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  » Infertility  »  Induction of ovulation

What is induction of ovulation?

Ovulation induction involves the use of medication to stimulate development of one or more mature follicles (where eggs develop) in the ovaries of women who have anovulation and infertility . These women do not regularly develop mature follicles without help from medication.

Some women with anovulation have a condition known as polycystic ovarian syndrome . These women usually have irregular menstrual cycles, increased body hair , and infertility.

Ovulation induction is somewhat different from controlled ovarian hyperstimulation which involves use of some of the same medications to stimulate development of multiple mature follicles and eggs in order to increase pregnancy rates with various infertility treatments.

Who should be treated with induction of ovulation?
Women who do not ovulate regularly on their own and want to become pregnant.

Ultrasound image of an ovary from a woman with polycystic ovarian disease
These women do not develop mature follicles or ovulate without medication
About 12 immature follicles (black circles) are seen here

Ultrasound image of an ovary from the same woman after clomiphene treatment
Multiple mature follicles are now present

How is induction of ovulation performed?

There are four basic types of medication that are used to induce ovulation. Treatment with these medications has the potential to result in pregnancy if the woman has good quality eggs remaining in her ovaries, and if other causes of infertility are not present.

For women with ovarian failure or extremely very poor quality eggs there is currently no medication available to allow a reasonable chance of conception with any type of ovarian stimulation. Egg donation is their best option for getting pregnant.

The four major types of drug therapy for ovulation problems include clomiphene citrate, injectable gonadotropins, GnRH pump, and bromocriptine. These are all discussed below.

Pregnancy rates for induction of ovulation:

Success rates for induction of ovulation vary considerably and depend on the age of the woman, the type of medication used, whether there are other infertility factors present in the couple, etc..

Clomiphene citrate for induction of ovulation

Clomiphene citrate is an oral tablet that is usually taken either days 3-7 or 5-9 of the woman's menstrual cycle. Many women with anovulation do not have regular menstrual cycles on their own and therefore the menses would be induced by having the woman take a medication. Either medroxyprogesterone acetate (Provera) or birth control pills can be used to induce menses.

She would then take the clomiphene beginning shortly after the induced menstrual period begins. Clomiphene is usually given at an initial dose of 1 tablet (50 mg) a day for 5 days and if this is not successful in causing ovulation the dose is increased in the next cycle to 2 tablets per day for 5 days.

If two tablets a day are not successful in causing ovulation we would either try 3 tablets per day or move on to injectable gonadotropins. Women who do not respond to two tablets per day have some chance for ovulating and conceiving with 3 or more tablets a day. However, at these doses pregnancy rates are low. If the clomiphene citrate stimulates good follicle development then the couple is instructed to have timed intercourse or to come to the office for intrauterine insemination at the time of ovulation.

The time of ovulation can be detected in several ways, including urine LH predictor kits that can be used at home, blood work that is drawn in the physician's office or ultrasound performed in the physician's office to determine when a mature follicle is present.

Giving the woman an injection of HCG (human chorionic gonadotropin) can control the time of ovulation. Ovulation will then occur approximately 36 hours later and allows proper timing of either timed intercourse or intrauterine insemination.

Clomiphene citrate is an inexpensive form of ovulation induction that often does not require much if any monitoring with blood or ultrasound. However many women do not respond to clomiphene and for these women other more expensive medications will be required.

Ovulation and pregnancy rates using clomiphene for induction of ovulation

On a per cycle basis, and pregnancy rates with clomiphene are about 10-15% per ovulatory cycle for the first 3 cycles. After 3 cycles without a pregnancy, pregnancy rates are lower for subsequent cycles. After 6-9 failed cycles, the chances are substantially lower that pregnancy will occur with further clomiphene therapy.

Although about 50-80% of anovulatory women will be able to have ovulation induced with this medication, pregnancy rates are approximately half of the ovulation rates. For example, if 80% of women in a large population of anovulatory women can be made to ovulate with clomiphene citrate only about 40% of the women will actually achieve pregnancy. Therefore, many women will ovulate and not become pregnant while using this medication.

There are probably several issues that contribute to this phenomenon. Possibilities include a decrease in the quality of the eggs when clomiphene citrate is used, the negative impact of the clomiphene citrate on the quantity and quality of cervical mucus, and a negative impact on the quantity and/or quality of the endometrial lining (lining of the inside of the uterine cavity).

Metformin therapy for clomiphene resistant women with polycystic ovarian syndrome

Metformin is an oral medication that has been used in the last few years by some infertility physicians to assist in inducing ovulation in some women with anovulation and polycystic ovaries. For more information on this new form of therapy, follow the link above.

Injectable gonadotropins for induction of ovulation

Injectable gonadotropins contain follicle stimulating hormone (FSH) which causes development of multiple follicles when injected into anovulatory women.

These medications are given by intramuscular injections or subcutaneous injections on a daily basis. The injections are started early in the menstrual cycle and are continued for approximately 8-14 days until one or more mature follicles are seen with ultrasound examination of the ovaries. At that point an injection of HCG is given which induces ovulation to occur approximately 36 hours later.

Over 90% of anovulatory women can have ovulation induced with this type of therapy. Pregnancy rates per month are better than those with use of clomiphene citrate and for relatively young women with no other contributing causes to the infertility pregnancy rates per month of approximately 15% can be expected when this form of treatment is combined with intrauterine insemination . Pregnancy rates with injectable gonadotropins combined with intercourse are somewhat lower.

This type of therapy is usually tried for 6-12 months and if it does not result in a pregnancy in vitro fertilization should be considered.

The cost of using this medication is substantial. In the United States injectable gonadotropins cost approximately $35-70 per ampule and the required dose will range from one half ampule per day to 6 or more ampules per day for about 8-14 days.

Ultrasound and blood monitoring of the stimulation cycle is essential when using injectable gonadotropins as there are substantial risks associated with overstimulation if the ovaries should over respond to the medication.

This monitoring is usually done 2-3 days a week during the time the woman is taking the injectable medications. This adds substantially to the cost of the cycle. Some health insurance plans will pay for the entire cost of ovulation induction including insemination if that is desired. Other health insurance plans will pay for some or none of the costs associated with this treatment.

Complications associated with use of these medications include the possibility of overstimulation, which is reported to occur in approximately 1% of cycles. Hyperstimulation involves enlarged ovaries, abdominal pain, fluid build-up within the abdomen, and may require hospitalization in extreme cases to control pain or manage the syndrome. Careful monitoring and use of the injectable gonadotropins can almost always avoid severe overstimulation.

Multiple pregnancy is also a possibility when these medications are used. In general approximately 85% are single, 15% are twins, 3% are triplets and 1% are quadruplets or higher.

In very rare cases, 9 or more fetuses have implanted and shown heartbeat activity on ultrasound studies. Rarely can a pregnancy of more than 5 fetuses result in viable live birth unless a fetal reduction procedure (selective abortion) is performed at about 9-11 weeks of gestation.

The risk of multiple pregnancy increases with the number of mature follicles that are seen on ultrasound examination of the ovaries. However, it is usually not possible to stimulate the patient so that only one mature follicle develops and multiple follicle development is the rule.

When many mature follicles develop the couple and the physician can have a discussion about the risks of multiple pregnancy and there is always the option of canceling the cycle by not giving the injection that causes ovulation. This essentially eliminates the risk of any pregnancy (single or multiple) occurring in that cycle.

GnRH Pump for induction of ovulation

A GnRH pump can induce ovulation in some anovulatory women. This pump must be worn at all times. It releases a very small bolus of medication in to the woman's body every 60-90 minutes.

The pump is a small devise that is worn on the body. Many women find this inconvenient, as they must also wear it while sleeping and it also involves placement of needles into her skin.

This form of treatment is relatively more effective for patients with hypothalamic amenorrhea, which is a relatively rare condition in which the woman has no menstrual periods and is lacking the proper production of a hormone that is released from the brain that is involved in follicle development.

The GnRH pump has also been used for women other types of anovulation. However it is less effective for these other cases.

The advantages of the GnRH pump include a much lower risk of multiple pregnancy and that little or no monitoring of the patient is required. Little monitoring is required because this therapy is supposed to induce a situation very similar to that of natural menstrual cycles with development of a mature follicle and natural ovulation without any additional injections.

Bromocriptine for induction of ovulation

Anovulation caused by an elevated level of the hormone prolactin can be treated with a medication called bromocriptine. This is an uncommon type of anovulation disorder. Women with this condition often have no menstrual periods - amenorrhea .

Bromocriptine is an oral medication that is given once or twice daily. It is not very expensive.

When women have a mild to moderate elevation in their prolactin, bromocriptine is very effective in reducing the level back down to the normal range in most cases. This usually allows normal ovulation to occur every month.

Women with high levels of prolactin are less likely to respond well to bromocriptine therapy.

All women with unexplained elevations of prolactin over about 50-100 (normal < 20) need to have specialized imaging studies (CT or MRI) of the area of the pituitary gland at the base of the brain. This is to make sure that there is not a significant tumor causing the disturbance.

The most common tumor that causes a high prolactin is a benign (non-cancerous) tumor called a prolactinoma. These tumors if very small can be managed with bromocriptine to keep the prolactin in the normal range and yearly CT or MRI scans to look for significant tumor growth. Larger tumors often will require surgery.