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Pyroglutamyl-N 3im-methyl-histidyl-prolineamide (methyl-thyrotrophin releasing hormone, methyl-TRH) is a potent synthetic analogue of TRH. N 3im-Methyl-histidine is present in mammalian brain and it has been suggested that methyl-TRH is a physiological releasing hormone normally present in the hypothalamus. A non-gradient cation-exchange chromatography system that uses SP-Sephadex C-25 and completely resolves methyl-TRH and TRH has been developed. Because methyl-TRH cross-reacts in the immunoassay for TRH, this assay was used to measure TRH and methyl-TRH in the chromatographic fractions. By this means it has been demonstrated that the amount of methyl-TRH present in the rat is less than 0·025 ng/hypothalamus.
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The immunoreactivity of a commercial preparation of human chorionic gonadotrophin (HCG) was determined in a homologous double antibody radioimmunoassay for HCG using antisera to the β-subunit of the hormone. The immunoreactivity of the commercial HCG was found to be 2·2 ± 0·3 (mean ± 2 s.d.) times the biological potency. Exclusion chromatography of the commercial HCG and then curve resolution of the elution profile derived from the radioimmunoassay revealed that on a molar basis, 21% of the immunoreactivity was attributable to β-HCG. The rate of clearance of this preparation of HCG from the plasma after intravenous administration was determined as a function of the dose administered to ten normal men (age 36–64 years). The doses ranged from 10 000 to 300 000 i.u. immunological potency. The rate of clearance decreased significantly (r = 0·574, P< 0·05) with increasing doses of HCG from a mean of 786 ml/h at the lowest dose to a mean of 298 ml/h at the highest dose. The renal clearance of administered HCG also decreased with increasing doses; the mean renal clearance of the 10 000 i.u. dose was 3·6 times the mean renal clearance after administration of 200 000 i.u. When the accumulated urinary HCG was expressed as a percentage of the dose administered, 14·1% of the 10 000 i.u. dose and 9·8% of the higher doses accumulated in the urine, suggesting that non-renal clearance increased with increasing dose.
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Thyrotrophin releasing hormone (TRH)-immunoreactive peptides have been quantified in canine serum, hypothalamus, liver, pancreas, adrenal, thyroid, prostate, testis, epididymis and semen by TRH radioimmunoassay, SP-Sephadex C-25 cation exchange chromatography, Sephadex G-10 exclusion chromatography and high pressure liquid chromatography. The total concentration of TRH and TRH-like peptides was highest in the hypothalamus, followed by liver, adrenal, pancreas, thyroid, prostate, epididymis, testis and serum. All of the TRH immunoreactivity (TRH-IR) within extracts of the hypothalamus was due to TRH. On the other hand, nearly all of the TRH-IR of extracts of liver, thyroid, prostate, epididymis, testis and semen was due to TRH-homologous peptides. Adrenal and pancreatic extracts contained a greater proportion of TRH in relation to the TRH-homologous peptides. Extracts of dog serum and semen were found to contain a TRH-binding substance which reduced the retention of added TRH by cation exchangers. The half-time of disappearance (t ½) of synthetic TRH incubated at 23 °C in 10% (w/v) homogenates in 0·15 m-NaCl–0·05 m-phosphate buffer, pH 7·5, ranged from 22±10 (s.d.) min for liver to 120 ±58 min for thyroid. The short t ½ for TRH added to dog liver homogenates contrasted with a previous report that dog liver is essentially free of TRH-degrading activity.
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ABSTRACT
Thyrotrophin-releasing hormone (TRH) occurs in high concentrations in the rat ventral prostate and its concentration is regulated in a positive dose–response manner by testosterone in castrated rats. α-Amidation of the tetrapeptide precursor, TRH-Gly, is a rate-limiting step in TRH biosynthesis. To investigate further the hormonal regulation of TRH biosynthesis in prostatic tissue, Sprague–Dawley rats of approximately 250 g were injected s.c. with either physiological saline or 3 mg propylthiouracil (PTU) daily for 5 days. The reproductive tissues were boiled in acetic acid (1 mol/l), dried and extracted with methanol. The methanol extracts were measured for TRH immunoreactivity (TRH-IR) and TRH-Gly-IR by radioimmunoassay. Hypothyroidism induced by PTU significantly increased TRH-IR and TRH-Gly-IR levels in prostate and testis and reduced these levels in epididymis but did not affect the serum concentrations of testosterone compared with those of controls. Corresponding changes in TRH and TRH-Gly in the rat prostate were established by high-pressure liquid chromatography. To control for possible pharmacological effects of PTU on TRH biosynthesis, additional experiments were carried out on castrated rats receiving testosterone replacement and treatment with PTU plus methimazole. Treatment with thyroxine (T4) significantly reduced the increase in prostatic TRH levels due to hypothyroidism, despite the drug-induced blockade of the conversion of T4 to tri-iodothyronine. These effects parallel similar observations made in rat spinal cord and pancreas. This study demonstrates that in the male rat reproductive system the levels of TRH and its immediate biosynthetic precursor, TRH-Gly, are regulated by thyroid hormones.
J. Endocr. (1987) 114, 271–277
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ABSTRACT
Orchidectomy has been reported to decrease concentrations of thyrotrophin (TSH) in the circulation of male rats without affecting serum levels of thyroid hormones. To understand the mechanism underlying this observation, we have measured the effect of gonadal status on the in-vitro release of TSH-releasing hormone (TRH) by male rat hypothalamic fragments. Because hormone release rates can be affected by changes in the post-translational processing of the hormonal precursors, we have also studied the corresponding changes in the concentrations of TRH and TRH-Gly, a TRH precursor peptide in hypothalamus and pituitary, by radioimmunoassay.
We observed a significant decline in the in-vitro release of TRH from incubated hypothalami 1 week after castration, which was quantitatively reversed by testosterone replacement. Concentrations of TRH and TRH-Gly in the posterior pituitary, on the other hand, which derive from neurones of hypothalamic origin, increased significantly with castration and were returned to the normal range by testosterone replacement.
We conclude that the primary effect of testosterone is the stimulation of hypothalamic TRH release, resulting in the depletion of TRH and TRH precursors from TRH-containing neurones which project into the median eminence and posterior pituitary.
Journal of Endocrinology (1990) 125, 263–270
