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The ovaries are the female gonads that are crucial for reproduction, steroid production, and overall health. Historically, the ovary was broadly divided into regions defined as the cortex, medulla, and hilum. This current nomenclature lacks specificity and fails to consider the significant anatomic variations in the ovary. Recent technological advances in imaging modalities and high-resolution omic analyses have brought about the need for revision of the existing definitions, which will facilitate the integration of generated data and enable the characterization of organ subanatomy and function at the cellular level. The creation of these high-resolution multimodal maps of the ovary will enhance collaboration and communication among disciplines and between clinicians and researchers. Beginning in March 2021, the Pediatric and Adolescent Gynecology Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development invited subject-matter experts to participate in a series of workshops and meetings to standardize ovarian nomenclature and define the organ's features. The goal was to develop a spatially defined and semantically consistent terminology of the ovary to support collaborative, team science-based endeavors aimed at generating reference atlases of the human ovary. The group recommended a standardized, 3-dimensional description of the ovary and an ontological approach to the subanatomy of the ovary and definition of follicles. This new greater precision in nomenclature and mapping will better reflect the ovary's heterogeneous composition and function, support the standardization of tissue collection, facilitate functional analyses, and enable clinical and research collaborations. The conceptualization process and outcomes of the effort, which spanned the better part of 2021 and early 2022, are introduced in this article. The institute and the workshop participants encourage researchers and clinicians to adopt the new systems in their everyday work to advance the overarching goal of improving human reproductive health., (Published by Elsevier Inc.)

Uterine leiomyomas or fibroids are the most common tumors of the female reproductive tract. Estrogen (E 2 ), a steroid-derived hormone, and its receptors (ERs), particularly ER-α, are important drivers for the development and growth of leiomyomas. We previously demonstrated that simvastatin, a drug used for hyperlipidemia, also possesses anti-leiomyoma properties. The aim of this work is to investigate the impact of simvastatin on ER-α signaling in leiomyoma cells, including its expression, downstream signaling, transcriptional activity, post-translational modification, trafficking and degradation. Primary and immortalized human uterine leiomyoma (HuLM) cells were used for in vitro experiments. Immunodeficient mice xenografted with human leiomyoma tissue explants were used for in vivo studies. Leiomyoma samples were obtained from patients enrolled in an ongoing double-blinded, phase II, randomized controlled trial. Here, we found that simvastatin significantly reduced E 2 -induced proliferation and PCNA expression. In addition, simvastatin reduced total ER-α expression in leiomyoma cells and altered its subcellular localization by inhibiting its trafficking to the plasma membrane and nucleus. Simvastatin also inhibited E 2 downstream signaling, including ERK and AKT pathways, E 2 /ER transcriptional activity and E 2 -responsive genes. To explain simvastatin effects on ER-α level and trafficking, we examined its effects on ER-α post-translational processing. We noticed that simvastatin reduced ER-α palmitoylation; a required modification for its stability, trafficking to plasma membrane, and signaling. We also observed an increase in ubiquitin-mediated ER-α degradation. Importantly, we found that the effects of simvastatin on ER-α expression were recapitulated in the xenograft leiomyoma mouse model and human tissues. Thus, our data suggest that simvastatin modulates several E 2 /ER signaling targets with potential implications in leiomyoma therapy and beyond., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Despite the high prevalence of uterine fibroids, the psychosocial impact of fibroids has not been evaluated across different quality of life indicators and compared with other chronic conditions. Here, we rigorously analyzed available evidence pertaining to the psychosocial burden of uterine fibroids in premenopausal women and compared validated quality of life and symptom scores before and after treatment., Data Sources: We searched PubMed, PsycINFO, ClinicalTrials.gov, Embase, and Cochrane Library for publications from January 1990 to January 2020., Study Eligibility Criteria: We considered English-language publications that evaluated the association between uterine fibroids diagnosed by imaging studies in premenopausal women and quality of life by standardized and validated questionnaires at baseline and after treatment. We used a detailed list of terms related to quality of life, questionnaires, and uterine fibroids to conduct the search., Methods: Three reviewers screened titles and abstracts and then obtained full-text articles for further analysis. The reviewers assessed risk of bias using established Cochrane and Newcastle-Ottawa Scale guidelines. The quality of life scores of premenopausal women with fibroids were reviewed at baseline and compared with those of published quality of life scores in other disease populations in addition to after fibroid treatment., Results: A total of 57 studies were included in the review: 18 randomized controlled trials and 39 observational studies. Of note, the 36-Item Short Form Survey and European Quality of Life Five-Dimension Scale questionnaires both indicated a diagnosis of uterine fibroids to have a disability score that was similar to or exceeded (was a greater psychosocial stressor) a diagnosis of heart disease, diabetes mellitus, or breast cancer. Quality of life scores were lower at baseline than after treatment in all instruments measuring these variables in women with uterine fibroids, indicating significantly impaired psychosocial functioning. Uterine fibroids were associated with significant patient-reported health disabilities related to bodily pain, mental health, social functioning, and satisfaction with sex life., Conclusion: A diagnosis of uterine fibroids was a significant psychosocial stressor among women at baseline and relative to other diseases. Validated quality of life instruments indicated therapeutic success and the improvement of both physical and emotional symptoms after treatment., (Copyright © 2020. Published by Elsevier Inc.)

Background: Uterine leiomyomas, the most common tumors of the female reproductive system, are characterized by excessive deposition of disordered stiff extracellular matrix and fundamental alteration in the mechanical signaling pathways. Specifically, these alterations affect the normal dynamic state of responsiveness to mechanical cues in the extracellular environment. These mechanical cues are converted through integrins, cell membrane receptors, to biochemical signals including cytoskeletal signaling pathways to maintain mechanical homeostasis. Leiomyoma cells overexpress β1 integrin and other downstream mechanical signaling proteins. We previously reported that simvastatin, an antihyperlipidemic drug, has antileiomyoma effects through cellular, animal model, and epidemiologic studies., Objective: This study aimed to examine the hypothesis that simvastatin might influence altered mechanotransduction in leiomyoma cells., Study Design: This is a laboratory-based experimental study. Primary leiomyoma cells were isolated from 5 patients who underwent hysterectomy at the Department of Gynecology and Obstetrics of the Johns Hopkins University Hospital. Primary and immortalized human uterine leiomyoma cells were treated with simvastatin at increasing concentrations (0.001, 0.01, 0.1, and 1 μM, or control) for 48 hours. Protein and mRNA levels of β1 integrin and extracellular matrix components involved in mechanical signaling were quantified by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. In addition, we examined the effect of simvastatin on the activity of Ras homolog family member A using pull-down assay and gel contraction., Results: We found that simvastatin significantly reduced the protein expression of β1 integrin by 44% and type I collagen by 60% compared with untreated leiomyoma cells. Simvastatin-treated cells reduced phosphorylation of focal adhesion kinase down to 26%-60% of control, whereas it increased total focal adhesion kinase protein expression. Using a Ras homolog family member A pull-down activation assay, we observed reduced levels of active Ras homolog family member A in simvastatin-treated cells by 45%-85% compared with control. Consistent with impaired Ras homolog family member A activation, simvastatin treatment reduced tumor gel contraction where gel area was 122%-153% larger than control. Furthermore, simvastatin treatment led to reduced levels of mechanical signaling proteins involved in β1 integrin downstream signaling, such as A-kinase anchor protein 13, Rho-associated protein kinase 1, myosin light-chain kinase, and cyclin D1., Conclusion: The results of this study suggest a possible therapeutic role of simvastatin in restoring the altered state of mechanotransduction signaling in leiomyoma. Collectively, these findings are aligned with previous epidemiologic studies and other reports and support the need for clinical trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Infertility is a common disease, which causes many couples to seek treatment with assisted reproduction techniques. Many factors contribute to successful assisted reproduction technique outcomes. One important factor is laboratory environment and air quality. Our facility had the unique opportunity to compare consecutively used, but separate assisted reproduction technique laboratories, as a result of a required move. Environmental conditions were improved by strategic engineering designs. All other aspects of the IVF laboratory, including equipment, physicians, embryologists, nursing staff and protocols, were kept constant between facilities. Air quality testing showed improved air quality at the new IVF site. Embryo implantation (32.4% versus 24.3%; P < 0.01) and live birth (39.3% versus 31.8%, P < 0.05) were significantly increased in the new facility compared with the old facility. More patients met clinical criteria and underwent mandatory single embryo transfer on day 5 leading to both a reduction in multiple gestation pregnancies and increased numbers of vitrified embryos per patient with supernumerary embryos available. Improvements in IVF laboratory conditions and air quality had profound positive effects on laboratory measures and patient outcomes. This study further strengthens the importance of the laboratory environment and air quality in the success of an IVF programme., (Published by Elsevier Ltd.)

Gonadotrophin-releasing hormone (GnRH) antagonist rescue is performed by replacing a GnRH agonist with a GnRH antagonist in patients with rapidly rising serum oestradiol who are at risk of ovarian hyperstimulation syndrome (OHSS) during stimulation. It results in a rapid reduction in serum oestradiol, allowing for the avoidance of cycle cancellation and the continuation of exogenous gonadotrophin administration. A total of 387 patients who underwent GnRH antagonist rescue for ovarian hyperresponse were compared with 271 patients who did not receive GnRH antagonist rescue and had oestradiol concentrations >4000 pg/ml on the day of human chorionic gonadotrophin (HCG) administration. GnRH antagonist rescue decreased the mean oestradiol concentration by 35% on the first day of use. There was no difference in oocyte maturity (82% versus 83%) or fertilization rate (69% versus 67%) between the antagonist rescue and comparison groups, respectively. The percentage of high-grade embryos on day 3 and the blastocyst development rate were also similar between groups. The live-birth rate was 41.9% in the antagonist rescue group and 36.9% in the comparison group. GnRH antagonist rescue enabled cycle completion with high live-birth rates in patients at risk for OHSS. GnRH antagonist was associated with high oocyte quality, blastocyst development and pregnancy. Gonadotrophin-releasing hormone (GnRH) antagonist rescue is a protocol to reduce the risk of ovarian hyperstimulation syndrome (OHSS) in assisted reproduction treatment. Patients who have a hyperresponse to medication during their treatment cycle have their GnRH agonist discontinued and a GnRH antagonist started in its place. This causes a rapid reduction in oestrogen concentrations and allows for the continuation of stimulation medication. We evaluated the effectiveness of this protocol by comparing patients who had GnRH antagonist rescue against high-responding patients who did not receive GnRH antagonist rescue. GnRH antagonist rescue resulted in a 35% reduction in oestrogen concentration and only a 1.5% cycle cancellation rate. There were no differences in oocyte maturity or fertilization between the two groups. There were no differences in the quality of day-3 and day-5 embryos between the two groups. The live birth rate was 41.9% in the antagonist rescue group and 36.9% in the comparison group. GnRH antagonist rescue reduced serum oestradiol concentrations and enabled cycle completion with high live-birth rates in patients at risk for OHSS. GnRH antagonist was associated with high oocyte quality, blastocyst development and pregnancy., (Published by Elsevier Ltd.)

Objective: The purpose of this study was to estimate the total annual societal cost of uterine fibroid tumors in the United States, based on direct and indirect costs that include associated obstetric complications., Study Design: A systematic review of the literature was conducted to estimate the number of women who seek treatment for symptomatic fibroid tumors annually, the costs of medical and surgical treatment, the amount of work time lost, and obstetric complications that are attributable to fibroid tumors. Total annual costs were converted to 2010 US dollars. A sensitivity analysis was performed., Results: The estimated annual direct costs (surgery, hospital admissions, outpatient visits, and medications) were $4.1-9.4 billion. Estimated lost work-hour costs ranged from $1.55-17.2 billion annually. Obstetric outcomes that were attributed to fibroid tumors resulted in a cost of $238 million to $7.76 billion annually. Uterine fibroid tumors were estimated to cost the United States $5.9-34.4 billion annually., Conclusion: Obstetric complications that are associated with fibroid tumors contributed significantly to their economic burden. Lost work-hour costs may account for the largest proportion of societal costs because of fibroid tumors., (Published by Mosby, Inc.)

Leiomyoma are common tumors arising within the uterus that feature excessive deposition of a stiff, disordered extracellular matrix (ECM). Mechanical stress is a critical determinant of excessive ECM deposition and increased mechanical stress has been shown to be involved in tumorigenesis. Here we tested the viscoelastic properties of leiomyoma and characterized dynamic and static mechanical signaling in leiomyoma cells using three approaches, including measurement of active RhoA. We found that the peak strain and pseudo-dynamic modulus of leiomyoma tissue was significantly increased relative to matched myometrium. In addition, leiomyoma cells demonstrated an attenuated response to applied cyclic uniaxial strain and to variation in substrate stiffness, relative to myometrial cells. However, on a flexible pronectin-coated silicone substrate, basal levels and lysophosphatidic acid-stimulated levels of activated RhoA were similar between leiomyoma and myometrial cells. In contrast, leiomyoma cells plated on a rigid polystyrene substrate had elevated levels of active RhoA, compared to myometrial cells. The results indicate that viscoelastic properties of the ECM of leiomyoma contribute significantly to the tumor's inherent stiffness and that leiomyoma cells have an attenuated sensitivity to mechanical cues. The findings suggest there may be a fundamental alteration in the communication between the external mechanical environment (extracellular forces) and reorganization of the actin cytoskeleton mediated by RhoA in leiomyoma cells. Additional research will be needed to elucidate the mechanism(s) responsible for the attenuated mechanical signaling in leiomyoma cells., (Published by Elsevier B.V.)

Objective: Uterine leiomyoma produce an extracellular matrix (ECM) that is abnormal in its volume, content, and structure. Alterations in ECM can modify mechanical stress on cells and lead to activation of Rho-dependent signaling and cell growth. Here we sought to determine whether the altered ECM that is produced by leiomyoma was accompanied by an altered state of mechanical homeostasis., Study Design: We measured the mechanical response of paired leiomyoma and myometrial samples and performed immunogold, confocal microscopy, and immunohistochemical analyses., Results: Leiomyoma were significantly stiffer than matched myometrium. The increased stiffness was accompanied by alteration of the ECM, cell shape, and cytoskeleton in leiomyoma, compared with myometrial samples from the same uterus. Levels of AKAP13, a protein that is known to activate Rho, were increased in leiomyoma compared to myometrium. AKAP13 was associated with cytoskeletal filaments of immortalized leiomyoma cells., Conclusion: Leiomyoma cells are exposed to increased mechanical loading and show structural and biochemical features that are consistent with the activation of solid-state signaling.

Microarray analysis has provided a novel means of identifying clues into the mechanisms of disease development. As a methodology, microarray analysis holds the promise for genome-wide screening in which 2 tissues (diseased and normal) are compared, and molecular pathways that defined the phenotype of the disease could be precisely defined. Alternatively, microarray experiments can be used to differentially compare pathologically similar diseased tissues to predict response to chemotherapy and risk of recurrence. However, the clinician should be aware that various sources of error can influence microarray analysis results. Sources of error can be minimized but not eliminated, explaining why meticulously conducted experiments in different laboratories or using different platforms result in different lists of genes. Confirmation and validation of genome-wide microarray results using ancillary methods remains a critical step. With proper confirmatory studies and cautious interpretation, microarray analysis represents a powerful tool for molecular discovery.

This article will discuss some recent insights based on our microarray studies that have emphasized the role the extracellular matrix, transforming growth factor beta, and collagen structure in fibroid formation. These studies led to appreciation of molecular similarities between fibroids and keloids. Collectively, these observations suggest a model of fibroid development based on an abnormal response to tissue repair, resulting in disordered healing and formation of an altered extracellular matrix.

Objective: The objective of this study was to examine the true-positive rates by level of training of the operator and to determine whether the accuracy of the procedure differed by the level of education after formalized training., Study Design: This was a retrospective analysis. The records of patients who underwent surgery for the indication of an abnormal saline sonohysterography were reviewed from January 2001 to April 2003 (n=73 patients). The nature of the saline sonohysterography abnormality, the intraoperative findings, and the level of training of the provider were recorded. Findings at saline sonohysterography were compared with findings at hysteroscopy or surgery. Statistical significance was determined by chi(2) test., Results: The overall true-positive rate was 86.3% (63/73 patients). The true-positive rates for nurse practitioners, second- and fourth-year residents, and fellows were 84%, 80%, 90%, and 89%, respectively. There was no significant difference among providers (P=.96)., Conclusion: The true-positive rates for saline hysterography were comparable among different provider levels.

In the post-Genome era, new concepts emerge about the growth regulation of uterine leiomyomata. Screening of leiomyoma and myometrial tissues with DNA arrays revealed numerous genes up-regulated in leiomyomata that were not known to be expressed in the human uterus. GluR2, a subunit of a ligand-gated cation channel, is up-regulated in leiomyomata relative to myometrium by 15- to 30-fold at the protein and mRNA level and is localized in endothelial cells. GluR2 pre-mRNA in leiomyoma and myometrial tissues is nearly 100% edited at the Q/R site, indicative of low Ca(2+) permeability of the ion channels. In spontaneous leiomyomata in women or leiomyomata induced in the guinea pig model, there is a likely synergism linking increased production of estradiol and all-trans retinoic acid with up-regulation of nuclear receptor PPARgamma and RXRalpha proteins to support tumor growth. GluR2 might be coupled to this synergism directly or via interleukin-17B, kinesin KIF5 or related genes also up-regulated in leiomyomata. GluR antagonists should be tested as inhibitors of leiomyoma growth.

Objective: We previously identified a protein, Brx, that interacted with estrogen receptor alpha. Sequence analysis determined that Brx is a novel member of the Dbl family of oncoproteins involved in signaling pathways that regulate cell growth. Because the Brx protein was found to be highly expressed in hormoneresponsive breast epithelium, the objective of this study was to determine whether Brx was expressed in both normal and neoplastic ovarian tissues., Study Design: A polyclonal antiserum directed against the Brx protein was used to perform immunolocalization on sections from 5 normal ovaries and 20 ovarian neoplasms. Chromosomal localization of the brx gene was accomplished by means of fluorescence in situ hybridization. Northern and Western blot analyses were performed on extracts prepared from human ovaries., Results: Brx protein was localized to the cytoplasm of granulosa cells from mature graafian follicles, the corpus luteum, and islands of hilar cells in normal ovaries. In tumors with low malignant potential and ovarian carcinomas the neoplastic epithelium stained strongly for Brx protein. Northern and Western blot analyses, respectively, confirmed expression of Brx messenger ribonucleic acid and protein in normal ovary. Finally, the brx gene was localized to 15q25., Conclusion: The proto-oncogene brx is expressed in specific normal human ovarian tissues and is also present in ovarian epithelial neoplasms.

The estrogen receptor (ER) is a ligand-dependent transcription factor which regulates growth, development, differentiation and reproduction. To test the hypothesis that the diverse effects of the ER could be mediated by interacting with other transcription factors/oncogenes, the present study assessed its interaction with the tumor suppressor p53. p53 is a transcription factor which is involved in cell cycle regulation and apoptosis. We found that the wild-type p53 physically interacted with ER in vivo and repressed the estrogen-activated transcriptional activity. However, p53 mutants had no or reduced repression effect, depending on the sites of mutation. These findings suggest that p53 can cross talk with the ER in hormone-activated signaling pathways in cells., (Copyright 1997 Academic Press.)