Fetal and maternal thyroid hormones

It is well known that insufficient production of thyroid hormones during the fetal and neonatal period of development may result in permanent brain damage unless treatment with thyroid hormone is instituted very soon after birth. But congenital hypothyroidism is not the only situation in which brain damage may be related to insufficient thyroid function. Cretinism is the most severe manifestation of iodine deficiency disorders found in areas where iodine intake is greatly reduced. Some of the manifestations of cretinism suggest that the insult to the developing brain starts earlier than in the case of congenital hypothyroidism. Hypothyroxinemia of mothers with adequate iodine intake may also leave permanent, though less severe, mental retardation. For these reasons the possible role of maternal transfer of thyroid hormones during early fetal development have been reinvestigated, using the rat to obtain various experimental models. It has been shown that thyroid hormones are found in embryonic tissues before onset of fetal thyroid function and that thyroidectomy of the mother results in delayed development of the concepta. The concentrations of T4 and T3 in embryonic tissues from thyroidectomized dams were undetectable before the onset of fetal thyroid function, and still reduced in some tissues near term, despite the onset of fetal thyroid function. Treatment of control and thyroidectomized dams with methyl-mercaptoimidazole to block fetal thyroid function reduced thyroid hormone concentrations in fetal tissues near term, but this decrease could be partially avoided by infusion of physiological doses of thyroxine to the mothers. Iodine deficiency of the mothers resulted in thyroid hormone deficiency of the developing embryo, which was very marked until term in all tissues including the brain. The results strongly support a role of maternal thyroid hormones in fetal thyroid hormone economy both before and after the onset of the fetal thyroid function, at least in the rat. They also support a role of the hypothyroxinemia of iodine-deficient mothers in initiating the brain damage of the endemic cretin, a damage which would not be corrected once the fetal thyroid becomes active, as iodine-deficiency of the fetus would impair adequate production of hormones by its own thyroid, and maternal transfer would continue to be low.     

Lithium suppresses elevated behavioural activity and brain catecholamines in developing hyperthyroid rats.

Neonatal hyperthyroidism in rats induced by daily administration of L-triiodothyronine for 30 days since birth resulted in a significant rise in mobility and the metabolism of brain norepinephrine and dopamine. Whereas administration of lithium carbonate (60 mg/kg ip) to normal rats for 6 days produced no effect on spontaneous locomotor activity and increased the synthesis and possibly release of this monoamine in several brain regions, this antimanic drug antagonized the L-triiodothyronine-stimulated increases in mobility as well as norepinephrine and dopamine metabolism of hypothalamus, midbrain, striatum, and cerebral cortex. Furthermore, lithium treatment restored the activity of catechol-O-methyl transferase (EC 2.1.1.6) in young hyperthyroid rats to virtually normal limits. Our data suggest that antiphasic or damping effects of lithium upon mood swings is controlled, at least in part, by catecholaminergic systems in the brain. The interrelationship between brain catecholamines and thyroid hormones seems to be important to our understanding of the action of lithium in affective illness.     

Effect of hyperthyroidism and hypothyroidism on rat red blood cell insulin receptors and catecholamines: relationship with cellular ageing

Insulin receptor activity and its relationship with catecholamines in rat young, middle aged and old red blood cells were investigated in experimental hypothyroidism and hyperthyroidism. In control animals, a loss of insulin receptor activity was found with cellular ageing and increased levels of norepinephrine, epinephrine and glycosylated hemoglobin. There was down regulation of insulin receptors together with alterations in membrane bound catecholamines in thyroid hormones imbalances. These results suggest that loss of insulin receptor in cellular ageing is probably part of a more generalised alteration and rat serves as an excellent model in defining the role of thyroid hormones in carbohydrate tolerance.     

Tyrosine content, influx and accumulation rate, and catecholamine biosynthesis measured in vivo, in the central nervous system and in peripheral organs of the young rat. Influence of neonatal hypo- and hyperthyroidism

The influence of neonatal hypo- and hyperthyroidism on different aspects of tyrosine metabolism in the hypothalamus, striatum, brainstem, adrenal glands, heart and brown adipose tissue (BAT) were studied in 14-day old rats. The synthesis rate of catecholamines (CA) was also determined in vivo after the injection of labelled tyrosine. Hypothyroidism increases tyrosinaemia and endogenous tyrosine concentration in the hypothalamus and BAT. Hyperthyroidism decreases tyrosinaemia and endogenous tyrosine levels in the striatum, adrenals and heart. The accumulation rate of tyrosine determined 30 min after an intravenous injection of the labelled amino acid has been determined in the organs, together with the influx of the amino acid, determined within 20s. Hypothyroidism increases tyrosine accumulation rate in all the organs studied, and tyrosine clearance is decreased in the striatum and brainstem; together with an increased tyrosinaemia, this leads to a normal influx. The influx of tyrosine is increased in the hypothalamus. Hyperthyroidism decreases tyrosine accumulation rate in all the organs except the adrenals. These results indicate that the thyroid status of the young rat can influence tyrosine uptake mechanisms, without modifying an organ's tyrosine content. The fact that hypothyroidism increases tyrosine influx in the hypothalamus without modifying it in the brainstem and striatum reflects an heterogeneous reactivity to the lack of thyroid hormones in different brain structures. Neonatal hypothyroidism decreases the CA synthesis rate in the striatum, the heart and the interscapular brown adipose tissue, while synthesis was enhanced in the brainstem and the adrenals. It is likely that these variations in CA synthesis are due to thyroid hormone modulation of tyrosine hydroxylase activity, the enzyme which catalyses the rate limiting step in CA biosynthesis.     

Differences in monoamine oxidase activity between cultured noradrenergic and cholinergic sympathetic neurons

Two types of monoamine oxidase activity (MAO-A and MAO-B) help regulate the levels of biogenic amines such as catecholamines and serotonin. Although MAO-A has greater activity toward most catecholamines than MAO-B, no direct experiments have determined the types and levels of MAO activity that are normally expressed in noradrenergic neurons. Noradrenergic neurons from neonatal rat superior cervical ganglia were isolated and cultured under conditions that permit either continued expression of the noradrenergic phenotype or promote a transition to a predominantly cholinergic phenotype. After 14-21 days in vitro, neurons from both types of cultures were assayed for the type and amount of monoamine oxidase activity using tryptamine, a common substrate for both MAO-A and MAO-B. Neurons cultured under noradrenergic conditions expressed sevenfold greater MAO activity than neurons cultured under cholinergic conditions. Essentially all MAO activity in the noradrenergic cultures was inhibited by preincubation with 10(-8)-10(-9) M clorgyline, which indicated that this activity was primarily MAO-A. Cultures grown under cholinergic conditions exhibited 6- to 10-fold lower MAO-A activity and an 8- to 10-fold lower level of catecholamine synthesis from labeled precursors compared to neurons grown under noradrenergic conditions. These results directly demonstrate that high MAO-A activity is expressed in noradrenergic neurons in vitro. The corresponding decreases in both MAO-A specific activity and catecholamine synthesis as neurons become cholinergic in vitro suggest that the expression of the noradrenergic phenotype involves the coordinate regulation of degradative as well as synthetic enzymes involved in catecholamine metabolism.     

Thyroid hormone and gamma-aminobutyric acid (GABA) interactions in neuroendocrine systems

Thyroid hormones (THs) have critical roles in brain development and normal brain function in vertebrates. Clinical evidence suggests that some human nervous disorders involving GABA(gamma-aminobutyric acid)-ergic systems are related to thyroid dysfunction (i.e. hyperthyroidism or hypothyroidism). There is experimental evidence from in vivo and in vitro studies on rats and mice indicating that THs have effects on multiple components of the GABA system. These include effects on enzyme activities responsible for synthesis and degradation of GABA, levels of glutamate and GABA, GABA release and reuptake, and GABA(A) receptor expression and function. In developing brain, hypothyroidism generally decreases enzyme activities and GABA levels whereas in adult brain, hypothyroidism generally increases enzyme activities and GABA levels. Hyperthyroidism does not always have the opposite effect. In vitro studies on adult brain have shown that THs enhance GABA release and inhibit GABA-reuptake by rapid, extranuclear actions, suggesting that presence of THs in the synapse could prolong the action of GABA after release. There are conflicting results on effects of long term changes in TH levels on GABA reuptake. Increasing and decreasing circulating TH levels experimentally in vivo alter density of GABA(A) receptor-binding sites for GABA and benzodiazepines in brain, but results vary from study to study, which may reflect important regional differences in the brain. There is substantial evidence that THs also have an extranuclear effect to inhibit GABA-stimulated Cl(-) currents by a non-competitive mechanism in vitro. The thyroid gland exhibits GABA transport mechanisms as well as enzyme activities for GABA synthesis and degradation, all of which are sensitive to thyroidal state. In rats and humans, GABA inhibits thyroid stimulating hormone (TSH) release from the pituitary, possibly by action directly on the pituitary or on hypothalamic thyrotropin-releasing hormone neurons. In mice, GABA inhibits TSH-stimulated TH release from the thyroid gland. Taken together, these studies provide strong support for the hypothesis that there is reciprocal regulation of the thyroid and GABA systems in vertebrates.     

Effect of experimental changes in thyroid function on oxidative metabolism and glutamate dehydrogenase activity in the limbic system of the rat

The oxidative metabolism and GDH activity has been studied in the following regions of the brain: frontal cortex, as tissue control, adenohypophysis, hypothalamus and limbic system in adult male rats subjected to alterations of the thyroid function due to excess (by hyperthyroidism with L-thyroxine and thyrotoxicosis with Tri-iodothyronine) or defect (chronic hypothyroidism by thyroidectomy, 131-I treatment and low iodine diet). A different influence of the H.T. was observed in these animals according to the areas studied and the experimental situation induced. All this seems to indicate an oxidative metabolic pattern peculiar to each area of the brain following H.T. administration. On the other hand, the decrease of the QO2 in chronic hypothyroidism in the majority of the areas studied is remarkable. In GDH results activity increased or decreased depending on the absence or presence of thyroid hormones.     

Thyroid Hormone Binding and Regulation of Adrenergic Enzymes in Two Neuroblastoma Cell Lines

Two neuroblastoma cell lines were cultured in control (euthyroid) and hypothyroid media and examined for protein, RNA and DNA content, activity of the catecholaminergic enzymes tyrosine hydroxylase (TH, EC 1.14.16.2) and monoamine oxidase-A (MAO-A, EC 1.4.3.4), and for L-triiodothyronine (T3) nuclear receptors. In the hypothyroid condition, the rate of cell division and the levels of RNA and protein as well as the activities of TH and MAO were lower than in the euthyroid condition, the reduction being more marked in the E than in the A2(1) cell line. T3 nuclear receptors, unaltered in affinity, were increased in number in the hypothyroid medium, possibly as a regulatory response to hormonal deficiency. Examination of a possible relationship between T3 occupancy and TH activity in the E cells, most sensitive to thyroid hormone deficiency, revealed that induction of TH activity by T3 is dose-dependent and correlates with the number of nuclear sites occupied by the hormone. When neuroblastoma cells were induced to differentiate by the addition of sodium butyrate to the medium, parameters of cell growth (protein, RNA) and enzyme activity (TH and MAO-A) increased in both cell lines irrespective of the presence of thyroid hormones. These data indicate that thyroid hormones, through their nuclear receptors, directly affect the activity of catecholaminergic enzymes in cultured, immature (undifferentiated) neurons.     

White fat cell alpha-adrenergic receptors and responsiveness in altered thyroid status

[³H]-Dihydroergocryptine was used to identify α-adrenergic receptors in a crude adipocyte membrane fraction obtained from hyperthyroid, hypothyroid and euthyroid hamsters. Hyperthyroidism produced a 35–45 % decrease in the number of both the high and the low affinity [³H]-dihydroergocryptine binding sites but failed to affect the respective affinities of both these sites. On the other hand, binding of [³H]-dihydroergocryptine was unaltered in membranes of hypothyroid animals. Hamster adipocyte α-adrenergic responsiveness, reflected by the increment of epinephrine-stimulated cyclic AMP synthesis induced by phentolamine, was 50 % reduced by hyperthyroidism but unchanged by hypothyroidism. These results which demonstrate that thyroid hormones can regulate the density of adipocyte α-adrenergic receptors, suggest that in human fat cells where catecholamines produce opposite α- and β-adrenergic effects on lipolysis, the increased α-adrenergic responsiveness found in hyperthyroidism could be due, at least in part, to a reduction in the number of α-adrenergic receptors.     

Congenital hyperthyroidism: the fetus as a patient

Congenital hyperthyroidism is less frequent than congenital hypothyroidism but its impact on growth and development can be as dramatic. The immune form of hyperthyroidism that is transmitted from a mother with Graves' disease to her foetus and then neonate is transient, but cases of persistent congenital hyperthyroidism had also been described, that can now be explained by molecular abnormalities of the thyrotropin receptor. The abundance of published data on the neonatal effects of maternal Graves' disease contrasts with the paucity of information on fetal effects. Recent studies showed that it is of utmost to scrutinize fetal thyroid by expert ultrasonographist and to have a team work with obstetricians and pediatric endocrinologists in pregnant women with Graves' disease. This allowed to accurately determine the fetal thyroid status and to adapt the treatment in the mothers successfully. Fetal hyperthyroidism does exist and needs an appropriate aggressive treatment. Clearly the fetus has become our patient!     

Leptin,NPY, Melatonin and Zinc Levels in Experimental Hypothyroidism and Hyperthyroidism: The Relation to Zinc

Since zinc mediates the effects of many hormones or is found in the structure of numerous hormone receptors, zinc deficiency leads to various functional impairments in the hormone balance. And also thyroid hormones have important activity on metabolism and feeding. NPY and leptin are affective on food intake and regulation of appetite. The present study is conducted to determine how zinc supplementation and deficiency affect thyroid hormones (free and total T3 and T4), melatonin, leptin, and NPY levels in thyroid dysfunction in rats. The experiment groups in the study were formed as follows: Control (C); Hypothyroidism (PTU); Hypothyroidism+Zinc (PTU+Zn); Hypothyroidism+Zinc deficient; Hyperthyroidism (H); Hyperthyroidism+Zinc (H+Zn); and Hyperthyroidism+Zinc deficient. Thyroid hormone parameters (FT₃, FT₄, TT₃, and TT₄) were found to be reduced in hypothyroidism groups and elevated in the hyperthyroidism groups. Melatonin values increased in hyperthyroidism and decreased in hypothyroidism. Leptin and NPY levels both increased in hypo- and hyperthyroidism. Zinc levels, on the other hand, decreased in hypothyroidism and increased in hyperthyroidism. Zinc supplementation, particularly when thyroid function is impaired, has been demonstrated to markedly prevent these changes.     

Changes in hexokinase isoenzymes in regions of rat brain during thyroid deficiency

In this work, activities of hexokinase isoenzymes Type I and Type II were measured in the soluble and particulate fractions from the brain regions (cerebral hemispheres (cerebrum), cerebellum and brain stem) of the thyroidectomized adult rats as well as of the thyroidectomized rats administered with triiodothyronine. Thyroidectomy generally decreased the hexokinase activity associated with particulate and soluble fractions. Hexokinase Type II isoenzyme was more affected than the Type I isoenzyme. Administration of triiodothyronine to the hypothyroid rats abolished the effect of thyroidectomy. Adult brain enzymes have been generally considered not be affected by thyroid hormones. The data obtained in this work are suggestive of an effect of thyroid hormones on hexokinase in the adult brain. Since the effects of thyroidectomy on the energy metabolism of the heart tissue are well known, the heart tissue was also studied for comparison.     

Thyroid Hormone Receptors in the Developing Rat Brain

It is widely believed that the adult mammalian brain is insensitiveto thyroid hormones unlike the neonatal brain which is criticallydependent on these hormones for the development of normal structureand function. Recent studies have demonstrated the presenceof limited capacity, high affinity, triiodothyronine (T3) bindingnuclear sites in tissues that are considered responsive to thyroidhormones. Furthermore, there is evidence from studies on peripheraltissues that these T3 binding sites act as true receptors ininitiating thyroid hormone action. This report examines whetherthe higher sensitivity of neonatal brain to thyroid hormonesand the purported decline in sensitivity in adulthood are relatedto changes in the concentration and affinity characteristicsof thyroid hormone receptors in rat cerebral nuclei. Analysisof Scatchard plots of in vitro T3 binding data indicate thatcerebral nuclei from adult rats contain T3 specific nuclearbinding sites at a concentration comparable to that presentduring the period when the brain is critically dependent onthe presence of thyroid hormones and exceed that in the liver,a tissue generally considered thyroid sensitive. Neonatal thyroidectomysignificantly increased the number of binding sites. The resultsshow that the apparent unresponsiveness of the cerebral cortexof adult rats to thyroid hormones is not due to the absenceor a low density of T3 nuclear binding sites. The significanceof these results is discussed.     

Effects of thyroid hormones on the evolution of monoamine oxidase activity in the brain and heart of the developing rat

The evolution of monoamine oxidase (MAO) activity towards tryptamine has been studied from birth to 20 days post-natal in the brain and heart of male rats. Hyperthyroidism was induced by thyroxine injections and hypothyroidism by PTU administration. The results are expressed per unit of fresh weight and per unit of protein weight. Cardiac MAO is higher in the hyperthyroid animals than in controls as soon as 5 days following birth; the difference between the 2 groups increases until 20 days. The deficiency in thyroid hormones, on the other hand, was followed by a slight decrease in the cardiac enzyme, this decrease reflecting the general deficit in protein synthesis. Brain MAO is not affected by hyperthyroidism, but a clear deficit follows PTU administration. This deficit is significant beginning at 10 days and the difference between the 2 groups increases up to 20 days. The effects of PTU-induced hypothyroidism can be corrected by thyroxine injections. Except for the decrease in the level of cardiac enzyme in hypothyroid animals, all the effects on MAO activity are independent of the total protein content of both organs.     

Hippocampal Up-Regulation of Apolipoprotein D in a Rat Model of Maternal Hypo- and Hyperthyroidism: Implication of Oxidative Stress

Thyroid disorders impair various functions of the hippocampus where thyroid hormone receptors are localized in the brain. Hyper and hypothyroidism are associated with large changes in brain oxidative stress. Apolipoprotein D (APOD) is a conserved glycoprotein that increased in response to oxidative stress in the brain and has been suggested function as an antioxidant in the brain. Thus, the goal of this work was to explore the effect of maternal hypo- and hyperthyroidism on the Apod expression in the pup’s brain regarding changes in oxidative stress. For induction hypo and hyperthyroidism in adult female rats, 100 ppm propylthiouracil (PTU) and 8 ppm levothyroxine administrated 1 month before copulation to the week 3 after delivery in drinking water. The hippocampal region of rat pups was isolated and used for immunohistochemistry and quantitative RT-PCR on postnatal day (PND)5, PND10 and PND20. Results revealed that APOD over-expressed in both hypo- and hyperthyroid groups on PND5, PND10, and PND20. There was a proportional increase between the Apod expression and oxidative stress in the hyperthyroid group but not the hypothyroid in different days. Regarding the wide functions of thyroid hormones, oxidative stress does not suggest to be the only mechanism that involves Apod gene expression in thyroid disturbances.

     

In Vivo Voltammetric Monitoring of Catecholamine Metabolism in the A1 and A2 Regions of the Rat Medulla Oblongata

Catecholaminergic metabolism was estimated in A1 and A2 noradrenergic nuclei of the rat medulla oblongata using differential normal pulse voltammetry combined with electrochemically treated carbon fiber microelectrodes. In both areas an oxidation peak appearing at +50 mV was recorded. Electrochemical data and pharmacological experiments indicated that 3,4-dihydroxyphenylacetic acid (DOPAC) synthesized by noradrenergic neurons was the major contributor to this signal. Indeed, alpha-methyl-p-tyrosine, by inhibiting tyrosine hydroxylase, and pargyline, by inhibiting monoamine oxidase, both totally suppressed the peak appearing at +50 mV in A1 and A2 areas. Conversely, FLA-63, an inhibitor of dopamine-beta-hydroxylase, increased it. Moreover, a local and unilateral injection of catecholaminergic neurotoxin (6-hydroxydopamine) in the vicinity of A1 induced a 60% decrease in the peak height. This effect was prevented by pretreatment with desipramine, an inhibitor of noradrenaline reuptake, which is known to protect noradrenergic neurons against the action of 6-hydroxydopamine. Finally, specific drugs acting on alpha-2-noradrenergic receptors (clonidine and piperoxane) modulated the peak height recorded from both structures. Thus, as previously shown in the locus ceruleus, the variations in the extracellular DOPAC levels reflect the metabolic activity of A1 and A2 noradrenergic neurons.     

The effects of thyroid hormones on memory impairment and Alzheimer's disease

Thyroid hormones (THs) have a wide and important range of effects within the central nervous system beginning from fetal life and continuing throughout the adult life. Thyroid disorders are one of the major causes of cognitive impairment including Alzheimer's disease (AD). Several studies in recent years have indicated an association between hypothyroidism or hyperthyroidism and AD. Despite available evidence for this association, it remains unclear whether thyroid dysfunction results from or contributes to the progression of AD. This review discusses the role of THs in learning and memory and summarizes the studies that have linked thyroid function and AD. Eventually, we elaborate how THs may be effective in treating AD by putting forward potential mechanisms.     

Footshock-induced changes in brain catecholamines and indoleamines are not mediated by CRF or ACTH

Stressful treatments have long been associated with increased activity of brain catecholaminergic and serotonergic neurons. An intracerebroventricular (icv) injection of the corticotropin-releasing factor (CRF) also activates brain catecholaminergic neurons. Because brain CRF-containing neurons appear to be activated during stress, it is possible that CRF mediates the catecholaminergic activation. This hypothesis has been tested by assessing the responses in brain catecholamines and indoleamines to footshock in mice pretreated icv with a CRF receptor antagonist, and in mice lacking the gene for CRF (CRFko mice). Consistent with earlier results, icv administration of CRF increased catabolites of dopamine and norepinephrine, but failed to alter tryptophan concentrations or serotonin catabolism. A brief period of footshock increased plasma corticosterone and the concentrations of tryptophan and the catabolites of dopamine, norepinephrine and serotonin in several brain regions. Mice injected icv with 25 microg alpha-helical CRF(9-41) prior to footshock had neurochemical responses that were indistinguishable from controls injected with vehicle, while the increase in plasma corticosterone was slightly attenuated in some experiments. CRFko mice exhibited neurochemical responses to footshock that were indistinguishable from wild-type mice. However, whereas wild-type mice showed the expected increase in plasma corticosterone, there was no such increase in CRFko mice. Similarly, hypophysectomized mice also showed normal neurochemical responses to footshock, but no increase in plasma corticosterone. Hypophysectomy itself elevated brain tryptophan and catecholamine and serotonin metabolism. Treatment with ACTH icv or peripherally failed to induce any changes in cerebral catecholamines and indoleamines. These results suggest that CRF and its receptors, and ACTH and other pituitary hormones, are not involved in the catecholamine and serotonin responses to a brief period of footshock.     

Thyroid hormones and the creatine kinase system in cardiac cells

The paper reviews the current evidence on the role of thyroid hormones in regulating the creatine kinase energy transfer system at multiple structures in cardiac cells. 1) Thyroid hormones modulate the overall synthesis of phosphocreatine (PCr) by increasing the rate of mitochondrial oxidative phosphorylation. 2) Thyroid hormones regulate the total activity of creatine kinase and its isoenzyme distribution. In comparison with normal thyroid state (euthyroidism), hypothyroidism is characterized by decreased total creatine kinase activity owing to diminished fraction of creatine kinase. On the other hand, hyperthyroidism, while causing no change in total creatine kinase activity, leads to increased fractions of neonatal isoforms of creatine kinase, and, in case of prolonged hyperthyroidism, to decreased fraction of mitochondrial creatine kinase. The latter change is associated with partial uncoupling between mitochondrial creatine kinase and adenine nucleotide translocase reflected by decreased PCr/O ratio. 3) Hyperthyroidism leads to increased passive sarcolemmal permeability due to which the leakage of creatine along its concentration gradient occurs. As a result of (i) increased sarcolemmal permeability for creatine, (ii) uncoupling of mitochondrial PCr synthesis, and (iii) increased energy utilization rate the steady state intracellular PCr content decreases under hyperthyroidism which, in turn, increases the myocardial susceptibility to hypoxic damage. Thyroid state also modulates the protective effects of exogenous PCr on energetically depleted myocardium.     

Thyroid status affects rat liver regeneration after partial hepatectomy by regulating cell cycle and apoptosis.

In rats, various growth factors and hormones, as well as partial hepatectomy (PH) are able to trigger the proliferative response of hepatocytes. Although recent evidence highlights the important role of thyroid hormones and thyroid status in regulating the growth of liver cells in vitro and in vivo models, the mechanism involved in the pro-proliferative effects of thyroid hormones is still unclear. Here we have investigated how in rats made hypo- and hyperthyroid after prolonged treatment respectively with propylthiouracil (PTU) and triiodothyronine (T3), the thyroid status affects liver regeneration after PH by regulating cell cycle and apoptosis proteins. Our results show that both in control and partially hepatectomized animals hyperthyroidism increases the cyclin D1, E and A levels and the activity of cyclin-cdk complexes, and decreases the levels of cdk inhibitors such as p16 and p27. On the contrary hypothyroidism induces a down-regulation of the activity of cyclin cdk complexes decreasing cyclin levels. Thyroid hormones control also p53 and p73, two proteins involved in apoptosis and growth arrest which are induced by PH. In particular, hypothyroidism increases and T3 treatment decreases p73 levels. The analysis of the phosphorylated forms of p42/44 and p38 MAPK revealed that they are induced during hepatic regeneration in euthyroid and hyperthyroid rats whereas they are negatively regulated in hypothyroid rats. In conclusion our data demonstrate that thyroid status can affects liver regeneration, altering the expression and the activity of the proteins involved in the control of cell cycle and growth arrest.