Márcia Cristina França Ferreira

The vasoactive peptide angiotensin-(1-7), its receptor Mas and the angiotensin-converting enzyme type 2 are expressed in the human endometrium.

Angiotensin (Ang)-(1-7) is one of the major active components of the renin-angiotensin system, produced from cleavage of Ang II by angiotensin-converting-enzyme type 2 (ACE2), which acts through a specific G protein-coupled receptor, Mas. We have investigated whether the human endometrium expresses these components during menstrual cycle. By radioimmunoassay, Ang-(1-7) was detected in endometrial wash fluid at picomolar concentrations. Using immunofluorescence, both the peptide and its receptor were identified in cultured endometrial epithelial and stromal cells. By immunohistochemistry, Ang(1-7) was localized in the endometrium throughout menstrual cycle, being more concentrated in the glandular epithelium of mid- and late secretory phase. This pattern corresponded to the ACE2 mRNA, which was more abundant in epithelial cells than in stromal cells (2-fold increase, p < 0.05) and in the secretory vs. proliferative phase (6.6-fold increase, p < 0.01). The receptor Mas was equally distributed between epithelial and stromal cells and did not change during menstrual cycle. The physiological role of this peptide system in normal and pathological endometrium warrants further investigation.

Activin A and follistatin in menstrual blood: low concentrations in women with dysfunctional uterine bleeding.

Activin A and follistatin are growth factors produced by several organs, comprising the endometrium, where they modulate cell and tissue differentiation. In this study, the authors tested whether activin A and follistatin are measurable in menstrual blood and whether their concentrations change in women with dysfunctional uterine bleeding (DUB). The authors evaluated healthy women with regular menstrual cycles (n = 15) and women with DUB (n = 12). Activin A and follistatin were measured in both menstrual and peripheral blood samples using highly sensitive enzyme immunoassays, whereas their respective mRNAs were quantified by real-time polymerase chain reaction in endometrial samples collected during the perimenstrual period. Activin A concentrations were 4-fold higher in menstrual than in peripheral serum of healthy women (mean ± SE, 4.24 ± 0.18 vs 1.00 ± 0.15 ng/mL, P < .001) and were significantly lower in women with DUB compared to healthy subjects (P < .001). Follistatin concentration was 8-fold higher in menstrual than in peripheral serum of healthy women (3.94 ± 0.49 vs 0.49 ± 0.04 ng/mL, P < .001) and was significantly lower in the menstrual serum of women with DUB compared to controls (P < .001). There was no correlation between menstrual and peripheral serum concentrations of both proteins. The endometrial expression of activin A and follistatin mRNA was lower in women with DUB compared to controls (P < .05). Both activin A and follistatin are measurable in high concentrations in human menstrual blood and are relatively lower in women with DUB. The quantitative assessment of activin A and follistatin in menstrual serum might be a putative clinical marker of endometrial function.

Activin-related proteins in bovine mammary gland: Localization and differential expression during gestational development and differentiation

Bovine mammary gland morphogenesis and differentiation are regulated by actions of growth factors including members of the transforming growth factor β superfamily. Activins A and B, which are members of the transforming growth factor β superfamily, bind selectively to ActRIB and ActRIIA receptors and their biological effects are antagonized by inhibins and follistatins. In the present paper we evaluated gene and protein expression of the activin and inhibin subunits βA, βB, and α-inhibin and follistatin and ActRIB and ActRIIA receptors in the mammary gland of nonpregnant and pregnant heifers. Mammary glands were obtained from nonpregnant Nelore (Bos indicus) heifers (n=9) and from primigravid Nelore heifers during early (n=9), mid (n=6), and late (n=5) pregnancy. Specimens of mammary tissue were analyzed by real-time PCR and immunohistochemistry. The βA and α-inhibin subunits and ActRIB and ActRIIA mRNA expression was higher in the early-pregnancy group compared with the nonpregnant group. In the mid-pregnancy group, the subunits βA, βB, and α-inhibin as much as follistatin mRNA expression was higher compared with the nonpregnant group, whereas ActRIB transcripts were absent in the late-pregnancy group. Immunostaining of these proteins, with the exception of ActRIB, was observed in the mammary tissue sections at all time points analyzed; these findings are in agreement with the observed pattern of mRNA expression. Staining and mRNA expression for ActRIB were undetected in the late-pregnancy group. In summary, the present study demonstrated that the activin-related proteins, βA, βB, and α-inhibin subunits, as much as follistatin and ActRIB and ActRIIA receptors display different patterns of expression regarding time of gestation in the bovine mammary gland. The modulation of the expression pattern during gestation suggests that activin-related proteins may play a key role in regulating bovine mammary branching morphogenesis and epithelial differentiation.

Identification of local angiogenic and inflammatory markers in the menstrual blood of women with endometriosis.

The aim of this study was to evaluate the presence of myeloperoxidase (MPO), N-acetyl-β-D-glucosaminidase (NAG), tumor necrosis factor alpha (TNF-α) and vascular endothelial growth factor (VEGF) in peripheral and menstrual blood in women with (n=10) and without (n=7) endometriosis. NAG and MPO activities were evaluated by enzymatic methods, whereas TNF-α and VEGF by immunoassay. No significant differences were found for these markers, neither in menstrual nor in peripheral blood between groups. Menstrual blood NAG (P=0.039) and MPO (P=0.0117) activities in the endometriosis group were significantly higher than in peripheral blood. NAG and MPO presented positive linear correlation in peripheral (P=0.07; r=0.641) and menstrual blood (P=0.01; r=0.603). These findings point to the existence of an increased local inflammatory activity in women with endometriosis.

Clinical Prediction of Deeply Infiltrating Endometriosis before Surgery: Is It Feasible? A Review of the Literature

Background. Endometriosis is a chronic benign gynecologic disease that can cause pelvic pain and infertility affecting almost 10% of reproductive-age women. Deeply infiltrating endometriosis (DIE) is a specific entity responsible for painful symptoms which are related to the anatomic location of the lesions. Definitive diagnosis requires surgery, and histological confirmation is advisable. The aim of this paper is to review the current literature regarding the possibility of diagnosing DIE accurately before surgery. Despite its low sensitivity and specificity, vaginal examination and evaluation of specific symptoms should not be completely omitted as a basic diagnostic tool in detecting endometriosis and planning further therapeutic interventions. Recently, transvaginal ultrasound (TVUS) has been reported as an excellent tool to diagnose DIE lesions in different locations (rectovaginal septum, retrocervical and paracervical areas, rectum and sigmoid, and vesical wall) with good accuracy. Conclusion. There are neither sufficiently sensitive and specific signs and symptoms nor diagnostic tests for the clinical diagnosis of DIE, resulting in a great delay between onset of symptoms and diagnosis. Digital examination, in addition to TVS, may help to gain better understanding of the anatomical extent and dimension of DIE which is of crucial importance in defining the best surgical approach.Background. Endometriosis is a chronic benign gynecologic disease that can cause pelvic pain and infertility affecting almost 10% of reproductive-age women. Deeply infiltrating endometriosis (DIE) is a specific entity responsible for painful symptoms which are related to the anatomic location of the lesions. Definitive diagnosis requires surgery, and histological confirmation is advisable. The aim of this paper is to review the current literature regarding the possibility of diagnosing DIE accurately before surgery. Despite its low sensitivity and specificity, vaginal examination and evaluation of specific symptoms should not be completely omitted as a basic diagnostic tool in detecting endometriosis and planning further therapeutic interventions. Recently, transvaginal ultrasound (TVUS) has been reported as an excellent tool to diagnose DIE lesions in different locations (rectovaginal septum, retrocervical and paracervical areas, rectum and sigmoid, and vesical wall) with good accuracy. Conclusion. There are neither sufficiently sensitive and specific signs and symptoms nor diagnostic tests for the clinical diagnosis of DIE, resulting in a great delay between onset of symptoms and diagnosis. Digital examination, in addition to TVS, may help to gain better understanding of the anatomical extent and dimension of DIE which is of crucial importance in defining the best surgical approach.

Plasma brain-derived neurotrophic factor in women with pelvic pain: a potential biomarker for endometriosis?

AIM To test whether plasma BDNF levels are useful to predict the presence of endometriosis in women with pelvic pain. PATIENTS & METHODS Prospective cross-sectional study including 67 consecutive women aged 24-49 years, scheduled for laparoscopy due to chronic pelvic pain. Preoperative plasma samples were assayed for BDNF using a commercial enzyme immunoassay. RESULTS Women with ovarian endometrioma had higher preoperative plasma BDNF (1063 ± 157 pg/ml) compared with women with other benign ovarian tumors (537 ± 131 pg/ml, F = 2.53; p = 0.02). However, plasma BDNF levels were not helpful to indicate the presence of peritoneal or deep infiltrating endometriosis. Plasma BDNF levels were positively correlated with the severity of pelvic pain (r = 0.489; p < 0.0001). CONCLUSION Plasma BDNF might be a biomarker of ovarian endometrioma but not a useful diagnostic marker to detect other forms of endometriosis in women with painful symptoms.

Non-hormonal and hormonal intrauterine contraception: survey of patients perceptions in four Latin American countries.

ABSTRACT Objectives: This study sought to understand women’s perceived barriers to the use of hormonal and non-hormonal intrauterine contraception in Latin America. Methods: We developed an online survey for women in Argentina, Brazil, Colombia and Mexico who were seeking contraception. The questions aimed at evaluating patient awareness of negative stories and statements, as well as perceived barriers to the copper intrauterine device (IUD) and the levonorgestrel-releasing intrauterine system (LNG-IUS). Results: The survey was mailed to 2300 women. A total of 1953 responses were received from Argentina (n = 465), Brazil (n = 380), Colombia (n = 613) and Mexico (n = 495). More women reported having heard negative stories about the copper IUD than about the LNG-IUS. More women believed that the copper IUD, rather than the LNG-IUS, was suitable only for those who had already had children. More women believed that weight gain (14.3% vs. 38.2%; p < 0.001), mood swings (14.1% vs. 38.7%; p < 0.001) and infertility (16.3% vs. 19.9%; p = 0.016) were possible side effects of the LNG-IUS. By contrast, more women believed that abortion (36% vs. 22.7%; p < 0.001), pelvic infections (42.1% vs. 15.7%; p < 0.001) and ectopic pregnancy (43.5% vs 23.5%; p < 0.001) were side effects more associated with the copper IUD. More believed the copper IUD was associated with less pain during placement and removal compared with the LNG-IUS (42.8% vs. 31.2%; p < 0.001). The perception of increased risk of contracting a sexual transmitted disease did not differ between the methods (IUD vs. LNG-IUS, 21.7% vs. 20.3%; p = 0.388). Conclusions: Respondents to a web-based survey in four Latin American countries have misperceptions regarding the adverse effects and risks of intrauterine contraception, which may hamper the use of these safe and efficient contraceptive methods. Education about the true risks and benefits involved is fundamental to improving patient acceptance and compliance as well as reducing unplanned pregnancies and unsafe abortions.

Accuracy of clinical signs and symptoms in the diagnosis of endometriosis

Endometriosis is a benign gynecological disease afffecting about 10% of all reproductive-age women which can significantly impair quality of life. As the clinical presentation is variable, with som...

18F-Fluorocholine Uptake and Positron Emission Tomography Imaging in Rat Peritoneal Endometriosis

Endometriosis is a debilitating disease that still needs surgery to be confirmed. Endometriosis is associated with increased plasma levels of phosphatidylcholines. 18F-fluorocholine ([18F]FCH) is a radiopharmaceutical that is metabolized to phosphatidylcholine inside the cells and can be traced by positron emission tomography (PET). Here we evaluate [18F]FCH as a potential tool for the noninvasive diagnosis of peritoneal endometriosis. Adult female Wistar rats had autologous uterine fragments dissected and grafted to the peritoneal wall to model peritoneal endometriosis. Ex vivo biodistribution assay and PET imaging studies were performed 30 minutes after [18F]FCH administration. The [18F]FCH uptake was 3-fold higher in endometriotic implant tissues than in muscle or peritoneum. Positron emission tomography imaging revealed the grafted uterine tissue in contrast to surrounding structures. Region-of-interest analysis of the reconstructed images showed higher accumulation of [18F]FCH by endometriotic lesions, 0.34 (0.04)% of injected dose per gram of tissue (ID/g), in comparison with muscle tissue, 0.08 (0.01)% ID/g. However, sham implants with fat tissue were also detectable in PET imaging. These preliminary findings of [18F]FCH uptake by ectopic uterine tissue implants and their localization by PET imaging encourage the future evaluation of this technique to detect small superficial endometriosis lesions in humans. Study protocols need to be further perfected and adapted for tests in women with endometriosis.

Implantation Failure Is Associated With Increased α-Inhibin and β-Glycan Gene Expression in Secretory Phase Endometrium: Nested Case–Control Study of Infertile Women Undergoing IVF/Fresh Embryo Transfer:

Embryo implantation involves a complex sequence of events, and a large amount of molecules have been postulated to be involved in the interaction of embryo and endometrium. This study evaluated the endometrial expression of α-inhibin and β-glycan in the mid-secretory phase of women scheduled to in vitro fertilization (IVF) and tested whether these markers are associated with implantation failure. We performed a nested case–control study including 52 women submitted to IVF and embryo transfer, divided into 2 groups: cases with implantation failure (n = 33) and controls with confirmed clinical pregnancy (n = 19). Endometrial α-inhibin and β-glycan gene expression was evaluated in the mid-secretory phase of the natural menstrual cycle immediately before IVF, using real-time polymerase chain reaction. We found a higher gene expression of α-inhibin (fold increase = 2.14 ± 0.32, P < .05) and β-glycan (fold increase = 1.44 ± 0.16, P < .05) in implantation failure patients compared to confirmed clinical pregnancy patients. The areas under the receiver operating characteristics curves for prediction of implantation failure in this context were 0.692 and 0.678 for α-inhibin and β-glycan, respectively. The present results suggest that high expression levels of α-inhibin and β-glycan transcripts in secretory phase endometrium are associated with a lower chance of achieving pregnancy with IVF.Embryo implantation involves a complex sequence of events, and a large amount of molecules have been postulated to be involved in the interaction of embryo and endometrium. This study evaluated the endometrial expression of α-inhibin and β-glycan in the mid-secretory phase of women scheduled to in vitro fertilization (IVF) and tested whether these markers are associated with implantation failure. We performed a nested case-control study including 52 women submitted to IVF and embryo transfer, divided into 2 groups: cases with implantation failure (n = 33) and controls with confirmed clinical pregnancy (n = 19). Endometrial α-inhibin and β-glycan gene expression was evaluated in the mid-secretory phase of the natural menstrual cycle immediately before IVF, using real-time polymerase chain reaction. We found a higher gene expression of α-inhibin (fold increase = 2.14 ± 0.32, P < .05) and β-glycan (fold increase = 1.44 ± 0.16, P < .05) in implantation failure patients compared to confirmed clinical pregnancy patients. The areas under the receiver operating characteristics curves for prediction of implantation failure in this context were 0.692 and 0.678 for α-inhibin and β-glycan, respectively. The present results suggest that high expression levels of α-inhibin and β-glycan transcripts in secretory phase endometrium are associated with a lower chance of achieving pregnancy with IVF.