Prepubertal Development of Gonadotropin-Releasing Hormone Neuron Activity Is Altered by Sex, Age, and Prenatal Androgen Exposure

Dulka, Eden A.; Moenter, Suzanne M.

doi:10.1210/en.2017-00768

Cited by 33 publications

(65 citation statements)

References 75 publications

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“…Although LH is low throughout prepubertal life, GnRH neurons are highly active throughout this period (58) and undergo dramatic morphological and synaptic plasticity prior to pubertal onset (33). Two very recent reports out of the Moenter laboratory have reported that both GnRH neuron firing activity (58) and GABAergic transmission to GnRH neurons (59) are present at 1 week of age and peak around 3 weeks of age, corresponding closely to the time point investigated here. Berg et al have shown that GABAergic inhibitory post-synaptic currents (IPSCs) in PNA females are higher than controls at 3 weeks of age, lending support to our anatomical findings.…”

Section: Discussionsupporting

confidence: 68%

“…Berg et al have shown that GABAergic inhibitory post-synaptic currents (IPSCs) in PNA females are higher than controls at 3 weeks of age, lending support to our anatomical findings. However, they also report that GnRH firing frequency and response to GABA application was unexpectedly blunted in PNA mice when compared with control females (58,59). It is tempting to speculate that increased GABAergic synaptic contact and synaptic transmission would be coincident with increased GnRH neuron activity even in the juvenile period.…”

Section: Discussionmentioning

confidence: 98%

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Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS

Silva¹,

Prescott²,

Campbell³

2018

JCI Insight

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Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP-transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 98%

Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS

Silva¹,

Prescott²,

Campbell³

2018

JCI Insight

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“…Interestingly, we reported that pituitary Amhr2 expression is also higher in female rats during this developmental period [16]. A higher GnRH neuron activity has recently been reported in infantile 2- to 3-week-female mice as compared to males [70]. Based on our present study, we can hypothesize that this contributes to dimorphism of pituitary Amhr2 expression and hence to the sexually dimorphic secretion of FSH during infancy.…”

Section: Discussionsupporting

confidence: 77%

GnRH Transactivates Human AMH Receptor Gene via Egr1 and FOXO1 in Gonadotrope Cells

et al. 2018

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Background/Objectives: Anti-Müllerian hormone (AMH) signaling is critical for sexual differentiation and gonadal function. AMH receptor type 2 (AMHR2) is expressed in extragonadal sites such as brain, and pituitary and emerging evidence indicates that AMH biological action is much broader than initially thought. We recently reported that AMH signaling enhances follicle-stimulating hormone synthesis in pituitary gonadotrope cells. However, mechanisms regulating AMHR2 expression in these extragonadal sites remain to be explored. Method/Results: Here, we demonstrated in perifused murine LβT2 gonadotrope cells that Amhr2 expression is differentially regulated by GnRH pulse frequency with an induction under high GnRH pulsatility. Furthermore, we showed that GnRH transactivates the human AMHR2 promoter in LβT2 cells. Successive deletions of the promoter revealed the importance of a short proximal region (–53/–37 bp) containing an Egr1 binding site. Using site-directed mutagenesis of Egr1 motif and siRNA mediated-knockdown of Egr1, we demonstrated that Egr1 mediates basal and GnRH-dependent activity of the promoter, identifying Egr1 as a new transcription factor controlling hAMHR2 expression. We also showed that SF1 and β-catenin are required for basal promoter activity and demonstrated that both factors contribute to the GnRH stimulatory effect, independently of their respective binding sites. Furthermore, using a constitutively active mutant of FOXO1, we identified FOXO1 as a negative regulator of basal and GnRH-dependent AMHR2 expression in gonadotrope cells. Conclusions: This study identifies GnRH as a regulator of human AMHR2 expression, further highlighting the importance of AMH signaling in the regulation of gonadotrope function.

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“…In the pituitary, AMH binds to AMHRII to increase FSH synthesis and secretion, specifically during the infantile period in the female rat (Garrel et al 2016). It would be of interest to specify the contribution of ovarian AMH to the transient increase in both GnRH neuron activity and gonadotropin levels observed during the infantile period (Dulka & Moenter 2017, François et al 2017.…”

Section: :2mentioning

confidence: 99%

FSH inhibits AMH to support ovarian estradiol synthesis in infantile mice

Devillers

Petit

Cluzet

et al. 2019

Journal of Endocrinology

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Anti-Müllerian hormone (AMH) regulates ovarian function in cyclic females, notably by preventing premature follicle-stimulating hormone (FSH)-mediated follicular growth and steroidogenesis. Its expression in growing follicles is controlled by FSH and by estradiol (E2). In infantile females, there is a transient increase in the activity of the gonadotrope axis, as reflected by elevated levels of both gonadotropins and E2. We previously demonstrated in mice that elevated FSH concentrations are necessary to induce E2 production by preantral/early antral follicles through the stimulation of aromatase expression without supporting their growth. However, whether this action of FSH could involve AMH is unknown. Here, we show that Amh mRNA and protein abundance and serum AMH levels are elevated in infantile mouse females, compared with those in adults. By experimentally manipulating FSH and E2 levels in infantile mice, we demonstrate that high FSH concentrations lower Amh expression specifically in preantral/early antral follicles, whereas E2 has no effect. Importantly, treatment of infantile ovaries in organotypic cultures with AMH decreases FSH-mediated expression of Cyp19a1 aromatase, but it does not alter the expression of cyclin D2-mediating granulosa cell proliferation. Overall, our data indicate that the infantile elevation in FSH levels suppresses Amh expression in preantral/early antral follicles, thereby favoring Cyp19a1 aromatase expression and E2 production. Together with recent discoveries that AMH can act on both the hypothalamus and the pituitary to increase gonadotropin levels, this work suggests that AMH is a critical regulator of the gonadotrope axis during the infantile period, thereby contributing to adult reproductive function programming.

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Prepubertal Development of Gonadotropin-Releasing Hormone Neuron Activity Is Altered by Sex, Age, and Prenatal Androgen Exposure

Cited by 33 publications

References 75 publications

Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS

Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS

GnRH Transactivates Human AMH Receptor Gene via Egr1 and FOXO1 in Gonadotrope Cells

FSH inhibits AMH to support ovarian estradiol synthesis in infantile mice

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