H.G. Huddleston

Racial and ethnic disparities in reproductive endocrinology and infertility.

This review examines racial and ethnic disparities in reproductive health focusing on 3 key topical areas: (1) infertility, (2) polycystic ovarian syndrome, and (3) reproductive aging. We report that an increasing body of knowledge points toward reduced infertility access and in vitro fertilization outcomes in Asian, black, and Hispanic women compared with white women. There are differences in the reproductive and metabolic phenotypes of Asian, black, and Hispanic women presenting with the polycystic ovarian syndrome compared with white women. Reproductive aging differences appear to exist in all racial and ethnic groups. Awareness of racial and ethnic disparities is critical to a complete understanding of the health issues facing women of reproductive age.

Endometrial stromal fibroblasts from women with polycystic ovary syndrome have impaired progesterone-mediated decidualization, aberrant cytokine profiles and promote enhanced immune cell migration in vitro

STUDY QUESTION Do endometrial stromal fibroblasts (eSF) in women with polycystic ovary syndrome (PCOS) (eSFpcos) exhibit altered estrogen and/or progesterone (P4) responses, which may explain some of the adverse reproductive outcomes and endometrial pathologies in these women? SUMMARY ANSWER In vitro, eSF from women with PCOS exhibit an aberrant decidualization response and concomitant changes in pro-inflammatory cytokine, chemokine and matrix metalloproteinase (MMP) release and immune cell chemoattraction. In vivo these aberrations may result in suboptimal implantation and predisposition to endometrial cancer. WHAT IS KNOWN ALREADY The endometrium in women with PCOS has several abnormalities including progesterone (P4) resistance at the gene expression level, likely contributing to subfertility, pregnancy complications and increased endometrial cancer risk in PCOS women. STUDY DESIGN, SIZE, DURATION Prospective, university-based, case-control, in vitro study. PARTICIPANTS/MATERIALS, SETTING, METHODS Cultures of eSFPCOS (n = 12, Rotterdam and NIH criteria) and eSFControl (Ctrl) (n = 6, regular cycle length, no signs of hyperandrogenism) were treated with vehicle, estradiol (E2, 10 nM) or E2P4 (10 nM/1 μM) for 14 days. Progesterone receptor (PGR) mRNA was assessed with quantitative real-time PCR (qRT-PCR) and eSF decidualization was confirmed by insulin-like growth factor-binding protein-1 (IGFBP-1) transcript and protein expression. Fractalkine (CX3CL1), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL) 6, 8 and 11, macrophage chemoattractant protein (MCP) 1 and 3, CCL5 (RANTES) and MMPs (MMP1, 2, 3, 7, 9, 10 and 12) were measured in conditioned media by Luminex multiplex assays, and chemotactic activity of the conditioned media was tested in a migration assay using CD14+ monocyte and CD4+ T-cell migration assay. Effects of IL-6 (0.02, 0.2, 2 or 20 ng/ml) or IL-8 (0.04, 0.4, 4, or 40 ng/ml) or combination (0.2 ng/ml IL-6 and 4.0 ng/ml IL-8) on 14-d decidualization were also tested. ANOVA with pre-planned contrasts was used for statistical analysis. MAIN RESULTS AND THE ROLE OF CHANCE Hormonal challenge with E2P4 to induce decidualization revealed two distinct subsets of eSFPCOS. Eight eSFPCOS (dPCOS) and all eSFCtrl (dCtrl) cultures showed a normal decidualization response to E2P4 as determined by morphology and IGFBP-1 secretion. However, 4 eSFPCOS cultures showed blunted decidualization (ndPCOS) in morphological assessment and low IGFBP-1 levels even though all three groups exhibited normal estrogen-mediated increase in PGR expression. Interestingly dPCOS had decreased IL-6 and GM-SCF secretion compared with dCtrl, whereas the ndPCOS cultures showed increased IL-6 and 8, MCP1, RANTES and GM-CSF secretion at base-line and/or in response to E2 or E2P4 compared with dCtrl and/or dPCOS. Furthermore, even though PGR expression was similar in all three groups, P4 inhibition of MMP secretion was attenuated in ndPCOS resulting in higher MMP2 and 3 levels. The conditioned media from ndPCOS had increased chemoattractic activity compared with dCtrl and dPCOS media. Exogenously added IL-6 and/or 8 did not inhibit decidualization in eSFCtrl indicating that high levels of these cytokines in ndPCOS samples were not likely a cause for the aberrant decidualization. LIMITATIONS, REASONS FOR CAUTION This is an in vitro study with a small sample size, utilizing stromal cell cultures from proliferative and secretory phase endometrium. The effect of PCOS on endometrial epithelium, another major histoarchitectural cell compartment of the endometrium, was not evaluated and should be considered in future studies. Furthermore, results obtained should also be confirmed in a larger data set and with mid/late secretory phase in vivo samples and models. WIDER IMPLICATIONS OF THE FINDINGS The alterations seen in ndPCOS may contribute to endometrial dysfunction, subfertility and pregnancy complications in PCOS women. The results emphasize the importance of understanding immune responses related to the implantation process and normal endometrial homeostasis in women with PCOS. STUDY FUNDING/COMPETING INTERESTS Sigrid Juselius Foundation, Academy of Finland, Finnish Medical Foundation, Orion-Farmos Research Foundation (to T.T.P.), the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) U54HD 055764-07 Specialized Cooperative Centers Program in Reproduction and Infertility Research (to L.C.G.), the NICHD the Ruth L. Kirschstein National Research Service Awards grant 1F32HD074423-03 (to J.C.C.). The authors have no competing interests.

Immune Interactions at the Maternal–Fetal Interface: a Focus on Antigen Presentation

Problem:  Viruses and fetuses face similar immunologic challenges. Each must evade immune detection and destruction. The virus must avoid host recognition of intracellular infection; the fetus allogenic recognition. Each has manipulated the process of antigen presentation to allow survival in an immunologic environment otherwise predictably hostile. How have these approaches co‐evolved? What can they teach us about viral pathogenesis and immunologic interactions at the maternal‐fetal interface?

Distributions of high-density lipoprotein particle components in human follicular fluid and sera and their associations with embryo morphology parameters during IVF

BACKGROUND High-density lipoprotein (HDL) is the sole lipoprotein present in follicular fluid (FF). The objectives of this study were to examine HDL lipid composition and associated enzyme activities in FF and serum and to relate these levels to embryo morphology parameters in women undergoing in vitro fertilization (IVF). METHODS Serum and FF were prospectively obtained from 60 women undergoing IVF. HDL lipids, apolipoprotein AI (ApoAI), paraoxonase 1 (PON1) and paraoxonase 3 (PON3) activities were determined. Bivariate analysis and ordinal logistic regression models were employed to examine the associations between biochemical measures and embryo morphology parameters [embryo cell number (ECN) and embryo fragmentation score (EFS)] as surrogate markers of oocyte health. RESULTS All biochemical parameters were significantly (P < 0.05) lower in FF than serum except PON3 levels which were significantly higher. FF-HDL cholesterol (OR 0.66, 95%CI 0.46-0.96) and ApoAI (OR 0.13, 95%CI 0.03-0.97) levels were negative predictors for EFS; however, their effects were not independent and the level of one moderated the effect of the other. Limited to Day 3 embryo transfers, FF-PON1-arylesterase activity was a significant positive predictor for ECN (OR 1.09, 95%CI 1.01-1.17). CONCLUSIONS In this pilot study, our data suggests that HDL and its component proteins within FF may play protective roles in the health of the human oocyte and subsequent early embryo development. We describe for the first time the activities of PON1 and PON3 in FF. We suspect that PON3 activity may be locally generated due to higher activities in FF compared with serum.

Advanced Age and Comorbidity Increase the Risk for Adverse Events After Revision Total Hip Arthroplasty

With the institution of quality-assurance parameters in health care, physicians must accurately measure and report the true baseline rates of adverse events (AEs) after complex surgical interventions. To better quantify the risk of AEs for revision total hip arthroplasty (THA), we divided a cohort of 306 patients (322 procedures) into age groups: group I (<65 years, n = 138), group II (65-79 years, n = 119), and group III (≥80 years, n = 65). Ninety-day rates of major AE were 9%, 19%, and 34% in the groups, respectively. Group III had an increased chance of experiencing major AE compared with groups I and II. Age and Charlson Comorbidity Index independently predicted major complications, whereas body mass index, sex, and type of revision did not.

Correlations of follicular fluid oxidative stress biomarkers and enzyme activities with embryo morphology parameters during in vitro fertilization

OBJECTIVE To measure antioxidant enzyme activities and lipid peroxidation levels within follicular fluid (FF) and evaluate correlations with early embryo quality. DESIGN Individual FF samples were obtained prospectively on the day of oocyte collection and assessed for lipid peroxidation as specific positional isomers of hydroperoxy and hydroxy fatty acids by high-performance liquid chromatography and antioxidant enzyme activities by automated kinetic enzyme assays. Spearman rank correlation coefficients, adjusted for age and day of transfer, were used to assess associations between antioxidant enzymes and lipid peroxidation products and embryo quality using a 1 follicle-1 oocyte/embryo approach. Post hoc power analysis was conducted to help interpret null results. SETTING A university clinic. PATIENT(S) Thirty-nine women undergoing IVF. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Embryo cell number and embryo fragmentation score (EFS) at transfer. RESULT(S) No significant correlations between lipid peroxidation derivatives or antioxidant enzyme activities and embryo quality were obtained. Post hoc power analysis indicated possible undetected associations between EFS and 13-hydroxy octadecatrienoic acid and 13-hydroperoxy octadecadieneoic acid. CONCLUSION(S) Our preliminary dataset suggests that most lipid peroxidation products and antioxidant enzyme activities within FF are not associated with the quality of embryos, using EFS and embryo cell number as end points. However, further consideration of associations between EFS and 13-hydroxy octadecatrienoic acid and 13-hydroperoxy octadecadieneoic acid is warranted.

Cost-effectiveness of cytogenetic evaluation of products of conception in the patient with a second pregnancy loss

OBJECTIVE To compare the cost of two strategies for managing the patient with recurrent pregnancy loss (RPL). DESIGN Cost analysis using a decision analytic model was used to compare obtaining an evidence-based workup (EBW) for RPL versus obtaining a karyotype of the products of conception (POC) and proceeding with an EBW only in the setting of euploid POC. SETTING Outpatient care. PATIENT(S) A simulated cohort of patients experiencing a second pregnancy loss. INTERVENTION(S) Not applicable. MAIN OUTCOME MEASURE(S) Total cost of investigating the cause of RPL after a second pregnancy loss. RESULT(S) For all age categories, obtaining a karyotype of POC was less costly than an evidenced-based RPL evaluation. Monte Caro analysis demonstrated a net economic benefit for the karyotype strategy (

Putative role for insulin resistance in depression risk in polycystic ovary syndrome

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Physical activity in women with polycystic ovary syndrome: prevalence, predictors, and positive health associations

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Asian ethnicity in anonymous oocyte donors is associated with increased estradiol levels but comparable recipient pregnancy rates compared with Caucasians

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