Hypothyroidism Reduces Content and Increases in vitro Release of Pro-Thyrotropin-Releasing Hormone Peptides from the Median Eminence

Abstract

To determine the effect of thyroid status on proTRH-derived peptide processing and secretion, the content and release of TRH and prepro-TR_25-50 (PYE₂₇), as well as somatostatin (SRIF) from median eminence (ME) or olfactory lobe (OL) tissue was studied in the rat. In hypothyroid animals treated by thyroidectomy (Tx), the ME content of TRH and PYE₂₇ was reduced by more than 50%; further, when compared with euthyroid controls there was a significant 2-fold enhancement of the in vitro release of these peptides from ME fragments in response to depolarizing concentrations (60 mM) of potassium. Hyperthyroidism (T₄ treatment) caused either no change or an increase in the ME content of these peptides and their response to K⁺ in vitro did not differ from control animals. The OL content of TRH and PYE₂₇ was unaffected by thyroid status. SRIF levels in both ME and OL as well as in vitro secretion from the ME did not change with either T_x or T₄ treatment. The ratio of TRH/PYE₂₇ secretion throughout release and content studies remained stable at 3:1 to 4:1. These findings support the view that TRH in the hypothalamus but not OL is regulated by thyroid hormone. In this location hypothyroidism enhances not only proTRH synthesis but also release of TRH and another proTRH-derived peptide. The consistent ratio of TRH/PYE₂₇ suggests that regulation of TRH production by thyroid hormone occurs predominantly at the transcriptional level and not through posttranslation processing.

Thyrotropin-Releasing Hormone Gene Expression in the Anterior Pituitary. IV. Evidence for Paracrine and Autocrine Regulation

“…Other processing products include several cryptic peptides, one of which is pYE 27 (23,24). We have previously determined the intracellular content of pYE 27 in AP cultures and found that the molar ratio of TRH/pYE 27 was similar to the theoretical value of 5:1 (11,12,22). The low levels of TRH-Gly in extracts of AP cultures determined in this study (TRH/TRH-Gly molar ratio of approximately 1:0.1) suggest that TRH-Gly is a transitional peptide that is immediately processed to TRH.…”

“…As predicted, exposure to Dis resulted in a dose-dependent decrease in the intracellular accumulation of TRH that was accompanied by an approximately equimolar increase in TRH-Gly levels, indicating that the biosynthesis of pro-TRH persisted. Processing of the rat TRH prohormone yields five copies of TRH-Gly, the immediate precursor of TRH, as predicted by its complementary DNA structure (22). Other processing products include several cryptic peptides, one of which is pYE 27 (23,24).…”

“…Lyophilized samples were reconstituted with RIA buffer and assayed for TRH and pYE 27 immunoreactivities as previously described (11,12,(21)(22)(23).…”

Cellular colocalization and coregulation between hypothalamic pro-TRH and prohormone convertases in hypothyroidism

“…lamic extracts was decreased in hypothyroidism, a paradox resolved by finding that hypothyroidism increased secretion of TRH and processed pro-TRH peptides from hypothalamic extracts (2). Thus hypothyroidism leads to increased paraventricular pro-TRH mRNA and pro-TRH intermediates, decreased paraventricular TRH, and increased TRH secretion, whereas hyperthyroidism leads to decreased pro-TRH mRNA, pro-TRH intermediates, and paraventricular TRH.…”

Regulation of Thyrotropin-Releasing Hormone in the Posterior Pituitary

“…Hypo-and hyperthyroidism have been shown to affect proTRH biosynthesis in the PVN [15][16][17][18][19], axonal transport of TRH from the PVN to the median eminence [20] and TRH release into hypo physial portal blood [21,22], In hypothyroidism TRH release into portal blood is increased [22] and the content ofTRH in the median eminence is decreased [20,23,24], The reverse is the case in hyperthyroidism [21,24], In the present study the content of TRH in the PP follows the same pattern as that in the median eminence, being nega tively correlated with hypothalamic TRH release and plasma levels of TSH. In only one other study has TRH content in the pituitary during altered thyroid status been investigated.…”