Gonadotropin-releasing hormone analogues for infertility

Gonadotropin-releasing hormone (GnRH) agonists and antagonists belong to a group of hormone drugs called GnRH analogues.

Gonadotropin-releasing hormone agonists

Gonadotropin-releasing hormone antagonists

How GnRH analogues are taken:

• Nafarelin acetate is sprayed into the nose (intranasally) twice a day.
• Cetrotide is injected under the skin once daily for several days, or once on day 7 of the menstrual cycle.
• Antagon is injected under the skin once daily for several days.
• Leuprolide acetate (Lupron) is injected under the skin, while depo leuprolide acetate (Lupron Depot) is injected into a muscle. About 10 days of injections are typically necessary to "shut down" ovulation before stimulating ovulation for an infertility treatment.

Daily GnRH agonist injections overstimulate the pituitary gland, triggering production of more luteinizing hormone (LH) and follicle-stimulating hormone (FSH) than normal, which makes it temporarily shut down. The "disabled" pituitary gland then stops producing LH and FSH, which in turn stops ovulation.

GnRH antagonist injection is a recent addition to infertility treatment. While agonists act over several days to stop ovulation, antagonists act almost immediately by blocking the effect of GnRH on the pituitary gland. Because an antagonist stops the pituitary from making LH within an hour or two, it doesn't have to be used for as many days as an agonist does.

GnRH analogue treatment is used to "shut down" the pituitary hormones that control the ovaries.

To treat infertility concerns, a GnRH analogue (agonist or antagonist) is used:

• To closely time and control ovulation before an assisted reproductive technology (ART) procedure by shutting down the pituitary gland. This is called "pituitary down-regulation." At the same time or afterward, an ovulation-stimulating medication is used to trigger ovulation, with the goal of harvesting good-quality eggs on a predictable schedule. Increasing numbers of doctors are now using a GnRH antagonist (instead of a GnRH agonist) at the same time that ovulation medication is used, quickly suppressing the luteinizing hormone that can cause early ovulation.
• To closely time ovulation before some insemination procedures, when unpredictable ovulation would make it difficult to know when to introduce sperm into a woman's reproductive tract.
• As an experimental treatment to protect the egg supply when chemotherapy is needed to treat cancer. When the ovaries are shut down with a GnRH agonist during chemotherapy, they are less likely to be rendered sterile.¹

GnRH analogues (agonists and antagonists) predictably stop ovulation and menstruation. Agonists take more days of treatment than antagonists do to shut down the ovaries.

Controlling ovulation timing before an infertility procedure. Shutting down the pituitary with GnRH analogue treatment, paired with a hormone to stimulate egg production, lowers the chance that an ART procedure will be canceled because of early ovulation. For controlling egg production before an infertility treatment, a longer course of GnRH agonist treatment has been shown to produce higher pregnancy and live birth rates, when compared with a short course of doses.²

Preventing sterility during cancer treatment. In a small study of women undergoing standard dose chemotherapy, 94% of those who also received GnRH agonist treatment were able to ovulate 3 to 8 months later. By contrast, only 39% of women receiving only chemotherapy were able to ovulate in the following months.¹ (The same effects may not be seen for women receiving high-dose chemotherapy before a bone-marrow transplant.)

When paired with ovulation-stimulating treatment, GnRH analogues don't cause low-estrogen symptoms. However, when taken alone, they produce a temporary condition similar to menopause, with many of the same effects.

Side effects that go away when a GnRH agonist is stopped include:

• Hot flashes.
• Mood swings.
• Vaginal dryness.
• Decreased sexual interest.
• Increased low-density lipoprotein (LDL) cholesterol level.
• Decreased high-density lipoprotein (HDL) cholesterol.
• Insomnia.
• Headaches.

Initially, GnRH antagonist treatment can cause headache, nausea, or swelling, redness, or itching at the injection site.

See Drug Reference for a full list of side effects. (Drug Reference is not available in all systems.)

Before insemination, GnRH analogue treatment paired with an ovulation-stimulating treatment increases the risk of conceiving a multiple pregnancy, which is dangerous for a mother and her fetuses. In the case of an assisted reproductive technology such as in vitro fertilization, this risk is controlled by limiting the number of fertilized eggs that are transferred to the uterus.

Drawbacks of GnRH analogue treatment are menopausal symptoms and cost of the medication.

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Citations

1. Posada MN, et al. (2001). Fertility options for female cancer patients: Facts and fiction. Fertility and Sterility, 75(4): 647–653.

2. Yao MWM, Schust DJ (2002). Treatment options section of Infertility. In JS Berek, ed., Novak's Gynecology, 13th ed., pp. 1018–1036. Philadelphia: Lippincott Williams and Wilkins.

Author:	Shannon Erstad, MBA/MPH	Last Updated April 7, 2006
Medical Review:	Joy Melnikow, MD, MPH - Family Medicine Kirtly Jones, MD - Obstetrics and Gynecology
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