The prevalence of occult leiomyosarcoma in women undergoing presumed fibroid surgery and outcomes after morcellation.

PURPOSE OF REVIEW: To review the data-derived prevalence rates for occult leiomyosarcoma (LMS), and outcomes for women who have these tumors inadvertently morcellated. RECENT FINDINGS: In 2014, the Food and Drug Administration presented data showing the prevalence rates of occult LMS at 2.02/1000 surgeries for presumed benign fibroids. They also attributed poorer outcomes for women undergoing power morcellation of these tumors. Two more recent meta-analyses have shown much lower rates, as low as one in 8300 surgeries when including only prospective studies, and one in 1428 surgeries when including both prospective and retrospective studies. When looking at outcomes, both studies show no difference in outcomes when comparing power or any other type of morcellation. The most recent data suggest that even intact removal has no advantage when looking at mortality rates. SUMMARY: Prevalence of occult LMS remains quite rare, but outcomes after intact removal or any type of morcellation appear to be no different.

What is the Future of Open Intraperitoneal Power-Morcellation of Fibroids?

In November 2014, the Food and Drug Administration (FDA) calculated that for every 498 women having surgery for presumed fibroids, one woman would be found to have an occult leiomyosarcoma (LMS). The FDA issued a safety communication warning against the use of laparoscopic morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids. This communication was prompted by concern that if a patient had an occult LMS, the morcellator might spread tumor cells within the peritoneal cavity. We submit that the FDA directive was based on a flawed and misleading analysis. More rigorous evidence estimates the prevalence of LMS among women operated upon for presumed uterine fibroids at approximately one in 2000 women, significantly lower than the FDA's estimate. In addition, there is no reliable evidence that morcellation influences survival or that power-morcellation is inferior to vaginal or mini-lap morcellation with a scalpel. Recent publication shows that open surgery carries more risk for women when compared with minimally invasive surgery. Although the possibility of occult LMS should be considered by women and their gynecologists, we suggest that current morcellation techniques be continued for women who wish to benefit from minimally invasive surgery. Investigation into new and, hopefully, better morcellating devices may make the procedure safer for women.

Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: a systematic review.

There is concern that morcellation of occult leiomyosarcomas during surgery to treat presumed myomas may substantially worsen patient outcome. We reviewed the existing medical literature to better understand whether such a risk was demonstrable and, if so, what the magnitude of that risk might be. We identified 4864 articles initially, of which 60 were evaluated in full. Seventeen were found to have outcomes information and are included in this review. Six studies addressed the question of whether morcellation of occult leiomyosarcomas resulted in inferior outcomes as compared with en bloc uterine and tumor removal. In these 6 studies, results suggested that en bloc removal may result in improved survival and less recurrence; however, the data are highly biased and of poor quality. There is no reliable evidence that morcellation, power or otherwise, substantially results in tumor upstaging. There is no evidence from these 17 studies that power morcellation differs in any way from other types of morcellation or even simple myomectomy insofar as patient outcome. Whether electromechanical morcellation poses a unique danger to the patient with occult leiomyosarcoma is an unanswered question and one clearly in need of more extensive investigation before conclusions are drawn and policies created.

Intramural Leiomyomas and Fertility: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate fertility outcomes based on size and number of intramural leiomyomas and outcomes after removal. DATA SOURCES: Online searches: MEDLINE, ClinicalTrials.gov , PubMed, Cochrane Library, and PROSPERO Library from 1994 to 2023. METHODS OF STUDY SELECTION: A total of 5,143 studies were identified, with inclusion of 13 study groups. TABULATION, INTEGRATION AND RESULTS: Outcomes for size and number of leiomyomas were reported with clinical pregnancy rates and ongoing pregnancy or live-birth rates. In data sets with maximum leiomyoma diameters of less than 6 cm for study inclusion, women with leiomyomas smaller than 3 cm had lower clinical pregnancy rates than women without leiomyomas, with an odds ratio (OR) of 0.53 (95% CI, 0.38-0.76) and, for ongoing pregnancy or live-birth rates, an OR of 0.59 (95% CI, 0.41-0.86). The ORs for clinical pregnancy rates in women with intermediately-sized leiomyomas (those between 3 cm and 6 cm) were lower than in women without leiomyomas, with an OR at 0.43 (95% CI, 0.29-0.63) and, for ongoing pregnancy or live-birth rates, an OR at 0.38 (95% CI, 0.24-0.59). In data sets without exclusion for women with larger-sized leiomyomas, clinical pregnancy rates were lower for those with leiomyomas smaller than 5 cm compared with those without leiomyomas, with an OR of 0.75 (95% CI, 0.58-0.96). Women with leiomyomas larger than 5 cm showed no differences in clinical pregnancy rate compared with women without leiomyomas, with an OR of 0.71 (95% CI, 0.32-1.58). Although women with a single leiomyoma in any location had no differences in outcomes, those with more than one leiomyoma had lower clinical pregnancy rates and ongoing pregnancy or live-birth rates, with an OR of 0.62 (95% CI, 0.44-0.86) and 0.57 (95% CI, 0.36-0.88), respectively. The clinical pregnancy rate for women undergoing myomectomy for intramural leiomyomas was no different than those with intramural leiomyomas in situ, with an OR of 1.10 (95% CI, 0.77-1.59). CONCLUSION: Even small intramural leiomyomas are associated with lower fertility; removal does not confer benefit. Women with more than one leiomyoma in any location have reduced fertility.

Letrozole for ovulation induction and controlled ovarian hyperstimulation.

PURPOSE OF REVIEW: Letrozole, an aromatase inhibitor, is the newest addition to our armamentarium in the treatment of infertility. It is utilized in much the same way as clomiphene citrate, but with some additional benefits. In this review, the latest studies will be summarized with emphasis on dose, duration of use, safety, number of mature follicles, and pregnancy outcomes. RECENT FINDINGS: Letrozole has fewer side effects, and a shorter half-life than clomiphene citrate, and no demonstrable effect upon the receptivity of the endometrium. It is efficacious in treating women with chronic anovulation, unexplained infertility and diminished ovarian reserve. Its safety is superior to clomiphene citrate. Utilizing bio-equivalent doses, letrozole pregnancy rates are equal or superior to clomiphene citrate. Several studies suggest situations where it is more efficacious than gonadotropin treatment. SUMMARY: With further study, this drug could replace clomiphene citrate as the primary medication for chronic anovulation and/or unexplained infertility. It could augment or even obviate the use of gonadotropins in the treatment of women who have been unsuccessful in achieving pregnancy with clomiphene citrate. It may also be an adjunct for women with diminished ovarian reserve. Further studies are needed to determine optimal dosing and long term safety for women treated with the drug.

MR hysterosalpingography with an angiographic time-resolved 3D pulse sequence: assessment of tubal patency.

OBJECTIVE: The purpose of our study was to determine if tubal patency can be assessed by MR hysterosalpingography (HSG) using a clinically available MR angiographic sequence (3D time-resolved imaging of contrast kinetics [TRICKS]). This capability would enhance the value of MRI in women with infertility. CONCLUSION: MR HSG effectively shows tubal patency and can be considered when both conventional HSG and standard MRI are necessary for the evaluation of women with infertility, such as in women with suspected uterine anomalies or extrauterine disease.

Conservative surgical management of uterine myomas.

Uterine fibroids are a major gynecologic problem in American women, and several alternatives have been developed. Conservative treatment, with the goal of treating the fibroid but retaining the uterus, is a frequent choice among women who require therapy during their early to middle reproductive years. A variety of conservative surgical approaches exist; each has advantages and disadvantages for the clinician and the patient. Some are well-established techniques, whereas others are still in the investigational stage. None has been evaluated adequately for its effects on future fertility. To this end, it is imperative that investigators continue to evaluate these surgical procedures so that the clinician can provide accurate and comprehensive information when faced with a patient who desires one or more of these approaches. Furthermore, it is critical for the practitioner to stay informed about these procedures so that patients can be given a full complement of options.

U.S. Food and Drug Administration's Guidance Regarding Morcellation of Leiomyomas: Well-Intentioned, But Is It Harmful for Women?

The U.S. Food and Drug Administration (FDA) is warning against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for the treatment of leiomyomas because of the concern for inadvertent spread of tumor cells if an undiagnosed cancer were present. The authors, representing a 45-member review group, reviewed the current literature to formulate prevalence rates of leiomyosarcoma in women with presumed leiomyomas and to asses reliable data regarding patient survival after morcellation. The authors disagree with the FDA's methodology in reaching their conclusion and provide clinical recommendations for care of women with leiomyomas who are planning surgery.

Angiogenic effects of norplant contraception on endometrial histology and uterine bleeding.

Norplant, a sc contraceptive device, releases levonorgestrel in a sustained fashion. Its effectiveness is offset by irregular bleeding patterns. Because vascular endothelial growth factor (VEGF) is stimulated by synthetic progestogens in vitro and in vivo, we postulated that correlations between this angiogenic factor and uterine bleeding patterns might exist. Twenty-eight women who were exposed to Norplant and 13 control women were prospectively followed for 6-8 months. Bleeding diaries were collected, hysteroscopies were performed, endometrial biopsies were obtained for standardized histological evaluation, and VEGF histochemical immunostaining (H)-scores were assigned. Cluster determination-34 (CD34) staining was also performed to quantify the number of endometrial blood vessels per high-power field. Irregular uterine bleeding was common among women using Norplant devices. Endometrial VEGF H-scores were greater in women using Norplant than in control women. New findings of this study show that vessel density did not correlate with epithelial VEGF H-scores but was highly associated with the intensity of stromal and perivascular VEGF. VEGF expression in the latter regions correlated significantly with hysteroscopic abnormalities and irregular bleeding. The expression of this angiogenic protein, particularly in the stromal and perivascular compartments, correlated with microvascular density, hysteroscopically documented hypervascularity, and uterine bleeding profiles. Irregular bleeding with Norplant use appears to reflect paracrine-mediated effects on vascular function by angiogenic factors, such as VEGF.

Therapy for polycystic ovarian syndrome.

Polycystic ovarian syndrome is the most common endocrine disorder in women of reproductive age. Women with this disorder exhibit an array of disorders, including oligo-ovulation, hyperandrogenism, obesity, hyperlipidemia, infertility and insulin resistance. Of the sequelae that women experience, insulin resistance is associated with the most profound long-term morbidity. Initially, treatment regimens targeted specific symptomatology in these women, such as oligomenorrhea or hirsutism. With the discovery of the common association between insulin resistance and polycystic ovarian syndrome, however, we are able to utilize a new class of systemically targeted drugs that work on many of the symptoms found in these women.

The prevalence of occult leiomyosarcoma at surgery for presumed uterine fibroids: a meta-analysis.

There is a concern regarding the risk of occult leiomyosarcomas found at surgery for presumed benign fibroids. We sought to produce a comprehensive review of published data addressing this issue and provide high-quality prevalence estimates for clinical practice and future research. A comprehensive literature search using the PubMed/MEDLINE database and the Cochrane Library was performed. Inclusion criteria were human studies, peer-reviewed, with original data, involving cases for surgery in which fibroid-related indications were the primary reason for surgery, and histopathology was provided. Candidate studies (4864) were found; 3844 were excluded after review of the abstract. The remaining 1020 manuscripts were reviewed in their entirety, and 133 were included in the Bayesian binomial random effect meta-analysis. The estimated rate of leiomyosarcoma was 0.51 per 1000 procedures (95 % credible interval (CrI) 0.16-0.98) or approximately 1 in 2000. Restricting the meta-analysis to the 64 prospective studies resulted in a substantially lower estimate of 0.12 leiomyosarcomas per 1000 procedures (95 % CrI <0.01-0.75) or approximately 1 leiomyosarcoma per 8300 surgeries. Results suggest that the prevalence of occult leiomyosarcomas at surgery for presumed uterine fibroids is much less frequent than previously estimated. This rate should be incorporated into both clinical practice and future research.

PPAR-gamma decreases endometrial stromal cell transcription and translation of RANTES in vitro.

An important step in the monthly turnover of the endometrial lining during the menstrual cycle is the cyclical recruitment and activation of inflammatory cells. Regulated Upon Activation Normal T Cell Expressed and Secreted (RANTES) has been shown to mediate inflammatory cell chemotaxis. This study investigated the effect of PPAR-gamma ligands upon transcription and translation of RANTES in human endometrial stromal cells. First, the expression of endogenous PPAR-gamma was confirmed in endometrial stromal cells. The human RANTES promoter was searched to identify likely PPAR response elements (PPREs), in which three putative sites were found. The effect of PPAR-gamma ligands upon RANTES promoter activity and protein production was analyzed. In cells transfected with RANTES promoter vectors containing 958 bp and 3 PPREs, the addition of PPAR-gamma ligands inhibited promoter activity by 60% (P < 0.01) and 48% (P < 0.02), respectively. Truncation of the gene promoter to delete all putative PPREs abrogated the ligand-induced inhibition. Stromal cells showed a 40% decrease in RANTES protein secretion when treated with a PPAR-gamma ligand (P < 0.01). The use of PPAR-gamma ligands to reduce chemokine production and inflammation may be a productive strategy for future therapy of endometrial disorders, such as endometriosis.

An evidence-based evaluation of endometriosis-associated infertility.

Although endometriosis is associated with infertility, a clear causal relationship has yet to be established, unless adhesive disease is found. Despite this indirect association, multiple theories have been promulgated and studies are currently underway to investigate theoretic pathogenetic mechanisms. The data regarding the treatment of endometriosis-associated infertility are limited and conflicting; however, some general preliminary conclusions can be drawn. It seems that, with early-stage disease, surgical treatment increases pregnancy rates. Using the US Preventive Services Task Force classification scheme, the evidence in support of this finding is of the highest quality, or level I. Surgical treatment for moderate and severe disease also confers benefit, although the evidence in support of this treatment is of lesser quality, level II-3 by the scheme. Medical treatment, particularly if it induces an anovulatory state, has no benefit and may delay fertility. This evidence is again of the highest quality, with a classification of level I. Although assisted reproductive technologies are of benefit regarding fertility for women with endometriosis, the IVF evidence is inconclusive, with both treatments being evaluated by at least one randomized, controlled trial conferring a level I classification to the evidence. It is unclear at this time whether endometriomas have an impact on IVF outcome. The evidence consists of only a few lower-quality studies, with a classification level of II-2. Despite the haziness of current insight into the treatment of endometriosis-associated infertility, well-designed clinical trials and basic mechanistic investigations are underway in many reproductive medicine centers. As the data from these scientific inquiries emerge, clinicians will have a clearer view of effective treatment regimens for endometriosis.

The treatment of endometriosis: a review of the evidence.

The treatment of endometriosis focuses upon amelioration of two symptoms: pain and infertility. The treatment of endometriosis-associated pain has been well studied and all major medical therapies appear to be superior to placebo. In addition, none seems to be drastically better than another. Surgical therapy also appears to be efficacious, albeit with a relatively high rate of recurrence of symptoms following conservative surgical intervention. There are no trials comparing the relative value of medical versus surgical therapy. Combination surgery/medical therapy has several high-quality trials for evaluation, but its value remains unclear. The treatment of endometriosis-associated infertility presents a different picture: medical therapy has not been shown to be of any value and may prove detrimental to fertility. Surgical treatment does improve fertility, probably for all stages of disease. Assisted reproduction also seems to be efficacious, with both controlled ovarian hyperstimulation and intrauterine insemination as well as in vitro fertilization shown to be of benefit. Finally, the combination of in vitro fertilization and either medical or surgical therapy may be beneficial with advanced endometriosis, but further study is required.

Systematic review of mifepristone for the treatment of uterine leiomyomata.

OBJECTIVE: To systematically review the effect of mifepristone on uterine leiomyoma size and symptoms and to summarize its adverse effects. DATA SOURCES: A computerized search in MEDLINE, EMBASE, LILACS, and Cochrane databases from 1985 to 2002 and hand searches of conference proceedings from 1995 to 2002 were performed with the search terms "mifepristone" and "leiomyomata" and publication type "clinical trial." METHODS OF STUDY SELECTION: Titles and abstracts were reviewed by 2 authors; there were no areas of disagreement. Inclusion criteria were clinical trials of daily mifepristone for uterine leiomyomata that measured uterine or leiomyoma volume before and after treatment. TABULATION, INTEGRATION, AND RESULTS: Data from each article were abstracted by 2 reviewers. The search identified 6 before-and-after clinical trials involving a total of 166 women with symptomatic uterine leiomyomata. The subjects received 5 to 50 mg/d of mifepristone for 3 to 6 months. No study was placebo-controlled or blinded. Meta-analytic techniques were not performed due to variation in outcome and mifepristone dose. Daily treatment with all doses of mifepristone resulted in reductions in uterine and leiomyoma volumes ranging from 27% to 49% and 26% to 74%, respectively. Mifepristone treatment reduced the prevalence and severity of dysmenorrhea, menorrhagia, and pelvic pressure. Rates of amenorrhea ranged from 63% to 100%. Transient elevations in transaminases occurred in 4%. Endometrial hyperplasia was detected in 10 (28%) of 36 women screened by endometrial biopsy. CONCLUSION: Published trials of mifepristone showed reduction in leiomyoma size and improvement in symptoms. A notable adverse effect of mifepristone was development of endometrial hyperplasia.

Progestins activate vascular endothelial growth factor gene transcription in endometrial adenocarcinoma cells.

OBJECTIVE: To determine whether progestins activate vascular endothelial growth factor (VEGF) gene transcription in endometrial adenocarcinoma cells. DESIGN: In vitro study. SETTING: University reproductive biology laboratories. PATIENT(S): None. INTERVENTION(S): Ishikawa cells were transfected with VEGF promoter-luciferase reporter constructs and expression vectors encoding human progesterone receptors (hPR) A or B. The cells were treated with different progestins and antiprogestins, and luciferase activity was compared with controls. MAIN OUTCOME MEASURE(S): Three functional progesterone response elements (PREs) in the VEGF promoter were identified by electrophoretic mobility-shift assay, and different constructs were created to assess each PRE. RESULT(S): In cells expressing hPRA or B, treatment with 10 nM R5020 or 100 nM medroxyprogesterone acetate statistically significantly increased luciferase activity (3.3- to 4.8-fold). Pretreatment with 100 nM RU486 blunted the effect of 10 nM R5020, resulting only in a slight, statistically nonsignificant increase in luciferase activity (1.3- to 1.7-fold). Although three different functional PREs could be identified, no single PRE accounted for the preponderance of the luciferase activity. Full VEGF promoter activation required all three PREs. CONCLUSION(S): Progestins have a direct effect on VEGF gene transcription. However, hPR-mediated transcriptional regulation of the VEGF promoter is complex and cannot be localized to confined PRE sequences. Other response element motifs are likely to play a contributory role.