Advancements in three-dimensional bioprinting for reproductive medicine: a systematic review.

Reproductive failure due to age, genetics and disease necessitates innovative solutions. While reproductive tissue transplantation has advanced, ongoing research seeks superior approaches. Biomaterials, bioengineering and additive manufacturing, such as three-dimensional (3D) bioprinting, are harnessed to restore reproductive function. 3D bioprinting uses materials, cells and growth factors to mimic natural tissues, proving popular for tissue engineering, notably in complex scaffold creation with cell distribution. The versatility which is brought to reproductive medicine by 3D bioprinting allows more accurate and on-site applicability to various problems that are encountered in the field. However, in the literature, there is a lack of studies encompassing the valuable applications of 3D bioprinting in reproductive medicine. This systematic review aims to improve understanding, and focuses on applications in several branches of reproductive medicine. Advancements span the restoration of ovarian function, endometrial regeneration, vaginal reconstruction, and male germ cell bioengineering. 3D bioprinting holds untapped potential in reproductive medicine.

Uterine cervical stenosis: from classification to advances in management. Overcoming the obstacles to access the uterine cavity.

BACKGROUND: To date hysteroscopy is the gold standard technique for the evaluation and management of intrauterine pathologies. The cervical canal represents the access route to the uterine cavity. The presence of cervical stenosis often makes entry into the uterine cavity difficult and occasionally impossible. Cervical stenosis has a multifactorial etiology. It is the result of adhesion processes that can lead to the narrowing or total obliteration of the cervical canal. PURPOSE: In this review, we summarize the scientific evidence about cervical stenosis, aiming to identify the best strategy to overcome this challenging condition. METHODS: The literature review followed the scale for the quality assessment of narrative review articles (SANRA). All articles describing the hysteroscopic management of cervical stenosis were considered eligible. Only original papers that reported data on the topic were included. RESULTS: Various strategies have been proposed to address cervical stenosis, including surgical and non-surgical methods. Medical treatments such as the preprocedural use of cervical-ripening agents or osmotic dilators have been explored. Surgical options include the use of cervical dilators and hysteroscopic treatments. CONCLUSIONS: Cervical stenosis can present challenges in achieving successful intrauterine procedures. Operative hysteroscopy has been shown to have the highest success rate, particularly in cases of severe cervical stenosis, and is currently considered the gold standard for managing this condition. Despite the availability of miniaturized instruments that have made the management of cervical stenosis more feasible, it remains a complex task, even for experienced hysteroscopists.

Dynamic view of assisted reproduction in Turkey from 1996 to 2020.

RESEARCH QUESTION: What are the trends and changes in patient demographics and practices in treatment with assisted reproductive technology (ART) in Turkey over 25 years? DESIGN: Data on patient demographics, cycle characteristics and clinical outcome of 29,541 cycles in 22,867 women who underwent treatment with ART between 1996 and 2020 were analysed according to calendar years. Regression and interrupted time series analysis were used to assess changes in patient characteristics, trends and effects of interventions on outcome. RESULTS: From 1996 to 2020, the average age of women undergoing treatment with ART increased from 32.1 to 36.0 years (r = 0.96), the proportion of women over 40 more than tripled (9% versus 28.7%; r = 0.97) and the average duration of infertility at presentation dropped from 8.4 to 4 years (r = -0.98) (P < 0.0001, for all). Diminished ovarian reserve became the major indication by 2015. Gonadotrophin-releasing hormone antagonists dominated ovarian stimulation by 2009. The average number of oocytes retrieved decreased from 11.5 to 7.8 (r = -0.86, P < 0.0001). Blastocyst-stage transfers gradually increased, comprising 51% of all transfers in 2020 (r = 0.86, P < 0.0001). The mean number of embryos transferred decreased from 3.9 to 1.5. Clinical pregnancy rates (CPR) per embryo transfer remained stable for fresh transfers (range: 31.6-43.9%) but increased from 13% to 30.3% in cryopreserved transfers. The estimate of effect of blastocyst vitrification was significant (P = 0.001). The multiple birth rate declined from 30.4% to 7.1%. CONCLUSIONS: Remarkable changes were seen in patient demographics, treatment indications, and clinical and laboratory practices. Increased use of single embryo transfer and improvements in cryopreservation techniques helped maintain high CPR while reducing multiple births.

Mini-plus percutaneous setting in total laparoscopic hysterectomy.

INTRODUCTION: We aimed to analyze the preliminary experience of a mini-plus percutaneous instrument (MpPc) setting in total laparoscopic hysterectomy (TLH). MATERIAL AND METHODS: Forty-three women who underwent a mini-plus percutaneous total laparoscopic hysterectomy at a tertiary-care university-based teaching hospital and academic affiliated private hospital between May 2017 and 2018 were included. MpPc-TLH was performed through one optical trans-umbilical 5-mm trocar, one 5-mm ancillary port on the right side, either one 2.4-mm percutaneous endoscopic instrument or 3-mm mini-laparoscopic port on the right upper quadrant and if required one 3-mm ancillary port on the left lower quadrant. RESULTS: A total of 43 patients were included, with a median age of 48 years (range, 38-71 years). Indication for surgery included uterine myomas (n = 20), benign adnexal mass (n = 7), endometrial intraepithelial neoplasia (n = 6), endometrial cancer (n = 5), adenomyosis with abnormal bleeding (n = 3), and high-grade cervical dysplasia (n = 2). The median operating time was 100 min (range, 60-180 min), and the median estimated blood loss was 30 ml (range, 20-60ml). The median postoperative abdominal pain Visual Analog Scale score was 3 (range, 0-6). CONCLUSIONS: The preliminary data suggest that MpPc approach is a feasible and safe surgical modality for total laparoscopic hysterectomy.

Prevalence of T-shaped uterus among fertile women based on ESHRE/ESGE and Congenital Uterine Malformation by Experts (CUME) criteria.

RESEARCH QUESTION: What is the prevalence of T-shaped uteri among fertile women based on ESHRE/ESGE and Congenital Uterine Malformation by Experts (CUME) criteria? DESIGN: A prospective cohort study of 258 women of reproductive age with a history of at least one natural pregnancy resulting in live birth. Participants were recruited from the family planning clinic between January 2018 and March 2020. The ESHRE/ESGE classification of congenital anomalies of the female genital tract was used for describing abnormal findings. CUME criteria were also used for diagnosing T-shaped uterus. Uterine cavity volume was measured. RESULTS: Mean age of participants was 35.4 ± 6.2 years. Participants were diagnosed with the following: congenital uterine abnormality (n = 9 [3.6%]); partial septate uterus (n = 5 [2.0%]) and hemiuterus (n = 2 [0.8%]). Two women (0.8%) were diagnosed with T-shaped uterus and borderline T-shaped uterus based on the ESHRE/ESGE criteria and CUME. Mean lateral indentation angle, lateral indentation depth and T-angle were 156.2° ± 9.53°, 2.85 ± 0.93 mm and 73.3° ± 9.85° in patients with normal uterine cavity. In patients with T-shaped and borderline T-shaped uteri, respective figures were 115° versus 121°, 10 mm versus 7.6 mm and 27.5° versus 70°. Median volume of the uterine cavity in patients with normal uterine cavity and T-shaped uterus was 3.71 ml (minimum 2.0 to maximum 9.03 ml, interquartile range 1.93) and 3.2 ml (2.9 and 3.62 ml), respectively. CONCLUSIONS: The prevalence of T-shaped uteri in fertile women is low, which corresponds to previous reports of women with poor reproductive history.

Decision regret and associated factors following oocyte cryopreservation in patients with diminished ovarian reserve and/or age-related fertility decline.

PURPOSE: To evaluate the prevalence and factors associated with decision regret following oocyte cryopreservation (OC) in women with diminished ovarian reserve (DOR) and/or age-related fertility decline (ARFD). METHODS: A cross-sectional survey study was conducted to five hundred fifty-two women with DOR and/or ARFD who underwent OC between 2014 and 2019 in two private-assisted reproductive units in Istanbul, Turkey. Decision regret was measured using the validated Decision Regret Scale (DRS). RESULTS: The median and mean DRS scores were 10 (interquartile range: 25) and 13.4 (SD: 13.2, range 0-70), respectively. Eighty-five (52.5%) women reported mild regret and 26 (16%) had moderate to severe regret. Decision regret was inversely associated with the belief in fate regarding childbearing and trust in the efficacy of OC. CONCLUSIONS: The prevalence of severe decision regret among patients with DOR and/or ARFD undergoing OC is low. Women who had belief in fate and trusted in the efficacy of oocyte cryopreservation had significantly lower decisional regret.

hCG Improves Luteal Function and Promotes Progesterone Output through the Activation of JNK Pathway in the Luteal Granulosa Cells of the Stimulated IVF Cycles†.

Human chorionic gonadotropin (hCG) is a luteotropic hormone that promotes the survival and steroidogenic activity of corpus luteum (CL) by acting through luteinizing hormone receptors (LHRs) expressed on luteinized theca and granulosa cells (GCs). Therefore, it is used to support luteal phase in in vitro fertilization (IVF) cycles to improve clinical pregnancy rates and prevent miscarriage. However, the molecular mechanism underlying this action of hCG is not well characterized. To address this question, we designed an in vitro translational research study on the luteal GCs obtained from 58 IVF patients. hCG treatment at different concentrations and time points activated c-Jun N-terminal kinase (JNK) pathway and significantly increased its endogenous kinase activity along with upregulated expression of steroidogenic enzymes (steroidogenic acute regulatory protein (stAR), 3ß-Hydroxysteroid dehydrogenase (3ß-HSD)) in a dose-dependent manner in the luteal GCs. As a result, in vitro P production of the cells was significantly enhanced after hCG. When JNK pathway was inhibited pharmacologically or knocked-down with small interfering RNA luteal function was compromised, P4 production was declined along with the expression of stAR and 3ß-HSD in the cells. Further, hCG treatment after JNK inhibition failed to correct the luteal defect and promote P4 output. Similar to hCG, luteinizing hormone (LH) treatment improved luteal function as well and this action of LH was associated with JNK activation in the luteal GCs. These findings could be important from the perspective of CL biology and luteal phase in human because we for the first time identify a critical role for JNK signaling pathway downstream LHR activation by hCG/LH in luteal GCs. SUMMARY SENTENCE: JNK signaling pathway plays a central role in the upregulated expression of the steroidogenic enzymes StAR and 3b-HSD and augmented progesterone production by hCG/LH in human luteal granulosa cells.

Mini-Laparoscopic Gynecological Surgery Using Smaller Ports Minimizes Incisional Pain and Postoperative Scar Size: A Paired Sample Analysis.

Objective. The aim of this study was to assess postoperative incisional pain and cosmetic scores in mini-laparoscopic gynecological surgeries undertaken with different port sizes. Material and Method. In this prospective study, all women who underwent mini-laparoscopic gynecological surgery with 2.4-, 3-, and 5-mm lateral ports for benign gynecological conditions between March 2017 and April 2019 were included. The primary outcome was postoperative incisional pain at rest, walking, and after a provoked Valsalva maneuver assessed by numeric rating scale scores at 6 hours, 12 hours, 24 hours, and 3 days and 7 days after surgery. Secondary outcome measures included cosmetic scores of each port site (evaluated by using patient-observer scar assessment scale [POSAS]), operation time, and intra- and postoperative complications. Results. A total of 330 lateral port sites in 110 patients who underwent benign gynecological surgery via mini-laparoscopy were assessed for pain and cosmetic appearance. Pain scores at each time point were significantly lower for 2.4- and 3-mm ports than those for 5-mm ports; however, no significant difference was detected between 2.4-mm and 3-mm port sites (P = .6). The difference was more evident at 24 hours when routine analgesic drugs were stopped (P = .004). For POSAS scores, both 2.4-mm and 3-mm ports were superior to 5-mm port sites (P = .002); however, there was no significant difference between 2.4-mm and 3-mm port sites (P = .2). There were 2 port-related complications: one subcutaneous emphysema and one bleeding from a 5-mm trocar site 1 hour after surgery. Conclusion. Mini-laparoscopic gynecologic surgery using smaller ports resulted in decreased postoperative incisional pain and superior cosmetic appearance.

Platelet-rich plasma another add-on treatment getting out of hand? How can clinicians preserve the best interest of their patients?

Add-on treatments in IVF are utilized to a great extent but without sufficient evidence showing their effectiveness. Since the offered treatments are usually costly and may be associated with yet unknown risks, this practice is not in the best interest of couples that may go to great lengths to conceive and have an offspring carrying their own genetic make-up. A recent addition to this armamentarium is the administration of platelet-rich plasma (PRP) in women with diminished ovarian reserve, implantation failures, and a thin endometrium. The only evidence for PRP comes from small scale and mostly before and after studies with clinically irrelevant end points. PRP has not been subjected to a rigorous clinical trial. It is a typical example of an add-on gaining widespread popularity based on biological plausibility and mind-bending theoretical presumptions. We should be extremely cautious prior to implementing PRP on a widescale and await the results of well-designed studies.

Luteal granulosa cells from natural cycles are more capable of maintaining their viability, steroidogenic activity and LH receptor expression than those of stimulated IVF cycles.

STUDY QUESTION: Are there any differences in the molecular characteristics of the luteal granulosa cells (GC) obtained from stimulated versus non-stimulated (natural) IVF cycles that may help explain the defective luteal phase in the former? SUMMARY ANSWER: Luteal GC of stimulated IVF cycles, particularly those of agonist-triggered antagonist cycles, are less viable ex vivo, express LH receptor and anti-apoptotic genes at lower levels, undergo apoptosis earlier and fail to maintain their estradiol (E2) and progesterone (P4) production in comparison to natural cycle GC. WHAT IS KNOWN ALREADY: Luteal function is defective in stimulated IVF cycles, which necessitates P4 and/or hCG administration (known as luteal phase support) in order to improve clinical pregnancy rates and prevent miscarriage. The luteal phase becomes shorter and menstruation begins earlier than a natural cycle if a pregnancy cannot be achieved, indicative of early demise of corpus luteum (premature luteolysis). Supra-physiological levels of steroids produced by multiple corpora luteae in the stimulated IVF cycles are believed to inhibit LH release directly via negative feedback actions on the hypothalamic-pituitary-ovarian axis resulting in low circulating levels of LH and a defective luteal phase. We hypothesized that some defects in the viability and steroidogenic activity of the luteal GC of the stimulated IVF cycles might contribute to this defective luteal phase in comparison to natural cycle GC. This issue has not been studied in human before. STUDY DESIGN, SIZE, DURATION: A comparative translational research study of ex vivo and in vitro models of luteal GC recovered from IVF patients undergoing natural versus stimulated IVF cycles was carried out. Luteinized GC were obtained from 154 IVF patients undergoing either natural (n = 22) or stimulated IVF cycles with recombinant FSH and GnRH agonist (long) (n = 44), or antagonist protocol triggered conventionally either with recombinant hCG (n = 46) or with a GnRH agonist (n = 42). GC were maintained in vitro for up to 6 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cellular viability (YO-PRO-1 staining), the expression of the steroidogenic enzymes, pro-apoptotic genes [Bcl-2-associated death promoter (BAD), Bcl-2-associated X protein (BAX) and Caspase-3 (CASP3)], anti-apoptotic genes [RAC-alpha serine/threonine-protein kinase (AKT-1) and Bcl-2-like protein 2 (BCL2-L2)], LH receptor, vascular endothelial growth factor (VEGF) (using real-time quantitative PCR at mRNA level and western blot immunoprecipitation assay at protein level) and in vitro E2 and P4 production (electrochemiluminescence immunoassay) were compared in GC among the groups. MAIN RESULTS AND THE ROLE OF CHANCE: Natural cycle GC were significantly more viable ex vivo (88%) compared to their counterparts of the stimulated IVF cycles (66, 64 and 37% for agonist and antagonist cycles triggered with hCG and GnRH agonist respectively, P < 0.01). They were also more capable of maintaining their vitality in culture compared to their counterparts from the stimulated IVF cycles: at the end of the 6-day culture period, 74% of the cells were still viable whereas only 48, 43 and 22% of the cells from the agonist and antagonist cycles triggered with hCG and agonist respectively, were viable (P < 0.01). The mRNA expression of anti-apoptotic genes (AKT-1 and BCL2-L2) was significantly lower, while that of pro-apoptotic genes (BAD, BAX and CASP3) was significantly higher in the stimulated cycles, particularly in the agonist-triggered antagonist cycles, compared to natural cycle GC (P < 0.01 for long protocol and antagonist hCG trigger, P < 0.001 for agonist trigger). The expression of steroidogenic enzymes (stAR, SCC, 3ß-HSD and aromatase) and VEGF was significantly higher in the agonist and hCG-triggered antagonist cycles compared to natural cycle GC. Therefore, in vitro E2 and P4 production in cells from the stimulated IVF cycles was significantly higher than their counterparts obtained from the natural cycles in the first 2 days of culture. However, after Day 2, their viability and hormone production began to decline very rapidly with the most drastic decrease being observed in the agonist-triggered cycles. By contrast, natural cycle GC maintained their viability and produced E2 and P4 in increasing amounts in culture up to 6 days. In vitro P production and the mRNA and protein expression of LH receptor, VEGF and 3ß-HSD were most defective in the agonist-triggered antagonist cycles compared to natural and agonist and hCG-triggered antagonist cycles. In vitro hCG treatment of a subset of the cells from the agonist-triggered cycles improved their viability, increased E2 and P4 production in vitro and up-regulated the mRNA expression of anti-apoptotic gene BCL-L2 together with steroidogenic enzymes stAR, SCC, 3B-HSD, LH receptor and VEGF. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: The limitations include analysis of luteinized GC only might not reflect the in vivo mechanisms involved in survival and function of the whole corpus luteum; GC recovered during oocyte retrieval belong to a very early stage of the luteal phase and might not be representative; effects of ovulation triggered with hCG may not equate to the endogenous LH trigger; the clinical characteristics of the patients may vary among the different groups and it was not possible to correlate stimulation-related molecular alterations in luteal GC with the clinical outcome, as no oocytes have been utilized yet. Therefore, our findings do not conclusively rule out the possibility that some other mechanisms in vivo may also account for defective luteal function observed in stimulated IVF cycles. WIDER IMPLICATIONS OF THE FINDINGS: Ovarian stimulation is associated with significant alterations in the viability and steroidogenic activity of luteal GC depending on the stimulation protocol and mode of ovulation trigger. Reduced survival and down-regulated expression of 3B-HSD, LH receptor and VEGF leading to compromised steroid production in stimulated cycles, and particularly in the agonist-triggered cycles, may at least in part help explain why the luteal phase is defective and requires exogenous support in these cycles. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the School of Medicine, the Graduate School of Health Sciences of Koc University and Koç University Research Center for Translational Medicine (KUTTAM), equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. All authors declare no conflict of interest.

High responders are not exempt from detrimental effects of prematurely rising progesterone levels in fresh embryo transfer cycles.

RESEARCH QUESTION: Are high-responder IVF patients protected from the deleterious effect of prematurely elevated serum progesterone level on the probability of pregnancy? DESIGN: In this retrospective cohort study, 2971 autologous fresh embryo transfer IVF cycles with gonadotrophin-releasing hormone agonist long protocol were analysed to investigate whether the detrimental effect of prematurely rising progesterone levels on clinical pregnancy rate (CPR) varies depending on the magnitude of ovarian response. Nine different evenly spaced intervals were constructed for serum progesterone level on the human chorionic gonadotrophin day (<0.5/0.5-0.9/1-1.4/1.5-1.9/2-2.4/2.5-2.9/3-3.4/3.5-3.9/>4 ng/ml). Then, IVF cycles in each of these intervals were further divided into low (≤3 oocytes), normal (4-15 oocytes) and high responders (≥16 oocytes). RESULTS: The progressive rise of serum progesterone from the <0.5 to the >4 ng/ml interval caused a gradual and continuous decline in the CPR of all three types of ovarian response. The absolute difference in the CPR between the lowest and the highest progesterone groups was not related to the magnitude of ovarian response (-26.6%, -37.7% and -40.7% for the low, normal and high responders, respectively). On multivariate logistic regression analysis, the detrimental effect of progesterone started at 1.5-1.9 ng/ml, 3.0-3.4 ng/ml and 4.0-4.4 ng/ml intervals for the low, normal and high responders, respectively. CONCLUSION: High responders are not exempt from the detrimental effects of prematurely rising serum progesterone levels but the threshold interval where the detrimental effect begins is higher in the high responders compared with the low and normal responders.

Bologna criteria are predictive for ovarian response and live birth in subsequent ovarian stimulation cycles.

PURPOSE: The ESHRE Working Group on Poor Ovarian Response defined a set of variables to define poor responders, named as the Bologna Criteria, but several concerns have been raised regarding their applicability and prognostic significance. In order to evaluate the clinical relevance of the criteria, we retrospectively analyzed the ovarian response and live birth rates in women who had consecutive IVF attempts, according to their fulfillment of the criteria. METHODS: The study group comprised 1153 and 288 women who had two and three consecutive ovarian stimulation (OS) cycles between May 2010 and January 2017, respectively. We compared the ovarian response and live birth rates in subsequent IVF attempts of Bologna criteria-defined poor responder women and women who did not fulfill the Bologna criteria. RESULTS: Women who fulfilled the criteria achieved higher rates of poor ovarian response (76.2% vs 14.3% and 60.3% vs 13.4%) and lower live birth rates (14.6% vs 33.3% and 12.9% vs 34.3%) in their second and third OS cycles, respectively (both p < 0.001) compared to women who did not fulfill the criteria. The former group also had lower number of oocytes and lower likelihood of having embryo transfer in their subsequent OS cycles. The criteria were able to predict both ovarian response and clinical outcome in the subsequent cycle in < 40-year-old women, whereas they were predictive only for the ovarian response but not for the clinical outcome in women over 40 years of age, who exhibited very low live birth rates regardless of the fulfillment of the criteria. CONCLUSIONS: The results of this study show that the Bologna criteria are clinically relevant in terms of prediction of ovarian response and clinical outcome in subsequent OS cycles.

Contained Power Morcellation Versus Transvaginal Extraction for Retrieval of Laparoscopically Removed Myomas: A Comparison of Perioperative Outcomes.

OBJECTIVE: To evaluate clinical and operative outcomes of transvaginal extraction (TVE) and contained power morcellation (CPM) for myoma retrieval after laparoscopic myomectomy. MATERIALS AND METHODS: Prospective data from 35 consecutive cases using CPM were compared with retrospective data of all cases using TVE from December 2014 to January 2017. Patients were matched 1:1 based on myoma diameter. A total of 62 women were included in the final analysis. Specimen retrieval was performed using the TVE or CPM within an insufflated isolation bag. RESULTS: Age, body mass index, mode of prior obstetric delivery, history of previous abdominal surgery, indication for myomectomy, and the myoma(s) characteristics were similar between groups. Retrieval time was significantly shorter in the TVE group compared with the CPM group: 10 minutes (3-15 minutes) versus 17 minutes (14-42 minutes); P < .001. Time required for placement of the instruments was 9.7 minutes for the isolation bag and 0.5 minutes for the vaginal extractor. Additional analgesic administration for pain relief was necessary in 13 patients (42%) in the TVE group and 23 patients (72%) in the CPM group ( P = .01). Total cost of the hospital stay was significantly higher in the CPM group compared with the TVE group ( P < .001). Estimated blood loss and duration of hospital stay were similar between groups. CONCLUSION: Both CPM and TVE can be used for safe retrieval of large myomas that are removed laparoscopically. Compared with CPM, TVE was associated with a shorter retrieval time, less postoperative pain, and less hospital costs.

Clermont-Ferrand versus Vectec uterine manipulator for total laparoscopic hysterectomy.

OBJECTIVE: To compare the operation time and performance of two uterine manipulators used for total laparoscopic hysterectomy (TLH). MATERIAL AND METHODS: Design: Retrospective cohort analysis. Design classification: Canadian Task Force Classification II-2. SETTING: Tertiary-care university-based teaching hospital and academic affiliated private hospital. PATIENTS: All consecutive patients who underwent for TLH between January 2014 and June 2017. All operations were performed by two expert endoscopic surgeons using one of the following uterine manipulators depending on surgeon preferences: Clermont-Ferrand (CF) or Vectec (VT) MAUT60. Patients were excluded if additional surgeries such as urogynecological procedures were performed, TLH was converted to laparotomy prior to colpotomy, and when their operation records could not be obtained. A total of 169 patients were added to final analysis. Operation time, colpotomy time and the subjective performance of manipulators such as movement of the uterus, visualization of the vaginal fornices, and maintenance of pneumoperitoneum were evaluated by watching un-edited operation videos. RESULTS: A total of 169 patients (83 patients in CF group; 86 patients in VT group) were included in the final analysis. Patients' baseline characteristics were comparable between groups. Operation time and time required for colpotomy were significantly shorter in the VT group. Lateral movements of the manipulators and elevation of the uterus were better with VT compared to CF (p = .001 for both). Compared to the CF, VT was superior for visualization of the vaginal fornices (p = .004) and maintenance of pneumoperitoneum (p < .001). Both surgeons had perfect agreement on the performance grading of manipulators (p < .001, Kappa values were between 0.86-0.92). There was no difference between groups in estimated blood loss and duration of hospital stay. Reinsertion or the need to change the manipulator was not required in either group. No pelvic or vaginal abscess, cuff cellulitis, dehiscence, or hematoma formations were noted. CONCLUSION: Laparoscopic hysterectomy assisted with the VT uterine manipulator is associated with shorter operation and colpotomy time. Furthermore, the movements of uterus, visualization of the vaginal fornices, and maintenance of pneumoperitoneum were significantly better with VT compared to the CF manipulator.

Ovarian and Uterine Functions in Female Survivors of Childhood Cancers.

Adult survivors of childhood cancers are more prone to developing poor reproductive and obstetrical outcomes than their siblings and the general population as a result of previous exposure to chemotherapy and radiation during childhood. Chemotherapy drugs exert cytotoxic effects systemically and therefore can damage the ovaries, leading to infertility, premature ovarian failure, and, to a lesser extent, spontaneous abortions. They have very limited or no deleterious effects on the uterus that can be recognized clinically. By contrast, radiation is detrimental to both the ovaries and the uterus, thereby causing a greater magnitude of adverse effects on the female reproductive function. These include infertility, premature ovarian failure, miscarriage, fetal growth restrictions, perinatal deaths, preterm births, delivery of small-for-gestational-age infants, preeclampsia, and abnormal placentation. Regrettably, the majority of these adverse outcomes arise from radiation-induced uterine injury and are reported at higher incidence in the adult survivors of childhood cancers who were exposed to uterine radiation during childhood in the form of pelvic, spinal, or total-body irradiation. Recent findings of long-term follow-up studies evaluating reproductive performance of female survivors provided some reassurance to female cancer survivors by documenting that pregnancy and live birth rates were not significantly compromised in survivors, including those who had been treated with alkylating agents and had not received pelvic, cranial, and total-body irradiation. We aimed in this narrative review article to provide an update on the impact of chemotherapy and radiation on the ovarian and uterine function in female survivors of childhood cancer. IMPLICATIONS FOR PRACTICE: Adult survivors of childhood cancers are more prone to developing a number of poor reproductive and obstetrical outcomes than their siblings and the general population as a result of previous exposure to chemotherapy and radiation during childhood. The impact of radiation therapy on the female genital system is greater than chemotherapy regimens because radiation is detrimental to both the uterus and the ovaries, whereas toxic effects of chemotherapy drugs are confined to the ovaries. Therefore, radiation-induced uterine damage accounts for most poor obstetrical outcomes in the survivors. These include infertility, miscarriages, stillbirths, fetal growth restrictions, preeclampsia, and preterm deliveries.

Do endometriomas grow during ovarian stimulation for assisted reproduction? A three-dimensional volume analysis before and after ovarian stimulation.

Whether endometriomas grow because of supraphysiological oestradiol levels attained during ovarian stimulation for assisted reproduction techniques is a concern. In this prospective study, 25 women with 28 endometriomas underwent three-dimensional ultrasound using sono-automated volume calculation software. Endometrioma volume was measured on the first day of gonadotrophin injection (V1) and the day of ovulation trigger (V2). Nine (36%) women were stimulated in a gonadotrophin releasing hormone antagonist protocol (GnRH), 13 (52%) in a long, and three (12%) in an ultra-long GnRH agonist protocol. Mean duration of stimulation was 10.3 days with median total gonadotrophin dose of 4500 IU/day. Median number of cumulus oocyte complexes was five, and metaphase-two oocytes was four. None of the endometriomas were punctured during oocyte retrieval. Median V1 was 22.2 ml (12-30 ml) and median V2 was 24.99 ml (11.2-37.4 ml) with P = 0.001. Twenty-three out of 28 endometriomas (82%) grew to some extent during ovarian stimulation. Endometrioma growth was positively correlated with prestimulation cyst volume (Correlation coefficient 0.664; P < 0.01). Although the 3-ml average growth was statistically significant, it could be regarded as clinically insignificant.

Unidirectional barbed suture for vaginal cuff closure without backward stitch in total laparoscopic hysterectomy.

AIM: To evaluate the safety and efficacy of unidirectional barbed suture technique for vaginal cuff closure in total laparoscopic hysterectomy (TLH). METHODS: In a retrospective chart review, data were analyzed from 165 patients who underwent a TLH with an unidirectional barbed suture technique for vaginal cuff closure from January 2012 to June 2016 at tertiary-care university-based teaching hospital and academic affiliated hospital. Vaginal cuff was closed by single layer 3/0 V-Loc unidirectional 9″, 180 day Absorbable Wound Closure Device (Covidien Healthcare, Mansfield, MA) and the suture was not stitched backward to secure distal end. RESULTS: A total of 165 patients were included and the median age was 50 years (range, 35-84 years). The median completion time for hysterectomy time was 100 min (range, 40-240 min) and the median vaginal cuff closure time was 7 min (range, 4-15 min). The median estimated blood loss was 87.8 mL (range 30-250 mL) and the median uterine weight was 200 g (range, 40-900 g). Intraoperative complication included bladder perforation (1.2%) and postoperative complications were vaginal cuff dehiscence (1.8%), cuff cellulitis (0.6%), vesicovaginal fistula (0.6%) and unexplained fever (0.6%). CONCLUSION: According to the results of current study, the use of unidirectional barbed suture without backward stitching appears to be safe for the vaginal cuff closure in TLH.

Intraoperative endoscopic ultrasound guidance for laparoscopic excision of invisible symptomatic deep intramural myomas.

The aim of this study was to evaluate the feasibility of intraoperative endoscopic ultrasound guidance for excision of symptomatic deep intramural myomas that are not otherwise visible at laparoscopy. Seventeen patients with symptomatic deep intramural myomas who underwent laparoscopic myomectomy with intraoperative endoscopic ultrasound guidance were followed up and reported. All myomas were removed successfully. The endometrium was breached in one patient. All patients were relieved of their symptoms and three patients presenting with infertility conceived. There were no short- or long-term complications associated with the procedure. One patient who had multiple myomas necessitated intravenous iron treatment prior to discharge. Laparoscopic removal of small symptomatic deep intramural myomas is facilitated by the use of intraoperative endoscopic ultrasound that enables exact localisation and correct placement of the serosal incision. Impact statement What is already known on this subject: When the myoma is symptomatic, compressing the endometrium, does not show serosal protrusion and is not amenable to hysteroscopic resection, laparoscopic surgery may become challenging. What do the results of this study add: The use of intraoperative endoscopic ultrasound under these circumstances may facilitate the procedure by accurate identification of the myoma and correct placement of the serosal incision. What are the implications of these findings for clinical practice and/or further research: Intraoperative ultrasound should be more oftenly used to accurately locate deep intramural myomas to the end of making laparoscopy feasible and possibly decreasing recurrence by facilitating removal of otherwise unidentifiable disease.

FSH Stimulation promotes progesterone synthesis and output from human granulosa cells without luteinization.

STUDY QUESTION: Can granulosa cells produce progesterone (P) in response to FSH stimulation? SUMMARY ANSWER: FSH actively promotes P synthesis and output from granulosa cells without luteinization by up-regulating the expression and increasing enzymatic activity of 3ß-hydroxysteriod dehydrogenoase (3ß-HSD), which converts pregnenolone to P. WHAT IS KNOWN ALREADY: Serum P level may rise prematurely prior to ovulation trigger in stimulated IVF cycles and adversely affect implantation and clinical pregnancy rates by impairing endometrial receptivity. STUDY DESIGN, SIZE, DURATION: A translational research study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human ovarian cortical samples (n = 15) and non-luteinizing FSH-responsive human mitotic granulosa cell line (HGrC1) were stimulated with rec-FSH at 12.5, 25 and 50 mIU/ml concentrations for 24 and 48 h. FSH receptor expression was knocked-down and up-regulated in the granulosa cells using short hairpin RNA (shRNA) technology and activin-A administration, respectively. The expressions of the steroidogenic enzymes were analyzed at mRNA level by real-time quantitative RT-PCR, and protein level by western blot and immunoprecipitation assay. The enzymatic activity of 3ß-HSD was measured using a spectrophotometric method. In vitro estradiol (E2) and P productions of the cells before and after FSH stimulation were measured by electro-chemiluminescence immunoassay method. MAIN RESULTS AND THE ROLE OF CHANCE: Stimulation of the HGrC1 cells with FSH resulted in a dose-dependent increase in the mRNA and protein level of 3ß-HSD. Overall, when all time points and FSH doses were analyzed collectively, FSH significantly up-regulated the mRNA expression of its own receptor (3.73 ± 0.06-fold, P < 0.001), steroidogenic acute regulatory protein (stAR, 1.7 ± 0.03-fold, P < 0.01), side-chain cleavage enzyme (SCC, 1.75 ± 0.03-fold, P < 0.01), aromatase (4.49 ± 0.08-fold, P < 0.001), 3ß-HSD (1.68 ± 0.02-fold, P < 0.01) and 17ß-hydroxy steroid dehydrogenase (17ß-HSD, 2.16 ± 0.02-fold, P < 0.01) in the granulosa cells. Expression of 17α-hydroxylase (17α-OH, 1.03 ± 0.01-fold P > 0.05) did not significantly change. Similar changes were observed in the protein expression analysis of these enzymes on western blotting after FSH stimulation. FSH significantly increased 3ß-HSD, 17ß-HSD and aromatase in a dose-dependent manner but did not affect 17α-OH. Protein expression of P was increased along with 3ß-HSD after FSH stimulation, which was further evidenced by immunoprecipitation assay. Enzymatic activity of 3ß-HSD was significantly enhanced by FSH administration in the HGrC1 cells in a dose-dependent manner. In line with these findings P output (1.05 ± 0.3 vs. 0.2 ± 0.1 ng/ml, respectively, P < 0.001) from the samples stimulated with FSH were significantly increased along with E2 (1918 ± 203 vs. 932 ± 102 pg/ml, respectively, P < 0.001) compared to unstimulated controls. FSH-induced increase in 3ß-HSD expression was amplified and reversed in the HGrC1 cells when FSH receptor expression was up-regulated by activin-A and down-regulated with shRNA, respectively. LIMITATIONS AND REASONS FOR CAUTION: As only the effect of FSH was studied we cannot extrapolate our findings to the potential effects of HMG and recombinant LH. WIDER IMPLICATIONS OF THE FINDINGS: This data provides a molecular explanation for the largely unexplained phenomenon of P rise during the follicular phase of gonadotropin stimulated IVF cycles. Our findings may progress the research to uncover potential mechanisms for preventing premature P rise that appears to be associated with inferior outcomes in women undergoing IVF. STUDY FUNDING/COMPETING INTEREST(S): Funded by the School of Medicine and the Graduate School of Health Sciences of Koc University. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: None.

Which is worse? Comparison of ART outcome between women with primary or recurrent endometriomas.

STUDY QUESTION: Are live birth rates (LBR) different after ART cycles between women with primary or recurrent endometrioma? SUMMARY ANSWER: Women with recurrent endometrioma have similar LBR as compared to patients with primary endometrioma. WHAT IS ALREADY KNOWN: Recurrence rate can be as high as 29% after endometrioma excision. Prior studies on management of endometrioma before ART involve primary endometriomas. There is limited information regarding the prognosis of women with recurrent endometriomas. STUDY DESIGN, SIZE, DURATION: A multicenter retrospective cohort study, including 76 women with primary and 82 women with recurrent endometriomas treated at the participating centers over a 6-year period. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with endometrioma who underwent ART at three academic ART centers. Couples with another indication for ART were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: Female age, median number of prior failed ART cycles, proportion of patients with bilateral endometrioma (28 versus 28.9%), ovarian stimulation protocols, and total gonadotropin consumption were similar between the study groups. Numbers of metaphase two oocytes (5 versus 6), number of embryos transferred, and the proportion of patients undergoing blastocyst transfer were similar across the study groups. Clinical pregnancy rates (36.6 versus 34.2%, absolute difference 2.4%, 95% CI: -12.5 to 17.3%, P = 0.83) and LBR (35.4 versus 30.3%, absolute difference 5.1%, 95% CI: -9.5 to 19.7%, P = 0.51) per started cycle in recurrent and primary endometrioma were similar. Comparable success rates were also confirmed with logistic regression analysis (OR: 1.14, 95% CI: 0.78-0.57, P = 2.3). LIMITATIONS, REASONS FOR CAUTION: The retrospective design has inherent limitations. Some women with severely decreased ovarian reserve after primary endometrioma excision may not have pursued further treatment. WIDER IMPLICATIONS OF THE FINDINGS: The management of endometrioma prior to ART is controversial but a different management strategy is not required for recurrent endometriomas. Since recurrent endometriomas do not have a worse impact on ART outcome than primary endometriomas, and repeat surgery has a higher risk for complications, conservative management without surgery can be justified. STUDY FUNDING/COMPETING INTEREST(S): No funding or competing interests to declare. TRIAL REGISTRATION NUMBER: None.