Biomedical subjects

Ennian Xiao

Publications and source records attributed to Ennian Xiao.

9 recordsLinked to original sources

PubMed2004

Central infusion of agouti-related peptide suppresses pulsatile luteinizing hormone release in the ovariectomized rhesus monkey.

Agouti-related peptide (AGRP), an endogenous melanocortin receptor antagonist, is a powerful orexigenic peptide when infused centrally. AGRP and neuropeptide Y (NPY), another orexigenic peptide, are colocated within the same neurons in the arcuate nucleus. Both NPY and AGRP mRNA expression increases during food restriction, a condition that is known to suppress the GnRH pulse generator and reproductive function. Although NPY has been shown previously to suppress LH secretion in the ovariectomized monkey, data on AGRP are lacking. In this study, we examined the effect of AGRP infusion into the third ventricle on pulsatile LH release in five adult monkeys. The 8-h protocol included a 3-h intraventricular saline infusion to establish baseline pulsatile LH release, followed by a 5-h infusion of AGRP (83-132) [5 microg/h (n=1) or 10 microg/h (n=4)]. In separate experiments, each animal received an 8-h saline treatment as a control. Blood samples were collected every 15 min for LH measurements. Cortisol levels were measured every 45 min. AGRP infusion significantly decreased LH pulse frequency (from a baseline of 0.74 +/- 0.07 pulse/h to 0.36 +/- 0.12 during AGRP infusion; P <0.01) and mean LH concentrations (to 41.1 +/- 7.5% of baseline by h 5 of AGRP infusion; P < 0.001). LH pulse amplitude was not modified by AGRP treatment. AGRP infusion also significantly increased cortisol release, as previously reported. The data demonstrate that central administration of AGRP inhibits pulsatile LH release in the monkey and suggest that AGRP, like NPY, may mediate the effect of a negative energy balance on the reproductive system by suppressing the GnRH pulse generator.

Agouti-Related Protein↗

PubMed2004

Decrease in luteinizing hormone pulse frequency during a five-hour peripheral ghrelin infusion in the ovariectomized rhesus monkey.

Ghrelin, a nutrition-related peptide secreted by the stomach, is elevated during prolonged food deprivation. Because undernutrition is often associated with a suppressed reproductive axis, we have postulated that increasing peripheral ghrelin levels will decrease the activity of the GnRH pulse generator. Adult ovariectomized rhesus monkeys (n = 6) were subjected to a 5-h iv human ghrelin (100- to 150-microg bolus followed by 100-150 microg/h) or saline infusion, preceded by a 3-h saline infusion to establish baseline pulsatile LH release. Blood samples were collected at 15-min intervals throughout the experiment. Ghrelin infusion increased plasma ghrelin levels 2.9-fold of baseline. Ghrelin significantly decreased LH pulse frequency (from 0.89 +/- 0.07/h in baseline to 0.57 +/- 0.10/h during ghrelin infusion; P < 0.05, mean +/- sem), whereas LH pulse frequency remained unchanged during saline treatment. LH pulse amplitude was not affected. Ghrelin also significantly stimulated both cortisol and GH release, but had no effect on leptin. We conclude that ghrelin can inhibit GnRH pulse activity and may thereby mediate the suppression of the reproductive system observed in conditions of undernutrition, such as in anorexia nervosa. Ghrelin also activates the adrenal axis, but the relevance of this to the inhibition of GnRH pulse frequency remains to be established.

Agouti-Related Protein↗

PubMed2003

Leptin modulates inflammatory cytokine and neuroendocrine responses to endotoxin in the primate.

Leptin, which plays a crucial role in regulating energy balance, can also modulate the inflammatory response. Although leptin-deficient rodents are more sensitive to the toxic effects of bacterial endotoxin, it is unknown if leptin can modulate inflammatory cytokine or neuroendocrine responses to inflammation in a primate model. We have therefore studied the effects of leptin on plasma cytokine and hypothalamic-pituitary-adrenal responses to endotoxin (5 microg iv) in nine ovariectomized rhesus monkeys. Human leptin (50 microg/h) or saline was infused iv for 16 h before and 4 h after endotoxin injection; mean plasma leptin increased from 3.6 +/- 1.0 ng/ml to 18 +/- 1.7 ng/ml (P < 0.001). Leptin infusion had no effect on baseline plasma cytokine and hormone levels before endotoxin injection. As expected, endotoxin stimulated TNF-alpha, IL-6, IL-1 receptor antagonist (IL-1ra), ACTH, and cortisol in the saline-infused animals (P < 0.001). There was a significant attenuation of the IL-6 (P < 0.005) and cortisol (P < 0.001) responses (repeated measures ANOVA) to endotoxin in the leptin-infused animals. There was a significant reduction (by paired analysis) in the responses of the leptin compared with saline-treated animals: 47% for TNF-alpha, 48% for IL-6, 30% for IL1ra, 42% for ACTH, and 22% for cortisol (P < 0.05). We conclude that an increase in circulating leptin, within the physiological range of our monkey colony, can blunt the inflammatory cytokine and hypothalamic-pituitary-adrenal responses to an inflammatory challenge. These results, coupled with our recent finding that endotoxin stimulates leptin release in the monkey, demonstrate that leptin can be both released in response to inflammatory cytokines and act to attenuate the responses to these cytokines.

Animals↗

PubMed2003

Agouti-related protein stimulates the hypothalamic-pituitary-adrenal (HPA) axis and enhances the HPA response to interleukin-1 in the primate.

alpha-MSH antagonizes many of the immune and neuroendocrine effects induced by inflammatory cytokines. Studies have shown that alpha-MSH attenuates the stimulatory effect of IL-1 on the hypothalamic-pituitary-adrenal (HPA) axis and plays a physiological role in limiting the HPA response to IL-1. Recently an alpha-MSH antagonist, agouti-related protein (AGRP), has been identified in the hypothalamus, which stimulates food intake by antagonizing the effects of alpha-MSH at specific melanocortin receptors. It is unknown whether AGRP can also modulate neuroendocrine responses to inflammatory cytokines. We have therefore examined the effects of AGRP on the HPA axis and on prolactin (PRL) at baseline and in response to stimulation by IL-1 beta in nine ovariectomized rhesus monkeys. In the first study, the effects of intracerebroventricular (i.c.v) infusion of 20 microg (n = 6) and 50 micro g (n = 4) of human AGRP (83-132)-NH(2) were compared with icv saline infusion. There was a significant stimulatory effect of 20 microg AGRP on cortisol release over time (P < 0.001). The area under the hormone response curve (AUC) for cortisol increased by 29% after 20 microg AGRP vs. saline; the AUC for ACTH increased by 166% (P = 0.028); the AUC for PRL increased by 108% (P = 0.046). There was a significant stimulatory effect of 50 microg AGRP on ACTH (P < 0.001), cortisol (P < 0.001), and PRL (P < 0.001) release over time. The AUC for ACTH after 50 microg AGRP increased by 98%; the AUC for cortisol increased by 37%; the AUC for PRL increased by 161%. The effects of AGRP on ACTH, cortisol, and PRL release were prevented by alpha-MSH infusion. In the second study, animals received icv either 50 ng of human IL-1 beta or 20 microg of AGRP followed by 50 ng IL-1 beta. AGRP significantly enhanced the ACTH (P < 0.05) response to IL-1 beta. The peak ACTH response to IL-1 beta alone was 124 +/- 55 pg/ml vs. 430 +/- 198 pg/ml after IL-1 beta plus AGRP; the peak cortisol response was 70 +/- 8.2 microg/dl vs. 77 +/- 6.2 microg/dl, but this was not significantly different. In conclusion, AGRP stimulated ACTH, cortisol, and PRL release in the monkey and enhanced the ACTH response to IL-1 beta. These studies suggest that, in addition to its known orexigenic effects, AGRP may play a role in neuroendocrine regulation and specifically that AGRP may interact with alpha-MSH to modulate neuroendocrine responses to inflammation.

Adrenocorticotropic Hormone↗

PubMed2003

Endotoxin stimulates leptin in the human and nonhuman primate.

Leptin, which plays a key role in regulating energy homeostasis, may also modulate the inflammatory response. An inflammatory challenge with endotoxin has been shown to stimulate leptin release in the rodent. This finding has not been reproduced in humans or in nonhuman primates, although leptin levels have been reported to increase in septic patients. We have therefore examined the effects of endotoxin injection on plasma leptin levels in nine ovariectomized monkeys and four postmenopausal women. In an initial study in five monkeys, mean leptin levels did not increase during the first 5 h after endotoxin treatment, but did increase significantly from 6.4 +/- 2.1 ng/ml at baseline to 12.3 +/- 4.4 ng/ml at 24 h (P = 0.043). In a second study, a significant increase in leptin over time was noted after endotoxin treatment (P < 0.001); leptin release during the 16- to 24-h period after endotoxin injection was 48% higher than during the control period (P = 0.043). A similar stimulatory effect of endotoxin on leptin was observed when monkeys received estradiol replacement. In a third study, repeated injections of endotoxin over a 3-d period stimulated IL-6, ACTH, cortisol, and leptin release (P < 0.001). Leptin increased during the first day of treatment in all animals, but only monkeys with baseline plasma leptin levels greater than 10 ng/ml exhibited a sustained increase in leptin throughout the 3-d period. There was a significant correlation (r = 0.81; P = 0.008) between the mean baseline leptin level and the percent increase in leptin over baseline on the last day of treatment. In the human subjects, plasma leptin concentrations did not change significantly during the 7-h period after endotoxin injection. However, leptin increased in all four women from a mean baseline of 8.34 +/- 3.1 to 13.1 +/- 4.3 ng/ml 24 h after endotoxin (P = 0.038). In summary, endotoxin stimulates the release of leptin into peripheral blood in the human and nonhuman primate, but the time course is different from that reported in the rodent. These results are consistent with previous reports of increased blood leptin levels in patients with sepsis. The significance of these findings and the potential role of leptin in modulating the response to inflammation in the human require further study.

Adrenocorticotropic Hormone↗

PubMed2003

Endocrine and metabolic responses to long-term monotherapy with the antiepileptic drug valproate in the normally cycling rhesus monkey.

An association between epilepsy and reproductive disturbances with an apparent increase in a polycystic ovarian syndrome (PCOS) has been reported. Whether this association can be attributed to epilepsy itself or is related to antiepileptic drug therapy, in particular valproate (VPA), remains controversial. We studied effects of a long-term VPA treatment on cycling monkeys, postulating that, if VPA monotherapy were to promote abnormal endocrine and metabolic parameters that are characteristic of PCOS, changes in cyclicity would be readily demonstrated. After a 2-month control, a 12- to 15-month VPA monotherapy was initiated in 7 regularly cycling rhesus monkeys. Overall mean levels of VPA were 88.7 +/- 4.0 (SE) microg/ml. Mean body weight increased progressively during VPA treatment from 8.5 +/- 0.5 kg before treatment to 9.6 +/- 0.7 kg in the last week of treatment (P < 0.05). Monkeys continued to have regular ovulatory menstrual cycles throughout VPA monotherapy. Length of the cycles was 28 +/- 0.58 d in control and 28.4 +/- 1.18 d in the last 3 months of VPA treatment. Follicular and luteal lengths and peak preovulatory estradiol and integrated luteal progesterone levels did not differ between control and treatment. Ovaries from VPA-treated monkeys showed histological evidence of ovulation, and none had characteristic features of PCOS. Endocrine PCOS markers, such as increased early follicular LH/FSH ratio and androgen levels were not different in control and VPA treatment cycles. LH and 17-hydroxyprogesterone responses to GnRH agonist challenges and the insulin response to glucose tolerance tests were similar in control and VPA groups. Lipid profiles were not affected by VPA treatment. The data indicate that a 12- to 15-month therapeutic exposure to VPA does not induce cyclic hormonal or morphological ovarian abnormalities or characteristics of the PCOS when administered to nonepileptic normally cycling nonhuman primates.

Animals↗

PubMed2002

Pharmacokinetics and pharmacodynamics of single-chain recombinant human follicle-stimulating hormone containing the human chorionic gonadotropin carboxyterminal peptide in the rhesus monkey.

OBJECTIVE: To compare the pharmacokinetics of a long-acting FSH analog containing the hCG-beta carboxyterminal peptide (recombinant hFSH-CTP) with native recombinant hFSH and describe the pharmacodynamics of recombinant hFSH-CTP after SC injection in female rhesus monkeys. DESIGN: Rhesus monkey study. SETTING: Academic research environment. ANIMAL(S): Ten female rhesus monkeys. INTERVENTION(S): Recombinant hFSH and recombinant hFSH-CTP were administered via a single SC or IV dose to rhesus monkeys, and serial phlebotomy was performed (n = 2 and n = 4 for SC recombinant hFSH and recombinant hFSH-CTP, respectively; for IV dosing, n = 1 in each group). An additional two monkeys were pretreated with SC ganirelix and received SC recombinant hFSH-CTP after confirmation of pituitary suppression. MAIN OUTCOME MEASURE(S): Plasma disappearance rate of recombinant hFSH and recombinant hFSH-CTP and serum estradiol levels. RESULT(S): The elimination half-life of recombinant hFSH-CTP was twofold and fourfold longer than that for recombinant hFSH after SC and IV dosing, respectively. The absorption half-life was approximately threefold longer for recombinant hFSH-CTP than for recombinant hFSH after SC administration. Recombinant hFSH-CTP stimulates estradiol secretion for 5-7 days after an isolated SC dose. CONCLUSION(S): Addition of the hCG-beta carboxyterminal peptide to hFSH-beta results in an FSH analog with longer absorption and elimination half-lives compared with native hormone. This analog is capable of prolonged ovarian stimulation in rhesus monkeys after an isolated SC injection.

Absorption↗

PubMed2002

Administration of antivascular endothelial growth factor receptor 2 antibody in the early follicular phase delays follicular selection and development in the rhesus monkey.

Angiogenic factors, including vascular endothelial growth factor (VEGF), are expressed during follicular development. Our objective was to investigate the role of VEGF in the early follicular phase to test whether early cyclic follicle development and selection are angiogenesis-dependent processes. After documentation of two normal ovulatory cycles, female rhesus monkeys (n = 6) received five iv injections of anti-VEGF receptor 2 (anti-VEGF-R2) antibody at 3-d intervals starting on cycle d 2-4. To evaluate nonspecific effects of the treatment antibody, all monkeys also received iv injections of nonspecific humanized mouse IgG, using an identical regimen. Daily measurements of FSH, LH, estradiol, and progesterone were obtained, throughout the entire period, to monitor cyclicity. Administration of anti-VEGF-R2 antibody resulted in a significant decline in mean inhibin B levels [control, 181.0 +/- 29.6 (mean +/- SE); treatment d 2, 44.5 +/- 13.1 pg/ml; P < 0.05]. No decrease was observed after IgG treatment. Anti-VEGF-R2 antibody treatment also delayed the first significant increase in estradiol and lengthened the follicular phase from 10-12 d in the preceding two control cycles to 20-42 d in treatment cycles. FSH and LH concentrations increased significantly, within 24 h after anti-VEGF-R2 antibody treatment, to levels 2-2.5 times over controls. Our results demonstrate that anti-VEGF-R2 antibody therapy in the early follicular phase interferes with the normal development of the cohort of recruited antral follicles. The data clearly indicate that the recruitment-selection process of follicles in the early follicular phase in the nonhuman primate is controlled by VEGF, through the VEGF-R2.

Animals↗

PubMed2002

Inadequate luteal function is the initial clinical cyclic defect in a 12-day stress model that includes a psychogenic component in the Rhesus monkey.

As part of our goal to develop nonhuman primate models to prospectively study how different types of stress may affect the menstrual cycle, we have investigated whether a short-term stress challenge that includes a significant psychogenic component can induce cyclic dysfunction. The study was performed in rhesus monkeys. The stress challenge had several components that included the psychological response to both a tethering system and to a simultaneous move to an unfamiliar environment and the response to the short surgical procedures required to install and disconnect the tethering system. The stress challenge lasted for 12 d and was initiated in the follicular (n = 5) or luteal (n = 6) phase of the menstrual cycle. At the end of the stress period, the tethering system was removed, and the animal was returned to its regular housing. To monitor cyclicity, FSH, LH, E2, and progesterone were measured daily throughout the two preceding control cycles, the experimental cycle, and the two poststress cycles, whereas the adrenal endocrine axis response was monitored by measuring cortisol. Animals remained ovulatory after the short-term stress; however, integrated progesterone secretion in the luteal phase (from the day of LH surge +1 to the day of menstruation -1) of the stress cycle was significantly decreased by 51.6% when the stress was initiated in the follicular phase and by 30.9% when it started in the luteal phase. Lower integrated LH levels (luteal d 5-13) accompanied the decreased progesterone. Cyclic parameters were still abnormal in the first poststress cycle, such as a prolonged follicular phase after a stress in the preceding follicular phase or inadequate luteal function after a stress in the preceding luteal phase. Within 4 h of the stress, there was a rapid 3-fold increase in cortisol levels over controls. Levels decreased progressively thereafter but remained significantly higher than controls during the entire short-term stress period. They were still significantly higher in the first 2 wk after stress. Overall, the data suggest that secretory inadequacy of the corpus luteum represents a first clinical stage in the damage that stress can inflict on the normal menstrual cycle. Of interest is the observation that this limited 12-d stress, which includes a significant psychogenic component, continues to produce detrimental effects on the menstrual cycle past the period during which it is exerted. Significant decreases in integrated luteal LH values in the poststress cycle suggest that these effects may be related to continuing disturbances in the neuroendocrine component of the reproductive axis.

Animals↗