Regulation of Hypothalamic Gonadotropin-Releasing Hormone Secretion in Experimental Uremia: In vitro Studies

Wibullaksanakul, Sunee; Handelsman, David J.

doi:10.1159/000125913

Cited by 20 publications

(5 citation statements)

References 26 publications

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“…Despite conserved GnRH burst frequency, total GnRH secretion rate was reduced by 35%. This finding is an in vivo confirmation of the recently reported 40% decrease in GnRH produc tion in superfused hypothalamic explants from uremic rats [48], The reduced secretion rate was due to a decrease in GnRH secretory burst mass, which in turn reflected diminished burst amplitudes. However, the ratio between the estimated burst masses of GnRH and LH was not dif ferent in uremic and control animals.…”

Section: Coincidence a Nalysissupporting

confidence: 89%

In vivo Alterations in the Gonadotropin-Releasing Hormone Pulse Generator and the Secretion and Clearance of Luteinizing Hormone in the Uremic Castrate Rat

et al. 1994

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To investigate the mechanisms subserving the reported alterations in the pulsatile release of LH in uremia, we simultaneously studied endogenous accumulation of GnRH in the pituitary gland and the secretion and clearance of LH in vivo in experimentally uremic, orchidectomized rats. The temporal pattern of GnRH secretion was assessed by intrapituitary microdialysis, the dynamics of plasma LH by continuous exchange transfusion. Studies were performed in rats rendered uremic by subtotal nephrectomy (n = 8) and control rats which were either fed ad libitum (n = 8) or pair-fed with the uremic animals (n = 8). Blood samples were obtained at 5-min and microdialysate samples at 10-min intervals over a period of 270 min. The pulsatile secretory characteristics of GnRH and LH and the half-life of plasma LH were estimated by multiple-parameter deconvolution analysis. The temporal relationship between the hormone concentrations and between the secretory events of GnRH and LH was assessed by cross-correlation analysis and hypergeometric coincidence analysis. We observed that: (1) the estimated half-life of plasma LH was prolonged in uremic (59 ± 10 min) rats compared to ad libitum-fed (17 ± 3 min, p = 0.014) and pair-fed controls (19 ± 3 min, p = 0.025); (2) the LH production rate was decreased in uremic animals (18 ± 5 ng/ml·270 min) compared to ad libitum-fed (37 ± 4 ng/ml-270 min, p = 0.002) and pair-fed controls (48 ± 9 ng/ml·270 min, p = 0.0006); (3) the reduction of LH secretion rate in the uremic animals was accounted for by a decrease in detectable LH pulse frequency (2.1 ± 0.2 peaks/h) compared to ad libitum-fed (3.1 ± 0.1 peaks/h, p = 0.01) and pair-fed controls (2.8 ± 0.2 peaks/h, p = 0.06) and a diminished mass of hormone released per burst (uremic 1.8 ± 0.2 ng/ml, ad libitum-fed 2.6 ± 0.3 ng/ml, p = 0.05, pair-fed 3.8 ± 0.8 ng/ml, p = 0.025); (4) the secretion rate of GnRH was reduced to a similar degree in uremic rats (180 ± 15 pg/tube -270 min, p = 0.04) and pair-fed controls (170 ± 26 pg/tube-270 min, p = 0.04) compared to ad libitum-fed controls (270 ± 36 pg/ tube-270 min). In contrast to the reduced number of detectable LH secretory events, the frequency of GnRH secretory peaks in uremic rats was not different from ad libitum-fed and pair-fed controls. The reduced GnRH secretion rate in uremic and pairfed animals was entirely attributable to a decrease mass of GnRH released per burst (uremic 18+ 1.5, p = 0.06; pair-fed 17 ± 2.2, p = 0.046; ad libitum-fed 27 + 3.6 pg/tube); (5) the number of coincident GnRH and LH secretory events exceeded the rate expected by chance alone (p < 10-⁵) in all three groups of animals. Cross-correlation analysis showed the highest concordance between GnRH and LH for LH concentrations lagging GnRH by 0-5 min. Eighty-two percent of the GnRH impulses observed in the control groups, but only 62% in the uremic group coincided within + 5 min with a GnRH impulse. In conclusion, our findings indicate that reduced metabolic clearance masks pituitary hyposecretion of LH in uremi...

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Section: Coincidence a Nalysissupporting

confidence: 89%

In vivo Alterations in the Gonadotropin-Releasing Hormone Pulse Generator and the Secretion and Clearance of Luteinizing Hormone in the Uremic Castrate Rat

et al. 1994

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“…The pathophysiology of hypogonadism in chronic illness is multifactorial; defects exist at all levels of the hypothalamic-pituitarytesticular axis [32][33][34][35][36][37]. Malnutrition, mediators and products of the systemic inflammatory response, drugs such as ketoconazole, and metabolic abnormalities produced by the systemic illness all contribute to a decline in testosterone production.…”

Section: High Prevalence Of Low Testosterone Concentrations In Hiv-inmentioning

confidence: 99%

Effects of Testosterone Administration on Fat Distribution, Insulin Sensitivity, and Atherosclerosis Progression

Bhasin

2003

CLIN INFECT DIS

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In spite of the widespread belief that testosterone supplementation increases the risk of atherosclerotic heart disease, evidence to support this premise is lacking. Although supraphysiological doses of testosterone, such as those used by athletes and recreational body builders, decrease plasma high-density lipoprotein (HDL) cholesterol concentrations, replacement doses of testosterone have had only a modest or no effect on plasma HDL in placebo-controlled trials. In epidemiological studies, serum total and free testosterone concentrations have been inversely correlated with intra-abdominal fat mass, risk of coronary artery disease, and type 2 diabetes mellitus. Testosterone administration to middle-aged men is associated with decreased visceral fat and glucose concentrations and increased insulin sensitivity. Testosterone infusion increases coronary blood flow. Similarly, testosterone replacement retards atherogenesis in experimental models of atherosclerosis. However, the long-term risks and benefits of testosterone administration in human immunodeficiency virus-infected men with fat redistribution syndrome have not been studied in randomized clinical trials.

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“…Irrespective of the mechanism(s) underlying the elevated local GABA and EAA tones, these must be assumed to affect the balance of stimulatory and inhibitory afferents that regulate GnRH neuron activity. In view of the reduced net hypothalamic GnRH release in experimental renal failure (8,9), our findings suggest that the increased inhibitory GABA tone outweighs the concomitant EAA elevation. Of course, this conclusion is still speculative because the design of our studies did not permit direct investigation of the effects of changes in hypothalamic neurotransmitter tone on GnRH release into the pituitary.…”

Section: Discussionmentioning

confidence: 73%

“…We and others demonstrated previously that the rate of luteinizing hormone release from the pituitary is diminished in human and experimental uremia (5)(6)(7)(8). Moreover, the rate of hypothalamic GnRH release is reduced markedly in chronically uremic rats (8,9). This finding prompted us to evaluate further the neurotransmitter milieu to which the neurons of the GnRH pulse generator are exposed.…”

mentioning

confidence: 90%

Experimental Uremia Affects Hypothalamic Amino Acid Neurotransmitter Milieu

Schaefer

Vogel

Kerkhoff

et al. 2001

Journal of the American Society of Nephrology

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Abstract. Chronic renal failure is associated with delayed puberty and hypogonadism. To investigate the mechanisms subserving the reported reduced pulsatile release of gonadotropin-releasing hormone (GnRH) in chronic renal failure, this study examined the amino acid neurotransmitter milieu in the medial preoptic area (MPOA), the hypothalamic region where the GnRH-secreting neurons reside, in 5/6-nephrectomized male rats and in ad libitum-fed or pair-fed controls. All rats were castrated and received either a testosterone or a vehicle implant to evaluate additional effects of the prevailing sex steroid milieu. Local excitatory (essential amino acids: aspartate, glutamate) and inhibitory (γ-aminobutyric acid [GABA], taurine) amino acid transmitter outflow in the MPOA was measured by microdialysis via stereotactically implanted cannulae in the awake, freely moving rats. In addition to basal extracellular concentrations, the neurosecretory capacity was assessed by the addition of 100 mM KCl to the dialysis fluid. The mechanisms of neurosecretion were evaluated further by inhibition of vesicular release with the use of Ca2+-free, Mg2+-enriched dialysis fluid and by local perfusion with inhibitors of voltage-dependent synaptic release (1 μM tetrodotoxin) and of GABA reuptake (0.5 mM nipecotic acid). In the uremic rats, basal outflow of GABA, glutamate and aspartate, and K+-stimulated aspartate outflow were increased. K+-stimulated GABA and glutamate release was less sensitive to Ca2+ depletion in the uremic than in the control rats. The elevated basal GABA and essential amino acid outflow in the uremic rats was due to a voltage- and Ca2+-independent mechanism. GABA reuptake was inhibited proportionately by nipecotic acid in uremic and pair-fed control rats. Testosterone supplementation had no independent effects on neurotransmitter outflow. In summary, the amino acid neurotransmitter milieu is altered in the MPOA of uremic rats by a nonsynaptic, nonvesicular mechanism. These abnormalities may contribute to the impaired function of the GnRH pulse generator.

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Regulation of Hypothalamic Gonadotropin-Releasing Hormone Secretion in Experimental Uremia: In vitro Studies

Cited by 20 publications

References 26 publications

In vivo Alterations in the Gonadotropin-Releasing Hormone Pulse Generator and the Secretion and Clearance of Luteinizing Hormone in the Uremic Castrate Rat

In vivo Alterations in the Gonadotropin-Releasing Hormone Pulse Generator and the Secretion and Clearance of Luteinizing Hormone in the Uremic Castrate Rat

Effects of Testosterone Administration on Fat Distribution, Insulin Sensitivity, and Atherosclerosis Progression

Experimental Uremia Affects Hypothalamic Amino Acid Neurotransmitter Milieu

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