Miscellaneous
	Thyrotropin (TSH) Persani et al., Milan, Italy, studied TSH glycosylation and bioactivity during its circadian rhythm. In 7 euthyroid male subjects (age 16-18 years) blood was withdrawn every 30-60 min, during 24 hours for measurement of free and total T4 and T3, Tg and TSH. With regard to TSH, immunoreactivity, biological activity (using CHO cells transfected with the human TSH receptor) and degree of sialylation was measured. A clear cut circadian variation of TSH was seen i.e. a steep rise starting near sleep onset leading to a nocturnal peak and followed by a progressive decline until the late morning hours. Despite this variation in TSH immunoreactivity no changes were seen in concentrations of serum thyroid hormone parameters or thyroglobulin. It appeared that the nocturnal TSH peak constituted by isoforms with a 30% reduction in biological activity and a 48% increase in terminal sialic acid residues. (Comment: This is an important study. It is known that the more sialic acid residues are bound to TSH, the more retarded its clearance from the circulation will be. At the same time it looses biological activity. From this study it seems that the primary event in the circadian rhythm may be at least in part related to differences in sialylation leading to differences in metabolic clearance rate and therefore TSH concentration. However, the biological activity of serum TSH is more or less kept constant because the increased concentration of TSH due to a higher degree of sialylation has reciprocally less biological activity. This is the reason that no changes in serum concentrations of thyroid hormone parameters and Tg are found during the 24hr period. Apparently there is a mechanism in the thyrotroph that controls and regulates sialylation of TSH, the theleological significance of which is so far obscure.) Reinhardt et al., Essen and Hannover, Germany, investigated the TSH-secretion pattern in 6 male patients with severe sleepapneasyndrome before, during the first night with continuous positive airway pressure (cpap) and after 4 weeks of cpap. Cpap resulted in an increase of 15% in REM-sleep and 32% increase in sleep stages 2 and 3. There was a drecrease of about 50% in TSH secretion in the first night of cpap as compared to the night before, but after 4 weeks pretreatment values were again seen. As prolactin secretion pattern was unchanged during cpap it is suggested that the temporary decrease in TSH is caused by a dopaminergic independent mechanism. Thyroid hormone and bone Faber et al., Frederiksberg and Herlev, Denmark, measured bone mineral density (MBD) in spine and hip in 27 otherwise healthy postmenopausal women with multinodular goiter and subclinical hyperthyroidism (reduced TSH but normal free T4 and free T3). After measurement, 15 women were treated with radioiodine to normalize serum TSH but 12 women were observed without treatment for 2 years. It appeared that BMD was below normal in all 27 women, but in RAJ treated women no further loss was seen after treatment to achieve euthyroidism. However, in the untreated women bone loss continued for the whole observational period. (Comment: Sawin et al. (NEJM 331:1249-1252; 1994) showed in an already classic study that in subclinical hyperthyroidism the risk for developing atrial fibrillation was three times increased. In the present study it is shown that subclinical hyperthyroidism in this group of patients leads to increased bone loss. From these and other studies it seems unjust not to treat patients with so-called subclinical hyperthyroidism. This is especially true for people above 50 years of age and it is particularly in this age group that subclinical hyperthyroidism prevales.) Pollution by polychlorinated biphenyls (PCBs) Langer et al., Bratislava, Slovakia and Kosice, Lubochna, reported an increased thyroid volume (mean 18.85 ml) as measured by ultrasound in 238 adult employees working in a factory that was polluted with PCBs as compared to 425 adult controls from 3 areas with a mean volume of 13.47 ml. Thyroid volume was also increased in adolescents between 16 and 17 years living in an area polluted by PCBs who had a mean thyroid volume of 9.37 vs 8.07 in controls. Iodine excretion in these groups showed no differences and adequate iodine intake. There was an increased prevalence of anti TPO and anti Tg, and anti TSH-R Ab in adult employees of the factory vs controls. PCBs are known to inhibit thyroid hormone serum binding and to increase thyroid hormone turnover. The authors explain the increased thyroid volume by an increased serum TSH due to the latter effect. It is unfortunate, however, that no TSH serum values are given, neither objective parameters of PCBs contamination. The increased prevalence of thyroid autoantibodies is explained by the effects of PCBs on the immune system. TSH secreting pituitary adenomas Caron et al., Paris, France, report a collaborative study from 9 different centers in Europe on the effects of injected slow-release lanreotide (SLN), a somatostatin analog, in 16 patients (9 females) with TSH secreting adenomas. Six patients underwent prior pituitary surgery and 3 radiotherapy. Free T4 and T3, TSH and alpha unit concentrations decreased significantly during treatment. Patients received 30 mg SLN i.m. every 10 or 14 days. A 20-30% reduction of pituitary tumor volume was observed in 6 patients. In 11 patients thyroid hormone values were normal after 6 months. Injections were generally well tolerated. Thyroid (dys)agenesis Bakker et al., Amsterdam, The Netherlands, studied retrospectively urinary iodine excretion in 54 term newborns with thyroid agenesis and 103 term newborns with thyroid dysgenesis. In the agenesis group iodine excretion was significantly lower than in controls (28 mg/24hr vs 46 mg/24hr). The dysgenesis group showed an inbetween mean value of 38 mg/24hr. The results apparently show a negative iodine balance in term healthy Dutch newborns, raising the question if, despite normal serum FT4 and TSH levels, iodine supply after birth has to be increased. T4 and preterm delivery Van Wassenaer et al., Amsterdam, The Netherlands, previouly found that when perterm infants of <30 weeks gestation were treated with or without T4 no difference in mortality was seen (14% vs 21% n.s.). Prednisone was in addition adminstered to both groups. In the present study the authors evaluated the effect of T4 administration in the presence or absence of co-administration of prednisone. No prednisone: T4+ n = 32, placebo n = 35; prednisone: T4+ n = 68, placebo n = 65. They found that only in the no-prednisone group mortality was significantly less in T4+ (= 16%) vs a mortality in T4- = 40%). (Comment: The mortality data in the infants receiving T4, prednisone, or a combination are similar. Thus, T4 + prednisone seem to have no additive effect on decreasing mortality.) Triiodothyroacetic acid (T3AC) Beale et al., Los Angeles, CA, USA, compared T3AC potency with T3 in 14 normal euthyroid subjects by measuring serial TSH values 1 day prior to, during, and 3.5 days following infusion of T3AC or T3. They found that 4 times more T3AC was required as compared to T3 to effect similar dose-response inhibitory patterns. However, the effect of T3AC disappeared within 6 hours whereas that of T3 continued more than 12 hours. From the reached serum concentrations of these compounds it was concluded that T3AC and T3 were equally potent to suppress TSH. Non-thyroidal illness (NTI) Pinna et al., Berlin, Germany, measured 3,3'- and 3,5-diiodothyronine (T2) in patients with different causes of NTI (sepsis, head and/or brain injury, liver diseases, and brain tumors). It has been shown previously that these T2s exert biological activity at the mitochondrial level. Patients with NTI have low serum T3 and sometimes also low serum T4 levels despite clinical euthyroidism. The authors argued that, if these T2s are elevated in NTI, clinical euthyroidism, despite low serum T3 (and T4) levels, could be explained on the basis of increased biological activity by these compounds. Values were compared with those of 62 healthy controls. 3,5 T2 was significantly elevated in patients with sepsis: 47 pmol/l; liver disease: 25 pmol/l; head and/or brain injury: 24 pmol/l; brain tumors: 22 pmol/l vs controls 16 pmol/l. 3,3'-T2 was significantly increased in liver disease: 72 pmol/l, brain tumors 89 pmol/l vs 46 pmol/l in controls. Patients with sepsis had a value of 57 pmol/l which was just not significant (p <0.06). In patients with head or brain injury a decreased value of 34 pmol/l was found. T3 and T2s were also measured in normal brain tissue and a T3 to 3,5-T2 ratio of 20 was found in all brain areas investigated, while the T3 to 3,3'-T2 ratio varied between 7 and 25 in the different normal brain areas. However, in NTI brain T3 level was markedly lower, while those of the T2s were increased, resulting in a value of about 1 for both ratios. (Comment: There have several different explanations been suggested in the literature to explain clinical euthyroidism in NTI. An important question is however, if patients who are seemingly clinically euthyroid are indeed also euthyroid at the tissue level.) Fliers et al., Amsterdam, The Netherlands, investigated the question why serum TSH is not elevated in NTI while serum T3 and sometimes also T4 are low. To this effect they measured TRH mRNA in 10 formalin-fixed, paraffin embedded hypothalamy of patients in whom plasma T3, T4 and TSH were measured 24hr before death. They found a positive correlation between total TRH mRNA in the paraventricular nucleus with serum T3, log TSH, but not with T4. They conclude that these findings suggest an important role of TRH in the absent rise of TSH in NTI. Leptin in thyrotoxicosis Serum leptin in humans correlate positively with body weight. Zimmermann-Belsing et al., Copenhagen, Denmark, measured serum leptin and total fat mass (TFM) before and after 6 months of thiamazol treatment in 11 fasting thyrotoxic patients (9 females) and in 37 fasting thiamazol treated euthyroid patients (32 females) at 3 and 9 months after treatment. In the untreated group serum leptin was 8 mg/l and increased to 18 mg/l after 6 months of treatment. However, TFM did not change significantly in this period. Serum leptin correlated significantly with TFM, both before and 6 months after treatment, but the absolute and relative changes between 0 and 6 months were not correlated. In the euthyroid patients on thiamazol treatment there was an absolute and relative positive correlation between serum leptin and TFM. The authors conclude that the increase of serum leptin after treatment, while TFM is unchanged, is caused by an increase of turnover of leptin during thyrotoxicosis. Resistance to thyroid hormone (RTH) RTH is seen autosomal dominant disease caused by mutations in the thyroid hormone b-receptor. Clinically the syndrome of attention deficit hyperactivity disorder is common in this abnormality. Hauser et al., Baltimore, MD, USA, performed a quantitative MRI study of brainstructures in subjects with RTH and compared results with unaffected family members and control subjects. They found that RTH patients have a smaller size of corpus callosum and their results also suggest that myelogenesis in RTH is adversely affected. These abnormalities may form a basis of the attention deficit hyperactivity disorder common in this syndrome.