Treating Fibroids and Endometriosis with Hormone-lowering Medications

Endometriosis and uterine fibroids are two very common women’s health conditions that have a frustratingly limited number of treatments. This describes a new type of medicine that has been approved to treat the pain and other symptoms associated with these conditions, and reviews what we have learned about the medication.

Endometriosis is a hormonal and immune system condition that causes uterine tissue to grow outside the uterus (such as in the abdomen, intestines, or bladder), which can cause intense pain. According to the federal Office of Women’s Health (OWH), about 11 percent of American women[1] between the ages of 15 and 44 may be affected by endometriosis.[2]

Uterine fibroids are non-cancerous tumors found within the walls of the uterus, which often changes the size and/or shape of the uterus. Fibroids can lead to heavy menstrual bleeding and severe pain for some people. According to the OWH, between 20 to 80 percent of women will develop fibroids by age 50.[3] For unknown reasons, Black women are three times as likely as white women to develop fibroids.[4]

Neither of these conditions has been fully researched—possibly because they are associated with menstrual pain, which is too often considered not to be a serious problem. People with fibroid tumors or endometriosis are often encouraged to have their entire uterus removed via hysterectomy, a type of surgery that can cause complications and lasting problems.

Because of the importance of these conditions, the NWHN carefully monitors new developments in medical treatment. Recently, one type of hormone-lowering medication (elagolix) was approved to treat endometriosis and uterine fibroids and is now available for use in the U.S. Another drug (ulipristal acetate), which also affects hormone levels, was approved in Europe and Canada, but is now heavily restricted.

Elagolix: approved to treat endometriosis and uterine fibroids

Elagolix stops a person’s ovaries from making estrogen and progesterone, which makes fibroids shrink, reduces menstrual bleeding, and diminishes pain. The drug works by blocking the pituitary gland’s signals to the ovaries. The U.S. Food and Drug Administration (FDA) approved elagolix to treat endometriosis[5] in 2018, and to treat uterine fibroids in 2020.[6] In both cases, the FDA ruled that the drug should not be taken indefinitely because its long-term use increases the risk of other, serious, problems.

The NWHN believes that elagolix may be useful for some people, possibly enabling them to postpone surgery until after they’ve had children, or keep symptoms in check until the condition naturally resolves after menopause.

Using elagolix for endometriosis: effectiveness[7]

The FDA based its approval of elagolix for endometriosis (brand name Orilissa) on the results of clinical trials involving 938 women who took the drug for 6 months.[8] The company tested two strengths of elagolix against a look-alike placebo. About half the women who took the lower-dose drug reported that they felt less pain during their menstrual cycle and also in between their periods. (Many people with endometriosis experience pain all month long.) The higher dose version of elagolix was more effective, reducing pain in about three-quarters of the women who used it.

Only 20 to 30 percent of women who took the look-alike placebo tablets reported having less pain—confirming that the drug’s hormone-reducing effect really makes a difference. The stronger dose of elagolix provided some relief from pain associated with penetrative sexual activity, while the lower dose did not. Other pain-relief products used by women with endometriosis may also be effective, but none have been studied in a placebo-controlled randomized trial of people with endometriosis.

The lower-strength version of elagolix (100 mg) is taken 1 time daily for up to 24 months; the higher-strength tablet (200 mg) is taken 2 times daily for up to 6 months.

One disappointing note: nearly 90% of the trial participants were white, so we don’t know as much as we should about the effect of this version of elagolix on people of color who have endometriosis.[9] This missing information makes it more difficult for people of color to make an informed decision about using Orilissa, and reinforces many health care professionals’ incorrect assumption that only white women get endometriosis.

What are the risks and side effects of using elagolix for endometriosis?[10]

Bone loss is the most important risk associated with using elagolix to treat symptoms of endometriosis. Women taking the higher dose lost two to three percent bone density while they were taking the drug. Two percent may sound small, but it’s actually a severe loss when it occurs in a short time-period—especially for women in their 20s 30s, when the body is either building or maintaining bone strength. For example, during the study, women taking the placebo tablets actually gained bone density. Using medications that cause bone loss can lead to painful fractures of the spine (vertebral fractures) and disabling hip fractures. Because of these findings, the FDA determined that no one should use the higher dose of Orilissa for more than six months.

The lower dose of Orilissa also caused bone loss, but much less, and the FDA approved use of low-dose Orilissa for up to two years. Bone density starts to recover once the drug is stopped, but, on average, it wasn’t fully restored in the first 6 to 12 months after discontinuation.

Another serious complication from using elagolix may be an increased likelihood of suicidal thoughts or feelings. Of the 938 people who took elagolix, 2 reported having suicidal thoughts and one person died by suicide. None of the 726 people who took the placebo reported having suicidal thoughts.

Participants in the study also reported side effects that are commonly experienced by people who take hormone-lowering medications. Hot flushes and night sweats were the most commonly reported side effects, experienced by half of those who took the higher dose, and one-quarter of those who took the lower dose, compared to only nine percent of the people who took the placebo. Headaches and nausea were also reported.

Elagolix alters menstrual bleeding, but it does not completely suppress the release of eggs from the ovaries, so it is possible to get pregnant while using elagolix. However, the altered hormone levels created by elagolix increase the risk of early pregnancy loss (miscarriage). Two babies were born with birth defects during the drug development program, which included more than 2,000 women exposed to elagolix. That may have happened by chance, and not because of elagolix, however. People who could potentially become pregnant are encouraged to use a non-hormonal method of contraception while taking elagolix. In the meantime, the FDA has asked the pharmaceutical company to track the outcomes of all pregnancies that occur in people taking elagolix.

Using elagolix to treat heavy bleeding caused by uterine fibroids

In May 2020, the FDA approved a different version of elagolix to treat uterine fibroids, using a much stronger dose of elagolix: 300 mg taken twice a day. In an attempt to stave off bone thinning, the pharmaceutical company combined elagolix with estrogen and progestin, which are typically given as menopause hormone therapy. The combination of these drugs is marketed under the brand name Oriahnn, and is approved for use for up to 24 months. It is not known whether it can safely be started again after a rest period.

The company’s tests of Oriahnn included a six-month randomized controlled trial comparing Oriahnn to elagolix alone, and Oriahnn to placebo. Two-thirds of the 591 women[11] who completed the six-month trial were Black.[12]  The company invited women who completed the six-month trial to participate in an extension of the study for a subsequent six months. Eventually, 182 women received Oriahnn for 12 months and 341 women took the drug for 6 months.

Elagolix plus estradiol and progestin significantly reduced menstrual bleeding in about seventy percent of women who took the combination pills.[13] Elagolix alone was slightly more effective at reducing bleeding, but caused significant bone loss, and the FDA did not approve it for use by itself. For the purposes of this study, “heavy menstrual bleeding” was defined as losing more than one-third of a cup (80 milliliters) of blood, about twice what most women experience when they menstruate.

Oriahnn works by taking 1 capsule (300mg of elagolix, 1mg of estradiol, and 0.5mg of norethindrone acetate, the progestin) in the morning and 1 capsule (300mg of elagolix) in the evening for up to 24 months.

What are the risks and side effects?[14]

Because Oriahnn includes both estrogen and progestin, all of the warnings that apply to hormonal contraception and menopause hormone therapy also apply to this drug.

Specifically, because of the risk of blood clots, the FDA advises that the drug not be taken by women over age 35 who smoke, have uncontrolled high blood pressure or migraine headaches with aura.[15] The FDA also cautions against, but does not completely rule out, the use of Oriahnn by women with other risk factors for blood clots, such as obesity.

These restrictions and warnings have major implications for who can safely use Oriahnn. For example, 4 out of every 10 U.S. women is are obese – and more than half of all adult Black women are obese.[16] The pharmaceutical company did not exclude obese women from the clinical trial and we know that at least two women taking Oriahnn developed blood clots during the study.[17]

If the company markets the drugs in ways that lead women and their clinicians to believe that women who are obese can safely take Oriahnn, women could experience harmful complications that could otherwise be avoided. At the very least, the NWHN urges women who want to use Oriahnn to be aware of the risk of blood clots and how to recognize early warning signs of blood clots.

Another complication from taking Oriahnn is developing bald patches or thinning hair. This was reported by 3.5 percent of the women who took Oriahnn in the clinical trial.[18] According to the FDA, the hair loss was significant enough to make some women stop taking the drug and, in some cases, hair loss continued after the drug was stopped.[19]  The FDA is requiring the company to do follow-up studies of hair loss in people who use Oriahnn, so more may be known about this in the future.

Bone loss in women who took Oriahnn was much less than in women who took elagolix alone, on average about 1.5 percent decrease in bone density over 12 months.[20] A few women, however, experienced much worse bone thinning, even with the added estrogen and progestin. People taking Oriahnn who have additional risk factors for osteoporosis might want to consider having bone density tests both before starting on the drug and again after six months, to make sure they are not experiencing severe bone thinning.

Other side effects included hot flushes in about 20 percent of women, and headache and fatigue, in less than 10 percent.[21] A few women reported mood swings, changes in menstrual bleeding, or reduced interest in sex (libido).

Ulipristal Acetate: European approval pulled back

For a while, it seemed as if the U.S. might have more than one FDA-approved treatment for fibroids. Starting in 2012, a second drug, ulipristal acetate (brand name Esmya), was widely used in Europe. By 2018, ulipristal acetate had been submitted to the FDA for approval. Like elagolix, the drug is a daily pill that reduces heavy bleeding by lowering hormone levels, in this case, by blocking progesterone.

However, also in 2018, reports started to emerge of serious liver problems in women who were using the drug. The European Medical Association, an agency similar to the U.S. FDA, investigated and found that at least eight women taking ulipristal acetate had developed serious liver damage — and half of them needed a liver transplant.[22]

At that time, the NWHN spoke out and publicly shared our concerns about ulipristal acetate’s possible safety risks. As a result of these developments, the FDA told the pharmaceutical company that the agency would not approve ulipristal unless it received more information about safety concerns.[23] In Europe, the EMA continued to allow ulipristal to be used, but only for up to three months to shrink fibroids prior to surgical treatment. However, in 2020, after even more women experienced liver damage, the EMA withdrew its approval for ulipristal to be used prior to surgery.[24] At this time, the drug is only approved for treating uterine fibroids in premenopausal women who cannot have surgery or uterine fibroid embolization, or for whom the surgical procedure has failed. As far as we know, it is no longer being considered for use in the U.S.

Conclusion

The NWHN is encouraged that pharmaceutical companies are finally taking endometriosis and uterine fibroids seriously. We will continue to track the progress of drugs to treat uterine fibroids, endometriosis, and other reproductive health conditions. We are committed to ensuring that unsafe and/or ineffective drugs are kept off the market, and empowering people with the information they need to make the best decisions about their individual health.

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[1] The NWHN uses the word “women” when referring to research or data developed solely from cis-gendered women.

[2] Office of Women’s Health website. Endometriosis Fact Sheet. Washington, D.C. Retrieved on January 25, 2021 from:  https://www.womenshealth.gov/a-z-topics/endometriosis#:~:text=How%20common%20is%20endometriosis%3F,the%20United%20States%2C%20have%20endometriosis.

[3] Office of Women’s Health website. Uterine Fibroids Fact Sheet. Washington, D.C. Retrieved on February 22, 2021 from:  https://www.womenshealth.gov/a-z-topics/uterine-fibroids

[4] Marshall LM, Spiegelman D, Barbieri RL, et al, “Variation in the incidence of uterine leiomyoma among premenopausal women by age and race,” Obstetrics & Gynecology 1997; 90(6): 967-73.

[5] Food and Drug Administration website. Orilissa Drug Trial Snapshot. Washington, D.C. Retrieved on January 24, 2021 from:  https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-orilissa

[6] Food and Drug Administration website. FDA Approves New Option to Treat Heavy Menstrual Bleeding Associated with Fibroids in Women. May 29, 2020. Washington, D.C. Retrieved on January 24, 2021 from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-option-treat-heavy-menstrual-bleeding-associated-fibroids-women

[7] Food and Drug Administration website. FDA approved label for Orilissa. Most recent version August 28, 2019. Washington, D.C. Retrieved on January 24, 2021 from:  https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210450s002lbl.pdf.

[8] No trans men were included in the company’s studies of Orilissa.

[9] Food and Drug Administration website. Orilissa Drug Trial Snapshot. Washington, D.C. Retrieved on January 24, 2021 from:  https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-orilissa

[10] Food and Drug Administration website. FDA approved label for Orilissa. Most recent version August 28, 2019. Washington, D.C. Retrieved on January 24, 2021 from:  https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210450s002lbl.pdf.

[11] No trans men were included in the company’s studies of Oriahnn.

[12] Food and Drug Administration website. FDA approved label for Oriahnn. Washington, D.C. Retrieved on January 24, 2021 from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213388s000lbl.pdf

[13] Food and Drug Administration website. FDA Approves New Option to Treat Heavy Menstrual Bleeding Associated with Fibroids in Women. May 29, 2020. Washington, D.C. Retrieved on January 24, 2021 from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-option-treat-heavy-menstrual-bleeding-associated-fibroids-women

[14] Food and Drug Administration website. FDA Approves New Option to Treat Heavy Menstrual Bleeding Associated with Fibroids in Women. May 29, 2020. Washington, D.C. Retrieved on January 24, 2021 from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-option-treat-heavy-menstrual-bleeding-associated-fibroids-women

[15] Food and Drug Administration website. FDA approved label for Oriahnn. Washington, D.C. Retrieved on January 24, 2021 from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213388s000lbl.pdf

[16] National Center for Health Statistics, Centers for Disease Control and Prevention.  “Prevalence of Obesity and Severe Obesity Among Adults: United States, 2017–2018.  NCHS Data Brief No. 360,” February 2020.  Hyattsville, MD. Retrieved on January 24, 2021 from:  https://www.cdc.gov/nchs/products/databriefs/db360.htm

[17] Food and Drug Administration website. FDA approved label for Oriahnn. Washington, D.C. Retrieved on January 24, 2021 from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213388s000lbl.pdf

[18] Food and Drug Administration website. FDA approved label for Oriahnn. Washington, D.C. Retrieved on January 24, 2021 from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213388s000lbl.pdf

[19] Food and Drug Administration website. FDA Approves New Option to Treat Heavy Menstrual Bleeding Associated with Fibroids in Women. May 29, 2020. Washington, D.C. Retrieved on January 24, 2021 from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-option-treat-heavy-menstrual-bleeding-associated-fibroids-women

[20] Food and Drug Administration website. FDA Approves New Option to Treat Heavy Menstrual Bleeding Associated with Fibroids in Women. May 29, 2020. Washington, D.C. Retrieved on January 24, 2021 from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-option-treat-heavy-menstrual-bleeding-associated-fibroids-women

[21] Food and Drug Administration website. FDA approved label for Oriahnn. Washington, D.C. Retrieved on January 24, 2021 from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213388s000lbl.pdf

[22] European Medicines Agency website: Esmya Assessment Report. May 17, 2018. Amsterdam, the Netherlands. Retrieved on January 24, 2021 from: https://www.ema.europa.eu/en/documents/variation-report/esmya-h-c-2041-a20-0043-epar-assessment-report-article-20_en.pdf

[23] PR NewsWire. “Allergan Receives Complete Response Letter from the U.S. Food and Drug Administration for Ulipristal Acetate New Drug Application,” August 21, 2018. Location unstated. Retrieved on January 24, 2021 from: https://www.prnewswire.com/news-releases/allergan-receives-complete-response-letter-from-the-us-food-and-drug-administration-for-ulipristal-acetate-new-drug-application-300700400.html

[24] European Medicines Agency website: Ulipristal acetate 5mg medicinal products. Ulipristal acetate 5mg medicinal products. November 12, 2020. Retrieved on January 24, 2021 from: https://www.ema.europa.eu/en/medicines/human/referrals/ulipristal-acetate-5mg-medicinal-products