Neonatal Hyperthyroidism Research Articles

Effects of mild hyperthyroidism on levels of amino acids in the developing Lurcher cerebellum.

This study examines the question of whether intrinsically defective mutant Lurcher Purkinje cells, which degenerate during postnatal weeks two to five, followed by later loss of granule cells are competent to respond to neonatal hyperthyroidism, which is known to cause premature differentiation of Purkinje cells and an acceleration of the peak of proliferation in granule cells in normal rodent cerebellum. Both total amounts and concentrations (per mg wet weight) of Tau, Glu, Asp and GABA were assayed as markers of cell function in Lurcher and wild-type mice made very mildly hyperthyroid by feeding nursing dams high-thyroxine food. Tau, which is present in relatively high concentrations in Purkinje cells, was affected by hyperthyroid treatment in the Lurcher in a manner that is most consistent with an acceleration of the degenerative process in Purkinje cells. The acidic amino acids Glu and Asp show later changes and response to hormone which seem to be a reaction to the Purkinje cell pattern, probably in the granule cells. We conclude that the Lurcher cerebellum is particularly sensitive to thyroid hormone, and that it responds to low levels of hyperthyroidism in a distinct way.

Thyroid hormone control of preganglionic innervation of the adrenal medulla and chromaffin cell development in the rat. An ultrastructural, morphometric and biochemical evaluation

In the rat, functional connections between the splanchnic nerve and the adrenal medulla are immature at birth and do not become fully competent until the first postnatal week. Neonatal administration of triiodothyronine (T 3) accelerates this process, and the present study was undertaken to elucidate the underlying mechanisms. Rats were given T 3 (0.1 mg/kg, s.c.) daily for 9 days beginning 1 day after birth. Preganglionic innervation of the adrenal medulla was examined by retrograde axonal transport of horseradish peroxidase (HRP). At 10 days of age, there was an increased number of labeled perikarya in the spinal cord of the hyperthyroid pups. Ultrastructural examination revealed a corresponding increase in synaptic density in the adrenal medulla and in the activity of choline acetyltransferase, a marker for preganglionic cholinergic nerve terminals. These effects were attenuated by 25 days of age, whereupon deficits in HRP-labeled neurons and adrenomedullary synapses were noted. Similarly, replication of chromaffin cells was enhanced transiently in the T 3 group during the initial stage of hyperthyroidism, but subsequent long-lasting deficits in cell numbers were noted, along with a corresponding retardation of ontogeny of adrenal catecholamine biosynthesis and storage. Thus, neonatal hyperthyroidism accelerates synaptic development in the sympatho-adrenal axis but suppresses maturation of the target chromaffin cells, ultimately leading to, impaired adrenomedullary function.

Universal Predictive Criteria for Neonatal Overt Thyrotoxicosis Requiring Treatment

The universal predictive criteria for neonatal overt thyrotoxicosis requiring treatment were examined in 108 neonates (including a pair of twins) born to mothers with Graves' disease (36 patients under treatment with antithyroid drugs [group A] and 71 in remission [group B]). Anti-thyroid-stimulating hormone (TSH) receptor antibody activity was measured by both radioreceptor assay (TSH-binding inhibitor immunoglobulin [TBII]) and biologic stimulation assay (thyroid stimulating antibody [TSAb]). For generalization of the predictive criteria, the expression of TBII activity was standardized using standard serum made taking units of Medical Research Council long-acting thyroid stimulator, standard B as a reference, and expression of TSAb activity was standardized using bovine TSH as a standard. TBII activity was positive in 22 mothers at delivery, and TSAb activity was positive in 18. In 12 cases, both activities were positive. Both the TBII and the TSAb activity of maternal serum at delivery correlated well with that of the cord serum. Neonatal thyrotoxicosis occurred in 9 of 108 neonates (8%), of whom five (5%) had clinical overt symptoms requiring antithyroid drug treatment. In all nine cases the TBII and TSAb activities were both positive, but no neonate without TBII or TSAb activity developed thyrotoxicosis. The prediction rate (42%) of neonatal overt thyrotoxicosis was higher when both TBII and TSAb were measured than when only TBII (23%) or TSAb (28%) was measured. Clinical overt thyrotoxicosis could be predicted in five of six neonates (83%) of mothers when the cutoff levels of antibody activities were increased to a TBII activity of above 8 U/ml and TSAb activity of above 1.0 TSH microUEq.(ABSTRACT TRUNCATED AT 250 WORDS)

FAMILIAL RESISTANCE TO THYROID HORMONE PRESENTING AS NEONATAL THYROTOXICOSIS

Familial resistance to thyroid hormone is characterized by elevated thyroid hormones and non-suppressed TSH in euthyroid individuals. We present a unique occurrence of an infant with neonatal hyperthyroidism and resistance to thyroid hormone in a family with 3 generations of resistance to thyroid hormone. He was born at 35 weeks gestation to a consanguinous relationship (first cousins), birth weight 1480 g, length 46 cm. He had fetal and neonatal (200 beats/min) tachycardia and exopthalmos. At 3 weeks of age the following was obtained: T4 50.7 ug/dL, T3RIA 1349 ng/dL, T3RU 45.9%, rT3 618 ng/dL, TSH 389 uIU/mL, free T4 25.7 ng/dL, free T3 5385 pg/dL, TBG 2.3 ng/dL, TBII 18 (n1<14), TSIg 167% (n1<130%), 4h 123I uptake 87% and 24h 50%, moderately enlarged gland on scan, negative thyroid antibodies. TRH increased the TSH from 317 to 413 at 30 min. Patient's father, paternal aunt and paternal grandmother have well documented resistance to thyroid hormone. One month postpartum the mother had the following: T4 19 ug/dL, T3RIA 298 ng/ dL, free T4 4.5 ng/dL, free T3 698 pg/dL, TSH 1.0 uIU/mL, TBG 2.8 ng/dL (n1 1.6-3.6), negative TBII and TSIg, nl TSH response to TRH. Maternal grandfather also had elevated thyroid indices (T4 15.2 ug/dL, T3RIA 229 ng/dL), nonsuppressed TSH 2.2 uIU/mL, and normal TRH stimulated TSH. We postulate that this neonate is a homozygote for this gene defect. We hypothesize that this infant's hyperthyroxinemia resulting in thyrotoxicosis may be expressed due to genetic inherited factors from both parents.

DIMINISHED TSH SECRETION ASSOCIATED WITH NEONATAL THYROTOXICOSIS

We report 3 1/2 year old twin boys with prolonged neonatal thyrotoxicosis and persistently low TSH secretion manifested by a diminished TSH response to hypothyroxinemia and to TRH stimulation. Features of neonatal thyrotoxicosis included: intrauterine growth retardation, microcephaly with ventriculomegaly, poor weight gain, hyperphagia, irritability, diarrhea, exophthalmos, tachycardia, hepatosplenomegaly, and direct hyperbilirubinemia. However, there was no goiter or history of maternal thyroid disease and diagnosis was delayed until 11 weeks of age (T4<29 ug/dl, T3>580 ng/dl). By age 6 mo., on propylthiouricil (PTU) 25 mg b.i.d., both infants had TSH levels <2 uU/ml (normal N=0.4-4.5) despite T4 levels <1 and 3.1 ug/dl (N=7.2-15.6) and free T4 (FT4) levels of 0.3 and 0.5 ng/dl (N=0.8-1.9). At 3 4/12 years, while on PTU 50 mg q.i.d., they again became hypothyroid withi FT4s of <0.2 and T3RIA of 47 and 43 ng/dl (N=80-220) with a TSH of 3.5. A TRH stimulation test revealed baseline TSH values of 8.5 and 11 and maximal stimulation values of 11 and 14. Normal hGH responses to L-Dopa (8.7 and 13.1 ng/ml), fasting A.M. cortisols (12.6 and 14.1 ug/dl), and normal genitalia make other pituitary hormone deficiencies unlikely. The diminished TSH responses to hypothyroxinemia and TRH stimulation indicate that the capacity to synthesize TSH, or the set point for pituitary-thyroid feedback control, may be altered by excess thyroid hormone concentrations during a critical stage of development.

Neonatal hyperthyroidism in the rat: thyroxine accelerates the development of unconditioned but not learned responses to tastes

The effects of neonatal hyperthyroidism induced by thyroxine injection on the development of unconditioned and learned behaviors mediated by the gustatory system of the rat were investigated. The development of unconditioned ingestive responses evoked by 10% sucrose and 0.1% HCl taste solutions was advanced several days by thyroxine treatment. However, the emergence of taste aversion learning involving 10% sucrose and LiCl injection was not advanced and may have been slightly delayed. Thus, the ontogenesis of unconditioned and learned behaviors mediated by the gustatory system was not influenced uniformly by neonatal thyroxine treatment.

Diminished thyroid-stimulating hormone secretion associated with neonatal thyrotoxicosis

lobacter may stimulate their production/ Alternatively, Campylobacter antibodies that penetrate the C S F may be responsible for neural damage. Kaldor and Speed have shown that patients with Guillain-Barr6 syndrome associated with Campylobacter gastroenteritis are more likely to have elevated C S F IgG titers than are similar patients with no history of Campylobacter infection. Another possibility is that the choleralike enterotoxin produced by C. jejum ~ may bind to neural tissue in a similar way to cholera toxin, causing neural damage. I~ Erythromycin therapy was not used initially because the child had made an uneventful recovery from her original illness. It was introduced later in her illness when she developed a febrile illness with exacerbation of diarrhea and was known to be still excreting Campylobacter. There is no evidence to suggest that erradication of the organism limits or prevents the neurologic syndrome2.5 We believe pediatricians should be more aware of the Campylobacter-Guillain-Barr6 syndrome association and that in patients with Guillain-Barr6 syndrome, particularly when associated with a gastrointestinal tract illness, C. jejuni should be sought as a possible etiologic agent.

Neonatal hyperthyroidism in mice has different effects on epidermal growth factor levels in submandibular gland, urine, and blood.

We examined long-term effects of neonatal hyperthyroidism in female mice by measuring the epidermal growth factor levels in the submandibular gland, urine, and serum at the age of 31 days. Hyperthyroxinemia was induced by thyroxine injections (0.4 microgram/g/day) on days 0-6. Littermate controls received the alkaline saline vehicle. The treatment accelerated incisor eruption and eyelid opening. It also retarded growth. The elevation of plasma thyroxine concentration which normally occurs during wk 2 to reach a peak around day 15 was abolished. Submandibular gland epidermal growth factor levels on day 31 were markedly subnormal, indicating maturational delay. In contrast, epidermal growth factor levels were unaffected in urine and supranormal in serum. These differences in response suggest that the regulatory mechanisms governing epidermal growth factor levels in tissues and fluids may acquire thyroid hormone dependence at different stages.

Neonatal hyperthyroidism impairs epinephrine-provoked secretion of nerve growth factor and epidermal growth factor in mouse saliva.

We examined long-term effects of neonatal hyperthyroidism on salivary secretions of nerve growth factor and epidermal growth factor in male and female mice at the age of 31 days. Hyperthyroidism was induced by thyroxine (T4) injections (0.4 microgram/g body weight/day) during days 0-6. Littermate control mice were treated with vehicle. T4 treatment did not alter the amounts of protein secreted into saliva but hormone administration induced alteration in the types of protein secreted. T4 treatment decreased the contents of both nerve growth factor and epidermal growth factor secreted into the saliva. A Sephadex G-200 column chromatographic profile revealed the presence of two distinct nerve growth factor immunoreactive peaks, while epidermal growth factor immunoreactivity predominantly eluted as a single low molecular weight form. T4 treatment did not alter the molecular nature of their secretion, but the treatment decreased their contents. These results indicate an impairment in salivary secretion of nerve growth factor and epidermal growth factor long after T4 treatment has been discontinued.

Neonatal hyperthyroidism causes impairment in submandibular gland-nerve growth factor (SMG-NGF) ontogeny in mice.

The effect of neonatal hyperthyroidism on submandibular gland (SMG) nerve growth factor (NGF) concentrations was studied in female Swiss-Webster mice. For this purpose, newborn female pups were treated with thyroxine (T4, 0.4 microgram/g body weight/day) from birth through day 6, while their littermate pups were treated with similar volumes of vehicle. Animals were sacrificed on days 7, 15, 21, 31 and 71. Somatic growth (body weight and nose to rump length), serum T4 and T3 concentrations, and SMG and serum-NGF concentrations were measured. The data indicate that neonatal hyperthyroidism a) causes inhibition of somatic growth; b) induces alterations in normal ontogenic patterns of serum T4 and T3; c) impairs the developmental rise in SMG-NGF concentration and d) transiently increases serum-NGF levels.

Autoimmune Thyroid Disease

The concept of thyroid autoimmune disease now includes the following clinical entities: 1 degree thyrotoxicosis and goitrous thyroiditis (Hashimoto) with their variants, and 1 degree myxedema (atrophic thyroiditis); some cases of sporadic nontoxic goiters; most cases of neonatal hyperthyroidism; and a proportion of congenital athyreotic cretinism. Endocrine exophthalmos, though clinically associated with Graves' disease, is now considered a separate immunological entity.

Influence of the neonatal suppression of TSH production (neonatal hyperthyroidism) on response to TSH in adulthood.

Six-day treatment of neonatal rats with T3 or T4 resulted in a considerable depression of T4 production in response to exogenous TSH in adulthood. This supports the hypothetical conclusion that hormonal imprinting, i.e. the presence of the hormone and its interaction with the cell during the period of receptor maturation, is important for receptor amplification, which accounts for normal response to the hormone in adulthood.

Transient neonatal hyperthyroidism results in hypothyroidism in the adult rat.

Adult rats who had neonatal hyperthyroidism (NH) have reduced BW and serum T4, T3, and TSH concentrations. Pituitary TSH responses to TRH administration under basal, T4-suppressed, and propylthiouracil-stimulated conditions suggest that the thyrotroph of these animals is more sensitive to the feedback effects of thyroid hormones. These studies were undertaken to examine, with the use of various thyroid hormone-responsive variables, thyroid status of adult NH rats. NH was induced by 12 daily sc injections of T4 (0.4 microgram/g BW) to neonatal male Sprague-Dawley rats. Adult NH and control rats were then studied at 120 days of age. Adult NH rats had significantly decreased mean BW (P less than 0.001), and serum T4 (P less than 0.005), T3 (P less than 0.001), and TSH (P less than 0.001) concentrations. The percent decreases were 12% for T4, 20% for T3, and 27% for TSH in adult NH rats. Mean pituitary GH concentration and hepatic alpha-glycerophosphate dehydrogenase and malic enzyme activities were significantly decreased in adult NH rats to 54% (P less than 0.005), 52% (P less than 0.025), and 39% (P less than 0.001), respectively, of control values. Mean pituitary TSH concentrations were similar in adult NH and control rats. Mean hepatic T4 5'-deiodinase activity of adult NH rats [200 +/- (SE) 23 fmol T3/min X mg protein] was significantly decreased to 56% of control levels (355 +/- 31 fmol T3/min . mg protein; P less than 0.005). Mean pituitary T4 5'-deiodinase activity of adult NH rats (32.8 +/- 3.3 fmol T3/min . mg protein) was significantly increased compared with that of control rats (21.2 +/- 1.7 fmol T3/min . mg protein; P less than 0.025). These changes are consistent with a hypothyroid state in adult NH rats. The observation of decreased serum TSH concentration and enhanced thyrotroph sensitivity to thyroid hormones in the face of increased pituitary T4 5'-deiodinase activity suggests that increased thyrotroph monodeiodination of T4 may be the central biochemical aberration responsible for the hypothyroid state in adult NH rats.

Increased pituitary thyroxine 5'-deiodinase activity in adult rats rendered hyper- or hypo-thyroid during perinatal life.

Perinatal thyroid dysfunction in the rat leads to permanent alterations in pituitary TSH secretion in the adult animal. Thus, neonatal hyperthyroidism (NH) and perinatal hypothyroidism (PH) both result in apparent increased pituitary sensitivity to the feedback effects of thyroid hormones in the adult rat. To determine if increased intrapituitary generation of triiodothyronine (T3) might account for these observations, we measured thyroxine (T4) 5'-deiodinase activity in pituitary homogenates of adult NH and PH rats. NH was induced by injecting neonatal rats with 12 daily sc injections of T4 (0.4 microgram/g body weight (BW]. Control rats received vehicle alone. PH was induced by administering 0.05% 6-n-propylthiouracil in the drinking water to pregnant dams from the 16th day of gestation through the 12th day postpartum. Thereafter, a normal water supply was substituted. NH and PH rats were allowed to mature and were sacrificed at 105 days of age. Serum T4, T3, and TSH concentrations were measured by radioimmunoassay. Pituitary T4 5'-deiodinase activity was assessed by the measurement of T3 formation by pituitary homogenates incubated in the presence of 0.65 microM T4 and 100 mM dithiothreitol at 37 degrees C for 90 min. Body weights of adult NH and PH rats were slightly but not significantly decreased compared with control rats. Relative pituitary gland weight (milligrams per 100 g BW) was significantly decreased in adult PH rats (P less than 0.005) but not in adult NH rats. In adult NH rats, serum T4 and T3 concentrations were significantly decreased (P less than 0.01) compared with control rats. Serum TSH concentrations were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of serotonergic and adrenergic receptors in the rat spinal cord: Effects of neonatal chemical lesions and hyperthyroidism

The sympathetic preganglionic neurons in the spinal cord receive dense serotonergic (5-HT) and catecholaminergic (CA) afferent inputs from the descending supraspinal pathways. In the rat spinal cord, the levels of these biogenic amines and their receptors are low at birth, but undergo rapid ontogenetic increases in the ensuing 2–3 postnatal weeks until the adult levels are reached. In many systems it has been shown that denervation of presynaptic neurons leads to an up-regulation of the number of postsynaptic receptors. To determine whether the 5-HT and CA receptors in the developing spinal cord are also subject to such transsynaptic regulation, we examined the ontogeny of serotonergic receptors and α- and β-adrenergic receptors in thoracolumbar spinal cord of rats given neurotoxins which destroy serotonergic (5,7-dihydroxytryptamine (5,7-DHT)) or noradrenergic (6-hydroxydopamine (6-OHDA)) nerve terminals. Intracisternal administration of 5,7-DHT or 6-OHDA at 1 and 6 days of age prevented, respectively, the development of 5-HT and CA levels in the spinal cord. Rats lesioned with 5,7-DHT displayed a marked elevation of 5-HT receptors with a binding of 50% greater than controls at 1 week and a continuing increase to twice normal by 4 weeks. A similar pattern of up-regulation was also detected with the α-adrenergic receptor, as rats lesioned with 6-OHDA exhibited persistent increases in receptor concentration. However, in these same animals ontogeny of the β-adrenergic receptor in the spinal cord remained virtually unaffected by the chemical lesion. In several other parts of the nervous system, it has been demonstrated that the β-adrenergic sensitivity can be modulated by hormonal signals, particularly that of the thyroid hormones. This phenomenon was examined in the spinal cord and in confirmation with previous studies neonatal treatment of triiodothyronine (0.1 mg/kg, s.c. daily) was capable of evoking persistent increases in β-adrenergic receptor binding. These results suggest that: (a) development of the postjunctional serotonergic and α-adrenergic receptors in the rat spinal cord can occur in the absence of the prejunctional nerve terminals and are subject to transsynaptic modulation; (b) β-adrenergic receptors in the spinal cord also can develop after prejunctional lesions but are regulated by hormonal rather than neuronal factors.

Adrenomedullary function in the neonatal rat: responses to acute hypoxia.

The mechanism of release of catecholamines from the adrenal medulla of neonatal rats was examined, together with the role of these amines in the ability of the organism to withstand acute O2 deprivation. Splanchnic innervation of the rat adrenal is non-functional until the end of the first postnatal week. Nevertheless, hypoxia caused depletion of adrenal catecholamines in 1-day-old rats as well as in 8-day-old animals. Pre-treatment with cholinergic receptor blocking agents did not prevent the catecholamine response at 1 day but did in older animals; these results indicate that the depletion mechanism is not neurogenic in 1-day-old animals but is neurogenic in 8-day-old animals. The proportions of noradrenaline and adrenaline released by hypoxic stress also differed at the two ages, with preferential release of adrenaline by the neurogenic mechanism but not by the non-neurogenic one. The ontogenetic replacement of non-neurogenic adrenomedullary responses by the neurogenic mechanism was directly related to the onset of splanchnic nerve function. Treatments which accelerated the development of neuronal connexions (neonatal hyperthyroidism, maternal stress) caused premature loss of the non-neurogenic response. Prior to the development of sympathetic nerve function, adrenal catecholamines plays a predominant role in enabling the neonate to survive hypoxia. Interference with the release of adrenal amines invariably increased mortality during hypoxia. In contrast, interference with sympathetic neural release of catecholamines did not affect the ability of 1-day-old rats to withstand hypoxia, indicating that survival during low PO2 conditions is not dependent on the sympathetic innervation at that stage of development. After functional development of the sympathetic nerves and disappearance of non-neurogenic adrenomedullary responses, the neonatal rats became partially dependent upon catecholamines derived from sympathetic terminals; administration of bretylium at 8 days significantly compromised survival during hypoxia. Interference with adrenergic receptor function also interfered with the ability of neonatal rats to withstand low PO2. At 1 day of age, either phenoxybenzamine or ICI-118551, but not atenolol, shortened the survival time during hypoxia. At 8 days, only phenoxybenzamine did so.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of dysthyroidism on central catecholaminergic neurons

After 15 years of research, it is clear that alterations in thyroidal status affect catecholaminergic neurons in the developing as well as in the adult brain. Experiments on fetal catecholaminergic brain areas grafted into the anterior eye chamber of adult thyroidectomized rat have shown the thyroid hormone dependency of the morphological differentiation of catecholaminergic neurons originating from the substantia nigra and the locus coeruleus. Furthermore, thyroid hormones also affect the metabolism of catecholaminergic neurons. Neonatal hypothyroidism induced either by (131)I or by an antithyroid drug decreases the concentration of dopamine, noradrenaline and the activity of tyrosine hydroxylase at least in whole brain studies. Treatments with l-thyroxine of neonatally thyroidectomized rats reverse these neurochemical changes in a both time and dose dependent manner. These presynaptic modifications are associated with a decrease in the number of catecholaminergic receptors in different brain areas. On the opposite, experimental neonatal hyperthyroidism induced by daily administration of l-triiodothyronine increases the synthesis as well as the utilization of catecholamines. These changes are also associated with an alteration of catecholaminergic receptors. Despite numerous studies, there is, so far, no clear conclusion on the effects of neonatal dysthyroidism on the development of each catecholaminergic group. However, from these studies, it appears that the intensity of neonatal dysthyroidism greatly varies, depending of the monoamine and the brain area studied. The utilization of fetal brain cell cultures growing in a chemically defined medium has permitted to demonstrate the direct effect of thyroid hormones on fetal brain cells and the morphological effects of triiodothyronine on the size and the neurite length and arborization of fetal hypothalamic dopaminergic neurons. In the adult brain, hypothyroidism induced by surgical thyroidectomy, decreases the rate of catecholamines synthesis, decreases the number of alpha noradrenergic receptors and has no effect on striatal dopaminergic receptors. In contrast, hyperthyroidism increases the rate of catecholamines synthesis and induced an hypersensitivity of noradrenergic receptors. The intensity of the effects of dysthyroidism seems to be dependent on the monoamine and the brain area studied. In conclusion, it can be proposed that in the neonate thyroid hormones act on CA neuron activity mostly through a morphogenetic effect whereas in the adulthood they directly affect CA metabolism.

Thyroid hormones modulate ornithine decarboxylase in the immature rat cerebellum.

In this study, we measured ornithine decarboxylase (ODC) activity as a potential parameter to evaluate the response of the developing rat brain to thyroid hormones. In cerebellum, neonatal hyperthyroidism (40 micrograms thyroxine/100 g body weight daily from birth) increased ODC activity at 2 and 5 days of age and then accelerated its developmental decline. Conversely, ODC activity was decreased in 2- and 5-day-old hypothyroid rats (propylthiouracil to the mother), but it was not significantly different from normal thereafter. No significant differences were observed in the forebrain following either treatment. In hypothyroid rat cerebellum, a single injection of triiodothyronine (T3, 100 micrograms/100 g 18 h before sacrifice) increased significantly ODC activity at all ages. A dose-response study showed that 0.5 micrograms T3/100 g is sufficient to obtain maximal stimulation. Finally, administration of antiserum against rat growth hormone had no significant effect on ODC response to T3. These results show that ODC is a useful marker of thyroid state and tissue response in the neonatal rat cerebellum.

Graves' disease in pregnancy years after hypothyroidism with recurrent passive-transfer neonatal Graves' disease in offspring: Therapeutic considerations

Symptoms and signs of severe hypothyroldism developed in a young woman at age 15. These symptoms progressed for a year; at age 16, she was found to have a firm goiter, thyroid autoantibodies, very low serum thyroxine and high thyrotropin values, indicating autoimmune thyroiditis with hypothyroidism. She received l-thyroxine, 0.20 mg per day, and was well until age 24 when she became pregnant. In the first trimester, manifestations indicative of hyperthyroidism developed; these were only ultimately recognized immediately after delivery of a 32-week still-born goitrous baby. Despite the discontinuation of thyroxine therapy, the hyperthyroidism persisted and was confirmed as Graves' disease by elevated thyroxine, triiodothyronine, and radioactive iodine uptake values, a diffuse scanning result, and the presence of thyroid-stimulating antibody. The patient was treated with propylthiouracil and became pregnant while receiving that regimen. Later, several months after delivery, the patient was treated with radioactive iodine, ultimately became hypothyroid, and has been treated ever since with thyroxine. She became pregnant again and, because of the continuing high titers of thyroid-stimulating antibody, received propylthiouracil, 100 mg daily, commencing in the third trimester of pregnancy, to avoid probable fetal hyperthyroidism due to the transplacental transfer of thyroid-stimulating antibody. In each of the last two pregnancies, when the infants were born, they seemed normal (because of the transplacental effect of propylthiouracil), but passive-transfer neonatal hyperthyroidism developed in each within 10 days after delivery, ultimately requiring treatment by conventional means. This case illustrates the following points: (1) Hyperthyroidism occasionally develops years after hypothyroldism. (2) In young women, high titers of thyroid-stimulating antibody may produce fetal and neonatal passive-transfer hyperthyroidism even at a time when the mother herself is no longer hyperthyroid; transplacental treatment of the fetus by maternal propylthiouracil ingestion may thus be necessary during the last trimester, but only when there is a high degree of probability that the fetus is at risk. (3) Because the infants had been protected in utero by the placental transfer of propylthiouracil, neonatal hyperthyroidism did not develop until several days after delivery. However, the possible severe effects of fetal hyperthyroidism in utero may well have been avoided by such therapy.

Serotonin, 5-hydroxyindoleacetic acid and substance P content of discrete brain nuclei in rats made hypo- or hyperthyroid in the neonatal period: Effect of growth hormone treatment

In order to determine the role of growth hormone (GH) in the therapeutic effect of thyroxine (T 4), we measured the content of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and substance P in discrete brain nuclei of neonatally-induced hypothyroid rats and in neonatally-induced hypothyroid rats subsequently maintained on bovine growth hormone (b-GH) injections. Substance P was measured by radioimmunoassay whilst 5-HT and 5-HIAA levels were determined by HPLC with electrochemical detection. In neonatal hypothyroid rats, substance P concentration increased in 5 out of 11 brain nuclei dissected while 5-HT and 5-HIAA level increased in 7 out of 19 brain nuclei selected. Although b-GH-replacement therapy abolished the hypothyroid-induced accumulation of 5-HT and 5-HIAA in brain nuclei with exception of the substantia nigra zona reticulata, it did not influence the substance P accumulation. This suggests that the abnormal brain development observed during hypothyroidism may, in part, result from absence of growth hormone. We also observed that neonatal hyperthyroidism induced very little modification of 5-HT, 5-HIAA and substance P concentrations in discrete nuclei of the rat brain.