Differential Role of Corticotrophin‐Releasing Factor Receptor Types 1 and 2 in Stress‐Induced Suppression of Pulsatile Luteinising Hormone Secretion in the Female Rat

Li, Xian-Fang; Je, Bowe; Kinsey‐Jones, James S.; Brain, Susan D.; Lightman, Stafford L.; O’Byrne, Kevin

doi:10.1111/j.1365-2826.2006.01450.x

Cited by 79 publications

(86 citation statements)

References 59 publications

(93 reference statements)

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“…Intracerebroventricular injection of CRF attenuates LH secretion by inhibiting immunoreactive GnRH release in the hypophysial-portal circulation in ovariectomized and estradiol-administered rats (37). Intravenous injection of CRF antagonist reverses the inhibitory effect of immobilization stress on LH secretion in rats (27). These findings suggest that hypothalamic CRF modifies reproductive function at the hypothalamic level during stress.…”

Section: Discussionmentioning

confidence: 73%

Role of urocortin 2 secreted by the pituitary in the stress-induced suppression of luteinizing hormone secretion in rats

Nemoto

Iwasaki-Sekino

Yamauchi

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Nemoto T, Iwasaki-Sekino A, Yamauchi N, Shibasaki T. Role of urocortin 2 secreted by the pituitary in the stress-induced suppression of luteinizing hormone secretion in rats. Am J Physiol Endocrinol Metab 299: E567-E575, 2010. First published July 27, 2010; doi:10.1152/ajpendo.00163.2010.-We have previously shown that urocortin 2 (Ucn 2), a member of the corticotropinreleasing factor (CRF) peptide family that binds to CRF type 2 receptor, is expressed in proopiomelanocortin (POMC) cells of rat pituitary and that its secretion and expression are increased by CRF in both the anterior and intermediate lobes and suppressed by glucocorticoids in the anterior lobe. We have also shown that Ucn 2 secreted by POMC cells acts on gonadotrophs expressing CRF type 2 receptors and inhibits the expression and secretion of gonadotropins. In the present study, we examined whether pituitary Ucn 2 is involved in stress-induced inhibition of gonadotropin secretion. A 90-min period of immobilization stress increased POMC mRNA expression without influencing Ucn 2 mRNA expression and suppressed luteinizing hormone (LH) ␤-subunit mRNA expression in the anterior lobe and plasma LH levels, while it increased both POMC and Ucn 2 mRNA expression in the intermediate lobe of the pituitary. Pretreatment with anti-CRF IgG blocked immobilization-induced increases in plasma ACTH and corticosterone and in POMC mRNA expression in both pituitary lobes and Ucn 2 mRNA expression in the intermediate pituitary. It also blocked immobilization-induced suppression of plasma LH and LH ␤-subunit mRNA expression. Pretreatment with anti-Ucn 2 IgG blocked immobilization-induced suppression of plasma LH and LH ␤-subunit expression without affecting immobilization-induced ACTH and corticosterone release and POMC or Ucn 2 mRNA expression. These results suggest that CRF suppresses the secretion and expression of LH probably through pituitary Ucn 2 in stress. luteinizing hormone; corticotropin-releasing factor; pituitary STRESS INHIBITS REPRODUCTIVE function (12,13,23). The hormones composing the hypothalamic-pituitary-adrenal (HPA) axis such as corticotropin-releasing factor (CRF), adrenocorticotropin (ACTH), ␤-endorphin, and corticosteroids reportedly play important roles in the suppressive influence of stress on reproductive function (41-43). CRF is a key stress mediator in the endocrine system, autonomic nervous system, emotion, and behavior (4,19,46). The various actions of CRF are mediated through two subtypes of CRF receptors (CRF-R), CRF-R1 and CRF-R2. CRF binds with a higher affinity to CRF-R1 than to CRF-R2 (4, 18). Urocortin 2 (Ucn 2) is a CRF peptide family and shows higher affinities to both CRF-R1 and CRF-R2 compared with CRF, in particular to CRF-R2 (40). Hypothalamic CRF inhibits gonadotropin-releasing hormone (GnRH) neuron activity either directly or indirectly through ␤-endorphin in the arcuate nucleus (42, 43). Intracerebroventricular infusion of CRF in the third ventricle inhibits the estrous cycle and ovulation and reduces immunoreactive GnRH s...

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Section: Discussionmentioning

confidence: 73%

Role of urocortin 2 secreted by the pituitary in the stress-induced suppression of luteinizing hormone secretion in rats

Nemoto

Iwasaki-Sekino

Yamauchi

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…hybridisation of mRNAs for GnRH and CRF-R1 failed to localize CRF-R1 mRNA in GnRH neurones in the rat (Hahn et al 2003). Nevertheless, we have recently shown that administration of a selective CRF-R1 antagonist reversed the inhibitory effects of restraint on LH pulses in the rat (Li et al 2006).…”

Section: Discussionmentioning

confidence: 80%

“…We have shown that the CRF-R2 antagonist, astressin 2 -B (Ast 2 -B), completely blocked restraint stress-induced suppression of pulsatile LH secretion and that central administration of the CRF-R2 specific ligand Ucn II induced a dosedependent suppression in LH-pulse frequency in the rat ). Further, we have shown that Ast 2 -B markedly attenuated the LH pulse-suppressing effects of insulin-induced hypoglycaemia and innate immunological challenge with lipopolysaccharide (LPS), while the latter two responses were not blocked by selective CRF-R1 antagonists (Li et al 2006). These data suggest a pivotal role of CRF-R2 in the control of the GnRH pulse generator.…”

Section: Introductionmentioning

confidence: 84%

“…However, further work is required to determine protein levels for the receptor in the GT1-7 cells. We have recently shown that CRF-R2 plays a pivotal role in restraint , LPS or hypoglycaemic (Li et al 2006) stress-induced suppression of LH pulses in the rat. Furthermore, central administration of UcnII, a highly selective ligand for CRF-R2, induced a dose-dependent suppression of pulsatile LH secretion .…”

Section: Discussionmentioning

confidence: 99%

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Corticotrophin-releasing factor type 2 receptor-mediated suppression of gonadotrophin-releasing hormone mRNA expression in GT1-7 cells

Kinsey‐Jones

Bowe

et al. 2006

Stress

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Corticotrophin-releasing factor (CRF) released during stress has been implicated in the suppression of the hypothalamo-pituitary-gonadal (HPG) axis, especially the gonadotrophin-releasing hormone (GnRH) pulse generator, the central neural regulator of pituitary LH and FSH secretion, resulting in reproductive dysfunction. The gonadal steroid 17beta-oestradiol (E2) has been shown to enhance CRF- and stress-induced suppression of pulsatile LH secretion. In the present study, we investigated the potential direct action of CRF on GnRH neurones by using GT1-7 cells, an established GnRH cell line. Furthermore, we investigated the modulatory influence of E2 on the effects of CRF and expression of CRF type 2 receptors (CRF-R2). Expression of CRF-R2 in the GT1-7 cells was detected by reverse transcription-polymerase chain reaction (RT-PCR). CRF produced a dose-dependent suppression of GnRH mRNA expression, an effect reversed by the selective CRF-R2 antagonist, astressin2-B (Ast2-B). E2 combined with CRF resulted in a greater suppression of GnRH expression compared with either treatment alone. E2 also increased CRF-R2 expression. These results demonstrate for the first time expression of CRF-R2 in the GT1-7 cells and suggest that CRF may directly regulate GnRH gene expression, an effect mediated, at least in part, by CRF-R2. They also raise the possibility that up-regulation of CRF-R2 may contribute to the sensitising influence of E2 on CRF- and stress-induced suppression of the GnRH pulse generator.

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“…Intracerebroventricular (icv) administration of Ucn2 reportedly suppresses LH secretion in rats, although the site of action of Ucn2 is unknown (17). Furthermore, icv administration of a selective CRF-R2 antagonist blocks restraint-, hypoglycemia-, or lipopolysaccharide-induced suppression of LH secretion in ovariectomized rats with estrogen replacement (16,17). These findings suggest that CRF-R2 probably mediates stress-induced LH suppression at some site(s) other than the pituitary and that Ucn2 may play a role in the control of LH secretion under stress in the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of miR-325-3p by urocortin 2 and its involvement in stress-induced suppression of LH secretion in rat pituitary

Nemoto

Mano

Shibasaki

2012

American Journal of Physiology-Endocrinology and Metabolism

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Nemoto T, Mano A, Shibasaki T. Increased expression of miR-325-3p by urocortin 2 and its involvement in stress-induced suppression of LH secretion in rat pituitary. Am J Physiol Endocrinol Metab 302: E781-E787, 2012. First published January 17, 2012; doi:10.1152/ajpendo.00616.2011.-Urocortin 2 (Ucn2) is a member of the corticotropin releasing factor (CRF) peptide family, which binds to CRF type 2 receptor. We previously reported on expression of Ucn2 in proopiomelanocortin cells of rat pituitary and its inhibitory action on LH secretion. We also demonstrated that Ucn2 is involved in the mechanism underlying immobilization-induced suppression of LH secretion; the details remain unclear. Here, we found that Ucn2 increased the expression of miR-325-3p, one of three microRNAs with predicted sequence for binding to LH ␤-subunit 3=-untranslated region (3=-UTR) in monolayer cultured rat anterior pituitary cells, and that miR-325-3p was expressed in LH cells of the anterior pituitary. Immobilization also increased miR-325-3p expression in the anterior pituitary, and its increase was blocked by pretreatment with anti-Ucn2 IgG. Overexpression of miR-325-3p in cultured pituitary cells significantly suppressed intracellular contents and secretion of LH, while miR-325-3p knockdown blocked Ucn2-induced suppression of intracellular contents and secretion of LH. Coexpression of miR-325-3p with LH ␤-subunit 3=-UTR-fused luciferase vector significantly suppressed luciferase activity compared with that of mock transfectants. These results suggest that miR-325-3p is involved in immobilization-induced suppression of LH translation and secretion and that Ucn2 plays a role in the increase in miR-325-3p expression. luteinizing hormone; microRNA; stress REPRODUCTIVE FUNCTION IS SUPPRESSED by corticotropin-releasing factor (CRF), adrenocorticotropin, ␤-endorphin, and glucocorticoids, composing the hypothalamic-pituitary-adrenal axis under stress exposure (28,29). We previously demonstrated that urocortin 2 (Ucn2), a member of the CRF peptide family (27), is expressed in proopiomelanocortin (POMC) cells of the anterior and intermediate lobes of the rat pituitary (32) and that in both sites CRF increases its mRNA expression (20). We also reported that Ucn2 suppresses luteinizing hormone (LH) secretion without influencing LH ␤-subunit mRNA expression, whereas a selective CRF type 2 receptor (CRF-R2) antagonist and a specific siRNA against CRF-R2 significantly increase LH secretion and LH ␤-subunit mRNA expression in monolayer cultured anterior pituitary cells of rats (23). A possible explanation for the inconsistency of effects between Ucn2 and its blockades on LH ␤-subunit mRNA expression is proposed; the expression level of LH ␤-subunit mRNA is already suppressed by endogenous Ucn2 secreted by POMC cells into the culture medium, and exogenous Ucn2 could not induce further suppression of LH ␤-subunit mRNA expression (6). Furthermore, we have shown that anti-Ucn2 IgG partially blocks immobilization-induced suppression of LH secretion and LH...

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Differential Role of Corticotrophin‐Releasing Factor Receptor Types 1 and 2 in Stress‐Induced Suppression of Pulsatile Luteinising Hormone Secretion in the Female Rat

Cited by 79 publications

References 59 publications

Role of urocortin 2 secreted by the pituitary in the stress-induced suppression of luteinizing hormone secretion in rats

Role of urocortin 2 secreted by the pituitary in the stress-induced suppression of luteinizing hormone secretion in rats

Corticotrophin-releasing factor type 2 receptor-mediated suppression of gonadotrophin-releasing hormone mRNA expression in GT1-7 cells

Increased expression of miR-325-3p by urocortin 2 and its involvement in stress-induced suppression of LH secretion in rat pituitary

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