Endometriosis: Becker CM

Wagstaff D, Becker CM. · No affiliation provided · Br J Hosp Med (Lond). · Pubmed #18646409 No free full text.

This publication has no abstract.

May K, Becker CM. · Nuffield Department of Obstetrics and Gynecology, University of Oxford, John Radcliffe Hospital, Oxford, UK. · Minerva Ginecol. · Pubmed #18547987 No free full text.

Abstract: Endometriosis is a common gynecological condition, responsible for significant morbidity and social-economic impact. Although the condition has been recognized for many years, the underlying pathophysiology is poorly understood. In turn, this results in inadequate treatment and high recurrence rates. Various theories try to explain the presence of endometrial tissue outside the uterine cavity. However, none of them can explain all disease locations and appearances, and it is unclear how these fragments establish into endometriotic lesions. New vessel formation has long been recognized as a feature of endometriosis, often clearly visible at laparoscopy. Recent work has focused on identifying the role of vascularization in the pathogenesis of endometriosis, by allowing lesions to establish and grow. In this review the authors outline the basic mechanisms of angiogenesis and vasculogenesis in the human eutopic endometrium, and consider how this data can be applied to endometriotic implants. Furthermore, the authors discuss molecular mechanisms of angiogenesis and vasculogenesis, and how this may be used to therapeutic advantage in the treatment of endometriosis.

Becker CM, D'Amato RJ. · Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, UK. · Microvasc Res. · Pubmed #17574280 No free full text.

Abstract: Endometriosis, the presence of endometrium-like tissue outside of the uterine cavity, is a common disease among women of reproductive age. Typical symptoms include abdominal pain and painful menstruation. In addition, endometriosis is associated with reduced fertility. Current treatment modalities, the surgical removal of endometriotic lesions and the hormonal suppression of estrogen are associated with significant morbidity, side-effects and recurrence rates. Despite uncertainties about the pathophysiology of the disease it has recently become apparent that angiogenesis plays a pivotal role in endometriosis. This review focuses on a multitude of factors involved in the angiogenic phenotype of endometriosis demonstrating that many biological systems such as the immune system and steroid hormones are closely connected to angiogenic pathways in this disease. In addition, experimental and clinical data are discussed that concentrate on the inhibition of angiogenesis as a novel therapeutic approach for endometriosis.

Becker CM, Bartley J, Mechsner S, Ebert AD. · Deutsches Endometriose Kompetenz-und Experten-Netzwerk, Frauenklinik und Poliklinik, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin. · Zentralbl Gynakol. · Pubmed #15389376 No free full text.

Abstract: Endometriosis is considered a chronic disease of women during their reproductive phase, which resembles many signs of malignancy. So far, therapeutic options for endometriosis-associated pain and infertility are unsatisfactory and often lead to recurrence of disease after termination of treatment. Angiogenesis seems to play an important role in the pathogenesis of endometriosis. The use of angiogenesis inhibitors may add an important new tool to well-established treatment schedules. Therefore, it is very important to thoroughly investigate the role of angiogenesis in endometriosis with respect to the female reproductive system.

Pakneshan P, Birsner AE, Adini I, Becker CM, D'Amato RJ. · Departments of Surgery, Harvard Medical School, Children's Hospital Boston, Boston, Massachusetts, USA. · Invest Ophthalmol Vis Sci. · Pubmed #18487370 No free full text.

Abstract: PURPOSE: Angiogenesis, the formation of new capillary blood vessels, is an essential biological process under physiological conditions, including embryonic development, reproduction, and wound repair. Under pathologic conditions, this process plays a critical role in a variety of diseases such as cancer, rheumatoid arthritis, atherosclerosis, endometriosis, diabetic retinopathy, and age-related macular degeneration. The purpose of this study was to examine the effects of cyclooxygenase inhibitors on basic fibroblast growth factor (bFGF)- and vascular endothelial growth factor (VEGF)-mediated ocular neovascularization and permeability. METHODS: A modified Miles vascular permeability assay was used to examine VEGF-induced vascular hyperpermeability, and the mouse corneal model of angiogenesis was used to compare the efficacy of systemic treatment with different nonsteroidal anti-inflammatory drugs (NSAIDs) on bFGF- and VEGF-induced angiogenesis. RESULTS: The authors demonstrated that systemic application of most NSAIDs, but not acetaminophen, blocked VEGF-induced permeability in mice. However, systemic treatment of mice with NSAIDs resulted in the differential inhibition of bFGF-induced (5%-57%) and VEGF-induced (3%-66%) corneal angiogenesis. The selective COX-2 inhibitors were more effective at suppressing bFGF-induced angiogenesis than VEGF-induced angiogenesis. CONCLUSIONS: Though most NSAIDS are effective at suppressing vascular leak, there exists a differential efficacy at suppressing the angiogenic response of specific cytokines such as bFGF and VEGF.

Becker CM, Rohwer N, Funakoshi T, Cramer T, Bernhardt W, Birsner A, Folkman J, D'Amato RJ. · Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Womens Centre Headington, University of Oxford, Oxford, OX3 9DU, UK. · Am J Pathol. · Pubmed #18202195 links to  free full text

Abstract: Endometriosis, the presence of ectopic endometrial tissue outside the uterine cavity, is a common disease affecting women during their reproductive years. Current therapeutic success is often unsatisfactory because of limited insight into disease mechanisms. Nevertheless, angiogenesis plays an essential role in the pathogenesis of the disease, making it a potential novel target for therapy. In the current study, we demonstrate in an established mouse model of endometriosis that transient hypoxia in transplanted endometriosis-like lesions results in the up-regulation of hypoxia-inducible factor-1alpha (HIF-1alpha), leading to the expression of vascular endothelial growth factor (VEGF), a key player in endometriosis-associated angiogenesis. Systemic treatment with the angiogenesis inhibitor 2-methoxyestradiol suppressed HIF-1alpha expression in vivo, resulting in a decreased downstream expression of HIF-1alpha target genes, such as for VEGF, phosphoglycerate kinase, and glucose transporter-1. 2-Methoxyestradiol also suppressed VEGF-induced vascular permeability, as demonstrated in a modified Miles assay. Finally, systemic treatment with 2-methoxyestradiol significantly inhibited the growth of endometriosis-like lesions in a dose-dependent manner. In conclusion, hypoxia appears to play an important role in the pathogenesis of endometriosis and endometriosis-associated angiogenesis, and the angiogenesis inhibitor 2-methoxyestradiol may be a potential candidate for systemic treatment in the future.

Becker CM, Wright RD, Satchi-Fainaro R, Funakoshi T, Folkman J, Kung AL, D'Amato RJ. · Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115, USA. · Am J Pathol. · Pubmed #16723720 links to  free full text

Abstract: Endometriosis, the presence of ectopic endometrial tissue, is a common disease associated with high morbidity and socioeconomic problems. Angiogenesis, the formation of new blood vessels, plays an important role in the formation and growth of endometriotic lesions. We have created a novel, noninvasive model to monitor the growth of these lesions and the associated angiogenesis in vivo. First, we generated luciferase-expressing transgenic mice by inserting the human ubiquitin C promoter coupled to the firefly luciferase reporter. Injection of luciferin in these mice causes full-body bioluminescence, which can be detected using a low-light CCD camera. Endometrial tissue from these transgenic mice was surgically implanted into nonluminescent recipients. Bioluminescence of lesions was noninvasively imaged after intravenous or intraperitoneal injection of luciferin. Transabdominal luminescence compared well with the location of the transgenic endometriotic lesions, and lesion size correlated with the intensity of luminescence. Systemic treatment with the angiogenesis inhibitors caplostatin and endostatin peptide mP-1 delayed and suppressed the onset and intensity of the luminescent signal. Caplostatin suppressed the growth of endometriotic lesions by 59% compared with controls. This novel, noninvasive model of endometriosis provides a means to study early angiogenesis in vivo and to monitor endometriotic growth and the efficacy of systemic antiangiogenic therapy.

Becker CM, Sampson DA, Short SM, Javaherian K, Folkman J, D'Amato RJ. · Department of Surgery, Vascular Biology Program, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Fertil Steril. · Pubmed #16412733 No free full text.

Abstract: OBJECTIVE: To determine the active peptide regions inside the angiogenesis inhibitor endostatin that can inhibit endothelial migration in vitro and also inhibit endometriosis in a mouse model. DESIGN: Pharmacologic intervention in a surgically induced mouse model of endometriosis and endothelial migration assay. SETTING: Animal research and laboratory facility. SUBJECT(S): Eight-week-old, female C57BL/6 mice and human microvascular endothelial cells. INTERVENTION(S): Eight overlapping synthetic peptides were tested for inhibitory potential on endothelial migration in vitro. The peptides with significant activity then were given for 4 weeks to mice after implantation of autologous endometrium. MAIN OUTCOME MEASURE(S): Inhibition of vascular endothelial growth factor-induced endothelial migration for in vitro studies. In vivo studies examined the growth rate of endometriotic lesions after 4 weeks of treatment, as well as the effect on estrous cycling and ovulation as assessed by corpus luteum formation. RESULT(S): The N-terminal mP-1 peptide and the internal mP-6 peptide inhibited endothelial migration in a dose-dependent manner. Additionally, both synthetic peptides suppressed growth of endometriotic lesions significantly in vivo. However, estrous cycling and corpus luteum formation were normal in both groups. CONCLUSION(S): Short endostatin fragments may be promising as a new, nontoxic therapeutic strategy for the treatment of endometriosis without inhibition of normal estrous cycles.

Becker CM, Sampson DA, Rupnick MA, Rohan RM, Efstathiou JA, Short SM, Taylor GA, Folkman J, D'Amato RJ. · Department of Surgery, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Fertil Steril. · Pubmed #16210006 No free full text.

Abstract: OBJECTIVE: To determine whether endometriosis can be treated with the angiogenesis inhibitor endostatin and the effect of this treatment on fertility and reproduction. DESIGN: Pharmacologic intervention in a surgically induced model of endometriosis and in female mice undergoing mating. SETTING: Animal research facility. ANIMAL(S): Eight-week-old, female C57BL/6 and SCID mice. INTERVENTION(S): After implantation of autologous endometrium, mice received endostatin or the vehicle-matched control for 4 weeks. For the reproductive function study, mice receiving endostatin or vehicle were mated and reproductive functions were observed. MAIN OUTCOME MEASURE(S): Growth of endometriotic lesions after 4 weeks of treatment; estrous cycling, corpus luteum formation, serum hormone levels, and mating time as fertility measures; and pregnancy rates, length of pregnancy, fetal vitality, number, and outcome of litter as reproductive measures. RESULT(S): Endostatin suppressed the growth of endometriotic lesions by 47% compared with controls. Estrous cycling and corpus luteum formation were normal in both groups. Female mice receiving endostatin were as fertile as mice receiving vehicle, had normal pregnancies, and delivered the same number of pups. The offspring were healthy without teratogenic stigmata and reproduced normally themselves. CONCLUSION(S): Antiangiogenic therapy with endostatin may present a promising novel, nontoxic therapeutic option for patients with endometriosis.