GnRH Analogs (GnRH agonists or antagonists)
Gonadotropin releasing hormone (GnRH) is a hormone produced in the brain which indirectly stimulates ovarian function. Analogs of GnRH are synthetic forms of this hormone which do not directly induce follicle development or ovulation but which have become very important in ART therapy. There are several advantages to using GnRH agonists or GnRH antagonists. First, they make ovarian stimulation easier to regulate, since the patient's own hormone production is suppressed. Second, patients who are treated with GnRH agonists or antagonists tend to produce a greater proportion of mature oocytes than patients who do not receive them. Third, GnRH analogs markedly decrease the risk of cycle cancellation for most patients. Prior to their use, 20-30 percent of IVF-ET cycles were canceled because patients would have a premature LH surge with spontaneous ovulation. Using GnRH analogs, the risk of cycle cancellation is less than 5%. Fourth, ovarian function can be suspended with GnRH analogs for variable periods of time if necessary, which allows for flexibility in cycle scheduling.
The major disadvantage of GnRH analogs is that most patients require more medication for ovarian stimulation. This increases the cost of an ART cycle. For most patients, this disadvantage is far outweighed by the advantages. Occasionally, patients require adjustments in dosage of GnRH analogs, or may respond better to treatment without analogs. Your doctor can discuss these issues with you.
Mechanism of Action
Agonists of GnRH initially stimulate the pituitary gland to release all the stored gonadotropins (LH and FSH - the hormones that normally stimulate ovarian function). Over the course of a week to ten days, GnRH agonists suppress the production of any new LH and FSH. This effect appears to prevent the ovaries from receiving mixed signals - from the patient's own LH and FSH and from the medications that we administer to stimulate follicle development. The result for many patients is a more synchronized development of mature oocytes. GnRH antagonists immediately suppress FSH and LH so they are given later in the stimulation cycle.
Dosage and Monitoring
The GnRH agonist we use most commonly is leuprolide acetate (Lupron®). Lupron® must be injected to be active. In ART therapy, we use a formulation of Lupron® which can be injected just under the skin, in a manner similar to insulin injections for diabetes therapy.
The usual dosage of Lupron® is 0.1 or 0.2 cc daily as a single injection. Menstruation usually occurs four to ten days later. During the time of actual ovarian stimulation, the dosage of Lupron® is halved (e.g., 0.1 cc to 0.05 cc daily). Lupron® is usually administered until the day of hCG administration. Some patients, because of their history or condition, are treated with a different dosage or schedule of Lupron®. Your physician will advise you if these changes apply to you.
Another GnRH analog used in ART therapy is nafarelin acetate (Synarel®). Synarel® is administered as a nasal spray. The usual starting dose is two sprays twice a day. The timing of administration is identical to Lupron®. The dosage of Synarel® is usually halved (e.g., from two sprays twice a day to one spray twice a day) when ovarian stimulation is begun.
GnRH antagonists (Cetrotide® or Ganirelix®) will be given usually as a daily dose once the lead follicles are >13 mm or the estradiol level is >1000 and will be continued through the day of receiving the HCG (trigger shot, most commonly Ovridel®)
Adverse effects from GnRH analogs are uncommon. Occasionally, ovarian cysts may form during therapy. These usually resolve spontaneously. Rarely, cysts may grow so large as to cause abdominal bloating and pain. Even less common is ovarian torsion, in which the ovary twists and cuts off its own blood supply. Surgical removal of the ovary may be necessary in these very rare circumstances.
Other adverse effects of GnRH analogs include headaches, mood changes, and altered sleep. Hot flashes may occur during prolonged therapy. Allergic reactions are rare. A slight redness and discomfort may occur at the Lupron®, Cetrotide® or Ganirelix® injection site, and patients using Synarel® may experience nasal stuffiness.
To increase the likelihood of pregnancy through ART, multiple oocytes must be produced. This is accomplished through the administration of gonadotropins-hormonal medications which stimulate the ovaries. Stimulation can be achieved with a variety of drug regimens. Gonadotropin medications come in several forms. Menopur® is a combination of FSH and LH. They replace a woman's own LH and FSH which are normally produced by the pituitary gland. Bravelle®,®Gonal-F® and Follistim® are preparations that contain only FSH. Gonal-F® and Follistim® are recombinant products which are made by genetically engineered cells. This process ensures uniform purity and potency. Microdose HCG is similar to LH and may be used with the other gonadotropins for stimulation depending upon the protocol your physician plans for you. Because the dose of hormones we use in ART is greater than what the body normally produces, the ovaries typically develop more than one oocyte as occurs in a natural cycle.
Gonadotropins act directly on the ovary to stimulate the growth of follicles (the structures in ovaries which contain eggs). Granulosa cells within the follicles grow and develop which cause the follicles to enlarge and fill with follicular fluid. These developing follicles can be counted and measured using transvaginal ultrasound. As the follicles grow, they produce increasing amounts of estrogen, which can be measured with a laboratory blood test. Some physicians prefer one formulation or another. Your doctor can discuss this with you in more detail.
Dosage and Monitoring
Gonadotropins are packaged in vials containing 75 or 150 International Units (IU) or in pens containing 300-900 IU that can be dialed to the proper unit dose planned for each injection. Your stimulation plan will be individually planned and developed by your physician. The dosage may vary depending on the patient's age and history. A few days after starting the ovarian stimulation medications, we then see patients in the office for regularly scheduled transvaginal ultrasound examinations and serum estradiol tests. The subsequent dose of gonadotropins is then determined by the result of the ultrasound and estradiol tests. Most women require between seven to ten days of gonadotropin therapy.
All of the gonadotropin stimulation medications are administered subcutaneously, like an insulin or allergy shot.
Gonadotropin preparations are strong medications. Although rare, a potentially serious adverse effect of gonadotropins is ovarian hyperstimulation. Even after oocyte retrieval, the ovarian tissue may continue to grow in response to the prior gonadotropin stimulation. As the ovaries enlarge, discomfort and bloating may occur. Occasionally, an enlarged ovary may become twisted. This condition is referred to as ovarian torsion. When this occurs, surgery may be required to either remove the ovary or untwist it.
In addition to discomfort, women suffering from severe ovarian hyperstimulation may develop ascites (a collection of fluid in the abdomen or pelvis). This fluid enters the pelvis by leaking through blood vessels. Although rare, this condition can be severe enough to produce swelling of the abdomen and shortness of breath. Hospitalization is required in cases of severe ovarian hyperstimulation. Treatment for ovarian hyperstimulation usually consists of bed rest and intravenous fluids. On rare occasions it is necessary to drain fluid from a patient's abdomen. Hyperstimulation is more severe when pregnancy occurs, as the developing pregnancy produces the hormone hCG, which stimulates the ovaries to continue to grow. Hyperstimulation can remain a potential problem for 2-3 months during the pregnancy.
There does not appear to be any increased risk of birth defects in offspring of women who take gonadotropins compared to conceptions in the general population. However, there may be a greater risk of early miscarriage in patients taking gonadotropins. Approximately 20-25 percent of gonadotropin induced conceptions miscarry within the first trimester. Multiple pregnancy is another adverse effect of gonadotropins therapy. Approximately 25 percent of IVF-ET pregnancies are multiple. The risk of more than twins is about 1 percent.
Although not truly an "adverse effect," the cost of gonadotropins must be taken seriously. One ampule (amp) of 75 IU typically costs about $75. As these medications are commonly administered for seven to ten days, it is not unusual for the medication cost for a single cycle to cost $2,000-$5,000. Some women have obtained gonadotropins in other countries. According to the FDA, it is illegal to import drugs from other countries for use in the United States. Some patients with poor response to stimulation have admitted to using imported gonadotropins.
In summary, gonadotropins are strong, effective medications for inducing follicle development. Their use must be monitored carefully, preferably with a combination of regular transvaginal ultrasound examinations and estradiol determinations. When administered and monitored carefully, the risk of adverse effects is acceptably low.
Human Chorionic Gonadotropin
Human chorionic gonadotropin (hCG) is an injectable medication that is administered to complete oocyte maturation (trigger shot). It can also be used in conjunction with clomiphene citrate, or in a natural cycle. The newest recombinant formulation called Ovridel® (choriogonadotropin alpha) comes in a pre-filled syringe and in a dose of 250 micrograms and is now routinely used as the trigger shot and has the advantage of subcutaneous injection but is more expensive costing approximately $130-$180 per injection. Other brand names for hCG that can be given are Profasi® and Pregnyl®. These medications come in 5,000 and 10,000 unit ampules. Typically a 10,000 unit ampule costs $35-$50. These older forms of hCG medications must be given intramuscularly.
Mechanism of Action
Human chorionic gonadotropin is structurally similar to the LH which is produced by a woman's pituitary gland. It acts on the ovary in a manner similar to a woman's own LH. Human chorionic gonadotropin, like LH stimulates the final maturation of the oocytes in the follicle. It also stimulates progesterone production from the ovary after egg retrieval. This progesterone is important to prepare the uterus for implantation of the embryo.
Dosage and Administration
Human chorionic gonadotropin can be administered several different ways. We commonly administer a single injection of Ovridel® (choriogonadotropin alpha) which comes in a pre-filled syringe and in a dose of 250 microgramsand is given subcutaneously. Once hCG is administered, ovulation usually occurs in approximately 36 to 40 hours. We therefore routinely schedule oocyte retrieval at 35 hours after hCG. This helps ensure maximal egg maturity, which is important for fertilization and embryo development.
It typically takes 8-10 days for single injection of 250 micrograms of hCG to be cleared from the blood stream. As hCG is the same hormone that is produced by a developing pregnancy, patients should not have a blood or urine pregnancy test sooner than ten days following the hCG injection. If a pregnancy test is performed earlier, it may measure the hCG that was given by injection rather than measure hCG produced by a pregnancy.
When given by itself, there are few, if any adverse effects to hCG. However, when given in conjunction with gonadotropins, ovarian hyperstimulation can occur. In fact, hyperstimulation is extremely rare if hCG is not administered.
Clomiphene citrate (Clomid® and Serophene®) is an oral medication that is commonly administered to induce ovulation in women who do not ovulate regularly. We also use clomiphene citrate for minimal stimulation IVF-ET. Typically, each 50 mg pill costs approximately $5.00 to $8.00.
Mechanism of Action
Clomiphene acts within the brain to promote the production of the hormone, GnRH. As a result, the pituitary gland makes more FSH and LH, the hormones that stimulate ovarian function. In particular, the increased FSH stimulates more follicles in the ovaries to grow.
Dosage and Monitoring
For minimal stimulation IVF-ET, the usual dosage of clomiphene is 100 mg daily for five days, beginning on day three of the menstrual period. Follicle development in response to clomiphene is most accurately determined by ultrasound. Typically, you will take a cycle (pack) of oral contraceptive pills to regulate the start of your period before stimulation. We perform an ultrasound to examine the ovaries around the time you finish the oral contraceptives. The next ultrasound will be performed the day after the last clomiphene citrate dose. Additional ultrasounds will be performed (usually every other day or daily) until the day the largest follicle measures 18-20 mm in diameter. On that day hCG, Ovridel® in a dose of 250 micrograms will be injected intramuscularly in the evening. Oocyte retrieval will be performed 35 hours after the hCG injection. A urine ovulation predictor kit may be used in addition to ultrasound monitoring. These kits detect large amounts of LH in the urine. Once a follicle is mature, the pituitary releases a large amount of LH, called an LH surge. Most women will ovulate within 24 hours of detecting a urinary LH surge. When a spontaneous LH surge is detected in a minimal stimulation cycle, the cycle may be canceled as it is difficult to time the egg retrieval to obtain a mature egg prior to ovulation.
Severe adverse effects are uncommon with clomiphene citrate. First, as multiple follicles can sometime develop, multiple pregnancy may occur. This complication is uncommon in minimal stimulation IVF-ET. Another complication is ovarian cyst formation. While these cysts usually resolve spontaneously, they may cause bloating and abdominal discomfort. On rare occasions, these cysts may rupture causing abdominal pain. Approximately 10 percent of women who take clomiphene citrate experience hot flashes, which may disrupt sleep. A small percentage of patients (less than 5 percent) report some visual changes during clomiphene citrate therapy. Some patients describe blurred vision, while other patients describe seeing spots or flashes of light after images. You should report any of these adverse effects to your physician.
There does not appear to be any increased risk of birth defects in offspring of women who take clomiphene citrate. In large studies, the risk of birth defects does not appear to be greater than that noted in the general population. Likewise, the risk of miscarriage in women taking clomiphene does not appear to be increased over that noted in the general population.
There has been some concern about an association of the use of clomiphene with the subsequent development of ovarian cancer. At this time, information about this subject is very limited. While several studies have suggested an increased risk of ovarian cancer in women who have taken clomiphene citrate, these studies have been widely criticized for many reasons. If the risk of ovarian cancer in women taking clomiphene is increased at all, this increase appears small. Additionally, numerous other studies have not shown an increased risk of ovarian cancer in women who took clomiphene citrate. The lifetime risk of ovarian cancer in all women is approximately 1 in 70. The risk has not been observed in women who have a successful pregnancy from clomiphene therapy so conceiving may decrease the risk of ovarian cancer in infertility patients.