Uterine fibroids: medical management options

Dr. Tulandi is Professor and Interim Chair of Obstetrics and Gynecology and Milton Leong Chair in Reproductive Medicine, McGill University, and Interim Chief of Department of Obstetrics and Gynecology, McGill University Health Center, Montreal, Canada. 

He reports serving as an advisor for Actavis Inc.

Dr. Al-Asmari is a former fellow in Reproductive Endocrinology and Infertility, McGill University, Montreal, Canada.

She has no conflicts of interest to report with respect to the content of this article.

Fibroids are the most common benign tumors of the female reproductive tract. In fact, 25% of women older than age 35 have uterine leiomyomas. Most are asymptomatic. When present, symptoms may include heavy menstrual bleeding, intermenstrual or postmenopausal bleeding, infertility, back pain, pressure, or urinary issues, and hydronephrosis due to ureteral compression.^1,2 The symptoms are related to the size, type, number, and location of the tumor(s).

Illustration by Alex Baker, DNA Illustrations, Inc.

Management of women with symptomatic uterine myomata depends on several factors including age; reproductive plans; size, location, and number of leiomyomas; and type and severity of symptoms. Asymptomatic women do not require any treatment and prophylactic surgery to prevent potential complications is not recommended.³ Many modalities are available for treatment of women with symptomatic myomata, including expectant management (especially for those close to menopause), medical treatment, and surgery.

This review is confined to medical management of uterine myomata. Medical treatment is particularly useful for women in whom surgery is contraindicated or who are at high surgical risk, and for those who do not wish to undergo procedures including uterine artery embolization. The purpose is to alleviate symptoms and improve quality of life. Medical management is also used preoperatively to improve the hematologic status of patients before surgery and to reduce myomata volume, enabling use of a minimally invasive surgical technique.

Symptomatic treatment

·               Oral contraceptive pills (OCPs): The influence of OCP on myomata is poorly understood and data on its effect on the size of myomata are conflicting. Yet, by inhibiting ovulation, both OCPs and pregnancy may have a protective effect against the recurrence of fibroids after myomectomy.⁴ OCP appear to improve short-term menstrual irregularities through their effects on the endometrium but they do not reduce the size of myomata.⁵ In a meta-analysis, the authors reported a 17% reduction in morbidity among women who had used OCP for 5 years or more.⁶

·               Tranexamic acid (TA): This antifibrinolytic lysine derivative reduces the amount of bleeding by preventing fibrin degradation. FDA-approved for treatment of menorrhagia in 2009, TA decreases menstrual bleeding within 2–3 hours of administration. Low-quality evidence suggests that the drug reduces intraoperative blood loss during myomectomy.⁷ Side effects include dizziness, gastrointestinal symptoms, and possible intralesional thrombosis leading to necrosis. Although the evidence for risk of thromboembolic event with TA is controversial, caution should be exercised with its use in combination with hormonal treatment such as OCP. The dose is usually 1–1.5 g 4 times daily; however, patients are advised to use TA sporadically only during acute episodes of heavy bleeding. 

·               Progesterone: Because it promotes endometrial atrophy and suppresses gonadotropin secretion, oral progesterone is often used to treat abnormal uterine bleeding. On the other hand, the levonorgestrel-releasing intrauterine system (LNG-IUS) seems to be effective and has fewer adverse effects compared to other progestin preparations. It does not reduce myomata volume, but after an initial period of irregular spotting, it causes amenorrhea in most cases and improves anemia. In a study of perimenopausal women with fibroid-related menorrhagia, use of the LNG-IUS alleviated the need for hysterectomy in 89.5% of patients.⁸ Yet, in women with submucous or intramural myomas distorting the cavity, the device might not stay in an appropriate location and might not be effective, and it is associated with a high risk of expulsion.

•          Others: Danazol is an isoxazole derivative of 17 alpha-ethinyl-testosterone. At a dose of 100–400 mg/day for 4–6 months, it reduces myomata size and uterine volume and induces endometrial atrophy.⁹ Because of danazol’s androgenic adverse effects, it is not commonly prescribed.

Courtesy Togas Tulandi, MD

Size reduction treatment

·               Gonadotropin-releasing hormone agonist (GnRHa): GnRHa works by desensitizing GnRH pituitary receptors. As a result, it is associated with an initial flare effect followed by a hypoestrogenic state after 2 weeks.¹ It has been used to treat uterine myomas for more than 3 decades. The most common GnRHa used for uterine myoma is leuprolide acetate. Intramuscular injection of 3.75 mg monthly-or a single dose of 11.25 mg every 3 months-reduces the mean uterine volume by 36% at 12 weeks and 45% at 24 weeks. However, the effects are temporary.¹⁰

GnRHa is useful for premenopausal women who opt for medical treatment and for preoperative treatment. It reduces the size of myomata, facilitating surgery with a minimally invasive technique and improving the patient’s hematologic status. However, it may lead to degeneration of myomata, making them soft and difficult to manipulate. Occasionally, the cleavage plane between a myoma and the pseudocapsule obliterates, making myoma enucleation challenging. Whether obliteration of the surgical plane is related to the presence of adenomyosis is not entirely clear.

GnRHa adverse effects, such as menopausal symptoms, are related to the hypoestrogenic state. When given alone, it is associated with up to 5.5% reduction in bone mass within the first 6 months of use.¹¹ Due to its adverse effects, GnRHa use should be limited to 3 to 6 months. In order to counter adverse effects and to maintain patient compliance, add-back treatment with low-dose estrogen and progestin therapy is advisable.

See also: SMFM Consult: Fibroids in pregnancy

•          Gonadotropin-releasing hormone antagonist (GnRHag): The main advantage of GnRHag over the agonists is immediate pituitary suppression, which is rapid hypoestrogenic and produces immediate clinical effects compared to GnRHa.¹² GnRHag reduces the extracellular matrix of fibroids and induces apoptosis. The compound has been used preoperatively to decrease myomata size before surgery. The drawbacks are absence of a long-acting preparation and cost. Daily administration may decrease patient compliance. Adverse effects are similar to those of GnRHa and disappear after drug discontinuation, with rapid return to the original leiomyoma size.¹³ Release of histamine by mast cells is a known adverse effect. Recent preparations are associated with less histamine release and thus better tolerated.¹⁴

·      Selective progesterone receptor modulators (SPRMs)

Mifepristone (RU-486): One of the earliest SPRMs, mifepristone works by competitively binding to progesterone receptors. Given at a dose of 2.5 mg/day orally for 3–6 months, it significantly reduces fibroid volume and cyclic bleeding without increasing risk of endometrial hyperplasia.¹⁵ In a review of 6 clinical trials including 166 women treated with 5 mg–50 mg/day of mifepristone for 3–6 months, there was a 26%–74% reduction in myoma volume and 63%–100% rate of amenorrhea.¹⁶ However, prolonged administration of high-dose mifepristone for more than 6 months is associated with development of cystic glandular dilatation (known as progesterone receptor modulator-associated endometrial changes [PAEC]).¹⁷ At high doses, mifepristone is used as an abortifacient.

Ulipristal acetate: The newest SPRM that has both agonist and antagonist selective tissue effect is ulipristal acetate, which induces apoptosis by suppressing neovascularization and cell proliferation without proliferating healthy uterine tissue. At a daily dose of 5 mg–10 mg, ulipristal acetate induced  amenorrhea in 50%–70% of women in 10 days, and resulted in suppression of uterine bleeding in all patients at the end of a 13-week course.¹⁸ A comparison of monthly injection of leuprolide acetate (3.75 mg) and daily administration 5 mg–10 mg ulipristal for 3 months by Donnez et al found that both drugs had the same effect on myomata.¹¹ Myomata maintained a size reduction 6 months after discontinuation of ulipristal, eliminating the need for further surgical interventions.¹⁹ Serum estradiol level in women treated with ulipristal is in the midfollicular phase range. In theory, it does not cause menopausal symptoms.¹¹ Like other SPRMs, it induces PAEC in more than half of patients,^11,18 which is reversible after discontinuation.¹¹ If treatment for more than 3 months is anticipated, a patient must wait for 2 menstrual periods before restarting ulipristal. In the first study of long-term medical management with ulipristal, 4 3-month courses led to a significant reduction in fibroid volume in 80% of cases. The volume of the largest fibroid was decreased by 72%.²⁰ The incidence of PAEC remained the same.

·      Aromatase inhibitors

Aromatase inhibitors work by directly blocking the conversion of androgen to estrogen, leading to a decrease in circulating estrogen levels without causing systemic adverse effects.

Letrozole: Letrozole is marketed for the treatment of breast cancer. It slows the growth of estrogen dependent breast cancer. Due to the concerns of reactivation of ovarian function, it is usually used in postmenopausal women. Parsanezhad et al randomized 60 women with uterine myomata larger than 5 cm to GnRHa or letrozole for 3 months. The total volume of myoma decreased by 33.3% in the GnRHa group and by 45.6% in the letrozole group.²¹

Anastrozole: This third-generation nonsteroidal medication does not alter cortisol or aldosterone levels. It is also not associated with androgenic, progestogenic, or estrogenic effects. At a dose of 1 mg/day for 12 weeks, anastrozole results in reduction in myoma volume of up to 32% and improves menstrual symptoms.²²

Fadrozole: Shozu et al reported a case of rapid regression of myoma symptoms and a 71% reduction in their size after the use of fadrozole for 8 weeks.²³ Today, there is still a paucity of information of the use of fadrozole for uterine myomata.

·      Selective estrogen receptor modulators: These drugs, known as SERMS, are used to prevent and treat estrogen receptor-positive breast carcinoma. The therapeutic efficacy of the SERM raloxifene for uterine myoma has been mixed, and evidence of its effect on fibroid size and symptoms is inconsistent.²⁴

·      Nonhormonal agents: Vitamin D, green tea, heparin and its nonanticoagulant analogs, pioglitazone, and pirfenidone have been used to treat myomata.^25-29 However, their clinical efficacy has not been proven in randomized trials.

·      Others:

Gestrinone: This synthetic steroid is commonly used in endometriosis and suppresses the growth of myomata by regulating the activity of multiple genes without inducing apoptosis.³⁰

Cabergoline: Small studies reported a reduction in myomata size with cabergoline, a dopamine agonist used to treat hyperprolactinemia .³¹

Practice guidelines: Ulipristal versus GnRHa

·      In women with excessive uterine bleeding, the authors use ulipristal acetate 5 mg daily for 3 months. It is associated with a rapid decrease in uterine bleeding. During the first few days of treatment, when the bleeding is still excessive, supportive treatment with tranexamic acid can be given. A second course of ulipristal is administered after 2 menstrual cycles.

·      Alternatively, a single course of GnRHa for 3 months can be given. However, it may be associated with increased uterine bleeding in the first week of treatment due to initial stimulation of the endometrium. Because of GnRHA’s pronounced menopausal adverse effects, add-back treatment should be considered.

·      Ulipristal or GnRHa can be given for 3 months preoperatively to reduce fibroid volume before myomectomy by laparoscopy or laparotomy.

·      For patients undergoing hysteroscopic myomectomy, the authors use GnRHa preoperatively a month before the procedure. It produces a thin endometrium, which facilitates the procedure and decreases fluid absorption. Ulipristal is associated with endometrial changes but not thin endometrium.

References

1.     Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril. 2009;91(4):1215–1223.

2.     Bansal T1, Mehrotra P, Jayasena D, Okolo S, Yoong W, Govind A. Obstructive nephropathy and chronic kidney disease secondary to uterine leiomyomas. Arch Gynecol Obstet. 2009;279(6):785–788.

3.     Laughlin SK, Hartmann KE, Baird DD. Postpartum factors and natural fibroid regression. Am J Obstet Gynecol. 2011;204(6):496.e1–6.

4.      Obed JY, Bako B, Usman JD, Moruppa JY, Kadas S. Uterine fibroids: risk of recurrence after myomectomy in a Nigerian population. Arch Gynecol Obstet 2011;283(2):311–315.

5.      Rackow BW, Arici A. Options for medical treatment of myomas. Obstet Gynecol Clin North Am. 2006;33(1):97–113.                                                                               

6.      Qin J, Yang T, Kong F, Zhou Q. Oral contraceptive use and uterine leiomyoma risk: a meta-analysis based on cohort and case-control studies. Arch Gynecol Obstet. 2013;288(1):139–148.

7.      Kongnyuy EJ, Wiysonge CS. Interventions to reduce haemorrhage during myomectomy for fibroids. Cochrane Database Syst Rev. 2009 Jul ;(3):CD005355.

8.     Machado RB, de Souza IM, Beltrame A, Bernardes CR, Morimoto MS, Santana N. The levonorgestrel-releasing intrauterine system: its effect on the number of hysterectomies performed in perimenopausal women with uterine fibroids. Gynecol Endocrinol. 2013;29(5):492–495.

9.     Fedele L, Bianchi S, Marchini M, Di Nola G. Histological impact of medical therapy–clinical implications. J Obstet Gynaecol. 1995;102 Suppl 12:8–11.

10.  Friedman AJ , Hoffman DI , Comite F , Browneller RW , Miller JD. Treatment of leiomyomata uteri with leuprolide acetate depot: a double-blind, placebo-controlled, multicenter study. The Leuprolide Study Group. Obstet Gynecol. 1991;77(5):720–725.

11.  Donnez J, Tomaszewski J, Vázquez F, et al; PEARL II Study Group. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med. 2012;366(5):421–432.

12.  Sankaran S, Manyonda IT. Medical management of fibroids. Best Pract Res Clin Obstet Gynaecol. 2008;22(4):655–676.

13.  Gonzalez-Barcena D, Alvarez RB, et al. Treatment of uterine leiomyomas with luteinizing hormone-releasing hormone antagonist Cetrorelix. Hum Reprod. 1997;12(9):2028–2035.

14.  Koechling W, Hjortkjaer R, Tankó LB. Degarelix, a novel GnRH antagonist, causes minimal histamine release compared with cetrorelix, abarelix and ganirelix in an ex vivo model of human skin samples. Br J Clin Pharmacol. 2010;70(4):580­587.

15.  Shen Q, Hua Y, Jiang W, Zhang W, Chen M, Zhu X. Effects of mifepristone on uterine leiomyoma in premenopausal women: a meta-analysis. Fertil Steril. 2013;100(6):1722-6.e1­10.

16.  Spitz IM. Mifepristone: where do we come from and where are we going?: Clinical development over a quarter of a century. Contraception. 2010;82(5):442–452.

17.  Steinauer J, Pritts EA, Jackson R, Jacoby AF. Systematic review of mifepristone for the treatment of uterine leiomyomata. Obstet Gynecol. 2004;103(6):1331–1336.

18.  Donnez J, Tatarchuk TF, Bouchard P, et al; PEARL I Study Group. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med. 2012;366(5):409–420.

19.  Donnez J, Vázquez F, Tomaszewski J, et al; PEARL III and PEARL III Extension Study Group. Long-term treatment of uterine fibroids with ulipristal acetate. Fertil Steril. 2014;101(6):1565-73.e1–18.

20.  Donnez J, Hudecek R, Donnez O, et al. Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids. Fertil Steril 2015;103:519–527.

21.  Parsanezhad ME, Azmoon M, Alborzi S, et al. A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status. Fertil Steril. 2010;93(1):192–198.

22.  Hilário SG, Bozzini N, Borsari R, Baracat EC. Action of aromatase inhibitor for treatment of uterine leiomyoma in perimenopausal patients. Fertil Steril. 2009;91(1):240–243.

23.  Shozu M, Murakami K, Segawa T, Kasai T, Inoue M. Successful treatment of a symptomatic uterine leiomyoma in a perimenopausal woman with a nonsteroidal aromatase inhibitor. Fertil Steril. 2003;79(3):628–631.                             

24.  Deng L, Wu T, Chen XY, Xie L, Yang J. Selective estrogen receptor modulators (SERMs) for uterine leiomyomas. Cochrane Database Syst Rev. 2012;10:CD005287.

25.  Zhang D, Al-Hendy M, Richard-Davis G, Montgomery-Rice V, Rajaratnam V, Al-Hendy A. Antiproliferative and proapoptotic effects of epigallocatechin gallate on human leiomyoma cells. Fertil Steril. 2010;94(5):1887–1893.

26.  Halder SK, Osteen KG, Al-Hendy A. Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and-9 in human uterine fibroid cells. Hum Reprod. 2013;28(9):2407–2416.

27.  Nowak RA. Novel therapeutic strategies for leiomyomas: targeting growth factors and their receptors. Environ Health Perspect. 2000;108 Suppl 5:849–853.

28.  Loy CJ, Evelyn S, Lim FK, Liu MH, Yong EL. Growth dynamics of human leiomyoma cells and inhibitory effects of the peroxisome proliferator-activated receptor-γ ligand, pioglitazone. Mol Hum Reprod. 2005;11(8):561–566.

29.  Young SL, Al-Hendy A, Copland JA. Potential nonhormonal therapeutics for medical treatment of leiomyomas. Semin Reprod Med. 2004;22(2):121–130.

30.  Zhu Y, Zhang T, Xie S, et al. Gestrinone inhibits growth of human uterine leiomyoma may relate to activity regulation of ERα, Src and P38 MAPK. Biomed Pharmacother. 2012;66(8):569–577.

31.  Melli MS, Farzadi L, Madarek EO. Comparison of the effect of gonadotropin-releasing hormone analog (Diphereline) and Cabergoline (Dostinex) treatment on uterine myoma regression. Saudi Med J. 2007;28(3):445–450.