CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial.

OBJECTIVE: To evaluate whether 3-month administration of CDB-2914, a selective progesterone receptor modulator, reduces leiomyoma size and symptoms. METHODS: Premenopausal women with symptomatic uterine leiomyomata were randomly assigned to CDB-2914 at 10 mg (T1) or 20 mg (T2) daily or to placebo (PLC) for 3 cycles or 90-102 days if no menses occurred. The primary outcome was leiomyoma volume change determined by magnetic resonance imaging at study entry and within 2 weeks of hysterectomy. Secondary outcomes included the proportion of amenorrhea, change in hemoglobin and hematocrit, ovulation inhibition, and quality-of-life assessment. RESULTS: Twenty-two patients were allocated, and 18 completed the trial. Age and body mass index were similar among groups. Leiomyoma volume was significantly reduced with CDB-2914 administration (PLC 6%; CDB-2914 -29%; P=.01), decreasing 36% and 21% in the T1 and T2 groups, respectively. During treatment, hemoglobin was unchanged, and the median estradiol was greater than 50 pg/mL in all groups. CDB-2914 eliminated menstrual bleeding and inhibited ovulation (% ovulatory cycles: CDB-2914, 20%; PLC, 83%; P=.001). CDB-2914 improved the concern scores of the uterine leiomyoma symptom quality-of-life subscale (P=.04). One CDB-2914 woman developed endometrial cystic hyperplasia without evidence of atypia. No serious adverse events were reported. CONCLUSION: Compared with PLC, CDB-2914 significantly reduced leiomyoma volume after three cycles, or 90-102 days. CDB-2914 treatment resulted in improvements in the concern subscale of the Uterine Fibroid Symptom Quality of Life assessment. In this small study, CDB-2914 was well-tolerated without serious adverse events. Thus, there may be a role for CDB-2914 in the treatment of leiomyomata. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,www.clinicaltrials.gov, NCT00290251 LEVEL OF EVIDENCE: I.

A suboptimal endometrial pattern is associated with a reduced likelihood of pregnancy after a day 5 embryo transfer.

This retrospective study examined the association of endometrial pattern and pregnancy after a day 5 ET. The pregnancy rate of women with a triple-line ultrasound endometrial pattern on the day of hCG administration was significantly higher than the pregnancy rate of women with the other ultrasound patterns. This observation suggests that, in a subset of patients, a suboptimal endometrial lining may interfere with assisted reproductive technology success.

CD10 immunohistochemical staining enhances the histological detection of endometriosis.

OBJECTIVE: To determine whether the use of CD10 immunohistochemistry in addition to hematoxylin and eosin (H&E) staining would increase the sensitivity of surgically suspected endometriosis lesions. DESIGN: Retrospective cohort study. SETTING: Tertiary care government research hospital. PATIENT(S): Thirty-one women with chronic pelvic pain. INTERVENTION(S): Immunohistochemical analysis for CD10 was performed on 108 possible endometriotic lesions and in the corresponding endometrial biopsy samples obtained during laparoscopy. When CD10 immunohistochemistry results were positive, the corresponding H&E section was reviewed to determine if the initial diagnosis should be revised. MAIN OUTCOME MEASURE(S): Histologic diagnosis of endometriosis by adjunctive use of CD10 immunohistochemistry in conjunction with H&E-stained specimens. RESULT(S): In endometrial stroma, CD10 was consistently present. Of the 70 specimens judged negative initially by H&E staining, CD10 staining led to the diagnosis of endometriosis in 11. The addition of CD10 immunohistochemistry detected more positive endometriosis lesions than H&E staining alone (45% vs. 35%). In three women with minimal endometriosis at surgery but initially negative histopathology, CD10 immunohistochemistry changed the histologic diagnosis to endometriosis. CONCLUSION(S): The adjunctive use of CD10 immunohistochemistry improves diagnostic sensitivity for endometriosis, especially for women with minimal disease.

Urine vascular endothelial growth factor-A is not a useful marker for endometriosis.

OBJECTIVE: To determine whether urine VEGF is elevated in women with endometriosis. DESIGN: Prospective observational study. SETTING: Tertiary care government and private hospitals. PATIENT(S): During laparoscopy for pelvic pain or infertility, urine was collected and possible endometriosis lesions were excised. Of 62 women, 40 had histology-proven endometriosis and 22 had no histological proof of the disease. INTERVENTION: None. MAIN OUTCOME MEASURE(S): Urine VEGF-A(121, 165) was measured and compared in women with and without biopsy-proven endometriosis. RESULT(S): Urine VEGF levels corrected for creatinine excretion were similar in women with (83.6 +/- 11.3 pg/mg Cr) and without (88.5 +/- 10.4 pg/mg Cr) endometriosis (P =.77). The frequency distribution of urine VEGF measurements for women with and without endometriosis was similar. No significant difference was noted in urine VEGF levels when comparing endometriosis stages or in those with endometriomas compared to controls. Urine VEGF did not vary significantly over the menstrual cycle or between groups by cycle phase. No cutoff point discriminated individuals with and without the condition. CONCLUSION(S): It is unlikely that urine VEGF-A(121, 165), as measured in this study, will be a useful non-invasive marker for endometriosis.

Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids.

Uterine leiomyomas are prevalent estrogen-responsive clonal tumors, but the specific genetic alterations that contribute to their development have not been elucidated. To identify genes involved in the formation of leiomyomas, we used global expression profiling to compare clonal tumors with normal myometrium. Contrary to expectation, genes involved in estrogen action were not differentially expressed between leiomyoma and normal myometrium. Genes encoding extracellular-matrix proteins were prominently featured, suggesting their involvement in formation of a myofibroblast phenotype. Analysis of the extracellular matrix in the leiomyomas revealed a disordered collagen fibril orientation. Expression of the collagen-binding protein dermatopontin was found to be consistently decreased in leiomyoma by both reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR (mean underexpression = 9.41-fold) regardless of leiomyoma size, leiomyoma location, patient race, and patient age. This expression pattern was observed in 11 subjects and a total of 23 leiomyoma:myometrium pairs. Decreased expression of dermatopontin was also associated with keloid formation, a fibrotic disease that shares epidemiologic similarities with leiomyoma. Immunohistochemical studies of leiomyomas and keloids demonstrated reduced levels of dermatopontin in both tissues. In addition, ultrastructural analysis revealed that the orientation of the collagen fibrils in the keloid tissues strongly resembled that in the leiomyomas. Reduction in dermatopontin was associated with an increase in transforming growth factor-beta3 (TGFB3) mRNA levels in leiomyomas, whereas other genes involved in dermatopontin signaling were not differentially expressed. These findings suggest that leiomyoma development involves a myofibroblast cell phenotype characterized by dysregulation of genes encoding extracellular-matrix proteins. In particular, decreased expression of dermatopontin represents a molecular link between the leiomyoma and keloid phenotypes.

Gene expression studies in leiomyomata: new directions for research.

Uterine leiomyomata (fibroids) are a leading women's health problem, resulting in significant morbidity and surgical intervention. As benign clonal tumors, leiomyomata also represent a target well suited to molecular analysis. Familial studies and genetic syndromes featuring leiomyomata provide compelling evidence that genetic alterations may cause fibroid development, but the specific genes involved in leiomyoma development have not been identified. Microarrays permit simultaneous comparison of the relative expression of thousands of genes, thereby highlighting specific genes that may play a role in the development of leiomyomata. Microarray studies conducted by several laboratories have identified candidate genes. However, few gene products have been confirmed with alternative experimental approaches. The objective of this article is to focus on the insights provided by microarray studies investigating leiomyoma development. Such studies suggest that although hormonal control of leiomyoma growth is observed, there are other critical pathways involved in development of the leiomyoma cell phenotype that warrant investigation. In particular, expression of extracellular matrix genes in leiomyomata is deranged and such genes represent potential novel targets for therapy.

Simple ovarian cysts in postmenopausal patients with breast carcinoma treated with tamoxifen: long-term follow-up.

PURPOSE: To assess the long-term natural history of simple ovarian cysts diagnosed in postmenopausal patients with breast carcinoma treated with tamoxifen citrate. MATERIALS AND METHODS: Of 332 postmenopausal women with breast cancer who were treated with tamoxifen, 32 (9.6%) had simple ovarian cysts. Long-term follow-up transvaginal ultrasonography (US) was performed in patients who had these simple ovarian cysts, and serum CA 125 samples were taken. Standard linear regression analysis with repeated measurements with irregular time points with the mixed-effects model was used to correlate cyst size at transvaginal US with the time elapsed since the diagnosis of ovarian cysts. Statistical analysis was performed by using the t test for regression slope. RESULTS: There was a significant decrease in cyst size over time (P =.017). Three (9%) of the 32 patients underwent surgery. Histologic evaluation of the removed ovaries revealed simple ovarian cyst, well-differentiated ovarian carcinoma, and metastatic adenocarcinoma. The remaining 29 (91%) continued with regular follow-up examinations only. In 11 (34%) of the 32 patients there were no changes in cyst size over time. In nine patients (28%) additional cysts appeared. Cysts disappeared, increased in size, disappeared and reappeared, or decreased in size in four (12%) patients each. Serum CA 125 levels were within the normal range. CONCLUSION: In postmenopausal patients with breast carcinoma who were treated with tamoxifen, long-term follow-up US of simple ovarian cysts demonstrates a significant decrease in cyst size over time.