Is the aging human ovary still ticking?: Expression of clock-genes in luteinized granulosa cells of young and older women

Abstract We studied the cellular distribution of inhibin α, βA and βB mRNAs in the normal human ovary and in polycystic ovarian syndrome (PCOS) by in situ hybridization. Our results show that human granulosa cells express inhibin α, βA and βB subunit mRNAs, and theca cells express inhibin α and βA subunit mRNAs. The co-localization of α and βA mRNAs in theca cells supports the hypothesis that inhibin also has an autocrine function in these cells. We did not detect any inhibin subunit mRNA in the granulosa cells of atretic follicles, while theca cells also expressed α subunit mRNA in those follicles. The present findings suggest that the expression of inhibin subunits is regulated differently in human follicular granulosa and theca cells. It has been speculated that inhibin may be involved in the development of PCOS. Our results show that the cellular localization of inhibin subunit mRNAs is not disturbed in PCOS ovaries. Journal of Endocrinology (1994) 143, 127–137

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Expression of brain-derived neurotrophic factor and tyrosine kinase b receptor in human ovary and their regulation on estradiol and progestone production in human granulosa cells

Fertility and Sterility ◽

10.1016/s0015-0282(03)01709-6 ◽

2003 ◽

Vol 80 ◽

pp. 278-279

Author(s):

Shiling Chen ◽

Juan Fu ◽

Fuqi Xing Dept

Keyword(s):

Tyrosine Kinase ◽

Granulosa Cells ◽

Neurotrophic Factor ◽

Brain Derived Neurotrophic Factor ◽

Human Ovary ◽

Human Granulosa Cells

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Leptin Receptor Mediates Bmal1 Regulation of Estrogen Synthesis in Granulosa Cells

Animals ◽

10.3390/ani9110899 ◽

2019 ◽

Vol 9 (11) ◽

pp. 899 ◽

Cited By ~ 1

Author(s):

Chu ◽

Ma ◽

Sun ◽

Zhu ◽

Xiang ◽

...

Keyword(s):

Granulosa Cells ◽

Leptin Receptor ◽

Clock Genes ◽

Concentration Addition ◽

Female Reproduction ◽

Expression Levels ◽

Hormone Synthesis ◽

Estrogen Synthesis ◽

E Box ◽

Genes Encoding

Chronobiology affects female fertility in mammals. Lepr is required for leptin regulation of female reproduction. The presence of E-box elements in the Lepr promoter that are recognized and bound by clock genes to initiate gene transcription suggested that circadian systems might regulate fertility through Lepr. However, it is unclear whether Bmal1, a key oscillator controlling other clock genes, is involved in leptin regulation in hormone synthesis through Lepr. In this study, serum estradiol (E2) concentration and the expressions of Bmal1, Lepr, Cyp19a1, and Cyp11a1 genes were found to display well-synchronized circadian rhythms. Knockdown of Bmal1 significantly reduced expression levels of Lepr, Fshr, and Cyp19a1 genes; protein production of Bmal1, Lepr, and Cyp19a1; and the E2 concentration in granulosa cells. Knockdown of Lepr reduced the expression levels of Cyp19a1 and Cyp11a1 genes and Cyp19a1 protein, and also reduced E2 concentration. Addition of leptin affected the expression of Cyp19a1, Cyp11a1, and Fshr genes. Bmal1 deficiency counteracted leptin-stimulated upregulation of the genes encoding E2 synthesis in granulosa cells. These results demonstrated that Bmal1 participates in the process by which leptin acts on Lepr to regulate E2 synthesis.

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GnRH agonist Leuprolide acetate does not protect human ovary and granulosa cells from chemotherapy induced damage

Reproductive BioMedicine Online ◽

10.1016/s1472-6483(14)50013-2 ◽

2014 ◽

Vol 28 ◽

pp. S7

Author(s):

Ozgur Oktem ◽

Gizem Nur Şahin ◽

Gamze Bildik ◽

Filiz Senbabaoglu ◽

Bulent Urman

Keyword(s):

Granulosa Cells ◽

Gnrh Agonist ◽

Leuprolide Acetate ◽

Human Ovary

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Circadian Clock genes Per2 and clock regulate steroid production, cell proliferation, and luteinizing hormone receptor transcription in ovarian granulosa cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2011.07.058 ◽

2011 ◽

Vol 412 (1) ◽

pp. 132-135 ◽

Cited By ~ 21

Author(s):

Takashi Shimizu ◽

Yuko Hirai ◽

Chiaki Murayama ◽

Akio Miyamoto ◽

Hitoshi Miyazaki ◽

...

Keyword(s):

Cell Proliferation ◽

Luteinizing Hormone ◽

Granulosa Cells ◽

Hormone Receptor ◽

Clock Genes ◽

Luteinizing Hormone Receptor ◽

Steroid Production ◽

Ovarian Granulosa Cells ◽

Circadian Clock Genes ◽

Production Cell

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Expression of Functional Leptin Receptors in the Human Ovary1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.82.12.4446 ◽

1997 ◽

Vol 82 (12) ◽

pp. 4144-4148 ◽

Cited By ~ 5

Author(s):

Cecilia Karlsson ◽

Kajsa Lindell ◽

Eva Svensson ◽

Christina Bergh ◽

Peter Lind ◽

...

Keyword(s):

Adipose Tissue ◽

Granulosa Cells ◽

Follicular Fluid ◽

Leptin Receptor ◽

Biological Response ◽

Human Ovary ◽

Leptin Receptors ◽

Short Isoforms ◽

Reverse Transcription Pcr ◽

Ovarian Cells

The size of body fat stores is known to influence fertility, indicating a link between adipose tissue and the reproductive system. Studies in mice have identified the adipocyte-derived hormone, leptin (Ob protein), as a possible mediator of this effect. The aim of this study was to investigate the possibility that leptin may have direct effects on the human ovary. To probe this hypothesis we first analyzed the expression of leptin receptors in the human ovary. Transcripts encoding both the long and short isoforms of the leptin receptor were present in human granulosa cells and thecal cells; however, the short isoforms were expressed at much higher levels. Immunoreactive leptin was present in follicular fluid at levels similar to those found in serum. ob gene expression, however, was undetectable in the ovary, as determined by reverse transcription-PCR, whereas it was easily detected in adipose tissue. To determine whether leptin could induce a biological response in ovarian cells, we examined the effect of leptin on estradiol production in cultured granulosa cells. Leptin (100 ng/mL) inhibited LH (0.1 ng/mL)-stimulated estradiol production. In contrast, leptin had no effect on estradiol production in the absence of LH. In conclusion, this study has demonstrated that the leptin receptor is expressed in the human ovary, that leptin is present in follicular fluid, and that leptin can induce a biological response in ovarian cells. These results suggest that leptin may have a direct effect on the human ovary.

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Aging attenuates the ovarian circadian rhythm

Journal of Assisted Reproduction and Genetics ◽

10.1007/s10815-020-01943-y ◽

2020 ◽

Author(s):

Ziru Jiang ◽

Kexin Zou ◽

Xia Liu ◽

Hangchao Gu ◽

Yicong Meng ◽

...

Keyword(s):

Circadian Rhythm ◽

Circadian Clock ◽

Granulosa Cells ◽

Clock Genes ◽

University Hospital ◽

Vitro Fertilization ◽

Human Granulosa Cells ◽

Circadian Clock Genes ◽

Young Mice

Abstract Objective To study the effect of aging on ovarian circadian rhythm. Design Human and animal study. Setting University hospital and research laboratory. Patients/animals Human granulosa cells were obtained by follicular aspiration from women undergoing in vitro fertilization (IVF), and ovarian and liver tissues were obtained from female C57BL/6 mice. Intervention(s) None. Main outcome measure(s) Expression of circadian genes in young and older human granulosa cells and circadian rhythm in ovaries and livers of young and older mice. Result(s) All examined circadian clock genes in human granulosa cells showed a downward trend in expression with aging, and their mRNA expression levels were negatively correlated with age (P < 0.05). Older patients (≥ 40 years of age) had significantly reduced serum anti-Müllerian hormone (AMH) levels. Except for Rev-erbα, all other examined circadian clock genes were positively correlated with the level of AMH (P < 0.05). The circadian rhythm in the ovaries of older mice (8 months) was changed significantly relative to that in ovaries of young mice (12 weeks), although the circadian rhythm in the livers of older mice was basically consistent with that of young mice. Conclusion(s) Lower ovarian reserve in older women is partially due to ovarian circadian dysrhythmia as a result of aging.

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Expression of Genes Encoding Corticotropin-Releasing Factor (CRF), Type 1 CRF Receptor, and CRF-Binding Protein and Localization of the Gene Products in the Human Ovary1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.82.8.4119 ◽

1997 ◽

Vol 82 (8) ◽

pp. 2720-2725

Author(s):

H. Asakura ◽

I. H. Zwain ◽

S. S. C. Yen

Keyword(s):

Granulosa Cells ◽

Stromal Cells ◽

Binding Protein ◽

Corticotropin Releasing Factor ◽

Human Ovary ◽

Antral Follicles ◽

Estrogen Production ◽

Thecal Cells ◽

Crf System

Recently, the presence of immunoreactive corticotropin-releasing factor (IrCRF) in the thecal-stromal cells of the human ovary and the ability of CRF to suppress estrogen production by human granulosa cells in vitro have been reported. To understand the functional role of ovarian CRF requires characterization of the human ovarian CRF system, which includes CRF, type 1 CRF receptor (CRF-R1), and the high affinity CRF-binding protein (CRF-BP). Accordingly, we have examined the ovarian CRF system and the cellular distribution of these proteins and their messenger ribonucleic acids (mRNAs) using immunohistochemistry and in situ hybridization, respectively. Normal ovaries from 10 premenopausal women undergoing hysterectomy with ovariectomy were used in the analyses. IrCRF and its mRNA were localized in thecal cells of small antral and mature follicles. A low abundance of IrCRF and mRNA was also detected in stromal cells of both stages of follicles. Expression of the gene encoding CRF was more prominent in mature follicles than in small antral follicles. CRF-R1 mRNA signal was found exclusively in thecal cells of mature follicles and moderately in small antral follicles. Granulosa cells were devoid of CRF and CRF-R1 mRNAs and proteins. The IrCRF-BP, but not its transcript, was detected in thecal cells and lumen of capillary vessels of the thecal/stromal compartment of mature follicles. The absence of CRF-BP gene transcript in human ovarian follicles was confirmed by reverse transcription-PCR, indicating that the IrCRF-BP detected is not derived from the ovarian transcript and suggesting that the presence of IrCRF-BP and luman of capillary vessels in the thecal compartment originates from the peripheral circulation. Thecal cells of mature follicles, relative to those of small antral follicles, exhibited an intensive immunostaining and mRNA signal for 17α-hydroxylase (P450c17) indicative of androgen biosynthesis. We conclude that the thecal compartment of the human ovary contains a CRF system endowed with CRF and CRF-R1 and the blood-derived CRF-BP. Granulosa cells are devoid of the CRF system. The parallel increases in intensity of CRF, CRF-R1, and 17α-hydroxylase proteins and gene expression with follicular maturation suggest that the intraovarian CRF system may play an autocrine role in androgen biosynthesis with a downstream effect on estrogen production by the granulosa cells. The functionality of the ovarian CRF system may be conditioned by the relative presence of circulating CRF-BP by virtue of its ability to compete with CRF for the CRF receptor.

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