Physiological Doses Of T3 Research Articles

A rise in T3/T4 ratio reduces the growth of prostate tumors in a murine model.

Thyroxine (T4) promotes cell proliferation and tumor growth in prostate cancer models, but it is unknown if the increase in the triiodothyronine (T3)/T4 ratio could attenuate prostate tumor development. We assessed T3 effects on thyroid response, histology, proliferation, and apoptosis in the prostate of wild-type (WT) and TRAMP (transgenic adenocarcinoma of the mouse prostate) mice. Physiological doses of T3 were administered in the drinking water (2.5, 5 and 15 µg/100 g body weight) for 6 weeks. None of the doses modified the body weight or serum levels of testosterone, but all of them reduced serum T4 levels by 50%, and the highest dose increased the T3/T4 ratio in TRAMP. In WT, the highest dose of T3 decreased cyclin D1 levels (immunohistochemistry) but did not modify prostate weight or alter the epithelial morphology. In TRAMP, this dose reduced tumor growth by antiproliferative mechanisms independent of apoptosis, but it did not modify the intraluminal or fibromuscular invasion of tumors. In vitro, in the LNCaP prostate cancer cell line, we found that both T3 and T4 increased the number of viable cells (Trypan blue assay), and only T4 response was fully blocked in the presence of an integrin-binding inhibitor peptide (RGD, arginine-glycine-aspartate). In summary, our data show that the prostate was highly sensitive to physiological T3 doses and suggest that in vivo, an increase in the T3/T4 ratio could be associated with the reduced weight of prostate tumors. Longitudinal studies are required to understand the role of thyroid hormones in prostate cancer progression.

Impact of gestational hypothyroidism on uterine implantation and reproductive performance in the rat

Impact of gestational hypothyroidism on uterine implantation and reproductive performance in the rat

Thyroid Replacement Therapy and Heart Failure

Heart failure (HF) is a major public health and economic problem in Western countries and is one of the most common causes of hospitalization and death. Coronary artery disease is the underlying cause in more than two thirds of chronic HF patients. By 2020, the World Health Organization projects that ischemic heart disease alone will be the most important global cause of morbidity and mortality. The estimated increases in HF-related morbidity and mortality suggest that our understanding of the pathophysiological mechanisms of this syndrome is inadequate. Interest in the role of thyroid hormones (THs) in HF has increased in recent years. The driving considerations can be summarized as follows: (1) the known effects of THs on contractile and relaxation properties of the heart; (2) experimental findings offering strong support for the hypothesis that TH signaling is critical in preserving cardiac structure and performance under normal conditions and after cardiac injury; and (3) evidence that mildly altered TH function is strongly associated with a worsening prognosis in cardiac patients in general and in HF patients in particular. Diastolic function and systolic function are clearly influenced by THs.1 Ventricular contractile function is also influenced by changes in hemodynamic conditions secondary to TH effects on peripheral vascular tone.1 TH homeostasis preserves positive ventricular-arterial coupling, leading to a favorable balance for cardiac work. A study in rats demonstrated that chronic hypothyroidism alone can eventually lead to HF.2 Other studies suggest reduced cardiac tissue triiodothyronine (T3) levels after myocardial infarction (MI) or with development of hypertension by upregulating type 3 deiodinase (D3), which leads to deactivation of T3 and T4 (thyroxine).3–6 This review highlights a growing body of evidence from animal studies and small-scale clinical trials suggesting that low cellular thyroid activity at the cardiac tissue level may adversely affect HF …

Acute effects of thyroid hormones on the production of adrenal cAMP and corticosterone in male rats.

The acute effects of thyroid hormones on glucocorticoid secretion were studied. Venous blood samples were collected from male rats after they received intravenous 3,5,3'-triiodothyronine (T3) or thyroxine (T4). Zona fasciculata-reticularis (ZFR) cells were treated with adrenocorticotropic hormone (ACTH), T3, T4, ACTH plus T3, or ACTH plus T4 at 37 degrees C for 2 h. Corticosterone concentrations in plasma and cell media, and also adenosine 3',5'-cyclic monophosphate (cAMP) production in ZFR cells in the presence of 3-isobutyl-1-methylxanthine, were determined. The effects of thyroid hormones on the activities of steroidogenic enzymes of ZFR cells were measured by the amounts of intermediate steroidal products separated by thin-layer chromatography. Administration of T3 and T4 suppressed the basal and the ACTH-stimulated levels of plasma corticosterone. In ZFR cells, both thyroid hormones inhibited ACTH-stimulated corticosterone secretion, but the basal corticosterone was inhibited only with T3 > 10(-10) M or T4 > 10(-8) M. Likewise, T3 or T4 at 10(-7) M inhibited the basal- and ACTH-stimulated levels of intracellular cAMP. Physiological doses of T3 and T4 decreased the activities of 3 beta-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11 beta-hydroxylase. These results suggest that thyroid hormones counteract ACTH in adrenal steroidogenesis through their inhibition of cAMP production in ZFR cells.

Presence and mRNA expression of T3 receptors in differentiating rat brown adipocytes

Nuclear T3 binding and T3 receptors (TR) expression were studied in brown adipocytes differentiated in culture from precursor cells. High affinity T3 receptors were found. During adipocyte differentiation maximal binding capacity (MBC) was doubled (up to 763 fmol T3/mg DNA), and an apparent decrease in receptor affinity was also observed (due to a decrease in the association rate constant). A very high disappearance rate of T3 was found in the cellular and nuclear fractions under binding assay conditions (serum-free medium). MBC increased 30% under hypothyroid conditions, but was not affected by physiological doses of T3 or retinoic acid. TRβ1, TRα1 and c-erbA-α2 mRNAs were detected in brown adipocytes. During differentiation TRβ1 decreased to 30%. Long exposure to T3 increased 2-fold TRβ1 and decreased TRα1 levels, when using insulin-depleted medium. Short exposure (4 h) to 10 nM insulin reduced both TRβ1 and TRα mRNAs species.

Alpha-, beta-MHC mRNA quantification in adult cardiomyocytes by in situhybridization: effect of thyroid hormone.

Cardiac myocytes isolated from adult rats and cultured for up to 5 days in a defined serum- and 3,5,3'-triiodothyronine-(T3) free medium were processed for in situ hybridization using [35S]cRNA probes specific for alpha- or beta-myosin heavy chain (MHC) mRNAs. A computer-assisted image analysis system was used to quantitate the hybridization signals within individual myocytes (100 cells/experimental point). The method was validated by comparison with dot-blot quantitation. The mean alpha-MHC mRNA density per cell decreased by 50% (P < 0.01) after 2 days in culture and remained stable thereafter, whereas the relative amount of beta-MHC mRNA did not increase until day 5. Addition of 10(-12) M T3 to the culture medium for 2 or 3 days was sufficient to maintain alpha-MHC mRNA levels similar to the day 0 values, whereas 10(-9) M T3 was necessary to completely inhibit beta-MHC mRNA expression. The independent analysis of myocytes exhibiting different morphological phenotypes with time in culture demonstrated that rounded myocytes contain relatively more alpha-MHC mRNA and were as sensitive to T3 as their rod-shaped counterparts. Their beta-MHC RNA content was similar to that found in rod-shaped cells and was still depressed by T3. In conclusion, we show that 1) physiological doses of T3 are sufficient to maintain in vitro a MHC phenotype close to that observed in vivo in adult, 2) the dose responsiveness of adult myocytes to T3 differs from that reported in neonatal myocytes, and 3) the alpha-MHC mRNA content and the T3 sensitivity of spheroidal myocytes imply that there is no alteration in their state of maturation.

Role of certain hormones with general metabolic action in the expression of sexual differentiation of the rat liver with respect to a special estrogen-binding protein

1. Administration of insulin does not significantly affect the level of SEBP in the livers of male rats. 2. Adrenalectomy and administration of dexamethasone do not cause any pronounced changes in the sexual differentiation of the SEBP content in the liver. 3. Administration of physiological doses of T3 produces a dose-dependent and reversible decrease in the level of SEBP in the livers of sexually mature male rats, and also decreases the degree of induction of this protein by androgens in the livers of females. 4. The action of T3 does not significantly depend on the sex hormones and pituitary factors. 5. Administration of STH raises the level of SEBP in the liver only in hypophysectomized males but not in intact or castrated males.

Low Doses of T3Induce a Rapid Metabolic Response in Young Lambs

Injection of 1 microgram/kg T3 resulted in an increase in metabolic rate (VO2) within an hour of administration to lambs (aged 27 to 180 h). A larger dose of 5 micrograms/kg T3 initially caused a slight inhibition of VO2, which was followed in the second post-injection hour by a significant increase. The increase in VO2 during the second post-injection hour after either 1 microgram/kg or 5 micrograms/kg T3 represented a rise of 22% above pre-injection VO2. The increase persisted and was slightly enhanced during the third post-injection hour. These changes were significantly greater than the smaller changes which followed control injection (P less than 0.005). No significant changes in Tre or Tesk occurred after any treatment. This rapid response to low, physiological doses of T3 emphasises a possible role for thyroid hormones in the short-term control of metabolism in young animals.

Regulation of myosin isoenzyme composition in fetal and neonatal rat ventricle by endogenous thyroid hormones.

The effect of thyroid hormone on the expression of ventricular isomyosins V1, V2, and V3 was studied in fetal and neonatal rats. Between 15 and 21 days gestation, V3 accounts for 80-90% of fetal ventricular myosin. After birth, there is a rapid transition from the fetal V3 isotype to an equal mixture of V1 and V3 at 3 days, and to 100% V1 at 3 weeks of age. The endogenous serum levels of thyroxine (T4) and triiodothyronine (T3) increase from trace amounts in the fetus to adult levels at 2-3 weeks of age; this increase correlates with the maximal expression of V1 during the same period. Expression of the V1 isomyosin can be eliminated in the neonatal rat if endogenous thyroid hormone synthesis is suppressed by propylthiouracil (PTU) treatment. In the PTU-treated rats, V3 is the only isomyosin synthesized between 1 and 30 days of age. In fetal ventricle, the amount of V1 is also decreased but not completely eliminated by PTU treatment. Conversely, the relative amount of V1 can be increased in the fetal ventricle by increasing the fetal serum concentrations of T4 and T3 to adult physiological levels. In these fetal ventricles, V1 represents greater than 85% of the total myosin. Likewise, the expression and accumulation of V1 could be stimulated in ventricles of PTU-treated, 12-day-old rats by administration of pharmacological or physiological doses of T3. Within 4 to 8 h after an initial dose of T3, V1 accumulates to 5-10% of the ventricular myosin, and by 72 h comprises 60-80% of the myosin. These results indicate that endogenous thyroid hormone induces the synthesis of ventricular heavy chain alpha, which as a dimer forms the V1 isomyosin, or plays a permissive role for the continued synthesis of heavy chain alpha in ventricles of fetal and neonatal rats.