GnRH Agonists for IVF, Endometriosis, and Fibroids

Risks and Side Effects of Lupron, Synarel, Suprecur, and Zoladex

syringe and GnRH agonist vial with Lupron on glass dish, used during IVF treatment
GnRH agonists like Lupron can cause unpleasant side effects.. Rafe Swan / Cultura / Getty Images

GnRH agonists are primarily used for the treatment of endometriosis and fibroids, but they are also frequently used “off label” during IVF treatment. Lupron is the most commonly used GnRH agonist for IVF.

Less commonly, a GnRH agonist can be used to stimulate ovulation instead of the usually hCG trigger shot during an IUI cycle.

The most common side effects of GnRH agonists are not dangerous – just unpleasant.

Between the mood swings, headaches, and hot flashes, most women consider Lupron the most disliked medication taken during IVF.

What Are GnRH Agonists? How Are They Used During IVF?

A kind of fertility drug, GnRH agonists are artificial hormones that mimic the body’s natural hormone gonadotropin-releasing hormone (GnRH).

A GnRH agonist first leads to a rapid increase in the production of the hormones FSH and LH. However, after this brief increase, the pituitary gland stops producing the hormones, preventing ovulation.

That initial boost in FSH and LH is why GnRH agonists can sometimes be used to trigger ovulation.

It is also why, when being used to treat endometriosis, symptoms can worsen at first. (See below for more information on this.)

In IVF treatment, GnRH agonists are used along with gonadotropins. The agonists prevent natural ovulation.

Instead, the fertility doctor will artificially stimulate ovulation with other fertility drugs, in a controlled manner known as superovulation.

The drug also prevents the natural LH surge. A natural LH surge could lead to the eggs ovulating before they can be retrieved from the ovaries. (If the eggs are ovulated before they are retrieved, they get “lost” inside the pelvic cavity.

If that happens, they cannot be used for IVF treatment.)

How Are GnRH Agonists Used to Treat Endometriosis and Fibroids?

When used to treat endometriosis, GnRH agonists are taken continually over a period of three to six months. How frequently you’ll received injections and/or the nasal spray depends on the drug being used.

The goal in endometriosis treatment is to stop the production of estrogen, which feeds the endometrial deposits. By “starving” these deposits, pain is reduced.

During the first two to three weeks of treatment, your symptoms may worsen. This occurs because of the initial boost in FSH and LH. You should talk to your doctor if you’re concerned, of course.

After about four to eight weeks, your endometriosis symptoms should improve.

When used to treat fibroids, the goal is usually to reduce the size of the fibroid before surgery. By “starving” the fibroid of estrogen, the mass shrinks. Treatment may take place for three or four months before scheduled surgery.

Because these drugs cause a temporary menopausal state, it’s important to know that you can’t get pregnant while taking GnRH agonists for endometriosis or fibroids.

They are not a fertility treatment for endometriosis or fibroids. They won’t improve your fertility.

If you want to get pregnant, you will need to discontinue treatment. Depending on the medication you’re taking, it may take anywhere from four to six weeks (with nasal spray agonists) or six to ten weeks (with injections) for your fertility to return.

Important note: you shouldn’t rely on GnRH agonists to absolutely prevent ovulation. When taken continuously, if you do get pregnant, GnRH agonists may harm a developing fetus.

For this reason, you may need to use a barrier method of birth control (like condoms or a diaphragm) to ensure you don’t conceive.

As always, talk to your doctor.

What Medications Are GnRH Agonists?

Leuprolide acetate, sold under the brand name Lupron Depot, is taken via injections, usually starting in the cycle before IVF treatment begins.

When used for IVF, Lupron may be given as one injection or daily injections.

Nafarelin acetate, sold under the brand name Synarel, and buserelin, sold under the brand name Suprecur, are GnRH agonists taken via a daily nasal spray.

They are also usually started the month before IVF is scheduled.

Goserelin, sold under the brand name Zoladex, is a GnRH agonists delivered via a small, biodegradable implant, injected just under the skin.

One implant lasts one month.

Side Effects of GnRH Agonists

GnRH agonists essentially put the body into a reversible, temporary menopausal state. Most of the side effects are similar to what women experience during menopause.

The good news is that once gonadotropin treatments are started, many of the side effects will be alleviated. (However, you will then be dealing with gonadotropin side effects and risks.)

Note: How many side effects you experience will depend on why and for how long you’re taking the GnRH agonists. Because Lupron is the most frequently used GnRH agonist during fertility treatment, the side effect percentages below refer to research done specifically on Lupron when taken for several weeks. While the percentages may differ between different forms of the GnRH agonists, the general list of possible side effects is similar.

Common side effects of Lupron include:

  • Hot flashes (70 - 80%)
  • Headache (25 - 32%)
  • Mood swings and depression (10 - 22%)
  • Vaginal dryness and irritation (11 - 28%)
  • Acne (10%)
  • General body aches (8 - 19%)
  • Nausea (8 - 13%)
  • Joint pain (7 - 8%)
  • Edema (5 - 7%)
  • Nervousness (4 - 6%)
  • General upset stomach (3 - 7%)
  • Weight gain (3 - 13%)
  • Decreased libido (2 - 11%)
  • Dizziness (2 - 11%)
  • Tingling (“pins and needles”) in the arms and legs (1 - 7%)
  • Breast tenderness (2 - 6%)

When taken long term, as they are when treating endometriosis or fibroids, you may stop getting your period. This isn’t technically a side effect since it’s an intended outcome of the drug (to shut down the hormones which cause menstruation).

When GnRH agonists are taken via injection, soreness and redness at the injection site may occur.

When taken as a nasal spray, irritation of the sinuses may occur.

Important note! Not all possible side effects and risks are listed. If you are experiencing severe side effects, unusual symptoms, or are concerned for any reason, contact to your doctor. The information in this article does not replace consultation with a medical professional.

Risks of GnRH Agonists

The FDA has not formally approved Lupron and other GnRH agonists for use in fertility treatments. Its use during IVF is considered “off-label.” Therefore, it’s not really known what all the risks are when used for fertility treatment.

With that said, these are the known risks when used to treat endometriosis, fibroids, or prostate cancer. The risks during IVF treatment may be similar.

Depression: If you have a history of depression, GnRH agonists may lead to severe depression.

Don’t keep this from your doctor; tell them if you experience worsening depression or are concerned about mood related side effects.

Decreased bone density: In women who used Lupron over a period of three months, bone density decreased 2.7%. Six months post treatment, bone density seemed to improve, but the long term after effects are not really known.

It is also not known at what point the decreased bone density become irreversible. For this reason, treatment for more than three to six months is not recommended.

Lupron is not recommended for women who are risk of having decreased bone density. If you have a family history of osteoporosis, mention this to your doctor.

Pituitary apoplexy: This is when a pituitary tumor (usually not yet diagnosed) bleeds. This is extremely rare, usually occurring within the first two weeks of treatment, and sometimes within the first hours.

If you experience sudden severe headache, vomiting, visual changes, paralysis of the muscles within or around your eyes, an altered mental status, or signs of a heart attack, get medical attention immediately.

Small increased risk for developing diabetes, heart attack, and stroke: These risks were primarily found in men taking GnRH agonists to treat prostate cancer. Whether they are a risk in women during IVF treatment is unknown.

Alternatives to GnRH Agonists

It’s important to know that GnRH agonist are not the only option for IVF.

An alternative includes GnRH antagonists, like Antagon (ganirelix acetate) and Cetrotide (cetrorelix).

Unlike GnRH agonists, GnRH antagonists are FDA approved for use during IVF treatment. You also take them for a shorter period of time. This may reduce the amount or length of time you experience side effects.

GnRH antagonists may be safer, according to some studies. When used during fertility treatment, women had a lower risk of developing ovarian hyperstimulation syndrome when compared to GnRH agonists.

The possible downsides are that GnRH antagonists are more expensive and not all fertility specialists are accustomed to using them.

More on fertility drugs and treatment:

Sources:

Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit J, Abou-Setta AM. “GnRH antagonists are safer than agonists: an update of a Cochrane review.” Hum Reprod Update. 2011 Jul-Aug;17(4):435. doi: 10.1093/humupd/dmr004. Accessed on January 23, 2014. http://humupd.oxfordjournals.org/content/17/4/435.extract

El-Nemr A, Bhide M, Khalifa Y, Al-Mizyen E, Gillott C, Lower AM, Al-Shawaf T, Grudzinskas JG. “Clinical evaluation of three different gonadotrophin-releasing hormone analogues in an IVF programme: a prospective study.” Eur J Obstet Gynecol Reprod Biol. 2002 Jul 10;103(2):140-5. http://www.ncbi.nlm.nih.gov/pubmed/12069736

FDA Drug Safety Communication: Update to Ongoing Safety Review of GnRH Agonists and Notification to Manufacturers of GnRH Agonists to Add New Safety Information to Labeling Regarding Increased Risk of Diabetes and Certain Cardiovascular Diseases. FDA: U.S. Food and Drug Administration. Accessed January 23, 2014.  http://www.fda.gov/Drugs/DrugSafety/ucm229986.htm

GnRH Agonist Therapy. Society for Assisted Reproductive Technology. Accessed January 23, 2014. http://www.sart.org/detail.aspx?id=1884

GnRH Antagonist Therapy. Society for Assisted Reproductive Technology. Accessed January 23, 2014.  http://www.sart.org/detail.aspx?id=1883

Lupron Depot (leuprolide acetate for depot suspension) Injection, Powder, Lyophilized, For Suspension. Abbott Laboratories. Accessed on January 23, 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019943s029,020011s036lbl.pdf

Medications for Inducing Ovulation: A Guide for Patients. American Society of Reproductive Medicine. Accessed February 3, 2008. http://asrm.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_and_Info_Booklets/ovulation_drugs.pdf

Wood, Ros. GnRH. Accessed on February 11, 2016. http://endometriosis.org/treatments/gnrh/

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