Kosin Medical Journal 2017;32:17-24. https://doi.org/10.7180/kmj.2017.32.1.17 KMJ Review Article Current Medical Therapy for Uterine Leiomyomas Suk Bong Koh Departments of Obstetrics and Gynecology, School of Medicine, Catholic University of Daegu, Daegu, Korea Uterine leiomyomas are benign tumors arising from the myometrium and largely prevalent in the woman's reproductive years. The majority of women with leiomyomas either remain asymptomatic or develop symptoms gradually over time. When patients are symptomatic, the nature of their complaints is often attributable to the number, size, and/or location of their fibroids. Depending on a patient’s symptomatology and reproductive plans, treatment options include expectant management, medical management (hormonal and non-hormonal), or surgical management (myomectomy or hysterectomy). Key Words: Medical therapy, Uterine leiomyomas PRINCIPLE OF TREATMENT HORMONAL MEDICAL MANAGEMENT The management of uterine leiomyomas varies 1. COMBINATION ORAL CONTRACEPTIVE significantly depending on the patient's age, PILLS symptoms, and reproductive plans. Appropriate To date, combination oral contraceptives selection of medical management (hormonal vs. (COCs) are one of the most commonly prescribed nonhormonal) is necessary and will vary based on therapies in the management of women with ab- the patient's medical history, symptomatology, normal uterine bleeding, despite their limited ef- and goals for treatment. Treatment should satisfy ficacy in the management of leiomyoma-related three purposes: relief of signs and symptoms, sus- uterine bleeding. As leiomyoma growth is stimu- tained reduction of fibroid size, and maintenance lated by both estrogens and progestins, COC use or improvement of fertility, while minimizing side should not be expected to provide symptomatic effects. Because of their benign nature, the most relief in terms of reducing the leiomyoma volume. conservative therapeutic choice should be con- In the short term, COCs can be used to improve sidered in order to minimize morbidity and/or heavy menstrual bleeding associated with fib- side effects, while optimizing the patient's roids, primarily through their suppressive effects outcome.1 on endometrial proliferation, but overall they Corresponding Author: Suk Bong Koh, Department of Obsterics and Gynecology, Catholic University. Received: Aug. 11, 2016 33, Duryugongwon-ro 17gil, Nam-gu, Daegu 42472, Korea Revised: Aug. 11, 2016 Tel: +82-53-650-4074 Fax: +82-53-650-4078 E-mail: [email protected] Accepted: Aug. 24, 2016 17 Kosin Medical Journal 2017;32:17-24. have no effect on decreasing leiomyoma volume investigators discovered that maintenance ther- or uterine size.2 The advantages of COCs are the apy with a low dose achieved similar reductions ease of accessibility, oral administration, low cost, in volume as did treatment with a high dose, with- and minimal side-effect profile. However, gen- out a reduction in bone mineral density.6,7 erally, COCs are not recommended for the treat- ment of abnormal uterine bleeding or bulk symp- 3. GONADOTROPIN-RELEASING HORMONE toms associated with leiomyomas, and patients (GnRH) ANTAGONIST should be offered alternative therapies for symp- GnRH antagonists act immediately to suppress tomatic relief.2 the secretion of FSH and LH by blocking pituitary GnRH receptors.8 The subsequent reduction in es- 2. GONADOTROPIN-RELEASING HORMONE tradiol levels leads to improvement in bleeding (GnRH) AGONIST patterns and reduction in leiomyoma size as early GnRH agonists were one of the first medical as 3 weeks after initiation of treatment. For exam- therapies to be used in the treatment of ple, the daily administration of ganirelix 2 ㎎ in leiomyomas. In 1999, the FDA approved the premenopausal women was associated with a short-term use of leuprolide acetate as a pre- 42.7% (14.1e77.0%) reduction in leiomyoma vol- operative adjunct in women with symptomatic ume and 46.6% (6.1e78.6%) reduction in uterine leiomyomas.3 Treatment with GnRH-a decreases volume over a median treatment duration of 19 uterine volume, fibroid volume, and bleeding. days.9 However, the benefits of GnRH-a are limited by side effects and risks associated with long term 4. LEVONORGESTREL INTRAUTERINE SYSTEM use. Hgh doses are associated with hypoestrogen- (LNG-IUS) ism, leading to decreased bone mineral density.4,5 In 2009, the FDA approved the LNG-IUS to treat A follow-up study examined the efficacy of heavy menstrual bleeding in women who opt for short-term therapy in symptomatic women al- an intrauterine device for contraception. In wom- ready scheduled for surgery, and demonstrated en with fibroids, uterine size no larger than 12 that such a protocol resulted a significant reduc- weeks, and a normal uterine cavity, LNG-IUS sub- tion in the rate of menorrhagia. Broekmans et al. stantially reduces menstrual bleeding.10 The re- treated a cohort of women with standard-dose duction in fibroid-related bleeding and symptoms triptorelin therapy for 8 weeks and saw a reduc- has been reported in several studies. One ob- tion in the myoma volume, similar to previous servational study of 60 perimenopausal women studies. They then randomized the women to re- with leiomyomas and excessive bleeding demon- ceive varying doses for a maintenance course. The strated that the LNG-IUS obviated the need for 18 Current Medical Therapy for Uterine Leiomyomas hysterectomy in 89.5% of users. Nevertheless, in leiomyoma volume with the use of gestrinone. some studies demonstrate little benefit in the The proposed mechanism of action of gestrinone treatment of fibroid-related symptoms. Mercorio is via an antagonistic effect at estrogen and pro- et al. reported no improvement in leiomyoma gesterone receptors, downregulating the activity symptomatology with the LNG-IUS, as well as an of multiple genes regulating growth and pro- expulsion rate of 12%. Because of these conflict- liferation, resulting in reduced fibroid size.14 ing studies, the LNG-IUS must be investigated fur- ther as a treatment modality for leiomyomas, and 5. AROMATASE INHIBITORS randomized controlled trials are needed to fully Aromatase inhibitors block estrogen synthesis elucidate the benefits of the LNG-IUS, if any, on by inhibiting or inactivating the microsomal cyto- the symptoms and size reduction of leiomyomas. chrome p450 enzyme aromatase, which catalyzes Once inserted, the LNG-IUS is effective for up to the synthesis of estrogens from androgens via 5 years, thus potentially providing women with hydroxylation.15 The reduction in estrogen syn- a long-term treatment option. Because it is not thesis is detectable within 1 day of treatment, and administered systemically, minimal side effects aromatase is inhibited not only at the level of the are reported, and patient compliance is not re- ovary but also peripherally. Aromatase mRNA has quired after insertion, as there is no need for dai- been detected in 90% of fibroids, but not in normal ly/monthly injections. However, given the in- myometrial tissue, which may explain how ar- creased risk of expulsion, the LNG-IUS is contra- omatase inhibitors act to suppress leiomyoma indicated in patients with severe uterine cavity growth. It has been demonstrated that African distortion. Nevertheless, because of the notable American women have a higher prevalence of reduction in bleeding, reinsertion of the LNG-IUS leiomyomas, and that the leiomyomas of African was requested by most women with symptomatic American women have higher aromatase ex- and large intramural leiomyoma who had a history pression than those of Caucasian or Japanese of spontaneous expulsion.11,12 women. Thus, compared to other races, African American women may be more responsive to ar- 4. GESTRINONE omatase inhibitors, making this class of medi- Gestrinone is a synthetic steroid derived from cations a beneficial target therapy.16 ethinyl nortestosterone that has both anti- estrogenic and antiprogestogenic properties in 6. SELECTIVE ESTROGEN RECEPTOR MODUL- the endometrium and other tissues containing es- ATORS(SERMs) trogen and progesterone receptors.13 A small Selective estrogen receptor modulators (SERMs) number of studies have demonstrated reduction are nonsteroidal estrogen receptor (ER) ligands 19 Kosin Medical Journal 2017;32:17-24. that display tissue-specific ER agonist and/or an- one receptors (PRs), and they can either have a tagonist estrogenic actions via tissue-specific al- complete PR agonist or antagonist profile or have terations in gene expression. These medications a mixed agonist/antagonist profile.20 These are most commonly used for the treatment of agents have emerged as a promising therapy for ER-positive breast carcinoma. Two of the most the management of uterine leiomyomas, given the commonly studied SERMs in the treatment of leio- important role of progesterone in the promotion myomas include tamoxifen and raloxifene.17,18 of leiomyoma growth. In vitro studies demon- Tamoxifen is a partial ER agonist in bone, car- strate that progesterone stimulates proliferative diovascular tissue, and the endometrium, but it activity in cultured leiomyoma cells, but not in has antagonistic effects in the breast and within normalmyometrial cells. Thus, by altering proges- the central nervous system. One small random- terone receptor signaling, SPRMs inhibit leiomyo- ized, blinded controlled trial compared tamoxifen ma cellular proliferation and stimulate the apop- 20 ㎎ daily versus placebo in women with sympto- tosis of leiomyoma cells without affecting normal matic leiomyomas.