Mechanisms and Biological Significance of Pulsatile Hormone Secretion (Novartis Foundation Symposia)

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Integrative Physiological and Behavioral Science 36, 75— Overmier, J. Anxiety and helplessness in the face of stress predisposes, precipitates, and sustains gastric ulceration. Behavioral Brain Research , — Sapolsky, R.

New York: Henry Holt. Szabo, S. Dopamine disorder in duodenal ulceration. Lancet 2 , — Weiner, H. From simplicity to complexity — : the case of peptic ulceration. I: Human studies. Psychosomatic Medicine 53, — II: Animal studies. All rights reserved. A hypothalamic peptide that acts at the kidney to moderate water excretion hence, also termed the antidiuretic hormone and acts synergistically with CRH to stimulate ACTH release from the anterior pituitary gland.

A brain peptide that mediates the neural control of ACTH release from the anterior pituitary gland and that has also been implicated in central neural actions related to anxiety and depression. An anterior pituitary gonadotropin responsible for stimulating the growth of ovarian follicles and the secretion of estrogen in the female and the development of sperm in the male. A receptor for glucocorticoids, of which cortisol is the main type in the human. A peptide that is secreted by the hypothalamus and that mediates the neural control of pituitary gonadotropin secretion.

One of the two main neuroendocrine stress response systems. A kinase with two phosphorylation sites, only one of which appears to be active. An anterior pituitary peptide that induces ovulation and the secretion of progesterone in the female and the secretion of testosterone in the male. A receptor for mineralocorticoid steroid hormones, of which aldosterone is the prototype. A molecule that transcribes the genetic code from DNA. A transcription factor implicated in cell differentiation and tumor formation.

Frequency encoding of intercellular signals is a wellaccepted mode of communication between neurons. More than this, however, it is actually a common mechanism of communication across a broad range of both inter- and even intracellular moieties. Even an organism as primitive as the slime mold Dictyostelium discoideum aggregates only in response to external pulses of cAMP delivered with a periodicity Ultradian Rhythms of 5 min and not to constant stimuli or frequencies greater than every 2 min. Within mammalian systems, frequency encoding is mediated by circulating hormones as major signaling molecules, and many of these signal through the mechanisms of ultradian rhythmicity.

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Similarly, sex differences in episodic release of growth hormone GH elicit significant differences in gene expression. High-amplitude GH bursts occur at intervals of 3—4 h in male rats, whereas more frequent low-amplitude pulses occur in females; these sexually diergic patterns are responsible for marked differences in the expression of liver enzymes and JAK-dependent STAT5 responses. Recent advances in our understanding of glucocorticoid receptor function suggest potential mechanisms for similar regulation of gene expression in cells exposed to pulsatile changes in glucocorticoid concentration.

At the level of the glucocorticoid receptor itself, Dekelbab et al described in a rapid downregulation of GR associated with prolonged exposure to glucocorticoids that can be avoided if corticosterone is administered intermittently. This suggests a more effective induction of GR target genes from intermittent pulses of glucocorticoids. Furthermore, it is now recognized that the binding of the GR to the promoter regions of target genes is not the static process that was previously accepted. The availability of GR tagged with fluorescent tags and the advent of chromatin immunoprecipitation ChIP techniques have revealed that the interaction among the GR, DNA, and other proteins involved in transcription is a highly dynamic process.

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Indeed the effective concentration of nuclear receptors on some promoters appears to vary after hormone stimulation in a wavelike or cycling fashion. The HPA axis shows classic hormone rhythmicity. In the basal state, normal HPA activity is characterized both by a circadian rhythm of cortisol and corticosterone and also an ultradian rhythm that results in a pulsatile release of ACTH and glucocorticoids throughout the h cycle. This ultradian rhythmicity is clearly a fundamental feature of HPA activity and ex vivo evidence from the monkey suggests that the pulse generator is located within the hypothalamus.

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This pulse generator results in the phasic release of CRH and AVP from the parvocellular neurons of the hypothalamic paraventricular nucleus into the portal blood, from which it has access to pituitary corticotrophs that secrete ACTH, which in turn regulates the production and release of glucocorticoids from the fasciculata cells of the adrenal cortex. Details of studies on the intrinsic dynamics of HPA function in free-running conscious animals reveals a complex ultradian rhythm of corticosterone secretion of approximately 1 h in duration.

This profile shows not only marked sexual diergism, but also shows marked plasticity in different physiological states such as lactation and aging, the presence of or susceptibility to disease, and early life programming.


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Similar ultradian rhythmicity is found in humans, resulting in complex patterns of cortisol secretion that have made the response to stress testing difficult to interpret. The rapidly changing concentrations of glucocorticoids have major potential implications with respect to the pharmokinetics of receptor occupancy and signal transduction because, over relatively short periods of time, there are widely changing concentrations of ligand available for both MR and GR binding.

Although there is little data on this, it appears likely that this is of a special relevance for GR occupancy because the high affinity of the MR suggests that short-term changes in ligand concentration have only relatively small effects on MR signal transduction. Pulsatility provides an added dimension to the regulation of hormone responsive pathways.

Not only can it provide an additional mode of signaling within the same amount of total hormone secreted, but it could also potentially have differential effects on different tissues within the same organism. This could be picked up both by different patterns of expression of the hormone receptors e. Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone. Science , — Darmon, M. Chemotactic signals induce cell differentiation in Dictostelium discoideum.

Dekelbab, B. Continuous versus intermittent administration of glucocorticoids: ligand-dependent down-regulation of glucocorticoid receptors revisited.

American Endocrine Society meeting, abstract P2— Folenius, M. Ultradian plasma corticotropin and cortisol rhythms: time-series analyses. Journal of Investigative Endocrinology 10 3 , — Goldbeter, A. Send us a comment.

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