Pigment epithelium-derived factor expression and role in follicular development.

RESEARCH QUESTION: What is the involvement of pigment epithelium-derived factor (PEDF), expressed in granulosa cells, in folliculogenesis? DESIGN: mRNA expression of PEDF and other key factors [Cyp19, anti-Müllerian hormone receptor (AMHR) and vascular endothelial growth factor (VEGF)] in mice follicles was examined in order to typify the expression of PEDF in growing follicles and in human primary granulosa cells (hpGC), and to follow the interplay between PEDF and the other main players in folliculogenesis: FSH and AMH. RESULTS: mRNA expression of PEDF increased through folliculogenesis, although the pattern differed from that of the other examined genes, affecting the follicular angiogenic and oxidative balance. In hpGC, prolonged exposure to FSH stimulated the up-regulation of PEDF mRNA. Furthermore, a negative correlation between AMH and PEDF was observed: AMH stimulation reduced the expression of PEDF mRNA and PEDF stimulation reduced the expression of AMHR mRNA. CONCLUSIONS: Folliculogenesis, an intricate process that requires close dialogue between the oocyte and its supporting granulosa cells, is mediated by various endocrine and paracrine factors. The current findings suggest that PEDF, expressed in granulosa cells, is a pro-folliculogenesis player that interacts with FSH and AMH in the process of follicular growth. However, the mechanism of this process is yet to be determined.

Impact of pre-treatment in GnRH-antagonist cycles triggered with GnRH agonist on reproductive outcomes.

OBJECTIVE: Pre-treatment (PT) therapies in IVF are known to be used as pre-stimulation modality to improve cycle outcomes. This study aims to assess whether PT in GnRH antagonist cycles triggered with GnRH-agonist impact oocyte maturation response. METHODS: Data were retrospectively collected for patients who underwent GnRH antagonist cycle with agonist triggering with and without PT. The patients were allocated to groups according to their PT status. The primary outcome evaluated was suboptimal maturation response. Suboptimal maturation to trigger was defined as no oocyte upon retrieval when adequate response was expected. RESULTS: The study population included 196 patients who underwent GnRH antagonist cycle with agonist triggering. The study group included 69 patients who received PT. The control group included 127 patients with no PT. In univariate analysis, the PT group significantly displayed suboptimal response compared to the controls (p = 0.008). All the patients in the study group with suboptimal response (with or without hCG re-triggering) were treated with GnRH-agonist as PT. Basal and pre-trigger LH values were significantly lower in the study group compared to controls (p < 0.001). Multivariate regression analysis revealed that PT with GnRH agonist was a significant predictor for suboptimal response. CONCLUSIONS: Pre-treatment, and particularly the use of GnRH-agonist as PT in antagonist cycles triggered with agonist, increases the risk of suboptimal response to GnRH-agonist trigger. This might be explained by prolonged pituitary suppression, which lasts beyond the PT cessation.

Comparison of pregnancy rates in antagonist cycles after luteal support with GnRH-agonist versus progesterone: prospective randomized study.

PURPOSE: To compare pregnancy rates in GnRH-antagonist cycles triggered with hCG after luteal phase support with intranasal GnRH-agonist as sole luteal phase support versus standard vaginal progesterone preparation. METHODS: Prospective randomized controlled study of patients who underwent antagonist-based IVF cycles triggered with hCG at university-affiliated tertiary medical center between 2020 and 2022. Patients meeting the inclusion criteria were randomly assigned to either intranasal GnRH-agonist or vaginal progesterone for luteal phase support. Pregnancy rates were the main outcome compared between the two study groups. RESULTS: A total of 150 patients underwent 164 cycles, 127 cycles of which were included in the study cohort. Of them, 64 (50.4%) and 63 (49.6%) cycles were treated with GnRH-agonist or progesterone, respectively, as sole luteal phase support. A significantly higher pregnancy rate was demonstrated in the GnRH-agonist group compared with the progesterone group. After adjustment of several potential confounders such as age, body mass index, past obstetric history, number of IVF cycles, oocyte retrieved and embryos transferred, GnRH-agonist was still associated with a higher pregnancy rate (odds ratio 3.4, 95% confidence interval 1.4-8.3). Ovarian hyperstimulation syndrome rates were similar between the groups. CONCLUSIONS: This prospective study suggests that nasal GnRH-agonist for luteal phase support is associated with higher pregnancy rates compared with standard progesterone support in an antagonist-based protocol triggered with hCG, while maintaining a similar safety profile. TRIAL REGISTRATION: Clinicaltrials.gov NCT05484193. Date of registration: August 02 2022. The trial was retrospectively registered.

The Role of PEDF in Reproductive Aging of the Ovary.

Reproductive aging is characterized by a decline in ovarian function and in oocytes' quantity and quality. Pigment epithelium-derived factor (PEDF), a pivotal player in ovarian angiogenic and oxidative balance, was evaluated for its involvement in reproductive aging. Our work examines the initial stage of reproductive aging in women and mice, and the involvement of PEDF in the process. Granulosa cells from reproductively-aged (RA) women and mice (36-44 years old and 9-10 months old, respectively) indicated an increase in the level of PEDF mRNA (qPCR), with yet unchanged levels of AMH and FSHR mRNAs. However, the PEDF protein level in individual women showed an intra-cellular decrease (ELISA), along with a decrease in the corresponding follicular fluid, which reflects the secreted fraction of the protein. The in vitro maturation (IVM) rate in the oocytes of RA mice was lower compared with the oocytes of young mice, demonstrated by a reduced polar body extrusion (PBE) rate. The supplementation of PEDF improved the hampered PBE rate, manifested by a higher number of energetically-competent oocytes (ATP concentration and mtDNA copy number of individual oocytes). Our findings propose PEDF as an early marker of reproductive aging, and a possible therapeutic in vitro agent that could enhance the number of good-quality oocytes in older IVF patients.

GqPCR-stimulated dephosphorylation of AKT is induced by an IGBP1-mediated PP2A switch.

BACKGROUND: G protein-coupled receptors (GPCRs) usually regulate cellular processes via activation of intracellular signaling pathways. However, we have previously shown that in several cell lines, GqPCRs induce immediate inactivation of the AKT pathway, which leads to JNK-dependent apoptosis. This apoptosis-inducing AKT inactivation is essential for physiological functions of several GqPCRs, including those for PGF2α and GnRH. METHODS: Here we used kinase activity assays of PI3K and followed phosphorylation state of proteins using specific antibodies. In addition, we used coimmunoprecipitation and proximity ligation assays to follow protein-protein interactions. Apoptosis was detected by TUNEL assay and PARP1 cleavage. RESULTS: We identified the mechanism that allows the unique stimulated inactivation of AKT and show that the main regulator of this process is the phosphatase PP2A, operating with the non-canonical regulatory subunit IGBP1. In resting cells, an IGBP1-PP2Ac dimer binds to PI3K, dephosphorylates the inhibitory pSer608-p85 of PI3K and thus maintains its high basal activity. Upon GqPCR activation, the PP2Ac-IGBP1 dimer detaches from PI3K and thus allows the inhibitory dephosphorylation. At this stage, the free PP2Ac together with IGBP1 and PP2Aa binds to AKT, causing its dephosphorylation and inactivation. CONCLUSION: Our results show a stimulated shift of PP2Ac from PI3K to AKT termed "PP2A switch" that represses the PI3K/AKT pathway, providing a unique mechanism of GPCR-stimulated dephosphorylation. Video Abstract.

Pigment epithelium derived factor as a novel multi-target treatment for uterine fibroids.

RESEARCH QUESTION: Does recombinant pigment epithelium derived factor (PEDF) have potential in treating uterine fibroids? DESIGN: In-vitro models that used human leiomyoma and Eker rat uterine leiomyoma (ELT-3) cell lines. The ELT-3 cell line was used to examine cellular targets after adding recombinant PEDF to the culture media. Athymic nude female mice were used as an in-vivo model. They were injected with ELT-3 cells to induce ectopic fibroid lesions, then treated with recombinant PEDF. RESULTS: RNA expression of PEDF and its receptors was found in both leiomyoma cell lines, as well as the expression of PEDF receptors. Addition of recombinant PEDF to the culture medium of leiomyoma cell lines activated ERK in a time-dependent manner, induced down-regulation of vascular endothelial growth factor mRNA and protein, as well as the mRNAs of oestrogen receptors alpha and beta and inhibited cellular proliferation. Treatment of mice-bearing fibroids with recombinant PEDF reduced fibroid growth rate and resulted in smaller tumours. CONCLUSIONS: This study suggests that recombinant PEDF is a putative novel potent physiological treatment for uterine fibroids. It targets several cornerstones of fibroid pathobiology in parallel, including vascular endothelial growth factor and oestrogen receptors, which are needed for vascularization, and restricts fibroid growth and final size in an animal model.

Pigment epithelium-derived factor (PEDF) negates hyperandrogenic PCOS features.

Polycystic ovary syndrome (PCOS), one of the most common female endocrine disorder, is a prevalent cause of infertility. Hyperandrogenism is a key feature in PCOS and is correlated with increased expression of VEGF and cytokines in the ovaries. We have previously shown that pigment epithelium-derived factor (PEDF), an endogenous protein, presents potent anti-angiogenic and anti-inflammatory activities in the ovary and negates the effects of cytokines and VEGF. Additionally, PEDF plays a role in both pathophysiology and treatment of ovarian-hyperstimulation syndrome (OHSS), frequently seen in PCOS patients. We established hyperandrogenic-PCOS models, both in vivo, using mice exposed prenatally to dihydrotestosterone (DHT) and, in vitro, using human primary granulosa cells (hpGCs) and human granulosa cell line (KGN). In PCOS-induced mice, the mRNA levels of I l-6, V egf and Amh were higher than those of control; yet, treatment with rPEDF decreased these levels. Moreover, treating OHSS-induced PCOS-mice with rPEDF alleviated all OHSS symptoms. Stimulation of hpGCs with DHT resulted in downregulation of PEDF mRNA expression, concomitantly with a significant increase in IL-6 and IL-8 mRNAs expression. However, co-stimulation of DHT with rPEDF attenuated the increase in cytokines expression. The anti-inflammatory effect of PEDF was found to be mediated via PPARγ pathway. Our findings suggest that rPEDF treatment may normalize the ovarian angiogenic-inflammatory imbalance, induced by PCOS-associated hyperandrogenism. Moreover, the therapeutic potency of PEDF in preventing OHSS symptomes offers a rationale for using PEDF as novel physiological treatment for PCOS sequels.

Elucidating the role of pigment epithelium-derived factor (PEDF) in metabolic PCOS models.

PCOS is the most common endocrinopathy in women; associated with obesity and insulin resistance (IR). IR leads to accumulation of advanced-glycation-end-products (AGEs) and their receptor, RAGE. PCOS patients have increased levels of vascular endothelial growth factor (VEGF), interleukin 6/8 (IL-6/8) and anti-Mϋllerian-hormone (AMH). PEDF is a secreted-glycoprotein known for its anti-angiogenic and anti-inflammatory properties. We aimed to elucidate the role of PEDF in the pathogenesis and treatment of PCOS. We used a prenatal PCOS mouse model and fed the female offspring a high-fat diet, inducing metabolic PCOS (met.PCOS) characteristics. Female offspring were divided into three groups: control; met.PCOS; met.PCOS + recombinant PEDF (rPEDF). Met.PCOS mice gained more weight, had elevated serum IL-6 and higher mRNA levels of AMH, PEDF and RAGE in their granulosa cells (GCs) than met.PCOS + rPEDF mice. An in vitro Met.PCOS model in human GCs (KGN) line was induced by prolonged incubation with insulin/AGEs, causing development of IR. Under the same conditions, we observed an elevation of VEGF, IL-6/8 mRNAs, concomitantly with an increase in PEDF mRNA, intracellular protein levels, and an elevation of PEDF receptors (PEDF-Rs) mRNA and protein. Simultaneously, a reduction in the secretion of PEDF from GCs, was measured in the medium. The addition of rPEDF (5 nM) activated P38 signaling, implying that PEDF-Rs maintained functionality, and negated AGE-induced elevation of IL-6/8 and VEGF mRNAs. Decreased PEDF secretion may be a major contributor to hyperangiogenesis and chronic inflammation, which lie at the core of PCOS pathogenesis. rPEDF treatment may restore physiological angiogenesis inflammatory balance, thus suggesting a potential therapeutic role in PCOS.

Gq-Induced Apoptosis is Mediated by AKT Inhibition That Leads to PKC-Induced JNK Activation.

BACKGROUND/AIMS: Gq protein-coupled receptors (GqPCRs) regulate various cellular processes including mainly proliferation and differentiation. In a previous study, we found that in prostate cancer cells, the GqPCR of GnRH induces apoptosis by reducing the PKC-dependent AKT activity and elevating JNK phosphorylation. Since it was thought that GqPCR induces mainly activation of AKT, we undertook to examine how general is this phenomenon and understand its signaling. METHODS: We used various cells to follow the phosphorylation of signaling components using western blotting. RESULTS: In a screen of 21 cell lines, we found that PKC activation results in the reduction of AKT activity, which correlates nicely to JNK activation and in some cases to apoptosis. To further understand the signaling pathways involved in this stimulation, we studied in detail the SVOG-4O and αT3-1 cells. We found that PGF2α and GnRH agonist (GnRH-a) indeed induce significant Gq- and PKC- dependent apoptosis in these cells. This is mediated by two signaling branches downstream of PKC, which converge at the level of MLK3 upstream of JNK. One branch consists on c-Src activation of the JNK cascade and the second involves reduction of AKT activity that alleviates its inhibitory effect on MLK3, to allow the flow of the c-Src signal to JNK. At the MAPKK level, we found that the signal is transmitted by MKK7 and not MKK4. CONCLUSION: Our results present a general mechanism that mediates a GqPCR-induced, death receptors-independent, apoptosis in physiological, as well as cancer-related systems.

Retained products of conception: What is the risk for recurrence on subsequent pregnancies?

OBJECTIVE: To investigate whether women who were surgically treated for retained products of conception (RPOC) by either suction curettage or hysteroscopy are at risk for recurrent RPOC on their subsequent pregnancies. STUDY DESIGN: Retrospective analysis of 442 women surgically treated for RPOC following delivery or abortion by suction curettage (N = 63, 14.3%) or hysteroscopy (N = 379, 85.7%). Information on subsequent pregnancies and their outcomes was available for 161 (36.4%) women. RESULTS: One or more live births were reported for 150 (93.2%) of the women for whom information on subsequent pregnancies was available. The overall rate of spontaneous abortions was 31/161 (19.3%). Recurrent RPOC were diagnosed in 25 (15.5%) cases, while third stage of labor placental problems (including retained placenta or cotyledons and placenta accreta) were found in 44 (27.3%) cases. Recurrent RPOC was associated with treatment by suction curettage compared with hysteroscopy for the initial RPOC on multivariate logistic regression analysis (Odds Ratio [OR] = 3.6, 95% Confidence Interval [CI]1.3-10.5, p = 0.01) and with the initial RPOC occurring after delivery compared with after abortion (OR = 8.4, 95%CI 1.8-39.5, p = 0.006). CONCLUSION: Women treated for RPOC are at risk for recurrent RPOC and for third stage of labor placental problems on their subsequent pregnancies, especially those who had been managed by suction curettage in comparison with operative hysteroscopy. Clinical and ultrasound follow-up in the early and late postpartum period should be considered in women with a history of RPOC.

Termination of pregnancy due to renal tract abnormalities: survey of 97 fetuses from a single medical center.

OBJECTIVE: The article aimed to assess the spectrum of fetal renal tract abnormalities as a major finding leading to termination of pregnancy (TOP). METHOD: The study population included all pregnant women with singleton pregnancy who underwent TOP in our institute because of fetal renal tract indications between 1998 and 2015. We specifically excluded TOPs performed because of multiple pregnancies, multisystem defects, abnormal karyotype and chromosomal or genetic defect not related to renal tract abnormalities. The patients were stratified into late TOP (≥24 weeks' gestation) and early TOP (<24 weeks' gestation). RESULTS: There were 97 (3.5%) cases of TOP because of fetal renal abnormalities and are the subjects of this study. Of these cases, 19 (19.6%) were at ≥24 weeks' gestation. Renal cystic disease was the leading indication for late TOP compared with early TOP group (31.8% vs 21.8%, respectively, p = 0.001). Routine prenatal care raised suspicion of abnormalities in 11 (50.9%) cases, and diagnosis was established by additional tests. Abnormal findings were either missed in one (5.3%) case or developed later in two (10.5%) cases. No routine prenatal screening was performed in the remaining five (26.3%) cases. CONCLUSIONS: We found a different distribution for fetal renal tract abnormalities leading to late versus early TOP. As many of renal tract malformations could have been diagnosed earlier (~32%), timely scanning may reduce the need for late TOPs in some cases. © 2016 John Wiley & Sons, Ltd.

The Dual Role of PEDF in the Pathogenesis of OHSS: Negating Both Angiogenic and Inflammatory Pathways.

CONTEXT: Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of assisted reproductive technologies. This complex syndrome is known to involve massive angiogenesis and inflammation. We have previously established the anti-angiogenic involvement of pigment epithelium-derived factor (PEDF) in the pathophysiology and treatment of OHSS. OBJECTIVE: Evaluate the anti-inflammatory role of PEDF in OHSS. DESIGN: In vivo mouse OHSS model and in vitro cultures of granulosa cells. MAIN OUTCOME: Changes in the expression of PEDF, IL-6, IL-8, and vascular endothelial growth factor (VEGF) were measured by quantitative PCR and ELISA; OHSS symptoms were recorded (body and ovarian weight gain and peritoneal vascular leakage quantified by the modified Miles's assay). RESULTS: Rat granulosa cell-line stimulated with lysophosphatidic acid (LPA), exhibited a significant increase in IL-6 expression, concomitantly with a decrease in PEDF level (P < .01). Co-stimulation with recombinant PEDF (rPEDF) decreased the expression of IL-6 significantly (P < .05). Furthermore, the expression of IL-6 and IL-8 increased in LPA-stimulated human primary granulosa cells (P < .01). Co-stimulation with rPEDF decreased the expression of LPA-induced IL-6 and IL-8 mRNA and protein by 4- and 2- to 5-fold, respectively. IL-8-stimulated human primary granulosa cells exhibited increased expression of VEGF mRNA; co-stimulation with hCG induced a significantly higher increase in the expression of VEGF mRNA (P < .001), which was counteracted by rPEDF. Subcutaneous injection of 0.5 mg/kg rPEDF to OHSS-induced mice reduced the increased expression of IL-6 in the ovary (P < .01) and alleviated the severity of all OHSS parameters. CONCLUSIONS: Our findings provide a framework that correlates down-regulation of OHSS symptoms caused by PEDF with both angiogenic and inflammatory pathways.

Pigment epithelium-derived factor regulation by human chorionic gonadotropin in granulosa cells.

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.

GnRH Agonist Triggering Modulates PEDF to VEGF Ratio Inversely to hCG in Granulosa Cells.

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.

Prevalence and risk factors of inadequate cervical dilation following laminaria insertion in second-trimester abortion--case control study.

OBJECTIVE: The objective was to explore the prevalence of and risk factors for inadequate cervical dilation following insertion of a single set of laminaria in women scheduled for dilation & evacuation (D&E) at 14-24 weeks' gestation. STUDY DESIGN: We retrospectively reviewed all cases of women who underwent pregnancy termination by D&E at 14-24 weeks' gestation between January 2003 and December 2013. All cases in which the surgical procedure was cancelled due to failure to achieve adequate cervical dilation after a single set of laminaria inadequate cervical dilation were included. The control group was women who underwent D&E following adequate cervical dilation after a single set of laminaria, and were matched according to gestational week in a ratio of 1:3. RESULTS: The overall dilation failure rate was 3.2%, with 4.0% among the induced-abortion patients and 1.5% among the patients with fetal demise (p=.002). Patients who had inadequate cervical dilation had lower rates of gravidity (p=.002) and previous spontaneous vaginal delivery (p<.001), along with higher rates of primigravidity, nulliparity (p<.001), previous cesarean section/s (p=.041), previous abdominal surgeries (p=.001) and previous cervical procedures (p=.003), compared to controls. A multivariable logistic regression analysis revealed two risk factors for inadequate cervical dilation following laminaria insertion, namely, previous cesarean section (p=.002) and previous cervical procedure (p<.001), whereas increased gravidity was found to protect against inadequate cervical dilation (p=.002). CONCLUSIONS: Previous cesarean section/s, cervical procedures and primigravidity were found to be risk factors for failure to achieve adequate cervical dilation after a single set of laminaria. Women who are scheduled for D&E, and in whom one of these risk factors exists, might benefit from additional interventions to achieve better cervical preparation.

Infertility following retained products of conception: is it the surgical procedure or the presence of trophoblastic tissue?

OBJECTIVE: To compare the reproductive outcome of women who underwent re-evacuation of the uterine cavity due to suspected retained products of conception (RPOC) and in whom trophoblastic tissue was confirmed by histopathologic examination to those with negative pathologic findings. STUDY DESIGN: We retrospectively reviewed all cases of women who underwent uterine re-evacuation due to suspected RPOC between January 2000 and December 2010. Reproductive outcomes were compared between women in whom trophoblastic tissue was confirmed by histopathologic examination and those with negative pathologic findings. RESULTS: A total of 240 patients underwent uterine re-evacuation due to suspected RPOC, of whom 162 (67.5%) had pathological examination positive for RPOC, and 78 (32.5%) had pathologically negative RPOC. The rate of a new infertility problem following resection of a positive pathologic finding was significantly higher compared with a negative finding (P=0.029). The mean time to conception was significantly longer after resection of a positive pathologic finding compared with a negative finding (P<0.001). A significantly higher rate of hypomenorrhea/amenorrhea was found following resection of a positive pathologic finding compared with a negative finding (P=0.017). CONCLUSION: RPOC-associated infertility is primarily related to the presence of trophoblastic tissue rather than the surgical intervention per se in the gravid uterus.

Role of pigment epithelium-derived factor in the reproductive system.

The physiological function of the female reproductive organs is hormonally controlled. In each cycle, the reproductive organs undergo tissue modifications that are accompanied by formation and destruction of blood vessels. Proper angiogenesis requires an accurate balance between stimulatory and inhibitory signals, provided by pro- and anti-angiogenic factors. As with many other tissues, vascular endothelial growth factor (VEGF) appears to be one of the major pro-angiogenic factors in the female reproductive organs. Pigment epithelium-derived factor (PEDF) is a non-inhibitory member of the serine protease inhibitors (serpin) superfamily, possessing potent physiologic anti-angiogenic activity that negates VEGF activity. The role of PEDF in decreasing abnormal neovascularization by exerting its anti-angiogenic effect that inhibits pro-angiogenic factors, including VEGF, has been investigated mainly in the eye and in cancer. This review summarizes the function of PEDF in the reproductive system, showing its hormonal regulation and its anti-angiogenic activity. Furthermore, some pathologies of the female reproductive organs, including endometriosis, ovarian hyperstimulation syndrome, polycystic ovary syndrome, and others, are associated with a faulty angiogenic process. This review illuminates the role of PEDF in their pathogenesis and treatment. Collectively, we can conclude that although PEDF seems to play an essential role in the physiology and pathophysiology of the reproductive system, its full role and mechanism of action still need to be elucidated.

A comparison of reproductive outcomes following hysteroscopic management versus dilatation and curettage of retained products of conception.

OBJECTIVE: To compare the reproductive outcome of women who underwent blind dilatation and curettage (D&C) with those who underwent hysteroscopic resection of pathologically confirmed retained products of conception (RPOC). METHODS: Medical records of women who underwent either D&C or hysteroscopic resection of RPOC at Assaf Harofeh Medical Center, Israel, between 2000 and 2010 were retrospectively reviewed. RESULTS: A total of 177 women with pathologically confirmed RPOC underwent either D&C (n=94, 53.1%) or hysteroscopy (n=83, 46.9%). Mean time to conception was significantly shorter after hysteroscopy than after D&C (7.4±7 vs 12.9±16.8 months, P=0.037). Rate of occurrence of a newly diagnosed infertility problem was significantly higher following D&C than hysteroscopy (23 [24.5%] vs 10 [12.0%]; P=0.034). Etiology of the new problem was mechanical, including tubal occlusion and intrauterine adhesions. Logistic regression comparing both methods revealed that hysteroscopic resection was associated with a significant reduction in the occurrence of a new infertility problem compared with D&C (OR 0.42; 95% CI, 0.18-0.96, P=0.04). CONCLUSION: Hysteroscopic removal of RPOC is associated with a shorter mean time to further conception and a lower rate of occurrence of newly diagnosed infertility problems than D&C.

Hormonal regulation of pigment epithelium-derived factor (PEDF) expression in the endometrium.

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.

Intercoat (Oxiplex/AP gel) for preventing intrauterine adhesions after operative hysteroscopy for suspected retained products of conception: double-blind, prospective, randomized pilot study.

STUDY OBJECTIVE: To evaluate the safety and effectiveness of Oxiplex/AP gel (Intercoat) in reducing intrauterine adhesion formation after hysteroscopic treatment because of retained products of conception (RPOC). DESIGN: Prospective double-blind, randomized, controlled pilot study (Canadian Task Force classification I). SETTING: Tertiary medical center. PATIENTS: All women who underwent hysteroscopic treatment because of RPOC at our institution between September 2009 and June 2012 were invited to participate. After operative hysteroscopy, participants were randomized to either have their uterine cavity filled with Oxiplex/AP gel (study group, n = 26) or not (control group, n = 26). INTERVENTIONS: Diagnostic office hysteroscopy to assess for adhesion formation was performed after 6 to 8 weeks. Findings were graded according to the American Fertility Society classification. Rates of subsequent pregnancy in the 2 groups were assessed. MEASUREMENTS AND MAIN RESULTS: Intraoperative complication rates were similar between the 2 groups. There were no postoperative complications after Oxiplex/AP gel application. Moderate to severe adhesions developed in 1 woman (4%) in the study group and 3 (14%) in the control group (p = .80). During follow-up of 20 months (range, 2-33 months), 7 women (27%) in the treatment group conceived, compared with 3 (14%) in the control group (p = .50). CONCLUSION: Intrauterine application of Oxiplex/AP gel after hysteroscopic removal of RPOC is safe. In this small sample, the difference in the rate of intrauterine adhesions was not statistically significant. A larger study would enable further establishment of the safety and efficacy of use of this gel.