VOLUAIE AKD CORTICO-AIEDVLLBRT RATIO O F THE ADULT HUMAN SUPRARESAL GLAND C . A. SWISYAIID Dcparttwiit o f A n a t o m y , Xedzcal College of the S t a t e of Sozitti Carolina, Chcirleston ONE FIGCRE Although there is considerable quantitative data regarding the volume and cortico-medullary ratio of the adrenal glands of lower animals there is insufficient information of this nature concerning the human suprarenal glands. The only quantitative volumetric study of the human suprarenals we have been able to find is that of TIammar ( '24) who computed the volume and cortico-medullary ratio of ten unselected suprarenal glands using a volumetric method previously described by hini (Hammar, '14). That there is need for additional data on the human gland is indicated by the quantitative relation of suprarenal cortical tissue to Addison's disease (Wilder, '38; Snell and Rowntree, '29) and to the adrenogenital and Cushing's syndromes (Broster, '37 ; Haymaker and Anderson, '38). I n the numerous reports concerning hypertrophy and atrophy of the cortex of the human suprarenal gland in different physiological and pathological states, almost without exception no information regarding the method of determining the size is given. It must be assumed that the question is decided by the weight of the entire gland o r only casual inspection of the gland at autopsy and study of several hematoxylin eosin sections. According to Grollman ('36) it is extremely difficult to estimate the size of the adrenal medulla by simple examination at autopsy. Clark and Rowntree ( '34) studied the hematosylin eosin sections made routinely from 511 pathologic cases and experienced great difficulty in confirming a previous diagnosis of 11;-pertrophy or atrophy. 69 70 C. A. S W I N Y A R D They found oiily four cases of cortical hypertrophy aiid in these there was no mention of symptoms in the clinical record. Seven cases of cortical atrophy were noted, in five of which emaciation and weakness mere indicated in tlie record. Nine cases of medullary enlargement were fo~iiid,in two of ~vhicha clinical diagnosis of malignant hypertension had been made. The clinical record of the other seven showed no evidence of paroxysmal hypertension. Quotations regarding the weights of the humaii suprarenal glands taken from four commonlv used textbooks of anatomy arc) given below: 3lorris ( ’33) ‘‘Tlie neiglit of tlie glands is given f i o m I t o 18 g m ~ n sand is liable to coiisiderable physiological nn4:ition. ” Gray ( ’36) “Their average weight is from I..? gin. t o 2.5 gi’ams each.” Cunningham ( ’31) “ weight about 7-12’ grams. ’ ’ Piersol ( ’30) “ They weigh six or Seven grams. ” In view of the above it is iiot surprising that there a r e diffwences of opinion regarding the size of the normal glands. What iiiay appear to be a slight hypertrophy to one observer map well be a noriiial gland in the light of another observer’s experience. Jackson ( ’13) found moderate variability and only a low coefficient of correlation with bodp weight in the 1.a t adrenal. The volume aiid coi.tico-iiiedullary ratio of the absolutely normal humaii suprarenal gland can be obtained only from fresh oi*gans in cases of sudden accidental death in which autopsy reveals no significant pathology. This gland rapidly nndergoes autolytic changes after death. Grollman ( ’36) believes that the changes in the suprarenal glands in infections are confined largely to the cortex and that many of the histological pictures described in the suprarenals as characteristic of certain diseases a r e actually post mortem autolytic changes. Hoerr (’31) has found that the slightest pressure on tlie guinea pig gland will introduce changes in the microscopic picture. Cowie ( ’19) and MacKenzie ( ’22) observed focal necrosis, hemorrhage, edema, and cloudy smelling in the cortex of the suprarenals in acute 1)acterial toxemias. None of these VOLUMETRIC STUDY O F HUAIAX SUP1;AREXALS 71 changes were shown in the glands considered here.l However, even though the glands appear to be histologically normal it is not improbable that they may have undergone unrecognized hypertrophy or atrophy. There a r e clear-cut cases of suprarenal hypertrophy associated with infections, a s i n the case reported by Broster and Vines ( '33), in which the adrenals of a n 8-month-old infant dying of acute enteritis weighed 16.5 gm. Nevertheless, many of the reports of slight hypertrophy or atrophy are not based on sufficiently accurate determination and some of the routine autopsy records a r e not reliable. Thus there a r e a number of accounts in which the dimensions given a r e certainly within normal limits while the weight of the same suprarenal may be given a s 25 or 30 g-m. I n such cases the extraneous fat and connective tissue probably was not completely removed. The f a t and connective tissue may u7eigl1 twice as much as the gland itself. I n final analysis, the actual response of the human suprarenal glands to different physiological and pathological states mill not be clearly understood until mere estimation gives way to accurate quantitative and cytological study such a s are used by Rasmussen ('28, '36) and Severinghaus ( '33) on the 1iypophTsis. A volumetric method applicable to the human suprarenal is here describecl. M A l ' E R I B L AND METHODS Due to the laborious and expensive methods necessary i n volumetric computation only small numbers of glands have been used in studies of this kind. Of the ten human glands computed by Hammar ( '24) only one female and five male glands fall within the age group reported here. We have selected for this study, twenty-six histologically normal appearing suprarenal glands f rom individuals dying from a variety of causes (table 2). Although the body weight of the individuals was not available, only glands from persons I wish t o express my npprcciation to the members of the department of pathology of this institution f o r providing the glands and studying the sections f o r pathological signs. 72 c. A. sw1xYAl:I) of approximately iiorinal weight were used. The cases i.angecl from 20 to 57 years of age. I n niost cases paired glands were used, but in some iiistaiices particularly in the white females, only one gland was available. I n tliese individuals the riglit gland was used. The left gland is usually slightlj- larger than the right hence the sex and racial differences a r e not exaggerated by size disparity in the right and left glands. Donaldson ( '19) found the left adrenal to be heavier than the right gland in the rat. Baker ('37) found no significant difference in the size of the right and left adrenal of the dog. All glands were carefully cleaned of extraneous connective tissue and fat and were weighed to 0.1 iiig. on an analytical balance. The specific gravity of the tissue was obtained by the suspension method, Swinyard ( '39). The true volume of the fresh gland was then obtained by dividing the weiglit by the specific gravity. The glands were then fixed in formalin, dehydrated in dioxan, enibedded in paraffin and serially sectioned at 20 p. Every fiftieth section was mounted and stained with heiriatoxylin and eosin. The sections were projected at ten diameters enlargement and the outline of the cortex, cortical zones and medulla were drawn on heavy paper. The area of the projected sections was measured with a planimeter. There is a minimal number of sections which must be measured to assure sufficient accuracy, therefore in two glands every tenth section was mounted and the volume computation made by grouping the sections so that the volume was determined by use of blocks of tissue which varied from 0.2 mni. to 2.0 mm. in thickness. The greatest difference in volume obtained by using these interrupted series amounted to 2.7p. The use of a 0.2 mm. interval (every tenth section) resulted i n about 250 sections per gland while a 2.0 mm. interval resulted in about twenty-five sections per gland. The interval used in determining the volume of the glands reported here was not more than 0.8 mm. and required mounting and drawing of fifty to eighty sections per gland. The difference in volumes obtained by measuring fifty sections per gland and that obtained by measuring 250 sections p e r gland was only VOLUMETItIC STUDY O F €€ UMAN SUPI:AEtEKhLS 73 0.1% , therefore fewer sections could be used with reasonable accuracy. The computed volumes were augmented to correspond to the true volume (obtained from weight and specific gravity) in order to conipensatc for the shrinkage mhicli ovcurred. O D S E R V A T I O S S A S D DISCITSSION A summary of the data thus obtained (table 1, fig. 1)indicates that the average volume of the suprarenal gland in the white male amounts to 5473.4 cu.mm., as compared with 6089.0 cu.nini. f or the white female. Tlie corresponding figures for negroes are, respectively, 4172.4 cu.mm. and 4413.3 cu.mm. Converting these figures into percentage form, it appears that the average volume of the gland in white females exceeds that of the white male by 10.1%, t h a t of the negro female by 19.3% and that of the male negro by 31.4%. The suprarenal glands of the female a r e thus significantly larger than those of the male in both whites and negroes, and those of the white race a r e larger than those of the negro race. I n these same specimens the medulla averaged 435.9 cu.mm. in the white male, 295.8 cu.mm. in the white female, 464.9 cu.mm. in the negro male and 286.0 cu.mm. in the negro female (table 1, fig. 1). As the average total volume of the gland u7as 25.7% greater in whites than in negroes, and the medulla of the white race averaged 2.6% less than the medulla in the negro, the larger gland of the white individual may, therefore, be attributed to the greater amount of cortical tissue. Also since the total gland is larger and the medulla is smaller in the female sex of both races it follows that the larger gland of the female is due, both relatively and absolutely, to the greater amount of cortical tissue. The percentage of cortex in the whole gland is likewise greater in the female of both races (fig. 1). The average cortico-medullary ratio of the two races and sexes is a s follows: white males 12.4 to 1, white females 20.4 to 1,negro males 8.3 to 1and negro females 14.2 to 1. rp -l I 26 21 22 23 24 25 26 40 49 4R 40 26 40 Average 17 18 -<It> 43 19 20 ~ 20 20 38 38 48 48 -.)a 9 21 29 31 31 30 30 33 . 13 14 13 1G ~~ Average 1 - TABIAE 1 ~ - - I ; i ', . . ._ . L 1, R R 1, Ti R I, r, R r, R I, I, R It I, R R R L R ~ I . 2985.8 2750.7 5510.0 5960.3 xi0.n 4940.5 4592.8 4331.9 3075.4 3550.3 --c . ) I 40.1 614.5.2 35.50.0 3375.7 4303.4 4885.2 ~ 7265.2 6815.3 6 3 2 1.1 (iL'23.4 G3.53.7 6365.1 4900.1 8n4o.o 5Gi0.0 5870.1 5040.3 5190.2 4300.7 5681.8 I 1 2843.6 2619.6 5306.6 5739.9 5211.2 j 4759.7 1 4413.4 , 4172.4 2963.8 3420.3 3558 .0 .59 19.6 3419.2 3249.5 4144.1 4704.8 G5G.i.l 6089.0 4720.5 6132.1 5997.2 6122.3 6997.2 467..? 3,582 628.8 576.8 336.7 247.8 435.9 7 74.5.6 5442.7 5654.0 48.i.i. 1 4999.3 4143.7 5473.4 ~ i eu.?nm. ~ c 1 1. ? r i m . 223.6 201.6 327.3 391.3 320.7 2.71.9 __ 286.0. 464.9 619.0 490.7 379.1 1I ~ ~ 1 - 8.3: 1 2619.9 11.7: 1 444.0 2m.n I 1.9 : 1 4979.3 1-52: 1 5348.1 13.6: 1 4890.4 , 1.i.2: 1 4.507.7 I _ - 17.8: 1 ___ -4127.2 14.2: - 1- 436.5-1 __ .__ 3707.3 4.2: 1 7.4: 1 11.4 : 1 _.__ 2629.6 3653.3 4325.7 Negro, male glaiitls 348.8 2614.9 7.4: 1 401.5 3018.8 7.5: 1 482.1 5075.9 10.5: 1 5.i29.0 14.1 : 1 ;?I.? 72T8.0 1.i.5: 1 875.8 ' 5084.5 14.1 : 1 766.0 c502t5..5 7.9: 1 4277.8 7.4: 1 4662.0 13.8: 1 3893.9 15.7 : 1 5037.2 12.4: 1 820.9 White, female 1 inds 331.3 I 4380.3 13.2-: 1 - I 871.9-273.3 ' 5858.8 31.4: 1 .m:; 28.3: 1 ' u*).).J 22.9: 1 s39.1 406.8 I (i589.8 16.2: 1 303.9 6260.3 cii.m?n. cn.m m. White, male g 5056.7 4392.0 1850.3 177,5..5 I 1925.2 I . 3216.2- -- I 6015.2 4098.3 cii ,111m ' 1 ~ 303.3 94.7 92.1 92.3 93.8 93.1 93.8 88.0 88.2 88.2 91.3 93.4 82.2 80.9 88.1 91.9 -~ 92.8 9Ti.5 96.6 9.5.8 94.1 9.3.3 95.0 -~ _ _ __ 231.8 93.3 25n.4 213.2 615.4 200.9 - ~ - , % 93.9 93.4 88.8 88.1 93.2 94.0 91.9 I*oliittie mid cortico-iiictiullar~ ratio of ?tiale and f e m a l e , ncgro and white IriiitLan suprarenal glaads ~~ 7.8 7.6 6.1 6.8 6.1 5.3 6.6 11.9 11.7 11.7 8.6 6.5 17.7 19.0 11.8 8.0 7.1 4.4 3.4 4.1 .5.8 4.6 4.9 -- ~~ 11.1 11.8 6.7 5.9 8.0 % 6.0 6.5 TOLUMETTtIC STUDY O F H U M A N SUPRABENALS 75 Turning now to tlie layers of the cortex, it was found that in six glands (table 1, fig. 1) the zona glomerulosa averaged l5.0%, the zona fascicnlata 78.4% and the zoiia reticularis 6.4% of the total cortical volume. The volume of the cortical CU.MM. 7000 6500$ a MEDULLA a CORTEX m S I J WHITE % $ NEGRO BOTH SEXES WHITE NEGRO Fig. 1 Graphic representation i n cubic milliineters of the total volume, cortical volume and medullary volume of male and female white and negro suprarenal glands. The percentages in the columns combining the sexes represent the proportion of the cortical zones t o the total cortical volume while in the other columns they indicate the proportion of cortex t o the total volume of the gland. Z.G. = zona glomerulosa; Z.F. = zona fasciculata; Z.R. = zona reticularis. zoiies varied widely, that of the zona reticularis being the most variable. No significant differences in sex o r race was apparent in the cortical zones of glands in which this measurement was made. 76 C. A. SWINYABD Hammar ('24) expressed the size of the suprarenal gland by weight. By applying the average specific gravity of our glands to the weight of Hammar's five male glands which fall within our age group, the total volume of his five male glands is within 3.0% of those reported here. The total volume of his five male glands averaged 5310.6 cu.mm. The cortex averaged 4978.7 cu.mm. and the medulla 331.8 cu.mm. The cortico-medullary ratio was 15.0-1. The observation that the human female suprarenal gland is larger than that of the male is in agreement with similar TABLE 2 Cause of death of the individuals whose suprarenal glands are listed in table 1 1. Lobar pneumonia 2. Pneumonocoecic meningitis 3. Sub-acute bacterial endocarditis Congenital malformation of aortic valve 4. Sub-acute bacterial endocarditis Congenital malformation of aortic valve 5. Carcinoma of stomach 6 . Carcinoma of stomach 7. Peptic ulcer-gastric hemorrhage 8. Pulmonary embolism 9. Pulmonary embolism 10. Korsakoff 's psychosis 11. Generalized arteriosclerosis. Cardiac infarction 12. Generalized arteriosclerosis. Cardiac infarction 13. Stab wound of chest 14. Stab wound of chest 15. Malignant nephrosclerosis 1G. Malignant nephrosclerosis 17. Pulmonary tuberculosis 18. Pulmonary tuberculosis 19. Carcinoma of stomach 20. Carcinoma of stomach 21. Diabetic coma 22. Diabetic coma 23. Malignant nephrosclerosis 24. Malignant nephrosclerosis 25. Cerebral thrombosis with softening Z G . Cerebral thrombosis with softening studies on the rat (Jackson, '13; Hatai, '13) and the dog (Baker, '37). Jackson ( '19) found the medulla of the newborn rat suprarenal (in thirty-six animals) constituted about 25.0% of the gland a t birth, decreasing to 7.0% of the total gland at 10 weeks of age. Donaldson ( '19) noted a similar trend in the cortico-medullary ratio of the rat (seventeen animals) and also found that the glands of the female contained relatively less medulla. Elliott and Tuckett ( '06) studied this problem in several species of animals and reported the following medullary percentages : Fowl 50.0%' dog 20.0%' cat 5.7%' rat 5.0%' rabbit 2.5% and guinea pig 1.6%. Their figures were based VOLUMETRIC STUDY OF H U M A N SUPRAXENALS 77 on two animals for each species. Flint ('00) estimated the medulla of the dog (in three animals) to be 33.0% of the total gland. Perhaps the most accurate figures for the dog are those of Baker ('37) who found the medulla to average 14.3% of the total gland (in six animals). These figures indicate the great variability of the suprarenal glands in the higher vertebrates. Elliott and Tuckett ( '06) suggest that the lower the animal is in the vertebrate scale the greater is the proportion of the medulla. While our figures do show a sex and racial difference in the ratio of the two parts of the human gland we feel that there is insufficient quantitative data to support their suggestion statistically. CONCLUSIONS The figures presented indicate that the suprarenal glands are significantly larger in the female than in the male sex in both the white and negro race. The larger gland of the female is due to the relatively and absolutely greater amount of cortex in this sex. The glands of the white race are larger than those of the negro race. The larger gland in the white race is due to the absolute greater amount of cortex. The volume of the medulla is less in the female than in the male of both negro and white individuals. The cortico-medullary ratio averages 12.4 to 1in the white males, 20.4 to 1 in white females, 8.3 to 1 in the negro males and 14.2 to 1in the negro females. LlTERATURE CITED D. D. 1937 Studies of the suprarenal glands of dogs. I. Comparison of BAKER, the weights of suprarenal 'glands of mature and immature male and female dogs. Am. J. Anat., vol. 60, pp. 231-252. BROSTER, L. R. 1937 Eight years experienae with the adrenal gland. 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