IGF1R Signaling Is Necessary for FSH-Induced Activation of AKT and Differentiation of Human Cumulus Granulosa Cells

Baumgarten, Sarah C.; Convissar, Scott M.; Fierro, M.A.; Winston, Nicola J.; Scoccia, Bert; Stocco, Carlos

doi:10.1210/jc.2014-1139

Cited by 91 publications

(94 citation statements)

References 43 publications

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“…The effect of IGFBP-4 on basal CYP19A1 mRNA abundance was statistically significant (P Ͻ .01) when control and IGFBP-4-treated groups were compared using a t test. These results suggest that IGF-2 actions are required for FSH-induced granulosa cell differentiation and for basal CYP19A1 expression and are in agreement with our previous findings demonstrating that IGF-1R activity is required for FSHinduced granulosa cell differentiation (7). In addition, because human granulosa cells produce only IGF-2, the results demonstrate that IGF-2 is a physiological activator of the IGF-1R in these cells.…”

Section: Igf-2 Is Essential For Fsh-induced Stimulation Of Cyp19a1 Ansupporting

confidence: 92%

“…We previously observed that cumulus cells express low levels of the preovulatory differentiation markers including aromatase (CYP19A1), P450 side chain cleavage (CYP11A1), LH/choriogonadotropin receptor, and steroidogenic acute regulator. In addition, we demonstrated that FSH stimulates the expression of these genes and estradiol synthesis (7). In this report, we show that IGF-2 and FSH synergize to promote the proliferation and the expression of differentiation markers in human cumulus cells and that IGF-2 is required for the stimulation of these cells by FSH.…”

mentioning

confidence: 52%

“…Cultured cumulus cells were harvested in ice-cold radioimmunoprecipitation assay lysis buffer, and whole cell lysates were used in Western blotting as previously described (6,7). The primary antibodies used were IGF-2 (1:200; Santa Cruz Biotechnology), CYP19A1 (1:1000; Epitomics), and ␤-actin (ACTB) (1:1000; Proteintech) as a loading control.…”

Section: Western Blottingmentioning

confidence: 99%

“…In rodents, granulosa cells produce mostly IGF-1 (8). In contrast, IGF-2 mRNA levels are high in human granulosa cells, and IGF-1 mRNA is not detectable (7,9,10). Consequently, the follicular fluid of human dominant follicles contains up to 10-fold more IGF-2 than IGF-1 (11,12).…”

mentioning

confidence: 98%

“…For example, in rodents that lack either FSH or the FSH receptor, the progression of follicles beyond the preantral stage is blocked (3,4); however, a block on preovulatory follicle formation is also observed in IGF-1 knockout mice (5), demonstrating that an active IGF system is required for follicle maturation to the preovulatory stage. In rodents and humans, IGF-1 receptor (IGF-1R) activity is necessary for FSH to stimulate CYP19A1 expression (6,7). Therefore, FSH and IGF signaling are crucial for the transition of follicles from the preantral to the preovulatory stage.…”

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confidence: 99%

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FSH Regulates IGF-2 Expression in Human Granulosa Cells in an AKT-Dependent Manner

Baumgarten¹,

Convissar²,

Zamah

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

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Section: Igf-2 Is Essential For Fsh-induced Stimulation Of Cyp19a1 Ansupporting

confidence: 92%

mentioning

confidence: 52%

Section: Western Blottingmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

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FSH Regulates IGF-2 Expression in Human Granulosa Cells in an AKT-Dependent Manner

Baumgarten¹,

Convissar²,

Zamah

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

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Naringenin improves ovarian health by reducing the serum androgen and eliminating follicular cysts in letrozole‐induced polycystic ovary syndrome in the Sprague Dawley rats

Rashid,

Tripathi,

Singh

et al. 2023

Phytotherapy Research

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Polycystic ovary syndrome (PCOS) is most common in women of reproductive age, giving rise to androgen excess and anovulation, leading to infertility and non‐reproductive complications. We explored the ameliorating effect of naringenin in PCOS using the Sprague Dawley (SD) rat model and human granulosa cells. Letrozole‐induced PCOS rats were given either naringenin (50 mg/kg/day) alone or in combination with metformin (300 mg/kg/day), followed by the estrous cycle, hormonal analysis, and glucose sensitivity test. To evaluate the effect of naringenin on granulosa cell (hGC) steroidogenesis, we treated cells with naringenin (2.5 μM) alone or in combination with metformin (1 mM) in the presence of forskolin (10 μM). To determine the steroidogenesis of CYP‐17A1, ‐19A1, and 3βHSD2, the protein expression levels were examined. Treatment with naringenin in the PCOS animal groups increased ovulation potential and decreased cystic follicles and levels of androgens. The expression levels of CYP‐17A1, ‐19A1, and 3βHSD2, were seen restored in the ovary of PCOS SD rats' model and in the human ovarian cells in response to the naringenin. We found an increased expression level of phosphorylated‐AKT in the ovary and hGCs by naringenin. Naringenin improves ovulation and suppress androgens and cystic follicles, involving AKT activation.

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Molecular crosstalk between insulin‐like growth factors and follicle‐stimulating hormone in the regulation of granulosa cell function

Hayes,

Winston,

Stocco

2024

Reprod Medicine & Biology

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BackgroundThe last phase of folliculogenesis is driven by follicle‐stimulating hormone (FSH) and locally produced insulin‐like growth factors (IGFs), both essential for forming preovulatory follicles.MethodsThis review discusses the molecular crosstalk of the FSH and IGF signaling pathways in regulating follicular granulosa cells (GCs) during the antral‐to‐preovulatory phase.Main findingsIGFs were considered co‐gonadotropins since they amplify FSH actions in GCs. However, this view is not compatible with data showing that FSH requires IGFs to stimulate GCs, that FSH renders GCs sensitive to IGFs, and that FSH signaling interacts with factors downstream of AKT to stimulate GCs. New evidence suggests that FSH and IGF signaling pathways intersect at several levels to regulate gene expression and GC function.ConclusionFSH and locally produced IGFs form a positive feedback loop essential for preovulatory follicle formation in all species. Understanding the mechanisms by which FSH and IGFs interact to control GC function will help design new interventions to optimize follicle maturation, perfect treatment of ovulatory defects, improve in vitro fertilization, and develop new contraceptive approaches.

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IGF1R Signaling Is Necessary for FSH-Induced Activation of AKT and Differentiation of Human Cumulus Granulosa Cells

Abstract: The cumulus cell response to FSH resembles the differentiation of preantral to preovulatory granulosa cells. This differentiation program requires IGF1R activity and subsequent AKT activation.

Cited by 91 publications

References 43 publications

FSH Regulates IGF-2 Expression in Human Granulosa Cells in an AKT-Dependent Manner

FSH Regulates IGF-2 Expression in Human Granulosa Cells in an AKT-Dependent Manner

Naringenin improves ovarian health by reducing the serum androgen and eliminating follicular cysts in letrozole‐induced polycystic ovary syndrome in the Sprague Dawley rats

Molecular crosstalk between insulin‐like growth factors and follicle‐stimulating hormone in the regulation of granulosa cell function

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