TRH and TRH-Like Peptide Levels Co-Vary with Reproductive and Metabolic Rhythms.

Photoperiod-synchronized rhythms in non-CSN tissues persist in total darkness. Clock genes involved in maintaining regular biorhythms within the suprachiasmatic nucleus (SCN) of the hypothalamus are expressed in extra-CNS tissues and continue periodic expression in vitro. Understanding the details of how the SCN clock is coupled with peripheral clocks is only incompletely understood and may involve a multiplicity of feedback systems. The present study is an extension of our previous work showing that brain levels of TRH (pGlu-His-Pro-NH2) and TRH-like peptides (X-TRH: pGlu-X-Pro-NH2, where "X" can be any amino acid residue) fluctuate throughout the day-night cycle. Male rats were maintained in a stable environment, lights on 6-18 h. TRH and TRH-like peptides in liver, pancreas, testis, prostate, epididymis, and heart were measured at 3, 10, 16, and 22 h. The greatest change in peptide level was a 12-fold increase for TRH in prostate at 16 h relative to the corresponding value at 3 h. The TRH, Tyr-TRH and Phe-TRH levels in liver declined steadily to about 40% of the 3-h values by 22 h. Changes, in the order of decreasing number of significant increases (↑) and/or decreases (↓), were: testis (5↑, 1↓), liver (3↓), epididymis (2↑), prostate (1↑, 1↓) and heart (1↑). Peptide levels in liver and testis correlated with serum leptin and serum corticosterone, respectively, which are potent releasers of these peptides. Testosterone and glucose were also highly correlated. These tripeptides may participate in the regulation of metabolic and reproductive functions, which change during the day-night cycle.

The TRH stimulation test and reverse T3 in depression.

Blunted TSH response to TRH and elevation of reverse T3 (rT3) have been reported in depression, though the relationship between these two abnormalities has not been clear. The authors measured basal levels of T4, T3, rT3 and the TSH response to TRH in a group of 28 depressed men and women, unipolar and bipolar subtypes. No significant difference was found between these two subtypes of depression with respect to mean basal hormonal levels or magnitude of the TSH response to TRH. Two males had slight, but significant elevations of rT3 though only one of them had a blunted TSH response to TRH levels and the TSH response to TRH. Finally no significant correlation was found between rT3 levels and the TSH response to TRH.

Methodological issues in the measurement of serum TSH--implications for psychiatry.

The TSH response to TRH has been reported to be blunted in endogenous depression. We compared two radioimmunoassay (RIA) techniques of TSH in 21 subjects (7 psychiatric inpatients, 14 normal controls) to determine whether differences in assay could account for discrepancies in the reported prevalence rates of blunted TSH responses in depression. A highly significant correlation (p less than 0.001) was found between the delta MAX TASH values of the two assays. The mean delta MAX TSH of one assay was significantly greater than the mean of the second assay. One assay yielded 6 blunted TSH responses to TRH, while the other yielded 9 such responses. Different TSH assay methods might account for discrepancies of the prevalence rates of blunted TSH response in depression.

Prolactin response to N3im-methyl-thyrotropin releasing hormone in euthyroid subjects.

The N3im-methyl analogue of thyrotropin releasing hormone (methyl-TRH) was compared with ordinary TRH as a prolactin (PRL) releaser in 32 euthyroid volunteers (20 male and 12 female, ages 17-66 years). The mean PRL response to 100 mug of methyl-TRH was greater (P less than 0.025) than the PRL response to 500 mug of TRH at 10 min and at all sampling times from 30 to 240 min after administration of the releasing factors. The mean peak PRL (at 10 min), maximum deltaPRL, and integrated PRL response area were greater (P less than 0.025) after administration of methyl-TRH than after TRH. The PRL response to methyl-TRH was greater (P less than 0.005) for the 12 women than for the 20 men in this study. The mean baseline PRL was correlated with the peak PRL (r=0.74, P less than 0.01) and the maximum deltaPRL (r=0.58, P less than 0.01) after methyl-TRH. Following administration of methyl-TRH, the peak PRL was correlated with the peak TSH (r=0.43, P less than 0.05), the maximum deltaPRL was correlated with the maximum deltaTSH (r=0.43, P less than 0.05), and integrated PRL response area was correlated with the integrated TSH response area (r=0.44, P less than 0.05). Similar correlations between PRL and TSH responses were seen after giving TRH. Age was inversely correlated with baseline PRL (r=-0.55, P less than 0.01), with maximum deltaPRL (r=-0.64, P less than 0.01), and with the PRL response area (r=0.48, P less than 0.01) after administration of methyl-TRH or TRH. Methyl-TRH did not significantly alter serum levels of growth hormone (16 subjects) and luteinizing hormone and follicle stimulating hormone (14 subjects). The results of this study indicate that methyl-TRH is a more potent prolactin releaser than TRH. Like TRH, methyl-TRH has specificity in its effects on the pituitary, releasing only TSH and PRL in normal man.

Patterns off recovery of the hypothalamic-pituitary-thyroid axis in patients taken of chronic thyroid therapy.

To determine the patterns of recovery of the hypothalamic-pituitary-thyroid axis following long-term thyroid hormone therapy, TRH tests were performed on 8 euthyroid nongoitrous patients, 5 euthyroid goitrous patients, and 5 hypothyroid patients while they were taking full doses of thyroid hormone and 3, 7, 10, 14, 17, 21, 28, 35, 42, 49, and 56 days after stopping it. Serum TSH, T3, and T4 were measured before and at multiple intervals over a 4-h period after giving 500 mug TRH iv. In euthyroid non-goitrous patients, the mean duration of suppressed TSH response to TRH (maximum deltaTSH less than 8 muU/ml) was 12 +/- 4 (SE) days after stopping thyroid hormone and the mean time to recovery of normal TSH response to TRH (maximum deltaTSH greater than 8 muU/ml) was 16 +/- 5 days. None of the euthyroid nongoitrous patients ever hyperresponded to TRH; their average maximal deltaTSH was 24.5 +/- 2.2 muU/ml. Serum T4 fell below normal in 4 euthyroid non-goitrous patients, reaching lowest values at 4 to 28 days. While serum T4 was low, deltaTSH was subnormal. Normal increments of T4 and T3 after TRH occurred at 19 +/- 5 and 22 +/- 6 days, respectively. In the 5 goitrous patients, patterns of recovery of pituitary and thyroid function assessed by the same parameters were much less consistent. In the 5 hypothyroid patients, the mean duration of suppressed basal TSH and suppressed deltaTSH was 13 +/- 3 days; mean time to attain a supranormal basal TSH (greater than 8 muU/ml) was 16 +/- 4 days and to reach a supranormal deltaTSH (greater than 38 muU/ml) after TRH was 29 +/- 8 days. Following prolonged thyroid therapy in euthyroid patients, recovery of normal TSH responsiveness to TRH preceded recovery of the normal T3 and T4 response to TRH by 3 to 6 days. Basal serum TSH may be used to differentiate euthyroid from hypothyroid patients 35 days after withdrawal of thyroid therapy; the response to TRH does not improve this differentiation.