Thyroid hormone adverse effects

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

Studies of low-dose perchlorate exposure in healthy human subjects A small number of studies have been published investigating the effects of low doses of perchlorate in thyroid function in healthy adults (without thyroid disease). One study was conducted in healthy male volunteers, involving the administration of 10 mg of perchlorate in drinking water for 14 days. A significant decrease in the uptake of iodine by the thyroid was observed at this dose, but there was no evidence of adverse effects on thyroid hormones or TSH concentrations [262]. Another recent study was conducted in healthy adults to determine the highest dose of perchlorate at which there is no effect on the uptake of iodine by the thyroid gland [263]. 

In recent years, concern that chemicals might inadvertently be disrupting the endocrine system of humans and wildlife has increased. The concerns regarding exposure to these endocrine disrupters are based on adverse effects observed in certain wildlife, fish, and ecosystems increased incidences of certain endocrine-related human diseases and adverse effects observed in laboratory animals exposed to certain chemicals. The main effects reported in both wildlife and humans concern reproductive and sexual development and function altered immune system, nervous system, and thyroid function and hormone-related cancers. Endocrine dismption is not considered a toxicological endpoint in its own right, but a functional change or toxicological mode(s) of action that may lead to adverse effects. Endocrine dismpters are addressed further in Section 4.11. 

Adverse reproductive effects have been observed in animals fed PCB in the diet. Fetal resorptions were common, and dose-related incidences of terata were found in pups and piglets when females were fed Arochlor 1254 at Img/kg/day or more. Long-term low-level maternal exposure of rats before breeding and throughout gestation and lactation caused permanent hearing deficits, decreased serum thyroid hormones, and reproductive effects. PCBs have been observed in human cord blood and in tissues of newborn humans and animals. ... 

ADVERSE EFFECTS OF TREATMENT WITH THYROID HORMONE... 

In patients with longstanding hypothyroidism and those with ischemic heart disease, rapid correction of hypothyroidism may precipitate angina, cardiac arrhythmias, or other adverse effects. For these patients, replacement therapy should be started at low initial doses, followed by slow titration to full replacement as tolerated over several months. If hypothyroidism and some degree of adrenal insufficiency coexist, an appropriate adjustment of the corticosteroid replacement must be initiated prior to thyroid hormone replacement therapy. This prevents acute adrenocortical insufficiency that could otherwise arise from a thyroid hormone-induced increase in the metabolic clearance rate of adrenocortical hormones. 

L All of the following are common adverse effects associated with drug overdose of thyroid hormone replacement therapy EXCEPT... 

Thyroid effects were produced in rats in acute-duration studies at doses as low as 3 mg/kg/day (reduced serum levels of T4 hormone) but not at 1 mg/kg/day, in intermediate-duration studies at doses as low as 0.05 mg/kg/day (increased number and decreased size of follicles), and in chronic-duration studies at doses as low as 1.3 mg/kg/day. The no-observed-adverse-effect level (NOAEL) of 1 mg/kg/day is used herein as the basis for an acute-duration minimal risk level (MRL) for oral exposure. The acute-duration lowest-observed-adverse-effect level (LOAEL) for hepatic effects is identical to the LOAEL for acute thyroid toxicity, but is a less appropriate basis for the MRL because organ functional implications are not as clear. The intermediate-duration LOAELs for thyroid and hepatic effects are also comparable to each other, but neither of these LOAELs are suitable for an intermediate MRL because reproductive and developmental toxicity occurred at a lower dosage. The thyroid LOAEL for chronic-duration exposure is unsuitable for deriving a chronic MRL because decreased survival occurred at the same dose (lower doses were not tested), and thyroid, liver, and other effects occurred at lower doses in intermediate-duration studies. 

Bartalena L, Bogazzi F, Martino E. Adverse effects of thyroid hormone preparations and antithyroid drugs. Drug Saf 1996 15(l) 53-63. 

Thyroid hormones are among the most commonly prescribed drugs in the developed world, with a prevalence of prescription of 5-10% in the over 60 age group (3,4). Since about 25% of those who use thyroxine (T4) take doses sufficient to suppress serum TSH (4,5), much attention has focussed on potential adverse effects of this degree of over-treatment. 

In 50 women taking levothyroxine either for primary thyroid failure or for hypothyroidism secondary to radioiodine treatment for hyperthyroidism, there was no difference between the two groups in terms of bone density at the hip or spine and no difference from the reference population (31). In addition, there was no correlation between bone density and circulating thyroid hormone concentrations or duration of levothyroxine replacement. These findings are reassuring, although large studies of fracture risk are required, in view of previous evidence of an adverse effect of levothyroxine on bone mineral density, especially in post-menopausal women (32). 

Data from more than 30 studies of the effect of thyroid hormone on bone have been reviewed (37). The results have supported the view, expressed before (38), that there is a small, but statistically significant, adverse effect on bone mineral density, especially in postmenopausal women. 

Abuse of thyroid hormones, causing factitious hyperthyroidism, can have adverse effects (53,54), including sudden death, attributed to ventricular fibrillation (55). 

Inadvertent excessive use of thyroid hormones (for example, by eating ground beef contaminated with thyroid hormones (64), the incorrect use of these drugs for the treatment of obesity (65), excessive thyroid substitution therapy, and factitious use of thyroid hormones for psychiatric reasons (66)) result in mild hyperthyroidism, but serious short-term adverse effects are rare. 

It has been suggested that potassium perchlorate should be used in the treatment of type 1 hyperthyroidism and glucocorticoids in the treatment of type 2 (SEDA-21, 199). Since hypothyroidism due to amiodarone tends to occur in areas in which there is sufficient iodine in the diet, it has been hypothesized that an iodinated organic inhibitor of hormone synthesis is formed and that the formation of this inhibitor is inhibited by perchlorate to a greater extent than thyroid hormone iodination is inhibited, since the iodinated lipids that are thought to be inhibitors require about 10 times more iodide than the hormone. However, there is a high risk of recurrence after treatment with potassium perchlorate, and it can cause serious adverse effects (SED-13,1281). 

---