Jul 20, 2012

Managing Uterine Fibroids: Alternatives to Hysterectomy: Medical Fibroid Therapies

The Modern Management of Fibroids

Fibroids are benign uterine tumors that have been reported in up to 75% of all women.[1] The many treatment options available for women with uterine fibroids include:

  • Observation;
  • Medical therapy;
  • Myomectomy;
  • Uterine artery embolization;
  • Focused ultrasonography; and
  • Hysterectomy.

Most women with fibroids can choose “watchful waiting” without harm. Predicting the growth of fibroids or the onset of new symptoms is impossible. A National Institutes of Health study found that although the average annual increase in fibroid volume was 9%, the range of change in fibroid size was very wide, from a 25% shrinkage to a 138% growth in a single year.[2] Furthermore, a nonrandomized study of women with fibroids and uterine size of 8 weeks or greater who chose watchful waiting found no significant changes in 77% of women in the self-reported amount of bleeding, pain, or degree of bothersome symptoms at the end of 1 year.[3] Watchful waiting can be considered in late perimenopause because after menopause, bleeding will stop and fibroids will shrink.

Medical Fibroid Therapies

Progesterone-Releasing Intrauterine Device

Some women with fibroid-associated heavy menstrual bleeding will benefit from treatment with the levonorgestrel-releasing intrauterine system (LNG-IUS). One study found that women with at least 1 fibroid smaller than 5 cm, with less than 50% of the fibroid in the endometrial cavity (type 2), had a 90% reduction in blood loss and an increase in hemoglobin levels 1 year after insertion of an LNG-IUS.[4]

Gonadotropin-Releasing Hormone Agonists

Gonadotropin-releasing hormone (GnRH) agonists have been shown to reduce uterine volume by 35% and bleeding in 95% of women.[5] However, 95% of women experience side effects, including hot flushes (78%), vaginal dryness (32%), and transient frontal headaches (55%).[6] Some women also experience arthralgia, myalgia, insomnia, edema, emotional lability, depression, or decreased libido.

In addition, the hypoestrogenic state induced by GnRH agonists can result in significant bone loss after 6 months of therapy.[7] Low doses of estrogen and progestins may be added while continuing treatment with GnRH agonists, but a study found no difference in bone loss between groups given estrogen/progestin and those treated with GnRH agonists alone over 6 years.[8] Of note, after discontinuation of therapy with GnRH agonists, menses returns in 4-8 weeks and uterine size returns to pretreatment levels within 4-6 months.

Women in late perimenopause with symptomatic uterine fibroids may consider short-term use of GnRH agonists. Thirty-one of 34 perimenopausal women treated with GnRH agonists for 6 months were able to avoid surgery.[9]

GnRH Antagonist

The immediate suppression of endogenous GnRH by daily subcutaneous injection of the GnRH antagonist ganirelix results in a 29% reduction in fibroid volume within 3 weeks.[10] Treatment, however, is accompanied by hypoestrogenic symptoms. When long-acting compounds are available, GnRH antagonists might be considered for medical treatment before surgery.

Progesterone-Mediated Medical Treatment

Ulipristal acetate, a selective progesterone-receptor modulator, was studied in 2 randomized, double-blind, phase 3 trials in women with uterine fibroids. More than 13 weeks of treatment with oral ulipristal acetate, 5 mg daily, controlled excessive uterine bleeding in at least 90% of patients and was shown to be noninferior to leuprolide acetate injected monthly over 3 months.[11] Uterine volume reduction was maintained for at least 6 months after discontinuation of treatment. The incidence of hot flushes was significantly lower than for women given leuprolide acetate.

Alternative Medicine Treatment

Most published studies of alternative medicine treatments have been nonrandomized, nonblinded, and small. A study reported that after 6 months of treatment with traditional Chinese medicine, ultrasonography showed that fibroids stopped growing or shrank in 59% of patients compared with 8% of controls.[12] In women with fibroids smaller than 10 cm that were treated with traditional Chinese medicine, heavy menstrual bleeding declined in 95% and dysmenorrhea improved in 94%.[13]

Surgical Treatments for Fibroids

Surgical treatment options currently include hysteroscopic myomectomy, abdominal myomectomy, laparoscopic myomectomy, and endometrial ablation. Many women with fibroids can be treated with these procedures and hysterectomy can be avoided.

Serious medical conditions, such as severe anemia or ureteral obstruction, often need to be addressed surgically. Symptoms that compromise quality of life, such as fibroid-associated heavy menstrual bleeding, pelvic pain or pressure, and urinary frequency or incontinence, also may be indications for surgery. Myomectomy has been reported to relieve symptoms in 80% of women with uterine fibroids.[14]

Hysteroscopic Myomectomy

Submucous fibroids, sometimes associated with increased menstrual bleeding or infertility, often can be removed hysteroscopically. A meta-analysis of the effect of fibroids on fertility found that submucous fibroids causing distortion of the uterine cavity reduced ongoing pregnancy/live birth rates by 70% (relative risk 0.32; 95% confidence interval, 0.12–0.85) and that fibroid resection increased ongoing pregnancy/live birth rates.[15] Hysteroscopic resection of submucous fibroids also can significantly reduce heavy menstrual bleeding in 82% of women with submucous pedunculated fibroids (type 0), 86% with sessile fibroids (type 1), and 68% with intramural fibroids (type 2).[16] A study of 285 consecutive women who had hysteroscopic resection of submucous fibroids for heavy menstrual bleeding found that additional surgery was required in 9.5% at 2 years, 10.8% at 5 years, and 26.7% at 8 years.[17]

Endometrial ablation, with or without hysteroscopic myomectomy, also may be considered in women who do not desire future childbearing. One study found that 94% of women had resolution of abnormal bleeding 1-5 years after endometrial ablation, and another found that only 12% eventually had hysterectomy.[18]

A small study of 22 women with known submucous fibroids up to 4 cm that were treated with hydrothermal ablation found that 91% of the women had amenorrhea, hypomenorrhea, or eumenorrhea after a minimum of 12 months of follow-up.[19] In 65 women with heavy menstrual bleeding and type 1 or 2 submucous myomas up to 3 cm in size, treatment with the NovaSure® endometrial ablation device (Hologic; Bedford, Massachusetts) resulted in normal bleeding or amenorrhea in 95% at 1 year.[20]

Abdominal Myomectomy

Case/control studies suggest that the risk for intraoperative injury with myomectomy may be lower than the risk for complications from abdominal hysterectomy. In women who had myomectomy, 5% experienced complications (bladder injury, reoperation for bowel obstruction, and ileus).[21] In contrast, 13% of women who had hysterectomy experienced complications (bladder injury, ureteral injury, bowel injury, pelvic abscess, and ileus). The risks for hemorrhage, febrile morbidity, unintended surgical procedures, life-threatening events, and rehospitalization did not differ between groups.

Blood loss during myomectomy can be limited by the use of tourniquets or vasoconstrictive agents (eg, vasopressin).[22] The use of vasopressin for this indication is off-label, and rare cases of bradycardia and cardiovascular collapse have been reported, so intravascular injection should be avoided and patients should be monitored carefully. A cell saver can reduce the need for preoperative autologous blood donation or heterologous blood transfusion. This device suctions blood from the operative field, mixes it with heparinized saline, and stores the blood in a canister. If blood loss is greater than 300 mL, the collected blood is washed, filtered, centrifuged, and given back to the patient intravenously.

Myomectomy may be considered even for women with large uterine fibroids. After myomectomy in 91 women with uterine size larger than 16 weeks (range, 16-36 weeks), investigators reported 1 bowel injury, 1 bladder injury, 1 reoperation for bowel obstruction, and no instances of conversion to hysterectomy.[23]

Laparoscopic Myomectomy

Currently available instruments make laparoscopic myomectomy feasible, although the wide application of this approach is limited by the size and number of fibroids that can be reasonably removed and by the technical difficulty of the procedure and of laparoscopic suturing. Although microprocessor-assisted (robotic) myomectomy can help the surgeon avoid these technical challenges, the added cost and longer operating times associated with this approach must be considered.

A systematic review of randomized controlled trials of laparoscopic vs abdominal myomectomy found that laparoscopic myomectomy was associated with longer operating times but reduced operative blood loss, less postoperative pain, fewer complications, and more patients who recuperated fully within 2 weeks.[24]

Laparoscopic myomectomy also may be feasible in women with large fibroids. In a series of 332 consecutive women undergoing laparoscopic myomectomy for symptomatic fibroids as large as 15 cm, only 3 required conversion to laparotomy.[25]

Uterine Artery Embolization

Uterine artery embolization can be an effective treatment for uterine fibroids, especially in women whose symptoms are sufficiently bothersome to warrant myomectomy or hysterectomy. Because the effects of uterine artery embolization on fertility and pregnancy are unclear, many interventional radiologists advise against the procedure for women considering future pregnancy.

Although very rare, complications of uterine artery embolization may necessitate life-saving hysterectomy; therefore, women who would not accept hysterectomy even for a life-threatening complication should not undergo this procedure. Other contraindications to uterine artery embolization include active genital infection, genital tract cancer, compromised immune status, severe vascular disease limiting access to the uterine arteries, allergy to intravenous contrast, and impaired renal function.

Percutaneous cannulation of the femoral artery is performed to gain access to and embolize the uterine artery and its branches. Total radiation exposure is similar to that of 1-2 CT scans or barium enemas. Management of postprocedural pain often requires a 1-day hospital stay, followed by 1-2 weeks of nonsteroidal anti-inflammatory medications. Many women return to normal activity within 1-3 weeks.

In a large prospective study, 555 women with heavy menstrual bleeding, pelvic pain, and urinary frequency underwent uterine artery embolization. Three months after the procedure, heavy bleeding improved in 83% of the women, dysmenorrhea in 77%, and urinary frequency in 86%.[26] A 33% reduction of volume in the dominant fibroid was reported, but improvement in heavy bleeding was not related to initial fibroid volume or to the degree of postprocedural volume reduction. Only 1.5% of the women required hysterectomy owing to complications of uterine artery embolization.

A prospective randomized trial comparing hysterectomy and uterine artery embolization in 177 women with symptomatic fibroids found that hospital stay was significantly shorter for women who had uterine artery embolization (2 days for uterine artery embolization vs 5 days for hysterectomy).[27] Although uterine artery embolization was associated with more readmissions for pain or fever (9 vs 0 for hysterectomy), major complications were rare in both groups.[27]

Worldwide, it is estimated that 12 deaths (2 from septic shock, 8 from pulmonary embolus, and 2 from uncertain causes) have occurred in association with more than 100,000 uterine artery embolization procedures (Spies J, personal communication, June 2011). Thus, the estimated mortality rate of 1 per 10,000 women for uterine artery embolization is lower than the mortality rate of approximately 3 per 10,000 women for hysterectomy.

The American College of Obstetricians and Gynecologists recommends that women who are considering uterine artery embolization have a thorough evaluation with a gynecologist to facilitate collaboration with an interventional radiologist and that responsibility for patient care be clear.[28]

MRI-Guided Focused Ultrasonography (MRgFUS)

Heat created by focused ultrasonography can denature protein and cause cell death. MRI can direct the targeting of fibroids and monitor therapy by assessing the temperature of treated tissue.[29]

The advantages of MRgFUS are very low morbidity and very rapid recovery, with return to normal activity in 1 day. Currently, the procedure is not recommended for women wishing future fertility.

Recent studies of larger treatment areas than the US Food and Drug Administration’s initial allowance reported that the average volume reduction was 31% ± 28%.[30] An evaluation of clinical outcomes found a significant reduction in symptoms in 71% of women at 6 months after treatment but in only 50% at 12 months.[31] Subsequent myomectomy, uterine artery embolization, or hysterectomy was necessary in 28% of the women. Of interest, because women actively sought treatment with MRgFUS and no control group (sham MRgFUS) was included, a placebo effect cannot be ruled out in these studies.

As the technology continues to develop, further studies will be needed to evaluate the risks and efficacy of MRgFUS in the treatment of uterine fibroids.

Consider the Options

Uterine fibroids are commonly found in women of reproductive age. Most women do not require treatment because fibroids are benign. For bothersome symptoms that interfere with quality of life, many treatment options exist and should be considered before the decision to perform hysterectomy.

— William H. Parker, MD

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