THE THYROID GLAND IN BLOOD GLUCOSE REGULATION
In 1825 the symptoms given by the disease produced in the thyroid gland were already described, but it was not known which was the cause nor what organ was diseased: It was not until 1914 when Kendall related the diseases of the thyroid with certain symptoms that later, in 1927, were completely clarified by Harrington.
The most voluminous and most visible gland to the naked eye, it is located in the antero-inferior part of the neck, on the trachea. This is the reason why in patients with this faculty, the movements produced by swallowing are seen when this organ is moving. In the superior part of the thorax and at the base of the skull, there are other formations similar or equal to the thyroid gland, called ABERRANCES; also their histologic constitution similar or equal to the thyroid demonstrates their equal operation.
In animals, there are various effects produced by the ablation of this gland; rabbits are those presenting the most constant signs, for which we will see its effects in them.
In young animals, during the first ten days, they do not have any symptoms. But after this time, various signs and general symptoms begin to appear. They are: apathy to everything, immobility, loss of appetite, loss of weight, and finally death. The halting of growth that is only observed in the young is due to the lack of fixation of calcium salts in the epiphysis, bony extremities, which prevents growth of bones. This is why, if they survive the ablation, we will see animals with very large heads, and extremities contrasting with their small size. Very delayed growth of teeth, and their decay, are other frequent symptoms. All the appendages of the skin, hairs, nails, etc., are stopped in their development.
Sexual activities stop or diminish to an extreme degree: the gonads keep their infantile characteristics; the formation of spermatozoa is lacking in males; and in females the ovaries do not undergo almost any development.
In the adult animals in the study, disorders of growth cannot be observed. There are, however, others more pronounced, and they are: apathy and hypothermia are more accentuated; basal metabolism reaches less than 25 to 40%; tolerance to glucids is increased; fat tends to accumulate in all the teguments; cholesterin increases and metabolism of protids stops; blood pressure drops considerably, as well as heart rate; finally intense anemia comes ending up with the death of the animals in experimentation. There is much symptomatologic difference between the different periods of life of the animal; when the conformation of the animal is taking place, which is during the last period of its embryonic life, the disorders caused by the ablation of the thyroid are IRREVERSIBLE. A cretin is an individual burdened with atrophy or degeneration of the thyroid gland since his birth; it is a congenital affection. However, in the myxedematous, the disease has been contracted when the whole development has reached the normal level.
Thyroid extract provided to healthy animals produces: cardiovascular disorders, tachycardia, increase of the number of heartbeats, and peripheral vasodilatation, where the action of the vagus does not intervene. Prolonged administration produces psychomotor excitation, characterized by: tremors, sexual excitation, trophic disorders of the skin and its annexes; fever with loss of weight. And metabolisms of all compounds are increased: acceleration of oxygen consumption and therefore greater anhydride carbonic production, greater excretion of creatinine and urea; increase of the basal metabolism; exhaustion of the reserves of glycogen in the liver and muscles.
This is one of the hormonal glands that has more relation with the regulation of glucids. In the animals which had the thyroid removed, sharp hypoglycemia and tolerance to the glucids is observed; the same occurs in myxedematous patients. All these symptoms followed by inverse dysfunction occur in the animals with hyperthyroidism. This hyperglycemic action is not due to diabetes of thyroidal nature, but to the acceleration of the intestinal absorption of glucids, caused by the stimulation of phosphorylation in the mucosa of the ileum. The oxidation of glucose in tissues is increased, which causes the reserves of glycogen of the liver to decrease.
This hormone also takes part in the metabolism of lipids. This is demonstrated by the destruction of globulins and the fixation of nucleo-albumins. For these reasons, as we already said, the elimination of creatinine increases.
Like the suprarenal, this gland has an important role in hydrous balance as well. In myxedematous patients, as well as in animal that have had the thyroid removed, edema is seen on all the teguments and in general, in all the tissues. But this edema is very discreet, without ever failing. As in all edemas, all serous fluid leakage can produce: ascites, pericarditis, and pleurisy. The diuretic role of thyroid extracts is sometimes used in therapeutics.
It regulates mineral metabolism, mainly of iodine and chlorine. The thyroid gland retains or releases iodine according to the needs of the organism. This keeps the quantity of thyroglobulin low, a mixture of diiodotyrosine and de thyroxine. All the functions of this gland are in relation with the metabolism of iodine. The thyroid body is the richest in this nonmetal; when it lacks iodine, extracts from thyroid become inactive. Administration of this substance modifies the cytology of the gland.
The vegetative and central nervous systems are maintained by the excitation of this hormone. It not only works as sympathomimetic but it is amphotrophic, meaning that it performs both functions: exciting the sympathetic and the pneumogastric. Both symptoms can be seen simultaneously in patients with sympatheticotonia, as they have diarrhea and profuse sweating along with tachycardia. In addition to this action on the nervous system of relational and vegetative life, it also has inter-endocrine action. It stimulates the genital organs; secondary sexual characteristics in men as well as in women are accelerated; and the pregnancy is maintained up to maturity when these glands work well. This hormone acts upon the liver, pancreas, hypophysis, suprarenal, and the thymus.
Various components have been extracted from this gland that are different from those with known hormonal function. All the extracts have only coincided with iodine, which is the main constant component: the true thyroidal hormone. In fact, it has been possible to extract triiodothyronine, thyroglobulin, thyroxine, and lately diiodotyrosine, which appear to be the chemical skeleton of diiodotyrosine, the one that seems to be the true hormone, THYROXINE. This is a white, insipid substance, formed of very small crystals; it contains 65% iodine. Thyroxine is already made synthetically, but its chemical qualities are different, which is why its therapeutic action is less effective.
The differences in performance of medications, depends on various chemical compositions presented to us by the laboratories.
In tadpoles, the experiments were done of adding homeopathic quantities of thyroxine to the water these animals inhabit. It quickly accelerated all the metamorphic changes. The activity of thyroxine is so effective in animals that had the gland removed and in myxedematous patients, which modifications of growth and basal metabolism almost happen inadvertently. In fact, one milligram of thyroxine administered during 2 weeks, elevates the metabolism of less than 30 by more than 12%. Both nervous systems, of relational and vegetative life, are greatly influenced by this hormone always producing excitation. The medulla-suprarenal hormone has an almost specific action over adrenaline, sensitizing the organism. This is why patients who have been given high doses of the thyroid gland sometimes experience serious cardiac dysfunction.
The mechanism of action of the hormone is not clear. It is agreed, as with all the other hormones, that it is by direct blood flow. But a fact that is against this theory is that, administered by any way of penetration, a lot of time passes, “wasted time”, for the effects of the hormone to take place. It has been thought, for this reason, that the manner in which it performs is not the same as for the other hormones; this fact is not clarified.
For some, this hormone accelerates cellular oxidation, as a simple catalyst, acting mainly on glucids. But it is also demonstrated that it has an effect on the metabolism of protids, taking part in the anaerobic stage and the processes of oxidoreduction.
The major influence on the secretion of this hormone comes from the hypophysis: activity of the hormone formation coming directly from the basophilic cells producing it, and excretion from these cells and into the blood flow. These two processes are due to tyro-stimulin produced by the hypophysis.
RELATIONSHIPS BETWEEN THE SEXUAL GLANDS AND BLOOD GLUCOSE REGULATION
The great chapter of sexual hormones is the one whose turn has come for us to deal with its relationship to the regulation of the OSES of the blood and consequently of all the cells.
Male and female sexual hormones are endowed with two main functions: external secretion — spermatozoa in the man and ovules in the woman — and internal secretion. We are only going to refer to internal secretions, the only ones related to blood-glucose regulation.
In both sexes the internal secretions or hormones, come, as it was already mentioned in another chapter, from the oxidation of CHOLESTEROL, and all have much physico-chemical similarity. But moreover, it seems that there are sexual hormones with opposite specifications in all their physiological functions.
The primitive ovum fecundated or fertilized by the spermatozoon, is going to produce or to evolve into quintillions of cells; meaning that from a microscopic cell will develop a very complex organism with different tissues and organs, but that is working as A WHOLE, in unison.
Like almost all the glands of internal secretion, the ovary is formed of two distinguishable histologically important parts: the main part, which is the medullar substance, and the peripheral or cortical part. From this last region has the OVULES producing tissues or cells. It pours into the blood some substances of hormonal nature; although a great deal is already known about their functions, they are not yet totally understood. These hormones influence, as we will see later, the evolution of the genital organs, the secondary sexual characteristics, and the preparation for pregnancy. But for the interest of our study, these are the hormones that have the most importance in the character, mentality, behavior, and almost all the manifestations of the mind of each person. We do not know their direct relations with the brain and therefore the psyche. They are not only considered as nervous, but as we already said, they are called PSYCHIC.
Clear observations have been made of the lesions of the brain caused in animals, and the following data have been obtained: a general imbalance of all internal secretions, but especially of the sexual ones is observed; there is a tumultuous general degeneration of the masculine as well as feminine sexual glands. The mitotic processes of the seminal cells stop until transforming into a shape and structure different from the norm; spermatogenesis is stopped. In women, all the processes of formation of the ovule also degenerate. In order to compensate these effects, the antithetical group of glands enters in greater activity putting in circulation an excess of hormones, especially the suprarenal, the hypophysis, and the thyroid. All this glandular decompensation in turn, brings as a consequence, outside of its orbit, in the mind of the animal in experimentation, very clear interference of psychic manifestation. If the cause that motivated the hormonal imbalance in the brain continues, it leads to a true disease, which by its manifestations, we are cataloguing as mental. But if the causes disappear, then comes a process of reintegration, as much of the testicles as of the ovaries and a recovery of the interglandular balance begins, and possibly, the mental state returns to normalcy.
Similar phenomena are observed in the so-called psychic traumas. That is not what they are, but that is the way they are judged now, for lack of sufficient arguments to demonstrate that they do not have such pathogeny. In both organic and psychic cases, in a special way the sexual glands always undergo alterations. We have observed in the sensorial sphere, for example: suppression of the auditory apparatus of the animal, even without touching the respective peripheral organs, quite serious metabolic imbalances are seen, and that generally brings repercussions in the processes of procreation.
It has already been demonstrated that there are in the hypothalamus and in the fluted body, vegetative centers directing or that are in intimate relationship with the whole so-called psychic processes. It seems also that they are disseminated in the whole cerebral mass and regulating the organic life in harmony with the psychic life, rendering uniform the rhythm of the processes of procreation in agreement with the exigencies of the surroundings in which the animal lives.
As these centers have massive activity, for this reason, any mutilation, in any degree, of the brain, always produces a deficiency in the organs that are governed by the cerebral centers.
As we are seeing from the previous chapters the vegetative-endocrine-genital complex, just as all the biological complexes, includes, as its name indicates it, all the so-called psychic phenomena, the parasympathetic-sympathetic field. They are the functions of vegetative life, governed by two innervations, one restraining and another exciting [parasympathetic and sympathetic], and the endocrine field, which is the one whose turn has come; to look at the relations existing between the regulation of sugars in the blood and all the cells.
Men as well as the women are subject to disorders of hormonal origin, with psychic symptoms, sometimes declared, and most of the times latent, hidden, mainly in the women.
As a peculiar fact, which is observed frequently in women, we found numerous cases of schizophrenia or some neuroses or psychoses, so common in individuals of feminine sex that almost all the manifestations or psychic symptoms are related to and are manifested by sexual disturbances: eroticism, in general, erotic attraction towards the opposite sex. In conscious state she is surrounded in a spiritual atmosphere, which is what differentiates us from animals, but in the final analysis, it is equal in all its manifestations, distinguishing itself by being essentially egoistic in animals and the human being.
For some, they are the two innervations of the sympathetic and the parasympathetic, those regularizing the sexual functions and for others they are essentially the same hormones, both sexual and others, those governing these functions. The pathology of the central and vegetative nervous system, in their intimate relations, when there is imbalance between the sympathetic and the parasympathetic, which are those innerving the genital sphere, is the same in the man as in the woman. Most important, for physiologists, is to cure and to understand these serious disorders, these imbalances of the vegetative system that make so many men unhappy, and a greater number of women. For other physiologists, it is the poverty of sexual hormones that produces this dysfunctioning and carries the disorders of spiritual appearance, but of clear manifestations of sexual order.
We must remember what we have observed daily: patients with eunuchoid appearance, little testicular development, and in general with all the appearances of hypoplasia, demonstrate, in real life, greater eroticism and greater capacity for all the functions of their sex. However, persons with a great development of the secondary sexual characters, and sometimes the most beautiful women, by the perfection of their physical and psychic development, often contradict these great qualities, since many have never understood, for not having felt, in spite of long periods of sexual life, the great phenomena of orgasm. This is a common cause of dramas of the individual and of much of humanity.
Brain, hormones, and the vegetative system intervene more or less, according to the case and the person, in these manifestations of sex.
In the segment from the second to the fourth sacral of the spinal cord, are located the nervous fibers which go to the genital organs, as well in the man as in the woman. All the manifestations observed, before, during, and after all the phenomena of sex, are subordinated to these nerves. The pudenda nerves are the ones that take the sensory feelings to the spinal cord and the response or the arch reflex is completed by the reply of the nerves coming out of these regions of the sacrum medulla. In addition to these medullar centers, hormones work in exciting the erotic center, on other parts and in diverse forms, and act on the cerebral cortex. The cortex receives the impressions: auditory, visual, olfactory, tactile, etc., to drive the orgasm centers, the same in the man as in the woman. By this the olfactory memory, the gustatory, visual, auditory, sensorial in general, produce the excitation of the cerebral cortex, and this acts on the centers of the sympathetic lumbar and on the centers of the parasympathetic sacrum. One recognizes that there is another channel of hormonal sexual excitation in addition to the circulatory: the nervous-hormonal, composed by the olfactory and optical nerves causing the sexual excitation by means of the optico-hypophysial and olfactory-hypophysial reflexes.
It is accepted that from the olfactory and optical nerves, come nervous fibers that act on the secretory centers of the hypophysis located in the diencephalon, causing on part of this gland, hypersecretion of gonadotropic or prolinic hormones; hormones produced by the hypophysis that are going to excite the hormonal functions of the sexual glands, in both sexes, that by the blood flow arrive at the testicle or the ovary exciting the formation of sexual hormones. This reflexive hormonal nervous channel, works more slowly than the channel of the images of the cerebral cortex, impressed by hearing, vision, sense of smell, or simply the memory of erotic cortical images.
From here, it can to be classified in two types, according to the sympathetic influence, the subjects for sympathetic-sthenic (vigorous, strong) of exaggerated sexual activity, sexual mentality and manifestations in the whole sphere of its life predominating the problem of sexuality. And the opposite, the sympathetic-labile, easily excitable, but of short, weak excitations, because the para-sympathetic is immediately overcome by its antagonist the ortho-sympathetic, vasoconstrictor. It dominates the ortho-sympathetic, which has vasoconstrictor nervous fibers and inhibiting fibers, which produces in all the organs of sexual orgasm, the calm, the rest, and the inhibition of all the genital functions. The excitation of these fibers produces the inhibition; the opposite occurs if these fibers are cut, then all the organs of erection, as well in the man as in the woman, present constant priapism that can last for months.
Experiments practiced in dogs have proven that the 4th and 5th are the ortho-sympathetic nerves corresponding to the branches from where the inhibiting fibers of the erection emerge. Not only the mechanical action of the section of these fibers but also of the touching action that arrives either from the brain or by a reflexive act can interrupt or reduce the whole orgasm, equal in both sexes.
Prolonged chastity, as well in the man as in the woman, can produce the lack of excitation and therefore cause impotence. The same as the excess, like in any other organ or system, produces, in the long run, exhaustion, impotence, and lack of response to regular excitations of the sexual sphere. Voluntary or forced chastity has an action on the cerebral cortex, producing inhibition by direct action of the cerebral cortex on hormonal secretions and action on the vegetative centers. It is not possible to specify how far each of these organs intervenes in these functions that are so complex.
It is verified in subjects with hyperthyroidism, with hyperadrenalism, with disturbances, in which occurs the immediate loss of sexual manifestations, until presenting in some cases feminoid or homosexual symptoms in both sexes. As well in the hyperadrenals as in the hyperthyroids, their endocrine secretions excite effectively the sympathetic sphere. Because of this endocrine cause of excitation, subjects or individuals are predisposed to a functional impotence, because the endocrine action has a greater effect on the ortho-sympathetic than on the pelvic para-sympathetic.
We must consider that our organic life is also subordinated not only to the antagonistic action of the ortho-sympathetic and para-sympathetic, but to the hormones, brain, and other mechanisms still not clarified, which intervene organically, in addition to the external stimuli as are the sensations pleasant or unpleasant. There are external or internal forces that we do not know how they are going to react or to predominate in a given moment. At the present time it has had much acceptance and the action of hormones is almost accepted as the cause of many mental and sexual disorders. But as we are observing by these explanations, the mechanism is extremely complicated and so far it is not possible to make a good diagnosis to know which it is, and in what quantity intervene each one of the organs in charge, or which has intervened in these functions so delicate.
THE PARATHYROlD GLANDS IN BLOOD GLUCOSE REGULATION
Hidden inside the thyroid, or at its side, are these small glands, which, despite of their size, have great importance for the subjects that we are treating here. Their situation is what caused them to be called like that. They are small yellow-brown masses from 5 to 10mm in length, 4mm in width, and 2mm in thickness; their weight is around 40mg.
In 1881, the great French physiologist, Gley, showed the importance of these small glands in the general metabolism, without being able to specify, then, their major role. It was not until 1909, when Voetglin and McCallum demonstrated their direct or indirect intervention through phosphocalcic compounds.
Parathyroid hormone administered in great doses increases calcemia from 10mg up to 20. This increase of blood calcium is accompanied by the elimination of a greater amount of calcium in the urine and the mobilization of calcium reserves of the organism. It is in the bones where this mobilization is the greatest.
The verification of these facts is demonstrated by the inverse phenomena: in the animal deprived of his parathyroid, immediately its blood calcium decreases to less than the normal amount, and its blood phosphorus increases in the same proportion. It is not known how these phenomena take place. It seems to be that the dislodging of calcium takes place by a chemical combination, which is in the organism under a calcium phosphate form. This occurs when there is an excess of calcium in the blood. In order for the calcium to remain, it must be combined with phosphorus, directing itself towards the bones, which are storing the calcium salts, when there is excess in the blood. As we will see later, these salts also have a CUSHIONING ROLE, with respect to the H ion blood concentration. That is to say, phosphates are some of the main REGULATORS of blood pH.
Some researchers have believed that the parathyroid gland also has an ANTITOXIC role towards some poisons; but there are no sufficient arguments to prove it.
The slowing of the elimination of phosphorus and calcium by the urine, with persistence of the excretion in fecal matters of tri-calcic phosphate insoluble and rich in calcium, from whose exit resulting finally in hyperphosphaturia and hypocalcemia, and the hyperparathyroidism by excess of formation of the soluble phosphocalcic complex whose considerable increase of urinary elimination of the rich phosphocalcic phosphorus compound and finally hypophosphoremia that brings the bony demineralization and consecutively hypercalcemia. p.195
From all this, it so happens that when the rate of plastic phosphorus drops, the parathyroid increases its production of the hormone and this removes from the bones of the skeleton the phosphorus necessary to replace the lack of supply by blood stream. Parathormone (parathyroid hormone) assures the regulation of phosphorus and calcium in the metabolism in such a way that the rate of these two elements always remains the same in the blood plasma, whatever may be the quantities contributed by ingestion or by whatever manner of entrance into the organism.
The regulation of the parathyroidal secretion is made mainly by the blood stream; it is regulated by the amount of blood calcium and phosphorus of the circulation. For that reason it is said that calcemia is regularized by calcium, and phosphorus is regulated by phosphorus using the secretion of the parathyroid.
The hypophysis secretes a stimulin that also intervenes in the regulation of the parathyroid secretion. The clear demonstration is seen when the hypophysis is removed totally. In these conditions, the removal is followed by a complete atrophy of the parathyroid glands. The opposite occurs with the injection of extracts of the anterior part of the parathyroid hypophysis that produces complete hypertrophy of the glands, with all its consequences. Therefore there is a PARATHYROSTIMULIN secretion of the hypophysis.
The parathyroid gland stimulates the secretion of insulin and reciprocally the pancreas stimulates the secretion of the parathyroid. About the internal secretions of the adrenal gland, we already saw its action in another chapter. The prolonged effect of the secretion of the parathyroid aggravates tetany by the entrance in activity of adrenaline. This is confirmed by hyperplasia, formation of pathological tissue at the expense of the healthy tissue, after the ablation of the suprarenals.
It seems also that the intervention of vitamin D in hypercalcemia combines with the action of the secretion of the parathyroid; the clear explanation of these phenomena has still not been given.
When the total ablation of the gland is performed, although sometimes it is difficult to remove it totally, by not knowing accurately the exact place where these glands are, the effects caused by this ablation are immediate. During the first two days the dog — this animal is chosen because of the topographic distribution of its parathyroid glands being almost always in fixed sites — becomes anxious, sad, thirsty, or without appetite. From this moment on appear fibrillar tremors of muscles of the face, of the paws, and the tail. Just a short time later, the tremors become general and those that appeared first increase, making true convulsive crises very similar to the epileptic. These crises are accompanied by acceleration of the breathing and the pulse, to end up in a coma. This situation lasts approximately one week, after which the temperature drops, emaciation becomes extreme, the stupor in the movements reaches its maximum and finally the dog succumbs in a cachexic state.
With these symptoms and signs, other humoral signs evolve in a parallel manner: exaggerated increase of blood phosphorus, with equal diminution of calcemia, without elimination of calcium salts by any of the emunctories. These humoral changes bring first alkalosis, and at the time of death of the animal, acidosis.
It is possible to realize when the ablation has not been complete, because these symptoms are less intense and they take more time in appearing and persisting. In this case, it is possible to favorably determine or to modify the state of the animal, by the administration of parathyroid compounds.
The most complete corroboration has been obtained by administering compounds of this gland to a healthy animal. In fact, the increase of calcium in the blood, and the diminution of phosphates are always in relation; and the elimination of these salts in greater amount, in the urine and in the fecal matter. Massive doses produce acute accidents, quickly lethal: vomiting, diarrhea, breathing difficulty, abundant hemorrhages, and finally, cardio-respiratory collapse.
The bone lesions are obvious; the decalcification of most of the bones is noticeable. The bone is replaced by fibrous tissue; the calcium accumulates in the kidneys and arteries.
Neuromuscular excitability is one of the specific functions of this hormone. It seems that the most real explanation about this phenomenon is due to the changes of the calcium ion existing in the blood and all the tissues. In fact, calcium ions and magnesium are moderating the motor nerves. Therefore, the lack or decrease of calcium salts brings, as consequence, the absence of nervous moderation and consequently the excitability. The increase of these salts carries inverse phenomena. It seems that it intervenes to produce this excitability, the acid-basic balance, although, as it is known, the alkalosis, increase of the ions OH– , oxhydryl, produces crisis of tetany, or what is the same, neuromuscular excitability although this alkalosis is a consequence of the lack of positive calcium ion.
We refer also to the role of the parathyroid hormone in the metabolism of toxic products derived from creatine, Guanidine, and Thioguanine. The urine of animals that had their parathyroids extracted is very toxic, which verifies the role carried out in the metabolism of the toxic elements derived from creatine. These elements are substances that when injected for this purpose produce convulsions, and they have been referred to as elements producing tetany, from the lack of elimination of these toxic substances.
As the main disorders of the phosphocalcic metabolism take place, the phosphagen, indispensable for muscular contraction, is disturbed in its chemical changes. The parathyroid hormone is necessary to metabolize this phosphagen, phosphocreatine, and plays the catalyst role. The suppression or diminution of the hormone prevents this metabolism, and the increase of phosphagen reduces the muscular reaction to faradic currents. Electrical reactions are in inverse relation to the quantity of muscular phosphagen. Because of this, chronaxie increases in tetany.
In 1925, Collip obtained in crystalline form an extracted substance of the parathyroid of the cow that has the following characteristics: polypeptide composed of many amino acids, still not determined, and probably together with a protein; it gives the reactions of proteins by chemical investigation (xantho-proteinic reaction); it contains traces of iron and sulfur; its pH is of 4.8; insoluble in fats and ether, somewhat soluble in alcohol and very soluble in acidulated water; it is destroyed by the digestive ferments and for this reason, it is not administered by the digestive tract. Ever since it was put on the market, the usual dosage has not varied. There are 20 units in 1cc. The unit is determined for an increase of 50mg of calcium per liter of blood, in a dog of 20kg (44lbs.); the result is obtained 15 hours after the subcutaneous injection of the hormone.
The medical indications are: parathyroid insufficiency, tetany caused or by manifestations of insufficiency, low calcium level in the blood, although it has not been defined if it is by parathyroid insufficiency. The production of the gland stops, when after a long period of administration, hypertrophy of parathyroid tissues is observed. It is necessary to avoid the prolonged use of parathyroid extract, due to the existing probability that intolerance is developed, which is manifested by the symptoms observed when there is hyperparathyroidism. The dose, generally, depends on the degree of hypocalcemia. For this, it is convenient, when administering this medication, to be frequently controlling calcemia. The increase of calcium in the blood shows, of course, an improvement. And once this is obtained, the same dose that obtained that improvement must be maintained, until blood calcium is regularized. It is frequent, within 8 to 18 hours of having injected the glandular extract, to notice a favorable change by sampling of blood. This change is obtained with a dose of 20 to 60 units. Later, to conserve a blood improvement, reduce by 8 units more or less and continue like that, until the normal dose of calcium is attained after many sampling. It is not only necessary, but also essential, when this hormone is being administered, to give salts of calcium and vitamin D. Without these medications administered simultaneously, the use of the hormone alone can be very dangerous. As we already said, when there is excess of glandular extract, these symptoms appear: vomiting, diarrhea, general asthenia, and lack of appetite, among the most constant obvious symptoms.
Of all the theories that the investigators have presented, about the manner in which this hormone works, it is in their interest to present irrefutable facts because it is easy to find out about each one of them.
The hormone maintains phosphate elimination in the urine at a low level. This is why there is hypophosphoremia, at the same time as the bony demineralization by liberation of tricalcic phosphate, in order to level out the amount of phosphorus in the blood. All this occurs when there is calcium accumulation that cannot be eliminated quickly by the kidneys and the fecal matter. For Collip and its collaborators, there is a direct activation of the osteoclasts by the parathyroid hormone. The osteoclasts are large cells of the bone marrow that are used for the destruction of the bony substance (myeloplax). It is inferred that the hormonal action would be achieved by exciting these cells and the consequence would result therefore in their destruction; hence the observed demineralization. The opponents to this theory point out that if this occurs, it is because there is hypocalcemia in tetany and hypophosphoremia in hyperparathyroidism. MacLean, Hastings, and Compére, give this explanation that is more suitable to the observed facts. The injection to the animal of some soluble phosphate determines the formation of a soluble non-ionizable phosphocalcic complex that is eliminated quickly by the urine. By the catalytic action of the hormone, this compound, rich in phosphorus, and calcium-poor, is formed.
The dosage of total calcium is of true interest in clinic and biology, but this data must be completed with the dosage of proteins of the blood. Alterations of hypo- and hypercalcemia, without participation of ionized calcium, are not of parathyroidal origin.
Phosphoremia does not have a great importance when it does not coincide with inverse values of calcemia; since, as we saw, the inverse dosages are interesting in the diagnosis and prognosis of the parathyroid affections of the gland.
Unfortunately this humoral sign of the inverse of calcemia and phosphoremia is not constant; but this is from the most precise biological tests.
The phosphatase dosage in the blood, the diastase able to be separated by hydrolysis, the phosphoric esters in phosphoric acid and alcohol, capable also to conduct the inverse operation of synthesis, needs 20cc of blood gathered without special preparations, with the condition that it be examined immediately after collection. The resulting serum of the immediate coagulation is put in the presence of a phosphoric ester, and after sufficient contact the phosphatase sets free a certain quantity of phosphoric acid and that is the dose obtained. The blood normally contains 0.15 Kay unit by cc of plasma, or 4 to 5 Bodansky units per 100cc of serum. This last measurement is used in the laboratories; children contain a greater quantity than adults.
The level of these ferments increases considerably in bone disorders caused by parathyroid insufficiency. This increase can go up to 400%. But these tests are not determinative in the hyperparathyroidism disorders; in addition they are not specific, since they do not represent more than a test of the activity of the osteoclasts. Verifying this last one, these increases are also observed in other disorders, as for example, in icterus by retention in cancers of the kidney, etc.
It has been very difficult to investigate, and consequently to establish the dosage of the parathyroid hormone in the blood. Only the indirect determination of the effects caused by the hormone in the metabolism of calcium is actually the research procedure closest to the truth, which led us to determine the dose that regularly circulates in the blood. In fact, the successive measurements of calcemia in the rabbit allowed us to get a slight idea of the clear action of the hormone.
Also excitability to electrical currents intervenes in the regularization of calcemia and phosphoremia.
Chronaxies are unstable and increase in hypoparathyroidism and decrease in hyperparathyroidism. Although this technique of investigation is not absolutely certain, no other more exact procedure has been found. We know, as it has already been mentioned in another chapter, that chronaxie depends, among other factors, on the quantity of calcium in the blood, on acid-alkaline balance, blood pH, and on the amount of phosphagen in the muscles.
One of the most exact procedures to investigate the action of this hormone is by means of X-rays that give precious data about the cases where hyperparathyroidism is suspected to exist; for example those showing the thinning out of the bones.
Indeed there are many procedures showing the operation of these glands, but they are all uncertain. Due to this, all the laboratory data, along with the clinical and the radiological ones, can give us a good idea of the operation of the parathyroid gland.
By order of importance in the blood-glucose regulation, we are making a quick review about the influence of each one of the glands of secretion, having begun with the least important ones. Perhaps it is due to lack of knowledge of their pharmaco-dynamic action that many have not even been studied.
Relying on the knowledge of the present time on the internal secretion glands, we will continue speaking about them, according to the importance these hormones have in Cellular Therapy, giving a brief review of each, until speaking finally of the pancreas.
The smallest gland, aberrant, of imprecise location, the parathyroid, as we just saw, is of foremost importance in the regulation of calcium. Among the most important functions, this regularization brings an endless number of metabolic changes of vital character in the organism. The action on ionized and non-ionized calcium has favored the electrical state in certain patients who have received several treatments of CELLULAR THERAPY.
None of the tests of parathyroid functioning has a definitive value. Many factors until now unknown in the phosphocalcic metabolism take place. And therefore the methods of biochemical exploration are not sufficiently studied, especially those referring to the intermediaries, since we only know the principle and the end of almost all the phenomena of life. But what there is in between is not known.
The dosage of total calcium in the blood, which is the most well-known test, resorting to the most precise method and always repeating it, demonstrates to us that calcemia is of 100mg per liter of blood.
In animals whose parathyroid had been removed, there are variations of less than half of calcium, and in those that have hyperparathyroidism, some have more than 150 and up to 200mg by liter.
Frequently there is no parallel between the humoral reactions and the clinical symptoms; for this reason it is better to always make all the dosages of calcium in the blood, in the forms in which it appears.
The blood calcium is constituted by two almost equal fractions: non-diffusible proteic calcium, lacking all physiological action, and representing nearly half of the total calcium; and PROTEIC CALCIUM, diffusible, that is truly active and partly ionized — in the proportion of two third parts — and the non-ionized. Diffusible calcium is completely ionized, and as Hastings and his collaborators demonstrate it, a simple and constant relation between the plasma proteins and their ion-calcium concentration exists. For this reason, there is no interest to do the dosages of ionized calcium.
Intravenous insulin injection produces the phenomena of hypoglycemia more quickly and with greater intensity than by ordinary routes, all appearing almost simultaneously. For reasons that we will later explain, we have almost always used this route for the introduction of medication, and the description corresponds to acute hypoglycemia.
Sensitivity is always variable even in the same individual, but anyway such variations are always within the description of hypoglycemia that we are going to give. This variability is according to the glucose reserves of the organism. In an individual who has received insulin injections and whose reserves have been exhausted, the hypoglycemic symptoms appear in a shorter time than in the first applications and with smaller quantity of insulin. In these cases a greater dose of glucose is always necessary to make the hypoglycemia disappear. All these facts were observed in a few thousand cases, confirming the theory that the symptoms are due mainly to the lack of glucose in the organism, being able to add to other phenomena, such as those of probable poisoning by lactic acid, which is one of the forms of diffusion of glucose.
From this exposé, we will conclude by saying that hypoglycemia accidents are due, primarily, to the lack of blood glucose, and to the excess of lactic acid and other products of cellular combustion. Consequently, we will have to attribute hypoglycemic symptoms to these factors.
DOSAGE OF INSULIN
Of the principal data susceptible to always produce the same hypoglycemic shock, having a special interest: the age of the individual, his weight, and the amount of glucose during fasting.
Surely the quantity of glucose stored in the form of glycogen in the liver and muscles, is a factor of great importance, but that, unfortunately so far, escapes our metering. It is probable that its quantity determines the intensity and the number of symptoms that will be present during hypoglycemia. Also, the central nervous systems and vago-sympathetic clearly influence the genesis of the symptomatology of hypoglycemia. Finally, a group of hormonal elements that have a close relation with insulin completes the symptomatologic picture. Without a doubt, this conglomerate so complex, that could not be physiologically unraveled, will clarify for us, with difficulty, the pathogeny of induced hypoglycemia.
The following description corresponds to an average, coming from patients who have been treated for disorders not related to diabetes.
The body responds to the action of insulin in very different ways. There are relatively insulin-resistant subjects, in which a greater amount of insulin is necessary to produce the same symptoms than in the individuals that react normally to the action of this hormone. There are others whose reaction is delayed, that is to say, who, with the same amount of insulin, need much more time to present the typical symptoms. These can also be called insulin-resistant, because of the time factor. Another group exists whose symptoms are not very obvious, following the curve of normal decrease and when arriving at its maximum decrease (less than half the glycemia), all the symptoms appear abruptly and almost simultaneously.
Finally, there is a group whose symptomatology and time of reactions are normal, but who, by themselves, regularize their quantity of blood glucose and, as a consequence, all the hypoglycemic symptoms disappear. It is observed clearly in these patients that the blood-glucose-regulator system has taken over the defense of the organism with the purpose of maintaining the physico-chemical properties; this is the pure insulin-resistant group. The individuals with these last characteristics are few.
The investigators who study the insulin resistance have observed it solely in diabetes patients in conditions different from glycemia. This, as it is known, varies with the food ingested prior to the time of application of insulin, as well as the psychological state of the patient at the moment the insulin is applied.
It is more common to observe insulin-sensitive individuals. Some, with a small dose of insulin, manage to lower glycemia in less than half in the same time. Others, with the normal amount of insulin, present the typical symptoms quickly. A third group, which we can call hypersensitive, with small doses and in a short time, give all the symptoms that correspond to much less than half of glycemia. A fourth group includes individuals in which appear, quickly, the symptoms that correspond to less than half, without, in fact, having reached this level. Finally, there are subjects that in just a short time and with small doses arrive quickly at less than half the glycemia, presenting all the symptoms of this state. Administering glucose to them intravenously raises their glycemia approximately two thirds, in five minutes, with the simultaneous disappearance of the corresponding symptoms; but it is sustained only a few minutes, to fall back near the primary hypoglycemia with the return of all the symptoms. These movements of rapid decrease and increase are repeated up to 5 times in the interval of two hours, more or less, eventually raising glycemia, as in the patients previously described. (See graphs, J.B. and N.J.)
For the previous classifications, we have taken into account 3 factors: dose of insulin, time of presentation of the symptoms, and their intensity.
The latter types described correspond to subjects hypersensitive to the action of insulin.
In spite of the observations that some investigators have made in experiments with animals, there are types clearly classified and perfectly defined, similar to those described. The physiological glycemia of 82mg percent normally rises, without clinical manifestations after the ingestion of glucose, reaching its maximum within 30 minutes, in such a way, that it gets to 100 and 110mg per 100cc, to normalize after 2 hours. Frequently, after this time, it drops slightly to less than normal, to return immediately to its starting point. There are no traces of glucose in the urine during this light hyperglycemia.
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