Serum follicular-stimulating hormone and luteinizing hormone as measured by radioimmunoassay correlated with sexual development in hypopituitary subjects.

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.

Serum thyrotropin responses to synthetic thyrotropin-releasing hormone in normal children and hypopituitary patients. A new test to distinguish primary releasing hormone deficiency from primary pituitary hormone deficiency.

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.

Human prolactin and thyrotropin concentrations in the serums of normal and hypopituitary children before and after the administration of synthetic thyrotropin-releasing hormone.

Synthetic thyrotropin-releasing hormone (TRH) was administered to normal children and hypopituitary patients in a dose of 7 mug/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.

Menopause in type 1 diabetic women: is it premature?

Women with type 1 diabetes have a delayed menarche and a greater prevalence of menstrual disorders than women without diabetes. However, little is known about the menopause transition among type 1 diabetic women. The Familial Autoimmune and Diabetes (FAD) Study recruited both adult individuals who were identified from the Children's Hospital of Pittsburgh Type 1 Diabetes Registry for the years 1950-1964 and their family members. Unrelated nondiabetic control probands and their relatives were also evaluated. Women with type 1 diabetes (n = 143) compared with nondiabetic sisters (n = 186) or unrelated control subjects (n = 160) were more likely to have an older age at menarche (13.5, 12.5, and 12.6 years, respectively, P < 0.001), more menstrual irregularities before 30 years of age (45.7, 33.3, and 33.1%, respectively, P = 0.04), and a younger age at menopause (41.6, 49.9, and 48.0 years, respectively, P = 0.05). This resulted in a 6-year reduction in the number of reproductive years (30.0, 37.0, and 35.2 years, respectively, P = 0.05) for women with type 1 diabetes. Risk factors univariately associated with earlier menopause included type 1 diabetes (hazard ratio [HR] 1.99, P = 0.04), menstrual irregularities before 30 years of age (HR 1.87, P = 0.04), nulliparity (HR 2.14, P = 0.01), and unilateral oophorectomy (HR 6.51, P < 0.0001). Multivariate analysis confirmed that type 1 diabetes (HR 1.98, P = 0.056), menstrual irregularities by 30 years of age (HR 2.36, P = 0.01), and unilateral oophorectomy (HR 9.76, P < 0.0001) were independent determinants of earlier menopause in our cohort. We hypothesize that an earlier menopause, which resulted in a 17% decrease in reproductive years, is a major unstudied complication of type 1 diabetes.

Receptors for insulin-like growth factors and growth effects of multiplication-stimulating activity (rat insulin-like growth factor II) in rat embryo fibroblasts.

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.

Cord blood reverse T3 in congenital hypothyroidism.

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) was significantly 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 over present screening methods.

Human serum spreading factor: relationship to somatomedin B.

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.

Hashimoto's thyroiditis and insulin-dependent diabetes mellitus: differences among individuals with and without abnormal thyroid function.

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.

Goiter in adolescents.

Enlargement of the thyroid gland during adolescence should be considered a pathologic rather than physiologic process. With diffuse enlargement in an asymptomatic patient, thyroid function tests and thyroid antibodies usually are the only tests needed to define the diagnosis of euthyroid autoimmune thyroiditis. Patients with lobular or nodular thyroid enlargement may require additional tests if the diagnosis of Hashimoto's thyroiditis cannot be established by the presence of thyroid antibodies in serum. The tests to define the anatomic and functional status of nodular thyroid disease include ultrasonography and radionuclide scintigraphy of the thyroid, but rarely fine needle biopsy. The only indications for surgical therapy of the thyroid are hyperfunctioning thyroid adenomas, the suspicion of thyroid carcinoma and Graves' disease in patients who are not responsive to antithyroid drug therapy and who are poor candidates for radioiodine ablative therapy. The prognosis of thyroid disease during c adolescence is usually excellent.

Adrenocortical tumor in a patient with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

An adrenal cortical tissue tumor developed in a patient with poorly controlled salt-losing congenital adrenal hyperplasia. A 16-year-old girl became progressively virilized from 13 to 16 years of age. Base line serum progesterone, 17-hydroxyprogesterone, and testosterone levels were high and there was a diurnal pattern of the hormones. Initially elevated urinary 17-ketosteroid and serum steroid levels were decreased by high dose dexamethasone therapy, and at laparotomy an adenoma was found in the cortex of the hyperplastic left adrenal gland. It is inferred that persistent adrenocorticotrophic hormone stimulation may result in neoplastic transformation of hyperplastic adrenal cortical tissue in patients with congenital adrenal hyperplasia.

Neonatal hypothyroidism detected by the Northwest Regional Screening Program.

The Northwest Regional Screening Program to detect congenital hypothyroidism in infants born in Oregon, Montana, Alaska, and Idaho (combined birthrate of 69,000/ yr) was added to our ongoing screening program in 1975. The program utilizes dried blood filter paper specimens collected routinely in the first few days of life in all four states and again at about 6 weeks of age in Oregon only. The screening test consist of an initial thyroxine (T4) measurement; a thyroid-stimulating hormore (TSH) determination is performed on those specimens with T4 concentrations in the lowest 3% group. Serum samples obtained by venipuncture are requested for confirmation of the diagnosis. In the first two years of the program, 25 infants with primary hypothyroidism were detected amont 110,667 infants screened, a frequency of 1:4,430. Fourteen cases of thyroxine-binding globulin deficiency were also detected, a frequency of 1:7,900. Using the T4 followed by TSH testing approach, the frequency of request for repeat specimens was 0.4% in Oregon and 0.05% in the other states. The cost per specimen was $1.96. The majority of infants lacked clinical signs or symptoms of hypothyroidism; only one infant was clinically suspected of having hypothyroidism prior to detection. The most common neonatal symptoms were constipation, lethargy, and prolonged jaundice, while the most common physical signs were hypotonia, umbilical hernia, and large fontanels. Thyroid scans showed the most common etiology to be thyroid aplasia, followed by an ectopic gland, hypoplasia, and goiter. Serum T4 concentrations were lowest in those infants with aplasia, intermediate in infants with an ectopic gland or hypoplasia, and normal in the infant with the goiter. Neonatal hypothyroidism varies in degree and has several different causes; the capacity to secrete thyroid hormone, the duration before hypothyroidism becomes clinically manifest, and possibly the eventual prognosis for intellectual function depend on the nature of the underlying cause. While the mean age at treatment was 59 days, the goal of diagnosing congenital hypothyroidism and treating affected infants by 1 month of age seems realistic.

Prevalence of thyroid antibodies among healthy middle-aged women. Findings from the thyroid study in healthy women.

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 < 0.001); this relationship was statistically significant even after excluding those with subclinical hypothyroidism (TSH > 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.

Spondylo-metaphyseal dysplasia Algerian type: confirmation of a new syndrome.

We report on a further case of a recently described type of spondylo-metaphyseal dysplasia in a 12(10/12)-year-old Polish boy. The original paper described the disorder in five relatives in an Algerian family.

Ectopic posterior pituitary tissue and paracentric inversion of the short arm of chromosome 1 in twins.

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 casual relationship between the chromosome 1 anomaly and hypopituitarism.

The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1.

BACKGROUND: Some experts maintain that (1) > 90% of patients with multiple endocrine neoplasia type 1 (MEN1) are first seen with hyperparathyroidism (HPTH) so that routine screening for other features is unnecessary and (2) MEN1 has > or = 94% penetrance by age 50 years. METHODS: We constructed a regional registry of patients with or at risk for MEN1 and examined phenotypic profiles in 34 patients. MEN1 was defined as (1) endocrinopathy of 2 of the 3 principal related tissues (parathyroid, gastrointestinal endocrine, pituitary) or (2) 1 such feature plus a first-degree relative with MEN1. RESULTS: The initial feature of MEN1 was HPTH in 50%, pituitary tumor in 18%, and gastrointestinal endocrine tumor in 32% of patients, with overall incidences of 82%, 65%, and 74%, respectively. HPTH developed by age 50 years in 73% of patients and by age 70 years in 83%. Penetrance of MEN1 at age 50 years was 82%. Associated features included renal (1) and rectal (1) cancer, malignant thymic carcinoid (1), and malignant pheochromocytoma (1). CONCLUSIONS: Expression of MEN1 can vary considerably from established patterns. In our geographic region HPTH does not routinely precede other features of MEN1 and cannot be used to distinguish affected patients among those at risk. MEN1 can be inapparent until late in life and may be significantly underdiagnosed.

Measurement of the production rate of human luteinizing hormone using the urinary excretion technique.

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.

Radioiodine treatment of juvenile Graves disease.

Ablation of the thyroid gland with radioactive iodine-I131 is an effective and safe method of therapy for older children and adolescents, as with adults, to treat hyperthyroidism of Graves disease (Graves-Basedow disease). The use of radioiodine as initial therapy or, as more often, the second line of therapy following antithyroid drug treatment is highly efficacious and rarely associated with short-term or long-term side effects. The indications for radioiodine therapy are failure of antithyroid drug therapy, idiosyncratic hypersensitivity reactions to antithyroid drugs, contraindications for surgical therapy including patients who refuse surgery, and the desirability to permanently prevent the development of hyperthyroidism. The treatment will induce permanent primary hypothyroidism within months after the use of ablative doses of radioiodine. The safety and simplicity of clinical management with L-thyroxine therapy for hypothyroidism favor radioiodine therapy for Graves disease over the potential risks from treatment with antithyroid drugs or surgery, and from untreated or relapsing hyperthyroidism. Radioiodine therapy is associated with the lowest morbidity and mortality among the currently available methods of therapy for Graves disease.

Assays for thyroid-stimulating hormone using dried blood spotted filter paper specimens to screen for hypothyroidism in older children and adults.

OBJECTIVE: Symptoms of hypothyroidism in adults can be mistaken for medical and psychiatric diseases, as well as for general signs of ageing such as weakness, lethargy and fatigue. The incidence of hypothyroidism is many-fold higher in adults than in newborn children. The latter have been routinely screened for the condition using filter paper dried blood spots (DBS) for nearly three decades but this cost-effective screening technique has only recently been applied to adults. This study was undertaken to show that DBS testing in adults and older children is an accurate way to screen for hypothyroidism. METHODS: Serum and DBS specimens were collected from adults and children. Assays were run on both specimens and the results correlated. In addition 972 specimens were collected from adults at community centres and nursing homes. Follow-up studies were performed on patients with positive results. RESULTS: The correlation coefficient for 118 matched serum and DBS specimens was 0.99. Thyroid-stimulating hormone (TSH) values were elevated in 50 of the 972 adults from nursing homes and community centres. Thirteen of these individuals were on thyroid medication and 28 had either high serum TSH or high thyroglobulin (TgAb) or thyroid peroxidase (TPOAb) antibody levels. CONCLUSIONS: Individuals can be screened for hypothyroidism by collecting finger stick DBS specimens at community centres, nursing homes and other locations which can be mailed by regular postal service to a central laboratory for accurate and inexpensive testing.

Developmental changes in pituitary-thyroid function in the human fetus and newborn.

Maturation of the hypothalamic pituitary thyroid axis as reflected in cord serum thyroid hormone concentrations was assessed in premature and full term infants born between 26 and 43 weeks gestation. Measurements of thyroxine (T4), free T4 (FT4), thyrotropin (TSH) and thyroxine binding globulin (TBG) in cord sera were correlated with gestational age, sex and birthweight and compared to similar measurements in well two month old infants and adults. There were significant increases in T4, FT4, and TBG with increasing gestational age (GA) between 26 and 33-35 weeks (P less than 0.001). After 34 weeks, none of these parameters varied with GA. When the infants were separated on the basis of sex the linear regression curves describing the relationships between hormone and TBG concentrations and GA were not different from the curves in the total population. The mean FT4/TSH ratio increased significantly with age throughout gestation (P less than 0.01) and was significantly lower in cord blood samples than in blood samples from the 2-month-old infants or the adults. The results suggest that the set point for negative feedback control of TSH secretion at the pituitary level is changing between 26 weeks GA and 2 months of life. Thyroid gland sensitivity to TSH stimulation also appears to be increasing between 26 and 33 weeks GA.

Thyrotoxicosis in childhood.

Evidence supports the presence of a genetic predisposition to an abnormality in immune surveillance, with environmental factors precipitating the development of Graves' disease.