Ovulation Induction

Ovulation Induction is a term that refers to the administration of medication to cause the follicles of the ovaries (that contain the eggs) to develop. There are a variety of medications that can be used and there are several reasons to undergo this therapy. To understand how ovulation induction works, let us first explain how a woman normally produces an egg.

Normal Follicle Development

In a normal menstrual cycle, Follicle Stimulating Hormone (FSH) is released from the pituitary gland in the brain and activates several follicles containing eggs in the ovary. In turn, the activated follicles make hormones that feedback to the brain, resulting in a limited amount of FSH being released. This means there is just enough FSH for only one follicle containing an egg to fully develop. When this growing follicle is mature, it sends signals to the brain resulting in the release of Luteinizing Hormone (LH), which in turn causes the follicle to release the egg (ovulation). The hormone estrogen is made by the growing follicle and it causes the lining of the uterus to grow. After the egg is released from the follicle, the follicle becomes the corpus luteum, which secretes progesterone. Progesterone makes the lining of the uterus receptive to the embryo. The ovulation induction process uses these basic principles to accomplish the goals of a given treatment.

The Medicines

There are two basic types of ovulation medications: oral medicines and injectable medicines. We also have our injectable “trigger” shots which can be an important part of these treatments.

Oral Medications

The oral medicines include clomiphene citrate, tamoxifen and letrozole. Interestingly, all were developed as breast cancer treatments: clomiphene in the 50’s, tamoxifen in the late 60’s and letrozole in the late 80’s. Although at a molecular level the actions are slightly different, they each work by causing the pituitary gland to release more FSH which in turn stimulates the ovaries to grow follicles containing eggs. These ovulation induction pills can be effective for women who do not ovulate (such as in Polycystic Ovary Syndrome) and can be used in combination with the injectable medications in other settings.

Injectable Medications (Gonadotropins)

The injectable medications include Gonal F, Follistim and Menopur. Gonal F and Follistim are pure FSH made by recombinant DNA technology and are given subcutaneously with tiny needles.  Both medicines come in “pens” with cartridges of various size doses to make dosing and delivery easy. Menopur is an equal mixture of both FSH and LH and is also highly purified – it can be given subcutaneously. There are a variety of uses for these medications including for women who do not ovulate, unexplained infertility when intercourse or intrauterine insemination (IUI) are used to deliver sperm. These medications are also an important part of the IVF process discussed elsewhere.

“Trigger Shots”

Trigger shots contain human chorionic gonadotropin, the “pregnancy hormone”.  Its actions are identical to LH, but it lasts longer.  It is used to simulate the normal midcycle LH surge, which causes the final maturation of the egg and egg release (ovulation). It is used primarily with the injectable medications because they have altered the normal feedback mechanisms and the LH surge may not occur on its own.  There are several forms of hCG that can be used.

Monitoring

The type of monitoring done of an ovulation induction cycle depends on the medications being used and the reason for doing the treatments. All of this is highly individualized. Generally, oral medications can be monitored simply with ovulation predictor kits, with intercourse or IUI occurring the day after the kit is positive. This is because the body’s feed-back system is fully functional and protects the woman from over-response.  Sometimes, though individuals using oral medications do need more advanced monitoring with ultrasound and bloodwork.

With injectable medicines, we must monitor the follicle development with ultrasound and blood work (estrogen and sometimes progesterone levels) because the body’s feed-back system has been by-passed using these drugs. Ultrasound tells us how many follicles are developing and the bloodwork tells us how active they are. Our goal is to get 1 to 4 follicles to mature, depending on the patient’s diagnosis. In most of these treatments we need to use the trigger shot hCG to start the ovulation process and help time intercourse or IUI because of the temporary alterations to the feedback system in the treatment.

Adverse Reactions and Risks to Ovulation Induction

Multiple Pregnancies

Multiple pregnancy is the biggest risk of ovulation induction and does not occur frequently. Naturally, the risk of twins is 1%. With the oral medicines the multiple risk is 4-5 % for Letrozole and 8-10% for clomiphene and tamoxifen. The gonadotropins, the risk of multiple pregnancy in our practice is about 10%.  The risk is somewhat proportional to the number of mature follicles but cannot be absolutely predicted. More than twins may occur with these treatments but are very uncommon. If you have over responded, we can aspirate excess follicles so that we have a safe number of eggs being ovulated. Another alternative is to cancel the cycle.

Ovarian Hyperstimulation Syndrome 

OHSS is a sudden enlargement of the ovaries and accumulation of fluid in the abdomen.  It can be a rapidly progressive medical emergency, which in its worst form may require hospitalization and even intensive care services.  The cause is not precisely known, but it is associated with high estrogen levels. Many of the women who develop OHSS are pregnant. The monitoring is designed to attempt to prevent OHSS from occurring. Fortunately, it is exceedingly rare in both our oral medication and gonadotropins cycles.

Adverse reactions to gonadotropins include local irritation at injection site, mood swings and irritability, nausea, breast fullness or tenderness, pelvic fullness or discomfort, constipation, or bloating. An extremely rare occurrence is ovarian torsion (twisting of an ovary, usually because it is enlarged), which causes severe pain and needs to be treated surgically.

An Example of Ovulation Induction Treatment: Controlled Ovarian Hyperstimulation and Intrauterine Insemination for Unexplained Infertility

Step 1: Complete basic infertility evaluation. This starts with making an appointment to see one of our Physicians or Nurse Practitioners. A semen analysis will be done to make sure the sperm parameters are sufficient for the IUI process. A hysterosalpingogram (HSG) makes sure the uterine cavity is normal and the fallopian tubes are open. Ovarian reserve testing will be done to evaluate ovarian function and they will also look for medical issues to be corrected to optimize the process.

Step 2: Ovarian stimulation. The goal in the setting of unexplained infertility is to get 2 to 4 mature follicles containing eggs.  We do this by starting the patient on the oral medicine letrozole for 5 days and then adding in a very low dose of an injectable medication after that. The injectable medication is continued until the follicles reach the mature size. There are typically 3 to 4 visits during the roughly 10 days of medication to monitor the progress where transvaginal ultrasound and bloodwork are done.

Step 3: Intrauterine Insemination. Once the follicles have reached the mature size (16-22 mm) and we have a safe number (4 or less), we give the “trigger shot” to initiate the egg release process. Typically, 24-36 hours after the trigger shot, the male partner produces a semen specimen, and it is processed to separate the sperm from the semen and concentrate it in a small volume of fluid (culture media). This typically takes about an hour to do. When the specimen is ready, the woman will have a speculum placed in the vagina to visualize the cervix (just like with a pap smear) and then the thin catheter is placed into the cervix and up into the uterine cavity and the sperm are released there. The IUI catheter and speculum are removed, and the woman is free to go about her day with no restrictions. The actual IUI itself takes just a couple of minutes.  A couple of days after the IUI, progesterone is given vaginally to make sure the uterine lining is receptive to the embryo. About 2 weeks after the IUI, a pregnancy test is done.