Serum GDF-8 levels change dynamically during controlled ovarian hyperstimulation in patients undergoing IVF/ICSI-ET

Fang, Lanlan; Yu, Yiping; Zhang, Ruizhe; He, Jiehua; Sun, Yingpu

doi:10.1038/srep28036

Cited by 4 publications

(10 citation statements)

References 26 publications

(53 reference statements)

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“…We and other groups have shown that GDF-8 and its receptors are expressed in human granulosa cells. In addition, secreted GDF-8 has been detected in human ovarian follicular fluid [10][11][12][13]. Functionally, we have demonstrated that granulosa cell proliferation, steroidogenesis, cumulus expansion, and oocyte maturation are regulated by GDF-8 [11][12][13][14][15][16][17].…”

Section: Ivyspringmentioning

confidence: 82%

High ovarian GDF-8 levels contribute to elevated estradiol production in ovarian hyperstimulation syndrome by stimulating aromatase expression

Fang¹,

Yan²,

Wang³

et al. 2021

Int. J. Biol. Sci.

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Rationale: Growth differentiation factor-8 (GDF-8), also known as myostatin, belongs to the transforming growth factor-beta (TGF-β) superfamily. GDF-8 is expressed in the ovary and regulates various ovarian functions. Ovarian hyperstimulation syndrome (OHSS) is one of the most serious disorders during in vitro fertilization treatment. Aromatase, encoded by the CYP19A1 gene, is the enzyme that catalyzes the final step in estradiol (E2) biosynthesis. It has been demonstrated that high serum E2 levels are associated with the development of OHSS. However, the effects of GDF-8 on aromatase expression and its roles in the pathogenesis of OHSS remain unclear. Methods: The effect of GDF-8 on aromatase expression and the underlying mechanisms were explored by a series of in vitro experiments in primary human granulosa-lutein (hGL) and KGN cells. Rat OHSS model and human follicular fluid samples were used to examine the roles of the GDF-8 system in the pathogenesis of OHSS. Results: We demonstrate that GDF-8 stimulates aromatase expression and E2 production in hGL and KGN cells. In addition, TGF-β type I receptor ALK5-mediated SMAD2/3 signaling is required for GDF-8-induced aromatase expression and E2 production. Using a rat OHSS model, we show that the aromatase and GDF-8 levels are upregulated in the ovaries of OHSS rats. Blocking the function of ALK5 by the administration of its inhibitor, SB431542, alleviates OHSS symptoms and the upregulation of aromatase. Clinical results reveal that the protein levels of GDF-8 are upregulated in the follicular fluid of OHSS patients. Moreover, the expression of GDF-8 is increased in hGL cells of OHSS patients. Conclusions: This study helps to elucidate the mechanisms mediating the expression of aromatase in human granulosa cells, which may lead to the development of alternative therapeutic approaches for OHSS.

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Section: Ivyspringmentioning

confidence: 82%

High ovarian GDF-8 levels contribute to elevated estradiol production in ovarian hyperstimulation syndrome by stimulating aromatase expression

Fang¹,

Yan²,

Wang³

et al. 2021

Int. J. Biol. Sci.

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“…Specifically, GDF8 regulates steroid production by increasing aromatase/estradiol production while decreasing StAR/progesterone production in primary hGL cells (Chang et al ., 2016b). Analysis of the data from clinical samples supports these findings, as there is a negative correlation between GDF8 concentrations and progesterone concentrations in the serum and follicular fluid (Fang et al ., 2015, 2016b). Moreover, GDF8 may enhance the FSH-induced aromatase/estradiol production, whereas GDF8 suppresses the LH-induced StAR/progesterone production in hGL cells (Chang et al ., 2016b).…”

Section: Novel Role Of Gdf8 In the Human Ovarymentioning

confidence: 99%

Oocyte–somatic cell interactions in the human ovary—novel role of bone morphogenetic proteins and growth differentiation factors

Chang

Qiao

Leung

2016

Hum. Reprod. Update

222

207

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BACKGROUNDInitially identified for their capability to induce heterotopic bone formation, bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor β superfamily. Using cellular and molecular genetic approaches, recent studies have implicated intra-ovarian BMPs as potent regulators of ovarian follicular function. The bi-directional communication of oocytes and the surrounding somatic cells is mandatory for normal follicle development and oocyte maturation. This review summarizes the current knowledge on the physiological role and molecular determinants of these ovarian regulatory factors within the human germline-somatic regulatory loop.OBJECTIVE AND RATIONALEThe regulation of ovarian function remains poorly characterized in humans because, while the fundamental process of follicular development and oocyte maturation is highly similar across species, most information on the regulation of ovarian function is obtained from studies using rodent models. Thus, this review focuses on the studies that used human biological materials to gain knowledge about human ovarian biology and disorders and to develop strategies for preventing, diagnosing and treating these abnormalities.SEARCH METHODSRelevant English-language publications describing the roles of BMPs or growth differentiation factors (GDFs) in human ovarian biology and phenotypes were comprehensively searched using PubMed and the Google Scholar database. The publications included those published since the initial identification of BMPs in the mammalian ovary in 1999 through July 2016.OUTCOMESStudies using human biological materials have revealed the expression of BMPs, GDFs and their putative receptors as well as their molecular signaling in the fundamental cells (oocyte, cumulus/granulosa cells (GCs) and theca/stroma cells) of the ovarian follicles throughout follicle development. With the availability of recombinant human BMPs/GDFs and the development of immortalized human cell lines, functional studies have demonstrated the physiological role of intra-ovarian BMPs/GDFs in all aspects of ovarian functions, from follicle development to steroidogenesis, cell–cell communication, oocyte maturation, ovulation and luteal function. Furthermore, there is crosstalk between these potent ovarian regulators and the endocrine signaling system. Dysregulation or naturally occurring mutations within the BMP system may lead to several female reproductive diseases. The latest development of recombinant BMPs, synthetic BMP inhibitors, gene therapy and tools for BMP-ligand sequestration has made the BMP pathway a potential therapeutic target in certain human fertility disorders; however, further clinical trials are needed. Recent studies have indicated that GDF8 is an intra-ovarian factor that may play a novel role in regulating ovarian functions in the human ovary.WIDER IMPLICATIONSIntra-ovarian BMPs/GDFs are critical regulators of folliculogenesis and human ovarian functions. Any dysregulation or variations in these ligand...

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“…Interestingly, Fang et al. ( 42 ) found the serum concentration of GDF-8 to change dynamically in patients undergoing controlled ovarian hyperstimulation (COH) during IVF treatment ( Figure 1A ). Blood samples from 19 patients undergoing COH were assayed at seven time points: GnRH-a day; Gonadotropin (Gn) day; human chorionic gonadotropin (hCG) day; 12 h after hCG administration; OPU day; 48 h after OPU day; and 14 days after embryo transfer (ET).…”

Section: Expression Of Gdf-8 and Its Functional Receptors In The Huma...mentioning

confidence: 99%

“…GDF-8 may have an inhibitory role in regulation of progesterone production in the human ovary. Data from two studies ( 37 , 42 ). involving 31 infertile women undergoing IVF procedures indicated GDF-8 expression to be negatively correlated with the progesterone level in serum and follicular fluid.…”

Section: Expression Of Gdf-8 and Its Functional Receptors In The Huma...mentioning

confidence: 99%

“…According to the studies mentioned above ( 37 , 38 , 49 – 51 ), cell experiments and clinical data showed GDF-8 expression to be related to levels of estrogen and progesterone. Therefore, studies focused on the relationship between GDF-8 expression in serum and pregnancy outcomes in IVF-ET patients were subsequently carried out ( 38 , 42 ). GDF-8 expression in serum was found to be a valuable predictor for pregnancy for patients treated with IVF-ET.…”

Section: Diagnostic Approaches and Potential Therapeuticmentioning

confidence: 99%

See 1 more Smart Citation

Regulatory Role and Potential Importance of GDF-8 in Ovarian Reproductive Activity

Zheng

Qin

et al. 2022

Front. Endocrinol.

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Growth differentiation factor-8 (GDF-8) is a member of the transforming growth factor-beta superfamily. Studies in vitro and in vivo have shown GDF-8 to be involved in the physiology and pathology of ovarian reproductive functions. In vitro experiments using a granulosa-cell model have demonstrated steroidogenesis, gonadotrophin responsiveness, glucose metabolism, cell proliferation as well as expression of lysyl oxidase and pentraxin 3 to be regulated by GDF-8 via the mothers against decapentaplegic homolog signaling pathway. Clinical data have shown that GDF-8 is expressed widely in the human ovary and has high expression in serum of obese women with polycystic ovary syndrome. GDF-8 expression in serum changes dynamically in patients undergoing controlled ovarian hyperstimulation. GDF-8 expression in serum and follicular fluid is correlated with the ovarian response and pregnancy outcome during in vitro fertilization. Blocking the GDF-8 signaling pathway is a potential therapeutic for ovarian hyperstimulation syndrome and ovulation disorders in polycystic ovary syndrome. GDF-8 has a regulatory role and potential importance in ovarian reproductive activity and may be involved in folliculogenesis, ovulation, and early embryo implantation.

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Serum GDF-8 levels change dynamically during controlled ovarian hyperstimulation in patients undergoing IVF/ICSI-ET

Cited by 4 publications

References 26 publications

High ovarian GDF-8 levels contribute to elevated estradiol production in ovarian hyperstimulation syndrome by stimulating aromatase expression

High ovarian GDF-8 levels contribute to elevated estradiol production in ovarian hyperstimulation syndrome by stimulating aromatase expression

Oocyte–somatic cell interactions in the human ovary—novel role of bone morphogenetic proteins and growth differentiation factors

Regulatory Role and Potential Importance of GDF-8 in Ovarian Reproductive Activity

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