To date, combination oral contraceptives (COCs) are one of the most commonly prescribed therapies in the management of women with abnormal uterine bleeding, despite their limited efficacy in the management of leiomyoma-related uterine bleeding. As leiomyoma growth is stimulated by both estrogens and progestins, COC use should not be expected to provide symptomatic relief in terms of reducing the leiomyoma volume. In the short term, COCs can be used to improve heavy menstrual bleeding associated with fibroids, primarily through their suppressive effects on endometrial proliferation, but overall they have no effect on decreasing leiomyoma volume or uterine size.2 The advantages of COCs are the ease of accessibility, oral administration, low cost, and minimal side-effect profile. However, generally, COCs are not recommended for the treatment of abnormal uterine bleeding or bulk symptoms associated with leiomyomas, and patients should be offered alternative therapies for symptomatic relief.2

GnRH agonists were one of the first medical therapies to be used in the treatment of leiomyomas. In 1999, the FDA approved the short-term use of leuprolide acetate as a preoperative adjunct in women with symptomatic leiomyomas.3 Treatment with GnRH-a decreases uterine volume, fibroid volume, and bleeding. However, the benefits of GnRH-a are limited by side effects and risks associated with long term use. Hgh doses are associated with hypoestrogenism, leading to decreased bone mineral density.45 A follow-up study examined the efficacy of short-term therapy in symptomatic women already scheduled for surgery, and demonstrated that such a protocol resulted a significant reduction in the rate of menorrhagia. Broekmans et al. treated a cohort of women with standard-dose triptorelin therapy for 8 weeks and saw a reduction in the myoma volume, similar to previous studies. They then randomized the women to receive varying doses for a maintenance course. The investigators discovered that maintenance therapy with a low dose achieved similar reductions in volume as did treatment with a high dose, without a reduction in bone mineral density.67

GnRH antagonists act immediately to suppress the secretion of FSH and LH by blocking pituitary GnRH receptors.8 The subsequent reduction in estradiol levels leads to improvement in bleeding patterns and reduction in leiomyoma size as early as 3 weeks after initiation of treatment. For example, the daily administration of ganirelix 2 mg in premenopausal women was associated with a 42.7% (14.1e77.0%) reduction in leiomyoma volume and 46.6% (6.1e78.6%) reduction in uterine volume over a median treatment duration of 19 days.9

In 2009, the FDA approved the LNG-IUS to treat heavy menstrual bleeding in women who opt for an intrauterine device for contraception. In women with fibroids, uterine size no larger than 12 weeks, and a normal uterine cavity, LNG-IUS substantially reduces menstrual bleeding.10 The reduction in fibroid-related bleeding and symptoms has been reported in several studies. One observational study of 60 perimenopausal women with leiomyomas and excessive bleeding demonstrated that the LNG-IUS obviated the need for hysterectomy in 89.5% of users. Nevertheless, some studies demonstrate little benefit in the treatment of fibroid-related symptoms. Mercorio et al. reported no improvement in leiomyoma symptomatology with the LNG-IUS, as well as an expulsion rate of 12%. Because of these conflicting studies, the LNG-IUS must be investigated further as a treatment modality for leiomyomas, and randomized controlled trials are needed to fully elucidate the benefits of the LNG-IUS, if any, on the symptoms and size reduction of leiomyomas. Once inserted, the LNG-IUS is effective for up to 5 years, thus potentially providing women with a long-term treatment option. Because it is not administered systemically, minimal side effects are reported, and patient compliance is not required after insertion, as there is no need for daily/monthly injections. However, given the increased risk of expulsion, the LNG-IUS is contraindicated in patients with severe uterine cavity distortion. Nevertheless, because of the notable reduction in bleeding, reinsertion of the LNG-IUS was requested by most women with symptomatic and large intramural leiomyoma who had a history of spontaneous expulsion.1112

Gestrinone is a synthetic steroid derived from ethinyl nortestosterone that has both antiestrogenic and antiprogestogenic properties in the endometrium and other tissues containing estrogen and progesterone receptors.13 A small number of studies have demonstrated reduction in leiomyoma volume with the use of gestrinone. The proposed mechanism of action of gestrinone is via an antagonistic effect at estrogen and progesterone receptors, downregulating the activity of multiple genes regulating growth and proliferation, resulting in reduced fibroid size.14

Aromatase inhibitors block estrogen synthesis by inhibiting or inactivating the microsomal cytochrome p450 enzyme aromatase, which catalyzes the synthesis of estrogens from androgens via hydroxylation.15 The reduction in estrogen synthesis is detectable within 1 day of treatment, and aromatase is inhibited not only at the level of the ovary but also peripherally. Aromatase mRNA has been detected in 90% of fibroids, but not in normal myometrial tissue, which may explain how aromatase inhibitors act to suppress leiomyoma growth. It has been demonstrated that African American women have a higher prevalence of leiomyomas, and that the leiomyomas of African American women have higher aromatase expression than those of Caucasian or Japanese women. Thus, compared to other races, African American women may be more responsive to aromatase inhibitors, making this class of medications a beneficial target therapy.16

Selective estrogen receptor modulators (SERMs) are nonsteroidal estrogen receptor (ER) ligands that display tissue-specific ER agonist and/or antagonist estrogenic actions via tissue-specific alterations in gene expression. These medications are most commonly used for the treatment of ER-positive breast carcinoma. Two of the most commonly studied SERMs in the treatment of leiomyomas include tamoxifen and raloxifene.1718

Tamoxifen is a partial ER agonist in bone, cardiovascular tissue, and the endometrium, but it has antagonistic effects in the breast and within the central nervous system. One small randomized, blinded controlled trial compared tamoxifen 20 mg daily versus placebo in women with symptomatic leiomyomas. Patients were treated for a 6-month duration, and those receiving tamoxifen showed a significant improvement in menstrual blood loss but no improvement in fibroid size or uterine volume. The study subjects reported many side effects, including hot flushes, dizziness, and benign endometrial thickening. Endometrial thickening occurs due to the ER agonist effect of tamoxifen on the endometrium, which places patients at an increased risk of endometrial hyperplasia and malignancy if used in the long term. Therefore, the negative side effects outweigh the marginal benefits of tamoxifen therapy, and its use is not recommended for the treatment of symptomatic leiomyomas.19

Selective progesterone receptor modulators (SPRMs) have tissue-specific effects at progesterone receptors (PRs), and they can either have a complete PR agonist or antagonist profile or have a mixed agonist/antagonist profile.20 These agents have emerged as a promising therapy for the management of uterine leiomyomas, given the important role of progesterone in the promotion of leiomyoma growth. In vitro studies demonstrate that progesterone stimulates proliferative activity in cultured leiomyoma cells, but not in normalmyometrial cells. Thus, by altering progesterone receptor signaling, SPRMs inhibit leiomyoma cellular proliferation and stimulate the apoptosis of leiomyoma cells without affecting normal myometrial cells. In addition, in vitro studies have shown that SPRMs increase alkaline phosphatase activity, upregulate cleaved caspase-3, and down-regulate Bcl-2 in leiomyoma cells, thereby decreasing cellular proliferation and increasing apoptosis. SPRMs also induce the suppression of neovascularization of cultured leiomyoma cells. SPRMs may be used for the management of leiomyomas in patients preoperatively or in those wanting to defer surgical management.21

Mifepristone is a synthetic 19-norsteroid SPRM with primarily PR antagonist activity, and was one of the first SPRMs to be developed and commonly utilized. In addition, mifepristone has some antiglucocorticoid activity, although this is typically only seen with doses exceeding 200 mg daily. Although mifepristone is most commonly recognized as RU-486, an antiprogesterone used as an abortifacient, it also exhibits inhibitory effects on myoma growth. Murphy and colleagues were the first to use mifepristone as a therapeutic agent in the management of leiomyomas.2223

Several studies have demonstrated that NSAIDs and tranexamic acid were effective in reducing menstrual blood loss. But, these drugs were not shown to be effective for the treatment of menorrhagia in women fibroids.26