Heavy Bleeding From Uterine Fibroids: Which Treatment Is Best?

Treating Heavy Menstrual Bleeding: What's Best?

Menometrorrhagia-excessive and prolonged uterine bleeding at irregular or frequent intervals^[1]—is most often caused by uterine fibroids, and symptom severity is determined by fibroid size and location. Intramural or submucosal fibroids that distort the uterine cavity can interfere with the normal uterine blood supply and contractility, and can lead to bleeding anomalies.^[2] Longstanding menometrorrhagia depletes iron stores, resulting in anemia. Anemia lowers a woman's physical endurance, significantly affecting her quality of life.

Medical treatments that suppress steroid hormone levels, such as gonadotropin-releasing hormone (GnRH) agonists, have been shown to be effective in heavy menstrual bleeding.^[3] GnRH antagonists also suppress estradiol levels, but through different mechanisms. A recent study^[4] compared the efficacy of an oral GnRH antagonist (relugolix) with a GnRH agonist (leuprorelin) in the clinical management of fibroids that cause heavy menstrual bleeding.

This was a double-dummy, double-blind, randomized, controlled trial. Reproductive-aged women (n = 281) with heavy menstrual bleeding (score > 120 on a pictorial blood loss assessment chart) related to fibroids were randomly assigned to receive 40-mg oral relugolix tablets daily or either 1.88 or 3.75 mg of leuprorelin (depending on weight) for 24 weeks. Baseline characteristics of the women, including fibroid and uterine volume as well as degree of heavy bleeding, were similar.

The findings included the following:

• The proportion of women with pictorial blood loss scores < 10 (the primary endpoint) for weeks 6-12 were similar (82.2% of the relugolix group vs 83.1% of the leuprorelin group);

• By study end (weeks 18-24), significantly more women had a pictorial blood loss score < 10 in the leuprorelin group (94.7%) than the relugolix group (84.1%);

• Relugolix was associated with an earlier effect on menstrual bleeding than leuprorelin;

• Significantly more women developed amenorrhea with leuprorelin (88.7%) than with relugolix (75.4%);

• Both treatments resulted an approximately 50% reduction in myoma/fibroid volumes;

• Upon discontinuation of the study drug, menstruation recurred sooner with relugolix (37 days) than with leuprorelin (65 days);

• Hemoglobin levels rose similarly and pain levels improved to the same degree in both treatment groups; and

• Adverse events leading to study termination were similar. Hot flushes were the most common serious side effect.

The conclusion was that relugolix, an oral GnRH antagonist, was not inferior to leuprorelin, an injectable GnRH agonist, to treat menometrorrhagia associated with uterine fibroids.

Viewpoint

Fibroids frequently cause menometrorrhagia by interfering with uterine contractility and vascular function. The definitive treatment is surgery, either myomectomy or hysterectomy. Severe anemia or very large fibroids may require preoperative medical therapy to make patients better surgical candidates. Standard preoperative therapy involves monthly injections of GnRH agonist.^[5] GnRH agonists bind to pituitary receptors, inducing a flare effect before hypogonadism is achieved upon downregulation and desensitization of GnRH receptors. Therefore, it may take a few weeks before therapeutic effect is reached. GnRH agonist treatment is complicated by hypoestrogenism and related side effects (hot flashes, reduced bone mineral density).

GnRH antagonists also suppress ovarian activity. As competitive inhibitors of the pituitary GnRH receptors, their effect is immediate. This was demonstrated in this study; the proportion of women who developed amenorrhea and achieved a significant reduction in bleeding early in the trial (2-6 weeks) was significantly higher with relugolix.

Both treatments deeply suppressed estradiol levels, and bone mineral density was reduced in both arms. Severe side effects were not common with either approach, but when they did occur, hot flushes dominated. Add-back therapy may ameliorate the hypoestrogenic side effects of GnRH agonists, an option that should also be explored with relugolix.

Oral administration is a clear benefit over parenteral administration. The efficacy of relugolix is not inferior and the side effect profile is similar to leuprorelin, but it is too early to compare costs. Oral GnRH antagonists could successfully be used for preoperative management of patients with symptomatic fibroids. Longer-term use to avoid surgery needs to be evaluated, but in such cases, add-back therapy will be required.

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