Am Fam Physician. 2005 May 1;71(9):1753-1756.
What are the effects of medical treatment alone?
LIKELY TO BE BENEFICIAL
Gonadorelin Analogues (GnRHa) Plus Progestogen (No Significant Difference in Heavy Bleeding Compared with GnRHa Alone, but Adding Progestogen Reduces Vasomotor Symptoms and Hot Flashes Associated with GnRHa). One small randomized controlled trial (RCT) found no significant difference between leuprorelin acetate plus progestogen and leuprorelin acetate alone in the proportion of women who had heavy bleeding at 12 months. One small RCT found that GnRHa plus medroxyprogesterone acetate significantly reduced vasomotor symptoms over 12 months compared with GnRHa alone. One small RCT found that leuprorelin acetate plus progestogen significantly reduced the proportion of women with hot flashes over 24 weeks compared with leuprorelin acetate alone.
Gonadorelin Analogues Plus Tibolone (No Significant Difference in Fibroid Symptoms Compared with GnRHa Alone but Adding Tibolone Reduces Hot Flashes and Prevents Loss in Bone Mineral Density Associated with GnRHa). Two small RCTs found no significant difference between GnRHa alone and GnRHa plus tibolone in fibroid-related symptoms or uterine and fibroid size. They found that adding tibolone reduced hot flashes, vaginal dryness, and night sweats and prevented loss in bone mineral density.
TRADE-OFF BETWEEN BENEFITS AND HARMS
Gonadorelin Analogues Alone. RCTs found that GnRHa reduced fibroid-related symptoms compared with placebo, but were associated with important adverse effects. Two RCTs found that GnRHa increased amenorrhea compared with placebo after about three months. One RCT provided insufficient evidence to compare nafarelin versus buserelin. One RCT found that higher doses of nafarelin increased amenorrhea at 16 weeks compared with lower doses. Two RCTs found that nafarelin reduced bone density from baseline after 16 weeks’ treatment compared with placebo, but that bone density returned to pretreatment levels six months after treatment was stopped. Two RCTs found that hot flashes were more common with nafarelin than with placebo or buserelin. One RCT found that hot flashes and sweating were more common with goserelin than placebo.
Gonadorelin Analogues Plus Combined Estrogen–Progestogen (Insufficient Evidence on Effects Compared with GnRHa Plus Progestogen). One small RCT provided insufficient evidence to compare GnRHa plus combined estrogen–progestogen hormone therapy versus GnRHa plus progestogen hormone therapy.
Gonadorelin Analogues Plus Raloxifene (Insufficient Evidence on Effects Compared with GnRHa Alone). One RCT found that adding raloxifene to GnRHa reduced fibroid size compared with GnRHa alone. It found no significant difference in fibroid-related symptoms or hot flashes.
Nonsteroidal Anti-inflammatory Drugs. Two small RCTs provided insufficient evidence to assess nonsteroidal anti-inflammatory drugs in women with fibroids.
Gestrinone; Levonorgestrel Intrauterine System; Mifepristone. We found no RCTs on the effects of these interventions.
In women scheduled for fibroid surgery, what are the effects of preoperative medical treatments?
LIKELY TO BE BENEFICIAL
Gonadorelin Analogues. One systematic review found that GnRHa for at least three months before fibroid surgery improved preoperative hemoglobin concentration and hematocrit, and reduced uterine and pelvic symptoms compared with placebo or no pretreatment. Preoperative gonadorelin also reduced the rate of vertical incisions during laparotomy. Women having hysterectomy were more likely to have a vaginal rather than an abdominal procedure after GnRHa pretreatment compared with placebo or no pretreatment. Preoperative goserelin reduced intraoperative blood loss, although the difference was small, and the clinical importance is uncertain. One subsequent RCT found no significant difference between preoperative triptorelin and immediate surgery in intraoperative blood loss. One small RCT found that GnRHa combined with endometrial resection reduced the need for further treatment (medical or surgical) over one year compared with GnRHa alone. However, preoperative GnRHa is associated with adverse hypoestrogenic effects, such as hot flashes, vaginal symptoms, and sweating, and women receiving GnRHa were more likely to withdraw from treatment because of adverse effects.
What are the effects of surgical treatments?
Laparoscopic Myomectomy (Maintains Fertility Compared to Hysterectomy; Reduces Recovery Time and Postoperative Pain Compared with Abdominal Myomectomy). Two RCTs found limited evidence that laparosopic myomectomy reduced postoperative pain, fever, and recovery time compared with abdominal myomectomy. We found no RCTs comparing laparoscopic myomectomy with total abdominal, vaginal, or laparoscopic hysterectomy, but the main benefit of myomectomy compared with hysterectomy is that it maintains fertility.
LIKELY TO BE BENEFICIAL
Laparoscopically Assisted Vaginal Hysterectomy (Reduces Recovery Time and Postoperative Pain Compared with Total Abdominal Hysterectomy, but Increases Operating Time and Blood Loss Compared with Total Vaginal Hysterectomy). Two RCTs found that women having laparoscopically assisted vaginal hysterectomy had shorter recovery times and less postoperative pain compared with women having total abdominal hysterectomy. One RCT found that women having laparoscopically assisted vaginal hysterectomy had longer operating times and more blood loss than women having total vaginal hysterectomy.
Total Abdominal Hysterectomy (Reduces Fibroid-Related Symptoms Compared with No Treatment.). We found no RCTs comparing total abdominal hysterectomy with no treatment or sham surgery. An RCT is unlikely to be conducted. There is consensus that total abdominal hysterectomy is superior to no treatment in reducing fibroid-related symptoms. RCTs found that women having total abdominal hysterectomy had longer surgery, more blood loss, more pain and fever, longer hospital stays, later return to work, and less satisfaction than women having total vaginal hysterectomy. Two RCTs found that women having total abdominal hysterectomy had longer recovery times and more postoperative pain but shorter operating times and less blood loss than women having laparoscopically assisted vaginal hysterectomy. One RCT found that women having total abdominal hysterectomy had more postoperative fever, longer hospital stays, and longer recovery times than women having total laparoscopic hysterectomy.
Total Laparoscopic Hysterectomy (Re duces Postoperative Fever, Hospital Stay, and Recovery Time Compared with Total Abdominal Hysterectomy). One RCT found that women having total laparoscopic hysterectomy had less postoperative fever, shorter hospital stays, and shorter recovery times compared with women having total abdominal hysterectomy.
Total Vaginal Hysterectomy (Reduces Operation Time, Blood Loss, Pain, Fever, and Hospital Stay Compared with Total Abdominal Hysterectomy, and Increases Satisfaction with Operation). Two RCTs found that women having total vaginal hysterectomy had shorter operating times, less blood loss, less pain and fever, shorter hospital stays, earlier return to work, and greater satisfaction than women having total abdominal hysterectomy. One RCT found that women having total vaginal hysterectomy had shorter operating times and less blood loss than women having laparoscopically assisted vaginal hysterectomy.
Thermal Balloon Ablation. We found no RCTs comparing thermal balloon ablation with nonsurgical treatment or hysterectomy. One RCT compared thermal balloon ablation with rollerball endometrial ablation in women with fibroids smaller than the average size of a 12-week pregnancy, all of whom had been pretreated with gonadorelin analogues. The trial found no significant difference between thermal balloon and rollerball ablation in amenorrhea rates, pictorial bleeding assessment chart scores, hemoglobin, or hysterectomy rates at 12 months. It found that thermal balloon ablation reduced operation time and intraoperative complicating rate compared with rollerball ablation. About one third of women reported being “not very satisfied” with either operation.
Fibroids (uterine leiomyomas) are benign tumors of the smooth muscle cells of the uterus. Women with fibroids can be asymptomatic or may present with menorrhagia (30 percent), pelvic pain with or without dysmenorrhea or pressure symptoms (34 percent), infertility (27 percent), and recurrent pregnancy loss (3 percent).1 Much of the data describing the relationship between the presence of fibroids and symptoms are based on uncontrolled studies that have assessed the effect of myomectomy on the presenting symptoms.2 The prevalence of fibroids in infertile women can be as high as 13 percent, but no direct causal relationship between fibroids and infertility has been established.3
The reported incidence of fibroids varies from 5.4 to 77 percent depending on the method of diagnosis (the gold standard is histological evidence). A random sample of 335 Swedish women 25 to 40 years of age was reported to have an incidence of fibroids of 5.4 percent (95 percent confidence interval [CI] 3 to 7.8 percent) based on transvaginal ultrasound examination.4 The prevalence of these tumors increased with age (25 to 32 years: 3.3 percent; 95 percent CI, 0.7 to 6 percent; 33 to 40 years: 7.8 percent; 95 percent CI, 3.6 to 12 percent).4 Another large case control study found that the rate of fibroids was higher in women younger than 50 years; it found a rate of pathologically confirmed fibroids of 4.24 per 1,000 person-years in women 50 years or older compared with 6.20 per 1,000 in women 45 to 50 years of age, 4.63 per 1,000 in women 40 to 45 years of age, 2.67 per 1,000 in women 35 to 40 years of age, 0.96 per 1,000 in women 30 to 35 years of age, and 0.31 per 1,000 in women 25 to 30 years of age.5 Based on postmortem examination, 50 percent of women were found to have these tumors.6 Gross serial sectioning at 2-mm intervals of 100 consecutive hysterectomy specimens revealed the presence of fibroids in 50 of 68 (73 percent) premenopausal women and 27 of 32 (84 percent) postmenopausal women. These women were having hysterectomies for reasons other than fibroids.7 The incidence of fibroids in black women is three times greater than that in white women, based on ultrasound or hysterectomy diagnosis.8 Submucosal fibroids have been diagnosed in 6 to 34 percent of women having a hysteroscopy for abnormal bleeding and in 2 to 7 percent of women having infertility investigations.9
The cause of fibroids is unknown. It is known that each fibroid is of monoclonal origin and arises independently.10,11 Factors thought to be involved include the sex steroid hormones estrogen and progesterone as well as the insulin-like growth factors, epidermal growth factor, and transforming growth factor. Risk factors for fibroid growth include nulliparity and obesity. There is a risk reduction to one fifth with five term pregnancies, compared with nulliparous women (P < .001).5 Obesity increases the risk of fibroid development by 21 percent with each 10 kg of weight gain (P = .008).5 The combined oral contraceptive pill also reduces the risk of fibroids with increasing duration of use (women who have taken oral contraceptives for four to six years compared with women who have never taken oral contraceptives: odds ratio [OR] 0.8, 95 percent CI, 0.5 to 1.2; women who have taken oral contraceptives for seven years or longer compared with women who have never taken oral contraceptives: OR 0.5, 95 percent CI, 0.3 to 0.9).12 Women who have had injections containing 150 mg of depot medroxyprogesterone acetate also have a reduced incidence compared with women who have never had injections of this drug (OR 0.44, 95 percent CI, 0.36 to 0.55).13
There are few data on the long-term untreated prognosis of these tumors, particularly in women who are asymptomatic at diagnosis. One small case control study reported that in a group of 106 women treated with observation alone over one year there was no significant change in symptoms and quality of life over that time.14 Fibroids tend to shrink or fibrose after the menopause.5
search date: December 2003
editor’s note: Gonadorelin analogues are called gonadotropin-releasing hormone analogs in the United States. Leuprorelin acetate is called leuprolide in the United States. Progestogen is called progestin in the United States. Tibolone, buserelin, and gestrinone are not available in the United States.
Adapted with permission from Lethaby A, Vollenhoven B. Fibroids (uterine myomatosis, leiomyomas). Clin Evid Concise 2004;11:490–3.
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6. Thompson JD, Rock JA, eds. Te Linde’s operative gynecology. 7th ed. London: JB Lippincott Company, 1992.
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9. Farquhar C, Arroll B, Ekeroma A, et al. An evidence-based guideline for the management of uterine fibroids. Aust N Z J Obstet Gynaecol. 2001;41:125–40.
10. Townsend DE, Sparkes RS, Baluda MC, et al. Unicellular histogenesis of uterine leiomyomas as determined by electrophoresis of glucose-6-phosphate dehydrogenase. Am J Obstet Gynecol. 1970;107:1168–74.
11. Hashimoto K, Azuma C, Kamiura S, et al. Clonal determination of uterine leiomyomas by analyzing differential inactivation of the X-chromosome-linked phosphoglycerokinase gene. Gynecol Obstet Invest. 1995;40:204–8.
12. Chiaffarino F, Parazzini F, La Vecchia C, et al. Use of oral contraceptives and uterine fibroids: results from a case-control study. Br J Obstet Gynaecol. 1999;106:857–60.
13. Lumbiganon P, Rugpao S, Phandhu-Fung S, et al. Protective effect of depot-medroxyprogesterone acetate on surgically treated uterine leiomyomas: a multicentre-case control study. Br J Obstet Gynaecol. 1995;103:909–14.
14. Carlson KJ, Miller BA, Fowler FJ Jr. Maine women’s health study: II. Outcomes of nonsurgical management of leiomyomas, abnormal bleeding, and chronic pelvic pain. Obstet Gynecol. 1994;83:566–72.
This is one in a series of chapters excerpted from Clinical Evidence Concise, published by the BMJ Publishing Group, Tavistock Square, London, United Kingdom. Clinical Evidence Concise is published in print twice a year and is updated monthly online. Each topic is revised every 12 months, and subscribers should view the most up-to-date version athttp://www.clinicalevidence.com. If you are interested in contributing to Clinical Evidence, please contact Klara Brunnhuber (firstname.lastname@example.org). This series is part of the AFP’s CME. See “Clinical Quiz” on page 1647.
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