Uterine leiomyomas (ie, fibroids or myomas) are benign clonal tumors arising from the smooth muscle cells of the uterus and containing extracellular matrix. They are surrounded by a thin pseudocapsule of areolar tissue and compressed muscle fibers. The treatment of uterine leiomyomas will be discussed here. The diagnosis and pathogenesis of these tumors is reviewed elsewhere. (See "Diagnosis and pathogenesis of uterine leiomyomas").
TREATMENT – Asymptomatic uterine leiomyomas are usually managed expectantly [1]. Factors that should be considered prior to initiating treatment include:
• Size of the myoma(s)
• Location of the myoma(s)
• Symptoms
• Woman's age (eg, is she near menopause?)
• Reproductive plans.
The type and timing of intervention should be individualized based upon the woman's discomfort, pregnancy plans and obstetrical history, and the likelihood of age or hormonal therapy-related progression or regression of the neoplasms.
Medical therapy – Medical therapy avoids the complications associated with surgery and permits uterine conservation. Since leiomyomas are common, it can be difficult to distinguish symptoms related to the neoplasm from those due to a concurrent problem (see "Terminology and differential diagnosis of genital tract bleeding in women", see "Evaluation of the adnexal mass", and see "Evaluation of the infertile couple"). Thus, a trial of medical therapy before surgical intervention is often reasonable, especially in patients in whom concomitant issues such as oligoovulation may exist. Several options are available, including gonadotropin-releasing hormone analogs, danazol, and gestrinone. However, many women prefer to proceed directly to surgery since there is a rapid rebound of symptoms after discontinuation of medical therapy.
Gonadotropin-releasing hormone analogs – Gonadotropin-releasing hormone (GnRH) analogs are the mainstay of medical therapy of uterine myomas. These drugs work by initially increasing the release of gonadotropins, followed by desensitization and downregulation to a hypogonadotropic, hypogonadal state clinically resembling menopause. Most women will develop amenorrhea and a significant reduction in uterine size with this therapy (show table 1) [2,3]. However, there is rapid resumption of menses and pretreatment uterine volume after discontinuation of the medication. In addition, significant symptoms can result from the severe hypoestrogenism that accompanies administration of GnRH analogs [2]. Bone loss leading to osteoporosis after long-term use is the most serious complication. (See "Diagnosis and clinical manifestations of menopause" section on Short and long term effects of estrogen deficiency). For these reasons, GnRH-analogs are primarily employed to temporize or to help prepare a woman for surgery.
Preoperatively administered GnRH analogs decrease blood loss at the time of surgery and increase the preoperative hematocrit when taken for two to three months before the procedure [4]. Since oral iron supplementation alone will improve the preoperative hematocrit in a significant number of patients, the cost and adverse effects of GnRH agonists must be weighed against their efficacy.
GnRH analogs with add-back therapy – The side effects of long-term GnRH-analog administration can be minimized by giving add-back therapy with an estrogen-progestin after the initial phase of downregulation. Low dose estrogen-progestin therapy (equivalent to 0.625 mg of conjugated estrogen) maintains amenorrhea and the reduction in uterine volume while preventing significant hypoestrogenic side effects (eg, osteoporosis, vasomotor symptoms) (show table 1) [5].
Similar clinical results have been achieved with GnRH-antagonists. The advantage of these medications is the rapid onset of clinical effects and absence of an agonist phase. The antiprogestin mifepristone (RU-486) reduces uterine volume comparable to that observed with GnRH-agonists, but maintains the estradiol concentration in the early follicular range [6] (See "Progesterone antagonists and progesterone receptor modulators").
Danazol and gestrinone – Danazol is a 19-nortestosterone derivative with progestin-like effects. Its mechanisms of action include inhibition of pituitary gonadotropin secretion, direct inhibition of endometriotic implant growth, and direct inhibition of ovarian enzymes responsible for estrogen production. Since it induces amenorrhea, danazol may control anemia due to fibroid-related menorrhagia.
A second androgenic steroid, gestrinone, decreases myoma volume and induces amenorrhea in women with fibroids [7]. An advantage of this drug is that there is a carry-over effect after it is discontinued. In one study, for example, uterine volume remained lower than pretreatment values at 18 months after discontinuation of therapy in 89 percent of women treated for six months [7].
Ineffective therapies – Medical treatments that are commonly prescribed but appear ineffective include progestational agents and nonsteroidal antiinflammatory drugs. However, they may be useful in women with coexisting problems (eg, pain).
• Progestational agents – Many algorithms for the treatment of abnormal bleeding due to myomas suggest a trial of oral contraceptive pills (OCPs) or progestin therapy prior to proceeding to definitive therapy. There is no evidence to suggest that these are effective therapies for myomas [2,3]. However, oligoovulation and endometrial atrophy induced by hormonal therapy may help to decrease overall bleeding.
• Nonsteroidal antiinflammatory drugs – Nonsteroidal antiinflammatory drugs (NSAIDs) and antifibrinolytic agents, which are useful in the treatment of idiopathic menorrhagia, have not been extensively studied in leiomyoma-related menorrhagia. NSAIDs do not appear to reduce blood loss in women with myomas [8,9].
Surgery – Surgery is the mainstay of therapy for leiomyomas. Hysterectomy is the definitive procedure; myomectomy by various techniques, endometrial ablation, and myolysis are alternative procedures.
Hysterectomy – Hysterectomy eliminates both current symptoms and the chance of recurrent problems from fibroids. For many women who have completed childbearing, this freedom from future problems provides an attractive option [10]. As an example, a two year follow-up study of 1299 women who had undergone hysterectomy for benign conditions found that more than 90 percent noted significant reductions in symptom severity, depression, and anxiety levels, and an improvement in quality of life [11].
Abdominal myomectomy – Myomectomy (resection of a myoma(s)) is an option for women who desire future pregnancies or otherwise wish to retain their uterus. A transabdominal myomectomy is the treatment of choice when there are multiple myomas or the uterus is significantly enlarged. The operative time, blood loss, and hospital stay are comparable to abdominal hysterectomy [12,13]. The risk of unplanned hysterectomy at the time of myomectomy is less than 1 percent for experienced surgeons [1].
Myomectomy is not a contraindication to subsequent pregnancy. The risk of uterine rupture after myomectomy prior to labor is very low (about 0.002 percent) compared to classical cesarean section, although these data are based upon small series without complete pregnancy follow-up [14,15]. The common clinical practice of counseling women who have had a myomectomy with a transmural uterine incision to undergo an elective cesarean section clearly biases the reported risk of rupture at term. It is important to judge new surgical alternatives to abdominal myomectomy according to their safety for women whose aim is future pregnancy.
Laparoscopic myomectomy – Women with a uterus less than 17 weeks' size or with a small number of subserosal or intramural fibroids can consider the option of laparoscopic myomectomy (LM). The uterus must be small enough to allow visualization of the procedure through an endoscope placed at the umbilicus. Most authorities suggest limiting this technique to the removal of three or fewer myomas and myomas not larger than 13 cm in diameter because this technique can take longer than open myomectomy, especially when laparoscopic suturing is employed. An electronic morcellator permits efficient removal of a large myoma in pieces through a small incision.
Whether reapproximation of the myometrium via laparoscopic suturing gives the uterine wall the same strength as multilayer closure at laparotomy is an area of controversy [15]. The authors of case reports describing uterine rupture after LM as early as 33 or 34 weeks of gestation have suggested that women with intramural fibroids undergo laparotomy or modified laparoscopic closure [16,17]. By comparison, one series of 100 deliveries after LM reported three cases of spontaneous uterine rupture, only one of which occurred in the LM scar [15]. No uterine ruptures occurred among the 72 patients who had a trial of labor. Until further data are available, laparoscopic myomectomy, especially when there is a deeply intramural fibroid, should be used with caution in women whose primary goal is to achieve a pregnancy.
Hysteroscopic myomectomy – Submucous myomas can be resected by hysteroscopic myomectomy. The submucous location of these tumors offers ready access to an operative endoscope placed through the cervix. Although this technique requires highly skilled practitioners, it has several advantages compared to abdominal procedures:
• It is performed as same day surgery.
• Local anesthetic and sedation can be used.
• The recuperation period is short.
• Good relief of symptoms is obtained. In one large series, fewer than 16 percent of women treated for menorrhagia underwent a second surgery in the nine year follow-up period [18].
• Fertility rates are excellent and there have been no case reports of uterine rupture after hysteroscopic myomectomy [19].
Disadvantages of myomectomy – Although myomectomy is an effective therapy for menorrhagia and pelvic pressure, the disadvantage of this procedure is the significant risk that more leiomyomas will develop from new clones of abnormal myocytes. Five years after myomectomy, approximately 50 percent of patients will have myomas detected by ultrasound [20], and 11 to 26 percent will require a second surgery after the first myomectomy [21-23].
Endometrial ablation – Endometrial ablation, either alone or in combination with hysteroscopic myomectomy, may alleviate bleeding with minimal invasiveness in women who have completed childbearing. Although most case series of endometrial ablation have excluded women with significant myomas, one study that examined endometrial ablation with hysteroscopic myomectomy reported only an 8 percent risk for a second surgery after a mean of six years of follow-up [18].
Myolysis – Myolysis refers to laparoscopic coagulation of leiomyoma tissue [24]. This technique is easier to master than resection, which requires suturing. However, localized tissue destruction without repair may increase the chance of subsequent adhesion formation or rupture during pregnancy [25].
Myolysis combined with endometrial ablation is a more effective therapy than either procedure alone. A descriptive study that compared ablation alone with the combined procedures in women with menorrhagia found that the risk of a second surgery was 38 and 13 percent, respectively [26].
FUTURE DIRECTIONS – The biology of uterine fibroids has traditionally been explained in terms of steroid hormones; thus, all current medical therapies are based upon manipulation of these hormones. However, an expanded view of the biology of this benign tumor (eg, the specific genes that are dysregulated) may open new avenues of pharmaceutical intervention and ultimately lead to strategies for prevention.
Uterine artery embolization is an innovative technique based upon the hypothesis that control of myometrial arterial blood flow will control symptoms. Preliminary studies suggest that the technique is useful in controlling leiomyoma-related menorrhagia [27-29]. Serious complications appear to be rare, but are more likely when there is a single large myoma [28,30]. Long-term studies assessing symptomatic and pregnancy outcomes are needed to assess how this technique fits into the therapeutic options.
Regulation of growth factor pathways is another area of innovative treatment. There is evidence that interferons can reverse the proliferative effects of bFGF on leiomyoma cells in culture [31]. As an example, a woman undergoing treatment with interferon-alfa for hepatitis C had dramatic and sustained shrinkage of a uterine leiomyoma after seven months of therapy [32].
TREATMENT RECOMMENDATIONS – Treatment recommendations for uterine myomas can be summarized as follows:
• Expectant management is appropriate for asymptomatic women. Exceptions may include women with significant submucosal fibroids who are contemplating pregnancy and women with ureteral compression.
• GnRH analogs reduce uterine bleeding and myoma size. These benefits should be weighed against the cost and side effects of these agents.
• Androgenic steroids can reduce metrorrhagia and, sometimes, uterine volume.
• Hysterectomy is the definitive procedure for relief of symptoms and prevention of recurrent problems.
• Laparoscopic myomectomy appears useful for removal of a small number of fibroids that are less than or equal to 13 cm. However, the integrity of the uterine incision during pregnancy has not been evaluated adequately.
• After an abdominal myomectomy, the risk of uterine rupture prior to labor is very low (eg, 0.002 percent) [14].
• Hysteroscopic myomectomy is the preferred treatment of symptomatic women with submucosal leiomyomas.
• Myolysis with endometrial ablation is more effective than either therapy alone.
• Hormone replacement therapy is not contraindicated in postmenopausal women with myomas, although fibroid-related symptoms may develop or persist.
• Couples should have a complete infertility evaluation before the woman undergoes myomectomy to improve fertility. (See "Evaluation of the infertile couple").
. Obstet Gynecol 1994; 83:556.
الأربعاء سبتمبر 24, 2008 1:28 am