GLANDULAR ADIPOSE TISSUE ASSOCIATED WITH CYTOTOXICSUPRARENAL CONTRACTION AND DIABETES MELLITUS *

G=T L. LAQuzum, MD, and MARLW B. ARRISON, MD.(From the Departments of Pathology axd Medicine, Staxford University School of

Medicine, San Francisco, Calif.)Subtotal and total bilateral destruction of the adrenal glands may

be accompanied by anatomical nges suggesting compensatory activ-ity for the loss of the normal adrenal cortex. Among these changes, theformation of -cortical nodules, often composed of bizarre and giantadrenal cortical cells, has been noted most frequently in cases of cyto-toxic contraction."' It has been assumed that the nodules arise fromcortical cells which remained after the injury to the adrenal glands as awhole. In other instances, growth of either accessory or aberrant adre-nal cortical tissue has been described following destruction of the adre-nals due to various causes.l 602The pathologic studies leave little doubt, however, about the practical

insignificance of the compensatory changes as far as maintaining lifeand preventing adrenal insufficiency are concerned. Yet they do presentgood anatomical evidence for what may happen when the normal inter-relationship between the adrenal cortical hormones and the pituitaryadrenocorticotrophic hormone is severely altered in man, and are ofconsiderable interest from that point of view.A case of bilateral adrenal destruction has been studied recently in

the Department of Pathology of the Stanford University School ofMedicine. In addition to areas of regeneration in the adrenal glands,there were unexpected changes in the periadrenal fatty tissue and inthe fat along the spermatic vessels which will be descrnbed in the presentreport. Moreover, the adrenal disease developed in a diabetic child.This occurrence, in itself, was of interest and instructive.

REPORT OF CASEThe patient was a white schoolboy, i8 years old, who had been known to have

diabetes since the age of I2. When first seen at the age of i6 by one of us, his diabeteshad been fairly well controlled by daily doses of 30 units of crystalline insulin and25 units of protamine insulim The results of physical examination were normal; theblood pressure was 120/80 mm of Hg. The blood sugar 4 hours after lunch wasdetermined to be I82 mg. per cent During the following 4 months, the daily dosagewas increased gradually to 45 units of crystalline and 25 units of protamine zincinsulin, the average monthly blood sugar levels being 140 mg. per cent. During thefollowing year, the patient developed mild insulin reactions, necessitating reductionto 30 units of crystalline insulin and ig units of protamine zinc insulin daily.

* Recived for publication, April 5, I950.

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Six months before the patient's death, following unusual he developed asevere insulin reaction, requiimng hospitation. He ded wel to gluosetherapy, but developedm smus puncture revealed an initial prssureOf 240 mM. of water. Routine studies of the spinal fluid, incldng cultu wenegative. The blood supr was 204 mg. pe cent at the time of the MuinsThe patient recovered coletely from this episode.

Duing the following 5 months, because of frequet moderately severe insulinractions, it became necessy to decrease insulin furher, so that just before hislast hopital admission his daily dosage was 25 units of crystaline insulin and 12units of protamine zinc insulin. Tle blood sugr at this time was II3 mg. per centA roentgenogram of the chest duing this period showed no abnormaty.

Five days before his death, the patient became unconscious and was hospitalzedagain. There was an acetone odor on the breath, and 2 phl acetone was found inthe urine. Trement with intravenous salne solution was started. On receipt of thevalues of the blood sugar and C02-combining power, 60 mg. per cent, and 39 vol-umes per cent r ly, glucose was added to the infusion, but the patient failedto respond. Routine studies of the blood and uine revealed no other abnomalities.Examination of the spinalfluid revealed an initial pre of 460 mm. of water, apositiVe Pandy teSt, and 12 eYthrocYte and 4 lYMPhOcYtes per high-power fieldCultures of the sinal fluid were negative, as were tests for virus encepaitis Duringthe remaining 4 days, the tenperatre rose gradually to 420 C. and the patient diedwithout regaining consaousne The blood pressme was constant at II0/8o mm.-of Hg. Except during the initial hospital day, the urne remained free of acetonebodies.

Durng the 2-year period of observation, results of routine physical eaminationsever 3 months were normal; the blood pressure rained constant at I20/80 mm.of Hrg.

The final clinical d ersre: (i) insulin reaction, severe; (2) cerebalhemorrhage, gross or microscopic, due to insuln reaction.

SUMMARY OF POST-MORTEM EXAMINATION

Necropsy was done 7 hours after death. The body measured 64inches in length and weighed 145 lbs.. External inspection showed awell developed boy with normal male distribution of hai and begnniggrowth of a beard. The testes were in the scrotal sac and were normalin size.The anterior mediastinum contained a prominent thymus gland which

weighed 30 gmi- The heart (260 gM.) was normal. The aorta appearedhypoplastic and measured 4.0 cm. in mamum cicumference in theascending portion. The lungs were heavy (I54o gi.) and contained alarge amount of edema fluid. The liver (2100 gMn) contained muchblood which escaped freely from cut surfaces, but was otherwise nor-mal. The portal systemwas not unusuaL The spleen weighed 260 gin.and contained numerous closely spaced malpighian bodies, I to 2 mm-broad. The pancreas weighed 30 gm. and appeared normaL Numerousgreatly enlarged lymph nodes were found throughout the abdominalcavity. Many of these had nodular surfaces which, upon sectioning,proved to be large lymphoid foflicles. The kidneys and the lower uri-

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nary tract were normaL The testes weighed 23 gm., and the seminalvesicles were well developed and contained mucoid materiaL The thy-roid gland was small and weighed io gmi The gastro-intestina tractwas normal but contained prominent lymphoid follicles in the mucosa.The adrenal glands were not identified at necropsy. The entire fatty

tissue extending from the suprarenal region to the pelvis on each sidewas dissected out in toto, and the specmens were labelled for later iden-tification. The strips of fatty tissue were placed in Zenker's formalde-hyde solution for 20 hours, washed thoroughly in running water over-night, and chromatization was continued for 24 hours in Miiller's fluid.The fat was then cut serially at 2 mm intervals, and samples were pre-pared for microscopic mination. During this procedure, brown tis-sue was visible grossly on each side in the usual position of the adrenalglands.The brain and meninges weighed 1700 gm. and appeared wet. There

was no evidence of meningitis, and intracerebral lesions were not found.The pituitary gland weighed 324 mg., which was considered normalfor the patient's age.

Summary of Microscopic FindingsPancreas. The acinar tissue was normal in the pancreas. The islets

were normal in size and number but were composed of small cells withlittle stainable cytoplasm. There was no evidence of fibrosis or hyalinedeposits in the islets. Best's carmine stain on alcohol-fixed materialfrom the liver and kidney failed to demonstrate abnormal glycogendeposits in these two sites.

Adrenal Glands. The right and left adrenal gland were similar. Thecortex was absent in most places, and the medulla was bordered by adense zone of collagenous fibrous tissue. The medulla was missing inseveral areas, and the thickness of the gland was composed of only twosheets of collagenous fibrous tissue with a central zone of dilated vascu-lar nnels surrounded by mononuclear cells. There were scatterednodules of irregular, large cortical cells often possessing giant nucleiand cytoplasmic pigment granules. The normal orientation of the corti-cal cells and the relationship to the capillary system were lacking (Fig.I). Other areas were composed of cortical cells which were separatedby strands of collagenous fibrous tissue through which lymphocytes andplasma cells were scattered. The inflammatory reaction was non-specificand varied in severity. No vascular lesions were found in the adrenalglands nor in the periadrenal fatty tissues which contained many fair-sized branches of the adrenal artery and vein.

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Periadrenal and Paravertebral Fatty Tissue. The adipose cells ofthe periadrenal fatty tissue were transformed into fat cells of the em-bryonal type in many places (Fig. 2). Scattered through the alteredfat were isolated cells and small groups of cells which possessed a finelygranular cytoplasm stained deeply with acid dyes. Some of the cellscontained small vacuoles, and in many, lipofuscin pigment granuleswere seen. The lobular pattern of the normal adipose tissue was main-tamed everywhere. The vascular bed, although increased over thatseen in normal fatty tissue, lacked a definite orientation to the embry-onal fat cells in most places.Numerous sections prepared from the fat along the course of the

spermatic vessels on both sides showed even more striking nges. Inaddition to the fat cell of embryonal type, large islets of protein-richcells were found, which occupied the greater portion of individual fatlobules (Fig. 3). Some of the cells contained small single or multiplevacuoles, and brown pigment granules, free of stainable iron, were foundin many of these cells. A definite vascular pattern was apparent here.The center of such an islet often was occupied by a large venous channelinto which smaller blood vessels converged from the periphery (Fig. 4).Each of the protein-rich cells was thus bordered, on two sides at least,by thin-walled vessels which probably contributed to the alignment ofthe cells in column-like fashion. There was no capsule at the mrgin ofthe islets. Using Foot's modification of Bielschowsky's method, a deli-cate network of reticulum fibrils bordered each glandular fat cell. Inview of the well developed vascular bed, it seemed most likely that thereticulum was derived from the vessels rather than being a product ofthe glandular fat ceBs. This was emphasized further by the fact thatthe reticulum was not demonstrable where normal adipose cells wereseen and where the vascular network was much less developed.

Hypophysis. Well granulated acidophils were seen throughout theanterior lobe of the hypophysis. The basophils, although present in ap-parently normal numbers, had fewer cytoplasmic granules thn usual.There were scattered small groups of large pale cells which possessedeccentrically placed nuclei. Aniline acid fuchsin-light green stain dem-onstrated granules which stained green in a few cells, and these wereinterpreted as large, poorly granulated basophils. There was no inter-stitial fibrosis. Sudan III stain applied to frozen sections showed onlya few droplets of fat, no more than can be found in many hypophyseswith routine fat stains.

Thyroid Gland. Lymphocytic infiltration in a few small patches wasthe only abnormality in the thyroid gland.

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Testes. The seminiferous tubules were of normal width and werelined by spermatogenic cells showing all stages of maturation. The in-terstitial cells were normal in number and structure.

Thymus. The lobular pattern of the thymus was well preserved. Thecortex and medulla were in approximately equal amounts. There was noevidence of fatty replacement.Spken and Lymph Nodes. Numerous hyperplastic lymphoid follicles

were seen in the spleen and lymph nodes. In spite of the number andsize of the follicles, reaction centers were rarely seen and most of thefollicles were composed of small lymphocytes only.

DIscUSSIoN

The reported cases of diabetes mellitus complicated by chronic ad-renal insufficiency have been summarized recently by Crampton, Scud-der, and Davis 13 and by Simpson."4 The case reported here is anadditional eam,ple and emphasizes once more the occurrence of pro-gressive diminution in insulin requirements, and of increased insulinsensitivity with a decrease in adrenal cortical function.As in the majority of cases of cytotoxic contraction, no lesions were

found which elucidated the cause for the adrenal destruction. Tubercu-losis, tumors, and vascular lesions were readily excluded. Although ahistory of an intercurrent disease was not obtained, it seems most likelythat the time of decreased insulin requirements was related to the onsetof the adrenal diease. At that time, the patient was 15 to I6 years oldand within the period of adolescence.

While searching for the adrenal glands, the changes in the periadrenalfatty tissue and in the adipose tissue along the course of the spermaticvessels were found and attracted our special attention. The structuralalterations of the fatty tissue appeared to be confined to these two areas.Even adipose tissue as close to the adrenals as that in the region of thetail of the pancreas was unchanged. The limitation of this type ofchange to the urogenital region may be important and, in this respect,the alterations differ from similar ones found in children and emaciatedadults in whom embryonal or multilocular adipose tissue may be seenin various sites.' There was a further change in the adipose tissuebeyond that usually referred to as embryonal fat, in that islets of pro-tein-rich cells were supported by an organized vascular system. Thecellular ges resembled those descrbed as glandular fat and thosewhich have been seen in the hibernating glands of animals during theperiod when activity is resumed.15 Their functional significance is un-lmown. Cramer,"6 who studied the response of the glandular fat and

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adrenal cortex to expermental alao in the rat, was impressedwith the similarity of the changes in these two sites and suggested thatthe glandular adipose tissue and the adrnal cortex are fuctionally re-laed. Recently, Selye and Timiras "I reported that the brown fat of therat responded to acute stress-producing agents with discharge of lipids,so that the cytoplasm of the cells contained almt nothing but protein-aceous materiaL This similarity of response to stress in the adrcortex and in brown fat is noteworthy. In two articles, Wells1' empha-sized, as lWte as I94o, the many features of adipose tissue still to bestudied.The extensive transformation of the adose tissue to glandular fat

was not anticipated, and fresh material was not retained for chemicalanalyses. Yet the over-all histologic pattern, and particularly the de-velopment of a vascular system cnsisting of a collecting vein into whichnumerous smaller vessels converged, strongly suggest functonal activ-ity on the part of the landul fat. It seems likely that the mechanismwhich leads to vascular growth in other organs during periods of in-creased celhllar activity, also governs the growth of the capillary chan-nels in the glandular adipose tissue. What the products of this cellularactivity were, and whether they were important in obscuring some ofthe more obvious dinical signs of adrel insuffincy, we do not know.The histologic appearance of the islets of glandular fat resembling

adrenal cortical cells ruled out the possibility that they were accessoryadrenal glands. There was no capsule and no glomerular zone, and thecolumnar arrangement of the cells which is always seen in accessoryadrenal tissue was lacing. Aberrant adrenal cortical tissue, althoughoccurring at the sites where the islets were found, could reasonably wellbe excluded by the fact that all stages 6f transition from an adult fatcell to the protein-rich fat cell or glandular fat cell were seen.Some thought ought to be given to the hani by which the glan-

dular fat was formed. Because there is no reason to suggest a congenitalanomaly of adipose tissue, such as has been presumed to be associatedwith certain tumors," there remains the alternative that the glandularfat developed from previously normal fat cells. The presence of alltransitonal stages, already referred to, is highly suggestive of an activeprocess of differentiation. If this concept is correct, two more factorsmust be assumed to have been instrmentaL One would be a substancein the body fluid possessing the faculty of acting upon fat cells, and thesecond, a local factor concerned with the ability to respond to the en-vironmental stimulus. The second factor would, of necessity, have to bewithin the adipose cells.With respect to the first factor, there is good evidence from the low

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PERIADRENAL GIANDULAR ADIPOSE TISSUE

level of the i 7-ketosteroid excretion in patients with Addison's disease,2as well as from the fate of untreated cases, that the nodules of regen-erated adrl cortical cells are iniicat as far as the productionof adrl hormones is concerned. It is well known, also, that the ab-sence or decreased function of an endocrine organ simultaneously re-moves the inhibitory effect of that organ upon the formation of its tro-phic hormone by the hypophysis. This relationship between hypophysisand peripheral target organ has been well established for the gonland thyroid glands."' It seems likely that a similar relationship tsbetween. the hypophysis and the adren glands. Suggestive evi-dence has been presented indiating that, as the level of cortical hor-mones is decreased in the circulation, the pituitary gland dischargesadrenocorticotrophic hormone.' This information was obtained inshort term animal ex ments.

After prolonged periods of adrenocortical deficiency, Taylor, Albet,and Sprague recently have demonstrated adrenotrophic activity ofsera which were obtained from patients with Addison's disease. Noconclusive evidence of activity was found in the sera of normal sub-jects and of those with evidence of adrenocortical hyperfunction. Theseobservations suggest that the anterior hypophysis continues to functionin Addison's disease, although it remais for future studies to deter-mine whether the rate of hormone production is altered.

Histologic investigations of the cellular nges in the anterior pi-tuitary gland have shown that a decrease in the number of well granu-lated basophils occurs in cases of Addison's disease. Furthermore,Crooke and Russell 7 described the appearance of large pale cells inthe anterior hypophysis, and they considered them to be chromophobesand abnormal basophils. The cytologic observations were confirmedby Nicholson 15 and by Laqueur and Bernstei." Such groups of largepale cells may be present in small or fairly large numbers, and wehave found them in9 of 15 hypophyses of patients dying with Addison'sdisease. It has been possible in a few cells to stain granules with lightgreen as the counterstain to aniline acid fuchsi. The granules stainblue with azocarmine and Mann's stain. We have considered theseceBs as basophils and have regarded the oss of granules as evidenceof increased celhllar activity.Of particular importance are the observations which Groat 2

made in the ground squirrel. He descnbed the differentiation of ovarianmesenchymal cells into adrenocortex-like cells in the adrlectomizedground squirreL Similar nges were seen in both iales and femalesin other sites, although they are not specifically described. The groupsof cells apparently functioned to some degree in that adrenalectomized

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animals could be mantained on water without the addition of sodiumchloride. They withstood prolonged periods of fasting as well as intactcontrol animals did. The ovarian changes did not occur in the hypo-physectomized animals, and Groat suggested that the differentiationof ovarian mesenchymal cells to adrenocortex-like cells was the resultof adrenocorticotrophic hormone activity.

The findings of Groat demonstrate that the hypophysis is necessaryfor the development of compensatory nges outside the adrenals.A much larger body of experimental data is available concerning thedependency of the adrenal cortex proper upon the hypophysis. Smith 2was the first to show that the adrenal cortex atrophies following hypoph-ysectomy, and that this change can be prevented by injections ofpituitary extracts. Since then, further work has shown that adrenalhyperplasia, such as can be observed following removal of one adrenalgland or in various types of stress, does not occur in the hypophysecto-mized animal. The many individual observations have been collectedand reviewed in detail by Tepperman, -Engel, and Long.30 Morerecently, Sayers and Sayers31 have shown that diminution in adrenalascorbic acid, regarded as a delicate indicator of increased corticalactivity, does not occur under stress following hypophysectomy. Thereis then good evidence that the hypophysis not only exerts a definiteinfluence upon the normal adrenal gland but also controls, to an im-portant degree, the growth of the adrenal gland under abnormal cir-cumstances. It has been shown that the pituitary substance, capableof producing these effects, is the adrenocorticotrophic hormone.

It is considerably more difficult to evaluate the role of local factorswithin the adipose cells. The transformation of adult adipose cellsto glandular fat has not been a regular observation when the adrenalglands are destroyed. Comparison of the present case with manyothers previously reported, and with 4 similar cases in the files of theStanford Department of Pathology in which glandular fat was notfound, suggests that the age of the patient at the time the adrenaldisease develops may be important. It seems possible that certainregions derived from the tissues of the celomic wall may retain anability to respond to appropriate stimuli during pre-adolescence andpuberty but not in the adult.The terminal episode in our patient, his progressive decrease in

insulin requirement, the sensitivity to insulin, and the generalizedlymphoid hyperplasia found at necropsy, indicate that the compensa-tory changes in both the fat and the adrenal glands did not replacethe function of the normal cortex. Nevertheless, there was a paucityof the classical signs and symptoms of chronic adrenal insufficiency.

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PERIADRENAL GLANDULAR ADIPOSE TISSUE 239

It seems possible, therefore, that the islets of glandular fat were func-tioning, and prevented some, although not all, of the cardinal featuresof Addison's disease. Indeed, the observations make one wonderwhether comparable changes may not occur more frequently thanindicated in the literature. Such findings as these, if confirmed, mayhelp in understanding some of the cases which have been consideredas early or less severe stages of the disease.

SUMMARYAn i8-year-old boy was known to have had diabetes mellitus since

the age of I2. At the age of I6, his insulin requirements progressivelydecreased and insulin reactions occurred. Severe reactions did notrespond to intravenous glucose therapy in the usual rapid fashion. Hedied 2 years after the insulin requirements had begun to decline. Atnecropsy, extensive bilateral adrenal destruction of the type commonlyseen in cytotoxic contraction of the adrenal cortex was found. Tinynodules of regenerated adrenal cortical cells were present. The fattytissue in the periadrenal region and along the spermatic vessels showedtransformation of the adult adipose cells to glandular fat. The isletsof glandular fat were supplied by a vascular system such as seen inorgans with endocrine function.The hypothesis has been advanced that the transformation of adipose

cells to glandular fat was the result of an interaction between pituitaryadrenocorticotrophic hormone, available in the body fluids after bi-lateral adrenal destruction, and the fatty tissue of the adrenogenitalarea. The possibility that the glandular fat was functioning to alimited degree would explain the fact that the adrenal insufficiencywas less severe than that usually observed, and that many of the car-dinal features were lacking.

REFERENCESi. Langerhans, M. Ueber Nebennierenverinderungen beim Morbus Addisonii.

Verhandi. d. deutsch. path. Gesellsch., I903, 6, 254-257.2. Kovacs, W. Zur Nebennierenpathologie. Beitr. z. path. Anat. u. s. allg. Path.,

I928, 79, 2I3-267.3. Kraus, E. J. Zur Pathologie des Morbus Addisonii (Befunde in Hypophyse und

Nebennieren). Beitr. z. path. Anat. u. z. allg. Path., I927, 78, 283-296.4. Brenner, 0. Addison's disease with atrophy of the cortex of the suprarenals.

Quart. J. Med., I928-29, 22, I2I-I44.5. Barker, N. W. The pathologic anatomy in twenty-eight cases of Addison's dis-

ease. Arch. Path., I929, 8, 432-450.6. Wells, H. G. Addison's disease with selective destruction of the suprarenal

cortex. Arch. Path., I930, 10, 499-523.7. Crooke, A. C., and Russell, D. S. The pituitary gland in Addison's disease. J.

Path. & Bact., I935, 40, 255-283.

240 LAQUEUR AND HARRISON

8. Weiner, H A. So-called atrphy of the adrenal cortex with intranuclear inclu-sions. Report of a case. Am. J. Path., 1936, 12, 411-422.

9. Duffin, J. D. Cortical necrosis of the adrenal glands associated with Addison'sdase. Report of eight cases. Arch. Patk., I943, 35, 649-66.

to. Karakasclhe, K. L Beitrige zur pathologischen Anatomie der Nebennieren.Beitr. s. path. Anat. u. s. aUg. Path., 19o4, 36, 40I-434.

II. H mann Beitrig zur pathologischen Anatomie der Nebennieren. Beitr.z. path. Anat. u. z. al1g. Path., I92I, 69, 352-365.

I2. Friedman, N. B. The pathology of the adrenal gland in Addison's disease withspecial reference to adrenocortical contraction. Endocrinology, I948, 42,I81-200.

I3. Crampton, J. H., Scudder, S. T., and Davis, C. D. Carbohydrate metabolism inthe combination of diabetes mellitus and Addison's disease, as illustrated by acase. J. CM. Endocrixol., 1949, 9, 245-254.

14. Simpson, S. L Addison's disease and diabetes mellitus in three patients. J. Clin.Endocrnol., I949, 9, 403-425.

I5. Rasm , A. T. The glandular status of brown multilocular adipose tissue.Endocrinology, 1922, 6, 760-770.

I6. Cramer, W. On glandular adipose tissue, and its relation to other endocrineorgans and to the vitamine problem. Brit. J. Exper. Path., I920, I, I84-I96.

17. Selye, H, and Timiras, P. s. Participation of 'brown fat' tissue in the alarmreaction. Nature, London, I949, i6, 745-746.

M8. Wells, H. G. Adipose tissue, a neglected subject. J. A. M. A., 1940, 'l4, 2177-2183; 2284-2289.

I9. Bines, 0. A., and Johnson, M. H HibERnoma, a special fatty tumor. Reportof a case. Am. J. Path., 1949, 25, 467-479.

20. Thorn, G. W. The Diagnosis and Treatment of Adrenal Insufficency. AmericanLecture Series No. 29. Charles C Thomas, Springfield, IEL, I949, 171 PP.

2I. Fluhmann, C. F. Anterior pituitary hormone in the blood of women withovarian defidency. J. A. Mf. A., 1929, 93, 672-674.

22. Emerson, K, Jr., and Cutting, W. C. Urinary thyrotropic hormone. Endocri-nology, 1938, 23, 439-445-

23. Sayers, G., and Cheng, C. P. Adrenalectomy and pituitary adrenocorticotrophichormone content. Proc. Soc. Exper. Biol. & Med., I949, 70, 6I-64.

24. Taylor, A. B., Albert, A., and Sprague, R. G. Adrenotrophic activity of humanblood Endocrinology, 1949, 45, 335-343.

25. Nicholson, W. M. Observations on the pathological changes in suprarenalec-tomized dogs, with particular reference to the anterior lobe of the hypophysis.A comparison with Addison's disease. Bull. Johns Hopkins Hosp., 1936, 58,405-41I7.

26. Laqueur, G. L., and Bemstein, D. E. The anterior hypophysis in chronicadrenal insufficiency. Stanford M. Bull., 1948, 6, 199-205.

27. Groat, R. A. Adrenocortical-ilke tissue in the ovaries of the adrenalectomizedgrouxd squirrel (Citelus tridecenlineatus). Endocrisology, 1943, 32, 488-492.

28. Groat, R. A. Formation and growth of adrenocortical-like -tissue in the ovariesof the adrenalectomized ground squirreL Anat. Rec., i944, 89, 33-41.

29. Smith, P. E. The disabilities caused by hypophysectomy and their repair.J. A. Mf. A., 1927, 88, I58-i6I.

30. Tepperman, J., Engel, F. L., and Long, C. N. H. A review of adrenal corticalhypertrophy. Endocrinology, 1943, 32, 373-402.

31. Sayers, G., and Sayers, M. A. The pituitary-adrenal system. Recent Progr.Hormone Research, I948, 2, 81-1I5.

[IIMUS&rtiom follow]

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F.m I. Nodule ped of bizarre and nt cortical cells from the ri adralgland X 220.

Ftm 2. Fatty tissue frm the left periadral isow one normal cell,several b or mu r fat cell and a few scattered gandulr fatcells indicated by arws.X 42.

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FIG. 4. Islet of glandular fat illustrating vascular pattern. The tissue is from anarea midway between the origin of the left renal artery and the bifurcation ofthe aorta. X 220.

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