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STUDY QUESTION: Does vitamin D attenuate the adverse effects of advanced glycation end products (AGEs) on steroidogenesis by human granulosa cells (GCs)? SUMMARY ANSWER: AGEs alter the expression of genes important in steroidogenesis while 1,25-dihydroxyvitamin D3 (vit D3) in vitro attenuates some of the actions of AGEs on steroidogenic gene expression, possibly by downregulating the expression of the pro-inflammatory cell membrane receptor for AGEs (RAGE). WHAT IS KNOWN ALREADY: Vitamin D attenuates the pro-inflammatory effects of AGEs in non-ovarian tissues. STUDY DESIGN, SIZE, DURATION: Women who were undergoing IVF were enrolled. Follicular fluid samples (n = 71) were collected and cumulus GCs (n = 12) were treated in culture. PARTICIPANTS/MATERIALS, SETTING, METHODS: Follicular fluid levels of the anti-inflammatory soluble RAGE (sRAGE), AGEs and 25-hydroxyvitamin D (25-OHD) were quantified for possible correlations. GCs of each participant were split equally and treated with either media alone (control) or with human glycated albumin (HGA as a precursor for AGEs) with or without vit D3 after which RT-PCR and immunofluorescence were performed and cell culture media estradiol (E2) levels were compared. MAIN RESULTS AND THE ROLE OF CHANCE: In follicular fluid, sRAGE levels were positively correlated with 25-OHD levels. HGA treatment (i) increased CYP11A1 (by 48%), 3ß-HSD (by 38%), StAR (by 42%), CYP17A1 (by 30%) and LHR (by 37%) mRNA expression levels (P < 0.05 for all) but did not alter CYP19A1 or FSHR mRNA expression levels; and (ii) increased E2 release in cell culture media (P = 0.02). Vit D3 treatment (i) downregulated RAGE mRNA expression by 33% and RAGE protein levels by 44% (P < 0.05); (ii) inhibited the HGA-induced increase in CYP11A1, StAR, CYP17A1 and LHR mRNA levels, but not the increase in 3ß-HSD mRNA levels; and (iii) did not inhibit the HGA-induced E2 release in cell culture media. LIMITATIONS REASONS FOR CAUTION: This study used luteinized GCs that were collected from women who received gonadotropins thus the results obtained may not fully extrapolate to non-luteinized GCs in vivo. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that there is a relationship between AGEs and their receptors (RAGE and sRAGE) with vitamin D. Understanding the interaction between AGEs and vitamin D in ovarian physiology could lead to a more targeted therapy for the treatment of ovarian dysfunction. STUDY FUNDING/COMPETING INTEREST(S): Funding was received from NIH (R01 NS045940), American Society for Reproductive Medicine, Ferring Pharmaceuticals Inc., and University of Vermont College of Medicine Bridge Funds. All authors have nothing to disclose.

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Obesity affects ovarian function, one of the main regulators of female fertility. Tissue levels of the proinflammatory advanced glycation end-products (AGEs) and their receptors (RAGE) are elevated in obesity. AGEs are key contributors to perturbations in the ovarian microenvironment. On this basis, the present review focuses on clinical and experimental studies supporting the role of AGE-RAGE system as a contributor to obesity-related ovarian dysfunction. Particular emphasis has been given to changes in AGEs, RAGE and the anti-inflammatory soluble receptor (sRAGE) levels in obesity state and following dietary interventions (high-fat diet and weight loss). Ovarian sensitivity, in particular granulosa cell function and oocyte meiosis, to the pro-inflammatory AGE-RAGE system as well as the relationship of follicular fluid AGEs and sRAGE to in vitro fertilization outcome are also discussed. Overall, obesity, with its alterations in the AGE-RAGE system, can disrupt the ovarian microenvironment potentially compromising oocyte competence and fertility. This review underscores a critical need to uncover the mechanistic actions of AGE-RAGE system in obesity-related ovarian dysfunction. Clinical and basic studies focusing on elucidating the patterns of accumulation and role of the AGE-RAGE system in human ovarian follicles are key steps in understanding their contribution to the health of human oocytes and embryos.

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PURPOSE: The association between pronuclear (PN) scoring of embryos from assisted reproductive technology (ART) and clinical pregnancy remains controversial. We hypothesized that embryos with PNs scored on the day of fertilization check offer better embryo selection on day 3 and higher CPR compared to non-PN scored embryos. METHODS: Patients (19-46 years) undergoing IVF/ICSI cycles at Montefiore's Institute for Reproductive Medicine and Health between January 2006 and December 2009 were included in our study. We analyzed fresh day 3 cycles only with autologous oocytes and partner's fresh sperm (n = 344). A total of 1,899 embryos were included. We compared CPR from non-PN scored embryos (Group 1, n = 835) with PN scored embryos (Group 2, n = 1,064). Composite scores by patient were developed based on embryo disposition. We also assessed traditional embryo grading derived from cell number, fragmentation and cell symmetry. Data analysis included chi square and t test to determine if PN scoring was associated with improved CPR, and to compare the additional variables. RESULTS: CPR between Group 1 and Group 2 were not different (p = 0.91). CPR was significantly associated with female age, number of mature oocytes retrieved, number of day 3 embryos and grade of embryos transferred on day 3 (p < 0.05). CONCLUSION: PN scoring was not associated with improved CPR in day 3 embryo transfers. Mean grade of transferred embryos continues to be a well-established, independent predictor of CPR. We conclude that further refinement of embryo grading by PN scoring is not beneficial.

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STUDY QUESTION: Do advanced glycation end products (AGEs) and their receptors play a role in female reproduction? SUMMARY ANSWER: AGEs might contribute to the etiology of polycystic ovary syndrome (PCOS) and infertility. WHAT IS KNOWN ALREADY: The endogenous AGEs are produced in the body by chemical reactions. Exogenous sources of AGEs are diet and smoking. AGEs have been proposed to be among the main intermediaries involved in several diseases, such as metabolic syndrome, type 2 diabetes mellitus, cardiovascular disease, ovarian aging, inflammation, neurodegenerative disorders and PCOS. STUDY DESIGN, SIZE, DURATION: A systematic review was performed for all available basic science and clinical peer-reviewed articles published in PubMed from 1987 to date. Abstracts of annual meetings of the Endocrine Society and American Society for Reproductive Medicine were also reviewed. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 275 publications and scientific abstracts were identified from the initial search. Sixty-two papers and four published scientific abstracts were selected for full review. The main outcomes were the regulatory effects of AGEs on: (i) granulosa cells, adipocyte physiology, obesity and insulin resistance in women with PCOS and in polycystic ovary animal models and (ii) infertility and measures of ovarian reserve. MAIN RESULTS AND THE ROLE OF CHANCE: There is an intricate relationship between the AGE-RAGE (receptor for AGEs) system and some aspects of PCOS, such as granulosa cell dysfunction, adipocyte pathophysiology, obesity and insulin resistance. Additionally, irregular ovarian AGE signaling might in part explain the abnormal ovarian histology observed in women with PCOS. The ovarian dysfunction due to AGEs in women without PCOS suggests a role for the AGE-RAGE system in the ovarian follicular environment, and might relate to assisted reproduction technology outcome and measures of ovarian reserve. LIMITATIONS, REASONS FOR CAUTION: The body of literature currently available limits these findings. The results obtained from granulosa cell lines and animal models may not fully extrapolate to humans. WIDER IMPLICATIONS OF THE FINDINGS: This review underscores a critical need to unveil the exact mechanistic actions of AGEs in reproductive physiology and more specifically the hypothalamic-pituitary-ovarian axis. AGE inhibitors might present an emerging therapeutic approach with significant applications in the context of PCOS and infertility. STUDY FUNDING/COMPETING INTEREST(S): American Society for Reproductive Medicine New Investigator Award and University of Vermont College of Medicine Internal Funds. No competing interests.

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STUDY QUESTION: Do the adipocytokines, leptin and adiponectin affect the granulosa cell expression of anti-Mullerian hormone (AMH) and its receptor (AMHR-II)? SUMMARY ANSWER: Leptin suppresses AMH mRNA levels in human luteinized granulosa cells through the JAK2/STAT3 pathway, while adiponectin has no such effect. WHAT IS KNOWN ALREADY: AMH is one of the most reliable markers of ovarian reserve. Serum AMH levels decline with obesity. Obesity is associated with elevated leptin and reduced adiponectin levels. STUDY DESIGN, SIZE AND DURATION: This prospective study included 60 infertile women undergoing fresh IVF and ICSI cycles utilizing autologous oocytes at Montefiore's Institute for Reproductive Medicine and Health between July 2010 and April 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Follicular fluid was collected from small (SFs; <14 mm) and large follicles (LFs; ≥14 mm) from 38 participants. Total RNA was extracted separately from mural and cumulus granulosa cells and mRNA levels were measured by RT-PCR. In an additional group of participants (N = 22), primary cumulus and mural granulosa cells (pooled SFs and LFs) were cultured in media alone or with addition of either leptin (N = 7), adiponectin (N = 8) or JAK2/STAT3 inhibitor + leptin (N = 7), and AMH and AMHR-II mRNA levels measured. Levels of AMH, leptin and adiponectin protein were measured in follicular fluid. MAIN RESULTS AND THE ROLE OF CHANCE: AMH and AMHR-II mRNA and follicular fluid AMH protein levels were inversely correlated with age. AMH mRNA expression was six times higher in cumulus compared with mural granulosa cells in SFs (P< 0.05) and eight times higher in cumulus compared with mural granulosa cells in LFs (P < 0.001). In follicular fluid, leptin protein level positively correlated (r = 0.7, P = 0.03), while adiponectin protein level inversely correlated (r = -0.46, P = 0.02) with BMI. Leptin treatment suppressed AMH and AMHR-II mRNA in both cumulus and mural granulosa cells (all P < 0.05). In the presence of JAK2/STAT3 inhibitor, leptin treatment did not alter AMH but continued to suppress AMHR-II mRNA in cumulus cells (P = 0.02). Adiponectin treatment did not alter AMH or AMHR-II mRNA levels. LIMITATIONS, REASONS FOR CAUTION: This study included a luteinized granulosa cell model as these cells were collected from women who were hyperstimulated with gonadotrophins. The results obtained may not fully extrapolate to non-luteinized granulosa cells. WIDER IMPLICATIONS OF THE FINDINGS: Leptin may program abnormal AMH signaling, thereby resulting in ovarian dysfunction. This study opens a new perspective for understanding the low ovarian reserve seen in obese women and provides new insights into potential mechanisms that explain the lower AMH seen in obese women. Whether our findings explain the worse response to ovulation induction observed in obese women needs to be further elucidated.

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The purpose of this article is to ascertain and appraise the ethical issues inherent to the utilisation of preimplantation genetic diagnosis for gender selection in infertile patients anticipating undergoing a medically indicated assisted reproductive technique procedure. Performance of preimplantation genetic diagnosis per request specifically for gender selection by an infertile couple undergoing medically indicated assisted reproductive technique may not breach the principles of ethics, and is unlikely to alter the population balance of sexes.

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Premature ovarian failure due to Xp duplication and Xq deletion has been reported in four patients, the youngest of whom was 18 years old. The diagnosis has been made with new techniques for genetic analysis, such as comparative genomic hybridization and fluorescence in situ hybridization. We report the youngest case (a 12-year-old who presented with irregular menses), of premature ovarian failure due to Xp duplication and Xq deletion and the first with 46,X,der(X)t(X;X)(q22.1;p11). The diagnosis was made using C-banding and fluorescent in situ hybridization with locus-specific probes. This case highlights the need to use advanced genetic strategies to determine karyotypic and phenotypic abnormalities.

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Hemorrhage continues to be a serious complication of both obstetrical and gynecologic surgeries. Physicians have used packing in cases of uncontrollable hemorrhage for many years, and this article reports on a modification of standard packing techniques that prevents some of the limitations of traditional packing. This technique was used in 1 patient after cesarean hysterectomy and 3 patients after debulking surgery for advanced gynecologic cancer. The pack consists of a wide piece of ribbon gauze and a Penrose drain. One end of the ribbon gauze is draped over a layer of surgicel (oxidized regenerated cellulose), while the rest is threaded through a 1-inch Penrose drain tightly folded several times to maintain pressure over the bleeding area. The other end of the Penrose drain, with the ribbon gauze visible within it, is inserted through a stab incision in the ipsilateral side of the lower abdomen. This technique allows for continuous bleeding assessment and easy removal of the gauze at bedside.

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