ARC® Fertility Articles

Management of Uterine Fibroids

By Millie A. Behera, M.D., FACOG, FRCPSC and Phyllis Leppert, MD, PhD©

Uterine fibroids, also known as leiomyomas or myomas, are the most common gynecologic tumor in women of reproductive age, affecting approximately 30 to 40 percent of premenopausal females. The prevalence increases with age, with an estimated 70 to 80 percent of women developing fibroids by age 50.1

While typically classified as benign, uterine fibroids can cause troublesome symptoms to approximately 30 percent of affected women, including heavy vaginal bleeding, pelvic pressure, pain, obstructive urinary and bowel symptoms, as well as reproductive difficulties.1,2Fibroids are one of the most common indications for hysterectomy in the U.S., accounting for approximately 200,000 cases per year. Fibroid-related morbidity has a significant economic impact on health care: the cost of health care for women with fibroids is more than double that of women without this condition, and annual costs related to the diagnosis of fibroids are over $2 billion.3

Fortunately, new approaches to managing uterine fibroids are improving the outlook. Minimally invasive and non-invasive treatments such as MRgFUS (MRI-guided focused ultrasound) – a novel therapy recently introduced at Duke – are providing effective treatment for fibroids while offering faster recovery and fewer complications than hysterectomy.4 At the same time, new studies have increased our understanding of the biology of uterine fibroids and created inroads for developing more effective medical therapies.

What Causes Uterine Fibroids, and Who Is at Risk?

While the exact etiology of fibroids is still unclear, physician-scientists at the Duke Center for Uterine Fibroid Biology and Therapy have co-authored several of the most recent studies examining the underlying disease process that leads to the formation of uterine fibroids.5,6,7These studies indicate that fibroids grow by accumulation of collagen and components of the extracellular matrix. This fibrosis is similar to that observed in the formation of keloid scars. The Center, which includes physician investigators, basic scientists, and epidemiologists, is currently involved in several studies to elucidate the molecular biology of uterine fibroid growth and etiology for associated bleeding and subfertility.

Factors implicated in the development of fibroids include genetic, hormonal, and growth factors, especially transforming growth factor beta (TGFb)-related cellular changes.8,9 Clinical risk factors associated with fibroids include obesity, hypertension, nulliparity (having no biological children), family history, and race. Up to 70 percent of African American women have uterine fibroids, and these generally tend to be larger, more numerous, and produce more severe symptoms.1

How Are Uterine Fibroids Best Diagnosed?

Given the fact that uterine fibroids are highly prevalent in childbearing women and are associated with decreased fertility, prompt and accurate diagnosis is important. Uterine fibroids are most often diagnosed by ultrasound as part of the evaluation for associated symptoms or when an enlarged uterus is found on physical examination. However, other imaging modalities such as saline infusion sonograpy (3-D) and MRI may provide more accurate diagnosis and better delineation of fibroid size and location.

Fibroids are classified based on location within the uterine wall: subserosal, intramural, and submucosal. These definitions are often used to determine appropriate interventions and/or surgical approach.

What Are Current Treatment Approaches – And What Therapies Are on the Horizon?

Current treatment options for uterine fibroids run the gamut from medical intervention to non-invasive and minimally invasive therapies to hysterectomy. Several factors must be addressed in determining the appropriate treatment for each individual, including size and location of fibroids, severity of symptoms, and desire to retain fertility or uterine preservation.

Medical options. Current medical options for fibroid management are limited. Of the established interventions, GnRh agonists are the most effective. GnRHa have been used to control bleeding and pressure-related symptoms by reducing fibroid size and decreasing bleeding. Within three to six months, fibroid size is reduced by approximately 30 to 50 percent. However, these effects are short- lived; fibroids grow and symptoms recur soon after treatment is discontinued. Furthermore, due to hypoestrogenic effects, treatment time is limited to six months, after which bone density can be affected. Add-back hormone therapy can be used to combat this effect, but some studies have found that this regimen may decrease the treatment efficacy. Hence GnRh agonists have been found to be most useful as an adjunct to surgical treatment of fibroids, since preoperative use results in improvement in hematocrit levels and less blood loss during surgery.10

Table 1 – Medical therapy for fibroids 10–16

DRUG CLASS MECHANISM EFFECTS CONSIDERATIONS
GnRH agonists Suppression of ovarian steroidogenesis production – delayed pituitary downregulation Fibroid size and symptom reduction up to 50% within 3-6 months Hypoestrogenic side effects: hot flashes, vaginal dryness, headaches. Prolonged use associated with reduced bone mineral density
GnRH antagonists Suppression of ovarian steroidogenesis production – immediate pituitary downregulation Reduction in fibroid size 25-40% and symptom improvement within 3 weeks Hypoestrogenic side effects: hot flashes, vaginal dryness, headaches. Prolonged use associated with reduced bone mineral density
Oral contraceptives Endometrial stabilization, variable effects on leiomyomas May improve uterine bleeding, but no significant decrease in fibroid size Use judiciously – both estrogen and progesterone may promote fibroid growth (increased mitotic activity)
Progestin only Endometrial stabilization/atrophy, variable effects on leiomyomas Mixed results – both fibroid shrinkage and enlargement have been shown; may induce amenorrhea Use judiciously – progesterone may promote fibroid growth (increased mitotic activity)
Androgens Combination hormonal and vascular effects (androgenic, progestogenic, antiprogestogenic, and antiestrogenic actions) 24% fibroid size reduction in 4 months, may improve bleeding symptoms Side effects: weight gain, edema, acne, oily skin, hirsutism, voice changes, headaches, hot flashes, altered libido, decreased breast size, and muscle cramps
Aromatase inhibitors* Reduces estrogen synthesis and effects Fibroid size reduced 60-70% within 1-2 months in case report Hypoestrogenic side effects; further studies needed
Antiprogestins* Anti-progesterone effect – reduces action and number of progesterone receptors in fibroids and myometrium Improved symptoms in 60-75%, may induce amenorrhea, reduction in fibroid volume 25-50% within 3 months Side effects include hot flashes, elevated hepatic enzymes, and endometrial hyperplasia
Mixed progesterone receptor antagonist/agonists* Local progesterone-mediated effects on leiomyomas and endometrium Decreased menstrual bleeding (up to 80%) and fibroid size reduction up to 36% within 12 wks, may induce amenorrhea Maintains follicular phase estrogen levels, no adverse endometrial effects – causes nonphysiologic secretory changes (clinical relevance unknown)
Mixed estrogen receptor antagonist/agonists* Estrogen antagonist effects on fibroid and endometrium Inconsistent results – trend to decreased fibroid size in small heterogeneous studies Side effects: leg cramps, hot flashes. Increased risk of thromboembolic events
Antifibrotics* Interfere with growth factors, leiomyoma cell proliferation and extracellular matrix/ collagen production Interfere with fibroid growth Long-term effects not known, further studies needed

*Investigational medical therapies

Several other hormone-related medical treatments have been used to treat uterine fibroids; however, most of these medications are still being evaluated in clinical trials and are considered investigational.11 Some of these proposed interventions are aimed at controlling fibroid growth and related symptoms by targeting ovarian steroid production. These include combined birth control pills, progestin-only preparations, androgens, both estrogen and progesterone receptor antagonists, and mixed receptor antagonist/agonists. Other medications, such as antifibrotic agents, target growth factors and affect extracellular matrix production and angiogenesis within the fibroid. These medical treatments are summarized in Table 1. The Duke Center for Uterine Fibroid Biology and Therapy is actively investigating new drug therapies to treat uterine fibroids, and we expect this to be an area of significant advancement and progress over the next several years.

Non-medical options. Since most medical options are investigational and not recommended as first-line, long-term treatment for symptomatic fibroids at this time, the most common treatments remain either conservative surgical intervention or definitive surgery. Until now, the most prevalent treatments have been hysterectomy (surgical removal of the uterus) and myomectomy (surgical removal of individual fibroids). However, more women are looking for options that provide minimal intervention and shorter recovery time.

Minimally invasive surgical treatments can provide excellent results when patient and fibroid characteristics are appropriate. In general, such treatments are best suited for women with a few, discrete symptomatic fibroids, while extensive fibroids are best treated with more definitive approaches. Minimally invasive approaches include laparoscopic and hysteroscopic myomectomy, as well as uterine artery embolization, a radiologic procedure that has also become more popular over the last several years.

 

Table 2. non-medical treatment interventions – conservative and definitive 4, 17 – 19

TREATMENT MECHANISM EFFECTS CONSIDERATIONS
Uterine artery embolization Ischemic necrosis Fibroid size reduction 40-60% within 4 months, menorrhagia improvement up to 85% Post-procedure pain, risk of major adverse events (such as serious infectious complications)1-2%, may be associated with adverse pregnancy outcomes, ovarian failure in 1-2%
MRI-guided focused ultrasound Localized thermal necrosis Symptomatic improvement up to 71% within 3 months, fibroid size reduction up to 30% – increased in proportion to treated fibroid volume, treatment effects sustained up to 24 months with low rates of secondary or repeat procedures Patient selection criteria and fibroid characteristics important – post-treatment volume determines efficiency/duration of clinical results; minimal risk of adverse events (skin burn, nerve injury)
Myolysis (Laparoscopic) Thermal necrosis Fibroid shrinkage up to 70% by 12 months Surgical risks, significant postoperative adhesions
Laparoscopic myomectomy Excision Removal of large fibroids, high patient satisfaction with symptomatic improvement Surgical risks; often requires cesarean delivery with future pregnancy – labor is not advised, due to small risk of uterine rupture
Abdominal myomectomy Excision Removal of all palpable fibroids, high patient satisfaction with symptomatic improvement Surgical risks; often requires cesarean delivery with future pregnancy – labor is not advised, due to small risk of uterine rupture
Hysterectomy Excision Definitive treatment – high patient satisfaction rate with symptomatic improvement Surgical risks

A recent addition to the treatment toolkit is MRI-guided focused ultrasound (MRgFUS), in which precisely pinpointed, high-intensity ultrasound waves are used to “burn away” fibroids without harming normal surrounding tissues. This cutting-edge technology, which offers women the option of same-day, non-surgical treatment, is available at Duke through the Duke MRI-Guided Focused Ultrasound Treatment Program. With increasing availability of conservative treatment choices, both patients and their physicians have the opportunity to individualize therapy based on the goals of each patient. More details on the pros and cons of various nonmedical therapies are in Table 2.

Phyllis C. Leppert, MD, PhD, is a professor and vice chair for research in the Duke Department of Obstetrics and Gynecology, and also director of the Duke Center for Uterine Fibroid Biology and Therapy. Millie Behera, MD, is a specialist in Reproductive Endocrinology and Infertility at Fertility Treatment Center in Arizona.

1 Day Baird D, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003 Jan;188(1):100 – 7

2 Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril. 1981 Oct;36(4):433 – 35

3 Hartmann KE, Birnbaum H, Ben-Hamadi R, Wu EQ, Farrell MH, Spalding J, Stang P. Annual costs associated with diagnosis of uterine leiomyomata. Obstet Gynecol. 2006 Oct;108(4):930 – 7

4 Stewart EA, Gostout B, Rabinovici J, Kim HS, Regan L, Tempany CM. Sustained relief of leiomyoma symptoms by using focused ultrasound surgery. Obstet Gynecol. 2007 Aug;110(2 Pt 1):279 – 87

5 Behera M, Feng L, Yonish B, Catherino W, Leppert PC. Thrombospondin-1 (TSP-1 and Thrombospondin-2 (TSP-2) mRNA and protein expression in uterine fibroids and correlation to COL1A1 and hydroxyproline. Reprod Sci. 2007 Dec;14(8S):63 – 76

6 Catherino WH, Leppert PC, Stenmark MH, Payson M, Potlog-Nahari C, Nieman LK, Segars J. Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids. Genes Chromosomes Cancer. 2004 Jul;40(3):204 – 17

7Leppert PC, Baginski T, Prupas C, Catherino WH, Pletcher S, Segars J. Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium. Fertil Steril. 2004 Oct;82 Suppl 3:1182 – 7

8Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril. 2007 Apr;87(4):725 – 36

9 Walker CL. Uterine fibroids: the elephant in the room. Science. 2005 Jun 10;308(5728):1589 – 92

10Lethaby A, Vollenhoven B, Sowter M. Efficacy of pre-operative gonadotrophin hormone releasing analogues for women with uterine fibroids undergoing hysterectomy or myomectomy: a systematic review. BJOG. 2002 Oct;109(10):1097 – 1108

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

12 Lingxia X, Taixiang W, Xiaoyan C. Selective estrogen receptor modulators (SERMs) for uterine leiomyomas (Review). Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005287.

13 Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel CA. A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata. Fertil Steril 2007 Jun;87(6):1399 – 412. Epub 2007 Feb 20

14 Maruo T, Ohara N, Wang J, Matsuo H. Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Hum Reprod Update. 2004 May – Jun;10(3):207 – 20

15 Shozu M, Murakami K, Inoue M. Aromatase and leiomyoma of the uterus. Semin Reprod Med. 2004 Feb;22(1):55 – 60

16 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 Mar;79(3):628 – 31

17 The REST Investigators. Uterine-artery embolization versus surgery for symptomatic uterine fibroids. N Engl J Med. 2007 Jan25;356(4):360 – 70

18 Marshburn PB, Matthews ML, Hurst BS. Uterine artery embolization as a treatment option for uterine myomas. Obstet Gynecol Clin North Am. 2006 Mar;33(1):125 – 44

19 Sharp HT. Assessment of new technology in the treatment of idiopathic menorrhagia and uterine leiomyomata. Obstet Gynecol. 2006 Oct;108(4):990 – 1003

©Millie Behera M.D., FACOG, FRCPSC and Phyllis Leppert, MD, PhD

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