ART Medications

GnRH Agonists

Gonadotropin releasing hormone (GnRH) is a hormone produced in the brain that indirectly stimulates ovarian function. Agonists 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. 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 tend to produce a greater proportion of mature oocytes than patients who do not receive them. Third, GnRH agonists markedly decrease the risk of cycle cancellation for most patients. Prior to their use, 20-50% of IVF-ET cycles were canceled because patients would have a premature LH surge with spontaneous ovulation. Using GnRH agonists, the risk of cycle cancellation is less than 5%. Fourth, ovarian function can be suspended with GnRH agonists for variable periods of time if necessary, which allows for flexibility in cycle scheduling.

The major disadvantage of GnRH agonists 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 agonists or may respond better to treatment with GnRH antagonists. Your doctor can discuss these issues with you.

Mechanism Of Action

Agonists of GnRH (such as Lupron®) 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 analogs 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.

New antagonists of GnRH are also available. These are started later in the cycle than Lupron® and directly and immediately inhibit FSH and LH production.

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.

Adverse Effects

Adverse effects from GnRH agonists 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 agonists 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® injection site, and patients using Synarel® may experience nasal stuffiness.

Over 300 inadvertent pregnancies have been reported in women who were taking GnRH agonists. Miscarriage and birth defect rates do not seem to increase. Some neurological problems have been observed in the children born from pregnancies conceived while the mother was on GnRH agonists.

Gonadotropins

To increase likelihood of pregnancy through ART, multiple oocytes must be produced. This is accomplished through the administration of gonadotropins-hormonal medications that directly stimulate the ovaries. Stimulation can be achieved with a variety of drug regimens. Gonadotropin medications come in several forms, Repronex® and Menopur® are a combination of FSH and LH. They replace a woman's own LH and FSH which are normally produced by the pituitary gland. Bravelle®, Follistim® AQ Cartridge for use with Follistim Pen®, Follistim® AQ Vial, Gonal-F®, and Gonal-F® RFF Pen are preparations that contain only FSH. Follistim® AQ Cartridge for use with Follistim Pen®, Follistim® AQ Vial, Gonal-F®, and Gonal-F® RFF Pen are recombinant products which are made by genetically engineered cells. This process ensures uniform purity and potency. 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 37.5, 75 or 150 International Units (IU). Follistim AQ Pens and Gonal-F RFF Pens are packaged in pre-mixed injectable pens. Multi-dose vials of some medications are also available. In the first cycle of IVF-ET we routinely administer 300 IU of gonadotropins daily for three days. This dosage may vary depending on the patient's history. We then see patients in the office for regularly scheduled transvaginal ultrasound examinations and serum estradiol tests. The 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.

Bravelle®, and Repronex® are administered subcutaneously or an intramuscular injection, usually into the muscles of the buttocks. Gonal-F,® Follistim,® Follistim AQ Pens, and Gonal-F RFF Pens are administered subcutaneously, like an insulin or allergy shot.

Adverse Effects

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, laparoscopy may be required to untwist it. Rarely, an ovary may need to be removed.

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 to 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 is a greater risk of early miscarriage in patients taking gonadotropins. Approximately 20-25% of gonadotropin-induced conceptions miscarry within the first trimester. Multiple pregnancies are another adverse effect of gonadotropin therapy. Approximately 30% of IVF-ET pregnancies are multiple. The risk of more than twins is less than 5%.

Although not truly an "adverse effect," the cost of gonadotropins must be taken seriously. One ampule (amp) of 75 IU typically costs between $35 and $70. 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 $1,500 to $3,000. 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. The brand names for hCG are Profasi®, Ovidrel®, Novarel ®,and Pregnyl®. These medications come in 5,000 and 10,000 unit ampules. Typically a 10,000 unit ampule costs $40-$70.

Mechanism of Action

Human chorionic gonadotropin is structurally similar to the LH that 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 10,000 units. Once hCG is administered, ovulation usually occurs in approximately 36 to 40 hours. We therefore routinely schedule oocyte retrieval at 34-36 hours after hCG. This helps ensure maximal egg maturity, which is important for fertilization and embryo development. Occasionally, several doses of 2,500 units (usually every three days) are administered after egg retrieval to stimulate progesterone production. If your response to stimulation is particularly exuberant, we may recommend decreasing the dose of hCG to 5000 units in an attempt to reduce the risk of ovarian hyperstimulation syndrome.

It typically takes 8-10 days for single injection of 10,000 units 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.

Adverse Effects

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

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 may 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 20 mm or more in diameter. On that day hCG, 10,000 units 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.

Adverse Effects

Severe adverse effects are uncommon with clomiphene citrate. First, as multiple follicles can sometimes develop, multiple pregnancies 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% of women who take clomiphene citrate experience hot flashes, which may disrupt sleep. A small percentage of patients (less than 5%) report some visual changes during clomiphene citrate therapy. Some patients describe blurred vision, while other patients describe seeing spots or flashes of light or 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 recent 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 some 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. The lifetime risk of ovarian cancer in all women is approximately 1 in 70. If the preliminary evidence turns out to be true, the increased rate of ovarian cancer in patients taking clomiphene may be as high as 3 to 4%. This increased risk of ovarian cancer in patients taking clomiphene seems to occur only in women who have taken clomiphene for greater than one year (12 cycles). The risk has not been observed in women who have a successful pregnancy from clomiphene therapy.

Infertility is also a well-known risk factor for ovarian cancer, which makes it difficult to determine the impact of clomiphene on patients’ risk. Having a successful pregnancy has been associated with a reduced risk of ovarian cancer, and this must be considered when weighing treatment options.

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