Twentieth Century History of Findlay and Hancock County, Ohio, and Representative Citizens, Part 117

Author: Jacob Anthony Kimmell
Publication date: 1910
Publisher:
Number of Pages: 1189

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However, one need not turn to actual morbid states to find striking illustrations of perverted tolerance for carbohydrates. A particularly good example occurs in pregnancy, with its re- markable alterations in metabolic activity-alterations which are unquestionably an expression of change in the activity af all of the glands of internal secretion and not of the ovar and its contained corpus luteum alone. The accompanying thyroid hyperplasia is well known, but an even more striking change, taking place in the hypophysis cerebri, has been brought to light by Erdheim and Stumme's important study.22 We have been able to substantiate their disclosure that the hypophysis is not only much enlarged during preg. nancy but that the pars anterior shows a characteristic and unmistakable histological picture.

Clinical observers have long- known that as a result of re- peated pregnancies evidences of hypophyseal hyperplasia may occur, even to the point of producing such neighborhood symptoms as a transient bitemporal hemianopsia. Further- more, in this state the carbohydrate metabolism becomes al- tered in ways which are similar in many respects to the changes which we have recounted. Thus in a series of preg- nant women observed by Reichenstein," it appeared that out of 93 cases 11.8 per cent showed actual mellituria, while in others a decreased carbohydrate assimilation limit, especially for lævulose, was demonstrated. Indeed, a transient sponta- neous lævulosuria occurred in some of the cases after parturi- tion.

Doubtless comparable alterations in sugar tolerance occur in other periods of physiological readjustment. It is not un- likely that the glycosurias of adolescence may prove to be coupled in some way with deviations in the internal secretion: which are on the borderline of the physiological normal. In view of the occurrence at this period of life of a rapid incre- ment particularly in skeletal growth, it is a natural conjecture that these glycosurias may be related as closely to an hypo- physeal hyperplasia as to the more obvious changes of the in- terstitial cells of testis and ovary which occur at this time. But the facts already established make a sufficiently connectel story to justify the avoidance of speculation.

We have already referred to the frequent coincidence of mellituria with acromegaly. Hanseman in 1897 collected re- ports of 97 cases, 17 of them having shown glycosuria, and he expressed the opinion that the percentage of positive find- ings would have been much larger had the cases been suffi- ciently observed. Strumpel, in the same year, suggested that future investigations of the sugar tolerance in this malady would demonstrate for all cases a lowered assimilation limit even though spontaneous glycosuria might be absent. It ap- parently was his view that some underlying factor affecting metabolism brought about both of these conditions rather than that one of them was dependent in any way upon the

17 It is to be noted that, if our view as to the method of secre- tory discharge from the posterior lobe into the cerebrospinal fluid is supported by the investigations of others, this part of the gland will be removed from the ductless gland series in so far as they are grouped together on the basis of their products of secretion being taken up directly by the blood stream.

18 McCurdy. The influence of thyroidectomy on alimentary gly- cosuria. J. Exper. Med., 1909, XI, p. 798.

" Eppinger, Falta and Rudinger. Ueber die Wechselwirkung der Drüsen mit innerer Sekretion. II Mitteil., Ztschr. f. klin. Med., LXVII, p. 380.

" Underhill and Clossen. Am. J. Physiol., 1907, XVII, p. 42. 21 Kraus and Ludwig: Klinische Beiträge zur alimentaren Gly- cosuria. Wiener klin. Wchnschr., 1891, IV, No. 46, p. 855 and No. 48, p. 897.

22 Erdheim and Stümme: Ueber die Schwangerschaftsverän- derung der Hypophyse. Beiträge z. path. Anat. u. z. all. Path .. 1909, XLVI.

" Reichenstein. Glykosurie und Schwangerschaft. Wiener klik. Wohnschr .. 1909, XXII, p. 1445.

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noted in 14 out of 130 reported cases of acromegaly, and sub- equently Launois and Roy " recorded 16 cases with " diabe- es " the post-mortem finding in three instances having shown pituitary enlargement.

The evident suggestion from these clinical observations, hat the hypophyseal lesion played at least a certain rôle in liciting the glycosuria, naturally led to certain experimental ttempts to reproduce the condition. These attempts were necessarily limited to destructive glandular lesions ; and that he end results of the partial extirpations by Rogowitsch, 'aselli, and Friedman and Mass were negative in this respect s now readily explained by the analysis of the protocols which we have given. The experiments, in other words, were roductive of an ultimate increase (unfortunately unobserved) ather than the expected persistent lowering of the sugar ssimilation limit.

The recent clinical and experimental studies of Borchardt " ave been far more suggestive than any heretofore made. In n investigation of 176 recorded cases of acromegaly he found hat spontaneous glycosuria had occurred in 63 and that in ight others there was a lowered assimilation limit-all told, herefore, 71 showed a deficient carbohydrate metabolism. On he other hand, none of the cases of hypophyseal tumor unas- ociated with acromegaly which had been reported since 1886 howed glycosuria. The query was naturally raised as to why uch a discrepancy should exist if the stimulation of a sup- osed sugar center in the tuber cinereum were actually the ause of the glycogenolysis in the former cases.

Borchardt was able to find in the literature only 10 cases f acromegaly without spontaneous glycosuria, in which the lerance for ingested sugars (" alimentary glycosuria ") had een tested. Of these, all but two were positive, that is, they howed an assimilation limit below the normal. He com- :ents, however, on the fact that there may be considerable triation from time to time in the individual's tolerance, and ves one specific instance of an acromegalic who had shown ontaneous glycosuria five years previously and yet at the me of his observation gave a negative reaction to 150 gms.

glucose. Had Borchardt looked upon this as the rule ther than the exception for the later stages of the disease, would doubtless have anticipated the main outcome of our 'n studies.

Acting on the assumption, therefore, that there was a per- tently lowered carbohydrate tolerance in the disease and at it was occasioned by an overactivity of the gland, he en- avored to simulate this condition, not by glandular extir- tion, but by the hypodermic administration of an extract ived from the whole gland. He was able to show, especially rabbits, that this extract caused hyperglycemia and gly- uria, the reducing body being glucose. With dogs his re-

Launois and Roy. Glycosurie et Hypophyse. Compt. rend. , de biol., 1903, LV.

Borchardt. Die Hypophysenglykosurie und ihre Beziehung 1 Diabetes bei der Akromegalie. Ztschr. f. klin. Med .. 1908, VI, p. 332.

sunts were much less convincing, the offy satisfactory result being obtained in a partially pancreatectomized animal soon after the operation. Later, however, in this same animal no glycosuria could be obtained. (Compare our Protocol No. 35.) Though appreciating the insufficiency of his experimen- tal proofs, Borchardt interpreted his results as at least sug- gestive of the fact that hypophyseal hyperactivity was re- sponsible in the clinical cases for the glycosuria. He made no distinction, it will be noted, between the anterior and pos- terior lobe and the possible individual rôles played by these subdivisions of the gland."

This brief sketch of some of the more important earlier studies suffices to show that glycosuria is known to be a fre- quent accompaniment of acromegaly associated with a hypo- physeal tumor or hyperplasia, and on the other hand, as pointed out by Borchardt, that tumors of the hypophyseal neighborhood unassociated with acromegaly do not cause this symptom, which therefore can hardly be attributed to the stimulation of a neighboring sugar center. Furthermore, experimental re- moval of the gland has failed to cause a permanent lowering of the tolerance, indeed, Borchardt's observations in the re- verse direction, simulating hyperfunction of the gland by the injection of the glandular extracts, have shown that under these circumstances there is at least a temporary tolerance lowering effect.

As the outcome of our laboratory and hospital studies we believe that not only these few established facts concerning the relation of the hypophysis to sugar tolerance but also some of the conjectural views, those of Rath and of Loeb for example, as well as many of the apparent discrepancies which have been the outgrowth of attempts to refute them, are easily correlated and readily explainable on a single basis. This is that conditions of overactivity or functional hyper- plasia of the posterior lobe. (pars nervosa et intermedia) foster glycogenolysis and occasion a lowered sugar tolerance if not an actual glycosuria, whereas in conditions of lowered

" Some doubt has been raised concerning Borchardt's results by the subsequent studies of Franchini (Die Function der Hypophy- sie und die Wirkungen der Injection ihres Extraktes bei Tieren. Berlin. klin. Wchnschr., 1910, No. 14-16), who was unable, except with massive doses either subcutaneously or intravenously to pro- duce glycosuria either in rabbits or dogs. Franchini is inclined to attribute the positive results obtained by Rossi (Il Tommasi, 1909, No. 25-26) in support of Borchart's findings to the fact that Rossi used carbolic acid as a preservative of his extracts, a substance which of itself may cause glycosuria. Our own results with the injection of posterior lobe extract and concentrated cerebro- spinal fluids confirm Borchardt's findings in so far as they show that a spontaneous glycosuria in normal rabbits is easily elicited, and we have found that a definite lowering of the assimilation limit occurs in .normal dogs.

These discrepancies are possibly attributable to the various methods of preparing the extracts. Our own extract is supplied from the dried and powdered posterior lobe. This, according to weight of powder, is dissolved in the desired number of centi- meters of boiling water. This sterilizes the powder and does not affect the active principle, which is not only very soluble but very resistant to heat. The supernatant fluid is used for the in- jection. For the feeding tests the powder itself is used.

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activity or hypoplasia the carbohydrate tolerance becomes distinctly higher than the normal.

Thus it is our belief that the experimental observations in the past have been for the most part regarded as negative through misinterpretations, three important factors having been overlooked: (1) that it is the posterior lobe secretion which is chiefly concerned in these deviations from the nor- mal in the tolerance for carbohydrates; (2) that a persistent lowering of the assimilation limit can be brought about only by an overactivation of this part of the gland and the phys- iological state is one which as yet cannot be experimentally reproduced. Finally (3) that glandular extirpations which include the posterior lobe lead to a terminal increase in sugar tolerance rather than to the long sought for lowering of the assimilation limit. So far, therefore, as the simulation of conditions of disease is concerned, experimental investigations of the function of this or of any other of the ductless glands is narrowed largely to the negative method of study through ex- tirpation, for we know of no way of stimulating any one of these structures into a condition of persistent overactivity, the injection of extracts by no means answering the purpose.

The past clinical observations on the relation of hypophy- seal disease to sugar tolerance have been similarly miscon- strued, as the following essential factors have been overlooked : (1) that the posterior lobe secretion is here again primarily concerned; (2) that in acromegaly, whether or not there exists, as there often does, an obvious tumor or hyperplasia of the pars anterior, there is in the early stages a coincident primary posterior lobe hyperplasia which is responsible for the glycosuria, or lowered assimilation limit; and (3) that inasmuch as the posterior lobe secretes into the cerebrospinal fluid rather than directly into the blood stream, a condition, comparable to a posterior lobe hypoplasia, is produced not only by all interpeduncular tumors which actually compress the gland but also by all distant ones which obstruct the cerebro- spinal fluid outflow ; and finally a functional hypoplasia occurs as the end-result of the actual pituitary struma which char- acterizes acromegaly. All of these stages are productive of posterior lobe insufficiency and lead to an over-tolerance for carbohydrates.

" There is still much difference of opinion in regard to the ætiology of acromegaly, and even in the minds of those who are inclined to attribute the disease to an hypophyseal lesion -implying usually the pars anterior-there are doubts as to whether it is the outcome of a lessened or an increased gland- ular activity. It is our own view that at least the skeletal changes of the malady are an expression of an anterior lobe hyperplasia, which occasionally becomes transformed into an extensive tumor formation (the adenomas and sarcomas of many writers). However this may be, in the early stages of · the disease there is seemingly an activation of the posterior lobe leading, among other symptoms. to the glycosuria or lowered tolerance which we have discussed; in the later stages, through actual destruction, or invasion, or compression of the posterior lobe and pars intermedia, a state of posterior lobe insufficiency supervenes, with an increase of carbohydrate tol- erance. /

This same effect upon posterior lobe secretion, and conse- quently upon sugar tolerance, is brought about in similar fashion by a primary hypoplasia of the posterior lobe or by a superimposed (interpeduncular) tumor, or, thirdly, by a re- mote lesion which has produced an internal hydrocephalus. Unfortunately in the past, studies of carbohydrate assimilation have been directed almost solely toward the investigation of states of lowered sugar tolerance, to the utter neglect of the more common states of greatly increased tolerance which not only seem to be inevitable in advanced cases of acromegaly but which constitute the main metabolic disturbance in the variously named cerebral, or what we should prefer to call hypophyseal, adiposities-dystrophia adiposo-genitalis, adi- posis dolorosa, and many of the hydrocephalies-as well as in some of the diverse states of feminism and infantilism which are encountered.

We think that our experiments have afforded the first satis- factory interpretation of the conflicting results of preceding studies, showing, as they appear to do, in the first place, that a discharge of posterior lobe secretion caused by manipula- tion of the infundibular stalk is responsible for the sponta- neous temporary glycosuria, which appears, as noted by Caselli and others, soon after the operation; in the second place, that a deficiency of posterior lobe secretion, as simu- lated by partial or total removal of this lobe in dogs, occa- sions an increased tolerance to carbohydrates; and thirdis. that administration of posterior lobe extract by mouth, hypo- dermically or intravenously has the power of diminishing this acquired overtolerance.

The precise manner of action of the posterior lobe secre- tion in producing hyperglycemia and glycosuria-whether br a direct glycogenolytic effect, or by some influence exerted or. the sympathetic antonomic nervous system as seems to be the case with adrenalin, or in other ways-must remain unan- swered for the present. It has been conjectured that the er- tract might have an action similar to phlorizin and cause : renal lesion, allowing the normal sugar content of the blood t? pass through the kidneys; but this seems unlikely in view « the fact that we have been able to show for the dog what Bor- chardt demonstrated for rabbits, namely, that the administra- tion of hypophyseal extract produces a hyperglycemia. Others have advanced the idea that some effect of the extrac: on the pancreas would prove to be the underlying factor i: the glycosuria; and this it will be recalled was the view e! Pineles and Strumpel. We have confirmed the statement !! Sweet and Pemberton that posterior lobe extract acts in fashion similar to adrenalin in inhibiting the external flow i pancreatic juice, and it is conceivable that it may likewi- exert an influence on the internal secretion of the islets, br: this hardly seems to be the direction which the final explana- tion of these phenomena will take.

On the clinical side, we believe that the data which we har- given will have a considerable therapeutic significance, for (! the basis of existent carbohydrate tolerance it should be previ- ble to determine whether a particular case of obvious hypophy- seal disease is associated with an over or under activity of it- posterior lobe, and thus whether it is advisable or not to al-

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stages of acromegaly the sugar tol- rance is apt to be low but that later in the disease there is an cquired overtolerance; furthermore, that a high assimilation mit may be expected from the outset when the gland is com- ressed or obstructed by a superimposed tumor which brings bout alterations comparable to those of a primary posterior be hypoplasia. Hence it may be assumed that in the early ages of acromegaly glandular therapy is contraindicated, hereas later in the disease its use would seem to be highly dvisable. The circumstances are similar to those relating to le administration of thyroid extract, which is contraindi- ated in Basedow's disease but gives such brilliant re- ilts in myxoedema. It is clear, furthermore, that hypophy- al extract is indicated in all of the cases of hypopituitarism hich are brought about by obstructive agencies (tumors or ydrocephalus). Our best clinical results of glandular therapy ave been seen in cases of this type, and the dosage, we believe, would be estimated for each case on the basis of the indi- idual's grade of tolerance for carbohydrates.

VI. SUMMARY.

I. Experimental Studies .- We have shown that the secre- ry product of the posterior lobe (pars nervosa et intermedia) discharged into the cavity of the third ventricle and be- mes dissolved in the cerebrospinal fluid, a medium which asses from the ventricles to the subarachnoid spaces and ience, in all probability, enters the blood stream by way of le dural sinuses.

Under various forms of operative manipulation of the in- indibulum and hypophyseal stalk-structures which appear hold the reserve deposit of posterior lobe secretion-a tran- ent hyperglycemia is produced, presumably due to the set- ng free of an excess of this secretion, which in turn causes e discharge of stored glycogen. For the succeeding few ys the assimilation limit for ingested carbohydrates is con- lerably diminished, " alimentary glycosuria " being pro- ced by a smaller amount of sugar than was previously re- ired.

If the operation has been so conducted as to create a subse- ent and permanent insufficiency of posterior lobe secretion ther owing to the removal of a considerable portion of this e with its epithelial investment, or through interference h its secretory discharge either by the placement of a "clip" the stalk, or by so damaging it that an infundibular cica- ‹ forms) the temporary lowering of the assimilation limit succeeded by an abnormal and enduring augmentation in tolerance for sugars.

Che assimilation limit for carbohydrates, greatly increased ler these circumstances, can be promptly lowered by the icident intravenous or subcutaneous injection of posterior extract. This extract, furthermore, has a pronounced it in lowering the sugar tolerance of the normal animal in m it may even cause glycosuria when given in sufficient lge.

creased tolerance for carbohydrates. One of these is a ten- dency toward the acquirement of a generalized adiposity, which suggests the conversion of the stored sugars into fat. Thus, during the tests to establish the carbohydrate tolerance, whether in experimental or clinical cases of posterior lobe de- ficiency, there often occurs a notable accretion in body weight. The individuals are apt to have a subnormal body tempera- ture, suggesting an imperfect oxidizing or metabolizing capacity, and this persistently lowered temperature can be raised by the injection of glandular extracts. Conversely, re- peated hypodermic injections of posterior lobe extract in the normal animal are apt to cause a profound degree of emacia- tion, presumably from excessive tissue katabolism ; and a low- ered carbohydrate tolerance is demonstrable during such an administration of the extract.

For these reasons we believe, contrary to the opinion ad- vanced in a previous paper by Crowe, Cushing and Homans, that the tendency toward adiposity displayed by partially hypophysectomized animals is not due solely to a deficiency of anterior lobe secretion.

II. Clinical Studies .- In view of the fact that the products of posterior lobe secretion enter the cerebrospinal fluid, it is apparent that any intracranial lesion occasioning stasis of this fluid will lead to symptoms of posterior lobe insufficiency. An internal hydrocephalus therefore, of whatever origin, is doubt- less the most common source of moderate grades of this con- dition. Tumors which arise in the interpeduncular space and directly compress and deform the infundibular attachinent and thus " block " the secretion furnish another not infrequent source of the same symptoms. A third form of posterior lobe deficiency occurs as a late manifestation of a pre-existing hypophyseal hyperplasia-much as, in the case of the thyroid gland, evidences of myxoedema in the course of time, are likely to supervene on states of hyperthyroidism.

"It is well known that hyperglycemia is of frequent occur- rence in acromegaly and gigantism-clinical states which pre- sumably represent, at the outset at least, a condition of hyper- pituitarism, the pars anterior doubtless being chiefly respon- sible for the skeletal changes. We believe, however, that there is an inevitable tendency in these states toward an ultimate glandular insufficiency-toward dyspituitarism, in other words. Hence, in all probability a lowered sugar tolerance will be found only during the active stages of these maladies. Thus in all but two of the ten cases of acromegaly that we have studied, the individuals have begun to show present evidences of posterior lobe hypoplasia which are recognizable through the laboratory experiences with animals suffering from com- parable states which have been experimentally produced. They are acquiring adiposity, have subnormal temperatures, and often show an extraordinarily high carbohydrate assimilation limit. AIn view of this marked transition from a low to a high sugar tolerance which occurs during the progress of the malady, the discordant results of the past studies of metabo- lism in acromegaly are not surprising.

- -

As polyuria is apt to be associated with these pituitary

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lesions, whether experimentally produced or the outcome of disease, a clinical picture readily mistaken for diabetes melli- tus or diabetes insipidus may be present. It is not improbable, furthermore, that the fleeting glycosurias following fractures of the base of the skull are induced by trauma of the posterior lobe or its infundibular attachment-glycosurias, in other words, which are comparable to those which can be elicited by operative manipulation of these structures.

In view of the ease with which a transient hyperglycemia may be produced by these hypophyseal lesions, it is possible that our views in regard to the glycosurias, at least those of supposed encephalic origin, need some revision.

If loss or diminution of the internal secretion of the pan- creas robs the tissues of their power of metabolizing carbohy-

drates, certainly loss or diminution of the secretion of the hypophyseal posterior lobe greatly enhances their power in this respect. In view of the generalized adiposity, not confine! to the panniculus alone, but observable also in liver and muscle as well as in the other organs in these states, it would seem that functional deficiency of the posterior lobe permite the excess of stored carbohydrates to be transformed into fat.

In these states of beginning adiposity indicating a pituitary hypoplasia, glandular administration is indicated, and it is possible that the therapeutic dosage for the individual case may be determinable on the basis of the quantity of extract necessary to produce mellituria with an amount of ingested sugar which would be expected to represent the individual's normal assimilation limit.

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Twentieth Century History of Findlay and Hancock County, Ohio, and Representative Citizens, Part 117

Author: Jacob Anthony Kimmell Publication date: 1910 Publisher: Number of Pages: 1189

Author: Jacob Anthony Kimmell
Publication date: 1910
Publisher:
Number of Pages: 1189