Lithium hormonal effects

Reduction of derivatives of estradiol 3-methyl ether (I) and hydrolysis of the initially formed enol ether II provides an efficient route to 19-norsteroids (111) of considerable importance in hormone therapy. A. J. Birch, who introduced the method (1949), used sodium in liquid ammonia with ethanol as proton donor. A. L. Wilds and N.A. Nelson (1953) found that yields are improved by use of lithium in place of sodium and that lithium is effective in some cases where sodium is not. The Wilds-Nelson procedure, which became the standard one, employs ether as co-solvent and involves adding the ethanol lust terminal decomposition is done with water after evaporation of ammonia, Since this reaction is the key step in processes developed by O. D. Searleand Co. for the production of two I V-norsteroids... 

As discussed above, lithium inhibits the synthesis of thyroid hormone and its release from the thyroid, and stimulates the formation of antithyroid antibodies in susceptible subjects [112]. Lithium-induced hypothyroidism responds to thyroxine therapy. Lithium can increase the secretion of parathyroid hormone and therefore can increase serum calcium concentrations, but symptomatic hypercalcemia is rare (see hormonal 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. 

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Lithium blocks the release of thyroid hormones, which are known to potentiate b-noradrenergic receptor sensitivity. This has led to the speculation that excessive thyroid activity may contribute to an episode of mania in susceptible patients, and that the antimanic effect of lithium is, at least in part, due to its antithyroid action (26). In this context, CBZ can also decrease various thyroid indices. 

Lithium has several effects on the endocrine system. For example, it can interfere with the synthesis and the release of testosterone, leading to an increase in luteinizing hormone levels. The thyroid system has been most implicated in neuroendocrine theories of lithium s antimanic effects. In particular, thyroid hormones can potentiate b-NE activity, and lithium s ability to block their release may subserve its mood-stabilizing properties (i.e., the thyroid-catecholamine receptor hypothesis)... 

There is no final consensus on whether normal use of lithium, without any episode of toxicity (the vast majority of patients), may result in permanent renal impairment. Polyuria occurs in 20-40% and is due to inhibition of antidiuretic hormone (ADH) by lithium. It usually resolves on cessation of lithium as do any effects on glomerular function. Interference with thyroid function is due to inhibition of the action of thyroid stimulating hormone (TSH) and is easily managed by administration of thyroxine. Lithium is contraindicated during pregnancy (major vessel anomalies in fetus) and breastfeeding. 

Antidiuretic hormone antagonists inhibit the effects of ADH in the collecting tubule. Conivaptan is a pharmacologic antagonist at Via and V2 receptors. Both lithium and demeclocycline appear to reduce the formation of cyclic adenosine monophosphate (cAMP) in response to ADH. 

Because lithium affects second-messenger systems involving both activation of adenylyl cyclase and phosphoinositol turnover, it is not surprising that G proteins are also found to be affected. Several studies suggest that lithium may uncouple receptors from their G proteins indeed, two of lithium s most common side effects, polyuria and subclinical hypothyroidism, may be due to uncoupling of the vasopressin and thyroid-stimulating hormone (TSH) receptors from their G proteins. 

People with exposure to anti-thyroid drugs (e.g., lithium), thyroid disease, or otherwise compromised thyroid function might have a more pronounced response to PBBs and PBDEs because of their underlying limitations in thyroid hormone production. Similarly, people with compromised function of other organs, such as those with liver or kidney diseases (e g., liver cirrhosis or hepatitis B), could be considered more susceptible to health effects of PBBs and PBDEs. 

The many effects of lithium on thyroid physiology and on the hypothalamic-pituitary axis and their clinical impact (goiter, hypothyroidism, and hyperthyroidism) have been reviewed (620). Lithium has a variety of effects on the hypothalamic-pituitary-thyroid axis, but it predominantly inhibits the release of thyroid hormone. It can also block the action of thyroid stimulating hormone (TSH) and enhance the peripheral degradation of thyroxine (620). Most patients have enough thyroid reserve to remain euthyroid during treatment, although some initially have modest rises in serum TSH that normalize over time. 

Lazarus JH. The effects of lithium therapy on thyroid and thyrotropin-releasing hormone. Thyroid 1998 8(10) 909-13. 

After several months of continuous therapy with lithium, diabetes insipidus and goiter may develop. The kidney tubules then become insensitive to the action of antidiuretic hormone, and its administration is ineffective. Either a dose reduction or discontinuation of the lithium corrects this side effect without leaving any residual pathology. In the... 

It has been suggested that thyroid hormone may minimize the cognitive effects of lithium (227) and a review of this suggested benefit in those patients taking lithium who had subclinical hypothyroidism (222). 

Tremont G, Stern RA. Minimizing the cognitive effects of lithium therapy and electroconvulsive therapy using thyroid hormone. Int J Neuropsychopharmacol 2000 3(2) 175-86. 

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