scholarly journals Physiological and Pathological Androgen Actions in the Ovary

Endocrinology ◽  
2019 ◽  
Vol 160 (5) ◽  
pp. 1166-1174 ◽  
Author(s):  
Olga Astapova ◽  
Briaunna M N Minor ◽  
Stephen R Hammes
Keyword(s):  
Granulosa Cells ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Follicle Development ◽  
Female Reproduction ◽  
Negative Effects ◽  
Androgen Excess ◽  
Male Sex ◽  
Androgen Effects

Abstract Androgens, although traditionally thought to be male sex steroids, play important roles in female reproduction, both in healthy and pathological states. This mini-review focuses on recent advances in our knowledge of the role of androgens in the ovary. Androgen receptor (AR) is expressed in oocytes, granulosa cells, and theca cells, and is temporally regulated during follicular development. Mouse knockout studies have shown that AR expression in granulosa cells is critical for normal follicular development and subsequent ovulation. In addition, androgens are involved in regulating dynamic changes in ovarian steroidogenesis that are critical for normal cycling. Androgen effects on follicle development have been incorporated into clinical practice in women with diminished ovarian reserve, albeit with limited success in available literature. At the other extreme, androgen excess leads to disordered follicle development and anovulatory infertility known as polycystic ovary syndrome (PCOS), with studies suggesting that theca cell AR may mediate many of these negative effects. Finally, both prenatal and postnatal animal models of androgen excess have been developed and are being used to study the pathophysiology of PCOS both within the ovary and with regard to overall metabolic health. Taken together, current scientific consensus is that a careful balance of androgen activity in the ovary is necessary for reproductive health in women.

scholarly journals CBX2 and the Ovary: Novel Insights into Regulatory Networks in Humans

2018 ◽  
Vol 2 (1) ◽  
Keyword(s):  
Ovarian Cancer ◽  
Granulosa Cells ◽  
Regulatory Networks ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Female Gonad ◽  
Ovary Syndrome ◽  
Interacting Protein ◽  
Human Ovaries

Background: Chromobox protein homolog 2 (CBX2) is a DNA-interacting protein present in humans in two isoforms, CBX2.1 and CBX2.2. Isoform-1 promotes testis development, butthe role of both variants in the female gonad pathway remains unknown. Methods: To understand its function in human ovaries, we evaluated expression of known female genes i.e.FOXL2, RSPO1 and WNT4 in human pre-granulosa cells after forced expression and RNA interference of CBX2 isoforms and vice versa. Results: The two isoforms appeared to be functionally distinct. CBX2.1 has proved to be a pro-male by enhancing SOX9, SF1 and androgen receptor (AR) expression, whereas CBX2.2 might be partly pro-female most likely via interaction with RSPO1 and the regulation of ovary developmental markers (i.e. OCT-4, AMH and ERβ). Conclusions: Both CBX2 isoforms might act as distinct regulatory agents protecting granulosa cells from uncontrolled growth and proliferation by adjusting WNT4 and RSPO1 signaling pathways, and participate to follicular development and fate by regulating the expression of SF1 and AR, thus potentially influencing fertility, menopause, ovarian cancer and perhaps polycystic ovary syndrome.

scholarly journals Comparative Analysis Among Different Species Reveals That the Androgen Receptor Regulates Chicken Follicle Selection Through Species-Specific Genes Related to Follicle Development

2022 ◽  
Vol 12 ◽  
Author(s):  
Ying Huang ◽  
Wei Luo ◽  
Xuliang Luo ◽  
Xiaohui Wu ◽  
Jinqiu Li ◽  
...  
Keyword(s):  
Sex Hormones ◽  
Granulosa Cells ◽  
Egg Production ◽  
Androgen Receptors ◽  
Follicular Development ◽  
Follicle Development ◽  
Follicle Selection

The differences in reproductive processes at the molecular level between viviparous and oviparous animals are evident, and the site in the ovary that synthesizes sex hormones (androgens and oestrogens) and the trends for enriching sex hormones during follicle development in chickens are different from those in mammals, suggesting that the effect of sex hormones on follicle development in chickens is probably different from that in viviparous animals. To explore the specific role of androgen receptors (ARs) on chicken follicular development, we matched the correspondence of follicular development stages among chickens, humans, cows and identified chicken-specific genes related to follicle development (GAL-SPGs) by comparing follicle development-related genes and their biological functions among species (chickens, humans, and cows). A comparison of the core transcription factor regulatory network of granulosa cells (or ovaries) based on super-enhancers among species (chicken, human, and mouse) revealed that AR is a core transcriptional regulator specific to chickens. In vivo experiments showed that inhibition of AR significantly reduced the number of syf (selected stage follicles) in chickens and decreased the expression of GAL-SPGs in F5 follicles, while in vitro experiments showed that inhibition of AR expression in chicken granulosa cells (GCs) significantly down-regulated the expression levels of GAL-SPGs, indicating that AR could regulate follicle selection through chicken-specific genes related to follicle development. A comparison among species (77 vertebrates) of the conserved genomic regions, where chicken super-enhancers are located, revealed that the chicken AR super-enhancer region is conserved in birds, suggesting that the role of AR in follicle selection maybe widespread in birds. In summary, we found that AR can regulate follicle selection through chicken-specific genes related to follicle development, which also emphasizes the important role of AR in follicle selection in chickens and provides a new perspective for understanding the unique process of follicle development in chickens. Our study will contribute to the application of androgens to the control of egg production in chickens and suggests that researchers can delve into the mechanisms of follicle development in birds based on androgen/androgen receptors.

scholarly journals MicroRNA Mediating Networks in Granulosa Cells Associated with Ovarian Follicular Development

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Baoyun Zhang ◽  
Long Chen ◽  
Guangde Feng ◽  
Wei Xiang ◽  
Ke Zhang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Granulosa Cells ◽  
Messenger Rna ◽  
Expression Patterns ◽  
Follicular Development ◽  
Functional Networks ◽  
Signal Pathways ◽  
Differentially Expressed Mirnas ◽  
Selection Of

Ovaries, which provide a place for follicular development and oocyte maturation, are important organs in female mammals. Follicular development is complicated physiological progress mediated by various regulatory factors including microRNAs (miRNAs). To demonstrate the role of miRNAs in follicular development, this study analyzed the expression patterns of miRNAs in granulosa cells through investigating three previous datasets generated by Illumina miRNA deep sequencing. Furthermore, via bioinformatic analyses, we dissected the associated functional networks of the observed significant miRNAs, in terms of interacting with signal pathways and transcription factors. During the growth and selection of dominant follicles, 15 dysregulated miRNAs and 139 associated pathways were screened out. In comparison of different styles of follicles, 7 commonly abundant miRNAs and 195 pathways, as well as 10 differentially expressed miRNAs and 117 pathways in dominant follicles in comparison with subordinate follicles, were collected. Furthermore, SMAD2 was identified as a hub factor in regulating follicular development. The regulation of miR-26a/b onsmad2messenger RNA has been further testified by real time PCR. In conclusion, we established functional networks which play critical roles in follicular development including pivotal miRNAs, pathways, and transcription factors, which contributed to the further investigation about miRNAs associated with mammalian follicular development.

miR-132 is up-regulated in polycystic ovarian syndrome and inhibits granulosa cells proliferation via targeting Foxa1

2020 ◽  
Author(s):  
Xiangrong Cui ◽  
Xuan Jing ◽  
Junfen Liu ◽  
Meiqin Yan ◽  
Xingyu Bi ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Polycystic Ovary ◽  
Tumor Cell Line ◽  
Cell Counting ◽  
Luciferase Assay ◽  
Polycystic Ovaries ◽  
Aberrant Expression ◽  
Over Expression ◽  
Ovulatory Dysfunction

Abstract Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine metabolic disorders characterized by hyperandrogenism, polycystic ovaries and ovulatory dysfunction. Several studies have suggested that the aberrant expression of miRNAs serves an important role in the pathogenesis of PCOS, though the role and underling mechanism of microRNA-132 (miR-132) in the development of PCOS remain unclear. Methods: The expression of miR-132 in granulosa cells (GCs) derived from 26 PCOS patients and 30 healthy controls was detected through RT-qPCR. And the apoptosis levels of granulosa cells were measured by TUNEL.Granulosa-like tumor cell line (KGN) was cultured for cell counting kit-8 (CCK-8) was assays after over-expression of miR-132 or knockdown TargetScan was applied to analysis the potential targets of miR-132, which was further verified by luciferase assay, RT-qPCR and western blot. Results: The expression of miR-132 was declined in granulosa cells of PCOS patients. Meanwhile, the significantly increased apoptotic nuclei were present GCs of PCOS patients. Furthermore, over-expressed of miR-132 inhibited the proliferation of KCN cells. In addition, our results verified that miR-132 directly targeted Foxa1, knockdown of which suppressed KGN cells proliferation. Conclusion: Our results revealed that miR-132 inhibits the cell viability and induces apoptosis by directly interacting with Foxa1, indicating a role of miR-132 to be a potential target in the PCOS patients.

Long Noncoding RNA HUPCOS Promotes Follicular Fluid Androgen Excess in PCOS Patients via Aromatase Inhibition

2020 ◽  
Vol 105 (4) ◽  
pp. 1086-1097 ◽  
Author(s):  
Qi Che ◽  
Miao Liu ◽  
Doudou Zhang ◽  
Yongning Lu ◽  
Jun Xu ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Follicular Fluid ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Polycystic Ovary ◽  
Androgen Excess ◽  
Aberrant Expression ◽  
Aromatase Expression ◽  
Relationship Of

Abstract Context Androgen excess is a key feature of polycystic ovary syndrome (PCOS), but the underlying molecular mechanism remains unclear. Objective To determine the role and mechanism of novel long noncoding RNA (lncRNA) highly up-regulated in PCOS (HUPCOS) in the androgen excess of PCOS patients. Design The lncRNA expression profile in granulosa cells derived from PCOS and non-PCOS women were analyzed by using microarray assay. Human granulosa cell line KGN was used for mechanism investigation. Setting This was a university-based study. Patients Thirty-eight PCOS and 38 control patients were recruited: 8 PCOS and 8 control samples used for microarray discovery, the remaining 30 PCOS cases and 30 controls for quantitative RT-PCR validation. Main Outcome Measures The aberrant expression lncRNA profile of PCOS patients was measured using microarray. The relationship of HUPCOS and follicular fluid testosterone was measured. Aromatase expression were analyzed after HUPCOS downregulation. HUPCOS interaction protein was confirmed by RNA pull-down. Results The significantly elevated lncRNA in PCOS granulosa cells was named HUPCOS, which was positively correlated with follicular fluid testosterone of PCOS patients. HUPCOS downregulation increased aromatase expression and promoted conversion of androgen to estrogen. RNA-binding protein with multiple splicing (RBPMS) was the most likely protein that combined with HUPCOS. Conclusions Our findings suggested that HUPCOS mediated androgen excess in follicular fluid of PCOS patients by suppressing aromatase expression via interaction with RBPMS.

Fetal programming by androgen excess in rats affects ovarian fuel sensors and steroidogenesis

2019 ◽  
Vol 10 (6) ◽  
pp. 645-658 ◽  
Author(s):  
Giselle Adriana Abruzzese ◽  
Maria Florencia Heber ◽  
Fiorella Campo Verde Arbocco ◽  
Silvana Rocio Ferreira ◽  
Alicia Beatriz Motta
Keyword(s):  
Fetal Programming ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Female Offspring ◽  
Mrna Levels ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Pregnant Rats ◽  
Reproductive Disorder ◽  
Main Factors

AbstractFetal programming by androgen excess is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS is more than a reproductive disorder, as women with PCOS also show metabolic and other endocrine alterations. Since both ovarian and reproductive functions depend on energy balance, the alterations in metabolism may be related to reproductive alterations. The present study aimed to evaluate the effect of androgen excess during prenatal life on ovarian fuel sensors and its consequences on steroidogenesis. To this end, pregnant rats were hyperandrogenized with testosterone and the following parameters were evaluated in their female offspring: follicular development, PPARG levels, adipokines (including leptin, adiponectin, and chemerin as ovarian fuel sensors), serum gonadotropins (LH and FSH), the mRNA of their ovarian receptors, and the expression of steroidogenic mediators. At 60 days of age, the prenatally hyperandrogenized (PH) female offspring displayed both an irregular ovulatory phenotype and an anovulatory phenotype with altered follicular development and the presence of cysts. Both PH groups showed altered levels of both proteins and mRNA of PPARG and a different expression pattern of the adipokines studied. Although serum gonadotropins were not impaired, there were alterations in the mRNA levels of their ovarian receptors. The steroidogenic mediators Star, Cyp11a1, Cyp17a1, and Cyp19a1 were altered differently in each of the PH groups. We concluded that androgen excess during prenatal life leads to developmental programming effects that affect ovarian fuel sensors and steroidogenesis in a phenotype-specific way.

scholarly journals Laminin-alpha6beta1 integrin interaction enhances survival and proliferation and modulates steroidogenesis of ovine granulosa cells

2002 ◽  
Vol 172 (1) ◽  
pp. 45-59 ◽  
Author(s):  
F Le Bellego ◽  
C Pisselet ◽  
C Huet ◽  
P Monget ◽  
D Monniaux
Keyword(s):  
Estrous Cycle ◽  
Granulosa Cells ◽  
Physiological Role ◽  
Follicular Development ◽  
Antral Follicles ◽  
Final Development ◽  
Beta 1 Integrin ◽  
Arginine Glycine Aspartic Acid

This study aimed to determine the physiological role of laminin (LN) and its receptor, alpha(6)beta(1) integrin, in controlling the functions of granulosa cells (GC) during follicular development in sheep ovary. Immunohistochemistry experiments showed the presence of increasing levels of LN (P<0.0001), and high levels of mature alpha(6)beta(1) integrin in GC layers of healthy antral follicles during the follicular and the preovulatory phases of the estrous cycle. In vitro, the addition of a function-blocking antibody raised against alpha(6) subunit (anti-alpha(6) IgG) to the medium of ovine GC cultured on LN impaired cell spreading (P<0.0001), decreased the proliferation rate (P<0.05) and increased the apoptosis rate (P<0.05). Furthermore, addition of anti-alpha(6) IgG enhanced estradiol (E2) secretion by GC in the presence or absence of follicle-stimulating hormone (FSH), luteinizing hormone or insulin-like growth factor-I in culture medium (P<0.0001), and inhibited progesterone (P4) secretion in basal conditions or in the presence of low (0.5 ng/ml) FSH concentrations only (P<0.0001). The anti-alpha(6) IgG effect was specific to an interaction of LN with alpha(6)beta(1) integrin since it was ineffective on GC cultured on heat-denatured LN, RGD (arginine-glycine-aspartic acid) peptides and non-coated substratum. Hence, this study established that alpha(6)beta(1) integrin 1) was expressed in GC of antral follicles, 2) mediated the actions of LN on survival, proliferation and steroidogenesis of GC, and 3) was able to dramatically modulate P4 and E2 secretion by GC in vitro. It is suggested that during the follicular and the preovulatory phases of the estrous cycle, the increasing levels of LN in GC of large antral follicles might support their final development to ovulation.

scholarly journals Female Fertility Is Reduced in Mice Lacking Ca2+/Calmodulin-Dependent Protein Kinase IV**This work was supported by an NIH Medical Scientist Training Program award (to J.Y.W.) and NIH Grants HD-07503 (to A.R.M.) and HD-1272 (to J.S.R.)

Endocrinology ◽  
2000 ◽  
Vol 141 (12) ◽  
pp. 4777-4783 ◽  
Author(s):  
Joy Y. Wu ◽  
Ignacio J. Gonzalez-Robayna ◽  
JoAnne S. Richards ◽  
Anthony R. Means
Keyword(s):  
Protein Kinase ◽  
Granulosa Cells ◽  
Critical Role ◽  
Follicular Development ◽  
Female Fertility ◽  
Female Reproduction ◽  
Dependent Protein Kinase ◽  
Medical Scientist ◽  
Dependent Protein ◽  
Medical Scientist Training Program

Abstract Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) is a serine/threonine protein kinase with limited tissue distribution. CaMKIV is highly expressed in the testis, where it is found in transcriptionally inactive elongating spermatids. We have recently generated mice deficient in CaMKIV. In the absence of CaMKIV, the exchange of sperm nuclear basic proteins in male spermatids is impaired, resulting in male infertility secondary to defective spermiogenesis. The involvement of CaMKIV in female fertility has not been addressed. Here we report that female fertility is markedly reduced in CaMKIV-deficient mice due to impaired follicular development and ovulation. CaMKIV is expressed in the ovary, where it is localized in granulosa cells. We further find that in cultured granulosa cells, CaMKIV expression and subcellular localization are hormonally regulated. As granulosa cells differentiate, CaMKIV levels decrease and the kinase translocates from the nucleus into the cytoplasm. Our results demonstrate a critical role for CaMKIV in female reproduction and point to a potential function in granulosa cell differentiation.

509. REGULATING MURINE FOLLICLE DEVELOPMENT BY STIMULATION OF THE JAK2/STAT3 SIGNAL TRANSDUCTION PATHWAY

2009 ◽  
Vol 21 (9) ◽  
pp. 108
Author(s):  
R. A. Keightley ◽  
B. Nixon ◽  
S. D. Roman ◽  
D. L. Russell ◽  
R. L. Robker ◽  
...  
Keyword(s):  
Significant Role ◽  
Granulosa Cells ◽  
Ovarian Follicle ◽  
Expression Patterns ◽  
Follicular Development ◽  
Janus Kinase ◽  
Follicle Development ◽  
Mrna Levels ◽  
Primordial Follicles ◽  
Stat3 Signalling

Follicular development requires the recruitment of primordial follicles into the growing follicle pool following initiation of multiple cytokine signalling pathways. Suppression of follicular development is thought to be key to maintaining the population of primordial follicles and allowing for controlled release of these follicles throughout the reproductive lifespan of the female. However, little is known of the processes and signalling molecules that suppress primordial follicle activation and early follicle growth. Our group has identified significant upregulation of the Janus Kinase 2 (JAK2)/ Signal Transducer and Activator of Transcription 3 (STAT3) signalling pathway inhibitor the Suppressor of Cytokine Signalling 4 (SOCS4) that coincides with the initial wave of follicular activation in theneonatal mouse ovary. Further studies by our group have localised the SOCS4 protein to the granulosa cells of activating and growing follicles, suggesting SOCS4 expression may be linked to follicular activation. We have focused on examining protein localisation and gene expression patterns of the eight SOCS family members CIS and SOCS1-7. We have recently demonstrated that co-culture of neonatal ovaries with Kit Ligand (KL) for 2 days increases the mRNA levels of all SOCS genes. We also demonstrated the co-localisation of SOCS2 proteins with the KL receptor c-kit in the mural granulosa cells of antral, and large pre-antral follicles suggesting a significant role for SOCS2 in the later stages of follicular development. We have also shown that culturing ovaries with the potent JAK2 inhibitor AG490 substantially reduces mRNA levels of all SOCS and STAT genes that we have so far measured. We hypothesise a significant role for JAK2/STAT3 signalling in promoting the activation and early growth of ovarian follicles. Our investigations have identified significant roles for JAK2/STAT3 and the SOCS family in the regulation of ovarian follicle development.

scholarly journals SMAD7 antagonizes key TGFβ superfamily signaling in mouse granulosa cells in vitro

Reproduction ◽  
2013 ◽  
Vol 146 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Yang Gao ◽  
Haixia Wen ◽  
Chao Wang ◽  
Qinglei Li
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cells ◽  
Transforming Growth Factor ◽  
Negative Regulator ◽  
Fine Tuning ◽  
Female Reproduction ◽  
Tgfβ Signaling ◽  
Tgfβ Superfamily

Transforming growth factor β (TGFβ) superfamily signaling is essential for female reproduction. Dysregulation of the TGFβ signaling pathway can cause reproductive diseases. SMA and MAD (mothers against decapentaplegic) (SMAD) proteins are downstream signaling transducers of the TGFβ superfamily. SMAD7 is an inhibitory SMAD that regulates TGFβ signalingin vitro. However, the function of SMAD7 in the ovary remains poorly defined. To determine the signaling preference and potential role of SMAD7 in the ovary, we herein examined the expression, regulation, and function of SMAD7 in mouse granulosa cells. We showed that SMAD7 was expressed in granulosa cells and subject to regulation by intraovarian growth factors from the TGFβ superfamily. TGFB1 (TGFβ1), bone morphogenetic protein 4, and oocyte-derived growth differentiation factor 9 (GDF9) were capable of inducingSmad7expression, suggesting a modulatory role of SMAD7 in a negative feedback loop. Using a small interfering RNA approach, we further demonstrated that SMAD7 was a negative regulator of TGFB1. Moreover, we revealed a link between SMAD7 and GDF9-mediated oocyte paracrine signaling, an essential component of oocyte–granulosa cell communication and folliculogenesis. Collectively, our results suggest that SMAD7 may function during follicular development via preferentially antagonizing and/or fine-tuning essential TGFβ superfamily signaling, which is involved in the regulation of oocyte–somatic cell interaction and granulosa cell function.

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