Cells have an amebic shape; a completely oriented micellar layer that can be modified under physico-chemical influences envelops them. Lipoido-proteinic compounds form this cellular membrane, apparently delicate. It is in intimate contact with the cytoplasm, is semi-permeable, and works like a reversible colloid.

The interphase zone of two heterogeneous systems that are in contact, originates a sort of membrane that tends to reduce its surface area, developing a force called surface tension.

The cellular membrane is formed by the intervention of tensio-active substances that, concentrating themselves in the separation area, give rise to superficial condensations. Also proteins and other substances forming the cell have a tendency to concentrate themselves in the separation area. This accumulation of molecules, necessary for balance in certain cases, results in coagulation or the gelatinization of the protein.

All living substance is composed, to a large extent, of substances that have the property to considerably diminish the surface tension of the water in which they are in solution within the organism. If a substance in solution has the property to diminish the surface tension of the solvent, it will be concentrated in the surface of separation, with the result that the final equilibrium of the system corresponds to the minimum free energy compatible with its total energy.

The tensio-active substances entering in the formation of the membrane decrease its permeability because it increases its surface tension, being generally little or not at all ionizable. Dissolved, ionizable salts decrease the surface tension, increasing the permeability of the membrane; an identical action forms anions and cations. The surface tension decreases with the temperature, disappearing completely as it reaches the critical temperature of the liquid.

THIS PERMEABILITY, WHICH IS SELECTIVE, DEPENDS ON ITS NEEDS, AND THESE ARE SUBDUED BY PHYSICO-CHEMICAL AFFINITIES, ACCORDING TO THE CHEMICAL COMPONENTS OF THE CELLULAR PROTOPLASM AND THE PHYSICAL PHENOMENA WHICH ARE FORCING OR PREVENTING THE REQUIRED SUBSTANCES TO PASS THROUGH THE MEMBRANE.

In order to make the cells permeable to the liking of the researcher, it is indispensable to modify the osmotic tension of the blood, the surface tension, pH, etc., of both elements in contact, cells and blood. These modifications produce physico-chemical changes first in the blood and later in the cells, which forces all the cells of the organism to become permeable.

The speed of diffusion will depend on the size of the molecules of the diffusible substance, as well as on their molecular weight and their electrical charge.

Crystalloids are substances that diffuse more quickly and almost all with the same speed. However, colloids do it with difficulty, or they do not diffuse.

The osmotic pressure of a solution depends on three main factors: concentration of the substance, its characteristics, and temperature. Electrolytes behave as true molecules.

The increase of temperature and of crystalloid concentration increases osmotic pressure; at the same concentration, electrolytes have more or less double osmotic pressure. Osmotic pressure of colloids is low or nil.

Any modification in the solubility of the protoplasm’s proteins as a result of pH change and with it osmotic pressure (that is most frequent) determines a change in the dimensions or the shape of the cell. Equally, it builds the concentration of the biological fluids within certain limits.

The solvent where these physico-chemical phenomena take place is water, which is found in the blood in a proportion of 68%. There is a state of permanent and fixed fluidity, which allows all the physiological functions to take place. We cannot determine yet what quantity of water is necessary to stop the vital activity, but it has been demonstrated that the less the quantity of water, the less, also, the activity of the beings or their organs. This demonstrates that vital activity is in close relation with the cellular water content.

The water of the cells is partially in chemical combination with the substances that are in contact with it, the existing true colloidal ions (micelles with variable electrical charge) more or less voluminous, that we can consider as nucleus of attraction, of a greater or lesser number of water molecules, with which it forms various compounds (degree of hydration or absorption of colloids).

When we want to extract water from colloids, we find a resistance that is the expression of the attraction force, which unites the solvent to the colloidal ions. Colloidal affinity between solvent and micelles is weak, as occurs in the case of glycogen. The water is not in absorption state and its physico-chemical properties are not deeply modified.

As micelles of a colloid are passing from the ion state to the state of electrically neutral micelles, a transformation of the water takes place, combined totally or partially in the protoplasm.

In 1896 Starling gave an explanation that seemed satisfactory, of the mechanism by which the watery balance between the blood and tissues is maintained. Landis indicated the four essential points established in the hypothesis of Starling, namely:

1. — The capillary wall, as a semi-permeable membrane, is permeable to water and crystalloids; but, normally, impermeable to the passage of proteins.

2. — Blood crosses the capillary network at a specific pressure, which, if it were not canceled by another opposing force, would cause the passage of plasma fluid into tissue spaces.

3. — As the crystalloid content of the plasma and tissue fluid is sensibly the same, the osmotic pressure cannot affect in permanent manner the distribution of water from the vessels to the tissues.

4. — Proteins of the plasma are retained within the capillaries, because of what represents a colloido-osmotic pressure (oncotic pressure) that would cause the fluid passage towards the blood, if the force that they caused were not canceled by another inverse force.

That is to say, the movement of fluids between tissues and blood would equalize by the action of two opposite forces that would work through a semi-permeable membrane that is the capillary wall: first, the pressure of the blood in the capillaries would move in the direction of the capillary to the tissues; second, the osmotic pressure of proteins would move in the opposite direction.

It was demonstrated that the defective operation of the endocrine glands brings physico-chemical modifications in humors, modifying consecutively the internal cellular operation. It is the vago-sympathetic system, working harmoniously with the hormonal complex, which maintains this balance.

The regulating humoral hormone par excellence is insulin.

To measure this phenomenon accurately and safely, the electrometric or ionometric method was employed, using the potentiometers of Hellige, Beckmann or Coleman, giving exact results of clinical interest. Colorimetric methods — as the great majority of those used in laboratory — have almost no value, being subject to the senses of man, because the results vary with individual appreciation, giving errors that are actually observed and which are often contradictory. For these measurements we used the potentiometer of Hellige (the simplest is Beckmann’s, but the most accurate is Hellige’s).

In microbiology the germs that can be developed in a medium varying in pH between 6.2 and 9.0 are called bacillo-ionic. These are extremely rare, and the great majority are called hemo-ionic in which the medium is always constant and certain. And others perish when these limits change.

The established theories affirm that any variation in acidity is necessarily fatal. Man is also considered as homo-ionic, as well as all the higher organisms. Humors and mainly the blood of man have a very precise and constant pH, with stability maintained by an aggregate of very effective mechanisms, not yet well studied. They are: the action of the secretion of hydrochloric acid of the stomach, the emunctory action of the intestine, the emunctory action of the cellular waste, the mono and bimetallic phosphates, the carbonic anhydride system and the carbonates, and the role of protids.

ROLE OF HORMONES

All the organic functions work under the action that we will specify later, of the internal endogenous regulatory resources, which are the hormones; and the external exogenous regulatory resources, which are the vitamins.

Various nervous and humoral mechanisms work in their harmonious complex: nervous fibers originating from the nervous cells of the ganglia; some belong to the sympathetic and the others to the para-sympathetic. For this reason the effects of these two fiber groups have an antagonistic action. It is necessary to remember, also, that the myelinic preganglionic fibers, coming from the neurons of the vegetative cerebrospinal centers, are uniting these centers to the corresponding sympathetic ganglia.

Glands also possess another intrinsic innervation; microganglias that are in their own parenchyma; which gives them autonomy when for some reason they lack the other innervation.

It is in the diencephalon (the subthalamic region of the brain, and wall of the third ventricle) and in the endocrine glands that are annexed to it (hypophysis and epiphysis), where is the central regulating system of most of the vegetative functions. Two centers are distinguished: one hypothalamo-hypophyseal and another epithalamo-epiphyseal, connected to diverse neighboring nervous formations that are united to each other, and to the other nervous centers by fibers of association. This is the great NEUROGLANDULAR regulating system that directs the great functions of the organism: metabolism of water, of glucids, protids, lipids, minerals, basal metabolism, and regulation of internal and external secretions.

These lipido-proteinic compounds that mainly form the cytoplasm of the cells and that are found in colloidal state, play a fundamental role in the intracellular chemical phenomena, particularly in the oxidoreduction processes. It is here where are observed processing products, which are included in the vacuoles constituting a VACUOMA. They have a variable aspect according to the state of secretion in the cell. Their morphology and their role are still in discussion.

Direct innervation or by intermediary of the sympathetic and parasympathetic ganglia, is what controls hormonal secretions. These orders, issued by the nerves, are reflexive and rapid, and the excitation of the other hormones arriving to them by blood vessels is slow; both complementing each other, and their work is delicately harmonious.

It is also important to note that certain metabolic products have influence in the hormonal regulation, for example: the islets of Langerhans adapt their insulin secretion to the variations of glycemia, outside any of the other controls. Hyperglycemia increases the production of insulin, however hypoglycemia inhibits it. Also the products retained in the blood by renal insufficiency cause a lipoidic overload in the cortico-renal cells.

It seems demonstrated that these glands function mainly by a CHANGE IN CELLULAR pH, produced by the dislodging of ions from their protoplasm.

ALL THE VITAL PHENOMENA ARE CONTROLLED BY HORMONES, from the fertilization of the ovum, the embryonic life, until the completion of the whole harmonious assembly of the physico-chemical phenomena, between which are very especially placed the so-called PSYCHOS, that by these hormonal actions, now clear and precise, can already be discarded as such.

They govern the growth, the inner and outer conformation of the individual, without forgetting that the personal genetic characters of each individual are hereditary, their transmission occurs by the “genes” of the chromosomes from the nucleus of the reproductive cells.

They take part in the general metabolism and in particular of almost all the cellular components: lipids, glucids, protids, minerals, water, and salts, etc. In the following chapters we will study the well-known details, to date, of these phenomena.

THE PITUITARY GLAND (hypophysis) IN BLOOD GLUCOSE REGULATION

The ablation of the anterior lobe of the pituitary gland produces in young animals the cessation of development. The verification that there is a hormonal substance favoring growth is that, in the animals to which the ablation had been performed, when they are injected with coarse extracts of the adenohypophysis, it is observed that they start developing again, and their growth accelerates. These facts demonstrate that a somatotropin hormone (growth hormone) exists.

It secretes a series of hormones whose action is to stimulate the operation of the various glands; for this reason they have been called “stimulins”.

So there are gonado-stimulins. In the woman they excite the germinal epithelium to form folliculin (estrogen); and in the man the seminal canaliculi, to form the spermatozoon. Another gonado-stimulin causes in the woman the formation of the yellow body and as a result the secretion of lutein; and in the man, hyperplasia of the interstitial cells to form testosterone, the hormone that has been so therapeutically useful, in our times.

The complete verification of the existence of these STIMULINS is in the fact that the hypophysectomy produces in the young animal the stopping of the development of the whole genital tract and in the adult animal the atrophy of the genital organs. From this we deduce the primary role of the hypophysis in the phenomena of reproduction.

Also the ablation of the hypophysis produces atrophy of the thyroid, with decrease of the basal metabolism, and which can return to its normal state with the injection of pre-hypophysial extracts; by the action of the thyroxin, which carries the appearance to the normalcy of the basal metabolism and iodine deficiency, modifications of the epithelium and of the colloids of the thyroidal vesicles.

This stimulin has been isolated in the urine; it is formed of very complete polypeptides. It has not been possible to synthesize it in laboratory.

It seems that there are several pancreatico-stimulins hormones of hypophysial origin. Hypophysectomy produces atrophy of the islets of Langerhans, however the injection of extracts produces hyperplasia of the same islets, from which one concludes that there are probably hypophysial-stimulins for the pancreas. Hypo and hyperglycemias correspond to these cytological signs.

The modifications of glycemia consecutive to the hypophysial influence are paradoxical; what we wanted to explain is that there is a pancreas-stimulating hormone and another diabetogenic hormone anti-insulin.

The knowledge that we have about the stimulins for the parathyroid is vague; but we have the assurance that they exist, since the ablation of the hypophysis determines atrophy of the parathyroid, as well as the injection of hypophysial extract causes hyperplasia and a structural modification of those organs. At the same time, the hypophysial extracts initiate hypercalcemia and the ablation of the hypophysis starts hypocalcemia. However we have not been able to isolate the parathyroid-stimulins. It seems that in the urine of pregnant women there are very similar substances that could well be these parathyroid-stimulins.

All the stimulins are of protein nature, thermolabile, and easily destructible by the digestive ferments.

Prolactin is another different stimulin, which stimulates the secretion of milk. It is also different in its chemical constitution. This stimulin only works during pregnancy and nursing.

THE HYPOPHYSIS IN THE METABOLISM OF GLUCIDS, LIPIDS, PROTIDS, AND WATER

The hypophysis plays an undeniable part in the metabolism of glucids: it is hypoglycemic for the action that exercises its stimulin on the islets of Langerhans, and activates the production of insulin by means of the pancreas-stimulin. The diabetogenic hormone is hyperglycemic.

If certain hypophysial extracts are injected during several days, we will see all the symptoms of diabetes appear. It seems that the diabetogenic hormone represents the antagonistic compound of insulin, but the experiments in dogs could not be well verified. We think that these mechanisms of glycemic regulation are more complicated than what at first sight seems so simple.

Patients give the verification of the experiments conducted in animals to us when hypophysial syndromes appear. In acromegalics and giants, diabetes is frequent, however in hypophysial insufficiency, it is frequent to observe hypoglycemia.

THE ANTERIOR LOBE OF THE HYPOPHYSIS IN THE METABOLISM OF LIPIDS

The specific dynamic power of proteins is the increase of the caloric production that is observed in the course of a meal that contains albumin; it is decreased by hypophysectomy. Grafting of hypophysial tissues in the hypophysectomised animal increases the specific dynamic power of proteins. In spite of all this, the action on proteins is not very accurately verified.

From the extract of the posterior lobe of the hypophysis, is extracted a substance called Pitressin, Vasopressin, or Beta-Hypophamine that causes intense and prolonged vaso-constriction in all the vessels, to such degree that the subject takes a pale haggard color because this hormone works on the small muscles of hair follicles; which produces a slight arterial hypertension with bradycardia and an increase of cardiac energy. It has in addition an antidiuretic action, which prevents the loss of water from tissues.

Hypophamine, Pitocin, or oxytocin, is the hormone of the posterior lobe that has an energetic action on smooth fibers; which is utilized in childbirth to bring or to reinforce uterine contractions. All the smooth muscles obey this hormone, which is taken advantage of clinically to move, when indicated, the intestine, the gall bladder, the bronchi, etc. The physiological action of these two hormones is not very well differentiated; their effects on man are very similar.

Classically it is not known how this syndrome of anuria takes place.

SUPRARENAL CAPSULES IN BLOOD GLUCOSE REGULATION

In 1543 Eustachio discovered the suprarenal glands. But it was three centuries later, in 1855, when Addison connected the suprarenal glands to a disease that gave to the teguments (skin) their bronzed color, and which was accompanied by cachexia and anemia; it has been called Addison’s disease since then.

Brown-Séquard, in removing these glands from animals, demonstrated that they die quickly and that therefore these are vital organs for the organism; with these experiments began the search for what makes these glands so interesting.

Takamine and Aldrich discovered an internal secretion of the suprarenals, secreted by the medullar part of the capsules, called Adrenaline. Ultimately, from the suprarenal cortex, have been isolated several hormonal secretions of true physiological and therapeutic interest. We will talk more about them later, in keeping with the spirit of this explanation.

To these clinical symptoms, metabolic disorders are added. The main ones are: marked decrease of the blood Na (sodium) with consequent water elimination through the emunctories; increase of blood K (potassium) from the lack of renal elimination; blood nitrogen increases and signs of renal insufficiency appear; creatine, that normally phosphorylases in muscles by the presence of the cortico-renal hormone, is eliminated by urine and as a consequence muscular phosphorylation does not occur, reason why the rate of phosphagen decreases; the amount of blood glucose, hepatic and muscular glycogen decreases to the minimum, to such degree that the researchers attribute the death of the animals under experimentation to this hypoglycemia; adynamia, hypothermia, great sensitivity to cold, and the lowering of basal metabolism from 15 to 30% accompany all these chemical, humoral, and tissular disorders.

We just finished considering the great disorders observed in experimental animals, whose whole glands are removed; then the metabolic disorders, especially those involving electrolytes and water, are those which suffer the most from the effects of decapsulation. If the cortico-renal hormone is administered to the animals at a strong dose, those disorders are immediately corrected, increasing the renal excretion of potassium and decreasing that of sodium and water. With this, the animal’s weight increases.

Research and chemical products laboratories of Mexico have managed to extract from tropical plants (cabeza de negro), abounding in the Republic, products almost equal chemically to the hormones of the suprarenal capsules. These hormones, extracted from plants, as well as the sexual hormones, have much chemical similarity. And for this reason, Mexican chemists have also managed to extract, from the same plants, male and female hormones: folliculin, testosterone, and progesterone, chemical substances derived from sterols.

Sterols are solid alcohols derived from LIPIDS. Besides having very important functions, they are part of essential compounds in the organism, of which the most important, is cholesterol that is formed of a polycyclic nucleus, including 2 hexagonal cycles and 1 pentagonal. We also found cholesterol, not only in the animal organism, but also in certain vegetables and certain yeasts. It is one of the components of bile; all the tissues contain it. Structurally, from the chemical point of view, it is one of the components of the suprarenal and sexual hormones. But it is also a carcinogenic, tumor producing substance.

It has been possible to extract from the suprarenal capsules, a crystallized desadrenalinized substance called “CORTIN,” a compound of three substances: corticosterone, 11-dihydro-17-hydroxycorticosterona, and desoxycorticosterone. The first is insoluble in water and is almost inactive; the second is soluble in water and is active; and the third is the most active. From the therapeutic point of view, a greater activity seems to be observed when the suprarenal extracts contain all three substances, than when there is only one. However, some manufacturers already produce the three substances synthetically, and to all three they attribute vitalizing effects. Cortin is a natural product, chemically very complex. It produces the same effects by mouth as well as parenterally. It is almost non-toxic. It seems to be a degradation product, by successive oxidations, of cholesterol. It also seems to precede the chemical formation of cholesterol.

The cholesterol content of bile oscillates from .04% to .16%. It remains free in the bile due to the bile salts. If the relation that exists between the quantity of bile salts and cholesterol changes, immediately the cholesterol precipitates and calculi form. Changes in blood cholesterol do not affect the amount of cholesterol contained in the bile; neither do ingested foods. As a result cholesterol continues to be excreted even when foods have no traces of it.

As the cause of this disease is not clear (all patients, even the most similar, have various apparent causes that induced the disease), they have been directed to hormone therapy, and in some cases there have been favorable results. This leads us to think about metabolic disorders, especially of the protids. In fact, there has been clear interference from tyrosine, histidine, and leucine. These metabolic interferences speak in favor of hormonal therapy, above all, the one that modifies protein compounds. The hormonal substance extracted from CORTIN has been called 17-hydroxy-11-dihydrocorticosterone by the North Americans.

Cortin is a very complex natural polyhormonal compound. Summarizing its functions within the organism, we have: it prevents the death of decapsulated animals, if administered to them before decapsulation; it prevents all the disorders and accidents caused by suprarenal insufficiency; when the decapsulated animal enters the comma state, before death, it performs true resurrections, administered on time primarily making myasthenia disappear, for a long time preventing the repetition of all accidents produced by the suppression of the suprarenal capsules. As corroboration of the preceding, in the animals to which the capsules have not been removed, the characteristic humoral modification of cortical hyper-adrenalinemia is observed; that is: increase of blood glucose, increase of hepatic glycogen, increase of blood glutathione, and increase of blood cholesterol.

The increase of muscular activity is observed in obvious form, as much in resistance, as in quality. All the sexual functions of experimental animals increase in all their aspects.

Cortin, or natural cortico-suprarenal hormone and desoxycorticosterone, are not equal products. As we already said previously, this last form splits off and perhaps; it is the most important of the constituents of the natural hormone.

Cortisone, or 11-dehydro-17-hydroxycorticosterone is one of the active substances isolated by Kendall. It modifies the electrolytic balance, decreases the K of the blood, increases the resistance of insulin, produces hyperglycemia, increases the creatinine and the elimination of uric acid, etc. When doses are excessive, the intolerance phenomena are manifested by: hirsutism, acne, thickening and striation of the skin, amenorrhea, etc. In many subjects it produces psychomotor activity and a sensation of euphoria; sometimes it has produced some reversible psychosis. It has been indicated for all forms of arthritis.

Desoxycorticosterone is the other crystalline fraction of the total extract of the cortex, which lately is obtained by synthesis. Its action is manifested by a greater chloride and sodium concentration in the serum and an increase of the plasmic volume, with decrease of potassium. It increases physical force, blood pressure, appetite, and weight. In affections of hepatic parenchyma, its use is indicated to stimulate synthesis of glycogen and to modify mineral exchanges.

Some pharmaceutical companies have made available to the doctor this hormone soluble in water, which has facilitated its intravenous use in 50mg doses. It is the most effective ANTI-SHOCK hormone known to date.

Cortin increases the volume of blood by extracting from cells the water they produce. As a mechanism, it has not yet been possible to explain clearly; it is considered as the hormone that acts on the water and salts contained in the organism. The metabolic influence, which is most interesting, then, in addition to its influence on organic salts and water, produces: an increase of sulfhydryls compounds, especially glutathione, reducing, by this action in the blood, neutral sulfur; the rate of nitrogen in the blood decreases; the alkaline reserve increases; muscular phosphagen also rises; and creatinuria disappears. This hormone is indispensable for the maintenance of glycogen reserves of the liver and muscles, since it increases glycogenesis, mainly in fasting, when the organism cannot have these foods. It takes part in the intestinal absorption of glucids and lipids, because for the absorption of these bodies and the lactoflavin contained in foods, the previous phosphorylation of the digestive tract walls is necessary.

The thermogenic function is tied to these muscular functions and is independent of the intervention of the thyroid glands, because, as we have seen, they have a special function on glucids during muscular contraction. In order to corroborate these thermogenic functions on decapsulated animals, great doses of CORTIN are administered to them and the immediate elevation of temperature is observed.

Experimentally, the great INTER-ENDOCRINE influence of CORTIN has been demonstrated. In males, injections of this substance produce the fast appearance of secondary sexual signs. And in females all the phenomena of ovulation with all the processes that accompany it are accelerated. In animals deprived of ovaries, the occurrence of the abortion is prevented, and the animal can continue its pregnancy when administered a CORTIN compound.

These clear demonstrations, that have shown us the great influence that cortin has on the sexual glands, have amazed the laboratories who have already launched on the market various VIRILIZING products, that actually have effects on sexual activities in all their manifestations. Howard has claimed to have discovered, in the suprarenal cortex, a special zone that he has called X, and which, according to him, disappears with age and seems to be the site where the suprarenal hormone is produced, that has as much influence on the male sexual hormones as on the female. Of all the functions of cortin, this has been the most exploited, as much from the economic as from the vital point of view. It is probable that in times not too distant and with the advance of hormone therapy and chemistry, man can live with all his faculties for many years; the path is laid out.

Only the results of the deprivation and administration of this hormone to animals are known; but the mechanism of how these vital phenomena take place is not known. The facts so far are clearly demonstrative and with them thousands of illusions have been dreamed up, by incomplete or prematurely aged men, as well as by private researchers and research laboratories, looking for the effectiveness of the products they are sending on the market.

How gonado-stimulin causes the sexual glands to react has not been explained satisfactorily. There are two explanations still not accepted: the catalytic action of oxidant-reduction similar to the one taking place in all the cells, and another reaction of phosphorylation, already explained in this same chapter, comprising the metabolic functions of all the cells. One theory or another, verified or not, does not have any importance; the facts are so far undeniable and well demonstrative. The direction of mental and physical activity and longevity are going this way.

There is a narrow chemical relation between sexual and capsular hormones; this relation has been corroborated by the physiological functions that they are both carrying out, in animal experimentation and in man. To a similarity of chemical structure corresponds, as a rule, a similarity of action.

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