Gonadotropin-releasing hormone (GnRH) agonists

Gonadotropin-releasing hormone (GnRH) agonists, also known as luteinizing hormone-releasing hormone (LHRH) agonists, are sometimes used as part of hormonal therapy in people with hormone receptor-positive breast cancer. They can be taken by premenopausal and perimenopausal women, as well as men.

GnRH agonists are given as injections to stop the ovaries from making estrogen that can fuel the breast cancer’s growth. They’re usually combined with the hormonal therapy medicines tamoxifen and aromatase inhibitors.

Common GnRH agonists are:

• Goserelin (Zoladex)
• Leuprolide (Lupron)
• Triptorelin (Trelstar)

How GnRH agonists work

In premenopausal women, gonadotropin-releasing hormone agonists suppress, or slow down, the ovaries, which lowers estrogen and progesterone levels. These medications work by stopping the signals from the brain that tell the ovaries to function.

A GnRH agonist is a lab-made form of gonadotropin-releasing hormone.

• This natural hormone causes the pituitary gland, located at the base of the brain, to release other hormones that are needed for the ovaries to work normally. These are called gonadotropins.
• One of the gonadotropins is known as luteinizing hormone. That’s why you’ll sometimes see GnRH agonists referred to as luteinizing hormone-releasing hormone (LHRH) agonists.

Gonadotropins play a key role in the menstrual cycle and the monthly release of an egg from the ovaries. They also tell the ovaries to make estrogen and progesterone.

How GnRH agonists work in women

• At first, the GnRH agonist stimulates the pituitary gland to release more hormones.
• Over time, the extra stimulation causes the gland to slow down.
• As a result, estrogen and progesterone levels in the body fall significantly.
• This can stop hormone receptor-positive breast cancer cells from growing.

How GnRH agonists work in men

• In men’s bodies, fat tissue can convert testosterone into estrogen.
• GnRH agonists suppress the function of the testicles (male reproductive glands).
• As a result, the testicles stop making testosterone. Lowering testosterone (and potential estrogen) can help slow or stop the growth of hormone receptor-positive breast cancer cells.

Who gets GnRH agonists and how they're used

In premenopausal and perimenopausal women, GnRH agonists are used in two ways:

• As part of treatment for hormone receptor-positive breast cancer
• To protect fertility during chemotherapy for breast cancer

Doctors may recommend suppressing the ovaries in premenopausal women diagnosed with early-stage breast cancer that has a high risk of recurrence. Factors that lead to high risk can include younger age, a high-grade cancer, and/or more advanced-stage (cancer being found in the lymph nodes). While the ovaries can be surgically removed or irradiated, these methods lead to permanent menopause.

GnRH agonists are used in combination with other hormonal therapies, including:

• Tamoxifen
• Aromatase inhibitors, such as anastrozole (Arimidex), exemestane (Aromasin), or letrozole (Femara).
• Selective estrogen receptor degraders, or SERDs, such as fulvestrant (Faslodex) or elacestrant (Orserdu)

GnRH agonists and hormonal therapy can also be combined with a CDK 4/6 inhibitor, a form of targeted therapy against breast cancer. CDK4/6 inhibitors include:

• Ribociclib (Kisqali)
• Abemaciclib (Verzenio)
• Palbociclib (Ibrance)

Aromatase inhibitors and SERDs are often given to postmenopausal women, who naturally have low estrogen levels. In premenopausal women, a GnRH agonist can be used to put the body into temporary menopause so these therapies can then be given.

• Two long-term clinical trials, called SOFT and TEXT, found that combining a GnRH agonist with an aromatase inhibitor in premenopausal women reduces the risk of recurrence more than tamoxifen does.
• This was true whether tamoxifen was used alone or with a GnRH agonist.

Your doctor can help you determine what treatment combination makes the most sense for you. In some cases, if you are premenopausal, they may recommend starting a GnRH agonist alone and then adding an aromatase inhibitor in 4-6 weeks once the GnRH agonist has fully taken effect.

Some studies have shown that giving GnRH agonists during chemotherapy may help protect the ovaries from damage caused by chemotherapy. This is the case whether or not the breast cancer is hormone receptor-positive. The medicine can be given before starting chemotherapy, and throughout treatment, to shut down the ovaries temporarily.

If you’re premenopausal and want to reduce the risk of early permanent menopause, and/or increase the chances of getting pregnant after chemotherapy, talk with your doctor about this option. Because GnRH agonists are still being studied for this use, it’s important to explore other ways to preserve fertility (such as freezing eggs). Learn more about protecting your fertility during treatment.

In men with metastatic hormone-receptor positive breast cancer, GnRH agonists can be used with:

• An aromatase inhibitor
• An aromatase inhibitor and a CDK 4/6 inhibitor, a type of targeted therapy
• Selective estrogen response degraders

How GnRH agonists are given

GnRH agonists are given by injection, either under the skin or into a muscle. Some of these medicines are available in a larger or longer-acting dose that can be given less often.

• Goserelin is given every 28 days, or every 3 months, as a tiny implant (about the size of a grain of rice) injected under the skin.
• Leuprolide is given every 28 days or once every 3 months.
• Triptorelin is given every 28 days.

Your insurance provider may determine which formulation your doctor chooses. Your doctor may need to request approval from your insurance provider before some or all of the cost is covered. This is called prior authorization.

Side effects and things to remember

GnRH agonists’ side effects are mainly due to the drop in hormone levels. Side effects vary from person to person, but common examples include:

• Pain and/or bruising at the injection site
• Menopausal symptoms, such as hot flashes, night sweats, vaginal dryness and irritation, mood changes, and stopping menstrual periods
• Insomnia and fatigue
• Loss of sexual interest
• Bone thinning
• Bone pain
• Depression
• Changes in breast size, and/or breast tenderness

In men, side effects can include:

• Hot flashes
• Loss of sexual interest
• Trouble having an erection (erectile dysfunction)
• Enlarged breasts
• Fatigue

These medicines can cause other side effects. Women who are pregnant or breastfeeding shouldn’t take GnRH agonists.

If you are still premenopausal when you stop taking a GnRH agonist, your brain will return to signaling your ovaries (or testicles) to start working again, but it may take weeks to months. Your doctor is the best source of advice for your individual situation.