Gonadotropin-Releasing Hormone Agonists (Gn-RH agonists)

Gonadotropin-releasing hormone agonists (Gn-RH agonists) are medications that suppress ovarian function and reduce levels of estrogen and other hormones in the body. Gn-RH agonists can be used by women to reduce endometriosis-related pain. They can also be used to prevent the recurrence or progression of certain types of cancer, or as palliative treatment option for several types of breast or prostate cancers. This means that they are intended to help reduce quality of life-impacting symptoms. When women take Gn-RH agonists, the level of estrogen in their body is decreased to a menopausal-like state. This can lead to menopausal-like side effects such as hot flashes, vaginal dryness, and a decreased libido (interest in sex). Gn-RH agonists can be administered as pills, injections, or nasal sprays.1-3

In order to lessen the severity or presence of some of these symptoms, Gn-RH agonists taken for endometriosis pain are often accompanied by an add-back therapy. An add-back therapy is often an orally administered medication that is taken daily and contains low amounts of estrogen and progestin, or progestin alone. Long-term use of Gn-RH agonists is typically not recommended, as Gn-RH agonists may increase the risk of developing cardiovascular complications as well as severely decreasing bone mineral density. Using an add-back therapy may also help prevent significant bone mineral density loss.1

What are the ingredients in Gn-RH agonists?

The active ingredient in a Gn-RH agonist can vary with the exact medication used, however, all Gn-RH agonists function in the same manner. Common Gn-RH agonists used for endometriosis-related pain and their active ingredients include:

  • Lupron: Injection of leuprolide
  • Lupaneta Pack: Injection of leuprolide with an oral add-back therapy that contains the progestin norethindrone
  • Zoladex: Implant containing goserelin
  • Synarel: Nasal spray containing nafarelin
  • Orilissa: Oral therapy containing elagolix5-8

How do Gn-RH agonists work?

Gn-RH agonists target the Gn-RH receptor in the body. The Gn-RH receptor is involved in the pathway that creates estrogen. By reducing the function of these receptors, the amount of estrogen made in the body can be decreased. Endometriosis lesions are often fueled to thicken, grow, and breakdown by changes in estrogen. The breakdown of these lesions can cause significant pain. If estrogen levels decline and stabilize, these lesions may shrink.

The method by which Gn-RH agonists affect the production of estrogen is by overwhelming the Gn-RH receptors to the point where they get desensitized. This means that for the first few weeks of treatment, a Gn-RH agonist will activate the Gn-RH receptors so much that they will eventually stop responding to everything, including their normal activators in the body. Although this will decrease the amount of estrogen made eventually, it can lead to an increase in the production of estrogen at first. This may lead to a worsening of endometriosis lesions and pain before things improve.

As mentioned, Gn-RH agonists can create a menopausal-like state, with many unpleasant side effects. In order to reduce these side effects, or to prevent bone mineral density loss, an add-back therapy may be used. Add-back therapies deliver estrogen or other hormones back to the body in a small enough amount that side effects may be relieved without impacting the overall Gn-RH agonist treatment regimen.1-3

What are the side effects of Gn-RH agonists?

Many clinical trials have evaluated the safety and efficacy of Gn-RH agonists. Some of the most common side effects with Gn-RH agonists include:

  • Hot flashes
  • Decreased libido (interest in sex)
  • Decrease in bone mineral density
  • Headaches
  • Unexpected vaginal bleeding
  • Dizziness
  • Trouble sleeping
  • Nausea and vomiting
  • Weight changes
  • Changes in mood or behavior such as depression, anxiety, or other signs of emotional instability5-7

This is not an exhaustive list of all potential side effects that can occur when taking a Gn-Rh agonist. Talk to your healthcare provider about your specific situation.

Things to note about Gn-RH agonists

Gn-RH agonists can increase the risk of developing cardiovascular complications, such as heart attack or stroke. They can also affect a developing fetus, as well as increase levels of calcium and sugar in the blood. Gn-RH agonists can cause bone mineral density loss, which can lead to a thinning of the bones. For all of these reasons, long-term Gn-RH use is not recommended. Seek medical attention if you experience any of the following:

  • Vision problems such as bulging eyes, double vision, or sudden loss of vision
  • Severe migraine-like headaches
  • Depression or worsening depression
  • Severe signs of mental or emotional instability
  • Fluid retention (severe swelling)
  • Pregnancy
  • Signs of an allergic reaction such as swelling of your face or mouth, breathing difficulties, chest pain, dizziness, itching, or skin rash

Before you start taking a Gn-RH agonist, tell your provider if you:

  • Are taking any other medications, vitamins, or supplements
  • Have a history of blood clots
  • Have a history of any cardiovascular-related conditions
  • Have diabetes
  • Have issues with your kidneys or liver
  • Have a history of cancer, especially hormone-sensitive cancers such as breast cancer
  • Have a history of mental illness such as depression
  • Have a history of seizures or epilepsy
  • Have a history of osteoporosis (thinning of the bones) or a family history or osteoporosis
  • Have high cholesterol
  • Have a history of migraines
  • Are pregnant or planning to become pregnant
  • Are breastfeeding or planning to breastfeed
  • Are a smoker
  • Regularly drink alcohol5-7

Dosage information

The dosing information for Gn-RH agonists varies with the Gn-RH taken and the way it is administered. Some Gn-RH medications are to be taken daily, or multiple times a day, such as the Synarel nasal spray, whereas others, such as the injectable Lupron, Lupaneta Pack, and Zoladex, are administered once every one to three months by a healthcare provider. Your provider will let you know what the appropriate dose and administration schedule are for you, and what to do if you miss a dose or an appointment for your next dosage. As mentioned, Gn-RH agonists are not indicated for use long-term. Instead, most Gn-RH agonists are used for up to six months at a time, with significant breaks in between.4-7

Written by: Casey Hribar | Last reviewed: June 2018
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