy may be necessary. If you have polycystic ovary syndrome, a trial of metformin (Glucophage) therapy may be advised.

Some 10% to 20% of women taking clomiphene or letrozole will experience side effects. By far, most of these are minor and temporary in nature. They include such things as hot flashes, blurred vision, nausea, bloating sensation, and headache. Serious side effects are rarely seen with either medication. There are two side effects associated with clomiphene or letrozole therapy that warrant specific discussion. The first is the possibility of multiple pregnancy. The frequency of twins occurring in women who conceive while taking clomiphene or letrozole has been reported to be as high as 10%. Triplets may occur as frequently as 1 in 400 births, and quadruplets in 1 in 800 births. Neither clomiphene nor letrozole is the "fertility drug" you may have heard in the news bulletins often associated with large numbers of infants, such as quintuplets. Newer studies suggest that long-term use of either clomiphene or letrozole for more than 12 cycles may place you at an increased risk of developing ovarian cancer. Secondly, clomiphene and letrozole have also been associated with the occasional development of ovarian cysts. These cysts are not true growths of the ovary and within a few weeks will resolve without treatment. However, on an extremely rare occasion, these cysts have been known to cause internal bleeding or twist, requiring surgery and removal of the involved ovary. However, I must again emphasize that such a complication is extremely rare.

Clomiphene or letrozole stimulated cycles are not unlike normal cycles in that there is only a 20-25% chance of conception occurring each cycle during the first three to four treatment cycles, even if the medication is working properly. (Results may be lower with unexplained infertility.) This means that at least four to six cycles of treatment are necessary before one has given either medication an adequate trial. Recent studies indicate that if a pregnancy occurs as a result of the clomiphene/letrozole treatment, there is no clinically significant increased risk of miscarriage or congenital birth defects when compared to other infertile couples who conceived without clomiphene/letrozole treatment. However, women with polycystic ovary syndrome may be at higher risk for miscarriage during a pregnancy conceived using either of these medications.

More than half the clomiphene/letrozole pregnancies occur during the first three cycles and more than 3/4 occur at the 50mg. (or 2.5 mg letrozole) dose. Rarely will pregnancy occur when more than 100mg/day (two tablets) are necessary. If you have not conceived after three cycles, intrauterine insemination will be recommended to improve your chances of conceiving. If you have not conceived after four to six cycles, either combined clomiphene (or letrozole)/hmg/insemination or Gonal-F/Follistim injections and intrauterine insemination will be recommended.

How is a treatment cycle with Clomiphene/Letrozole carried out?

    1. Beginning on cycle day 3, start clomiphene citrate 50 mg (or letrozole 2.5 mg), one by mouth each day through cycle day 7.

    2. On day 9 or 10,  lab work may be carried out (LH and FSH). If the LH level is two to three times higher than the FSH level, clomiphene citrate/letrozole is less likely to work for you.

    3. On day 12, you will begin daily/alternate day ultrasounds - called follicular monitoring. This helps show the exact size and growth of both the follicles [eggs] as well as the thickness of the endometrium [lining of the inside of the uterus]

    4. When the follicle is "ripe" you may be given an injection for it to rupture

    5. Around the time of rupture you will be asked to have timed sexual intercourse OR to come in for an IUI

    6. If you miss your period you will be asked to come in for a pregnancy test and if the pregnancy test is positive, you will be asked to carry out some blood tests (a specific kind of pregnancy test, a quantitative hCG). You will then be asked to return in two days to have this specific pregnancy test repeated. This test is repeated so that we can measure the amount of hCG (human chorionic gonadotropin, which is produced after pregnancy occurs), looking for at least a 60% increase in the level. This helps us to know whether this is a pregnancy that is progressing appropriately.

    7. If it appears the pregnancy is progressing appropriately, you would then be scheduled for your first pregnancy ultrasound approximately 2 weeks later.