Oral medication for uterine fibroids shows promise for limiting menstrual bleeding
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The oral gonadotropin-releasing hormone antagonist elagolix substantially decreased excessive menstrual bleeding for women with uterine fibroids, according to findings published in The New England Journal of Medicine.
“The problem with heavy bleeding relating to uterine fibroids is a huge and significant problem [and] is the most common indication for hysterectomy in the United States,” William D. Schlaff, MD, professor and chairman of the department of obstetrics and gynecology at the Sydney Kimmel Medical College of Thomas Jefferson University in Philadelphia, told Healio. “A medical treatment that will reduce the burden of bleeding in and of itself is a value.”
Schlaff and colleagues assessed 6-month changes in menstrual bleeding and bleeding during menstrual cycles of greater than 80 mL via sanitary products that were used by women with uterine fibroids who participated in the Elaris UF-1 and UF-2 trials.
In both trials, the researchers randomly assigned participants to 300 mg of elagolix (Orilissa, AbbVie) taken twice per day alone (UF-1: n = 104; mean age, 42.6 years; UF-2: n = 95; mean age, 42.2 years) or with “add-back” therapy — 1 mg estradiol and 0.5 mg norethindrone acetate (UF-1: n = 206; mean age, 42.6 years; UF-2: n = 189; mean age, 42.5 years) or to placebo (UF-1: n = 102; mean age, 41.6 years; UF-2: n = 94; mean age, 42.5 years) for 6 months.
According to the researchers, if participants’ menstrual blood loss at 6 months was 50% lower than it was at baseline and if they lost less than 80 mL of menstrual blood in month 6, they achieved the trials’ primary endpoint.
UF-1 findings
When treated with elagolix and add-back therapy, the proportion of women who reached the primary endpoint was 68.5% while placebo yielded a rate of 8.7% (P < .001). In addition, the proportion was 84.1% for those treated with elagolix alone.
Menstrual blood loss at 6 months decreased by 194.7 mL from baseline for those assigned elagolix and add-back therapy, by 236.2 mL for those assigned elagolix alone and by 2.3 mL for those assigned placebo (P < .001). Additionally, the researchers noted that 62% of women achieved at least a 2 g/dL rise in hemoglobin after having a baseline measure of 10.5 g/dL or lower when treated with elagolix and add-back therapy; rates were 66% for those treated with elagolix alone and 16% for those assigned placebo (P < .001).
In UF-1, adverse events were reported by 90.4% of women assigned elagolix alone and 69.6% of women assigned placebo (P < .001); researchers observed no difference between placebo and elagolix plus add-back therapy. The researchers observed that 20.4% of those assigned elagolix plus add-back therapy and 8.8% of those assigned placebo reported hot flushes (P < .01) vs. 64.4% of those assigned elagolix alone (P < .001 vs. placebo). In addition, 26.9% of women assigned elagolix alone and 2.9% of those assigned placebo reported night sweats (P < .001); 6.3% of those assigned elagolix and add-back therapy had metrorrhagia vs. no participants assigned placebo (P < .01).
UF-2 findings
When treated with elagolix and add-back therapy in the UF-2 trial, the proportion of women who reached the primary endpoint was 77% while placebo yielded a rate of 10% (P < .001). In addition, the proportion was 77% for those treated with elagolix alone.
Menstrual blood loss at 6 months decreased by 198.1 mL from baseline for those assigned elagolix plus add-back therapy and by 223.7 mL for those assigned elagolix alone; blood loss rose by 28.5 mL with placebo (P < .001). Half of women achieved at least a 2 g/dL rise in hemoglobin after having a baseline measure of 10.5 g/dL or lower when treated with elagolix plus add-back therapy vs. 40% for those assigned elagolix alone and 21% for those assigned placebo (P = .02).
In UF-2, adverse events were reported by 75.7% of women assigned elagolix plus add-back therapy and 63% of women assigned placebo (P < .05); researchers observed no difference among women assigned placebo and elagolix alone. The researchers also noted that 19.6% of those assigned elagolix plus add-back therapy, 43% of those assigned elagolix alone and 4% of those assigned placebo reported hot flushes (P < .001) and that in both trials, this greater incidence was “because of the mechanism of action” of the medication. In addition, 25% of women assigned elagolix alone and 5% of those assigned placebo reported night sweats (P < .001).
Bone mineral density at the lumbar spine, total hip and femoral neck was lower in both trials for those assigned elagolix alone vs. placebo, but the add-back therapy “attenuated decreases in bone mineral density.”
Potentially superior to current options
“There is an oral gonadotropin-releasing hormone antagonist which in this study is shown to quickly reduce the hormonal stimulation to fibroids, which results in a relatively rapid decrease in heavy menstrual bleeding associated with fibroids,” Schlaff said. “It leads to speculation that this could be a longer-term treatment, which would be relevant for women who are approaching the latter years of their reproductive life. ... It could help a lot of women avoid surgery, which is really the fundamental alternative.”
Schlaff also said the results of these studies could indicate that elagolix may be preferable to the options that are currently available, which are primarily injectable and slower to take effect.
“This is oral as opposed to injectable, and the injectable depot formulations that have been around for quite some time take a while longer to work and substantially longer to wear off,” Schlaff said. “This oral medication ... has a rapid onset and wears off sooner, which is relevant because you don’t want to prolong the effects longer than you need them.” – by Phil Neuffer
Disclosures: This study was supported by AbbVie. Schlaff reports he has received consultant fees from AbbVie and Antares Pharma and grant support from AbbVie. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Nanette Santoro, MD
Uterine fibroids are exceedingly common, estrogen dependent, benign tumors that are a major cause of hysterectomy in the U.S. They disproportionately affect African American women and cause heavy menstrual bleeding, pain, bulk symptoms due to their size, and infertility in some cases. Clinical vs. surgical management decisions hinge upon the desire of a woman to maintain childbearing capacity, which she must often balance against the monthly burden of bleeding and pain. Few temporizing measures have been effective in controlling fibroid-related bleeding. Combined hormonal contraception works for many women with this condition, and is not contraindicated, but some women’s fibroids will grow as a result of the exposure to high-dose estrogen. Levonorgestrel-medicated intrauterine devices have been tried in women with fibroids that do not distort the uterine cavity, but they have had mixed results.
The current study provides an intellectually satisfying and effective approach to treating the heavy bleeding that accompanies fibroids by using two agents that are well known to OB/GYNs: GnRH antagonists and sex steroids. The striking reduction in bleeding with either elagolix alone or with “add-back” hormones was measured using rigorous methodology and is very convincing. The population of women studied includes many African American women, representative of the population of women with the most bothersome fibroids, and the amount of menstrual bleeding at the onset of the study is impressive — almost a unit of blood per menstrual period for these patients.
Some caveats to keep in mind are that the dose of elagolix used in this study was higher than what is currently FDA approved — the highest approved dose for endometriosis is 200 mg twice a day — and this dose resulted in significant bone density loss when used without any add-back therapy. Add-back therapy was relatively low dose, and even though it was effective in keeping heavy bleeding at bay, women using add-back had more hot flashes than women taking placebo elaglolix and had some bone loss. This bone loss may limit the duration of use of this effective temporizing treatment for uterine fibroid-related bleeding. A final caveat is that cost issues may limit access to this approach. Elagolix is currently very expensive so it may also limit the duration of use.
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