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Aim: To assess thyrotropin (thyroid-stimulating hormone; TSH) suppression and serum thyroxine (T(4)) concentrations in infants with congenital hypothyroidism in relation to T(4) dose and pretreatment parameters., Method: A retrospective study of all cases treated in a single centre since neonatal screening began was performed., Results: In 54 infants treated with a mean daily T(4) dose of 9.8 microg/kg, the TSH concentration was suppressed (<6 mU/l) in 65% of the cases by 6 months with the serum T(4) level at the upper end of the infant reference range. Infants who suppressed their TSH later did not differ in pretreatment serum TSH or T(4) concentration. T(4) dose and serum T(4) level were lower in infants whose TSH was not suppressed., Conclusions: TSH suppression in congenital hypothyroidism is significantly related to serum levels and dosage of T(4). We suggest that a delay in TSH suppression is mainly due to undertreatment., (Copyright 2003 S. Karger AG, Basel)

Objective: A clinicopathological and clonal study of a pituitary tumor was made in a 26-year-old woman with chronic thyroiditis to differentiate TSH-producing adenoma from TSH hyperplasia., Methods: Tumor specimens were subjected to histopathological study and clonal analysis (HUMARA)., Results: Immunohistochemical examination disclosed TSH-beta, PRL, GH, ACTH, FSH-beta, LH-beta, and alpha-subunit production in the adenoma cells. These heterogeneous phenotypes are characteristic of both thyrotroph hyperplasia and plurihormonal TSH-producing adenoma. However, the HUMARA method demonstrated monoclonality of the tumor cells., Conclusion: Monoclonality of the tumor cells proved that the pituitary tumor was plurihormonal TSH-producing adenoma, not TSH hyperplasia., (Copyright 2003 S. Karger AG, Basel)

A 16-year-old Brazilian girl presented with severe growth retardation (-6.3 SDS), obesity, delayed pubertal development, facial dysmorphia, dry skin, and borderline low intelligence (IQ 89). Endocrinological evaluation showed primary hypothyroidism (no uptake of iodine-131 of the right thyroid lobe). Basal and stimulated gonadotropins were increased and ultrasonography revealed hypoplastic ovaries. The karyotype of peripheral lymphocytes was 46,X,i(Xq). The GH response in euthyroid condition after stimulation with GHRH and insulin was diminished. MRI of the pituitary region showed a suprasellar mass (12 x 15 mm) which was removed by transsphenoidal surgery because of extension to the optic chiasm. Histological examinations revealed regular pituitary tissue with hyperplasia of TSH- and FSH-producing cells. Thyroxine treatment was adjusted and GH was given. We conclude that the suprasellar mass was the consequence of long-lasting hypothalamic overstimulation with TRH and LHRH, due to gonadal and thyroid insufficiency.

The expression of the alpha-subunit of the glycoprotein hormones was studied in the developing rat pituitary by in situ hybridization and immunocytochemical techniques. The alpha-subunit mRNA labelling was detected in Rathke's pouch at 12 days' gestation (E12); at E13, it was exclusively concentrated in the pars tuberalis primordium (the lateral lobes) where its intensity rapidly increased at following stages. The alpha-subunit was first immunocytochemically detectable in the pars tuberalis at E14. Labelling of the whole pars tuberalis primordium with both techniques indicated that the specific glandular cells were involved. Immunocytochemical detection of bromodeoxyuridine, injected into the pregnant rat 4 h prior to fixation, revealed a total arrest of cell divisions in the pars tuberalis between E13 and E17, which was not the case in the pars distalis or the pars intermedia at any stage. In the pars distalis, the onset of alpha-subunit expression was detected much later than in the pars tuberalis, at E16-17 by in situ hybridization and at E17-18 by immunocytology. The functional significance of the early secretory differentiation of the pars-tuberalis-specific cells remains to be established.

Sixteen patients with acromegaly have been treated with octreotide [100 micrograms twice daily to 200 micrograms 3 times daily according to growth hormone (GH) response] for between 3 and 44 months. The mean serum GH concentrations fell from 39.3 mU/l before treatment to 10.5 mU/l on day 1 of treatment and, with continued treatment (and higher doses in 8 of 16 patients), to 7.9 mU/l. In 2 patients there was no GH suppression. GH suppression after the first administration of octreotide appeared to predict long-term response. Pre-treatment serum insulin-like growth factor 1 levels were elevated in 11 of 12 patients investigated, but were normalized on continued octreotide therapy in 10 of 12. Octreotide suppressed prolactin secretion in all 6 hyperprolactinaemic patients. Steatorrhoea occurred in 15 of 16 patients at initiation of treatment, but resolved in all within 7 days. Two patients developed gallstones. In summary, octreotide is a safe and effective treatment for acromegaly, producing clinical and biochemical improvement in up to 90% of patients. Octreotide is a valuable adjunctive treatment where surgery has failed and also in those with contra-indications to surgery.

We are interested in the mechanisms by which endocrine and developmental factors regulate TSH synthesis at both pre-translational and post-translational levels. Thyroid hormone profoundly decreases transcription of the TSH-beta gene, while TRH and agents modifying cyclic AMP increase transcription. To elucidate the molecular mechanisms underlying these effects, human embryonal kidney cells were transfected with constructs of the human TSH-beta gene fused to the chloramphenicol acetyltransferase gene. The first exon of human TSH-beta, contains an element that increases basal expression and mediates T3-induced gene repression, probably through a direct interaction with c-erbA beta. This transcriptional repression by T3 appears aberrant in thyrotropic tumors. In contrast, TRH and agents modifying cyclic AMP mediate increased transcription of TSH-beta through interacting with upstream regulatory elements. Thyroid hormone, TRH and developmental factors also regulate the branching pattern and relative sialylation of TSH carbohydrate chains, which may affect TSH action in vitro and in vivo. Certain thyrotropic tumors produce TSH with more complex carbohydrate branching patterns, which may increase its biologic activity.

The appearance and relative distribution of immunoreactive gonadotropic and thyrotropic cells of the anterior pituitary of normal rat fetuses were studied by immunocytology with anti-rat luteinizing hormone serum, anti-porcine luteinizing hormone beta serum, anti-bovine thyrotropic hormone serum after saturation with bovine luteinizing hormone. The thyrotropic cells appeared at 17 days of gestation. They were preferentially localized in the dorsal part of the anterior lobe. The gonadotropic cells localized in the ventral part of the same lobe, appeared 1 day later. The number of immunoreactive cells of the two populations increased until the end of gestation. In the pituitaries of 21-day-old rat fetuses encephalectomized at 16 days of gestation, the same number of gonadotropic and thyrotropic cells was observed as in control fetuses at the same age. Gonadotropic cells were also observed in rat adenohypophysial primordia explanted at 14 days of gestation and maintained in organ culture for 7 days. Thyrotropic cells were stained when the primordia were explanted at 15 days of gestation and cultured for 6 days. No immunoreactive gonadotropic or thyrotropic cells were detected when explantation was performed before 14 days of gestation. These results clarify the problem of the role of hypothalamus on the differentiation of these two cell types.

Actinomycin D and cycloheximide were used to clarify the tight relationship between protein synthesis and heterogeneous carbohydrate synthesis of rat pituitary thyroid-stimulating hormone (TSH) under thyrotropin-releasing hormone (TRH) stimulation in vitro. Rat anterior pituitaries were incubated with [3H]glucosamine in the presence of TRH, cycloheximide and actinomycin D at 37 degrees C for 3 and 6 h. The TSH fraction of pituitary homogenates was obtained using affinity chromatography coupled with anti-TSH globulin, and was analyzed by isoelectric focusing. Anterior pituitary in the presence of TRH showed heterogeneous components of [3H]glucosamine-labeled TSH with 6 different isoelectric points (components I-VI). Radioactivities of the components increased with the incubation period. Cycloheximide changed these heterogeneous components. Actinomycin D also caused a striking change in the heterogeneity of pituitary [3H]glucosamine-labeled TSH: components I and II decreased and components III and IV increased as compared to the control group after a 6-hour incubation. The present study implies that actinomycin D affects the TRH-induced heterogeneous components of pituitary TSH glycosylation. The data indicate that messenger RNA is essential for the normal processing of carbohydrate synthesis of pituitary TSH.