Animal models of polycystic ovary syndrome: A review of hormone‐induced rodent models focused on hypothalamus‐pituitary‐ovary axis and neuropeptides

Osuka, Satoko; Nakanishi, Natsuki; Murase, Toshiro; Nakamura, Tomoko; Goto, Maki; Iwase, Akira; Kikkawa, Fumitaka

doi:10.1002/rmb2.12262

Cited by 73 publications

(87 citation statements)

References 67 publications

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“…Several researchers (15, 143) suggest that androgen excess is the most important symptom in PCOS. Women diagnosed with PCOS may have abnormal theca cell function and increased androgens, leading to abnormal ovarian follicular development (15, 144, 145). Excess circulating androgen is associated with ovarian dysfunction and metabolic disorders in women (146).…”

Section: Perturbations In Gene Expression In Granulosa or Theca Cellsmentioning

confidence: 99%

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Perturbations in Lineage Specification of Granulosa and Theca Cells May Alter Corpus Luteum Formation and Function

et al. 2019

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Anovulation is a major cause of infertility, and it is the major leading reproductive disorder in mammalian females. Without ovulation, an oocyte is not released from the ovarian follicle to be fertilized and a corpus luteum is not formed. The corpus luteum formed from the luteinized somatic follicular cells following ovulation, vasculature cells, and immune cells is critical for progesterone production and maintenance of pregnancy. Follicular theca cells differentiate into small luteal cells (SLCs) that produce progesterone in response to luteinizing hormone (LH), and granulosa cells luteinize to become large luteal cells (LLCs) that have a high rate of basal production of progesterone. The formation and function of the corpus luteum rely on the appropriate proliferation and differentiation of both granulosa and theca cells. If any aspect of granulosa or theca cell luteinization is perturbed, then the resulting luteal cell populations (SLC, LLC, vascular, and immune cells) may be reduced and compromise progesterone production. Thus, many factors that affect the differentiation/lineage of the somatic cells and their gene expression profiles can alter the ability of a corpus luteum to produce the progesterone critical for pregnancy. Our laboratory has identified genes that are enriched in somatic follicular cells and luteal cells through gene expression microarray. This work was the first to compare the gene expression profiles of the four somatic cell types involved in the follicle-to-luteal transition and to support previous immunofluorescence data indicating theca cells differentiate into SLCs while granulosa cells become LLCs. Using these data and incorporating knowledge about the ways in which luteinization can go awry, we can extrapolate the impact that alterations in the theca and granulosa cell gene expression profiles and lineages could have on the formation and function of the corpus luteum. While interactions with other cell types such as vascular and immune cells are critical for appropriate corpus luteum function, we are restricting this review to focus on granulosa, theca, and luteal cells and how perturbations such as androgen excess and inflammation may affect their function and fertility.

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Section: Perturbations In Gene Expression In Granulosa or Theca Cellsmentioning

confidence: 99%

“…Excess circulating androgen is associated with ovarian dysfunction and metabolic disorders in women (146). Androgenized rats had fewer estrous cycles and lower numbers of mature and ovulated follicles (142, 145).…”

Section: Perturbations In Gene Expression In Granulosa or Theca Cellsmentioning

confidence: 99%

Perturbations in Lineage Specification of Granulosa and Theca Cells May Alter Corpus Luteum Formation and Function

et al. 2019

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“…There is considerable interest in establishing models of PCOS for examination of the basis of the reproductive as well as metabolic phenotypes that have been characterized in PCOS. The existing animal models of PCOS have been mainly produced by treating rodents with androgens [10,11] or inhibitors of aromatase, the enzyme that metabolizes androgens into estrogens [12]. PCOS-like phenotypes have also been produced by prenatally exposing sheep or rhesus macaque fetuses to androgens in utero [13,14].…”

Section: Introductionmentioning

confidence: 99%

Human DENND1A.V2 Drives Cyp17a1 Expression and Androgen Production in Mouse Ovaries and Adrenals

Teves

Modi

Kulkarni

et al. 2020

IJMS

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The DENND1A locus is associated with polycystic ovary syndrome (PCOS), a disorder characterized by androgen excess. Theca cells from ovaries of PCOS women have elevated levels of a DENND1A splice variant (DENND1A.V2). Forced expression of this variant in normal theca cells increases androgen biosynthesis and CYP17A1 expression, whereas knockdown of the transcript in PCOS theca cells reduced androgen production and CYP17A1 mRNA. We attempted to create a murine model of PCOS by expressing hDENND1A.V2 using standard transgenic approaches. There is no DENND1A.V2 protein equivalent in mice, and the murine Dennd1a gene is essential for viability since Dennd1a knockout mice are embryonically lethal, suggesting that Dennd1a is developmentally critical. Three different hDENND1A.V2 transgenic mice lines were created using CMV, Lhcgr, and TetOn promoters. The hDENND1A.V2 mice expressed hDENND1A.V2 transcripts. While hDENND1A.V2 protein was not detectable by Western blot analyses, appropriate hDENND1A.V2 immunohistochemical staining was observed. Corresponding Cyp17a1 mRNA levels were elevated in ovaries and adrenals of CMV transgenic mice, as were plasma steroid production by theca interstitial cells isolated from transgenic ovaries. Even though the impact of robust hDENND1A.V2 expression could not be characterized, our findings are consistent with the notion that elevated hDENND1A.V2 has a role in the hyperandrogenemia of PCOS.

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“…Although this prescription is used clinically to treat female infertility, experimental evidence obtained from in vitro and in vivo laboratory studies is lacking [ 6 ]. Mifepristone (also known as RU486) is a potent antiprogesterone agent, which can be used orally to induce abortion [ 16 ] or as an effective emergency contraceptive [ 17 ], and has often been used to induce embryo implantation failure or polycystic ovary syndrome in experimental animal models [ 10 , 18 , 19 ]. In the present study, we investigated the effects of a BCB water extract on endometrial receptivity and embryo implantation under normal conditions and in an RU486-induced mouse model of implantation failure.…”

Section: Introductionmentioning

confidence: 99%

Administration of a herbal formulation enhanced blastocyst implantation via IκB activation in mouse endometrium

et al. 2020

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Background BaelanChagsangBang (BCB), a herbal formulation consisting of eleven herbs, may be prescribed as a reproductive functional supplement to improve ovulation and implantation during the treatment of infertility and recurrent abortion in Korean Medicine. This study aimed to investigate the effects and action mechanisms of water-extracted BCB on endometrial receptivity and blastocyst implantation under normal conditions and in a mifepristone (RU486)-induced implantation failure murine model. Methods In vitro, the antioxidant potentials of BCB were evaluated using DPPH and superoxide anion radical scavenging assays and a DCFH-DA assay, and the cytotoxic and cytoprotective effects of BCB were confirmed using an MTT assay. In vivo, C57BL/6 female mice (n = 6 per group) orally received BCB (300 mg/kg/day), a dose similar to that used clinically, from 7 days before pregnancy until the end of the experiment. On day 4 of pregnancy, RU486 (4 mg/kg) was injected subcutaneously to induce implantation failure. The effect of BCB on embryo implantation was evaluated by implantation rate analysis, histological examination, and western blotting of uterus tissues. Results BCB water extract showed strong anti-oxidative and cytoprotective effects in vitro. In vivo administration of BCB water extract increased the number of newborn pups in BCB-treated mice versus sham-treated mice under normal conditions and improved the number of implantation sites in pregnant mice despite RU486 injection. BCB increased the protein levels of cyclooxygenase-2 and inducible nitric oxide synthase through IκB activation. Moreover, the expression levels of matrix metalloproteinases at uterus implantation sites were up-regulated in the BCB-treated group as compared with those in the RU486-treated group. Conclusion These results show BCB improved embryo implantation through IκB activation in our mouse model and suggest that BCB has therapeutic potential in the context of poor endometrial receptivity.

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Animal models of polycystic ovary syndrome: A review of hormone‐induced rodent models focused on hypothalamus‐pituitary‐ovary axis and neuropeptides

Cited by 73 publications

References 67 publications

Perturbations in Lineage Specification of Granulosa and Theca Cells May Alter Corpus Luteum Formation and Function

Perturbations in Lineage Specification of Granulosa and Theca Cells May Alter Corpus Luteum Formation and Function

Human DENND1A.V2 Drives Cyp17a1 Expression and Androgen Production in Mouse Ovaries and Adrenals

Administration of a herbal formulation enhanced blastocyst implantation via IκB activation in mouse endometrium

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