Navigation problems of ICSI or naive blastocyst can be solved with artificial blastocyst.

Embryos have evolved a remarkable capacity to find implantation site. The impressive navigation ability of natural blastocysts may rely on highly sensitive signals arising from embryos and specialized signal processing strategies in the endometrium. Navigation capabilities may be compromised in ICSI embryos because of altered biochemical signaling. The design and delivery of artificial blastocyst (AB) carrying strong chemical signals may allow ICSI embryos to more easily locate to and be retained in the implantation zone. ICSI embryos will attach easily to the implantation zone after it is found by the AB. Co-transfer of the AB together with the ICSI embryo may overcome potential difficulties in implantation due to impaired embryo-maternal communication in cases with implantation failure.

Patatin-like phospholipase domain containing 3-gene (adiponutrin), preptin, kisspeptin and amylin regulates oocyte developmental capacity in PCOS.

This study was planned to test whether follicular fluid (FF) levels of patatin-like phospholipase domain containing 3-gene (PNPLA3:adiponutrin), preptin, kisspeptin, and amylin change in polycystic ovarian syndrome (PCOS). A total of 40 infertile volunteers undergoing IVF/ICSI were included in the study. They were divided into two groups as PCOS (n=20) and control group without PCOS (n=20). The controls were recruited from subjects with a poor ovarian response. The PCOS and control participants were matched according to their body mass index (BMI). Each group of participants underwent ovarian stimulation with GnRH antagonist protocol. Blood and FF samples of one dominant follicle were obtained from each subject during the oocyte pick-up. FF and serum levels of PNPLA3, preptin, kisspeptin and amylin were measured through ELISA. Amylin and adiponutrin median values were not different according to study groups (p>0.05). FF-preptin median values in the control group were similar to the serum preptin values of control and PCOS groups (Z=0.970, p=1.000 and Z=2.631, p=0.051, respectively). Medians of the serum preptin in control and PCOS groups were the same (Z=1.649; p=0.595). FF-preptin median values of PCOS group were significantly lower than the preptin median values of the control group. Serum preptin levels were positively correlated with HOMA-IR, but not with pregnancy rates and the number of retrieved oocytes. Serum kisspeptin levels were negatively correlated with the number of retrieved oocytes and pregnancy rates. While amylin and adiponutrin have no role in the folliculogenesis, kisspeptin and preptin work together for regulating follicle developmental capacity in PCOS.

DHEA supplementation improves endometrial HOXA-10 mRNA expression in poor responders.

OBJECTIVE: The study was planned to investigate whether DHEA supplementation had an impact on endometrial receptivity in women who were poor responders (POR). MATERIAL AND METHODS: Twenty-eight POR women who were undergoing hysteroscopy and five fertile control subjects were included. The POR women were equally subdivided into two separate groups as patients who were currently using DHEA and those who were not. Endometrial samples of the subjects were obtained during hysteroscopy at the late follicular phase. Expression levels of endometrial HOXA-10, HOXA-11, and LIF mRNA were measured with the using real-time polymerase chain reaction. Spontaneous clinical pregnancy rates were also noted. RESULTS: Compared with POR women who were not given DHEA, upregulated endometrial HOXA-10 (7.33-fold) and HOXA-11 (2.39-fold) mRNA expression were detected in POR women on DHEA. The increase in HOXA-10 mRNA was significant (p<0.03). The fold increase in HOXA-11 mRNA was found as 2.39, which indicated a positive upregulation. However, this fold increment was insignificant (p<0.45). An insignificant increase in spontaneous clinical pregnancy rates in POR women on DHEA (53.3%) was observed compared with POR women who were not given DHEA (43.8%). CONCLUSION: Oral DHEA supplementation in POR upregulates endometrial HOXA-10 mRNA expression, which is known to positively modulate endometrial receptivity.

Nuclear factor-κB expression in the endometrium of normal and overweight women with polycystic ovary syndrome.

The aim of this study was to investigate whether the expression levels of endometrial NFκB p65 differ between normal weight and overweight PCOS women and to compare them with BMI-matched control subjects without PCOS. The study group comprised 20 normal weight (BMI: 18.5-24.9 kg/m2) and 15 overweight PCOS women (BMI: 25-29.9 kg/m2) with infertility. Healthy fertile women without PCOS were recruited as the control group. The patients in the normal weight PCOS group and control group were age and BMI-matched. Endometrial samples were obtained during the mid-luteal phase for immunohistochemical staining. The H-Score method was used to evaluate NF-κB p65 (Rel A) expression. Both normal and overweight PCOS women demonstrated significantly higher endometrial NF-κB p65 expression than the women without PCOS. The H-scores of endometrial NF-κB p65 expression were similar in both groups of PCOS women. NF-κB p65 was positively correlated with serum insulin, HOMA-IR and total testosterone levels in PCOS women. By leading to pathological inflammation, an increase in NF-κB p65 expression in the endometrium of normal and overweight PCOS women may contribute to PCOS-related subfertility. Impact statement What is already known on this subject: Although the pathogenesis of PCOS has not yet been clarified, low-grade chronic inflammation is gradually being established as an important pathogenetic factor. Increased levels of inflammatory cytokines such as IL-6 and TNF-α have been reported in women with PCOS. Causes of pathological endometrial inflammation may arise from either a local endometrial disease or linked to diseases which are located in a distant reproductive tissue. Nevertheless, possible role of endometrial NF-κB, basic cellular regulatory of inflammation, in the pathophysiology of PCOS related implantation defect has not been elucidated yet. What do the results of this study add: This study provides first and novel insights into the relationship between PCOS related infertility and pathological endometrial inflammation. We demonstrated that there is a close association between PCOS and pathological endometrial inflammation. Moreover, we clearly showed that pathological endometrial inflammation occurs in both normal and overweight women with PCOS. Further, endometrial NF-κB p65 (Rel A) expression were found to be positively correlated with serum insulin levels and hyperandrogenism in overweight PCOS women. What are the implications of these findings for clinical practice: If we can analyse pathological endometrial inflammation by measuring endometrial NF-κB p65 (Rel A) expression, treatment could be directed towards eliminating the source of pathological endometrial inflammation.

Hypothesis: Co-transfer of genuine embryos and implantation-promoting compounds via artificial containers improve endometrium receptivity.

As with other organs endometrial functions are altered with the advancing age. Age related decrease in reproductive functions leads to decline in the number of oocytes retrieved and the synthesis of endometrial receptivity molecules. Despite the significant improvement in assisted reproductive technologies we do not have so many options to enhance endometrial receptivity. Due to lack of drugs having endometrium receptivity enhancement properties, oocyte donation seems to be the only solution for women with implantation failure. The euploid oocytes come from young and healthy donors may overcome age associated endometrial receptivity defect. Nevertheless, many reasons restrict us from using oocyte donation in women with implantation failure. We, therefore, hypothesized that by mimicking a young blastocyst's effect on endometrium, the transfer of genuine embryos and implantation-promoting compounds together might be the new treatment option for infertile women with recurrent implantation failure. Artificial beads, MI or GV oocytes, and empty zona can be used as a container for intrauterine replacement of implantation-promoting compounds.

Frozen embryo transfer prevents the detrimental effect of high estrogen on endometrium receptivity.

OBJECTIVE: To investigate whether serum levels of estradiol affect reproductive outcomes of normoresponder women undergoing fresh embryo transfer (ET) versus frozen-thawed ET (FET). MATERIAL AND METHODS: Two hundred fifty-five normoresponder women underwent fresh ET in their first or second in vitro fertilization cycle. Ninety-two women with negative pregnacy test results underwent FET. Clinical and ongoing pregnancy rates, implantation, and live birth rates of women undergoing fresh ET versus FET were compared. RESULTS: One hundred forty-seven (57.65%) out of the 255 normoresponder women receiving FET had positive beta-human chorionic gonadotrophin (hCG) results. The remaining 108 women had negative beta-hCG results. The clinical pregnancy rates of the fresh ET group were found as 55.69% (n=142). Ninety-two of the 108 women with failed pregnancies underwent FET; 72.83% had positive beta-hCG results (n=67), and 70.65% had clinical pregnancy (n=65). Both biochemical and clinical pregnancy rates of women undergoing FET increased significantly (p<0.012 and p<0.013, respectively). Ongoing pregnancy (60.87% vs. 52.94%) and live birth rates (59.87% vs. 48.63%) were similar in both fresh and FET groups. Serum E2 levels of women who failed to conceive were significantly higher than those women did conceive. Serum progesterone levels of women who conceived versus those that did not were similar. CONCLUSION: The detrimental effect of high serum estradiol levels on endometrial receptivity could be prevented by FET.

Follicular fluid cerebellin and betatrophin regulate the metabolic functions of growing follicles in polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to assess the changes of follicular fluid (FF) and serum levels of cerebellin precursor protein 1 (cbln1) and betatrophin in patients with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) with a gonadotropin-releasing hormone (GnRH) antagonist protocol. METHODS: Twenty infertile women with PCOS and 20 control women diagnosed as poor responders undergoing ovarian stimulation with a GnRH antagonist were included. Blood samples were obtained during ovum pick-up. Follicular fluid from a dominant follicle was collected from the subjects. Using enzyme-linked immunosorbent assays, FF and serum levels of cbln1 and betatrophin were measured in both groups of participants. Metabolic and hormonal parameters were also determined and correlated with each other. RESULTS: Both groups of women had similar serum and FF betatrophin levels (55.0±8.9 ng/mL vs. 53.1±10.3 ng/mL, p=0.11). The serum and FF betatrophin levels of poor responders were found to be similar (49.9±5.9 ng/mL vs. 48.9±10.7 ng/mL, p=0.22). Conversely, the FF cbln1 levels of PCOS women were found to be significantly higher than the serum cbln1 levels (589.1±147.6 ng/L vs. 531.7±74.3 ng/L, p<0.02). The FF cbln1 levels of control participants without PCOS were significantly higher than their serum cbln1 levels (599.3±211.5 ng/L vs. 525.3±87.0 ng/L, p=0.01). Positive correlations were detected among body mass index, insulin resistance, serum insulin, total testosterone, and betatrophin levels in the PCOS group. CONCLUSION: Follicular fluid betatrophin and cbln1 concentrations may play a pivotal role on follicular growth in PCOS subjects undergoing IVF/ICSI with an antagonist protocol.

The role of vitamin B1-B2 and plasma lipid profile in intrahepatic cholestasis of pregnancy.

AIM: The present study aimed to determine the levels of total cholesterol, triglycerides (TG), low-density lipoproteins (LDL), high-density lipoproteins (HDL), and vitamins B1 and B2 in intrahepatic cholestasis of pregnancy (ICP) patients, and to evaluate if these were involved in the pathophysiology of the disease. METHODS: The prospective randomized study included 35 pregnant patients who were admitted to the Gynecology and Obstetrics Polyclinic, Faculty of Medicine at Dicle University and who were diagnosed with ICP (Group 1), and 40 healthy pregnant women who were admitted in the same period and who had no systemic diseases that might complicate the pregnancy during the pregnancy follow-up (Group 2). Serum lipid levels and vitamins B1 and B2 were determined and compared, and statistical comparisons of the groups were made. RESULTS: There was no difference between the TG levels of the two groups (P=0.631). Total cholesterol, LDL, HDL, and vitamin B1 and B2 levels were higher in Group 1 than in Group 2 (P=0.001, P=0.001, P=0.001, P=0.001, and P=0.032, respectively). CONCLUSIONS: Increased levels of vitamins B1 and B2 may indicate a need for increased energy metabolism at the fetus. So we believe that new studies are required, which will be supported by the placental analyses of the pyruvate and lactate levels in maternal blood at delivery and fetal cord blood in order to develop a better understanding on the fetal effects of energy metabolism.

Impact of Endometrioma Resection on Eutopic Endometrium Metabolite Contents: Noninvasive Evaluation of Endometrium Receptivity.

The aim of this study was to determine whether endometrioma resection alters most commonly defined endometrial metabolites, lactate (Lac), N-acetylaspartate (NAA), creatine 1 (Cr1), creatine 2 (Cr2), and choline (Cho) during the window of implantation. Twenty patients with uni- or bilateral endometrioma and 7 patients having nonendometriotic benign ovarian cyst were included. Midluteal phase magnetic resonance spectroscopy analysis of eutopic endometrium was performed before surgery. Second spectrum of endometrium was obtained 3 to 5 months after laparoscopic endometrioma resection. Pre- and postoperative endometrial peaks of Lac, NAA, Cr, and Cho were measured in units and denominated in parts per million (ppm). Compared to preoperative peak values, significantly decreased NAA, Lac, and Cr1 signals were noted in patients undergoing endometrioma surgery. Nearly 5-fold decline in the NAA signal occurred after endometrioma surgery (1.94 ± 3.24 vs 0.37 ± 0.55). Likewise, 2.5-fold decline in Lac signals was noted after endometrioma resection (2.81 ± 2.64 vs 1.06 ± 1.88). Both uni- and bilateral endometrioma affected endometrium signals the same. The peak intensity of Cho, Cr1, Cr2, NAA, and Lac did not alter significantly after nonendometriotic cyst surgery. Endometrioma surgery straightens endometrial NAA, Lac, and Cr1 peaks, suggesting improvement in endometrial receptivity.

Surgery for Benign Gynecological Disorders Improve Endometrium Receptivity.

Regardless of the anatomical locations, some benign gynecological disorders (BGDs) such as peritoneal endometriosis, ovarian endometrioma, adenomyosis, uterine leiomyomas, endometrial polyps, uterine septum, and hydrosalpinges may lead to implantation failure. Despite progress in medical therapies, surgery remains a mainstay of BGDs treatment. Although our knowledge of endometrial receptivity after BGDs surgery is limited, it has allowed for significant improvement in the treatment of female subfertility. Many researchers studied on pregnancy outcome following BGDs surgery, but they did not investigate the possible impact of surgery on endometrial receptivity. They, therefore, concluded that pregnancy rates improved after BGDs surgery based on clinical observations. Many of these clinicians believe that surgical resection of BGDs leads to removal of local mechanical effect over the endometrium. Moreover, they accept that BGDs surgery may inhibit the detrimental signaling and secretion of some molecules from the BGDSs into the endometrium that may lead to favorable effect on the endometrium. However, so far, data from randomized controlled trials or systematic review or meta-analyses to answer the question whether surgical treatment of BGDs can improve endometrial receptivity are lacking. The purpose of this systematic review was to evaluate the results of available publications dealing with the impact of reproductive surgery for BGDs on endometrial receptivity.

The effects of polycystic ovary syndrome on gestational diabetes mellitus.

The aim of this study was to explore the inter-relationship between polycystic ovary syndrome and gestational diabetes mellitus, and demonstrate maternal and fetal outcomes. This was a case-control study in 1360 pregnant women who received a diagnosis of gestational diabetes mellitus between 24 and 28 weeks of gestational age. Among all diagnosed with gestational diabetes mellitus, 150 pregnant women had received a polycystic ovary syndrome, and 160 women who did not have polycystic ovary syndrome were designated as controls. The incidence of pregnancy-induced hypertension was 26.3% and 12% in the case and control groups, respectively. Preeclampsia was seen at an incidence of 12% and 6% in case and in control groups, respectively. The difference in neonatal hypoglycemia between the two groups was statistically significant, with an incidence of 17% and 5% in the case and in control groups, respectively. This study demonstrated that the presence of polycystic ovary syndrome along with gestational diabetes mellitus increases the risk of pregnancy induced hypertension by 2.4 fold, preeclampsia by 2 fold and neonatal hypoglycemia by 3.2 fold, compared to gestational diabetes mellitus alone.

Ghrelin action on GnRH neurons and pituitary gonadotropes might be mediated by GnIH-GPR147 system.

Acylated ghrelin (AG) effect on GnRH secretion is mediated, at least in part, by GH secreta-gogue receptor (GHS-R) which is present in the GnRH neurons. As the acylation is mandatory for binding to GHS-R, unacylated isoform of ghrelin (UAG) action on gonadotropin secretion is likely to be mediated by other receptors or mediators that have not been identified yet. UAG, therefore, may act partially via a GHS-R-independent mechanism and inhibitory impact of UAG on GnRH neurons may be executed via modulation of other neuronal networks. Ghrelin and gonadotropin inhibitory hormone (GnIH), two agonistic peptides, have been known as important regulators of reproductive events. Potential impact of ghrelin on the activity of GnIH neurons is not exactly known. Both GnIH and ghrelin are potent stimulators of food intake and inhibitors of gonadotropin release. By binding G-protein coupled GnIH receptor (GnIH-R), GPR147, which is located in the human gonadotropes and GnRh neurons, GnIH exerts an inhibitory effect on both GnRH neurons and the gonadotropes. The GnIH-GPR147 system receives information regarding the status of energy reservoir of body from circulating peptides and then transfers them to the kisspeptin-GnIH-GnRH network. Due to wide distribution of this network in brain GnIH neurons may project on ghrelin neurons in the arcuate nucleus and contribute to the regulation of UAG's central effects or vice versa. Together, the unidentified ghrelin receptor in the hypothalamus and hypophysis may be GnIH-R. Therefore, it is reasonable that ghrelin may act on both hypothalamus and hypophysis via GnIH-GPR147 system to block gonadotropin synthesis and secretion.

Premature Progesterone Elevation Does Not Affect Pregnancy Outcome in High-Responder Patients Undergoing Short-Interval Coasting in IVF Cycles.

BACKGROUND We aimed to present the relationship between premature progesterone elevation (PPE) and clinical outcomes in high-responder patients who had a coasting period of <4 days in length due to their high risk of developing ovarian hyperstimulation syndrome (OHSS) and who were treated with a long-acting gonadotropin-releasing hormone agonist (GnRH-agonist) protocol in in vitro fertilization-embryo transfer (IVF-ET) cycles. MATERIAL AND METHODS This retrospective study was conducted at the University Hospital Assisted Reproductive Technology Center. The outcomes of 101 patients undergoing IVF- intracytoplasmic sperm injection (ICSI) cycles who showed a high response to COH (estradiol >4000 pg/ml and/or >20 follicles each ≥10 mm in diameter and at least 20% ≥15 mm) and who were coasted for <4 days were evaluated. Number of oocytes, 2 pronuclei (PN) embryos, implantation rate, and live birth rate were measured. RESULTS The incidence of PPE was 32.6%. Compared with those without PPE, patients with PPE had a higher number of oocytes retrieved. Total mature and fertilized oocytes and the mean number of embryos transferred were not significantly different between groups. Live birth rates (41.9% vs. 38.7%) and implantation rates (26.5% vs. 23%) were also not significantly divergent in the PPE and non-PPE groups, respectively. CONCLUSIONS P concentrations ≥1.3 ng/ml on the day of human chorionic gonadotropin (hCG) administration, designated in this study as PPE, does not appear to be related to adverse effects in terms of clinical outcomes in high-responder patients undergoing coasting <4 days due to their high risk of developing OHSS treated with a long-acting GnRH-a protocol in IVF-embryo transfer cycles.

Gestational diabetes mellitus screening and outcomes.

OBJECTIVE: To verify the usefulness of the World Health Organization criteria for the diagnosis of gestational diabetes mellitus in pregnant women and its effectiveness in the prevention of maternal and neonatal adverse results in women younger than 35 years without apparent risk factors for gestational diabetes mellitus. MATERIAL AND METHODS: This is a retrospective study based on population involving 1360 pregnant women who delivered and who were followed-up in a university hospital in Istanbul. All women underwent the 75-g oral glucose tolerance test screening, usually in between the 24(th)-28(th) weeks of pregnancy. In all cases, the identification of gestational diabetes mellitus was determined in accordance with the World Health Organization criteria. RESULTS: Approximately 28% of the pregnant women aged younger than 35 years with no risk factors for gestational diabetes mellitus were diagnosed with the oral glucose tolerance test in this study. In the gestational diabetes mellitus group, the primary cesarean section rate was importantly higher than that in the non-gestational diabetes mellitus group. Preterm delivery was also associated with gestational diabetes mellitus. The diagnosis of gestational diabetes mellitus was strongly associated with admittance to the neonatal intensive care unit. Neonatal respiratory problems didn't showed any significant deviation between the groups. There was a moderate association between gestational diabetes mellitus and metabolic complications. CONCLUSION: Pregnant women with no obvious risk factors were diagnosed with gestational diabetes mellitus using the World Health Organization criteria. The treatment of these women potentially reduced their risk of adverse maternal and neonatal hyperglycemia-related events, such as cesarean section, polyhydramnios, preterm delivery, admission to neonatal intensive care unit, large for gestational age, and higher neonatal weight.