Objective To determine 1 expression levels of both DNA methyltransferases (DNMTs) and methyl-CpG-binding domain proteins (MBDs) in human endometrium throughout the menstrual cycle and in eutopic and ...ectopic endometrium of patients with endometriosis and 2 hormone responsiveness of DNMT and MBD expression in explant cultures of proliferative phase endometrium. Design In vitro study. Setting Academic medical center. Patient(s) Premenopausal women with and without endometriosis. Intervention(s) Explant cultures of proliferative phase endometrium were treated with vehicle, 17β-E2 , or a combination of E2 and P (E2 + P) for 24 hours. Main Outcome Measure(s) Expression levels of DNMT1, DNMT2, and DNMT3B and MBD1, MBD2, and MeCP2 with use of real-time quantitative polymerase chain reaction. Result(s) Expression levels of DNMT1 and MBD2 were significantly higher in secretory-phase endometrium compared with proliferative endometrium and menstrual endometrium. In explant cultures, treatment with E2 + P resulted in significant up-regulation of DNMT1 and MBD2. Expression levels of several DNMTs and MBDs were significantly lower in endometriotic lesions compared with eutopic endometrium of women with endometriosis and disease-free controls. Conclusion(s) These findings suggest a role for DNMTs and MBDs in the growth and differentiation of the human endometrium and support the notion that endometriosis may be an epigenetic disease.
It is widely known that angiogenesis plays a key role in endometriotic lesion formation and development. Antiangiogenic treatments aimed at inhibiting new vessel formation have proven efficient in ...experimental models. However, as antiangiogenic strategies do not target pre-existing pericyte-protected vessels, they require chronic administration and are likely to be beneficial for early-stage disease only or to prevent recurrence after surgery. Moreover, they may have detrimental effects on reproductive function. Vascular-disrupting agents (VDAs) have emerged as a promising new tool for the treatment of tumors. VDAs target established blood vessels, resulting in tumor ischemia and necrosis. These agents may therefore be more efficient against advanced disease. Two major types of VDAs are being developed for cancer: ligand-directed VDAs using antibodies, peptides and growth factors to deliver toxic effectors to tumor endothelium; and small-molecule VDAs exploiting physiological differences between tumor and normal endothelium to induce acute vascular shutdown. The ongoing evolution in genomics and proteomics is revolutionizing the discovery of novel endothelial markers. Several studies suggest that the vasculature of endometriotic lesions may have particular pathophysiological properties, which could be exploited for the development of selective VDAs. The aim of this review is to explore the merits and limitations of vascular therapy for the treatment of endometriosis.
BACKGROUND: Elective single embryo transfer (eSET) in a selected group of patients (i.e. young patients with at least one good quality embryo) reduces the number of multiple pregnancies in an IVF ...programme. However, the reduced overall multiple pregnancy rate (PR) is still unacceptably high. Therefore, a randomized controlled trial (RCT) was conducted comparing eSET and double embryo transfer (DET) in an unselected group of patients (i.e. irrespective of the woman’s age or embryo quality). METHODS: Consenting unselected patients were randomized between eSET (RCT-eSET) (n = 154) or DET (RCT-DET) (n = 154). Randomization was performed just prior to the first embryo transfer, provided that at least two 2PN zygotes were available. Non-participants received our standard transfer policy SP-eSET in a selected group of patients (n = 100), otherwise SP-DET (n = 122). RESULTS: The ongoing PR after RCT-eSET was significantly lower as compared with RCT-DET (21.4 versus 40.3%) and the twin PR was reduced from 21.0% after RCT-DET to 0% after RCT-eSET. The ongoing PRs after SP-eSET and SP-DET did not differ significantly (33.0 versus 30.3%), with an overall twin PR of 12.9%. CONCLUSION: To avoid twin pregnancies resulting from an IVF treatment, eSET should be applied in all patients. The consequence would be a halving of the ongoing PR as compared with applying a DET policy in all patients. The transfer of one embryo in a selected group of good prognosis patients leads to a less drastic reduction in PR but maintains a twin PR of 12.9%.
Endometriosis is defined as the presence of endometrial tissue outside the uterus. It affects 10-15% of women during reproductive age and has a big personal and social impact due to chronic pelvic ...pain, subfertility, loss of work-hours and medical costs. Such conditions are exacerbated by the fact that the correct diagnosis is made as late as 8-11 years after symptom presentation. This is due to the lack of a reliable non-invasive diagnostic test and the fact that the reference diagnostic standard is laparoscopy (invasive, expensive and not without risks). High-molecular weight gadofosveset-trisodium is used as contrast agent in Magnetic Resonance Imaging (MRI). Since it extravasates from hyperpermeable vessels more easily than from mature blood vessels, this contrast agent detects angiogenesis efficiently. Endometriosis has high angiogenic activity. Therefore, we have tested the possibility to detect endometriosis non-invasively using Dynamic Contrast-Enhanced MRI (DCE-MRI) and gadofosveset-trisodium as a contrast agent in a mouse model. Endometriotic lesions were surgically induced in nine mice by autologous transplantation. Three weeks after lesion induction, mice were scanned by DCE-MRI. Dynamic image analysis showed that the rates of uptake (inwash), persistence and outwash of the contrast agent were different between endometriosis and control tissues (large blood vessels and back muscle). Due to the extensive angiogenesis in induced lesions, the contrast agent persisted longer in endometriotic than control tissues, thus enhancing the MRI signal intensity. DCE-MRI was repeated five weeks after lesion induction, and contrast enhancement was similar to that observed three weeks after endometriosis induction. The endothelial-cell marker CD31 and the pericyte marker α-smooth-muscle-actin (mature vessels) were detected with immunohistochemistry and confirmed that endometriotic lesions had significantly higher prevalence of new vessels (CD31 only positive) than the uterus and control tissues. The diagnostic value of gadofosveset-trisodium to detect endometriosis should be tested in human settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Antiangiogenesis Therapy for Endometriosis Nap, Annemiek W; Griffioen, Arjan W; Dunselman, Gerard A. J ...
The journal of clinical endocrinology and metabolism,
2004-March, Letnik:
89, Številka:
3
Journal Article
Recenzirano
Odprti dostop
It is known that angiogenesis is of pivotal importance for the development of endometriosis. However, in the treatment of endometriosis patients, prevention of endometriosis lesion development only ...will not be sufficient as a therapy. Treatment options, aimed at interfering with established lesions, have to be developed. In this study we evaluated whether inhibition of angiogenesis by angiostatic therapy is also effective in antagonizing the sustentation of endometriosis. We evaluated the effect of the angiostatic compounds antihuman vascular endothelial growth factor, TNP-470, endostatin, and anginex on the growth of established endometriosis lesions in the nude mouse model. We show that human endometrium in the proliferative endometrium is highly angiogenic and that vascular endothelial growth factor-A is the most important angiogenesis promotory factor. The angiostatic compounds significantly decreased microvessel densities and the number of established endometriosis lesions. In the remaining lesions, the number of pericyte-protected vessels is not different in control and treated mice; however, the number of unprotected vessels was significantly reduced in the groups treated with the angiostatic agents. Our data demonstrate that inhibitors of angiogenesis effectively interfere with the maintenance and growth of endometriosis by inhibiting angiogenesis. This suggests that the use of angiostatic agents may be promising as a therapy for endometriosis.
Previous studies examining reproductive parameters in men with galactosemia have inconsistently demonstrated abnormalities. We hypothesized that men with galactosemia may demonstrate evidence of ...reproductive dysfunction. Pubertal history, physical examination, hormone levels and semen analyses were examined in 26 males with galactosemia and compared to those in 46 controls. The prevalence of cryptorchidism was higher in men with galactosemia than in the general population 11.6 % vs. 1.0 % (95%CI: 0.75–1.26; p < 0.001). Testosterone (461 ± 125 vs. 532 ± 133 ng%; p = 0.04), inhibin B (144 ± 66 vs. 183 ± 52 pg/mL; p = 0.002) and sperm concentration (46 ± 36 vs. 112 ± 75 × 10
6
spermatozoa/mL; p = 0.01) were lower and SHBG was higher (40.7 ± 21.5 vs 26.7 ± 14.6; p = 0.002) in men with galactosemia compared to controls. Semen volume was below normal in seven out of 12 men with galactosemia. Men with galactosemia have a higher than expected prevalence of cryptorchidism and low semen volumes. The subtle decrease in testosterone and inhibin B levels and sperm count may indicate mild defects in Sertoli and Leydig cell function, but does not point towards severe infertility causing reproductive impairment. Follow-up studies are needed to further determine the clinical consequences of these abnormalities.
Several assisted reproduction procedures, such as IVF and ICSI, are available for a variety of infertility problems. In fertility clinics, patients are screened for blood-borne viral infections, ...including hepatitis B virus (HBV). Reasons for screening are prevention of vertical transmission and laboratory safety. We present the case of a 26-year-old female patient with a chronic HBV infection, whose husband tested negative for hepatitis B. She and her husband were referred to our fertility clinic because of subfertility. Analysis of the husband's semen indicated the necessity of an ICSI procedure. The current Dutch guidelines advise against ICSI in chronic HBV carriers, since the risks and effects of chromosomal integration of HBV DNA in the fetus are not well-known. In this article, we review the scientific evidence for the risk of introducing HBV virus into the oocyte and subsequent integration of HBV DNA into the human genome, and debate the question of whether to do, or not to do, IVF and ICSI.
The diagnosis of peritoneal endometriosis during laparoscopy may be difficult due to the polymorphic aspects of the lesions. Enhanced imaging using contrast agents has potential to provide a better ...identification of peritoneal endometriosis. The aim of this systematic review is to provide an overview of the literature on what is known about the intraoperative laparoscopic visual enhancement of peritoneal endometriosis using contrast agents.
A systematic review was done of studies about enhanced imaging during laparoscopy for endometriosis using contrast agents. Clinical studies which contained a description of imaging with a contrast agent and also reported visual findings of endometriosis during laparoscopy, were included.
Nine suitable studies were identified. Intraoperative visualization of endometriosis was analyzed with or without histologic confirmation. Four studies evaluated 5-aminolevulinic acid-induced fluorescence (5-ALA), 1 study evaluated indigo carmine, 2 studies evaluated methylene blue (MB), 1 study evaluated indocyanine green (ICG) and 1 study evaluated so-called bloody peritoneal fluid painting. All studies, with a combined total of 171 included patients, showed potential of enhanced visibility of endometriosis using contrast agents. A combined total of 7 complications, all related to the use of 5-ALA, were reported.
We conclude that the use of contrast-based enhanced imaging during laparoscopy is promising and that it can provide a better visualization of peritoneal endometriosis. However, based on the limited data no technique of preference can yet be identified.
Twin pregnancies after IVF are still frequent and are considered high-risk pregnancies leading to high costs. Transferring one embryo can reduce the twin pregnancy rate. We compared ...cost-effectiveness of one fresh cycle elective single embryo transfer (eSET) versus one fresh cycle double embryo transfer (DET) in an unselected patient population. METHODS: Patients starting their first IVF cycle were randomized between eSET and DET. Societal costs per couple were determined empirically, from hormonal stimulation up to 42 weeks after embryo transfer. An incremental cost-effectiveness ratio (ICER) was calculated, representing additional costs per successful pregnancy. RESULTS: Successful pregnancy rates were 20.8% for eSET and 39.6% for DET. Societal costs per couple were significantly lower after eSET (€ 7334) compared with DET (€10 924). The ICER of DET compared with eSET was €19 096, meaning that each additional successful pregnancy in the DET group will cost €19 096 extra. CONCLUSIONS: One cycle eSET was less expensive, but also less effective compared to one cycle DET. It depends on the society’s willingness to pay for one extra successful pregnancy, whether one cycle DET is preferred from a cost-effectiveness point of view.
PDF
