TSH-stimulated Release Research Articles

Inhibition of Thyrotropin- and Dibutyryl Cyclic AMP-Induced Secretion of Thyroxine and Triiodothyronine by Catecholamines12

Thyrotropin (TSH), 1 MU/ml and N6, O2'-dibutyryl adenosine 3',5-cyclic monophosphoric acid (dbcAMP) greatly enhanced the release of thyroxine (T4) and triiodothyronine (T3) from mouse thyroids incubated in vitro. L-Epinephrine (E) and L-norepinephrine (NE) strongly inhibited the TSH and dbcAMP-stimulated release of thyroid hormones; L-isoproterenol (IPNE) exerted a relatively weak inhibition. The inhibition by catecholamines was prevented by the alpha-adrenergic blocker, phentolamine; L-propranolol, a beta-adrenergic blocker, had no effect on the inhibition. The TSH-induced release of thyroid hormones was not affected by adrenergic blockers. Epinephrine did not affect the increase in thyroidal cAMP content induced by TSH. These results indicate that catecholamines act by way of an alpha-adrenergic receptor to suppress TSH-stimulated release of thyroid hormones at a point beyond cAMP formation.

Transport of thyrotropin-releasing hormone from cerebrospinal fluid to hypophysial portal blood and the release of thyrotropin.

The capacity of the medium eminence to transport thyrotropin-releasing hormone (TRH) from cerebrospinal fluid (CSF) to hypophysial portal blood, and the ability of TRH when introduced into a lateral ventricle to stimulate TSH release from the pituitary gland were investigated. Male rats were injected either intraventricularly or intravenously with 0, 1, 10, or 100 ng of TRH, and plasma TSH concentrations were determined at various times thereafter. TRH administration via both routes resulted in substantial release of TSH. Following intraventricular injection of TRH, there was a delay in reached maximal TSH concentration when compared with the faster elevation and faster decline in TSH concentrations which followed intravenous injection of the same dose of TRH. In a second experiment, 7 muCi of [3H]TRH were introduced intraventricularly or intravenously, and hypophysial portal and arterial blood were simultaneously collected and examined for the presence of radioactivity. The intraventricular injection of [3H]TRH resulted in a peak of radioactivity in portal blood within minutes, which was maintained for 20--30 min and then declined. The concentration of radioactivity in arterial blood from the same animals was considerably lower than that in portal blood. The intravenous administration of [3H]TRH resulted in radioactive peaks in both portal and arterial blood with a higher concentration of radioactive substances in arterial blood. However, the level of radioactivity in portal blood following intravenous injection of [3H]TRH comprised no more than 5--10% of that found following intraventricular administration of the saem dose. The data support the view that TRH is able to cross the medium eminence from CSF into hypophysial portal blood and that it is capable of stimulating the pituitary gland to release TSH.

Different effects of oral doses of triiodothyronine or thyroxine on the inhibition of thyrotrophin releasing hormone (TRH) mediated thyrotrophin (TSH) response in man.

Since contradicting results about the existence of T3 or T3 and T4 receptors in pituitary tissue have been reported, the influence of L-triiodothyronine (L-T3) or L-thyroxine (L-T4) on TRH stimulated TSH release was investigated. Oral administration of 50 mug L-T3 caused an increasing inhibition of TSH response to 400 mug TRH from 64% 2 h after L-T3 intake to 29% after 24 h, while serum T3 peaks up to 5.45 ng/ml occurred between 2 to 4 h after L-T3 ingestion and became normal after 8 to 10 h. This delay in the T3 action on TRH inhibition agrees with the postulate that T3 induces the synthesis of an inhibiting protein which is blocking TSH liberation. Oral administration of 1000 mug L-T4 induced increments of serum T4 up to 221 ng/ml between 6 to 24 h after intake; however, a TRH inhibition of 62% did not become evident before 48 h. At this time T3 levels had risen to the upper normal range. These results support the theory that T3 is responsible for the regulation of TSH secretion. An intra-pituitary conversion from T4 to T3 seems more likely the cause of the TRH inhibition rather than the peripheral T4-T3 conversion or a direct action by T4 binding sites in the pituitary.

The effect of hypoglycemia on TSH release in man.

The effect of insulin-induced hypoglycemia on TSH release was studied in 7 normal subjects (Group I), 5 patients with sellar enlargment, 1 patient with idiopathic panhypopituitarism (Group II-A) and 2 acromegalic patients (Group II-B). Serial measurements of TSH, GH and corrtisol, after a bolus of insulin (0.1 U/kg body weight), were made over a period of 120 min. The peak TSH value of 8.3 plus or minus 0.9 pU/ml (mean plus or minus SEM) did not differ statistically from the basal value of 6.0 plus or minus 1.3 pU/ml in Group I. GH levels, however, increased from 1.0 plus or minus 0.0 ng/ml to 28.1 plus or minus 4.3 ng/ml, which was highly significant (P less than 0.001). In contrast, Group II-A patients had an increase in serum TSH from 4.3 plus or minus 1.4 pU/ml to 28.6 plus or minus5.7 pU/ml (P less than 0.02). The peak GH levels of 4.0 plus or minus 1.7 ng/ml did not differ significantly from the basal value of 1.2 plus or minus ng/ml. In group II-B, the untreated acromegalic patient (G) did not show alterations in TSH levels consonant with the increase in GH from a basal value of 34.9 ng/ml to a peak of 46.9 ng/ml with the induction of hypoglycemia. In the treated acromegalic subject (H), basal GH increased from 7.8 ng/ml to 11.4 ng/ml with no significant changes in TSH. Serum cortisol levels in Groups I, II-A and II-B did not show consistent inverse relationship to circulating TSH. The observations in this study suggest that hypoglycemia may stimulate TSH release in certain pituitary disorders. Through GH release might play an inhibitory role on TSH secretion, the results suggest other unidentified factor(s).

Distribution and concentration of TRH in the rat brain.

Qualitative and quantitative criteria indicate that TRH is present in methanolic extracts prepared from all regions of the rat brain. The conclusion that TRH in the extracts of rat brain is the same as synthetic TRH is based on the following criteria: (a) immunoreactivity with a specific antiserum to synthetic TRH, (b) chromatographic properties on Sephadex G-10, (c) electrophoretic mobility on cellulose acetate, (d) susceptibility to degradation by plasma, and (e) capacity of the extracts to stimulate TSH release in vitro from anterior pituitary tissue. The greatest concentration of TRH, determined by radioirnmunoassay, was found in the hypothalamus, followed by the posterior pituitary gland, thalamus, brain stem, cerebrum, anterior pituitary gland, and cerebellum. The total quantity of TRH in the rat brain was 18.2 ng. Of this amount, 33.6% was present in the thalamus; 26.7% in the cerebrum; 18.8% in the hypothalamus; 18.6% in the brain stem; 1.6% in the cerebellum; 0.42% in the posterior pituitary glan...

Thyrotrophin secretion from rat pituitary autografts infused with synthetic thyrotrophin releasing factor.

SUMMARY Thyroidal uptake and release of 131I were used to study the response of pituitary autografts to locally infused synthetic thyrotrophin releasing factor (TRF) and porcine median eminence extract (MEE). Thyroidal release rates of 14% 131I/24h were maintained during continuous infusion of grafts with MEE (equivalent to 4 hypothalami/day) while 12·6% 131I/24 h was lost from thyroids of rats whose pituitary autografts were infused with 1000 ng synthetic TRF/day. Infusion of autografts with 5, 50 and 250 ng synthetic TRF/day resulted in lower, but dose-dependent, thyroidal responses suggesting that synthetic TRF could induce thyrotrophin (TSH) synthesis in the grafts. At all doses of TRF, thyroidal 131I release was significantly increased by daily injection of cortisone (2 mg s.c.). Local TRF stimulation of TSH release from pituitary grafts significantly increased the dose of thyroxine (T4) needed to decrease thyroid activity, and while 1·0 μg T4/100 g depressed activity in rats receiving saline infusions, 1·7–2·7 μg T4/100 g was needed to inhibit 131I release in rats receiving 250 ng TRF/day, and 3 μg T4/100 g was needed by rats receiving 1000 ng TRF/day. Continuous TSH infusion (25–28 mu./day) into hypophysectomized rats induced thyroidal 131I release at rates similar to those in rats with TRF-stimulated pituitary autografts. It is suggested that while synthetic TRF can enhance TSH synthesis in the pituitary its effects on TSH synthesis may normally be potentiated by other humoral substances.

Failure of TRH (Thyrotropin—Releasing Hormone) to Stimulate Thyroid. Function in the Chick

The effect of synthetic TRH (L— (Pyro)Glu—L—His—L—Pro(NH2)) on the release of TSH from the pituitary was observed in the mouse TSH bioassay by measuring 125I release from the thyroid gland. Two different synthetic TRH preparations stimulated TSH release. This bioassay showed a dose—related response at doses larger than 20 ng of TRH. The response was the same after ip or iv injection. The stimulating effects of these synthetic TRH preparations also were examined in a chick bioassay for TSH in which the release of 125I from the thyroid is measured. The synthetic TRH preparations known to be active in the mouse and human were not active in the chick bioassay. In amounts 250–fold greater than the dose required for an active response in the mouse, no thyroid stimulating effects were noted at 2.5 or 8 hr in the chick. These results suggest that synthetic TRH (L—(Pyro)Glu— L—His—L—Pro(NH2)) responses may only be active in mammalian species. (Endocrinology 91: 832, 1972)

Effect of cold on TSH secretion in man.

Short term cooling of adult human subjects fails to stimulate TSH release, whereas a prompt increase in serum TSH is observed in infants and children in response to cooling. Heat loss in infants is known to be augmented in response to cold exposure and it is possible that more effective catecholamine thermogenesis in the adult obviates the TSH response. To test this hypothesis the serum TSH response to cooling at 2 to 4° C was measured in adolescent and young adult subjects with and without administration of alpha or beta adrenergic receptor blocking drugs. Neither drug augmented the TSH response although significant hypothermia occurred. Thus, it seems that the hypothalamus of the adult has become refractory to the acute cold stimulus. Although cooling fails to evoke an acute TSH release in adults, some delayed TSH response to cooling can be observed probably in response to increased thyroxine utilization.

Thyroid Secretionin Vitro: Inhibition of TSH and Dibutyryl Cyclic-AMP Stimulated131I Release by Li+1

The effect of various Li+ treatments on the release of 131I in vitro by mouse thyroid glands was studied. Chronic Li+ feeding and acute Li+ injection inhibited both DBCAMP- stimulated release of 131I and TSH-stimulated release of 131I. By use of preincubation with Li+, inhibition of TSH-stimulated 131I release was demonstrated in a completely in vitro system. 131I release and colloid droplets were decreased in parallel. Li+ inhibition of thyroid secretion thus occurs at a step between the generation of intracellular cyclic-AMP and colloid droplet formation. (Endocrinology 88:1385,1971)

Porcine thyrotropin releasing hormone is (pyro)glu-his-pro(NH2).

Porcine thyrotropin releasing hormone, isolated from the hypothalamus, and synthetic L-(pyro)Glu-L-His-L-Pro(NH2) are biologically identical. (pyro)Glu-His-Pro(NH2) is active in vivo at 1 ng in mice. It stimulates TSH release from rat anterior pituitary glands in vitro. The in vivo and the in vitro responses are inhibited by triiodothyronine. (pyro) Glu-His-Pro (NH2) raises plasma TSH levels in rats and mice as well as hypophysectomized rats with pituitary transplants under the renal capsule. When incubated in human serum it is inactivated, (pyro) Glu-His-Pro (NH2) is active orally as well as ip, iv and sc in mice. Minor modifications in the (pyro) Glu-His-Pro (NH2) chemical structure decrease its biological activity. (Endocrinology 86: 1143, 1970)

IN VITRO SECRETION OF THYROTROPIN (TSH): STIMULATION BY A HYPOTHALAMIC PEPTIDE (TRF).

Identical populations of anterior pituitary tissue were obtained by separating rat anterior pituitary in halves or quarters. When incubated in vitro in Krebs-Ringer bicarbonate glucose buffer, such identical fragments of pituitary released identical minute amounts of TSH into the incubation fluid. Addition of hypothalamic TSH-releasing factor (TRF) of sheep origin (prepared by molecular sieving and characterized with an in vivo bio-assay) increased the amount of TSH present in the incubation fluid of the experimental pituitary population when compared to its control. The stimulation of TSH release was a linear function of the log of the dose of added TRF. The ability of TRF to stimulate TSH release in vitro was inhibited by in vivo pretreatment or in vitro preincubation with L-thyroxine. TRF does not act by inhibiting destruction (in vitro) of released TSH nor by potentiating TSH in the bioassay. LRF (LH-releasing factor), CRF (corticotropin- releasing factor), lysine-vasopressin, oxytocin, α-MSH and β-MS...

Effect of di-ethyl ether anesthesia on thyroid function of rats: pituitary, adrenal and thyroid relationship.

The possible role of the pituitary and adrenal hormones in the depressive effect of ether anesthesia on thyroid function in rats was studied. Di-ethyl ether anesthesia for two hours significantly depressed release of radioiodine (I131) from the thiouracil blocked thyroid gland in both bilateral adrenalectomized rats maintained with cortisone and in the bilateral adrenal-medullectomized rats. Administration of ether anesthesia depressed thyroidal uptake of radioiodine in the hypophysectomized rats treated with small doses of exogenous TSH, although no significant effect was noted inthe absence of thyrotropin. Ether anesthesia inhibited the TSH-stimulated release of thyroidal I131 in the hypophyscctomized rats. Recovery from this inhibition by ether was rapid and more marked when larger amounts of TSH were used. These findings indicate that the effect of di-ethyl ether anesthesia in rat thyroid was not mediated through the adrenal cortex or medulla. It is suggested that the ether anesthesia might influence ...