TION).
Adrenalin.—Oliver and Schafer in 1895 showed that an ex tract of the suprarenal glands contained a substance which when injected caused a large rise in the arterial blood pressure. They showed also that this "pressor" substance was present only in the medulla, and was absent from the cortex of the gland.
The active substance adrenalin was isolated in 1901 by Taka mine and later by various workers shown to have the constitution by the synthesis of this corn pound and the demonstration of its identity with the natural hor mone the formula was finally established.
Natural adrenalin is optically active, rotating the plane of polar ized light to the left. When a small amount of adrenalin is in jected into the blood stream it produces constriction of almost all the small arterioles of the body with resulting rise of blood pres sure. Its action, however, is not confined to the blood vessels but extends to all structures in the body which normally receive a nerve supply from the sympathetic nervous system. Thus it in creases the force of the heart, inhibits the movements of the diges tive tract and (in many animals) of the bladder ; it may also pro duce sweating, erection of hair, contraction of the pregnant uterus and dilatation of the pupil. Adrenalin is an intensely active sub stance; 0.0025 milligram per kilogram of body weight, when in jected into the circulation, produces a definite rise in blood pres sure. At a dilution of I:250,000,000 its effect on the vessels of the rabbit's ear could be detected. The exact point of action of adre nalin appears to be not on the true sympathetic nerve ending but on some receptive substance which lies between the actual nerve ending and the muscular fibre.
Owing to its constrictor effect on the blood vessels, adrenalin has proved of great value in checking haemorrhage when applied lo cally. It is probably more valuable in preventing than in checking haemorrhage, and is largely used in intranasal surgery. Its effect is, however, very temporary. The remarkable relationship between the hormone of the suprarenal medulla and the sympathetic nerv ous system has excited great interest ; and it is worthy of note that Balfour showed in 1878 that developmentally the suprarenal medulla has the same origin as the sympathetic system. There is little doubt that adrenalin is discharged into the blood stream from the suprarenal medulla; indeed, its presence in the blood leaving the suprarenal gland has been clearly shown.
Cannon (1915) has collected a considerable amount of evidence that in states of violent emotion such as rage, fear or pain the output of adrenalin is considerably increased and by its action on the blood vessels and other tissues the reaction of the animal to these emotional conditions (in defence or in attack) are made more effective. Other workers, notably Stewart and Rogoff, have called into question the relation of such stimuli to the secretion of adrenalin. Whatever may be the final decision, it is clear that adrenalin is a hormone which is used only for special purposes, and there is no evidence that the suprarenal medulla plays a prominent or indispensable part in regulating the activities of the normal mammalian organism.
The cortex of the suprarenal gland, on the other hand, is indis pensable to the life of the organism. In 1855 Addison described in man a fatal disease which is characterized by prostration, mus cular wasting, vomiting and brown pigmentation of the skin, and showed that it was associated with disease or atrophy of the suprarenal glands. There is also evidence that overgrowth of the cortex in children is associated with sexual precocity and prema ture adolescence. Subsequent investigation has thrown little light on the functions of the cortex; it is not yet clear what are the relative parts played by loss of cortex or loss of medullary sub stance in the causation of the symptoms of Addison's disease, nor indeed is there any definite evidence that the cortex actually elaborates and discharges a hormone into the blood stream.
Deficiency or absence of the gland at birth results in a condi tion known as cretinism in which mental and physical growth is tremendously retarded. The cretin of i8 years of age may have the mental intelligence of a normal child of two or three. Ex tracts of the gland, or the whole gland itself, given by the mouth, lead to complete recovery in myxoedema and marked improve ment in cases of cretinism. Further evidence of the connection be tween the thyroid gland and growth is provided by the remarkable effects of thyroid extract on the metamorphosis of tadpoles. Feed ing tadpoles with thyroid gland causes a greatly accelerated meta morphosis, so that, compared with an untreated control, a minute frog results much before the usual time.
Operative removal of the thyroid gland in man or animals is frequently complicated owing to the presence in the thyroid sub stance of the parathyroid glands. If the latter are left undis turbed, typical myxoedema results from removal of the thyroid gland, and the myxoedema so produced is completely cured by feeding the gland or extracts of it.
The thyroid is hypertrophied in the disease known as exoph thalmic goitre or Graves disease, and the symptoms are the re verse of those noted in myxoedema. The patient loses weight, the pulse rate is increased, the excretion of nitrogen and carbon dioxide is higher than normal, and the resting consumption of oxygen may be increased by 5o%. There is also great nervous ex citability and in severe cases protrusion of the eyeballs.
Chemically the interesting fact about the thyroid gland is that it has a high content of iodine. Kendall in America in 1914. suc ceeded in isolating a crystalline compound containing iodine to which he gave the name thyroxin. Thyroxin possesses all the characteristic activities of the gland itself and is to be regarded as the hormone of the thyroid gland. Kendall suggested a chemi cal formula for thyroxin (which contains 65% of iodine), but the recent work of Harington in 1926 and Harington and Barger in 1927 in England has culminated in the elucidation of its structure and a brilliant synthesis of the natural product.
Thyroxin is an extremely active substance and a dose of one milligram produces definite effects on the oxygen consumption of a normal individual at rest. Daily doses of 2-3 milligrams may in crease this resting oxygen usage by 3o% above normal, but no effect is produced until about five days after a dose has been given. The human thyroid gland is believed to produce about one milli gram of thyroxin per day. Thyroxin can of course completely replace thyroid gland substance or thyroid extracts in the cure of myxoedema or in the treatment of cretinism.
Direct evidence of the presence of thyroxin in the blood stream is not yet available, nor is it at present known at what particular point or tissue thyroxin exerts its action.
It is evident, however, that the hormone exerts an important control over the metabolism of the adult body and over the pro cesses of mental and physical development; in its absence normal growth does not occur.
The condition is known as tetany, and is frequently fatal, par ticularly in the case of carnivorous animals. Two hypotheses con cerning this condition of tetany have been advanced. Noel Paton and his collaborators reached the conclusion that the tetany is due to accumulation of guanidine derivatives in the blood after removal of the parathyroids, and showed that the introduction of guanidine into the circulation of a normal animal produced symp toms similar to those observed after parathyroid removal. These views have not met with universal acceptance and MacCallum has drawn attention to the beneficial results of calcium administration in cases of parathyroid tetany, and to the fact that the tetanic symptoms are also characteristic of deficiency in the calcium con tent of blood. Various workers confirmed these suggestions and showed that after removal of the parathyroid glands there is a fall in blood calcium content, and that the fatal effects of the ensuing tetany in a carnivorous animal such as the dog can be prevented by the administration of sufficient quantities of calcium lactate. A new light has been thrown on the question following the success of Collip in 1925 in obtaining an extract from parathyroid glands which has a strong effect on the calcium content of the blood in normal dogs and in dogs which have had the parathyroid glands removed.
Injection of the extract raises the blood calcium in both cases; the rise is greater in the case of the animals from which the parathyroids have been removed. Continued injections not only raise the calcium content to a more normal level, but completely prevent the appearance of the tetany which is normally the sequel of loss of the parathyroids.
Further information is required before it can be assumed that the extract prepared by Collip contains the parathyroid hormone. It has yet to be shown that the power of raising the blood calcium is a specific property of the extract, or that under normal condi tions the parathyroid glands liberate the active substance into the circulation.
Although it is the anterior lobe which microscopically is the glandular portion of the pituitary, yet it is from the posterior lobe that is obtained the extract which exercises so powerful an effect on a variety of bodily functions.
Though no definite active principle has yet been obtained from the anterior lobe, there is little doubt that is does exercise the function of producing an internal secretion. The evidence is clear that overgrowth of the anterior lobe of the gland produces in man the disease known as acromegaly. This disease is characterized by enlargement of the bones of the face, hands and feet. Where overgrowth of the anterior lobe of the pituitary occurs in early life, there is produced a condition known as gigantism, in which there is general elongation of the long bones of the body. Admin istration of anterior lobe substance to developing amphibian larvae has been shown by various workers to cause accelerated meta morphosis and growth, while A. M. Evans has recently by similar means succeeded in producing experimental gigantism in rats. Some workers, as a result of extirpation of the anterior lobe, claim that it is essential for the life of the animal. The results are con fusing, but it would appear that removal of the anterior lobe in a young animal greatly retards growth, and stops sexual develop ment.
A strikingly active extract can, on the other hand, be obtained from the posterior lobe. Oliver and Schafer showed, as in the case of the suprarenal gland, that an extract having a powerful pressor action could be obtained from the pituitary gland. Later it became clear that this active principle was confined to the posterior lobe, and that with a second or subsequent injection the blood pressure actually fell. In other words, the pressor effect was replaced by a depressor effect. The depressor substance can be removed from the gland by alcoholic extraction, leaving a pure pressor principle behind. The evidence is satisfactory that this depressor substance is not a specific principle of the pituitary but one which can be obtained from almost any organ of the body.
A second action is an effect on the secretion of urine. In an aesthetised animals the effect is an inhibition of the secretion of urine which lasts until the rise of blood pressure has passed its maximum, and is then followed by an increased flow of urine. It is to be regarded as a corollary of the general pressor effect ; the primary inhibition being due to constriction of the blood vessels of the kidney along with those of the body in general, and the later increase to the disappearance of the constriction of the kid ney vessels sooner than in other organs, so that a larger volume of blood passes through the kidney.
A third action of the pituitary extract, which is the basis of its commonest therapeutic application, was observed by H. H. Dale in England. This is its intense stimulating action on the plain muscle of the uterus. By the use of this test some idea of the astounding activity of this oxytocic principle can be obtained. Abel of Baltimore has obtained a preparation from the posterior lobe which is capable of causing powerful uterine contractions in a dilution of i in i oo,000,000,000. As the product is probably still not pure the actual activity of the pure principle will be even more impressive.
Schafer and his co-workers observed yet another action of the extract—the galactagogue action, a rapid outpouring of milk from the lactating mammary gland when the pituitary extract is admin istered intravenously. There is no evidence of an increased forma tion of milk and it is probably a squeezing out of milk already formed in the gland. It is doubtful whether this action is of any serious importance or is even a specific effect of pituitary extract.
The same remarks apply to the action of the extract in causing expansion of the pigment cells of the skin of the frog. The is exceedingly delicate, but it is difficult to assign any functional importance to it in the mammal. More important is the effect of posterior lobe extract in checking the flow of urine following on the ingestion of water, and in reducing the abnormal flow of dilute urine in cases of the disease diabetes insipidus. This antidiuretic effect must be clearly distinguished from the effect on the kidney mentioned previously as probably a corollary of the pressor effect.
The final effect which must be mentioned is the control which the extract appears to exercise over the metabolism of carbo hydrates. This is of such a nature as to act antagonistically to the rise of blood sugar caused by adrenalin, and to the fall in blood sugar produced by the pancreatic hormone insulin.
The question arises whether the effects described are due to various activities of a single principle or whether there are several distinct principles present in the posterior lobe extract. The evi dence obtained from the distribution of these activities in extracts of different parts of the gland, and on the results of chemical fractionation of the extracts, makes it necessary to assume that there are at least three different principles. One combines the pressor and diuretic action, the second the oxytocic and galacta gogue, and the third is the principle causing expansion of the pigment cells in the frog's skin. Whether the antidiuretic effect and the action on sugar metabolism are due to still other principles is not yet ascertained.
Evidence that the various principles found in extracts of the posterior lobe of the pituitary gland function as true hormones is as yet slight.
The pressor substance does apparently play a part in the normal maintenance of the tone of the blood vessels, since removal of the posterior lobe in the frog causes loss of tone and oedema. The observations of W. E. Dixon and F. H. A. Marshall also suggest that the oxytocic principle acts as a true hormone. They observed that injection of an ovarian extract made towards the end of preg nancy brought about the appearance of an oxytocic principle in the cerebrospinal fluid. They suggest that the hormone reaches the circulation via the cerebrospinal fluid and is concerned in a mechanism for bringing into play the contractile mechanism of the uterus at the termination of pregnancy. The striking effect of the posterior lobe extract in checking the excessive secretion of urine in diabetes insipidus, and the fact that the latter is frequently associated with lesions of the pituitary gland, also suggest a hor monal control over some part of the kidney function.
The same general effects are found in animals. Castration pre vents the appearance of such secondary sexual characters as the comb of the cock and the antlers of the stag. It has been shown conclusively by many workers that transplantation of the testes under the skin of a castrated animal results in a normal develop ment of these secondary sexual characteristics. Indeed so marked is the effect that if testes are transplanted into animals congeni tally female, the secondary male characters may develop. Exam ination of these transplanted testes reveals the fact that the spermatogenetic tissue of the testes degenerates, but that, the tissue being between the spermatic tubules, the interstitial tissue persists.
That the testis when removed from its normal position and transplanted in an abnormal position, where it no longer possesses its usual nerve connections, still retains its influence on the sec ondary male characters and on the accessory sexual glands, is evi dence of the clearest type that it secretes a hormone or hormones into the blood which act on other distant organs in the body. In jections of testicular extracts into castrated animals, although not so convincing, also support this conclusion. The interstitial cells are presumably the source of the internal secretion.
The idea of a connection between the testicular influence and re juvenation has recently been revived by Steinach and others, particularly with reference to this interstitial tissue or "puberty" gland. The grafting into man of testicles from apes (the so-called "monkey glands") has been practised by Voronoff and others with resulting rejuvenation. Steinach also claims that rejuvenation can be brought about by section or ligature of the vas deferens which results in atrophy of the seminiferous tubules without in terference to the interstitial tissue. Steinach indeed suggests that under these conditions the interstitial tissue increases in amount and attributes the resulting rejuvenation to this hypertrophy of the puberty gland. Although it is not easy to discriminate between improvement due to such causes as changed nutrition and environ ment, and suggestion, and that due to the operations described, it must be admitted that both vasectomy and transplantation of the testis lead frequently to a general improvement in condition which may be regarded as rejuvenation.
Removal of the ovaries in the human, before puberty, prevents the occurrence of menstruation, and their removal after puberty brings about the cessation of menstruation and the atrophy of the uterus. In animals, removal of the ovaries results in similar changes. The uterus degenerates and the cyclical changes (known as the oestrous cycle), which result in the animal coming on heat, also stop. If, instead of being completely removed, the ovaries are transplanted to an abnormal position, menstruation (or the oes trous cycle) continues and the uterus remains normal. Much re cent work suggests that the onset of heat in mammals is closely connected with the activity of the cells lining the follicle in which the ripening ovum is found. It has been shown by Allen and Doisy that "heat" can be induced in rats, of ter removal of the ovaries, by injecting an oil they obtained from the liquid contents of the ovarian follicles. Other workers have confirmed and extended their results.
The ovarian hormone (for such it must be regarded) is an oil soluble in alcohol, ether and chloroform. Its chemical nature is not yet known. The possible connection between the ovary and the uterus through the intermediation of the pituitary gland has al ready been mentioned. After the discharge of the ovum from the ovarian follicle, the cavity of the latter is filled with a mass of cells known as the corpus luteum. In pregnancy this corpus luteum persists for a considerable period. There is general agreement that this organ is responsible for changes which occur in the uterus and mammary glands during pregnancy. Although the actual hormone has not been isolated, there is a considerable amount of evidence that the corpus luteum exercises this control by means of an internal secretion.