RANKL/RANK Pathway and Its Inhibitor RANK-Fc in Uterine Leiomyoma Growth.

Context: Uterine leiomyomas are the most common type of gynecologic tumor in women. Objective: To determine the role of the cytokine receptor activator of nuclear factor κ-Β ligand (RANKL); its receptor, receptor activator of nuclear factor κ-Β (RANK); and the RANKL/RANK pathway inhibitor RANK-Fc in leiomyoma growth. Design: Messenger RNA (mRNA) or protein levels of RANKL, RANK, and proliferation markers cyclin D1 and Ki67 were assessed in various leiomyoma tissues and cell populations. Human xenograft experiments were performed to determine the effects of RANK-Fc on leiomyoma growth in vivo. Setting: Research laboratory. Patients: Twenty-four regularly cycling premenopausal women (age 28 to 49 years) who were not receiving hormone therapy. Interventions: None. Main Outcome Measure: Tumor growth in a murine xenograft model following targeting of the RANKL/RANK pathway with RANK-Fc. Results: RANKL mRNA levels in leiomyoma were significantly higher than those in myometrial tissues. The highest RANK levels were found in the leiomyoma stem cell population, which is deficient in progesterone receptor (PR). Conversely, the highest RANKL levels were found in the PR-rich leiomyoma intermediate cell (LIC) population. R5020, a PR agonist, specifically increased RANKL expression in LICs. RANK-Fc blocked RANKL-induced expression of the proliferative gene cyclin D1. Treatment with RANK-Fc also significantly decreased tumor growth in vivo and diminished the expression of proliferation marker Ki67 in tumors (P < 0.01; n = 4). Conclusions: Treatment with the RANKL/RANK pathway inhibitor RANK-Fc significantly decreased human leiomyoma cell proliferation and tumor growth. This suggests that the RANKL/RANK pathway could serve as a potential target for the prevention and treatment of uterine leiomyoma.

Literature Review on the Role of Uterine Fibroids in Endometrial Function.

Uterine fibroids are benign uterine smooth muscle tumors that are present in up to 8 out of 10 women by the age of 50. Many of these women experience symptoms such as heavy and irregular menstrual bleeding, early pregnancy loss, and infertility. Traditionally believed to be inert masses, fibroids are now known to influence endometrial function at the molecular level. We present a comprehensive review of published studies on the effect of uterine fibroids on endometrial function. Our goal was to explore the current knowledge about how uterine fibroids interact with the endometrium and how these interactions influence clinical symptoms. Our review shows that submucosal fibroids produce a blunted decidualization response with decreased release of cytokines critical for implantation such as leukocyte inhibitory factor and cell adhesion molecules. Furthermore, fibroids alter the expression of genes relevant for implantation, such as bone morphogenetic protein receptor type II, glycodelin, among others. With regard to heavy menstrual bleeding, fibroids significantly alter the production of vasoconstrictors in the endometrium, leading to increased menstrual blood loss. Fibroids also increase the production of angiogenic factors such as basic fibroblast growth factor and reduce the production of coagulation factors resulting in heavy menses. Understanding the crosstalk between uterine fibroids and the endometrium will provide key insights into implantation and menstrual biology and drive the development of new and innovative therapeutic options for the management of symptoms in women with uterine fibroids.

Relationship between obesity and anti-Müllerian hormone in reproductive-aged African American women.

OBJECTIVE: To determine whether there is an association between obesity and anti-Müllerian hormone (AMH) among reproductive-aged African American women (AAW). METHODS: From the women participating in an ongoing National Institute of Environmental Health Sciences study, 1,654 AAW aged 23 to 35 were included in this study. Anthropometric measurements, personal health information, and serum AMH and adipokine levels were analyzed. RESULTS: The median body mass index (BMI) was 32.4 kg/m2 , and the median AMH was 3.18 ng/mL. Participants with obesity had AMH concentrations that were 23.7% lower than those with a BMI ≤25 kg/m2 (2.9 ng/mL vs. 3.8 ng/mL). In multivariable linear regression models, current BMI (ß = -0.015; 95% CI -0.021 to -0.009), BMI at age 18 (ß = -0.016; 95% CI -0.024 to -0.008), heaviest reported lifetime weight (ß = -0.002; 95% CI -0.003 to -0.001), and leptin (ß = -0.016; 95% CI -0.025 to -0.007) were inversely associated with AMH. There was no significant association between adiponectin and AMH. AMH was significantly lower (mean log = 0.91, SE = 0.11) in participants with obesity at age 18 and at enrollment when compared with those who were underweight or normal weight at age 18 but had obesity at enrollment (mean log = 1.16, SE = 0.12). CONCLUSIONS: In reproductive-aged AAW there is a significant association between obesity and AMH, suggesting that excess adiposity may compromise ovarian reserve. Effects of obesity on AMH may be cumulative.

Reproductive Outcomes After Hysteroscopic Resection of Retained Products of Conception.

STUDY OBJECTIVE: To characterize pregnancy outcomes after hysteroscopic resection of retained products of conception (RPOCs), especially as it relates to abnormal placentation. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Academic medical center. PATIENTS: All women who underwent hysteroscopic resection of RPOCs at Northwestern Prentice Women's Hospital between January 2004 and December 2014. INTERVENTIONS: Hysteroscopic resection of RPOCs. MEASUREMENTS AND MAIN RESULTS: The medical records of all cases of hysteroscopic resection of RPOCs between January 2004 and December 2014 were reviewed. Demographic characteristics, operative findings, surgical procedure, surgical pathology, and pregnancy outcomes for preceding and subsequent pregnancies were obtained. Our primary outcome was abnormal placentation in the pregnancy after the procedure. There were a total of 55 subsequent pregnancies and 38 live births. Among these pregnancies, 54.5% (30/55) were vaginal deliveries, 34.5% (19/55) were cesarean deliveries, and 7.3% (4/55) were early pregnancy losses. Abnormal placentation was present in 18.1% of subsequent pregnancies (10/55). This consisted of 3 patients with placenta previa, 2 with placenta accreta, and 5 with retained placenta. CONCLUSION: Women who undergo hysteroscopic resection of RPOCs have a higher rate of abnormal placentation in subsequent pregnancies when compared with the general population. Although the etiology is likely multifactorial, the underlying pathology leading to the initial diagnosis of RPOCs is believed to play a major role.

Feasibility of Washings at the Time of Laparoscopic Power Morcellation: A Pilot Study.

STUDY OBJECTIVE: To determine the feasibility and role of abdominopelvic washings at the time of laparoscopic power morcellation and to determine if endometrial or myometrial tissue will be detected before and after laparoscopic power morcellation. DESIGN: A prospective pilot study (Canadian Task Force classification II-3). SETTING: An academic medical center. PATIENTS: All women who underwent laparoscopic myomectomy by a single provider at Northwestern Prentice Women's Hospital between August 2014 and October 2015. INTERVENTIONS: Abdominopelvic washings were performed before and after laparoscopic power morcellation in a specimen bag. Washings were evaluated for the presence of intra-abdominal endometrial or myometrial tissue using cell block and cytospin techniques. MEASUREMENTS AND MAIN RESULTS: A total of 13 cases were performed. Eleven subjects underwent multiport laparoscopy, and 2 underwent laparoendoscopic single-site surgery. Morcellation was performed within a 15 mm Tissue Retrieval System 100SB2 (Anchor Products, Addison, IL). Two sets of abdominopelvic washings were performed after completion of myomectomy: one before morcellation and the second after morcellation. As a control, washings of the inside of the empty specimen bag were performed after completion of morcellation in 1 patient. The operative outcomes analyzed included a median specimen weight of 313 g (range, 43-940 g), a median operative time in minutes of 161 minutes (range, 94-243 minutes), and a median estimated blood loss of 200 mL (range, 100-700 mL). There was no visual or cytologic evidence of intra-abdominal dissemination of uterine tissue before or after enclosed morcellation on evaluation by cytospin or cell block techniques. Only the washings from the inside of the specimen bag were found to have myometrial tissue on evaluation using the cell block technique. CONCLUSION: Performing abdominopelvic washings at the time of laparoscopic power morcellation is a feasible method by which to evaluate and document the presence or absence of microscopic dissemination, with comparable operative parameters to what is already reported in the literature. When abdominopelvic washings are used as an intermediate outcome measure, enclosed bag morcellation appears to minimize tissue dissemination during laparoscopic power morcellation; however, additional and larger studies are needed.