Human Endometrial Fibroblasts Derived from Mesenchymal Progenitors Inherit Progesterone Resistance and Acquire an Inflammatory Phenotype in the Endometrial Niche in Endometriosis.

Human endometrium undergoes cyclic regeneration involving stem/progenitor cells, but the role of resident endometrial mesenchymal stem cells (eMSC) as progenitors of endometrial stromal fibroblasts (eSF) has not been definitively demonstrated. In endometriosis, eSF display progesterone (P4) resistance with impaired decidualization in vivo and in vitro. To investigate eMSC as precursors of eSF and whether endometriosis P4 resistance is inherited from eMSC, we analyzed transcriptomes of eutopic endometrium eMSC and eSF isolated by fluorescence-activated cell sorting (FACS) from endometriosis (eMSCendo, eSFendo) and controls (eMSCcontrol, eSFcontrol) and their derived primary cultures. Differentially expressed lineage-associated genes (LG) of FACS-isolated eMSC and eSF were largely conserved in endometriosis. In culture, eSFcontrol maintained in vitro expression of a subset of eSF LG and decidualized in vitro with P4 The eMSCcontrol cultures differentiated in vitro to eSF lineage, down-regulating eMSC LG and up-regulating eSF LG, showing minimal transcriptome differences versus eSFcontrol cultures and decidualizing in vitro. Cultured eSFendo displayed less in vitro LG stability and did not decidualize in vitro. In vitro, eMSCendo differentiated to eSF lineage but showed more differentially expressed genes versus eSFendo cultures, and did not decidualize in vitro, demonstrating P4 resistance inherited from eMSCendo Compared to controls, cultures from tissue-derived eSFendo uniquely had a pro-inflammatory phenotype not present in eMSCendo differentiated to eSF in vitro, suggesting divergent niche effects for in vivo versus in vitro lineage differentiation. These findings substantiate eMSC as progenitors of eSF and reveal eSF in endometriosis as having P4 resistance inherited from eMSC and a pro-inflammatory phenotype acquired within the endometrial niche.

Perivascular human endometrial mesenchymal stem cells express pathways relevant to self-renewal, lineage specification, and functional phenotype.

Human endometrium regenerates on a cyclic basis from candidate stem/progenitors whose genetic programs are yet to be determined. A subpopulation of endometrial stromal cells, displaying key properties of mesenchymal stem cells (MSCs), has been characterized. The endometrial MSC (eMSC) is likely the precursor of the endometrial stromal fibroblast. The goal of this study was to determine the transcriptome and signaling pathways in the eMSC to understand its functional phenotype. Endometrial stromal cells from oocyte donors (n = 20) and patients undergoing benign gynecologic surgery (n = 7) were fluorescence-activated cell sorted into MCAM (CD146)(+)/PDGFRB(+) (eMSC), MCAM (CD146)(-)/PDGFRB(+) (fibroblast), and MCAM (CD146)(+)/PDGFRB(-) (endothelial) populations. The eMSC population contained clonogenic cells with a mesenchymal phenotype differentiating into adipocytes when cultured in adipogenic medium. Gene expression profiling using Affymetrix Human Gene 1.0 ST arrays revealed 762 and 1518 significantly differentially expressed genes in eMSCs vs. stromal fibroblasts and eMSCs vs. endothelial cells, respectively. By principal component and hierarchical clustering analyses, eMSCs clustered with fibroblasts and distinctly from endothelial cells. Endometrial MSCs expressed pericyte markers and were localized by immunofluorescence to the perivascular space of endometrial small vessels. Endometrial MSCs also expressed genes involved in angiogenesis/vasculogenesis, steroid hormone/hypoxia responses, inflammation, immunomodulation, cell communication, and proteolysis/inhibition, and exhibited increased Notch, TGFB, IGF, Hedgehog, and G-protein-coupled receptor signaling pathways, characteristic of adult tissue MSC self-renewal and multipotency. Overall, the data support the eMSC as a clonogenic, multipotent pericyte that displays pathways of self-renewal and lineage specification, the potential to respond to conditions during endometrial desquamation and regeneration, and a genetic program predictive of its differentiated lineage, the stromal fibroblast.

Offspring gender rates in active duty fighter pilots and flight officers.

INTRODUCTION: It has been reported in small studies that fighter pilots have a higher likelihood of producing female offspring secondary to job-related exposures. No large-scale study has investigated this potential gender disparity. METHODS: This retrospective study utilized electronic medical record systems to identify men with flight-related occupations within the U.S. military from September 2012 to January 2018. The gender of offspring born to those men at least one year after entry into the flight community were compared to gender rates of children born to the U.S. general population during the same time period. RESULTS: 10,879 and 62,624 children born to fighter pilots and pilots of non-fighter type aircraft respectively were compared. The gender distribution of children born to both communities was similar to U.S. general population trends. CONCLUSIONS: This large-scale study provides social reassurances that the degree of risk imposed on our nation's air defense force does not influence the gender balance of the subsequent generation.

Does ethnicity influence in vitro fertilization (IVF) birth outcomes?

OBJECTIVE: To determine if ethnicity influences IVF birth outcome. DESIGN: Retrospective cohort study. SETTING: University-based IVF program. PATIENT(S): All African American women (n = 71) and Caucasian women (n = 180) who underwent initial fresh, nondonor IVF/embryo transfer (ET) cycles between January 1, 2004 and December 31, 2005. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Gonadotropin dose, duration of stimulation, peak estradiol levels, oocyte yield, implantation, clinical pregnancy, and live birth rates. RESULT(S): African American women generated significantly fewer embryos than Caucasian women (5.3 +/- 3.7 vs. 6.6 +/- 4.8) despite having similar ages, day 3 FSH, peak estradiol levels, length of stimulation, and number of oocytes retrieved. In addition, compared with Caucasian women, African American had significantly greater body mass indices (26.5 +/- 5.2 vs. 23.7 +/- 4.8) and required significantly more total gonadotropin (IU) (4,791 +/- 2,161 vs. 3,725 +/- 2,005) for ovarian stimulation. African American women were more likely to have uterine fibroids (21% vs. 3%) and tubal factor infertility (23% vs. 9%). Caucasian women were more likely to have unexplained infertility (53% vs. 32%). Differences in embryo yield between patient groups persisted after accounting for differences in infertility diagnosis and prevalence of fibroids. Biochemical, clinical pregnancy, and live birth rates as well as implantation rates (number of sacs visualized/number of embryos transferred) did not significantly differ between groups. CONCLUSION(S): Although African Americans yield fewer embryos than Caucasian women with IVF, these ethnic groups do not seem to differ with regard to IVF pregnancy outcomes.