Vascular endothelial growth factor C is increased in endometrium and promotes endothelial functions, vascular permeability and angiogenesis and growth of endometriosis.

Endometriosis is an angiogenesis-dependent disease. Many studies demonstrated inhibition of angiogenesis leads to inhibition of endometriotic growth, however underlying mechanism is still not fully understood. Our previous study suggested vascular endothelial growth factor C (VEGF-C) as a target of anti-angiogenesis therapy for endometriosis. In this study, VEGF-C in endometrium and its role in angiogenesis of endometriosis were studied. Human endometrium were obtained from women with and without endometriosis for molecular studies. VEGF-A, VEGF-B, VEGF-C and VEGF-D mRNA and proteins in eutopic and ectopic endometrium were measured. Human endothelial cells were transfected with VEGF-C siRNA in vitro, effects of VEGF-C on endothelial cell migration, invasion and tube formation were investigated in vitro. Angiogenesis was inhibited in wild type mice, vascular permeability in dermal skin was determined in vivo. Transplanted endometrium were inhibited by VEGF-C siRNA in immunocompromised mice, development, growth and angiogenesis of the experimental endometriosis were compared in vivo. The results showed that VEGF-C mRNA and protein were increased in eutopic and ectopic endometrium of endometriosis patients. VEGF-C siRNA significantly inhibited endothelial cell migration and tube formation. VEGF-C siRNA significantly inhibited development and angiogenesis of the experimental endometriotic lesions in mice. Supplementation and over-expression of VEGF-C significantly reversed the inhibitory effects on the endothelial functions, vascular permeability and endometriotic growth. In conclusion, VEGF-C is increased in endometrium and it promotes endothelial functions, vascular permeability and development of experimental endometriosis. VEGF-C is important for angiogenesis in endometriosis.

Origin of circulating 18-oxocortisol in the normal human adrenal.

18-Oxocortisol is the product of the metabolism of 11-deoxycortisol by the mitochondrial enzyme aldosterone synthase (CYP11B2). The traditional concept is that the CYP11B2 is exclusively expressed in zona glomerulosa cells and the 17α-hydroxylase (CYP17A1) enzyme, required to synthesize 11-deoxycortisol, is in the zona fasciculata of the human adrenal. It has been postulated that the substrate for 18-oxocortisol is either cortisol from the circulation or from zona fasciculata cells adjacent to the zona glomerulosa. P-glycoprotein, which is highly expressed in steroidogenic cells of the adrenal gland, efficiently expels cortisol from the cell. Double immunofluorescence staining for the CYP11B2 and CYP17A1 enzymes in 7 human adrenals demonstrated that a highly variable number of cells in different areas of the zona glomerulosa co-expressed both enzymes. In addition, there were a variable number of cells that exclusively expressed the CYP17A1 embedded within the zona glomerulosa surrounded by CYP11B2-expressing cells. 18-Oxocortisol in the media of human adrenocortical HAC15 cells was measured by ELISA after incubation with and without 10 nM of angiotensin II to stimulate CYP11B2 activity, with and without the 3ß-hydroxysteroid dehydrogenase (HSD3B) inhibitor trilostane, and with variable amounts of cortisol or 11-deoxycortisol. Cortisol was a poor substrate, while 11-deoxycortisol was a significant substrate for the synthesis of 18-oxocortisol. These data suggest that the biosynthesis of 18-oxocortisol in the human adrenal is likely catalyzed by co-expression of the two crucial enzymes CYP17A1 and CYP11B2 in a small proportion of cells within the zona glomerulosa. It is also possible that 11-deoxycortisol diffusing from cells expressing only CYP17A1 interspersed with cells expressing the CYP11B2 enzyme may be a paracrine substrate in the synthesis of 18-oxocortisol.

Lymphadenectomy for the management of endometrial cancer.

BACKGROUND: Endometrial carcinoma is the most common gynaecological cancer in western Europe and North America. Lymph node metastases can be found in approximately 10% of women who clinically have cancer confined to the womb prior to surgery and removal of all pelvic and para-aortic lymph nodes (lymphadenectomy) is widely advocated. Pelvic and para-aortic lymphadenectomy is part of the FIGO staging system for endometrial cancer. This recommendation is based on non-randomised controlled trials (RCTs) data that suggested improvement in survival following pelvic and para-aortic lymphadenectomy. However, treatment of pelvic lymph nodes may not confer a direct therapeutic benefit, other than allocating women to poorer prognosis groups. Furthermore, a systematic review and meta-analysis of RCTs of routine adjuvant radiotherapy to treat possible lymph node metastases in women with early-stage endometrial cancer, did not find a survival advantage. Surgical removal of pelvic and para-aortic lymph nodes has serious potential short and long-term sequelae and most women will not have positive lymph nodes. It is therefore important to establish the clinical value of a treatment with known morbidity. OBJECTIVES: To evaluate the effectiveness and safety of lymphadenectomy for the management of endometrial cancer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2009. Cochrane Gynaecological Cancer Review Group Trials Register, MEDLINE (1966 to June 2009), Embase (1966 to June 2009). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. SELECTION CRITERIA: RCTs and quasi-RCTs that compared lymphadenectomy with no lymphadenectomy, in adult women diagnosed with endometrial cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. Hazard ratios (HRs) for overall and progression-free survival and risk ratios (RRs) comparing adverse events in women who received lymphadenectomy or no lymphadenectomy were pooled in random effects meta-analyses. MAIN RESULTS: Two RCTs met the inclusion criteria; they randomised 1945 women, and reported HRs for survival, adjusted for prognostic factors, based on 1851 women.Meta-analysis indicated no significant difference in overall and recurrence-free survival between women who received lymphadenectomy and those who received no lymphadenectomy (pooled HR = 1.07, 95% CI: 0.81 to 1.43 and HR = 1.23, 95% CI: 0.96 to 1.58 for overall and recurrence-free survival respectively).We found no statistically significant difference in risk of direct surgical morbidity between women who received lymphadenectomy and those who received no lymphadenectomy. However, women who received lymphadenectomy had a significantly higher risk of surgically related systemic morbidity and lymphoedema/lymphocyst formation than those who had no lymphadenectomy (RR = 3.72, 95% CI: 1.04 to 13.27 and RR = 8.39, 95% CI: 4.06, 17.33 for risk of surgically related systemic morbidity and lymphoedema/lymphocyst formation respectively). AUTHORS' CONCLUSIONS: We found no evidence that lymphadenectomy decreases the risk of death or disease recurrence compared with no lymphadenectomy in women with presumed stage I disease. The evidence on serious adverse events suggests that women who receive lymphadenectomy are more likely to experience surgically related systemic morbidity or lymphoedema/lymphocyst formation.