Altered expression of miRNAs in a dihydrotestosterone-induced rat PCOS model

Hossain, Munir; Cao, Mingju; Wang, Qi; Kim, Ji Young; Schellander, K.; Tesfaye, Dawit; Tsang, Benjamin K.

doi:10.1186/1757-2215-6-36

Cited by 80 publications

(74 citation statements)

References 59 publications

(64 reference statements)

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“…Notably studies report (18,28) that miR-125b is similarly up-regulated by androgens in prostate cancer, and may play a crucial role in cancer cell proliferation and metastasis (29). With respect to miRs in female reproductive tissue, most work has focused on miR profiling rather than mechanism, and miR125b is reported to be one of the most abundant miRs in the ovary among different species (30,31). In fact, little is known about the expression, regulation, and function of miRs in the ovary (32).…”

Section: Nonspecific) (D-f)mentioning

confidence: 99%

Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression

Sen

Prizant

Light

et al. 2014

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

249

186

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Although androgen excess is considered detrimental to women's health and fertility, global and ovarian granulosa cell-specific androgen-receptor (AR) knockout mouse models have been used to show that androgen actions through ARs are actually necessary for normal ovarian function and female fertility. Here we describe two AR-mediated pathways in granulosa cells that regulate ovarian follicular development and therefore female fertility. First, we show that androgens attenuate follicular atresia through nuclear and extranuclear signaling pathways by enhancing expression of the microRNA (miR) miR-125b, which in turn suppresses proapoptotic protein expression. Second, we demonstrate that, independent of transcription, androgens enhance follicle-stimulating hormone (FSH) receptor expression, which then augments FSHmediated follicle growth and development. Interestingly, we find that the scaffold molecule paxillin regulates both processes, making it a critical regulator of AR actions in the ovary. Finally, we report that low doses of exogenous androgens enhance gonadotropin-induced ovulation in mice, further demonstrating the critical role that androgens play in follicular development and fertility. These data may explain reported positive effects of androgens on ovulation rates in women with diminished ovarian reserve. Furthermore, this study demonstrates mechanisms that might contribute to the unregulated follicle growth seen in diseases of excess androgens such as polycystic ovary syndrome. O ther than the obligatory role of androgens as estrogen precursors in steroidogenesis (1), little is known about the direct involvement of androgens in the female ovary. For many decades, excess androgens in women have been considered detrimental to women's health, as diseases such as polycystic ovary syndrome (PCOS) are associated with reduced fertility. In the past, these negative effects of androgens on female fertility were thought to occur primarily at the level of the hypothalamus and pituitary (2, 3), although important data across different species (4-7) suggested that androgens could also directly promote follicle growth (8, 9). Attitudes about androgen actions in female fertility changed with the development of global androgenreceptor knockout (ARKO) mice (10-12). The female ARKO mice had considerable reproductive defects, with decreased fertility, defective follicular development, reduced ovulation, and premature ovarian failure. In other words, the phenotype of these ARKO mice suggested that androgen signaling might actually be important for normal female reproductive health. Intriguingly, through the generation of granulosa cell (GC)-specific ARKO mice, we (13) and then others (14) demonstrated that essentially all the observed reproductive phenotypes in the complete AR-null mice are caused by androgen actions in GCs. These results highlighted that, with regard to fertility, androgen signaling in the ovary is at least as important as androgen signaling in the pituitary or hypothalamus. By using this GC-specific ARK...

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Section: Nonspecific) (D-f)mentioning

confidence: 99%

Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression

Sen

Prizant

Light

et al. 2014

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

249

186

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“…The authors go on to demonstrate a direct effect of miR-93 on GLUT4 and that this miRNAs is over-expressed in PCOS patients and women with insulin resistance and hypothesized that this miRNA may partially explain the overlap of these two conditions (Chen et al 2013). In a rodent PCOS model, rats were given dihydrotestosterone (DHT) to induce a PCOS-like phenotype and ~25 highly expressed miRNAs were found in both control and DHT ovaries (Hossain et al 2013). Interestingly, of the differentially expressed RNAs several were shown to be selectively expressed in theca cells (Hossain et al 2013).…”

Section: 5 Non-coding Rnas Involved In Ovarian Diseasesmentioning

confidence: 99%

“…In a rodent PCOS model, rats were given dihydrotestosterone (DHT) to induce a PCOS-like phenotype and ~25 highly expressed miRNAs were found in both control and DHT ovaries (Hossain et al 2013). Interestingly, of the differentially expressed RNAs several were shown to be selectively expressed in theca cells (Hossain et al 2013). This is an important observation as theca cells are the predominant source of elevated androgens in PCOS women and these studies provide evidence that dysregulation of miRNA expression should be further evaluated in human ovarian theca cells.…”

Section: 5 Non-coding Rnas Involved In Ovarian Diseasesmentioning

confidence: 99%

Non-coding RNA in Ovarian Development and Disease

Fitzgerald

George

Christenson

2015

Advances in Experimental Medicine and Biology

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The ovary’s primary function is to produce the mature female gamete, the oocyte that, following fertilization, can develop into an embryo, implant within the uterus and ultimately allow the mother’s genetic material to be passed along to subsequent generations. In addition to supporting the generation of the oocyte, the ovary and specific ephemeral tissues within it, follicles and corpora lutea, produce steroids that regulate all aspects of the reproductive system, including the hypothalamic/pituitary axis, the reproductive tract (uterus, oviduct, cervix), secondary sex characteristics all of which are also essential for pregnancy and subsequent nurturing of the offspring. To accomplish these critical roles, ovarian development and function are tightly regulated by a number of exogenous (hypothalamic/pituitary) and endogenous (intraovarian) hormones. Within ovarian cells, intricate signalling cascades and transcriptional and post-transcriptional gene regulatory networks respond to these hormonal influences to provide the exquisite control over all of the temporal and spatial events that must be synchronized to allow this organ to successfully complete its function. This book chapter will focus specifically on the role of non-coding RNAs, their identification and described functional roles within the ovary with respect to normal function and their possible involvement in diseases, which involve the ovary.

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“…Further studies are needed to determine whether miRNAs play a role in the etiology of PCOS or if they are downstream effects of other PCOS risk factors. Hossain et al (2013) examined changes in miRNA expression in a rat model of dihydrotestosterone (DHT)-induced PCOS. This study found significant changes in miRNA content within follicular fluid (17 up-and 72 downregulated).…”

Section: Polycystic Ovarian Syndromementioning

confidence: 99%