Neonatal superior ovarian nerve transection inhibits follicle development by enhancing follicular atresia and suppressing granulosa cell proliferation in rats

2010 ◽  
Vol 22 (7) ◽  
pp. 1148 ◽  
Author(s):  
Xiaoxin Zhang ◽  
Lei Zhang ◽  
Shuying Huo ◽  
Jianlin Wang ◽  
Sheng Cui
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Sympathetic Nerve ◽  
Ovarian Function ◽  
Hormone Secretion ◽  
Neonatal Rat ◽  
Ovary Development ◽  
Follicle Development ◽  
Follicular Atresia ◽  
Superior Ovarian Nerve

The ovarian sympathetic nerves participate in the regulation of mammalian ovarian function, but it is still not known whether the neonatal ovarian sympathetic nerve is involved in follicular development and related mechanisms. In the present study, the superior ovarian nerve (SON) of the neonatal rat was transected on postnatal day (PD) 2, and follicle development, ovarian hormone secretion, ovulation rate, granulosa cell proliferation and apoptosis were analysed on PD 30 and PD 90. The results demonstrate that SON transection decreases follicle number and size, reduces ovulation induced by gonadotrophin and enhances follicular atresia. Bromodeoxyuridine (BrdU) and cleaved caspase-3 immunohistochemistry staining provide evidence that SON transection inhibits granulosa cell proliferation and promotes granulosa cell apoptosis. In addition, SON transection increases serum oestradiol levels, but has no influence on serum progesterone levels. These results suggest that the sympathetic nerve supply to the ovaries is important in regulating follicle development and ovary function. These results are critical for further understanding of the neuroendocrine regulation of ovary development and function, although the mechanism needs to be elucidated in future studies.

Effect of growth hormone on steroidogenesis, insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 production and DNA synthesis in cultured human luteinized granulosa cells

1994 ◽  
Vol 140 (2) ◽  
pp. 313-319 ◽  
Author(s):  
P Ovesen ◽  
H J Ingerslev ◽  
H Ørskov ◽  
T Ledet
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Ovarian Function ◽  
Thymidine Incorporation ◽  
Factor I ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein

Abstract Numerous clinical and experimental observations have suggested that GH is important in ovarian function. We have investigated the effect of GH alone and GH in combination with FSH on the secretion of oestradiol, progesterone, insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) and on [3H]thymidine incorporation in cultured human luteinized granulosa cells. Granulosa cells from patients undergoing treatment for in vitro fertilization were isolated and cultured for 2 days in culture medium with 10% serum. After this preincubation, the medium was removed and the cells were incubated with GH (1, 10 and 100 μg/l) with or without FSH in serum-free medium and in the presence of [3H]methylthymidine (2 μCi/ml). GH alone resulted in a significant dose-dependent increase of oestradiol (P<0·05) and in IGFBP-1 (P<0·002) in the medium. The release of IGF-I was undetectable and there was no increase in [3H]thymidine incorporation with GH alone. Neither GH nor FSH alone stimulated granulosa cell proliferation or progesterone release, while the combination induced increases (P<0·001) in both. The stimulatory effect of GH on steroidogenesis, IGFBP-1 production and granulosa cell proliferation supports a putative role for GH in the regulation of ovarian function. Journal of Endocrinology (1994) 140, 313–319

scholarly journals Human BM-MSC secretome enhances human granulosa cell proliferation and steroidogenesis and restores ovarian function in primary ovarian insufficiency mouse model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hang-soo Park ◽  
Rishi Man Chugh ◽  
Abdeljabar El Andaloussi ◽  
Elie Hobeika ◽  
Sahar Esfandyari ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mouse Model ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Cellular Proliferation ◽  
Ovarian Function ◽  
Human Mesenchymal Stem Cells ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
And Function

AbstractPrimary ovarian insufficiency (POI) is defined as the loss of ovarian function before 40 years of age. It clinically manifests as amenorrhea, infertility, and signs of estrogen insufficiency. POI is frequently induced by chemotherapy. Gonadotoxic chemotherapy reagents damage granulosa cells, which are essential for follicular function and development. Our recently published studies demonstrated that intraovarian transplantation of human mesenchymal stem cells (hMSCs) can restore fertility in a chemotherapy-induced POI mouse model. However, the regenerative mechanism underlying the hMSC effect in POI mice is not fully understood. Here, we report that the hMSC secretome increased the proliferation of human granulosa cells (HGrC1). We showed by FACS analysis that treatment of HGrC1 cells with hMSC-conditioned media (hMSC CM) stimulates cellular proliferation. We also demonstrated that the expression of steroidogenic enzymes involved in the production of estrogen, CYP19A1 and StAR, are significantly elevated in hMSC CM-treated HGrC1 cells. Our data suggest that hMSC CM stimulates granulosa cell proliferation and function, which may explain the therapeutic effect of hMSCs in our chemotherapy-induced POI animal model. Our findings indicate that the hMSC secretome may be a novel treatment approach for restoring granulosa cell and ovarian function in patients with POI.

scholarly journals Insulin-like growth factor 2 is produced by antral follicles and promotes preantral follicle development in macaques

2020 ◽  
Author(s):  
Olena Y Tkachenko ◽  
Shally Wolf ◽  
Maralee S Lawson ◽  
Alison Y Ting ◽  
Jhenifer K Rodrigues ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Steroid Hormone ◽  
Follicle Development ◽  
Hormone Regulation ◽  
Preantral Follicle ◽  
Paracrine Factor ◽  
Preantral Follicles ◽  
Antral Follicles ◽  
And Function

Abstract Insulin-like growth factors (IGFs) are known for their involvement in endocrine and paracrine regulation of ovarian function. While IGF2 is the predominant circulating and intra-ovarian form of IGFs in primate species, the stage-specific follicular expression, action and regulation of IGF2 are not well defined. Therefore, experiments were conducted to investigate the follicular IGF production in response to steroid hormone regulation and the direct IGF actions on follicular development and function in vitro. Preantral follicles were isolated from rhesus macaque ovaries and cultured to the antral stage in media supplemented with follicle-stimulating hormone and insulin. Follicles were randomly assigned to treatment groups: (a) control, (b) trilostane (a steroid synthesis inhibitor), (c) trilostane + estradiol, (d) trilostane + progesterone, and (e) trilostane + dihydrotestosterone. Media was analyzed for IGF concentrations, which were correlated to follicle growth. Follicles produced IGF2, but not IGF1, at the antral stage. Steroid depletion decreased, while steroid replacement increased, IGF2 production by antral follicles. Media IGF2 levels correlated positively with antral follicle diameters. Macaque preantral follicles and granulosa cells were subsequently cultured without (control) and with recombinant human IGF2 supplementation. Follicle survival, growth and paracrine factor production, as well as granulosa cell proliferation and gonadotropin receptor gene expression, were assessed. IGF2 addition increased follicle survival rates, diameters and inhibin B production, as well as granulosa cell proliferation. These data demonstrate that IGF2 produced by antral follicles, in response to steroid hormone regulation, could act as a paracrine factor that positively impacts preantral follicle development and function in primates.

scholarly journals Synergistic inhibition of csal1 and csal3 in granulosa cell proliferation and steroidogenesis of hen ovarian prehierarchical development†

2019 ◽  
Vol 101 (5) ◽  
pp. 986-1000 ◽  
Author(s):  
Hongyan Zhu ◽  
Ning Qin ◽  
Xiaoxing Xu ◽  
Xue Sun ◽  
Xiaoxia Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Molecular Mechanisms ◽  
Current Data ◽  
Follicle Development ◽  
Translocation Mechanism ◽  
Development In Vitro

Abstract SALL1 and SALL3 are transcription factors that play an essential role in regulating developmental processes and organogenesis in many species. However, the functional role of SALL1 and SALL3 in chicken prehierarchical follicle development is unknown. This study aimed to explore the potential role and mechanism of csal1 and csal3 in granulosa cell proliferation, differentiation, and follicle selection within the prehierarchical follicles of hen ovary. Our data demonstrated that the csal1 and csal3 transcriptions were highly expressed in granulosa cells of prehierarchical follicles, and their proteins were mainly localized in the cytoplasm of granulosa cells and oocytes as well as in the ovarian stroma and epithelium. It initially revealed that both csal1 and csal3 may be involved in chicken prehierarchical follicle development via a translocation mechanism. Furthermore, our results showed an abundance of CCND1, Bcat, StAR, CYP11A1, and FSHR mRNA in granulosa cells, and the proliferation levels of granulosa cells from the prehierarchical follicles were significantly increased by siRNA-mediated knockdown of csal1 or/and csal3. Conversely, the overexpression of csal1 or/and csal3 in the granulosa cells led to a remarkably decreased of them. Moreover, csal1 and csal3 together exert a much stronger effect on the regulation than any of csal1 or csal3. These results indicated that csal1 and csal3 play synergistic inhibitory roles on granulosa cell proliferation, differentiation, and steroidogenesis during prehierarchical follicle development in vitro. The current data provide a basis of molecular mechanisms of csal1 and csal3 in controlling the prehierarchical follicle development and growth of hen ovary in vivo.

scholarly journals 220.TGFβ1 deficient mice exhibit impaired follicle growth and luteal maintenance

2004 ◽  
Vol 16 (9) ◽  
pp. 220
Author(s):  
R. L. Robker ◽  
W. V. Ingman ◽  
S. A. Robertson
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Transforming Growth Factor ◽  
Ovarian Function ◽  
Follicular Development ◽  
Luteal Cell ◽  
Corpora Lutea ◽  
Normal Female ◽  
Female Reproduction ◽  
Antral Follicles

Transforming Growth Factor β1 (TGFβ1) is essential for normal female reproduction. Mice with a targeted deletion in the TGFβ1 gene (TGFβ1–/–) have severely impaired fertility with pregnancy occurring in <25% of mated females. TGFβ1 is implicated in several aspects of ovarian function, including potentiation of granulosa cell proliferation and suppression of luteal cell apoptosis. Our initial observations indicate that estrous cycling is disrupted in TGFβ1–/– mice and that ovulation rate is reduced. To further investigate how impaired ovarian function contributes to the infertility of TGFβ1–/– mice, ovaries were isolated from TGFβ1+/+ and TGFβ1–/– littermates at proestrus and fixed and sectioned for examination of follicle morphology and growth. BrdU labelling was performed to detect granulosa cell proliferation and blood samples were obtained for analysis of gonadotrophins and ovarian steroid hormones. Histological examination showed that ovaries from TGFβ1–/– mice were smaller than those of TGF–1+/+ mice, however large antral follicles were observed, indicating that TGFβ1 is not essential for granulosa cell proliferation. Compared to TGFβ1+/+ ovaries however, there were fewer antral follicles and only rare corpora lutea. Interestingly, in some cases there were large numbers of macrophages surrounding small follicles suggesting increased follicular atresia and/or altered macrophage activity in the TGFβ1–/– ovaries. Ovaries and serum were also isolated from females at d4 post-coital for assessment of corpora lutea morphology. TGFβ1–/– ovaries weighed less and had fewer corpora lutea than TGFβ1+/+ ovaries. TGFβ1–/– corpora lutea also contained increased numbers of apoptotic cells and infiltrating macrophages indicative of premature luteal regression. Circulating progesterone levels were reduced in TGFβ1–/– females, as was progesterone production per corpus luteum further indicating a functional defect in luteal maintenance. Cumulatively these observations show that TGFβ1 has essential roles in regulation of ovarian macrophage populations, in normal follicular development and in the generation, maintenance and steroidogenic function of corpora lutea.

scholarly journals R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth

2020 ◽  
Vol 27 (10) ◽  
pp. 2856-2871 ◽  
Author(s):  
Marie-Cécile De Cian ◽  
Elodie P. Gregoire ◽  
Morgane Le Rolle ◽  
Simon Lachambre ◽  
Magali Mondin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Cell Cycle Progression ◽  
Ovarian Function ◽  
Follicular Growth ◽  
Oocyte Growth

Abstract R-spondin2 (RSPO2) is a member of the R-spondin family, which are secreted activators of the WNT/β-catenin (CTNNB1) signaling pathway. In the mouse postnatal ovary, WNT/CTNNB1 signaling is active in the oocyte and in the neighboring supporting cells, the granulosa cells. Although the role of Rspo2 has been previously studied using in vitro experiments, the results are conflicting and the in vivo ovarian function of Rspo2 remains unclear. In the present study, we found that RSPO2/Rspo2 expression is restricted to the oocyte of developing follicles in both human and mouse ovaries from the beginning of the follicular growth. In mice, genetic deletion of Rspo2 does not impair oocyte growth, but instead prevents cell cycle progression of neighboring granulosa cells, thus resulting in an arrest of follicular growth. We further show this cell cycle arrest to be independent of growth promoting GDF9 signaling, but rather associated with a downregulation of WNT/CTNNB1 signaling in granulosa cells. To confirm the contribution of WNT/CTNNB1 signaling in granulosa cell proliferation, we induced cell type specific deletion of Ctnnb1 postnatally. Strikingly, follicles lacking Ctnnb1 failed to develop beyond the primary stage. These results show that RSPO2 acts in a paracrine manner to sustain granulosa cell proliferation in early developing follicles. Taken together, our data demonstrate that the activation of WNT/CTNNB1 signaling by RSPO2 is essential for oocyte-granulosa cell interactions that drive maturation of the ovarian follicles and eventually female fertility.

Recombinant FSH-induced follicle development in immature rats treated with an LHRH antagonist: a direct effect of RU486 on follicular atresia

1996 ◽  
Vol 150 (1) ◽  
pp. 85-92 ◽  
Author(s):  
J Th J Uilenbroek ◽  
P Kramer ◽  
E C M van Leeuwen ◽  
B Karels ◽  
M A Timmerman ◽  
...  
Keyword(s):  
Direct Effect ◽  
Ovarian Function ◽  
Female Rats ◽  
Follicle Development ◽  
Follicular Atresia ◽  
Antral Follicles ◽  
Serum Lh ◽  
Tenfold Increase ◽  
Immature Rats ◽  
Lhrh Antagonist

Abstract To investigate whether the progesterone antagonist RU486 has a direct effect on ovarian function, it was administered to immature female rats rendered hypogonadotrophic by administration of an LHRH antagonist and in which follicle development was stimulated by recombinant human FSH (recFSH). In the first experiments the effects of LHRH antagonist and recFSH on follicle growth were evaluated. Female rats of 22 days of age were injected with an LHRH antagonist (Org 30276; 500 μg/100 g body weight) every other day. This treatment resulted in a tenfold decrease in serum LH concentrations and a twofold decrease in serum FSH concentrations at day 30 and caused a reduction in the number and size of antral follicles. Treatment with recFSH (Org 32489) twice daily from day 26 for 4 days in a total dose ranging from 5 to 20 IU/animal increased the number and size of antral follicles in a dose-related manner and resulted after 20 IU recFSH in a tenfold increase in the concentration of inhibin in serum and ovaries at day 30. Once it was established that LHRH antagonist treatment in immature rats could be used to study the effects of gonadotrophins or steroids on follicle function, this animal model was used to study the effects of RU486 on the ovary. RU486 was administered (twice daily for 4 days, 1 mg/injection) to LHRH antagonist-treated rats in which follicular growth and differentation were stimulated by 10 IU recFSH or by 10 IU recFSH plus 0·5 IU human chorionic gonadotrophin (hCG). RU486 had no effect on circulating levels of LH and FSH, but stimulated follicular atresia both in rats treated with recFSH alone and in rats treated with recFSH and hCG. Inhibin concentrations both in serum and ovaries were significantly increased after hCG treatment. RU486, however, did not increase inhibin in the rats treated with recFSH and in those treated with recFSH and hCG. In summary, the present study has demonstrated that (1) immature rats treated with an LHRH antagonist can be used to study the effects of gonadotrophins and steroids on follicular function and (2) RU486 has a direct stimulatory effect on follicular atresia. Journal of Endocrinology (1996) 150, 85–92

scholarly journals Effect of cell shape and packing density on granulosa cell proliferation and formation of multiple layers during early follicle development in the ovary

2008 ◽  
Vol 121 (23) ◽  
pp. 3890-3900 ◽  
Author(s):  
P. Da Silva-Buttkus ◽  
G. S. Jayasooriya ◽  
J. M. Mora ◽  
M. Mobberley ◽  
T. A. Ryder ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Packing Density ◽  
Cell Shape ◽  
Follicle Development

scholarly journals Regulation of Follicular Atresia by WIP1-Mediated Apoptosis and Autophagy

2021 ◽  
Author(s):  
Su Zhou ◽  
Yueyue Xi ◽  
Yingying Chen ◽  
Wei Yan ◽  
Meng Wu ◽  
...  
Keyword(s):  
Phosphatase Activity ◽  
Granulosa Cells ◽  
Ovarian Reserve ◽  
Ovarian Function ◽  
Signal Pathway ◽  
Follicle Development ◽  
Follicular Atresia ◽  
Wip1 Phosphatase

Abstract Female endocrine homeostasis and reproductive success depend on the number and quality of follicles. The follicle is the basic functional unit within mammalian ovaries. Excessive follicular atresia is responsible for the accelerated ovarian aging process. Therefore, exploring the molecular mechanism of follicle development and atresia is essential for protecting ovarian function. In this study, we interrogate the striking correlation between follicular atresia and wild-type p53-induced phosphatase 1 (WIP1) expression in mouse ovaries to understand how WIP1 phosphatase activity regulates follicle development. WIP1 is mainly expressed in granulosa cells of healthy growing follicles, and atretic follicles exhibit significantly weaker WIP1 expression compared with the healthy ones. Our in vivo study indicates that inhibition of WIP1 phosphatase activity causes endocrine disorder, fertility decline and decreased ovarian reserve by triggering excessive follicular atresia through promoting autophagy and apoptosis. By in vitro follicle culture, we determine that inhibiting the WIP1 activity impairs the follicle development, causing more follicular atresia and decreased oocyte quality. Besides, downregulating WIP1 expression in granulosa cells in vitro also promotes apoptosis and autophagy via WIP1-p53 and WIP1-mTOR signal pathway. Our findings from the in vitro and in vivo experiments revealed that appropriate Wip1 expression is required for follicle development. Downregulation of WIP1 expression accelerates follicle atresia via WIP1-p53 and WIP1-mTOR signal pathway related apoptosis and autophagy. It is speculated that moderate up-regulation of WIP1 expression may help delaying the decline of ovarian reserve.

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