Prolonged inappropriate TSH suppression during hypothyroidism after thyroid ablation in a patient with nonautoimmune familial hyperthyroidism.

Prolonged TSH suppression was reported in a patient with nonautoimmune hyperthyroidism. These observations were made during L-thyroxine treatment and it was not possible to investigate a possible increase in serum TSH concentrations to levels observed in untreated hypothyroidism. We describe nonautoimmune familial hyperthyroidism identified in an Israeli woman, which is remarkable for the prolonged inappropriate TSH suppression after thyroid ablation. After 2 radioiodine treatments for several years, her TSH was always lower than 0.03 mU/l with 1.6 µg/kg/day (100 µg) thyroxine. 14 years after the radioiodine treatments, she discontinued thyroxine for 3.5 months and developed myxoedema with fT4 <6.0 and fT3 1.3 pmol/l and TSH of only 4.4 mU/l, which rose to only 8.6 after TRH. Genomic analysis showed a germline substitution M626I in the TSHR gene. Both exons of the thyroid-releasing hormone receptor revealed no mutations in this gene. Functional in vitro characterization of M626I showed a cell surface expression of 70% compared with the wt (100%), a significant increase of basal activity (5-fold over wt basal), which was confirmed by linear regression analysis (LRA) (slope: M626I=7, wt=1). No TRH-receptor mutation was detected. Therefore, this is the first patient with nonautoimmune hyperthyroidism with unequivocal evidence for inappropriately prolonged TSH suppression documented by a clearly insufficient TSH increase during clinical hypothyroidism. The in vitro characterization of the TSH-receptor mutation did not show any explanations for the prolonged TSH suppression. Therefore, other possible candidate genes remain to be investigated for potential explanations for this prolonged TSH suppression.

Hypothyroidism increases substance P concentrations in the heterotopic anterior pituitary.

The regulatory effects of thyroid hormone on adenohypophysial substance P (SP) were studied in heterotopically implanted anterior pituitaries. Three or four anterior pituitaries from 21-day-old rat pups were implanted under the renal capsule in 175- to 200-g adult rats. The donor and recipient animals were sex matched. One week after implantation, animals were thyroidectomized or sham operated. A separate group of animals received daily T4 treatment (1.5 g/100 g, ip). After 2 weeks, the native and heterotopic pituitaries were assayed for SP, TSH, PRL, and LH. Thyroidectomy resulted in a 3- to 10-fold increase in the SP concentration in both the heterotopic and native pituitaries compared to euthyroid values. T4 treatment suppressed the SP levels in the heterotopic pituitaries of the thyroidectomized rats. In contrast to the reduction of TSH concentrations in native pituitaries in thyroidectomized animals vs. controls, TSH concentrations in the heterotopic pituitaries of thyroidectomized rats were approximately 10 times greater than those in euthyroid animals. PRL concentrations were unaffected by hypothyroidism in native and heterotopic pituitaries. Thyroidectomy resulted in a decrease in LH concentrations in the native anterior pituitary, without affecting LH concentrations in the implanted pituitary. These findings indicate that a direct link from the hypothalamus to the anterior pituitary is not required for the pituitary SP response to hypothyroidism.

The differential effects of thyroid and gonadal hormones on substance P content in the anterior pituitary of the prepubertal rat.

The effects of thyroid and gonadal status on the content of substance P in the anterior pituitary (AP-SP) were examined in prepubertal rats. A sex difference in AP-SP is evident by age 50 days [males, 287 +/- 35 fmol/mg protein (mean +/- SE); females, 103 +/- 17; P less than 0.05], and this difference becomes greater by 75 days (males, 543 +/- 54; females, 146 +/- 11.5; P less than 0.01). Hypothyroidism was induced in male and female pups by giving lactating dams 0.1% methimazole (wt/vol) in their drinking water after parturition. There was a marked and significant increase in AP-SP in 21-day-old hypothyroid compared to euthyroid control pups. Male pups were made thyrotoxic by daily treatment with T4 (10 micrograms/rat, sc) from age 8 to 15 days. AP-SP was 4 times lower in the thyrotoxic than in the euthyroid pups (P less than 0.001). Rats ovariectomized at age 22 days and killed on day 35 revealed no change in AP-SP, in contrast to the rise in AP-SP in the ovariectomized adult rat. Female pups were treated with dihydrotestosterone (DHT; 50 micrograms/day) or testosterone (50 micrograms/day) from age 8-20 days. Neither androgen induced a change in AP-SP. Female pups which received estradiol (E2; 0.5 micrograms/day) or testosterone (75 micrograms/day) from age 8-20 days also had no change in AP-SP. As opposed to the lack of effect of E2 and DHT on AP-SP in female rats younger than 22 days, E2 (1 microgram/100 g BW daily) caused a decrease and DHT (100 micrograms/100 g BW daily) caused an increase in AP-SP in female rats treated from 22-35 days of age [E2, 91 +/- 6.9; DHT, 226 +/- 31 (P less than 0.05 vs. control for both); control, 154 +/- 13]. We conclude that the responsiveness of AP-SP to alterations in thyroid status is present at the youngest age studied. In contrast, the responsiveness of AP-SP to changes in the levels of gonadal steroids is absent in the infantile period and requires a maturational process that becomes evident during the juvenile state of sexual development.

Diabetes insipidus caused by extramedullary hematopoiesis.

Myeloid metaplasia involving the central nervous system is a rare occurrence most frequently found as an incidental finding at autopsy. A case is presented of a 56-year-old man with myeloid metaplasia and myelofibrosis, who developed diabetes insipidus. Postmortem examination revealed posterior pituitary involvement by extramedullary hematopoiesis with fibrosis and gliosis. Diabetes insipidus caused by extramedullary hematopoiesis is a rare event and is thus noteworthy.

Female pseudohermaphroditism with adrenal cortical tumor in adulthood.

Data are presented concerning a case of female pseudohermaphroditism of unknown etiology. The child was born with labioscrotal fusion and clitoromegaly. From the age of 5 to the age of 25 there was no clinical evidence of a hormonal abnormality. At the age of 25 the patient presented with masculinization and Cushing's syndrome, and a left adrenal tumor was removed. The patient was restudied at the age of 29, when 21-hydroxylase deficiency was excluded. Other types of congenital adrenal hyperplasia are considered unlikely. The possible relationship between the ambiguous genitalia present at birth and the virilizing tumor diagnosed at the age of 25 is analyzed.

The effects of gonadal steroids on the content of substance P in the rat anterior pituitary.

The effects of gonadectomy and of the administration of gonadal steroids on the content of substance P in the anterior pituitary (AP-SP) were studied in adult rats. The effect of gonadal status on the AP-SP content of thyroidectomized (TX) rats was also studied. We have confirmed that the AP-SP content in adult males is higher than that in adult females. Ovariectomy (OVX) caused an increase in AP-SP content which was apparent 6 days after surgery. Estradiol (E2; 2 micrograms/rat daily) administered for 13 days beginning the day after OVX prevented the increase in AP-SP content induced by OVX. Orchiectomy of adult rats had no effect on AP-SP content 14 and 45 days after surgery. E2 administered to adult female rats for 13 days caused a reduction in the AP-SP content, whereas dihydrotestosterone (0.2 mg/rat daily for 13 days) caused an increase that was even more pronounced in TX rats. E2 administration to TX adult female rats caused a significant decrease in the AP-SP content both when treatment was begun on the day after surgery or 2 weeks later. Administration of T4 (1.5 and 25 micrograms/100 g BW daily for 7 days) to rats made hypothyroid by thyroidectomy 2 weeks earlier abolished the increase in AP-SP content seen in TX animals. Neither E2 nor dihydrotestosterone had an effect on the substance P content of any of the brain regions examined. The AP-SP content of pregnant or lactating rats was not different from that of age-matched controls. The content of substance P in the AP and median eminence did not vary significantly throughout the estrous cycle. The data indicate that AP-SP content is dependent on the gonadal status of the animal and that gonadal steroids interact with thyroid hormones in the regulation of substance P turnover in the AP.

Regulation by thyroid hormone of the concentration of substance P in the rat anterior pituitary.

The content of immunoreactive substance P (iSP) in the male rat anterior pituitary was measured after thyroidectomy and excess T4 administration. Baseline values for iSP content (mean +/- SE, 400 +/- 37 fmol/mg protein) increased progressively after thyroidectomy (4 days, 893 +/- 100; 6 days, 1321 +/- 242; 14 days, 1897 +/- 509). Administration of pharmacological doses of T4 (50 micrograms daily) for 2 and 14 days significantly decreased anterior pituitary iSP content (2 days, 196 +/- 30; 14 days 138 +/- 12). Thyroid status did not affect iSP content in the hypothalamus, caudate nucleus, amygdala, or brainstem. Partial chemical characterization of SP immunoreactivity in the anterior pituitary was obtained by gel permeation chromatography on Sephadex G-25, high pressure liquid chromatography, and the use of two antisera in RIAs, one directed against the amino-terminus and one directed against the carboxyl-terminus of the peptide. SP in the anterior pituitary was readily releasable in vitro by 44 mM potassium chloride in a calcium-dependent manner. The present study demonstrates that the concentration of iSP in the rat anterior pituitary is affected by the thyroid status of the animal and supports the probability that thyroid hormones participate in the regulation of the synthesis and/or release of iSP from the anterior pituitary.

Hypo-osmolal syndrome due to prolonged nausea.

Hyponatremia and hypo-osmolality developed in a 70-year-old patient. It was probably mediated by hypersecretion of antidiuretic hormone, which, in turn, was due to prolonged nausea and vomiting. Severe esophagitis was the cause of the nausea. The patient was not given large amounts of fluids intravenously, and it is likely that she continued to drink for nondipsetic reasons. In view of her medical history of neurosyphilis, the possibility of a disturbance in the mechanism of thirst regulation is discussed, but remains unproved.

A carcinoid-like syndrome caused by a prostaglandin-secreting renal cell carcinoma.

We report a case of carcinoid-like syndrome in a patient with metastatic renal cell carcinoma. Peripheral venous plasma levels of prostaglandin (PG) E and of a derivative of PGF2 alpha were raised during the attacks. The urinary excretion of 5-hydroxyindoleacetic acid was repeatedly normal. The flushing attacks were not prevented by therapy with antihistamines, phenothiazines, antiserotonin agents, or glucocorticoids. Treatment with aspirin completely prevented the attacks, and its withdrawal led invariably to their recurrence.

Characterization of mouse ACTH in plasma and in extracts of pituitary and of adrenotropic pituitary tumor.

The predominant component of immunoreactive ACTH in the plasma of adrenalectomized normal mice and of mice bearing the adrenotropic mouse pituitary tumor, AtT-20, and in extracts of the normal mouse pituitary and pituitary tumor, has an elution volume on Sephadex G-50 gel filtration approximately midway between the void volume and the elution volume of human ACTH (1-39 peptide). The tumor extracts are shown to contain, in addition to this intermediate ACTH, 2 other components of immunoreactive ACTH, one which coelutes with 131I-labeled albumin (big ACTH) and the other with [125I]hACTH (little ACTH). Big and intermediate ACTH are urea-stable. Controlled tryptic digestion of mouse-tumor big ACTH results within 10 seconds in conversion to an intermediate component followed by continued loss of immunoreactivity. Under the same conditions of tryptic digestion of intermediate ACTH, there is only continuous loss of immuno-reactivity with no change of hormonal form. These findings strengthen the hypothesis that mouse intermediate ACTH is not a precursor for little ACTH.