Unusual features of neonatal thyroid function in small-for-gestational-age lambs. Origin of plasma T4 and T3 deficiencies

Thyroid function was studied in small for gestational age (SGA) or control newborn lambs. Neonatal changes in plasma concentrations of TSH, T3, rT3, total and free T4 were monitored, and thyroid scintigraphs were performed. Responsiveness of the hypothalamic-pituitary-thyroid axis to cold exposure and TRH or TSH administration was assessed. In addition, T4 and T3 kinetic studies were performed. In agreement with results obtained in babies, plasma T3, total T4 and free T4 concentrations were depressed in low birth weight animals, whereas TSH and rT3 levels were not affected. Thyroid size expressed relatively to the body weight was higher in SGA animals, thus suggesting that a partial compensation for low thyroid hormone levels had occurred during the fetal life. Plasma TSH and T4 concentrations increased by a same extent after exposure to cold and TRH or TSH administration in SGA and control lambs; however, the rise in T3 levels was depressed in the former in all stimulation tests. T3 and T4 production rates were similar in the two experimental groups. In SGA lambs, the metabolic clearance rate and the total distribution space of these two hormones were significantly increased; the fast T3 pool was higher, and the slow T3 pool lower than in control animals. All these results demonstrate that, despite low circulating thyroid hormone concentrations, SGA lambs are not hypothyroid. An increased T4 and T3 storage in the extravascular compartment is probably the major factor involved in the occurrence of this plasma deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pituitary-thyroid axis sensitivity and neonatal changes in plasma iodothyronine, thyreostimulin and cortisol levels in the preterm lamb: comparison of two experimental models

The influence of a 7 days prematurity, induced by oestrogen or dexamethasone injection to the mothers, on neonatal changes in plasma T4, T3, reverse T3 (rT3), TSH and cortisol levels was studied in 6 full term, 6 oestrogen preterm and 6 dexamethasone preterm lambs. In addition, the pituitary-thyroid axis sensitivity was assessed by the magnitude of the response to TRH administration. At birth, plasma cortisol and T3 levels, as the value of the T3/T4 ratio, were significantly lower in the two groups of preterm lambs than in full term animals; however, whereas plasma T3 concentrations and values of the T3/T4 ratio remained low in oestrogen lambs, they were quickly restored and elevated T3 levels associated to high T4 levels could be even observed in dexamethasone lambs; in this last group, these abrupt changes could be a consequence of raised TSH plasma concentrations recorded at birth. Moreover, if plasma rT3 levels and values of the rT3/T4 ratio were similar during the first hours of life in dexamethasone and full-term lambs, they were significantly higher in oestrogen animals. The responsiveness of the pituitary-thyroid axis to TRH was normal in dexamethasone animals, but was significantly enhanced in oestrogen ones, probably as a consequence of low T3 levels.     

Influence of experimental acidosis on the concentrations of thyreostimulin (TSH) and iodothyronines (total T4, free T4, T3) in the plasma of the newborn lamb

The effects of acute acidosis on neonatal thyroid function were studied by infusing HCl for 4 h in 42 to 54-h-old lambs. Animals of the same age, used as controls, were simultaneously infused with physiological saline. HCl infusion induced a sharp decrease in blood pH and total restoration did not occur before 48 h. When compared to control lambs, this experimental acidosis was associated with slight, but significant, decreases in plasma TSH, total T4, free T4 and total T3 levels, and in values of the free T4/total T4 ratio; the T3/FT4 ratio was not affected. The values of RT3/FT4 ratio were significantly increased in acidotic lambs. It is concluded that acidosis induced only modest secretory changes in neonatal thyroid function and slightly reduced the proportion and the amount of free T4.     

Long-term perspectives of thyroxine administration in neonatal rats.

Newborn pups were injected with normal saline (group A) and exogenous thyroxine (group B). Elevated T4 and decreased TSH levels from day 7 in group B continued until day 35. T4 and TSH were in normal range by day 42 and were similar to group A. Weight gain was significantly lower in group B. On day 45, half hourly injections (subcutaneous) of TRH were given to half of group A and group B each. Remaining halves were injected with saline. TSH response to TRH was significantly decreased in group B rats. Thus, neonatal hyperthyroidism results in (1) permanent decrease in pituitary reserve of TSH secretion and (2) a permanent imprinting regarding growth and thyroidal development and thus, neonatal period is critical for thyroidal development.     

Circulating LH, FSH, prolactin, testosterone, delta 4-androstenedione, dehydroepiandrosterone sulfate and cortisol levels in the fetus in late gestation and in newborn male and female lambs

Gonadotropins, prolactin (PRL), testosterone (T), delta 4-androstenedione, dehydroepiandrosterone sulfate and cortisol (F) levels were determined from 14 days before birth to term in 3 female and 3 male ovine fetuses with a chronically implanted venous catheter, and in the same animals from birth to 72 h of age. In both sexes, plasma gonadotropins and androgens were low throughout the period of study while plasma F increased with gestational age. After birth, plasma gonadotropins and PRL tended to increase progressively with time while PRL concentrations were significantly higher in female than in male lambs. F and T concentrations decreased significantly within the first 12 and 6 h of postnatal life. Higher T values were again observed at 36 h in male lambs. These data indicate that the fetal hypothalamic-pituitary-gonadal axis is relatively quiescent in the last 14 days of gestation but is activated within the first 72 h after birth.     

Effect of Ambient Salinity,Food-deprivation and Prolactin on the Thyroidal Response to TSH,and in vitro Hepatic T4 to T3 Conversion in Yearling Coho Salmon,Oncorhynchus kisutch

This study examines the effect of food deprivation, increased ambient salinity and prolactin administration on the thyroidal response to ovine TSH, and in vitro hepatic monodeiodination of T4 to T3 in coho salmon, Oncorhynchus kisutch. Fed fish and fish food-deprived for 18 days showed similar significant increases in plasma T4 9 and 24 h after a single injection of TSH. Plasma T3 levels were also elevated in both fed and food-deprived fish 9 h after the TSH injection but plasma T3 levels in the food-deprived fish were markedly lower than in the fed salmon. The increase in T4 and T3 evident in freshwater-acclimated fish after TSH administration was not found in salmon acclimated to 65% sea water. Prolactin, given alone (either as a single injection or a series of three daily injections) had no effect on plasma T4 or T3 levels. When given together with TSH prolactin prolonged the T4 and T3 elevating effect of TSH. Food-deprived salmon had lower in vitro hepatic T4 to T3 conversion rates than fed groups but T4 to T3 conversion did not appear to be affected by increased ambient salinity, or by prolactin and/or TSH administration.     

Simultaneous observations of iodothyronine content in the thyroid gland, serum and thyroxine 5'- and 5-monodeiodinase activity in liver, during the neonatal period of the pig

Serum T4 and rT3 were high at about 4-12 h after birth, then they decreased to a nadir on day 3 (rT3) and day 7 (T4). Serum T3 concentration fell immediately after birth but then increased to a relatively stable level during the next 2-6 weeks, then fell after weaning. Reciprocal concentration profiles of T4, T3 and rT3 in the thyroid were found. The thyroidal iodothyronine content increased significantly after weaning. In the liver, 5'-monodeiodinating activity, low after birth, rose until day 3 and then decreased concomitantly with T3 in serum. The 5-monodeiodinating activity, high at birth, fell to a nadir at about 3 weeks. No changes in 5- and 5'-deiodinase activity after 3 weeks were observed. Opposite to the variations in absolute content, the iodothyronine relative proportion in thyroid tissue was practically unchanged until weaning time (6 weeks), when they rose. Serum T3/T4 and rT3/T4 ratios increased with age until weaning. The post-weaned pigs had T3/T4 and rT3/T4 ratios about two times smaller than 6-weeks-old pigs. Serum rT3/T3, high after birth, decreased with age. Summarizing, the results indicate that neither changes in the thyroid iodothyronine content nor in the liver T4-monodeiodinating activity can solely account for variations in serum TH during the early neonatal period in the pig. It is suggested that the rapid variations in serum TH levels can reflect changes in the thyroidal secretory activity in preferential T3 secretion and/or blood disappearance rates.     

Thyroxine-binding globulin, triiodothyronine, thyroxine and thyrotropin in newborn infants and children.

Thyroxine-binding globulin (TBG), triiodothyronine (T3), thyroxine (T4) and thyrotropin (TSH) have been determined by radioimmunoassay in plasma of newborn infants and throughout childhood until puberty. Mean maternal TBG concentration was 1.65 +/- 0.09 mg/100 ml (SEM) and significantly higher (p less than 0.01) than cord blood levels of TBG (1.16 +/- 0.08 mg/100 ml (SEM). Throughout infancy and childhood TBG remained significantly elevated (p less than 0.01) compared to a middle age control group of healthy blood donors. T3, T4 and TSH concentrations behaved postnatally as known from previous studies. The T3 and T4 increase observed immediately after birth was not a secondary phenomenon due to changes in TBG concentration since this globulin did not change significantly during this period.     

Variations in immunocytochemical localization of cathepsin B and thyroxine in follicular cells of the rat thyroid gland and plasma TSH concentrations over 24 hours

Summary Immunocytochemical localization of cathepsin B and thyroxine (T4) in follicular cells of the rat thyroid gland and plasma concentrations of thyroid stimulating hormone (TSH) were examined at six evenly spaced times over 24 h. By light- and electron microscopy, immunodeposits for cathepsin B were localized in cytoplasmic granules of various sizes, whereas those for T4 were detected mainly in larger granules of the cells and in the colloid lumen. The size and location of cytoplasmic granules showing immunoreactivity for cathepsin B and T4 in the cells varied over 24 h, corresponding to a change in plasma TSH concentrations. These immunopositive large granules appeared in the apical cytoplasm at 12.00 h, when the level of TSH was highest. At 20.00 h when the level of TSH was lowest, T4-positive granules almost disappeared, and cathepsin B-positive small granules were abundantly seen in the basal region. From 00.00 h to 08.00 h, these positive granules changed in the same manner as those seen from 12.00 h to 20.00 h, associated with an increase in plasma TSH levels. These results suggest that newly formed colloid droplets migrate from the apical to the basal regions. Cathepsin B may play a role not only in the degradation of thyroglobulin but in the maturation of thyroid hormones during the migration of the granules.     

Effects of anti-thyrotropin-releasing hormone anti-serum treatment during the neonatal period on the development of rat thyroid function

Effects of anti-thyrotropin-releasing hormone (TRH) anti-serum treatment during the neonatal period on the development of rat thyroid function were studied. On postnatal days 2 and 4, rats were administered anti-TRH anti-serum ip, and they were serially decapitated at the 4th, 8th and 12th week after birth. TRH, thyrotropin (TSH), thyroxine (T4) and 3,3',5-triiodothyronine (T3) were measured by radioimmunoassay. Immunoreactive TRH (ir-TRH) in the hypothalamus did not change significantly after anti-TRH anti-serum treatment, and plasma ir-TRH tended to decrease. The plasma ir-TRH and TSH responses to cold were significantly inhibited. The plasma TSH response to TRH was also significantly inhibited. The plasma basal TSH levels were significantly lower than in controls. The plasma T4 and T3 levels were found to be lower than those in the controls. Findings suggested that treatment with anti-TRH anti-serum during the neonatal period disturbed the development of rat thyroid function, inhibiting TRH release and altering thyrotroph sensitivity to TRH.     

Influence of environmental events immediately after birth on postnatal testosterone secretion and adult sexual behavior in the male rat

A rise in plasma testosterone (T) levels occurs in male rats during the first 2 hr after birth which is of importance for the process of sexual differentiation. To study the influence of environmental factors on the postnatal T surge and sexual development, newborn male rats were subjected to various treatments immediately after cesarean delivery including cooling, ether anesthesia, and mother-infant separation. In adulthood, the animals were observed for masculine and feminine sexual behavior. Males anesthetized at 0 hr showed elevated levels of feminine sexual behavior and impaired masculine sexual behavior. Pups subjected to cooling or mother-infant separation showed slightly prolonged intromission latencies, but otherwise normal levels of feminine sexual behavior. Significantly elevated plasma T levels were found in intact pups 2 hr after birth but not in pups subjected to cooling or ether anesthesia. Significantly higher levels of T were observed in pups subjected to cooling 4 hr after birth, suggesting a delay of the T surge. The most pronounced impairing effects were seen in the defeminization process, but the masculinization process also is affected by ether anesthesia. It was concluded that ether anesthesia immediately after birth may permanently interfere with the sexual development by suppressing the neonatal T surge.     

Studies of the in vitro sensitivity of iodothyronine synthesis to methimazole in normal human thyroid cells

The comparative effects of methimazole (MMI) on resting and thyrotropin (TSH) — stimulated human thyroid cell cultures were investigated in terms of the release of iodoprotein and newly — synthesised iodothyronine hormones into the culture medium during a 48h period of incubation.Iodoprotein recovery was increased after TSH, but both basal and TSH — enhanced iodoprotein release were depressed by MMI. TSH increased the release of tri-iodothyronine (T3) and thyroxine (T4), and although the TSH — enhanced T3 and T4 levels were depressed after MMI, (i) the basal levels found in control cultures were not attained, and (ii) T3 was more susceptible than T4 to MMI suppression, at high TSH levels.These findings indicate a retention of the $\text{in vivo}$ thyroidal sensitivity to MMI, under basal conditions and moderate TSH stimulation $\text{in vitro}$. The system may therefore facilitate further investigation into the mode of MMI suppression of peroxidase systems involved in iodothyronine hormone synthesis within the intact human thyroid cell.     

Increased thyroidal T4/T3 ratio in nodular and paranodular tissues of nontoxic goiter following suppressive treatment with thyroid hormones

The effect of suppressive treatment with thyroid hormones on thyroidal iodothyronines and T4/T3 ratio in nodular and paranodular tissues was investigated in 12 patients with nontoxic goiter. Results were compared to those from 11 nontreated patients. Continuous thyroid hormone administration produced a significant increase in thyroidal T4 and T4/T3 ratio in nodular tissues while T3 remained unchanged. In paranodular tissues a significant rise of T4/T3 ratio, an insignificant increase in T4 and a decrease in T3 were observed following the administration of thyroid hormones. The results are very similar to those obtained in paranodular tissue of autonomously functioning thyroid nodule, and are probably the consequence of suppressed TSH secretion, as TSH predominantly stimulates the synthesis of T3 and/or thyroidal T4 monodeiodination.     

Effects of reproductive state on concentrations of thyroxine, 3,5,3'-triiodothyronine and cortisol in serum of dogs

Reproductive state of animals frequently is overlooked when examining endocrine functions of the thyroid gland and adrenal cortex. This experiment was done to determine effects of reproductive state on basal and stimulated concentrations of thyroxine (total T4), 3,5,3'-triiodothyronine (total T3) and cortisol in serum of adult Beagle dogs. Five male, 5 anestrous, 5 proestrous, 5 diestrous, 5 pregnant and 5 lactating dogs were fasted for 18 h before each dog received 5 IU of thyrotropic hormone (TSH) i.v. and 2.2 IU/kg of body weight of adrenocorticotropic hormone (ACTH) i.m. Blood samples were collected via jugular cannulas or by jugular venipuncture at 60, 45, 30, 15 and 1 min before and 0.5, 1, 2, 3, 4, 5, 8, 12 and 24 h after injection. Concentrations of T4 were similar in serum from diestrous and pregnant bitches but were greater (P less than 0.025) than those in dogs of other reproductive states before and after treatment with TSH. Concentrations of T3 were greater (P less than 0.005) in serum from diestrous bitches before and after TSH injection than in serum from dogs of all other reproductive states. Concentrations of T3 in males, anestrus, proestrus, pregnancy and lactation did not differ. Basal concentrations of cortisol did not differ consistently among reproductive states. However, concentrations post-ACTH were different (P less than 0.05) with anestrus = diestrus greater than lactation = pregnancy = male greater than proestrus. These results indicate that reproductive state of experimental animals must be considered when studying thyroidal and adrenal functions.     

Adrenal inhibition of corticotropin-releasing hormone-induced thyrotropin release: a comparative study in pre- and posthatch chicks

Recent evidence indicates that corticotropin-releasing hormone (CRH) acts as a potent stimulator of thyrotropin (TSH) release in the chicken. In this study adrenal and thyroidal feedback mechanisms were studied. Administration of corticosterone 30 min prior to an ovine CRH (oCRH) challenge diminished the in vivo sensitivity of thyrotrophs to oCRH in 19-day-old chicken embryos (E19) (20 micrograms corticosterone; 2 micrograms oCRH) but not in 8-day-old chickens (C8) (40 micrograms corticosterone; 4 micrograms oCRH). At both ages studied, corticosterone (0.01 and 1 microM) did not alter the in vitro TSH response to oCRH (100 nM) indicating that an indirect mechanism is involved at the embryonic stage which is no longer present in posthatch chickens. In vitro, 3,5,3'-triiodothyronine (T3) pretreatment (0.01 and 1 microM) resulted at both ages studied in a dose-dependent drop in the in vitro oCRH-induced TSH release. As recorded previously, corticosterone treatment provoked a rise in plasma T3 in embryonic but not in posthatch chickens. The presence of an indirect adrenal feedback mechanism in chicken embryos may therefore be linked to the increase in plasma T3 which will alter the sensitivity of thyrotrophs to hypothalamic releasing factors. In conclusion, corticosterone does not directly modulate the responsiveness of thyrotrophs to CRH, but its feedback mechanism may be dependent on the evoked increase in plasma T3 which is only present in embryonic chickens. Corticosterone may in this regard play an essential role during embryonic development by coordinating thyroidal feedback mechanisms at the level of the chicken pituitary.     

Erythrocyte carbonic anhydrase I concentration in patients receiving thyroxine.

We recently reported that the red blood cell (RBC) carbonic anhydrase I (CAI) concentration in patients with hyperthyroidism is reduced and reflects the patient's mean thyroid hormone level over the preceding months. In this study, RBC CAI concentrations were measured in patients with thyroid nodules who were receiving suppressive doses of thyroxine (group I) and compared with those obtained in patients with primary hypothyroidism receiving replacement doses of thyroxine (group 2). Of the 17 patients in group 1, 16 (94%) had elevated plasma free T4 levels, but all 17 had normal free T3 levels. Of the 17 patients in group 2, 16 (94%) had normal free T4 levels and all 17 had normal free T3 levels. Plasma TSH concentrations in group 1 were all below the lower limit of sensitivity of 0.04 mU/l. In group 2, 11 had normal and 6 had slightly elevated plasma TSH concentrations. The mean (+/- SD) RBC CAI concentration in group 1 (300 +/- 53 nmol/g Hb) was significantly lower than that in group 2 (340 +/- 57 nmol/g Hb). The RBC CAI concentration was significantly correlated with both the concentration of plasma free T4 and free T3. These observations indicate that in patients receiving suppressive doses of thyroxine a slight increase in the plasma free T4 concentration produces a slight but significant decrease in RBC CAI levels.     

Effects of thyroxine and 3,5,3'-triiodothyronine in brown adipose tissue of rats

Rats of both sexes were either cold acclimated (6 +/- 1 degree C) or treated with thyroxine (T4) or 3,5,3'-triiodothyronine (T3) (500 micrograms/kg body wt daily s.c. for 3 weeks). Wet weight, total proteins, lipids and nucleic acids in the interscapular brown adipose tissue (IBAT) were measured. Values obtained with T4 treatment were similar to those obtained with T3 treatment. T3 is the main thyroidal hormone in the rat and it is formed from T4 deiodination in liver and kidney. As T4-treated rats have not received T3 directly and its IBAT has a similar composition to that of T3-treated rats, it is concluded that peripheral T4 deiodination is governed by the plasma T4 levels. Total proteins and DNA content were similar in cold-acclimated and T3- or T4-treated rats, which is interpreted as thyroidal hormones having an action at these levels.     

Placental restriction alters circulating thyroid hormone in the young lamb postnatally

Intrauterine growth restriction (IUGR) is associated with accelerated growth and increased adiposity in early life due to unknown mechanisms, which could include increased thyroid hormone (TH) action. We hypothesized that placental restriction (PR) of fetal growth would increase circulating TH concentrations and alter their response to fasting, and that these would relate to growth and body composition in the young lamb. PR reduced size at birth, increased fractional growth rates (FGRs) of soft and skeletal tissues up to 30 days of age, and slowed the ontogenic decrease in plasma total T3 and plasma total T3/T4. PR did not alter the abundance of plasma THs after short-term fasting. In general, plasma total T3 and total T3/T4 ratio correlated negatively, whereas plasma total T4 correlated positively with size at birth. Absolute growth rates of weight and crown-rump length correlated positively with plasma total T3 and total T4 between days 15 and 35. Current FGRs for weight and metatarsal length correlated positively with plasma total T3 between days 20 and 35. In conclusion, PR and small size at birth reduce plasma total T4 and increase plasma total T3 postnatally, whereas catch-up growth relates to increased abundance of the more bioactive forms of TH. Finally, greater soft tissue growth occurs in PR compared with control lambs at the same circulating TH concentrations. This suggests that PR and small size at birth may increase activation of T4 to T3 and sensitivity of soft tissues to TH, which may contribute to catch-up growth following IUGR.     

Suppression of TSH in congenital hypothyroidism is significantly related to serum levels and dosage of thyroxine

AIM: To assess thyrotropin (thyroid-stimulating hormone; TSH) suppression and serum thyroxine (T(4)) concentrations in infants with congenital hypothyroidism in relation to T(4) dose and pretreatment parameters. METHOD: A retrospective study of all cases treated in a single centre since neonatal screening began was performed. RESULTS: In 54 infants treated with a mean daily T(4) dose of 9.8 microg/kg, the TSH concentration was suppressed (<6 mU/l) in 65% of the cases by 6 months with the serum T(4) level at the upper end of the infant reference range. Infants who suppressed their TSH later did not differ in pretreatment serum TSH or T(4) concentration. T(4) dose and serum T(4) level were lower in infants whose TSH was not suppressed. CONCLUSIONS: TSH suppression in congenital hypothyroidism is significantly related to serum levels and dosage of T(4). We suggest that a delay in TSH suppression is mainly due to undertreatment.     

Thyroid function and polyamines. III. Changes in ornithine decarboxylase activity and polyamine contents in the rat thyroid during hyperplasia and involution

Changes in ornithine decarboxylase (ODC) activity and in polyamine contents of the rat thyroid were studied under various experimental conditions. Methylthiouracil (MTU) treatment produced several-fold increases in the thyroid ODC activity and in the content of putrescine, spermidine and spermine within a week. While serum thyrotropin (TSH) levels increased gradually up to 3 weeks, the content of both putrescine and spermidine tended to reach a plateau after 2 weeks of the goitrogen treatment; spermine content continued to increase progressively for 3 weeks. Discontinuance of MTU at 7 days resulted in a rapid decline in the elevated thyroid ODC activity, followed by a diminution of putrescine, spermidine and RNA contents. Thyroidal putrescine, spermidine and RNA responded more sensitively to both introduction and withdrawal of TSH stimulation than thyroidal spermine and DNA. Excess iodide, having no effect on the basal level of thyroid ODC, suppressed the MTU-induced increase in this enzyme activity without affecting circulating TSH, thyroxine (T4) and triiodothyronine (T3) levels. There was a significant negative correlation between the ODC activity and intrathyroidal concentration of iodine in MTU-pretreated rats. Theophylline increased the thyroid weight and ODC activity when given to rats fed with a subeffective dose of MTU. Analyses of serum TSH, T4, T3 and of thyroidal iodine revealed that TSH-induced thyroid ODC activity was suppressed by increased circulating thyroid hormones and/or intrathyroidal iodine. Furthermore, it was suggested that thyroid hormones and excess iodide acted directly on the thyroid to alter polyamine biosynthesis, possibly by changing the responsiveness of the gland to TSH.