Alessandro Fasciani

Changes in vascular endothelial growth factor levels and the risk of ovarian hyperstimulation syndrome in women enrolled in an in vitro fertilization program

OBJECTIVE To evaluate plasma and follicular fluid levels of vascular endothelial growth factor (VEGF) in women undergoing controlled ovarian hyperstimulation to establish the possible role of this growth factor as a predictive marker of ovarian hyperstimulation syndrome (OHSS). DESIGN Prospective observational study. SETTING University hospital infertility unit. PATIENT(S) Fifteen women at risk of OHSS and 15 controls. INTERVENTION(S) An IM injection of hCG was administered; plasma and follicular fluid samples were collected 34-38 hours after administration of hCG. MAIN OUTCOME MEASURE(S) VEGF levels in plasma and in follicular fluid. RESULT(S) VEGF levels increased after hCG administration in the patients at risk of developing OHSS and in those who developed OHSS. Further, on the day of the oocyte retrieval the increase in the VEGF levels in the plasma of the patients who developed OHSS was statistically significant compared with the increase in the levels in the women who did not. On the same day, the levels of VEGF in follicular fluid were 10 times greater than those in plasma. CONCLUSION(S) Plasma levels of VEGF peak after hCG administration and are related to the risk of developing OHSS.

Vascular endothelial growth factor and interleukin-8 in ovarian cystic pathology

OBJECTIVE To determine the levels of the angiogenic factors vascular endothelial growth factor (VEGF) and interleukin (IL-8) in ovarian cysts. DESIGN Prospective descriptive study. SETTING University hospital. PATIENT(S) One hundred women, of whom 9 had ovarian carcinomas, 38 had ovarian endometriomata, 43 had serous ovarian cysts, and 10 had follicular ovarian cysts. INTERVENTION(S) Sampling of serum and ovarian cystic fluid before and during surgery. MAIN OUTCOME MEASURE Levels of VEGF and IL-8 in cystic fluid and serum. RESULT(S) Levels of both VEGF and IL-8 were found to be significantly higher in the cystic fluid of ovarian carcinomas and endometriomata than in serous and follicular cysts. In endometriomata fluid, levels of VEGF and IL-8 were found to be directly correlated (r = 0.68; P=.0074). Serum levels of VEGF were significantly higher in women with ovarian carcinomas and endometriomata than in those with serous and follicular cysts. Ovarian cancers and endometriomata were similar in terms of cystic concentrations of VEGF and IL-8 and in serum levels of VEGF. CONCLUSION(S) An increase in angiogenic factors that differentiate ovarian carcinomas and endometriomata from other kinds of ovarian pathology is demonstrated.

In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists.

Background  Endothelial cells of human blood vessels (arteries and veins) show high levels of somatostatin subtype‐1 receptor (sst1). The aim of the present study is to investigate the inhibitory effects of novel somatostatin analogs, highly selective for human sst1, on in vitro angiogenesis and their modulation of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor‐2 (VEGFR‐2) expression.

Vascular endothelial growth factor, interleukin-6 and interleukin-2 in serum and follicular fluid of patients with ovarian hyperstimulation syndrome

BACKGROUND The pathogenesis of ovarian hyperstimulation syndrome (OHSS) is not completely understood. OBJECTIVE To investigate the presence of VEGF, IL-6 and IL-2, in serum and follicular fluid, in patients developing severe OHSS. STUDY DESIGN We enrolled 101 women undergoing in vitro fertilization. Eight patients developing severe OHSS were compared with 43 high risk patients and 50 controls. We analyzed VEGF and IL-6 in serum collected before hCG administration, and in both serum and follicular fluid on the day of oocyte retrieval. RESULTS OHSS patients presented follicular fluid IL-6 levels higher than both the patients at risk and controls (P<0.05). On the day of the oocyte retrieval the patients developing OHSS showed serum and follicular VEGF values higher than the ones of the patients at risk (P<0.05). Serum and follicular fluid IL-2 levels showed no differences between the examined groups. IL-2, IL-6 and VEGF values were not correlated with each other. CONCLUSIONS Angiogenesis and inflammation processes are both present in severe OHSS.

Three-dimensional in vitro culture of endometrial explants mimics the early stages of endometriosis

OBJECTIVE To reproduce the earliest phases of endometriosis using a new in vitro model in which cells from a cultured endometrial fragment can proliferate, invade, reconstitute new endometrial-like tissue, and generate blood vessels. DESIGN Experimental in vitro study. SETTING A hospital-based academic research institute. PATIENT(S) Five normal ovulating women undergoing surgery for various benign gynecological indications. INTERVENTION(S) Endometrial samples obtained from the fundus of the uterine cavity were placed in a three-dimensional fibrin matrix culture system. MAIN OUTCOME MEASURE(S) Degree of proliferation of stromal cells and invasion of the fibrin matrix, gland, and stroma formation, vessel sprouting, and immunohistochemical characterization of various cellular components. RESULT(S) During the first week of culture, an endometrial cell outgrowth was observed from the original fragments in 120 of 144 wells (83.3%). Subsequently, cell outgrowths could be quantified in 132 (91.6%), 129 (89.5%), and 127 (88.1%) of the wells after 15, 60, and 90 days, respectively. An invasion of the matrix by the human endometrial cells led to the formation of tubular structures that coalesced into tissue, architecturally resembling endometrium and in which the glands were immunohistochemically positive for cytokeratin. New capillaries, immunohistochemically positive for CD31 and vimentin, sprouted from the endometrial outgrowths at the beginning of the fifth week of culture. CONCLUSION(S) These data show that cells from endometrial explants can proliferate and invade a fibrin matrix in vitro generating new glands, stroma, and vessels consistent with endometriosis. The three-dimensional fibrin matrix used in the present study provides an opportunity to observe the earliest biological events of endometriosis in a quantifiable way.

Correlation between the amount of follicle-stimulating hormone administered and plasma and follicular fluid vascular endothelial growth factor concentrations in women undergoing in vitro fertilization

Vascular endothelial growth factor (VEGF) is a powerful mediator for vessel permeability and it is strongly implicated in angiogenesis, stimulating endothelial cell proliferation as well as capillary permeability. We studied 30 women undergoing in vitro fertilization (IVF) programs and evaluated, on the day of oocyte retrieval, VEGF levels in plasma and follicular fluid and related such concentrations to the amount of follicle-stimulating hormone (FSH) administered. Furthermore, the correlation between the number of oocytes retrieved and the VEGF concentrations both in plasma and in follicular fluid were also investigated. Results indicate that follicular fluid VEGF concentrations and the amount of pure FSH administered were directly proportional (p < 0.05). On the day of oocyte retrieval, the VEGF plasma concentrations and the number of oocytes collected were directly proportional (p < 0.05). VEGF plasma levels increased after human chorionic gonadotropin (hCG) administration (30.37 +/- 18.60 pg/ml up to 52.62 +/- 43.63 pg/ml). In conclusion, this study demonstrates that the doses of pure FSH administered to women undergoing IVF cycles have a crucial role in hCG-dependent VEGF production.

Serum vascular endothelial growth factor levels before starting gonadotropin treatment in women who have developed moderate forms of ovarian hyperstimulation syndrome

The study aims to evaluate whether serum vascular endothelial growth factor (VEGF) levels, before treatment with gonadotropins, may be considered a predictive marker of moderate ovarian hyperstimulation syndrome (OHSS). At the University of Pisa hospital infertility unit we have retrospectively selected 10 patients who developed moderate forms of OHSS and 30 control patients who presented a normal response to ovarian stimulation among 400 women undergoing in vitro fertilization (IVF). Serum samples were collected before starting pFSH administration (150-300 IU/day). VEGF levels in serum were measured. No statistically significant difference was found between the serum VEGF levels of patients who developed moderate forms of OHSS and women without any symptoms of the syndrome. Further, serum VEGF concentrations were not significantly correlated with the age of the patients, the number of international units of FSH administered during the cycle of stimulation, the follicle and oocyte numbers counted on the day of the egg retrieval or estradiol levels detected on the same day. This study demonstrates that serum VEGF levels, before starting gonadotropin treatment, are not predictive of the subsequent development of moderate forms of ovarian hyperstimulation syndrome.

Overexpression and Functional Relevance of Somatostatin Receptor-1, -2, and -5 in Endometrium and Endometriotic Lesions

CONTEXT Somatostatin plays a role in physiological and pathological cell proliferation and angiogenesis. Five subtypes of somatostatin receptors have been identified, and the therapeutic use of somatostatin receptor-selective agonists has been reported in several diseases. OBJECTIVES The aim was to describe the expression and the functional relevance of three human somatostatin receptors (sst1, sst2, and sst5) in tissues of women with and without endometriosis. PATIENTS AND METHODS This pilot study analyzed endometrium, ovarian endometriomata, and peritoneal lesions in 15 patients affected by endometriosis and the endometrium of five women without endometriosis. 111In-pentetreotide scintigraphy was used to detect endometriotic lesions; real-time RT-PCR and immunohistochemistry for sst1, sst2, and sst5 were performed. Migration and proliferation assays were performed on human endometrial stromal cells (ESC) treated with somatostatin and octreotide for 48 h. RESULTS 111In-pentetreotide scintigraphy was able to correctly identify and locate pelvic endometriotic lesions as confirmed by computed tomography scans. The endometrium of women with endometriosis expressed significantly more sst1, sst2, and sst5 in comparison to that of control women. Moreover, sst1, sst2, and sst5 were highly expressed in ovarian endometriomata and peritoneal lesions. The sst receptor ligand octreotide significantly inhibited ESC migration and proliferation with a maximum effect at 10(-6) m, whereas somatostatin was effective only on ESC growth. CONCLUSIONS This is the first report characterizing the overexpression and functional relevance of somatostatin receptors in eutopic endometrium and lesions of patients affected by endometriosis. Thus, the use of these receptors may provide new strategies for the diagnosis and treatment of endometriosis.

Fertility drugs and ovarian cancer

Recent case reports of ovarian cancer associated with infertility treatment raise the question of a possible etiopathogenetic role of fertility drugs in ovarian cancer. In this paper, the possible relationship between infertility treatment and ovarian cancer is reviewed with respect to the epidemiological and pathogenetic profiles of ovarian cancer and the potential risk factors associated with fertility drugs; a case report review and a critical reappraisal are also provided within this article. Currently available data in the literature, from epidemiological studies and case reports, suggest that a direct causal effect of infertility treatment on ovarian cancer seems unlikely. Since infertile women are likely to have a higher risk for the development of ovarian cancer, and the role of fertility drugs in the etiopathogenesis of ovarian carcinoma is not established, a close clinical examination of infertile patients before, during and after infertility treatment is recommended. Moreover, further investigation is required to resolve the question of the possible association between fertility drugs and ovarian cancer through large prospective epidemiological or retrospective case-control studies.

Endometriosis Index: A software-derived score to predict the presence and severity of the disease

ObjectiveTo develop a clinical index that will positively predict the presence of endometriosis.DesignProspective single-center observational study. Setting: A hospital-based institute.Patients120 patients affected by chronic pelvic pain, infertility or with clinical suspicion of endometriosis. Interventions: Electronic processing of clinical data with software-assistance at the end of each consultation and digital video recording of surgeries.Main Outcome MeasuresEndometriosis Index (EI), the score calculated using clinical parameters correlated with macroscopic/microscopic presence or absence of endometriosis.ResultsEndometriosis was staged and treated in 95 cases, the remaining 25 women presented benign pathology with no endometriosis. Patients with positive operative findings of endometriosis had a mean (± standard deviation) pre-operative EI score of 22 ± 12, while mean EI value of patients with no operative findings of endometriosis was 8 ± 6 (p 28 (75th percentile value) versus women with EI score ...