The hypothalamicpituitarythyroid axis

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It has been recognized for more than a century that adult patients with hypothyroidism exhibit profound disturbances in CNS function, including cognitive impairment and depression. In more recent years, attention has focused on more subtle alterations of the hypothalamic-pituitary-thyroid ( HPT) axis in depressed patients. Hypothyroidism is most frequently subclassified as in four grades as follows.

• Grade 1 hypothyroidism is classic primary hypothyroidism (increased thyroid-stimulating hormone ( TSH), decreased peripheral thyroid hormone concentrations, and an increased TSH response to thyrotrophin-releasing hormone (TRH)).

• Grade 2 hypothyroidism is characterized by normal, basal thyroid-hormone concentrations, but an increase in basal TSH concentrations and an exaggerated TSH response to TRH.

• Grade 3 hypothyroidism can only be detected by a TRH-stimulation test; patients have a normal basal thyroid hormone and TSH concentrations, but an exaggerated TSH response to TRH.

• Grade 4 hypothyroidism is defined as normal findings on the three thyroid axis function tests noted above, but the patients have antithyroid antibodies.

Left untreated, most, if not all, patients progress from grade 4 to grade 1 hypothyroidism. Several studies have revealed an inordinately high rate of HPT axis dysfunction, largely hypothyroidism, in patients with major depression. In our pilot study, patients with comorbid depression and anxiety were especially likely to exhibit HPT axis abnormalities, especially the presence of grade 4 hypothyroidism, i.e. symptomless autoimmune thyroiditis. Patients with other major psychiatric diagnoses including schizophrenia appear to exhibit normal HPT axis function.

For patients who require thyroid-hormone replacement secondary to thyroid ablation, Bunevicius et al.(2) recently reported that treatment with a combination of tri-iodothyronine (T3) and thyroxine (T4) is optimal for mood and cognitive function, rather than the standard medication of T 4 alone.

In addition, a blunted TSH response to TRH is observed in approximately 25 per cent of patients with major depression. This observation, first reported by Prange et al.(3) and Kastin et al.,(4) more than 25 years ago, has been replicated in many studies. Unfortunately, the pathophysiological underpinnings of this observation remain obscure, though there is considerable evidence that it may be due, at least in part, to chronic hypersecretion of TRH and subsequent TRH-receptor downregulation in the anterior pituitary gland. Indeed, our group(5) and others have reported elevated TRH concentrations in the cerebrospinal fluid of drug-free depressed patients.

TRH was the first of the hypothalamic-releasing factors to be chemically characterized. It is a tripeptide with the sequence pGlu-His-Pro-NH2. Once it was sequenced and antisera were raised against the peptide, immunohistochemical and radio-immunoassay methods revealed a heterogeneous brain distribution of TRH. This was the first in a series of experimental results that led to the inexorable conclusion that this peptide, and, as discussed below, other release and release-inhibiting hormones, function in extrahypothalamic brain regions as neurotransmitter substances. Thus TRH has been shown to produce direct brain effects, independent of its action on the pituitary thyrotrophs. Antidepressant effects of intravenously and intrathecally applied TRH have been reported, (3) but the results have not been confirmed in large, controlled clinical trials. (6) In contrast, several reports over the last 30 years have documented the efficacy of T3 (25-50 mg daily) in both accelerating the rate of onset of antidepressant response,(7) and in converting antidepressant non-responders to responders.(8) These studies were initiated when it became apparent that patients (and laboratory animals) with hypothyroidism do not respond to antidepressant agents. This led to the hypothesis that patients with subtle forms of hypothyroidism (grades 2-4) may not respond optimally to antidepressants unless they are adequately treated with exogenous thyroid hormone. This hypothesis is currently being tested in a large clinical trial, which seeks to determine whether the effectiveness of T 3 augmentation in antidepressant non-responders is associated with subtle HPT axis dysfunction. With the cloning of the thyroid hormone receptor and its localization within the CNS, studies of its regulation in depression, as well as the regulation of TRH biosynthesis, can now be conducted in postmortem brain tissue.

A few other salient points are worth making, though a comprehensive discussion of each is beyond the scope of this review with its attendant space constraints. First is the critical role that thyroid hormones play in CNS development, and the tragic consequences of hypothyroidism early in life, namely cretinism, which is a syndrome associated with severe mental retardation.(9) The second is the reported presence within the CNS of each of the constituent hormones of the HPT axis, i.e. thyroid hormone, TSH, and TRH. The significance of this latter observation remains obscure, although TRH is considered to be a neurotransmitter in extrahypothalamic brain tissue. Third is the report by Hauser et al.(1,,9 that an inordinately high percentage of patients with attention-deficit hyperactivity disorder exhibit thyroid hormone receptor resistance. It is likely that the development of positron emission tomographic ligands for thyroid hormone and TRH receptors will result in data that will incrementally advance the field.

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