The expression of corticotropin-releasing hormone family peptides in premalignant and malignant vulvar lesions

Objectives To examine the relation of corticotropin-releasing hormone (CRH) family peptides with inflammatory processes and oncogenesis, emphasizing in vulvar inflammatory, premalignant and malignant lesions, as well as to investigate the possibility of lesion cells immunoescaping, utilizing FAS/FAS-L complex. Methods Immunohistochemical expression of CRH, urocortin (UCN), FasL and their receptors CRHR1, CRHR2 and Fas was studied in vulvar tissue sections obtained from patients with histologically confirmed diagnosis of lichen, vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell carcinoma (VSCC). The patient cohort was selected from a tertiary teaching Hospital in Greece, between 2005 and 2015. For each of the disease categories, immunohistochemical staining was evaluated and the results were statistically compared. Results A progressive increase of the cytoplasmic immunohistochemical expression of CRH and UCN, from precancerous lesions to VSCC was observed. A similar increase was detected for Fas and FasL expression. Nuclear localization of UCN was demonstrated in both premalignant and VSCC lesions, with staining being significantly intensified in carcinomas, particularly in the less differentiated tumor areas or in the areas at invasive tumor front. Conclusions Stress response system and CRH family peptides seem to have a role in inflammation maintenance and progression of vulvar premalignant lesions to malignancy. It seems that stress peptides may locally modulate the stroma through Fas/FasL upregulation, possibly contributing to vulvar cancer development (AU)

The expression of corticotropin-releasing hormone family peptides in premalignant and malignant vulvar lesions.

OBJECTIVES: To examine the relation of corticotropin-releasing hormone (CRH) family peptides with inflammatory processes and oncogenesis, emphasizing in vulvar inflammatory, premalignant and malignant lesions, as well as to investigate the possibility of lesion cells immunoescaping, utilizing FAS/FAS-L complex. METHODS: Immunohistochemical expression of CRH, urocortin (UCN), FasL and their receptors CRHR1, CRHR2 and Fas was studied in vulvar tissue sections obtained from patients with histologically confirmed diagnosis of lichen, vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell carcinoma (VSCC). The patient cohort was selected from a tertiary teaching Hospital in Greece, between 2005 and 2015. For each of the disease categories, immunohistochemical staining was evaluated and the results were statistically compared. RESULTS: A progressive increase of the cytoplasmic immunohistochemical expression of CRH and UCN, from precancerous lesions to VSCC was observed. A similar increase was detected for Fas and FasL expression. Nuclear localization of UCN was demonstrated in both premalignant and VSCC lesions, with staining being significantly intensified in carcinomas, particularly in the less differentiated tumor areas or in the areas at invasive tumor front. CONCLUSIONS: Stress response system and CRH family peptides seem to have a role in inflammation maintenance and progression of vulvar premalignant lesions to malignancy. It seems that stress peptides may locally modulate the stroma through Fas/FasL upregulation, possibly contributing to vulvar cancer development.

Biological therapies for premature ovarian insufficiency: what is the evidence?

Premature Ovarian Insufficiency (POI) is a multi-factorial disorder that affects women of reproductive age. The condition is characterized by the loss of ovarian function before the age of 40 years and several factors have been identified to be implicated in its pathogenesis. Remarkably though, at least 50% of women have remaining follicles in their ovaries after the development of ovarian insufficiency. Population data show that approximately up to 3.7% of women worldwide suffer from POI and subsequent infertility. Currently, the treatment of POI-related infertility involves oocyte donation. However, many women with POI desire to conceive with their own ova. Therefore, experimental biological therapies, such as Platelet-Rich Plasma (PRP), Exosomes (exos) therapy, In vitro Activation (IVA), Stem Cell therapy, MicroRNAs and Mitochondrial Targeting Therapies are experimental treatment strategies that focus on activating oogenesis and folliculogenesis, by upregulating natural biochemical pathways (neo-folliculogenesis) and improving ovarian microenvironment. This mini-review aims at identifying the main advantages of these approaches and exploring whether they can underpin existing assisted reproductive technologies.

Electronic versus conventional spatiotemporal image correlation (STIC) fetal echocardiography: a direct comparison.

OBJECTIVES: Recent advances in Spatial Temporal Image Correlation (STIC) 4 D fetal echocardiography include the application of eSTIC based on electronic probe image acquisition. We aimed to directly compare the performance of conventional STIC versus eSTIC technique (B-Mode and color Doppler imaging) during off-line reconstruction of STIC/eSTIC fetal heart volume pairs. METHODS: Pairs of B-Mode and Color Doppler STIC volumes were acquired sequentially by firstly conventional (STIC) followed by electronic (eSTIC) probes during 33 consecutive obstetric scans at median 23 (range 13-31) gestational weeks. The resulting 66 fetal heart volume pairs were assessed blindly off-line by a fetal cardiologist who documented feasibility of reconstruction, presence of motion artifacts, subjective image quality on a 4-level scale: 1-best to 4-non-diagnostic and morphological diagnosis, to enable a paired comparison of STIC and eSTIC in the same fetus under similar scanning conditions. RESULTS: eSTIC volumes had higher temporal resolution (37 vs. 24 frames per second, p < .001), less motion during acquisition (12 vs. 20 cases, O.R. 7.0, p = .002) and better average image quality (1.9 vs. 2.2, p = .006) compared to STIC volumes. More diagnostic reconstructions were achieved by eSTIC (n = 55, 86%) than STIC (n = 52, 78.8%), p = .001), in a comparable analysis time (mean 4.96 vs. 4.94 min). During a comparison of image quality of the original acquisition (A) and reconstructed planes (B and C planes) e STIC was superior in 22 (33%), 39 (59%) and 21 (38%) volumes, respectively, with the remaining cases being of similar quality (<10% in each plane in favor of STIC). Imaging mode and gestational age had a similar impact on both eSTIC and STIC performance: diagnostically acceptable studies in 49 (75.8%) vs. 48 (72.2%) by B-Mode, 60 (90.9%) vs. 56 (84.8%) by Color Doppler Mode, 8 (62.5%) vs. 10 (50%) in early scans, 38 (95%) vs. 38 (95%) in mid-gestation scans, and 7 (70%) vs. 6 (60%) in third trimester scans. Eight obstetric scans identified a fetus with a cardiac variant or structural abnormality. Diagnostic concordance of the two STIC approaches was comparable (40/48 concordant interpretations, kappa 0.657) all confirmed by fetal and/or postnatal echocardiography. CONCLUSIONS: eSTIC was associated with more effective 4 D fetal heart reconstruction due to reduced motion artifacts and superior image quality in all planes, when compared to STIC. Early gestation reconstructions were not generally successful using either technology. Further study is needed to define the cost-effectiveness and diagnostic impact of eSTIC over conventional STIC and their role over, or in addition to, screening 2 D fetal echocardiography by appropriately trained sonographers.

Antifungal activity of amniotic fluid against different Candida species.

BACKGROUND: Although Candida is a commensal of the urogenital tract, intrauterine fungal infections are extremely uncommon in clinical practice. AIMS: In the present work we evaluated whether amniotic fluid (AF) possesses direct antifungal activity against clinical isolates of Candidaalbicans and other Candida species. METHODS: A total of 23 AF samples from pregnant women with gestational age of 38-41 weeks were obtained under aseptic conditions by the aspiration of the amniotic sac during cesarean section. Different Candida species were inoculated in amniotic fluid and Sabouraud broth, used as control, and were incubated at 37°C for 48h. Quantitative cultures of test samples and controls were performed at 0, 4, 8, 12, 24, and 48h. RESULTS: AF collected from 23 pregnant women had consistent and significant inhibitory activity against all Candida isolates tested. Nonetheless, a complete inhibition of growth by all 23 AF samples tested was observed only against Candida glabrata. CONCLUSIONS: It is likely that the antifungal activity of the AF against C. albicans, C. glabrata and Candida parapsilosis observed in vitro also exists in vivo, contributing to protect against intrauterine fungal infections.

Approaches to Improve Endometrial Receptivity in Case of Repeated Implantation Failures.

Repeated implantation failures are a constant challenge in reproductive medicine with a significant impact both on health providers and on infertile couples. Several approaches have been proposed so far as effective; however, accumulative data have clarified that most of the treatment options do not have the evidence base for a generalized application to be suggested by the relevant societies. Implantation failures are attributed to either poor quality embryos or to defected endometrial receptivity. The current review aims to summarize in a systematic way all the new trends in managing RIF via interference with endometrial receptivity. The authors focus mainly, but not exclusively, on endometrial injury prior to embryo transfer and endometrial priming with autologous cells or biological agents. To this direction, a systematic search of the Pubmed database has been conducted taking into account the emerged evidence of the last two decades. All the suggested interventions are herein presented and analyzed in terms of reproductive outcomes. It is evident that properly powered and designed randomized trials are needed to support a new standard approach in RIF treatment that will safely be incorporated in national and international guidelines.

Role of Peroxisome Proliferator-Activated Receptors (PPARs) in Trophoblast Functions.

Peroxisome proliferator-activated receptors (PPARα, PPARß/δ, and PPARγ) belong to the transcription factor family, and they are highly expressed in all types of trophoblast during pregnancy. The present review discusses currently published papers that are related to the regulation of PPARs via lipid metabolism, glucose metabolism, and amino acid metabolism to affect trophoblast physiological conditions, including differentiation, maturation, secretion, fusion, proliferation, migration, and invasion. Recent pieces of evidence have proven that the dysfunctions of PPARs in trophoblast lead to several related pregnancy diseases such as recurrent miscarriage, preeclampsia, intrauterine growth restriction, and gestational diabetes mellitus. Moreover, the underlying mechanisms of PPARs in the control of these processes have been discussed as well. Finally, this review's purposes are to provide more knowledge about the role of PPARs in normal and disturbed pregnancy with trophoblast, so as to find PPAR ligands as a potential therapeutic target in the treatment and prevention of adverse pregnancy outcomes.

Splenic pregnancy treated with transcatheter embolization and methotrexate.

BACKGROUND: Primary splenic pregnancy is a rare entity, usually treated with splenectomy. CASE PRESENTATION AND REVIEW OF THE LITERATURE: We report the first case of conservative management of splenic pregnancy with selective embolization and intramuscular methotrexate administration. Postoperative treatment was uneventful. We have further systematically reviewed the literature upon the treatment options in case of splenic pregnancy. It has been evident that most cases were treated with spleenectomy, especially in case of active hemorrhage. Spleen preservation is rarely achieved, only in cases of hemodynamically stable, uncomplicated patients. CONCLUSION: Splenic selective embolization could be a treatment option in case of uncomplicated splenic pregnancy with the benefit of splenic preservation.

Update on the management of poor ovarian response in IVF: the shift from Bologna criteria to the Poseidon concept.

Despite the considerate progress to which assisted reproduction technology (ART) has been subject since 1978, some issues remain unresolved. Notably, the clinical management of patients with a poor ovarian response is still a challenge in everyday practice, frustrating to both the patient and the fertility expert. Poor ovarian responders (PORs) embody 9-24% of patients undergoing ovarian stimulation, meaning that up to one in four patients conceals a poor reproductive prognosis. The last decade has witnessed the attempts of the medical community to standardize diagnosis of POR with the developing of the Bologna Criteria and the subsequent evolution of the low prognosis patient elaborated in the POSEIDON classification. The aim of this article is to summarize all evidence concerning etiology and management of poor ovarian response, including the most recent advances and future prospects in this regard.

Acceptability of Self-Sampling for Human Papillomavirus-Based Cervical Cancer Screening.

Background: Human papillomavirus (HPV)-DNA testing combined with self-sampling could increase cervical cancer screening effectiveness, utilizing a sensitive screening modality and an easy sampling method with minimal pain or discomfort. Self-sampling acceptability, though, is pivotal. Materials and Methods: This study is a nested cross-sectional survey within GRECOSELF, a cross-sectional study on HPV-based screening with self-sampling, aiming at investigating self-sampling acceptability among Greek women residing in rural areas, and the factors affecting it. Women between 25 and 60 years old were recruited by midwives participating in a nationwide midwifery network. Participants, after self-sampling, filled out a questionnaire with three sections, one regarding demographic characteristics, a second with questions pertaining to the participants' cervical cancer screening history, and a third with questions regarding the self-sampling process per se. Results: The sample included 13,111 women. Most participants (67.9%), including those screened or not in the past, would prefer self-sampling if assured that the results are not inferior to standard testing. Discomfort or pain during self-sampling was absent or minimal in 97.1% and 96.5% of the cases, respectively, and 74.4% of the women felt adequately confident that they followed the instructions correctly. Women mostly preferred self-sampling at home compared with health care facilities. Pain and discomfort during the procedure, although rare, were significant factors against acceptance. Most of the women reporting a negative impression had a negative experience with conventional sampling in the past. Conclusion: Self-sampling is highly acceptable. Acceptance can be further improved with proper communication of the process and its noninferiority compared with conventional screening.

Correction to: ICSI does not offer any benefit over conventional IVF across different ovarian response categories in non-male factor infertility: a European multicenter analysis.

The original article unfortunately contained 2 mistakes.

ICSI does not offer any benefit over conventional IVF across different ovarian response categories in non-male factor infertility: a European multicenter analysis.

PURPOSE: To evaluate whether ICSI offers any benefit compared with IVF in different ovarian response categories in case of non-male factor infertility. METHODS: This is a retrospective multicenter analysis using individual patient data, conducted in 15 tertiary referral hospitals in Europe (1 center in Belgium and 14 in Spain). The study included the first cycle of all patients undergoing ovarian stimulation for IVF or ICSI in a GnRH antagonist protocol. Only patients having either IVF or ICSI for non-male factor infertility were included. Patients were divided into 4 groups based on their ovarian response as follows: group A, poor responders (1-3 oocytes); group B, suboptimal responders (4-9 oocytes); group C, normal responders (10-15 oocytes); group D, high responders (> 15 oocytes). RESULTS: In total, 4891 patients were analyzed, of whom 4227 underwent ICSI and 664 IVF. There was no significant difference for the insemination method (ICSI vs. IVF) used among the different ovarian response categories: 87% vs. 13%, 87% vs. 13%, 86% vs. 14%, 84% vs. 16%, for groups A, B, C, and D, respectively, p value = 0.35. Mean fertilization rates and embryo utilization rates were comparable between IVF and ICSI in the whole cohort. Fresh and cumulative LBR did not differ significantly for IVF and ICSI in poor, suboptimal, normal, and high responders. CONCLUSION: There is no advantage of ICSI over IVF as insemination method for non-male factor infertility, irrespective of the ovarian response. The number of oocytes retrieved has no value for the selection of the insemination procedure in case of non-male infertility.

Systematic and standardized hysteroscopic endometrial injury for treatment of recurrent implantation failure.

RESEARCH QUESTION: To investigate the effect of hysteroscopic endometrial injury for treatment of recurrent implantation failure (RIF). DESIGN: This prospective and randomized controlled trial included 239 patients who had failed to achieve a clinical pregnancy after the transfer of at least four good-quality embryos in a minimum of three fresh or frozen-thawed embryo transfer cycles and were under the age of 40 years, who were randomized into two groups. The injury group (n = 124) received endometrial injury during their hysteroscopic procedure, whereas the control group (n = 115) did not. Patients who had endometrial pathologies were excluded from the study. RESULTS: There were no statistically significant differences in duration of gonadotrophin use (8.23 versus 8.30 days), total dose of gonadotrophins (2330 versus 2338 IU), number of oocytes (7.03 versus 8.21), number of mature oocytes (5.27 versus 6.02), number of fertilized oocytes (4.19 versus 4.55), number of good-quality embryos (2.07 versus 2.43), number of embryos transferred (1.97 versus 1.93) or endometrial thickness (9.04 versus 9.35 mm) between the injury group and control group, respectively. Clinical pregnancy rates (25.8% versus 15.6%, P = 0.047), live birth rates (21.8% versus 12.2%, P = 0.049) and implantation rates (14.2% versus 8.8%, P = 0.036) were significantly different, favouring the injury group. CONCLUSION: This study suggests that endometrial injury is beneficial in RIF patients to increase the odds of implantation, clinical pregnancy and live birth.

Implementation of HPV-based Cervical Cancer Screening Combined with Self-sampling Using a Midwifery Network Across Rural Greece: The GRECOSELF Study.

Self-sampling for human papillomavirus (HPV) testing is an alternative to physician sampling particularly for cervical cancer screening nonattenders. The GRECOSELF study is a nationwide observational cross-sectional study aiming to suggest a way to implement HPV-DNA testing in conjunction with self-sampling for cervical cancer screening in Greece, utilizing a midwifery network. Women residing in remote areas of Greece were approached by midwives, of a nationwide network, and were provided with a self-collection kit (dry swab) for cervicovaginal sampling and asked to answer a questionnaire about their cervical cancer screening history. Each sample was tested for high-risk (hr) HPV with the Cobas HPV test. HrHPV-Positive women were referred to undergo colposcopy and, if needed, treatment according to colposcopy/biopsy results. Between May 2016 and November 2018, 13,111 women were recruited. Of these, 12,787 women gave valid answers in the study questionnaire and had valid HPV-DNA results; hrHPV prevalence was 8.3%; high-grade cervical/vaginal disease or cancer prevalence was 0.6%. HrHPV positivity rate decreased with age from 20.7% for women aged 25-29 years to 5.1% for women aged 50-60 years. Positive predictive value for hrHPV testing and for HPV16/18 genotyping ranged from 5.0% to 11.6% and from 11.8% to 27.0%, respectively, in different age groups. Compliance to colposcopy referral rate ranged from 68.6% (for women 25-29) to 76.3% (for women 40-49). For women residing in remote areas of Greece, the detection of hrHPV DNA with the Cobas HPV test, on self-collected cervicovaginal samples using dry cotton swabs, which are provided by visiting midwives, is a promising method for cervical cancer secondary prevention.

Management of Endocrinopathies in Pregnancy: A Review of Current Evidence.

Pregnancy in women with associated endocrine conditions is a therapeutic challenge for clinicians. These disorders may be common, such us thyroid disorders and diabetes, or rare, including adrenal and parathyroid disease and pituitary dysfunction. With the development of assisted reproductive techniques, the number of pregnancies with these conditions has increased. It is necessary to recognize symptoms and correct diagnosis for a proper pharmacotherapeutic management in order to avoid adverse side effects both in mother and fetus. This review summarizes the pharmacotherapy of these clinical situations in order to reduce maternal and fetal morbidity.

Intrauterine CRH-treated PBMC in repeated implantation failure.

BACKGROUND: The intrauterine administration of activated autologous peripheral blood monocytes (PBMC) prior to embryo transfer seems to improve reproductive outcomes in women with repeated implantation failure (RIF). We have previously shown that the intrauterine administration of PBMC treated with corticotropin-releasing hormone (CRH) prior to blastocyst transfer (day 5) improves significantly the clinical pregnancy rate of women with RIF. In the present crossover pilot study, we have investigated whether CRH-PBMC treatment could be of benefit in case of fresh early cleavage stage embryo transfer (day 3) in women with RIF. METHODS: Twenty-six (n = 26) women with at least three previous failed IVF attempts and no history of clinical pregnancy in the past were recruited in this study. Ovarian stimulation was performed following either the long or the short protocol. PBMC were collected during the oocyte retrieval, were treated with CRH, and transferred in the uterine cavity 2 days later. Good quality cleavage stage embryos were transferred at day 3, following oocyte retrieval. RESULTS: Following the intrauterine administration of CRH-treated autologous PBMC, 15/26 clinical pregnancies occurred (57.69%). Compared to the null result of the same women prior to recruitment, this observation was considered significant (P < 10-2 ). CONCLUSION: Our findings further support the role of the intrauterine administration of CRH-treated PBMC as an effective approach when transferring cleavage stage embryos in women with RIF. Prospective randomized studies are needed to clarify whether such intervention could be of benefit in clinical practice.

The Effect of Metformin on the Endometrium of Women with Polycystic Ovary Syndrome.

OBJECTIVES: To investigate the effect of metformin on endometrial receptivity in women with polycystic ovary syndrome (PCOS). METHODS: Twenty volunteer women with polycystic ovaries and oligomenorrhea were prospectively investigated. All women were treated with exogenous estradiol and progesterone to simulate a normal menstrual cycle (28-day duration) after GnRH-induced pituitary desensitization. Ten of the women received no other medication (group A, control), while the remaining 10 received metformin (group B, metformin). Endometrial biopsy was performed in all women on day 21 of the 2 simulated cycles. RESULTS: The expression of corticotropin - releasing hormone and urocortin in the endometrium was investigated. There was no significant difference between the 2 groups. A 3-day delay in the secretory maturation of the glandular epithelium relatively to the stroma was observed in 7 out of 10 women of group B (70%) as compared to only 1 out of 10 women of group A (10%, p = 0.02). CONCLUSIONS: It is shown for the first time that metformin administration to women with PCOS did not affect the expression of endometrial receptivity markers but delayed histological glandular maturation. It is suggested that metformin may have an impact on the function of the endometrium in PCOS.