C.M. Owen

Imprinting Disorders and Assisted Reproductive Technology

Worldwide use of assisted reproductive technology (ART) accounts for an estimated 1 to 3% of births. Since 2002, a series of reports have suggested an increased risk of imprinting disorders (Beckwith-Wiedemann syndrome and Angelman syndrome) in children conceived by ART. Definitive conclusions are difficult to substantiate due to the rarity of imprinting disorders and the variability in ART protocols. Despite these limitations, there is biological plausibility for alteration in nongenomic inheritance caused by ART. Animal studies have shown that ART procedures can alter normal imprinting, specifically DNA methylation patterns. Collectively, studies suggest an association between ART and loss of maternal methylation. More recent reports examined a possible association between ART and global hypomethylation of DNA. Three other imprinting disorders (Silver-Russell syndrome, maternal hypomethylation syndrome, and retinoblastoma) have also been implicated, but there is insufficient evidence to establish an association of these syndromes with ART. Based on current evidence, the absolute risk of imprinting disorders after ART remains small and does not warrant routine screening. Large prospective studies are needed to better understand the risks associated with imprinting disorders, imprinting defects, and ART.

Characterization of tissue biomechanics and mechanical signaling in uterine leiomyoma.

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 tumors 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.

Clinical Management of Leiomyoma

Uterine leiomyoma, benign monoclonal tumors, afflict an estimated 60% of reproductive-aged women, with higher rates among African American women. Leiomyoma are associated with significant medical costs, impaired fertility potential, obstetric complications, and gynecologic morbidity. Currently, the effective clinical management of leiomyoma is limited by the fact that hysterectomy is the only cure. The purpose of this article is to provide the practitioner with a practical overview of the clinical management of this disease.

Biomechanics and mechanical signaling in the ovary: a systematic review

PurposeMammalian oogenesis and folliculogenesis share a dynamic connection that is critical for gamete development. For maintenance of quiescence or follicular activation, follicles must respond to soluble signals (growth factors and hormones) and physical stresses, including mechanical forces and osmotic shifts. Likewise, mechanical processes are involved in cortical tension and cell polarity in oocytes. Our objective was to examine the contribution and influence of biomechanical signaling in female mammalian gametogenesis.MethodsWe performed a systematic review to assess and summarize the effects of mechanical signaling and mechanotransduction in oocyte maturation and folliculogenesis and to explore possible clinical applications. The review identified 2568 publications of which 122 met the inclusion criteria.ResultsThe integration of mechanical and cell signaling pathways in gametogenesis is complex. Follicular activation or quiescence are influenced by mechanical signaling through the Hippo and Akt pathways involving the yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), phosphatase and tensin homolog deleted from chromosome 10 (PTEN) gene, the mammalian target of rapamycin (mTOR), and forkhead box O3 (FOXO3) gene.ConclusionsThere is overwhelming evidence that mechanical signaling plays a crucial role in development of the ovary, follicle, and oocyte throughout gametogenesis. Emerging data suggest the complexities of mechanotransduction and the biomechanics of oocytes and follicles are integral to understanding of primary ovarian insufficiency, ovarian aging, polycystic ovary syndrome, and applications of fertility preservation.