Response of xenografts of developing human female reproductive tracts to the synthetic estrogen, diethylstilbestrol.

Human female fetal reproductive tracts 9.5-22 weeks of gestation were grown for 1 month in ovariectomized athymic adult female mouse hosts that were either untreated or treated continuously with diethylstilbestrol (DES) via subcutaneous pellet. Normal morphogenesis and normal patterns of differentiation marker expression (KRT6, KRT7, KRT8, KRT10, KRT14, KRT19, ESR1, PGR, TP63, RUNX1, ISL1, HOXA11 and α-ACT2) were observed in xenografts grown in untreated hosts and mimicked observations of previously reported (Cunha et al., 2017) non-grafted specimens of comparable age. DES elicited several notable morphological affects: (a) induction of endometrial/cervical glands, (b) increased plication (folding) of tubal epithelium, (c) stratified squamous maturation of vaginal epithelium and (d) vaginal adenosis. DES also induced ESR1 in epithelia of the uterine corpus, cervix and globally induced PGR in most cells of the developing human female reproductive tract. Keratin expression (KRT6, KRT7, KRT8, KRT14 and KRT19) was minimally affected by DES. Simple columnar adenotic epithelium was devoid of TP63 and RUNX1, while DES-induced mature vaginal epithelium was positive for both transcription factors. Another striking effect of DES was observed in grafts of human uterine tube, in which DES perturbed smooth muscle patterning. These results define for the first time IHC protein markers of DES action on the developing human reproductive tract, which provide bio-endpoints of estrogen-induced teratogenesis in the developing human female reproductive tract for future testing of estrogenic endocrine disruptors

Reproductive tract biology: Of mice and men.

The study of male and female reproductive tract development requires expertise in two separate disciplines, developmental biology and endocrinology. For ease of experimentation and economy, the mouse has been used extensively as a model for human development and pathogenesis, and for the most part similarities in developmental processes and hormone action provide ample justification for the relevance of mouse models for human reproductive tract development. Indeed, there are many examples describing the phenotype of human genetic disorders that have a reasonably comparable phenotype in mice, attesting to the congruence between mouse and human development. However, anatomic, developmental and endocrinologic differences exist between mice and humans that (1) must be appreciated and (2) considered with caution when extrapolating information between all animal models and humans. It is critical that the investigator be aware of both the similarities and differences in organogenesis and hormone action within male and female reproductive tracts so as to focus on those features of mouse models with clear relevance to human development/pathology. This review, written by a team with extensive expertise in the anatomy, developmental biology and endocrinology of both mouse and human urogenital tracts, focusses upon the significant human/mouse differences, and when appropriate voices a cautionary note regarding extrapolation of mouse models for understanding development of human male and female reproductive tracts

Schistosomiasis and Vesicovaginal Fistula

Schistosoma haematobium is presented as a cause of vesicovaginal fistula in a nulliparous adolescent. The possible role of S. haematobium in failure of fistula repair and the importance of screening and treatment in endemic areas prior to repair are discussed (Afr J Reprod Health 2009; 13[3]:137-140)

An Innovative Interactive Modeling Tool to Analyze Scenario-Based Physician Workforce Supply and Demand

Effective physician workforce management requires that the various organizations comprising the House of Medicine be able to assess their current and future workforce supply. This information has direct relevance to funding of graduate medical education. We describe a dynamic modeling tool that examines how individual factors and practice variables can be used to measure and forecast the supply and demand for existing and new physician services. The system we describe, while built to analyze the pathologist workforce, is sufficiently broad and robust for use in any medical specialty. Our design provides a computer-based software model populated with data from surveys and best estimates by specialty experts about current and new activities in the scope of practice. The model describes the steps needed and data required for analysis of supply and demand. Our modeling tool allows educators and policy makers, in addition to physician specialty organizations, to assess how various factors may affect demand (and supply) of current and emerging services. Examples of factors evaluated include types of professional services (3 categories with 16 subcategories), service locations, elements related to the Patient Protection and Affordable Care Act, new technologies, aging population, and changing roles in capitated, value-based, and team-based systems of care. The model also helps identify where physicians in a given specialty will likely need to assume new roles, develop new expertise, and become more efficient in practice to accommodate new value-based payment models

Human uterine leiomyoma-derived fibroblasts stimulate uterine leiomyoma cell proliferation and collagen type I production, and activate RTKs and TGF beta receptor signaling in coculture

BACKGROUND: Uterine leiomyomas (fibroids) are benign smooth muscle tumors that often contain an excessive extracellular matrix (ECM). In the present study, we investigated the interactions between human uterine leiomyoma (UtLM) cells and uterine leiomyoma-derived fibroblasts (FB), and their importance in cell growth and ECM protein production using a coculture system. RESULTS: We found enhanced cell proliferation, and elevated levels of ECM collagen type I and insulin-like growth factor-binding protein-3 after coculturing. There was also increased secretion of vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor-2, and platelet derived growth factor A and B in the media of UtLM cells cocultured with FB. Protein arrays revealed increased phosphorylated receptor tyrosine kinases (RTKs) of the above growth factor ligands, and immunoblots showed elevated levels of the RTK downstream effector, phospho-mitogen activated protein kinase 44/42 in cocultured UtLM cells. There was also increased secretion of transforming growth factor-beta 1 and 3, and immunoprecipitated transforming growth factor-beta receptor I from cocultured UtLM cells showed elevated phosphoserine expression. The downstream effectors phospho-small mothers against decapentaplegic -2 and -3 protein (SMAD) levels were also increased in cocultured UtLM cells. However, none of the above effects were seen in normal myometrial cells cocultured with FB. The soluble factors released by tumor-derived fibroblasts and/or UtLM cells, and activation of the growth factor receptors and their pathways stimulated the proliferation of UtLM cells and enhanced the production of ECM proteins. CONCLUSIONS: These data support the importance of interactions between fibroid tumor cells and ECM fibroblasts in vivo, and the role of growth factors, and ECM proteins in the pathogenesis of uterine fibroids

Cervical Screening and General Physical Examination Behaviors of Women Exposed In Utero to Diethylstilbestrol

Objective. To estimate whether women exposed in utero to diethylstilbestrol (DES) report receiving more cervical and general physical examinations compared to unexposed women. Materials and Methods. 1994 Diethylstilbestrol Adenosis cohort data are used to assess the degree of recommended compliance of cervical screenings found in 3,140 DES-exposed and 826 unexposed women. Participants were enrolled at 4 sites: Houston, Boston, Rochester, and Los Angeles. Logistic regression modeling was used to analyze mailed questionnaire data, which included reported frequency over the preceding 5 years (1990-1994) of Papanicolaou smears and general physical examinations. Results. Diethylstilbestrol-exposed women exceeded the recommended frequency of Papanicolaou smear screenings [adjusted odds ratio (aOR) = 2.15, 95% CI (confidence interval) = 1.60-2.88] compared to the unexposed. This association held among those without a history of cervical intraepithelial neoplasia (aOR = 1.88, 95% CI = 1.35-2.62). Diethylstilbestrol-exposed women exceeded annual recommendations for physical examinations (aOR = 2.27, 95% CI = 1.16-4.43) among women without a history of chronic disease when compared to unexposed women. Conclusions. Most DES-exposed women are receiving cervical cancer screening at least at recommended intervals, but one third of the women are not receiving annual Papanicolaou smear examinations

Long-Term Effects of Neonatal Exposure to Hydroxylated Polychlorinated Biphenyls in the BALB/cCrgl Mouse

The neonatal mouse model has been a valuable tool in determining the long-term effects of early exposure to estrogenic agents in mammals. Using this model, we compared the effects of 2′,4′,6′-trichloro-4-biphenylol (OH-PCB-30) and 2′,3′,4′,5′-tetrachloro-4-biphenylol (OH-PCB-61) as prototype estrogenic hydroxylated PCBs (OH-PCBs) because they are reported to exhibit relatively high estrogenic activity both in vivo and in vitro. The purpose of this study was to examine the relationship between estrogenicity and carcinogenicity of OH-PCB congeners. The OH-PCBs were tested individually and in combination to determine whether effects of combined OH-PCBs differed from those of these OH-PCBs alone. We evaluated the long-term effects of neonatal exposure to OH-PCBs with treatment doses that were based on the reported binding affinity of specific OH-PCB congeners to estrogen receptor α. BALB/cCrgl female mice were treated within 16 hr after birth by subcutaneous injections every 24 hr, for 5 days. The mice treated with OH-PCB-30 (200 μg/day) or 17β-estradiol (5 μg/day) showed similar increased incidences of cervicovaginal (CV) tract carcinomas (43% and 47%, respectively). In addition, when mice were treated with OH-PCBs as a mixture, a change in the type of CV tract tumor was observed, shifting from predominantly squamous cell carcinomas to adenosquamous cell carcinoma. From our results, we conclude that the individual OH-PCBs tested were estrogenic and tumorigenic in mice when exposed during development of the reproductive tract. These data support the hypothesis that mixtures may act differently and unexpectedly than do individual compounds

The Natural History of Uterine Leiomyomas: Morphometric Concordance with Concepts of Interstitial Ischemia and Inanosis

Based upon our morphologic observations, we hypothesize and also provide morphometric evidence for the occurrence of progressive developmental changes in many uterine fibroids, which can be arbitrarily divided into 4 phases. These developmental phases are related to the ongoing production of extracellular collagenous matrix, which eventually exceeds the degree of angiogenesis, resulting in the progressive separation of myocytes from their blood supply and a condition of interstitial ischemia. The consequence of this process of slow ischemia with nutritional and oxygen deprivation is a progressive myocyte atrophy (or inanition), culminating in cell death, a process that we refer to as inanosis. The studies presented here provide quantitative and semiquantitative evidence to support the concept of the declining proliferative activity as the collagenous matrix increases and the microvascular density decreases