Effect of thyrotropic hormone on the membrane potential of thyroid gland cells and thyroid hormone secretion with aging

Effect of thyrotropic hormone (TTH) on membrane potential (MP) of thyroid cells and thyroid hormone secretion was studied in experiments on male rats of two age groups (7--12- and 27--32-month-old animals). It was found that during the first 3 hours after TTH administration (5 U/100 g i. v.) the depolarization of secretory cell membranes of adult rats was done pronounced and developed more rapidly than in old ones and that an increase in free thyroxin (T4) correlation with MP changes with time. In a dose of 0.5 U/100 g TTH caused a significant rise in T4 secretion only in old rats. The cAMP level in the thyroid gland declined with aging. In a dose of 5 U/100 g TTH provoked a significant increase in the cAMP content in adult rats and had no effect on its content in old ones. A relationship between the MP level of thyroid secretory cells and thyroid hormone secretion is discussed.     

Epiphysis cerebri-thyroid interrelations. Distorting effect of partial thyroidectomy on the antithyroid action of epiphyseal methoxyindoles in animal experiments

The effect of pineal methoxyindoles (MI) on hypothalamus-hypophysis-thyroid gland system was studied in intact and partially thyroidectomized male Wistar rats in conditions of a short light day (winter). Melatonin administration for 10 days suppressed 131I uptake by the thyroid gland and decreased the levels of T3, T4 and thyrotropic hormone (TTH) in the blood serum of intact animals, with TTH reaction to thyroid hormone (TH) retained. 5-methoxytryptamine administration was less effective. Partial thyroidectomy distorted the direction of MI effect: melatonin and to a lesser extent 5-methoxytryptamine caused a marked normalization of a decreased TH content and an increased TTH level in the blood serum of partially thyroidectomized rats. TTH-TH reaction also corresponded to the control. A predominantly modulating character or pineal MI effect on thyroid system is suggested.     

Effect of thyroliberin (thyrotropin-releasing-hormone) on secretion of thyrotropic hormone and prolacting in a monolayer cultrue of rat adenohypophysis]

Cells of the adenohypophysis in the primary 5--8 day monolayer culture responded to the administration of the thyrotropin-releasing-hormone (TRH) by a rapid dose-dependent release of thyrotropic hormone (TTH) and prolactin into the culture medium. This effect is independent of the serum content in the nutrient medium. Thyroxin, the thyroid gland hormone, blocks the stimulating action of TRH with respect to the TTH secretion, but not to prolactin. The blocking effect of thyroxin is apparently expressed not on the cell membranes, but in the cytoplasm, distal to cAMP, by way of the hormonal signal transmission.     

Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment

There are two basic mechanisms whereby chemicals produce thyroid gland neoplasia in rodents. The first involves chemicals that exert a direct carcinogenic effect in the thyroid gland and the other involves chemicals which, through a variety of mechanisms, disrupt thyroid function and produce thyroid gland neoplasia secondary to hormone imbalance. These secondary mechanisms predominantly involve effects on thyroid hormone synthesis or peripheral hormone disposition. There are important species differences in thyroid gland physiology between rodents and humans that may account for a marked species difference in the inherent susceptibility for neoplasia to hormone imbalance. Thyroid gland neoplasia, secondary to chemically induced hormone imbalance, is mediated by thyroid-stimulating hormone (TSH) in response to altered thyroid gland function. The effect of TSH on cell proliferation and other aspects of thyroid gland function is a receptor mediated process and the plasma membrane surface of the follicular cell has receptors for TSH and other growth factors. Small organic molecules are not known to be direct TSH receptor agonists or antagonists; however, various antibodies found in autoimmune disease such as Graves' disease can directly stimulate or inhibit the TSH receptor. Certain chemicals can modulate the TSH response for autoregulation of follicular cell function and thereby increase or decrease the response of the follicular cell to TSH. It is thus important to consider mechanisms for the evaluation of potential cancer risks. There would be little if any risk for non-genotoxic chemicals that act secondary to hormone imbalance at exposure levels that do not disrupt thyroid function. Furthermore, the degree of thyroid dysfunction produced by a chemical would present a significant toxicological problem before such exposure would increase the risk for neoplasia in humans.     

Phorbol esters modulate cyclic AMP accumulation in porcine thyroid cells

In cultured porcine thyroid cells, during 60 min incubation phorbol 12-myristate 13-acetate (PMA) had no effect on basal cyclic AMP accumulation and slightly stimulated cyclic AMP accumulation evoked by thyroid stimulating hormone (TSH) or forskolin. Cholera toxin-induced cyclic AMP accumulation was significantly stimulated by PMA. On the other hand, cyclic AMP accumulation evoked by prostaglandin E1 or E2 (PGE1 or PGE2) was markedly depressed by simultaneous addition of PMA. These opposing effects of PMA on cyclic AMP accumulation evoked by PGE and cholera toxin were observed in a dose-related fashion, with half-maximal effect of around 10(-9) M in either case. The almost same effects of PMA on cyclic AMP accumulation in basal and stimulated conditions were also observed in freshly prepared thyroid cells. The present study was performed in the presence of phosphodiesterase inhibitor, 3-iso-butyl-1-methylxanthine (IBMX), indicating that PMA affected adenylate cyclase activity. Therefore, it is suggested that PMA may modulate the production of cyclic AMP in response to different stimuli, possibly by affecting several sites in the adenylate cyclase complex in thyroid cells.     

Effects of prostaglandins and other drugs on the cyclic AMP content of cultured bone cells.

Prostaglandins of the E-series (PGE1 and PGE2) may be involved in disease-related, localized loss of bone. E-prostaglandins increase the cyclic AMP content of many cells; and, to determine if their effects on bone are mediated by cyclic AMP, we examined the effects of E-prostaglandins and of other agents on the cyclic AMP content of cultured bone cells. PGE2 produced a rapid, marked and dose-related increase in the cyclic AMP content of confluent monolayers of bone cells isolated from newborn rat calvaria. At 2.8 X 10(-6) M, PGE1 and PGE2 had approximately the same effect, while the effect of PGF2alpha was much less pronounced. In the presence of theophylline, PGE2 had a more marked effect than parathyroid hormone (PTH) and the combination of PGE2 and PTH had a synergistic effect. The divalent, cationic, ionophore, A23187, produced an increase in cellular cyclic AMP and had an additive effect in combination with PGE2. Synthetic salmon calcitonin (CT), which inhibits the bone resorptive effect of PGE2, increased cellular cyclic AMP and had an additive effect in combination with PGE2. A prostaglandin antagonist, SC-19220, partially inhibited the resorptive effect of PGE2 and reduced its effect on cellular cyclic AMP. The calcium antagonist, D600, inhibited the bone resorptive effects of PGE2 but had no effect on increased cellular cyclic AMP produced by PGE2. The marked effect of PGE2 on bone cell cyclic AMP suggests that this action is involved in the mechanism of PGE2-related bone loss. The fact that agents with different effects on PGE2-induced increases in cellular cyclic AMP can inhibit its resorptive actions, suggests that PGE2-induced changes in cyclic AMP may be related less to its resorptive actions than to its inhibitory effect on bone formation.     

Evidence for a functional role of cholecystokinin receptors in the rat thyroid gland.

The aim of the present study was to examine the role of cholecystokinin (CCK) and/or cholecystokinin receptors subtypes (CCK1R and CCK2R) in the regulation of the thyroid gland structure and function. Animals were autopsied after 6 days of treatment with CCK or CCK receptor-specific antagonists (CCK1a--PD 140,548 or CCK2a--PD 135,158) solely or in combination with CCK. Results suggest that CCK exerts a stimulatory effect on follicular thyroid cells manifested by increased epithelium/colloid volume fraction ratio (E/C). Application of selective antagonists of CCK receptor subtypes has demonstrated that CCK acts through the CCK1 receptor subtype at the level of pituitary TSH. The model of endogenous hormone action reveals that thyroid CCK1 is responsible for the thyroid growth. It can be concluded that the physiological activity of CCK1 receptor plays a significant role in a complex interrelationship between TSH, vagal system and CCK1-dependent function of the thyroid gland.     

Peripheral Thyroid Hormone Dynamics in Precocial and Altricial Avian Development1

SYNOPSIS. Precocial and altricial birds have distinctly differentpatterns of general ontogeny and metabolic/thermoregulatorydevelopment. In my laboratory, we have studied the developmentof thyroid function in Japanese quail (Coturnix japonica) andRing doves (Streptopelia risoria) as examples of precocial andaltricial development, respectively. In this paper, I reviewthe literature and our work on the factors that influence peripheralhormone dynamics in birds. The first section of the paper describesadult peripheral thyroid function to set the stage for the developmentalpicture. Thyroid development is divided into two phases: PhaseI, in which the thyroid gland develops functional capacity butthere is low thyroid activity in the periphery, and Phase II,in which peripheral thyroid function increases and approachesadult levels. In precocial development Phase I occurs duringembryonic life and Phase II begins at the perinatal period.In altricial development, the pattern of thyroid functionaldevelopment is different and delayed. Peripheral thyroid hormonepatterns in both developmental modes are discussed with referenceto the factors that determine their dynamics: hormone availabilityfrom the thyroid gland, total serum hormone concentrations,the roles of serum binding proteins in regulating freehormoneconcentrations, hormone turnover and excretion, hormone receptorsand thyroid hormone metabolism, especially extrathyroidal productionof triiodothyronine from thyroxine.     

Guanine nucleotide-independent inhibition of adenylate cyclase by a stimulatory hormone.

Stimulation of basal adenylate cyclase activity in membranes of neuroblastoma x glioma hybrid cells by prostaglandin E1 (PGE1) is half-maximal and maximal (about 8-fold) at 0.1 and 10 microM respectively. This hormonal effect requires GTP, being maximally effective at 10 microM. However, at the same concentrations that stimulate adenylate cyclase in the presence of GTP, PGE1 inhibited basal adenylate cyclase activity when studied in the absence of GTP, by maximally 60%. A similar dual action of PGE1 was observed with the forskolin-stimulated adenylate cyclase, although the potency of PGE1 in both stimulating and inhibiting adenylate cyclase was increased and the extent of stimulation and inhibition of the enzyme by PGE1 was decreased by the presence of forskolin. The inhibition of forskolin-stimulated adenylate cyclase by PGE1 occurred without apparent lag phase and was reversed by GTP and its analogue guanosine 5'-[gamma-thio]triphosphate at low concentrations. Treatment of neuroblastoma x glioma hybrid cells or membranes with agents known to eliminate the function of the inhibitory GTP-binding protein were without effect on PGE1-induced inhibition of adenylate cyclase. The data suggest that stimulatory hormone agonist, apparently by activating one receptor type, can cause both stimulation and inhibition of adenylate cyclase, and that the final result depends only on the activity state of the stimulatory GTP-binding protein, Gs. Possible mechanisms responsible for the observed adenylate cyclase inhibition by the stimulatory hormone PGE1 are discussed.     

Selenium and thyroid function in infants, children and adolescents

Selenium is an integral component of the enzymes glutathione peroxidase (GPx) and iodothyronine deiodinases. Although selenium nutrition could conceivably affect thyroid function in infants, children and adolescents, available data suggest that the effect of selenium deficiency on thyroid function is relatively modest. In patients with isolated selenium deficiency (such as patients with phenylketonuria receiving a low-protein diet), peripheral thyroid hormone metabolism is impaired but there are no changes in thyrotropin (TSH) or clinical signs of hypothyroidism, suggesting that these patients are euthyroid. Selenium supplementation may be advisable to optimize tissue GPx activity and prevent potential oxidative stress damage. In areas where combined selenium and iodine deficiencies are present (such as endemic goiter areas in Central Africa), selenium deficiency may be responsible for the destruction of the thyroid gland in myxoedematous cretins but may also play a protective role by mitigating fetal hypothyroidism. In these areas, selenium supplementation should only be advocated at the same time or after iodine supplementation. In patients with absent or decreased production of thyroid hormones and who rely solely on deiodination of exogenous L-thyroxine for generation of the active triiodothyronine (such as patients with congenital hypothyroidism), selenium supplementation may optimize thyroid hormone feedback at the pituitary level and decrease stimulation of the residual thyroid tissue.     

Action of luteinizing hormone-releasing hormone and synthesis of prostaglandin in the pituitary gland.

The possibility that prostaglandin E2 (PGE2) may play a role in luteinizing hormone (LH) release was examined using an in vitro model. Addition of luteinizing hormone-releasing hormone (LH-RH) to the culture medium stimulated cyclic AMP accumulation and LH-release by incubated hemipituitaries, but did not affect the level of PGE2 or prostaglandin synthetase activity in the gland. Aspirin and indomethacin reduced both prostaglandin synthetase activity and PGE2 or prostaglandin synthetase activity in the gland. Aspirin and indomethacin reduced both prostaglandin synthetase activity and PGE2 content in the pituitary, but did not impair the stimulatory action of LH-RH on either cyclic AMP accumulation or LH-release. Flufenamic acid on its own caused LH-release, but the drug abolished the effect of LH-RH on cyclic AMP accumulation. The mechanism of this action of flufenamic acid is not understood. It is concluded that the stimulatory action of LH-RH on pituitary cyclic AMP production and LH release is not mediated by prostaglandins.     

Effects of retinoic acid on estrogen- and thyroid hormone-induced growth in a newly established rat pituitary tumor cell line.

In order to elucidate the complex mechanism(s) of action of steroid hormones, thyroid hormone and retinoic acid in pituitary mammotrophs, a clonal cell line (G3) was isolated from the rat pituitary tumor MtT/F84. G3 cells were found to secrete prolactin constitutively and to contain receptors for estrogen, glucocorticoid, progesterone and thyroid hormone. Stimulation of G3 cells with thyroid hormone resulted in a modest but significant increase in estrogen and progesterone receptor levels, however, retinoic acid treatment had no effect. Simultaneous addition of thyroid hormone and estrogen showed an additive effect on progesterone receptor levels in G3 cells. Thyroid hormone as well as estrogen enhanced the growth of G3 cells. Interestingly, retinoic acid was also found to enhance their growth but its enhancement was less potent than thyroid hormone and estrogen. Low concentrations of estradiol and thyroid hormone showed additive effects, but G3 cells stimulated with high concentrations of thyroid hormone failed to elicit an additive effect with estrogen, suggesting the presence of a common pathway in the growth-stimulatory actions of these hormones. In addition, exposure of G3 cells to retinoic acid completely abolished the effects of estrogen or thyroid hormone in terms of cell growth. These results suggest that there are complex interactions in the signalling pathways for estrogen, thyroid hormone and retinoic acid action in G3 cells.     

Involvement of prostaglandin E2 in the inhibition of osteocalcin synthesis by human osteoblast-like cells in response to cytokines and systemic hormones

The stimulation of the production of osteocalcin by human osteoblast-like cells in response to 1,25(OH)2D3 is antagonized by several agents that induce the synthesis of prostaglandin E2 (PGE2) including interleukin 1 (IL-1), tumour necrosis factor (TNF) and parathyroid hormone (PTH). The mechanism whereby these agents inhibit the synthesis of osteocalcin is not known. In this report we show that exogenous PGE2 inhibits this stimulatory action of 1,25(OH)2D3 on human osteoblast-like cells in a dose-dependent manner, suggesting that PGE2 may contribute to the inhibition of osteocalcin synthesis in response to these agents. Assessment of the inhibitory role of endogenous PGE2 synthesis in the action of rhIL-1 alpha, rhIL-1 beta and rhTNF alpha on the production of osteocalcin demonstrated that the inhibition by these agents could be partially overcome by the addition of indomethacin, an inhibitor of PGE2 synthesis. In contrast, the inhibitory action observed with bPTH (1-84) was unaffected by indomethacin. These observations indicate that endogenous PGE2 synthesis mediates, in part, some of the inhibitory actions of the cytokines on the induction of osteocalcin synthesis in response to 1,25(OH)2D3, but not of PTH. Since the antagonism of the synthesis of osteocalcin by rhIL-1 alpha, rhIL-1 beta and rhTNF alpha was not completely abolished following the inhibition of PGE2 synthesis this would indicate that additional PGE2-independent mechanisms also account for the action of these cytokines on osteocalcin production. The nature of these mechanisms is currently not known.     

Effect of physical conditioning on measures of thyroid hormone action

Serum thyroid function tests (T4, T3, rT3 and TSH levels) and measures of peripheral thyroid hormone action (serum dopamine-beta-hydroxylase activity (DBH) and sex hormone binding globulin (SHBG] were determined in 6 women before and one month after initiating an aerobic physical conditioning program. The same measurements were made in a control group of 6 women who did not increase their activity during this time. In physically conditioned subjects, the resting heart rate decreased from 65.1 +/- 3.9 (mean +/- SE) at baseline to 58.0 +/- 2.9 beats per minute after one month (P less than 0.025), indicating an appreciable state of physical conditioning was achieved. However, there were no statistically significant changes in thyroid function test, serum DBH or SHBG levels in either the physically conditioned or the control group. These data indicate that being physically conditioned has a negligible effect on thyroid status.     

The role of oxidative stress in physiological and pathological processes in the thyroid gland; possible involvement in pineal-thyroid interactions

Reactive oxygen species (ROS) play an important role in physiological processes, but - when being in excess - ROS cause oxidative damage to molecules. Under physiological conditions, the production and detoxification of ROS are more-or-less balanced. Also in the thyroid, ROS and free radicals participate in physiological and pathological processes in the gland. For example, hydrogen peroxide (H2O2) is crucial for thyroid hormone biosynthesis, acting at different steps of the process. Additionally, H2O2 is believed to participate in the Wolff-Chaikoff's effect, undergoing in conditions of iodide excess in the thyroid. Much evidence has been accumulated indicating that oxidative stress is involved in pathomechanism of thyroid disease, e.g., Graves' disease, goiter formation or thyroid cancer. Melatonin (N-acetyl-5-methoxytryptamine) - the main secretory product of the pineal gland - is a well-known antioxidant and free radical scavenger, widely distributed in the organism. Mutual relationships between the pineal gland and the thyroid have - for a long time - been a subject of intensive research. The abundant to-date's evidence relates mostly to the inhibitory action of melatonin on the thyroid growth and function and - to a lesser extent - to the stimulatory effects of thyroid hormones on the pineal gland. It is highly probable that under physiological conditions melatonin and, possibly, other antioxidants regulate ROS generation for thyroid hormone synthesis. We believe that melatonin may protect against extensive oxidative damage in the course of certain thyroid disorders or in case of a harmful action of some external factors on the thyroid. Thus, oxidative damage and the protective action of antioxidants, melatonin included, may occur during both physiological and pathological processes in the thyroid, however, this assumption, requires further studies.     

A measurable consequence of the Mitchell theory of phosphorylation

Thyroid hormones elevate the protonic electrochemical potential difference across the liver mitochondrial respiratory membrane, which may in turn enhance the organelle's oxidative capacity (Shears &; Bronk,1979). Such an effect can explain many of the consequences of the short-term interaction of the thyroid gland with mitochondria. There are several possible mechanisms by which this hormone action could arise, and it may constitute a significant and novel means of regulating cellular metabolism.     

Endocrine, neural, and immune control of secretory component output by lacrimal gland acinar cells.

Androgens regulate the synthesis and secretion of secretory component (SC), the IgA antibody receptor, by acinar cells from the lacrimal gland. However, this hormone action may be susceptible to significant modification by other agents from the endocrine, nervous, or immune systems. To investigate the nature of this neuroimmunoendocrine interaction, the present study examined the impact of hormones, neurotransmitters, and lymphokines on basal and androgen-induced SC production by lacrimal gland acinar cells in vitro. Our results demonstrated that vasoactive intestinal peptide, the beta-adrenergic agonist, isoproterenol, PGE2, IL-1 alpha, IL-1 beta, and TNF-alpha significantly increased media SC levels in control or androgen-containing cell cultures. In contrast, the cholinergic agonist, carbachol, significantly decreased cellular SC output. These effects may be mediated through the agents' known capacity to alter intracellular cAMP levels. In support of this hypothesis, exposure of acinar cells to stimulators or analogues of cAMP resulted in a significant enhancement of SC production. Thus, these findings indicate that SC output in lacrimal tissue may be modulated by interactions between the endocrine, nervous and immune systems.     

Mechanisms of gonadotropin-releasing hormone and prostaglandin action on luteal cells

Both gonadotropin-releasing hormone (GnRH) and prostaglandin F2 alpha (PGF2 alpha) can inhibit cAMP and progesterone production in the corpus luteum; however, their mechanism of action is not known. GnRH or PGF2 alpha causes a rapid and marked increase of labelling of phosphatidylinositol (PI) and phosphatidic acid (PA) in rat luteal cells in culture. The incorporation of radioactivity is increased as early as 2 and 5 min into PA and PI, respectively. The labelling of the other phospholipids is not affected. GnRH and PGF2 alpha exert their stimulatory effects on PA-PI turnover at a mean effective dose value of ca. 15 and 100 nM, respectively. Their effects appeared to be additive when both agents were present in the same incubations. Interestingly, addition of the calcium ionophore A23187 also causes a dramatic increase of PA-PI turnover in luteal cells. By contrast, human chorionic gonadotropin and isoproterenol, agents that stimulate cAMP and progesterone production in luteal cells, as well as PGE2 (1 microM), all fail to alter phospholipid labelling; dibutyryl or 8-bromo-cAMP (2-5 mM) actually attentuates the GnRH or PGF2 alpha effect on PI and PA. A very similar PA-PI response to GnRH and PGF2 alpha has also been observed using rat granulosa cells in culture. It seems that following their binding to membrane receptors, GnRH and PGF2 alpha may share a common mechanism in the ovarian cell, possibly involving the stimulation of PA-PI metabolism.