- Uterine fibroids are extremely common; approximately 70% to 80% of women will develop fibroids by age 50.
- The 2 main types of symptoms are prolonged heavy bleeding or bulk symptoms; the fibroids get so large that they cause pelvic and back pain and pressure.
- Clinicians are moving away from surgical interventions such as hysterectomy and myomectomy to medical management of uterine fibroids.
- Oral gonadotropin-releasing hormone (GnRH) receptor antagonists, which induce a rapid and reversible suppression of ovarian sex hormones, have become an important addition to the management of heavy fibroid-associated bleeding, with few side effects.
- The first critical step for providers is to raise their index of suspicion and make the diagnosis of uterine fibroids and the consequent heavy bleeding.
Andrea Lukes, MD, MHSc, FACOG, is a board-certified obstetrician/gynecologist and the founder and CEO of the Carolina Women’s Research and Wellness Center in Durham, North Carolina. Dr Lukes’ clinical expertise and research interests focus on heavy or irregular periods, uterine fibroids, endometriosis, abnormal Pap smears, menopause, all forms of contraception, weight loss, hereditary cancer screening, and preconception counseling. Dr Lukes is also the Chief Medical Officer of Premier Research in Morrisville, North Carolina, a provider of project management, clinical research, and monitoring services for pharmaceutical and medical device companies.
Many women reach out to health care providers with symptoms that indicate the presence of uterine fibroids. How common are they and which populations of women are most at risk of developing uterine fibroids?
Dr Lukes: Uterine fibroids are a common and benign monoclonal tumor arising from smooth muscle cells and fibroblasts of the myometrium. They are a remarkably common disorder that can have a significant impact on the quality of life for millions of women. In our practice, approximately 70% to 80% of women will develop fibroids by age 50, which align closely with the published literature.1,2 We don’t really know why uterine fibroids occur, but there may be a genetic disposition to their development.
Of note, uterine fibroids are more common in Black women than White women. Some studies have found that Black women are twice as likely to develop fibroids as Hispanic women and up to 4 times more likely than White women.3 Black women also present with earlier age of onset, more and larger growths, and increased severity of symptoms. Approximately 25% of women with uterine fibroids will experience symptoms severe enough to require treatment, most often heavy menstrual bleeding, which is often associated with anemia.
What are some of the key risk factors and symptoms associated with uterine fibroids?
The 2 main types of symptoms are prolonged heavy bleeding or bulk symptoms—the fibroids get so large that they cause pelvic and back pain and pressure. Bulk symptoms also result in increased urination, constipation, and abdominal distention. Age of menarche, obesity, hypertension, alcohol, gravidity, family history of fibroids, and race also clearly increase the risk of developing fibroids.
Because symptoms overlap with other gynecologic disorders such as endometriosis and adenomyosis, the average time to diagnose fibroids can be significantly prolonged.4 Furthermore, once a patient is diagnosed, heterogeneity in the size, number, and location of the fibroids can make treatment difficult. Of note, uterine fibroid-associated pain is the second most debilitating problem.5 Fibroids may also compromise reproductive functions, possibly contributing to subfertility, untoward pregnancy outcomes, health related quality of life, economic burden, and work productivity.6
What are the current standards of care for the management of uterine fibroids?
I tend to individualize treatment. It depends on whether a woman does or does not want to have children. In our practice we used to predominantly use birth control pills or nonhormonal tranexamic acid to reduce the bleeding, and nonsteroidal anti-inflammatory drugs for the pain.
Current medical management approaches to treating symptomatic fibroids also include oral contraceptives, injectable long-acting GnRH agonists (eg, leuprolide acetate), progestins, and, in some cases, the intrauterine device Mirena®, which can be used to treat abnormal bleeding.
Although contraceptives are used for the management of uterine fibroid symptoms, the quality of evidence for their use is low. Injectable GnRH agonists are effective; however, hypoestrogenic sequelae limit their duration of use or lead to the administration of additional hormonal therapy to mitigate side effects. Data show that coadministration with progestins (eg, leuprolide acetate with medroxyprogesterone acetate) may attenuate these effects. As I noted earlier, although hormone-regulating therapies are effective in treating fibroids, they also inhibit fertility.
Hysterectomy and myomectomy (only removal of the fibroids) are the most common surgical procedures for uterine fibroids. Some research suggests that hysterectomy, even with ovarian conservation, affects ovarian function and leads to early menopause, but it shows better outcomes for fibroids within 3 to 5 years post-surgery, compared with other medical treatments. However, in the longer term, hysterectomy (particularly when conducted with oophorectomy) is associated with increased risk of cardiovascular disease, fracture risk, pelvic floor dysfunction, and neurologic issues. It should be emphasized that these complications are not fully understood and often are not adequately discussed with patients.
Radio-frequency ablation and uterine artery embolization are less invasive procedures, but they also can inhibit fertility. Alternatively, magnetic resonance-guided focused ultrasound is an emerging noninvasive treatment recommended for patients who have fewer and larger fibroids. Patients report symptom improvement within the first 2 years, but one-third of women will need another procedure to treat recurrent disease.
With an estimated $34 billion in health care costs associated with fibroids in the United States alone in 2010,7 there is a major need for a nonsurgical long-term treatment option, particularly one that addresses women’s usual preference for uterine-sparing alternatives regardless of their reproductive plans.8
What are your thoughts on the newer oral GnRH receptor antagonists for the management of uterine fibroids?
The oral GnRH receptor antagonists, elagolix and relugolix, which induce a rapid and reversible suppression of ovarian sex hormones, have become, in my view, a great addition to the management of heavy fibroid-associated bleeding, with few side effects.
Schlaff and colleagues reported that patients who participated in 2 identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2])9,10 of the oral GnRH receptor antagonist elagolix at a dose of 300mg twice daily, either alone or with hormonal “add-back” therapy of estradiol, 1mg, and norethindrone acetate, 0.5mg, once daily (to reduce side effects and replace reduced levels of endogenous hormones), achieved significant reductions in fibroid-associated menstrual bleeding.11
The study revealed that 68.5% of women in UF-1 and 76.5% of women in UF-2 met the primary endpoint—menstrual blood loss of <80mL during the final month and at least a 50% reduction in menstrual blood loss in the final month—compared with placebo, 8.7% and 10.0%, respectively (P <.001). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2.
Similar findings have been reported with relugolix, a once-daily GnRH receptor antagonist formulation. Findings from the LIBERTY-1 and LIBERTY-2 (L-1 and L-2) trials demonstrated similar statistically reductions in uterine fibroid symptoms compared with placebo.12,13 A total of 73% of the participants in the combination therapy group (40mg of relugolix, 1mg of estradiol, and 0.5mg of norethindrone acetate) in trial L1 and 71% of those in trial L2 met the primary endpoint (volume of menstrual blood loss <80mL and a >50% reduction in volume at baseline), compared with 19% and 15%, respectively, of those in the placebo groups (P <.001). I should emphasize that in this trial, there was an 84% reduction in bleeding at 6 months, which is huge, and at a year, it goes up to 90%.14
Of note, approximately 50% of women in the 4 trials under study achieved amenorrhea in the final stages of the treatment period, compared with placebo (UF-1: 4% and UF-2: 5%; L-1: 6% and L-2: 3%).
Hot flashes were the most frequently reported adverse event across these 4 trials. Reductions in bone mineral density observed in select patient populations can be mitigated by the inclusion of add-on therapy to the GnRH receptor antagonist.
Apart from the effectiveness in reducing fibroid-associated bleeding, the GnRH receptor antagonist class also has had a substantial impact on enhancing the quality of life among women with uterine fibroids. These agents substantially reduce pain, and the distress from bleeding and pelvic discomfort that women must endure. They are so effective that we do not have to think of hysterectomy first-line, or uterine-sparing procedures that so often result in reoperation.
There was a time when uterine and fibroid volume and fibroid location were criteria to exclude women from medical therapy. Data from these studies make eminently clear that all women should be offered a medical trial for the treatment of heavy menstrual bleeding associated with fibroids.
What overall management advice would you give to Ob-Gyns and primary care providers?
The first critical step for providers is to raise their index of suspicion and make the diagnosis. On average, it takes almost 4 years from the time a woman presents to a provider to when she is finally diagnosed with uterine fibroids. Providers, particularly primary care providers, have to think of the problem. It’s also important to perform an ultrasound. If primary care providers are not comfortable prescribing appropriate medication, they should refer to an Ob/Gyn in the early stages. I also try to allay women’s concerns because uterine fibroids are so common. I also tend to favor nonsurgical options, and it is exciting that new effective pharmacologic options are now available.
When assessing a patient’s gynecologic health, health care providers must consider objective measures as well as subjective factors, such as the ‘‘normalcy’’ of an individual’s menstrual cycle. What is viewed as normal for each patient varies widely and is typically defined by their background and environment. Health care professionals beyond gynecologic specialists should be well versed and trained to recognize key indicators of symptomatic fibroids. For example, primary care physicians and nurse practitioners conduct general wellness examinations and are often the first provider an individual visits with concerns about persistent pain or anemia.
Do you have any final thoughts you’d like to share about uterine fibroids?
The epidemiology and unmet health care needs concerning fibroids warrant further investigation to better understand the factors that influence the prevalence and disparities associated with the disease and to ameliorate the financial burden on patients and the health care system.
The impact of uterine fibroids on health and quality of life can be severe. Fibroids are a public health issue that will benefit from general awareness and policy intervention. Concerted efforts to increase awareness, reduce bias, and promote provider and patient education are fundamental to empower patients throughout their life-course journey as they live with and manage symptomatic uterine fibroid disease.
- Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003;188:100-107. doi:10.1067/mob.2003.99
- Wise LA, Laughlin-Tommaso SK. Epidemiology of uterine fibroids: from menarche to menopause. Clin Obstet Gynecol. 2016;59:2-24. doi:10.1097/GRF.0000000000000164
- Othman EER, Al-Hendy A. Molecular genetics and racial disparities of uterine leiomyomas. Best Pract Res Clin Obstet Gynaecol. 2008;22:589-601. doi:10.1016/j.bpobgyn.2008.01.014
- Ghant MS, Sengoba KS, Vogelzang R, Lawson AK, Marsh EE. An altered perception of normal: understanding causes for treatment delay in women with symptomatic uterine fibroids. J Womens Health. 2016;25:846-852. doi:10.1089/jwh.2015.5531
- David M, Pitz CM, Mihaylova A, Siedentopf F. Myoma-associated pain frequency and intensity: a retrospective evaluation of 1548 myoma patients. Eur J Obstet Gynecol Reprod Biol. 2016;199:137-140. doi: 10.1016/j.ejogrb.2016.02.026
- Marsh EE, Al-Hendy A, Kappus D, Galitsky A, Stewart EA, Kerolous M. Burden, prevalence, and treatment of uterine fibroids: A survey of U.S. women. J Womens Health. 2018;27:1359-1367. doi:10.1089/jwh.2018.7076
- Cardozo ER, Clark AD, Banks NK, Henne MB, Stegmann BJ, Segars JH. The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol. 2012;206(3):211.e1-9. doi:10.1016/j.ajog.2011.12.002.
- Borah BJ, Nicholson WK, Bradley L, Stewart EA. The impact of uterine leiomyomas: a national survey of affected women. Am J Obstet Gynecol. 2013;209(4):319.e1-319.e20. doi:10.1016/j.ajog.2013.07.017
- Efficacy and safety of elagolix in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. ClinicalTrials.gov Identifier: NCT02654054. Updated June 29, 2020. Accessed March 24, 2022. https://clinicaltrials.gov/ct2/show/NCT02654054.
- Efficacy and safety of elagolix in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women (replicate study). ClinicalTrials.gov Identifier: NCT02691494. Updated July 13, 2021. Accessed March 24, 2022. https://clinicaltrials.gov/ct2/show/NCT02691494.
- Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med. 2020;382(4):328-340. doi:10.1056/NEJMoa1904351
- LIBERTY 1: efficacy & safety study of relugolix in women with heavy menstrual bleeding associated with uterine fibroids. ClinicalTrials.gov Identifier: NCT03049735. Updated December 8, 2020. Accessed March 24, 2022. https://clinicaltrials.gov/ct2/show/NCT03049735.
- LIBERTY 2: efficacy & safety study of relugolix in women with heavy menstrual bleeding associated with uterine fibroids. ClinicalTrials.gov Identifier: NCT03103087. Updated November 17, 2020. Accessed March 24, 2022. https://clinicaltrials.gov/ct2/show/NCT03103087.
- Al-Hendy A, Lukes AS, Poindexter III AN, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384(7):630-642. doi:10.1056/NEJMoa2008283