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HLA antigens A and B were determined in a group of 41 patients with congenital hypothyroidism and 36 of their mothers. Twenty-nine patients had thyroid dysgenesis of whom 23 were functionally athyreotic, four had ectopic and two had hypoplastic thyroid glands. Twelve patients had thyroid dyshormonogenesis, seven of whom had iodide organification defect. A total of 48 antigens were typed in the A and B loci. The results were analyzed in comparison to 388 normal adult subjects from the general population. The only statistically significant difference was an increase in the frequency of HLA-Bw44(12) (48.8% vs 19.3%, P less than 0.02). The incidence of HLA-Bw44(12) was 44.2% in the mothers. There was a decreased frequency of HLA-B7 in the patients which was not significant.

Insulin-dependent diabetes mellitus probands from the Familial Autoimmune and Diabetes Study were evaluated for autoimmune thyroid disease (n = 265). The prevalence of Hashimoto's thyroiditis was 26.6%; 42.0% of these individuals were euthyroid, and 58.0% were hypothyroid. There was a female predominance among hypothyroid and euthyroid Hashimoto's cases compared to those with no thyroid disease (75% vs. 72.4% vs. 41.6%; P < 0.001). Insulin-dependent diabetes mellitus patients with hypothyroid Hashimoto's thyroiditis were more likely to report another autoimmune disease compared to euthyroid Hashimoto's patients or individuals with no thyroid disease (30.8% vs. 17.2% vs. 13.9%; P < 0.01). Sex-specific analysis revealed that this difference was significant for men but not for women. Both euthyroid and hypothyroid Hashimoto's cases were more likely to have a family history of the disease (66.7% vs. 69.2% vs. 47.7%; P < 0.05). No differences were observed in the prevalence of DQA1*0501-DQB1*0201 or DQA1*0301-DQB1*0302 across the three groups. Body mass index, lipid levels, glycemic control, and diabetes complications were also similar. However, euthyroid Hashimoto's women were more likely to report spontaneous abortions than those with hypothyroid Hashimoto's thyroiditis or no thyroid disease (23.8% vs. 61.5% vs. 29.1%; P < 0.05). These data suggest that gender-specific risk factors may be primary determinants of Hashimoto's thyroiditis and other autoimmune diseases among women. However, disease-specific determinants may also increase susceptibility to other autoimmune diseases.

Siegel SF, Ahdab-Barmada M, Arslanian S, Foley Jr TP. Ectopic posterior pituitary tissue and paracentric inversion of the short arm of chromosome 1 in twins. Eur J Endocrinol 1995;133:87–92. ISSN 0804–4643 Twin boys with hypopituitarism, hypoplasia of the anterior pituitary gland, ectopic posterior pituitary tissue and paracentric inversion of the short arm of chromosome 1 are described. The smooth appearance at the base of the median eminence and the absence of a pituitary stalk at autopsy in these boys implies that the hypopituitarism resulted from a developmental aberration. It remains to be determined if there is a causal relationship between the chromosome 1 anomaly and hypopituitarism. Selma F Siegel, Division of Endocrinology, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA, 15213, USA

Autoimmune thyroiditis is the most common cause of subclinical hypothyroidism in North America, is more common in women than men, and is a risk factor for the development of coronary heart disease (CHD). We measured thyroid-stimulating hormone (TSH) and two thyroid antibodies, thyroid peroxidase and thyroglobulin, in stored sera of the participants (aged 44 to 54 years) of the Healthy Women Study. We selected 254 samples from the premenopausal baseline examination in 1983 to 1985 and from a follow-up examination that occurred an average of 5.7 years later (range, 3 to 7.7 years). At follow-up, 95 women remained premenopausal, 98 had ceased menstruating for at least 12 months, and 61 were taking postmenopausal hormone therapy. Overall, the prevalence of the thyroid antibodies in this healthy population was high at both time points (21 to 26%). Women with antibodies had higher TSH concentrations than did those with no antibodies (2.68 +/- 1.3 versus 1.51 +/- .73 mU/L, P 6.0 mU/L). TSH and antibody levels did not differ by menopausal status or hormone therapy use at follow-up. Given the high prevalence of thyroid antibodies among healthy middle-aged women, long-term follow-up is warranted to ascertain whether the presence of antibodies is associated with subsequent excess risk of disease, in particular, CHD.

Thyroid disease is the most common endocrine disorder during adolescence. Approximately one third of adolescents with insulin-dependent diabetes mellitus develop autoimmune thyroid disease. Goiter or thyromegaly are synonymous terms used to describe an enlargement of the thyroid gland. This article discusses many aspects of goiter in adolescents, indicating that prognosis of thyroid disease in adolescents is usually excellent.

Background Thyroxin (T 4 ) plays an important role in the regulation of the rate of metabolism of proteins, fats, and carbohydrates. Congenital hypothyroidism, an inherited deficiency of thyroid hormones, is screened in newborns using a variety of methods that include total T 4 or thyroid stimulating hormone (TSH). Some laboratories measure either total T 4 or TSH as a means of detecting infants with hypothyroidism with a subset that analyzes both total T 4 and TSH as a primary screen or a combination of primary and secondary screens. Methods We have developed a new MS/MS method that measures T 4 from a filter paper blood spot following methanol extraction using the essentially the same method as MS/MS analysis of amino acids. Product ion spectra show a transition of 833.8 → 731.8 (102 Da). An SRM for T 4 and 13 C 6 –T 4 was added to the MS/MS analysis of acylcarnitines and amino acids. Results Analysis of T 4 by MS/MS compares well with the immunoassay. The mean of 10,225 newborn screening specimens was 14.4 μg/dl (range 2.4–33) for MS/MS and 16.9 μg/dl (range 1.4–71.8) for AutoDELFIA. The MS/MS assay was linear with a correlation coefficient of 0.998. Regression analysis of MS/MS with the AutoDELFIA had a slope of 0.7, a y -intercept of 3.25, and a correlation coefficient of 0.727. We determined a MS/MS detection limit of 0.97 μg/dl and a lower LoQ (limit of quantification) of 2 μg/dl. Conclusion This method may provide a cost effective means of analyzing both T 4 and TSH by consolidating a T 4 analysis into the MS/MS panel.

Aim/hypothesis: To assess the prevalence of autoimmune thyroid disease (ATD) in insulin-treated youth with clinical features of type 2 diabetes mellitus (T2DM). Methods: We evaluated prevalence of thyroid peroxidase (TPO) and thyroglobulin (TGA) antibodies at onset of insulin-treated diabetes and follow-up in 183 White and Black children. Of these, 136 had a body mass index (BMI)

Near-adult height (AH) was determined in 121 children (72 males and 49 females) with GH deficiency (GHD) who were prepubertal when they began treatment with recombinant DNA-derived preparations of human GH. AH as a SD score was -0.7 +/- 1.2 (mean +/- SD), significantly greater than the pretreatment height SD score (-3.1 +/- 1.2), the predicted AH SD score (-2.2 +/- 1.2; Bayley-Pinneau method), and the height SD score at the start of puberty (-1.9 +/- 1.3). In contrast to studies of GH treatment outcome, which used pituitary-derived GH (pit-GH) in lower doses, we found that males did not have a higher AH SD score than females, spontaneous puberty did not diminish AH, and AH was significantly greater than that predicted at the start of GH treatment. In a multiple regression equation, the statistically significant variables (all P < 0.0001) related to AH (r2 = 0.70) were the following: duration of treatment with GH, sex (males were taller than females, as expected for the normal population), age (younger children had a greater AH) and height at the start of GH, and growth rate during first year of GH. For the AH SD score (r2 = 0.47), pretreatment predicted AH, duration of GH, and bone age delay were significant (P < 0.0002) explanatory variables. Bone age delay (chronological age-bone age) had a negative impact on the AH SD score. Target height, etiology of GHD, previous treatment with pituitary GH, and the presence or absence of spontaneous puberty did not significantly improve the prediction of AH. Early diagnosis of GHD and continuous treatment with larger doses of GH to near AH should improve the outcome in children with short stature due to GHD.

Thyroid hormones play major roles in the regulation of a wide range of metabolic and physiologic processes, but the genes and environmental factors that affect normal, quantitative variation in thyroid hormone concentrations are largely unknown. Using quantitative genetic methods, we evaluated the effects of genes and environmental factors on thyroid hormone variation in 586 women and 425 men from 27 randomly ascertained Mexican-American families from the San Antonio Family Heart Study. Data were available on free and total T(4), free and total T(3), TSH, thyroglobulin, and T(4)-binding globulin, as well as on covariates, including sex, age, weight, lifestyle habits, physical activity, and others. These covariates accounted for 2-18% of total phenotypic variation, whereas genes accounted for 26-64% of the variation. Overall, free T(3) had the highest heritability, which is noteworthy because it is the most biologically active thyroid hormone and accounts for the vast majority of metabolic and physiologic effects of thyroid hormones. Our results indicate that genes account for a substantial portion of variation in human thyroid hormone levels, and suggest that further studies to identify the genes involved in this variation could reveal important insights into the processes that govern thyroid-mediated metabolism.

Throughout pregnancy the fetus is dependent upon the placental transport of nutrients from the mother to support growth and differentiation. By this same mechanism the fetus is exposed to a variety of maternal factors that may adversely affect thyroid embryogenesis and function during pregnancy and postnatal life. The maternal factors include altered concentrations of iodide, immunoglobulins primarily in the G class (IgG), drugs, environmental goitrogens and other substances that are poorly understood or defined.

We evaluated the longitudinal response in 43 infants with congenital primary hypothyroidism during the first year of L-thyroxine therapy. Diagnosis was confirmed by serum thyroid hormone measurements by 4 weeks of age in 38 infants and between 40 and 80 days of age in the remainder. This group of infants was divided by radionuclide thyroid imaging into 34 infants with thyroid dysgenesis and nine with dyshormonogenesis. The group with thyroid dysgenesis was subdivided into 21 infants with athyreosis and 13 with residual thyroid tissue (11 ectopic and 2 hypoplastic glands). L-Thyroxine therapy, at an average dose of 10 to 14 micrograms/kg/day, was begun immediately after diagnosis, and serum concentration of total thyroxine, free thyroxine, triiodothyronine, reverse triiodothyronine, and thyroid-stimulating hormone were determined serially. Serum concentration of total and of free thyroxine became normal within 1 week of the start of therapy in all groups. Despite a similarly mild degree of hypothyroidism at diagnosis observed in infants with dyshormonogenesis or with ectopia or hypoplasia, those with dyshormonogenesis had a more sensitive response to initial thyroid hormone replacement than did patients with thyroid dysgenesis, as judged by L-thyroxine does and thyroid-stimulating hormone suppression. We conclude that the prompt restoration of clinical and biochemical euthyroidism during early infancy with doses of L-thyroxine between 10 and 14 micrograms/kg/day is a safe and effective method of therapy for children with congenital hypothyroidism.

Thyrotropin receptor antibodies (TRAb) were measured in serum from 49 patients with active and inactive juvenile Graves disease, and the results were compared with values from control subjects and patients with Hashimoto disease. With a thyrotropin binding inhibition immunoglobulin (TBII) assay, TRAb were found in serum from 25 (93%) of 27 patients with untreated, active Graves disease. The TRAb values remained positive in 20 (72%) of 29 patients during the first 6 months of antithyroid therapy and in 13 (54%) of 24 patients during the second 6 months. After discontinuation of antithyroid therapy, 15 patients experienced 18 episodes of relapse of thyrotoxicosis; during relapse TRAb values were positive in all but one patient. Among 19 patients who remained clinically and biochemically euthyroid after cessation of antithyroid therapy, TRAb were not detected in 28 (78%) of 36 serum specimens. Of the eight positive values from six patients, no antiidiotypic antibodies were found, and thyroid stimulating immunoglobulins (TSI) were not detected in four specimens. The TRAb determination correctly predicted the subsequent clinical course in 26 (72%) of 36 patients. Furthermore, TRAb values and results of triiodothyronine suppression tests were in agreement in 27 of 36 patients, or 75% of the time. TSI were present in serum from only 19 (73%) of 26 patients with active disease; however, TSI were negative in all patients with inactive Graves disease. During the management of Graves disease, TRAb measurements by TBII determinations are valuable in the diagnosis of active disease, assist in the decision to discontinue antithyroid drug therapy, and are useful as the T3 suppression test to predict the clinical course of the disease. The TSI measurement is most useful to determine the activity of the disease when TRAb values are positive in a euthyroid patient.

The seasonal and chronological distributions of birth dates of 820 patients with congenital hypothyroidism due to thyroid dysgenesis were analysed in eight areas in the world. The incidence had some seasonal variations in certain areas. These observations suggest that some environmental factors cause this disease.

Thirty-six children with growth hormone deficiency were treated for up to 48 months with methionyl human growth hormone (hGH) synthesised by DNA recombinant methods. The growth rate for these children increased from 3.2 +/- 1.1 cm/yr to 10.5 +/- 2.2 cm/yr (mean +/- SD). This was similar to the effect of pituitary hGH in ten GH deficient children, 3.8 +/- 1.0 to 10.1 +/- 1.1 cm/yr. Serum somatomedin C rose from 0.26 +/- 0.23 U/ml to 0.79 +/- 0.53 U/ml after 6 months of methionyl-hGH therapy, similar to the effect of pituitary hGH. The incidence of antibody formation to methionyl-hGH was higher than that observed with pituitary hGH (Kabi) but poor growth was observed only in the one patient on methionyl-hGH who acquired high-titre high-binding-capacity antibodies to hGH. No consistent changes in levels of antibodies to Escherichia coli proteins were detected. No other allergic manifestations or systemic side-effects were demonstrable.

Twelve patients with low birth weights and/or birth lengths for gestational age were treated with one or more daily doses of human growth hormone (hGH) ranging from 1.0 to 10.2 mg. per square meter of body surface area per day for five to 18 months. Significant delay in skeletal maturation was found in all but one patient. Of the eight patients aged seven years or younger at the time of treatment, the growth rates of five (62.5 per cent) during treatment with hGH were at least twice their pretreatment growth rate; in six (75 per cent) the pretreatment growth rates were exceeded by 3.5 cm. or more per year. Among those patients who received their initial course of hGH therapy in a dose of 2 mg. or more per square meter of body surface area per day, five of eight patients (62.5 per cent) more than doubled their pretreatment growth rates during hGH therapy; seven of eight (88 per cent) increased their pretreatment growth rates by more than 3.5 cm. per year during hGH therapy. In sufficient dose hGH is an effective therapeutic agent in some young patients who have had intrauterine growth retardation.

The clinical, neuroradiologic, and endocrine features in 16 patients with septo-optic dysplasia are reviewed. All of the patients had clinical optic nerve hypoplasia with varying degrees of nystagmus and visual impairment. Only one-half of the patients had absence of the septum pellucidum. Fourteen children were growth hormone deficient, 9 were adrenocorticotrophic hormone deficient, 3 were thyroid-stimulating hormone deficient, and 4 had diabetes insipidus. In most instances, the diagnosis of septo-optic dysplasia can be established by physical examination and neuroradiologic findings, at which point a thorough evaluation of the hypothalamicpituitary endocrine function is indicated because of the high incidence of hypopituitarism with this syndrome.

Altered carbohydrate metabolism associated with fibrosarcomas and chondrosarcomas has been well-documented in past literature. This report describes abnormal carbohydrate metabolism in 2 osteosarcoma patients, and abnormalities in growth hormone and somatomedin serum levels. Experimental evidence is presented showing in vitro suppression of osteosarcoma tumor cell proliferation by 17 beta Estradiol. Estrogen inhibition of linear bone growth, cartilage proliferation, and somatomedin is discussed with reference to possible estrogen therapy in osteosarcoma.

Synthetic thyrotropin-releasing hormone (TRH) was administered intravenously in a dose of 7 mug/kg to 20 normal children ages 4-13 yr. Serum thyroid-stimulating hormone (TSH) was measured by radioimmunoassay and rose from a mean value of 1.7 muU/ml (range = < 1.25-7.2) to a mean peak value of 21.5 muU/ml (5.2-33.2) at 15 or 30 min after administration.13 patients with idiopathic hypopituitarism and apparent normal thyroid function, ages 3-19 yr, responded to TRH in a manner very similar to the control subjects: TSH rose from a mean value of 1.8 muU/ml (range < 1.25-4.3) to a mean peak value of 18.5 muU/ml (range = 9.5-45.0) which occurred between 15 and 60 min after TRH.13 idiopathic hypopituitary patients with documented thyroid deficiency were tested after thyroid therapy had been discontinued for a minimum of 10 days. The serum TSH values in 10 of 13 patients rose from a mean base line level of 2.2 muU/ml (< 1.25-5.3) to a peak mean value of 32.5 muU/ml (9.6-61.3) between 30 and 120 min after TRH. In three patients, however, little or no TSH response was detected, even when serum thyroxine levels were extremely low. Similar to the latter group, three of five patients with hypopituitarism secondary to craniopharyngiomas had undetectable or barely measurable TSH levels before and after TRH. Two of these five patients had significant responses which were compatible with hypopituitarism resulting from damage to the hypothalamus or hypothalamic vessels instead of the pituitary. Side effects were experienced in 41 of 54 patients (76%). The effects were limited to a mild nausea-like sensation in 63% of the patients and occurred within the first 5 min after receiving TRH. No evidence of serious toxicity or long-term side effects was noted. The TRH test is a safe, effective way to measure TSH reserve in children. The positive response in 10 of 13 patients with secondary hypothyroidism supports data previously accumulated that most patients with idiopathic hypopituitarism have an abnormality of their hypothalamic-releasing hormone function, whereas the remaining minority probably have primary pituitary disease.

Serum FSH and/or LH concentrations were determined by radioimmunoassay in 39 males (ages 15–45 yr) with myotonic dystrophy and compared with serum FSH and/or LH concentrations in 35 normal males (ages 18–45 yr). Plasma testosterone concentrations were determined by competitive protein binding in 36 of the males with dystrophy and compared with those observed in 30 normal males. The mean serum FSH concentration (65.4 ± 17.0 mIU/ml) of 32 males with myotonic dystrophy was significantly greater (p < 0.005) than the mean serum FSH concentration (9.3 ± 3.1 mIU/ml) of 28 normal males. All serum FSH concentrations (18.3 to 92.5 mIU/ml) were greater than the range of serum FSH concentrations (5.2 to 14.5 mIU/ml) of normal males. The mean serum LH concentration (20.1 ± 13.9 mIU/ml) of 39 males with myotonic dystrophy was significantly greater (p < 0.005) than the mean serum LH concentration (9.2 ± 5.1 mIU/ml) of 35 normal males, and 14 of the 39 had serum LH concentrations which were greater than 2 standa...

To test the possibility that osteosarcoma cells produce their own growth factors, we measured levels of insulin and somatomedin C (SMC), an insulin-like growth factor, in culture media of two cell lines derived from patients with that disease. SMC but not insulin levels increased three- to ten-fold over a period of 7 days paralleling the increases in cell number. Production of SMC was inhibited by cycloheximide.

Somatomedin activity was determined by the simultaneous incorporation of 35S-sulfate and 3H-methyl thymidine into costal cartilage from hypophysectomized rats in cord sera from term and preterm infants and infants with intrauterine growth retardation. Mean Sm activity by sulfate incorporation was 0.49 +/- 0.04, 0.35 +/- 0.05, and 0.09 +/- 0.03 units/ml (+/- SE) in the term, preterm, and IGR cord sera, respectively. The levels for each group were significantly different from each of the other groups. There was no significant difference between the mean Sm activity by thymidine incorporation in cord sera from term (0.92 +/- 0.09 units/ml) and preterm (0.87 +/- 0.08 units/ml) infants. These levels were significantly higher, however, than the Sm activity by sulfate incorporation for the respective groups, P less than 0.001 for both groups. The mean Sm activity by thymidine incorporation in cord sera for IGR infants was 0.36 +/- 0.13 units/ml, and significantly lower than the levels in cord sera of term and preterm infants (P less than 0.01). Inhibition of Sm activity by mixing cord serum and pooled adult serum was found in one of the two cord specimens tested from IGR infants. The low levels of Sm activity in cord sera from IGR infants may reflect altered intrauterine nutrition. The discrepancy in the thymidine and sulfate incorporation by the costal cartilage bioassay for term and preterm cord sera might result from Sm-like factors in human fetal serum with greater mitogenic or thymidine transport activity compared to the activity for proteoglycan synthesis in cartilage.

Labeled and/or unlabeled human luteinizing hormone (hLH) was injected into normal and abnormal males and into hypopituitary patients. In two patients, two phases of disappearance (T 1/2) were found to be 1.2 and 2.4 hr. Labeled and unlabeled hormone were excreted in the same proportion. Of the injected hormone, normal males excreted 10.1% plus or minus 0.9%, hypopituitary patients excreted 11.4%- 17.5% and two other patients excreted 10.3% and 5.3% over 48 hr. The urinary excretion of unlabeled hLH in normal males was 22.1 plus or minus 4.9 IU/24 hr. The production rate of hLH in normal males was 224.3 plus or minus 65.3 IU/24 hr and, in the two abnormal males, was five times higher. The advantages of this methodology are discussed.

Human serum spreading factor (SF) is a blood glycoprotein that promotes the attachment and spreading of a variety of cell types in serum-free culture, as well as affecting migration, proliferation and differentiation of some cell types under appropriate conditions. The amino acids occupying 17 of the first 23 positions from the NH2-terminus of SF were determined, and this sequence was found to be identical to that reported for somatomedin B (SmB) by Fryklund and Sievertsson (FEBS Letters 87:55). Immunoassay of SF in plasma from subjects with conditions related to altered GH levels indicated that serum SF levels were not GH-responsive to any marked degree. No effect of purified SF was observed in a cell growth assay used previously to detect mitogenic activity in SmB preparations. These results support the conclusion that SF acts as a substratum molecule to elicit its biological effects in cell culture, and does not act in a manner similar to peptide growth factors. These data also are consistent with the conclusion of Heldin et al. (Science 213:1122) that the mitogenic activity of SmB preparations is derived from a contaminating factor, and is not due to SmB.

Serum total and free triiodothyronine (T3) and thyroxine (T4) concentrations and thyrotropin (TSH) levels were measured in cord serum (n = 30), and serum from the same infants 3 days (n = 26) and 6 weeks of age (n = 15). Mean total T3 levels at these times were 48 ± 3, 125 ± 8 and 163 ± 6 ng/100 ml respectively (all values mean ± sem). The corresponding values for mean free T3 concentrations were 130 ± 10, 410 ± 20 and 400 ± 20 pg/100 ml. The total and free T3 levels in 6-week-old infants were higher than those of normal adults (p < 0.001). The mean T4 levels were 10.9 ± 0.3, 17.2 ± 0.5 and 10.3 ± 0.4 μg/100 ml and free T4 levels 2.23 ± 0.12, 4.87 ± 0.33 and 2.07 ± 0.08 ng/100 ml in the same sera. Free T4 levels were elevated over the values in normal adults only in sera from the 3-day-old infants. Mean TSH levels were 8.5 ± 0.7 and 7.3 ± 1.0 /μU/ml in cord serum and at age 3 days and were

Levels of multiplication-stimulating activity (MSA) in fetal rat serum are high (2-4 micrograms/ml), suggesting that MSA may have a role in fetal growth. We now demonstrate that fibroblasts derived from rat embryos (REFs) have specific MSA receptors and respond to MSA with increased DNA synthesis. Two types of insulin-like growth factor (IGF) receptors were demonstrated by competitive binding of radioiodinated MSA, IGF-I, and IGF-II and by chemical cross-linking of [125I]iodo-MSA and [125I]iodo-IGF-I to REFs. One type of receptor (mol wt, 260,000 under reducing conditions) did not interact with insulin, and another type of receptor (mol wt, 130,000, under reducing conditions) was recognized by insulin. Scatchard analysis of [125I]iodo-MSA binding data was consistent with one class of noninteracting binding sites. A biological response of MSA, increased DNA synthesis, was demonstrated with autoradiography in REFs. During a 16-hr incubation, DNA synthesis was stimulated by normal rat serum, and platelet-poor plasma plus platelet-derived growth factor (PDGF), but not by serum from hypophysectomized (hypox) rats or hypophysectomized (hypox) platelet-poor plasma plus PDGF. However, when MSA was added to hypox serum or to hypox platelet-poor plasma plus PDGF, DNA synthesis was stimulated to the level achieved by normal rat serum. By contrast, during a longer cell multiplication experiment, REFs grew equally well in normal or hypox rat serum, raising the possibility that REFs may produce a MSA-like factor.

• To determine if pharmacologic and physiologic tests are equally effective in the assessment of growth hormone (GH) secretory status, serum GH levels were measured during sequential tests with intravenous arginine infusion and insulin-induced hypoglycemia (arginine-insulin tolerance test [AITT]) and during sleep in 62 children, aged 2.1 to 17.3 years. Responses during AITT and sleep were concordant in 53 patients and discordant in nine patients. Arginine-insulin tolerance test results were consistent with the subsequent clinical course in 80% of the patients while nocturnal sampling was consistent with the subsequent clinical course in 93% of the patients. Thus, the failure of a normal serum GH response to pharmacologic stimuli is not always a diagnostic indicator of GH deficiency. Additional investigation of discordant GH responses to pharmacologic and physiologic stimuli may lead to a further understanding of the control mechanisms of GH secretion. ( AJDC 1984;138:540-543)

Thyroiditis ranks with diabetes as the most common of the endocrine disorders of childhood. The term encompasses all forms of thyroid gland inflammation and infection, although chronic lymphocytic thynoiditis is overwhelmingly the most frequent. Thyroiditis may appear as a mass in the neck of an asymptomatic child or it may be a painful, erythematous goiter in a sick child. The affected thyroid gland may be small on large, with varying degrees of dysfunction. Most commonly, thyroiditis causes euthyroid function, although the disease process can result in transient or permanent thyroid dysfunction. The causes of thyroiditis in childhood, as well as the less common thyroid disorders in the differential diagnosis of goiter, are listed in Table 1. Thyroid physiology and pathophysiology will be discussed briefly to explain the rationale for diagnostic studies and treatment strategies. The more recent diagnostic techniques and therapeutic controversies regarding thyroiditis will be included. The goal is to provide the clinician with renewed awareness of this most common pediatric problem. THYROID PHYSIOLOGY Thyroid hormone production is regulated by a classical negative feedback system (Fig 1). Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and secretion of thyroid-stimulating hormone (TSH) from the pituitary. TSH, in turn, stimulates production and release of thyroxine (T4) and triiodothyronine (T3).

Four families with growth hormone (GH) deficiency, either isolated or with other pituitary hormonal deficits are described. Members of each underwent pharmacological testing for GH secretion and infusions of GH releasing hormone (GHRH) to determine the locus of the defect in GH secretion. In addition, we have extracted DNA from white blood cells to characterize the GHRH and GH genes. All members tested had the normal complement of GH and GHRH genes. Four generations of one family with isolated GH deficiency, autosomal dominant were studied. The younger members showed minimal GH responsiveness to a single infusion of GHRH. However, the older members did not respond even after 30 doses of GHRH given intravenously every 3 h. Two members of a family with the autosomal recessive type of isolated GH deficiency had large GH increases after GHRH infusion. Thus in these families the GH secretory defect lies within the hypothalamus. Members of two families with pituitary deficiency (GH and other tropic hormones) of the autosomal recessive type had variable responses to GHRH and varying amounts of pituitary tissue seen on high resolution CT scans. Although it is not possible to delineate the precise location of the secretory defects in these latter two families, a hypothalamic defect is probable based on the responses to multiple trophic stimuli. Heterogeneity of structure and function exists within and between families with isolated GH deficiency and within and among families with pituitary deficiency. It is from the study of such families in which all members presumably have the same underlying defect that one can more readily decide on a pathogenetic mechanism.

The linear growth of 8 patients with Turner's syndrome during human growth hormone (GH) administration was documented. Mean growth velocity was significantly greater during GH treatment (4.9 +/- 0.8 cm/year) than before treatment (3.3 +/- 0.8 cm/year, p less than 0.001). Growth velocity was related to dosage but not correlated with chronologic age, skeletal age or weight.

Reverse triiodothyronine (rT3) was measured in cord serum from 5 infants with congenital hypothyroidism and compared with normal values in 70 euthyroid control infants. The mean (and SEM) value in the affected infants (135 ± 12 ng/dl) wassignificantly lower than that in the control population (270 ± 9 ng/dl). However, the large overlap in range of concentrations in affected and control infants indicates that newborn screening based on the determination of rT3 in cord blood specimens offers no advantage qver present screening methods. (J Clin Endocrinol Metab 46: 336, 1978)

Synthetic thyrotropin-releasing hormone (TRH) was administered to normal children and hypopituitary patients in a dose of 7 μg/kg i.v. over 30-60 sec. Serum thyrotropin (TSH) and prolactin (HPr) concentrations were measured by radioimmunoassay before and at 15-min intervals for 2 hr after TRH. In 20 normal children HPr rose from a mean baseline value of 7.0±1.2 (SEM) ng/ml to a mean peak value of 39.5±5 ng/ml. In 11 patients with growth hormone (GH) deficiency without TSH deficiency. HPr values rose from a mean baseline of 3.6±0.8 ng/ml to a mean peak value of 13.9±2.8, a significantly less peak response as compared with normal children (P < 0.005). The TSH responses to TRH, however, were statistically indistinguishable from those of normal children. In 10 patients with GH and TSH deficiency both the mean baseline HPr levels (25.0±5 ng/ml) and the mean peak HPr levels after TRH (68.5±10 ng/ml) were significantly higher (P < 0.005 and < 0.025) than those of normal children. Similar comparisons were also true for the peak TSH responses (P < 0.05). Two panhypopituitary patients released no TSH and only small amounts of HPr after TRH. After thyroid replacement therapy in eight of the patients with GH and TSH deficiency, the mean HPr baseline levels (7.6±1.0 ng/ml) and peak levels (23.3±4.6 ng/ml) after the same dose of TRH were significantly less than their pretreatment levels (P < 0.001 and < 0.01) and were within the range for normal children. Synthetic TRH stimulates the simultaneous release of TSH and HPr in normal children and most hypopituitary patients. When the concentrations of thyroxine (T4) and triiodothyronine (T3) are low, the levels of HPr before and after TRH are elevated. After thyroid replacement therapy, HPr levels decrease to normal. T4 and/or T3 may condition the production or effects of prolactin-inhibiting factor (PIF) activity. The TSH and HPr responses after TRH in hypopituitary patients will determine whether the primary defect resides in the pituitary or hypothalamus, but cannot delineate the hypothalamic defect as a deficiency of hypothalamic hormone production or neurohumoral transmission.

Mild hypercalcemia was recognized in a 7-year-old boy during an evaluation for headaches. Subsequently, an additional eleven members of four generations of the family were found to have mild hypercalcemia, normal levels of immunoassayable parathyroid hormone (IPTH) during hypercalcemia, normal or low serum phosphate for age, and low urinary calcium excretion. Administration of prednisone for ten days did not decrease serum calcium values. Ionized calcium was increased proportional to the elevation of the total serum calcium. Surgical exploration of the proband revealed three histologically normal parathyroid glands and a fourth which was grossly normal, with no tumor in the anterior medastinum. Calcium infusion increased serum calcium values while IPTH leveis decreased. The persistence of normal IPTH concentration despite elevated serum total and ionized calcium values suggests an abnormality of the receptor mechanism for the calcium ion control of the secretion of parathormone by the parathyroid glands. The family pedigree indicates an autosomal dominant mode of inheritance.

Serum follicular-stimulating hormone (FSH) and luteinizing hormone (LH) as determined by radioimmunoassay, were correlated with sexual development in 29 patients with hypopituitarism (ages 14.2-29.9 yr).16 of 25 idiopathic hypopituitary patients (20 males and 5 females) exhibited some degree of sexual development. Stage III of sexual development or beyond was achieved by 12 of the 16. Of 13 patients with growth hormone (GH), adrenocortical-stimulating hormone (ACTH), and thyroid-stimulating hormone (TSH) deficiency, 8 did not develop beyond stage I. In contrast, five of six patients with GH deficiency without ACTH or TSH deficiency developed to stage III of sexual development or beyond. The mean (+/-sd) serum LH concentration while in stage I (4.3 +/-0.9 mIU/ml) of eight patients (seven males and one female) who developed beyond stage I was significantly (P < 0.005) greater than the mean serum LH concentration (2.3 +/-0.9 mIU/ml) in nine patients (seven males and two females) who had not developed beyond stage I. Mean serum FSH concentrations were not different. Three of four males with organic hypopituitarism did not develop beyond stage I of sexual development. Serum FSH and LH concentrations in the idiopathic and organic hypopituitary patients were more compatible with stage of sexual development than with age. A serum LH concentration below the range of normal for stage I of sexual development in a prepubertal patient suggests that the patient will remain sexually infantile as an adult.

Twenty patients with the syndrome of testicular feminization have been studied along with a group of normal subjects of both sexes and of comparable ages. Peripheral and gonadal venous blood were analysed for their content in testosterone (T), androstenedione (Δ), dihydrotestosterone (DHT), testosterone-oestradiol binding globulin (TeBG), luteinizing hormone (LH) and follicle stimulating hormone (FSH). Normal or even higher than normal male concentrations of T, Δ, and DHT were observed. An actual secretion of the three androgens by the testis was demonstrated. Elevated levels of serum LH were found despite normal male or higher levels of T, Δ, and DHT. High concentrations of TeBG presumably could alter the dynamics of plasma androgens. The gonadal production of DHT and the normal levels of DHT in peripheral plasma shows that 5α-reductase activity is definitely present in the patients.

We have previously demonstrated a significantly increased rate of growth in hypopituitary children treated chronically with CPH and growth hormone (GH) compared to those treated with GH alone. To determine the effect of chronic CPH in adrenocortical function, the cortisol (F) response to insulin hypoglycemia was determined in 10 hypopituitary children (8 idiopathic, 2 organic) treated for at least 4 months with GH and CPH (12-16 mg/day). All had previously normal oral metyrapone tests. While receiving CPH, five of the ten patients had a normal peak F response (> 15 μg/dl) to insulin hypoglycemia while five of the ten had subnormal peak F concentrations (6.4 ± 2.7 μg/dl). All patients were retested two or more months after cessation of CPH therapy. The five patients with a normal peak F response during CPH therapy did not have an increased peak response after cessation of CPH. Four of the 5 patients with an abnormal response subsequently had a normal peak F response significantly greater than that while receiving CPH (16.3 ± 1.3 μg/dl; p < .01). The patient who had persistent subnormal peak F response to hypoglycemia had received radiation therapy for craniopharyngioma. None of the ten patients experienced any symptoms of glucocorticoid insufficiency. We conclude that in some cases, long-term administration of CPH to hypopituitary children may be associated with decreased F response to insulin hypoglycemia.

Top of pageAbstract To determine if serum TRAb measurements are useful in diagnosis and management of JGD, we studied 48 pts with JGD & 113 controls: 41 adults; 41 children & 31 with Hashimoto's Disease (HD), 9 with ↑ TSH levels. We tested 3 groups of JGD pts, I: active and untreated disease; II: recurrent disease; III: in remission on no therapy. TRAb was measured by displacement of labeled bTSH from porcine thyroid membranes (C1. Endocr. 20:539,1984), and values expressed as % inhibition of tracer TSH binding. No antiidiotypic antibodies were detected. There was no correlation between TRAb and TSH in HD with ↑ elevated TSH. False negative TRAb results occurred in 2 JGD-I (7%) pts and 1 JGD-II (6%) pt; false positive TRAb results occurred in 6 JGD-III (17%) pts, and were not associated with relapse of the disease. In conclusion: Abnormal TRAb values will confirm the diagnosis of JGD in > 90% of pts with hyperthyroidism, and are found in > 90% of JGD pts in relapse. TRAb values are greater at initial diagnosis than during relapse, probably reflecting a shorter duration and less severity of disease during relapse. Abnormal TRAb values during remission may result from TRAb without thyroid stimulation, or the development of co-existing HD.

HHG in AIP has not been reported. A 20 yr. old male with AIP and inappropriate secretion of ADH was hyposmic, tall (178 cm), eunuchoid (U/L, 0.84), had a high-pitched voice, absent facial hair and Tanner 2-3 pubic hair. His testes were small (R, 8 ml; L, 10 ml). Karyotype was XY. Basal serum FSH, 5.5 mIU/ml; LH, 5.6 mIU/ml and T, 54 ng/dl were all low and PRL was normal. Mean nocturnal LH (6.5 ± 0.2 (SE) mIU/ml) was low and showed no periodic pulses. Mean nocturnal T (156 ± 13 ng/dl) was also low, with minimal fluctuations between 2200 h and 0300 h; however, between 0300 h and 0800 h two peaks of T occurred simultaneously with those of cortisol. The responses of LH to LHRH and TSH and PRL to TRH were normal. Nocturnal GH secretion was characterized by 3 peaks. Basal GH was normal and increased to 16 ng/ml during AITT and remained above 10 ng/ml between 60 and 150 minutes. Basal T, 252 ng/dl, increased to 2049 ng/dl after 4 days of im hCG (5000 units/d). Basal 24 h urine Δ amino levulinic acid (ALA), 18 mg and porphobilinogen (PBG), 68 mg, respectively, were high and did not change after 4 days of hCG (ALA, 25 mg/d; PBG, 51 mg/d). Three attacks of AIP occurred during 8 months prior to T therapy, but none occurred during 7 months of hCG or T therapy. Conclusions: 1) Hypothalamic dysfunction in AIP may cause HHG 2) hCG and T do not alter ALA and PBG excretion and may protect these patients from repeated attacks.

Among 15 infants with CH, 6 were identified in our screening program with an elevated cord TSH ( > 100 μU/ml) and low T4 (< 5 μg/dl), and placed on thyroid hormone therapy within the first month of life. Within 4 weeks of therapy their serum TSH was suppressed below 12 μU/ml either by treatment with T4 alone or T3 and T4 combination therapy. An additional 9 infants not involved in a screening program were identified by clinical symptoms and referred for evaluation. Three infants were initially treated with 25 μg qd of T3, and serum TSH was < 12 μU/ml in all within 4 weeks. However, among 5 of 6 infants treated with T4 alone, the TSH did not suppress below 12 μU/ml until ≥ 3 months of therapy. During therapy in the 7 infants treated with T4 alone, serial reverse T3 (rT3) determinations revealed peak concentrations (106 ± 13.8 ng/dl, mean ± SEM) simultaneous with the initial suppression of TSH to normal and significantly greater than the rT3 levels just prior to suppression of TSH (66.7 ± 15 ng/dl, p

During the period from 5/75 to 12/76, 74,050 newborns were screened in the States of Oregon, Montana, and Alaska for neonatal hypothyroldism. Filter paper blood specimens were analyzed for T4 in the newborn period and in a follow-up sample at 6 weeks of age. The lowest 3% of dally T4 assays (

In 60 newly diagnosed children with JDM we measured serum T4, T3, reverse T3 (rT3) and free T4 (FT4) before and serially at 1, 3 and 5 days and up to 6 months during therapy. The mean ± SEM serum T3 before therapy (71 ± 6 ng/dl) was lower (p 15 mEq/L, but low before therapy when −HCO3 < 15 and increased to normal by day 3. Serum T3 was lower in patients with low −HCO3 before therapy. The elevated rT3 and FT4 were unaffected by low −HCO3. HbAl fell significantly by paired t test (p < .001) during the first 5 days of therapy, and further decreased during the ensuing 3 months (p < .001). HbA1 correlated with rT3 and inversely with T3 during the study period (p < .001). We speculate that the metabolic disturbance in untreated JDM resembles the "Low T3 Syndrome" of starvation. The association of low −HCO3 and low total T4 and T3 but normal TSH and high FT4 suggests an impairment of binding to the serum thyroid binding proteins. Correlation of T3 and rT3 with HbAl may reflect their dependency on the severity of the disease.

Sexual precocity at age 5 years was treated at age 6 years by radiation of an optic neurofibroma. Rapid pre-treatment growth rate and normal GH response to arginine-insulin provocation (ATT-ITT) were followed (post radiation) by decelerating growth rate with failure of GH response to ATT, ITT and during sleep. T4 fell to 1.6 μg% but TRH induced TSH release indicating hypothalamic deficiency and this was treated with L-T4 replacement. ACTH was normal (metyrapone test). FSH (390 ng% LER 907) and LH (96 ng%) were normal adult. Menarche at age 9 years was followed by amenorrhea. The data suggested selective hypothalamic damage. Therefore, estradiol 15 ng/kg/d was given IM × 5 days. FSH and LH were incompletely suppressed and both showed rebound after, but no “surge” during estrogen administration. Control → during estrogen → post control values respectively were FSH 310 -340; 190 - 224; 213 - 242 and LH 80 - 90; 43 - 74; 89 - 140 ng% LER 907. Conclusion: The data are consistent with the hypothesis that in this patient there was preservation of the “tonic” gonadotrophin releasing center with tumor and/or radiation damage to the “cyclic” center; anatomically the latter may be situated near the growth hormone and TRH releasing centers in the hypothalamus.

Six boys with CD ranging in age from 14 5/12 to 16 2/12 yrs. were evaluated with measurements of 24 hr. integrated concentrations (IC) of LH, T, and androstenedione (Δ), the LH and FSH response to LH-RH, and growth hormone (GH) concentration following arginine-insulin (AITT). Each boy was treated with 3 monthly injections of 200 mg T enanthate and the same studies were repeated 2 months after the last injection of T. The mean growth rate was 3.75 cm/5 mo. and there was no significant increase in bone age. All boys had a progression in sexual development to Tanner Stage II or III with appropriate increase in testicular volume. Following T therapy, all boys had significant increase (p < .01) in the IC of LH, testosterone and Δ, especially the nocturnal IC LH. There was no significant difference in the IC GH. After T therapy, all boys had significantly increased concentrations of LH and FSH following LH-RH (p < .01). There was no significant difference in GH concentrations during AITT following T therapy. In the 8 months following T therapy, 5 of 6 boys have continued their pubertal maturation and increased statural growth with appropriate skeletal maturation. One boy has not had the expected pubertal progression. Further longitudinal studies are needed but small doses of T may be safe and beneficial in the treatment of CD.

The response to exogenous testosterone enanthate (TE) (200mg IM once each month for three months) was evaluated in 10 males, age 16 ± 0.8 years (mean ± 1 S.D.) diagnosed as constitutional delay of puberty (CD). Prior to the onset of therapy, the following were measured: serum LH and GH every 30 min. for 24 hrs; FSH-LH conc. following a single 100 μg bolus of Gonadotropin Releasing Hormone (GnRH); the GH conc. following sequential arginine-insulin stimulation. Two months after the last injection of TE, the same series of tests were performed. Patients have been followed 1 – 2-1/2 yrs. All 7 patients who were Tanner Stage I had a significant increase (p < .01) in both the mean 24 hr concentration of LH and GH, a significantly increased LH conc. following GnRH, p < .01, and a significantly increased plasma testosterone conc. (p < .001), although the last dose of TE was 60 days earlier. All patients have continued their pubertal progression as evidenced by continued increase in plasma testosterone, progression in secondary sex characteristics and normal osseous maturation without compromise in predicted height. These results may be compatable with a testosterone induced maturation of hypothalamic pituitary function.

To assess the risks of dehydration and hemodilution during potentially normal circumstances in patients treated with DDAVP, we tested 9 children aged 7 2/12 - 17 9/12 with central DI. Three patients with other hormone deficits were receiving appropriate replacement. All had been stabilized on DDAVP for 1 yr with doses varying from 5 μg b.i.d. to 15 μg am and 10 μg pm. Urine volume and osmols and serum osmols were measured hourly from 8 am to 4 pm with 1) food and fluid ad lib, 2) food and water deprivation from 12 mn, 3) water load 20 ml/kg at 8 am. In most children the unine volume and osmols were similar during the 3 days. Serum osmols hardly varied during normal fluid intake and water deprivation despite a mean 0.5 kg weight loss during the latter. However, only 26.5±9% of the water load was excreted in 8 hrs resulting in a significant (p

Utilizing the EMIT system we have determined phenobarbital and diphenylbydantoin levels in 77 neonates with seizures. In addition, brain tissue was obtained for diphenylhydantoin and phenobarbital levels in ten neonates coming to autopsy. Following intravenous loading doses of 15-20mg/kg of phenobarbital, levels of 19.4 ± 3.4 mg/L were achieved. The volume of distribution of phenobarbital was 0.97 ± 0.20 L/kg and was not influenced by gestational age. Following intravenous loading doses of 15-20 mg/kg of diphenylhydantoin, levels of 14.9 ± 2.8 mgm/L were achieved. The volume of distribution of diphenylhydantoin was 1.19 ± 0.19 L/kg. Maintenance doses of 5 mg/kg/d IV, IM or PO phenobarbital or 5 mg/kg/d IV dlphenylhydantoin resulted in accumulation of each agent in the first seven days of therapy. Although the volume of distribution of both agents is significantly greater in the newborn than the adult, the brain to plasma ratio was significantly less in the newborn. It would appear that therapeutic brain concentrations of phenobarbital and diphenylhydantoin are difficult to achieve even when large loading doses of these agents are used.