Environmental Health Perspectives Volume 108, Supplement 5, October 2000
Clinical Decision Making Regarding Leiomyomata: What We Need in the Next Millenium
A. F. Haney
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA
Abstract
Leiomyomata represent the most common gynecologic tumors and are responsible for over 200,000 hysterectomies per year. They are almost invariably benign and represent clonal expansion of individual myometrial cells. They can cause a variety of symptoms including menometrorrhagia, dysmenorrhea, pelvic pain, reproductive failure, and compression of adjacent pelvic viscera, or be totally asymptomatic. Leiomyomata are more common in African-American women and have a non-Mendelian inheritance pattern with up to a 50% recurrence rate after surgical removal. The therapeutic choices depend on the goals of therapy, with hysterectomy most often used for definitive treatment, and myomectomy when preservation of childbearing is desired. Intracavitary and submucous leiomyomata can be removed by hysteroscopic resection. Laparoscopic myomectomy is now technically possible but apparently with an increased risk of uterine rupture during pregnancy. Although gonadotropin-releasing hormone-agonist-induced hypogonadism can reduce the volume of leiomyomata, the severe side effects and prompt recurrences make them useful only for short-term goals such as reversing anemia or shrinking an intracavitary tumor prior to hysteroscopic resection. Nonextirpative approaches such as myolysis and uterine artery embolization are being evaluated, and may provide more options if they prove to be safe and efficacious in long-term follow-up. Ultimately, if the genetic basis for fibroid development and/or the molecular mechanism(s) of myometrial proliferation are understood, additional nonsurgical therapeutic interventions may be forthcoming. Current clinical needs are to
a) determine an effective prevention strategy in genetically predisposed individuals;
b) slow the growth of leiomyomata;
c) identify the mechanisms of infertility;
d) improve early detection;
e) develop better surgical techniques;
f) reduce recurrences after myomectomy;
g) develop nonextirpative options; and
h) evaluate their long-term results.
Key words: hysterectomy, leiomyomata, leiomyosarcoma, myomectomy. --
Environ Health Perspect 108(suppl 5):835-839 (2000).
http://ehpnet1.niehs.nih.gov/docs/2000/suppl-5/835-839haney/abstract.html
This article is based on a presentation at the conference on Women's Health and the Environment: The Next Century--Advances in Uterine Leiomyoma Research held 7-8 October 1999 in Research Triangle Park, North Carolina, USA.
Address correspondence to A.F. Haney, Box 2971, Duke University Medical Center, Durham, NC 27710 USA. Telephone: (919) 684-6160. Fax: (919) 681-7904. E-mail: haney001@mc.duke.edu
Received 23 February 2000; accepted 18 August 2000.
Uterine leiomyomata are by far the most common benign tumors of the female genital tract and likely the most common soft-tissue tumors in the entire body. Approximately 200,000 hysterectomies and 20,000 myomectomies are performed annually in the United States because of symptoms caused by leiomyomata (
1). These tumors can attain very large size with few if any symptoms; alternatively, small leiomyomata may cause massive uterine bleeding and pain. Although representing one of the most frequent indications for gynecologic surgery, the incidence of leiomyomata far exceeds the frequency of clinical problems attributable to them, with estimates as high as 70% of women having identifiable leiomyomata present in their uterus at menopause.
Leiomyomata come to clinical attention for a variety of reasons.The following symptoms depend upon tumor size and location:
- Excessive uterine bleeding
- Dysmenorrhea
- Chronic pelvic pain
- Pressure on adjacent viscera
- Infertility
- Repetitive pregnancy loss
- First trimester
- Second and third trimester
- Abdominal enlargement
Excessive uterine bleeding leading to anemia, debilitating dysmenorrhea, generalized pelvic pain, or pressure on the adjacent pelvic viscera may occur, but chronic pelvic pain is typically a very late symptom. Leiomyomata occasionally rapidly enlarge during pregnancy and undergo necrosis, degenerating myomas, and this can result in a great deal of pain to the point of requiring narcotics. As the size of the leiomyomata and the total uterine volume increase, particularly with single large subserosal leiomyomata, the adjacent pelvic viscera may be compressed, causing urinary frequency, constipation, and dyspareunia.
Leiomyomata represent benign sex steroid-responsive smooth uterine muscle tumors originating as clonal expansions of individual myometrial cells (
2,3). The histology is virtually indistinguishable from normal myometrium, with the cellularity being highly variable. Areas of fibrosis and calcification are often interspersed, especially after degeneration and in postmenopausal women. Leiomyomata typically grow in a spherical nodular fashion, with a distinct demarcation from the surrounding normal myometrium, reflecting their clonal origin (
2,3). When rapid growth does occur, as is occasionally observed in pregnancy, the central area of individual tumors may undergo necrosis and be replaced by hyalinized degeneration.
Rarely, a leiomyosarcoma is encountered that is clinically indistinguishable from simple leiomyomata, but these are typically in older, postmenopausal women. The histologic criteria for malignancy are increased numbers of mitoses, cellular pleomorphism, and thrombotic degeneration within the tumor. Because of the difficulty identifying mitoses on frozen section microscopy, an intraoperative diagnosis by frozen section cannot be made with confidence and permanent sections are required. Leiomyosarcomas are estimated to comprise 0.1% of all uterine tumors, but 1.7% of women undergoing hysterectomy for leiomyomata in their seventh decade of life (4). For practical purposes, these tumors should be considered benign in premenopausal women, but all specimens should undergo careful pathologic examination.
Although a variety of treatment options exist, it is important that the treatment be goal directed. Simply because leiomyomata can be identified does not imply that they will be symptomatic in the future. Clearly, any therapeutic intervention should be focused on the alleviation of symptoms, and observation of asymptomatic women is all that is necessary. When the symptoms are mild, nonsteroidal anti-inflammatory agents and oral contraceptives are often useful, and the symptoms will improve sufficiently to avoid further intervention.
Many leiomyomata have limited growth potential and will remain static in size until the reproductive age level of sex steroids declines at menopause. The most critical questions are whether future reproduction is desired and how soon menopause can be anticipated. As simple hysterectomy represents a definitive cure, this is an attractive option for many women when maintenance of reproduction is not desired and medical therapy has failed. When the preservation of future childbearing is desired, a myomectomy is currently the primary choice (5). However, the recurrence of clinically symptomatic leiomyomata occurs in approximately one-third of patients (6), so the surgical treatment is of limited value. It must be made clear that this procedure provides only a disease-free interval. Furthermore, increasing numbers of women today desire the preservation of the uterus, even in the absence of any intention of future childbearing.
Despite the fact that the presenting symptoms, clinical course, and pathologic spectrum of leiomyomata have long been appreciated, there remain many issues that urgently require attention. The following are current clinical needs regarding leiomyomata:
- Develop an effective prevention strategy
- Reduce progression of fibroid growth
- Reduce recurrences after myomectomy
- Identify the mechanism(s) by which leiomyomata impair reproduction (fertility and pregnancy loss)
- Improve the detection of leiomyomata
- Imaging techniques
- Biochemical markers
- Improve surgical extirpation
- Better endoscopic approaches
- Reduce pelvic adhesions after myomectomy
- Determine when operative delivery is necessary
- Develop effective nonextirpative options
- Evaluate the long-term results of all medical and surgical treatment options
As the age at which first pregnancy rises in this country, women will be confronted increasingly with symptomatic leiomyomata before they have completed their childbearing. These features heighten the importance of finding optimal ways of detecting, predicting the clinical course, and ultimately treating leiomyomata without loss of the uterus.
It is estimated that over 40% of first-degree female relatives of women with leiomyomata will develop them sometime during their lifetime. Additionally, although leiomyomata are common in all races, African-American women appear to have a higher incidence than women of other races, and when undergoing hysterectomies have increased numbers of leiomyomata that are larger in size (
7). This familial pattern seems most consistent with a multifactorial genetic inheritance pattern modified by confounding cofactors, and not simple Mendelian genetics. Aside from noting that the disease has apparent familial, age, and racial associations, there is little clinical predictability for an individual woman. As the prevalence of leiomyomata is very high, virtually all women are at risk of developing them in their later reproductive years.
Leiomyomas represent monoclonal neoplasms, a situation in which etiologic genetic alterations in the tumors are likely. Cytogenetic studies of individual leiomyomas reveal that approximately one-third have some type of clonal chromosomal aberration, and this is not consistent between individual leiomyomata, even in the same woman (
3). Undoubtedly, myometrial cells become neoplastic as a result of a complex interaction of factors, including genetic mutation, endogenous sex-steroid production, reproductive patterns, and environmental and medicinal hormonal exposure. Molecular geneticists have noted abnormal expression of a variety of individual growth factors in individual leiomyomata, but there is no consensus regarding a single predominant genetic defect underlying their development and growth (
8,9). Although this dysregulation may be related to the propensity to grow disproportionately with respect to the normal myometrium, the molecular evidence does not suggest a progression from benign leiomyomata to leiomyosarcoma. Undoubtedly, the mechanism of clonal expansion of individual myometrial cells involves an interplay of gonadal steroids and endocrine, paracrine, and autocrine growth factors. In the coming years, this molecular puzzle will undoubtedly be unraveled. Clarifying the pathophysiologic mechanism(s) of growth of this most common of neoplasias should provide opportunities for better predicting the clinical course, as well as the optimal prevention and therapeutic strategies.
There is little doubt that the growth of leiomyomata is related to gonadal steroids, as they
a) are not noted prior to puberty;
b) typically regress after menopause;
c) possess sex-steroid receptors (estrogen and progesterone);
d) often dramatically enlarge during pregnancy; and
e) can be made to shrink with medically induced hypogonadism. There is no evidence that higher or aberrant patterns of ovarian secretion of estrogens, progestins, or androgens contribute to the development of leiomyomata, but this possibility remains an open issue. The use of oral contraceptives has not been demonstrated to be associated with an increased incidence of leiomyomata or more rapid recurrence or progression. Similarly, treatment of postmenopausal women with hormonal replacement therapy has not been correlated with the growth of leiomyomata. For clinical purposes, withholding hormone replacement therapy for fear of stimulating leiomyomata in otherwise appropriate candidates for postmenopausal hormonal replacement is not appropriate, given the well-documented benefits of this therapy. Special note should be made of postmenopausal women with breast cancer treated with tamoxifen; this compound has both estrogen agonist and antagonist activity, which has the potential to influence the pattern of growth. Undoubtedly, gonadal steroids are important in the development or growth of leiomyomata. As more selective estrogen- and progestin-response modulators become available for clinical use, their impact on the development or growth of leiomyomata will become apparent and, hopefully, some will be therapeutically useful.
The ultimate goal of understanding the nature of leiomyomata is to prevent their occurrence in genetically susceptible as well as other women. The following will be required to improve our treatment of leimomyomata:
- Identify genetic markers of susceptibility
- Determine the etiologic molecular mechanisms
- Characterize the impact of hormones and growth factors
- Identify different patterns of growth (single vs multiple)
- Determine the impact of commonly prescribed hormonal medications (oral contraceptives and hormone replacement therapy)
With further insight regarding the molecular mechanism(s) of growth, it may be possible to identify medicinal approaches to interfere with the molecular pathway(s) and reduce the risk of development, progression, and recurrence of leiomyomata. This will be particularly useful for women with a familial history of leiomyomata and those women with symptomatic leiomyomata approaching menopause who can anticipate spontaneous regression once ovarian function ceases. This approach may also be useful for women after myomectomy, extending the interval until development of additional leiomyomata. Additionally, understanding the impacts of childbearing, lactation, various forms of steroidal contraception, and estrogen and hormone replacement therapy on the development, progression, and recurrence of leiomyomata should help optimize clinical recommendations.
The impact of leiomyomata on the ability to reproduce remains controversial. Mechanisms of infertility with leiomyomata include
- Impaired implantation
- Submucous
- Intracavitary
- Enlarged uterine cavity volume
- Tubal distortion/obstruction
There is general agreement that intracavitary and significant submucosal leiomyomata are likely to be causally related to infertility on the basis of implantation failure, comparable to the effect of an intrauterine device. With intramural leiomyomata, the relationship is more uncertain, and all other potential etiologies should be considered before concluding that the leiomyomata are etiologic. Intramural leiomyomata have been associated with a reduced pregnancy rate following assisted reproductive technology therapy (in vitro fertilization and gamete intrafallopian transfer), which supports their interference with implantation (10). If the clinical problem is repetitive first-trimester pregnancy loss, preterm labor, or intrauterine growth restriction, or if the leiomyomata are extremely large, preconception removal of intramural leiomyomas is appropriate. Overall, term delivery rates following myomectomy vary from 40 to 50% (11,12).
The vast majority of leiomyomata are detected on pelvic examination performed because of a gynecological symptom. The uterus is typically noted to be enlarged and irregular and a pelvic ultrasound used to distinguish leiomyomata from other pelvic masses such as ovarian tumors. Diagnostic imaging is usually undertaken to ensure that the abnormal examination reflects the presence of leiomyomata and not another type of tumor with more potential to be a malignancy. Diagnostic acumen can be improved by the use of
- Endovaginal sonography
- Sonohysterography
- Hysterosalpingography
- Magnetic resonance imaging
- Computerized tomography
- Radionucleotide scanning
- Serum markers
The proximity of the leiomyomata to the endometrial cavity can usually be demonstrated by using the acoustic differences between the normal myometrium, the tumors, and the endometrium. The endometrial stripe is a reliable marker of the endometrial cavity and simultaneously injecting saline into the endometrial cavity (sonohysterography) improves the delineation of intracavitary and submucous leiomyomata. Hysterosalpingography is often used if infertility is simultaneously present, as this technique can identify intracavitary tumors or a large but otherwise normal endometrial cavity caused by stretching the normal myometrium around leiomyomata. When either of these features is present, removal of the leiomyomata can be expected to improve the likelihood of conception.
Another uterine disease, adenomyosis, may be difficult to distinguish from leiomyomata by imaging studies. This disease process involves the infiltration of endometrial glands and stroma within the myometrium itself, typically immediately adjacent to the endometrial cavity. Frequently, a marked fibrotic reaction is present around the fragments of endometrium isolated within the myometrium, presumably because of the menstrual shedding in the midst of the muscle. Magnetic resonance imaging may be useful, as it can help delineate the borders of the pathologic process. Adenomyosis tends to be less well demarcated and has more variability in shape; however, the two pathologic entities may occasionally be indistinguishable by any of the currently available imaging techniques and the diagnosis made only after excision of the lesion.
At present, there are no biochemical markers for either leiomyomata or adenomyosis. If a screening tool could be identified, particularly one that detects leiomyomata too small to be palpated on routine pelvic examination, this would prove to be useful for early detection. Because the majority of leiomyomata are identified only after symptoms develop, this would assist in determining the true prevalence, better define the natural history, and lead to earlier intervention, reducing the need for surgical intervention.
The current mainstay of treatment for symptomatic leiomyomata is surgical: either hysterectomy or myomectomy. Given the risks inherent with all surgical procedures, the decision to proceed with any surgery should be based on a clinical risk-benefit assessment personalized for each woman, with the pivotal issue being her desire for future reproduction. The following improvements in surgical technique, particularly relating to minimally invasive surgery, would provide the most immediate benefits for women with leiomyomata:
- Improve endoscopic techniques
- Supracervical hysterectomy
- Myomectomy
- Reduce postmyomectomy pelvic adhesions
- Improve incisional barrier materials
- Reduce de novo adhesions
- Ensure identification of all leiomyomata for excision
- Reduce surgical blood loss
- Determine when operative delivery is necessary
In addition, comparative clinical trials of the various surgical approaches are needed.
Hysterectomy
When future childbearing is not desired and the symptoms are severe enough to warrant a surgical procedure, a simple hysterectomy is often chosen. It is a curative procedure and allows estrogen alone to be used as hormone replacement at menopause. The decision to proceed with removal of the uterus should be based on a risk-benefit decision, weighing the severity of the symptoms with the surgical risk, not on concern that the leiomyomata are or might be malignant. The surgical approach should be tailored to the individual circumstances, e.g., abdominal, vaginal, or laparoscopically assisted hysterectomy, and preservation of the cervix should be more frequently considered in appropriately selected women. The myometrium is the portion of the uterus at risk for growth of leiomyomata. Because the cervix is composed primarily of fibrous tissue, the potential for the development of a leiomyomata in the cervix is extremely low. The structural support for the cervix and vaginal apex remains intact when a supracervical hysterectomy is performed. Additionally, a major portion of the morbidity from hysterectomy involves the removal of the cervix, and the risk of a later cervical dysplasia is very low, and when it occurs, it is easily treated as an outpatient. However, the woman choosing to retain the cervix needs to be aware of the need for continued annual cervical cytology.
Hysteroscopic Myomectomy
With recent improvements in endoscopic surgery, it was logical that intracavitary and submucous leiomyomata would be resected via hysteroscopy. If the tumor is completely intracavitary, a hysteroscopic resection is the most cost-effective method of removal (13). When a significant percentage of a submucosal leiomyoma protrudes into the endometrial cavity, it is similarly amenable to removal via hysteroscopic resection. However, if the tumor is predominantly within the myometrial wall, then the access afforded by hysteroscopy is not useful.
This technique typically utilizes a resectoscope comparable to that used for transurethral prostate resection. It is inserted through the cervix; the leiomyoma is resected and removed via the cervix, but careful preoperative selection and a high level of surgical skill are required. Preoperative shrinkage of the leiomyoma by the use of a gonadotropin-releasing hormone (GnRH)-agonist is often helpful. Additionally, care must be taken to avoid excessive intravascular absorption of the distending medium, which can cause either congestive heart failure or a bleeding diathesis, depending upon the choice of the distending medium.
Abdominal Myomectomy
When symptomatic leiomyomata are not located within the endometrial cavity, an abdominal surgical approach is usually required. The goal of a myomectomy is to remove all the identifiable leiomyomata with the least possible distortion of the reproductive tract (5). As the uterus is well vascularized, significant intraoperative blood loss is frequently encountered. Myomectomy at the time of operative delivery is particularly hazardous because of the increased vascularity of the myometrium during pregnancy. Careful attention to surgical blood loss, application of tourniquets on vascular pedicles, intramyometrial injection of vasospastic agents such as vasopressin, or employment of an intraoperative blood scavenger system can reduce the net surgical blood loss. These steps, coupled with the preoperative correction of anemia and storage of autologous blood, have dramatically reduced the need for homologous transfusion. When the intramyometrial injection of vasopressin is used, care must be taken that postoperative myometrial incisional bleeding after clearance of the vasopressin does not occur.
Once the myometrium has sustained a surgical injury to a significant depth of the uterine wall, an elective Cesarean section is generally recommended. The integrity of the uterine wall during labor should be a concern, even if the endometrial cavity has not been entered. Following a myomectomy, the couple should wait 2-3 months before attempting pregnancy to allow the uterine incisions to heal and minimize the potential for myometrial scar disruption during pregnancy. This recommendation is based on clinical experience with the classic Cesarean section scar, where the incision is located in the contractile portion of the uterus. As the myomectomy incision is comparable in location, it may not be capable of withstanding the force of a prolonged labor without rupture, a catastrophic occurrence for both the mother and fetus. Selection for an operative delivery should be based on the depth and extent of the incision and the adequacy of the incisional repair, as the risk of uterine rupture is not well defined in the modern era (14). Further data are needed regarding the need for Cesarean section with less significant surgical injuries sustained at myomectomy.
Laparoscopic Myomectomy
Improvements in laparoscopic technology have now allowed myomectomy to be accomplished via laparoscope. It seems clear that pedunculated, serosal, and superficial intramural leiomyomas can be removed via laparoscopy, but the surgery is lengthy and technically difficult, and should be undertaken only by the most experienced endoscopic surgeons. Furthermore, as only clearly obvious leiomyomata can be removed via laparoscopy, this therapy should be undertaken only when removal of a specific tumor can be anticipated to relieve the symptoms. Closure of the uterine incisions is technically difficult endoscopically, and there have been several reports of spontaneous uterine rupture after laparoscopic myomectomy (15,16). The disconcerting issue is this may occur during pregnancy prior to labor, which is distinct from that observed with abdominal myomectomy, where the risk of uterine rupture is felt to be primarily during labor. This suggests that even with careful attention to incisional closure by skilled endoscopic surgeons, the incidence of uterine rupture should be judged the major risk factor considered in choosing the endoscopic approach. In the absence of long-term safety studies, selection of patients for laparoscopic myomectomy should be done very carefully and the surgery performed by experienced surgeons, primarily when subsequent reproduction is not desired.
Postoperative Pelvic Adhesions
A major risk of myomectomy is the development of postoperative adhesions to the incision sites and other de novo adhesions caused by peritoneal trauma during surgery (17). These can result in reduced subsequent fertility or bowel obstruction. Interestingly, endoscopic surgery has not been demonstrated to reduce the adhesion rate at the site of surgery, but it does reduce the de novo adhesion rate, e.g., adhesions in the pelvis at nonsurgical sites (18). Minimizing the degree of surgical trauma, confining the incisions to the anterior uterine surface so as to protect the bowel and adnexal structures, and covering the posterior uterine incisions with surgical barriers have been advocated to minimize the rate of postoperative adhesions. The materials used as adhesion prevention barriers are quite varied and include oxidized regenerated cellulose that is degraded by leukocytes, polytetrafluoroethylene, a permanent material typically removed after an appropriate interval, and a hydrolyzable combination of hyaluronic acid and carboxymethylcellulose (17). Improvements in surgical barrier technology and alternative surgical strategies will undoubtedly be forthcoming to reduce the rate of postoperative adhesions.
Medical Suppression
Many medicinal agents have been considered for the treatment of leiomyomata, including estrogen antagonists, progesterone antagonists, androgens, and pituitary suppression. However, only suppression of ovarian steroid production with a GnRH-agonist has been clearly demonstrated to reduce leiomyomata size and relieve symptoms (19,20). The following have been proposed as nonextirpative treatments:
- Cryo-, electro-, diathermic, and laser myolysis
- Uterine artery embolization
- Medically induced hypogonadism
- GnRH-agonist
- ;GnRH-agonist with add-back therapy
- GnRH-antagonist
- New medicinal strategies
- Antiestrogens
- Antiprogestins
- Androgens
- Pharmacological manipulation of growth factors
- Gene therapy
Although the volume of the leiomyomata typically decreases by 35% (21), this is somewhat misleading. Physicians consider a reduction in the diameter to be the most clinically useful measure of shrinkage, and the diameter decreases much less than the total volume, as determined by mathematical calculations using measurements derived from imaging. Furthermore, hypogonadism cannot be sustained for a prolonged interval because of significant side effects such as vasomotor hot flashes, accelerated bone loss, genital tract atrophy, and loss of the cardiovascular benefits of estrogenization. Approximately 1% of bone mass is lost per month after the onset of hypoestrogenism, and hot flashes and genital tract atrophy can be very debilitating. Although most of the bone mass is regained if the therapy is limited to 6 months in young women, longer intervals of therapy or use in women closer to menopause may result in a permanent lowering of the age-adjusted bone mineral density. Unfortunately, leiomyomata rapidly return to pretreatment size upon discontinuance of GnRH-agonist therapy, and the symptoms parallel the enlargement. In an attempt to alleviate the severity of the hypogonadal symptoms, the simultaneous administration of low doses of estrogen and progestin with GnRH-agonists, the so-called add-back regimens, have been advocated (22). Although these regimens certainly relieve the hypoestrogenic symptoms associated with GnRH-agonist treatment, they are very expensive and have yet to be demonstrated to be as efficacious as GnRH-agonists alone. The add-back approach will require a substantial amount of long-term data before it can be considered a viable therapeutic option.
The important question to ask is "what is the goal of medical suppression?" The main indications for using a GnRH-agonist are to stop excessive vaginal bleeding and improve the hemogram prior to surgery, or to temporarily delay surgery in order to correct other medical problems posing an increasedsurgical risk. Although reduced surgical blood loss and shortened operative time by preoperative use of a GnRH-agonist are often espoused as benefits of such pretreatment, there are scant data to support this contention. Indeed, the softening of small intramural leiomyomata by the hypogonadism may make it impossible to palpate small leiomyomata during a myomectomy. Thus, small viable leiomyomas may not be detected during surgery and lead to an apparent "rapid recurrence," when in fact all the leiomyomata were not excised at myomectomy.
Myolysis
There have been many attempts at inducing necrosis of cells within leiomyomata e.g., myolysis, thereby shrinking the tumor and relieving the symptoms, or preventing progressive growth of the tumors (23). This is typically accomplished by repeatedly inserting a surgical probe into the tumor at a laparoscopy and destroying tissue by a) mono- or bipolar electrocautery; b) laser hyperthermia; c) fiber laser vaporization; or d) cryotherapeutic injury. All these techniques require a great deal of operative time and cause a variable amount of cellular injury, with necrosis of the leiomyoma and occasionally a portion of the uterus. The necrosis may cause significant pain in the posttreatment interval, comparable to that observed with degeneration of leiomyomata seen in pregnancy. None of these techniques have long-term data regarding efficacy, particularly with respect to the normalcy of subsequent pregnancy, complications, and persistence/recurrence rates. As a result of these concerns, myolysis should be considered experimental until these issues are clarified by long-term comparative clinical trials.
Uterine Artery Embolization
When excessive uterine bleeding is the primary problem and either the surgical risk is judged unacceptable or the patient declines surgery, therapeutic embolization of the uterine arteries has been advocated to deprive leiomyomata of blood supply (24). As the vascular pattern around individual leiomyomata varies widely and each tumor does not have a dominant vascular pedicle, bilateral embolization of the uterine arteries has been used as a means of depriving leiomyomata of vascular supply. A similar approach has been useful as a palliative measure in women with unremitting bleeding caused by an advanced cervical cancer eroding into the uterine vasculature. However, its safety and efficacy in women with leiomyomata remains to be demonstrated, particularly in women wishing retain fertility. This approach should be considered primarily for women in whom future reproduction is not desired and undertaken only to relieve symptoms. Similar to therapeutic myolysis, significant postprocedure pain can be encountered with uterine artery embolization and necrosis of leiomyomata, and the persistence/recurrence rates are not yet known.
When all of the palpable leiomyomata have been removed by myomectomy, the rate of recurrence has been variably reported as high as one-third of patients, depending on the number of tumors present and the length of follow-up (
6). It can be anticipated that greater recurrence rates will be noted with endoscopic procedures and myolysis, as it is difficult to identify all the tumors present at the time of treatment. Many small leiomyomata with the potential to enlarge will simply not be identified. Undoubtedly, the technical skill to remove all the identifiable leiomyomata is critically important and will influence the rate of apparent recurrence. The typical time frame for a clinically significant recurrence is 3-5 years. Those women with single, large leiomyomata appear to have lower recurrence rates than women with multiple intramural tumors (
25). Women should clearly understand that myomectomy, at best, provides an interval of symptoms with the opportunity to reproduce but does not definitively cure an inherited predisposition to the development of leiomyomata. No long-term data are available regarding the recurrence risks with destructive procedures or uterine artery embolization. When the recurrence data are available for the newer proposed treatments, clinical decision-making will need to incorporate these findings.
Leiomyomata represent the most common gynecologic tumors and can grow to impressive size, despite being almost invariably benign in the reproductive age group. They cause a variety of gynecologic symptoms and account for a substantial proportion of gynecologic surgery. The current therapeutic choices focus on extirpation, with hysterectomy most often used for definitive treatment, and myomectomy when preservation of childbearing is desired, albeit with a high recurrence risk. Medical therapies are not successful at preventing development of leiomyomata or reducing the morbidity. Until a better understanding of the factors involved in initiating and maintaining leiomyomata is achieved, the treatment will remain primarily surgical, with all the risks that surgery entails. Much remains to be learned about this most common of gynecologic tumors with respect to the molecular mechanisms of tumor growth and additional therapy options. Given the high prevalence of leiomyomata, this represents a unique opportunity to bring advances in molecular medicine to clinical care.
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Last Updated: October 3, 2000
