Linna Xia-Zhang

Inhibitory effects of endotoxin on LH secretion in the ovariectomized monkey are prevented by naloxone but not by an interleukin-1 receptor antagonist.

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-1 in the primate. In contrast, endogenous opioid pathways appear to be involved in this process.

A 5‐Day Estradiol Therapy, in Amounts Reproducing Concentrations of the Early‐Mid Follicular Phase, Prevents the Activation of the Hypothalamo‐Pituitary‐Adrenal Axis by Interleukin‐1α in the Ovariectomized Rhesus Monkey

In a previous report, we have shown that intracerebroventricular (icv) administration of the cytokine interleukin‐1a (IL‐1α) in the ovariectomized (OVX) rhesus monkey results in the acute activation of the hypothalamo‐pituitary‐adrenal (HPA) axis and the inhibition of LH and FSH secretion. Here, we compare the cortisol response to IL‐1α administration in OVX monkeys and in OVX animals replaced with estradiol (E) to reproduce E concentrations typical of the early‐mid follicular phase. Cortisol, LH and FSH were measured after an icv infusion of physiological saline or IL‐1α (2.1 or 4.2 μg/30 min) in both groups. E‐containing capsules were implanted sc 5 days prior to the experiment. In OVX, E concentrations were <5 pg/ml. Cortisol concentrations decreased throughout the afternoon after saline infusion (to 49.7 ± 5.1% of baseline at 5 h; n = 7), but increased significantly after IL‐1α to 158.3 ± 13.8% (n = 7). In OVXE, cortisol also declined after saline (to 76.4 ± 16.2%; n = 5). There were 2 types of response to IL‐1α: in grp 1 (mean E 18.0 ± 0.7 pg/ml), the cortisol response was similar to that in OVX (160.8 ± 17.0%; n = 5), while in grp 2 (E: 30.7 ± 3.1 pg/ml), the cortisol response was absent (66.6 ± 7.2% of baseline at 5 h; NS vs saline in OVXE; n = 7). The cortisol response to IL‐1α was restored in 2 monkeys when E was increased to >100 pg/ml, confirming our previous observations. While saline infusion did not affect LH (102.3 ± 10.2% of baseline at 5 h) or FSH (102.5 ± 4.4%) secretion in OVX monkeys, there was a significant decrease in both hormones after IL‐1α (LH: 33.3±3.7%, FSH: 66.2 ± 6.5%; P<0.05 vs saline). This effect was lessened in OVXE animals: By 5 h, areas under the LH curve were 62.8 ± 10.9% of baseline in grp 1 and 85.3 ± 7.9% in grp 2 (NS vs saline), while those under the FSH curve were 84.0 ± 6.5% in grp 1 and 77.7 ± 4.3% in grp 2 (NS vs saline).

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

In the primate, arginine vasopressin (AVP) is known to activate the hypothalamo-pituitary-adrenal axis and to inhibit LH secretion. In the present study, we investigate the role of the endogenous opioid peptides and corticotropin-releasing hormone (CRH) in these processes. Adult ovariectomized rhesus monkeys bearing a chronic cannula in the lateral ventricle for intraventricular (i.c.v.) infusion were used. In experiment 1, the effects of 5-hour i.c.v. infusions of saline (n = 7), AVP (50 micrograms/h, n = 7), naloxone (2 mg bolus + 2 mg/h i.v., n = 4) and AVP plus naloxone (n = 4) on LH and cortisol secretion were investigated. As compared to saline and naloxone alone, LH pulse frequency was significantly decreased by AVP (p < 0.05) and by 5 h, the mean LH expressed as a percentage from the 3-hour baseline was also significantly reduced (saline 100.9 +/- 5.1%; naloxone 112.3 +/- 2.9%; AVP 63.3 +/- 8.2%). Coadministration of naloxone abolished the effects of AVP on LH (107.3 +/- 12.1% of baseline). AVP increased cortisol secretion (p < 0.05 vs. baseline), but naloxone did not prevent the increase. In experiment 2, the LH and cortisol responses to AVP were compared in the absence and presence of a CRH antagonist. The antagonist was infused intraventricularly at two doses: 60 and 180 micrograms/h. At both doses, the inhibitory effect of AVP on LH was significantly attenuated (at 4 h, 86.9 +/- 3.2% of baseline; NS vs. saline). However, the CRH antagonist did not block the AVP-induced increase in cortisol. The results confirm previous evidence in the primate of a role of vasopressin in inhibiting the hypothalamo-pituitary-gonadal axis and demonstrate a role of hypothalamic opioid peptides in this process. They also demonstrate that, although CRH is a prerequisite for AVPs action on the hypothalamo-pituitary-gonadal axis, AVP can stimulate the adrenal axis in the primate in the presence of decreased CRH activity.