The Thyroid Hormone Axis

Thyroid Factor

The Natural Thyroid Diet

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The effects of central orexins on TSH secretion have not been investigated in detail. Mitsuma et al. (26) administered orexin-A (50 pg/kg iv) and observed a dose-dependent decrease in plasma TSH. They also observed a reduction in hypothalamic TRH secretion in response to orexin-A and suggested a hypothalamic mechanism for the action of systemic orexin-A since no pituitary effect was observed. No significant changes in TRH secretion were observed when orexin-A was administered to hypothalamic explants (27). It is possible that the effects of icv orexins on TSH secretion are time dependent, since there was suppression of plasma TSH by icv orexin-A at 10 min, but at no other time point, until 90 min, when there was again a suppression in plasma TSH (28). There were no effects on pituitary hormone secretion with chronic intra-paraventricular nucleus (iPVN) injections of orexin-A. Since orexins also stimulate the stress axis, it is possible that any suppression of plasma TSH by orexins is mediated by glucocorticoids. Jones et al. (16) administered increasing doses of icv orexins and studied plasma TSH 40 min after. They did not observe any effects on TSH by orexin-A but observed increases in plasma TSH induced by orexin-B. This is surprising because most feeding studies fail to show any effect of icv orexin-B on feeding, and kinetic studies suggest that orexin-B is unstable when administered icv (29). It would be unexpected that orexin-B will last long enough to produce an effect at 40 min, unless the TSH changes observed are a consequence of a more immediate effect. In this case, it would be expected for orexin-A to produce a more pronounced effect based on receptor potency and greater stability.

TRH neurons are located in the paraventricular nucleus where the presence of the orexin-2, but not orexin-1 receptor mRNA has been reported (30). The presence of OX2R or OXjR receptors specifically on TRH neurons and orexin (hypocretin) projections to TRH neurons have not been reported. Nevertheless, an interaction between orexins and the thyroid axis is intriguing and requires further study since thyroid hormones are important in the regulation of energy expenditure and catecholaminergic responses and, the orexins also influence these systems. No changes in prepro-orexin mRNA or orexin receptor levels with medical thyroidectomy or hyperthyroidism, however, have been observed (31). The effects of thyroid hormone manipulations on peptide content and release have not been reported.

Since the orexins have been shown to have profound effects on sleep, wakefulness, and locomotor activity, changes in orexin levels may parallel or oppose the effects of low thyroid hormone status on these parameters. A reduction in spontaneous motor activity has been observed in hypothyroid rats, which agrees with low orexin action (32). In humans, however, sleep stages 3 and 4 and REM sleep may be markedly shortened or absent in hypothyroidism, which agrees with increased orexin action (33). The sleep effects of hypothyroidism in humans have not been observed in the rat; however, there were more frequent awakenings in slow-wave sleep in hypothyroid rats (34). Interestingly, one severely hypothyroid patient whose CSF orexin-A levels were measured by Mignot et al. (35) had low levels. A larger human CSF study is necessary to substantiate this observation. There is no known association between narcolepsy and thyroid function, but subtle abnormalities cannot be excluded. The interaction between the orexins and the thyroid axis are therefore complex and require further investigation.

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