T4 Replacement Therapy Research Articles

Thyroxine withdrawal is accompanied by decreased circulating levels of insulin-like growth factor-binding protein-1 in thyroidectomized patients.

We carried out a study on the effect of T4 withdrawal on serum insulin-like growth factor-binding protein-1 (IGFBP-1) levels in 10 thyroidectomized patients with papillary thyroid cancer receiving T4 replacement therapy. As controls we also measured serum sex hormone-binding globulin (SHBG) levels, known to be regulated by T4. Each patient acted as his/her own control, studied both before and 30 days after T4 withdrawal. On the average, the IGFBP-1 level decreased by 36% from 66 +/- 9 to 44 +/- 8 micrograms/L (mean +/- SE; P = 0.0007) during T4 withdrawal. The SHBG level decreased by 47% from 78 +/- 17 to 46 +/- 13 nmol/L (P = 0.0001). The fasting insulin levels were unaffected by T4 withdrawal. There also was an 18% decline in the serum IGF-I concentration after T4 withdrawal (P = 0.011). It is concluded that in athyreotic patients receiving T4, withdrawal of the drug decreases serum IGFBP-1 and SHBG concentrations and IGF-I levels. In view of the possible role of IGFBP-1 in glucose counterregulation, these results indicate a novel mechanism by which T4 may exert its metabolic action on liver carbohydrate metabolism.

Dependence of body growth on thyroid activity in turtles

AbstractWe surgically thyroidectomized (Tx) or sham‐operated hatchling slider turtles—Trachemys (Pseudemys) scripta—and measured their growth (mass and carapace length) for 5 to 7 months. Autopsy at the end of the experiments revealed that up to 30% of the thyroidectomized animals had regenerated thyroid follicles (thyroids had few but enlarged follicles). Therefore, we segregated thyroidectomized turtles a posteriori into two groups: those with observable thyroid tissue at autopsy, greater than 3 ng/ml plasma thyroxine (T4), and normal plasma T4 binding capacity were designated partial Tx (PTx), and others with no observable thyroid tissue, less than 3 ng/ml plasma T4, and low plasma T4 binding capacity were designated Tx. Growth rate was significantly reduced 6–8 weeks after thyroidectomy in the Tx animals; length‐specific growth rate was affected sooner than mass‐specific growth rate. Growth of Tx animals continued to diverge from sham turtles through the end of the experiment; PTx animals did not differ from shams at any time. In a second experiment growth rate was reduced in Tx turtles maintained under both varibale (14L:10D, thermal gradient of 19 to 40°C) and constant (constant light and temperature—30°C) environmental conditions (i.e., reduced growth rate was probably not related to a thermoregulatory dysfunction). However, all animals maintained under the constant conditions stopped growing after 3 months, whereas turtles kept under varibale conditions continued to grow to the end of the experiment (4.5 months). Thyroxine (T4) replacement therapy of long‐term Tx turtles restored growth after 6 weeks.Plasma thyrotropin (TSH) was greatly elevated in Tx turtles (301 ± 48.7 ng/ml) and at low to nondetectable levels in controls (⩾ 1 ng/ml). T4 replacement therapy was effective in reducing TSH levels in Tx turtles. Plasma T4 and TSH concentrations showed the expected inverse relationship. However, although PTx animals had elevated plasma T4 levels that were in the lower range of the sham controls (PTx: 36.6 ± 8.2 vs. 112.7 ± 17.1 ng/ml in sham), their plasma TSH was also significantly elevated (36.5 ± 9.3 ng/ml vs. 0.8 ± 0.2 ng/ml in sham). These results demonstrate the requirement of an intact thyroid gland for normal growth of turtles, and provide the first direct evidence for a role for the thyroid in body growth of a reptile. They also reveal that the set‐point for the feedback between the thyroid and pituitary secretion can be altered by perturbation of thyroid activity.

Thyroid Disease and Pregnancy

Thyroid disease is common in younger women and may be a factor in reproductive dysfunction. This probably only applies to severe cases of hyper- or hypothyroidism. Once adequately treated, neither of these disorders significantly impacts on fertility. The key is to recognize and to treat thyroid disorders in the reproductive-age woman before conception. Thyroxine therapy and even antithyroid drug therapy should be continued during pregnancy as necessary. Pregnancy is a euthyroid state that is normally maintained by complex changes in thyroid physiology. The fetal and neonatal hypothalamic-pituitary-thyroid system develops independently, but it may be influenced by thyroid disease in the mother. Early pregnancy is characterized by an increase in maternal T4 secretion stimulated by hCG and an increase in TBG, resulting in the elevated total serum T4 in pregnancy. The debate continues as to whether maternal T4 is important in early or late fetal brain development. If so, the physiologic changes in thyroid hormone secretion and transport in early pregnancy would help to ensure that a sufficient amount of thyroid hormone was available. There is new evidence in human subjects that substantial maternal T4 can cross the placenta during pregnancy, and this may be particularly important when fetal thyroid function is compromised as a result of congenital hypothyroidism. Maternal and fetal/neonatal outcomes in pregnancy are adversely affected if severe hypothyroidism is undiagnosed or inadequately treated. Thyroid function tests should be obtained during gestation in women taking T4 and appropriate dose adjustments should be made for TSH levels outside a normal range. The TSH-receptor blocking antibodies from the mother are a recognized cause of congenital hypothyroidism in the fetus and neonate that can be permanent or transient. If neonatal hypothyroidism is detected through neonatal screening programs, and prompt and adequate T4 replacement therapy is instituted as soon as possible following delivery, subsequent growth and development are usually normal. Paradoxically, pregnancy often has a favorable effect on the course of maternal Hashimoto's disease, although there is the risk of relapse postpartum. Pathophysiologic conditions of hCG secretion such as gestational trophoblastic disease and hyperemesis gravidarum may present as thyrotoxicosis in pregnancy, but the main cause of this syndrome is Graves' disease. The mainstay of treatment is antithyroid drugs and either propylthiouracil or methimazole may be used safely. Subtotal thyroidectomy, after medical control, is the alternative treatment, but radioiodine ablation is contraindicated.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth hormone and thyroxine affect lipoprotein metabolism in hypothyroid and hypophysectomized rats

The aim of this study was to evaluate the effect of thyroxine (T4) and GH replacement therapy on serum lipoproteins in rats with primary and secondary hypothyroidism and to see whether recovery of GH activity was associated with normalization of serum lipoproteins. In both the primary and secondary hypoproteins. In both the primary and secondary hypothyroid rats, total cholesterol (TC) was higher than in normal controls, due to an increase in low-density lipoprotein cholesterol (LDL-c) and to a lesser extent also in high-density lipoprotein cholesterol (HDL-c). Treatment of hypophysectomized rats with GH induced a decrease in the concentration of TC, LDL-c and HDL-c, while liver lipase activity (LLA) increased. The effect of GH on HDL-c was correlated with the increase in LLA. T4 replacement therapy of hypophysectomized rats normalized LDL-c, but HDL-c and LLA were unaffected. During primary hypothyroidism, T4 treatment induced GH activity, increased LLA and reduced the HDL-c concentration. GH treatment of primary hypothyroid rats had a similar influence on the lipid levels and LLA as in hypophysectomized animals, although the lowering of HDL-c was less prominent. These results demonstrate that GH determines serum lipoproteins during both primary and secondary hypothyroidism.

169 THE ETIOLOGY OF CONGENITAL HYPOTHYROIDISM (CHT) IN THE NETHERLANDS

The Dutch national thyroid screening (measuring T4 and in the 20% samples with lowest T4 also TSH) was started in 1981. The abnormal screening results were evaluated 4 till 6 years later. Of the 176,311 screened children (98.7% of all neonates in 1981) 1637 (0.93%) had been referred. Especially the cases with elevated TSH levels (> 25 mU/l in blood spots and/or >10 mU/l in venous samples) were re-examined; in case of a permanent CHT of unknown cause the T4 replacement therapy was interrupted for investigation. Permanent primary CHT was found in 51 cases (incidence 1:3500): 14 ageneses, 3 cryptic thyroids, 27 sublingual thyroids, 4 total organification defects, 1 Pendred syndrome and 2 other dyshormonogeneses. Secondary/tertiary CHT was found in 6 cases (1:30,000): the 3 having an abnormal screening result were already under pediatric control since birth; in the other 3, having normal screening values, the diagnosis congenital TSH deficiency was made after referral for growth retardation. Transient primary CHT, comprising 89 cases (1:2000), outnumbers permanent CHT. In 45 cases a plausible etiology was found retrospectively: one mother used PTU during pregnancy, one child with a congenital nephrotic syndrome and 43 cases in which the fetus or neonate was exposed to high doses of iodine. Severity and duration of the CHT in the other 44 cases were comparable, however the cause remained unknown. In conclusion, the Dutch overall incidence of CHT amounts to 1:1200.

Immunoradiometric assay for basal thyroid-stimulating hormone levels: strategy for the management of thyroxine replacement.

Basal levels of thyroid-stimulating hormone (TSH) as determined by a highly sensitive immunoradiometric assay (IRMA) were evaluated in 30 clinically euthyroid patients receiving levothyroxine (T4) replacement therapy for primary hypothyroidism. In each patient, the serum TSH level had been normal as determined by conventional TSH radioimmunoassay while the patient had been receiving a constant dosage of T4 for at least three months before the study. Correlation of the TSH levels by IRMA with the concurrent concentrations of serum T4 and triiodothyronine (T3) showed that basal TSH levels by IRMA were not predictable from the serum T4 and/or T3 levels. We observed a relatively high frequency of suppression of basal TSH levels (8/30, 27%), a finding compatible with, though not necessarily indicative of, overmedication with T4. In view of the reasonable suspicion that modest but protracted overmedication with T4 may be detrimental and that suppressed TSH levels are commonly observed in conventionally managed patients, and since suppression of TSH levels is now identifiable, it seems prudent to revise the guidelines of T4 replacement therapy accordingly. In addition to maintaining clinical euthyroidism, we propose that titrating the T4 dosage to establish lower normal TSH concentrations without suppression (eg, 0.1 to 3.0 microU/ml) would assure the resolution of frank hypothyroidism, reduce the likelihood of persistent goiter, and minimize the potential for subtle but chronic overmedication.

Effect of thyroxine replacement therapy on the growth patterns of body, brain, and cerebellum in the neonatal hypothyroid rat

The reversibility of the effects of propylthiouracil induced neonatal hypothyroidism by daily subcutaneous injections of l-thyroxine (T4) was investigated in the rat. Four groups of rat pups were used in this experiment: Group I (control) received equivalent amounts of saline sucutaneously; Group II (hypothyroid) received propylthiouracil injections daily; Group III (T4-14) are hypothyroid rats who received daily T4 replacement therapy (2.5 μg/day) subcutaneously starting on Day 14; Group IV (T4-21) are also hypothyroid rats whose T4 replacement therapy (2.5 μg/day) was started on Day 21. The four parameters studied were body length, body weight, brain weight, and cerebellar weight in these four groups of animals at 4, 7, 10, 14, 21, 28, 35, and 42 postnatal days. A minimum of eight animals were studied for each time sequence. The present study clearly indicated the beneficial effect of T4 therapy on the length and body weight of the hypothyroid animals, whether therapy was started at Postnatal Day 14 or 21. In addition, a more important finding of this study was the significant increase in brain and cerebellar weights of T4-treated animals compared to the hypothyroid animals, this beneficial effect being more striking in the T4-14 group when compared to that in the T4-14 animals.

Long term follow-up of patients with Cushing's disease treated by interstitial irradiation.

The first 86 patients with Cushing's disease treated with interstitial irradiation (by needle implantation) as the sole therapy were reviewed. In the 82 patients who were reassessed 1 yr after treatment 63 (77%) achieved remission. This study comprises the outcome and complications in the 54 patients who had a remission and whom we were able to follow. The follow-up period ranged from 3-26 yr (mean, 10.5) from the time of remission. No instance of clinical or radiological relapse has occurred. Of these 54 patients, yttrium-90 alone was used in 32, of whom 12 (37%) required corticosteroid or T4 replacement therapy in a mean time of 3.5 months; in 7 of these 12 we elected to give an ablative dose. Gold-198 alone was used in 15 patients, of whom 7 (47%) developed hypopituitarism in a mean time of 76 months. Both isotopes were used in 7 patients. A diurnal serum cortisol rhythm was found in 28 of the 31 patients who were not receiving corticosteroid therapy. In 5 of the 7 patients with an initially abnormal pituitary fossa, serial radiological studies revealed remodelling in 3. There have been no complications in the last 17 years. Pituitary implantation with yttrium-90 is an effective alternative to transsphenoidal hypophysectomy, with a high remission rate, no recurrence (as yet), no operative complications, and avoidance of hormone replacement in the majority.

Effect of thyroxine replacement therapy on plasma insulin-like growth factor 1 levels and growth hormone responses to growth hormone releasing factor in hypothyroid patients.

The aim of this study was to evaluate the effect of T4 replacement therapy on plasma insulin-like growth factor 1 (IGF-1) levels in patients with primary hypothyroidism to see whether recovery of pituitary GH responsiveness to GRF was associated with increased plasma IGF-1 levels. IGF-1 levels and GH responses to GRF (1 microgram/kg) were measured in 21 patients with primary hypothyroidism before and after T4 replacement therapy. T4 increased plasma IGF-1 levels (57.2 +/- 4.4 vs 75.9 +/- 8.8 ng/ml, mean +/- SEM, P less than 0.05) and GH responses to GRF as assessed both by peak GH levels (9 +/- 1.5 ng/ml before treatment vs 16.7 +/- 3 ng/ml after treatment, mean +/- SEM, P less than 0.05) and area under curve (496 +/- 92 before treatment vs 896 +/- 161 after treatment, mean- +/- SEM, P less than 0.05). Linear regression analysis showed a positive correlation between free T3 and IGF-1 levels after treatment (r = 0.37, P less than 0.05) and a negative relationship between plasma IGF-1 levels before treatment and delta IGF following T4 replacement therapy (r = 0.45, P less than 0.025). However, no correlation was found between plasma IGF-1 levels and GH responses to GRF, suggesting that GH responses to GRF are of no predictive value in relation to the recovery of plasma IGF-1 levels following T4 replacement therapy in hypothyroid patients.

Galactorrhea in Subclinical Hypothyroidism.

Galactorrhea was found in 5 patients with subclinical hypothyroidism. The galactorrhea consisted of the discharge of a few drops of milk only under pressure. Serum T4 was in the lower level of the normal range, but serum T3 was normal (T4: 6.3 +/- 1.2 micrograms/dl, T3: 113 +/- 7 ng/dl). Basal serum TSH and PRL were slightly increased only in 2 and 1 cases, respectively. The PRL responses to TRH stimulation were exaggerated in all cases, although the basal levels were normal. An enlarged pituitary gland was observed in 1 patient by means of CT scanning. All patients were treated by T4 replacement. In serial TRH tests during the T4 replacement therapy, the PRL response was still increased even when the TSH response was normalized. Galactorrhea disappeared when the patients were treated with an increased dose of T4 (150-200 micrograms/day). Recurrence of galactorrhea was not observed even though replacement dose of T4 was later decreased to 100 micrograms/day in 4 cases. In patients with galactorrhea of unknown origin, subclinical hypothyroidism should not be ruled out even when their serum T4, T3, TSH and PRL are in the normal range. The TRH stimulation test is necessary to detect an exaggerated PRL response, as the cause of the galactorrhea. To differentiate this from pituitary microadenoma, observation of the effects of T4 replacement therapy on galactorrhea is essential.

Analysis of Thyrotropin‐Thyroxine Secretory Dynamics in Infantile Hyperthyrotropinemia: An Aid for Early Differential Diagnosis

AbstractFor the purpose of differentiating neonatal hyperthyrotropinemia, the interrelation between serum thyrotropin (TSH) and thyroxine (T4) was examined in 10 infants with primary hypothyroidism during 12 months of T4 replacement therapy. A significant inverse correlation was obtained between elevated TSH (Y) (above 12 μU/ml) and T4 (X) levels; Y = 324 ‐ 22 X (r = ‐0.801, p < 0.001). One patient had an abnormally high threshold of TSH‐inhibition by T4. Based on this regression line, a scattergram of TSH‐T4 correlation and changes in the time course was analyzed in 13 infants with neonatal hyperthyrotropinemia, including eight with transient hyperthyrotropinemia (t‐TSH), three with compensated hypothyroidism (c‐Hypo) and two with transient hypothyroidism (t‐Hypo). All plots from t‐TSH were distributed under the regression line and shifted downward with concomitant rise in T4 and free T4 levels. In contrast, plots from c‐Hypo and t‐Hypo showed a vertical upward shift above the line during 3–4 months of observation without treatment. These results indicate that (1) using the TSH‐T4 regression line, differentiation of c‐Hypo from t‐TSH is possible by 3 months of age, (2) the cause of t‐TSH is not an elevated threshold for TSH release, but rather the maturational delay in responsiveness of the thyroid to TSH, and (3) suppression of TSH alone should not be used as the index of adequate T4 dose in infantile hypothyroidism, because of the existence of patients with a high threshold of TSH‐inhibition by T4.

Growth hormone responses to GRF 1-29 in patients with primary hypothyroidism before and during replacement therapy with thyroxine.

It is well known that hypothyroidism is frequently associated with impaired GH responses to different stimuli. In the present study we have evaluated GH responses to GH-releasing factor (GRF) in patients with primary hypothyroidism before and during T4 replacement therapy. Fourteen patients (age range 26-60 years) underwent two GRF tests (1 microgram/kg) before and during replacement therapy (150 micrograms/d). Administration of T4 increased peak GH responses to GRF in 9 patients and in the group as a whole (mean +/- SEM, 17.0 +/- 2.8 vs 32.6 +/- 5.7 mU/l, P less than 0.02). When the data are analysed by means of area under the curve (AUC), the GH response to GRF was increased by T4 in 10 patients and in the group as a whole (mean +/- SEM, 51.7 +/- 14.3 vs 101.5 +/- 28.1, P less than 0.02). These data indicate that thyroid hormone replacement therapy enhances the responsiveness of the somatotroph to GRF 1-29 in patients with primary hypothyroidism.

Persistent TRH-induced growth hormone release after short-term and long-term L-thyroxine replacement therapy in primary congenital hypothyroidism.

No appreciable changes in plasma GH levels after TRH stimulation have been observed in normal subjects, whereas acute GH release has been reported in primary hypothyroidism and other pathophysiological states. To evaluate the effect of the T4 replacement therapy on TRH-induced GH release, 28 patient volunteers with primary congenital hypothyroidism (PCH), were studied before (11 subjects), after 1 month (nine subjects) and after long-term T4 replacement therapy (eight subjects). All patients underwent a TRH test with measurement of TSH, PRL and GH levels, and were compared to 28 age-matched normal subjects. An increase of plasma GH after TRH was found in 46% of patients without any therapy, in 67% of patients after one month of T4 administration and in 75% of patients after long-term therapy. No changes were observed in plasma GH levels in controls. The TSH response to TRH was inhibited and the response of PRL was reduced step by step by T4 replacement therapy in our patients with PCH. Our results suggest that: (i) Replacement T4 therapy in PCH does not abolish the paradoxical GH response to TRH, in spite of inhibiting the TSH response and reducing the exaggerated PRL response; (ii) the GH response to TRH in PCH seems to be unrelated to low thyroid hormone levels and/or to high TSH levels, but it could be due to changes in hypothalamic-pituitary regulation which are not improved by T4 replacement therapy.

Caloric restriction does not alter thyrotropin secretion in hypothyroidism.

The effect of caloric restriction, as a model of nonthyroid illness, on serum thyroid hormone and TSH concentrations in hypothyroid patients was studied to determine if pituitary-thyroid function is altered in such patients, as it is in euthyroid subjects. Serum T4, T3, and TSH concentrations and serum TSH responses to TRH were measured in 5 untreated hypothyroid patients and 10 hypothyroid patients receiving T4 replacement therapy before and after restriction of caloric intake to 500 cal daily for 7 days. In 5 untreated hypothyroid patients, the mean serum T3 concentration declined 17%, from 75 +/- 14 (+/- SE) to 62 +/- 11 ng/dl. The mean basal serum TSH concentrations were 154 +/- 67 (+/- SE) microU/ml before and 161 +/- 75 microU/ml at the end of the period of caloric restriction, and the serum TSH responses to TRH were similar on both occasions. In 10 T4-treated hypothyroid patients, the mean serum T3 concentration declined 35%, from 110 +/- 8 to 71 +/- 8 ng/dl. In this group, mean basal serum TSH concentrations were 17 +/- 5.1 microU/ml before and 18.2 +/- 7.0 microU/ml at the end of the period of caloric restriction, and as in the untreated hypothyroid patients, the serum TSH responses to TRH were similar on both occasions. Mean serum T4 concentrations and serum free T4 index values did not change in either group. These results indicate that caloric restriction in both untreated and T4-treated hypothyroid patients is accompanied by 1) reduced serum T3 concentrations, as it is euthyroid subjects, and 2) no alterations in basal or TRH-stimulated TSH secretion.

Comparative effects of neonatal hypothyroidism and euthyroidism on TRH and substance P content of lumbar spinal cord in saline and PCPA-treated rats

The effects of neonatal thyroidectomy and thyroid hormone replacement therapy on the content of substance P and TRH in the lumbar segment of the rat spinal cord were studied. The peptide content of discrete spinal cord regions removed by punches of frozen serial slices was measured by RIA. Animals receiving T4 replacement therapy were indistinguishable from normal littermates. In hypothyroid animals without PCPA-treatment, levels of TRH and substance P were significantly increased by 100% in the ventral and the dorsal lumbar spinal cord, respectively. Inhibition of serotonin biosynthesis by PCPA increased by 90% the substance P content in the dorsal horn of euthyroid rats and abolished completely the stimulatory effect of hypothyroidism on the TRH content of the ventral horn. These findings suggest the existence of a physiological relationship between substance P and TRH with the serotoninergic system in the rat spinal cord and that thyroid hormone is implicated in the normal development of the peptide-containing neurons in the rat spinal cord.

Visual field defects and pituitary enlargement in primary hypothyroidism.

In 14 patients with overt primary hypothyroidism, we examined visual fields by Goldmann's isopter perimetry. An unexpectedly high incidence (10 patients, 71.4%) of visual field defects was found. Two patients complained of visual failure, whereas 12 had no subjective symptoms. The extent of visual field change varied over a wide range, from early chiasmal compression to apparent bitemporal hemianopsia. The abnormality was characteristically restriction in the central visual field; peripheral vision was less often affected. The sella turcica was significantly enlarged in these patients as compared to controls. The volume of the sella turcica correlated significantly with both basal serum TSH and total pituitary reserve of TSH (r = 0.82, P less than 0.001). There was no correlation between the extent of visual field change and the volume of the sella turcica or pituitary TSH reserve. Of 10 patients with visual field defects, 8 improved during 1-4 months of T4 replacement. In 2 patients, however, the visual field defect deteriorated during replacement. The deterioration occurred when serum TSH levels had decreased to about 50% and 20% of pretreatment values, respectively. The peak serum TSH after TRH stimulation was higher at the time of deterioration than before treatment. Visual fields became normal during treatment with an increased dose of T4 (200 micrograms/day), when serum TSH was suppressed to an undetectable level. The paradoxical course of visual failure during T4 replacement may be due to an imbalance between TSH synthesis in the pituitary and TSH release which may induce an increase in pituitary size. The data suggest that visual field defects and their deterioration are due to pituitary hyperplasia and are reversible with T4 replacement. In order to rule out a pituitary tumor, hypothyroid patients with visual failure should be followed during T4 replacement therapy.

External pituitary irradiation as a cause of TRH deficiency in patients with pituitary adenomas.

The influence of external pituitary irradiation (XRT) on thyrotroph function and PRL secretion was studied in twenty-five patients with pituitary adenomas, of whom eight had acromegaly. Twenty-one patients had undergone subtotal operative removal of their adenomas 8-190 weeks (median 12 weeks) before XRT. Following irradiation there was a significant reduction in peak serum TSH levels in response to i.v. TRH (P less than 0.05, compared with before XRT). Peak TSH levels returned to normal at 3 months. Similarly a transient reduction in TRH-stimulated beta-TSH release was observed. Serum T3 and T4 concentrations also fell after XRT, the levels at 3 months being significantly lower than control values (P less than 0.02), though no difference was seen at 6 and 12 months. A delayed (hypothalamic) serum TSH response to TRH (60 greater than 20-min level) developed at 6 months. In contrast, PRL concentrations (basal and TRH stimulated) were not altered during the 12 months following XRT. These findings demonstrate that thyrotroph function can be transiently impaired following external pituitary irradiation. None of the patients studied required T4 replacement therapy. The development of a delayed TSH response to i.v. TRH may indicate endogenous TRH deficiency. It was not associated with supra-sellar tumour enlargement in our patients and may be due to hypothalamic damage by irradiation.

Serum concentrations of 3, 3'-diiodothyronine, 3', 5'-diiodothyronine, and 3, 5-diiodothyronine in altered thyroid states.

To investigate the thyroid hormone metabolism in altered states of thyroid function, serum concentrations of 3, 3'-diiodothyronine (3, 3'-T2), 3', 5'-T2 and 3, 5-T2 as well as T4, T3 and rT3 were determined by specific radioimmunoassays in 17 hyperthyroid and 10 hypothyroid patients, before and during the treatment. Serum T4, T3, rT3, 3, 3'-T2 and 3', 5'-T2 concentrations were all higher in the hyperthyroid patients than in age-matched controls and decreased to the normal ranges within 3 to 4 months following treatment with antithyroid drugs. In the hypothyroid patients, these iodothyronine concentrations were lower than in age-matched controls and returned to the normal ranges after 2 to 3 months treatment with T4. In contrast, serum 3, 5-T2 concentrations in hyperthyroid patients (mean +/- SE : 4.0 +/- 0.5 ng/dl) were not significantly different from those in controls (3.9 +/ 0.4 ng/dl), although they tended to decrease in 3 of 6 patients after the antithyroid drug therapy. Serum 3, 5-T2 levels in the hypothyroid patients (3.8 +/- 0.6 ng/dl) were also within the normal range and showed no significant change following the T4 replacement therapy. However, serum 3, 5-T2 as well as 3, 3'T2 concentrations rose significantly with a marked rise in serum T3 following T3 administration, 75 micrograms/day for 7 days, in Graves' patients in euthyroid state.(ABSTRACT TRUNCATED AT 250 WORDS)

甲状腺疾患における高比重リポ蛋白コレステロールの検討

Plasma high density lipoprotein cholesterol and other serum lipids were evaluated in 45 patients with hyperthyroid and 5 patients with hypothyroid and compared with 21 sex- and age-matched controls.Total cholesterol, HDL-C and LDL-C were reduced in hyperthyroid as compared with normal controls. 8 patients were restudied after restoration of euthyroid and showed significant increase in serum lipids.Total cholesterol and LDL-C were increased in hypothyroid but HDL-C was reduced as compared with normal. After T4 replacement therapy total cholesterol and LDL-C were normalized rapidly, but HDL-C was increased gradually. Atherogenic index was higher in patients with hypothyroid. This finding seems to enhance the risk of coronary atherosclerosis.Total cholesterol and LDL-C showed inverse relation to changes of T4. However no clear correlation was found in HDL-C.

Effect of neonatal thyroid deficiency on the catecholamine, substance P, and thyrotropin-releasing hormone contents of discrete rat brain nuclei.

The effects of neonatal thyroidectomy and thyroid hormone replacement therapy on the development of catecholamine-, TRH-, and substance P-containing neurons in discrete rat brain nuclei were studied. Newborn male rats were rendered hypothyroid by the injection of 125 muCi 131I and, after 45 days, were compared with normal littermate controls and 131I-injected animals subsequently maintained on T4 injections. The peptide or catecholamine content of discrete brain nuclei removed by punches of frozen brain slices was measured by RIA or radioenzymatic assay, respectively. The success of the thyroidectomy was verified by criteria of weight, length, plasma T4, and pituitary GH content. Animals receiving T4 replacement therapy were indistinguishable from normal littermates. Substance P was measured in 32 different brain nuclei and was significantly increased in 19 of these areas in hypothyroid animals. No changes in norepinephrine were detected, and the dopamine content of all but 3 brain nuclei was increased by thyroidectomy. The TRH concentration was drastically reduced in the median eminence of hypothyroid animals and also changed in 3 other extrahypothalamic areas. All of the changes seen in catecholamine, TRH, and substance P distribution in hypothyroid animals were completely reversed by T4 replacement therapy. These results demonstrate changes in brain peptide neurotransmitters during the hypothyroid state and open new vistas for comprehension of biochemical mechanisms underlying central nervous system malfunction.