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EDITORIAL COMMENT |
University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599-7160
While deepening our understanding of posttraumatic stress disorder, Wang and Mason (1) have posed a challenge, and thus an opportunity, for psychosomatic medicine in general and for psychoendocrinology in particular—how to understand the remarkable work that they have presented in this issue of Psychosomatic Medicine. To appreciate their findings, it is necessary to review, however briefly, the dynamics of the hypothalamic-pituitary-thyroid axis.
Thyrotropin-releasing hormone, from the hypothalamus, stimulates the secretion of thyrotropin from the anterior pituitary gland. Thyrotropin, in turn, stimulates the thyroid gland to secrete thyroxine and triiodothyronine. All thyroxine comes from the thyroid gland, but under usual circumstances, only about 20% of triiodothyronine. The remaining 80% of triiodothyronine comes from deiodination of thyroxine by tissues, including brain. Although there is always much more thyroxine than triiodothyronine in serum, the ratio between them is important because triiodothyronine is more potent and faster acting. Apparently each tissue makes triiodothyronine according to its need; thyroxine is chiefly a prohormone (2). Within this arrangement, there are two general mechanisms that may shift the balance between triiodothyronine and thyroxine: the thyroid gland may change its pattern of secretion; other tissues may change their rates of deiodination.
Wang and Mason (1) report that, in combat veterans who have suffered for decades from posttraumatic stress disorder, serum triiodothyronine concentrations, but not serum thyroxine concentrations, are higher than in normal men. Serum thyrotropin concentrations are also higher, although only slightly and statistically insignificantly. Probably these changes are the result of the disorder or are part of its process. It seems unlikely that 50 years ago, it was men with this pattern of thyroid axis hormones who were especially vulnerable to posttraumatic stress disorder.
How can serum triiodothyronine concentrations become persistently elevated? Before trying to answer this question, consider how the opposite can occur, ie, how serum triiodothyronine concentrations can be persistently decreased. Such adjustment is made largely, if not entirely, by peripheral tissues. They simply deiodinate less thyroxine. Certain drugs and hormones cause this to happen (3). It also occurs in many patients with nonthyroidal illness (4).
How could the balance shift toward increased triiodothyronine? The authors suggest increased deiodination as an explanation. To be sure, this happens when normal subjects are required to eat more than they would otherwise choose (5). In such a case, the shift toward the more potent hormone may represent an attempt on the part of the subject not to accumulate unneeded fat. However, an increased ratio of triiodothyronine to thyroxine could just as readily be caused not by increased deiodination, but by increased glandular secretion of the former. Under certain circumstances, the thyroid gland does secrete triiodothyronine preferentially. This happens, for example, when dietary iodine is scarce (6), which is a marvelous adaptation, because while making the more potent hormone, the gland uses three of the scarce iodine atoms instead of four. Although these observations help to establish a context, they probably have no immediate relevance for the findings of Wang and Mason: their patients were not force-fed (or obese); in developed countries, it is difficult to avoid sufficient dietary iodine.
The search for an explanation might focus profitably on whether the thyroid axis is capable of emergency responses. Traditionally it was thought to respond sluggishly, but not necessarily inconsequentially, to stress (7). However, with the identification and synthesis of thyrotropin-releasing hormone, new evidence suggested that the axis might indeed be capable of quick responses. For example, intravenous administration of a bolus of thyrotropin-releasing hormone results in a prompt rise in serum thyrotropin concentration, then serum triiodothyronine concentration, and then serum thyroxine concentration (8). Because of this sequence, the triiodothyronine surge is unlikely the result of enhanced deiodination outside the thyroid gland; it is likely the product of enhanced glandular triiodothyronine secretion. Here it seems reasonable to think that the surge in serum triiodothyronine is part of an arousal signal. It is known that thyrotropin-releasing hormone, in addition to its action on thyrotropin (and thus on the thyroid gland), has direct effects on the brain. These effects have been called, in the language of Hess (9), ergotropic, ie, arousing (10). Thus, thyrotropin-releasing hormone, like some other hormones, may have dual and harmonious action (11). While directly shifting the brain to an ergotropic mode, it may indirectly, through thyrotropin, recruit the potent, fast-acting hormone, triiodothyronine. This hormone readily enters brain, and among many other functions, it tends to promote noradrenergic neurotransmission (12), an element of the arousal response. Thus, enhanced levels of triiodothyronine may be the consequence of an arousal response, even while tending to perpetuate arousal, a failure of negative feedback and an adaptation gone wrong. This leads to statement of "the thyroid axis sustaining hypothesis of posttraumatic stress disorder." Under certain conditions of severe and prolonged stress, the hypothalamic-pituitary-thyroid axis may become activated in such manner that an increased secretion of triiodothyronine feeds forward on certain brain structures, thus contributing to additional activation, and thus sustaining arousal. This notion gains support from the preliminary findings, cited by Wang and Mason, that propranolol, while lowering triiodothyronine concentrations, has some value in treating posttraumatic stress disorder.
The evidence that permits the above hypothesis has limitations. First, in physiologic circumstances, thyroid hormones have negative feedback effects, certainly on thyrotropin secretion, and probably on thyrotropin-releasing hormone secretion. Whether these properties can be escaped in disease conditions is unsure. (Feedback effects on neurotransmitter systems are unknown.) Second, when thyrotropin-releasing hormone is given chronically, the dynamics of the hypothalamic-pituitary-thyroid axis are such that values tend to return to baseline (13). But could an increase in triiodothyronine secretion be sustained if the initiating stimulus is severe or persistent long enough? The slight elevation of serum thyroid-stimulating hormone concentration in the patients of Wang and Mason might be biologically, if not statistically, significant. It does suggest that the thyroid gland is being driven excessively. Finally, as a limitation of the hypothesis, it seems doubtful that any endocrine aberration could account for the discrete content (eg, specific flashbacks) of posttraumatic stress disorder, although such aberrations may indeed lower the threshold for discrete events.
Another explanation, if apt, would not negate the above notions. Many years ago, it was generally thought that the thyroid gland, like the adrenal cortex and the gonads, was controlled solely by the anterior pituitary gland. No input from the brain was acknowledged (14). Still earlier, it was thought that the thyroid gland might be regulated, at least in part, by the sympathetic nervous system, perhaps through the stellate ganglion. Is it possible, after all, that under conditions of severe and sustained stress, the sympathetic nervous system can command the thyroid gland or other elements of the thyroid axis to respond as if to an emergency? Perhaps this can happen when the "emergency," having disappeared from the environment, persists in the brain itself and there as a rooted terror.
REFERENCES
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