Dan I. Lebovic

Angiogenic Factors in Endometriosis

Abstract: Similar to tumor metastases, endometriotic implants require neovascularization to establish, grow, and invade. The peritoneal environment is ideally suited to provide a proangiogenic milieu. Nevertheless, endometriotic lesions are found only in a minority of reproductive‐age women (∼10%) with retrograde menstruation. In this paper, we review the major cytokines, growth factors, steroid hormones, and eicosanoids responsible for angiogenesis in endometriosis. We postulate that interference with angiogenic principles expressed in the peritoneum may constitute novel therapeutic opportunities for the prevention, amelioration, or treatment of pelvic endometriosis.

Neutrophils infiltrating the endometrium express vascular endothelial growth factor: potential role in endometrial angiogenesis☆

OBJECTIVE(S) To identify leukocytes within the human endometrium expressing vascular endothelial growth factor (VEGF). DESIGN(S) Prospective cohort study. SETTING(S) Healthy volunteers in an academic research environment. PATIENTS(S) Twenty-one normal cycling women without abnormal menstrual bleeding or infertility. INTERVENTION(S) Endometrial tissue collection by Pipelle de Cornier aspiration. MAIN OUTCOME MEASURES(S) Histologic, immunohistochemical (CD3, CD34, CD56, CD68, neutrophil elastase, estrogen and P receptors, VEGF), and simultaneous double immunoenzymatic labeling analysis of VEGF-positive cells within the human endometrium. RESULT(S) Ten endometrial samples were obtained in the proliferative (cycle days 5-10) and 11 samples in the secretory phase (cycle days 15-26). Immunohistochemical analyses showed the expected distribution of the different leukocyte cell types. Besides epithelial and stromal endometrial cells, the predominant cells that stained for VEGF were neutrophil granulocytes. Neutrophils were more abundant in the secretory phase but they expressed neither estrogen-a nor P receptors. CONCLUSION(S) Neutrophil granulocytes infiltrating the human endometrium express VEGF and regulate cyclical endometrial vascular proliferation. Ovarian steroids indirectly influence neutrophil migration.

Vascular endothelial growth factor in reproductive biology.

The critical role of angiogenesis in embryology and tumor biology has been recognized for more than 20 years. However, the fact that neovascularization is essential to processes in mammalian female reproduction has only recently been appreciated widely. In this review we focus on a single angiogenic growth factor, vascular endothelial growth factor. As scientists have discovered in many aspects of cell biology, multiple and redundant signaling pathways have evolved in nature, presumably to protect essential biological functions from inactivating diseases or mutations. Despite this redundancy, some factors are of hierarchical importance. Vascular endothelial growth factor appears to be such a factor in the regulation of angiogenesis.

Effects of progestins and relaxin on glycodelin gene expression in human endometrial cells

OBJECTIVE Glycodelin is an endometrial protein proposed to play an important role in embryonic implantation. We examined the effects of progestins and relaxin on glycodelin transcription, synthesis, and secretion. STUDY DESIGN Northern blotting, metabolic labeling, and fluorography were used to assess glycodelin messenger ribonucleic acid and protein synthesis in endometrial tissue and cells. Luciferase reporter constructs transfected into endometrial adenocarcinoma cells (Ishikawa cells) were used to determine whether progestins or relaxin could activate the glycodelin gene promoter. RESULTS Progestins but not relaxin stimulated glycodelin secretion in primary epithelial cell cultures. A 452-base pair fragment of the glycodelin gene promoter was activated 4.3 +/- 0.7 times normal by 10-nmol/L promegestone; however, addition of relaxin to the same construct repressed progestin-stimulate promoter activation by >30%. CONCLUSION Glycodelin transcription, synthesis, and secretion by endometrial epithelial cells were stimulated by progestins. However, relaxin failed to stimulate production of this immunomodulatory protein and, in fact, repressed progestin-stimulated activation of the glycodelin gene promoter.

New paradigms in the diagnosis and management of endometriosis.

Purpose of review Endometriosis is a common gynecologic condition estimated to affect 10–15% of reproductive-aged women, 30% of women with subfertility, and 80% of women with chronic pelvic pain. Although mainstays of diagnosis and treatment are still commonly applied, there have been various advances in the modalities of diagnosis and management of this complex condition. This article provides an updated review of novel findings regarding the diagnosis and management of this challenging disease. Recent findings Despite an abundance of studies on noninvasive diagnostic markers for endometriosis, there is no single imaging study, biomarker or panel of biomarkers that has been validated for clinical diagnosis. New technologies, such as use of indocyanine green and fluorescence, which visualize neovascularization often associated with endometriosis may improve diagnostic detection of endometriosis at the time surgery, but have not been demonstrated to improve pain outcomes after surgery. Hormone suppression remains the mainstay therapy prior to and following surgery. Although most methods demonstrate similar efficacy in reducing endometriosis-associated pain, newer pharmacologic agents that may prove advantageous include oral gonadotropin receptor antagonists, selective progesterone receptor modulators, and angiogenesis inhibitors. Summary Although there have been some advances in the study of noninvasive imaging and biomarkers, more investigation into effective modalities are being conducted and are needed.

Pathogenesis of endometriosis: Interaction between Endocrine and inflammatory pathways

Despite an estimated prevalence of 11% in women and plausible historical descriptions dating back to the 17th century, the etiology of endometriosis remains poorly understood. Classical theories of the histological origins of endometriosis are reviewed below. Clinical presentations are variable, and signs and symptoms do not correlate well with the extent of disease. In this summary, we have attempted to synthesize the growing evidence that hormonal and immune factors conspire to activate a local inflammatory microenvironment that encourages endometriosis to persist and elaborate mediators of its two cardinal symptoms: pain and infertility. Surprisingly, in the search for novel therapeutics for medical treatment of endometriosis, some compounds appear to have dual pharmacological functions, simultaneously modifying the endocrine and immune system facets of this complex gynecologic syndrome. We predict that these lead drugs will provide more therapeutic choices for patients in the future.

Evaluation of Total, Active, and Specific Myeloperoxidase Levels in Women with and without Endometriosis

Myeloperoxidase (MPO) is a proinflammatory enzyme and a marker for neutrophil activation and oxidative stress. Since oxidative stress and inflammation are linked to the pathogenesis of endometriosis, we hypothesized that the total, active, and specific (active/total) MPO levels were significantly different in plasma of women with and without endometriosis. Samples were selected from our biobank from women with endometriosis (n = 212) and controls without endometriosis (n = 121) across the menstrual cycle. Total MPO plasma levels were measured by immunoassay and MPO activity by enzymatic assay. Total and active MPO levels did not differ significantly among endometriosis cases and controls, whereas the specific MPO activity was significantly lower in women with endometriosis than that in controls (p = 0.0159). After the subdivision of control patients into women with a normal pelvis and women with other benign gynecological disorders, a significant difference was observed only between women with endometriosis and women with other benign gynecological disorders (p = 0.0266). In conclusion, systemic MPO levels may not be suited as a single biomarker for endometriosis. Our data support the involvement of MPO in other gynecological disorders but do not provide any evidence for an association with endometriosis.

Incidence of ovarian endometrioma among women with peritoneal endometriosis with and without a history of hormonal contraceptive use

OBJECTIVE(S) To determine if, among women with peritoneal endometriosis, the incidence of ovarian endometrioma at first laparoscopy differs between those with and without a history of hormonal contraceptive use. STUDY DESIGN Retrospective case-control study of women who were patients at a fertility center and had first laparoscopy from 2009 through 2015 showing, at minimum, evidence of peritoneal endometriosis (n=136). Chart review was conducted for history of prior birth control use as well as operative and pathology notes of surgeries. Study subjects were grouped as follows: women with peritoneal endometriosis diagnosed by laparoscopy who had a history of hormonal contraceptive use (n=93) and women with peritoneal endometriosis diagnosed by laparoscopy who had never used hormonal contraceptives (n=43). The main outcome measure was the incidence of ovarian endometrioma among women with peritoneal endometriosis who had a history of hormonal contraceptive use as compared to women with peritoneal endometriosis who had a history of no hormonal contraceptive use. RESULTS Among women with peritoneal endometriosis who had a history of hormonal contraceptive use, 17/93 (18.3%) were found to have endometriomas. Among women with peritoneal endometriosis who had a history of no hormonal contraceptive use, 21/43 (48.8%) were found to have endometriomas. The chi-square statistic was 13.6 (P-value<0.001). CONCLUSION(S) Among women with peritoneal endometriosis, those with a history of hormonal contraceptive use had a lower incidence of ovarian endometrioma than those with a history of no hormonal contraceptive use. Possible mechanisms of action include reducing the risk of a corpus luteum formation and subsequent transformation into an ovarian endometrioma or reducing the risk of ectopic endometrium implantation into the ovary via the diminution of retrograde menstruation. Although larger, prospective studies are needed, the findings of this study suggest that the use of hormonal contraception may decrease the likelihood of ovarian endometrioma formation among women with peritoneal endometriosis.

Natural Orifice Specimen Extraction (NOSE) during Laparoscopic Bowel Resection for Colorectal Endometriosis: Technique and Outcome

STUDY OBJECTIVE To present a detailed description of a modified natural orifice specimen extraction (NOSE) colectomy technique. We also report the postoperative outcomes of our prospective case series when compared with conventional laparoscopic bowel resection in a relatively large series of patients. DESIGN Canadian Task Force classification II-1. SETTING A university tertiary referral center. PATIENTS The last 90 consecutive patients in our care with deep infiltrating endometriosis of the bowel are presented in this study. Patients were diagnosed at the 1st Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary. INTERVENTIONS We performed laparoscopic bowel resection using the transrectal NOSE technique and compared the results of the new operative method (n = 30) with traditional laparoscopic bowel resection (n = 60). MEASUREMENTS AND MAIN RESULTS The median duration of surgery was 121 minutes in the control group and 96 minutes in the NOSE group (p = .005). According to the Clavien-Dindo classification, we observed a severe, grade IIIb or higher, overall complication rate of 3.3% among all 90 patients. In the control group, anastomosis insufficiency occurred in 3.3% of patients (2/60 cases), and in 1 patient with anastomotic leakage a rectovaginal fistula was observed (1.7%). There was no significant difference in the rates of severe postoperative complications (p = .55). The length of hospital stay in the control group was a median of 7 days (range, 5-13 days), whereas in the NOSE group it was 6 days (range, 3-11 days) (p < .001). CONCLUSION According to our findings, the use of NOSE colectomy offers a shorter recovery time and can eventually lead to a shorter surgery duration compared with traditional laparoscopic bowel resection.

Reproductive endocrinology and infertility fellowships: is the 'reproductive endocrinology' portion obsolete?

Purpose of review To take inventory of the past and present and project the future direction of our field to help train the next generation of providers. Recent findings Review the history of the subspecialty and factors contributing to its evolution. Summary Reproductive endocrinology and infertilitys in-vitro fertilization future is shaping the intellectual priorities and surgical skill requirements of the next generation.