Thyroid hormone modulation of TRH precursor levels in rat hypothalamus, pituitary, thyroid and blood

Simard, Marie; Ae, Pekary; Vp, Smith; Jm, Hershman

doi:10.1016/0196-9781(89)90091-0

Cited by 21 publications

(13 citation statements)

References 36 publications

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“…This observation is consistent with other studies which have found high concentrations of these peptides in rat hypothalamus [7,16,17], spinal cord [18], pancreas [ 19], prostate [8,11], anterior and posterior pituitary [17], semen [20,21] and frog skin [6], The levels of TRH-Gly-IR in CSF from MS and ALZ patients were significantly elevated compared to control CSF samples, which is consistent with earlier reports of elevation of TRH-1R in CSF from these patients [I], The lack of correlation of the TRH-and TRH-Gly-IR levels in CSF may have been due, in part, to the inadequate sensitivity of our TRH RIA in relation to the very low TRH-1R levels of CSF.…”

Section: Discussionsupporting

confidence: 82%

“…The 100-and 300-fold greater levels of TRH-Gly-IR com pared to the TRH-IR levels in human CSF is similar to the cor responding ratio in extrahypothalamic tissue extracts [8,9] but this ratio is essentially reversed in extracts of brain tissue [17,22]. Possible explanations for the unexpectedly high values of TRH-Gly-IR in CSF include (I) extra-CNS tissues secrete TRH-containing vesicles with a high proportion of TRH-Gly-IR into the CSF, and (2) the TRH-Gly-binding substance of CSF protects TRH-Gly from enzymatic degradation while TRH re mains unprotected and subject to rapid destruction.…”

Section: Discussionmentioning

confidence: 57%

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High Levels of Thyrotropin-Releasing Hormone Precursor Peptide Immunoreactivity and Binding Substance Occur in Human Cerebrospinal Fluid

Pekary¹,

Gwirtsman²,

Tourtellotte³

et al. 1991

Neuroendocrinology

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A thyrotropin-releasing hormone (TRH) precursor peptide, pGlu-His-Pro-Gly (TRH-Gly) and related peptides were measured in human cerebrospinal fluid (CSF) with a TRH-Gly radioimmunoassay and the levels of immunoreactivity (IR) were found to be 136- to 352-fold higher than the corresponding levels of TRH-IR. TRH-IR levels in CSF are elevated during the active phase of multiple sclerosis (MS). We have used this TRH-Gly RIA to determine whether this TRH precursor peptide is also elevated in CSF from MS and Alzheimer’s (ALZ) disease patients in comparison with the corresponding levels in non-central nervous system disease (control) patients. A highly significant increase in TRH-Gly-IR was observed in MS and ALZ CSF samples compared to control CSF. Cation exchange and exclusion chromatography of extracts of mixtures of CSF and synthetic TRH-Gly revealed two peaks of TRH-Gly-IR. One cochromatographed with synthetic TRH-Gly and the other was attributable to the formation of a complex between TRH-Gly and a binding substance originating in CSF. Corresponding studies with extracts of mixtures of CSF and synthetic TRH revealed no evidence for TRH binding with any component of CSF. Reverse-phase high-pressure liquid chromatography of pooled extracts of normal CSF revealed that about a third of the total TRH-Gly-IR coeluted with synthetic TRH-Gly. The half-time for in vitro metabolism of synthetic TRH-Gly in fresh CSF was 5 times longer than for synthetic TRH at 37 °C. This greater stability of the TRH-Gly-CSF binding substance complex may explain the higher levels of TRH-Gly-IR in CSF compared to TRH despite the much lower levels of TRH-Gly-IR in brain tissues compared to TRH-IR.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 57%

High Levels of Thyrotropin-Releasing Hormone Precursor Peptide Immunoreactivity and Binding Substance Occur in Human Cerebrospinal Fluid

Pekary¹,

Gwirtsman²,

Tourtellotte³

et al. 1991

Neuroendocrinology

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“…In only one other study has TRH content in the pituitary during altered thyroid status been investigated. Simard et al [25] report no changes in TRH content of the PP during altered thyroid status. In their study, however, T4 treatment for the induction of hyper thyroidism did not result in increased levels of T4 and T3, and TRH-IR in the PP was not further characterized by chromatography.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Thyrotropin-Releasing Hormone in the Posterior Pituitary

Rondeel

Klootwijk²,

Linkels³

et al. 1995

Neuroendocrinology

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Although the presence of thyrotropin-releasing hormone (TRH) in the posterior pituitary (PP) was reported more than one decade ago, knowledge on its origin, regulation and functional significance is lacking. In the present study we investigated the regulation of TRH in the rat PP. Analysis by specific RIA, anion and cation exchange chromatography and reverse-phase HPLC showed that all TRH immunoreactivity in the PP is accounted for by authentic TRH. Induction of hyperthyroidism with thyroxine increased levels of TRH in the PP by 20%, whereas in methimazole-treated, hypothyroid rats the content decreased by 25% versus untreated, euthyroid controls. Food deprivation for 3 days increased levels by 35% and refeeding completely normalized TRH content again. Also 14–17 days after castration, TRH in the PP was increased by 25% while testosterone substitution prevented this increase. Castration did not affect proTRH mRNA levels in the hypothalamus. One week after adrenalectomy or daily subcutaneous dexamethasone injections, TRH content in the PP was not affected. Treatment with disulfiram, an inhibitor of the peptidylglycine α-amidating monooxygenase (PAM), reduced levels of TRH in the PP by 20%. ProTRH and PAM mRNA levels were not affected in the hypothalamus by this treatment. Since TRH in the PP has been suggested to play a role in prolactin (PRL) release, we determined the content of TRH in the PP during a 6-hour suckling stimulus that increased PRL levels in peripheral blood 30-fold. Whereas TRH in the median eminence increased by 35%, 6 h after the initiation of suckling, TRH levels in the PP remained constant. In conclusion, (1) authentic TRH accounts for all TRH immunoreactivity in the PP, (2) TRH content in the PP is increased in conditions in which hypothalamic TRH release is reportedly decreased (hyperthyroidism, starvation, castration) and decreased when TRH release is increased (hypothyroidism) – its levels may thus be used as a parameter of TRH content in hypothalamic hypophysiotropic neurons; (3) the changes in TRH levels in the PP in conditions that alter thyroid-stimulating hormone (TSH) levels in peripheral plasma suggest a role in TSH secretion, and (4) TRH in the PP does not seem to be important for the suckling-induced PRL release.

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“…These levels are increased significantly in CSF from patients with multiple sclerosis (MS) or Alzheimer's disease (ALZ) relative to CSF from patients with noncentral nervous system (non-CNS) disorders [1|. High levels of TRH-Gly-IR have also been measured in rat tissues and whole blood (2,3]. These levels are positively correlated with the serum thyrotropin (TSH) and tissue and whole blood TRH concentrations and are negatively correlated with serum thyroid hormone values [3].…”

mentioning

confidence: 99%

“…High levels of TRH-Gly-IR have also been measured in rat tissues and whole blood (2,3]. These levels are positively correlated with the serum thyrotropin (TSH) and tissue and whole blood TRH concentrations and are negatively correlated with serum thyroid hormone values [3]. Received: February 6, 1990 Accepted after revision: June 7, 1990 We have hypothesized that TRH-Gly is cosecreted with TRH from secretory vesicles, primarily in extrahypothalamic brain and spinal cord, and in non-CNS tissues such as the pancreas, gut and reproductive system [3].…”

mentioning

confidence: 99%

Release of Thyrotropin and Prolactin by a Thyrotropin-Releasing Hormone <i>(TRH) </i>Precursor, TRH-Gly: Conversion to TRH Is Sufficient for in vivo Effects

et al. 1990

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The mechanism by which TRH-Gly (pGlu-His-Pro-Gly), a biosynthetic precursor of thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH₂), stimulates pituitary thyrotropin (TSH) and prolactin release has been studied in urethane-anesthetized 2-month-old (250 g) male Sprague-Dawley rats and in vitro with GH₃ cells, a rat anterior pituitary tumor cell line. We used specific radioimmunoassays to measure TRH-Gly and TRH levels in rat cortex, hypothalamus, medulla, eyes and whole blood as a function of the intracisternal (IC) dose of TRH and TRH-Gly administered 40 min prior to sacrifice. IC injection of 1.0 mg of TRH-Gly led to a significant (p < 0.005) increase in the TRH levels in hypothalamus, medulla and blood. The relative potency of IC and intracardiac (IK) TRH and TRH-Gly release of rat TSH was compared by radioimmunoassay and further refined using estimates based on in vivo kinetics of TRH-Gly alpha-amidation. The binding of TRH-Gly to the plasma membrane receptors for TRH on GH₃ cells was also investigated. In regard to TSH release, TRH-Gly given IC had only 0.042% of the potency of TRH given IC and was consistent with its rate of IC alpha-amidation. IK TRH-Gly had 0.16% of the potency of IK TRH of TSH release and was also consistent with its rate of intravascular conversion to TRH. The mean peak TSH response occurred at 20 min after IC TRH-Gly or IC TRH injection but the post-peak decline was slower for IC TRH-Gly. The maximum levels of blood TRH-Gly and TRH both occurred at 20 min after IC administration of TRH-Gly and TRH, respectively. The agreement between the directly measured relative potency for TSH release following IC TRH-Gly and that derived from the rate of IC TRH-Gly conversion to TRH suggests that IC TRH-Gly must first be converted to TRH by alpha-amidating enzymes in the cerebrospinal fluid before it transits the blood-brain barrier. TRH-Gly cross-reactivity with the TRH receptor of GH₃ cells was 0.45% of that for TRH while the in vitro potency of prolactin release by GH₃ cells in response to TRH-Gly was 0.41% that for TRH. GH₃ cells incubated for 3 h with or without 50 µg TRH-Gly/ml revealed no significant increase in extracellular or intracellular TRH concentration. We conclude that conversion of TRH-Gly to TRH is the most likely explanation for the stimulation of TSH release in rats but in vitro release of prolactin from GH₃ cells in response to TRH-Gly administration may be mediated via TRH-Gly cross-reaction with the TRH receptor.

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Thyroid hormone modulation of TRH precursor levels in rat hypothalamus, pituitary, thyroid and blood

Cited by 21 publications

References 36 publications

High Levels of Thyrotropin-Releasing Hormone Precursor Peptide Immunoreactivity and Binding Substance Occur in Human Cerebrospinal Fluid

High Levels of Thyrotropin-Releasing Hormone Precursor Peptide Immunoreactivity and Binding Substance Occur in Human Cerebrospinal Fluid

Regulation of Thyrotropin-Releasing Hormone in the Posterior Pituitary

Release of Thyrotropin and Prolactin by a Thyrotropin-Releasing Hormone <i>(TRH) </i>Precursor, TRH-Gly: Conversion to TRH Is Sufficient for in vivo Effects

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