Thyroid-stimulating hormone, prolactin, and growth hormone response to thyrotropin-releasing hormone in treated children with congenital hypothyroidism

The purpose of the present study was to assess thyroid-stimulating hormone (TSH), prolactin, and growth hormone responses to TRH stimulation in 12 congenitally hypothyroid children adequately treated with L-thyroxine from the first weeks of life. Although clinically euthyroid, six of these children were found to have abnormally high basal serum TSH concentrations despite clinical euthyroidism. Serum triiodothyroxine and L-thyroxine concentrations were normal and did not differ whether the children had elevated or normal basal serum TSH. All six of the children with high basal TSH had an exaggerated TSH response to TRH and 4 of them also had an augmented prolactin response to TRH. The children with normal basal TSH concentrations had normal TSH and prolactin responses to TRH. An abnormal ("paradoxical") elevation of growth hormone concentration in response to TRH was found in four of seven children in a separate group of patients who had prolonged, untreated primary hypothyroidism, but such responses were not found in any of the adequately treated children. These findings suggest the following conclusions: 1) the phenomenon of high serum concentrations of TSH in conjunction with normal L-thyroxine and triiodothyronine levels (and clinical euthyroidism), is prevalent in congenital hypothyroid patients. 2) These patients have an exaggerated response of their pituitary thyrotroph and lactotroph cells to TRH, presumably caused by selective and relative resistance of these cells to the inhibitory effects of thyroid hormones. 3) Congenital hypothyroidism is not associated with abnormal somatotroph cell responses to TRH.     

Changes in hypothalamic-pituitary function following bone marrow transplantation in children

Patients who undergo bone marrow transplantation (BMT) frequently experience impaired pituitary function, but precise assessment using repeated provocative tests has not been described. We studied 32 children (16 boys) who had BMT after receiving preparative irradiation. Assessment of pituitary function was performed by infusing insulin, luteinizing hormone-releasing hormone (LHRH), and thyrotropin-releasing hormone (TRH) on several occasions at various intervals during the follow-up period. Serum free thyroxine (FT4) and thyrotropin (TSH) levels tended to be low during the early period following BMT. Serum FT4 concentrations reverted to the low-normal range 1 year after transplant, and eight of 29 patients had subnormal and delayed TSH response to TRH consecutively. No children showed overt hypothyroidism. Basal and peak serum gonadotropin levels in response to LHRH were elevated in the patients who had received transplant around the time of puberty. Leydig cell function assessed by human chorionic gonadotropin test was normal. Three girls experienced menarche, and one male patient fathered a normal boy 7 years after BMT. Pituitary-adrenal function and prolactin secretion were not affected. A high incidence of transient hypothyroidism which did not require replacement therapy and gonadal failure among pubertal children were observed. Shielding of gonads should be attempted, if possible, at the time of preparative irradiation to prevent resultant hypogonadism.     

Endocrine disorders in children with neurofibromatosis von Recklinghausen (author's transl)]

Endocrine disturbances have been studied in 4 children with neurofibromatosis von Recklinghausen, aged 5.0-10.5 years. Hypothalamic precocious puberty was seen in three boys; growth hormone deficiency was diagnosed in a girl. After TRH stimulation one boy and the girl showed a diminished TSH-response. Another boy showed a relatively high basal level of TSH and an elevated TSH-response to TRH. All children were euthyroid. Two boys had a hyperprolactinemia even under basal conditions; the one with elevated TSH-response showed an excessive response of prolactin as well. In all our patients a suprasellar tumor caused the endocrine disorders described.     

Thyroid dysfunction in antiretroviral treated children

BACKGROUND: A high rate of thyroid disorders has been described in HIV-infected adults treated with highly active antiretroviral therapy (HAART), but data on children are lacking. We aimed to assess thyroid function in pediatric patients. METHODS: Fifty-two HIV-infected children receiving HAART were assessed for signs of thyroid dysfunction and serum concentrations of thyrotropin (TSH), free thyroxin (FT4), free triiodothyronine (FT3), thyroglobulin (TG), reverse triiodothyronine (rT3), anti-TG and antimicrosomal (anti-TSM) antibodies. RESULTS: Eighteen (35%) children showed thyroid abnormalities: isolated low FT4 value in 16; subclinical hypothyroidism in 1; and symptomatic hypothyroidism in 1.Children with low FT4 values as compared with the 34 children without thyroid dysfunction were similar for stage of disease, number of patients with undetectable HIV-RNA, FT3, TSH, TG, rT3, anti-TSM and anti-TG values, whereas they had shorter duration of HAART exposure (P = 0.019) and lower CD4 cell percentage (P = 0.035). The thyrotropin-releasing hormone (TRH) test was normal in all children with low FT4 values. Among children with low FT4, FT4 concentrations correlated positively with CD4 cell percentage (P < 0.05) and duration of HAART exposure (P < 0.05).The case with subclinical hypothyroidism had high basal TSH (7.3 microunits/ml), normal TSH response to TRH test and normal FT4, FT3, TG, rT3, anti-TG and anti-TSM antibodies.The case with symptomatic hypothyroidism had low FT4 (6.6 pg/ml) and high TSH (44 microunits/ml), TG (55 ng/ml), anti-TG (666 IU/ml) and anti-TSM (123 IU/ml). CONCLUSION: Thyroid abnormalities occur frequently in HAART-treated children even in the absence of clinical symptoms. These data suggest a need of regular thyroid function monitoring.     

Changes in thyroid function after bone marrow transplant in young patients

BACKGROUND: Changes in thyroid function among young patients who received bone marrow transplantation (BMT) were evaluated. METHODS: The study included 91 patients (50 males) who underwent BMT from 1985 to 1995 at the age of 0.6-21 years. Sixty patients had neoplastic disease such as leukemia or lymphoma, and the remainder had non-neoplastic diseases. Preconditioning regimen for BMT included 12 Gy of fractionated-total body irradiation (TBI) for patients with neoplastic disease and 3-8 Gy of irradiation for the remaining patients, in addition to chemotherapy. Evaluation of thyroid function was performed by serial assessment of basal serum FT4, FT3, TSH concentrations as well as by TRH test. RESULTS: No patient had overt hypothyroidism or elevated basal TSH concentrations (>10 mU/L). However, 6 (7%) of patients experienced exaggerated peak TSH response to TRH stimulation several years after BMT. In 33 patients whose thyroid status was evaluated before, within 3 months, and 1 year after BMT, serum FT3 concentrations as well as peak TSH response to TRH stimulation significantly decreased immediately after BMT (<3 months) and normalized within 1 year. However, serum FT4 concentrations did not change significantly. One patient developed primary hypothyroidism and another developed follicular adenoma of the thyroid 5 and 12 years after BMT, respectively. CONCLUSION: Short-term changes in thyroid function after BMT can indicate euthyroid sick syndrome rather than tertiary hypothyroidism. It must be noted that overt hypothyroidism may occur several years after BMT, hence long-term follow-up of thyroid function is warranted.     

Anorexia nervosa in male adolescents. II. Psychoneuroendocrinologic findings

Female patients with anorexia nervosa (a.n.) are characterized by distinct endocrine features probably due to hypothalamic pituitary dysfunctions. There is only a limited number of case reports available on patients with a.n.; mostly with few data on hormones. In six male patients with a.n. we examined basal and stimulation values of several hormones performing three pituitary function tests. Basal and stimulated values of luteinizing hormone (LH) and of follicle stimulating hormone (FSH) after LHRH were low comparable to results in prepuberal boys. Similarly, testosterone levels in serum were also markedly reduced. By exploring the pituitary-thyroidal axis total T4 was diminished in one patient and at the lower limit in two patients; concentration of free T4 was in the normal range, while five of six subjects had reduced total T3 concentration and two of six patients showed increased reversed T3 levels; TBG concentration was always in the normal range. Basal TSH was normal, while in two patients the TSH stimulation levels after TRH were diminished; in all patients the TSH stimulation levels were found to be delayed. The basal levels of growth hormone were normal, but the growth hormone response after insulin was diminished in four patients. In all six patients basal prolactin (PRL) and PRL concentration after TRH stimulation was in the normal range. The neuroendocrine results in the six patients with a.n. confirm in males a similar hypothalamic-pituitary dysfunction as it is already known for female patients.     

TSH and PRL response to thyrotrophin-releasing hormone in children with chronic renal failure undergoing haemodialysis.

Eight children (aged between 8 1/2 and 15 1/2 years) with chronic renal failure receiving intermittent haemodialysis, and 2 children with renal transplants were studied. The response of TSH and prolactin (PRL), and basal T4 and T3 values was measured. Basal TSH was normal, and rose only slightly after TRH stimulation. Plasma T4 and T3 were below normal levels in 6 children. Mean basal PRL was raised and could not be stimulated by TRH. This study demonstrates the involvement of the hypothalamus and pituitary in chronic renal disease. The cause of the abnormal secretion of TSH and PRL in chronic renal failure is discussed in the light of clinical importance.     

Longitudinal study on thyroid function in patients with thalassemia major

Primary hypothyroidism is one of the most frequent complications observed in patients suffering from thalassemia. We investigated thyroid function in a group of patients attending the Pediatric Department of Cardarelli Hospital in order to determine in how many patients thyroid function worsened during a 12 year-period of follow up. PATIENTS AND MEASUREMENTS: Fifty patients with beta-thalassemia major (27 females and 23 males), mean age 25.7+/-1.4 years, were re-evaluated according to the criteria of Faglia et al. Thyroid dysfunction was defined as follows: overt hypothyroidism (low FT4 and increased TSH levels >10 microU/ml); compensated hypothyroidism (normal FT4, TSH 5-10 microU/ml, and abnormal TRH test); subclinical hypothyroidism (normal FT4, basal TSH 0-5 microU/ml, abnormal TRH test). Correlation with hematological, biochemical and growth parameters was evaluated. RESULTS: Ten out of 50 patients evaluated in a previous study had moved to other centers, and four patients had died from cardiac problems. Thus, 36 patients completed a 12 year-period of follow-up. In 25% of the patients the degree of thyroid dysfunction worsened with different degrees of severity. The prevalence of overt hypothyroidism had risen to 13.9% from 8.4%. No cases of secondary hypothyroidism were observed, and anti-thyroglobulin and anti-thyroperoxidase (TPO) antibody titers were negative in all patients. Five (28%) out of 17 patients with normal thyroid function previously (one female, four male) showed an exaggerated TSH response to a TRH test, with normal serum levels of FT4, and they were classified as having subclinical hypothyroidism; while another patient died of cardiac complications. Four out of twelve patients with previous subclinical hypothyroidism showed worsening with a different degree of severity: two females changed to compensated hypothyroidism, and two males to overt hypothyroidism. Furthermore, two out of six patients with compensated hypothyroidism and one out of four patients with overt hypothyroidism died of cardiac failure. In all patients there was no correlation between serum ferritin levels, blood transfusion, pretransfusion Hb levels and worsening of thyroid function. Echographic data showed features of dishomogeneity of the parenchyma with different degrees of severity in accordance with the criteria of Sostre and Reyes. The highest score was observed in all patients with overt and compensated hypothyroidism. CONCLUSIONS: A slow worsening of thyroid function was observed in 25% of the studied patients and only two of them developed overt hypothyroidism. The echographic pattern seems to be strongly predictive of thyroid dysfunction.     

Short-term hyperthyroidism followed by transient pituitary hypothyroidism in a very low birth weight infant born to a mother with uncontrolled Graves' disease

Transient hypothyroxinemia in infants born to mothers with poorly controlled Graves' disease was first reported in 1988. We report that short-term hyperthyroidism followed by hypothyroidism with low basal thyroid-stimulating hormone (TSH) levels developed in a very low birth weight infant born at 27 weeks of gestation to a noncompliant mother with thyrotoxicosis attributable to Graves' disease. We performed serial thyrotropin-releasing hormone (TRH) tests in this infant and demonstrated that TSH unresponsiveness to TRH disappeared at 6.5 months of age. The maternal thyroid function was free triiodothyronine (FT(3)), 21.1 pg/mL; free thyroxine (FT(4)), 8.1 ng/dL; TSH, <0.03 microU/mL; thyroid-stimulating hormone receptor antibody, 52% (normal: <15%); thyroid-stimulating antibody, 294% (normal: <180%); and thyroid-stimulation blocking antibody, 9% (normal: <25%) on the day of delivery. A nonstress test revealed fetal tachycardia >200 beats per minute, and a male infant weighing 1152 g was born by emergency cesarean section. Thyroid-stimulating hormone receptor antibody was 16% and thyroid-stimulating antibody was 370% in the cord blood. We administered 10 mg/kg per day of oral propylthiouracil from day 1. Tachycardia along with elevated FT(4) and FT(3) levels in the infant decreased from 200/minute to 170/minute, 4.7 ng/dL to 2.9 ng/dL, 7.0 pg/mL to 4.8 pg/mL, respectively, in the first 33 hours. At 5 days, FT(4) and FT(3) were 1.1 ng/dL and 2.9 pg/mL, respectively, and we stopped propylthiouracil administration. Although FT(4) decreased to 0.4 ng/dL, TSH was quite low and did not respond to intravenous TRH by 14 days of age. We began daily levothyroxine 5-micro/kg supplementation. The responsiveness of TSH to TRH did not become significant until 4 months old and normalized at 6.5 months old. At this time, levothyroxine was stopped. We conclude that placental transfer of thyroid hormones may cause hyperthyroidism in the fetal and early neonatal periods and lead to transient pituitary hypothyroidism in an infant born to a mother with uncontrolled Graves' disease.     

Response to TRH in suspected hypopituitarism.

A retrospective analysis was made of 405 thyrotrophin-releasing hormone (TRH) stimulation tests on children who were successful applicants for growth hormone (GH) therapy in the UK between 1977 and 1981 inclusive. Thyroid-stimulating hormone (TSH) responses to TRH were divided into normal and those indicating pituitary or hypothalamic disease on the basis of criteria which eliminated variation in TSH assay between laboratories. Among children known to be hypothyroid 93% had abnormal TRH stimulation tests, but 35% of those children who were clinically euthyroid and who had normal serum thyroxin levels also had abnormal TSH responses to TRH. Abnormal TRH tests in the latter group were most common in euthyroid children who had GH deficiency with clearly defined aetiology and least common in those with idiopathic GH deficiency. Further work is required to clarify the interpretation of an abnormal TRH stimulation test in this group of children, but until this is done, such patients should be kept under regular review with respect to thyroid function.     

Precocious puberty in juvenile hypothyroidism.

Three children, two girls and one boy, presented with hypothyroidism and precocious sexual development. Serum TSH and PRL were elevated in all cases. In the male patient, pituitary stimulation with TRH produced exaggerated TSH and PRL responses. Elevated serum LH, FSH, estrone, estradiol, and an attenuated gonadotropin response to GnRH were documented in the male patient and in one of the female patients. Serum testosterone was elevated for age in one of the female patients but prepubertal in the male patient. After treatment with L-thyroxine, elevated hormonal levels decreased to normal in one patient who returned for follow-up. Evidence is presented that precocious puberty in juvenile hypothyroidism may be the result of PRL hypersecretion.     

THYROTROPIN RESPONSE TO THYROTROPIN-RELEASING HORMONE IN FULLTERM, EUTHYROID AND HYPOTHYROID NEWBORNS

Abstract. The serum concentration of thyrotropin (TSH) and the TSH response following thyrotropin-releasing hormone (TRH) were studied in 16 euthyroid babies from 16 to 172 hours after birth and in 2 primary hypothyroid babies, 3 and 28 days of age. Serum-TSH was measured before an intravenous injection of 40 μug TRH and after 30 and 180 min. In the euthyroid babies increased basal levels of TSH were seen shortly after birth, followed by a pronounced decline. The extent of TSH increase after TRH could be correlated with the basal levels, and the relative increase was comparable to that which occurs in adults. In the hypothyroid babies very high basal levels of serum-TSH were seen, 125 and 400 μ/ml respectively, with no further increase following TRH stimulation. It was concluded that in euthyroid fullterm newborn, the relative response of serum-TSH to TRH was equal to that of adults, in spite of elevated thyroid hormone concentrations. In the hypothyroid newborn very high levels of serum-TSH were seen and a supplementary TRH-test seems without diagnostic value in congenital hypothyroidism.     

Thyrotropin (TSH) secretion in L-thyroxine treated children: assessment by a ultrasensitive TSH immunoradiometric assay

The clinical usefulness of the measurement of basal TSH by an ultrasensitive assay (IRMA) versus the TRH test has been challenged in 49 children treated with L-thyroxine. They were given suppressive or replacement therapy depending on the underlying disease. An absent response of TSH to TRH could be predicted from a basal TSH value less than 0.1 mU/l in 88.8% of the cases, while only in 77.7% from a basal TSH value = 0.1 mU/l. A basal TSH value found in the range of the normal children always predicted a normal TRH test. We conclude that a sensitive TSH assay has some clinical application in monitoring L-thyroxine therapy, but can not absolutely replace the TRH test.     

Euthyroid sick syndrome in children with acute viral hepatitis A.

According to the clinical findings, the activity of serum asparate aminotransferase (EC 2.6.1.1), alanine aminotransferase (EC 2.6.1.2) and the level of total bilirubin, 45 children with acute viral hepatitis A were divided into two groups: with mild and moderately severe degree of disease. By determining the products of the peripheral thyroxine metabolism-T3 and rT3, as well as the other thyroid parameters (T4, FT4, TSH and TBG) we have found significantly lower T3 level and significantly higher T4 and TBG levels in both groups of patients in comparison with control group. At the same time, the level of biologically less active rT3 was increased in patients with moderately severe form of disease, while no differences were found in the values of TSH between the ill and control patients. TRH induced TSH release was normal in all patients. The results of this study point to the development of euthyroid sick syndrome or low T3 syndrome in children with viral hepatitis A.     

Hyperfunctioning thyroid nodules in children

We studied two cases of hyperfunctioning thyroid nodules in children. A 9-year-old girl and an 11-year-old girl had thyroid masses in otherwise nonpalpable thyroid glands. Scintiscan showed hyperfunctioning thyroid nodules. The former patient had elevated values for T4 and T3, and plasma thyrotropin (TSH) level failed to respond to stimulation with thyrotropin releasing hormone (TRH), whereas the latter patient had normal values for T4, and T3 and plasma TSH response to TRH was normal. After the surgical removal of nodules, scintiscan exhibited radioactivity in the contralateral lobe of the thyroid gland in the former and in the ectopic thyroid tissue in the latter. Results of microscopic examinations of thyroid nodules were consistent with adenomatous goiter.     

Familial growth retardation with isolated thyroid-stimulating hormone deficiency

Three brothers with isolated thyroid-stimulating hormone (TSH) deficiency were observed at ages 17, 15, and 10 years. They suffered from severely retarded growth, with a marked retardation in bone maturation. Their serum T4, T3, and TSH levels were low. Serum thyrotropin-releasing hormone (TRH) concentration was normal. No increases in TSH levels were elicited during the TRH test. The other pituitary hormones, adrenocorticotropic hormone, growth hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin hormone, responded normally to stimulation. Thyroxin treatment triggered a growth acceleration. Genetic investigation revealed several instances of small stature on the father's side.     

Normal values for circulating thyroid hormones, T3 uptake and thyrotropin before and after TRH. Radioimmunoassay determinations on 182 euthyroid children (author's transl)

Measurements of T4, T3, rT3, T3U, and TSH (before and after TRH stimulation) were performed by RIA. 182 children, apparently euthyroid, age 2/12--14 years, were investigated in a cross sectional study. Free T4RIA and free T3RIA Indices and the ratio rT3/T3 and T4/T3 were calculated. Statistical analysis showed the following results: 1. Geometric mean serum concentrations of T4, T3, rT3 and TSH (basal) show no age related differences; T4 showed a not significant negative slope with age.--2. The ratio rT3/T3 and T4/T3 remains constant.--3. TRH induced TSH release (indicating the activity of the regulatory system) is unchanged from 2/12 to 14 years. Geometric means values, standard deviations and normal ranges are given.     

苯巴比妥、苯妥英、卡马西平对癫痫患儿甲状腺激素的影响

观察常用抗癫痫药物对癫痫患儿血清甲状腺激素的影响。对无甲状腺功能减退临床表现的癫痫患儿(各组均20例)共80例,应用RIA法测定血清TT4、TT3、FT4、FT3、rT3、TSH浓度。结果未经治疗癫痫患儿所有激素水平与正常对照组比较无显著差异,苯巴比妥组FT4值低于正常对照组(P<0.01),卡马西平组TT4、FT4值也明显降低(P<0.01),苯妥英组TT4、FT4、FT3值均显著降低(P<0.01),所有各组rT3、TSH无改变。资料表明,抗癫痫药物对甲状腺激素影响强度依次为苯妥英钠、卡马西平、苯巴比妥。     

Congenital hypothyroidism. Therapeutic strategy at the early stage of treatment

The aim of this work was to determine the optimum dosage of L-thyroxine (L-T4) given to infants with congenital hypothyroidism (CH). Thirty seven hypothyroid infants diagnosed through the French screening programme for CH have been treated in our clinic. The study analysed the biochemical parameters (TSH, FT4, FT3) and the L-T4 doses during the first year of life. Treatment was started at 23 days of age (range: 13 to 37). A dose of 7.5 micrograms/kg/d of L-T4 was given at diagnosis. After 2 weeks of treatment, FT3 was normal and FT4 at the upper limit of the normal values. At that time, TSH plasma levels were normal (less than 6 micro UI/ml) in 47% of cases. After 1.7 month of treatment, 22% of patients had TSH levels greater than 10 micro UI/ml despite normal FT4 and FT3. This group of patients, despite being given an identical L-T4 dose, had a significantly lower FT4. They were not different from those who normalized TSH levels in terms of etiology, delayed bone maturation and levels of FT4 or FT3 at diagnosis. In conclusion, an initial dose of 7.5 micrograms/kg of L-T4 normalized FT4, FT3 and TSH in 80% of our patients. Twenty percent of patients seem to need more L-T4 to bring TSH levels back to normal at the end of the second month of treatment.     

Cyclical combination chemotherapy and thyroid function in patients with advanced hodgkin's disease

Clinical and biochemical assessment of thyroid function was undertaken in patients with Hodgkin's disease at designated points following diagnosis. At diagnosis, two of 20 patients had either abnormally low routine thyroid indices, or elevated thyroid stimulating hormone (TSH) levels that were not due to iodine-based investigations. Following lymphography, 76.5% of patients had TSH levels that remained elevated for a median period of 3 months. No detectable thyroid dysfunction was induced during chemotherapy. Fifty-four patients were studied at a median time of 35 months after chemotherapy. One euthyroid patient had a nodular goitre, and one had abnormal thyroid indices. TSH levels were elevated in 44% of patients, although the median TSH level for the group was normal. Half the patients had abnormal TRH stimulation tests. Sixty patients were studied after irradiation and chemotherapy. Four patients had clinical thyroid dysfunction, and 10% of routine thyroid indices were abnormal. TSH levels were abnormal in 80%, with a markedly elevated median level. All thyroid releasing hormone stimulation tests were abnormal.