Surgery then enters upon the scene. The great Swiss surgeon. Theodore Kocher, performed the first excision of the thyroid gland in human beings for goitre, in the same year. In 1882, J.L. Reverdin, another surgeon of Geneva, noticed that in man complete removal of the thyroid was followed by symptoms identical with those collected under the name of myxedema, and used the phrase "operative myxedema" to emphasize his conviction of the connection between them. Then Schiff, in 1884, neglected twenty-five years, came back, with an array of demonstrations, proving that the various symptoms, tremors, spasms and convulsions, following removal of the thyroid, could be prevented by a previous graft of a piece of the gland under the skin, or by the injection of thyroid juice into a vein or under the skin, or by the ingestion of thyroid juice or the raw thyroid by mouth.

A crystallization of ideas about the true function of the thyroid was now inevitable. In 1884, Sir Victor Horsley produced an experimental myxedema by removal of the thyroid in monkeys, resembling closely in its symptom-picture the disease as it occurs in human beings. Moebius, a German neurologist, came out boldly for the conception that a number of ailments could be due to qualitative and quantitative changes in the secretion of the thyroid, and that just as myxedema and cretinism were due to an insufficiency of the secretion, Parry's disease was to be ascribed to an excessive outpouring of it. The next steps were easy. In 1888, Sir Felix Semon, as an outcome of a collective investigation, established for all time that cretinism, myxedema and post-operative myxedema were one and the same.

It was bound to occur to someone that if human myxedema and animal experimental myxedema were one and the same, Schiff's procedure of prevention and cure by feeding thyroid gland by mouth in the latter could be applied to the former. The idea occurred to two men, Murray and Howitz, in 1891. Murray's patient, a Mrs. H., was shown before the Northcumberland and Durham Medical Society, an English country medical organization, in February, 1891. She was forty-two years old and had borne nine children. The illness attacking her had begun insidiously, with a gradual enlargement and thickening of her face and hands. She had become very slow in speech and gait, sensitive to cold, and languid and depressed in spirit to the point of inability to go about alone. Murray, employing the glycerin extract of the thyroid gland of a freshly killed sheep, injected twenty-four drops hypodermically, twice a week. There was an immediate and marvelous improvement, which continued steadily, Murray finding that it could be maintained by feeding the gland by mouth. The features and skin returned to the normal, speech quickened and she became able to walk about and live her life without hesitation or assistance. She lived to the age of seventy-four, dying in 1919. In the twenty-eight years, during which it was always necessary to administer the thyroid, she consumed over nine pints of thyroid, comprising the glands of 870 sheep.

Giants and dwarfs and fat people have always interested people as freaks, departures from the usual and the normal, and have formed the stock of popular museum, circus and country fair. Every mythology has concerned itself with them. The Titans among the Greeks, Og, Gog and Magog among the Hebrews, are examples of the fascination of the superlarge. John Hunter, the founder of experimental surgery, spent a fortune in chasing after the skeleton of a famous Irish Giant in 1783. Dwarfs have also fascinated—witness the short-limbed satyrs of the Greeks and the dwarf gods (Ptah and Bes) of Egypt, as well as the vogue of the court dwarf-buffoons, of whom Velasquez has left us some portraits. Fat people, obesity as a manifestation of personality, have aroused wonder and amusement the world over. The Fat Boy has always furnished good sport to the Sam Wellers.

All these characters, tall or short, fat or lean, are related to the activity of a gland of internal secretion in the head, the pituitary, which became a centre of interest in the late eighties. Because of its situation, the opinion of the ancients was that it was the source of the mucus of the nose, an opinion reinforced by the greatest anatomist of the Dark Ages, Galen, and held up to the seventeenth century. In other words, it was considered simply a gland of external secretion. Experimental removal of the pituitary was essayed by Horsley in 1886, the same man who two years before had reproduced myxedema successfully in monkeys. Others succeeded his attempt. But the conclusions drawn were uncertain or contradictory, resulting from the difficulties of the operative technique of getting at a gland placed at the base of the brain. Not until 1908 was the problem solved by Paulesco of Bucharest, who devised a way of reaching it by trepanning the skull. He was thus able to prove beyond a doubt that the pituitary gland was essential to life, and that without it no animal could continue to live for any length of time. Soon after, Harvey Gushing and his associates at Johns Hopkins Hospital discovered that removal of part of the gland was followed by a pronounced obesity and sluggishness. A basis for the understanding of obesity and growth was then established.

In the eighties, there came to the clinic of Pierre Marie in Paris, a pupil of the great Charcot, various women complaining of headache. They also told him about an enlargement of their hands and feet, and an alarming change in the bones of the face. He differentiated the affection from its imitators, and created its present designation of "acromegaly" (enlargement of the extremities). Also he correlated their relationship to the giants who have been mentioned. Acromegalics have been also likened to the Neanderthal Man, who had probably, as the gorillas may have, an excess of the pituitary in their systems. For four years he studied the morbid phenomena in the tissues of these sufferers at last consigned to their end. First one, and then another, and then a third and a fourth exhibited a striking hypertrophy of the pituitary body and a consequent widening of the portion of the base of the skull which cradles the gland. He proceeded to say so in the graduating thesis of his pupil, Souza Leite. The inference was inevitable that the entire process was to be put down to an overactivity of the pituitary. Ever since, too, the growth of the skeleton has been accepted as controlled by that gland.

About this time another set of old observations came to life again, related to those of Docent Berthold on the auto-grafting of the testes of a cock, with complete retention of its sexual characters, which he said, must be due "to the productive action of the testes, i.e., to its effect upon the blood, and thence to the corresponding effect of such blood upon the entire organism." Of course, stock raisers and poultry fanciers have noted the interesting outcome of castration for about as long as their professions have existed. And for ages the diminution of sexual activity as a predecessor to the decadence of senility has been harped upon. Rejuvenation, especially in connection with sexual activity, as well as with tissue and spiritual elasticity, has been one of the haunting phantoms of the imagination for as long as we have records of articulate humanity. Together with El Dorado, the Elixir of Youth has shared the honors with the Philosopher's Stone. The idea of employing the chemical materials of the sex glands, the testes or the ovaries, to bring back youth, to restore juvenility, had not, as far as we know, occurred to anyone who at any rate put himself on record, by word or deed, until 1889. The hero of the new departure was the hero of so many daring adventures among speculative experiments, Brown-Sequard.

At this time the wanderer was an aged sage, seventy-two years old, fit, as custom goes, only for retirement and resignation to the fate of all flesh. The old passion of experimenting upon himself as well as upon the guinea-pigs, dogs, cats and monkeys, by which he was always surrounded, was as alive and kicking as ever. I suppose he had been thinking for years concerning some method for the resumption of youth, for we find him exclaiming, when the opportunity loomed of a great laboratory on Agassiz Island, Long Island, on one of his recurrent flights to New York: "Would that I were thirty!" And other passages in his personal communications refer again and again to his consciousness of growing old. The miracles that were being performed by injecting thyroid and feeding thyroid in animals probably acted as the spark to an inflammable mass of ideas long smouldering in the subcellars of his mind. The effects were reported to the Society of Biology in Paris, one memorable evening, June 1, 1889, in two notes on the results of the hypodermic injection in man of the testis juice of monkeys and dogs, and certain generalizations deduced therefrom. Such juices, he stated, had a definite energy-mobilizing or, as he put it, dynamogenic action upon the subject himself, stimulating amazingly his general health, muscular power and mental activity.

These experiments, their nature, the manner in which they were conducted, the character and age of the experimenter, and the results claimed, were exquisitely good stuff for ridicule. Cartoonists and reporters leaped upon the theme with the avidity of the true-blue interviewer. Paris, where to be ridiculed is to be killed in public with the most ignominious of deaths, reacted as only the French temperament can react. The wits of the salons crackled, the bourgeoisie chortled, the proletariat roared. The Elixir of Life had been discovered and it was excellent sport.

But Brown-Sequard remained unshaken. He had all the roues of Paris running to him, and consequent charges of quackery and charlatanism. How much of these unsavory epithets really applied to him will not be determined until we have a better acquaintance with his more intimate life. A biography and collection of his letters is needed. But it is certain that the general principles he arrived at, aided as much by the wings of intuition as by the clues of incomplete and incompletely controlled experiments, survive as the foundations of whatever we know about the internal secretions, and all our present viewpoints. He summed these up in 1891 as follows:

"All the tissues, in our view, are modifiers of the blood by means of an internal secretion taken from them by the venous blood. From this we are forced to the conclusion that, if subcutaneous injections of the liquids drawn from these parts are ineffectual, then we should inject some of the venous blood supplying these parts.... We admit that each tissue, and, more generally, each cell of the organism, secretes on its own account, certain products or special ferments, which, through this medium (the blood), influence all other cells of the body, a definite solidarity being thus established among all the cells through a mechanism other than the nervous system.... All the tissues (glands and other organs) have thus a special internal secretion, and so give to the blood something more than the waste products of metabolism. The internal secretions, whether by direct favorable influence, or whether through the obstacles they oppose to deleterious processes, seem to be of great utility in maintaining the organism in its normal state."

The only part of this statement not conceded today is that relating to the formation of internal secretions by tissues other than those of which the cells are definitely glandular, that is secretory: as can be determined under the microscope. Brown-Sequard added to the concept of internal secretions, fathered by Claude Bernard, the idea of a correlation, a mutual influencing of them and of the different organs of the body through them. The nervous system had hitherto been regarded as the sole means of communication between cells, by its telegraphic arrangements of nerve filaments reaching out everywhere, interweaving with each other and the cells. The Brown-Sequard conception inferred the existence of a postal system between cells, the blood supplying the highway for travel and transmission of the post, the post consisting of the chemical substances secreted by the glands. To be sure, the doctrine was only an inference, though well-founded, of which the direct experimental proof was not to be obtained until the researches of Bayliss and Starling. Yet to Brown-Sequard belongs the immortal credit, if not of the originator, at any rate of the resurrector of the idea of using gland extracts to influence the body. The unwarranted hopes aroused by his enthusiastic reports of rejuvenating miracles have long since been dissipated. Moreover, they smeared the whole subject with a disrepute which clings to certain narrow and unreasonable minds to this day. But as every physiologist since has acknowledged, he was and remains the great path-breaker in the conquest of the internal secretions.

THE HORMONES

The problem of the internal secretions was now attacked from another angle. A great Russian physiologist, Pawlow, called attention to the fact that the introduction of a dilute mineral acid, such as the hydrochloric acid, normally a constituent of the stomach digestive fluid, into the upper part of the intestine, provoked a secretion of the pancreas, which is so important for intestinal digestion. He explained the phenomenon as a reflex, a matter of the nerves going from the intestine to the pancreas.

His pupil, Popielski, threw doubt upon so easy an explanation, by proving that the same reaction could be elicited even after all the nerve connections between the gut and the spinal cord were severed. If the relation was a reflex, it would have to be classed now as one of those local nerve circuits, which are pretty common among the viscera, a local call and reply as it were, without mediation of the great long distance trunk lines in the spinal cord and the medulla oblongata.

The work of Bayliss and Starling, two English physiologists, was commenced then to test the hypothesis. They soon found that the experiment could be so devised as to exclude any influence whatever on the part of the nervous tissues, and yet result positively. Thus, if a loop of intestine was so prepared as to be attached to the rest of the body only by means of its blood vessels, all the nerves being cut, putting some acid into it was still followed by a flow of pancreatic juice, no less marked than when none of the parts about the piece of gut had been disturbed. It was evident that the stimulus to the pancreas was carried by way of the blood stream. That the stimulating substance was not the acid itself, was shown by the failure of the reaction to occur when the acid was injected directly into the blood stream. Since there was this difference in the effects between acid in the intestine and acid in the blood, it was manifest that the active substance must be some material elaborated in the intestinal mucous membrane under the influence of the acid. So they scraped some of the lining of the bowel, rubbed it up with acid, and injected the filtered mixture into the blood. They were rewarded by a flow of pancreatic juice greater in amount than any obtained in their other experiments. From the filtered mixture they isolated in an impure form, a solid substance which, when introduced into the circulation, has a similar action. To this, of which the exact chemical make-up is as yet an unknown, they gave the name secretin.

Secretin and its properties they used to generalize as a perfectly direct and amply demonstrable example of an internal secretion. Metaphors are no less valuable in physiology than in poetry. They declared that the internal secretions appeared to them to be chemical messengers, telegraph boys sent from one organ to another through the public highways, the blood (really more like a moving platform). So they christened them all hormones, deriving the word from the Greek verb meaning to rouse or set in motion. As a science is a well-made language, a new word is an event. It sums up details, economizes brain-work and so is cherished by the intellect. The study of the internal secretions has advanced by leaps and bounds since it became convenient to speak of them as hormones. Withal, the brilliant work of Bayliss and Starling stands as the third great foundation stone, the first Claude Bernard's and the second Brown-Sequard's, in the architecture of the modern concepts of the internal secretions.



CHAPTER II

THE GLANDS: THYROID AND PITUITARY

The glands of internal secretion, the history of which, as tools of thought, I reviewed in the previous chapter, have each an interesting evolutionary story. Without some acquaintance with that story, the rough outline of their physical architecture, and the particular work they are called upon to perform in the body, no adequate understanding of their influence upon types of human nature and personality is possible.

THE THYROID GLAND

This gland consists of two maroon colored masses astride the neck, above the windpipe, close to the larynx. These are bridged by a narrow isthmus of the same tissue. They remind one of the flaps of a purse opened up. The gland has always attracted much attention because its enlargement constitutes the prominent deformity known as goitre.

To begin with, the thyroid was once a sex gland, pure and simple. In the lowest vertebrates and in the homologous tissues of the higher invertebrates, the fractions of the thyroid are intimately connected with the ducts of the sexual organs. They are indeed accessory sexual organs, uterine glands, satellites of the sex process. From Petromyzon upward that relationship is lost, the thyroid migrates more and more to the head region, to become the great link between sex and brain. How alive that function still is, is grossly shown by the swelling of the gland with sexual excitement, menstruation and pregnancy.

Relative to the body weight it is largest in the mammalia, and smallest in the fishes. It therefore grows larger as the vertebrate ascends in the scale. It has, in fact, developed in direct proportion to and side by side with the fundamental, differentiating vertebrate characteristics. Of these, the possession of a dry hairy skin instead of a moist or mucus bearing, chitinous skin, the ownership of an internal bony skeleton and a large skull, and a complicated development of brain, are the diagnostic signs. Thyroid internal secretion has a very definite controlling relation to all of them: to skin, its hairiness, moisture and amount of mucus, to the growth and size of the bones, especially the bones of the extremities and the skull, and to intelligence and the complexity of the convolutions of the brain. Injury to the thyroid, especially in growing animals, is followed by profound retrogression or arrest of development in skin, skeleton and brain.

In the fishes and the cyclostomes the thyroid is represented only by some small scrubby patches, little larger than the heads of pins, scattered along the aorta, the great blood vessels from the heart, and out a little way along each gill. It becomes larger and more compact among the amphibians and reptiles, but still remains quite small. Large and prominent among the birds and mammalia, it is largest and most prominent among the primates and man. It is hence permissible to think of the thyroid as a dictator of evolution, to crown it as the vertebrate gland par excellence, and to call the typical vertebrate brand marks secondary thyroid characteristics in precisely the sense of Darwin classing the horns of cattle as secondary sexual characteristics.

In such enthusiasm for the thyroid as a determinant of evolution, its pillar of cloud by day and column of fire by night, one should not forget the other glands of internal secretion. In them all, we may suppose, Life, tired of inventing merely prehensile, destructive and reproductive organs, hit upon the happy thought of contrivances which are in essence chemical factories to speed up the rate of variation and so of a higher evolution.

CREATOR OF THE LAND ANIMAL

According to this conception the thyroid played a fundamental part in the change of sea creatures into land animals. Experimentally, thyroid has been used to transform one into the other. Thus the occasional change of a Mexican axolotl, a purely aquatic newt, breathing through gills, into the amblystoma, a terrestrial salamander, with spotted skin, breathing by means of lungs, has long been known. Feeding the axolotl on thyroid gland produces the metamorphosis very quickly, even if the axolotl is kept in water. In the reptile house at the London Zoological Gardens full-grown examples of the common black axolotl and the pretty white variety are exhibited. Some are nearly three inches long. Alongside are shown several examples of the amblystoma stage, produced in one of the laboratories of Oxford University and at the gardens by thyroid feeding. A variation of the thyroid in the direction of increased secretion was probably responsible for the first land animals.

THYROXIN, SECRETION OF THE THYROID

Under the microscope, as in the test tube, the thyroid shows remarkable and unique features. Closed spherules lined by a single layer of cells enclosing a gelatinous material known as colloid, which stains deeply with acid dyes, comprise the units of its architecture. Essentially, it may be pictured as a series of jelly bubbles secreted by outlying cells.

A relatively high percentage of iodine is the unique distinctive fact in its chemistry. Discovered by Baumann in 1895, the presence of the element has focused the intelligence of chemists upon the gland, with the consequent demonstration of arsenic also in it. It was soon manifest that the secretion of the gland was dependent upon the iodine content for its activity. Active extracts of the thyroid like thyreoglobulin and iodothyrin were proven to contain iodine, and to become inactive when the iodine was removed. Efforts to isolate the iodine containing active principle in pure form were fruitless until the work of Kendall at the Mayo Foundation. He obtained it as a white, finely crystalline, odorless and tasteless substance, heat stable, and analyzable. The free form separates as a sheaf of fine needles. Kendall at first called it the a-iodine compound, then named it thyroxin.

There are other internal secretions of the thyroid, with a function of their own, that have no iodine. But they are secondary, and obscure. Thyroxin is accepted today as the purified internal secretion of the thyroid because all the effects of the whole gland may be elicited with it. Thyroxin produces results with doses amazingly minute compared with the quantity of whole gland necessary. Moreover, a dose of thyroxin appears to last an organism in need of it over a period of time; the other has to be administered continuously.

Studies with thyroxin carried on in recent years have rounded out the whole concept of the business of the thyroid in the body economy. One may sum it up by saying that the thyroid secretion is the great controller of the speed of living. The more thyroid one has, the faster one lives; the less one has, the more slowly one lives.

That is not to imply any direct proportion between the amount of thyroid secretion in an individual, and the length of life to which he is destined. The speed of living, in the chemical sense (which is the fundamental sense), and the rate at which the chemical reactions go on that constitute the process of life, are dependent upon the thyroid. When the reactions go faster, more oxygen and food material are burned up or oxidized, more energy is liberated, the metabolic wheel rotates more quickly, the individual senses, feels, thinks and acts more quickly.

Likening one energy machine to another, the thyroid may be compared to the accelerator of an automobile. That is a rough and superficial comparison because an accelerator lets in more of the fuel to be burned up, while the thyroid makes the fuel more combustible. It thus resembles more the primer, for a rich mixture of gasoline and air burns at a greater velocity than a poor one. But the action of thyroid could really be simulated only by some substance that could be introduced into the best possible of gasoline mixtures, to increase its combustibility by a hundred per cent or more. For that is what thyroid will do to our food. Nor has it only this destructive or combustion side. Withal there is at the same time a constructive action, for the process frees energy to be used for heat, motion or other need. The thyroid, therefore, in addition to its role as an accelerator, acts, too, as the efficient lubricator for energy transformations. So we see it as accelerator, lubricator and transformer of our energies.

THE GLAND OF ENERGY PRODUCTION

The isolation of thyroxin has made possible the determination of the influence of the thyroid hormone upon the evolution of energy in any higher animal organism. There is, for every individual, a constant, known as the metabolic rate, or the combustion rate, a reading of the rate at which his cells are consuming material for heat. The metabolic rate is thus a gauge of the energy pressure within the organism. It may be calculated by measuring the amount of carbon dioxide gas exhaled during a unit of time, and the number of calories of heat radiated by the skin simultaneously. A simplified device has lately rendered it practicable to make actual determinations by a few five-minute readings of the rate of oxygen absorption by the lungs. Plummer, also connected with the Mayo Foundation, has shown that what would amount to less than a grain of the thyroxin would more than double the amount of energy produced in a unit of time. To be exact, one milligram of thyroxin increases the metabolic rate two per cent. That illustrates some of the power of the internal secretion of the thyroid and its importance to normal life.

THE MOBILIZATION OF ENERGY

But not only is the height of pressure of energy in the cells controlled by the thyroid. The mobility of that energy is also controlled. Without it, rapid and large fluctuations of energy output, and elasticity and flexibility of energy mobilization for any sudden mental or muscular act, let alone an emergency, become impossible. A woman suffering with myxedema, the condition described by the English physician Gull as a cretinoid state supervening in the adult life of woman, has an insufficient amount of thyroxin in her blood and tissues. She is clumsy and awkward and will stumble when endeavoring to walk upstairs. Any effort is almost paralyzed because the range of fluctuation of energy, the ability to mobilize energy, in turn dependent upon an ability to increase the metabolic rate, is limited. In slang phrase, she cannot step on it. Her existence is set to go at a rate in the neighborhood of forty per cent below the normal. By the administration of thyroxin, her metabolic rate can be raised to any desired figure, the spark can be adjusted, so to speak, to any point we like, and it can be so maintained for years.

In the normal animal, to be sure, the internal secretion of the thyroid is not absolutely essential to life. So it contrasts with the hormone of the minute parathyroids placed so closely to it, a minimum dose of which is absolutely a prerequisite for continued life. The fundamental chemical reactions within the cells occur in the complete absense of thyroxin. But they go on in a relatively fixed, rigid and unvarying way, confined within the narrow limits of a constant figure. Under such conditions, the level of energy production is bound to be low, and to remain low, and the modus of its mobilization slow and unwieldy. With thyroid is introduced the trick of catalysis, or the speeding up of the vital chemical reactions, through the agency of an intermediate which accelerates the process. It is par excellence the great catalyst of energy in the body. (A catalyst is an intermediary like the trace of water, which will bring about an explosion between dry oxygen and hydrogen that without it have stayed inert with the strongest currents of electricity.) Thus it supplies a mechanism not only for quantity output of that subtle reality we label energy, but also an apparatus for varying the available amount of it, and for permitting the maximum range in ease and rapidity of its utilization. The thyroid is still another device of life for procuring more and more variation and differentiation, its goal, as far as we can peer through the opalescent screen upon which its manifestations quiver.

From another point of view, the thyroid may be looked upon as the organ evolved for maintaining the same amount of iodine in the blood as there is in sea water. Sea water was our original habitat, since, like Venus, we have all come up out of the sea.

The more intimate study of the composition of the blood has revealed the most astonishing parallelism between it and the compounds of sea water. The blood is sea water, to which has been added hemoglobin as a pigment for carrying oxygen to the cells not in direct contact with the atmosphere, nutrients to take the place of the prey our marine ancestors gobbled up frankly and directly, and white cells to act as the first line of defense. To keep the concentration of iodine in the blood a constant, the thyroid evolved, since there is no iodine in most foods and very little in those which do contain it.

That a minimum amount of iodine in the food is necessary to health is shown by the existence of goitre regions. Around some of the Great Lakes in the United States, for instance, the water does not contain enough iodine. As a result, numerous cases of goitre occur. Iodine in the form of sodium iodide in small doses will act as a prophylactic. The amount of iodine in the blood is about one or two parts to ten millions, and that of the liver is about three or four parts to ten millions. Since the liver is the most complex and active chemical factory in the body, its appropriation of a greater amount of iodine for itself is understandable.

When thyroxin is administered in a single dose, there is a distinct lag in the absorption of it by the tissues. A single dose does not generate its maximum effect until the tenth day. This effect continues for about ten days. Then there is a gradual decrease in the intensity of reaction for another ten days. So that the length of time a single administration of thyroxin functions within the body is about three weeks. Again we have occasion to notice a protective device of the cells. Since the presence of thyroxin in the tissues determines the rate at which they burn themselves up, it is obvious that if there were no mechanism for retarding its action, and at need varying it, they really would set fire to themselves. That is to say, if the tissues held a maximum of the thyroid internal secretion, and had to take up more and more as it was fed out to them by the thyroid through the blood, the pressure of energy production would attain the state of a boiler without a safety valve. Even if self-destruction were avoided by the ingestion of the largest quantities of energy-bearing foods, rest for the cells would be difficult, if not impossible.

The thyroxin in the tissues diminishes after a period of great exertion, the thyroxin probably being carried back to the thyroid gland and kept there as reserve until further demand. So it has been discovered that during the winter months, the thyroid glands of beef, sheep and hogs all contain much less iodine than during the summer months. During the winter months, manifestly, more energy is required to maintain body temperature, hence the gland surrenders more of its secretion to the tissues and so keeps less of it itself. There must be, too, a certain wearing out of the potency of the iodine with time. Even dead inorganic catalysts, made of simple elements, wear out after having been used time and time again.

Though the thyroid is the supreme energizer, life is incompatible with a certain excess of it. Death can be produced by successive daily injections of its internal secretion. But it has, besides the energizing effect, certain formative and nervous influences equally marvelous. As illustrations, there are the cases of thyroid deprivation in human beings, cretinism and myxedema, as well as those in which it is believed there occurs an excess of the thyroid secretion in the blood and tissues, the condition of hyperthyroidism.

CRETINISM AS THYROID DEFICIENCY

Not that there is any arresting contrast of startling difference between the phenomena presented by different species. The younger the animal, the grosser the morbid symptoms witnessed. The animal fails to grow. The bones and cartilage, except of the skull, fail to develop. The abdomen projects and becomes large and flabby. The sex organs atrophy. There is sterility. Pregnant rabbits abort, hens produce very small eggs or none at all. These are the results of removing the thyroid in animals.

Apathetic, indifferent, dirty, awkward, apparently idiotic, describe the human cretins. Their skin is rough and coarse, peeling in sheets. In some it is considerably knarled and creased as in the aged, and in others swollen, hard and resistant. The hair becomes shaggy and rough, losing all luster, and tends to grow irregularly and fall out. The temperature becomes subnormal and an anemia supervenes. There is a distinct reduction in the resistance to infections and intoxications.

Cretinism in the human is a condition in which the burning taper we call Life flickers and smoulders and smokes. Thirty years ago it was an example of the most hopeless idiocy. Whole populations were afflicted with it. But neither man of science, nor bigot-fanatic, assured by the Divine Confidence of its meaning as a visitation, believed it could be modified an iota. Today, that inept word "cure" may be applied to our power of attack upon it, provided it is permitted to attack early enough. Modification, in the direction of the most surprising betterment, is the miracle that has been wrought.

The history of a cretin runs somewhat as follows: A baby is born, which in all appearances seems normal. Perhaps the nose is a trifle squatter than even the average new-born's flat nose. There may also be abnormal sleepiness, greater even than that of the normal baby in the first month or two in that there is no spontaneous awakening from the coma for food. But in most cases this is put down to normal variability, or maybe to that limbo of all a baby's troubles: weakness. After some months, it is noticed that the infant is failing to grow at the normal rate, either physically or mentally. Examination at this time reveals a curious thickening of the dental ridges. Then the tongue takes the centre of the scene, by becoming unusually thick and prominent, to the point of projecting beyond the mouth at all times, and interfering with breathing, when the infant is in a recumbent position.

More and more of the characteristics of the affection turn up. The queer, repulsive, pitiful face of the cretins, which makes them all seem brothers or twins, shapes itself. A yellowish, white or waxy pallor; rough, dry, scaly, bloated skin; swollen, often wrinkled brow; watery eyes, often almost concealed by the thickened eyelids; the depressed pug nose with its wide, thick nostrils; large, erect ears; the wobbly, drooling tongue, sticking out at one, yet not in derision; the hair thin, and like tow in texture rather than human; eyebrows and eyelashes are scant, and often absent; the nails short, thin and brittle; the teeth, very late in coming, may be represented by a few sharp points, irregular, decaying quickly, sometimes not succeeded at all by those of the second dentition.

Whatever growth occurs is irregular and disproportionate. The trunk, though small compared with the head, appears massive against the background of the diminutive extremities. The back is somewhat humped, arching at the waist-line, while the abdomen protrudes like a balloon, with a hernia, often, at the navel. The extremities are short, bowed, cold, and livid, covered with rolls of the infiltrated skin, rolls which cannot be smoothed out. Hands and feet are broad, pudgy, and floppy, the fingers stiff, square and spade-like, the toes spread apart, like a duck's, by the solid skin. Above the collar bones there are frequently great pads of fat which sometimes encircle the narrow bull neck.

The mental state varies with the degree of deprivation of the internal secretion of the thyroid. In the worst cases it is repulsively vegetable. Even the intelligence common to the higher animals is wanting. The cretins of the "human plant" kind, as they have been nicknamed, will not recognize mother or father or any person about them, or even a person from an object, and manifest no interest in anything or anybody, not even toys. Hunger and thirst they manifest by grunts and inarticulate sounds, or by screaming. They neither smile, cough, nor laugh, but sit like sphinxes, breathing, but not reacting.

There are, of course, all grades and varieties. There are those who recognize parents and familiar faces, and exhibit some evidence of affection for them, acquire a limited vocabulary, and then cease, no progress possible even with the alphabet. They attain the size and age of two or three years and there stop altogether, as if a permanent brake were applied to the wheels of their growth. Some higher types may even come to speak connected sentences, and exhibit a certain mild spontaneity, though stupid and slow and abnormally deliberate, resembling the acquired form of thyroid deprivation or insufficiency, for which Ord invented the name myxedema.

I have filled in with some detail this thumbnail sketch of thyroid deprivation as it occurs in infancy to illustrate how wide a sweep the gland's lariat embraces. Skin, hair, bones, muscle and fat, brain and intelligence, growth and development, are modified precisely as the size and shape of certain crystals are modified by the presence or absence of ingredients in an apparently homogeneous solution. A fertilized ovum, in which the predecessor of the thyroid gland is present, that is to say, in which there is the seed and soil for its sprouting, looks the same as one without that formative material. Yet, when the time comes for the internal secretion of the thyroid to put in its oar in the metabolic game, its presence or absence makes all the difference in the world to the individual.

In the middle of the nineteenth century, when the concentration of phosphorus in the brain was established as significant, the cry for the emphasis of that fact was—without phosphorus no thought is possible. We can much more relevantly declare that without thyroid, no thought, no growth, no distinctive humanity or even animality is possible. For the epigram about phosphorus was bombast, since it can be declaimed with equal truth that without oxygen, without carbon, without nitrogen, without any of the food elements that go to make up the chemical composition of brain matter, no thought is possible. Indeed, if one were set upon the indictment of a single chemical element as the begetter of consciousness, the prisoner at the bar would have to be copper. There is more copper in the brain by a considerable degree than in any other organ of the body. Which perhaps will be exceedingly regretted by the patrons of the aristocracy of the soul who would have it as an emanation of a deposit in the brain of silver at least, if not gold. They are like the old lady who would never permit herself to be cured of her ailments except by gold plated pills. Copper, however, is not necessary to intelligence. Without thyroid there can be no complexity of thought, no learning, no education, no habit-formation, no responsive energy for situations, as well as no physical unfolding of faculty and function, and no reproduction of kind, with no sign of adolescence at the expected age, and no exhibition of sex tendencies thereafter.

EFFECTS OF FEEDING THYROID

How subtly the internal secretion affects every phase and aspect of child as well as adult, by doing something to the speed of activities in their cells, is told straightway by the effects of it when eaten or introduced into the skin or blood of various people. A cretin, idiotic, dwarfish, deformed, hopeless, an incessantly prodding burden of sorrow to the mother, who looks upon the masterpiece she had labored to bring forth, and beholds a terrible gargoyle, becomes transformed when fed thyroid.

In a few days the cretin will get warmer, and require much less wrapping and bed-clothing. With the improvement in circulation, the color becomes better and the extremities lose their coldness. In a week or so, irritability and resentment at disturbance appear. He will begin to recognize and know his parents, smile and play. There is a gradual return to the normal of the facial appearance, and a resumption of growth. All kinds of marvelous growth effects occur. Twenty teeth may be cut in six months. Coarse, rough dry, shaggy hair becomes fine, silken, long and curly. The skin becomes soft, moist and roseate. Inches in height may be added every month. Bright, active, even talkative, are the descriptive terms an observer would apply after a few months. A complete remaking of body and soul is apparently affected.

Yet, should the administration of the thyroid cease, an almost immediate reversion to the original vegetative condition is inevitable. After a few days, reactiveness slows down, the child will speak only when spoken to, will sit quietly in a chair all day and act semi-anesthetized. Gradually hair and skin return to the previous cold-blooded animal state, and the whole picture of the cretin is in full bloom. Supplying the internal secretion of the gland promptly repeats the transformation.

One wonders what is to be the ultimate fate of these reformed cretins. Since the tale of the opening of life to them, once considered hopeless idiots, is scarce a generation old, we have no data, as yet, as to the character of their children or grandchildren, their adventures and vicissitudes, in short, their life history. Those of whom we have any record are normal and healthy school children or workers, alive to the interests of childhood or their occupation and social circles. No one outside their family knows that they are cretins, and the most acute observer would be hard put to it to suspect. What a theme for the reflections upon appearances the eminent Victorians loved!

There are possibilities the imagination may envisage. One may suppose such a cretin, with all his other ductless glands intact, grown successfully to manhood under careful medical guidance. No one but himself is aware of his affliction, outside of his medical advisers. Luck aids him to rise in the world, or perhaps he has been born with a spoon of the precious metals in his mouth. Adolescence, love and marriage dance their sequence. Our hero of course keeps his dread secret to himself. Whether such an omission of confidence would entitle his wife to a divorce is something courts will be called upon to decide sooner or later. But, without anticipating, the honeymoon involves a trip to the South Seas. A storm and a wreck throws them alone on an island, tropical, easy to live on, and rescue in the course of a few months certain. The man, to his horror, discovers that he has saved of his medicaments only a pill box containing half a dozen of thyroid tablets, his requirement being one a day. He sees them go day by day. Finally they are all gone. He feels his faculties slipping hour by hour. Shall he tell her? Indecision grips him, and he delays until the day when his consciousness sinks to the point where his mind no longer grasps his problem. The wife must endure the spectacle of the enchantment of her husband, and his change from gallant lover to dull animal ogre. A new version of Beauty and the Beast!

Cretinism as one manifestation of a soul without thyroid or without enough thyroid is not all. The first great successes with thyroid were achieved in adults, particularly adult women, exhibiting a peculiar obesity, coldness, loss of hair and teeth and a remarkable lassitude and torpor that might be summed up as a chronic drowsiness, like a saturation of the blood with some narcotic drug. Or there may be a melancholia, or a lack of ability to seize the finer points of a mental process, or an argument treated in the abstract. Children are said to be lazy, slow or dull. They experience an irritating difficulty in understanding questions and expressing their wants and desires, and so are declared to be vicious, or stupid.

All these are grades of the degeneration which Ord, the Englishman, named myxedema. At its worst it is a sort of bloating and drying of the body and the mind. Then there is infantilism, which is helped by the giving of thyroid extract. It differs from the ordinary cretinism in that, while one is reminded of the latter by the physical stunting and the other stigmata, there is a certain amount of intelligence which enables the individual to hold his own while he is a child. He becomes a grown-up baby: at twenty prefers the company of children of ten, and passes under the evil influence of designing so-called normal persons. So dominated he will lie, steal, start fires, commit almost any crime, with no inherent flair for criminality, but because of a lack of independent judgment and inability to resist suggestion, and a desire to please friends. He is simply an overgrown child who still loves to play with toys, laughs and cries, becomes angry or afraid, unreasonably and ridiculously, and yells for mamma when thwarted or scared.

So much for what happens when there is not sufficient of the thyroid secretion in the blood and tissues. Now to consider the effects of an excess of it, the condition called hyperthyroidism, as the insufficiency of it is labelled subthyroidism. Too much thyroxin can be introduced into the system of a normal individual, or even a cretin by the simple administration of too large doses or over too long a time. Also a train of symptoms similar to those evoked by an oversecretion of the thyroid may be mobilized by the taking of too much iodine. Great sorrow, great joy, a sudden severe jolt to the nervous equilibrium, sexual excitement, an overwhelming anger or grief may leave in their wake a permanent hyperthyroidism. The symptoms are the reverse of cretinism and myxedema. There is an over-excitability of the nerves in place of sluggishness, and an over-reactivity of the whole organism to its environment. The heart's action is too fast, and under the slightest stimulus gets faster to the point of obtruding itself into the conscious mind as a palpitation. Instead of the lowered temperature and coldness of the cretin, there is a heightened temperature, one or two degrees above the normal, and a feeling of heat. The individual has a high warm color, does not sleep well, becomes or remains thin no matter how much he or she eats, is abnormally susceptible sexually, may suffer from a definite insomnia, is emotional, and perspires freely. Alert, neurotic or high-strung, magnetic, and imaginative are some of the descriptive adjectives applicable. The eyes are bright and prominent, large and beautiful, when they have not reached the stage entitled "pop-eyed." Or they may even become so protuberant and bulging as to develop the expression of one staring aghast at some ineffable horror. The latter is the feature of only the severest types, when there is an associated goitre, the combination designated as exopthalmic goitre.

There are, too, individuals in whom hyperthyroidism and hypothyroidism are mixed, or rather alternate. At one time they present the phenomena of the one, at another of the other. They are the people who complain of the cyclic quality of their moods and purposes. Their mood will be a heaven of exaltation and exhilaration, and then descend into a slough of despond from which they feel themselves inextricable. They are always talking about the ups and downs of their mental states. Headache and languor and fatigability, dry skin and lack of appetite for food or exertion on one day or for one week, give way on the next day, or for the next week, to an energetic gayety, and sweaty, flushed skin, a prominent appetite for food and every sort of activity. Driven to be forever on the go, for one period, in the next they feel like lying down most of the day, with no inclination for any life whatever. The stage of depression may go as far as a melancholia, the stage of stimulation as far as mania. They may simulate manic-depressive or cyclic insanity. Something restrains them, and holds them bound as in a vise in the one cycle. And then they are driven on beyond themselves by some invisible whip in the next.

THYROID AS DIFFERENTIATOR

Besides the action of the thyroid as energizer, lubricator, and growth catalyzer, it has a remarkable power as a differentiator of tissues. It determines the embryonic etchings of the different organs which in their totality comprise the unique individual. Every multicellular animal must first have existed as a single cell, the impregnated ovum. With the body and personality of the ovum, the creature is one and continuous, literally something the single cell has made of itself by sub-dividing and differentiating. In the process, the cell mass often goes through stages which stand out as individualities in themselves, that appear on the surface absolutely unrelated. So the caterpillar and the butterfly, to the naive child, seem as far apart as worm and bird. In the case of the frog, the tadpole as a first sketch seems completely an impossible and wild absurdity. Yet we know that there is an orderly progression of events, a propagation of cells, a forward going arrangement of chemical reactions, that results in expansion and intricate complication of the organism. Just what the forces at work in this most mysterious of all natural processes are, has been an intellectual mystery that the best minds of the race have attempted to get rid of with words like pangenesis (Darwin). Words of Black (Mediterranean or Greek and Latin) origin, as Allen Upward has named them, always cover a multitude of ignorances. The glands of internal secretion, here, as in so many other dark places, provide the open sesame to certain long closed doors of biology. They offer themselves to us as the first definitely tangible agents which are known to keep the process of growth going, and undoubtedly initiate the marvelous unfolding of tissues and functions, organs and faculties summed up as development or differentiation.

Thus by the direct feeding of thyroid at particular points in the differentiating history most curious effects have been elicited. If the gland is made part of the nutriment, the bathing environment, of the tadpole, a hastening of its metamorphosis is attained. The tadpole lives not out its day as a tadpole, but precociously turns into a frog. But such a frog! It is a miniature frog, a dwarf frog, a frog seen by looking through the wrong end of the telescope, a frog not magnified, but micrified. Frogs have been so created the size of flies. There has occurred a splitting of the two reactions which ordinarily go hand in hand: the reaction of growth which is just brute increase of total mass or weight and volume, and the reaction of differentiation which is the finer process. The picture is a frog, but a frog the size of a tadpole, a frog which has missed its childhood, adolescence and youth, skipping over these transition stages into the adult age, as a pigmy.

It is all as if a baby were suddenly to grow a beard and moustache, evolve and shed teeth, and acquire the manner of an earnest citizen, and yet retain the height and weight of a baby. That the spectacle of such a superbaby is not quite the most fantastic of all improbabilities is shown by the condition of progeria, first recorded by the Briton, Hastings Guilford. A queer spectacle in which a child incontinently grows old without having lived—in the course of a few weeks or months. You look upon him and see senility on a small scale, but with all its peculiarities: wrinkled skin, apathy, gray hair and all the rest of it. All we can say about it is that it is probably due to a paralysis of all the glands of internal secretion, a removal of their influence upon the cells. Contrariwise to the feeding of thyroid, removal of the thyroid of tadpoles will prevent their development into frogs. If iodine is then fed to them, say mixed with flour, normal metamorphosis will occur. If Body is the tool chest which we carry about with us, as Samuel Butler said, then to the thyroid belongs the name of tool-maker.

Another function of thyroid that must be taken into consideration is what has been spoken of as its antitoxic function—in plainer English, its power to prevent poisoning, or to increase resistance against poisons, including the bacteria and other living agents which cause the infectious diseases. Each molecule of food, ingested for assimilation into our substance, accumulates a history of wanderings and pilgrimages, attachments and transformations beside which the gross trampings of a Marco Polo become the rambling steps of a seven-league booted giant. In the course of its peregrinations, it becomes a potential poison, potential because it is never allowed to grow in concentration to the danger point. The thyroid plays its role of protector like all the internal secretory machines. In an animal deprived of a thyroid the feeding of meat shortens life—a single sample of how it works to guard against intoxication from within. The feeding of thyroid will also raise the ability of the cells to stand poisons introduced from without—intoxications of all sorts. Alcohol and morphine will affect in much smaller doses the subthyroid person than the normal or the hyperthyroid. As regards the infections, which directly or indirectly kill most of us, the injection of thyroid will increase the content in the blood of the protective antibodies which preserve us, temporarily at any rate, against malignant invaders. The opsonins, for example, those substances which butter the bacteria so that the appetite of the white cells for them is properly roused, are mobilized by thyroid feeding or injection. Other substances in the blood which destroy and dissolve bacteria are also increased. The thyroid probably performs these functions by sending its secretion to the cells directly responsible for the immunity reactions, and stimulating them to activity.

A sketch of the thyroid like the foregoing shows it as the wondrous controller of vitality and growth, and indefatigable protector against intoxicants and injuries. When it is sufficiently active, life is worth while; when it is defective, life is a difficult threatening blackness. That would make it out as the gland of glands. It is tremendously important, without a doubt, in normal everyday life. But no more so than the other members of the cast. The position of star it may claim, but in vain. The other glands of internal secretion to be sketched will each, when the marvels of its business in the cell-corporation are considered, present itself as candidate for the honors of the president. Justice should give fair credit to all the organs which fabricate the reagents of individuality, and the regulators of personality.

THE PITUITARY

In the human skull, the pituitary is a lump of tissue about the size of a pea lying at the base of the brain, a short distance behind the root of the nose. It is of a grayish-yellow color, unpretentious and insignificant enough in appearance, and so long neglected by the scientists who boast their immunity to the glamor of the spectacular. Guesses at its nature date back to Aristotle.

Like most of its colleagues among the glands of internal secretion, it is really two glands in one, two glands with but a single name. At least it consists of two different parts, distinct in their origin, history, function and secretions, but juxtaposed and fused into what is apparently a homogeneous entity. They are conveniently spoken of as the anterior gland and the posterior gland.

In the embryo, the anterior gland is derived by a proliferation of cells from the mouth area. The posterior gland represents an outgrowth of the oldest part of the nervous system. When it is traced back along the tree of the vertebrate species, it is found to be present in all of them. An ancient invention, its precursor has been identified in worms and molluscs and even among the starfish. "The pituitary is practically the same, from myxine to man." A trusted veteran, therefore, among the internal secretory organs, its importance can be surmised.

To understand the story of the pituitary, variously acquired bits of information concerning it have been assembled and fitted together like the fragments of a picture puzzle, as Cushing has so well put it. Here and there pieces stick out, obviously out of place. The relations of some of them to one another or to the whole design are not at all clear. Parts appear to have been irrevocably lost, or not yet to have turned up. Chance bystanders will select odd figures and articulate them into a new harmony. Yet out of the jumble of fragments, a fairly respectable insight has been gained in less than a half century.

The pituitary is cradled in a niche at the base of the skull which, because of its form, is known as the Sella Turcica or Turkish saddle. So situated, an operative approach to it is overwhelmingly difficult. On the other hand, X-ray studies are favored. "Nature's darling treasure" it might be called, since there has been provided a skull within the skull to shelter it.

Under the most highly magnifying lenses of the microscope, three kinds of cells have been distinguished. The anterior gland is a collection of solid columns of cells, surrounded by blood spaces into which their secretion is undoubtedly directly poured. A gelatinous material, presumed to be the internal secretion of the gland, has, in fact, been observed emerging from the cells into the blood spaces. The posterior lobe, or gland, consists of secreting cells producing a glassy substance which finds its way into the spinal fluid that bathes the nervous system. The spinal fluid itself is a secretion of another gland at the base of the brain, the choroid. Nerves and internal secretion are associated here with a closeness symbolic of their general relations.

From each portion of the gland (to stick to the accepted nomenclature of speaking of the two glands as one) an active substance has been isolated. Robertson, an American chemist, separated from the anterior lobe a substance soluble in the fat solvents, like ether and gasoline, which he christened tethelin. But P.E. Smith has shown that the active material is soluble neither in boiling water nor in boiling alcohol, the typical fat solvent. A number of facts favor the idea of the anterior lobe cells as stimulants of growth of bone and connecting and supporting tissues generally. From the posterior lobe, pituitrin, believed its internal secretion, has been obtained in solution.

Pituitrin is a substance of many marvelous functions. In general, it controls the tone of the tissues, of involuntary or smooth muscle fibres of the blood vessels and the contractile organs of the body like the intestines, the bladder and uterus. When injected, it will slowly raise the blood pressure and keep it raised for some time, and will increase the flow of urine from the kidneys and of milk from the breasts. It will also cause an intense continued contraction of the bladder and the uterus. It is also said to control the salt content of the blood upon which its electrical conductivity and other properties depend. Normally, there is a certain fixed ratio of the salts in the blood, which keeps them like the ratio in sea-water. Again, we have an example of the curious atavism of the internal secretions. The thyroid, remember, keeps the iodine concentration of the blood like that of the ocean, our original habitat. Pituitrin likewise does its part to maintain our internal environment as near as possible to what was once the surrounding medium. A substance somewhat similar has been found in the skin glands of toads.

The extraordinarily well protected position of the pituitary, its persistence throughout life, and its abundant blood supply, emphasize its vital importance. No other gland of internal secretion can adequately substitute for it. Complete expiration means death, in two or three days, with a peculiar lethargy, unsteadiness of gait and loss of appetite, emaciation, and a fall of temperature, so that the animal becomes cold-blooded, its temperature the same as that of the atmosphere it occupies. If only part of the anterior lobe is taken away, there occurs a remarkable degeneration of the individual. The degeneration is not a mucinous infiltration of the skin and the internal organs which occurs with thyroid deprivation, but a fatty degeneration, with a tendency to inversion of sex. A singular somnolence, a dry skin, loss of hair, a dull mentality, sometimes epilepsy, and a noticeable craving for and tolerance of sweets appear. These are but a few of the observations obtained in experimental sub-pituitarism, that is, underaction or insufficient secretion of the pituitary, produced by removing part of the anterior gland.

If such an experimental sub-pituitarism is started in infancy, for instance in puppies, there is a cessation, or marked hindering and slowing of growth. That is, dwarfs are artificially created. Apropos, pathologists have shown that in several true human dwarfs the gland is rudimentary or inadequate. All of which goes hand in hand with the evidence that the skeleton stands directly under the domination of the pituitary.

REGULATOR OF ORGANIC RHYTHMS

There are certain other singular by-effects of the gland in its relation to the periodic phenomena of the organism like hibernation, sleep, and the critical sex epochs of both sexes. In hibernation, or winter sleep, the animal in cold weather passes into a cataleptic state in which it continues to breathe, more deeply but more slowly than when awake, but shows no other signs of consciousness or life. A lowered blood pressure and a marked insensitivity to painful and emotional stimuli go with it. There is a preliminary storage of starch in the liver, and of fat throughout the fat depots of the body. These are so like what happens after part of the pituitary is removed, that a comparison of the two becomes inevitable. Common to both conditions is a drop in the rate of tissue combustion or metabolism, which can be relieved by injection of an extract of the pituitary, a rise of temperature occuring simultaneously. Moreover, examination of the glands of internal secretion of hibernating species, like the woodchuck, during the period of hibernation, shows changes in all of them, but most marked in the pituitary, the shrunken cells staining as if they too were asleep, or in a resting stage. The characteristic alive qualities of these cells return, without relation to food or climate, when the animal comes to in the spring, at the vernal equinox. Hibernation may, perhaps, be put down to a seasonal wave of inactivity of the pituitary gland.

Now winter sleep may be looked upon as an exaggeration of ordinary night sleep, the latter differing from the former only in its brevity. In the natural sleep of non-hibernating species there occurs, too, a fall in temperature. Moreover, they all, even man, have a certain capacity for winter sleep, as the experiences of travellers and explorers in the arctic regions indicate. In certain parts of Russia, where there is a scarcity of food during the winter months, the peasants pass weeks at a time in a somnolent state, arousing once a day for a scant meal. Just as the sex glands influence the body and mind profoundly with a certain cyclic periodicity of activity and inactivity (rut, heat, menstrual period and so on), which has been demonstrated to have a very close functional relationship with the pituitary, so sleep and hibernation will bear interpretation as products of a temporary dormancy of the same gland. We have, then, to set up in the place of Morpheus and Apollo, the new gods of the internal secretion of a chemical-making bit of the brain, as an explanation of the rhythms of sleep and wakefulness.

There are individuals who go about outside of hospital walls, quasi-normally, who are semi-hibernators or partial hibernators, and who are really in a state of subpituitarism. They are people who may have something wrong or inferior with their pituitary, but not to the extent of interference with their daily life. They go about with their type stamped upon them for the seeing eye. The classical type is obese, with fat distributed everywhere, but more so in the lower abdomen and the lower extremities. They are slow and dull, and sexually inactive, often impotent. They are sometimes tall, but most often dwarfish, and may be subject to epileptic seizures. They recall the picture of what happens to young dogs partially deprived of the pituitary. Dickens delivered a perfect likeness of an extreme degree of the condition in the Fat Boy of the "Pickwick Papers," whose employment with Mr. Wardle consisted in alternate sleeping and eating.

WHEN THE PITUITARY OVERACTS

All grades of overaction of the pituitary exist. Then its peculiar power to act as a stimulant to the growth of bone and the soft supporting and connecting tissues like tendons and ligaments comes into play. If the overaction or excess of secretion begins in childhood or adolescence, that is, before puberty, there results a great elongation of the bones, so that a giant is the consequence. Now giants have always appealed to the imagination of the little man, and have had all kinds of wonderful abilities ascribed to them by him. The giants and ogres of folk-lore and fairy tales are favored with the most extraordinary mental advantages. Direct and analytic acquaintance with the giants of our own day, as well as a probing of their conduct in the past, has shown that normal giants—persons of exceptional size free from physical or mental deformities—are rare. There are people with hyper-pituitarism who exhibit the highest mental powers. In them is an increased activity of the posterior lobe in association with enlargement and hyperfunction of the anterior, overgrowth is not so marked, and the individual is lean and mentally acute. But the ordinary giant is one in whom there is degeneration of the pituitary after too much action of the anterior and too little of the posterior glands. A tumor or disease process in the gland is most often responsible.

If the overaction of the anterior happens after puberty, when the long bones have set, and can not grow longer, a peculiar diffuse enlargement of the individual occurs, especially of his hands and feet and head. The nose, ears, lips and eyes get larger and coarser. As these people are rather big and tall to begin with, the effect produced is that of a heavy-jawed, burly, bulking person, with bushy overhanging eyebrows, and an aggressive manner. For there is, too, something distinctive about their mentality which has been as often portrayed as those of the pathologic giant. Rabelais' most famous character, Gargantua, belongs to the group. We recruit more drum-majors than prime ministers from among these people. They often suffer much from torturing boring headaches, and a consequent despondency and feeling of hopelessness which colors gray the entire spiritual spectrum. Up to a certain point these sufferers have a remarkable alertness and capacity. When conscious of the malady, they often meet it with a doggedly courageous optimism, which is another characteristic, although women occasionally commit suicide.

In both the semi-hibernators who remind one of cattle, and in the giant or acromegalic types who remind one of the anthropoid ape, there develops a distinct diminution of sexual life. An abnormal process in the anterior gland, whether of oversecretion or of undersecretion, may interfere with the proper functioning of the posterior gland, the secretion of which is tonic not only to the brain cells, but also to the sex cells. Thus, young animals deprived of the pituitary will not, if male, grow spermatozoa, nor ripe ova in the female. Moreover, the feeding of pituitary increases sexual activity. In the case of hens, this has been demonstrated to be about thirty per cent by a pretty experiment. At a time of the year when eggs diminish, six hundred and fifty-five hens laid two hundred and seventy-three eggs upon an ordinary diet. When pituitary was added to their food for four days, the number of eggs rose to three hundred and fifty-two, an increase of seventy-nine. In addition, the fertility of the chicks born of these eggs was augmented, especially if both parents had been fed on pituitary. There are other aspects of the relation of the pituitary to sex, which will be treated in another chapter.

THE BONY CRADLE OF THE PITUITARY

Always, in attempting to understand the pituitary, it is necessary to remember that it is tightly packed in the bony cradle, the Turkish Saddle or Sella Turcica. Should some stimulus, local, or in the blood, arouse the gland to growth, a good deal will depend upon whether it has room to grow in, or it will make room by eroding the bone. With space for the formation of a large anterior and posterior pituitary gland, there will be created the long, lean individual, with a tendency to high blood pressure and sexual trends, great mental activity, initiative, irritability and endurance. An outstanding trait of these favorites of fortune is that they remain thin no matter how much food they consume, and they have the best of appetites. They often are subject to severe headaches because of intermittent swelling of the gland against the bone of its container.

If the bony container is or becomes too small for its contents, it is interesting that along with the other signs of pituitary insufficiency, such as undersize, obesity, and asymmetry, there developes conspicuous moral and intellectual inferiority. The unfortunates suffer from compulsions and obsessions and lack inhibitions. They are the pathological liars with little or no initiative or conscience—amoral, not merely theoretically, but instinctively and unconsciously, with all the certitude and perfection of the unconscious accomplishment.

THYROID AND PITUITARY

The thyroid and the pituitary have often been compared. The anterior gland and the thyroid arise from almost the same spot in the embryonic oesophagus, the thyroid being an outgrowth in front, the anterior pituitary an outgrowth behind of the same soil. They both control growth marvelously, also the differentiation, the mass and intricacy of the tissues. But they differ in the site of their control. The thyroid bears more directly upon the inner and outer coverings of the body, the skin, the skin glands and the hair, the mucous membranes, and the irritability and the preparedness for response of the nerves. The pituitary acts more upon the framework of the body, the skeleton and the mechanical supports and movers. Bone and ligament, muscle and tendon seem to be within its immediate sway. The secretion or secretions of the pituitary diffuse directly into the fluid bathing the nervous system, supplying beneficent stimulants and aiding in the abstraction of harmful waste. So while the thyroid raises the energy level of the brain, and the whole nervous system, as a byproduct of its general awakening effect upon all the cells of the body, the pituitary probably stimulates the brain cells more directly, perhaps in the manner of caffeine or cocaine.

The difference between the thyroid and the pituitary might be put this way: that while the thyroid increases energy evolution and so makes available a greater supply of crude energy, by speeding up cellular processes, the pituitary assists in energy transformation, in energy expenditure and conversion, especially of the brain, and of the sexual system. In short, the thyroid facilitates energy production, the pituitary its consumption. The pituitary appears therefore as the gland of continued effort. Hence fatigability, an inability to maintain effort, is one of the prominent complaints when there is destruction or an insufficiency of it for one reason or another. As such, it contrasts with the glands of emergency effort, known as the adrenals.



CHAPTER III

THE ADRENAL GLANDS, THE GONADS, AND THYMUS

Like the pituitary, each adrenal gland is a double gland, that is, consists of two distinct portions, united together, one might say, by the accident of birth. It would be confusing, however, to speak of each as two glands, because there are, as a matter of fact, two separate adrenal glands, one in the right side of the abdomen, and the other in the left. Each gland is composite, or duplex. How the two parts came to be united is a long story, interesting but too long to be recounted here. In fishes they are apart and independent.

Each adrenal is a cocked hat shaped affair, astride the kidneys, easily recognized because of its yellowish fatty color. Indeed, for centuries the glands were not given a separate status as organs, but were passed up as part of the fat ensheathing the kidney. In childhood and youth, in common with the other glands, they are relatively larger and more prominent than in the adult. Also, at every age, the amount of blood passing through them is very large compared to their size. Their tremendous importance in the body economy accounts for their being so favored.

The two parts of which each gland is composed, are known as the cortex or outer portion (literally the bark) and the medulla or inner portion (literally the core). No clean-cut boundary sharply delimits the two, as strands and peninsulas of tissue of one portion penetrate the other. In the history of their development in the species and the individual, and in their chemistry and function, a sharp difference contrasts them.

In the embryo, the cortex is derived from the same patch that gives rise to the sex organs, the ovaries in the female, and the testes in the male, described as the germinal epithelium. How intimately the two sets of glands are connected is neatly pointed by this fact of a common ancestor. All vertebrates possess adrenal glands. In the lowest of the vertebrates, Petromyzon, the two parts are distinct, the cells of the cortex-to-be are situated in the walls of the kidney blood vessels, projecting as peninsulas in the blood stream, the blood sweeping over and past them. The medulla-to-be consists of cells accompanying the vegetative nerves. Among reptiles, the two become adjacent for the first time, and among birds one part occupies the meshes of the other. The size of the cortex varies directly with the sexuality and the pugnacity of the animal. The charging buffalo, for example, owns a strikingly wide adrenal cortex. The fleeing rabbit, on the other hand, is conspicuous for a narrow strip of cortex in its adrenal. Human beings possess a cortex larger than that of any other animal.

No definite chemical substance has as yet been isolated from the cortex. That remains a problem for the investigator of the future. But certain observations, especially concerning the relation between the development and behaviour of the so-called secondary sex characteristics, those qualities of skin, hair and fat distribution, physical configuration and mental attitudes, which distinguish the sexes, and the condition of the gland, indicate clearly that an internal secretion will be isolated, and that it will in its activity furnish certain predictable features.

Three different layers of cells, arranged in strings, that interpenetrate to form a network directly bathed by blood, that breaks in upon them from open blood vessels, compose the cortex. Most remarkable is this method of blood supply for it is exceedingly common among the invertebrates and rare among the vertebrates.

In certain disturbances of these glands, especially when there are tumors, which supply a massive dose of the secretion to the blood presumably, peculiar sex phenomena and general developmental anomalies and irregularities are produced. If the disease be present in the fetus, taking hold before birth, and so brought into the world with the child, there evolves the condition of pseudo-hermaphroditism. The individual, if a female, presents to a greater or less extent the external habits and character of the other sex. So that she is actually taken for a man, although the primary sex organs are ovaries, often not discovered to be such except when examined after an operation or death. How closely such an occurrence touches upon the problems of sex inversion and perversion comes at once to mind.

If the process involving the adrenal cortex attacks it after birth, the symmetrical correspondence and harmony of the primary sex organs and the secondary sex characters are not affected. But there follows a curious hastening of the ripening of body and mind summed up in the word puberty, a precocious puberty, with the most startling effects. A little girl of 2, 3, or 4 years of age perhaps will come to exhibit the growth and appearance of a girl of 14. She begins to menstruate, her breasts swell, she shoots up in height and weight, sprouts the hair distribution of the adult, and the mentality of the adolescent, restless, acquiring, doubting, emerge. A tot bewitched into puberty! A boy of six or seven may suddenly, in the course of a few weeks or months, become a little man, robust, rather short and stocky, but moustached, with the muscular strength and sexual powers of a man and thinking as a man. It is all as if into some fermentable medium or solution a little yeast were dropped that changed the quiet calm of its surface into a bubbling, effervescing revolution. It suggests at once that maturation, the transformation of the child into the man or woman, must be due to the pouring into the blood and the body fluids of some substance which acts like the yeast in the fermentable solution. The adrenal cortex is one source of the maturity-producing internal secretions.

If trouble in the adrenal cortex starts after puberty, phenomena of the same type, but of a different order, exhibit themselves. A woman, say in the thirties, becomes thus afflicted. Slowly or quickly her body will be covered by an abundant growth of hair, more or less of a beard and moustache appear upon the face, her voice will become deep and penetrating, her muscles will harden, and she will show a capacity for hard physical labor. Sexually she appears to be made over, masculinity now predominates in her make-up. Virilism is the name by which the French in particular have popularized the knowledge of the condition. Virilists have to shave or be shaved regularly and are not bothered in the least by the cares, responsibilities, jealousies and anxieties of personal beauty, for the change in their spirituality makes them immune to the preoccupations of the feminine. The cause of such a transformation in a previously entirely normal woman has been found to be a tumor of the adrenal cortex.

But not only is sexuality, and the conduct of the secondary sex characters, connected with the adventures of the adrenal cortex. The development of the master tissues of the body, the brain, the pride and darling of evolution, is in some subtle way correlated with it. The adrenal cortex contains more of the phosphorus-containing substances of the general nature of those found in the central nervous system than any other gland or non-nervous tissues in the body. During human intrauterine life the adrenal glands are large and conspicuous, in the first half of the second month being twice as large as the kidneys. Most of this relatively huge size, which happens in the human alone, and not in other animals, is due to enlargement of the cortex. Should this preponderance of the cortex over the medullary portion not occur in the human, that is, if the proportions remain like those of other animals, the brain fails to develop properly, or an entirely brainless monster is generated. The human brain, therefore, probably owes its superiority over the animal brain, to the adrenal cortex, in development anyhow. The growth of the brain cells, their number and complexity is thus controlled by the adrenal cortex.

Besides its action upon the sex cells and the brain cells, the internal secretion of the adrenal cortex acts upon the pigment cells of the skin, blunting their sensitiveness to light. In degeneration of the interior of the gland, which destroys the medulla, but not the cortex, the color of the skin is left unmodified. If, however, the cortex is invaded, as happens most often in the classical tuberculosis of the adrenals which drew the attention of the Englishman Addison to them, then a darkening of the skin, which may go on to a negroid bronzing, follows. That means an increased sensitiveness of the pigment cells of the skin to light. Skin color control may therefore be looked upon as an adrenal cortex function.

So much is known about the adrenal cortex. Upon the medulla, the interior gland of the gland, there has been lavished an amount of attention beside which the cortex is to be classed as a neglected wall-flower. Nearly everything that possibly could be determined about an internal secretion has in its case been settled or plausibly guessed at. The cells manufacturing the secretion, its exact chemistry and function, its action upon the blood, the liver and spleen, the heart and lungs, the brain and nervous system, have been minutely investigated, studied and charted. Its source in the food, its fate in the body, its place in the history of the individual and the species, its importance as a weapon in the struggle for existence, and the survival of the fittest have been made the subject of an astonishing number of researches, considering the short period of scarce three decades that intensive science has centered its barrage upon it.

In the first place, the medulla contains numerous nerve cells, belonging to the vegetative, also called the sympathetic nervous system. But these nerve cells are merely minor notes of the symphony. The motif is settled by a majority of large, granular cells, which stain a distinctive yellowish-brown when the gland is fixed in a solution of bichromate of potash. All chromium salts, in fact, stain the therefore labelled chromaffin cells. The characteristic staining power appears to be dependent upon, or correlated with, the presence of the internal secretion of the medulla of the adrenal, adrenalin. For the content of adrenalin, as calculated chemically, and the depth of stain as seen under the microscope, rise and fall together. Chromaffin reaction and adrenalin content go together. The poisonous skin glands of the toad have been found to give a marked chromaffin reaction, and to contain a large amount of adrenalin. Other masses of cells in the human body, especially along the course of the sympathetic nervous system, have been shown to give the reaction and to contain adrenalin.

The erratic Brown-Sequard pounded and hammered away for more than thirty years on the importance to life of the adrenal glands, since death occurred so quickly after their removal. But it was not until Schaefer, the Scotch physiologist, (who has done more than any other living man to stimulate study of the internal secretions) found that an extract of them, when injected into a vein, produced a remarkable though temporary rise of the blood pressure, that a real enthusiasm for its investigation was generated. As the upshot, a number of other significant properties besides the first of blood-pressure raising, have been put down to its credit. Chemical tests demonstrated that it originated in the medulla. The exact amount of it present in the medulla, in the blood issuing from the adrenals and in the circulation in general have been determined. The concentration in the blood is about one part in twenty million, while there is about a hundred thousand times as much stored in the gland as reserve. In infections and intoxications, after muscular exertion, and with profound emotions, there is a decrease of it in the gland and an increase in the blood. Pain and excitement, especially fear and rage, will bring about its discharge from the gland. With its entry into the blood, there is a tremendous heightening of the tone, a tensing, of the nervous system. The nerve cells become more sensitive to stimuli, more sugar is poured into the blood from the liver, more red blood corpuscles are squeezed into the circulation from the blood lakes of the liver and spleen. There is a redistribution of the whole blood mass, a good deal of it being withdrawn from the internal viscera, and hurried to the skeleton muscles and the brain. The heart beats more strongly, the eye sees more clearly, the ear hears more distinctly, and the breathing is more rapid. The temperature rises, the hair of the head and the body becomes erect, the skin gets moist and greasy. It will help a fatigued muscle to regain its normal tone. In short, it has a reinforcing action upon the nutritive properties of the blood, the tone of the muscles, and the activity of the brain and the vegetative nerves.

Chemists set themselves the task of discovering just what was the substance possessed of such extraordinary and hitherto unimagined properties. The pure adrenalin was isolated, capable of evoking all the reactions of the impure adrenal extract mixtures. The final triumph was the preparation of it artificially in the laboratory, its synthesis. When a substance can be synthesized in the chemist's laboratory, it means that its composition has become thoroughly understood. Here at last was an example of those mysterious internal secretions, the existence of which had indeed been postulated and proven, but which had never actually been inspected by the eye of mortal man. To have it in a test-tube, indeed to possess it in large quantities in bottles, to be able to manipulate and examine it without fear of the co-action of admixed impurities, to see it with the eye, and to taste it with the tongue, was truly a marvel. The miracle aroused at once scores of researches.

THE GLAND OF COMBAT AND FIGHT

Considering its effects, one is reminded at once of the similarity to the expression of a primitive emotion like anger or fear. So, by turning a relation upside down, it was argued that if artificial adrenalin could produce all these effects of an emotion like fear, the emotion itself should produce an increase of the natural adrenalin in the blood. This was found to be the case. Cannon of Harvard has built up an entire theory of the adrenal as the gland of emergencies upon the basis of these effects. In the facing of crises the adrenal functions as the gland of combat. And indeed, as I have mentioned, the more combative and pugnacious an animal, the more adrenal it has, while the timid and meek and weak have less.

The Glands of Combat, the glands of emergency energy, the glands of preparedness,—such are the adrenal glands when viewed from the adrenalin standpoint. A picture of its activity in the evolutionary scheme of struggle and survival is something like the following: meeting an enemy, the animal is put in danger. It must fight or flee for its life. In either case, certain conditions must be fulfilled, if the body of the animal endangered is to be saved. To prevent injury to itself, and to do as much injury as possible to the foe—that becomes its immediate urge and necessity. Of the two animals, if in one the heart should begin to beat more strongly, the blood pressure to rise, the blood to flow more rapidly through the attacking instruments, the muscles, the teeth and claws, the brain and its eyes, while the other animal experiences none of these, the former will be the victor in fight or flight. Adrenalin may be looked upon as the invention for the mobilization at a moment's notice, or as we say, after generations of use, by instinct, of all these visceral and blood advantages in the struggle of combat or flight.