scholarly journals The Role of the Locus Coeruleus in Corticotropin-Releasing Hormone and Stress-Induced Suppression of Pulsatile Luteinizing Hormone Secretion in the Female Rat

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 323-331 ◽  
Author(s):  
J. C. Mitchell ◽  
X. F. Li ◽  
L. Breen ◽  
J.-C. Thalabard ◽  
K. T. O’Byrne
Keyword(s):  
Glutamic Acid ◽  
Locus Coeruleus ◽  
Stress Responses ◽  
Pulse Generator ◽  
Critical Role ◽  
Ovariectomized Rats ◽  
Female Rat ◽  
Central Administration ◽  
17Β Estradiol ◽  
Lh Secretion

Despite a wealth of evidence for CRH mediating stress-induced suppression of the hypothalamic GnRH pulse generator, and hence reproductive dysfunction, the site and mechanism of action remains elusive. The locus coeruleus (LC), a prominent noradrenergic brain stem nucleus, is innervated by CRH neurons, mediates several behavioral stress responses, and is implicated in the control of pulsatile LH secretion. The aim of this study was to test the hypothesis that LC CRH has a critical role in mediating stress-induced suppression of pulsatile LH secretion in the rat. Ovariectomized rats with 17β-estradiol or oil-filled sc capsules were implanted with bilateral LC and iv cannulae. Central administration of CRH (10 ng to 1 μg) resulted in a dose-dependent suppression of LH pulses, which was reversed by a CRH receptor antagonist (α-helical CRF9–41, 1 μg). The induction of c-fos expression in glutamic acid decarboxylase67 immunostained neurons in the preoptic area suggests activation of the secretion of γ-aminobutyric acid in response to intracoerulear administration of CRH; 17β-estradiol further increased the percentage of glutamic acid decarboxylase67-positive neurons that expressed fos and augmented suppression of LH pulses. Furthermore, intracoerulear administration of α-helical CRF9–41 completely blocked restraint stress-induced suppression of LH pulses, without affecting the inhibitory response to hypoglycemia. These results suggest that CRH innervation of the LC may play a pivotal, but differential, role in the normal physiological response of stress-induced suppression of the GnRH pulse generator and hence the reproductive system.

scholarly journals Neurokinin B Signaling in the Female Rat: a Novel Link Between Stress and Reproduction

Endocrinology ◽  
2014 ◽  
Vol 155 (7) ◽  
pp. 2589-2601 ◽  
Author(s):  
P. Grachev ◽  
X.F. Li ◽  
M.H. Hu ◽  
S.Y. Li ◽  
R.P. Millar ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Arcuate Nucleus ◽  
Pulse Generator ◽  
Ovariectomized Rats ◽  
Female Rat ◽  
Dynorphin A ◽  
Receptor Antagonists ◽  
Neurokinin B ◽  
Hypothalamic Arcuate Nucleus ◽  
Systemic Stress

Acute systemic stress disrupts reproductive function by inhibiting pulsatile gonadotropin secretion. The underlying mechanism involves stress-induced suppression of the GnRH pulse generator, the functional unit of which is considered to be the hypothalamic arcuate nucleus kisspeptin/neurokinin B/dynorphin A neurons. Agonists of the neurokinin B (NKB) receptor (NK3R) have been shown to suppress the GnRH pulse generator, in a dynorphin A (Dyn)-dependent fashion, under hypoestrogenic conditions, and Dyn has been well documented to mediate several stress-related central regulatory functions. We hypothesized that the NKB/Dyn signaling cascade is required for stress-induced suppression of the GnRH pulse generator. To investigate this ovariectomized rats, iv administered with Escherichia coli lipopolysaccharide (LPS) following intracerebroventricular pretreatment with NK3R or κ-opioid receptor (Dyn receptor) antagonists, were subjected to frequent blood sampling for hormone analysis. Antagonism of NK3R, but not κ-opioid receptor, blocked the suppressive effect of LPS challenge on LH pulse frequency. Neither antagonist affected LPS-induced corticosterone secretion. Hypothalamic arcuate nucleus NKB neurons project to the paraventricular nucleus, the major hypothalamic source of the stress-related neuropeptides CRH and arginine vasopressin (AVP), which have been implicated in the stress-induced suppression of the hypothalamic-pituitary-gonadal axis. A separate group of ovariectomized rats was, therefore, used to address the potential involvement of central CRH and/or AVP signaling in the suppression of LH pulsatility induced by intracerebroventricular administration of a selective NK3R agonist, senktide. Neither AVP nor CRH receptor antagonists affected the senktide-induced suppression of the LH pulse; however, antagonism of type 2 CRH receptors attenuated the accompanying elevation of corticosterone levels. These data indicate that the suppression of the GnRH pulse generator by acute systemic stress requires hypothalamic NKB/NK3R signaling and that any involvement of CRH therewith is functionally upstream of NKB.

scholarly journals Overexpression of Corticotropin Releasing Factor in the Central Nucleus of the Amygdala Advances Puberty and Disrupts Reproductive Cycles in Female Rats

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 3934-3944 ◽  
Author(s):  
X. F. Li ◽  
M. H. Hu ◽  
S. Y. Li ◽  
C. Geach ◽  
A. Hikima ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Hpa Axis ◽  
Pulse Generator ◽  
Female Rats ◽  
Central Nucleus ◽  
Ovariectomized Rats ◽  
Human Society ◽  
Central Administration ◽  
Corticosterone Secretion ◽  
Stress Changes

Abstract Prolonged exposure to environmental stress activates the hypothalamic-pituitary-adrenal (HPA) axis and generally disrupts the hypothalamic-pituitary-gonadal axis. Because CRF expression in the central nucleus of the amygdala (CeA) is a key modulator in adaptation to chronic stress, and central administration of CRF inhibits the hypothalamic GnRH pulse generator, we tested the hypothesis that overexpression of CRF in the CeA of female rats alters anxiety behavior, dysregulates the HPA axis response to stress, changes pubertal timing, and disrupts reproduction. We used a lentiviral vector to increase CRF expression site specifically in the CeA of preweaning (postnatal day 12) female rats. Overexpression of CRF in the CeA increased anxiety-like behavior in peripubertal rats shown by a reduction in time spent in the open arms of the elevated plus maze and a decrease in social interaction. Paradoxically, puberty onset was advanced but followed by irregular estrous cyclicity and an absence of spontaneous preovulatory LH surges associated with proestrous vaginal cytology in rats overexpressing CRF. Despite the absence of change in basal corticosterone secretion or induced by stress (lipopolysaccharide or restraint), overexpression of CRF in the CeA significantly decreased lipopolysaccharide, but not restraint, stress-induced suppression of pulsatile LH secretion in postpubertal ovariectomized rats, indicating a differential stress responsivity of the GnRH pulse generator to immunological stress and a potential adaptation of the HPA axis to chronic activation of amygdaloid CRF. These data suggest that the expression profile of this key limbic brain CRF system might contribute to the complex neural mechanisms underlying the increasing incidence of early onset of puberty on the one hand and infertility on the other attributed to chronic stress in modern human society.

scholarly journals Neonatal Lipopolysaccharide Exposure Exacerbates Stress-Induced Suppression of Luteinizing Hormone Pulse Frequency in Adulthood

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 5984-5990 ◽  
Author(s):  
X. F. Li ◽  
J. S. Kinsey-Jones ◽  
A. M. I. Knox ◽  
X. Q. Wu ◽  
D. Tahsinsoy ◽  
...  
Keyword(s):  
Pulse Generator ◽  
Pulse Frequency ◽  
Inhibitory Influence ◽  
Adult Rats ◽  
Treatment Groups ◽  
Early Life Exposure ◽  
Stress Responsivity ◽  
17Β Estradiol ◽  
Lh Secretion

Early life exposure to immunological challenge has programming effects on the adult hypothalamo-pituitary-adrenocortical axis stress responsivity, and stress is known to suppress GnRH pulse generator activity, especially LH pulses. We investigated the effects of neonatal exposure to endotoxin on stress-induced suppression of pulsatile LH secretion and the involvement of corticotropin-releasing factor (CRF) receptor mechanisms in adult rats. Pups at 3 and 5 d of age were administered lipopolysaccharide (LPS, 50 μg/kg, ip). At 12 wk of age, they were ovariectomized and implanted with sc 17β-estradiol capsules and iv cannulas. Blood samples (25 μl) were collected every 5 min for 5 h for LH measurement. After 2 h of sampling, rats were given LPS (25 μg/kg, iv). CRF and CRF-R1 and CRF-R2 receptor mRNA was determined by RT-PCR in medial preoptic area (mPOA) micropunches collected at 3 h after LPS administration. There was no difference in basal LH pulse frequency between neonatal LPS- and neonatal saline-treated controls. However, neonatal endotoxin-treated rats exhibited a significantly greater LPS stress-induced suppression of LH pulse frequency. Basal mPOA CRF-R1 expression was unchanged in neonatal LPS- and neonatal saline-treated rats. However, CRF-R1 expression was significantly increased in response to LPS stress in neonatal LPS-treated animals but not in neonatal saline-treated controls. CRF and CRF-R2 expression was unchanged in all treatment groups. These data demonstrate that exposure to bacterial endotoxin in early neonatal life programs long-term sensitization of the GnRH pulse generator to the inhibitory influence of stress in adulthood, an effect that might involve up-regulation of CRF-R1 expression in the mPOA.

scholarly journals Estrogen and Estrogen Receptor-β (ERβ)-Selective Ligands Induce Galanin Expression within Gonadotropin Hormone-Releasing Hormone-Immunoreactive Neurons in the Female Rat Brain

Endocrinology ◽  
2005 ◽  
Vol 146 (6) ◽  
pp. 2760-2765 ◽  
Author(s):  
Istvan Merchenthaler ◽  
Gloria E. Hoffman ◽  
Malcolm V. Lane
Keyword(s):  
Ovariectomized Rats ◽  
Female Rat ◽  
Dependent Manner ◽  
Neuronal System ◽  
Selective Ligands ◽  
Gnrh Neurons ◽  
17Β Estradiol ◽  
Selective Agonists ◽  
The Many

Abstract Among the many factors that integrate the activity of the GnRH neuronal system, estrogens play the most important role. In females, estrogen, in addition to the negative feedback, also exhibits a positive feedback influence upon the activity and output of GnRH neurons to generate the preovulatory LH surge and ovulation. Until recently, the belief has been that the GnRH neurons do not contain estrogen receptors (ERs) and that the action of estrogen upon GnRH neurons is indirect involving several, estrogen-sensitive neurotransmitter and neuromodulator systems that trans-synaptically regulate the activity of the GnRH neurons. Based on our recent findings that GnRH neurons of the female rat coexpress galanin, that galanin is a potent GnRH-releasing peptide, and that ERβ is present in GnRH neurons, we have evaluated the effect of 17β-estradiol and two ERβ-selective agonists (WAY-200070, WAY-166818) on the expression of galanin within GnRH neurons. By combining immunocytochemistry for GnRH and in situ hybridization histochemistry for galanin, we demonstrate that 17β-estradiol (20 μg/kg, sc) stimulates galanin expression within GnRH-immunoreactive neurons in a time-dependent manner. A significant increase was observed 2 h after its administration to ovariectomized rats. However, a more robust expression required 3-d treatment regimen. Treatment with the β-selective ligands resulted in similar observations, although no statistical analysis is available for the 2 hr survival. These observations strongly suggest that estrogen and the ERβ-selective ligands stimulate galanin expression within GnRH neurons via ERβ, although an indirect mechanism via interneurons still cannot be ruled out.

scholarly journals Erythropoietin-producing hepatocellular receptor A7 restrains estrogen negative feedback of luteinizing hormone via ephrin A5 in the hypothalamus of female rats

2020 ◽  
Vol 319 (1) ◽  
pp. E81-E90 ◽  
Author(s):  
Shang Li ◽  
Junyu Zhai ◽  
Bing Xu ◽  
Jiansheng Liu ◽  
Weiwei Chu ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Negative Feedback ◽  
Female Rats ◽  
Female Rat ◽  
Female Reproduction ◽  
Systemic Injection ◽  
Serum Luteinizing Hormone ◽  
Serum Lh ◽  
17Β Estradiol ◽  
Lh Secretion

We have previously shown that systemic injection of erythropoietin-producing hepatocellular receptor A7 (EPHA7)-Fc raises serum luteinizing hormone (LH) levels before ovulation in female rats, indicating the induction of EPHA7 in ovulation. In this study, we aimed to identify the mechanism and hypothalamus-pituitary-ovary (HPO) axis level underlying the promotion of LH secretion by EPHA7. Using an ovariectomized (OVX) rat model, in conjunction with low-dose 17β-estradiol (E2) treatment, we investigated the association between EPHA7-ephrin (EFN)A5 signaling and E2 negative feedback. Various rat models (OVX, E2-treated OVX, and abarelix treated) were injected with the recombinant EPHA7-Fc protein through the caudal vein to investigate the molecular mechanism underlying the promotion of LH secretion by EPHA7. Efna5 was observed strongly expressed in the arcuate nucleus of the female rat by using RNAscope in situ hybridization. Our results indicated that E2, combined with estrogen receptor (ER)α, but not ERβ, inhibited Efna5 and gonadotropin-releasing hormone 1 ( Gnrh1) expressions in the hypothalamus. In addition, the systemic administration of EPHA7-Fc restrained the inhibition of Efna5 and Gnrh1 by E2, resulting in increased Efna5 and Gnrh1 expressions in the hypothalamus as well as increased serum LH levels. Collectively, our findings demonstrated the involvement of EPHA7-EFNA5 signaling in the regulation of LH and the E2 negative feedback pathway in the hypothalamus, highlighting the functional role of EPHA7 in female reproduction.

scholarly journals The influence of 17β-estradiol on annexin 1 expression in the anterior pituitary of the female rat and in a folliculo-stellate cell line

2007 ◽  
Vol 192 (2) ◽  
pp. 429-442 ◽  
Author(s):  
Evelyn Davies ◽  
Selma Omer ◽  
John F Morris ◽  
Helen C Christian
Keyword(s):  
Cell Line ◽  
Estrous Cycle ◽  
Anterior Pituitary ◽  
Stellate Cell ◽  
Ovariectomized Rats ◽  
Female Rat ◽  
Annexin 1 ◽  
17Β Estradiol ◽  
Estrous Cycle Stage

Annexin 1 (ANXA1) is a Ca2+- and phospholipid-binding protein that plays an important role as a mediator of glucocorticoid action in the host-defence and neuroendocrine systems. Sex differences in hypothalamo–pituitary–adrenal (HPA) axis activity are well documented and a number of studies have demonstrated that gonadal steroids act as regulators of HPA activity. The aim of this study was to investigate the effect of ovariectomyand 17β-estradiol replacement, and estrous cycle stage, on anterior pituitary ANXA1 content. The amount of anterior pituitary ANXA1 determined by western blotting varied with estrous cycle stage with a peak at estrus declining to a trough at proestrus. Ovariectomy resulted in a significant (P<0.05) decrease in anterior pituitary ANXA1 content. Administration of 17β-estradiol (1 μg/100 g) significantly (P<0.01) increased anterior pituitary ANXA1 expression in the ovariectomized animals. In contrast, there was no change in pituitary ANXA1 content in response to 17β-estradiol in adrenalectomized and adrenalectomized/ovariectomized rats. Treatment of TtT/GF cells, a folliculo-stellate cell line, with 17β-estradiol (1.8–180 nM) increased ANXA1 mRNA expression and increased the amount of ANXA1 protein externalized in response to a dexamethasone stimulus. These results indicate that 17β-estradiol stimulates ANXA1 expression in the anterior pituitary and in vivo an adrenal factor contributes to the mechanism of action.

scholarly journals The Role of the Medial and Central Amygdala in Stress-Induced Suppression of Pulsatile LH Secretion in Female Rats

Endocrinology ◽  
2011 ◽  
Vol 152 (2) ◽  
pp. 545-555 ◽  
Author(s):  
Yuanshao Lin ◽  
Xiaofeng Li ◽  
Micol Lupi ◽  
James S. Kinsey-Jones ◽  
Bei Shao ◽  
...  
Keyword(s):  
Pulse Generator ◽  
Reproductive Function ◽  
Ibotenic Acid ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Inhibitory Effects ◽  
Cardiac Catheters ◽  
Response To Stress ◽  
Lh Secretion

Abstract Stress exerts profound inhibitory effects on reproductive function by suppressing the pulsatile release of GnRH and therefore LH. Although the mechanisms by which stressors disrupt the hypothalamic GnRH pulse generator remain to be fully elucidated, numerous studies have implicated the amygdala, especially its medial (MeA) and central nuclei (CeA), as key modulators of the neuroendocrine response to stress. In the present study, we investigated the roles of the MeA and CeA in stress-induced suppression of LH pulses. Ovariectomized rats received bilateral ibotenic acid or sham lesions targeting the MeA or CeA; blood samples (25 μl) were taken via chronically implanted cardiac catheters every 5 min for 6 h for the measurement of LH pulses. After 2 h of baseline sampling, the rats were exposed to either: restraint (1 h), insulin-induced hypoglycemia (IIH) (0.3 U/kg, iv), or lipopolysaccharide (LPS) (25 μg/kg, iv) stress. The restraint but not IIH or LPS stress–induced suppression of LH pulses was markedly attenuated by the MeA lesions. In contrast, CeA lesioning attenuated LPS, but not restraint or IIH stress–induced suppression of LH pulses. Moreover, after restraint stress, the number of Fos-positive neurons and the percentage of glutamic acid decarboxylase67 neurons expressing Fos was significantly greater in the GnRH-rich medial preoptic area (mPOA) of rats with intact, rather than lesioned, MeA. These data indicate that the MeA and CeA play key roles in psychogenic and immunological stress-induced suppression of the GnRH pulse generator, respectively, and the MeA-mediated effect may involve γ-aminobutyric acid ergic signaling within the mPOA.

scholarly journals Neuromedin S as Novel Putative Regulator of Luteinizing Hormone Secretion

Endocrinology ◽  
2007 ◽  
Vol 148 (2) ◽  
pp. 813-823 ◽  
Author(s):  
E. Vigo ◽  
J. Roa ◽  
M. López ◽  
J. M. Castellano ◽  
R. Fernandez-Fernandez ◽  
...  
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Hormone Secretion ◽  
Ovariectomized Rats ◽  
Potential Contribution ◽  
Female Rat ◽  
Central Administration ◽  
Luteinizing Hormone Secretion ◽  
Dark Light ◽  
Potential Implication ◽  
Reproductive Axis

Neuromedin S (NMS), a 36 amino acid peptide structurally related to neuromedin U, was recently identified in rat brain as ligand for the G protein-coupled receptor FM4/TGR-1, also termed neuromedin U receptor type-2 (NMU2R). Central expression of NMS appears restricted to the suprachiasmatic nucleus, and NMS has been involved in the regulation of dark-light rhythms and suppression of food intake. Reproduction is known to be tightly regulated by metabolic and photoperiodic cues. Yet the potential contribution of NMS to the control of reproductive axis remains unexplored. We report herein analyses of hypothalamic expression of NMS and NMU2R genes, as well as LH responses to NMS, in different developmental and functional states of the female rat. Expression of NMS and NMU2R genes was detected at the hypothalamus along postnatal development, with significant fluctuations of their relative levels (maximum at prepubertal stage and adulthood). In adult females, hypothalamic expression of NMS (which was confined to suprachiasmatic nucleus) and NMU2R significantly varied during the estrous cycle (maximum at proestrus) and was lowered after ovariectomy and enhanced after progesterone supplementation. Central administration of NMS evoked modest LH secretory responses in pubertal and cyclic females at diestrus, whereas exaggerated LH secretory bursts were elicited by NMS at estrus and after short-term fasting. Conversely, NMS significantly decreased elevated LH concentrations of ovariectomized rats. In summary, we provide herein novel evidence for the ability of NMS to modulate LH secretion in the female rat. Moreover, hypothalamic expression of NMS and NMU2R genes appeared dependent on the functional state of the female reproductive axis. Our data are the first to disclose the potential implication of NMS in the regulation of gonadotropic axis, a function that may contribute to the integration of circadian rhythms, energy balance, and reproduction.

scholarly journals Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat

2011 ◽  
Vol 300 (1) ◽  
pp. E202-E210 ◽  
Author(s):  
Víctor M. Navarro ◽  
Juan M. Castellano ◽  
Sarah M. McConkey ◽  
Rafael Pineda ◽  
Francisco Ruiz-Pino ◽  
...  
Keyword(s):  
Critical Role ◽  
Fold Increase ◽  
Serum Levels ◽  
Female Rat ◽  
Neurokinin B ◽  
Hypothalamic Nuclei ◽  
Lh Secretion ◽  
Circulating Levels ◽  
Lateral Cerebral Ventricle

Neurokinin B (NKB) and its cognate receptor neurokinin 3 (NK3R) play a critical role in reproduction. NKB and NK3R are coexpressed with dynorphin ( Dyn) and kisspeptin ( Kiss1) genes in neurons of the arcuate nucleus (Arc). However, the mechanisms of action of NKB as a cotransmitter with kisspeptin and dynorphin remain poorly understood. We explored the role of NKB in the control of LH secretion in the female rat as follows. 1) We examined the effect of an NKB agonist (senktide, 600 pmol, administered into the lateral cerebral ventricle) on luteinizing hormone (LH) secretion. In the presence of physiological levels of estradiol (E2), senktide induced a profound increase in serum levels of LH and a 10-fold increase in the number of Kiss1 neurons expressing c -fos in the Arc ( P < 0.01 for both). 2) We mapped the distribution of NKB and NK3R mRNAs in the central forebrain and found that both are widely expressed, with intense expression in several hypothalamic nuclei that control reproduction, including the Arc. 3) We studied the effect of E2 on the expression of NKB and NK3R mRNAs in the Arc and found that E2 inhibits the expression of both genes ( P < 0.01) and that the expression of NKB and NK3R reaches its nadir on the afternoon of proestrus (when circulating levels of E2 are high). These observations suggest that NKB/NK3R signaling in Kiss1/NKB/Dyn-producing neurons in the Arc has a pivotal role in the control of gonadotropin-releasing hormone (GnRH)/LH secretion and its regulation by E2-dependent negative feedback in the rat.

Roles of catecholamine at the preoptic region in the regulation of cyclic ovulation and gonadotropin

1987 ◽  
Vol 116 (3) ◽  
pp. 357-363 ◽  
Author(s):  
Ryuhei Hashimoto ◽  
Fukuko Kimura
Keyword(s):  
Third Ventricle ◽  
Oestrous Cycle ◽  
Ovariectomized Rats ◽  
Blood Levels ◽  
Female Rat ◽  
Preoptic Region ◽  
Gonadotropin Secretion ◽  
The Third ◽  
Lh Secretion ◽  
Intact Rats

Abstract. Experiments were designed to see how a transplantation of newborn norepinephrine (NE) neurons from A-6 groups or dopamine (DA) neurons from A-10 groups in the third ventricle at the level of the preoptic region affected the vaginal oestrous cycle and gonadotropin secretion in the female rat. Sixty-two rats that had tissues in contact with the preoptic region were evaluated as having surviving transplants by histological examination after sacrifice. The rats that had surviving NE-neuron transplants frequently showed prolongation of oestrus during the 70-day study period, indicating that ovulation was severely impaired in these rats. However, after ovariectomy, they showed a pulsatile secretion of LH with a remarkably large amplitude. The DA-neuron transplants sustained the oestrous cycle unchanged, but increased blood levels of FSH prior to the ovulatory secretion of gonadotropin. Pulsatile LH secretion was not affected. Sham and cerebellum control rats did not show any significant changes in the oestrous cycle. The results suggest that the NEneuron transplants at the preoptic region somehow inhibit gonadotropin secretion in intact rats, whereas they facilitate it in ovariectomized rats. The DA-neuron transplants appear to exert facilitatory effects on FSH secretion in intact rats.

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