By Robert W. Rebar, MD
Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo
Dr. Rebar reports no financial relationships relevant to this field of study.
SYNOPSIS: Uterine fibroids occur commonly and are the most frequent reason for hysterectomy in the United States. Recognizing the risk factors for developing fibroids can help clinicians identify affected individuals and may lead to new approaches to treatment.
SOURCE: Stewart EA, Cookson CL, Gandolfo RA, Schulze-Rath R. Epidemiology of uterine fibroids: A systematic review. Br J Obstet Gynaecol 2017;124:1501-1512.
This is the first systematic review reported exploring risk factors for uterine fibroids. The authors identified 60 registries and other observational studies with more than 1,000 patients and single-center studies with more than 100 patients published between January 1995 and April 2015 for inclusion in their analysis. The early date was selected because diagnostic techniques that might have affected the rate of fibroid diagnosis were developed in the mid-1990s. Because of the heterogeneity of the data, it was not possible to perform a meta-analysis. More than half of the studies (60%; 36 of 60) relied on self-report and may have been subject to recall bias. Selection bias was present in the vast majority of included studies, with populations randomly selected in only five studies. In 58% (35 of 60) of the studies, participants responded to a survey (and thus self-selected), and in 30% (18 of 60) of the studies, participants were gynecologic patients. Only pelvic examination was used to identify women with fibroids in 20% (12 of 60) of the studies, whereas ultrasonography, magnetic resonance imaging, or surgical pathology were used in 66% (40 of 60).
The range in the incidence of fibroids was wide, from 217 cases per 100,000 women-years in one study of California teachers to 3,745 cases per 100,000 women-years in the Black Women’s Health Study. The prevalence of fibroids also varied widely across the studies, ranging from 4.5% to 68.6%. Black race was the only factor that consistently was associated with an increased risk of fibroids in cohort registry studies, ranging from two- to three-fold. In their analysis, the authors focused on and identified 11 risk factors for which the magnitude of the effect was approximately equal to or greater than the effect of race. Age, premenopausal status, hypertension, positive family history, time since last birth, and food additive and soybean milk consumption increased the risk for fibroids. However, use of oral contraceptives or injectable medroxyprogesterone acetate, smoking in women with low body mass index, and increasing parity decreased the risk of fibroids. The authors emphasized the need for high-quality prospective observational data to better understand the epidemiology of fibroids, with the intent of improving management.
COMMENTARY
Although uterine fibroids are a leading cause of morbidity in many women — resulting in heavy menstrual bleeding, anemia, fatigue, dysmenorrhea, abdominal pain, a sense of pelvic pressure, dyspareunia, reduced fertility, and bladder and bowel dysfunction — in other women, uterine fibroids are asymptomatic. We know astonishingly little about their epidemiology, let alone their pathogenesis.
An accompanying editorial by two clinicians from a leading group of investigators noted that the findings from this systematic review support the hypothesis that ethnic/genetic predisposition and ovarian hormone exposure are the principal determinants of fibroid development.1 In fact, experimental evidence supports both postulates.
It long has been recognized that fibroids are generally monoclonal proliferations of benign smooth muscle.2 Moreover, it now is clear that each monoclonal myoma may be associated with various chromosomal translocations, duplications, and deletions.3 The majority of myomas contain nonrandom cytogenetic abnormalities, and most of the mutations are found in genes involved in cellular growth or are responsible for architectural transcription. Several genome-wide association studies (GWAS) have been conducted and indicated that particular ethnic groups may have loci associated with the development of fibroids. For example, a multi-stage GWAS study of uterine fibroids in African Americans identified a novel risk locus within CYTH4 that affects gene expression in the thyroid and potentially in fibroids.4
Endocrinologically, the estrogen receptor, the progesterone receptor, and the epidermal growth factor receptor appear to play important roles in the development of myomas.5-7 In addition, aromatase p450 is overexpressed in leiomyomas, indicating that the local conversion of androgens to estrogens also may be important in potentiating the actions of estrogen with fibroids.8
The suggestion that these endocrine changes affect fibroid growth is supported by the evidence of which agents inhibit fibroid growth, at least temporarily. We know that medical treatment can alleviate pain and affect menstrual bleeding. Both gonadotropin-releasing hormone agonists and antagonists, which in the long term suppress ovarian steroid secretion, are known to reduce fibroid volume.9 Selective progesterone receptor modulators (SPRMs), such as mifepristone and ulipristal acetate, have been shown to reduce fibroid size as well.10 A recent Cochrane analysis concluded that short-term use of SPRMs resulted in improved quality of life, reduced menstrual bleeding, and higher rates of amenorrhea than seen with placebo.11 Similarly, aromatase inhibitors also hold promise for short-term relief.12 It remains to be determined whether medical congeners of any of these agents will be developed that can treat fibroids over the long term without resorting to any of the more invasive therapies, including myomectomy and hysterectomy, uterine artery and fibroid embolization, cryomyolysis, and magnetic resonance imaging-guided focused ultrasound therapy.
What is certain is that until more is known about the epidemiology, as well as the etiology and pathogenesis of uterine fibroids, our treatment measures will remain interventional rather than preventive. That is why studies such as the one reviewed are so important.
REFERENCES
- Vercellini P, Frattaruolo MP. Uterine fibroids: From observational epidemiology to clinical management. Br J Obstet Gynaecol 2017;124:1513.
- Stewart EA. Uterine fibroids. Lancet 2001;357:293-298.
- Catherino W, Salama A, Potlog-Nahari C, et al. Gene expression studies in leiomyomata: New directions for research. Semin Reprod Med 2004;22:83-90.
- Hellwege JN, Jeff JM, Wise LA, et al. A multi-stage genome-wide association study of uterine fibroids in African Americans. Hum Genet 2017 Aug 23. Doi:10.1007/s00439-017-1836-1.
- Shimomuro Y, Matsuo H, Samoto T, Maruo T. Upregulation by progesterone of proliferating cell nuclear antigen and epidermal growth factor expression in human uterine leiomyoma. J Clin Endocrinol Metab 1998;83:2192-2198.
- Brandon DD, Betheq CL, Strawn EY, et al. Progesterone receptor messenger ribonucleic acid and protein are over expressed in human uterine leiomyomas. Am J Obstet Gynecol 1993;169:78-85.
- Brandon DD, Erickson TE, Keenan EJ, et al. Estrogen receptor gene expression in human uterine leiomyomata. J Clin Endocrinol Metab 1995;80:1876-1881.
- Bulun Se, Simpson ER, Word RA. Expression of the CYP19 gene and its product aromatase cytochrome p450 in human uterine leiomyoma tissues and cells in culture. J Clin Endocrinol Metab 1994;78:736-743.
- Friedman AJ, Lobel SM, Rein MS, et al. Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing hormone agonists: The estrogen threshold hypothesis. Am J Obstet Gynecol 1990;163(4 Pt 1):1114-1119.
- Safrai M, Chill HH, Reuveni Salzman A, Shushan A. Selective progesterone modulators for the treatment of uterine leiomyomas. Obstet Gynecol 2017;130:315-318.
- Murji A, Whitaker L, Chow TL, Sobel ML. Selective progesterone receptor modulators (SPRMs) for uterine fibroids. Cochrane Database Syst Rev 2017; Apr 26. CD 010770. doi:10.1002/14651858.CD010770.pub2.
- Parsanezhad ME, Azmoon M, Alborzi S, et al. A randomized, controlled trial of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status. Fertil Steril 2010;93:192-198.
Uterine fibroids occur commonly and are the most frequent reason for hysterectomy in the United States. Recognizing the risk factors for developing fibroids can help clinicians identify affected individuals and may lead to new approaches to treatment.
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