Zinc may play a role in the regulation of thyrotropin function

We studied the in vitro and in vivo influence of physiologically relevant zinc concentrations on the thyrotropin function both at the pituitary and hypothalamic level. Zinc gluconate (Zn Glu) concentrations from 5 to 100 microM decreased basal TSH release from anterior pituitary gland in vitro, but did not affect TSH-stimulated release by TRH, cAMP or high K+ concentrations. Zn Glu altered neither the basal nor stimulated production of TRH by hypothalami in vitro. In vivo brain third ventricle injection of Zn Glu decreased serum TSH 30-60 min after injection. The ability of physiological concentrations of zinc to influence TSH secretion both in vitro and in vivo suggest that this trace element might be involved in the regulation of thyrotropin function.     

Effects of orexin A on thyrotropin-releasing hormone and thyrotropin secretion in rats.

Effects of orexin A on secretion of thyrotropin-releasing hormone (TRH) and thyrotropin (TSH) in rats were studied. Orexin A (50 microg/kg) was injected iv, and the rats were serially decapitated. The effects of orexin A on TRH release from the rat hypothalamus in vitro and on TSH release from the anterior pituitary in vitro were also investigated. TRH and thyroid hormone were measured by individual radioimmunoassays. TSH was determined by the enzyme-immunoassay method. The hypothalamic TRH contents increased significantly after orexin A injection, whereas its plasma concentrations tended to decrease, but not significantly. The plasma TSH levels decreased significantly in a dose-related manner with a nadir at 15 min after injection. The plasma thyroid hormone levels showed no changes. TRH release from the rat hypothalamus in vitro was inhibited significantly in a dose-related manner with the addition of orexin A. TSH release from the anterior pituitary in vitro was not affected with the addition of orexin A. The findings suggest that orexin A acts on the hypothalamus to inhibit TRH release.     

A physiological role of E and F series prostaglandins in the regulation of TSH secretion

The regulation of TSH secretion by E1, E2, E1 alpha and F2 alpha prostaglandins was studied by means of a monolayer culture system of dispersed rat anterior pituitary cells which was appropriately responsive to TRH, T3 and SRIF. PGEs and Fs induced significant increases in basal TSH release of the order of 30% at 10(-9) or 10(-8) to 10(-5) or 10(-4) M. Only PGEs accentuated the TSH release induced by a half maximal dose of TRH (10(-9) M) of the order of 60% in a dose dependent manner (10(-9) to 10(-6) M of PGEs), whereas PGFs did not. SRIF (10(-8) or 10(-9) M) alone failed to alter basal TSH release but did completely inhibit the TSH response to TRH (10(-9) M). SRIF also significantly inhibited both the increase in basal TSH release and the accentuation of the TSH response to TRH induced by PGEs (10(-6) M) but did not diminish the enhancement of basal TSH release induced by PGFs (10(-6) M). 7-oxa-13-prostynoic acid (PY1), a prostaglandin antagonist, which can act as an agonist in some systems, itself exhibited agonistic properties of PGEs with respect to basal and TRH induced TSH release. PY1 failed to inhibit the TSH release induced by all PGs, but partially inhibited the accentuated TSH response to TRH induced by PGEs. Indomethacin, PG synthetase inhibitor, did not affect basal or TRH induced TSH release in our system. These data suggest that PGs of the E and F series probably modulate TSH release via different mechanisms and that the PGE effect on basal TSH release differs from its augmentation of TRH induced TSH response. It is speculated that these effects of PGs may have physiological significance.     

Increase of thyrotropin response to thyrotropin-releasing hormone (TRH) and TRH release in rats during pregnancy

Regulation of thyrotropin (TSH) release by thyrotropin releasing hormone (TRH) in the anterior pituitary gland (AP) of pregnant rats was studied. The pregnant (day 7, 14, and 21) and diestrous rats were decapitated. AP was divided into 2 halves, and then incubated with Locke's solution at 37 degrees C for 30 min following a preincubation. After replacing with media, APs were incubated with Locke's solution containing 0, or 10 nM TRH for 30 min. Both basal and TRH-stimulated media were collected at the end of incubation. Medial basal hypothalamus (MBH) was incubated with Locke's medium at 37 degrees C for 30 min. Concentrations of TSH in medium and plasma samples as well as the cyclic 3':5' adenosine monophosphate (cAMP) content in APs and the levels of TRH in MBH medium were measured by radioimmunoassay. The levels of plasma TSH were higher in pregnant rats of day 21 than in diestrous rats. The spontaneous release of TSH in vitro was unaltered by pregnancy. TRH increased the release of TSH by AP, which was higher in pregnant than in diestrous rats. Maternal serum concentration of total T3 was decreased during the pregnancy. The basal release of hypothalamic TRH in vitro was greater in late pregnant rats than in diestrous rats. After TRH stimulation, the increase of the content of pituitary cAMP was greater in late pregnant rats than in diestrus animals. These results suggest that the greater secretion of TSH in pregnant rats is in part due to an increase of spontaneous release of TRH by MBH and a decrease of plasma thyroid hormones. Moreover, the higher level of plasma TSH in rats during late pregnancy is associated with the greater response of pituitary cAMP and TSH to TRH.     

Inhibitory effects of cysteamine on neuroendocrine function

The action of cysteamine on anterior pituitary hormone secretion was studied in vivo using conscious, freely moving male rats and in vitro using anterior pituitary cells in monolayer culture. Administration of 500 micrograms cysteamine into the lateral cerebral ventricles of normal rats caused the complete inhibition of pulsatile GH secretion for a minimum of 6 h. This treatment also significantly decreased plasma concentrations of LH for at least 6 h in orchiectomized rat, TSH in short-term (0.5 month) thyroidectomized rats, and PRL in long-term (6 months) thyroidectomized rats. The in vivo stimulation of GH, LH, TSH and PRL with their respective releasing hormones 60 min after administration of cysteamine was not different from the response observed in rats pretreated with saline except for PRL where cysteamine pretreatment significantly inhibited the expected PRL increase. In vitro, 1 mM cysteamine decreased basal and TRH stimulated PRL release while not affecting basal or stimulated GH, LH, TSH and ACTH secretion. These data demonstrate the dramatic and wide-ranging effects of cysteamine on anterior pituitary hormone secretion. This action appears to be mediated through hypothalamic pathways for GH, LH and TSH and through a pituitary pathway for PRL.     

Effect of caerulein on pituitary response to TRH in humans

The effect of caerulein (100 ng/kg/h X 1 h) on basal as well as on thyrotropin-releasing hormone (TRH)-stimulated prolactin and thyroid-stimulating hormone (TSH) secretion was studied in healthy male volunteers. The peptide did not change the basal levels of prolactin and TSH. However, during the infusion of caerulein, prolactin response to TRH was significantly increased whereas the TSH response was decreased. These data, showing an action of caerulein (a frog peptide which mimics the biological actions of cholecystokinin) on prolactin and TSH release, suggest that cholecystokinin may be involved in the physiological control of human pituitary secretion.     

The stimulatory effect of chronic lithium treatment on basal thyrotropin secretion in rats: In vivo antagonism by methylparaben

Chronic treatment of rats with lithium chloride was examined in order to determine its effect on hypothalamic monoamine and metabolite content, basal thyrotropin (TSH) secretion and thyroid function. The hypothalamic concentrations of noradrenaline (NA), dopamine (DA) and its metabolites, dihydroxyphenylacetic acid. (DOPAC) and homovanillic acid (HVA) in the lithium treated rats remained unaltered when compared to control levels. NA turnover and the NA metabolite, 3-methoxy-4-hydroxyphenylglycol (total MHPG), were significantly lower (p<0.01), whereas both serotonin (5-HT) and its metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), were significantly higher (p<0.01 and p<0.02, respectively) in the lithium treated rat hypothalami than in controls. Chronic lithium treatment significantly elevated basal TSH levels (p<0.05). This effect was antagonized by methylp-hydroxybenzoate (methylparaben, p<0.01), which did not itself affect basal TSH levels. Free serum T₃ and T₄ levels were not significantly affected by chronic lithium treatment, although T₄ tended to be slightly lower than control levels. The monoamine changes observed in the hypothalamus of lithium treated rats did not appear to account for the elevated TSH levels observed in these rats since NA activity which is generally regarded as stimulatory was decreased and 5-HT which has an inhibitory effect on TSH secretion, was increased. The elevated TSH levels may have been due to a reduced negative feedback inhibition of TSH release by the mildly reduced circulating T₄ levels caused by chronic lithium treatment. A further possibility is that the pituitary cGMP (and hence TSH) response to TRH may have been enhanced by chronic lithium treatment and methylparaben may have antagonized this effect.     

Central regulation of thyrotropin secretion in rats: methodological aspects, problems and some progress

The concept of the regulatory role of the hypothalamic and brain neurotransmitters in the secretion of the hypothalamic releasing hormones and corresponding anterior pituitary hormones has been generally accepted. The tuberoinfundibular portal vessels form an anatomical framework for regulating these hormones. Our present knowledge about the origin and course of the main aminergic and peptidergic bundles and their collaterals into the hypothalamus conforms with the accepted concept. The general methods in neuroendocrinology are well established. In our study, the unique TSH burst induced by a short cold-exposure has proved very useful, since it is mediated through the activation of TRH in the hypothalamus. When used together with the TSH-response caused by the exogenous TRH and with stereotaxic microinfusions of various chemicals into specific areas in the brain, the level of action of the pharmacological agents can be determined. Methodological pitfalls are, however, possible unless care is taken to avoid unspecific stress factors, general anaesthesia and intracerebral injections at unphysiological concentrations. The role of different neurotransmitters in the central TRH-TSH regulation has been clarified in recent years and the simple concepts of the early days elaborated accordingly. The cold-stimulated TSH secretion can be modified by several neurotransmitters. Noradrenaline is a stimulatory transmitter at high hypothalamic centers, but it may also retard TRH release into the portal vessels. It also seems possible that alpha 1- and alpha 2-receptors mediate opposite effects. Nigrostriatal (but not tuberoinfundibular) dopamine has only an inhibitory action on TRH release and/or synthesis. The importance of 5-HT is still controversial, partly because of the unspecificity of the experimental tools available. Evidently both stimulating and inhibiting components are involved. The role of different 5-HT receptors remains to be established. The function of GABA is complicated, too, the real GABAergic action being an inhibition of TRH release from the medial basal hypothalamus. Only histamine and some amino acids affect TRH-induced TSH secretion. Hence the anterior pituitary in the rat is not so important a locus as the hypothalamus in the action of neurotransmitters on the TRH-TSH regulation.     

Variations in the response of enzyme-dissociated rat pituitary cells to thyrotropin releasing hormone.

While exploring the interaction between thyrotropin releasing hormone (TRH) and normal rat anterior pituitary cells in monolayer culture we observed that cells dissociated with the use of trypsin did not respond to TRH with an increase in either TSH or prolactin (PRL) release. The dissociated cells were cultured for 3 days, then washed to remove serum proteins and exposed to 10^?6M TRH for 3 hours. TSH and PRL secretion from stimulated and unstimulated cultures was determined by radio-immunoassay and normalized using cell protein. When such trypsin-dissociated cells were exposed to 0.5 mM dibutyryl cyclic AMP the release of both TSH and PRL doubled indicating that the intracellular secretory machinery was functional and that the block to TRH was proximal to the formation of cyclic AMP and presumably at the level of a TRH surface receptor. Previous studies have shown that such trypsin-dissociated cells respond to LHRH and a crude hypothalamic extract with a dose dependent increase in LH, FSH and ACTH release. This rules out a non-specific effect of trypsin. When pituitary cells were dissociated with a non-trypsin technique, the unstimulated release of both TSH and PRL was comparable to that found with the trypsin-dissociated cultures. However, these cultures did respond to TRH with an increase in TSH release although again no effect was seen with PRL. The susceptibility of the cells to trypsin suggests the possibility that a protein moiety may be closely associated with the function of the receptor.     

Abnormalities of the thyroid hormone negative feedback regulation of TSH secretion in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) are characterized by several neuroendocrine abnormalities including a chronic hypersecretion of thyrotropin (TSH) of unknown etiology. We hypothesized that the inappropriately high TSH secretion in SHR may be the result of an impaired thyroid hormone negative feedback regulation of hypothalamic thyrotropin-releasing hormone (TRH) and/or pituitary TSH production. To test this hypothesis, SHR or their normotensive Wistar-Kyoto (WKY) controls were treated with either methimazole (0.02% in drinking water) to induce hypothyroidism or administered L-thyroxine (T4) at a dose of 0.8 or 2.0 micrograms/100 g body weight/day to induce hyperthyroidism. All treatments were continued for 14 days after which animals were killed under low stress conditions. TSH concentrations in plasma and anterior pituitary tissue were 2-fold higher (P less than 0.01) in euthyroid SHR compared to WKY control rats while thyroid hormone (T3 and T4) levels were in the normal range. Hypothyroidism induced by either methimazole or thyroidectomy caused a significant (P less than 0.01) rise of plasma TSH levels in both WKY and SHR rats. However, relative to the TSH concentrations in control animals, the increase of plasma TSH in SHR was significantly blunted (P less than 0.01) in comparison to the WKY group. Hypothyroidism caused a significant depletion of TRH in stalk-median eminence (SME) tissue in both groups of rats. However, no differences between SHR and WKY rats were observed. The administration of thyroid hormone caused a dose dependent suppression of plasma TSH levels in both strains of rats. However, at both doses tested plasma TSH concentrations in SHR rats were significantly less suppressed (P less than 0.05) than those in WKY animals. Under in vitro conditions basal and potassium induced TRH release from SMEs derived from SHR was significantly (P less than 0.05) higher than that from WKY rats, whether expressed in absolute terms or as percent of content. These findings suggest that the thyroid hormone negative feedback regulation of TSH secretion may be impaired in SHR rats. Our data do not allow conclusions as to whether defects in the regulation of TSH production are located exclusively at the hypothalamic level. Since the overproduction of hypothalamic TRH and hypophysial TSH should lead to an increased thyroid hormone biosynthesis other defects in the hypothalamus-pituitary-thyroid-axis may contribute to the abnormal regulation of TSH secretion in SHR rats.     

Neuro-endocrine correlations of hypothalamic-pituitary-thyroid axis in healthy humans

Neuro-endocrine hormone secretion is characterized by circadian rhythmicity. Melatonin, GRH and GH are secreted during the night, CRH and ACTH secretion peak in the morning, determining the circadian rhythm of cortisol secretion, TRH and TSH show circadian variations with higher levels at night. Thyroxine levels do not change with clear circadian rhythmicity. In this paper we have considered a possible influence of cortisol and melatonin on hypothalamic-pituitary-thyroid axis function in humans. Melatonin, cortisol, TRH, TSH and FT4 serum levels were determined in blood samples obtained every four hours for 24 hours from ten healthy males, aged 36-51 years. We correlated hormone serum levels at each sampling time and evaluated the presence of circadian rhythmicity of hormone secretion. In the activity phase (06:00 h-10:00 h-14:00 h) cortisol correlated negatively with FT4, TSH correlated positively with TRH, TRH correlated positively with FT4 and melatonin correlated positively with TSH. In the resting phase (18:00 h-22:00 h-02:00 h) TRH correlated positively with FT4, melatonin correlated negatively with FT4, TSH correlated negatively with FT4, cortisol correlated positively with FT4 and TSH correlated positively with TRH. A clear circadian rhythm was validated for the time-qualified changes of melatonin and TSH secretion (with acrophase during the night), for cortisol serum levels (with acrophase in the morning), but not for TRH and FT4 serum level changes. In conclusion, the hypothalamic-pituitary-thyroid axis function may be modulated by cortisol and melatonin serum levels and by their circadian rhythmicity of variation.     

Effects of histamine and related compounds on thyrotropin secretion in rats

The effects of histamine (HA) and related compounds on thyrotropin-releasing hormone (TRH) and thyrotropin (TSH) secretion in rats were studied. Histidine (1.0 g/kg), HA (5.0 mg/kg) or histamine antagonists mepyramine (MP) (100 mg/kg) or famotidine (FA) (5.0 mg/kg) were injected intraperitoneally, and the rats were decapitated at various intervals after the injection. The hypothalamic immunoreactive TRH (ir-TRH) content increased significantly after histidine or HA injection, decreased significantly after FA injection, but was not changed by MP. The plasma ir-TRH concentration did not change significantly after injection of these drugs. The plasma TSH levels decreased significantly in a dose-related manner after histidine or HA injection and increased significantly in a dose-related manner after FA injection. The plasma thyroid hormone levels showed no changes. In the FA-pretreated group, the inhibitory effect of histidine or HA on TSH levels was prevented, but not in the MP-pretreated group. The plasma ir-TRH and TSH responses to cold were inhibited by histidine or HA and enhanced by FA. The plasma TSH response to TRH was inhibited by histidine or HA and enhanced by FA. The inactivation of TRH immunoreactivity by hypothalamus or plasma in vitro after histidine, HA, MP or FA was not different from that of the control. These findings suggest that histamine may act both on the hypothalamus and the pituitary to inhibit TRH and TSH release, and that its effects may be mediated via H2-receptor.     

Dexamethasone stimulates thyrotropin-releasing hormone production in a C cell line

The hypothalamic peptide hormone TRH is also found in other tissues, including the thyroid. While TRH may be regulated by T3 in the hypothalamus, other regulators of TRH have not been identified and the regulation of TRH in nonhypothalamic tissues is unknown. We recently demonstrated the biosynthesis of TRH in the CA77 neoplastic thyroidal C cell line. We studied the regulation of TRH by dexamethasone in this cell line because glucocorticoids have been postulated to inhibit TSH secretion by decreasing TRH in the hypothalamus. Furthermore, TRH in the thyroid inhibits thyroid hormone release. Thus by regulating thyroidal TRH, glucocorticoids could also directly affect thyroid hormone secretion. Treatment of CA77 cells for 4 days with dexamethasone produced dose-dependent increases in both TRH mRNA and cellular and secreted TRH. Increases in TRH mRNA and peptide levels could be seen with 10(-9) M dexamethasone. A 4.8-fold increase in TRH mRNA and a 4-fold increase in secreted peptide were seen with 10(-7) M dexamethasone. Dexamethasone treatment did not increase beta-actin mRNA levels or cell growth. These results suggest that glucocorticoids may be physiological regulators of TRH in normal C cells. In addition to their inhibitory effects on TSH, glucocorticoids may decrease thyroid hormone levels by increasing thyroidal TRH. Since the glucocorticoid effects on C cell TRH are the converse of what is expected for hypothalamic TRH, glucocorticoid effects in these two tissues may be mediated by different regulators.     

Thyrotropin Releasing Hormone (TRH) in goldfish (Carassius auratus): role in the regulation of feeding and locomotor behaviors and interactions with the orexin system and cocaine- and amphetamine regulated transcript (CART)

TRH is a peptide produced by the hypothalamus which major function in mammals is the regulation of TSH secretion by the pituitary. In fish, TRH does not appear to affect TSH secretion, suggesting that it might regulate other functions. In this study, we assessed the effects of central (intracerebroventricular, icv) injections of TRH on feeding and locomotor behavior in goldfish. TRH at 10 and 100 ng/g, but not 1 ng/g, significantly increased feeding and locomotor behaviors, as indicated by an increase in food intake and in the number of total feeding acts as compared to saline-injected fish. In order to assess possible interactions between TRH and other appetite regulators, we examined the effects of icv injections of TRH on the hypothalamic expression of orexin, orexin receptor and CART. The mRNA expression levels of all three peptides were significantly increased in fish injected with TRH at 100 ng/g as compared to saline-injected fish. Fasting increased TRH, orexin, and orexin receptor hypothalamic mRNA levels and decreased CART hypothalamic mRNA levels. Our results suggest that TRH is involved in the regulation of feeding/locomotor activity in goldfish and that this action is associated with a stimulation of both the orexin and CART systems.     

Effect of bromocriptine on serum TSH in euthyroid patients with endocrine disorders

In 10 euthyroid subjects a single 2.5 mg per os dose of bromocriptine caused rapid and remarkable decreases in serum TSH. As much as a 0.85 +/- 0.18 (s.d.) microU/ml decrease from the basal level (56 +/- 9%) was observed at 5 hours. A good correlation was observed between the basal TSH level and the TSH decrease after bromocriptine (r = 0.786). In 4 patients taking 5 to 15 mg bromocriptine daily (chronic administration group), another 2.5 mg bromocriptine also caused significant decreases in serum TSH, but the degree (0.42 +/- 0.03 microU/ml, 43 +/- 26% of basal) and duration (maximal at 4 hours) were less than those observed in the untreated group. The lowest TSH levels in these two groups did not differ significantly (0.80 +/- 0.45 and 0.78 +/- 0.53 microU/ml, respectively). The TSH decrease after bromocriptine in the untreated group was found not to correlate significantly with TRH induced TSH increase (r = 0.300). TRH induced TSH increase in the chronic administration group was similar to or greater than that of control subjects with matched basal TSH. The TSH lowering effects of per os prednisolone and triiodothyronine were also studied. Prednisolone exerted a quite similar effect to bromocriptine, but a certain time lag was observed in the case of triiodothyronine. A single dose of bromocriptine was found to lower serum TSH levels even in euthyroid subjects. The effect was considered to be independent of TRH-TSH regulation and to act directly on the TSH release.     

Potentiation by indomethacin of TRH-induced TSH secretion in the rat.

We have studied the effect of two inhibitors of prostaglandin synthesis on the basal and TRH-stimulated plasma TSH levels in the rat. Animals were injected sc daily with indomethacin 3 mg/0.5 ml) or aspirin (16--30 mg/0.5 ml) for 3 days. The plasma T4 and T3 were consistently lower in the indomethacin or aspirin groups than in the controls, while the basal TSH levels did not change. Indomethacin treatment significantly potentiated the TSH response to synthetic TRH (20 ng. iv) in intact and thyroidectomized rats. The pituitary TSH content was markedly increased by indomethacin, while hypothalamic TRH content did not change. In contrast, aspirin inhibited the TSH response to TRH in intact rats, when pituitary TSH content decreased significantly. No potentiation by aspirin of TRH-stimulated TSH response in the thyroidectomized rats was observed. The increased sensitivity of plasma TSH response to exogenous TRH in the indomethacin group is presumably due to higher pituitary TSH content than in the controls. The action of indomethacin appears to be mediated, at least in part, at the pituitary level. In addition, there is a dissociation between the action of indomethacin and the action of aspirin in the TSH response to TRH.     

Cell swelling induced secretion of TRH by posterior pituitary,hypothalamic paraventricular nucleus and pancreatic islets: effect of L-canavanine

The aims of this study were to test if ethanol induces thyrotropin-releasing hormone (TRH) secretion in vitro from the posterior pituitary and hypothalamic explants by a mechanism involving cell swelling, and to characterize the pathway of stimulated secretion. Ethanol, at a concentration of 80 mM, stimulated the release of TRH from the posterior pituitary, the hypothalamic paraventricular nucleus, the median eminence, and the brain septum, when administered only in isosmolar but not in hyperosmolar medium. This indicates the involvement of a cell swelling-inducing mechanism. L-canavanine in a concentration of 3 mM, increased the basal and hyposmosis-induced TRH secretion from the posterior pituitary and the paraventricular nucleus, and both basal and ethanol-induced TRH secretion from isolated pancreatic islets. This indicates the presence of both constitutive and regulatory secretory pathways. Our results suggest that cell swelling induces exocytosis from clathrin coated granules.     

Nociceptin stimulates thyrotropin secretion in rats

Effects of nociceptin on thyrotropin (TSH) and thyrotropin-releasing hormone (TRH) secretion in rats were studied. Nociceptin (150 microgram/kg) was injected intravenously and rats were serially decapitated after the injection. The effects of nociceptin on TRH release from the hypothalamus and TSH release from the anterior pituitary in vitro were also investigated. TRH and thyroid hormones were measured by individual radioimmunoassays. TSH was determined by enzyme immunoassay. TRH contents in the hypothalamus decreased significantly after nociceptin injection, whereas plasma TRH concentrations showed no changes. Plasma TSH concentrations increased significantly in a dose-related manner. The TRH release from the hypothalamus was enhanced significantly in a dose-related manner with the addition of nociceptin. The TSH release from the anterior pituitary in vitro was not affected by the addition of nociceptin. The plasma thyroxine and 3,3',5-triiodothyronine levels did not change significantly after nociceptin administration. The inactivation of TRH by plasma or hypothalamus in vitro after nociceptin injection did not differ from that of controls. The findings suggest that nociceptin acts on the hypothalamus to stimulate TRH and TSH secretion.     

Effect of 3-hydroxy-4-1(H)pyridone on the basal and thyrotropin-releasing hormone-stimulated release of thyroid-stimulating hormone from perifused anterior pituitary fragments

This study investigated the direct effect of 3-hydroxy-4-1(H)-pyridone (DHP), the breakdown product of mimosine in the rumen, on thyroid-stimulating hormone (TSH) secretion by perifusion of rat anterior pituitary fragments. During a 2-h perifusion with thyrotropin-releasing hormone (TRH), the total release of TSH increased linearly (P less than 0.05, r = 0.966) with increasing concentration of TRH from 1 to 100 ng/ml. The release was maximal at 100 ng/ml. There were no differences in total basal TSH release among control and DHP-treated pituitary fragments. DHP at concentrations of 1, 10, and 100 micrograms/ml had no significant effect on the TSH response to TRH. However, DHP at the concentration of 1 mg/ml significantly suppressed the TSH response to TRH administered continuously or as a 10-min pulse. These results suggest that DHP modulates the pituitary thyrotroph's response to TRH.