By Karlee Ausk, BS, and Susan D. Reed, MD, MPH
Uterine leiomyomas, or fibroids, are benign smooth muscle tumors diagnosed in approximately 25% of symptomatic women in the United States.1,2 Using routine ultrasound examination, uterine leiomyomas are observed in nearly 50% of white women and 73% of black women in the fifth decade of life.3 Leiomyomas are the most common indication for hysterectomy in the United States, account for one in five visits to a gynecologist, and are associated with health expenditures of more than $1.2 billion annually.4
Most women with symptomatic leiomyomas present in their 30s and 40s. The main symptoms are abnormal uterine bleeding, pelvic pain, dysmenorrhea, and pressure.5 Abnormal vaginal bleeding manifests as menorrhagia, metrorrhagia, or both. Symptomatic leiomyomas can lead to significant problems with iron-deficiency anemia, social embarrassment, and diminished work productivity. As a fibroid expands, it causes an increasing girth and sense of fullness. Its irregular shape can cause urinary frequency, constipation, and dyspareunia. Leiomyomas may reduce reproductive capability.
Women’s desire for nonsurgical intervention has prompted both allopathic and naturopathic physicians to consider and develop nonsurgical treatments for leiomyomas. Disenchantment with allopathic medicine and traditional medical approaches6 has led many women to question the use of hysterectomy, the most common allopathic therapy for uterine leiomyomas.7 Because of the number of women with symptomatic uterine leiomyomas, an effective treatment that minimizes risk and also maximizes satisfaction would have great social impact. Complementary and alternative medicine (CAM) therapies for uterine leiomyomas are designed to minimize risk and to treat symptomotology, but are not necessarily aimed at diminishing leiomyoma size.8 Unfortunately, there is little research on CAM therapies for symptomatic uterine leiomyomas. Therefore, women are using these therapies with little information as to safety and efficacy. This review discusses the theoretical rationale for choosing CAM therapies for the relief of dysmenorrhea and menorrhagia in women with uterine leiomyomas and reviews information from the existing literature in this area.
Risk Factors Affecting Incidence and Growth
Multiple reproductive characteristics, including early menarche,9 may be associated with the development of uterine leiomyomas. The risk of developing leiomyomas decreases with each pregnancy beyond 20 weeks gestation, but increases as time passes since the last birth.10,11 There may be a small decrease in risk associated with medroxyprogesterone acetate, especially with increased length of use,10 and with oral contraceptive use, except when that use is at an early age (13-16 years).11 Smoking is associated with a 20-50% decreased risk of developing uterine leiomyomas.9,12
Other risk factors for leiomyomas, not linked to reproduction, include increasing body mass index,9 diabetes mellitus, hypertension, Black race, and a family history of leiomyomas.12
Leiomyoma Pathophysiology
An understanding of the pathophysiology of leiomyoma growth and development is important as we attempt to evaluate the potential value of CAM therapies. Leiomyomas grow and become symptomatic because of smooth muscle cell proliferation and apoptosis inhibition, as well as by increased angiogenesis occurring within the leiomyoma and in surrounding myocytes. Leiomyomatous tissues upregulate extracellular matrix components, mainly type I and type III collagen, as compared to adjacent normal myometrium, and increase water content of tissues. Leiomyomatous tissue has an increased number of estrogen and progesterone receptors and expresses more aromatase P450 enzyme than normal surrounding smooth muscle cells. Consequently, a leiomyoma has the potential to produce endogenous estradiol from androgens.13
It is postulated that smooth muscle cell proliferation is mediated by a number of different growth factors found in cells destined to become leiomyomas. The leiomyomatous smooth muscle cells show an abnormal balance in the expression of transforming growth factor ß (TGF-ß) mRNA.14 This imbalance in TGF-ß leads to increased extracellular matrix production and decreased collagenase. There is a 60% decrease in the number of TGF-ß2 receptors, which normally act to control cell proliferation, and an increase in TGF-ß3 receptors.15 In addition, insulin-like growth factors (IGF-1 and IGF-2) are enhanced in leiomyomatous tissue and promote cell proliferation. Menopause and GnRH-agonist therapy are associated with diminished leiomyoma growth and are also associated with decreased IGF-1 levels.15 Uterine leiomyomas are well-vascularized tumors with abnormal blood vessel structure and function, and secrete increased levels of many heparin-binding growth factors. Heparin-binding growth factors are implicated not only for their mitogenic activity on smooth muscle cells, but also for their angiogenic activity.15
Methods
We conducted a systematic literature search utilizing the CONSORT16 and MOOSE guidelines.17 We searched Medline, Embase, Cinahl, and Cochrane Library, attempting to retrieve all relevant randomized or controlled comparisons related to CAM therapy of symptomatic leiomyomas. The search terms were "leiomyoma," "complementary therapies," "dysmenorrheal," "menorrhagia," "acupuncture," or "traditional Chinese medicine" (TCM), and the search was limited to the English language. The citation lists of relevant publications, review articles, abstracts of scientific meetings, and included studies also were searched. Only randomized or controlled clinical studies were included. Search results showed: Medline—12 English-language controlled clinical trials; Cochrane Library—nine reviews, three relevant to this paper; Embase—10 citations but none were controlled clinical trials; Cinahl—28 citations with two controlled clinical trials.
Findings from the Review
The studies on CAM therapies for leiomyoma treatment are extremely limited. Only two observational studies directly related to diet or CAM therapies and leiomyoma were found. (See Table 1.) The first, a nutrition case control study, did not investigate nutritional CAM therapy of leiomyoma, but rather assessed the development of leiomyoma based on dietary intake.18 A standardized, previously validated questionnaire to evaluate the consumption frequency of selected dietary items was administered among women with histologically confirmed leiomyomas (cases) and women without leiomyomas (controls) with a 98% response rate. The results suggest that women whose diet is rich in green leafy vegetables are less likely to be diagnosed with leiomyoma, odds ratio (OR) = 0.5 (95% confidence interval [CI] 0.4-0.6). Women with diets high in red meat had an increased risk of a leiomyoma diagnosis, OR = 1.7 (95% CI 1.4-2.2).18 The findings of this study are potentially biased because of the possibility of misclassification in the identification of women with and without leiomyomas and because questionnaires were administered up to two years after the clinical diagnosis of uterine fibroids had been made.
A second case control study evaluated a weekly treatment program of TCM, somatic therapy, body therapy, and guided imagery.19 TCM is based on the tenet that disease is caused by an imbalance in vital energy or qi.20 Symptoms associated with leiomyoma are related to stagnant qi (vital energy) and cold damp, deficient blood; therefore, TCM modalities aim to correct an imbalance of qi and relieve pelvic congestion. In this study, the diagnosis of leiomyoma was confirmed by ultrasound among 37 cases, recruited by word of mouth. The control group consisted of patients with ultrasound confirmed leiomyomas identified from records of emergency department visits matched to cases by age, presenting symptoms, fibroid size, health insurance status, and who underwent standard therapy leiomyoma therapy. Leiomyoma had growth cessation or shrinkage in nearly 60% of the CAM-treated cases compared to 8% of nontreated controls (P = < 0.01). There was not a significant difference in symptom relief between groups. However, the treatment group had higher satisfaction with care despite an increased cost to the patient above the traditional allopathic medicine approach (P = < 0.05). Bias due to misclassification could have confounded results. Cases were potentially of higher socioeconomic status (SES); treatments were paid for out of pocket. Although controls were matched to cases by health insurance status, one might question whether a comparison between individuals presenting to an emergency room for care (controls) to otherwise healthy outpatient women recruited by word of mouth (cases) is appropriate. Unfortunately, the complex therapeutic approach that was studied, including TCM, somatic therapy, body therapy, and guided imagery is potentially difficult to replicate, and although Chinese medicines usually are safe, an increasing number of significant and even fatal outcomes due to contaminants in Chinese herbal preparations have been reported.21 Thus, quality of products is an ongoing concern.
Many of the studies of CAM modalities for the treatment of dysmenorrhea, the second most frequent clinical complaint among women with fibroids, are of marginal quality and have not been replicated, but met inclusion criteria for review. (See Table 2.) Successful therapies may include: topical heat,22 vitamin and dietary intervention,23 relaxation training,24 high frequency TENS,25-28 acupuncture/acupressure,29-31 and herbal therapies.32 Acupuncture may be the most promising.33 It has long been used in the treatment of gynecological problems and appears to activate endogenous opioid systems.29 There is currently poor evidence to suggest that spinal manipulation improves dysmenorrhea.34,35
Potential for CAM Treatment Modalities
CAM modalities that potentially affect smooth muscle cell and collagen proliferation, angiogenesis, and steroid metabolism could be effective therapies. However, to our knowledge, no specific studies of the effect of CAM therapies on these physiologic processes have been reported. Naturopathic practitioners have justified treatment choices based on theoretical treatment effects.8
A principle CAM therapeutic focus is nutritional intervention. Patients are encouraged to adopt a diet high in fiber, low in dietary fat, and high in soy products and legumes. Poor nutrition is believed to inhibit the health of the liver, thereby slowing the metabolism of estrogen.
Nutritional supplements commonly used include lipotropic factors and pancreatic enzymes. The lipotropic factors (inositol and choline) promote removal of fat from liver, thereby speeding estrogen metabolism. Pancreatic enzyme use is controversial, but in theory, digests the fibrous and smooth muscle tissue surrounding the leiomyoma, dissolving it.
Herbal phytoestrogen use has been encouraged in women with leiomyomas. Phytoestrogens are selective estrogen receptor modulators and are hypothesized to act as antagonists at estrogen receptors in the myometrium and endometrium. Natural progesterone cream also is used in the treatment of leiomyomas. Progesterone therapy is reported to counteract the estrogen dominance that may lead to the development of leiomyomas. There is an important counter-argument, however, that in vitro, progesterone causes fibroid growth, so this therapy remains controversial.36
Conclusion
This review highlights the need for further studies on CAM therapies for uterine leiomyoma. There are limited data to support a variety of alternative therapies to decrease uterine leiomyoma growth and symptoms including dietary modification, TENS, acupuncture/ acupressure, and TCM. More rigorously designed studies are needed to clarify current recommendations regarding CAM modalities in the treatment of leiomyomas. Because of the high incidence of uterine leiomyoma, any further research on the use of CAM therapies for leiomyoma could have a dramatic impact.
Ms. Ausk is a fourth-year medical student in the School of Medicine, University of Washington. Dr. Reed is Assistant Professor, Department of Obstetrics and Gynecology, University of Washington and Harborview Medical Center, Seattle, WA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center; and Center for Health Studies, Group Health Cooperative, Seattle, WA.
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