Medical Hypotheses 12 : 179 - 184, 1983
THYROID HORMONE IN BIOLOGICAL RHYTHMS Cuthbert Simpkins, Boston University School of Medicine, Department of Surgery 75 East Newton Street, Suite LglGC, Boston, MA 02118
ABSTRACT An essential role for thyroid hormone in the production of biological rhythms is proposed. In order for a system to oscillate it must have two stable states. It is possible that thyroid hormone alters the concentration of substrate and product in such a way that the system moves cyclically between these two states. Experimental evidence and clinical facts are invoked to complement the theoretical considerations. INTRODUCTION In spite of numerous publications on biological rhythms their mechanism is not known. What has emerged is a sense that these rh y-W ber of body systems from the adrenal gland ,"',"i~~~~~2~a:"e~,~~.~~ Such ubiquity leads to the conclusion that biological rhythms represent something fundamental about the way cells behave. We are a long way from understanding how these rhythms come about and perhaps even further from knowing the depth of their significance. This presentation of thyroid hormone as a "modifier" of precursor and product places this well-studied hormone in a new light. The Role of Thyroid Hormone-Chemical Oscillators In 1979 Epstein and Kustin identified three conditions that are important in the production of oscillations in chemical systems. These conditions are: 1.
the system should be far from equilibri~ul;
2.
the system should have a feedback mechanism; and
3.
the system should have bistability, i.e. be able to exist in two different but stable states.
There must also be a substance which can link the two states in such a
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manner that the system will oscillate between them.
(3) (4)
Bistability can be represented in two dimensions with the y axis representing the precursor and the x axis representing the product. The two states are represented by two curvilinear lines.
Figure 1.
Transitions in a Bistable System
b
a X
On each of these curvilinear lines the system is at a steady state. As x increases y decreases until x=a when the system moves suddenly to the lower line. If x continues to increase the system moves further to the right. If the reaction can be made to proceed from right to left the system stays on the lower line until a critical amount of y is produced at x=b. The system then moves suddenly to the upper line. Further movement to the right yields a point where x=o and y equals a finite value. There is no explanation known for these sudden transitions from one state to the other. The phenomenon has been observed in inorganic chemical reaction systems where the concentrations of y and x can be controlled.(3) It is also curious that the system makes the transition from one state to another at two different values of x. This phenomenon, termed hysteresis, is analogous to magnetism. When a piece of iron is subjected to an increasing and then a decreasing magnetizing force two different curves are followed.
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Figure 2.
Magnetization vs. Magnetizing Force
Magentizing Force a
Magnetization
In a chemical system an oscillation results if a substance T is added which interacts with y to produce x in such a way that a certain amount of x is produced when the system is in one state and another amount is produced when the system is in another state. The action of T is illustrated below.
Figure 3.
Pseudoconcentrations Effected by T
Y
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T reacts with y so that the system "sees" x=c when the system is on the upper line and "sees" x=d when the system is on the lower line. Without T the system would be at x=e. With T present, when the system is on the upper line it strives to reach x=c but before it does, it reaches x=a where it shifts suddenly to the lower line. When the system is on the lower line it strives to reach x=d, but before reaching that point it reaches x=b, where it shifts suddenly to the upper line. This repeated striving and shifting continues upon reaching each new state thus forming an oscillation. It is proposed that in oscillating biological systems thyroid hormone is the equivalent of T. Meier demonstrated that thyroxine was necessary for the existence of a diurnal rhythm for plasma corticosterone concentration in rats. In this experiment adult rats were hypophysectomized in order to remove the source of ACTH and thyroid stimulating hormone. The hypophysectomy resulted in a lowering of amplitude and loss of rhythm in the output of corticosterone. When ACTH was added in a subcutaneous pellet the output of corticosterone increased dramatically but was still arrhythmic. A diurnal rhythm was restored when thyroxine was added to the subcutaneous pellet as shown in Table l.(4) Table I.
Group
Restoration of Diurnal Rhythm in Male Rats with ACTH and Thyroxine
Treatment
ug 100 ml Plasma Corticosteroids ! Early Late 2-O hr. before l-2 hr. after onset of light onset of dark 3.4:
2.0
17.1 + 3.1
Hypophysectomized
None
0.8:
0.2
1.0 + 0.2
Hypophysectomized
ACTH pellets
8.1: 1.0
8.6 + 1.3
Hypophysectomized
ACTH and Thyroxine Pellets
7.8:
0.9
12.7 _f2.1
Thyroxine's link to steroid secretion is strengthened by the observation that thyroxine increases cholesterol biosynthesis.(5) Furthermore, patients who are hypothyroid have a lower rate of cortisol turnover because of a decrease in ll-B-hydroxysteriod dehydrogenase activity. Occasionally, in hypothyroidism the adrenal response to ACTH is seen to be sluggish. In severe hypothyroidism stress will precipitate the signs of adrenal insufficiency.(6) Therefore, if y=cholesterol or a cholesterol precursor and x=cortisol or a cortisol precursor then thyroid hormone can be said to affect both the y and the x axes.
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In the chemical oscillator model, y and x are inversely related. One would expect that, if thyroxine acts to modify precursor and product in such a way as to produce oscillations, there would be an inverse relationship between cholesterol, or a cholesterol precursor, Parker, et al showed that changes and cortisol, or a cortisol precursor. in mevalonic acid, a cholesterol precursor, are directly related to the Superimposition of the curves of rate of cholesterol biosynthesis. cortisol and mevalonic acid vs. time illustrates that the expected relationship does exist. (7) (8) Figure
4.
Superimposition and Cortisol Concentrations
of Mevalonic
Acid
vs. Time
4isolMevalonic I
Acid
.
9123690369
Clock Time
It can be seen from this graph that when cortisol is low, rnevalonic acid is high. When the slope of the cortisol curve is greatest the mevalonic acid curve is at its peak.
CONCLUSION Thyroid hormone is essential to the production of biological rhythms. Thyroid hormone acts differently on each state to produce different amounts of product. T?.is propertyi of thyroid hormone causes the system to oscillate between two stable states. There is evidence to suggest that thyroid hormone increases cortisol output at the cellular P. reciprocal level. Thyroxine also increases cholesterol biosynthesis. relationship between cholesterol biosynthesis and cortisol is consistent with the proposed role as a "modifier" for thyroid hormone.
REFERENCES 1.
Shiotsuka R, Jovonovich J, Jovonovich J. In Vitro Data on drug sensitivity: circadian and ultradian corticosterme rhythms in adrenal organ cultures: in chronological aspects of endocrinology. (J Aschoff, F Ceresa, F Halberg, eds) FK Schattauer Verlag , Stuttgart, New York, 1974.
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2.
Stevenson NR et al Circadian rhythmicity in several small intestinal functions is indepent of the use of the intestine. American Journal of Physiology 238:G203, 1980.
3.
Epstein IR, et al. Oscillating American 248~112, 1983.
4.
Orban M, Epstein IR. Bistability in the oxidation of iron (II) by nitric acid. Journal of the American Chemical Society, 104:5918, 1982.
5.
Meier AH. Daily variation in concentration of plasma corticosteriod in hypophysectomized rats endocrinology 98:1475, 1976.
6.
Kritchevsky D. Influence of thyroid hormones on cholesterol biosynthesis and degradation: 9:984, 1960.
7.
in textbook of Ingbar SH, Woeber KA. The thyroid gland: endocrinology (RH Williams ed) WB Saunders Company, 1981.
8.
relationship Parker TS et al. Mevalonic Acid in human plasma: of concentration and circadian rhythm to cholesterol synthesis rates in man. Proceedings of the National Academy of Sciences, USA 79:3037, 1982.
9.
McIntosh TK et al. Circadian rhythm of cortisol is altered in Journal of Clinical Endocrinology and postsurgical patients. Metabolism 53:117, 1981.
chemical reactions.
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Scientific
and related compounds a review. Metabolism