triiodothyronine--reverse and Growth-Disorders

Thyroid hormones are essential for a variety of developmental and metabolic processes. Congenital hypothyroidism (CHT) results in severe defects in the development of different tissues, in particular brain. As an animal model for CHT, we studied Pax8(-/-) mice, which are born without a thyroid gland. We determined the expression of iodothyronine deiodinase D1 in liver and kidney, D2 in brain and pituitary, and D3 in brain, as well as serum T(4), T(3), and rT(3) levels in Pax8(-/-) vs. control mice during the first 3 wk of life. In control mice, serum T(4) and T(3) were undetectable on the day of birth (d 0) and increased to maximum levels on d 15. In Pax8(-/-) mice, serum T(4) and T(3) remained below detection limits. Serum rT(3) was high on d 0 in both groups and rapidly decreased in Pax8(-/-), but not in control mice. Hepatic and renal D1 activities and mRNA levels were low on d 0 and increased in control mice roughly parallel to serum T(4) and T(3) levels. In Pax8(-/-) mice, tissue D1 activities and mRNA levels remained low. Cerebral D2 activities were low on d 0 and increased to maximum levels on d 15, which were approximately 10-fold higher in Pax8(-/-) than in control mice. D2 mRNA levels were higher in Pax8(-/-) than in control mice only on d 21. Cerebral D3 activities and mRNA levels were high on d 0 and showed a moderate decrease between d 3 and 15, with values slightly lower in Pax8(-/-) than in control mice. One day after the injection of 200 ng T(4) or 20 ng T(3)/g body weight, tissue deiodinase activities and mRNA levels were at least partially restored toward control levels, with the exception of cerebral D3 activity. In conclusion, these findings show dramatic age and thyroid state-dependent changes in the expression of deiodinases in central and peripheral tissues of mice during the first 3 wk of life.

Topics: Aging; Animals; Brain; Congenital Hypothyroidism; Disease Models, Animal; DNA-Binding Proteins; Female; Gene Expression Regulation, Enzymologic; Growth Disorders; Hypothyroidism; Iodide Peroxidase; Kidney; Liver; Male; Mice; Mice, Knockout; Nuclear Proteins; Paired Box Transcription Factors; PAX8 Transcription Factor; Pituitary Gland; RNA, Messenger; Thyroxine; Trans-Activators; Triiodothyronine; Triiodothyronine, Reverse

The effects of GH therapy on thyroid function among previous reports have shown remarkable discrepancies, probably due to differences in hormone assay methods, degree of purification of former pituitary-derived GH preparations, dosage schedules, diagnostic criteria, patient selection, duration of treatment and study design. These considerations motivated us to investigate whether and how GH replacement therapy changes serum thyroid hormone levels, including the much less studied rT3 levels, in a group of unequivocally GH-deficient children receiving long-term recombinant human GH therapy.. Twenty clinically and biochemically euthyroid children were studied in two therapeutic conditions: on GH replacement therapy for at least 6 months and without GH replacement, either before GH was started or after GH was withdrawn for 30-60 days. Eight patients were on thyroxine replacement treatment and thyroxine doses were kept constant during the study. Blood was collected before and after 15, 20 and 60 minutes of TRH administration in both therapeutic conditions (with GH and without GH).. Concentrations of thyroid hormone levels were determined only in sera obtained before TRH administration. FT4, T3 and TSH were measured by immunoflourimetric assays and rT2 was measured by immunoradioassay.. Patients were classified into two groups, according to basal TSH levels: group I (TSH > 0.4 mU/l, n = 12) and group II (on thyroxine and TSH < 0.05 mU/l, n = 8). In both groups, serum FT4 levels decreased (17. 0 +/- 1.1 vs. 14.3 +/- 0.9 mU/l, P < 0.001, and 18.0 +/- 1.7 vs. 14. 2 +/- 1.7 mU/l, P < 0.01, respectively), serum T3 levels increased (1.8 +/- 0.1 vs. 2.4 +/- 0.2 nmol/l, P < 0.001, and 1.9 +/- 0.3 vs. 2.4 +/- 0.2 nmol/l, P < 0.05, respectively), and serum rT3 levels decreased (0.35 +/- 0.03 vs. 0.25 +/- 0.03 nmol/l, P < 0.01, and 0. 48 +/- 0.06 vs. 0.34 +/- 0.06 nmol/l, P < 0.01, respectively). Basal (3.2 +/- 0.50 vs. 2.6 +/- 0.72 mU/l, P = 0.28, paired t-test), TRH-stimulated peak TSH levels (13.9 +/- 5.3 vs. 15.9 +/- 8.0 mU/l, P = 0.35, paired t-test) and TRH-stimulated TSH secretion, expressed as area under the curve (609 +/- 97 vs. 499 +/- 53 mU/l.minutes-1, P = 0.15, paired t-test), remained unchanged during GH replacement in group I patients. Low serum FT4 and high serum T3 levels were observed in only one patient each, but low serum rT3 levels were found in six patients (four in group I and two in group II) during GH replacement.. These results show that long-term GH replacement therapy in children with unequivocal GHD significantly decreases serum FT4 and rT3 levels and increases serum T3 levels; that these changes are independent of TSH and result from increased peripheral conversion of T4 to T3 and that GH replacement therapy in GH deficient children does not induce hypothyroidism, but simply reveals previously unrecognized cases whose serum FT4 values fall in the low range during GH replacement.

Topics: Adolescent; Adult; Child; Female; Follow-Up Studies; Growth Disorders; Growth Hormone; Hormone Replacement Therapy; Humans; Hypothyroidism; Male; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse