Actions of anti-Müllerian hormone on the ovarian transcriptome to inhibit primordial to primary follicle transition

Nilsson, Eric; Rogers, Natalie; Skinner, Michael K.

doi:10.1530/rep-07-0119

Cited by 171 publications

(117 citation statements)

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“…Conservation of the ovarian reserve after injection of recombinant AMH into young mice has also been observed (Hayes et al 2016). Exogenous application of AMH inhibits primordial follicle activation in explant cultures of human, rat, mouse and goat ovary tissue (Durlinger et al 2002, Gigli et al 2005, Carlsson et al 2006, Nilsson et al 2007, Rocha et al 2016. Similar experiments have shown that positive regulators of primordial follicle activation such as KIT-ligand, fibroblast growth factor 2, 7 or gremlin antagonise the effects of AMH (Nilsson et al 2007.…”

Section: :1mentioning

confidence: 76%

A putative role for anti-Müllerian hormone (AMH) in optimising ovarian reserve expenditure

Pankhurst

2017

Journal of Endocrinology

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The mammalian ovary has a finite supply of oocytes, which are contained within primordial follicles where they are arrested in a dormant state. The number of primordial follicles in the ovary at puberty is highly variable between females of the same species. Females that enter puberty with a small ovarian reserve are at risk of a shorter reproductive lifespan, as their ovarian reserve is expected to be depleted faster. One of the roles of anti-Müllerian hormone (AMH) is to inhibit primordial follicle activation, which slows the rate at which the ovarian reserve is depleted. A simple interpretation is that the function of AMH is to conserve ovarian reserve. However, the females with the lowest ovarian reserve and the greatest risk of early reserve depletion have the lowest levels of AMH. In contrast, AMH apparently strongly inhibits primordial follicle activation in females with ample ovarian reserve, for reasons that remain unexplained. The rate of primordial follicle activation determines the size of the developing follicle pool, which in turn, determines how many oocytes are available to be selected for ovulation. This review discusses the evidence that AMH regulates the size of the developing follicle pool by altering the rate of primordial follicle activation in a context-dependent manner. The expression patterns of AMH across life are also consistent with changing requirements for primordial follicle activation in the ageing ovary. A potential role of AMH in the fertility of ageing females is proposed herein.

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Section: :1mentioning

confidence: 76%

A putative role for anti-Müllerian hormone (AMH) in optimising ovarian reserve expenditure

Pankhurst

2017

Journal of Endocrinology

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“…S2A). Reports of the effect of MIS on follicles have been mixed, with some studies suggesting an activating effect (45,46) and others implying a direct inhibitory effect (18,47), indirect inhibition via gonadotropins (48,49), or even regulation of meiosis (50). In past studies, the magnitude of inhibition of primordial follicle recruitment in vivo and in vitro has been perceived as relatively modest because of difficulties in achieving high concentrations of the protein.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, when ovaries from Misr2-knockout mice are implanted in the chicken embryos, the primordial follicles are recruited at a high rate, equivalent to wild-type ovaries implanted in gonadectomized chicks with no MIS (17). Similarly, in ovarian cultures from postnatal day 4 rats, a stage at which only primordial follicles are present, 50 ng/mL MIS was sufficient to inhibit, albeit modestly, the transition of primordial to primary follicles compared with controls (18).…”

mentioning

confidence: 92%

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

Kano

Sosulski

Zhang

et al. 2017

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

166

171

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The ovarian reserve represents the stock of quiescent primordial follicles in the ovary which is gradually depleted during a woman's reproductive lifespan, resulting in menopause. Müllerian inhibiting substance (MIS) (or anti-Müllerian hormone/AMH), which is produced by granulosa cells of growing follicles, has been proposed as a negative regulator of primordial follicle activation. Here we show that long-term parenteral administration of superphysiological doses of MIS, using either an adeno-associated virus serotype 9 (AAV9) gene therapy vector or recombinant protein, resulted in a complete arrest of folliculogenesis in mice. The ovaries of MIS-treated mice were smaller than those in controls and did not contain growing follicles but retained a normal ovarian reserve. When mice treated with AAV9/MIS were paired with male breeders, they exhibited complete and permanent contraception for their entire reproductive lifespan, disrupted vaginal cycling, and hypergonadotropic hypogonadism. However, when ovaries from AAV9-MIS-treated mice were transplanted orthotopically into normal recipient mice, or when treatment with the protein was discontinued, folliculogenesis resumed, suggesting reversibility. One of the important causes of primary ovarian insufficiency is chemotherapy-induced primordial follicle depletion, which has been proposed to be mediated in part by increased activation. To test the hypothesis that MIS could prevent chemotherapy-induced overactivation, mice were given carboplatin, doxorubicin, or cyclophosphamide and were cotreated with AAV9-MIS, recombinant MIS protein, or vehicle controls. We found significantly more primordial follicles in MIS-treated animals than in controls. Thus treatment with MIS may provide a method of contraception with the unique characteristic of blocking primordial follicle activation that could be exploited to prevent the primary ovarian insufficiency often associated with chemotherapy.M üllerian inhibiting substance (MIS), also known as antiMüllerian hormone (AMH), has long been appreciated for its role in sex differentiation and reproduction, and sensitive ELISAs measuring blood levels are used in fertility clinics around the world as a measure of ovarian reserve (1-6). MIS plays important roles in the development of the gonad and the differentiation of the urogenital ridge. In the male fetus, MIS produced by the developing testes causes regression of the Müllerian duct (7). In the female fetus, MIS may play a role in early follicle assembly in the gonad by primordial germ cells (not to be confused with primordial follicles), since mice overexpressing MIS are devoid of germ cells shortly after birth (8), and, similarly, ex vivo incubation of fetal ovaries with MIS results in the inhibition of follicle assembly (9). These data highlight a role of MIS during fetal development that is distinct from its regulatory role of folliculogenesis postnatally.In the adult, MIS is produced predominantly by the cumulus (less so by the mural) granulosa cells of secondary and early antral...

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“…Several growth factors have been identified that regulate primordial to primary follicle transition by paracrine and autocrine signaling pathways including: kit ligand (KL); leukemia inhibitory factor (LIF); bone morphogenetic protein 4 (BMP4); BMP7; platelet-derived growth factor (PDGF); basic fibroblast growth factor (bFGF); and glial-derived neurotrophic factor (GDNF; Fortune 2003, Skinner 2005, Visser & Themmen 2005, Dole et al 2008. Anti-Müllerian hormone/Müllerian inhibitory substance and stromal-derived factor-1 (SDF-1/ CXCL12) inhibit primordial to primary follicle transition (Ikeda et al 2002, Holt et al 2006, Nilsson et al 2007. Once the supply of follicles in the ovary is exhausted reproduction ceases and, in humans, women enter menopause (Gosden et al 1983, Richardson et al 1987, Faddy 2000.…”

Section: Introductionmentioning

confidence: 99%

Neurotrophin Nt3 Promotes Ovarian Primordial to Primary Follicle Transition.

Nilsson

Dole²,

Skinner³

2009

Biology of Reproduction

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Neurotrophins are growth factors that are known to have a role in promoting cell survival and differentiation. The focus of the current study is to examine the role of neurotrophins in regulating ovarian primordial follicle development. Ovaries from 4-day old rats were placed into organ culture and cultured for 10 days in the absence or presence of neurotrophin-3 (NT3), brain-derived neurotrophic factor (BDNF), or nerve growth factor (NGF). Treatment of ovaries with NT3 resulted in a significant (P<0.01) increase in primordial follicle development (i.e. primordial to primary follicle transition). Treatment with BDNF at high doses of 100-250 ng/ml also significantly (P<0.01) increased primordial follicle development, but NGF had no effect. Immunohistochemical studies determined that NT3 was present in granulosa cells, interstitial tissue, and in the oocytes of primordial and primary follicles. The NT3 receptor NTRK3 was present in oocytes at all stages of development. Analysis of ovaries that contain predominantly primordial follicles demonstrated the transcripts for NT3, NTRK3, NGF, and the BDNF/ neurotrophin-4 (NT4) receptor NTRK2 are expressed, while BDNF, NT4, and the NGF receptor NTRK1 are not detectable. Inhibition of the NTRK3 receptor with the tyrphostin AG 879 resulted in oocyte death and a significant (P<0.01) reduction in follicle pool size. Inhibition of the NTRK receptors with K252a slowed primordial to primary follicle transition. A microarray analysis demonstrated that a small number of genes were differentially expressed after NT3 treatment. Observations indicate that the neurotrophin NT3, acting through the NTRK3 receptor in oocytes, promotes the primordial to primary follicle transition.

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Actions of anti-Müllerian hormone on the ovarian transcriptome to inhibit primordial to primary follicle transition

Cited by 171 publications

References 102 publications

A putative role for anti-Müllerian hormone (AMH) in optimising ovarian reserve expenditure

A putative role for anti-Müllerian hormone (AMH) in optimising ovarian reserve expenditure

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

Neurotrophin Nt3 Promotes Ovarian Primordial to Primary Follicle Transition.

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