The thyroid-pituitary homeostatic mechanism

The paper develops a mathematical theory of thyroid-pituitary interaction. It is assumed that the pituitary gland produces thyrotropin, which activates an enzyme of the thyroid gland. The rate of production of thyroid hormone is considered to be proportional to the concentration of that enzyme. It is further assumed that in the absence of the thyroid hormone the rate of production of thyrotropin is constant, but, in general, it is a linear function of the concentration of the thyroid hormone. This picture leads to a system of non-linear differential equations, which present great difficulties. This system, however, may be conveniently “linearized”, by considering that the relations between different variables are linear, but that within different ranges of the variables the coefficients are different. Using this approximation, it is possible to show that the system admits periodic solutions of the nature of relaxation oscillations. Such oscillations are actually observed in some mental disorders, such as periodic catatonia. The study of the effects of different parameters of the system suggests different possible approaches to clinical treatment. In the light of this theory, the experimental determination of the parameters of the system becomes desirable and important.     

The switch mechanism in periodic catatonia and manic-depressive disorder.

Both in periodic catatonia and in manic-depressive disorders sudden switches occur in behavior, in the autonomic nervous system and in the catecholamine metabolism during the transition from interval or depression into catatonia or mania. Both the manic and the catatonic attacks seem to be superimposed on the basic depressive or schizophrenic illnesses. The attacks can be counteracted or suppressed by psychotropic drugs such as alpha-methyldopa, disulfiram, reserpine, haloperidol or chloropromazine which interfere with the catecholamine metabolism or their receptor sites. The involvement of the catecholamines may however be secondary to primary defects in the thyroid, the hypothalamus or the limbic system. The strict periodicity in periodic catatonia points to an accumulation of some active metabolite which may be produced centrally during the interval. At a certain level it may trigger the switch-mechanism and then be reduced during the catatonic phase. In periodic catatonia both the basic schizophrenic disease as well as the periodic manifestations are compensated by thyroxine-thyroid treatment.     

Mathematical models of endocrine systems

There is proposed a generalized mathematical model of endocrine systems, consisting of a set of differential equations which describe a chain of chemical reactions. The product of each reaction stimulates or inhibits some other reaction in the chain except possibly the last, which may or may not influence the system. At least one reaction must be independent and able to proceed without stimulation or inhibition by the products of other reactions. If only two reactions of the type assumed constitute a closed chain, sustained periodic variations in the concentrations of the reaction products cannot occur. If the chain consists of three or more reactions forming a closed loop, sustained oscillations, such as are observed in the menstrual cycle or in the mental disorder called periodic catatonia, can occur under suitable conditions. In this case, the concentrations of the system components exhibit relaxation oscillations characterized by periodic degeneration of the system when an independent reaction becomes completely inhibited by other reaction products. A set of conditions sufficient to produce periodicities in component concentrations is presented. Application of the model to the normally periodic system of the menstrual cycle and to the abnormal endocrine system which causes periodic catatonia is discussed.     

HORMONAL REGULATION: MORPHOGENETIC AND ADAPTIVE SYSTEMS

1. The endocrine glands of vertebrates develop from all three germ layers; those arising from ecto- and endoderm produce hormones of an amino-acid or polypeptide-type, while those arising from the mesoderm secrete hormones of a steroid nature. 2. All mesodermal glands and a single endodermal gland, the thyroid, are under hypophyseal control. 3. All pituitary-controlled endocrine glands act upon morphogenetic processes after a certain stage of phylogenesis, and the same applies to the directly-acting hypophyseal hormone STH. It follows that the pituitary acts not so much as the ‘conductor of endocrine glands’ in general, but as the central regulator of morphogenetic processes in particular. 4. Incorporation of the thyroid gland into the morphogenetic system took place at the phylogenetic level at which its morphogenetic role came to the fore in processes of metamorphosis. 5. The other main hormone system, the adaptive system, includes all endocrine glands of ecto- or endodermal origin. These account for short-term homeostatic regulation and depend on the pineal body for higher control. 6. While hypophyseal regulation is stimulatory and is operated through a precise feed-back mechanism, regulation by the pineal body is more primitive and inhibitory, with minimal indications of feed-back. The influence becomes stimulatory only in those instances in which the target glands are controlling the same function in an opposite manner, e.g. the parathyroid and the C-cell. The pineal influence also inhibits the function of the thyroid, and hypophyseal stimulation becomes superimposed on this inhibitory effect, in accordance with an actual requirement.     

Mathematical biophysics of sustained nonperiodic oscillations of excitation and inhibition in the central nervous system

There are a number of phenomena in the central nervous system which are not periodic in the strict sense of the word. The simplest example is the α-rhythm which represents an oscillation that is not strictly periodic in a mathematical sense. Some diseases like periodic relapsing catatonia or the manic-depressive psychoses are almost strictly periodical but such phenomena as attacks of epilepsy repeat themselves perhaps at average intervals but those intervals are not equal and are not predictable. We consider that even such phenomena like a fit of creative work has the same mechanism. All those phenomena deal with sporadic spontaneous nonperiodic overexcitation of certain parts of the brain. Depending on which part of the brain is overexcited, we might have either a grand or a petit mal epilepsy, or a fit of creativity. This paper gives a model of two neuronic circuits which can produce nonperiodic spontaneous overexcitation of the cortex. That part of the cortex which happens to have the lowest threshold will be most strongly affected. The location of such parts of the cortex vary from person to person. The paper does not in any way imply that the mechanism described here is responsible for all types of epilepsy. Many of them may have an entirely different origin. The paper does, however, contain a suggestion for an actual cure of some types of epilepsy, which is different from the symptomatic treatment mostly used so far.     

Application of the describing function to the Danziger-Elmegreen equations

The describing function method is used as a guide to the behaviour of the solutions of the equations of Danziger and Elmergreen, proposed as a model of periodic catatonia. The method suggests that whenever the equilibrium point is unstable it is surrounded by a stable closed periodic orbit. This is confirmed in specific cases by computation.     

Iodine-Induced Thyroid Blockade: Role of Selenium and Iodine in the Thyroid and Pituitary Glands

The purpose of this study was to determine the content of iodine and selenium in the thyroid and pituitary glands of rats under iodine-induced blockade of the thyroid gland. Electron probe microanalysis, wavelength-dispersive spectrometry, and point analysis were used in this investigation. We also determined the expression of sodium iodide symporter and caspase 32 in the thyroid and pituitary glands and the expression of thyroid-stimulating hormone in the pituitary. The samples for iodine analysis must be thoroughly dehydrated, and for this purpose, we developed a method that produced samples of constant mass with minimal loss of substrate (human thyroid gland was used for the investigation). Normal levels of iodine and selenium were found in the thyroid, pituitary, ovaries, testes hypothalamus, and pancreas of healthy rats. The levels of iodine and selenium in I- or Se-positive points and the percentage of positive points in most of these organs were similar to those of controls (basal level), except for the level of iodine in the thyroid gland and testes. Blockade of the thyroid gland changed the iodine level in iodine-positive points of the thyroid and the pituitary glands. On the sixth day of blockage, the iodine level in iodine-positive points of the thyroid gradually decreased to the basal level followed by an abrupt increase on the seventh day, implying a rebound effect. The opposite was found in the pituitary, in which the level of iodine in iodine-positive points increased during the first 6 days and then abruptly decreased on the seventh day. Expression of the thyroid-stimulating hormone in the pituitary decreased during the first 5 days but sharply increased on the sixth day, with a minimum level of iodine in the thyroid and maximum in the pituitary, before normalization of the iodine level in both glands preceding the rebound effect. The expression of sodium iodide symporter increased during the first 4 days of blockage and then decreased in both glands. The fluctuations of the thyroid-stimulating hormone in the pituitary gland reflected the changes of iodine in the thyroid gland more precisely than the changes of sodium iodide symporter. The selenium level in the selenium-positive points changed only in the pituitary, dropping to zero on the second and fifth day of the blockade. Simultaneously, the maximum induction of caspase 32 was observed in the pituitary gland. We believe that these results may help to clarify a role of the pituitary gland in the thyroid blockade.     

Dynamics of thyroid diseases and thyroid‐axis gland masses

Thyroid disorders are common and often require lifelong hormone replacement. Treating thyroid disorders involves a fascinating and troublesome delay, in which it takes many weeks for serum thyroid‐stimulating hormone (TSH) concentration to normalize after thyroid hormones return to normal. This delay challenges attempts to stabilize thyroid hormones in millions of patients. Despite its importance, the physiological mechanism for the delay is unclear. Here, we present data on hormone delays from Israeli medical records spanning 46 million life‐years and develop a mathematical model for dynamic compensation in the thyroid axis, which explains the delays. The delays are due to a feedback mechanism in which peripheral thyroid hormones and TSH control the growth of the thyroid and pituitary glands; enlarged or atrophied glands take many weeks to recover upon treatment due to the slow turnover of the tissues. The model explains why thyroid disorders such as Hashimoto''s thyroiditis and Graves'' disease have both subclinical and clinical states and explains the complex inverse relation between TSH and thyroid hormones. The present model may guide approaches to dynamically adjust the treatment of thyroid disorders.     

Induction of epidermal growth factor by tri-iodo-L-thyronine in the submandibular glands of mice with testicular feminization

The content of epidermal growth factor (EGF) as a high molecular weight complex (HMW-EGF) in the submandibular glands of mice was measured simply by a single radial immunodiffusion method. In female mice, the amount of HMW-EGF was increased 10-fold by tri-iodo-L-thyronine (T3) and 60-fold by 5 alpha-dihydrotestosterone (5 alpha-DHT). In mice with testicular feminization (Tfm), which are genetically deficient in androgen receptor, T3 but not 5 alpha-DHT increased the HMW-EGF from a non-detectable level to 5.4 +/- 0.94 micrograms/mg protein. It was concluded that EGF is also synthesized under the control of thyroid hormone in vivo, and that androgen was not involved in this induction of EGF by thyroid hormone.     

Functional state of the thyroid gland following exposure to ultrasound

Changes are described in the content of butanol-extracted iodine in the blood serum and total iodine in thyroid tissue of white rat males under ultrasonic effect of various intensity (0.2, 0.6, 1.0 Watt/cm2) and analysed at different time intervals after ultrasound application. A decrease in total iodine content in thyroid glands (at initial level 0.315 mg%) and an increase of butanol-extracted iodine content in the blood serum were observed in all the experimental groups. The data obtained compared with the earlier found increase of the thyroid hormone content in the serum and thyreotropic hormone at a decreased content of thyroxins in the thyroid gland seem to point to the activation of the thyroid function after the application of ultrasound.     

Forskolin stimulation of 3, 5, 3'-triiodothyronine release from perifused rat thyroids

In a perifusion system in the presence of 3-isobutyl-1-methylxanthine, forskolin stimulated secretion of not only cAMP but also 3, 5, 3'-triiodothyronine (T3) from rat thyroid glands. The increases in both cAMP and T3 were dose-dependent at forskolin concentrations of 2.0 X 10(-7)M to 2.0 X 10(-5)M. After perifusion for 4 h, tissue concentrations of cAMP also increased as a result of forskolin treatment. Since forskolin is regarded as a specific activator of the cAMP generating system, this observed forskolin stimulation of T3 secretion from perifused rat thyroid glands indicates that cAMP is involved in regulating thyroid hormone secretion.     

Hypothalamic and rate feedback in the thyroid hormone regulation system: An hypothesis

Several alternative models of the system regulating the plasma concentration of thyroid hormones are presented and investigated from the point of view of certain optimal system performance indices. The models differ from each other in the number and types of feed-back pathways. Various combinations of thyroid hormone feedback actions at pituitary and/or hypothalamic chemoreceptor sites, having proportional and/or rate characteristics, are considered in terms of minimum energy consumption and minimum sensitivity to the maximum number of model parameters likely to vary. It is concluded that the model which includes proportional inhibitory feedback of thyroid hormone at the hypothalamic level and rate feedback of thyroid hormone at the level of the pituitary provides the best performance.     

Adrenocortical and thyroid systems of rats at the initial stage of nociceptive influence

There are two phases in the initial period of formation of adrenocortical response to sharp nociceptive influence. The first phase (within 10-15 sec.) involves emergency mobilization of "basal" reserves of hormone active substances. It is characterized by reduction of corticoliberine activity in hypothalamic and extrahypothalamic structures of the rat brain with a parallel increase of corticotrophin concentration in plasma, devastation of corticosteroid reserves in adrenal glands; a decrease in the level of corticosteroids in blood against the background of accumulating hormone in bodies-targets. In the second phace: the phase of hypercompensation, the progressive increase of credit of the substances under study was quite obvious. The authentic changes in a level of aldosterone in adrenal glands and blood took place only in 2.5 minutes after the stress. The nociceptive influence was also biphasic when acting upon the reorganization of thyroid status number. However, unlike the initial adrenocortical response to stress in the first phase of thyroid reaction, the elevation of plasma thyroxine and tri-iodothyronine level was obvious. At the second stage, selective decrease in concentration of thyroxine to normal amounts occurred.     

Splitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15

The nature of subtypes in schizophrenia and the meaning of heterogeneity in schizophrenia have been considered a principal controversy in psychiatric research. We addressed these issues in periodic catatonia, a clinical entity derived from Leonhard's classification of schizophrenias, in a genomewide linkage scan. Periodic catatonia is characterized by qualitative psychomotor disturbances during acute psychotic outbursts and by long-term outcome. On the basis of our previous findings of a lifetime morbidity risk of 26.9% of periodic catatonia in first-degree relatives, we conducted a genome scan in 12 multiplex pedigrees with 135 individuals, using 356 markers with an average spacing of 11 cM. In nonparametric multipoint linkage analyses (by GENEHUNTER-PLUS), significant evidence for linkage was obtained on chromosome 15q15 (P = 2.6 x 10(-5); nonparametric LOD score [LOD*] 3.57). A further locus on chromosome 22q13 with suggestive evidence for linkage (P = 1.8 x 10(-3); LOD* 1.85) was detected, which indicated genetic heterogeneity. Parametric linkage analysis under an autosomal dominant model (affecteds-only analysis) provided independent confirmation of nonparametric linkage results, with maximum LOD scores 2.75 (recombination fraction [theta].04; two-point analysis) and 2.89 (theta =.029; four-point analysis), at the chromosome 15q candidate region. Splitting the complex group of schizophrenias on the basis of clinical observation and genetic analysis, we identified periodic catatonia as a valid nosological entity. Our findings provide evidence that periodic catatonia is associated with a major disease locus, which maps to chromosome 15q15.     

Precocious testicular growth in metamorphosis-arrested larvae of a salamander Hynobius retardatus: role of thyroid-stimulating hormone

Precocious maturation of testes occurs in goitrogen-treated larvae of a salamander Hynobius retardatus, a particular population of which has been reported to show a neotenic reproduction in a specific environment. Similar precocious growth of testes also was confirmed in thyroidectomized larvae in this study. A possible involvement of thyroid-stimulating hormone (TSH) in the precocious maturation of testes was examined in metamorphosis-arrested larvae whose thyroid or pituitary glands had been removed surgically at embryonic stages or which had been reared in goitrogens. The pituitary glands of both the thyroidectomized and goitrogen-treated larvae contained extraordinarily large number of TSH cells, which were called "thyroidectomy cells." When homogenates of the pituitary glands from the goitrogen-treated larvae were injected into the hypophysectomized larvae for a month, the testes grew larger than those in larvae injected with the pituitary glands from normally metamorphosed controls. These results are consistent with the idea that an extraordinarily high concentration of TSH, which is induced by either thyroidectomy or goitrogen-treatment, causes the precocious maturation of testes in the metamorphosis-arrested larvae of Hynobius retardatus. In contrast to the precocious testicular development, ovarian development in the metamorphosis-arrested larvae was almost identical to that in normally metamorphosed animals within our experimental period. This also suggests that in males the absence of thyroid hormones allows a gonadal response that in females may require another activator in addition to or following thyroid axis stimulation.     

Release of thyroid stimulating hormone from chick anterior pituitary glands by thyrotropin releasing hormone (TRH)

Chicks two and ten days-of-age respond to a wide range of thyrotropin releasing hormone (TRH) dosages as measured by thyroid uptake of ³²P. The duration of hormone and ³²P action is important. Excellent responses were obtained with the injection of 1.0 μCi³²P at one hour and TRH either at one or four hours before autopsy in both two-day and ten-day-old birds. The ³²P uptake in the thyroid glands was increased by doses of hormone which ranged from 40 nanograms to 125,000 nanograms and was bimodal. Analysis of the data when calculated using log¹⁰ of dose was best accomplished by the use of 5th-degree polynomial equations. It is suggested that the bimodal response is a result of a dual action of TRH. First, TRH initiates the release of stored TSH from the anterior pituitary; and second, TRH stimulates the secretion of newly synthesized TSH by the anterior pituitary.     

The geometrical analysis of a predator-prey model with two state impulses

Using successor functions and Poincaré-Bendixson theorem of impulsive differential equations, the existence of periodical solutions to a predator-prey model with two state impulses is investigated. By stability theorem of periodic solution to impulsive differential equations, the stability conditions of periodic solutions to the system are given. Some simulations are exerted to prove the results.     

Thyroid gland development in a neotenic goby (ice goby,Leucopsarion petersii) and a common goby (ukigori,Gymnogobius urotaenia) during early life stages

In order to study the characteristics of neoteny in teleosts, development of the thyroid system and digestive tract of a neotenic goby (ice goby, Leucopsarion petersii) and a non-neotenic goby (ukigori, Gymnogobius urotaenia) were compared. In juvenile ukigori, the intestine was found to be convoluted once in the antero-midpart, and gastric glands were present. In the ice goby, the alimentary canal was straight, and no gastric gland was observed even in adult, suggesting that the ice goby retains larval features, not only in appearance but also in internal organs. A marked difference was also found in the thyroid system. In ukigori, activity of the thyroid gland and thyroid stimulating hormone (TSH) cells increased between flexion and postflexion larval phases. However, in the ice goby, thyroid glands remained inactive, and no TSH cells were observed. A delayed development of the thyroid system was suggested as a major factor contributing to neoteny in the ice goby.     

Aspects ultrastructuraux et synthèse de la thyroglobouline dans les cultures de thyroides avant et après transplantation chez des rats hypophysectomisés

Two aspects concerning the study of thyroglobulin synthesis and of the ultrastructure of thyroid glands in organotypic cultures have been studied: (1) the chronology of ultrastructural alterations in thyroid cultures leading to the loss of thyroglobulin synthesis; and (2) the role of TSH in the re-establishment of the characteristic features in the cultured cells following transplantation.Alterations of the endoplasmic reticulum start on the very first day of culture. The ribosomes detach themselves from the membranes which then disappear. On the third and fourth day, significant alterations are observed on mitochondria and nuclei. The lysosomes disappear, while the Golgi apparatus is hardly affected.All the above modifications are reversible, since it is possible to re-establish the characteristic features of the endoplasmic reticulum and the synthesis of thyroglobulin after transplantation of the cultured glands into normal animals.The reappearance of phenotypic traits of the thyroid cells can also be obtained after transplantation into hypophysectomized rats. However, the level of thyroglobulin synthesis in these transplants, which is similar to that in the host gland, is lower than in grafts into normal animals.This results shows that TSH is not required for differentiation and for manifestation of the phenotypic traits of the thyroid gland. It seems therefore that the role of TSH is not to stimulate differentiation, but to maintain and regulate the level of specific processes in the already differentiated thyroid cell.     

Congenital hypothyroidism, dwarfism, and hearing impairment caused by a missense mutation in the mouse dual oxidase 2 gene, Duox2

Dual oxidases generate the hydrogen peroxide needed by thyroid peroxidase for the incorporation of iodine into thyroglobulin, an essential step in thyroid hormone synthesis. Mutations in the human dual oxidase 2 gene, DUOX2, have been shown to underlie several cases of congenital hypothyroidism. We report here the first mouse Duox2 mutation, which provides a new genetic model for studying the specific function of DUOX2 in the thyroid gland and in other organ systems where it is hypothesized to play a role. We mapped the new spontaneous mouse mutation to chromosome 2 and identified it as a T>G base pair change in exon 16 of Duox2. The mutation changes a highly conserved valine to glycine at amino acid position 674 (V674G) and was named "thyroid dyshormonogenesis" (symbol thyd) to signify a defect in thyroid hormone synthesis. Thyroid glands of mutant mice are goitrous and contain few normal follicles, and anterior pituitaries are dysplastic. Serum T(4) in homozygotes is about one-tenth the level of controls and is accompanied by a more than 100-fold increase in TSH. The weight of adult mutant mice is approximately half that of littermate controls, and serum IGF-I is reduced. The cochleae of mutant mice exhibit abnormalities characteristic of hypothyroidism, including a delayed formation of the inner sulcus and tunnel of Corti and an abnormally thickened tectorial membrane. Hearing thresholds of adult mutant mice are on average 50-60 decibels (dB) above those of controls.