Lupron is a gonadotropin-releasing hormone (GnRH) agonist—a hormonal medication that is currently used by some providers to treat endometriosis. Often it is prescribed for suspected or confirmed endometriosis and general abdominal pain. This article will be breaking down how Lupron and GnRH agonists work, their high side effect profile, and their overall effectiveness and usefulness for endometriosis.

First off, how do Lupron and other GnRH agonists attempt to combat endometriosis?

GnRH agonists attempt to combat endometriosis by eliciting hypoestrogenism (low levels of estrogen). This is done by blocking estrogen production in the ovaries. A low estrogen environment is hypothesized to regress the size or stunt the growth of endometrial implants, as estrogen is known to promote endometrial tissue growth. (1)

So what exactly is a GnRH agonist?

A GnRH agonist is an agonist for GnRH receptors on the pituitary gland. (2) This means that a GnRH agonist is essentially a “supplement” for the body’s naturally produced GnRH, increasing the body’s levels beyond what they otherwise would be.

Know that we know that GnRH agonists essentially increase the body’s GnRH levels, what does GnRH do in the body anyways?

Gonadotropin-releasing hormone (GnRH) is produced by the hypothalamus—a structure in the human brain—and binds to receptors on the pituitary gland to trigger the secretion of two other hormones: follicle stimulating hormone (FSH) and luteinizing hormone (LH). (2) These hormones have a variety of functions, including promoting estrogen production in the female ovaries. (2)

So if GnRH agonists essentially increase the levels of GnRH in the body, and GnRH increases estrogen levels, how do GnRH agonists achieve their aim of decreasing estrogen levels?

As you would suspect, taking a GnRH agonist does initially cause a short “flare” of estrogen levels. With time, however, abnormally high levels of GnRH from taking a GnRH agonist will desensitize the GnRH receptors on the pituitary gland. This desensitization causes a decrease in the secretion of FSH and LH in response to GnRH, and thus a decrease in estrogen production to similarly low levels of women in menopause. This low estrogen state has been termed by some as “pseudomenopause”. (2)

Are there any side effects of GnRH agonists and the “pseudomenopause” state they promote?

Lupron and GnRH agonists as a drug class have a notably high side effect profile, with many of the side effects similar to symptoms of menopause. The following list includes side effects with taking Lupron of high frequency identified by a study reported by the FDA. (3)

• Hot flashes and sweats in 98% of patients
• Headache or migraine in 65% of patients
• Depression or mood swings in 31% of patients
• Insomnia in 31% of patients
• Nausea and vomiting in 25% of patients
• General pain in 24% of patients
• Vaginitis in 20% of patients
• Weakness and lack of energy in 18% of patients
• Dizziness or vertigo in 16% of patients
• Change in bowel function in 14% of patients
• Weight changes in 12% of patients
• Changes in libido in 10% of patients

Another potential side effect is possibly irreversible bone thinning. A controlled study reported by the FDA showed a 3.2% average decrease in bone mineral density of the lumbar spine after 6 months of Lupron usage, and a 6.3% average decrease in bone mineral density of the lumbar spine after 12 months of Lupron usage. (3)

Along with the high risk of side effects outlined above, risk for several severe adverse effects are noted specifically in patients with conditions such as asthma, sinusitis, certain allergies, and depression. (4) Use is contraindicated in patients planning pregnancy during the course of therapy, individuals that are currently pregnant, and individuals that are lactating. (4) Furthermore, patients with a history of conditions or social habits that may increase the chance of bone thinning such as smoking, excessive alcohol intake, taking medications that also may cause bone loss, or a family history of osteoporosis are recommended to take add-back therapy (of estrogen and/or progesterone) while using Lupron. (4)

How effective are GnRH agonists for treating endometriosis?

In a systematic review of multiple articles and studies, the following breakdown of effectiveness of GnRH agonists was observed.

A median of 14% of patients showed no improvement in endometriosis symptoms with GnRH agonists, while a median of 40% of patients had pain symptoms remaining at the end of treatment. (5) A median of 8% of patients taking GnRH agonists needed to stop treatment due to lack of efficacy or adverse events (i.e. reactions to the medication or intolerable side effects). (5) In studies that evaluated recurrence of pain symptoms in patients who had an initial resolution of their symptoms with GnRH agonists, it was found that a median of 37% of patients experienced a recurrence of pain symptoms after initial treatment. (5)

Lupron is not indicated to be taken for more than 6 months at a time. (3) If symptoms persist or recur, which was found to be the case in a large portion of patients, another 6 month trial with add-back therapy is permitted, but beyond this additional trial a repeat trial is not recommended for safety reasons. (3) Subsequently, there is a rather high possibility that treatment may take place two times over the course of a year, with significant exposure to several side effects and irreversible bone loss, and possibly little to no improvement of symptoms in that temporary period of time.

Now that we covered the high side effects and inconsistent efficacy of GnRH agonists, what is the problem with how it is used?

There are many problems with how Lupron is utilized. Often OB/GYN’s and other physicians give GnRH agonists for endometriosis or even nonspecific pelvic pain due to lack of skills and awareness in properly diagnosing and treating endometriosis, which is unfortunately rather common. (6) This is especially troublesome for a handful of reasons. Menopause (and therefore the pseudomenopause state that GnRH agonists elicit) is not yet scientifically proven to cause a resolution of endometrial implants. (7) While many patients with endometriosis-induced pain do have a decrease and sometimes resolution of pain with menopause, this is not the case in all. (7) On an even larger scale, as displayed in the study above, hormonal treatments including GnRH agonists are notorious for decreasing symptoms temporarily, only to have a recurrence of symptoms occur. (8) However, there are several hormonal treatments and other treatments such as birth control and progesterone that decrease endometriosis-associated pain temporarily with significantly less side effects, leaving Lupron’s usefulness in most scenarios up for question.

What does this mean, for me, the patient?

It is critical to be aware that Lupron and GnRH agonists are not cures for endometriosis. Furthermore, the costs of these medications are astronomical. The cost of one six month treatment with Lupron is roughly $11,000, putting the maximum 12 month trial of Lupron at a lofty $22,000—a hefty price to pay for a drug that may only decrease pain symptoms temporarily and replace them with a myriad of side effects, instead of curing the disease. (9) These drugs should only be prescribed after a shared decision with the patient and a professional gynecological surgeon that specializes in endometriosis and only after discussing thoroughly with the serious risks and minimal benefits of such treatment. It should not be offered as a generalized treatment for pelvic pain or endometriosis-associated pain.

Schedule an appointment with CEAPS online, by email at [email protected], or over the phone by calling (703) 505-0444 to discuss treatment options for endometriosis.

Citations:

1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794019/
2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193774/
3) https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020011s040lbl.pdf
4) https://www.luprongyn.com/lupron-for-endometriosis
5) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494290/
6) https://pubmed.ncbi.nlm.nih.gov/18715240/
7) https://www.health.harvard.edu/womens-health/will-my-endometriosis-go-away-after-menopause
8) https://www.health.harvard.edu/diseases-and-conditions/endometriosis2
9) https://www.drugs.com/price-guide/lupron-depot