Kisspeptin: a potential therapeutic target in patients with unexplained infertility?

BACKGROUND: Kisspeptin has recently emerged as a key regulator of the reproductive axis in women. Kisspeptin, acting centrally via the kisspeptin receptor, stimulates the secretion of the gonadotrophin-releasing hormone (GnRH). AIMS: To investigate serum kisspeptin levels in infertility patients for its clinical utilisation in management and understanding of the pathophysiology of infertility in a wide array of patients. METHODS: This prospective case-control study analysis involved 92 primary infertile women with PCOS, diminished ovarian reserve (DOR), unexplained infertility (UEI), and male factor infertility between 20 and 42 years of age. Serum samples were collected between the second and fifth day of the menstrual cycle. The kisspeptin level was determined using a human kisspeptin ELISA kit according to the manufacturer's procedure. RESULTS: The median value of serum kisspeptin in the PCOS infertility group was significantly higher than that in the UEI group (p = 0.011). There was a statistically significant (p = 0.015, r = -0.182) negative weak correlation found between serum kisspeptin levels and age. The optimal cutoff value obtained to differentiate the UEI from others (PCOS infertility + DOR + male factor infertility) according to the serum kisspeptin level was 214.3 ng/L with a sensitivity of 55% and specificity of 80.9%. CONCLUSIONS: Understanding the role of kisspeptin may lead to its use as a biomarker in infertility diagnosis in UEI patients and might guide the use of kisspeptin analogues in selected patients for infertility management.

Evaluation of YouTube laparoscopic hysterectomy videos as educational materials during the COVID-19 era using the LAParoscopic surgery Video Educational GuidelineS (LAP-VEGaS) and LAP-VEGaS video assessment tool.

With increasing numbers of laparoscopic hysterectomies, surgical trainees are compelled to learn more about endoscopy. Owing to coronavirus disease-related social distancing requirements, online education has gained prominence. Here, we aimed to investigate the laparoscopic hysterectomy video quality on YouTube using the LAParoscopic surgery Video Educational GuidelineS (LAP-VEGaS). YouTube was searched on June 7, 2020 using 'laparoscopic hysterectomy'. Three examiners evaluated videos using Global Operative Assessment of Laparoscopic Skills (GOALS). Subsequently, videos were assessed for their conformity to the LAP-VEGaS and LAP-VEGaS Video Assessment Tool. Interobserver reliability was estimated using intraclass coefficients and Cronbach's alpha. Cochran's Q test was used to determine correlations among quantitative data. The median GOALS score was 21.50. The observers' GOALS scores were significantly correlated. The results showed low conformity to the LAP-VEGaS. YouTube is the most used platform among trainees. The low YouTube video educational quality highlights the necessity for peer review, as trainees increasingly seek such resources during the pandemic.IMPACT STATEMENTWhat is already known on this subject? YouTube is the most commonly used online resource for educational material among surgical trainees. Online videos usually do not undergo a peer-review process. The LAParoscopic surgery Video Educational GuidelineS (LAP-VEGaS) may be used to assess the educational quality of surgical videos.What do the results of this study add? To our knowledge, this is the first study on the quality of laparoscopic hysterectomy videos available on YouTube and the first study to evaluate YouTube laparoscopic surgery videos using the LAP-VEGaS Video Assessment Tool (VAT). Our study revealed the low educational quality of YouTube laparoscopic hysterectomy videos. The LAP-VEGaS VAT seems to be a valid and practical tool for assessing online laparoscopic hysterectomy videos.What are the implications of these findings for clinical practice and/or further research? Medical communities, especially tertiary care or academic centres, may upload educational peer-reviewed videos for trainees seeking this type of resource, especially during the coronavirus disease pandemic, as surgical education alternatives are limited.

Novel metabolic marker Afamin: A predictive factor for Large-for-Gestational-Age (LGA) fetus estimation in pregnancies with gestational diabetes mellitus?

OBJECTIVE: Gestational diabetes mellitus (GDM) affects both maternal and fetal/infant outcomes during and after pregnancy. The reason for the high incidence of large-for-gestational-age (LGA) infants in GDM patients despite close monitorization of glucose levels with early detection of the disease remains unclear to date. Our study aims to investigate the levels of the third-trimester novel marker afamin in GDM versus non-GDM pregnancies in terms of glycemic control status and their utility in the prediction of LGA fetuses. MATERIAL AND METHODS: This prospective case-control study analysis involved 49 pregnant women with GDM diagnosed using the 75-g oral glucose tolerance test (75-g OGTT) and 40 randomly selected women with a similar body mass index (BMI) and gestational age (GA). Blood samples were collected in the third trimester of pregnancy. The afamin level was determined using a human afamin ELISA kit according to the manufacturer's procedure. RESULTS: There was no significant difference found in BMI or GA of patients. Third-trimester afamin levels were 93.91 mg/L and 83.87 mg/L in the GDM and non-GDM groups, respectively (p=0.625). Afamin values of patients were not correlated with age, BMI, GA, HgA1c, 75-g OGTT fasting and 75-g OGTT 1-hour, or 75-g OGTT 2-hour values (p>0.05). GDM patients with LGA fetuses had significantly higher afamin values than patients with appropriate-for-gestational-age (AGA) fetuses (120.8 mg/L versus 91.26 mg/L, respectively). Between GDM patients with either LGA or AGA fetuses, there was no statistically significant difference found for age, BMI, GAs, insulin dose, 75-g OGTT results, or HgA1c values. CONCLUSION: Our findings conclude that novel marker afamin levels could predict the risk of LGA infants independently of glycemic control status and provide insight into the pathogenesis of LGA fetuses, thus helping to reduce the risk of associated complications.

Predictive Value of Hematological Inflammatory Markers in Endometrial Neoplasia

Objective: To investigate the predictive role of neutrophil lymphocyte ratio (NLR) and the platelet lymphocyte ratio (PLR) as hematological inflammatory markers in cases of endometrial hyperplasia and cancer. Material and Method: This retrospective study was performed between 2005-2015 with 247 cases of 83 endometrial adenocarcinoma (group 1), 64 of endometrial hyperplasia (group 2) and 100 controls (group 3) who underwent a curettage due to abnormal uterine bleeding and had a normal histopathology in our tertiary clinic. The cases were chosen from patients without chronic diseases, that do not have infection or medication that could affect the systemic inflammatory response. Preintervention blood parameters were taken into account. The neutrophil/ lymphocyte and platelet/lymphocyte ratios were and statistical comparisons of the groups were conducted. Results: The age distribution of 247 patients was between 26 and 85 years, and the mean age was 48.8 ± 8.92.The median age was 54 in group 1, 46 in group 2 and 45 in group 3. The age was significant between group 1 and the other groups (p=0.001). Some 71% of the cases were premenopausal and 29% were postmenopausal, the latter being significantly more frequent in group 1 (62.7%; p=0.001). Of the cases with endometrial hyperplasia, 42 (65.6%) had simple and 22 (34.4%) have atypical-complex lesions. The median NLRs in groups 1, 2, and 3 were 2.15, 2.10, and 1.92, respectively, with median PLRs of 135.1, 134.0 and 145.6. There was a statistically significant difference between the NLR measurements of the cases from different groups (p=0.048; p<0.05). The NLR value for the endometrial adenocarcinoma group was significantly higher than for the control group (p=0.033; p<0.05). The optimum cut-off value was calculated to be ≥4, at which sensitivity was 20.5%, specificity 99%, positive predictive value (PPV) 94.4% and negative predictive value (NPV) 60%. Conclusion: The value of NLR ≥4 has predictive significance in distinguishing endometrial pathologies before intervention in patients with abnormal uterine bleeding. Simple, cheap and easy-to-perform, the NLR can be used as a potential hematological marker for endometrial malignancy.

Implications of circulating irisin and Fabp4 levels in patients with polycystic ovary syndrome.

The aim of the study was to evaluate the fatty acid-binding protein-4 (FABP4) and irisin concentrations in women with polycystic ovary syndrome (PCOS). Forty-nine women with PCOS, diagnosed according to Rotterdam criteria and 39 healthy women matched for body mass index (BMI) and age. Serum irisin and plasma FABP4 concentrations were measured in both groups. The association of irisin and FABP4 concentrations with metabolic parameters were also tested. Women with PCOS had significantly lower mean serum irisin concentrations than control subjects (158.5 ± 123.3 versus 222.9 ± 152.2 ng/ml, p < 0.05). Concentrations of FABP4 in PCOS and control groups were not significantly different (10.5 ± 4.4 versus 10.9 ± 4.2 ng/ml, p > 0.05). FABP4 concentrations were correlated with BMI, waist-hip ratio (WHR) and HOMA-IR (r = 0.57, p = 0.001; r = 0.26, p = 0.03; r = 0.26, p = 0.03, respectively). No associations between irisin and all the others parameters except serum levels of LH were found. Serum irisin concentrations of women with PCOS were lower compared to the controls. Moreover, there were no difference in plasma FABP4 concentrations between women with PCOS and controls.

The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells.

STUDY QUESTION: Do different chemotherapy drugs exert the same magnitude of cytotoxicity on dormant primordial follicles and the growing follicle fraction in the ovary in vivo and on mitotic non-luteinized and non-mitotic luteinized granulosa cells in vitro? SUMMARY ANSWER: Cyclophosphamide (alkylating agent) and cisplatin (alkylating like) impacted both primordial and pre-antral/antral follicles and both mitotic and non-mitotic granulosa cells, whereas the anti-metabolite cancer drug gemcitabine was detrimental only to pre-antral/antral follicles and mitotic non-luteinized granulosa cells. WHAT IS KNOWN ALREADY: It is already known that anti-metabolite cancer drugs are less detrimental to the ovary than alkylating and alkylating like agents, such as cyclophosphamide and cisplatin. This assumption is largely based on the results of clinical reports showing lower rates of amenorrhea in women receiving anti-metabolite agent-based regimens compared with those treated with the protocols containing an alkylating drug or a platinum compound. But a quantitative comparison of gonadotoxicity with a histomorphometric proof of evidence has not been available for many chemotherapy drugs. Therefore, we combined in this study in vivo and in vitro models of human and rat origin that allows a comparative analysis of the impact of different chemotherapy agents on the ovary and granulosa cells using real-time quantitative cell indices, histomorphometry, steroidogenesis assays, and DNA damage and cell death/viability markers. We also aimed to investigate if there is a difference between mitotic and non-mitotic granulosa cells in terms of their sensitivity to the cytotoxic actions of chemotherapy drugs with different mechanisms of action. This issue has not been addressed previously. STUDY DESIGN, SIZE, DURATION: This translational research study involved in vivo analyses of ovaries in rats and in vitro analyses of granulosa cells of human and rat origin. PARTICIPANTS/MATERIALS, SETTING, METHODS: For the in vivo assays, 54 4- to 6-week old Sprague-Dawley young female rats were randomly allocated into four groups of 13 to receive a single IP injection of: saline (control), gemcitabine (200 mg/kg), cisplatin (50 mg/kg) or cyclophosphamide (200 mg/kg). The animals were euthanized 72 h later. Follicle counts and serum AMH levels were compared between the groups. In vitro cytotoxicity studies were performed using mitotic non-luteinized rat (SIGC) and human (COV434, HGrC1) granulosa cells, and non-mitotic luteinized human (HLGC) granulosa cells. The cells were plated at a density of 5000 cells/well using DMEM-F12 culture media supplemented with 10% FBS. Chemotherapy agents were used at their therapeutic blood concentrations. The growth of mitotic granulosa cells was monitored real-time using xCelligence system. Live/dead cell and apoptosis assays were also carried out using intravital Yo-Pro-1 staining and cleaved caspase-3 expression, respectively. Estradiol (E2), progesterone (P) and anti-Mullerian hormone (AMH) levels were assayed with ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: Cyclophosphamide and cisplatin caused massive atresia of both primordials and growing follicles in the rat ovary whereas gemcitabine impacted pre-antral/antral follicles only. Cyclophosphamide and cisplatin induced apoptosis of both mitotic non-luteinized and non-mitotic luteinized granulosa cells in vitro. By contrast, cytotoxicity of gemcitabine was confined to mitotic non-luteinized granulosa cells. LIMITATIONS, REASONS FOR CAUTION: This study tested only three chemotherapeutic agents. The experimental methodology described here could be applied to other drugs for detailed analysis of their ovarian cytotoxicity. WIDER IMPLICATIONS OF THE FINDINGS: These findings indicate that in vivo and in vitro cytotoxic actions of chemotherapy drugs on the ovarian follicles and granulosa cells vary depending upon the their mechanism of action and the nature of the granulosa cells.