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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/3
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Publication Metadata only Endometriosis, staging, infertility and assisted reproductive technology: time for a rethink(Elsevier Inc., 2024) Somigliana, Edgardo; Ata, Mustafa Barış; School of MedicineHow endometriosis causes infertility, with the exception of tubal dysfunction caused by adhesions, is unclear. The inflammatory milieu in the pelvis and impaired receptivity of the eutopic endometrium are considered to be possible factors. Anatomical staging systems fail to predict the fertility status of endometriosis patients. Data from assisted reproductive technology cycles consistently suggest that oocytes from patients with endometriosis have a normal potential to develop into euploid blastocysts. Moreover, oocyte or embryo recipients with endometriosis seem to have similar or slightly lower pregnancy and live birth rates compared with recipients without endometriosis, suggesting that eutopic endometrium is not or is only minimally affected, which may be caused by undiagnosed adenomyosis. In-vivo observations from women with endometriomas provide evidence against a detrimental effect of endometriomas on oocytes. Combined with the absence of an obvious improvement in fertility following the surgical destruction or excision of peritoneal endometriosis or from temporary medical suppression of the disease and the associated inflammation, the available evidence makes endometriosis-associated infertility questionable in the absence of tubal dysfunction caused by adhesions. It is likely that no anatomical staging will correlate with fertility beyond assessing tubal function. In patients with endometriosis assisted reproductive technology is as effective as for other indications.Publication Metadata only Does the holy grail of the evidence pyramid vindicate the controversial practice of endometrial scratching or is there room for healthy skepticism?(Oxford University Press, 2024) N/A; Ata, Mustafa Barış; Kalafat, Erkan; School of MedicineN/APublication Metadata only Endometriosis and adenomyosis: shared pathophysiology(Elsevier Science Inc, 2023) Bulun, Serdar E.; Adli, Mazhar; Chakravarti, Debabrata; Parker, James Brandon; Milad, Magdy; Yang, Linda; Chaudhari, Angela; Tsai, Susan; Wei, Jian Jun; Yin, Ping; Yıldız, Şule; School of MedicineEndometriosis and adenomyosis are closely related disorders. Their pathophysiologies are extremely similar. Both tissues originate from the eutopically located intracavitary endometrium. Oligoclones of endometrial glandular epithelial cells with somatic mutations and attached stromal cells may give rise to endometriosis if they travel to peritoneal surfaces or the ovary via retrograde menstruation and/or may be entrapped in the myometrium to give rise to adenomyosis. In both instances, the endometrial cell populations possess survival and growth capabilities conferred by somatic epithelial mutations and epigenetic abnormalities in stromal cells. Activating mutations of KRAS are the most commonly found genetic variant in endometriotic epithelial cells, whereas the adenomyotic epithelial cells almost exclusively bear KRAS mutations. Epigenetic abnormalities in the stromal cells of endometriosis and adenomyosis are very similar and involve an abnormal expression pattern of nuclear receptors, including the steroid receptors. These epigenetic defects give rise to excessive local estrogen biosynthesis by aromatase and abnormal estrogen action via estrogen receptor-b. Deficient progesterone receptor expression results in progesterone resistance in both endometriosis and adenomyosis.Publication Metadata only Adenomyosis: single-cell transcriptomic analysis reveals a paracrine mesenchymal-epithelial interaction involving the WNT/SFRP pathway(Elsevier Science Inc, 2023) Kinali, Meric; Wei, Jian Jun; Milad, Magdy; Yin, Ping; Adli, Mazhar; Bulun, Serdar E.; Yıldız, Şule; School of MedicineObjective: To assess the cellular and molecular landscape of adenomyosis.Design: Single-cell analysis of genome-wide messenger RNA (mRNA) expression (single-cell RNA sequencing) of matched tissues of endometrium, adenomyosis, and myometrium using relatively large numbers of viable cells.Setting: Not applicable. Patient(s): Patients (n 1/4 3, age range 40-44 years) undergoing hysterectomy for diffuse adenomyosis. Main Outcome Measure(s): Definition of the molecular landscape of matched adenomyotic, endometrial and myometrial tissues from the same uterus using single-cell RNA sequencing and comparison of distinct cell types in these tissues to identify disease-specific cell populations, abnormal gene expression and pathway activation, and mesenchymal-epithelial interactions.Result(s): The largest cell population in the endometrium was composed of closely clustered fibroblast groups, which comprise 36% of all cells and seem to originate from pericyte progenitors differentiating to estrogen/progesterone receptor-expressing endometrial stromal-cells. In contrast, the entire fibroblast population in adenomyosis comprised a larger (50%) portion of all cells and was not linked to any pericyte progenitors. Adenomyotic fibroblasts eventually differentiate into extracellular matrix protein-expressing fibroblasts and smooth muscle cells. Hierarchical clustering of mRNA expression revealed a unique adenomyotic fibroblast population that clustered transcriptomically with endometrial fibroblasts, suggestive of an endometrial stromal cell population serving as progenitors of adenomyosis. Four other adenomyotic fibroblast clusters with disease-specific transcriptomes were distinct from those of endometrial or myometrial fibroblasts. The mRNA levels of the natural WNT inhibitors, named, secreted frizzled-related proteins 1, 2, and 4, were higher in these 4 adenomyotic fibroblast clusters than in endometrial fibroblast clusters. Moreover, we found that multiple WNTs, which originate from fibroblasts and target ciliated and unciliated epithelial cells and endothelial cells, constitute a critical paracrine signaling network in adenomyotic tissue. Compared with endometrial tissue, unciliated and ciliated epithelial cells in adenomyosis comprised a significantly smaller portion of this tissue and exhibited molecular evidence of progesterone resistance and diminished regulation of estrogen signaling.Conclusion(s): We found a high degree of heterogeneity in fibroblast-like cells in the adenomyotic uterus. The WNT signaling involving differential expression of secreted frizzled-related proteins, which act as decoy receptors for WNTs, in adenomyotic fibroblasts may have a key role in the pathophysiology of this disease.Publication Metadata only Revitalizing female fertility: platelet-rich plasma - hype or hope?(Elsevier Sci Ltd, 2024) Serdaroğulları, Münevver; Raad, Georges; Makieva, Sofia; Liperis, Georgios; Fraire-Zamora, Juan J.; Özenci, Çiler Çelik; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of MedicinePlatelet-rich plasma (PRP) has gained popularity as an experimental tool in regenerative medicine, with potential applications in reproductive medicine. This review will assess the existing literature on the role of PRP in female fertility enhancement, focusing on ovarian rejuvenation and increased endometrial thickness. PRP is being explored as a treatment for recurrent implantation failure, primary ovarian insufficiency and poor ovarian response. While the influence of PRP on endometrial thickness and implantation success is postulated, its effectiveness remains the subject of debate due to protocol variability and unclear patient selection criteria. This narrative review includes 36 articles published before December 2022, and highlights the lack of comprehensive molecular studies examining the impact of PRP on reproductive capacity. This review underscores the importance of standardizing PRP preparation protocols in reproductive medicine. However, challenges persist, and there is a need for well-planned randomized controlled trials and a deeper understanding of the patient population that would gain the greatest benefit from PRP treatment. Clarifying these aspects is crucial to improve outcomes for low-prognosis patients undergoing assisted reproductive technology.Publication Metadata only Ongoing pregnancy rates in single euploid frozen embryo transfers remain unaffected by female age: a retrospective study(Elsevier Sci Ltd, 2024) Lawrenz, B.; Del Gallego, R.; Melado, L.; Bayram, A.; Elkhatib, I.; Fatemi, H.; Kalafat, Erkan; Ata, Mustafa Barış; School of MedicineResearch question: Is female age a signi fi cant factor in the likelihood of an ongoing pregnancy in single euploid frozen embryo transfers (FET)? Design: Retrospective study of 1923 single euploid FET cycles in 1464 women, either in a natural cycle or a hormone replacement therapy cycle. The primary outcome was the ongoing pregnancy rate (OPR). Results: There were 990 (51.48%) ongoing pregnancies among 1923 included transfers. The OPR were 51.4%, 49.1%, 53.3% and 52.3% for women aged < 35, > 35 -< 37, > 37 -< 40 and > 40 years at oocyte retrieval (OCR), without a signi fi cant trend for decreasing OPR ( P = 0.679). No signi fi cant differences in female age at embryo transfer ( P = 0.609) and female age at OCR ( P = 0.816) were found between the groups (ongoing pregnancy versus no pregnancy or miscarriage). Women who received good-quality embryos ( P < 0.001), had a lower body mass index (BMI) ( P < 0.001), had achieved at least one pregnancy previously ( P < 0.001), and underwent natural cycle endometrial preparation ( P < 0.001) were more likely to achieve an ongoing pregnancy. Multivariable regression analysis (adjusted for BMI, embryo quality and endometrial preparation) did not show a signi fi cant effect of female age at OCR on achieving an ongoing pregnancy. Compared with women aged < 35 years, none of the age groups had signi fi cantly higher or lower OPR. A multinomial regression analysis showed that BMI, embryo quality and endometrial preparation were associated with miscarriage/no pregnancy versus ongoing pregnancy ( P = 0.001, 0.001 and 0.001, respectively). Female age had no signi fi cant association with either outcome. Conclusions: Female age in itself does not have a substantial impact on the OPR in single euploid FET cycles, but the OPR is impacted signi fi cantly by embryo quality, BMI, previous parity, and a natural cycle endometrial preparation protocol.Publication Metadata only Advancements in three-dimensional bioprinting for reproductive medicine: a systematic review(Elsevier Sci Ltd, 2024) Aydın, Serdar; Yaşlı, Mert; Yıldız, Şule; Urman, Cumhur Bülent; School of Medicine; Koç University HospitalReproductive 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 untapped potential in reproductive medicine.Publication Metadata only Response to: cumulative live birth rate following progestin-primed ovarian stimulation: controversial results with own and donated oocytes(Reproductive BioMedicine Online, 2024) Ata, Mustafa Barış; Kalafat, Erkan; School of MedicinePublication Metadata only Do probiotic interventions improve female unexplained infertility? A critical commentary(Elsevier Sci Ltd, 2024) Favaron, Alessia; Elbadawi, Moe; Gaisford, Simon; Basit, Abdul W.; Orlu, Mine; Türkgeldi, Engin; School of MedicineDisruption of women's gut and cervicovaginal microbiota has been associated with multiple gynaecological diseases such as endometriosis, polycystic ovary syndrome, non-cyclic pelvic pain and infertility. Female infertility affects 12.6% of women worldwide;its aetiology is complex and multifactorial and can be underpinned by uterine pathologies, systemic diseases and age. In addition, a new perspective has emerged on the role of the gut and vaginal microbiomes in reproductive health. Research shows that the administration of precisely selected probiotics, often in combination with prior antibiotic treatment, may facilitate the restoration of symbiotic microbiota to increase successful conception and assisted reproductive technology outcomes. However, clarity on this issue from fuller research is currently hampered by a lack of consistency and harmonization in clinical studies: various lactobacilli and bifidobacteria species have been delivered through both the oral and vaginal routes, in different dosages, for different treatment durations. This commentary explores the intricate relationship between the microbiota in the cervicovaginal area and gut of women, exploring their potential contribution to infertility. It highlights ongoing research on the use of probiotic formulations in improving pregnancy outcomes, critically examining the divergent findings in these studies, which complicate a conclusive assessment of the efficacy of these interventions.Publication Metadata only Progesterone signaling in the regulation of luteal steroidogenesis(Oxford Univ Press, 2023) Yakın, Kayhan; Hela, Francesko; Öktem, Özgür; School of Medicine; Graduate School of Health SciencesThe corpus luteum is the major source of progesterone, the essential hormone for female reproductive function. While progesterone activity has been the subject of extensive research for decades, characterization of non-canonical progesterone receptor/signaling pathways provided a new perspective for understanding the complex signal transduction mechanisms exploited by the progesterone hormone. Deciphering these mechanisms has significant implications in the management of luteal phase disorders and early pregnancy complications. The purpose of this review is to highlight the complex mechanisms through which progesterone-induced signaling mediates luteal granulosa cell activity in the corpus luteum. Here, we review the literature and discuss the up-to-date evidence on how paracrine and autocrine effects of progesterone regulate luteal steroidogenic activity. We also review the limitations of the published data and highlight future research priorities.