Cellular and extracellular vaginal changes following murine ovarian removal.

Loss of estrogen as a result of aging, pelvic cancer therapy, genetics, or eating disorders affects numerous body systems including the reproductive tract. Specifically, a chronic hypoestrogenic state fosters debilitating vaginal symptoms like atrophy, dryness, and dyspareunia. Current treatment options, including vaginal estrogen and hyaluronan (HA), anecdotally improve symptoms, but rectifying mechanisms are largely understudied. In order to study the hypoestrogenic vaginal environment, in particular the extracellular matrix (ECM), as well as understand the mechanisms behind current treatments and develop new therapies, we characterized a reliable and reproducible animal model. Bilateral ovariectomies (OVX) were performed on 9-week-old CD1 mice. After 1 month of estrogen loss due to ovarian removal, a phenotype that is similar to human vaginal tissue in an estrogen reduced state was noted in mice compared to sham-operated controls. The uterine to body weight ratio decreased by 80% and vaginal epithelium was significantly thinner in OVX compared to sham mice. Estrogen signaling was altered in OVX, but submucosal ERα localization did not reach statistical differences. HA localization in the submucosal area was altered and CD44 expression decreased in OVX mice. Collagen turn-over was altered following OVX. The inflammation profile was also disrupted, and submucosal vaginal CD45+ and F4/80+ cell populations were significantly reduced in the OVX mice. These results show altered cellular and molecular changes due to reduced estrogen levels. Developing new treatments for hypoestrogenic vaginal symptoms rely on better understanding of not only the cellular changes, but also the altered vaginal ECM environment. Further studies using this mouse model has the potential to advance women's vaginal health treatments and aid in understanding the interplay between organ systems in both healthy, aged, and diseased states.

Animal Models and Alternatives in Vaginal Research: a Comparative Review.

While developments in gynecologic health research continue advancing, relatively few groups specifically focus on vaginal tissue research for areas like wound healing, device development, and/or drug toxicity. Currently, there is no standardized animal or tissue model that mimics the full complexity of the human vagina. Certain practical factors such as appropriate size and anatomy, costs, and tissue environment vary across species and moreover fail to emulate all aspects of the human vagina. Thus, investigators are tasked with compromising specific properties of the vaginal environment as it relates to human physiology to suit their particular scientific question. Our review aims to facilitate the appropriate selection of a model aptly addressing a particular study by discussing pertinent vaginal characteristics of conventional animal and tissue models. In this review, we first cover common laboratory animals studied in vaginal research-mouse, rat, rabbit, minipig, and sheep-as well as human, with respect to the estrus cycle and related hormones, basic reproductive anatomy, the composition of vaginal layers, developmental epithelial origin, and microflora. In light of these relevant comparative metrics, we discuss potential selection criteria for choosing an appropriate animal vaginal model. Finally, we allude to the exciting prospects of increasing biomimicry for in vitro applications to provide a framework for investigators to model, interpret, and predict human vaginal health.

An Avant-Garde Model of Injury-Induced Regenerative Vaginal Wound Healing.

Objective: To design and validate a novel murine model of full-thickness (FT) vaginal wound healing that mirrors postinjury tissue repair and underscores the impact of estrogen signaling-driven healing kinetics, inflammation, and neovascularization. Approach: Five-week-old female CD1 mice were subjected to two 1-mm FT wounds. To assess wound healing kinetics, vaginas were harvested at 6, 12, 18, 24, 48, and 72 h and 7 days postinjury. Wounds from all time points were analyzed by hematoxylin and eosin and trichrome to, respectively, assess the rate of wound closure and tissue deposition. Inflammatory leukocyte (CD45), neutrophil (Ly6G), and macrophage (F480 and CD206) infiltration was examined by immunohistochemistry (IHC) and the resulting anti-inflammatory M2 (CD206)/total (F480) macrophage ratio quantified. Neovascularization (CD31) and estrogen receptor-α (ERα) expression levels were similarly determined by IHC. Results: We observed rapid healing with resolution of mucosal integrity by 48 h (p < 0.05), and overall neutrophils and polarized type 2 macrophages (M2) apexed at 12 h and reduced to near control levels by day 7 postinjury. Tissue repair was virtually indistinguishable from the surrounding vagina. CD31+ vessels increased between 12 h and day 7 and ERα trended to decrease at 12 h postinjury and rebound at day 7 to uninjured levels. Innovation: A proof-of-concept murine model to study vaginal wound healing kinetics and postinjury regenerative repair in the vagina was developed and verified. Conclusion: We surmise that murine vaginal mucosal repair is accelerated and potentially regulated by estrogen signaling through the ERα, thus providing a cellular and molecular foundation to understand vaginal healing responses to injury.

Emerging technologies in pediatric gynecology: new paradigms in women's health care.

PURPOSE OF REVIEW: The current review highlights the complexity of the pediatric and adolescent gynecology subspecialty as well as the recent and exciting opportunities for innovation within the field. RECENT FINDINGS: The opportunities for concept, treatment, instrument, and knowledge-transfer innovation to better serve the specific needs of pediatric gynecology patients include novel approaches to neovagina creation using magnets, improving postoperative vaginal wound healing through newly designed and degradable vaginal stents, and complex Mullerian reconstructive surgical planning using virtual reality immersive experiential training. SUMMARY: There is a significant window of opportunity to address the needs of pediatric, adolescent and adult gynecological patients with new innovative concepts and tools.

Noncytotoxic-Related Primary Ovarian Insufficiency in Adolescents: Multicenter Case Series and Review.

STUDY OBJECTIVE: Primary ovarian insufficiency (POI) in adolescents not due to cytotoxic therapy has not been well studied. Causes of POI have been described in adults, but adolescents might represent a unique subset necessitating a targeted approach to diagnosis, workup, and treatment. We sought to better characterize adolescent POI through a descriptive multicenter study. DESIGN: Case series of patients with POI. SETTING: Six tertiary care institutions. PARTICIPANTS: Patients presenting from 2007 to 2014 aged 13-21 years diagnosed with noncytotoxic POI, with exclusions for those who received gonadotoxic therapy, with 46XY gonadal dysgenesis, or lack of evidence of hypergonadotropic hypogonadism on chart review. INTERVENTIONS: Review and data extraction of records identified according to International Classification of Diseases Ninth or Tenth Revision codes. MAIN OUTCOME MEASURES: Data were analyzed for signs and symptoms, workup, and treatments. Complete workup was on the basis of American College of Obstetricians and Gynecologists guidelines. Characteristics of patients with POI who presented with delayed puberty/primary amenorrhea vs secondary amenorrhea were compared. RESULTS: One hundred thirty-five records were identified. Those who had received cytotoxic therapy (n = 52), 46XY gonadal dysgenesis (n = 7), or on review did not have POI (n = 19) were excluded. Of 57 remaining cases, 16 were 45X, 2 had galactosemia, and 4 had X-chromosome abnormalities. Most did not undergo full etiologic evaluation. Girls diagnosed after primary amenorrhea/delayed puberty were less symptomatic and more likely to receive an estrogen patch than those diagnosed after secondary amenorrhea. CONCLUSION: Noncytotoxic POI in adolescents is an uncommon condition with, to our knowledge, only 64 cases in 6 institutions over 7 years. These patients might not undergo complete etiological workup. Aside from 45X, the most common etiologies were X-chromosome abnormalities or galactosemia.