Cancer treatments can damage the ovaries, causing primary ovarian insufficiency (POI), a condition associated with numerous sequelae that impact long-term quality of life. This article systematically reviews the literature on the prevalence, surveillance, and treatment of POI in survivors of pediatric and adolescent and young adult (AYA) cancers. A systematic review of the literature was conducted in January 2018 through a search of Medline, Embase, Web of Science, and SCOPUS, alongside the screening of relevant reference lists. An initial search identified 746 potentially relevant studies. A total of 36 studies were included in the final review. Studies were categorized into one of the following categories: incidence/prevalence of POI, measurement of ovarian reserve, and other. Depending on patient characteristics, cancer diagnosis, and treatment, the prevalence of POI ranged from 2.1% to 82.2%. Risk factors for POI included exposure to alkylating agents and abdominal/pelvic radiation. POI may be associated with a number of complications, including low bone mineral density and poor cardiovascular health. Radiotherapy and chemotherapy are known to cause gonadal damage in female survivors of pediatric and AYA cancers. Acute or chronic effects depend on the dose of treatment, age of the individual, radiotherapy field, and ovarian reserve of the individual. Some women experience short-term loss of reproductive function and then may resume menstrual cycles, months or even years later. Although protecting fertility through banking of mature eggs, embryos, and tissue samples has become standard of care, additional steps need to be taken to ensure that patients have adequate hormone levels to maintain whole-body health, including life expectancy, bone health, cardiovascular health, quality of life, sexual and genitourinary function, and neurologic function. Surveillance and management of each of these comorbidities is critically important to survivor health.

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Extracellular vesicles (EVs) are nanometer-scale particles that are secreted by cells and mediate intercellular communication by transferring biomolecules between cells. Harnessing this mechanism for therapeutic biomolecule delivery represents a promising frontier for regenerative medicine and other clinical applications. One challenge to realizing this goal is that to date, our understanding of which factors affect EV uptake by recipient cells remains incomplete. In this study, we systematically investigated such delivery questions in the context of breast cancer cells, which are one of the most well-studied cell types with respect to EV delivery and therefore comprise a facile model system for this investigation. By displaying various targeting peptides on the EV surface, we observed that although displaying GE11 on EVs modestly increased uptake by MCF-7 cells, neuropeptide Y (NPY) display had no effect on uptake by the same cells. In contrast, neurotensin (NTS) and urokinase plasminogen activator (uPA) display reduced EV uptake by MDA-MB-231 cells. Interestingly, EV uptake rate did not depend on the source of the EVs; breast cancer cells demonstrated no increase in uptake on administration of breast cancer-derived EVs in comparison to HEK293FT-derived EVs. Moreover, EV uptake was greatly enhanced by delivery in the presence of polybrene and spinoculation, suggesting that maximal EV uptake rates are much greater than those observed under basal conditions in cell culture. By investigating how the cell's environment might provide cues that impact EV uptake, we also observed that culturing cells on soft matrices significantly enhanced EV uptake, compared to culturing on stiff tissue culture polystyrene. Each of these observations provides insights into the factors impacting EV uptake by breast cancer cells, while also providing a basis of comparison for systematically evaluating and perhaps enhancing EV uptake by various cell types.

The fallopian tube epithelium is the site of origin for a majority of high grade serous ovarian carcinomas (HGSOC). The chemical communication between the fallopian tube and the ovary in the development of HGSOC from the fallopian tube is of interest since the fimbriated ends in proximity of the ovary harbor serous tubal intraepithelial carcinoma (STICs). Epidemiological data indicates that androgens play a role in ovarian carcinogenesis; however, the oncogenic impact of androgen exposure on the fallopian tube, or tubal neoplastic precursor lesions, has yet to be explored. In this report, imaging mass spectrometry identified that testosterone is produced by the ovary when exposed to tumorigenic fallopian tube derived PTEN deficient cells. Androgen exposure increased cellular viability, proliferation, and invasion of murine cell models of healthy fallopian tube epithelium and PAX2 deficient models of the preneoplastic secretory cell outgrowths (SCOUTs). Proliferation and invasion induced by androgen was reversed by co-treatment with androgen receptor (AR) antagonist, bicalutamide. Furthermore, ablation of phosphorylated ERK reversed proliferation, but not invasion. Investigation of two hyperandrogenic rodent models of polycystic ovarian syndrome revealed that peripheral administration of androgens does not induce fallopian proliferation in vivo. These data suggest that tumorigenic lesions in the fallopian tube may induce an androgenic microenvironment proximal to the ovary, which may in turn promote proliferation of the fallopian tube epithelium and preneoplastic lesions.

The physical properties of the ovarian extracellular matrix (ECM) regulate the function of ovarian cells, specifically the ability of the ovary to maintain a quiescent primordial follicle pool while allowing a subset of follicles to grow and mature in the estrous cycle. Design of a long-term, cycling artificial ovary has been hindered by the limited information regarding the mechanical properties of the ovary. In particular, differences in the mechanical properties of the two ovarian compartments, the cortex and medulla, have never been quantified. Shear wave (SW) ultrasound elastography is an imaging modality that enables assessment of material properties, such as the mechanical properties, based on the velocity of SWs, and visualization of internal anatomy, when coupled with B-mode ultrasound. We used SW ultrasound elastography to assess whole, ex vivo bovine ovaries. We demonstrated, for the first time, a difference in mechanical properties, as inferred from SW velocity, between the cortex and medulla, as measured along the length (cortex: 2.57-0.53 m/s, medulla: 2.87-0.77 m/s, p < 0.0001) and width (cortex: 2.99-0.81 m/s, medulla: 3.24-0.97 m/s, p < 0.05) and that the spatial distribution and magnitude of SW velocity vary between these two anatomical planes. This work contributes to a larger body of literature assessing the mechanical properties of the ovary and related cells and specialized ECMs and will enable the rational design of biomimetic tissue engineered models and durable bioprostheses. Impact Statement Shear wave (SW) ultrasound elastography can be used to simultaneously assess the material properties and tissue structures when accompanied with B-mode ultrasound. We report a quantitative difference in mechanical properties, as inferred from SW velocity, between the cortex and medulla, with SW velocity being 11.4% and 8.4% higher in the medulla than the cortex when measured along the length and width, respectively. This investigation into the spatial and temporal variation in SW velocity in bovine ovaries will encourage and improve design of more biomimetic scaffolds for ovarian tissue engineering.

IntroductionLesbian, gay, bisexual, and transgender (LGBT) students face challenges in achieving their educational goals. By understanding concepts surrounding sexual orientation and gender identity, faculty, staff, and students can support LGBT community members and provide a safe educational space. In order to address this we created a condensed training resource that focused on skill building and is easily implemented institution-wide for students, residents, fellows, faculty, and staff.MethodsThis module serves as an introduction to concepts integral to the LGBT community. It is structured into two sections and takes approximately 30 minutes to complete, including pre-/postevaluations. The first section of the module focuses on presenting basic information about the LGBT world experience and basic terminology. The second section contains two real-world scenarios aimed at demonstrating skills used to create a safe educational learning space. Each scenario contains interactive questions that allow participants to practice applying their new skills.ResultsTo date, 89 institutional community members at the Northwestern University Feinberg School of Medicine have completed the module. Survey results demonstrate that the module was well-received and effective at improving attitudes towards creating a safe space.DiscussionWhile this module provides a foundation in terminology and phenomena relevant to the LGBT experience, it is just one part of creating a positive institutional climate for LGBT community members. Additional in-person skills-based training should also be considered to complement and enhance this module's contents.

Prior work has demonstrated that murine ovarian explants and isolated ovarian follicles can recapitulate human-like 28-day cycles in vitro with normal patterns of estradiol and progesterone secretion in response to gonadotropin stimulation. The objective of this study was to manipulate the gonadotropin stimulation protocol to mimic polycystic ovary syndrome (PCOS) and assess the resulting changes in ovarian steroidogenesis. A secondary aim of the study was to develop a high-throughput, sensitive, and specific liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay to measure seven steroid hormones (estrone, estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone, and dihydrotestosterone) in conditioned culture media. Ovaries were harvested from 12-day-old CD-1 mice and cultured for 28 days, with ovulation induction on culture day 14. Media were supplemented human chorionic gonadotropin (hCG, a luteinizing hormone analog) and follicle stimulating hormone (FSH) at ratios of 1:0 (standard media), 1:1 (physiologic ratio), and 3:1 (PCOS-like ratio). Ovaries cultured in PCOS-like media displayed hyperandrogenism and impaired ovulation, two key features of a PCOS-like phenotype. Taken together, this first-of-its-kind presentation of hormone levels from single tissues creates a map of the enzymatic steps most acutely affected by gonadotropin dysregulation and may provide opportunities for assessing other potential insults in PCOS pathogenesis.