Gonadotropin-Releasing Hormone (Gn-RH) Agonists and Antagonists

Gonadotropin-releasing hormone agonists (Gn-RH agonists)

Gonadotropin-releasing hormone agonists (Gn-RH agonists) are medications that suppress ovarian function by reducing levels of estrogen and other hormones in the body. Women can take Gn-RH agonists to reduce endometriosis-related pain. Other uses include preventing the recurrence or progression of certain types of cancer, and as a palliative treatment option for some breast or prostate cancers. They are valuable as a mechanism to reduce the painful symptoms that affect quality of life.

When women take Gn-RH agonists, the level of estrogen in their body is decreased to a menopausal-like state. This can lead to side effects experienced in menopause such as hot flashes, vaginal dryness, and a decreased libido (interest in sex). Gn-RH agonists are available in pill form, as injections, or nasal sprays.1-4

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. Add-back therapy is often a supplement taken daily which contains low amounts of estrogen and progesterone, or just progesterone. They diminish the side effects of Gn-RH treatment including prevention of bone mineralization. Long-term use of Gn-RH agonists is typically not recommended, as they may increase the risk of developing high cholesterol, cardiovascular complications, as well as severely decreasing bone mineral density.

Available Gn-RH agonists

Common Gn-RH agonists used for endometriosis-related pain and their active ingredients include:5-8

  • Lupron: leuprolide injections
  • Lupaneta Pack: leuprolide injections with an oral add-back therapy containing the progestin norethindrone
  • Zoladex: Implant containing goserelin
  • Synarel: nafarelin nasal spray

How do Gn-RH agonists work?

Gn-RH agonists target receptors in the brain along the pathway that influences estrogen production. Elevated estrogen levels causing tissue to thicken and grow often exacerbate endometrial lesions. These lesions can cause significant pain. As estrogen levels decline and stabilize, these lesions may shrink.

Gn-RH agonists initially work by affecting the production of estrogen saturating the Gn-RH receptors to the point where they get desensitized. During the first few weeks of treatment, these medications over activate the Gn-RH receptors and flood the body with estrogen that signals the brain to stop reacting, giving the message to the brain that it no longer needs to produce it. Although this will decrease the amount of estrogen made eventually it may lead to a worsening of endometrial lesions and pain before the condition improves.

Gn-RH agonists create a low estrogen menopausal-like state that can have unpleasant side effects. In order to reduce these side effects, or to prevent bone mineral density loss, add-back therapy may be used. Add-back therapies deliver estrogen or other hormones back to the body in small enough amounts 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:5-7

  • 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 instability

These are not all the possible side effects of Gn-Rh agonists. Talk to your doctor about what to expect or if you experience any changes that concern you during treatment with Gn-Rh agonists.

Things to note about Gn-RH agonists

Gn-RH agonists can increase the risk of developing cardiovascular complications, such as heart attack or stroke. Other areas of impact include increased levels of calcium and sugar in the blood, a loss of bone mineral density, which can deplete the strength of the bones, and also affect a developing fetus. For 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:5-7

  • 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 alcohol

Gonadotropin-releasing hormone antagonists (Gn-RH antagonists)

Gonadotropin-releasing hormone antagonists (Gn-RH antagonists) are another class of medications used to treat endometriosis pain. Orilissa is an example of a Gn-RH antagonist. Although not a first line treatment, like nonsteroidal anti-inflammatory drugs (NSAIDs) and progesterone-containing oral contraceptives, Gn-RH antagonists are nonpeptide hormonal suppressive treatments effective for pain management.9-11 Well tolerated and effective after just a few doses, the effects of Gn-RH antagonists are quickly reversed after the medication is stopped.12

How do Gn-RH antagonists work?

Gn-RH receptor agonists and antagonists both bind receptors to stop the production of estrogen production using two different mechanisms. Both result in low estrogen (hypoestrogenic) conditions, mimicking menopause.11-13 Gn-RH antagonists are molecules that lessen the effect of Gn-RH by binding to receptors in the hypothalamus preventing the receptor from sending a message to the ovaries to produce estrogen.12

Although similar in structure to Gn-RH agonists, they have a quicker effectiveness because of the mode of action. Gn-RH antagonists are also noted for fewer side effects. There is no initial flare of hormone levels either before or after the onset of action. This is a significant addition to the available treatment options for endometriosis-related pain.10-12

What are the side effects of Gn-RH antagonists?

Taken in pill form by mouth, Gn-RH antagonsits are convenient to administer and achieve therapeutic effectiveness quickly.10,11 The blocking of pituitary receptors is nearly immediate, and largely reversible when the medication is stopped.11,12 They are well tolerated and as noted, women generally experience fewer of the Gn-RH agonist side effects including mood changes, flushing, loss of sexual drive, and vaginal dryness*.11 For many, they can be taken without the need for add-back therapy generally required when using agonists to reduce the debilitating, life style affecting side effect.13 There are some hypoestrogenic effects that your doctor should monitor including changes in bone mineral density and lipid levels.14

These are not all the possible side effects of Gn-Rh antagonists. Talk to your doctor about what to expect or if you experience any changes that concern you during treatment with Gn-Rh antagonists.

Things to note about Gn-RH antagonists

Unlike Gn-RH agonists, Gn-RH antagonists do not typically cause hypoestrogenic effects (low estrogen levels, often resulting in mood swings, vaginal dryness, and hot flashes). Additionally, unlike agonists, Gn-RH antagonists are not associated with changes in liver enzyme levels in patients with normal liver function. Severe adverse reactions may include acute hypersensitivity reactions, suicidal ideation and mood disorders, and significant bone loss with extended therapy.8,11,15

Orilissa is contraindicated in pregnant women (or women who may be pregnant), patients with known osteoporosis or severe hepatic impairment, and/or patients who are taking strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (such as cyclosporine orgemfibrozil). Patients using Orilissa should use non-hormonal contraceptive during treatment and for 28 days after stopping treatment.8

Before taking Orilissa, patients should tell their healthcare provider if they:8

  • Have or have had broken bones
  • Have other conditions or take medicines that may cause bone problems
  • Have or have had depression, mood problems or suicidal thoughts or behavior
  • Have liver problems
  • Think they may be pregnant
  • Are breastfeeding or plan to breastfeed
  • Take birth control pills, other medications, vitamins, and/or supplements

Seek medical attention if you experience any of the following while taking Orilissa:8

  • Suicidal thoughts, suicidal behavior, or worsening of mood
  • Sudden changes in your mood, behaviors, thoughts, or feelings
  • Abnormal liver tests

Other warnings and precautions for Orilissa include the possibility of bone loss, reduced ability to recognize pregnancy, dose-dependent elevations in serumalanine aminotransferase (ALT), and potential for reduced efficacy with estrogen-containing contraceptives. Increased monitoring or dose adjustments may be necessary for patients who are taking Orilissa in combination with digoxin, midazolam, rosuvastatin, and/or omeprazole. Ongoing concomitant use of Orilissa and rifampin is not recommended. Ask your doctor if any of your medications or health conditions would prevent you from using Orilissa.8 

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Written by: Casey Hribar | Last reviewed: February 2021