Antagonism of prostaglandin-promoted pituitary cyclic amp accumulation and growth hormone secretion in vitro by 7-oxa-13-prostynoic acid

The studies reported here confirm the previously observed potent stimulus to growth hormone (GH) secretion by prostaglandin E₁ (PGE₁). Proportional increments in GH secretion were observed following $\text{in vitro}$ addition of PGE₁ over a concentration range of 10^?7 to 10^?5 M. Growth hormone secretion could not be further stimulated by higher concentrations of prostaglandin. Prostaglandin E₁ also increased cyclic AMP concentration in the pituitary explants in a proportional fashion, which correlated closely with its potency as a growth hormone secretogogue. In order to define more precisely the mechanism by which prostaglandin acts, the effects of prostaglandin antagonist, 7-oxa-13-prostynoic acid, on GH secretion and cyclic AMP accumulation were investigated. Addition of the antagonist alone had no consistent effects on GH secretion or cyclic AMP levels in the pituitary. However, the antagonist significantly reduced the stimulation of hormone release and cyclic AMP accumulation found following addition of PGE₁. Increasing the concentration of antagonist further diminished prostaglandin stimulated hormone release and nucleotide accumulation. The antagonist failed to block the stimulatory effects of theophylline and dibutyryl cyclic AMP on GH release, indicating that the inhibition observed occurred prior to intracellular accumulation of the cyclic nucleotide. These results are consistent with the hypothesis that a prostaglandin receptor on the pituitary somatotrope is linked to the adenyl cyclase-cyclic AMP system.     

The regulation of growth hormone secretion from the isolated rat anterior pituitary in vitro. The role of adenosine 3′:5′-cyclic monophosphate

1. The release of growth hormone from isolated fragments of rat anterior pituitary tissue incubated in vitro was studied by employing a double-antibody radioimmunoassay. 2. In the absence of added stimuli, two phases of hormone release could be distinguished, an early phase of 2h duration and a subsequent late phase. In the early phase, hormone release was rapid but could be significantly decreased by calcium depletion and by 2,4-dinitrophenol whereas the rate of release in the late phase was uninfluenced by these incubation conditions. These results have been interpreted as indicating the existence of a secretory component in the early phase of release. 3. In subsequent experiments, the effects of various agents on the rate of hormone output during the late phase of incubation were investigated. Hormone release was increased by theophylline and by dibutyryl cyclic AMP (N(6)-2'-O-dibutyryl-adenosine 3':5'-cyclic monophosphate), the response to both of these agents being related to the concentration of the stimulant employed. 4. The stimulation of growth hormone output by theophylline was significantly decreased by calcium deprivation and by 2,4-dinitrophenol. The response to dibutyryl cyclic AMP was diminished by 2,4-dinitrophenol, iodoacetate and 2-deoxyglucose but not by malonate or colchicine. 5. Arginine, beta-hydroxybutyrate, albumin-bound palmitate and variation in the glucose concentration of the incubation medium over a wide range were without any statistically significant effect on the rate of hormone release from either control pituitary fragments or those subject to secretory stimulation by dibutyryl cyclic AMP. 6. It is suggested that the regulation of growth hormone secretion is mediated by cyclic AMP (adenosine 3':5'-cyclic monophosphate). The secretion observed in response to cyclic AMP requires the presence of ionized calcium and a source of metabolic energy but is independent of pituitary protein synthesis de novo. The integrity of the glycolytic pathway of glucose metabolism appears to be essential for cyclic AMP-stimulated growth hormone secretion to occur.     

Verapamil: influence upon basal and stimulated rat growth hormone and prolactin release in vitro

Verapamil is an organic calcium antagonist which is believed to prevent the passage of calcium (Ca2+) across the cell membrane into the cell. In a rat pituitary perifusion-immunoprecipitation system, verapamil (50 microM) prevents the inhibitory effect of increased extracellular Ca2+ (5.4 mM) on basal and stimulated release of stored, prelabeled [3H]GH and [3H]PRL. [3H]GH release from pituitary explants perifused in standard medium (GIBCO Minimum Essential Medium: 1.8 mM Ca2+) is transiently increased by 50 microM verapamil while [3H]PRL release is suppressed. With continued exposure to 50 microM verapamil, [3H]GH release rates fall below (89.8 +/- 2.1% of base) preverapamil levels while [3H]PRL release rates simply remain suppressed (48.2 +/- 7.3% of base). With 250 microM verapamil, poststimulatory inhibition of [3H]GH release occurs more quickly, and after its withdrawal rebound release of both GH and PRL occur. Inhibition of [3H]GH release by 25 nM somatostatin (SRIF) and post-SRIF rebound [3H]GH release is not prevented by 50 microM verapamil. The early, rapid [3H]GH release phase of 1 mM dibutyryl cyclic AMP (dbcAMP) stimulation is potentiated by verapamil pretreatment, but only if the verapamil is continued during dbcAMP stimulation. Potassium (21 mM K+)-stimulated release of both 3H-labeled hormones is inhibited after similar pretreatment 50 microM verapamil. Conclusions: (a) verapamil antagonizes the inhibitory effects of increased extracellular Ca2+ on basal or dbcAMP-stimulated [3H]GH and [3H]PRL release; (b) in standard medium (1.8 mM Ca2+), 50 microM verapamil increases basal [3H]GH release suggesting either a direct effect or an antagonism of 1.8 mM extracellular Ca2+; (c) although verapamil-sensitive Ca2+ movement is not necessary for dbcAMP stimulation of [3H]GH release, verapamil potentiates dbcAMP-stimulated release; (d) because verapamil also inhibits K+-stimulated [3H]GH and [3H]PRL release, these observations support previous suggestions that K+- and dbcAMP-stimulated rapid hormone release occurs from different intracellular sites; and (e) because verapamil does not prevent any phase of SRIF action and since these two agents differentially alter K+- and cAMP-stimulated release, their mechanisms of action must partially differ.     

Effects of antimicrotubule agents, potassium and inhibitors of energy production on hCG secretion

The BeWo trophoblastic cell line was employed to assess the requirement for microtubules and cellular energy in human chorionic gonadotropin (hCG) secretion. In contrast to the general inhibitory effect of colchicine and vincristine on hormone secretion in systems involving exocytosis, wide concentration ranges of these antimicrotubule agents caused enhancement of hCG secretion. Similarly, cytochalasin B, an agent that interferes with microfilament function, doubled both basal hCG secretion, and secretion of hCG stimulated by 1 mM dibutyryl cyclic AMP plus 1 mM theophylline (dbT). Inhibitors of cellular energy production (2,4-dinitrophenol, malonate, azide) decreased both secreted and cellular levels of hormone. High concentrations of K+ gave no enhancement of basal or dbT-stimulated hCG secretion, nor any reduction of cellular hCG levels. These findings contrasted with observations of others in secretory systems involving exocytosis, in which high K+ potentiated basal or stimulated hormone release and depleted cellular stores of hormone. It was concluded that the process of hCG secretion in the malignant trophoblast is fundamentally different from the mechanism of protein hormone secretion in other tissues.     

Calmodulin modulates prolactin secretion in vitro: studies with calmodulin containing liposomes

The control of prolactin secretion by Ca calmodulin and cyclic AMP was studied. Ca++ ionophore A23187 stimulated both cyclic AMP accumulation and prolactin release by primary culture of anterior pituitary cells in vitro. The increase of cyclic AMP formation by A23187 preceded that of prolactin release. To test the calmodulin involvement in these processes we used either selective calmodulin antagonist, the naphthalene sulphonamide derivative W7, or calmodulin containing liposomes. W7 dose dependently inhibited both basal or A23187 stimulated cyclic AMP accumulation and prolactin secretion. Insertion of Ca calmodulin within the cells stimulated prolactin secretion without modifying cyclic AMP accumulation. W7 inhibited the Ca calmodulin containing liposomes stimulation of prolactin release. These results suggest that calmodulin participates to the process of prolactin release.     

Effects of growth hormone-releasing factor and somatostatin on growth hormone secretion and cellular cyclic AMP levels. Cultured ovine and rat anterior pituitary cells show markedly different responses

Human pancreatic growth hormone-releasing factor (GRF-44-NH2) stimulated growth hormone (GH) secretion and intracellular cyclic AMP levels in cultured pituitary cells from both sheep and rat. Somatostatin (SRIF), over a wide range of doses and time, showed no significant effect on the elevated cyclic AMP levels in sheep cells, but did block the GH release in a dose-dependent manner. In rat cells, however, SRIF inhibited GRF-stimulated cyclic AMP levels by 75% maximum (still 8-fold greater than the basal levels) and GH release to almost half the basal value. We conclude that somatostatin inhibits GRF-elevated cyclic AMP levels in rat pituitary cells but not in sheep cells.     

Effects of growth hormone-releasing factor, somatostatin and dopamine on growth hormone and prolactin secretion from cultured ovine pituitary cells

A synthetic form of human pancreatic growth hormone releasing factor (GRF-44-NH2) was shown to be a potent stimulator of growth hormone (GH) secretion and cellular cyclic AMP levels in cultured sheep pituitary cells. A small dose-dependent stimulation of prolactin secretion was also observed. Somatostatin (0.5 microM) completely blocked the maximal GRF (1 nM)-stimulated secretion without a significant effect on cyclic AMP levels. Dopamine (0.1 microM) inhibited the GRF-elevated GH secretion by 50% and lowered cyclic AMP levels by 30%. Dopamine (0.1 microM) inhibition of basal prolactin secretion was not affected by GRF (1 nM). The data support the hypothesis that cyclic AMP is involved in the action of GRF but suggest that somatostatin can inhibit GRF-induced secretion of GH independently of cyclic AMP.     

Adenosine 3'',5''-cyclic monophosphate-dependent release of prolactin from GH3 pituitary tumour cells. A quantitative analysis.

The involvement of cyclic AMP in mediating regulatory peptide-controlled prolactin release from GH3 pituitary tumour cells was investigated. Cholera toxin and forskolin elicited concentration-dependent increases in both GH3 cell cyclic AMP content and prolactin release. The maximum rise in prolactin release with these agents was 2-fold over basal. 8-Bromo-cyclic AMP produced a similar stimulation of prolactin release. The phosphodiesterase inhibitor isobutylmethylxanthine also produced an increase in prolactin release and GH3 cell cyclic AMP content. However, the magnitude of the stimulated prolactin release exceeded that obtained with any other agent. Thyrotropin-releasing hormone (thyroliberin) and vasoactive intestinal polypeptide produced a concentration-dependent rise in both cell cyclic AMP content and prolactin release. However, only vasoactive intestinal polypeptide elicited an increase in cell cyclic AMP content at concentrations relevant to the stimulation of prolactin release. Vasoactive intestinal polypeptide and thyrotropin-releasing hormone, when used in combination, were additive with respect to prolactin release. Vasoactive intestinal polypeptide and forskolin, at concentrations that were maximal upon prolactin release, were, when used in combination, synergistic upon GH3 cell cyclic AMP content but were not additive upon prolactin release. In conclusion the evidence supports a role for cyclic AMP in the mediation of vasoactive intestinal polypeptide- but not thyrotropin-releasing hormone-stimulated prolactin release from GH3 cells. A quantitative analysis indicates that a 50-100% rise in cyclic AMP suffices to stimulate cyclic AMP-dependent prolactin release fully.     

Effects of antimicrotubule agents,potassium and inhibitors of energy production on hCG secretion

Summary The BeWo trophoblastic cell line was employed to assess the requirement for microtubules and cellular energy in human chorionic gonadotropin (hCG) secretion. In contrast to the general inhibitory effect of colchicine and vincristine on hormone secretion in systems involving exocytosis, wide concentration ranges of these antimicrotubule agents caused enhancement of hCG secretion. Similarly, cytochalasin B, an agent that interferes with microfilament function, doubled both basal hCG secretion, and secretion of hCG stimulated by 1mm dibutyryl cyclic AMP plus 1mm theophylline (dbT). Inhibitors of cellular energy production (2,4-dinitrophenol, malonate, azide) decreased both secreted and cellular levels of hormone. High concentrations of K⁺ gave no enhancement of basal or dbT-stimulated hCG secretion, nor any reduction of cellular hCG levels. These findings contrasted with observations of others in secretory systems involving exocytosis, in which high K⁺ potentiated basal or stimulated hormone release and depleted cellular stores of hormone. It was concluded that the process of hCG secretion in the malignant trophoblast is fundamentally different from the mechanism of protein hormone secretion in other tissues. This investigation was supported by Grant No. CA 23357 awarded by the National Cancer Institute, DHEW.     

Dexamethasone is a potent stimulator of growth hormone-releasing factor-induced cyclic AMP accumulation in the adenohypophysis

The stimulatory effect of maximal concentrations of synthetic human pancreatic growth hormone (GH)-releasing factor (GRF)(1-40)NH on cyclic AMP accumulation in rat anterior pituitary cells in culture is 4.5-fold increased following a 48-h preincubation with the potent glucocorticoid dexamethasone while the sensitivity of GRF action is increased by approximately 4-fold. Dexamethasone pretreatment, on the other hand, has no effect on basal cyclic AMP levels but approximately doubles both basal and GRF-induced GH release. The present data suggest that the potent stimulatory effect of glucocorticoids on GH secretion is exerted on the adenylate cyclase system at a step preceding cyclic AMP formation.     

Effects of dopamine on prolactin secretion and cyclic AMP accumulation in the rat anterior pituitary gland

The effects of dopamine on pituitary prolactin secretion and pituitary cyclic AMP accumulation were studied by using anterior pituitary glands from adult female rats, incubated in vitro. During 2h incubations, significant inhibition of prolactin secretion was achieved at concentrations between 1 and 10nm-dopamine. However, 0.1–1μm-dopamine was required before a significant decrease in pituitary cyclic AMP content was observed. In the presence of 1μm-dopamine, pituitary cyclic AMP content decreased rapidly to reach about 75% of the control value within 20min and there was no further decrease for at least 2h. Incubation with the phosphodiesterase inhibitors theophylline (8mm) or isobutylmethylxanthine (2mm) increased pituitary cyclic AMP concentrations 3- and 6-fold respectively. Dopamine (1μm) had no effect on the cyclic AMP accumulation measured in the presence of theophylline, but inhibited the isobutylmethylxanthine-induced increase by 50%. The dopamine inhibition of prolactin secretion was not affected by either inhibitor. Two derivatives of cyclic AMP (dibutyryl cyclic AMP and 8-bromo cyclic AMP) were unable to block the dopamine (1μm) inhibition of prolactin secretion, although 8-bromo cyclic AMP (2mm) significantly stimulated prolactin secretion and both compounds increased somatotropin (growth hormone) release. Cholera toxin (3μg/ml for 4h) increased pituitary cyclic AMP concentrations 4–5-fold, but had no effect on prolactin secretion. The inhibition of prolactin secretion by dopamine was unaffected by cholera toxin, despite the fact that dopamine had no effect on the raised pituitary cyclic AMP concentration caused by this factor. Dopamine had no significant effect on either basal or stimulated somatotropin secretion under any of the conditions tested. We conclude that the inhibitory effects of dopamine on prolactin secretion are probably not mediated by lowering of cyclic AMP concentration, although modulation of the concentration of this nucleotide in some other circumstances may alter the secretion of the hormone.     

Zinc supplementation does not inhibit basal and metoclopramide-stimulated prolactinemia secretion in healthy men.

Dopamine (DA) and zinc (Zn++) share common mechanisms in their inhibition of prolactin (PRL) secretion. Both substances are present in the same brain areas, where Zn++ is released together with DA, suggesting a modulatory effect of Zn++ on dopaminergic receptors. The aim of the present study was to evaluate the effect of Zn++ supplementation on basal and PRL secretion stimulated by metoclopramide (MCP), a dopaminergic antagonist. Seven healthy men were evaluated in controlled study, where MCP (5 mg) was given intravenously, before and after 3 months of oral Zn++ (25 mg) administration. Our results indicate that chronic Zn++ administration does not change basal or MCP-stimulated plasma PRL secretion suggesting that, in humans, Zn++ does not interfere on PRL secretion mediated through dopaminergic receptors.     

Insulin release from BK virus-induced and in vitro maintained insulinoma cells of Syrian golden hamster

The pancreatic tumor cells (In 111) derived from BK virus-induced insulinoma of Syrian golden hamsters were maintained in culture for several passages and were studied for their insulin secretory ability under various stimulatory conditions. Insulin release was not increased by D-glucose stimulation (27.8 mM), while dibutyryl cyclic AMP (1 mM), theophylline (1 mM), 3-isobutyl-l-methylxanthine (0.1 mM) and elevation of medium calcium from 0.5 to 2.7 mM stimulated insulin release 2.5- to 4-fold. There was a concomitant increase of medium cyclic AMP with addition of theophylline. Streptozotocin (2 mM) treatment for 48 hours significantly reduced insulin release, while alloxan (2 mM), had no inhibitory effect on insulin release. The results indicate that while in vitro-maintained islet tumor cells, In 111, have a cyclic AMP-mediated process involved in insulin secretion analogous to normal beta cells, these cells lack the ability to recognize glucose as an insulin secretagogue probably due to a defect in the cell membrane, though the possibility of alteration in glucose metabolism cannot be fully excluded.     

Cyclic AMP and platelet prostaglandin synthesis.

The present study has investigated the influence of agents which elevate intracellular levels of endogenous platelet adenosine 3'5'-cyclic monophosphate (cyclic AMP), and the effect of the exogenous cyclic AMP analog, dibutyryl cyclic AMP, on the conversion of 14C-arachidonic acid by washed platelets. Prostaglandin E1 (PGE1), PGE1 with theophylline, or dibutyryl cyclic AMP incubated with washed platelets prevented arachidonic acid induced platelet aggregation, but had no effect on the conversion of arachidonic acid to 12L-hydroxy-5,8,10, 14-eicosatetraenoic acid (HETE), 12L-hydroxy-5,8,10 heptadecatrienoic acid (HHT), or thromboxane B2. Ultrastructural studies of the platelet response revealed that agents acting directly or indirectly to increase the level of cyclic AMP inhibited the action of arachidonic acid on washed platelets and prevented internal platelet contraction as well as aggregation. The influence of PGE1 with theophylline, and dibutyryl cyclic AMP on the thrombin induced release of 14C-arachidonic acid from platelet membrane phospholipids was also investigated. These agents were found to be potent inhibitors of the thrombin stimulated release of arachidonic acid from platelet phospholipids, due most likely to an inhibition of platelet phospholipase A activity. The results show that dibutyryl cyclic AMP and agents which elevate intracellular cyclic AMP levels act to inhibit platelet activation at two steps 1) internal contraction and 2) release of arachidonic acid from platelet phospholipids.     

Effects of pretreatment with tetradecanoyl phorbol acetate on regulation of growth hormone and prolactin secretion from ovine anterior pituitary cells

Tetradecanoyl phorbol acetate (TPA) stimulates growth hormone (GH) and prolactin secretion from ovine anterior pituitary cells. Pretreatment of the cells with TPA abolishes this effect, presumably due to down-regulation of protein kinase C. Such pretreatment did not alter effects of thyrotropin-releasing hormone or dopamine on prolactin secretion, suggesting no involvement of protein kinase C. Pretreatment with TPA attenuated actions of GH-releasing hormone on GH release (but not actions on cyclic AMP levels), possibly due to depletion of cellular stores of GH. Such pretreatment also attenuated inhibition of GH release by somatostatin, possibly due to phosphorylation of receptors or associated proteins by protein kinase C.     

Muscarinic acetylcholine receptor activation causes inhibition of cyclic AMP accumulation, prolactin and growth hormone secretion in GH3 rat anterior pituitary tumour cells

Acetylcholine, oxotremorine and carbachol, compounds that exhibit muscarinic agonist activity, maximally inhibited basal prolactin secretion from GH3 cells by approx. 50% and intracellular cyclic AMP levels by approx. 20%. Both parameters were inhibited with similar potencies by each agonist. These inhibitory effects were blocked by a muscarinic but not by a nicotinic receptor antagonist. In the presence of VIP or IBMX, which raise intracellular cyclic AMP levels and stimulate hormone release, the degree of muscarinic inhibition was increased, but the potency remained unchanged. Similar changes in the secretory rate of prolactin and growth hormone occurred in these and in cell perifusion experiments. These results suggest that the inhibition of hormone secretion from GH3 cells by muscarinic agonists is mediated by a decrease in intracellular cyclic AMP levels.     

Evidence for differential synthesis of thyroxine and tri-iodothyronine by cultured human thyroid cells following exposure to thyrotrophin or dibutyryl cyclic AMP.

Cultured human thyroid cells treated with thyrotrophin (TSH) or dibutyryl cyclic AMP release more tri-iodothyronine (T3) and thyroxine (T4) than unsupplemented cells. Column chromatography was used to investigate the secretion of newly-synthesised 125-I labelled T3 and T4 from cells cultured with 125-I and TSH or dibutyryl cyclic AMP. Radioimmunoassays were used to determine total T3 and T4 release from cells cultured with unlabelled iodide.Iodothyronines released after TSH addition contained more 125-I than those released after dibutyryl cyclic AMP. This increase in 125-I was primarily in “new” T4. Release of “new” T3, however, was increased more by dibutyryl cyclic AMP than by TSH. Dibutyryl cyclic AMP and TSH were comparable in their stimulation of total T3 and total T4 release.Interpretation of these observations suggests that TSH and dibutyryl cyclic AMP may differ in some aspects of their in vitro effects on cellular iodination and iodothyronine coupling systems.     

Endocrine actions of opioids

The widespread occurrence of opioid peptides and their receptors in brain and periphery correlates with a variety of actions elicited by opioid agonists and antagonists on hormone secretion. Opioid actions on pituitary and pancreatic peptides are summarized in Table 1. In rats opioids stimulate ACTH and corticosterone secretion while an inhibition of ACTH and cortisol levels was observed in man. In both species, naloxone, an opiate antagonist, stimulates the release of ACTH suggesting a tonic suppression by endogenous opioids. In rats, a different stimulatory pathway must be assumed through which opiates can stimulate secretion of ACTH. Both types of action are probably mediated within the hypothalamus. LH is decreased by opioid agonists in many adult species while opiate antagonists elicit stimulatory effects, both apparently by modulating LHRH release. A tonic, and in females, a cyclic opioid control appears to participate in the regulation of gonadotropin secretion. Exogenous opiates potently stimulate PRL and GH secretion in many species. Opiate antagonists did not affect PRL or GH levels indicating absence of opioid control under basal conditions, while a decrease of both hormones by antagonists was seen after stimulation in particular situations. In rats, opiate antagonists decreased basal and stress-induced secretion of PRL. Data regarding TSH are quite contradictory. Both inhibitory and stimulatory effects have been described. Oxytocin and vasopressin release were inhibited by opioids at the posterior pituitary level. There is good evidence for an opioid inhibition of suckling-induced oxytocin release. Opioids also seem to play a role in the regulation of vasopressin under some conditions of water balance. The pancreatic hormones insulin and glucagon are elevated by opioids apparently by an action at the islet cells. Somatostatin, on the contrary, was inhibited. An effect of naloxone on pancreatic hormone release was observed after meals which contain opiate active substance. Whether opioids play a physiologic role in glucose homeostasis remains to be elucidated.     

An increase of pituitary 3', 5' cyclic adenosine monophosphate produced by estradiol benzoate in vitro: possible implication of this increase in the secretion of luteinizing hormone.

In an attempt to study the site and mechanism of action of estrogen in producing positive feedback control, porcine anterior pituitary slices were incubated in vitro in the presence of estradiol benzoate (EB). EB elevated pituitary cyclic AMP concentration within 5 min and augmented pituitary release of luteinizing hormone (LH). The magnitude of increase of cyclic AMP and LH release was related to the doses of EB used. Also, luteinizing hormone releasing hormone (LH-RH) elevated pituitary cyclic AMP concentration and stimulated pituitary release of LH. The magnitude of increase of cyclic AMP and LH release was inversely related to the doses of LH-RH used. EB and LH-RH were additive in increasing cyclic AMP. Progesterone and clomiphene citrate interfered with an increase of pituitary cyclic AMP produced by EB, but did not significantly affect the basal level of pituitary cyclic AMP. Testosterone propionate, human chorionic gonadotropin and hexestrol were without effect on either basal or stimulated level of pituitary cyclic AMP. Since cyclic AMP and dibutyryl cyclic AMP (DBC) stimulated LH release, it is suggested that EB directly stimulates the release of LH by augmenting cyclic AMP synthesis in the anterior pituitary.     

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.