The Luteinizing Hormone but Not the Cortisol Response to Arginine Vasopressin Is Prevented by Naloxone and a Corticotropin-Releasing Hormone Antagonist in the Ovariectomized Rhesus Monkey

Xiao, Ennian; Xia‐Zhang, Linna; Thornell, David; Shalts, Edward; Ferin, Michel

doi:10.1159/000127121

Cited by 15 publications

(10 citation statements)

References 29 publications

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“…Other studies concur with ours in suggesting the involvement of substances other than CRH in the negative regulation of the reproductive axis during stress (21,34,37). The suppression of reproductive function following activation of the HPA axis also appears to be species-specific.…”

Section: Discussionsupporting

confidence: 89%

“…Plasma LH levels were decreased following restraint or food withdrawal in both WT and CRH KO mice, suggesting that CRH is not a required inhibitory regulator of LH secretion during the stress response judged by our CRH KO mice model. Therefore, it is possible that other central factors known to restrain LH secretion, such as endogenous opioids (3,33,34,41,42), cytokines (4), or AVP (21,43), may instead act together to inhibit LH secretion (1) in CRH deficiency to compensate the lack of CRH. For example, endogenous opioids have been shown to be involved in the inhibition of LH secretion in rats FIG.…”

Section: Discussionmentioning

confidence: 99%

“…For example, arginine vasopressin (AVP) has also been found to inhibit LH secretion in monkeys (21), and CRH has been shown to stimulate LH secretion in gonadal steroid-treated sheeps (22). It is also possible that the CRH antagonists administered in many of the above studies might block the action of CRHrelated molecules such as urocortin (23), rather than that of CRH.…”

Section: T He Hypothalamic-pituitary-gonadal Axismentioning

confidence: 99%

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Normal Suppression of the Reproductive Axis Following Stress in Corticotropin-Releasing Hormone-Deficient Mice*

et al. 1999

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The hypothalamic neuropeptide CRH has been postulated to inhibit LH secretion by a central action within the brain. To characterize the physiological significance of CRH in stressor-induced inhibition of LH secretion, CRH-deficient and wild-type mice were subjected to restraint or food withdrawal, and plasma LH levels were determined. The proestrus LH surge of female mice was equally suppressed by restraint in both genotypes, and central administration of a CRH antagonist did not alleviate this suppression in either genotype. Male mice of both genotypes also demonstrated suppression of both LH and testosterone secretion following restraint. Furthermore, food withdrawal caused similar suppression of LH secretion in both female and male mice regardless of CRH status. These data demonstrate that CRH is not necessary to inhibit LH secretion following either restraint or food withdrawal and that other molecules are able to suppress LH secretion during the response to stress in the context of CRH deficiency. (Endocrinology 140: 1702(Endocrinology 140: -1708(Endocrinology 140: , 1999 T HE HYPOTHALAMIC-PITUITARY-GONADAL AXIS in humans and rodents is maintained by the activity of GnRH neurons, whose cells are distributed throughout the preoptic region including the medial preoptic area (mPOA) of the anterior hypothalamus (1). The nerve terminals of these neurons project to the median eminence, where the release of GnRH into the hypophysial portal circulation occurs. The pulsatile secretion and surge of LH depend on the activity of GnRH neurons (2). GnRH or LH secretion can be modulated by various inhibitory [endogenous opioids (3), cytokines (4), and inhibitory amino acids (5)] and stimulatory [catecholamines (6), neuropeptide Y (7), and excitatory amino acids (8)] modulators.CRH has been proposed to negatively regulate GnRH secretion. An imbalance of central CRH has been implicated in the suppression of reproductive function in humans under stressful conditions. Patients with major depression or anorexia nervosa show suppressed reproductive function (9) and also have a high concentration of CRH in the cerebroventricular system (10). In rodents, intracerebroventricular (icv) administration of CRH attenuates GnRH level in the hypophysial portal circulation of female rats (11). Central, but not iv, injection of CRH also inhibits LH secretion over 5 h in a dose-dependent manner in ovariectomized female rats (12). These studies suggest a central inhibitory effect of endogenous CRH on the reproductive system, possibly acting upon GnRH neurons. Furthermore, 5 h of restraint, which activates the hypothalamic-pituitary-adrenocortical (HPA) axis and CRH gene expression (13), completely inhibits the proestrus LH surge and ovulation in intact cycling rats (14). Other stressors (undernutrition, hypoglycemia, or electric foot-shock) also inhibit LH secretion and pulsatility (15-17) as well as GnRH gene expression in the mPOA (18), and these effects are reversed following administration of a CRH antagonist in gonadectomized ...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: T He Hypothalamic-pituitary-gonadal Axismentioning

confidence: 99%

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Normal Suppression of the Reproductive Axis Following Stress in Corticotropin-Releasing Hormone-Deficient Mice*

et al. 1999

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“…LH and cortisol were measured in duplicate at 15-or 45-min intervals, respectively. LH levels were measured by a recombinant homologous radioimmunoassay previously described [20]. Assay sensitivity (95% binding) was 0.06 ng/ml.…”

Section: Hormone Measurements and Data Analysismentioning

confidence: 99%

“…Hourly areas under the curve following experimental treatment were then calculated as a percentage of the 3-hour baseline and analyzed statistically by the KruskalWallis ranking test followed by the Tukey test. LH pulse analysis has been described previously [20]. Differences in LH pulse frequency, LH pulse amplitude and LH concentrations between morning baseline and treatment periods were evaluated by paired t test.…”

Section: Hormone Measurements and Data Analysismentioning

confidence: 99%

Inhibitory Effects of Endotoxin on LH Secretion in the Ovariectomized Monkey Are Prevented by Naloxone but Not by an Interleukin-1 Receptor Antagonist

Xiao¹,

Xia‐Zhang²,

Ferin³

1999

Neuroimmunomodulation

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Endotoxin (lipopolysaccharides, LPS), the pathogenic moiety of gram-negative bacteria, is a well-known trigger for the central release of cytokines. The objective of this study is to evaluate the effects of systemic endotoxin administration on LH and cortisol secretion in a non-human primate model and to investigate whether these endocrine effects are mediated by centrally released interleukin-1 (IL-1) using the receptor antagonist to IL-1 (IL-1ra). An additional objective is to investigate whether endogenous opioid peptides mediate these endocrine effects of LPS, using the opiate antagonist naloxone. The experiments were performed in long-term-ovariectomized rhesus monkeys. Blood samples for hormone determination were obtained at 15-min intervals for a period of 8 h, which included a 3-hour baseline period. Since the effective central dose of IL-1ra in the monkey was unknown, in the first experiment we tested the potency of several doses of this antagonist in preventing the effects of centrally administered IL-1α, a cytokine which is known to inhibit LH and stimulate cortisol release. Rhesus monkeys received a 30-min intracerebroventricular infusion of IL-1α (4.2 μg/30 min) alone or together with various doses of IL-1ra (30–180 μg/h i.c.v.). IL-1ra infusion was initiated 1 h before IL-1 and extended over the experimental period. As previously reported, IL-1α induced a significant inhibition of LH, to 36.5 ± 3.3% (mean ± SE) by 5 h as a percentage from the 3-hour baseline. This inhibitory effect was reversed by cotreatment with the 180 µg/h dose of IL-1ra (to 82.5 ± 3.8% by 5 h; NS vs. saline) but not with the lower doses. IL-1 stimulated cortisol release to 165.9 ± 7.7%, but this increase was prevented by IL-1ra (66.6 ± 8.9%; p < 0.05 vs. IL-1, NS vs. saline). In the second experiment, LPS (50 μg) was administered intravenously, alone or in combination with intracerebroventricular IL-1ra infusion. LPS induced a significant decrease in LH secretion (to 57.1 ± 5.2%). These effects were not reversed by intracerebroventricular administration of IL-1ra (52.5 ± 9.6%). Cortisol secretion increased in response to LPS, but this stimulatory effect was not affected by IL-1ra (178.3 ± 13.4 vs. 166.9 ± 5.7%). There were no effects of IL-1ra alone. In experiment 3, we investigated whether the opiate antagonist naloxone reverses the endocrine effects of endotoxin. Both LPS (50 μg) and naloxone (5-mg bolus + 5 mg/h) were infused intravenously. Naloxone was effective in preventing the inhibitory effect of LPS on LH (to 124.6 ± 22.1%, NS vs. saline) but not the increase in cortisol (to 166.7 ± 16.7%; p < 0.05 vs. saline, NS vs. LPS). Naloxone alone has no significant effect on LH or cortisol secretion. These data demonstrate that, in the ovariectomized monkey, a systemic inflammatory/immune- like stress challenge acutely inhibits tonic LH secretion while concomitantly stimulating cortisol release. Although endotoxin is known to affect central cytokine release, these endocrine effects do not require a mediatory role of central IL-...

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Neurobiology of Stress-Induced Reproductive Dysfunction in Female Macaques

2008

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It is now well accepted that stress can precipitate mental and physical illness. However, it is becoming clear that given the same stress, some individuals are very vulnerable and will succumb to illness while others are more resilient and cope effectively, rather than becoming ill. This difference between individuals is called stress sensitivity. Stress-sensitivity of an individual appears to be influenced by genetically inherited factors, early life (even prenatal) stress, and by the presence or absence of factors that provide protection from stress. In comparison to other stress-related diseases, the concept of sensitivity versus resilience to stress-induced reproductive dysfunction has received relatively little attention. The studies presented herein were undertaken to begin to identify stable characteristics and the neural underpinnings of individuals with sensitivity to stress-induced reproductive dysfunction. Female cynomolgus macaques with normal menstrual cycles either stop ovulating (Stress Sensitive) or to continue to ovulate (Stress Resilient) upon exposure to a combined metabolic and psychosocial stress. However, even in the absence of stress, the stress sensitive animals have lower secretion of the ovarian steroids, estrogen and progesterone, have higher heart rates, have lower serotonin function, have fewer serotonin neurons and lower expression of pivotal serotonin-related genes, have lower expression of 5HT2A and 2C genes in the hypothalamus, have higher gene expression of GAD67 and CRH in the hypothalamus and have reduced GnRH transport to the anterior pituitary. Altogether, the results suggest that the neurobiology of reproductive circuits in stress sensitive individuals is compromised. We speculate that with the application of stress, the dysfunction of these neural systems becomes exacerbated and reproductive function ceases.

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The Luteinizing Hormone but Not the Cortisol Response to Arginine Vasopressin Is Prevented by Naloxone and a Corticotropin-Releasing Hormone Antagonist in the Ovariectomized Rhesus Monkey

Cited by 15 publications

References 29 publications

Normal Suppression of the Reproductive Axis Following Stress in Corticotropin-Releasing Hormone-Deficient Mice*

Normal Suppression of the Reproductive Axis Following Stress in Corticotropin-Releasing Hormone-Deficient Mice*

Inhibitory Effects of Endotoxin on LH Secretion in the Ovariectomized Monkey Are Prevented by Naloxone but Not by an Interleukin-1 Receptor Antagonist

Neurobiology of Stress-Induced Reproductive Dysfunction in Female Macaques

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