thyroidectomy, and there seems no real ground for the belief that the two thyroid, mainly on the ground of increase in size and amount of colloid in

Transcription

1 THE HUMAN PITUITARY BODY. By W. D. HALLIBURTON, F.R.S., J. P. CANDLER, M.D., and A. W. SIKES, M.D. (Froli the Physiological Laboratory, King's College, London; and the Pathological Laboratory, Claybury Asylum.) (With four figures in the text.) (Received for publication 7th February 1909.) INTRODUCTORY. NEARLY all our recent knowledge on the structure and functions of the pituitary body is derived from observation and experiment on the pituitaries of the lower animals. The present research was undertaken with the object of ascertaining whether the data so obtained are also true of the human pituitary. It was extremely improbable that the results obtained with the pituitary of man would be in any marked degree different from what has been found in other mammals, and, as a matter of fact, the main outcome of our work has been to confirm the conclusions arrived at by Howell and by Schafer and his fellow-workers from their investigations of this organ in other animals. A second object of the research was to ascertain whether any departures from the normal are discoverable in the class of cases treated in lunatic asylums, and one of us (J. P. C.) has been afforded the necessary facilities for obtaining pituitary bodies from the autopsies carried out at Claybury Asylum. It has, however, been found that such is not the case, the results from nearly all specimens being those yielded by the normal gland. We have not had the opportunity of examining the pituitary body in any cases of thyroid insufficiency. Herring' found in thyroidectomised rabbits that the colloid in the pituitary body is increased, and the view has been advanced by several workers 2 that the pituitary can act vicariously for the thyroid, mainly on the ground of increase in size and amount of colloid in the pituitary which follows disease or atrophy of the thyroid gland. As a matter of fact, many tissues are hypertrophied or otherwise modified after thyroidectomy, and there seems no real ground for the belief that the two organs in question are closely related in the manner suggested. We know 1 Quart. Journ. Exp. Physiol., vol. i. p. 281, Rogowitsch appears to have been the first to put forward this hypothesis (Ziegler's Beitrage, Bd. iv., 1886). Boyce and Beadles (Journ. of Pathol. and Bacteriol., vol. i. p. 223, 1893), among others, call attention to cases of nlyxcedema and cretinism in which the pituitary is much enlarged and the colloid increased.

2 230 Halliburton, Candler, and Sikes of nothing in common betveen the functions of the two glands; the.symptoms that follow their removal or disease are entirely different; injections of their extracts give quite contrary results, and, as we shall show later in this paper, the pituitary does not contain the iodine compound which is so characteristic of the thyroid secretion. GENERAL PLAN OF WORK. After removal, each pituitary was cleaned and weighed, and a slice, shaved off so as to include both anterior and posterior lobes, was preserved for microscopical purposes. The remainder was weighed, then rapidly dried in vacuo, and placed in well-stoppered bottles for the subsequent making of extracts in order to test their physiological behaviour. In some cases the anterior and posterior lobes were preserved separately. In view of the action of the pituitary on the kidneys, an examination was also made of the kidneys in each case. The collection of material occupied several months, but the cases to which we shall direct particular attention are the last twenty-four of the series. Here the methods adopted were the same throughout, and in these cases we possess the fullest clinical and post-mortem details. The histological portion of the work was carried out in the Pathological Laboratory, Claybury, by one of us (J. P. C.), and the experimental portion by the other two of us at the Physiological Laboratory, King's College, London. We have to thank Professor P. T. Herring for useful hints regarding the removal of the pituitary; AIr Sydney Mann of Claybury for his care in the drying, weighing, etc., of the specimens, and for the clinical and post-mortem notes of the cases; Dr Rosenheim of King's College for advice in relation to certain points of chemical interest; and Dr Mott for suggesting the research and for his helpful co-operation throughout. The expenses of the work were defrayed from grants received from the Government Grant Committee of the Royal Society, and front the Science Committee of the British Medical Association. WEIGHT AND MOISTURE OF THE HUMAN PITUITARY. We had at our disposal the weighed pituitaries of eighteen m-nales and twenty-six females. The average weight of the fresh gland in males was granmme, and in only four of the eighteen cases did the organ weigh more than half a gramnme. The average weight of the gland in females is a little greater being grammnie, and in only four of the twenty-six cases was it less than half a grammne. As a rough average one may therefore say that the human pituitary weighs 0 5 grammne, and the samne figure is given in Vierordt's Tabellen.t Boyce and Beadles 2 give the average in fifty cases from women as 0 6 grainmne. Their specimens, like ours, were obtained from asylum cases. 1 Second edition, 1893, p Loc. cit.

3 The Human Pituitary Body 231 The percentage of water in the gland in the two sexes is practically identical, so the greater weight of the female organ is not due to excess of water. The following table gives the principal data in reference to this point: PERCENTAGE OF WATER IN HUMAN PITUITARY BODIES. Males. Females. Maximum Minimum Average Taking all the cases together, the human pituitary body thus contains per cent. of water and per cent. of solids. BRIEF NOTES OF THE INDIVIDUAL CASES. It will be convenient here to enumerate the twenty-four consecutive cases which were systematically examined, and add in relation to each the main clinical and other data. CASE 1.-Male, aet. 40. Suffered from tabo-paralysis, and died of tuberculosis of lungs and intestine. The kidneys showed a slight increase of connective tissue and some thickening of the arterial coats. CASE 2.-Female, wet. 66. Melancholia; died of mitral stenosis. Had a suprarenal adenoma and a floating kidney. Kidneys granular and cystic; albumin in urine. CASE 3. -Female, wet. 51. Epileptic melancholia; died of cardiac failure with thrombosis of iliac arteries and commencing gangrene of limb. Kidneys showed marked sclerosis. CASE 4.-Female, met. 61. Mania; died of ureemia. Granular contracted kidneys. CASE 5.-Female, met. 33. General paralysis; died of tuberculosis of lungs. Kidneys normal. CASE 6.-Male, wet. 62. Delusional insanity; died of syncope. Kidneys practically normnal. CASE 7.-Female, net. 65. Alcoholic dementia; died of bronchopneumonia. Kidneys slightly fibrotic. CASE 8.-Male, met. 38. General paralysis; died of exhaustion after seizures. Syphilitic lesions found. Kidneys normal. CASE 9.-Male, met. 51. Imbecility with mania; died of bronchopneumonia. Kidneys normal. CASE 10.-Female, met. 63. Senile dementia; died of cardiac failure. Right kidney congenitally atrophied; left granular contracted. CASE 11.-Female, met. 54. Mania; died of cardiac failure. Kidneys practically normal.

4 232 Halliburton, Candler, and Sikes CASE 12.-Male, wet. 43. General paralysis; died of purulent broncho-pneumonia. Cystitis and consecutive suppurative nephritis. CASE 13.-Female, at. 38.-Melancholia; died from exhaustion due to Graves' disease. Catarrhal nephritis. CASE 14.-Female, at. 36. Melancholia; died from tuberculosis of lungs and intestine. Kidneys practically normal. CASE 15. -Female, Pet. 55. Melancholia; died from septic meningitis. Suppurative nephritis. CASE 16.-Male, awt. 38. General paralysis; died from bronchopneumonia. Some increase of fibrous tissue in kidneys. CASE 17.-Female, aet. 36. Acute melancholia; died of dysentery. Kidneys normal. CASE 18.-Male, at. 57. General paralysis; died of phthisis. Kidneys show some excess of fibrous tissue. On the upper surface of the right kidney suprarenal tissue invaded the superficial layers of the cortex. CASE 19. -Female, et. 38. General paralysis; cystitis and pulmonary congestion. Kidneys normal. CASE 20.-Male, Bet. 51. General paralysis; died of gangrene of lung. Kidneys normal. CASE 21.-Male, at. 29. General paralysis; phthisis; died of broncho-pneumonia. Kidneys normal. CASE Male, set. 49. Dementia; died of pneumonia. Kidneys fibrous. CASE 23.-Male, set. 34. Melancholia; died of tuberculosis of lungs and intestines. Kidneys normal. CASE 24.-Female, et. 48. Died of hypostatic pneumonia; kidneys somewhat fibrous. MICROSCOPICAL EXAMINATION OF THE PITUITARY BODIES. We have very little to add to the very thorough description of the microscopical appearances of the pituitary body already given by P. T. Herring.1 The account which he gives of the mammalian pituitary applies equally to that structure in man. We would only like to emphasise his observation of the way in which the cells of the pars intermedia invade the posterior lobe and its stalk and the adjacent brain surface; his view that the physiological activity of the posterior lobe is to be attributed to this invasion we regard as extremely probable. The colloid cysts, which are mainly found adjoining the posterior lobe, are very variable both in number and in size. In only one case was anything noteworthy found on naked-eye examination; this was case No. 18. There the pituitary was markedly cystic and calcareous. In fact, it was so hard that all attempts to obtain microscopic sections proved fruitless. The cysts noted in other cases were not visible to the naked eye. In one case (No. 19) there was a necrotic area in a part of the anterior lobe. I Quart. Journ. of Exp. Physiol., vol. i. pp , 1908.

5 The Human Pituitary Body But beyoncl this, -tind a sli(,ht increase in the c'onnlectiv-e tissue in a few othler cases, tlle pitllitalie~s preselsted llo abllormlal features. 2i33 ~~~~~~~~~~~~~~~~ l~~~~~~ FI.L Cse3 Aclodcssithpasitemdaotepiutrboy Bicesei coneciv tisue iiiato daees Sofra heciia ecrsyter per oabe otigi h syptm duin lie i hpstmrnapaacst orsodwt

6 234 Halliburton, Candler, and Sikes aniy diniitsution of the pituitaiy function. The invasion of one kidney by suprarenal tissue, noted in Case 1S, can hardly bear any relatioiiship to the pituitary degenerationi. The accompanying photo-micirographs show the colloid cysts in two cases (figs. 1 and 2) and the necrotic area referred to in Case 19 (fig,. 83). EXPERIMENTAL INVESTIGATION(OF PITUITARY EXTRACTS. These experiments were niade on cats; the animal was first ana~sthetised with A.C.E. mixture, and anitsthesia was maintained during the course of FIG. 2.-Case 7. Colloid cysts arising from the epitheliurn of the pars interinedia. Magnification 120 diameters. the experiment with ether, the animnal being completely unconscious throughout, and killed at the conclusion of the experimient, before it recovered fromt the effects of the aniesthetic. The method of the experiment was almost exactly the saille as that adopted by Schafer and Herring.' A cannula in the external jugular vein served for the injection of the extract; another in the carotid artery was connected to a mercurial manometer for the registration of arterial blood-pressure. One kidney was enclosed in a gutta-percha oncoineter, which was connected to a Locke's bellows recordel 2 for tlme registration of changes in kidney volume. A tube was tied into the bladder, and tlme drops of urine as they flowae(l from-i its open end were signalled on the abscissa of the blood-pressure. rthe record was completed by a time-marlkler tracingr 1 Phil. Trans;. Roy. Soc., v-o1. CXCix., 1. pp. 1-29, Quart. Journ. of Exp. Physiol., vol. i. pp :370, 1908.

7 The Human Pituitary Body 235 seconds. At the conclusion of the experiment, the total volume of the kidney experimented with was roughly taken by immersing it in water in a graduated cylinder; the bellows recorder was calibrated by inserting 1 c.e. of water into the tube leading to it; and the rise of the oncometer lever corresponding to a volume increase of 1 c.c. was marked upon the tracing. The extracts were also made in the way described by SchaXfer and Herring; in some preliminary experiments from material collected and dried six months previously, the pituitary bodies from several cases were powdered and mixed together; this was ground up with Ringer's solution in the proportion of 1 gramme of dry material to 100 of the solution, boiled FIG. 3.-Case 19. An area of focal necrosis situated in the anterior lobe. At the periphery is seen the commencement of connective tissue formation, whilst in the centre red blood corpuscles can be seeu in large numbers. Magnification 120 diameters. and filtered. This gives what Schafer and Herring call their 1 per cent. solution. It was warmed to body temperature, and 5 c.c. of this were injected into the cat's jugular vein, a control experiment being, however, always at first made by the injection of 5 c.c. of pure Ringer's solution. The control experiment produced uniformly a negative result, but the injection of the extract caused the three effects described by Schafer and Herring, viz.: 1. A rise of arterial pressure. A second injection usually causes no rise at all, or only an insignificant one; the effect of the second and following injections is usually to produce a fall of pressure similar to that caused by the injection of most tissue extracts. 2. A marked and prolonged dilatation of the kidney, sometimes preceded by a slight and very temporary fall of the oncometer recording lever. 3. Diuresis, as registered by the increase in the rate of the drops of VOL. II., NO

8 236 Halliburton, Candler, and Sikes urine. The second and third effects are produced not only by the first, but also by the subsequent injections. The occurrence of these effects confirms the statement of Schidfer and Herring that the keeping of the dried organ for many months does not materially impair its activity. Nevertheless, we thought it advisable to confine our systematic investigation of the pituitaries to the twenty-four which were collected last, and which in any case had not been preserved for more than a month or two. In order to investigate these separately. it therefore became necessary to make another preliminary experiment to ascertain whether sufficient of the active substance could be obtained from a single pituitary body for the purpose. We found that it could. A single pituitary body was extracted with 10 c.c. of Ringer's solution; so that we had sufficient for the injection of two doses of 5 c.c. each. Perfectly typical results were obtained. Another preliminary series of experiments consisted in making similar extracts of the anterior and posterior lobes separately. We had at our disposal seven specimens in which the separation had been effected, and the two lobes dried separately. We selected three of these at random, and all gave the same results. The remaining four were mixed together for a single experiment, the glandular portions serving for the making of one extract, the nervous portion for the making of another. The results of these experiments confirm those obtained by Schaifer and Herring: extracts of the anterior lobe caused no rise of blood-pressure, no effect on the kidney, and no diuresis; a slight fall of arterial pressure occurred in a few cases. On the other hand, extracts of the posterior lobe gave typically the three effects already noted. Passing now to the systematic investigation of the twenty-four selected cases, the method of procedure was as follows: Each pituitary body (minus the portion reserved for microscopical purposes) was ground up and extracted with 10 to 12 c.c. of Ringer's solution, the mixture was boiled and filtered, and the filtrate divided into two parts for successive injections. In these specimens no attempt had been made to separate the two lobes, and, allowing for the weight of the anterior lobe being approximately half that of the entire pituitary, the strength of the extracts was about one-quarter of that which Schafer and Herring term their 1 per cent. solution. The extract was injected at body temperature, and was always preceded by a control injection of 5 c.c. of Ringer's solution. A separate cat was employed for each of the twenty-four experiments. The results of the experiments may be very briefly stated: the great majority gave the usual three effects quite typically. There was naturally some variation in the degree of the effects, the rise of blood-pressure and the effects on the kidney being sometimes greater and sometimes less marked than in other cases. It will be sufficient to illustrate the results by a single tracing, namely that obtained from the pituitary of Case 16 (fig. 4).

9 CX Ca- -~ f f C) rsd w - *- %- CO- C - Cs t En ;q Q) -e e- - t- 90 -ncr r,n - a 3 4-D -0 CZCC CCa 4,*

10 238 Halliburton, Candler, and Sikes The only exceptions to this rule were the following:- CASE 13.-The injection produced a slight rise of blood-pressure; but there was no diuresis and no expansion of the kidney. Such an experiment confirms the view of Schafer and Herring that the vascular and kidney effects are probably due to different substances. CASE 17.-The injection produced no rise of blood-pressure, but a slight fall, the usual effect of most tissue extracts. There was also no swelling of the kidney and no diuresis. CASE 19.-Here the rise of blood-pressure was very insignificant (viz. from 140 to 144 mm. Hg). There was no effect on the kidney and no diuresis. CASES 20 and 21.-All these effects, though present, were extremely slight. Cardiac slowing, which was noted by Schafer and Vincent' as an occasional effect of pituitary injections, was only obtained by us in one out of the twenty-four experiments, namely in the experiment with extract No. 5, but was occasionally seen in one or two other experiments not included in the selected list of cases. The effects on the pupil, on the uterus, and on other varieties of involuntary muscular tissue were not examined. CORRELATION OF CLINICAL, HISTOLOGICAL, AND EXPERIMENTAL RESULTS. We may now proceed to the correlation of the three sets of results, clinical, histological, and experimental. i. Relation of Pituitary Structure and Physiological Activity. -The magnitude of the physiological effects shows no relationship to the degree of development of the colloid cysts, nor to the amount of growth of interstitial connective tissue which was noted in a few cases. Two cases only in the series presented any marked evidence of abnormal appearances. These were Cases 18 and 19. In Case 18 the pituitary body was cystic even to the naked eye, and too calcareous for the preparation of sections; yet the extract produced well-marked physiological effects. Case 19 was the one in which there was focal necrosis; in this case the physiological effects were practically absent, although the abnormality noted was in the anterior lobe. ii. Relation of Nervous Disease and Pituitary Function and Structure.-No relation is discoverable between the nervous affections for which the patients were admitted to the asylum, and the condition of the pituitary. Both Cases 18 and 19 referred to above suffered from general paralysis, but there are other cases of the same disease in the list, in which the pituitary was normal. There appears also to be an absence of cause and effect between the disease which ultimately carried off the patient and the pituitary condition. As already stated, we have not yet examined any cases of thyroid insufficiency. 1 Journ. of Physiol., vol. xxv. pp , 1899.

11 The Human Pituitary Body 239 iii. Relation between Kidney Disease and the Condition of the Pituitary.-In view of the undoubted relation between the functions of the pituitary and kidney, it is necessary to inquire whether there is any indication in our cases of a pathological relationship. Here again, however, the answer is in the negative. In ten of the twenty-four cases, kidney disease was absent, and in eight of these the pituitary was normal, and the extracts gave a good physiological effect. One of the ten cases was Case 19, where the anterior portion of pituitary was necrotic, and the extract gave negative results; and the remaining case was No. 17, where the pituitary showed no histological change, and yet the extract gave negative results. In the other fourteen cases where the kidneys gave evidence of more or less disease, the condition of the pituitary showed no parallel condition; this includes Case No. 4, where the patient had a granular kidney and died of uraemia, yet the pituitary was normal or showed only some increase of connective tissue, and its extract produced a well-marked physiological effect. In Case 18, where the pituitary was cystic to the naked eye and calcareous, one kidney was invaded by suprarenal tissue, but the physiological effects of the pituitary injection were normal. In Case 16, where we obtained one of the best physiological results (see fig. 4), the kidneys were fibrotic. In Case 13, where no effects on the kidney were produced by the injection of the extract, there was nephritis. We have no notes in any case of the quantity of urine secreted during life. iv. Relation between Effects of Pituitary Injection and Length of Time between Death and Autopsy.-A possible cause of the failure to obtain physiological effects with the extracts in the few cases where such failure occurred is the onset of post-mortem changes. The use of the cold chamber at Claybury when the performance of the autopsy has to be postponed beyond a few hours, will necessarily minimise such effects. The following table gives at a glance the length of the interval in each of the twenty-four cases: Time in hours Physiological Time in hours Physiological between death effect of between death effect of and autopsy. extracts. and autopsy. extracts. 1 2 Good Slight. Kidney 2 5 Good effect absent 3 28 Fair Good 4 10 Good Good 5 2 Good 16 8 Good 6 19 Good 17 3 Nil 15 Good Good 8 26 Good Nil 9 19 Good Slight 10 8 Good Slight 11 3 Good Good Good Good Good

12 240 2Halliburton, Candler, and Sikes The length of the interval may possibly, at any rate in part, explain the slight effect of the extract observed in Cases 3, 19, 20, and 21; but it will be noted that there are other cases in which the interval was as long or even longer, and yet the extracts gave good results. Case 17 appears entirely inexplicable; the interval was only three hours, and nothing was found histologically abnormal, either in pituitary or kidney, and yet the result of the injection of the extract was nil, on blood-pressure, kidney expansion, and secretion of urine. CHEMICAL PROPERTIES OF THE PHYSIOLOGICALLY ACTIVE MATERIALS. There is evidence that the substances which produce the physiological effects on injection of extracts of the posterior lobe are at least two in number, one being responsible for the rise in arterial pressure, and the other for the local effects on the kidney. The former substance is probably the one which causes dilatation of the pupil.' We have seen that there is also evidence that the posterior lobe owes its activity to the cells of the pars intermedia which invade it. There appear, however, no data at present for determining whether the colloid material of the cysts contains either one or the other of these substances. Our knowledge of the chemical properties of the active principles is rather negative than positive; we know, for example, that neither of them are proteins, for the extracts remain active after boiling. We know also that the pressor substance is not adrenaline, seeing that its effect is demonstrable only at the first injection, unless the intervals between the injections are much prolonged. The only research we are acquainted with relating to its chemistry is one by T. B. Aldrich, who at present has only published a preliminary notice of his work.2 He separated from the posterior lobe a basic material, of which he obtained a crystalline picrate and sulphate, and also a double salt with platinum. This substance produces a rise of arterial blood-pressure. We have not pursued the matter on these lines, but, in view of the suggested correlation of function between the thyroid and the pituitary, have attempted to ascertain whether the pituitary body contains any iodinecontaining substance, analogous to or identical with the iodothyrin of the thyroid gland. For this purpose we obtained from twenty-two human pituitaries a total dry residue after it was finely powdered of 1-2 grammes. The method employed for the detection of iodine is that used by previous observers in their work on the thyroid.3 One gramme of the finely divided material was mixed with 2 2 grammes of pure sodium hydroxide and 0-5 gramme of pure potassium nitrate, 1 Cramer, Quart. Journ. of Exp. Physiol., vol. i. p. 189, " On the Chemistry of the Infundibular Body," Proc. Amer. Physiol. Soc., , xxii.-xxiv.; Amer. Journ. of Physiol., vol. xxi., Baumann, Zeitsch. f. physiol. Chem., xxii. p. 2, 1896; S. Jolin, Hammarsten's Festschrift, 1906.

13 The Human Pituitary Body 5 c.c. of water were added, and the mixture heated in a silver crucible in the water bath until it was nearly dry. It was then heated carefully over a small flame until the dry residue was white, and then completely fused over a larger flame, a little more of the potassium nitrate being added during the process. It was then taken up with about 30 c.c. of water, heated some time in the water bath, and then filtered. The filtrate was placed in a stoppered cylinder, and about 10 c.c. of chloroform added. It was then acidified with sulphuric acid carefully, and well shaken after every addition; a few drops of potassium nitrate solution were also added. After thorough shaking, the chloroform remained absolutely colourless, and therefore iodine was absent. We repeated the same experiment with 1 gramme of dried ox-pituitary (which represents about 4 grammes of the fresh material), and obtained the same negative result. Previous Observations.-E. Baumann (Munch. med. Wochenschr., April 7, 1896, p. 311) repeatedly examined the hypophysis of man for iodine, with negative results. But J. Schnitzler (Wiener med. Wochenschr., July 16, 1896, p. 657) states in a brief paragraph that by the use of Baumann's method he had been successful in obtaining positive proof of the presence of iodine in the human hypophysis. In one experiment he used 19 and in another 24 grammes of moist material collected in the Vienna Institute for Pathological Anatomy, and he attributes his success to the employment of such large quantities of material. From this it would appear that the total yield of iodine was small, although no figures are given. He assumes that the iodine is present as iodothyrin, and adduces his result as confirmatory of the view that the thyroid and the pituitary may act vicariously. He admits that some of his material was putrefying, but gives no details of the cases from which the organ was obtained. It appears desirable that the point should be reinvestigated by those who have the opportunity of obtaining large quantities of material both in health and disease. SUMMARY OF CONCLUSIONS The human pituitary body weighs about half a gramme, and on the average is somewhat larger in females than in males. It contains in the mean 76-6 per cent. of water. 2. In the cases of nervous disease (asylum cases) from which our material was obtained, there is in the pituitary body, as a rule, no noteworthy departure from the normal condition. 3. The anatomical description of the mammalian pituitary body, as given by Herring, applies equally well to that of the human subject. The invasion of the posterior lobe by the cells of the pars intermedia is a marked feature. The number and size of the cysts which contain a colloid material is variable; as a rule, these are most numerous in the pars intermedia.

14 242 The Human Pituitary Body 4. Sufficient material is available in a single human pituitary body for the examination of the physiological action of extracts. If one pituitary is ground up and boiled with c.c. of Ringer's solution, and filtered, sufficient is obtained for injecting two quantities of about 5 c.c. each. The strength of such solutions is about one-quarter of that employed by Schafer and Herring, who mainly used what they term a 1 per cent. solution, i.e., 1 gramme of the dried posterior lobe, to 100 c.c. of Ringer's solution. 5. The dried glands maintain their physiological activity for manymonths. 6. Extracts of the posterior lobe produce the same effects as those described by Schafer and Herring for that of other mammals. In anaesthetised cats these effects are: i. Rise of arterial blood-pressure; this occurs only on the first injection. ii. A prolonged expansion of the blood-vessels of the kidney, though arterial constriction is produced in other parts. iii. Diuresis. 7. Extracts of the anterior lobe are wholly inactive in all these directions; occasionally a slight fall of pressure "the usual effect of most tissue extracts) is obtained. 8. In the cases examined, no relationship was found to exist between the condition and activity of the pituitary body on the one hand, and the nervous disease from which the patient suffered on the other. There was a similar absence of discoverable relationship between thepituitaryand the disease from which the patients ultimately died, and the condition of their kidneys. 9. The pituitary bodies examined presented no noteworthy departure from the normal, except in two cases; in one of these (Case 18) the cysts were visible to the naked eye, and the pituitary was markedly calcareous; yet extracts of it produced the usual effects. In the other case, the anterior lobe of which presented a necrotic appearance (Case 19), the extract was inactive. 10. In five other cases negative or slight effects were also obtained as the result of the injection of the extracts. In Cases 3, 13, 20, and 21 this may possibly be explained by the length of the interval between the autopsy and the death of the patient; although in other cases, where the interval was as long, no deterioration due to post-mortem changes was observable. In Case 17 the extract was inactive, although the interval between death and autopsy was only three hours, and the pituitary body was normal histologically. 11. The substances in the posterior lobe responsible for these actions appear to be two in number, one producing the rise in blood-pressure, the other the effect in the kidney, since occasionally one or other action may be absent. 12. Although these substances are probably developed in connection with the activity of the cells of the pars intermedia, there is no available evidence for connecting either of them with the colloid material in the cysts. 13. In view of the suggested vicarious relationship between thyroid and pituitary, we have examined the latter organ for iodine both in man and ox, but with negative results.