Current Management of Uterine Fibroids

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Uterine fibroids are hormone-driven diseases that can are estimated to affect approximately 70% to 80% of women by the onset of menopause.¹ Although they often cause no symptoms, uterine fibroids, depending on their location and number, may cause some women to experience heavy bleeding, pelvic pain, and lower back pain, which can have a notable impact on quality of life.¹ Fibroid size, often exceeding 10 cm in diameter, can lead to other direct symptoms, including abdominal protrusion, pelvic pressure, urinary urgency and frequency, incontinence, constipation, and/or tenesmus.¹ Additionally, uterine fibroids are seen in approximately 10% of infertility cases and are associated with several pregnancy-related complications, such as spontaneous abortion, preterm delivery, and cesarean delivery.¹

According to Ayman Al-Hendy, MD, a professor of obstetrics and gynecology at The University of Chicago Pritzker School of Medicine, and Magdy Milad, MD, chief of Gynecology and Gynecologic Surgery at Northwestern Memorial Hospital in Chicago, the goals of treating uterine fibroids is to relieve the symptoms in a way in which the benefits outweigh the risks and side effects while maintaining quality of life. In a new video, Drs. Al-Hendy and Milad discuss the current challenges and standards of care, as well as future opportunities in the management of patients with uterine fibroids. This article recaps key points from the conversation.

Risk Factors and Treatment

Several risk factors for uterine fibroids are worth noting. Increased age, hypertension, breast cancer, and ovarian cancer are each associated with a higher likelihood of uterine fibroids.¹ Notably, there is a relationship between race and prevalence of uterine fibroids.¹ “In general, women of color tend to have a higher risk of uterine fibroids compared to their White counterparts,” Dr. Al-Hendy notes. “The risk factor in African American women or Black women is about 4 times more than European American or Caucasian women. In Hispanic women, it’s probably around 2.5 times.”

A negative correlation between serum vitamin D levels and total uterine fibroid volume has also been noted.¹ “Vitamin D deficiency is now a well-recognized risk factor for uterine fibroids, and it’s very likely contributing to that first factor that I mentioned because as you know, we get our vitamin D from the sun mostly, and when you have darker skin, you don’t utilize the ultraviolet rays from the sun as effectively.”

Other risk factors include obesity and family history of uterine fibroids.¹ “More recently, some research suggests that adolescent menorrhagia, or young women or adolescent girls who have heavy menstrual bleeding even before they have fibroids, is [a risk factor for] developing fibroids later on in life,” says Dr. Al-Hendy.

The goal of therapy is to relieve the signs and symptoms associated with the patient’s complaint, whether it’s menstrual bleeding, pelvic pain, bulk symptoms, or infertility. According to Dr. Milad, the risk-benefit ratio is a key consideration no matter what therapy is instituted. “Ideally, therapy would sustain reduction in the size of the fibroids, prohibit fibroid growth, and maintain quality of life, including, for example, bone health.” To achieve optimal treatment, Dr. Milad states that shared decision-making is critical. “Shared decision-making is a process [in which] clinicians empower their patients to make optimal health care decisions that align with their priorities, so the burden is really on the clinician.” According to Dr. Milad, clinicians should help the patient clarify her goals, offer reasonable options, and explain the risks associated with those options, framing it in such a way that the patient can make her own decision. “This type of individualized care leads to high satisfaction and virtually eliminates the concerns regarding regret,” says Dr. Milad.

Regarding the treatment of bleeding, Dr. Al-Hendy points out that hormones can help make the endometrium thinner and potentially decrease the amount of bleeding, despite not really treating the fibroids themselves. Thus, oral contraceptives have been used to reduce blood loss from fibroids.² “We’ve been using medications such as oral contraceptives for that purpose because the progesterone component works on the endometrium, makes it thinner, and tends to help with the bleeding, at least temporarily,” says Dr. Al-Hendy. Another approach to managing bleeding is with intrauterine devices (IUDs), which also reduce blood loss and decrease fibroid volume.² Although clinical trials indicate that oral contraceptives and IUDs show efficacy initially, Dr. Al-Hendy notes that response tends to fail; the heavy bleeding returns, along with the potential adverse effects, rendering an IUD’s utility short term. Other potential therapies for uterine fibroids include selective progesterone receptor modulators (SPRM), which reduce blood loss and serve as an effective preoperative treatment; SPRMs are also not associated with hypoestrogenic side effects.² However, none of these compounds are currently approved in the US. Another agent that’s been evaluated for the reduction of heavy bleeding is tranexamic acid. “[This agent] works mainly on the clotting fibrinolytic system and tries to inhibit fibrinolysis, and as such, it decreases the amount of bleeding,” says Dr. Al-Hendy. “The early clinical studies suggest some efficacy. Although in fibroid patients, it has been very limited.”

Surgical Options for the Treatment of Uterine Fibroids

Beyond traditional pharmacological and device-based treatments, surgical interventions are commonly performed for uterine fibroids. Uterine fibroids are the most common cause for hysterectomy in the United States, accounting for approximately 30% to 50% of all procedures.¹ Another surgical option is myomectomy, a surgical or endoscopic excision of tumors that preserves fertility. It is worth mentioning, however, that repeated myomectomies can significantly increase risk of complications, such as pelvic adhesions.¹

Careful planning and understanding of the location, number, and size of the uterine fibroids, along with other factors, are essential in the decision to treat uterine fibroids surgically, according to Dr. Milad. “While ultrasound can be helpful, MRI is really the gold standard, particularly when considering myomectomy,” he says. “It allows optimizing the surgical approach, whether it’s hysteroscopy, laparoscopy with or without robotic assistance, minilaparotomy, [or] traditional laparotomy, and it may also prompt preoperative suppression to reduce bulk.”

It is also important to note that not all patients are candidates for surgical procedures, and the potential for adverse events must be considered. “The ideal surgical patient is free of all comorbidities; has no evidence of diabetes, high blood pressure, and thromboembolic disease; is not anemic; and has no previous surgery or history of pelvic adhesive disease,” notes Dr. Milad. “Some people estimate that the complication rate for myomectomy and hysterectomy may be as high as 5%.”

Long-term complications remain an area of continued inquiry and discovery and should also be a concern when considering hysterectomies, according to Dr. Al-Hendy. “It seems like we don’t [fully understand] the effect of that because some of those epidemiological data suggest increased risk for dementia and some [risk for] depression and [decrease in] cognitive function in women who had hysterectomy versus those who didn’t, even when you rule out contribution of the oophorectomy part,” says Dr. Al-Hendy. “I want to highlight some of the recent work, mostly coming from Mayo Clinic but also now being confirmed by other centers; when they looked at the long-term records of patients who had hysterectomy 20, 30 years earlier, and they’re looking at the incidence of heart disease, cognitive disorders, such as dementia, etc, the risk of dementia and heart disease is actually higher in those who had hysterectomy, even after you exclude the oophorectomy contribution. It suggests that maybe we don’t really have full understanding at the biological and molecular level of the contribution of the uterus. Maybe it does more than just harbor the baby during pregnancy, etc.”

The Evolving Role of GnRH Antagonists

In recent years, gonadotropin-releasing hormone (GnRH) antagonists have emerged as a unique class of oral drugs for the treatment of uterine fibroids. “[GnRH receptor antagonists] are nonpeptide compounds, and because they are nonpeptide, we can actually take them orally without [them] being digested or destroyed by the [gastrointestinal] enzymes,” notes Dr. Al-Hendy. “That’s a major advancement in the field, much more convenient for the patient, and hopefully will help the compliance.”

The other main distinction of GnRH antagonists is that they bind to the receptor immediately, and within a few hours, inhibit the release of the GnRH-releasing hormone. “Eventually, it leads to a decrease in [follicle-stimulating hormone] and [luteinizing hormone], suppresses folliculogenesis and ovulation, and then suppresses estrogen and progesterone production. This family of compounds works directly and without having this flare issue,” Dr. Al-Hendy explains.

GnRH antagonists should not be used long term as monotherapies, according to Dr. Al-Hendy. To achieve that window of therapeutic efficacy without suffering the adverse effects, he says you need approximately 40 to 60 pg/mL of estrogen. “These compounds are used to bring the estrogen level down, but then we add to all of them a very little amount of estradiol, typically 1 mg, and 0.5 mg of norethindrone acetate, progestin, all together to achieve the target, which is bringing the estrogen to the therapeutic range while not suffering or causing the undesirable side effects,” Dr. Al-Hendy explains.

Elagolix is the first and only GnRH antagonist to have achieved FDA approval for the treatment of heavy menstrual bleeding associated with uterine fibroids. However, agents within this class, relugolix and linzagolix, are completing clinical trials and undergoing evaluation for potential FDA approval. “This family of compounds has been developed through rigorous phase 3 placebo-controlled clinical trials in a large number of fibroid patients,” notes Dr. Al-Hendy.

In the pivotal Elaris Uterine Fibroids 1 and 2 (UF-1 and UF-2) trials, researchers randomized patients to receive elagolix 300 mg twice daily with once-daily hormonal add-back therapy or placebo. Among the women who received elagolix, the primary end point was met in 84.1% of women in UF-1 and in 77% of women in UF-2.³ “The vast majority of patients in those studies managed to normalize their heaviness of bleeding back to the normal range. Some patients in those studies [who] had very heavy bleeding, up to 90% of them up to 1 year of treatment, their menstrual blood loss was back to the normal range,” says Dr. Al-Hendy. Additionally, while amenorrhea might not be the main goal for many patients, approximately 50% of the patients achieved amenorrhea. Furthermore, fifty percent of the patients who started with anemia managed to cure or correct their hemogloblin levels. Dr. Al-Hendy adds that the adverse event profile for elagolix is tolerable. “There was an increase in the hot flash range, roughly around 20% versus around 11% in the placebo group, but most of these incidents were mild and a single incident per day.”

The efficacy and safety of investigational agent relugolix combination therapy (relugolix 40 mg plus estradiol 1 mg and norethindrone acetate 0.5 mg) has been studied in two Phase 3 trials, LIBERTY 1 and LIBERTY 2. Findings from the LIBERTY 1 and 2 studies demonstrated that relugolix combination therapy met the responder criteria (P < 0.0001), with 73.4% and 71.2% of women achieving the primary end point of reducing their menstrual blood loss to <80mL and by at least 50% from baseline compared with 18.9% and 14.7% of women receiving placebo, respectively.4 On average, women receiving relugolix combination therapy in both studies experienced an 84.3% reduction in menstrual blood loss from baseline (P < 0.0001). Dr. Al-Hendy notes that hemoglobin levels improved in women with anemia at baseline, and the amenorrhea rate was roughly around 50% in this program.

The LIBERTY trials are also notable because they evaluated pain, according to Dr. Al-Hendy. “From those patients who started with moderate or severe pain, based on a numerical [rating] scale that’s called NRS, about 50% of [them] managed to bring their pain to 0 or 1, which is considered minimal or non-existing pain.” The overall incidence of adverse events between relugolix combination therapy and placebo was comparable. The most common adverse reaction was hot flush. Additionally, bone mineral density was preserved after 1 year of treatment.

Phase 3 data for the investigational agent linzagolix with and without hormonal add-back therapy were presented at the 2020 ASRM Scientific Congress. Linzagolix was associated with a significantly improved menstrual bleedingand other symptoms of uterine fibroids at 24 weeks, with results being maintained at 52 weeks.⁴ In PRIMROSE 1, results showed responder rates of 56%, 67%, 71%, and 76% in the 100 mg, 100 mg plus hormonal add-back therapy, 200 mg, and 200 mg plus hormonal add-back therapy groups, respectively.⁵ In the PRIMROSE 2 trial, results showed responder rates of 57%, 77%, 78%, and 94% in the 100 mg, 100 mg plus hormonal add-back therapy, 200 mg, and 200 mg plus hormonal add-back therapy groups, respectively.⁵

Future Directions and Considerations

Women wait an average of 3.6 years before seeking treatment for uterine fibroids–related symptoms, and 41% of those seek treatment from at least 2 health care providers before diagnosis.⁶ Many who do seek treatment pursue surgical approaches. “We think that 1 in 3 women may undergo a hysterectomy by the age of 60, [which] highlights the need to follow [the American College of Obstetricians and Gynecologists] guidelines and offer alternative therapies before hysterectomy,” says Dr. Milad. Thus, it is important to increase awareness among patients regarding the growing treatment spectrum for uterine fibroids. Newer modalities, such as GnRH antagonists, present clinicians and patients with alternatives to surgical treatment.

The need for nonsurgical interventions will likely continue to expand. “It’s not uncommon to see women who are interested in retaining their uterus but not for fertility. We recently performed a study that suggested that in a subset of women, body image and sexual function play a role in choosing between conservative therapies and hysterectomy,” Dr. Milad explains.

When considering the utility of emerging nonsurgical options, Dr. Milad says that understanding their limitations is important. “Even with these new tools that we talked about, I will still consider them fertility unfriendly because [with] those treatments, you get ovulation suppression or ovulation inhibition [as the] mechanism of action, so you cannot pursue an attempt to get pregnant while on these agents,” says Dr. Milad. “We have a lot of options for patients that have symptomatic fibroids, but there’s definitely a gap in those therapies.”

References

1. Al-Hendy A, Myers ER, Stewart E. Uterine fibroids: burden and unmet clinical need. Semin Reprod Med. 2017;35(6):473-480. doi:10.1055/s-0037-1607264
2. De La Cruz MSD, Buchanan EM. Uterine fibroids: diagnosis and treatment. Am Fam Physician. 2017;95(2):100-107.
3. 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/NEJMoa190431
4. Al-Hendy A, Lukes A, Poindexter III A, et al. Treatment of Symptomatic Uterine Fibroids with Relugolix Combination Therapy: Efficacy and Safety Results from Two Double-blind, Randomized, Placebo-controlled, Phase 3 Clinical Trials. Presentation at the 2019 American Society for Reproductive Medicine Scientific Congress.
5. Stewart E, Taylor H, Taylor R, et al. Efficacy and Safety of Linzagolix for the Treatment of heavy Menstrual Bleeding Due to Uterine Fibroids: Results From Two Phase 3 Randomized Clinical Trials. Presentation at the 2020 American Society for Reproductive Medicine Scientific Congress. October 21, 2020. https://els-jbs-prod-cdn.jbs.elsevierhealth.com/pb/assets/raw/Health%20Advance/journals/fns/
   FNS_114_3_S%20final%20complete%20proof.pdf. Accessed October 27, 2020.
6. Marsh EE, Al-Hendy A, Kappus D, Galitsky A, Stewart EA, Kerolous M. Burden, prevalence, and treatment of uterine fibroids: a survey of US women. J Womens Health (Larchmt). 2018;27(11):1359-1367. doi:10.1089/jwh.2018.7076

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