Entity

Time filter

Source Type


Miller I.,Assaf Harofeh Medical Center | Chuderland D.,Assaf Harofeh Medical Center | Ron-El R.,IVF and Infertility Unit | Shalgi R.,Assaf Harofeh Medical Center | Ben-Ami I.,IVF and Infertility Unit
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: GnRH agonist (GnRH-a) triggering is associated with a reduced risk of ovarian hyperstimulation syndrome (OHSS) compared with human chorionic gonadotropin (hCG) in assisted reproduction technology cycles. We have shown that ovarian pigment epithelium derived factor (PEDF), a potent antiangiogenic factor, counteracts vascular endothelial growth factor (VEGF) expression and that OHSS is correlated with hCG-induced impaired PEDF to VEGF ratio. Objective: The objective of the study was to explore whether GnRH-a triggering could directly modulate PEDF/VEGF balance in granulosa cells. Design: The design of the study was a mouse model and cultured granulosa cells. Main Outcome: Changes in PEDF and VEGF were measured by quantitative PCR and Western blot analysis. OHSS symptoms were recorded by changes in body weight and in peritoneal vascular leakage, quantified by the modified Miles vascular permeability assay. Results: GnRH-a stimulation significantly increased PEDF and decreased VEGF mRNA and protein levels both in rat granulosa cell line and human primary granulosa cells in vitro. GnRH-a and hCG triggering inversely modulated PEDF mRNA and protein level in human granulosa cells in vivo. In the GnRH-a triggering mouse model, we showed similar increase in PEDF to VEGF ratio as in the in vitro results. OHSS-predisposed mice did not develop OHSS parameters after GnRH-a triggering, opposed to hCG-triggered mice. Finally, GnRH-a triggering of OHSS-predisposed mice significantly increased ovarian PEDF to VEGF ratio compared with hCG-triggered mice and control mice. Conclusions: GnRH-a triggering induces a direct effect on PEDF/VEGF balance in granulosa cells inversely to hCG. Our results suggest a novel elucidation to the GnRH-a triggering-mediated risk reduction of OHSS and may clarify the pros and cons of this triggering method. Copyright © 2015 by the Endocrine Society.


Bar-Joseph H.,Tel Aviv University | Ben-Ami I.,IVF and Infertility Unit | Ben-Ami I.,Tel Aviv University | Ron-El R.,IVF and Infertility Unit | And 3 more authors.
Reproduction | Year: 2016

Human chorionic gonadotropin (hCG) is a known trigger of ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening complication of assisted reproduction. Administration of hCG results in the release of vascular endothelial growth factor (VEGF) from the ovary.We have previously shown that expression of pigment epithelium-derived factor (PEDF) in granulosa cell line is regulated by hCG, reciprocally to VEGF, and that the PEDF-VEGF balance is impaired in OHSS. Our aim was to explore the signaling network by which hCG downregulates the expression of PEDF mRNA and protein in granulosa cells. We applied specific chemical inhibitors and stimuli to human primary granulosa cells and rat granulosa cell line. We found that PKA and protein kinase C, as well as EGFR, ERK1/2 and PI3K, participate in the signaling network. The finding that hCG-induced PEDF downregulation and VEGF upregulation are mediated by similar signaling cascades emphasizes the delicate regulation of ovarian angiogenesis. © 2016 Society for Reproduction and Fertility.


Chuderland D.,Tel Aviv University | Ben-Ami I.,IVF and Infertility Unit | Kaplan-Kraicer R.,Tel Aviv University | Grossman H.,Tel Aviv University | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of assisted reproduction. OHSS is induced by an ovarian release of vasoactive, angiogenic substances that results in vascular hyperpermeability, leakage, and shift of fluids from blood vessels into the extravascular space with consequent ascites and edema that are attributed to vascular endothelial growth factor (VEGF). Objective: Our objective was to examine a physiological approach for preventing and treating OHSS, based on negating the VEGF network. Design: We used a mouse OHSS model and cultured granulosa cells. Main Outcome: Changes in pigment epithelium-derived factor (PEDF) and VEGF were measured by quantitative PCR and Western blot analysis. OHSS was recorded by changes in body weight and in peritoneal vascular leakage, quantified by the modified Miles vascular permeability assay. Results: Granulosa cells produced and secreted the anti-angiogenic factor, PEDF, in an inverse fashion to VEGF. The physiological PEDF-VEGF counterbalance was found to be impaired in the mouse OHSS model. Treatment of OHSS-induced mice with low doses of recombinant PEDF (rPEDF) alleviated OHSS signs including edema (P < .001) and vascular leakage (P < .001) and reduced the level of ovarian VEGF mRNA. Low doses of rPEDF also reduced VEGF mRNA levels in granulosa cells in vitro. However, these effects were not seen at higher doses of rPEDF, suggesting a hormetic mechanism of rPEDF action. Conclusion: These observations provide a new perspective into the pathophysiology of OHSS, namely, high expression level of VEGF together with a nearly undetectable level of PEDF. A replacement therapy with rPEDF is suggested as an innovative physiological treatment for OHSS. Finally, control of the PEDF-VEGF reciprocal relationship could open new therapeutic avenues for other angiogenic-related fertility pathologies. Copyright © 2013 by The Endocrine Society.


Chuderland D.,Tel Aviv University | Ben-Ami I.,IVF and Infertility Unit | Ben-Ami I.,Tel Aviv University | Friedler S.,IVF and Infertility Unit | And 7 more authors.
Molecular and Cellular Endocrinology | Year: 2014

Pigment epithelium-derived factor (PEDF) is highly expressed in the female reproductive system and is subjected to regulation by steroid hormones in the ovary. As the uterine endometrium exhibits morphological and functional changes in response to estrogen (E2) and progesterone (P4), we aimed at characterizing the expression of PEDF in this component of the female reproductive tract and further at exploring the hormonal regulation of its expression. We found that PEDF is expressed in human and mouse endometrium. We further showed that this expression is subjected to regulation by steroid hormones, both in vivo and in vitro, as follows: E2 decreased PEDF expression and P4 increased its levels. In human endometrial samples, PEDF levels were dynamically altered along the menstrual cycle; they were low at the proliferative and early secretory phases and significantly higher at the late secretory phase. The expression levels of PEDF were inversely correlated to that of vascular endothelial growth factor (VEGF). We also showed that PEDF receptor was expressed in the endometrium and that its stimulation reduced VEGF expression. Illustrating the pattern of PEDF expression during the menstrual cycle may contribute to our understanding of the endometrial complexity. © 2014 Elsevier Ireland Ltd.


Orbach-Zinger S.,Rabin Medical Center | Orbach-Zinger S.,Tel Aviv University | Eidelman L.A.,Rabin Medical Center | Eidelman L.A.,Tel Aviv University | And 8 more authors.
European Journal of Obstetrics Gynecology and Reproductive Biology | Year: 2016

Objectives In vitro fertilization (IVF) induced elevated estrogen levels are associated with a hypercoagulable state. Thromboelastogram (TEG) is a point of care whole blood hemostasis analyzer which measures functionality of clotting parameters. Our study's objective was to examine the influence of the early and late follicular phase of an IVF simulation cycle on coagulation parameters as measured by TEG and to evaluate the influence of age on coagulation parameters. Study design In a single center, prospective, observational trial, 46 women undergoing IVF therapy were studied. All women received a standardized IVF treatment protocol. Venous blood was drawn on the first day of the stimulation cycle and on the day of hCG injection and assessed by TEG. Parameters assessed by were R (represent clotting time), K and Angle (reflect clot strength and development), MA (maximum platelet-fibrin clot strength), CI (represents overall coagulability), and LY30 (represents lysis). Results Data from 46 women were analyzed. A statistically significant difference was found in all TEG parameters between early and late follicular phase, indicating a hypercoagulable state. R (p < 0.0001), K (p = 0.008), angle (p = 0.008), MA (p = 0.004), CI (p < 0.001), LY30 (p = 0.59). Age was a significant independent predictor for R at the early follicular phase (p = 0.042). Both age and estrogen levels were found to be independent predictors for CI at late follicular phase. Age (p = 0.011), estrogen (p = 0.019). Conclusions There was a significant difference in all coagulation parameters between early and late follicular phase, indicating a hypercoagulable state. © 2016 Published by Elsevier Ireland Ltd.

Discover hidden collaborations