Treatment of inappropriate secretion of thyrotropin with somatostatin analog SMS 201-995

Inappropriate thyrotropin secretion (IST) may originate from either neoplastic disease (nIST) or non-neoplastic resistance to thyroid hormone (nnIST). An inhibitory effect of somatostatin on TSH secretion has been documented. In an attempt to elucidate the possible therapeutic effect of this peptide on nIST and nnIST, a study was conducted in 7 such patients. Sandostatin (SMS 201-995) was administered in daily doses of 100 micrograms for several days to 1 month. Four patients with nIST responded with a fall in circulating TSH as well as alpha-subunit with concomitant normalization of free thyroxine and clear symptomatic improvement. In the 3 nnIST patients this effect was considerably less apparent and a partial TSH escape was observed on long-term treatment in 2 cases. The importance of somatostatin and its analogs in the management of thyroid malignancy is stressed.     

Insulin-induced hypoglycemia, L-dopa and arginine stimulate GH secretion through different mechanisms in man

We sought to clarify the mechanisms of growth hormone (GH) secretion induced by insulin hypoglycemia, L-dopa, and arginine in man. The secretion of GH as measured by increased plasma level, in response to oral administration of 500 mg L-dopa or 30 min-infusion of arginine, was not modified by prior intravenous administration of 200 micrograms GH-releasing hormone (GHRH). It was, however, completely blocked by preadministered 50 micrograms SMS201-995, a long-acting somatostatin (SRIH) analog. GH release with 200 micrograms GHRH was completely blocked by 100 micrograms SMS201-995. GH secretion caused by insulin-induced hypoglycemia was significantly reduced but still present after administration of 100 micrograms of the analog. These results suggest that a suppression of SRIH release may be partially involved in the stimulatory mechanism of GH secretion by L-dopa. Coadministration of GHRH accentuated the stimulatory effect of arginine on GH secretion. Arginine significantly raised plasma TSH levels. These findings suggest that arginine suppresses SRIH release from the hypothalamus to cause GH secretion because SRIH suppresses TSH secretion. It is also suggested that some factor (or factors) other than GHRH and SRIH are involved in the mechanism by which insulin-induced hypoglycemia stimulates GH secretion, because the effect of insulin was not fully blocked in the presence of SRIH analog. Thus all the tests for GH release appear to act via different mechanisms.     

Effect of subcutaneous injection of a long-acting analogue of somatostatin (SMS 201-995) on plasma thyroid-stimulating hormone in normal human subjects

SMS 201-995 (SMS), a synthetic analogue of somatostatin (SRIF) has been shown to be effective in the treatment of the hypersecretion of hormones such as in acromegaly. However, little is known about the effects of SMS on the secretion of thyroid-stimulating hormone (TSH) in normal subjects. In this study, plasma TSH was determined with a highly sensitive immunoradiometric assay, in addition to the concentration of SMS in plasma and urine with a radioimmunoassay, following subcutaneous injection of 25, 50, 100 micrograms of SMS (4 subjects/dose) or a placebo (6 subjects) to normal male subjects, at 0900 h after an overnight fast. The plasma concentrations of SMS were dose-responsive and the peak levels were 1.61 +/- 0.09, 4.91 +/- 0.30 and 8.52 +/- 1.18 ng/ml, which were observed at 30, 15 and 45 min after the injection of 25, 50 and 100 micrograms of SMS, respectively. Mean plasma disappearance half-time of SMS was estimated to be 110 +/- 3 min. Plasma TSH was suppressed in a dose dependent manner and the suppression lasted for at least 8 hours. At 8 hours after the injection of 25, 50 and 100 micrograms of SMS, the plasma TSH levels were 43.8 +/- 19.4, 33.9 +/- 9.4 and 24.9 +/- 3.2%, respectively, of the basal values. The results suggest that SMS suppresses secretion of TSH from the normal thyrotrophs in man and thus also that attention should be paid to possible hypothyroidism during the long-term treatment of patients such as those with acromegaly with this potent analogue of SRIF.     

Treatment of acromegaly with long acting somatostatin analogue SMS 201-995

Ten acromegalic patients were treated with the somatostatin analogue SMS 201-995 (SMS) for 3-38 weeks in various doses and by different administration routines (thrice daily or multiple sc injection). Plasma GH daily profiles, plasma IGF-I, urinary GH, serum TSH, IRI and fasting blood glucose (FBG) concentrations were measured before and during SMS treatment. Plasma GH rapidly decreased within one hour in all patients and was suppressed for at least 4 h after a 50 micrograms sc injection of SMS in 8 patients. Multiple injections of 300-600 micrograms/day SMS (25-50 micrograms X 12) suppressed GH throughout the day. Plasma IGF-I was completely normalized in 4 patients, and, in all but one of the others, decreased markedly. Urinary GH decreased within the first week of treatment in all patients and normalization was obtained in 3 patients. Shrinkage of the pituitary tumor, as determined by CT or MRI, was observed in 7 of 9 patients. Other clinical improvements, such as diminution or complete disappearance of swelling of soft tissues, excessive perspiration, and headache, were observed in 7 of 8 patients. Changes in serum TSH, IRI and FBG were seen in 3-4 patients, but without any apparent clinical problems. In conclusion, SMS is a useful clinical tool for treatment of acromegaly, and a multiple sc injection method seems to be preferable.     

Thyroid function and body weight programming by neonatal hyperthyroidism in rats - the role of leptin and deiodinase activities.

Several authors have shown that secondary hypothyroidism was programed by neonatal thyroxine (T4) treatment. However, the associated changes of body weight (BW) were less studied, especially those related to the body fat proportion. Here, we have evaluated the effect of neonatal thyroxine treatment on BW, fat proportion, serum leptin, and thyroid function of 60-day-old rats. Wistar rats were treated with thyroxine (50 microg/100 g BW, ip) (T) or saline (S), during the first 10 days of life. BW, nose-rump length (NRL), and food consumption were monitored for 60 days, when the animals were sacrificed. Thyroid function was evaluated by thyroid radioiodine uptake (RAIU), serum T3, T4, TSH, and liver mitochondrial alpha-glycerophosphate dehydrogenase (mGPD) and type 1 and 2 deiodinases (D1 and D2) activities, which are thyroid hormone-dependent enzymes. T animals showed lower food intake, BW and NRL, but higher total fat mass (+33%) and serum leptin (+46%). They also showed lower serum T3 (-23%), T4 (-32%), TSH (-36%), RAIU (-29%) and mGPD activity (-22%). Hypothalamic and pituitary D2 activities were higher (+24% and 1.4 fold, respectively), while brown adipose tissue (BAT) D2 and skeletal muscle D1 activities were lower (-30% and -62%, respectively). Thus, neonatal hyperthyroidism programs for a higher fat proportion and hyperleptinemia, which can explain the lower food intake. The TH-dependent enzymes activities changed accordingly, except for the decrease in BAT D2, which may be due the role played by the hyperleptinemia. Finally, the decrease in peripheral deiodination may contribute to a lower me-tabolic rate that may increase the adiposity.     

Effect of a single administration of somatostatin analogue (SMS 201-995) on GH, TSH and insulin secretion in patients with acromegaly

The effect of a long-acting somatostatin analogue SMS 201-995 on GH secretion was investigated. Eleven acromegalic patients received a single dose of 50 micrograms SMS 201-995 administered subcutaneously, and plasma GH, IGF-I, GRF, TSH, IRI and blood glucose were determined at regular intervals. Nine of 11 patients had elevated basal plasma GH levels above 5 ng/ml. In all patients, plasma GH levels fell immediately from 39.5 +/- 17.3 ng/ml (mean +/- SEM) to 4.3 +/- 1.6 ng/ml (P less than 0.05) with a maximal inhibition of 82.9 +/- 3.3% of the basal levels and the suppression persisted for about 6 h of the observation period. IGF-I and GRF levels were not apparently altered. TSH and IRI levels also rapidly fell. Blood glucose levels fell slightly by 0.5 h. Ten of 11 patients had pain at injection sites. Except for this, no side effects were observed. Our results show that the new somatostatin analogue SMS 201-995 may inhibit GH hypersecretion in acromegalic patients for significant periods, suggesting that this agent can be a useful clinical tool for the treatment of acromegaly.     

Effect of a long-acting somatostatin derivative SMS 201-995 (sandostatin) on glucose homeostasis in type I diabetes mellitus

The infusion of natural somatostatin (SRIF) has been able to partially correct postprandial hyperglycemic reactions in insulin-dependent diabetes mellitus (IDDM). SMS 201-995 (Sandostatin) is a long-acting derivative with a growth hormone-suppressive effect 10-60 times more potent than the native peptide. The effect of SMS 201-995 (50 micrograms s.c.) on glucose control by exogenous insulin has been documented in a series of type I diabetics after stabilization of blood sugar by an artificial pancreas. Inhibition of counterregulatory mechanisms significantly diminished the postprandial hyperglycemia, and insulin requirements, both total and 2 h after meals, were markedly decreased. Also the effect of a single s.c. injection of 100 micrograms SMS 201-995 on the dawn phenomenon in a patient with poorly adjustable diabetes was investigated. The glucose escape observed during the control night was blocked by SMS 201-995. Thus, the stabilizing action of this peptide on postprandial and nocturnal hyperglycemia in unstable diabetes warrants further studies.     

Inappropriate secretion of thyrotropin by the pituitary

Inappropriate secretion of thyrotropin (IST) is characterized by elevated serum free thyroid hormone and unsuppressed thyrotropin (TSH) levels, and results from either a TSH-secreting pituitary tumor (nIST) or a selective resistance to thyroid hormone action (nnIST). Although in most patients TSH levels are definitely high, in a quarter of the cases they are within the 'normal range'. In some of these cases, TSH had an elevated biologic activity and an apparent molecular weight smaller than in normals. The current availability of ultrasensitive TSH immunoradiometric assay, able to distinguish suppressed from unsuppressed TSH levels enables the recognition of the disease. The distinction between nnIST and nIST rests on clinical, neuroradiological, and biochemical criteria, the most useful of which are the alpha-subunit:TSH molar ratio (increased in nIST), and the evaluation of the TSH responses to thyrotropin-releasing hormone and high doses of 3,5,3'-triiodothyronine, both qualitatively normal in nnIST, while absent in nIST. The therapy of choice for patients with nIST is pituitary surgery, followed by irradiation in case of surgical failure. Chronic administration of bromocriptine is effective in a minority of cases. The long-acting somatostatin analogue SMS 201-995 has given promising results in 2 patients. In nnIST, bromocriptine is frequently uneffective, while small doses of 3,5,3'-triiodothyronine or 3,5,3'-triiodothyroacetic acid, a thyroid hormone derivative with a strong inhibitory effect on TSH secretion but poor thyromimetic activity on peripheral tissues, are effective in controlling TSH hypersecretion.     

Central action of somatostatin analog, SMS 201-995, to stimulate gastric acid secretion in rats

The effects of intracisternal and intravenous injections of the somatostatin analog, SMS 201-995, on gastric acid secretion were investigated in rats with pylorus ligation or gastric cannula. Intracisternal injection of SMS 201-995 induced a dose-related (0.1-0.3 microgram) and long-lasting stimulation of gastric acid output with a peak response at 3 h postinjection in conscious, pylorus-ligated rats. Intracisternal SMS 201-995 increased histamine levels in the portal blood, whereas plasma gastrin levels were not modified. Atropine, cimetidine and adrenalectomy abolished the stimulatory effect of intracisternal SMS 201-995 (0.3 microgram). SMS 201-995 (0.03 microgram), microinjected unilaterally into the dorsal vagal complex, increased gastric acid output in urethane anesthetized rats. SMS 201-995, injected intravenously at 0.5 microgram, did not alter gastric secretion, whereas higher doses (5-20 micrograms) resulted in a dose-related inhibition of gastric acid secretion in conscious pylorus-ligated rats. These data indicate that SMS 201-995, a selective ligand for somatostatin-1 receptor subtype, induces a centrally mediated stimulatory effect on gastric acid secretion in rats. The central action involves the parasympathetic system, muscarinic and H2 receptors as well as adrenal-dependent pathways.     

Serum TSH, T4, T3, FT4, FT3, rT3, and TBG in youngsters with non-ketotic insulin-dependent diabetes mellitus

Several parameters of thyroid function were studied in 112 non-ketoacidotic youngsters with insulin-dependent diabetes mellitus (IDDM). Levels of thyroxine (T4), reverse triiodothyronine (rT3), thyroxine-binding globulin (TBG) and T3 were lower than in controls, whereas FT4, and FT3 were normal. T4 levels in IDDM patients were positively related to T3, rT3 and TBG, and inversely related to haemoglobin A1 (HbA1). However, only 4 patients showed biochemical hypothyroidism (T4 less than 5 micrograms/100 ml), whereas their FT4, FT3 and thyroid-stimulating hormone (TSH) levels were normal. Concurrent variations of T3 and rT3 levels were found in IDDM patients; thus, their T3/rT3 ratios were stable or higher than in controls, indicating that peripheral deiodination of T4 is preferentially oriented to production of rT3 only during ketoacidosis. Although changes in thyroid function may reflect the degree of metabolic control of diabetes in a large population, the clinical usefulness of serum thyroid hormone measurements in an individual case still appears to be limited.     

Plasma alpha-subunit levels during the treatment of pituitary adenomas with the somatostatin analog (SMS 201-995)

The effect os SMS 201-995 (Sandostatin), a long-acting somatostatin analog, on different types of pituitary adenomas including alpha-subunit elevation is illustrated in this report. Treatment induced a fall in hCG levels in a woman with a pituitary adenoma producing only alpha-subunit. In 3 acromegalic patients, there was only a partial drop in GH and alpha-hCG. The same effect was observed in a woman with menopausal FSH and LH levels. SMS reduced plasma TSH and alpha-hCG in a case of thyrotropic adenoma. Two patients exhibiting FSH- and alpha-hCG-secreting adenomas did not respond to acute administration of SMS 201-995. More patients have to be treated before a definitive statement can be made on the usefulness of somatostatin analogs in the management of different types of pituitary adenomas.     

Effects of a long-acting somatostatin analogue on pituitary-adrenocortical secretion in normal human subjects

A potent and long-acting somatostatin analogue, SMS 201-995 (SMS) is currently employed for the treatment of various diseases with hypersecretion of hormones such as acromegaly and gastrinoma. The suppressive effects of SMS are also reported on the other pituitary and gastrointestinal hormones. The corticotropic-adrenocortical axis is a crucial hormonal complex in maintaining normal activity and life itself. In this study, the effects of SMS on corticotropic-adrenocortical functions were studied, since the effects of SMS on this hormonal axis are not well established. Seven normal males received a sc injection of 100 micrograms SMS or placebo at 0830 h and 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) intravenously (SMS-hCRH study). Five of the 7 subjects were given an injection of a synthetic (1-24) ACTH (250 micrograms or 63 micrograms) at 0900 h after 100 micrograms SMS or a placebo at 0830 h (SMS-ACTH study). Blood samples were drawn at -30, 0, 15, 30, 60, 90 and 120 min after the hCRH injection for the determination of ACTH and cortisol in the SMS-hCRH study, and cortisol and aldosterone in the SMS-ACTH study. Although significant rises in plasma ACTH and cortisol levels were observed regardless of the preinjection of SMS, their responses to hCRH were significantly lower with the pretreatment with SMS than without SMS. A significant increase in plasma cortisol and aldosterone was observed in response to synthetic ACTH with both ACTH alone and the combined administration of SMS and ACTH, at either dose of ACTH. However, no significant difference in cortisol and aldosterone secretion was detected with and without SMS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improvement of diabetes after treatment with somatostatin analogue SMS 201-995 in an acromegalic patient

The beneficial effects of long acting somatostatin analogue SMS 201-995 in an acromegalic patient affected by severe diabetes mellitus are reported. Neither human insulin alone nor human insulin plus bromocriptine allowed satisfactory metabolic control though, with the latter treatment, virtually normal plasma GH levels were reached. Conversely, addition of SMS 201-995 to insulin treatment led to normalization of blood glucose. This result was obtained with a dose of SMS 201-995 of 400 micrograms/day and only after 3 weeks of therapy.     

Somatostatin analogue (SMS 201-995) decreases plasma levels of corticotropin (ACTH) and corticotropin-releasing hormone in a patient with ectopic ACTH-producing tumors

Effects of long-acting somatostain analogue (SMS 201-995) on plasma corticotropin (ACTH) and corticotropin-releasing hormone (CRH) levels were studied in a patient (63-year-old woman) with ectopic ACTH-producing tumors associated with type I multiple endocrine neoplasia (MEN-I). The patient had undergone bilateral adrenalectomy. Plasma CRH, as well as plasma ACTH, beta-endorphin and alpha-MSH, increased. The hormone levels were dramatically decreased by acute administration of SMS 201-995. Moderately higher doses of dexamethasone (0.05 or 0.1 mg/kg a day) did not decrease plasma CRH or ACTH. An extremely high dose of dexamethasone (0.2 mg/kg a day), however, decreased plasma ACTH, but failed to decrease plasma CRH. Acute administration of SMS 201-995 further lowered the level of plasma ACTH even in this condition. In addition to the decrease in ACTH, SMS 201-995 decreased plasma CRH. Chronic administration of SMS 201-995 continuously decreased plasma CRH, ACTH and beta-endorphin. The decrease in these hormone concentrations accompanied the disappearance of hyperpigmentation. These results suggested that SMS 201-995 inhibits hypersecretion not only of ACTH but also of CRH, and that the agent is therapeutically useful in normalizing the hypersecretion of these hormones.     

Inhibitory effect of bombesin and SMS 201-995 on DNA synthesis in the rat thyroid lobes incubated in vitro

The effects of 4-h incubation in the presence of bombesin on the incorporation of [3H]-thymidine into DNA of the rat thyroid lobes, collected from animals treated in vivo with a long-acting somatostatin analog (SMS 201-995) or with 0.9% NaCl, were investigated. It was shown that not only in vivo injections of SMS 201-995, but also, unexpectedly, in vitro incubation with bombesin inhibited [3H]-thymidine incorporation. The two examined substances did not reveal any additive action in their inhibitory effects on the thyroid growth.     

Different ionic requirements for somatostatin receptor subpopulations in the brain

Two populations of brain somatostatin (SS) receptors, one with high affinity for the somatostatin octapeptide analogue SMS 201-995 (SS1 type) and one poorly sensitive to this analogue (SS2 type) have been characterised in regard to their ionic requirements using two radioligands, the iodinated Tyr3 derivative of the octapeptide SS analog SMS 201-995 and the iodinated [Tyr11]-SS. Specific binding of 125I-[Tyr11]-SS to rat cortex membrane homogenates can be increased by approximately 180% in presence of 5 mM Mg2+. The increase in number of binding sites seen by Mg2+ is not accompanied by a marked increase in affinity for SS but for SMS 201-995: the low affinity binding for SMS 201-995 seen in absence of Mg2+ is replaced in part by higher affinity binding in presence of these ions. SMS 201-995 sensitive SS1 receptor subpopulation measured with 125I-204-090, a specific ligand for SS1 subpopulation, is massively increased in presence of Mg2+. However, SMS 201-995 insensitive SS2 receptor population measured with 125I-[Tyr11]-SS in presence of excess SMS 201-995 is unchanged in presence of Mg2+. The Mg2+-dependency can also be observed with autoradiography for extra cortical, i.e. hippocampal, brain SS receptors. 120 mM Na+ does not affect the total brain SS receptor population, but reduces the specific binding of SS1 receptors and increases that of SS2 receptors. Therefore, the rat brain, in particular the cortex, possesses a SMS 201-995-sensitive, Mg2+-dependent SS receptor subpopulation (SS1) as well as a SMS 201-995-insensitive, Mg2+-independent SS population (SS2).     

Suppression of growth hormone and somatomedin C by long-acting somatostatin analog SMS 201-995 in type I diabetes mellitus

The effect of a new long-acting somatostatin analog SMS 201-995 (SMS) on hormonal mechanisms controlling the glucose metabolism was tested in 8 type I diabetics over a 3-day period. In addition to dietary measures and conventional insulin therapy, the patients received a subcutaneous dose of 50 micrograms SMS three times daily for 3 days. Serum growth hormone (GH) was measured at various intervals throughout the investigational period. Glucagon, somatomedin C (SM-C), triiodothyronine, thyroxine, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) were also determined before and at the end of the therapy with SMS. Basal GH and plasma SM-C had decreased significantly (p less than 0.05 and p less than 0.01, respectively) by the 3rd day. In all cases the insulin requirements could be reduced (mean 28%) without deterioration of the metabolic control. Moreover, blood glucose profiles showed a tendency to lower postprandial peaks after SMS treatment. Glucagon, triiodothyronine, thyroxine, LH, FSH and PRL showed no significant changes. No side effects or alterations in laboratory chemistries were recorded. Dampening of glucose oscillations and counterregulatory mechanisms, and reduction of insulin dosage by SMS may enable a better control of unstable diabetes. Its slow plasma clearance and long action compared to the native peptide will warrant the use of this analog as a additive to standard diabetes therapy in more prolonged trials.     

The effect of a somatostatin analogue (SMS 201-995, Sandostatin) on the concentration of phosphoribosyl pyrophosphate and the activity of the pentose phosphate pathway in the early renal hypertrophy of experimental diabetes in the rat

The effect of a long-acting somatostatin analogue on the acute renal hypertrophy following induction of experimental diabetes in the rat has been studied. The kidney weight increase occurring at 2 and 7 days after alloxan injection was significantly lower in the diabetic group receiving somatostatin. Similarly, the previously reported increase in glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (EC 1.1.1.44) found in the kidney at 2 and 7 days of diabetes was less marked in the group receiving SMS 201-995. The fall in renal phosphoribosyl pyrophosphate associated with early diabetic renal hypertrophy (7) was also lessened by administration of SMS 201-995. No effects of the drug were found in the normal rat on the same regimen of treatment. These observations indicate involvement of glucagon and/or growth hormone in the initiation of kidney growth in diabetes.     

Hormonal regulation of thyrotropin alpha and beta subunit mRNAs

We have examined the effects of 3,5 3'-triiodo-L-thyronine (T3), dexamethasone, bromocriptine, thyrotropin releasing hormone (TRH) and estrogen on the levels of pituitary alpha and TSH-beta protein and mRNA levels in hypothyroid mice. After 3 days of treatment with T3 (0.5 micrograms/100 g body weight) serum TSH, alpha and TSH-beta levels were 77%, 79% and 44% of control, respectively. Pituitary alpha and TSH-beta mRNA content was estimated by dot blot hybridization of total RNA with 32P-labelled alpha and TSH-beta plasmid probes. There was no change in alpha mRNA after 3 days of T3 treatment but TSH-beta mRNA had decreased to 60% of control. With T3 at 2 micrograms/100 g body weight for 3 days, TSH protein was 27% of control and TSH-beta was undetectable, but there was no change in alpha. TSH-beta mRNA was decreased to 40% of control at 1 day and was barely detectable at 3 days, whereas alpha mRNA was 70% of control at 1 day and 42% at 3 days. Dexamethasone and bromocriptine caused no consistent change in pituitary levels of alpha and TSH-beta mRNA. Treatment with TRH caused small increases in serum TSH and in both alpha and TSH-beta mRNA levels. Estrogen treatment increased serum TSH and subunit levels and TSH-beta mRNA, but not alpha. We conclude that thyroid hormones decrease alpha and beta subunit mRNA levels discordantly in both the hypothyroid pituitary and in thyrotropic tumors and that the suppressive effect of thyroid hormone is the major regulator of TSH.     

Thyrotropic and peripheral activities of thyrotrophin and thyrotrophin-releasing hormone in the chick embryo and adult chicken

The influence of an intravenous injection of thyrotrophin-releasing hormone (TRH) and bovine thyrotrophin (TSH) on circulating levels of thyroid hormones and the liver 5'-monodeiodination (5'-D) activity is studied in the chick embryo and the adult chicken. In the 18-day-old chick embryo, an injection of 1 microgram TRH and 0.01 I.U. TSH increase plasma concentrations of triiodothyronine (T3) and of thyroxine (T4). TRH, however, preferentially raises plasma levels of T3, resulting in an increased T3 to T4 ratio, whereas TSH preferentially increases T4, resulting in a decreased T3 to T4 ratio. The 5'-D-activity is also stimulated following TRH but not following TSH administration. The increase of reverse T3 (rT3) is much more pronounced following the administration of TSH. In adult chicken an injection of up to 20 micrograms of TRH never increased plasma concentrations of T4, but increases T3 at every dose used together with 5'-D at the 20 micrograms dose. TSH on the other hand never increased T3 or 5'-D, but elevates T4 consistently. It is concluded that TSH is mainly thyrotropic in the chick embryo or adult chicken whereas TRH is responsible for the peripheral conversion of T4 into T3 by stimulating the 5'-D-activity. The involvement of a TRH induced GH release in this peripheral activity is discussed.