Changes in serum thyroid hormones levels and their mechanisms during long-term growth hormone (GH) replacement therapy in GH deficient children.

OBJECTIVE: 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. PATIENTS AND DESIGN: 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GH replacement therapy for at least 6 months and without GH replacement, either before GH was started or after GH was withdrawn for 30-60 days.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). MEASUREMENTS: 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. RESULTS: 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. CONCLUSIONS: 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.

Abnormal circadian rhythm and increased non-pulsatile secretion of thyrotrophin in Sheehan's syndrome.

OBJECTIVE: It has previously been shown that patients with postpartum pituitary necrosis (Sheehan's syndrome, SS) have paradoxically increased TSH levels and loss of the nocturnal TSH surge. This study sought to determine the circadian and pulsatile characteristics of TSH secretion underlying those abnormalities. DESIGN AND PATIENTS: Chronobiological and cluster analyses of 24-h TSH profiles were performed in nine SS patients (43-61 years, median = 52 years) and nine healthy female controls (33-47 years, median = 42 years). MEASUREMENTS: Serum concentrations of T3, T4, free T4 (fT4) and cortisol were measured by radioimmunoassay; TSH, GH, PRL and LH were determined by immunometric assays. RESULTS: All patients and controls showed significant circadian TSH rhythms, but the percentage amplitude was decreased (7.5% vs. 21.3%, P < 0.0001) and the acrophase was markedly displaced in SS patients, occurring between 0315 h and 1515 h in seven/nine patients and in two/nine controls (P = 0.057). Patients showed increased total 24-h TSH secretion (6054 +/- 2293 vs. 2193 +/- 340 mU/l/min, mean +/- SE, P = 0.04) due to increased non-pulsatile or tonic 24-h TSH secretion (5631 +/- 2105 vs. 1925 +/- 301 mU/l/min, P = 0.026), but no difference was detected in pulsatile secretion (424 +/- 191 vs. 268 +/- 41, P = 0.82). The contribution of non-pulsatile to total TSH secretion was also increased in SS patients (93.8% vs. 87.6%, P = 0. 002). No significant changes were found in TSH pulse frequency, amplitude, duration or interpeak interval. When cluster parameters were individually analysed in two distinctive 12-h periods corresponding to acrophase and nadir, patients showed increased non-pulsatile TSH secretion in both periods, but no differences were found in pulsatile TSH secretion, pulse frequency or amplitude. The increment of TSH secretion during the acrophase in SS patients was exclusively due to increased non-pulsatile TSH secretion, as opposed to controls who displayed significant increments in both non-pulsatile and pulsatile TSH secretions. CONCLUSIONS: Sheehan's syndrome patients have increased total TSH secretion due to increased tonic TSH secretion. A circadian TSH rhythm is still present in these patients, but shows decreased magnitude and markedly displaced acrophase.

Increased thyrotrophin levels and loss of the nocturnal thyrotrophin surge in Sheehan's syndrome.

OBJECTIVE: Since panhypopituitarism in patients with Sheehan's syndrome is due to massive pituitary necrosis with only minor hypothalamic involvement, we hypothesized that serum TSH levels would be low but its circadian rhythm preserved in these patients. DESIGN AND PATIENTS: Basal and TRH-stimulated mean afternoon (1500-1700 h) and nocturnal (0100-0300 h) TSH levels were determined in 10 patients with Sheehan's syndrome before and during T4/glucocorticoid replacement and in seven controls. MEASUREMENTS: Serum concentrations of T3, T4, free T4 (fT4) and cortisol were measured by radio-immunoassay; TSH, GH, PRL and LH were determined by immunofluorimetric assay. RESULTS: Afternoon TSH levels were markedly increased in Sheehan's syndrome patients compared with controls (3.3 +/- 1.0 vs 0.5 +/- 0.15 mU/l, respectively, P = 0.002). At night, TSH levels remained unchanged in Sheehan's syndrome patients (3.3 +/- 1.1 mU/l) but rose significantly in controls (1.1 +/- 0.34 mU/l, P = 0.016). The nocturnal TSH increment was significantly higher in controls than in patients (143 vs approximately 4.9%, respectively, P = 0.0001). In eight patients with normal serum fT4 levels during treatment, basal TSH levels decreased to 0.16 +/- 0.05 mU/l (P < or = 0.008), being barely detectable or undetectable in four patients. In the six patients with detectable TSH during treatment, nocturnal TSH increments were normal in four and blunted in two. There was a strong correlation between pre- and post-treatment basal TSH (r = 0.82, P = 0.012) and between pre- and post-treatment peak TSH after TRH (r = 0.91, P = 0.0017), but no significant correlation between TSH and thyroid hormone levels. The per cent ratio of peak TSH after TRH between treated patients and controls, an estimate of the relative size of the functional thyrotroph pool in Sheehan's syndrome patients, was 7%. CONCLUSIONS: Loss of TSH rhythm in Sheehan's syndrome is usually secondary to hormonal deficiency and results from maximally increased secretory activity of a decreased pool of thyrotrophs. The paradox of increased TSH levels and decreased thyroid function in Sheehan's syndrome could result from decreased TSH bioactivity and/or from a critically reduced thyrotroph population that fails to sustain sufficient TSH secretion in the face of rising serum thyroid hormone levels.

Conservative management of pituitary apoplexy: a prospective study.

A prospective study was conducted to evaluate the usefulness and limitations of conservative treatment in patients with pituitary apoplexy. Twelve patients presenting sudden headache, visual impairment, or ophthalmoplegia had the diagnosis of pituitary apoplexy established by computerized tomographic scans. Initially, 11 patients received iv dexamethasone (2.0-16.0 mg/day). Surgery was indicated when dexamethasone failed to improve visual or consciousness impairment. Among the 7 patients who were treated conservatively, ophthalmoplegia recovered completely in 6 and improved in 1. Follow-up computerized tomographic scans showed resolution of the tumor in 4 patients and residual masses in 3 patients who were treated conservatively. Five patients had surgery and experienced improvement of vision and consciousness. Follow-up computerized tomographic scans showed residual masses in all surgical patients. Recurrences were observed in 2 patients, one in each group. The prevalence of pituitary deficiencies in the conservative group (9 of 17) was similar to that of the surgical group (3 of 14), but when only patients whose tumors were resolved by the apoplexy were analyzed, a significantly higher prevalence (8 of 12) was observed (P = 0.02). A retrospective analysis of presenting clinical and computerized tomography data on the basis of the response to dexamethasone showed that visual impairment did not improve during treatment with dexamethasone, whereas the presence of a large hypodense area within the tumor predicted complete tumor resolution. These results support conservative management of pituitary apoplexy in patients who are selected on the basis of clinical and tomographic findings.

Isodicentric X chromosome and mosaicism: report on two cases of 45,X/46,X,idic(Xq)/47,X,idic(Xq),idic(Xq) and review of the literature.

We present 2 instances of Ullrich-Turner syndrome with mosaicism 45,X/46,X,idic(Xq)/47, X,idic(Xq),idic(Xq) and X-isochromosomes with 2 C-bands. The mosaicism with the 3 cell lines points to the presence of the isodicentric chromosome in the zygote and a subsequent nondisjunction event.