Researcher: Akın, Nazlı
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Akın, Nazlı
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Publication Metadata only The expressions of ovarian steroidogenic enzymes do not increase proportionally after FSH, creating a shunting that promotes progesterone output in the granulosa cells without luteinization(Oxford University Press (OUP), 2016) Seyhan, A.; Keles, I.; Balaban, B.; N/A; N/A; N/A; N/A; Akın, Nazlı; Bildik, Gamze; Urman, Defne; Urman, Cumhur Bülent; Öktem, Özgür; Master Student; Teaching Faculty; Master Student; N/A; Faculty Member; Faculty Member; Graduate School of Health Sciences; School of Medicine; Graduate School of Health Sciences; N/A; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; 12147; 102627N/APublication Metadata only Molecular evidence against the preventive actions of GnRH agonists in chemotherapy induced damage in human ovary and granulosa cells(2015) Güzel, Y.; Urman, B; N/A; Bildik, Gamze; Akın, Nazlı; Taşkıran, Çağatay; Selek, Uğur; Öktem, Özgür; Teaching Faculty; Master Student; Faculty Member; Faculty Member; Faculty Member; School of Medicine; Graduate School of Health Sciences; School of Medicine; School of Medicine; School of Medicine; Koç University Hospital; N/A; N/A; 134190; 27211; 102627N/APublication Metadata only FSH stimulation promotes progesterone synthesis and output from human granulosa cells without luteinization(Oxford Univ Press, 2017) Alper, Ebru; Balaban, Basak; N/A; Öktem, Özgür; Akın, Nazlı; Bildik, Gamze; Yakın, Kayhan; Urman, Cumhur Bülent; Faculty Member; Master Student; Teaching Faculty; Faculty Member; Faculty Member; School of Medicine; Graduate School of Health Sciences; Graduate School of Health Sciences; School of Medicine; School of Medicine; 102627; N/A; N/A; 106822; 12147STUDY 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 3 beta-hydroxysteriod dehydrogenoase (3 beta-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 3 beta-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 electrochemiluminescence 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 3 beta-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), 3 beta-HSD (1.68 +/- 0.02-fold, P < 0.01) and 17 beta-hydroxy steroid dehydrogenase (17 beta-HSD, 2.16 +/- 0.02-fold, P < 0.01) in the granulosa cells. Expression of 17 alpha-hydroxylase (17 alpha-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 3a-HSD, 17 beta-HSD and aromatase in a dose-dependent manner but did not affect 17 alpha-OH. Protein expression of P was increased along with 3a-HSD after FSH stimulation, which was further evidenced by immunoprecipitation assay. Enzymatic activity of 3 beta-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 3 beta-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.Publication Metadata only Luteal phase ovarian stimulation protocol for gynecological cancer patients with time constraints(Lippincott Williams & Wilkins, 2015) Arvas, M; N/A; N/A; N/A; N/A; N/A; Taşkıran, Çağatay; Mısırlıoğlu, Selim; Bildik, Gamze; Akın, Nazlı; Öktem, Özgür; Faculty Member; Doctor / Faculty Member; Teaching Faculty; Master Student; Faculty Member; School of Medicine; School of Medicine; School of Medicine; Graduate School of Health Sciences; School of Medicine; 134190; N/A; N/A; N/A; 102627N/APublication Metadata only Can we use gemcitabine for the treatment of granulosa cell tumor of the ovary?(Lippincott Williams & Wilkins, 2015) Arvas, M; N/A; N/A; N/A; N/A; N/A; Taşkıran, Çağatay; Mısırlıoğlu, Selim; Bildik, Gamze; Akın, Nazlı; Öktem, Özgür; Faculty Member; Doctor / Faculty Member; Teaching Faculty; Master Student; Faculty Member; School of Medicine; School of Medicine; School of Medicine; Graduate School of Health Sciences; School of Medicine; 134190; N/A; N/A; N/A; 102627N/APublication Metadata only Imatinib mesylate accelerates follicle death andis not protective against chemotherapy induced damage in human ovary(Elsevier Science Inc, 2016) Keles, I.; Balaban, B.; Bildik, Gamze; Akın, Nazlı; Urman, Defne; Urman, Cumhur Bülent; Öktem, Özgür; Teaching Faculty; Master Student; Researcher; Faculty Member; Faculty Member; School of Medicine; Graduate School of Health Sciences; Graduate School of Health Sciences; School of Medicine; School of Medicine; N/A; N/A; N/A; 12147; 102627N/APublication Metadata only Molecular evidence against ovarian protection with the co-administration of GnRH agonist with chemotherapy in human.(Sage, 2016) Selek, Ugur; Iwase, Akira; Bildik, Gamze; Akın, Nazlı; Şenbabaoğlu, Filiz; Öktem, Özgür; Teaching Faculty; Master Student; PhD Student; Faculty Member; School of Medicine; Graduate School of Health Sciences; Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; 102627N/APublication Metadata only hCG ımproves luteal function and promotes progesterone output through the activation of JNK pathway in the luteal granulosa cells of the stimulated IVF cycles(Oxford Univ Press Inc, 2020) N/A; Bildik, Gamze; Akın, Nazlı; Esmaeilian, Yashar; Hela, Francesko; Yakın, Kayhan; Önder, Tamer Tevfik; Urman, Cumhur Bülent; Öktem, Özgür; Teaching Faculty; Master Student; Researcher; PhD Student; Faculty Member; Faculty Member; Faculty Member; Faculty Member; School of Medicine; Graduate School of Health Sciences; N/A; Graduate School of Health Sciences; School of Medicine; School of Medicine; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; 106822; 42946; 12147; 102627Human 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), 3β-Hydroxysteroid dehydrogenase (3β-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 3β-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.Publication Metadata only GNRH agonist leuprolide acetate neither activates antiapoptotic genes nor protects human ovary and granulosa cells from dna damage and apoptosis induced by cyclophosphamide(Lippincott Williams & Wilkins, 2015) Arvas, M; N/A; N/A; N/A; N/A; N/A; Taşkıran, Çağatay; Mısırlıoğlu, Selim; Bildik, Gamze; Akın, Nazlı; Öktem, Özgür; Faculty Member; Doctor / Faculty Member; Teaching Faculty; Master Student; Faculty Member; School of Medicine; School of Medicine; School of Medicine; Graduate School of Health Sciences; School of Medicine; 134190; N/A; N/A; N/A; 102627Objective: Inconsistent results of randomized controlled trials (RCTs) and lack of a proven molecular mechanism of action with ovarian protection with co-administration GnRH agonists (GnRHa) with chemotherapy places GnRHa under scrutiny as a fertility preservation strategy. We aimed in this study to provide molecular evidence for-or-against the role of GnRHa in the prevention of cyclophosphamide induced damage in human ovarian tissue samples and granulosa cells. Design: A translational research study. Materials and Methods: Ovarian cortical pieces (n=15, age 14-37) and human mitotic non-luteinized (COV434, HGrC1) and non-mitotic luteinized (HLGC) granulosa cells were treated with 4-hydroperoxy cyclophosphamide (in vitro active metabolite of cyclophosphamide used at 50 and 100 μM) with and without GnRHa leuprolide acetate (50 ng/mL: peak intraovarian concentration of the drug) for 24 hrs. Cell proliferation (real-time quantitative assessment by xcelligence system),DNA damage (p-histone H2AX), apoptosis (cleaved caspase-3, YO-PRO-1), follicle counts, hormonal markers of ovarian function and reserve (estradiol, progesterone and AMH), and the expression of anti-apoptotic genes (bcl-2, bcl-xL, bcl-2L2, Mcl-1, BIRC-2 and XIAP) were compared among control, chemotherapy and chemotherapy+GnRHa groups. Results: GnRH receptor expression and its activation by GnRHa were validated with qRT-PCR and measuring intracellular cAMP level, respectively. Exposure to cyclophosphamide resulted in massive follicle loss, arrested cell growth, increased DNA damage/apoptosis and decreased hormone productions in the tissue samples and granulosa cells. The co-administration of GnRHa with cyclophosphamide did not prevent or attenuate any of these cytotoxic effects. Furthermore, GnRHa did not up-regulate the anti-apoptotic genes compared to control and cyclophosphamide treated samples.Mcl-1 and BIRC2 expressions were further decreased after cyclophosphamide+GnRHa (Table). Conclusions: GnRH agonist leuprolide acetate does not offer any protection against cyclophosphamide induced damage in human ovary and granulosa cells via its cognate receptors.Publication Metadata only Gonadotropin stimulation alters the expression of local growth factors in the granulosa cells involved in paracrine communication, dominant follicle selection and luteinization(Elsevier, 2015) Güzel, Yılmaz; Alper, Ebru; Ata, Ayşe Seyhan; Balaban, Başak; N/A; Bildik, Gamze; Akın, Nazlı; Yakın, Kayhan; Urman, Cumhur Bülent; Öktem, Özgür; Master Student; Master Student; Faculty Member; Faculty Member; Faculty Member; Graduate School of Health Sciences; Graduate School of Health Sciences; School of Medicine; School of Medicine; School of Medicine; N/A; N/A; 106822; 12147; 102627
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