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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/3
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Publication Metadata only Exposure of antral follicles to medroxyprogesterone acetate during stimulation does not cause molecular perturbations in gonadotropin-responsiveness and steroidogenic function of granulosa cells in progestin-primed cycles(Oxford University Press, 2024) ; Öktem, Özgür; Esmaeilian, Yashar; İltümür, Ece; Yusufoğlu, Sevgi; Uğurlu Çimen, Deniz; İncir, Said; Yakın, Kayhan; Ata, Mustafa Barış; Urman, Cumhur Bülent; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Health Sciences;Study question: Does medroxyprogesterone acetate (MPA) exposure in progestin-primed ovarian stimulation (PPOS) cycles cause molecular perturbations in the steroidogenic function and gonadotropin responsiveness of the granulosa cells? Summary answer: PPOS cycles are identical to traditional GnRH antagonist cycles not only for clinical IVF characteristics but also for gonadotropin receptor expression, response to gonadotropins, and steroidogenic function at the molecular level. What is known already: PPOS is increasingly used as an alternative to GnRH antagonists due to the inhibitory effect of progesterone on LH release by reducing GnRH pulsatility at the hypothalamic level. Although a growing body of evidence from clinical studies did not indicate significant differences between PPOS and antagonist protocols for IVF cycle characteristics and obstetrical outcomes, it is still unknown whether exposure of the antral follicle cohort to progesterone or its synthetic derivatives during ovarian stimulation causes any subtle molecular aberrations in terms of steroidogenesis and gonadotropin responsiveness. To address this issue, detailed comparative molecular analyses were conducted in the luteinized mural granulosa cells (GCs) obtained from normal responding IVF patients undergoing PPOS and antagonist cycles. Study design, size, duration: A clinical translational research study was conducted with IVF patients. Participants/materials, setting, methods: This study included 55 normal responding IVF patients who underwent ovarian stimulation with either PPOS using MPA (5 mg twice daily) or GnRH antagonist cetrorelix acetate. Recombinant forms of FSH and hCG were used for ovarian stimulation and ovulation triggering, respectively. Luteinized mural GCs obtained during the oocyte retrieval procedure were used for the experiments. Cell culture, quantitative real-time PCR, immunoblotting, confocal time-lapse live cell imaging, and hormone assays were used. Main results and the role of chance: Demographic and IVF cycle characteristics of the patients undergoing ovarian stimulation with PPOS and GnRH antagonist were similar, including ovarian response, mature oocyte yield, and fertilization rates. Molecular analyses revealed that the expression of the enzymes involved in sex-steroid synthesis (StAR, SCC, 3β-HSD, 17β-HSD, aromatase) and the uptake/storage/utilization of cholesterol (LDL receptor, Hormone-sensitive lipase, hydroxy-methyl glutaryl Co-enzyme-A reductase, and Sterol O-acyltransferase1) in the GCs of the PPOS cycles were comparable to those of the antagonist cycles. The expression of the receptors for gonadotropins, estrogen, and progesterone hormones was also similar. Basal and hCG-induced increases in 3β-HSD expression and progesterone production and basal and FSH-induced increases in aromatase expression and E2 output of the GCs from PPOS patients did not exhibit any meaningful differences when compared with GCs from antagonist cycles. Furthermore, basal and hCG-induced up-regulation in the LDL receptor expression and cholesterol uptake did not differ between the groups. Confocal imaging also revealed similar patterns of expression for the steroidogenic enzymes and their co-localization with mitochondria. Lastly, the expression of the other important genes regulating cumulus expansion, ovulation, and luteal function [Relaxin, ADAMTS-1, and epidermal growth factor (EGF)-like growth factor amphiregulin] in the GCs of the PPOS and antagonist cycles were similar. Large scale data: N/A. Limitations, reasons for caution: Caution should be exercised when interpreting our data which was derived from normally responding patients whose ovulation was triggered with hCG. It is unclear whether the molecular parameters assessed vary according to infertility etiologies, magnitude of ovarian response, mode of trigger, and any other underlying ovarian pathologies or systemic diseases. MPA was the progestin used for PPOS and whether these findings can be generalized to other progestins is unknown. Wider implications of the findings: This study provides reassuring molecular evidence that exposure of antral follicle cohorts to MPA during the follicular growth phase does not have any detrimental effects on steroidogenic, ovulatory, and luteal functions when compared with GnRH antagonist 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), and equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. All authors declare no conflict of interest.Publication Metadata only Undetected, natural conception pregnancies in luteal phase stimulations-case series and review of literature(Oxford University Press, 2024) Lawrenz, B.; Del Gallego, R.; Selim, S.; Edades, J.; Fatemi, H.; Kalafat, Erkan; Ata, Mustafa Barış; ; School of Medicine;STUDY QUESTION: What is the risk of an undetected natural conception pregnancy during luteal phase ovarian stimulation, and how does it impact the pregnancy's course? SUMMARY ANSWER: The risk for an undetected, natural conception pregnancy in luteal phase ovarian stimulation is low and it appears that ovarian stimulation is unlikely to harm the pregnancy. WHAT IS KNOWN ALREADY: Random start ovarian stimulation appears to be similarly effective as early follicular stimulation start;and it allows ovarian stimulation to be started independent of the cycle day and throughout the cycle, in accordance with the patients' and clinics' schedule as long as there is no intention of a fresh embryo transfer in the same cycle. Starting ovarian stimulation in the luteal phase bears the possibility of an-at the timepoint of stimulation start-undetected, natural conception pregnancy that has already occurred. There is scarce data on the incidence of this event as well as on the possible implications of ovarian stimulation on the course of an existing pregnancy. STUDY DESIGN, SIZE, DURATION: This retrospective observational study, performed between June 2017 and January 2024, analyzed luteal phase stimulations, in which a natural conception pregnancy was detected during the ovarian stimulation treatment for IVF/ICSI. Luteal phase stimulation was defined as ovarian stimulation started after ovulation and before the next expected menstrual bleeding, with a serum progesterone (P4) level of >1.5 ng/ml on the day of stimulation start or 1 day before. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who underwent a luteal phase ovarian stimulation in a tertiary referral ART center. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 488 luteal phase stimulation cycles were included in the analysis. Luteal phase stimulation was only started after a negative serum hCG measurement on the day or 1 day before commencement of ovarian stimulation. Ten patients (2.1%) had an undetected natural conception pregnancy at the time of luteal phase stimulation start. Eight of these patients underwent an ovarian stimulation in a GnRH-antagonist protocol and two in a progestin-primed stimulation protocol (PPOS). Recombinant FSH was used as stimulation medication for all patients, the patients with a PPOS protocol received additional recombinant LH. One pregnancy (0.2%) was detected after the oocyte retrieval, the other nine pregnancies were detected either due to persistent high serum progesterone levels or due to an increasing progesterone level after an initial decrease before oocyte retrieval. In the cycles with an undetected natural conception pregnancy, the median number of stimulation days was 8 days (range: 6-11 days) and median serum hCG at detection of pregnancy was 59 IU hCG (range: 14.91-183.1). From 10 patients with a pregnancy, three patients delivered a healthy baby, two patients had ongoing pregnancies at the time of summarizing the data, three patients had biochemical pregnancies (patient age: 30, 39, and 42 years), one patient had an ectopic pregnancy which required a salpingectomy, and one patient (age: 34 years) had an early pregnancy loss. LIMITATIONS, REASONS FOR CAUTION: The retrospective study design and the small sample size can limit the accuracy of the estimates. WIDER IMPLICATIONS OF THE FINDINGS: Overall, there is a small risk of undetected natural conception pregnancies when luteal phase stimulation is undertaken. It appears that there are no adverse effects through either direct effect on the embryo or indirectly through a detrimental effect on the corpus luteum function on the pregnancy in our cohort.Publication Metadata only Progestin-primed ovarian stimulation and aneuploidy, innocent until proven guilty(Oxford University Press, 2024) ; Ata, Mustafa Barış; ; School of Medicine;N/APublication Metadata only Unexplained infertility: Diagnosis by exclusion(Oxford University Press, 2023) Bhattacharya, S.; Bosch, E.; Costello, M.; Dos Santos-Ribeiro, S.; Gersak, K.; Homburg, R.; Le Clef, N.; Mincheva, M.; Norman, R.; Piltonen, T.; Scicluna, D.; Somers, S.; Sunkara, S. K.; Verhoeve, H.; Romualdi, D.; Ata, Mustafa Barış; ; School of Medicine;N/APublication Metadata only The Impact of application of CRISPR /dCas9 systems for increasing the expression of FSH receptor in human granulosa cells(Oxford University Press, 2023) Güller, A. S.; Kayabölen, G. N. Şahin; Comar, M. Y.; Sivaslıoğlu, A.; Söyler, Gizem; Yılmaz, İpek; Karahüseyinoğlu, Serçin; ; Graduate School of Health Sciences; School of Medicine;N/APublication Metadata only Does recurrent implantation failure exist? Prevalence and outcomes of five consecutive euploid blastocyst transfers in 123 987 patients(Oxford University Press, 2024) Gill, Pavan; Arnanz, Ana; Cimadomo, Danilo; Vaiarelli, Alberto; Fatemi, Human M.; Ubaldi, Filippo Maria; Garcia-Velasco, Juan A.; Seli, Emre; Ata, Mustafa Barış; ; School of Medicine;Study question: What are the clinical pregnancy and live birth rates in women who underwent up to two more euploid blastocyst transfers after three failures in the absence of another known factor that affects implantation? Summary answer: The fourth and fifth euploid blastocyst transfers resulted in similar live birth rates of 40% and 53.3%, respectively, culminating in a cumulative live birth rate of 98.1% (95% CI = 96.5-99.6%) after five euploid blastocyst transfers. What is known already: The first three euploid blastocysts have similar implantation and live birth rates and provide a cumulative live birth rate of 92.6%. Study design, size, duration: An international multi-center retrospective study was conducted at 25 individual clinics. The study period spanned between January 2012 and December 2022. A total of 123 987 patients with a total of 64 572 euploid blastocyst transfers were screened for inclusion. Participants/materials, setting, methods: Patients with a history of any embryo transfer at another clinic, history of any unscreened embryo transfer at participating clinics, parental karyotype abnormalities, the use of donor oocytes or a gestational carrier, untreated intracavitary uterine pathology (e.g. polyp, leiomyoma), congenital uterine anomalies, adenomyosis, communicating hydrosalpinx, endometrial thickness <6 mm prior to initiating of progesterone, use of testicular sperm due to non-obstructive azoospermia in the male partner, transfer of an embryo with a reported intermediate chromosome copy number (i.e. mosaic), preimplantation genetic testing cycles for monogenic disorders, or structural chromosome rearrangements were excluded. Ovarian stimulation protocols and embryology laboratory procedures including trophectoderm biopsy followed the usual practice of each center. The ploidy status of blastocysts was determined with comprehensive chromosome screening. Endometrial preparation protocols followed the usual practice of participating centers and included programmed cycles, natural or modified natural cycles. Main results and the role of chance: A total of 105 (0.085% of the total population) patients met the criteria and underwent at least one additional euploid blastocyst transfer after failing to achieve a positive pregnancy test with three consecutive euploid blastocyst transfers. Outcomes of the fourth and fifth euploid blastocyst transfers were similar across participating centers. Overall, the live birth rate was similar with the fourth and fifth euploid blastocysts (40% vs 53.3%, relative risk = 1.33, 95% CI = 0.93-1.9, P value = 0.14). Sensitivity analyses excluding blastocysts biopsied on Day 7 postfertilization, women with a BMI >30 kg/m2, cycles using non-ejaculate or donor sperm, double-embryo transfer cycles, and cycles in which the day of embryo transfer was modified due to endometrial receptivity assay test result yielded similar results. Where data were available, the fourth euploid blastocyst had similar live birth rate with the first one (relative risk = 0.84, 95% CI = 0.58-1.21, P = 0.29). The cumulative live birth rate after five euploid blastocyst transfers was 98.1% (95% CI = 96.5-99.6%). Limitations, reasons for caution: Retrospective design has its own inherent limitations. Patients continuing with a further euploid embryo transfer and patients dropping out from treatment after three failed euploid transfers can be systematically different, perhaps with regard to ovarian reserve or economic status. Wider implication of the findings: Implantation failure seems to be mainly due to embryonic factors. Given the stable and high live birth rates up to five euploid blastocysts, unexplained recurrent implantation failure should have a prevalence of <2%. Proceeding with another embryo transfer can be the best next step once a known etiology for implantation failure is ruled out.Publication Metadata only Ovarian stimulation without LH suppression in the freezeall era(Oxford University Press, 2023) Gürbüz, A. S.; Gürbüz, Zeynep Umay; ; School of Medicine;N/APublication Metadata only Short-time or overnight co-incubation with sperm in conventional IVF delivers similar pre-implantation development outcomes: A sibling cumulus-oocyte complex study(Oxford University Press, 2023) Bayram, A.; Elkhatib, I.; Abdala, A.; De Munck, N.; Melado, L.; Lawrenz, B.; Nogueira, D.; Fatemi, H.; Kalafat, Erkan; ; School of Medicine;N/APublication Metadata only Predictive value of intra-cycle FSH measurements for blastocyst euploid rate: a longitudinal cohort study(Oxford University Press, 2023) Del Gallego, R.; Melado, L.; Lawrenz, B.; Elkhatib, I.; Fatemi, H.; Kalafat, Erkan; Ata, Mustafa Barış; ; School of Medicine;N/APublication Metadata only Fertility and anatomical outcome following hysteroscopic adhesiolysis of intrauterine adhesions classified according to symptoms, imaging findings and hysteroscopic appearance of the uterine cavity(Oxford University Press, 2023) Ertaş, S.; Alper, E.; Aksakal, E.; Vitale, S. G.; Urman, Cumhur Bülent; Yakın, Kayhan; ; School of Medicine;N/A