Addressing Disparities in Care in Women’s Reproductive Health - Episode 13

Addressing disparities in care in women’s reproductive health. Uterine fibroids: burden and management

Uterine fibroids (UF), also referred to as leiomyomas or myomas, are benign lesions of the uterus, comprising fibroblasts, smooth muscle cells and extracellular matrix.1 Heavy menstrual bleeding (HMB), the most common symptom of UF, affects approximately 40.7% to 92.9% of women with this condition.2-5 Other common symptoms of UF include pain, pelvic pressure and urinary and gastrointestinal symptoms.1 Associated pain is experienced by as many as 78.8% of women with UF; its intensity varies widely depending upon the size and location of the leiomyomas.3,5,6

The incidence and prevalence of UF are hard to estimate accurately. Results of 4 large epidemiologic studies performed in the United States from 1989 to 2006 (Nurses Health Study II [1989-1993], California Teachers Study [1991-2006], Uterine Fibroid Study [1996-2005] and Black Women’s Health Study [1997-2001]) showed incidence rates of 217.4 to 3,745 per 100,000 women-years. However, the Black Women’s Health Study, involving Black women exclusively, showed notably higher rates of UF than reported in trials having an underrepresentation of Black women.7-12 The estimated prevalence rates over the same time periods are similarly broad and range from 4.5% to 68.6%, depending on subject populations, region and study designs.7 UF most likely is not diagnosed for various reasons. For example, women often are unaware that their menstrual symptoms are abnormal and do not actively seek treatment, and there is no consensus about how best to detect the condition. Thus, true estimates of its prevalence are skewed.6

The effect of UF on quality of life (QOL) often is severe, because the condition can have detrimental effects on relationships with partners and family members, activities of daily living and employment and career advancement.13 The heavy clinical burden of UF is accompanied by an equally large economic burden. In 2010, the estimated annual costs in the United States were as high as $34 billion; indirect costs accounted for roughly half of this total and direct costs were largely related to surgical interventions. In particular, surgical costs involved hysterectomies. From 2001 to 2005, approximately 32% of all hysterectomies performed in the United States were related to UF.14,15

Management of UF

The main goals of UF management are relief of symptoms, reduction in size or elimination of fibroids, maintenance of fertility (in patients for whom it is a priority) and avoidance of patient harm.16,17 Various guidelines for UF treatment have been published, but opinions on optimal treatment strategies and their place in therapy are fairly diverse, partially because robust clinical data are lacking on several of the most commonly used approaches.1 Moreover, most published treatment guidelines were produced five to 10 years ago; they generally do not include information on recently approved medical treatments for UF symptoms.

Some treatment guidelines for symptomatic UF recommend medical management approaches for first-line therapy, with surgical approaches reserved for second- or third-line treatment. Others, depending on the location of the fibroids, advocate that symptomatic UF be managed with less or more invasive surgery as a first-line strategy.18-21 Among medical therapies approved in the United States, the levonorgestrel intrauterine device is one of the most commonly recommended contraceptive agents used to manage UF.18 Tranexamic acid, a lysine derivative with antifibrinolytic activity, is recommended for treating patients with HMB, although evidence for its use is limited.18,19 In 2021, gonadotropin-releasing hormone (GnRH) agonists were recommended by the American College of Obstetricians and Gynecologists (ACOG) for short-term treatment of HMB and as a bridge therapy prior to longer-term therapies.18 GnRH agonists are limited to short-term use because of a significant risk of bone loss with long-term therapy; also, these agents may induce menopausal symptoms.22

The ACOG guidelines recommend hysterectomy as the definitive management of HMB and UF in women for whom fertility is not a priority and who accept the removal of their uterus.18 This serious surgical intervention, however, is associated with risk of morbidity and mortality. For women who want to retain their uterus and their fertility, the ACOG guidelines recommend myomectomy, a minimally invasive procedure that may result in fibroid recurrence. Other recommended alternatives include uterine artery embolization and radiofrequency ablation. Both allow uterine preservation, although their effects on reproductive health remain uncertain. Whatever treatment for UF is selected, the choice of therapy should depend upon patient preference and women should be advised about all the available treatment options and informed of the risks and benefits of each modality.

GnRH antagonists

GnRH antagonists offer a novel option for the treatment of HMB associated with UF. These medications have demonstrated a high degree of efficacy without many of the side effects associated with other oral therapies, although they must be used with hormonal “add-back” to avoid hypoestrogenic side effects and loss of bone mineral density.22,23

The first GnRH antagonist to receive FDA approval for treating HMB associated with UF — and the first oral therapy approved for this indication — was elagolix with add-back hormonal therapy given orally twice daily (in the morning, a capsule containing elagolix 300 mg plus estradiol 1 mg/norethindrone acetate 0.5 mg; in the evening, a capsule containing only elagolix 300 mg).24 The FDA approval of elagolix was accompanied by a limitation-of-use statement that it should not be used for more than 24 months based on the risk of permanent bone loss.24 Two identical and pivotal phase 3 trials — Elaris Uterine Fibroids 1 and 2 (UF-1 and UF-2) — involved 791 premenopausal women randomly assigned 2:1:1 to receive twice-daily oral doses of elagolix 300 mg with add-back therapy (estradiol 1 mg/norethindrone acetate 0.5 mg), elagolix 300 mg alone or placebo.23 The primary end point (menstrual blood loss < 80 mL and reduced blood loss ≥ 50% from baseline to the last month of a six-month treatment period) was achieved by 68.5% and 76.5% of patients treated with elagolix plus add-back therapy in UF-1 and UF-2, respectively, as compared with 8.7% and 10% of women receiving placebo (both comparisons, P < 0.001).23 Women receiving elagolix alone and those given combination therapy achieved similar results.23

Relugolix is the first once-daily GnRH antagonist to receive FDA approval for managing HMB associated with UF. As with elagolix, the approval was accompanied by a 24-month limitation-of-use statement.25 This once-daily oral formulation includes relugolix 40 mg plus estradiol 1 mg/norethindrone acetate 0.5 mg.26 In all, 770 premenopausal women participated in two identical phase 3 trials (LIBERTY 1 [L1] and LIBERTY 2 [L2]) to evaluate its efficacy and safety.26 The primary end points (menstrual blood loss < 80 mL and ≥ 50% reduction of blood loss from baseline) were similar to those of the Elaris trials, but the evaluation involved the last 35 days of the treatment period.26 The women were randomly assigned 1:1:1 to receive the once-daily oral combination of relugolix plus estradiol/norethindrone acetate for 24 weeks, relugolix 40-mg monotherapy for 12 weeks followed by the combination therapy for another 12 weeks (to assess a delayed add-back therapy approach), or placebo for 24 weeks.26 Among patients given 24-week combination therapy, the primary end point was achieved by 73% of patients in L1 and 71% of those in L2 as compared with 19% and 15%, respectively, of the placebo groups (both P < 0.001).26 Similar results were observed in the delayed add-back treatment and the 24-week combination therapy groups. Effects on bone marrow density and incidences of side effects were similar among the combination therapy and placebo groups; however, decreased bone mineral density was seen in the monotherapy group.26

Conclusions

Many women with UF underestimate its consequences and the availability of viable treatments that could improve their symptoms and QOL. Available treatment options for UF include medical therapies and surgical interventions of varying invasiveness. The use of several medications and drug classes that can reduce HMB has been limited by side effects (e.g., risk of liver toxicity, downstream effects of hypoestrogenism). GnRH antagonists offer a safe, efficacious therapeutic option for UF with a limited possibility of side effects when used with add-back hormonal therapy to reduce the risks of hypoestrogenism. The once-daily oral GnRH antagonist relugolix provides the therapeutic advantages of this drug class and a once-daily dosing regimen.

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