Abstract and Introduction
In recent years, there has been an increasing focus on the contributory role of uterine fibroids to infertility. The prevalence of these tumors increases with age, which becomes significant as more women are delaying childbearing. Therefore, fibroids and infertility frequently occur together. Treatment varies with fibroid location and size. The various methods of treatment include open myomectomy, laparoscopic or robot-assisted myomectomy, medical treatment, uterine artery embolization and magnetic resonance guided focused ultrasound surgery. While there is a general consensus on the treatment of submucosal fibroids, the management of intramural fibroids in the infertility patient remains controversial. This paper aims to review and summarize the current literature in regards to the approach to uterine fibroids in the infertile patient.
Fibroids (also referred to as myomas and leiomyomas) are benign, monoclonal tumors of the uterus that are composed largely of smooth muscle cells. They are the most common tumor of the female genital tract, with some studies estimating over a 70% incidence.[1,2] Fibroids are the reason for approximately 30% of the hysterectomies performed in the USA. There are many variations in the size and location of these tumors. Fibroids are described by their location in relation to the uterine wall. Subserosal fibroids are located on the external surface of the uterus and grow outward. Intramural fibroids grow within the uterine wall. Submucosal fibroids develop near the endometrium and tend to grow in toward the uterine cavity. Additionally there are pedunculated fibroids, which grow on a stalk, and can either be further classified as subserosal or submucosal depending on their location. Although most women are asymptomatic, approximately 25% of women develop symptoms such as pain, menorrhagia or other symptoms of mass effect from fibroids.[1,4]
The pathogenesis of uterine myomas is still under investigation. It is accepted that their growth is stimulated by both estrogen and progesterone; however, the mechanisms surrounding the initial genesis of these tumors are not known. A number of studies have shown that as many as 40% of individual fibroids have some chromosomal alteration. The most common chromosomal abnormality found is a translocation of chromosomes 12 and 14. The HMGA2 gene, which was found in this translocation, is a proliferation modulator that is found in proliferative tissues. An in vitro study of HMGA2 antagonism found a resultant decrease in proliferation of leiomyoma cells. Several other genetic loci and gene products have also been implicated in fibroid development and growth, including STE-20-like kinase, AKAP13 and MED12, among many others. In addition, several chemokines, cytokines, extracellular matrix components (collagens, fibronectins) and growth factors have also been implicated in myoma growth. For example, TGF-β, particularly the β3 subunit, appears to be overexpressed in uterine fibroids. These biochemical components have been the focus of research to attempt to find potential treatments of fibroids. Furthermore, several neuropeptides, including substance P, neurotensin, neuropeptide tyrosine and vasoactive intestinal peptide have been found at similar levels in the pseudocapsule of myomas compared with normal myometrium.[8,9] Many of these neuropeptides have been implicated in healing and uterine contractility/peristalsis. This suggests that performing a myomectomy that spares the pseudocapsule may maintain the overall integrity of the myometrium, thus aiding in healing and potentially in future pregnancy outcomes. Additionally, a study by Baird et al. showed that vitamin D deficiency was associated with an increased likelihood of fibroid occurrence in both white and black women. Further investigation of the molecular biology and genetics of fibroids will be required before any concrete conclusions can be made.
In recent years, there has been a growing interest in the effect that these tumors have on fertility. It is generally accepted that submucous fibroids, which inherently distort the uterine cavity, have a detrimental effect on fertility. A 2009 review by Pritts et al. found that fibroids causing intracavitary distortion result in decreased rates of clinical pregnancy, implantation and ongoing pregnancy/livebirth, as well as an increased rate of spontaneous miscarriage. By contrast, there is controversy as to whether fibroids that do not cause distortion of the uterine cavity have any effect on fertility. However, in the same review, Pritts et al. found that patients with fibroids with no intracavitary involvement (particularly intramural fibroids), when compared with controls without fibroids, had decreased rates of implantation and ongoing pregnancy/live birth, and an increased rate of spontaneous miscarriage. Proposed etiologies for such effects of fibroids without intracavitary involvement include alterations of uterine peristalsis and vascular flow as well as disruption of sperm and ovum transportation and embryo implantation.[12–16] One weakness of Pritt's review is that most of the studies did not fully evaluate the involvement of the uterine cavity. No evidence was found that subserosal fibroids decreased any measure of fertility. Nonetheless, the data provide compelling evidence that there may be situations in which surgical removal of nonsubmucosal fibroids is indicated in the infertile patient. Furthermore, several studies have shown a detrimental effect of fibroids without intracavitary involvement on IVF outcomes, particularly myomas larger than 4 cm.[17–19] Although other studies refute this evidence, more high quality research is needed to further evaluate the role of intramural fibroids in the setting of infertility.[20,21]
One of the biggest gaps in this area of clinical research is the lack of consistency of the precise localization of fibroids in each of the different studies that have been performed. There is often no explanation of how fibroids were classified into one group versus another (e.g., imaging modality, precise cut offs, etc.). Additionally, subserosal and intramural fibroids are often considered as a single entity in these studies. The ESGE/FIGO leiomyoma subclassification system may aid in addressing this inconsistency (Figure 1). Although there have been some studies using this classification system, there is a dearth of large, randomized control trials using it to describe the myomas being studied.[22,23] This review will focus on the accepted evidence in the diagnosis and treatment of uterine fibroids as they pertain to infertility, as well as suggested directions for future research.
Women's Health. 2014;10(6):645-653. © 2014 Future Medicine Ltd.