Serum growth hormone (GH)-binding protein and insulin-like growth factor-I levels in Turner's syndrome before and during treatment with recombinant human GH and ethinyl estradiol.

Serum levels of GH-binding protein (GH-BP) and insulin-like growth factor-I (IGF-I) were measured in 14 adolescent girls with Turner's syndrome (TS) before and during treatment with recombinant human GH (rhGH) and oral ethinyl estradiol (EE2). Before treatment, the mean +/- SE GH-BP level in TS patients was 33.2 +/- 2.0%; this was higher (P < 0.05) than that in bone age-matched (27.9 +/- 1.1%; n = 13) or chronological age-matched (28.1 +/- 0.8%; n = 17) control girls. The mean +/- SE IGF-I level in TS girls (283 +/- 26 micrograms/L) was comparable to that in bone age-matched controls (255 +/- 17 micrograms/L), but lower (P < 0.005) than that in chronological age-matched pubertal controls (568 +/- 35 micrograms/L). In 7 TS girls treated with daily sc injections of rhGH in a dose of 0.8 U/kg.week for 18 months, serum levels of IGF-I increased from 330 +/- 39 to 707 +/- 48 micrograms/L after 3 months of treatment and remained elevated for the entire observation period (P < 0.002). In contrast, GH-BP levels did not change significantly. In 7 other TS girls, puberty was induced after 2 yr of daily sc injections with rhGH (1 U/kg.week) by adding 100 ng/kg.day EE2, orally, during ongoing rhGH therapy. During 18 months of pubertal induction, serum GH-BP levels increased gradually from 31.4 +/- 2.7% at the start of EE2 treatment to a maximum of 49.2 +/- 0.8% after 1 yr (P < 0.001). Serum IGF-I levels, in contrast, did not change significantly. These results show that in adolescent TS patients 1) pretreatment serum GH-BP levels are higher than in bone age-matched or chronological age-matched control girls, and IGF-I levels are similar to those in bone age-matched but lower than those in chronological age-matched controls; 2) during rhGH treatment GH-BP levels do not change, whereas IGF-I levels increase significantly; and 3) oral EE2 treatment during ongoing rhGH treatment increases GH-BP levels markedly, but does not modify IGF-I levels.     

Effects of growth hormone therapy on thyroid function of growth hormone-deficient adults with and without concomitant thyroxine-substituted central hypothyroidism

Administration of human GH to GH-deficient patients has yielded conflicting results concerning its impact on thyroid function, ranging from increased resting metabolic rate to induction of hypothyroidism. However, most studies have been casuistic or uncontrolled and have used pituitary-derived GH of varying purity, often contaminated with TSH. Therefore, we conducted a double blind, placebo-controlled cross-over study of the effect of 4 months of biosynthetic human GH therapy (Norditropin; 2 IU/m2.day) on thyroid function in GH-deficient adults (8 females and 14 males; mean +/- SE age, 23.8 +/- 1.2 yr). One group (I) was euthyroid without T4 substitution (n = 13), whereas the other (group II) received T4 (n = 9). Serum T4 (nanomoles per L) decreased in both groups after GH treatment [group I, 100 +/- 8 (mean +/- SE) vs. 89 +/- 8 (P less than 0.01); group II, 145 +/- 18 vs. 115 +/- 10 (P less than 0.05)]. Conversely, GH treatment caused an increase in serum T3 (nanomoles per L) in both groups [group I, 1.9 +/- 0.1 vs. 2.0 +/- 0.1 (P less than 0.1); group II, 1.7 +/- 0.1 vs. 1.9 +/- 0.1 (P less than 0.05)]. Similar changes were seen in serum free T4 and T3. The serum T3 level during the placebo period of group I was significantly lower than that in an age-matched reference group (P less than 0.02). Serum rT3 (nanomoles per L) was low in group I and decreased significantly, as in group II, after GH treatment [group I, 0.26 +/- 0.02 (placebo) vs. 0.20 +/- 0.02 (GH; P less than 0.01); group II, 0.38 +/- 0.05 (placebo) vs. 0.29 +/- 0.02 (GH; P less than 0.01)]. Serum TSH decreased in both groups during GH therapy, though not significantly. Serum thyroglobulin was unaltered and did not differ from that in the reference group. In conclusion, our data are consistent with a GH-induced enhancement of peripheral deiodination of T4 to T3. GH thus seems to play an important role, either directly or indirectly, in the regulation of peripheral T4 metabolism.     

Thyroid abnormalities in the McCune-Albright syndrome: ultrasonography and hormonal studies

Hyperthyroidism and goiter have been reported frequently in association with the McCune-Albright syndrome (MAS). To assess the prevalence and extent of thyroid abnormalities in girls with MAS, we studied 19 patients [mean age, 6.6 +/- 1 (+/- SE) yr; mean bone age, 9.5 +/- 1 yr] and 18 normal control girls (mean age, 10.3 +/- 0.5 yr). All patients appeared euthyroid when examined; 1 was taking antithyroid medication. Ultrasonography revealed thyroid abnormalities in 7 patients, including generalized inhomogeneity, small (2-4 mm) and large (greater than 10 mm) hypoechoic regions, and echogenic nodule-like regions. Repeat ultrasonography after intervals of 9-18 months showed enlargement of large hypoechoic regions in 2 patients. In the patients with abnormal ultrasound findings, serum TSH was uniformly low or suppressed both at baseline and after administration of 7 micrograms/kg TRH. The mean serum T3 level in this group was significantly higher than that in controls (2.9 +/- 0.2 vs. 2.3 +/- 0.1 nmol/L; P less than 0.05), whereas mean serum T4, free T4, and T4-binding globulin levels did not differ from those of controls. In the remaining 11 patients, thyroid ultrasonography was normal, and the serum levels of T3, T4, free T4, and TSH were normal. Bioassay showed no detectable thyroid-stimulating activity in the plasma of the MAS patients with suppressed TSH levels. None of the patients became overtly thyrotoxic over 3-6 yr of observation, and their serum iodothyronine levels remained stable. We conclude that thyroid dysfunction is common in girls with MAS, but that it may be clinically occult and not rapidly progressive. The thyroid dysfunction, like that of the ovaries, is associated with structural abnormalities in the gland itself, together with suppressed levels of the respective stimulating hormones.     

Fasting induces a decrease in serum thyroglobulin in normal subjects

Fasting decreases serum T3 concentrations by reducing peripheral conversion of T4 to T3. Whether it affects TSH and thyroid secretion is controversial. Thyroglobulin (Tg) is a secretory product of the thyroid gland. To determine if fasting might alter thyroid secretion, we measured serum Tg concentrations during and after a 4-day fast in seven normal subjects and examined its correlation with serum TSH, T4, and T3 concentrations. Serum TSH concentrations significantly decreased from a mean prefasting value of 1.55 +/- 0.19 (+/- SE) mU/L to a nadir of 0.82 +/- 0.09 mU/L (P = 0.01) after 3 days of fasting. The mean serum Tg level decreased from 30 +/- 5 to 12 +/- 3 micrograms/L (P = 0.005) and serum T3 from 160 +/- 8 (2.46 +/- 0.12) to 69 +/- 7 ng/dL (1.06 +/- 0.11 nmol/L) (P less than 0.0001) after 4 days of fasting. Serum T4 did not change significantly. Serum TSH, T3, and Tg concentrations returned to prefasting values within 3 days after initiation of refeeding. A significant correlation was found between the mean serum TSH and Tg concentrations (r = 0.77; P less than 0.05) and between the mean serum Tg and T3 concentrations (r = 0.78; P less than 0.05). The individual Pearson's correlation coefficients between serum Tg and serum T3 ranged from 0.67-0.93 and were significant (r greater than 0.70; P less than 0.05) in five of the seven subjects. In conclusion, the parallel changes in serum TSH, Tg, and T3 concentrations during fasting suggest that in addition to the well known decrease in serum T3 concentrations, decreased TSH and thyroid secretion (reflected by serum Tg) may be an adaptive response to fasting.     

Defective thyroidal iodine concentration in protein-calorie malnutrition

Although protein-calorie malnutrition (PCM) is known to result in various abnormalities of thyroid function, the exact relationship between the two is not clearly understood. Therefore, the thyroid function of 10 men, 13-55 yr of age, with severe PCM was studied in a clinical research ward before and 3-4 months after protein-calorie repletion. Before repletion, all subjects had low serum T4 (mean +/- SEM, 5.1 +/- 0.5 micrograms/dl) and T3 (74 +/- 6 ng/dl) concentrations. Eight subjects were chemically euthyroid, and their free T4 (1.5 +/- 0.1 ng/dl) and serum TSH (2.9 +/- 1.4 microU/ml) values were normal. Two subjects were chemically hypothyroid, with low free T4 values and high serum TSH values. After repletion, the 8 euthyroid subjects had significant increases in serum T4 (P less than 0.01) and T3 (P less than 0.005), but TSH did not change. Serum T4 and T3 were still lower (P less than 0.05-0.001) and TSH higher (P less than 0.01) than in 28 normal men of comparable age coming from the same area. After repletion, values remained unchanged in the 2 hypothyroid subjects, except for moderate increases in serum T3 and slight decreases in TSH. In all PCM subjects, values of thyroidal exchangeable iodine (23.1 +/- 7 vs. 42.9 +/- 8 mg; P less than 0.02), estimated thyroidal I per g wet wt (1.05 +/- 0.3 vs. 1.99 +/- 0.36 mg; P less than 0.02), and thyroidal iodide clearance (13.8 +/- 1.6 vs. 19.4 +/- 1.3 ml/min; P less than 0.002) were lower before repletion than after; the protein-bound 131I level (72 h; 0.27% vs. 0.08 dose/liter; P less than 0.05) was higher, but thyroid hormone secretion rates (200 +/- 49 vs. 153 +/- 25 micrograms/day) were not significantly different. Thyroid iodide clearance was lower even though plasma inorganic iodine (6.3 +/- vs. 12.5 +/- 3 micrograms/liter; P less than 0.05) and daily urinary iodine excretion (158 +/- 43 vs. 395 +/- 62 micrograms; P less than 0.01) were lower before than after repletion. In 2 PCM euthyroid subjects, baseline thyroid 131I uptake was lower before than after repletion, and the magnitude of the increase after TSH (10 U, im) stimulation was greater when the malnourished state improved. TSH increased concentrations of serum T4 and T3 both before and after protein repletion. After repletion, one hypothyroid patient failed to respond to TSH; the other had a small increase in 131I uptake but not in serum T4 or T3. The results indicate defective thyroid iodine concentration in human PCM, but adequate hormone secretion. This situation leads to depletion of thyroid iodine stores. This alteration, if extreme, might result in hypothyroidism. Adequate protein-calorie intake tends to reverse these abnormalities.     

Thyroid hormone and immunological studies in endemic goiter

Iodized oil (1 ml im) was given to 58 goitrous patients from a mildly iodine-deficient area in Greece. Goiter size, urinary iodine, and serum T4, T3RU, T3, rT3, TSH, thyroxine-binding globulin (TBG), and thyroid autoantibodies were measured before and 1, 3, and 6 months after the injection. Goiter size decreased. Serum T4 remained relatively constant, but TBG decreased and therefore T3RU and FTI increased. Serum T3 and rT3 initially decreased (P less than 0.001) and then increased at the sixth month (P less than 0.001), both showing roughly parallel changes. Serum TSH, initially normal (1.42 +/- 0.11 (SEM) mU/liter), decreased to 0.65 +/- 0.01 and 0.76 +/- 0.05 mU/liter at the third and sixth month (difference from baseline P less than 0.001). Thyroid autoantibodies, both against thyroglobulin and the microsomal antigen, were undetectable before treatment, but became positive in 42.8% of the patients 3 and 6 months later. Three patients developed transient hyperthyroidism. This occurred 3 or 6 months after treatment, and was associated with high titers of thyroid autoantibodies. These results indicate that: 1) transient hyperthyroidism may occur after the administration of iodized oil, possibly because of thyroid tissue necrosis and leakage of hormones, and 2) serum TBG decreases after iodized oil, a finding not previously reported and one whose cause is not known.     

Effects of acute high dose and chronic low dose estrogen on plasma somatomedin-C and growth in patients with Turner's syndrome

Previously reported data with regard to the effects of estrogen on plasma somatomedin-C (Sm-C) concentrations are contradictory. This study was designed to evaluate, in the same subjects with Turner's syndrome, the effects of both acute high dose and chronic low dose estrogen treatment on plasma Sm-C concentrations. Eight girls with Turner's syndrome, aged 10 8/12 to 14 9/12 yr, were admitted to the Clinical Research Center for 3 days. Each received an iv infusion of conjugated estrogens (1.25 or 2.5 mg) in 12 h. Plasma Sm-C and serum GH and estrone levels were measured before, during, and after the infusion. The mean serum concentrations in the girls who received 1.25 mg conjugated estrogen increased from less than 222 pmol/L to 1905 +/- 240 (+/- SE), 825 +/- 166, and 296 +/- 74 pmol/L immediately after, 12 h after, and 24 h after completion of the infusion, respectively. Serum GH concentrations were undetectable (less than 1 microgram/L) before, during, and after the infusion. The mean plasma Sm-C concentrations decreased significantly (P = 0.02) after the infusion was terminated, falling from a mean basal value of 1.3 +/- 0.2 (+/- SE) to a nadir of 0.6 +/- 0.1 U/mL 12 h after completion of the infusion. The same girls then were treated with low dose (5 micrograms ethinyl estradiol) estrogen therapy for 9-14 months. Seven of the eight girls had an increase in growth rate. The mean growth rate increased from 2.0 +/- 0.5 to 5.4 +/- 0.8 and 3.8 +/- 0.4 cm/yr from 3 to 6 (P less than 0.05) and from 9 to 14 months of treatment, respectively. Individual variability was great, however, and two of the eight girls never grew at a rate faster than 4.0 cm/yr during therapy. No consistent alteration in bone age relative to chronological age was found, and the growth response was not predicted by the bone age at the beginning of treatment. Mean plasma Sm-C concentrations did not change. These studies demonstrated a growth spurt in girls with Turner's syndrome during chronic low dose estrogen therapy, which was not associated with any change in plasma Sm-C concentrations. Acute high dose iv estrogen infusion resulted in a significant decline in plasma Sm-C concentrations. These results support the concept that in girls with Turner's syndrome the plasma Sm-C response to estrogen is influenced by multiple, as yet undefined, factors.     

Normal bone density of the wrist and spine and increased wrist fractures in girls with Turner's syndrome.

Turner's syndrome is associated with multiple skeletal abnormalities, including osteoporosis. We evaluated the hypothesis that girls with Turner's syndrome may have deficient bone density before the expected age of pubertal onset (9-13 yr) by comparing the bone mineral content of the wrist and lumbar spine in 78 girls with Turner's syndrome (4-13 yr old) and 28 normal prepubertal girls who were matched for age, bone age, body mass index, or height age. The bone mineral content of the wrist and spine was measured by single photon absorptiometry (SPA) and dual photon absorptiometry (DPA), respectively. SPA values for girls with Turner's syndrome vs. normal subjects (4-6.9, 7-9.9, and 10-12.9 yr old) were (mean +/- SD) 0.27 +/- 0.05 vs. 0.36 +/- 0.05, 0.35 +/- 0.06 vs. 0.41 +/- 0.06, and 0.41 +/- 0.05 vs. 0.45 +/- 0.03 g/cm2, respectively. SPA values in the Turner's syndrome girls were decreased compared to those in normal prepubertal girls, matched for age (P less than 0.0001), bone age, (P less than 0.001), and body mass index (BMI; P less than 0.0001), but not for height age. DPA values for girls with Turner's syndrome vs. normal girls in the same age categories were 0.65 +/- 0.06 vs. 0.70 +/- 0.09, 0.77 +/- 0.08 vs. 0.79 +/- 0.09, and 0.83 +/- 0.12 vs. 0.78 +/- 0.07 g/cm2. DPA values in Turner's syndrome girls (as a group) were decreased compared to those in normal prepubertal girls matched for age (P less than 0.05) and BMI (P less than 0.02), but not for bone age or height age. The annual incidence rate of wrist fractures in Turner's syndrome girls (9.1 of 1000) was significantly increased compared to the reported annual incidence rate in normal children (3.5 of 1000; P less than 0.003). We conclude that prepubertal-aged girls with Turner's syndrome (less than 13 yr old) have normal bone density for height age, but significantly decreased bone density of the wrist for chronological age, bone age, and BMI. They also have significantly more wrist fractures than normal girls, but it is not clear that this is related to their bone density.     

Long-term treatment with growth hormone has no persisting effect on lipoprotein(a) in patients with Turner's syndrome

Treatment with recombinant human GH (rhGH), alone or in combination with the anabolic steroid oxandrolone (OX), has been recommended for girls with Turner's syndrome to improve final height. Several cardiovascular risk factors have been described in patients with Turner's syndrome, but the effect of therapy with rhGH and OX on lipoprotein(a) [Lp(a)] has not been investigated. Lp(a) serum levels and apolipoprotein(a) phenotypes were determined in 46 girls with Turners syndrome (aged 6-15 yr) during treatment with different combinations of rhGH and OX for 24-36 months (median, 27 months). Lp(a) serum levels showed little variation during 30 months of treatment in all treatment groups. Lp(a) levels showed no significant change in 25 patients receiving only rhGH and in 21 patients receiving rhGH and OX in combination. Treatment effects were independent of apolipoprotein(a) phenotypes and were not influenced by pubertal status. These data indicate that long term administration of rhGH has no significant impact on serum Lp(a) levels in girls with Turner's syndrome.     

Exercise training benefits growth hormone (GH)-deficient adults in the absence or presence of GH treatment

Reduced aerobic capacity is a prominent manifestation among patients with GH deficiency (GHD). Exercise training may improve the physiological capacity to undertake aerobic activity. The ability of patients with GHD to participate in and benefit from a structured program of aerobic exercise with or without replacement recombinant human GH (rhGH) was investigated. We examined the effect of aerobic training on cycle ergometers in a double-blind crossover trial. Ten patients with GHD trained for 3 months with rhGH (6 microg/kg.d) or placebo, stopped both exercise and drug for 2 months, and resumed training for another 3 months with the other agent. Peak oxygen uptake (VO(2)peak) and ventilation threshold (VeT) were measured during a progressive cycle ergometer test to fatigue or symptom-limited maximum. Serum IGF-I levels were monitored to assess compliance with GH treatment. VO(2)peak was low at the two baseline measures (B1, 19.3 +/- 5.5; B2, 19.9 +/- 6.9 ml/kg.min; normal, approximately 30 ml/kg.min) as was VeT (B1, 11.6 +/- 2.2 ml/kg.min; B2, 11.7 +/- 2.6 ml/kg.min; normal, approximately 16 ml/kg.min). Exercise training increased VeT with (8.6%) or without (9.4%) rhGH treatment. Similarly, exercise training resulted in significant reduction in submaximal heart rate in the presence (-5 +/- 4 beats per minute; P < 0.05) or absence of rhGH treatment (-4 +/- 4 beats per minute; P < 0.05). Peak oxygen uptake was not significantly affected by training with or without rhGH treatment. Our findings suggest that exercise training is a feasible intervention in GH-deficient adults that can measurably improve their submaximal responses to exercise. The beneficial effects of exercise can mimic and are not additive to the effects of GH treatment alone.     

Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T(4) therapy become mandatory?

The effect on thyroid function of GH administration to 66 adult patients with severe GH deficiency was studied. Seventeen patients were euthyroid, and 49 had central hypothyroidism and were adequately treated with L-T(4). Forty patients were assigned to a low recombinant human GH (rhGH) regimen (3 microg/kg body wt.d for 3 months followed by 6 microg/kg body wt.d for another 3 months) and 26 to a higher one (6 microg/kg body wt.d for 3 months followed by 12 microg/kg body wt.d for another 3 months). Serum IGF-I, TSH, free T(4) (FT(4)), free T(3) (FT(3)), reverse T(3), T(4)-binding globulin, and antithyroid autoantibody (TgAb and TPOAb) were measured in basal condition and after 3 and 6 months of therapy. Normalization of IGF-I levels was obtained after 6-month rhGH treatment in 67% of patients, independently from the dose, whereas a significant reduction in FT(4) and reverse T(3) levels was recorded (P < 0.01), without variations in all the other parameters studied, including serum TSH, FT(3), and T(4)-binding globulin circulating levels. Antithyroid autoantibodies were detected in 11 of 66 patients (16.6%). Eight of 17 (47%) euthyroid subjects and 9 of 49 (18.3%) central hypothyroid patients, despite adequate substitution at baseline, showed FT(4) levels under the normal range at the end of the study. Altogether, 17 of 66 patients (25.7%) worsened their thyroid function. This study shows that GH deficiency masks in a consistent number of adult patients a state of central hypothyroidism. Therefore, during rhGH treatment, a careful monitoring of thyroid function is mandatory to start or adjust L-T(4) substitutive therapy.     

Effects of chronic retinoid administration on pituitary function

It has been reported that retinoids may affect hypothalamic-pituitary-thyroid axis, causing central hypothyroidism. In the present study, we evaluated pituitary function in 11 male psoriatic patients at baseline and after 1 and 3 months of treatment with acitretin (all-trans retinoic acid, 35 mg/day). Serum LH, FSH, testosterone, cortisol, GH and IGF-I levels were not affected by the treatment. By contrast, we observed a significant decrease in TSH levels (from 0.92 +/- 0.3 to 0.80 +/- 0.3 mU/I, p < 0.05) at 1 month, that reverted to baseline after 3 months. No change in free T4 (FT4) levels occurred, while free T3 (FT3) levels were reduced at 1 and 3 months (from 6.7 +/- 0.5 to 6.2 +/- 0.3 and 6.1 +/- 0.6 pmol/l; p < 0.05, respectively). Moreover, acitretin treatment induced a significant reduction of PRL levels after 3 months (from 182 +/- 70 to 150 +/- 56 mU/l, p < 0.05). During treatment, no change in TSH and PRL response either to TRH or dopamine infusion was observed. In conclusion, we demonstrated that treatment with low dose of acitretin induced a series of hormonal modifications that, in addition to a mild and transient reduction of TSH levels, included a persistent reduction of FT3, probably due to changes in thyroid hormone metabolism, and a decrease in PRL levels.     

Is the low tri-iodothyronine state a crucial factor in determining the outcome of coronary artery bypass patients? Evidence from a clinical pilot study

The cardiovascular system is an important target for thyroid hormones. The present study evaluates the changes affecting thyroid hormone metabolism during and 6 days after coronary artery bypass and their relationship with the post-operative outcome of the patients. Thirty-three patients were enrolled in the study; their thyroid hormone profiles were determined at 13 sampling points during surgery and for 6 days afterwards. Serum total tri-iodothyronine (T3) and free T3 (FT3) concentrations decreased significantly after surgery (P<0.001) and they remained significantly low until the end of the study. Free thyroxine (FT4) and T4 declined significantly immediately after surgery (P<0.05 for FT4, P<0.001 for T4) but they returned to baseline values (24 h and 96 h post-surgery respectively). Serum reverse T3 increased remarkably 36 h after surgery (P<0.001) and remained significantly higher than the baseline value throughout the study. A relevant finding was that the days of post-operative hospitalization (10+/-3 days, means+/-S.D.) was inversely correlated with the slope of the recovery of T3 concentration (P<0.001) or with the area under the plasma curves of T3 (P=0.024, time range 72-144 h) and the FT3/FT4 ratio (P=0.037, time range 72-144 h) during the post-operative period. Our data suggest a prolonged reduction of T4 to T3 conversion in patients undergoing cardiac surgery and indicate that the recovery period is the most critical in the evaluation of a possibly successful approach for T3 substitutive therapy.     

Growth hormone has anabolic effects in glucocorticosteroid-dependent children with inflammatory bowel disease: a pilot study.

The present studies were designed to determine whether recombinant human growth hormone (rhGH) can counteract some of the catabolic effects of glucocorticosteroid therapy in children chronically treated with glucocorticosteroids. Whether rhGH can safely improve short-term linear growth was also investigated. The effect of rhGH on disease activity was also assessed. Ten children (6 boys, 4 girls) with inflammatory bowel disease (IBD) on oral prednisone for at least 4 months prior to these studies were recruited (mean +/- SE, 11.9 +/- 0.9 years). Leucine and glucose isotope studies, body composition, substrate oxidation and energy expenditure rates, and growth factors were measured at baseline (D1) and at 4 months after treatment with rhGH (0.05 mg/ kg. d subcutaneously [SC]) while continuing oral prednisone. Dual-emission x-ray absorptiometry (DEXA) and calcium kinetic analysis ((42)Ca/(46)Ca) were performed also. rhGH was continued for 6 months to assess linear growth in all 10 subjects, 7 of whom continued rhGH for 12 months. Body composition changed favorably with increased fat free mass (+3 kg, P =.001) and decreased percent fat mass (-3.5%, P =.001) after 4 months of treatment. Rates of whole body protein turnover, oxidation, and synthesis remained invariant, with no changes in substrate oxidation or resting energy expenditure rates. Linear growth velocity increased from 3.5 +/- 0.4 cm/yr when the patients were treated with prednisone only, to 7.7 +/- 0.9 after 6 months of combined prednisone/rhGH (P =.001). The growth velocity was sustained in the 7 patients treated with rhGH for 12 months. Plasma insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) concentrations also increased significantly while on rhGH treatment. No changes in calcium absorption were observed but there was a significant increase in kinetic rates of bone calcium accretion (P =.045) as well as in bone-specific alkaline phosphatase concentrations, a measure of bone formation (P =.03). Fasting and 2-hour postprandial glucose concentrations, fasting insulin levels, and HbA(1C) were invariant during combined rhGH/prednisone treatment. The Crohn's disease activity score was unchanged with rhGH therapy. In summary, rhGH treatment of corticosteroid-dependent patients with IBD was associated with positive changes in body composition, bone metabolism, and linear growth, without deterioration of carbohydrate tolerance or intermediate metabolism of substrates. We conclude that treatment with rhGH has beneficial effects in prednisone-dependent growing children. Larger studies will be needed to assess the long-term safety and efficacy of this approach.     

重组人生长激素治疗对生长激素缺乏症患者甲状腺功能的影响

为探讨生长激素治疗对甲状腺功能的影响及其机制，给１９例特发性生长激素缺乏症患者每日皮下注射重组人生长激素（ｒｈＧＨ）Ｇｅｎｏｔｒｏｐｉｎ０．１ＩＵ／ｋｇ体重，治疗１年，观察治疗前后甲状腺功能及血促甲状腺激素（ＴＳＨ）对静脉推注促甲状腺素释放激素（ＴＲＨ）的反应。经Ｇｅｎｏｔｒｏｐｉｎ治疗后，患者血清Ｔ４及ＦＴ４水平较治疗前明显下降（Ｐ＜０．０１）；治疗半年后，血清ＦＴ３水平亦较治疗前下降（Ｐ＜０．０５）；而血清Ｔ３、３，３′，５′－三碘甲状腺原氨酸及ＴＳＨ水平无明显变化（０．２＜Ｐ＜０．３）。治疗１年后，８例患者血清ＦＴ４水平降至正常范围以下，依此将患者分为治疗后甲状腺功能正常组及降低组，结果证实甲状腺功能降低组在治疗前或治疗后ＴＳＨ对ＴＲＨ兴奋的反应均较甲状腺功能正常组高（Ｐ＜０．０５）。血清ＴＳＨ对ＴＲＨ的反应增强提示患者治疗前就已有潜在的ＴＲＨ缺乏，后者可能是ｒｈＧＨ治疗过程中ＦＴ４及Ｔ４水平下降的潜在基础。因此在ｒｈＧＨ治疗过程中需监测特发性生长激素缺乏症患者的甲状腺功能，以及时给予替代治疗。     

Regulation of a thyroid hormone-dependent protein by growth hormone: the induction of hepatic alpha 2U globulin and its messenger ribonucleic acid in adult male hypothyroid rats

Studies in the adult male hypothyroid rat, a known GH-deficient animal, have shown hepatic alpha 2U-globulin mRNA to be dependent on thyroid hormones. To study the effects of GH on alpha 2U-globulin synthesis in the absence of thyroid hormones, adult male rats were rendered hypothyroid before hormone treatment. The relative effects of bovine GH or T3 were studied by RIA of alpha 2U-globulin in hepatic cytosol in rats 6 weeks after thyroid ablation. alpha 2U-Globulin levels in vehicle-treated controls were 1.3 +/- 0.7 micrograms (+/- SD) alpha 2U-globulin/mg protein. After 2 days, GH (200 micrograms/100 g X day) resulted in an increase to 5.7 +/- 1.0 micrograms alpha 2U-globulin/mg (P less than or equal to 0.05), and T3 50 micrograms/100 g X day) resulted in an increase to 11.5 +/- 3.6 micrograms/mg (P less than or equal to 0.01). After 7 days, GH resulted in an increase to 12.4 +/- 4.6 micrograms/mg (P less than or equal to 0.01), and T3 resulted in an increase to 28.7 +/- 8.7 micrograms/mg (P less than or equal to 0.01). After 4 months of thyroid ablation, baseline hepatic alpha 2U-globulin levels fell to 4.8 ng alpha 2U-globulin/mg protein. Hepatic alpha 2U-globulin was determined 4 and 8 h after the injection of GH (200 micrograms/100 g). In these animals with markedly diminished hepatic alpha 2U-globulin levels, significant (P less than or equal to 0.01) increases occurred 4 h (25.4 ng/mg) and 8 h (57.2 ng/mg) after GH injection. The effects of treatment with bovine GH (200 micrograms/100 g X day) for 3 days on hepatic alpha 2U-globulin synthesis in liver slices and alpha 2U-globulin poly (A)+ RNA levels were measured in rats 10 weeks after thyroid ablation. GH significantly (P less than 0.05) increased alpha 2U-globulin synthesis as a percentage of total protein synthesis (from 0.01% to 0.035%) and alpha 2U-globulin mRNA as a percentage of total mRNA (from 0.03% to 0.24%). The results show that GH rapidly and specifically stimulates hepatic alpha 2U-globulin and its mRNA activity in thyroid hormone-deficient rats.     

Effect of sodium ipodate and iodide on free T4 and free T3 concentrations in patients with Graves' disease

Graves' hyperthyroid patients were treated daily for 10 days with 1 g sodium ipodate, a cholecystographic agent which exerts a blocking effect on the peripheral conversion of T4 to T3, or with 12 drops of saturated solution of potassium iodide (SSKI). Serum concentrations of free T4 (FT4) and free T3 (FT3) were measured before, during and 5 and 10 days after the administration of each drug. Sodium ipodate treatment induced a rapid decrement of serum FT4 concentrations which declined from 48.9 +/- 6.6 pg/ml to 26.0 +/- 2.7 pg/ml. In these patients serum FT3 concentrations declined from 12.4 +/- 2.0 pg/ml to 2.5 +/- 0.4 pg/ml. Ten days after sodium ipodate withdrawal, serum FT4 and FT3 concentrations returned to baseline values. In patients treated with SSKI serum FT4 concentrations declined from 51.1 +/- 8.8 pg/ml to 11.3 +/- 1.4 pg/ml and FT3 from 15.7 +/- 2 pg/ml to 2.6 +/- 0.3 pg/ml. Moreover, after therapy interruption serum free thyroid hormone concentrations returned to baseline values in these patients. Serum FT4 pattern during the study was not different between the two groups of subjects whereas serum FT3 concentrations were significantly lower in patients treated with sodium ipodate. These findings indicate that SSKI and sodium ipodate are effective in inducing a rapid decrement of serum free thyroid hormone concentrations. Therefore the employment of these drugs may be useful in the treatment of patients with thyroid storm and those undergoing thyroidectomy.     

Changes in serum angiotensin-converting enzyme in acutely starved non-obese patients. A possible dissociation between angiotensin-converting enzyme and the thyroid state

We investigated changes in the serum angiotensin-converting enzyme, as an index of thyroid hormone action, before, during and after fasting in 15 non-obese, hospitalized patients. Serum angiotensin-converting enzyme decreased significantly from 14.6 +/- 1.1 U/l before fasting to 13.2 +/- 1.1 U/l on the 5th day (P less than 0.05, N = 15) during fasting, and to 10.6 +/- 1.0 U/l on the 10th day (P less than 0.05, N = 8). The serum TSH and T3 levels decreased significantly to below the normal range, and the serum T4 level decreased gradually during fasting, whereas free T4 (Amerlex) changed slightly, but within normal range. Although re-feeding did not lead to any reduction in the serum TSH, T3, or T4 level, the serum angiotensin-converting enzyme further decreased to 8.7 +/- 0.9 U/l on the 5th day of re-feeding compared with that on the 10th day of fasting (P less than 0.01, N = 8). There was a delay in the re-elevation of serum angiotensin-converting enzyme following a rise in serum T3. No correlations were found between serum angiotensin-converting enzyme levels and thyroid hormone levels throughout the study period. It is concluded that a significant reduction in the serum angiotensin-converting enzyme level occurs under a 'low T3' state during acute starvation, although there is no clear association between serum angiotensin-converting enzyme and thyroid hormone levels.     

Thyroid stimulating immunoglobulins in Graves' disease with goitre growth, low thyroxine and increasing triiodothyronine during PTU treatment

In 50 consecutive patients with Graves' disease treated with PTU, 7 (group 1) developed increasing goitre in spite of unmeasurable TSH. Thyroid variables were compared with those from 10 controls with an ordinary response to PTU (group 2). Serum T4 decreased in group 1 from 246 +/- 47 nmol/l (mean +/- SD) to 40 +/- 9 nmol/l after 6 weeks of PTU treatment and continued to be below the normal range during the next 4 months. In group 2 serum T4 decreased from 190 +/- 35 to 88 +/- 47 nmol/l and stayed in the normal range. Serum T3 was normalized in both groups after 6 weeks but increased to values above the normal range in group 1 after that time. In spite of unmeasurable TSH during the 6 months of treatment in group 1, thyroid volume, determined ultrasonically, increased significantly from 60 +/- 29 to 93 +/- 68 ml (P less than 0.05), but was unaltered in group 2 about 25 ml. Thyroid stimulating antibodies (TSAb) measured by adenylate cyclase activation (normal below 109%) decreased in group 2 from 117 +/- 23 to 90 +/- 17% (P less than 0.01) (6 months of therapy), but increased significantly in group 1, from 201 +/- 47% to a maximum value of 234 +/- 69% (P less than 0.05). TSH binding inhibitory immunoglobulins (TBII) (given as per cent inhibition, normal below 26%) decreased in group 2 from 43 +/- 29 to 29 +/- 27% (P less than 0.05) but were unaltered high in group 1, 66 +/- 25% before therapy and 57 +/- 26% after 6 months of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in thyroid function tests during short-term salsalate use

Although long-term administration of salsalate depresses blood levels of both total thyroxine (T4) and total triiodothyronine (T3) and at least transiently decreases serum thyrotropin (TSH), changes in thyroid function tests have not been fully characterized during its short-term use. It is also unclear if the observed changes are solely the result of decreased hormone binding to carrier proteins or if reduced hepatic 5'-monodeiodinase activity is important. Blood was sampled at baseline (day 0) and after 24 hours (day 1) and 72 hours (day 3) in eight subjects taking a therapeutic dose of salsalate 1,500 mg twice daily. Total T4 decreased from 90.1+/-7.7 nmol/L (mean+/-SD) on day 0 to 82.9+/-8.6 nmol/L on day 1 (P=.1 v baseline) and 68.6+/-8.7 nmol/L on day 3 (P=.0001). Total T3 decreased from 1.76+/-0.20 nmol/L to 1.61+/-0.16 nmol/L on day 1 (P<.05) and 1.31+/-0.27 nmol/L on day 3 (P=.002). The T4/T3 ratio was 51.7+/-7.7 at baseline and remained unchanged after 3 days. Levels of reverse T3 (rT3) were reduced from 0.24+/-0.05 nmol/L to 0.18+/-0.02 nmol/L on day 3 (P<.05). While the free T4 index (FTI) declined in parallel with total T4, the free T4 level by direct equilibrium dialysis (FTD) was unchanged after 3 days. Serum TSH decreased from 1.47+/-0.47 mU/L to 0.91+/-0.27 mU/L after 1 day (P<.05) and remained suppressed after 3 days (0.95+/-0.49 mU/L, P<.05). In conclusion, (1) therapeutic doses of salsalate significantly decrease serum concentrations of total T4, total T3, and rT3 to about 75% of baseline levels after 3 days without altering the T4/T3 ratio; (2) although the FTD does not change, serum TSH concentrations remain suppressed; and (3) the proportionate decrease in total thyroid hormone levels suggests that inhibition of hormone binding to serum proteins is more important in producing these changes than reduced hepatic 5'-monodeiodinase activity.