Prevention of ovarian hyperstimulation syndrome in a rat model: comparison of the efficacy of tocilizumab with that of ranibizumab, cabergoline, and a gonadotropin-releasing hormone antagonist

Taşkın, Mine İslimye; Topcu, Onur; Yay, Arzu; Erken, Gülten; Balcıoğlu, Esra; Adalı, Ertan; Hişmioğulları, Adnan Adil

doi:10.3109/09513590.2015.1077218

Cited by 7 publications

(3 citation statements)

References 21 publications

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“…6a-c). Similar to previous studies 38,39 , histological analysis showed that an increase in the number of corpus lutea was observed in the OHSS group. Blocking TGF-β1 signaling by treatment with SB431542 reduced the number of corpus lutea (Fig.…”

Section: Blocking Tgf-β1 Signaling Attenuates the Pathogenesis Of Ohssupporting

confidence: 88%

TGF-β1 induces VEGF expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome

Fang

Wang

et al. 2020

Exp Mol Med

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Ovarian hyperstimulation syndrome (OHSS) is one of the most serious and iatrogenic complications that can occur during in vitro fertilization treatment. Although the pathogenesis of OHSS is not fully understood, vascular endothelial growth factor (VEGF) has been recognized as an important mediator of the development of OHSS. Transforming growth factor-beta-1 (TGF-β1) is known to regulate various ovarian functions. However, whether VEGF can be regulated by TGF-β1 in human granulosa cells has not been determined. In addition, the role of TGF-β1 in the pathogenesis of OHSS remains unknown. In the present study, we demonstrate that TGF-β1 stimulates VEGF expression in and secretion from both immortalized human granulosa-lutein (hGL) cells and primary hGL cells. Our results demonstrate that the SMAD2/3, ERK1/2, and p38 MAPK signaling pathways are involved in TGF-β1-induced VEGF expression and secretion. Using a mouse OHSS model, we show that the expression levels of TGF-β1 and VEGF are increased in the ovaries of OHSS mice. Blocking TGF-β1 signaling inhibits the development of OHSS by attenuating VEGF expression. Moreover, clinical results reveal that the protein levels of TGF-β1 and VEGF are increased in the follicular fluid of patients with OHSS, and that the levels of these two proteins in the follicular fluid are positively correlated. The results of this study help to elucidate the mechanisms by which VEGF expression is regulated in hGL cells, which could lead to the development of alternative therapeutic approaches for treating OHSS.

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Section: Blocking Tgf-β1 Signaling Attenuates the Pathogenesis Of Ohssupporting

confidence: 88%

TGF-β1 induces VEGF expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome

Fang

Wang

et al. 2020

Exp Mol Med

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“…5 G-H). Similar to previous studies, histological analysis showed that an increase in corpus luteum number was observed in the OHSS group [ 39 , 40 ]. Interestingly, ELISA results showed that the serum levels of SPARC protein were not varied between control and OHSS rats (Fig.…”

Section: Resultssupporting

confidence: 88%

TGF-β1 upregulates secreted protein acidic and rich in cysteine expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome

et al. 2023

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Background Ovarian hyperstimulation syndrome (OHSS) is a serious complication during in vitro fertilization (IVF) treatment. The upregulation of ovarian transforming growth factor-beta 1 (TGF-β1) is involved in the development of OHSS. The secreted protein acidic and rich in cysteine (SPARC) is a secreted multifunctional matricellular glycoprotein. Although the regulatory effects of TGF-β1 on SPARC expression have been reported, whether TGF-β1 regulates SPARC expression in the human ovary remains unknown. In addition, the role of SPARC in the pathogenesis of OHSS is unclear. Methods A steroidogenic human ovarian granulosa-like tumor cell line, KGN, and primary culture of human granulosa-lutein (hGL) cells obtained from patients undergoing IVF treatment were used as experimental models. OHSS was induced in rats, and ovaries were collected. Follicular fluid samples were collected from 39 OHSS and 35 non-OHSS patients during oocyte retrieval. The underlying molecular mechanisms mediating the effect of TGF-β1 on SPARC expression were explored by a series of in vitro experiments. Results TGF-β1 upregulated SPARC expression in both KGN and hGL cells. The stimulatory effect of TGF-β1 on SPARC expression was mediated by SMAD3 but not SMAD2. The transcription factors, Snail and Slug, were induced in response to the TGF-β1 treatment. However, only Slug was required for the TGF-β1-induced SPARC expression. Conversely, we found that the knockdown of SPARC decreased Slug expression. Our results also revealed that SPARC was upregulated in the OHSS rat ovaries and in the follicular fluid of OHSS patients. Knockdown of SPARC attenuated the TGF-β1-stimulated expression of vascular endothelial growth factor (VEGF) and aromatase, two markers of OHSS. Moreover, the knockdown of SPARC reduced TGF-β1 signaling by downregulating SMAD4 expression. Conclusions By illustrating the potential physiological and pathological roles of TGF-β1 in the regulation of SPARC in hGL cells, our results may serve to improve current strategies used to treat clinical infertility and OHSS.

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“…On the other side, Orvieto et al [ 27 ] provided a firm evidence for the presence of interleukin (IL)-2 and IL-2 mRNA expression in luteinized granulosa cells of the hyperstimulated human ovaries and suggested that IL-2 could activate the systemic inflammatory response characteristic of OHSS. Taskin et al [ 28 ] detected significantly lower ovarian weight, estrogen levels and corpus luteum counts with lower IL-6 intensity and VEGF expression in GnRH antagonist treated animals than in OHSS animals and attributed development of OHSS to increased expression of VEGF secondary to increased IL-6 intensity; thus raising a possibility of inflammatory basis for development of OHSS.…”

Section: Discussionmentioning

confidence: 99%

Sequential E2 levels not ovarian maximal diameter estimates were correlated with outcome of cetrotide therapy for management of women at high-risk of ovarian hyperstimulation syndrome: a randomized controlled study

et al. 2017

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BackgroundOvarian hyperstimulation syndrome (OHSS) is an important condition with considerable morbidity and a small risk of mortality and most commonly results as an iatrogenic condition following follicular stimulation of the ovaries. We aimed to evaluate safety and efficacy of 3-day cetrotide therapy started on day of oocyte retrieval (Day-0) in women at high-risk for development of ovarian hyperstimulation syndrome (OHSS) after GnRH agonist induction protocol.MethodsForty-eight women fulfilling inclusion criteria underwent ultrasound scanning for maximal ovarian diameter (MOD) estimation and ascites grading. Patients underwent embryo freezing, but the study group received 3-day Cetrotide sc injection (0.25 mg/day) started on Day-0. Serum E2, pain scores and MOD were checked daily. Hematocrite value (Ht%), total leucocytic count (TLC), gastrointestinal (GI) manifestations and ascites grading were re-evaluated on Day-3, 6 and 8.ResultsSequential serum E2 levels decreased significantly in both groups with significantly lower levels in the study group. Sequential MOD estimates showed non-significant difference between the two groups and versus Day-0 estimates. On Day-2, pain scores showed progressive significant decrease compared to Day-0 scores in both groups with significantly lower scores in the study group. On Day-3; four control patients still had vomiting and by Day-6, 6 of the control patients still had GI manifestations with significant difference versus the study group. Compared to Day-0 estimates, Ht% and TLC were significantly lower on Day-3, 6 and 8 in the study group, but only on Day-8 in the control group. Day-3 and Day-8 ascites grading in both groups was significantly lower compared to respective Day-0 grading with significant difference in favor of the study group. Six patients required hospitalization, but without mortalities. Day-3 E2 levels in the study group showed positive significant correlation with clinical and other laboratory data and ascites grading, while the correlation was non-significant with MOD.ConclusionThe 3-day cetrotide therapy starting after oocyte retrieval with embryo transfer freezing could be an appropriate management policy for women received GnHR-agonist induction protocol and were at high-risk for OHSS. Sequential E2 serum levels could predict outcome more perfectly than sequential MOD estimates.Trial registrationTrial registration (clinicaltrial.gov registration) NCT02823080 (retrospective) Initial Release 21–6-2016 Last Release 3–1-2017 Unique Protocol ID: Benha U Secondary IDs: kmsalama.

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Prevention of ovarian hyperstimulation syndrome in a rat model: comparison of the efficacy of tocilizumab with that of ranibizumab, cabergoline, and a gonadotropin-releasing hormone antagonist

Cited by 7 publications

References 21 publications

TGF-β1 induces VEGF expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome

TGF-β1 induces VEGF expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome

TGF-β1 upregulates secreted protein acidic and rich in cysteine expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome

Sequential E2 levels not ovarian maximal diameter estimates were correlated with outcome of cetrotide therapy for management of women at high-risk of ovarian hyperstimulation syndrome: a randomized controlled study

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