A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells

Qu, Fan; Wang, Fangfang; Yin, Rong; Ding, Guo‐Lian; Elprince, Mohamed; Gao, Qian; Shi, Biwei; Pan, Hui-Hui; Huang, Yi‐Ting; Jin, Min; Leung, Peter C.K.; Sheng, Jian‐Zhong; Huang, He‐Feng

doi:10.1007/s00109-012-0881-4

Cited by 122 publications

(102 citation statements)

References 32 publications

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“…Thus, the constant stimulation of androgens induces changes in ARs or even induces epigenetic changes, leading to ovarian dysfunction in PCOS. 24 In relation estradiol in a previous study we also obtained higher levels on PCOS group, results which meet the current immunohistochemical findings, given that the CYP1A1 enzyme that catalyzes the formation of estrogens from androgens showed greater reactivity in the PCOS group. CYP19A1 (aromatase) is normally present in granulosa cells, whereas in ovaries belonging to the PCOS group we found both immunoreactivity in granulosa cells and in the interstitial cells, which may explain the increase in estrogens.…”

Section: Resultssupporting

confidence: 90%

“…It is believed that the theca interna cells that produce androgens act in a paracrine manner in granulosa cells. 24 Another function would be to modulate the signaling of follicle stimulating hormone (FSH) through the androgen receptors (ARs) in granulosa cells to amplify the cAMP concentration. Thus, the constant stimulation of androgens induces changes in ARs or even induces epigenetic changes, leading to ovarian dysfunction in PCOS.…”

Section: Resultsmentioning

confidence: 99%

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Immunohistochemical evaluation of proliferation, apoptosis and steroidogenic enzymes in the ovary of rats with polycystic ovary

Lombardi

Simões

Maganhin

et al. 2014

Rev. Assoc. Med. Bras.

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ImmunohIstochemIcal evaluatIon of prolIferatIon, apoptosIs and steroIdogenIc enzymes In the ovary of rats wIth polycystIc ovary rev assoc med Bras 2014; 60(4):349-356 349original articleImmunohistochemical evaluation of proliferation, apoptosis and steroidogenic enzymes in the ovary of rats with polycystic ovary Conflict of interest: noneObjective: to evaluate the immunohistochemical expression of proliferative, apoptotic and steroidogenic enzyme markers in the ovaries of rats with polycystic ovary syndrome (PCOS). Methods: twenty rats were divided into two groups: GCtrl -estrous phase, and PCOS -with polycystic ovaries. The GCtrl animals were subjected to a lighting period from 7 am to 7 pm, while the animals with PCOS group remained with continuous lighting for 60 days. Subsequently, the animals were anesthetized, the ovaries were removed and fixed in 10% formaldehyde, prior to paraffin embedding. Sections were stained using H.E. or subjected to immunohistochemical methods for the detection of Ki-67, cleaved caspase-3, CYP11A1, CYP17A1 and CYP19A1. The results were analyzed using Student's t-test (p < 0,05). Results: morphological results showed evidence of interstitial cells originating from the inner theca cells of degenerating ovarian cysts in PCOS. Immunoexpression of Ki-67 was higher in the granulosa cells in GCtrl, and the theca interna cells in PCOS, while cleaved caspase-3 was higher in granulosa cells of ovarian cysts from PCOS and in the theca interna cells of GCtrl. Immunoreactivity of CYP11A1 in the theca interna, granulosa and interstitial cells was similar between the two groups, while CYP17A1 and CYP19A1 were higher in the granulosa and interstitial cells in the PCOS group. Conclusion: the results indicate that the interstitial cells are derived from the theca interna and that enzymatic changes occur in the theca interna and interstitial cells in ovaries of rats with PCOS, responsible for the high levels of androgens and estradiol.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Immunohistochemical evaluation of proliferation, apoptosis and steroidogenic enzymes in the ovary of rats with polycystic ovary

Lombardi

Simões

Maganhin

et al. 2014

Rev. Assoc. Med. Bras.

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“…The ovarian morphology assessed by ultrasound in the controls was normal for every patient. The long agonist protocol for controlled ovarian hyperstimulation (COH) and the collection of follicular fluids and GCs, obtained by follicular aspiration from women undergoing oocyte retrieval for IVF, were performed as described (25). All patient studies were approved by the Ethics Committee of the Women's Hospital, School of Medicine, Zhejiang University.…”

Section: Methodsmentioning

confidence: 99%

“…TT levels in serum were measured after exaction (26) using CLIA (Roche). TT, SHBG, E 2 levels in follicular fluids were detected as described (25). FAI was calculated as TT divided by SHBG × 100 (27).…”

Section: Measurement Of Hormonesmentioning

confidence: 99%

Alternative splicing of the androgen receptor in polycystic ovary syndrome

Wang

Pan

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders and a leading cause of female subfertility. The mechanism underlying the pathophysiology of PCOS remains to be illustrated. Here, we identify two alternative splice variants (ASVs) of the androgen receptor (AR), insertion and deletion isoforms, in granulosa cells (GCs) in ∼62% of patients with PCOS. AR ASVs are strongly associated with remarkable hyperandrogenism and abnormalities in folliculogenesis, and are absent from all control subjects without PCOS. Alternative splicing dramatically alters genome-wide AR recruitment and androgeninduced expression of genes related to androgen metabolism and folliculogenesis in human GCs. These findings establish alternative splicing of AR in GCs as the major pathogenic mechanism for hyperandrogenism and abnormal folliculogenesis in PCOS.n ovarian follicles, oocytes are surrounded by granulosa cells (GCs), which have crucial endocrine functions. Polycystic ovary syndrome (PCOS) is a heterogeneous hormonal disorder affecting one in 15 women, and is one of the most common causes of female infertility (1). Hyperandrogenism and abnormal follicle development, associated with excessively small follicles and ovulatory dysfunction largely due to GCs dysfunction, characterize the pathogenesis of PCOS. Although the underlying etiology remains unclear, androgens and the androgen receptor (AR) are considered important on account of their critical roles in the prevalence of hyperandrogenism and ovarian folliculogenesis in this disorder (1-3).Androgens elicit their effects upon binding to AR, and AR functions primarily via genomic activities as a nuclear receptor. In the ovary, AR is predominantly expressed by GCs throughout most stages of follicular development. Nearly all reproductive phenotypes observed in global AR knockout mice have been attributed to a lack of AR expression in GCs (3). Haploinsufficiency for exon 3-deleted mutant AR is associated with a premature reduction in female fecundity (4), verifying the crucial role of classical genomic AR activity in normal ovarian function. Clinical studies have suggested that PCOS might be associated with AR (CAG)n repeats (5) and rs6152A (6) gene polymorphisms. These studies promoted interest in investigating the effects of AR in GC dysfunction in PCOS women. We therefore hypothesized that abnormally expressed and/or dysfunctional AR plays an important role in the pathogenesis of PCOS. ResultsAlternative Splice Variants of AR in GCs of PCOS Women. Nested RT-PCR (Fig. S1A) was used to amplify AR cDNAs from GCs of Southeastern Han Chinese women undergoing in vitro fertilization and embryo transfer. We identified two alternative splice variants (ASVs) expressed exclusively in PCOS women. One ASV inserted 69 bp into intron 2 (ivs2) between exons 2 and 3 (insertion isoform, ins) whereas the other skipped exon 3 (deletion isoform, del), as demonstrated by agarose gel electrophoresis (Fig. 1A) and PCR product sequencing (Fig. 1B). AR ASVs were not detected in ...

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“…As early as 2003, it was ever suggested that even mild forms of hyperandrogenism must be considered seriously and dysregulations of the steroidogenic pathway and ovarian abnormalities must be evaluated carefully to determine the risk of functional ovarian hyperandrogenism of PCOS (Cetinkaya et al, 2003). The follicular hyperandrogenism may induce the epigenetic alterations of PPARG1, NCOR1 and HDAC3 in the ovarian granulosa cells, which may be involved in the underlying mechanism of the ovarian dysfunction in hyperandrogenism PCOS women (Qu et al, 2012). These results indicate that it is through regulating PPARG1 and HDAC3 expression levels in the ovaries that CHM significantly alleviates hyperandrogenism of PCOS rats induced by testosterone propionate.…”

Section: Discussionmentioning

confidence: 99%

Chinese herbal medicine alleviating hyperandrogenism of PCOS rats through regulating PPARG1 and HDAC3 expression in the ovaries

Gu¹,

Ff²,

Dx³

et al. 2015

Afr. J. Trad. Compl. Alt. Med.

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#The first two authors contributed equally to the present study. Abstract Background: Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women hence Chinese herbal medicine (CHM) has been chosen by many clinicians and patients as alternative treatment for PCOS. The present study was to explore the effects of CHM in alleviating hyperandrogenism of PCOS rats induced by testosterone propionate and the possible underlying mechanism. Materials and methods:A total of forty female Sprague-Dawley rats were randomly divided into normal control group, PCOS model group, CHM1 group and CHM2 group, with ten rats in each group. The rat models with PCOS were established by single injection of testosterone propionate at the 9th day after birth. The status of estrous cyclicity for each rat was observed. After the treatment for 12 weeks ended, the serum levels of total testosterone (TT), sex hormone binding globulin (SHBG), androstenedione, follicle stimulating hormone (FSH) and luteinizing hormone (LH) of the rats were measured with ELISA and mRNA expression levels of peroxisome proliferator-activated receptor gamma 1(PPARG1) and histone deacetylase 3 (HDAC3) in the ovaries of the rats were detected with real-time quantitative PCR. Results:The serum levels of LH/FSH, FAI and androstenedione of the PCOS model rats were the highest among all the groups (P<0.05) and no significant differences on the serum levels of LH/FSH and FAI between the rats from CHM1 and CHM2 groups were found (P>0.05). The serum levels of androstenedione of the rats from CHM1 group were significantly lower than those of CHM2 group (P<0.05). In the ovaries of PCOS model rats, PPARG1mRNA expression levels were significantly lower, and HDAC3 mRNA expression levels were significantly higher than the other three groups (P<0.05). There were no significant differences existed between CHM1 and CHM2 groups on mRNA expression levels of PPARG1 and HDAC3 in the ovaries of the rats(P>0.05). Conclusion:It is through regulating PPARG1 and HDAC3 expression levels in the ovaries that CHM significantly alleviates hyperandrogenism of PCOS rats induced by testosterone propionate.

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A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells

Cited by 122 publications

References 32 publications

Immunohistochemical evaluation of proliferation, apoptosis and steroidogenic enzymes in the ovary of rats with polycystic ovary

Immunohistochemical evaluation of proliferation, apoptosis and steroidogenic enzymes in the ovary of rats with polycystic ovary

Alternative splicing of the androgen receptor in polycystic ovary syndrome

Chinese herbal medicine alleviating hyperandrogenism of PCOS rats through regulating PPARG1 and HDAC3 expression in the ovaries

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