LA CHIRURGIE GLANDES SURRÉNALES
Transcripción
LA CHIRURGIE GLANDES SURRÉNALES
LA CHIRURGIE DES GLANDES SURRÉNALES POSTOPERATIVE COURSE A N D T R E A T M E N T I N A D R E N A L SURGERY Sentaro SHISHITO Department of Urology, Tohoku University School of Medicine, Sendai. PREFACE The number of patients with adrenal disorders has rapidly increased during these past several years. Ten years ago, only 2 or 3 patients per year received adrenal surgery in our clinic. As compared with that, we carried out 12 cases of adrenal exploration last year. This number amounts to about 6% of all surgical teatments performed in our clinic, which is almost equal to the percentage of nephrolithotomy. Nowadays, adrenal surgery is one of the essential fields in urology. Although thus important, many urologiste seem to misunderstand that adrenal surgery is troublesome and requires a special knowledge an technique of surgeons. Certainly, it is not so easy a task to approach and manipulate the adrenal gland which is located in the deepest site of the body. Even though surgery has been successfully accomplished, the postoperative course of the patients is often hazardous. The technical difficulty of operative procedure should be mastered by training. However, the postoperative management can be, and must be, simplified in order to extend and popularize adrenal surgery. From this point of view, I will discuss a simplified and standardized postoperative treatment technique for adrenal surgery, which is based on recent developments in the field of applied physiology or pharmacology, and also on data from 80 cases treated in our clinic since 1956 (Table 1). As postoperative treatment is quite different according to each adrenal disorder, the discussion will be carried on for each disease in order. At first, I will mention primary aldosteronism. PRIMARY ALDOSTERONISM Since discovery of primary aldosteronism by Prof. Conn in 1955, a large number of patients have been treated all over the world, for this disease seems not so uncommon at present. In this country, 191 reported cases were surveyed lats year by Prof. Torikai, Tohoku University. We have treated 30 cases (Table 2). Recent introduction of a new clinical entity of so-called "normokalemic primary aldosteronism", of which two cases have been experienced in our clinic, will give impetus to increasing the number of patients. TABLE 1 A D R E N A L S U R G E R Y P E R F O R M E D IN O U R Disease Year 1956 1957 1958 1959 19(5(1 19(51 19(52 1963 19(54 19(55 19(56 1967 1968 1969 Total Primary aldosteronism 1 1 1 1 4 1 1 1 3 3 1 5 7 30 Cusliing's syndrome 1 1 1 1 3 4 2 2 3 1 19 Pheochromocytonia 1 1 3 CLINIC .Miscellaneous 1 3 3 3 3 3 1 1 4 17 3 1 14 Total 1 2 2 3 5 11 4 8 1 6 11 4 10 12 80 It may be generally supposed that the postoperative course of primary aldosteronism is rather easy to manage. However, serious complications due to the change in electrolyte metabolism during pre- and post-operative courses will occasionally result if sufficient care is not taken. Electrolyte replacement therapy is specially important for this disease. Although the electrolyte metabolism in the kidney is very complicated, it may be divided practically into the following three mechanisms (Fig. 1). At first, glomerular filtration rate (GRF) control by the renin-angiotensin system; in the second, proximal tubular reabsorption under the regulation of an unknown substance which is called "the third factor"; and lastly, sodium-potassium exchange in the distal tubule, which is influenced by aldosterone. In patients with primary aldosteronism, sodium-potassium exchange in the distal tubule is stimulated by a large amount of aldosterone secreted from adrenal adenoma, which is followed by a remarkable sodium conservation and potassium deprivation. However, a rejection of sodium re-absorption in the proximal tubule due to activation of the third factor prevents the patient from the hypernatremic state. For that reason, a manifest symptom in primary aldosteronism is not hypernatremia, but hypokalemia. This is the well-known "renal escape phenomenon". Sodium and potassium balance before and after the extirpation of aldosteronoma is shown in Fig. 2 as the mean value from 20 cases. In the usual surgical operation, sodium conservation and potassium deprivation is a basic pattern of the postoperative electrolyte balance. In primary aldosteronism, a negative balance of both sodium and C ~ " a s ¡ a i a s c s s a ! S 5 « o c o o 2 c c o c o e i o o O o e C E G a s I I e c = c D O O WC J 0 1a zjO J o aj o ir(-C "S r! -tj'C'C'G < U O "d T 3 "0 "3 "C " C "8•a -aT T 3 3 •a -a ' ; n a -a -a "a "0 3 C 3 C 3 > C S c 3 « « C c: a s s a s £ o O o S c c I I I ¡ 1 s g i -ODC.O «v w. w r 1 r < ph t-" ci co co r H a « Q S - e 1) ¿ a c- E = o £< § ^ "< Z c/: ^ >o vff >(i «g O rt a * o % C £ c c oc oc M oo cc c. c: c; e. ^ o o fc® e ¿3 C 3 « 3 53 ° < c e? io "ti * > > ~ & o o 5 3 O C J c £ 5 h io oo m oo oo COC1''+Ci-+COOOinE-"-r^ o n n c o i ^ a o r r - H i i i i M M M W N n r- n H T — CI C H J T H T H C M CI rCI C M T H C M T H ri T H M C M ce Ci O oo C Mo ce Ci v Mr i -CI io C O ce C Oco co ci co co C o " co' C Oco co' ci Oco ci co c C M *ci ci co C 1 v OC oc T M MCi co oo — •C Mvo Ci co co IO 00 C H *ci T HC T Hci ci T —ci ci Hci ci Oco" T ci ci ci ci r C Moc 3 S C / 3w » o in co co co co io oo rH o O co ci co C Om «o t^ v co m ÌC Ci Hci T Hci ci ci ci co ci T 5» t^ o ffl ^ ri- oo > inffiifl w io iq o o o H o ^ o o H o o c o ifl ri t^ m w in' o co • o c r c ro i _ >iO r* : rtNr' Ch 5. ^ 'u o zi Vi — : P \ te w O C M OOOOOOt-ÌOOO «O C M co c ir: T H C ^ l 05C:00 05t^c:WI>CDI>'i'ii5iCìii5!COii5ii5l>M»i5 « ci to © O O © © CI ( M * CI ci ci ci d > C J w . y. ^iud uo c / 3 M C / 2 < K c / 2 c/i Ci - 00 T H T H ce oo J C CI Tf »f? vfl ci 00 in t^" > Ì 5 1 ( 5 ?5 v!5 o vii M C o«+CìT-ir—ccm^GiOOT— ci«cr»cìceci;c , <+ ! r * - ce ìc •> COCOCO-^tf-lOT—"iniOCOCl^-T—' T H Ci r- T — > ( M T H C J — C OO C J O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 3 u ¡ó rf 1 ( 5 h Ol 1 W r- n CI c: r- -t tt r- C M ( M c ci C ( M Tf (N Tf w ri Ol C C r r r T r T r T T 7 r T7 T T , V r V r T . ^ m 7 i i i i » • • • • \ i i « • A Ò O O O O O O O O O O O O O O O O O O O O O O O O O O O O PSOOlMCìMCCiOCC; t O C C C ! O C I C i C O c t H C C 5 C C C O C Ì t > -s "2 6 5 « 0 C o o Q O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 1 1 T T " C V « tj T H r — W " « « ' - C —C —C — C — M C M C M r > C M C M C M • « C M d C M-C M M C M C M C M M M M C M — CI C M — C MC CI C •M ( ( ( ( ( ( ó o ò o o ó o o ò o o o ò o o o o o o o o o o o o o o o o o << ^^^^C^OOt^CÌ^CMinr-HCìT-HOlOvOCM^iCO^OO^OO^WOT-H W c/i i r" tri w H H — T " . cico" Tf' co « « H ui s < < ts s 00 Ci o vi o w <i P S ci co co oc ci o t h ci co ' t »ò d t^ oo q o C1CMCMCMCMC1CMCMCMCMCO C L Preoperative Immediatly after operation Second post operation weck Electrolyte Strum H J, \ ÎÎ ÎÎ ÎÎ II \ \ metabolism of the FIG. kidney in 1 patients with primary aldosteronism "] (mEj\/l) 4 0 J K bufarne (m%) Biccd pivssutî ISO (inmHif) (JG. urine I 'ctume 1 a ) „ Before Opt. If pustcperathf * FIG. 2 Postoperative serum K. Na, K. Na balance, blood pressure and urine volume. value from 20 cases of p r i m a r y aldosteronism.) (Mean 50 100 "H/day Na Intake FIG. Na balance and K balance (Mean v a l u e 25 K 50 ^ A y i T t t a i e 3 on second and third postoperative day). mEq/day 60 - £ ® © © O • — » QJ 40- © U © 0 20 - (00 200 Na Na excretion and K FIG. itf/daq excretion 1 e x c r e t i o n (Mean v a l u e on second a n d t h i r d Q : Cases w i t h Cortisol s u b s t i t u t i o n postoperative day). Na K L 2 CD 1.5 - J§1 " 5 1 1 1 - - £ • -J 3 0.5 0.5 50 100 150 200m%tiay Na excretion FIG. 50 100mct/da, K excretion 5 t r i n e v o l u m e and Xa.lv excretion (Mean value on second and t h i r d p o s t o p e r a t i v e ^9/L 5 H X • 4 • i £ 2 31 10 100 50 K excretion FIG. Serum K level and K excretion 6 (Second postoperative day). day). potassium was observed during Ihe first postoperative week. For c l a r i f y i n g the m e c h a n i s m of this c h a r a c t e r i s t i c pattern, further studies were made on the second and third postoperative day w h e n the body should be free from direct stress by surgery. As shown on Fig. 3, a correlation was observed between sodium intake and sodium output on the second and third postoperative day. T h e more sodium was given, the higher the degree of negative balance of sodium observed. It is, therefore, c o n s i d e r e d that an acute sodium diuretion against sodium loading due to proximal tubular r e j e c t i o n induced by activation of the third factor still remained even after removal of the aldosteronoma. Potassium loss was from 25 to (¡0 milliequivalents per day, independent of the administration dosis. In this period, no correlation was noticed between sodium and potassium excretion (Fig. 4). T h i s suggests a lack of active sodiumpotassium transport in the distal tubule. It is easily c o m p r e h e n s i b l e that the function of the distal tubule t e m p o r a r i l y r e a c h e s a very low level when the excess aldosterone production is interrupted by extirpation of the tumor. Sodium flowing from the distal tubule to the collecting duct contains water, due to osmotic diuresis. If the hypo-function of the distal tubule is present, the volume of urine may be directly affected by the excretion rate of sodium. Also from our data, a correlation was evident between sodium excretion and urine volume (Fig. 5). A close relationship between potassium excretion and the serum potassium level was noticed on the second post-operative day (Fig. (i). It is accepted that potassium c o n c e n t r a t i o n in the terminal part of the p r o x i m a l tubule is similar to, or slightly lower than the serum potassium level. S i n c e tlie distal tubule is inactive in this period, potassium flowing into the distal tubule may pass through it without any exchange. T h e n , if the GFR be not sufficiently regulated, and remain within a limited range, u r i n a r y potassium excretion will be p r i m a r i l y correlative with serum potassium level, as shown in our results. It was reported practically that the renin-angiotensin system was stilt suppressed during certain postoperative period. Accordingly, G R F regulation under this system is also still considered insufficient. As mentioned above, electrolyte metabolism immediately after removal of aldosteronoma could be explained by the following three mechanisms: an i n s u f f i c i e n c y of G R F regulation, a rejection of p r o x i m a l tubular re-absorption and an inactivation of the distal tubule. These might be followed by a c h a r a c t e r i s t i c pattern a tendency toward negative balance in both sodium and potassium. Although a potassium supplement is possible in this period, therapy by substitution of sodium is quite ineffective because sodium administration results in more sodium loss. After a week, the correlation between the potassium excretion and serum potassium level disappeared (Fig. 7). Although suppression of the renin-angiotensin system stilt remains during the second or third p o s t o p e r a t i v e . week, a reduction of the extracellular fluid and of the circulating plasma volume due to postoperative sodium loss leads to a decrease of GRF. Fall of the blood pressure may augment this tendency of the decrease. Such regulating m e c h a n i s m s of G R F other than the renin-angiotensin system are effective in sodium retention. ^ H / lL 5 x. iCU 4 - 3- T ' ! 50 1 1 100 - excretion K FIG. 7 Serum K level and K excretion (8th postoperative day). 60 Q HÜ g> 40 H o 8 20T-— r 100 1 Na FIG. 8 1— 200 I 300 ~T" excretion Na excretion and K excretion (Mean value on 8th and 9th postoperative day). A relation between sodium and potassium excretion was observed to some extent (Fig. 8). It is presumed from this that sodium-potassium exchange in the distal tubule is beginning to improve, though passively in the second post-operative week. Now I wish to mention how we administer the electrolyte balance of (he patient. Since a supplement for massive sodium loss immediately after surgery is impossible, a preoperative sodium storage is necessary. On the contrary, potassium replacement is possible even during the postoperative period. Moreover, the higher serum potassium level leads to greater potassium loss. Accordingly, a standard level of serum potassium to be maintained preoperatively may be within lower normal limits at the most. In other words, the electrolyte to be retained would be not potassium, but sodium. From this point of view, the preoperative treatment which is usually performed, namely, aldactone administration or salt restriction, could not be supported because it aimed at only potassium conservation in exchange for sodium deprivation. During a week after the surgery, the minimum dosis of sodium which is required lo maintain a proper urine volume should be administered for preventing the sodium loss as much as possible. Potassium should be supplemented in proportion to its excretion rate. In the second postoperative week, when an improvement of the abnormal electrolyte metabolism has occurred, the sodium deficiency must be dissolved rapidly by replacement of the large amount of salt. Table 3 shows a program for the electrolvte supplement before and after llie removal of aldosteronoma which is based on abovementioned idea. We applied this program to 7 cases of primary aldosteronism and obtained excellent results respectively. The pre- and post-operative course in one of these cases is demonstrated on Fig. 9. The electrolvte balance changed as Ave expected and the serum potassium and sodium level was kept stable between ± 5 % through all the processes. We believe that this program is a reasonable and advisable method for preventing the postoperative electrolyte unbalance. Steroid substitution is unnecessary for the surgery of primary aldosteronism, except that the bilateral adrenals are totally dissected. Patients after the surgery show a normal 17-OHCS excretion and a normal response to ACTH stimulation. However, we usually give 100 mg of Cortisol intramuscularly at one time during the operation as a precaution against temporary cortical insufficiency from adrenal manipulation. CUSHIN'S SYNDROME Cushing's syndrome may be divided into three groups according to their types of etiology. The first group is one that harbors an adrenal tumor, of which 6 cases have been treated in our clinic. A satisfactory prognosis is obtained by extirpation of the tumor in this group. The second group is a case with bilateral adrenal hyperplasia. We have experienced 12 cases. In this group, opinions differ as to the methods of treating the patients. Although bilateral total adrenalectomy may give relief for the symptoms, some disadvantages remain in the incidence of Nelson's syndrome or in a life-long steroid substi- Table 3 ELECTROLYTE SUPPLEMENT PROGRAM FOR PATIENTS WITH PRIMARY ALDOSTERONISM (Watanabe) sodium administered (mEq/day) potassium administered (mEq/day) Exemple for practical use preoperative 5 - 7 days 200 - 250 120 - 150 KC1 5-10g orally solid food (contained NaCl 10-15g, K 2-3g) 30 30 - 40 EL No. 3 solution lOOOcc liquid food -» paps (salt restricted) 200 30 - 40 Ringer solution lOOOcc paps (salt contained) 300 - 400 50 - 70 NaCl 5-1 Og orally solid food 1st 1 5th day (ith 1 8th day 9th 14th day a fter 15th day without restriction | postoperative period Some corrections are available after daily examination of serum and urine electrolyte. Red cefi K ("Efr/L » 80 Serum K UE«/ ) 4.0 + 100 K- bafaiuf " (•nEaJ ol + 5 0 Red cea Ha Serum Na 1 5 0 l-mfy/U 1 4 |j +3M +2« Ha-balance tlM m Untie v m W 15 ptotoperotue i Fig. il Postoperative serum K.Na, K.Na balance, K.Na concentration in red cells and volume in case with electrolyte supplement shown on Table :t. S H a S o tí a z = C= B OOO O S tí tí S3 - tí tí "S 'S "S tí a tí + « +++ a+ 51 •§ <j ^ < £ < ^ < 5 s S ^ 5 < b 3.Sd 5 b Sä; a tí tí r+ + s < < V. r- iu v. •x. rtsîKnnnncs ci c - a a a a ir. "35 'So S "c/j S . SSS» : » s s n K es.« 0 K reuooo^oa £•&£•£• & g" J "&ÌI11 &l & aa B M ca Sfr ftftl&ftl-ft .c .c j: .c .c l." jS — -G H ¿H* ¿í _C3 î/î c: & 0» S S a V o z s « D 3 JÍ j? n ö 5 ;zs> C- 00 Cl 00 ce »e ai 7 CI — r r-< Cl ci ci -+ H W c </2 U l ï i se "S >, >1 be ^ -S > I I 00 -t" 0 ce O i-t CD ÎC ^ C 0C 0C C"1 ÎO ci 00 T— r—11 00 ce ci oc 00 Cï l0 MCl i!î IO CC Ot^ — 4 ^ '4 o 2 — 5 < H < i*§ a £ O Cl w Ol O COOCi c c i> S 0 C. 2 00 S S OOOOOOCÎO c e -f ce c« îo c*. I I r^r-iT-xCIrHi-i^r- 170/ 170/ 180/ 150/ u z 0 1 t3i.Stfc.Sb b b noo^f cl r- Q O « ^ilOriOn r- C. ÎO ::C-t1-^I « -f -r :i ^ r; ^»Í3 01 O) con < à È. ~~ 4 5-e 0 ¿2 + 55 & « i '-5 I l i ! Sbbbbgbb « t¿ -i «' z S t Z. o H i¿ 'À > H >•' « ~ ¿ s ^ i- g s H ¡¿ —< — < ci-t ^10 ~ —' ri zfi O í¿ !>• 00* ïsgj? < S tution. These past 6 years we have employed total adrenalectomy on one side and 90% resection of the contralateral adrenal with preand post-operative irradiation to the hypophysis by large of telecobalt"" over 4000 roentgen respectively. All patients who have undergone this combination of therapy have been cured within a few years. I would like to emphasize that hypophyseal irradiation should be thoroughly performed. The third group of the syndrome is the ectopic ACTH-producing tumor, of which only a few cases have been found in this country, including one case of our own. Patients in this group should be treated with extirpation of the original tumor not with adrenal sur°'erv (Table 4). Table 5 shows a standard program of steroid substitution in our clinic. The administration dose is in general less than that usually reported. Since a marked suppression of ACTH occurs in cases with adrenal adenoma, such a minimized substitution may be effective for early stimulation of ACTH secretion. For the same reason, ACTH administration, which suppresses the intrinsic ACTH secretion, should be avoided. If adrenal insufficiency is apparent, additional Cortisol should be given. After the second postoperative week instead of Cortisol, dexamethasone, which has a less mineralocorticoids effect, is employed because postoperative potassium loss was occasionally also observed in this disease. Of course, a supplement of mineralocorticoids is u n n e c e s sary. The substitution for cases with adrenal hyperplasia treated with subtotal adrenalectomy can be discontinued within several weeks. On the contrary, a long term of administration extending over one or two years is often required for the majority of cases with adrenal adenoma, though the dosis is not so much. This might be partly due to the slow recovery of Cortisol secretion from the remaining adrenal tissue, and partly to a request by the patient himself, who realized and fears the discomfort from adrenal insufficiency. PHEOCHROMOCYTOMA Pheochromocytoma is one of the most hazardous diseases. Surgery for this disease in former times was just like a tight-rope between dramatic cure and catastrophe. The modern technique for treatment of the patient, however, brings a remarkable reliability to the postoperative course. In general, three methods have been presented for blood pressure control after the removal of pheochromocytoma. They are the noradrenaline drip method, the blood over-transfusion method and the treatment with receptor blocking drugs. We have applied each method to 17 cases treated in our clinic, as shown in Table 6. Then I will evaluate them, presenting some typical cases. 1° Noradrenaline drip method. The noradrenaline drip method has been generally employed for the past few decades. This method consists of a continous infusion of noradrenaline diluted by 5% glucose or other solution, which is TABLE STEROID SUBSTITUTION PROGRAM SYNDROME post-operative WITH CUSHING'S Without substitution Preoperative Operative d a y 5 FOR PATIENTS (Watanabe) During After Cortisol 100mg surgery Cortisol 50mg i.v.X2 surgery i.v. 2nd - 4th day Cortisol 50mg i.m.X4 5th - 6th day Cortisol 50mg i.m.X3 Cortisol 50mg i.m.x2 7th day 8th - 10th day D e x a m e t h a s o n e 0.5mg 11th - 13th day Dexamethasone 0.5mg p.o.x3 Dexamethasone 0.5mg p.o.X2 After 14th day p.o.X4 started immediately after removal of the tumor, and is reduced gradually to keep a reasonable blood pressure at 100 to 130mmHg systolic. Six cases, from Case No. 1 to No. 6, w e r e treated after a c c o r d i n g to this method. Fig. 10 shows on a semi-logarithmic graph the relationship between the dose of n o r a d r e n a l i n e required and the time elapsed the extirpation of the p h e o c h r o m o c y t o m a in these cases. Case No. 1 was excluded from the graph because of insufficient description of n o r a d r e n a l i n e given. A group, Case No. 2 and 3 r e q u i r e d larger doses of n o r a d r e n a l i n e and for a longer duration of infusion than that in another group including Case No. 4, No. 5 and No. 6. Curves of the noradrenaline administration in Cases No. 3 - 0 w e r e almostly linear on the semi-logarithmic graph, and their gradients w e r e r a t h e r similar in each case, giving a ratio of 1 / 1 0 during a period of about 10 hours. Case No. 2 was an exception, because this case had multiple tumors and only one tumor between them could be extirpated by surgery. In T a b l e 7, the first three columns show the pre-operative u r i n a r y excretion of c a t e c h o l a m i n e s in these 6 cases. S i n c e about 1 - 5 % of secreted c a t e c h o l a m i n e was usually excreted into the urine, we calculated the total value of c a t e c h o l a m i n e secretion per minute, namely, " t h e meaning minutely s e c r e t i o n " from the value of the preoperative u r i n a r y e x c r e t i o n , using 3 % as the ratio of u r i n a r y excretion to c a t e c h o l a m i n e secretion. T h e fourth column in T a b l e 7 presents this meaning minutely secretion value. On the other hand, the fifth column of T a b l e 7 shows the amounts of n o r a d r e l a n i n e w h i c h w e r e actually required just after the removal of the tumor to maintain a reasonable blood pressure. W e call this " t h e initial dose". W h e n the initial dose is compared w i t h the abovementioned meaning minutely secretion, both data almost c o i n c i d e in Cases No. 4, 5 and (5, although an additional amount of the initial dose w a s r e q u i r e d in Cases No. 2 and 3. F r o m these results, the cases may be divided into two groups; the one including Cases No. 4, 5 and (i that had almost the same initial dose as their meaning minutely secretion, and the other one 0 6 Postoperative 12 time FIG. The relationship between 18 duration 2C ' 30 h 10 noradrenaline administration duration in Case 2-P>. doses and postoperative time TABLE 7 U R I N A R Y E X C R E T I O N OF C A T E C H O L A M I N E S (CA), M E A N I N G S E C R E T I O N OF T O T A L CA (MMS), A N D I N I T I A L DOSIS Urinary Case No. A (mg/day) excretion NA (mg/day) of CA MINUTELY (ID). MMS* ID Total (mg/day) (mg/min) (mg/min) 0.8 2.4 2.7 0.06 9 3.5 4.3 7.8 0.18 1.0** 3 2.8 4.8 7.6 0.18 1.0** 4 0.29 2.4 2.69 0.06 0.06 1 5 0.95 0.32 1.27 0.03 0.02 (i 0.35 1.3 1.65 0.04 0.03 * calculated as 3% of secreted CA m i g h t be excreted ' * presumed data f r o m the curve on the graph. into the urine. including Cases No. 2 and 3, w h i c h required a larger initial dose than their m e a n i n g minutely secretion. Although we could not find a reasonable difference between these two groups as far as their clinical features w e r e c o n c e r n e d , the significant finding was that a very large amount of adrenaline was excreted from the tumor in the second group as c o m p a r e d w i t h the first. T h e s e results could be summarized as follows: a) T h e initial dose was almost equal to the preoperative meaning minutely secretion of the patient. b) But in some cases with too much adrenaline secretion, a larger initial dose than the m e a n i n g minutely secretion might be required. c) T h e administration dose of n o r a d r e n a l i n e logarithmo-linearly to 1 / 1 0 during about 10 hours. If w e suppose these conditions w e r e following formula may be i n t r o c u d e d ; M = M„ : 10 the might case in be reduced general, the t T M = Administration Mo Mt=o = t = = dose of noradrenaline. Initial dose of noradrenaline. T i m e elapsed after the removal of the tumor. x is a time constant w h i c h includes the time duration within w h i c h the dose is being reduced to 1 / 1 0 of the initial one. Its dimension is [ h o u r ] . W e named it as " t h e reducing t i m e " , and it shows a fixed value in most cases, namely, T = 10 (hours) In usual cases, Mo = Meaning minutely secretion However, in cases w i t h M 0 > Meaning minutely excress adrenaline secretion, secretion Now I will demonstrate a case in w h i c h this formula was applied. U r i n a r y c a t e c h o l a m i n e excretion in Case No. 6 was 1.65mg/day. This might be equivalent to 3 % of the total secretion from p h e o c h r o m o cytoma. Accordingly, approximately 50mg of c a t e c h o l a m i n e would be secreted in a day. T h e m e a n i n g minutely secretion was thus calculated as 0 . 0 3 m g / m i n . T h i s value might apply to the formula as Mo. Consequently, the postoperative administration dosis of noradrenaline for a patient was determined as Fig. 11. T h e postoperative course was uneventful and the blood pressure was kept stable, as shown in Fig. 12. T h e n o r a d r e n a l i n e drip method is a reasonable procedure, for the substance the patient lacks is r e p l a c e d by an substance identical with the one removed. Some disadvantages, however, may he pointed out as follows; a) T h e control of the noradrenaline drip is a troublesome job. b) T h e load on the heart is not relieved even after extirpation of the tumor, since the vasoconstriction still continues almost the same as in the preoperative condition. mg/min O.H M=M -10"T 0 0 5 X) t 15 20 h FIG. 11 Postoperative noradrenaline administration schedule for Case 6. M„ = ID = 0.03mg/min. = 10 hour. r mm Hg 150H 50 J 0.03 002 NA administration doses Cutting o f f trial of NA dropping £ 0.01 E Ol E 0 Tumor removed FIG. 12 Postoperative blood pressure change in Case 6 treated with the noradrenaline drip method. c) A large dosis of noradrenaline was required in cases with adrenaline-dominant pheochromocvtoma. For that reason, surgeons who advocate this method have been getting fewer in recent years. The technique of noradrenaline drip, however, is necessary when the other method proves ineffective for maintenance of blood pressure. 2" Blood over transfusion method. Ten years ago, Brunjes et al. first mentioned the abnormal hemodynamic state in patients with pheochromocytoma. Since then, it has been generally accepted that this abnormal state is a primary factor for hypotensive shock after removal of the tumor. Fig. 13 demonstrates the results of circulating blood volume determination before and after the surgery in our cases. A characteristic pattern of blood volume in pheochromocytoma may be summarized as follows: a marked reduction of red cell volume, a slightly decreased or subnormal total blood volume, and a discrepancy between peripheral venous hematocrit and total hematocrit, which means the ratio of red cell volume to the total blood volume. This pattern may be explained by a self-defense mechanism against the severe constriction of arterioli due to excess secretion of catecholamines. Red cells might be decreased for the sake of facility in passing through narrow vascular space. However, a pooling of red cells might occur simultaneously in veins, where the blood flow was slower than in arteries. Since tlie vessels suddenly relax on removal of the tumor, a remarkable deficiency of circulating blood volume, which leads to hypotensive shock, may result. The blood overtransfusion method is a procedure to keep the postoperative blood pressure up bv means of supplementing this blood volume deficiency, in addition to the operative blood loss. We appfied this method in 5 cases, from Case No. 7 to No. 11. Table 8 shows the detailed data on blood volume determination in Case No. 8. This patient had the 530cc reduced red cell volume and the 380cc expanded plasma volume, as compared with the standard value obtained from normal Japanese adults. If the 530cc reduced red cell volume could be supplied with the whole blood of which hematocrit was 40%, 1325cc should be administered after removal of the tumor. Practically, the overtransfusion of 1500cc of whole blood was performed. The postoperative course of the patient was uneventful and the needed no vasopressors at all. The blood pressure rose gradually and remained at the upper limit of the normal range for about two postoperative weeks (Fig. 14). Postoperative examinations revealed a significant improvement in the hemodynamic balance. The blood overtransfusion method is simple and easily feasible, but it seems to be somewhat questionable whether it is good for the constricted vessels to be suddenly dilated with a large amount of blood infused in a short time, without regard to tension of the vessels. For mild and smooth management with this method, a combined treatment with receptor blockes will be necessary, as I will mention in the next section. RCV" PT % Hct ratio TBV % = PCV+PT 90- 30- 80- 25- 70- / 60 20- 5(H 15- Pre- ?ostOpe. Pre- Post- Ope. FIG. 13 Pre- and postoperative blood determinations in cases ot" pheochromocytoma. PRE- AND POSTOPERATIVE TABLE 8 BLOOD DETERMINATIONS Preoperative PV* ROM* TBV ( P V + R C M ) T o t a l Hct. P e r i p h e r a l Hct. Hct. ratio*** Body w e i g h t 2690 cc 1010 cc 3700 cc 27.3% 38.0% 0.71 51.0 leg IN CASE 8. Estimated normal value Postoperative * * * * 2310 cc 1540 cc 3850 cc 40% 44% 0.91 2600 cc 1810 cc 4410 cc 41.0% 45.5% 0.90 51.5 kg — • Evans blue dilution method. Cr labelled red cell dilution method. Hct ratio = THct/PHct. 60th postoperative day. s, 3° Treatment with receptor blocking agents. It is well known that the adrenotropic receptors can be divided into two types; «-receptor and |3-receptor. The a-receptor is associated with most of the excitatory functions, including vasoconstriction. The |3-receptor is associated with most of the inhibitory functions and one excitatory function, that is, myocardial stimulation due to chronotropic and inotropic action. Adrenaline is a stimulant to both the «- and /3-receptor, while noradrenaline has only a-stimulating action. When this idea is applied to the clinical feature of pheochromocytoma, hypertension may be dependent upon the a-receptor and tachycardia upon the p-receptor. Tumor removed rnm Hg 200 150100- 50 -1550CC overtransfused 0 5 10 15 day FIG. 14 Postoperative blood pressure change in Case 8 treated with the overtransfusion method. TABLE 9 VARIOUS RECEPTOR STIMULANT AND BLOCKER Stimulant a-receptor /3-reeeptor adrenaline noradrenaline phenylephrine (Neo-Synephrine adrenaline (noradrenaline) isoproterenol (Isprel Blocker R ) R ) ergotamine tolazoline phentolamine (Regitine R ) phenoxybenzamine (Dibenzyline R ) pronethalol dichloroisoproterenol (DCI) propranolol (Inderal R ) H 56/28, LB 46, I.C.I. 50, 172, MJ 1999 In recent years, some drugs have been introduced which block each reccptor selectively, as shown in Table 9. Administration of these blocking agents eliminates the action of catecholamines secreted from pheochromocytoma. It is surely reasonable to adapt the patient to the postoperative state by such a treatment prior to surgery. We have treated 6 cases, from Case No. 12 to No. 17, with this method, and I would like to present an example from among them (Fig. 15). Case No. 12 was a patient seriously ill with severe hypertension. A frequent dosage of Regitine administered for the treatment of hypertensive paroxysms brought a little and unreliable relief, since its effect persisted for only a short duration. However, after oral administration GOmg of Dibensyline and Inderal respectively, three times daily, symptoms almost disappeared. T h e blood pressure remained stable and the pulse rate decreased to normal range. Dibenzyline had a much longer duration of action than Regitine. As shown in Table 10, the intense peripheral vascular resistance and the decreased cardiac output accompanied with reduction of the red cell volume were manifest before treatment with the blocking agents in this patient. During treatment, a remarkable improvement in the peripheral resistance and the cardiac output were observed. However, the reduced red cell volume was still unchanged, though slight expansion of plasma volume occurred. T h e amount of 500cc of whole blood was infused during the surgery. T h e intra- and post-operative course of the patient was uneventful, except for a temporary hypotensive episode immediately after removal of the tumor, which was relieved by 0,3mg of intravenous noradrenaline (Fig. 16). As mentioned above, treatment with adrenotropic blocking drugs is effective for improvement of the abnormal hemodynamic state, but is ineffective for red cell volume deficiency itself. Accordingly, more reasonable management would be expected from a preoperative prophylactic blood supplement transfused gradually after dilatation of vascular space with receptor blockers. A standard procedure in our clinic is as follows: Administration of 30 or 60mg of Dibenzyline and Inderal three times daily is started from one or two weeks prior to surgery. Replacement of an amount of blood equal to the estimated blood volume reduction is performed during two or three days immediately before the operative day. Such a method combined with overtransfusion and receptor blockers is the latest and most reliable technique for treatment of pheochromocytoma. ' 5 0 60 »¿v f i j s ' g ' " V a y " " ™ Inderal 8 9 10 / / d a y ' 2 3 Dibenzyline FIG. 4 5 6 fc&i^l 15 Preoperative course in Case 12. >J chO U c/2 7 d a y / 0 20 3 0 d a y ® RegUineS»g im inj. ANESTHESIA RECORD NO. DATE SERVICE WARD J. NAME ROOM K . ACE PRIVATE 16 WEIGHT 4 2 SEX PROPOSED OPERATION PREMEDICATION SURG. INDUCTION : SATIS. SLOW SECRETION ANESTHETIC AGENTS : INDUCTION ANES. METHOD Semiclosed ENDOTRACHEAL: OPERATION SURGEONS LOJJO COMO SPASM OTHERS TOO UG*T Thiamylal Sod. Circle System NASOfR. I..) |o CUFF c PACK MAINTENANCE G 0 E COa Absorber TUBE S 3D BLADE MdC< . S Extirpation of Tumor S . S. ANESTHESIOLOGISTS 1 DURATION OF OPERATION FTOPICAL POSITION Y. Y. 3 H - 2 0 0 CONDITION IMMEDIATELY POST-OP. : RFSP. DEPRESSION C * Scapatané» PttMdlru O. R. EXCITE, EMESIS 19 _ 6 1 _ BLOOO T Y F C PHYSICAL STATUS PhtQchromocyfoma Extirpation of Tumor PRE-OPERATIVE DIAGNOSIS PROPOSED TIME 7 / V * INSURANCE .... INSTRUCTOR DURATION OF ANESTHESIA I f . SECRETIONS ( + 1 2 5 / 8 0 - REFLEX ( + - ) FIG. RESPONSE t + 16 course in Case 3 0 R. R. REMARKS : Intraoperative . 3 P. R. J i } 5 12. - ) EMESIS ( + - ) 0,4 3Q P R E - AND P O S T O P E R A T I V E HEMODYNAMIC D E T E R M I N A T I O N S IN CASE 12. period P e r i p h e r a l r e d cell c o u n t H e m o g l o b i n c o n t e n t (Sahli, %) Plasma protein .. (g/dl) Peripheral venous hematocrit estimated normal value before treatment during treatment with Dibenzyline & Inderal 450X10' 539X10' 340 X10 4 80 -100 (i. 2 - 8 3 (%) 42 (5 80 6 8 41 o 00 7 0 31 7 after surgery 138X10* 85 6. G 36.0 Red cell v o l u m e (cc) 1240 710 680 1250 P l a s m a v o l u m e (cc) 1950 1220 1700 2580 T o t a l blood v o l u m e (cc) 3190 1930 2380 3830 T o t a l b o d v h e m a t o c r i t (%) 38 9 3(5 8 Hematocrit ratio 0 91 0 89 Cardiac output (1/min) 4. 83 1 31 Total peripheral vascular tance (dynes/sec/cm~5) resis- Mean f e m o r a l a r t e r i a l blood sure (mmHg) pres- 28 (i 0 90 0 (¡7 1358 110470 3435 83 175 100 32.6 0.91 CONCLUSION I have so far discussed and explained the recent postoperative management of adrenal surgery. As already emphasized above, this field of medical investigation has developed and will develop with the advancement of fundamental medicine. On the other hand, patients with adrenal tumor may be, as it were, experimental subjects for excess endocrine stimulation accidentally done by Nature. Therefore, the various types of pathologic states will surely feed back the most valuable data necessary for the advancement of fundamental medicine. So, we should not easily and hastily reach the decision to remove the tumor, but we should closely examine each cases, and always try to seek after the newer and more important truth. SUMMARY A simplified and standardized pre- and postoperative treatment technique for adrenal surgery was discussed on experiences on 80 cases treated in our clinic since 1956. Results were summarized as follows: 1° Primary aldosteronism. During a few days after removal of the adrenal tumor, a remarkable loss of both sodium and potassium was observed. This might be caused by the following three factors; proximal tubular rejection of sodium disturbance of distal tubular function and suppression of renin-angiotensin-aldosterone system. A low sodium and high potassium supplement during nearly five postoperative days and a high sodium administration after that period would be necessary. A program of the electrolyte supplement based on the above-mentioned findings was demonstrated. 2" Cushing's syndrome. A subtotal adrenalectomy with pre- and postoperative irradiation to the hypophysis by large dosis of tele-cobalt 00 was effective for the cases with bilateral adrenal hyperplasia. A standard program of postoperative substitution therapy, w h i c h was composed of minimized Cortisol supplement without ACTH administration, was described. 3° Pheochromocytoma. Three methods presented for blood pressure control after the removal of pheochromocytoma, i.e., noradrenaline drip method, blood overtransfusion method and the treatment w i t h receptor blocking drugs, were evaluated. The most reliabe management might be obtained from a combined technique with overtransfusion and receptor blockers. RESUME Une technique de traitement simplifié et standardisé pré et postopératoire de la chirurgie de la surrénale est discutée en se fondant sur l'expérience de 80 cas traités dans notre clinique depuis 1956. Les résultats se résument ainsi : 1. Aldostéronisme primaire Pendant quelques jours après l'ablation de la tumeur de la surrénale une perte importante du sodium et du potassium est constatée. Cette perte est due aux trois facteurs suivants : rejet du sodium p a r le tube excréteur, trouble de la fonction du tube distal et suppression du système rénin-angiotensin-aldostérone, Un supplément d'un peu de sodium et de beaucoup de potassium pendant les cinq premiers jours postopératoires et une administration importante de sodium après cette période sera nécessaire. Un programme d'un supplément électrolytique basé sur les découvertes sont mentionnées est nécessaire. 2. Syndrome de Cushing Une surrénalectomie subtotale avec irradiation pré et postopératoire de l'hypophyse par de larges doses de télécobalt 60 sera efficace dans les cas d'hyperplasie bilatérale de la surrénale. Un programme standard de thérapeutique substitutive postopératoire qui est composé de doses minimes de cortisone sans ACTH est décrit. 3. Phéochromocijtome Trois méthodes utilisées pour le contrôle de la pression artérielle après l'ablation d'un phéochromocytome c'est-à-dire la méthode du goutte à goutte de noradrénaline, la méthode de la transfusion sangnine et le traitement avec les médicaments inhibiteurs du receveur sont étudiés. Les résultats les plus favorables ont été obtenus par une combinaison de la transfusion et des inhibiteurs du receveur. ZUSAMMENFASSUNG Anhand der Erfahrungen bei SU an unserer Klinik seit 1956 behandelten Fällen wurde ein vereinfachtes und standardisiertes prä- und postoperatives Beliandlungsschema für die Nebennieren-Chirurgie erörtert. Die Ergebnisse wurden folgendermassen zusammengefasst : 1. Primärer Aldosteronismus Im Verlauf einiger Tage nach Entfernung des Nebennierentumors war ein deutlicher Verlust an Natrium und Kalium zu beobachten. Dies könnte durch die folgenden drei Faktoren verursacht sein : Natriumausscheidung im proximalen Tubulusbereich, Störung der distalen Tubulusfunktion und Unterdrückung des Benin-Angiotensin-AldosteronSystems. Eine niedrige Natrium- und Kaliumzufuhr während etwa fünf postoperativen Tagen und im Anschluss daran hohe Natriumzusätze wären notwendig. Es wurde ein Schema der Elektrolytzufuhr, basierend auf den oben erwähnten Befunden, vorgestellt. 2. Cushing-Syndrom Eine subtotale Adrenalektomie mit hochdosierter Telekobalt 60 Bestrahlung der Hypophyse prä- und postoperativ erwies sich für die Fälle mit doppelseitiger Nebennierenhvperplasie als wirksam. Es wurde ein Standardprogramm für die postoperative Substitutionstherapie beschrieben, welche aus minimaler Hydrokortisonzufuhr ohne ACTHVerabreichung bestand. 3. Phäochromozytom Es wurden drei Methoden zur Blutdruckkontrolle nach der Entfernung des Phäochromozytoms geprüft, nämlich die Noradrenalintropfmethode, das Verfahren der Blutübertransfusion und die Behandlung mit rezeptorblockierenden Medikamenten. Die zuverlässigsten Ergebnisse dürften durch eine Kombination aus Uebertransfusion und Rezeptorenblockern zu erzielen sein. RIASSUNTO Una tecnica per la terapia semplificata e standardizzata pre e postoperatoria della chirurgia della surrenale è discussa basandosi sulla esperienza di 80 casi curati nella nostra Clinica dopo il 195(5. 1 risultati si riassumono così : 1. Aldosteronismo primario Dopo qualche giorno dall'asportazione del tumore surrenalico si constata una importante perdita di sodio di potassio. Questa perdita è dovuta ai tre fattori seguenti : rigetto del sodio da parte del tubolo escretore, turbe nella funzione del tubolo distale e sopressione del sistema renina-angiotensina-aldosterone. Un supplemento di un po' di sodio e di molto potassio durante i primi giorni post-operatori ed una notevole somministrazione di sodio dopo questo periodo sarà necessario. 2. Sindrome di Cushing Una surrenalectomia subtotale con irradiazione pre e post-operatoria dell'ipofisi con forti dosi di telecobalto 00 sarà efficace nei casi di iperplasia della surrenale bilaterale. E' descritto inoltre un programma standard di terapia sostitutiva post-operatoria con dosi minime di cortisone senza A.C.T.H. 3. Feocromocitoma Sono studiati tre metodi utilizzati al controllo della pressione dopo ablazione del tumore, cioè il metodo goccia a goccia di noradrenalina, il metodo della trasfusione sanguigna e la terapia con medicamenti inibitori del ricevente. I risultati più favorevoli sono stati ottenuti attraverso una combinazione della trasfusione e degli inibitori del ricevente. RESUMEN Se discute una técnica del tratamiento simplificado y estandarizado pre y posoperatorio de la cirugía de la suprarrenal, fundándose en la experiencia de 80 casos tratados en nuestra Clínica desde el año 1956. Aldosteronismo primario Algunos días despues de la ablación del tumor de la suprarrenal, se observó una perdida importante de sodio y potasio. Esta perdida es debida a los tres factores siguientes : rechazo de sodio por el tubo excretor, trastornos de la función del tubo distal y supresión del sistema renina-angiotensina-aldosterona. Es necesario un suplemento de un poco de sodio y mucho potasio durante los cinco primeros dias posoperatorios así como una administración importante de sodio después de este periodo. Es indispensable un programa con un suplemento electrolítico ¿asado sobre los descubrimientos anteriormente dichos. Síndrome de Cushing Una suprarrenalectomia subtotal con irradiación pre y posoperatorio de la hipófisis a grandes dosis de telecobalto 60 será eficaz en el caso de hiperplasia bilateral de la suprarrenal. Se describe un programa estandar de tratamiento substitutivo posoperatorio con dosis mínimas de cortisona sin ACTH. Feocromocitoma Para el control de la presión arterial después de la extirpación de 1111 feocromocitoma, se utilizan tres métodos, es decir el método del gota a gota de noradrenalina, el método de transfusión sanguínea y el tratamiento con medicamentos inhibidores de los receptores. Los resultados más favorables han sido obtenidos con una combinación de la transfusión e inhibidores de los receptores. — H45 — DIE CHIRURGIE DER NEBENNIEREN L0KAL1SATI0NSDIAGN0SE mittels Cavographie VON und PHAEOCHROMOCYTOMEN Venenkatheterismus Von W.H. ZIEGLER und G. MAYOR Aus der Medizinischen Universitätsklinik Zürich (Direktoren : Prof. A. Labhart, Prof. P. Frick) und der Urologischen Universitätsklinik Zürich (Direktor : Prof. G. Mayor). Das klinische Bild der Phaeochromocytome ist gekennzeichnet durch die pharmakologischen Eigenschaften der durch diese Tumoren des sympathischen Gewebes sezernierten Katecholamine, Adrenalin und Noradrenalin. Die Kreislauf- und Stoffwechselstörungen, welche dabei in Erscheinung treten, sind abhängig von der ausgeschütteten Menge dieser endokrin aktiven Amine. Das führende Symptom ist in der überwiegenden Zahl der Fälle eine von der essentiellen Hypertonie vielfach nicht zu unterscheidende Dauerhypertonie. Seltener ist die paroxysmale Form der Erkrankung, welche klinisch durch die charakteristischen, sehr verschieden lange dauernden Anfälle von Hypertonie, Tachykardie, Blässe, kaltem Schweiss, Tremor, Herzklopfen, Nausea und Kopfschmerzen in Erscheinung tritt. Häufig magern diese Patienten ab, die Glucosetoleranz ist vermindert und der Grundumsatz ist ohne Hyperthyreose erhöht. Die vermutete Diagnose ist stets zu sichern, bevor das eigentliche Ziel der Therapie, die Entfernung der Geschwulst, durch den Chirurgen angestrebt wird. Ist die Diagnose durch den chemischen Nachweis vermehrter Katecholamine und deren Metaboliten im Urin, in Zweifelsfällen ergänzt durch pharmakologische Tests, gestellt, so ist der Lokalisation des Tumors einerseits und der Hypovolämie dieser Patienten anderseits im Hinblick auf die Operation besondere Aufmerksamkeit zu schenken. Die häufig zu beobachtende Hypovolämie beim Phaeochromocytom stellt eine Kontraindikation für die Operation dar, indem mit der Tumorentfernung eine schlagartige Erweiterung der Gefässe einsetzt und dadurch der gefährliche Zustand des hypovolämischen Schocks droht. Mit der praeoperativen Verabreichung von Alpha-Rezeptorenblockern lässt sich jedoch diese - oft maskierte — Hypovolämie beheben, so dass heute diese Gefahr weitgehend gebannt ist. Die Lokalisation des Tumors in situ ist im Hinblick auf die Wahl des optimalen operativen Zuganges von erheblicher Bedeutung. Bereits die Bestimmung von Adrenalin und Noradrenalin im Urin lässt in begrenztem Masse einen Schluss über den Sitz des Tumors im Körper zu. Erhöhte Ausscheidung sowohl von Adrenalin als auch von Noradrenalin sprechen fast ausnahmslos für die Nebenniere und deren nächste Umgebung als Ursprung der Geschwulst, seltener auch für das Zuckerkandl'sche Organ. Dasselbe hat Gültigkeit in r u n d 2/3 der Fälle, die vorwiegend Noradrenalin im Urin ausscheiden, während im verbleibenden Drittel dieser Patienten mit jeder möglichen extraadrenalen Lokalisation dem Grenzstrang entlang gerechnet werden muss (in ca. 20 % der Fälle). Trotzdem stösst das Auffinden und damit die chirurgische Entfernung immer wieder auf erhebliche Schwierigkeiten, so dass eine zusätzliche praeoperative Abklärung erforderlich ist. Das intravenöse Pyelogramm und eine Thoraxaufnahme p.a. und seitlich werden routinemässig angefertigt. Sie erlauben gelegentlich bereits die Lokalisation eines grossen Phaeochromocytoms. Hingegen sind Aortographie und Retropneumoperitoneum mit Tomographie bereits Untersuchungen, welche den Patienten erheblich belasten können, indem mit einem Auftreten hypertensiver Krisen und gelegentlich irreversibler Schockzustände zu rechnen ist. Zudem sind abgesehen von oft schwieriger Interpretation der Befunde die Aussichten auf eine Darstellung des Tumors mittels dieser Untersuchungen relativ klein und stehen in keinem Verhältnis zu dem dabei eingegangenen Bisiko. Der Katheterismus der Vena cava dagegen stellt einen nur kleinen Eingriff dar, welcher praktisch frei von Zwischenfällen ist und die zumeist schwerkranken Patienten kaum belastet. Dieses Verfahren ist allerdings an das Vorhandensein eines Speziallabors gebunden, welches die Katecholamine im Plasma zu bestimmen in der Lage ist. Vorgehen : Zu Beginn und während der Dauer der Untersuchung werden Blutdruck und Puls des Patienten regelmässig überwacht. Nach lokaler Anaesthesie inguinal w i r d unter Böntgenkontrolle, ausgehend von einer der beiden Venae femorales, die Vena cava katheterisiert. Dabei wird im Verlaufe der obern und untern Hohlvene an mehreren Stellen Blut zur Katecholaminbestimmung entnommen, welches-20 ml pro Entnahme — unter Zugabe von Edta im Eisbad aufgefangen und dem Laboratorium unverzüglich zur Aufarbeitung zugeführt wird. Der höchste im Plasma gefundene Katecholaniinwert entspricht der E i n m ü n d u n g des venösen Tumorabflusses. In der Begel erfolgen die Entnahmen aus der Vena cava cran. zur Erfassung eines Phaeochromocytoms im Bereiche des Mediastinums bzw. Kopf-Halsgebietes. Dann aus der Vena cava caud. unmittelbar unterhalb des Diaphragmas als Abgrenzung des Abdomens, auf Höhe der Vena suprarenalis rechts und selektiv aus den Venae renales beidseits, wobei diese Entnahmen die Seitenloalisation in die Nebennierenlogen gestatten. Schliesslich aus der Bifurkalionsstelle der untern Hohlvene für den Blasenbereich und das kleine Becken. Der Ort der Entnahme wird jeweils durch Kontrastmittel gesichert (Abb. 1). ABB. 1 Entnahme des venösen Hintes zur Katecholamin-Bestimmun» von verschiedenen Höhen der \'ena Cava. al Punktion der Vena Cava cran. (nicht auf dem Schema), b) Vena Cava caudalis unterhalb des Zwerchfells II), c) Vena suprarenalis rechts (2), dl Vena renalis links (3), el Vena renalis rechts (4), f) Bifurkationssteile der Vena Cava. Nur die Gegenüberstellung sämtlicher gefundenen Werte erlaubt es, den Tumor nicht nur in Bezug auf seine Höhe, sondern meist auch nach einer Seite hin zu lokalisieren. Multiple venöse Abflusswege und unter Umständen auch Gefässanomalien können die Interpretation der Befunde gelegentlich erschweren. Durch den Chirurgen erfolgt dann im Bereiche der durch den Katheter bezeichneten Stelle eine eingehende Exploration, wobei palpatorisch zugängliche Möglichkeiten weiterer Phaeochromocytome sorgfältig überprüft werden. Eigene Ergebnisse : Seit dem Jahre 1963 haben wir in Zürich nach Anwendung dieser Methode insgesamt 15 Patienten mit Phaeochromocyton operiert, wobei in einem Falle ein maligner Tmnor, in einem zweiten Falle doppelseitige Tumoren vorlagen. Dabei konnte eine Geschwulst in bezug auf die Höhe, eine zweite in bezug auf die Seite richtig lokalisiert werden, während in 11 Fällen Höhe und Seite mit dem Operationsbefund übereinstimmten. Bei einer sehr adipösen Patientin wurde der Tumor auf der vermuteten Seite nicht gefunden ; ein zweiter Katheterismus entspricht unverändert dem ersten Befund, die Wiederholung des Eingriffes nach erfolgter Abmagerungskur ist vorgesehen. Bei einer Patientin stimmte der Katheterbefund, welcher für die rechte Nebennierenloge sprach, nicht mit demjenigen der Operation überein. Die Geschwulst wurde in der gleichen Sitzung paraaortal links unterhalb der Niere gefunden und extirpiert. Ueberdies wurde der Katheterismus der Vena Cava bei weiteren 12 Phaeochromocytompatienten angewendet, dis uns zum Zwecke der Tumorlokalisation zugewiesen wurden. Darunter befinden sich 4 Kinder, wovon zwei multiple Phaeochromocytome aufwiesen. Dabei konnten zwei Geschwülste in bezug auf die Höhe, eine dritte in bezug auf die Seite richtig lokalisiert werden, während in 8 Fällen Höhe und Seite dem Operationsbefund entsprachen. Auch in dieser Gruppe fand sind ein Patient, dessen Katheterbefund nicht dem Operationsbefund entsprach, indem die Geschwulst nicht in der rechten Nebennierenloge, sondern über der Aortenbifurkation lag. Die nachfolgende Tabelle fasst die insgesamt 27 Patienten zusammen : I. Lokalisation : Nebennierenmark 17 (63 %) Nebennierenloge 4 (15 %) Extraadrenal 6 (22 %) 27 II. Seitenlokalisation : Links 14 (52 %) Rechts 9 (33 %) Multipel 3 (11 %) Nicht gefunden 1 ( 4 %) 27 III. Höhen- und Seitenlokalisation : Höhe 3 (11 %) Seite 2 ( 7 %) Höhe und Seite 19 (71 %) Falsche Lokalisat 2 ( 7 %) Malignom 1 ( 4 %) 27 Diskussion : Die beiden falsch lokalisierten Geschwülste gehören zur Gruppe der extraadrenalen Phaeochromocytome, welche rund einen Fünftel sämtlicher Fälle betragen. Die Zahl der Tumoren, die, sei es nach der Höhe, sei es nach der Seite oder aber in beiden Dimensionen, richtig lokalisiert wurde, beläuft sich auf nahezu 90 %. Während der Untersuchung kam es in keinem Falle zu Zwischenfällen ; insbesonders traten keine bedrohlichen Blutdruckkrisen oder schockartige Zustände in Erscheinung. Bei 5 Patienten w u r d e der Katheterismus im Abstand von 1 Monat bis 1 J a h r nach der ersten Untersuchung zur E r h ä r t u n g eines Befundes oder zur Feststellung von Rezidiven bzw. multiplen Phaeochromocytomen wiederholt. Mit dieser Untersuchungsmethode w i r d als Folge der Kontrastmittelanwendung eine Cavographie mit anschliessendem Ausscheidungspyelogramm neben den Blutentnahmen zur Katecholaminbestimmung im gleichen Arbeitsgang vorgenommen. Die Cavographie vermag gelegentlich zusätzliche Informationen über die Topographie eines Tumors zu bringen (Abb. 2). ABB. 2 F r . R.M., 1911 : D a r s t e l l u n g eines N e b e n n i e r e n t u n i o r s d u r c h d i r e k t e selektive F ü l l u n g der Vena s u p r a r e n a l i s rechts. venöse So vermuteten wir ein Phaeochromocytom im Bereiche des linken Nierenhilus, welches durch ventilartige Gefässkompression zu einer retrograden Kontrastfüllung der varikös erweiterten Vena ovarica bis ins kleine Becken führte (Abb. 3). Der Befund w u r d e operativ bestätigt. Ann. Ii Fr. L.C., 1915 : Phaeochromocytom a m Hilus links mit Kompression der Vena renalis und venösem Reflux in die Vena ovarica links, so dass positive Katecholaminwerte an der untern Entnahmestelle in der Vena cava festgestellt wurden. Die Patientin liiit dem metastasierenden Phaeochromocytom wies eine massive Eindellnng der Vena cava inferior im untersten Abschnitt auf, welche das Lumen um ca. 30 % einengte und bereits ein Malignom vermuten liess (Abb. 4 und 5). Auch hier fand sich der inoperable Tumor an erwähnter Stelle. In beiden Fällen stimmte der radiologische Befund mit der blutchemischen Lokalisation überein. Chirurgische Betrachtungen. Bevor ein Patient mit einem phaeochromocytom operiert wird, muss man dafür sorgen, dass das Blutvolumen normalisiert wird, sonst riskiert man bei der Ligatur der Gefässe des Phaeochromocvtoms einen ABB. -1 F r . H.P., 1917 : Massive E i n t e i l u n g der Vena Cava m i t V e r d r ä n g u n g nach lateral rechts d u r c h ein m a l i g n e s P h a e o c h r o m o c y t o m . hypovolämischen Schuck, der von einem plötzlichen Herzversagen gefolgt sein kann. Dieser P u n k t ist f ü r die Betreuung des Patienten und für das Gelingen des operativen V e r f a h r e n s ausserordentlich w i c h tig. Es sind immer w i e d e r Fälle publiziert w o r d e n , bei w e l c h e n aus angeblich unverständlichen Gründen der Patient w ä h r e n d des E i n g r i f f e s ad exitum gekommen ist. Bei diesen angeblich unverständlichen Momenten handelt es sich in W a h r h e i t 11111 einen h y p o v e l ä m i s c h e n S c h o c k . ABB. 5 Gleiche Patientin wie Abb. 4. Schräge A u f n a h m e m i t noch besser zur Darstellung gebrachter E i n t e i l u n g u n d Impression der Vena cava. Deswegen ist es erforderlich, dass der Patient während der ganzen Operation gleichzeitig vom Anaesthesisten und Internisten dauernd überwacht wird. Bei einem klinisch festgestellten Phaeochromocytom mit fast sicherer Seiten- und Höhenlokalisation erfolgt die Freilegung am besten durch einen transthorako-retroperitonealen Schnitt, der einen genauen Ueber- blick vom lateralen Rand der grossen Gefässe zwischen Nebenniere und kleinem Becken gestattet. Als erste Stelle wird die durch Venenkatheterismus vermutete Lokalisation eingehend exploriert. Es darf bei der Operation der Tumor nicht digital angefasst werden, da diese Manipulation die Gefahr einer weiteren Blutdrucksteigerung mit der Möglichkeit von weiteren Komplikationen wie z.B Apoplexie bedeutet. Die Gefässe des Tumors müssen daher zuerst sorgfältig zur Darstellung gebracht und isoliert werden. Dann werden sie vorsichtig mit einer Gefässklemme komprimiert, wobei die Veränderungen des Blutdrucks genau zu beobachten sind, wozu die automatischen Blutdruck-Schreibapparate unerlässlich sind. Bei einem klinisch gesicherten Phaeochromocytom mit den entsprechenden Merkmalen kann man feststellen, dass der Blutdruck nach Kompression der Gefässe des Phaeochromocytoms absinkt. Nach Ligatur und Durchtrennung der Gefässe des Phaeochromocytoms senkt sich der Blutdruck innerhalb von 10 Minuten auf normale Werte. Dies bedeutet, dass das Phaeochromocytom solitär ist. Wenn der Blutdruck innerhalb dieser Zeitspanne sich nicht normalisiert hat, besteht Verdacht auf das Vorliegen eines zweiten Tumors, so dass die Exploration der gleichen Seite bis ins kleine Becken erfolgen muss. Im Falle eines negativen Befundes sollte die andere Seite in einer zweiten Sitzung exploriert werden, keineswegs aber in der gleichen, um den Patienten nicht zu gefährden. Die spätere zweite Operation erfolgt dann durch gleiche Schnitt-führung auf der Gegenseite nach nochmaliger genauer klinischer Durchuntersuchung. Die operative Technik der Entfernung eines Phaeochromocytoms kann unter Umständen sehr schwierig sein, da diese Gebilde, besonders solche, die sich nicht in der Nebennierenloge, sondern entlang der grossen Gefässe befinden, meistens mit denselben sehr stark fixiert sind, so dass ihre Ablösung grosse Mühe bereiten kann. Schlussfolgerungen. Mit dem Kalheterismus der Vena cava es uns heute bei Vorliegen eines Phaeochromocytoms möglich, den Tumor in ca. 90 % der Fälle richtig zu lokalisieren und eventuell sogar multiple Geschwülste zu erfassen. Damit ist die lokale Exploration viel gezielter und sicherer geworden, ohne dass der Patient dabei gefährdet wird. ZUSAMMENFASSUNG Die Diagnose des Phäochromocytoms ist eine rein biochemische Angelegenheit. De lokalisation des Tumors erfolgt fast mit Sicherheit durch Kavakatheterismus und Dosierung des Adrenalins und des NorAdrenalins auf verschiedenen Höhen der Vena cava. Technik und praktische Anwendung des Katheterismus der Vena cava als schonender Eingriff zur praeoperativen Lokalisation des Phäochromocytoms werden anhand von 27 Fällen besprochen : rund ein Fünftel der Tumoren liegt ausserhalb der Nebennierenregion, wovon zwei Tumoren falsch lokalisiert worden sind. Ein Tumor wurde in situ nicht gefunden, während annähernd 90 % derselben in bezug auf die Höhe oder Seite bzw. in beiden Dimensionen richtig lokalisiert wurden. Anhand von 2 Patienten wird beschrieben, dass es gelegentlich durch Ivavographie während der Untersuchung gelingt, zusätzliche Information über die Topographie des Tumors zu erhalten. Die Fehler in der Interpretation der Bestimmung der Katecholamine können auf einer venösen Anomalie oder einer Stauung an der Vena spermatica beruhen. Die Aortographie ist wegen der Gefahr einer hypertensiven Komplikation abzulehnen. Bei der Operation, die immer nach Normalisierung des Blutvolumens erfolgen muss, beobachtet man, dass der Blutdruck nach Entfernung des Tumors sofort auf normale Werte absinkt. Ist dies nicht der Fall, so muss eine Multiplizität des Tumors angenommen werden. Deshalb ist es notwendig, durch grosse transthorako-retroabdominale Schnittführung den ganzen retroperitonealen Baum zur Darstellung zu bringen. Im Falle einer doppelseitigen Lokalisation der Läsion sollte grundsätzlich der Eingriff nie in der gleichen Sitzung beidseitig erfolgen. BESUME Le diagnostic du phéochromocytome représente un problème biochimique. La localisation de la tumeur peut être déterminée de façon presque certaine par une détermination du taux des catécholamines dans le sang veineux de la veine cave qui est ponctionnée à différentes hauteurs. La technique du cathétérisme de la veine cave de même que ses applications pratiques pour le diagnostic préopératoire du phéochromocytome sont exposés en se basant sur l'observation de 27 cas. 20 % des tumeurs se trouvent en-dehors de la région surrénalienne. Un faux diagnostic de localisation a été observé dans deux cas. Dans un seul cas, la tumeur suspectée n'a pu être mise en évidence au cours de l'exploration opératoire. Dans plus de 90 % des cas, l'exploration chirurgicale a confirmé la présence de la tumeur spécialement en ce qui concerne la localisation de côté et de hauteur. On a pu démontrer chez deux malades que la cavographie est capable de donner des indications précises en ce qui concerne la topographie de la tumeur qui est visible sur les clichés radiologiques. Les erreurs d'interprétation dans la détermination des catécholamines peuvent être en relation avec une anomalie veineuse ou une stase de la veine spermatique. L'exploration par aortographie est contre-indiquée par le fait qu'elle risque d'entraîner une complication hypertensive. L'opération ne doit être effectuée qu'après avoir normalisé le volume sanguin. On observe pendant l'opération que la pression sanguine reprend ses valeurs normales immédiatement après l'extirpation de la tumeur, sinon il convient d'envisager une localisation multiple. Il est nécessaire d'explorer toute la loge rétropéritonéale par un abord trans-thoraco-rétroabdominal. Dans le cas d'une localisation bilatérale, l'exploration chirurgicale ne doit pas être faite des deux côtés au cours de la même séance opératoire. SUMMARY T h e diagnostic of the p h e o c h r o m o c y t o m e represents a b i o c h i m i c a l problem. T h e localization of the tumour can be almost certainly determined by calculating the rate of the c a t e c h o l a m i n e s in the venous blood of the cave vein w h i c h is tapped at various heights. T h e t e c h n i c of the catheterism of the cave vein as well as its p r a c t i c a l applications for the p r e o p e r a t o r y diagnostic of the pheochromocytome are stated in taking for basis the observation of 27 cases. 20 % of the tumours have been found outside the surrenal region. A false diagnostic of localization has been observed in two cases. In one case only, it has not been possible to set forth the evidence of the suspected tumour during the operatory exploration. in more than 90 % of cases the surgical exploration has confirmed the p r e s e n c e of the tumour specially with regard to the side and the height of the localization. It has been possible to point out in two patients that cavography is able to give p r e c i s e indications about the topography of the tumour w h i c h is visible on the radiologic plates. T h e e r r o r s of interpretation in determining the c a t e c h o l a m i n e s may be in c o n n e x i o n with a venous anomaly or a stase (slackening of the circulation) of the spermatic vein. T h e aortographic exploration is counter indicated from the fact that it risks to b r i n g over an hypertensive complication. T h e operation must be effected only after having normalised the sanguine volume. It is observed during the operation that the sanguine pression gets its normal valours anew immediately after the tumour has been extirpated, otherwise it is right to p r e s c r i b e a multiple localization. It is necessary to explore the whole retroperitoneal lodge throng a trahsthoraco-retro-abdominal access. In the case of a bilateral localization, the surgical operation must not be practised on the two sides during the same intervention. RIASSUNTO La diagnosi di f e o c r o m o c i t o m a rappresenta un problema b i o c h i m i c o . La localizzazione del tumore può essere determinata in modo quasi sicuro attraverso la determinazione del tasso delle catecolamine nel sangue venoso della vena cava che è giunta a diversi livelli. La t e c n i c a del cateterismo della vena cava così come le sue p r a t i c h e applicazioni per la diagnosi pre-operatoria del feocromocitoma sono qui esposte basandosi sull'esperienza di 27 casi. 20 % dei tumori si trovano al di fuori della regione Una falsa localizzazione è stata osservata in due casi. surrenalica. In un sol caso il sospettato tumore non si è potuto mettere in evidenza durante l'esplorazione operatoria. In più del 90 % dei casi l'esplorazione chirurgica ha confermato la presenza del tumore specie per ciò che riguarda la localizzazione del lato e dell'altezza. Si è potuto dimostrare che la cavografia è capace di fornire indicazioni ìrecise sulla topografìa del tumore che risulta visibile sulle radiografìe. Gli errori di interpretazione nella determinazione delle catecolamine possono dipendere da una anomalia venosa o da una stasi della vena spermatica. L'uso della ortografìa è controindicata per la facilità che essa determini una crisi ipertensiva. L'intervento non deve essere eseguito se non dopo aver normalizzato il volume sanguigno. Durante l'operazione si osserva che la pressione sanguigna riprende il suo valore normale subito dopo asportato il tumore : se ciò non avviene bisogna pensare ad una localizzazione multipla. E' necessario esplorare tutta la loggia retroperitoneale attraverso una via trans-toraco-addominale. Nel caso di localizzazioni bilaterali, l'esplorazione non deve essere fatta dai due lati nella stessa seduta operatoria. RESUMEN El diagnostico del feocromocitoma representa un problema bioquímico. La localización del tumor puede determinarse de una forma casi cierta por una determinación del total de las catécolaminas en la sangre venosa de la vena cava puncionadas en diversas alturas. Se expone la técnica del cateterismo de la vena cava así como sus aplicaciones practicas para el diagnostico preoperatorio de feocromocitoma basandose en la observación de 27 casos. El 20 % de los tumores se encuentran fuera de la región suprarrenal. Se observó un falso diagnostico de localización en dos casos. En un solo caso, el tumor sospechado no ha podido ser puesto en evidencia en el curso de la exploración operatoria. En más del 90 % de los casos, la exploración quirúrgica confirmó la presencia de un tumor especialmente en lo concerniente a la localización de lado y altura. Se ha podido démostrar en dos enfermos que la cavografia puede darnos las condiciones exactas en lo que concierne la topografía del tumor que es visible en los clichés radiologicos. Los errores de interpretación en la determinación de las catécolaminas pueden estar relacionadas con una anomalía venosa o estasis de la vena espermatica. La exploración por aortografia esta contraindicada por e) hecho de que puede provocar complicaciones hipertensivas. La operación no debe llevarse a cabo hasta haber normalizado el volumen sanguíneo. Se observa durante la operación que la presión sanguínea alcanza sus valores normales immediatemente después de la extirpación del tumor, de no ser así conviene sospechar una localización múltiple. Es necesario explorar toda la cavidad retroperitoneal. mediante un abordaje transtoraco-retroabdominal. En el caso de una localización bilateral, la exploración quirúrgica no debe hacerse de los dos lados durante la misma sesión operatoria. DISORDERS OF THE A D R E N A L CORTEX THEIR M E D I C A L A N D SURGICAL M A N A G E M E N T by J. HARTWELL HARRISON, M.D., M.A., F.A.C.S. Elliott Carr Cutler Professor of Surgery Harvard Medical School and DALTON JENKINS, M. D. Professor of Medicine University of Colorado School of Medicine HISTORICAL EVENTS WITH RELATION TO THE ADRENALS The first clinical intimation of the function of the adrenal glands occurred in 1855 when Thomas Addison (1) gave his brilliant description of the condition which bears his name. He correlated the findings at autopsy of destruction of the adrenal glands by tuberculosis with symptoms of severe wasting, fatigue, and pigmentation noted during life. In 1894 Oliver and Schafer (2) demonstrated the pressor effect of adrenal medullary extract by showing its ability to raise the blood pressure and pulse of a cat. Cannon (3) in 1914 discovered the close relationship of the action of the thoracolumbar autonomic nervous system to that of adrenal medullary extract and found that adrenin-like substances were secreted at the nerve endings. Holmes (4) described the first removal of an adrenal tumor by Thornton in 1899. This tumor weighed 20 pounds, recurrence did not occur, the patient's state of virilism reverted to normal and she continued in good health thereafter. Holmes' description of this tumor showed that it was derived from the adrenal cortex by histologic criteria. Identification of epinephrine and later norepinephrine as products of the adrenal medulla and the sympathetic ganglion constituted a most important discovery. Cushing (5) in 1913 and in 1932 (6) described the syndrome which now bears his name and attributed the pathologic physiology to a basophilic adenoma of the anterior pituitary. His work has great importance in relation to both primary and secondary operations of the adrenal glands. Charles Mayo (7) in 1927 removed the first pheochromocytoma, and Shipley and Pincoffs (8) in 1929 made the first preoperative diagnosis of pheochromocytoma. Crile (9) manifested an intensive interest in the comparative anatomy and physiology of the adrenal glands as well as the relation of these organs to hypertension in human beings. Young (10) in 1938 summarized the literature available at that time on surgery of th? adrenal cortex, summarizing the results of surgical intervention in 33 adults and 31 children having tumors of the adrenal cortex. Thorn (11) in 1940 showed the efficacy of desoxycorticosterone acetate in the treatment of patients having Addison's Disease. Reichstein (12) at Basle and Kendall (13) at the Mayo Clinic in 1938 simultaneously isolated, identified and synthesized cortisone acetate. It remained however for Hench (14) at the Mayo Clinic in 1949 to illustrate the physiologic benefits of this substance in the treatment of rheumatoid arthritis and for Thorn (15) subsequently in 1950 to show that cortisone acetate and desoxycorticosterone acetate furnished substitution therapy adequate for survival and normal existence after bilateral total adrenalectomy in human beings. Charles Huggins (10) in 1944 carried out the first bilateral total adrenalectomy in man and temporary survival was accomplished with Thorn's assistance by means of adrenocortical extract and desoxycorticosterone acetate. Li and Evans (17) working with Armour Laboratories isolated adrenocorticotrophic hormone from beef pituitary. In 1947 Goldenberg, Snyder and Aranow (18) published their work with benzodioxane showing its transitory effect in producing a fall in blood pressure in patients having sustained hypertension due to pheochromocytoma. In 1952 Gifford, Roth and Kvale (19) described the similar effects of phentolamine and elaborated the importance of this substance in differentiating hypertension due to pheochromocytoma. In 1953 Simpson-Tait, Wettstein, Neher, von Euler and Reichstein (20) accomplished the isolation and crystallization of aldosterone. In 1954 Jerome Conn (21) at the University of Michigan described the clinical condition of hyperaldosteronism and emphasized the significance clinically of alkalosis and hypokalemia in patients having hypertension as suggesting the possibility of the presence of this condition. It is now 18 years since the first bilateral total adrenalectomy was performed at the Pete.Bent Brigham Hospital and the patient treated successfully with prolonged survival because of cortisone acetate and desoxycorticosterone acetate therapy (22). Since then the indications for total and subtotal adrenalectomy have been clearly defined (23). HYPERADRENOCORTICISM DUE TO HYPERPLASIA AND NEOPLASMS OF THE ADRENAL CORTEX The adrenal glands have attained a growing importance in the practice of urology due to the anatomic location in the natural domain of the urologic surgeon, the availability of adequate adrenocortical substitution therapy, increased knowledge of the patho-physiology of adrenal disorders, greater appreciation of the effect of adrenocortical disorders on sexual differentiation and new insight into renal-adrenal interrelations in the regulation of blood pressure and blood volume. Surgical Anatomy: For a detailed review of the surgical anatomy of the adrenals the reader is referred to Campbell's Urology (24), Chapter 09, Volume 3. Hormone Secretion of the Adrenal Cortex: Although more than 40 steroids have been isolated from the adrenal cortex only a few are actively secreted. The major secretory product in man having glucocorticoid action is Cortisol. Corticosterone has been isolated but only in small amounts. Aldosterone is the major mineral corticoid. Quantitatively dehydroepiandrosterone sulfate is the main androgen. Smaller amounts of 11 beta hydroxy-A-5 androstenedione and dehydroepiandrosterone are also secreted. While compounds having estrogenic and progestational activity may be released in minute amounts by normal adrenals the contribution is so small that they are not ordinarily classified as adrenal cortical hormones. In certain abnormalities of biosynthesis those steroids may be secreted in relatively large amounts to cause hormonal disturbances. This is certainly the case in the rare instances of feminizing tumors of the adrenal cortex. Steroid Metabolism: The major circulating glucocorticoid is Cortisol. According to Daughaday (25) most of the circulating Cortisol is bound to a specific alpha globulin, transcortin or corticosteroid binding globulin (CBG). The bound Cortisol is in reversible equilibrium with a small part in presolution and in all likelihood it is the latter fraction which is directly involved in the biologic actions of the hormone. When the binding sites of CBG become saturated at plasma Cortisol levels of 20-27 micrograms per 100 millileters the quantity present in free solution rises significantly. One effect of protein binding is to reduce the glomerular filtration of Cortisol in contrast to the hormonally inactive metabolites of Cortisol conjugated mainly as water soluble glucoronides are not protein bound and are excreted much more efficiently by the kidneys. The half life of free Cortisol in plasma is 60 to 100 minutes, this relatively rapid rate of removal is accomplished by the liver. Cortisol and cortisone are interchangeable via reversible reduction oxydation at Gil. The production of cortisone produces tetrahydrocortisone and cortilone. In adults the average daily urinary excretion of these metabolites is tetrahydrocortisone 5 mgms; tetrahydrocortisol 3 mgms; cortol plus cortilones 3 mgms; and 11 hydroxylated 17-ketosteroids 1-2 mgms. Only a very small fraction of Cortisol is excreted unchanged into the urine; 20-125 micrograms per day. The metabolic turnover of aldosterone is more rapid, possibly because it is only weakly bound to protein. Aldosterone undergoes reduction to tetrahydro derivatives in conjunction with glucuronic acid. However, a small fraction appears in the urine probably as a glucuronide conjugated at C-18 which is usually estimated in the clinical laboratory and on the average amounts to 5-15 micrograms per day. Dehvdroepiandrosterone and A-5 androstenedione are reduced to androsterone and etiocholanalone. These 17-ketosteroids are also conjugated at the C-3 position in the liver and excreted in the urine as sulfates or glucuronides. Testosterone is the most important androgen in man and its output primarily reflects testicular activity and serves as an excellent index of Leydig cell function. However, in some adrenal disorders overt virilization occurs reflecting potent androgen activity and recent studies indicate that the adrenal androgen is testosterone. It appears that much of the testosterone originates from peripheral (probably hepatic) metabolism of normal adrenal cortical products to testosterone rather than from adrenal secretion of testosterone (Camacho and Migeon, 1966) (26). Just as the placenta may utilize the adrenal dehvdroepiandrosterone derivatives to produce estrogen, the liver can also utilize adrenal androgens to produce testosterone. It has been shown that dehvdroepiandrosterone and its sulfate can be converted by the liver to testosterone but only in minute amounts. Present evidence indicates that A-5 androstenedione is the main peripheral precursor (Korenman and Lipsett, 1964) (27), forming both testosterone glucuronide and testosterone, some of which reenters the circulation as active hormone. In normal females as much as 50 % of the small amount of circulating testosterone may be derived from androstenedione of adrenal and ovarian origin (Tsit and Horton, 1965) (28). Functions of the Adrenal Cortex: The cortical hormones influence the function of all body cells in both inorganic and organic metabolism. The inorganic functions comprise sodium retention and an increased excretion of potassium and hydrogen ions. Steroids controlling these functions have been called mineralocorticoids. The organic functions related to the control of carbohydrate, fat and protein metabolism are controlled by glucocorticoids. The distinction between mineralocorticoids and glucocorticoids is by no means complete because Cortisol has a significant effect on electrolyte metabolism in addition to its other actions. Other hormones exhibit their full actions only in the presence of small amounts of glucocorticoids such as fat mobilization by epinephrine or vasoconstriction by norepinephrine requiring the presence of small amounts of Cortisol for these actions to take place. Inorganic Metabolism: The absence of the adrenal cortex results in sodium chloride and water loss leading to hyponatremia, dehydration, a reduction of plasma volume, hypotension and, in extreme cases, vascular shock. In addition, the excretion of potassium may be inadequate to prevent the accumulation of circulating as well as tissue potassium. Excessive secretion may result in lowered blood and tissue levels of potassium which can be severe enough to produce characteristic abnormalities of neuromuscular and cardiac function. Hypokalemia may be accompanied by hypochloremia and an elevated level of plasma C02. Regulation of electrolyte secretion is influenced predominantly by aldosterone acting on the ion exchange mechanism of the distal renal tubules. Organic Metabolism: Adrenal cortical failure causes inability to maintain normal blood sugar concentration during fasting. The defect results primarily from a decrease in hepatic glocuneogenesis normally regulated by Cortisol. Aldosterone is largely devoid of this action at physiologic levels. An excess of Cortisol produces hyperglycemia and glycosuria (steroid diabetes in some patients). Regulation of gluconeogenesis depends primarily on the influence of Cortisol on the balance between synthesis and degradation of proteins: Synthesis from aminoacid precursors is diminished and it is probable that the breakdown of cellular proteins is accelerated. The aminoacid residues are deaminized in the liver with the resultant decrease in the production of urea and in the formation of liver glycogens. The net result is a deviation of body proteins to available carbohydrates. Cellular Effects: With excessive levels of Cortisol the changes in protein metabolism impair body growth, interfere with the formation of osteoid tissue resulting in osteoporosis and interfere with wound healin. Muscular strength simultaneously is diminished. Cortisol overdosage produces neutrophilic leucocytosis, eosinopenia, lymphopenia and reduction in fixed lymphoid tissue. The structure of all connective tissue elements including reticular cells, fibrils and gland substance may be affected. The reactivity of mesenchymal tissues to irritants, foreign protein and bacteria is impaired. As a result of these deleterious effects the ability to withstand injury and particularly infection may be seriously deranged. Large doses of Cortisol reduce the production of anibodies presumably by the lysis of fixed plasma cells and lymphocytes. Cortisol increases gastric acidity and pepsin production. Psychiatric disturbances may occur when it is given in excess. The production of angiotensinogen is enhanced by Cortisol leading to higher levels of angiotensin, an extremely potent vasoconstrictor and stimulator of aldosterone production. In addition cor- tisol sensitizes the arterioles to the pressor effects of norepinephrine. Primary adrenal failure is associated with increased deposition of melanin in the skin. The increased pigmentation is due to elevated plasma levels of ACTH. One portion of the corticotropin molecule is identical in structure with the melanocyte stimulating hormone. Sexual Effects: The adrenal cortex secretes steroids which are weakly androgenic normally. The growth of axillary hair and public hair in females appears to be partially controlled by adrenal androgens. It is probably that in females the adrenal androgens provide a weak anabolic effect enhancing protein synthesis from amino amino acids. However, with hyperplasia of the zona reticularis or tumors involving this segment of the cortex excessive hair growth, oligomenorrhea, amenorrhea and greatly increased muscularity will occur from the increased production of potent androgen by the lesion of the adrenal cortex. Extensive studies have showed that the adrenal cortex plays a significant role in the normal response to major stress (Selye 1947) (29). The importance of an adequate adrenal response to changes in the external environment and to changes in the external environment and to dislocations of the internal milieu is best demonstrated by the marked vulnerability of tlie patients with adrenocortical insufficiency to stress of all types. Eng'le has showed that a normal circulating level of Cortisol may be adequate to resist brief stresses of moderate intensity. However, with prolonged or severe insults the pituitary-adrenal cortical system is activated, primarily as a result of neuro hormonal stimuli involving the hypothalamus with resultant acceleration of Cortisol production. It has been repeatedly demonstrated that major surgical procedures constitute a serious stress eliciting a marked increase in adrenocortical secretion. Therefore it is evident: a. Activation of the pituitary adrenal cortical system is requisite to the safe conduct of major surgery; b. Patients with adrenocortical insufficiency cannot be safely subjected to surgical procedures unless adequate quantities of Cortisol are administered; c. Surgery directed toward the removal of the adrenal glands can only be safely performed when cortical steroid substitution therapy is available; d. The resection of functioning adrenocortical tumors and the performance of either subtotal or total adrenalectomy require preoperative coticosteroid preparation and postoperative hormonal maintenance. Control of Adrenocortical Function: Growth and maintenance of normal adrenocortical structure are controlled by corticotrophin from the anterior pituitary gland as demonstrated by the influence of ACTH on tlie incorporation of C14 acetate into adrenal proteins. Corticotrophin regulates the sj'nthesis and secretion of Cortisol and the adrenocortical sex steroids. This hormone alphcorticotropliin has been isolated and is a polypeptide with 39 amino acids and a molecular weight of 4,540. Human corticotrophin has been purifed and is almost identical with ACTH from animal sources (Li et al 1959) (30). Certain basophilic cells in the anterior pituitary gland appear to be the source of corticotrophine since tluorsine labeled antibodies to corticotrophine are found by these cells. Schally (31) (1964) and others have extracted from hypothalamic tissue corticotrophine releasing factors which augment ACTH secretion by the pituitary gland. Since the hypothalamus has long been regarded as the head ganglion of the autonomic nervous system it is probable that the emergency stress responses of both the adrenal medulla and the adrenal cortex are regulated and correlated by the hypothalamus. Ganong (32) has showed that Cortisol has an important role in regulating the rate of corticotrophic secretion, probably through its effects on the hypothalamic production c.r.f. A fall in plasma Cortisol leads to a rise in corticotrophin output and conversely a rise in Cortisol inhibits corticotropin secretion. This servomechanism maintains the level of plasma Cortisol within stable limits. Protracted administration of Cortisol may so effectively inhibit hypothalmic pituitary function that adrenocortical atrophy ensues. This has been observed in patients with carcinoma of the prostate and carcinoma of the breast treated with steroids. Several mechanisms have been recognized in the control of aldosterone output: a. Corticotrophin does increase aldosterone secretion but the effect is far less than that on Cortisol output and is not sustained so that the secretion rate returns to previous levels despite continued corticotrophin administration. b. An elevated serum potassium level appears to lead directly to increased aldosterone secretion. c. The primary mechanisms for control of aldosterone production appears to reside in a feed back system involving the kidney rather than the hypothalamic pituitary system. The sensor apparatus resides in the juxtaglomerular apparatus and decreased renal blood flow causes an increased release of renin which acts on the circulating globulin to produce angiotensin I and the latter is converted into angiotensin II by a specific plasma enzyme. Angiotensin 11 is a stimulator of the zona glomerulosa of the adrenal cortex resulting in increase of aldosterone output. The common stimuli of increased aldosterone secretion are sodium restriction, reduction in intravascular volume, hemorrhage and dehydration. Laboratory evaluation of adrenocortical function: For years measurement of the urinary 17-ketosteroids was a major method for evaluating adrenocortical activity and was viewed as the index of adrenal androgen secretion. Although the procedure does reflect the output of steroids with androgenic activity the implied correlation with androgenicitv is often lacking because testosterone is the most potent androgen and is not a 17-ketosteroid while etiocholanolone is one the major 17-ketosteroids and has very weak androgenic activity. The measurement of the urinary 17-ketosteroids does provide a reliable index of adrenocortical secretion of Cortisol. Normal range for adult males is 7-20 mgms. per 24 hours and for females 5-15 mgms. per 24 hours. Over the age of 40 the excretion gradually declines. One-third of the urinary 17-ketosteroids in males arises in the testis.. The urinary 17-ketosteroids often fail to provide a good index for adrenal function and hyperadrenocorticism. In Cushing's Syndrome normal levels are found in many patients with adrenocortical hyperplasia or adrenal adenoma but high values usually accompany adrenal carcinoma. In adrenal tumors producing virilizing effects urinary 17-ketosteroids are significantly elevated. Urinary 17-hydroxycorticoids are measured by the Porter-Silber (33) technique and measure chiefly tetrahydrocortisone and tetrahydrocortisol. While the excretion of urinary 17-hvdroxycorticoids does not always reflect the plasma Cortisol level the correlation in most circumstances is excellent and affords a reasonably good guide to adrenocortical activity. Patients with hyperadrenocorticism leading to increased Cortisol secretion show in most instances elevated urinary 17-hydroxyc.or- ticoids. These patients may also show an increase in urinary corticoid levels but plasma Cortisol values are often normal which reflects an increased rate of Cortisol catabolism. Normal values for excretion of 17-hvdroxycorticoids in adult males are 4-12 mgms. per day and in the female 2-10 mgms. per day. Many prefer Norimbursky's technique for measuring a larger fraction of urinary Cortisol metabolites known as the urinary 17-ketogenic steroids. Normal values are higher. Adult males excrete 8-22 mgms. per day and ad It females 5-18 mgms. per day. The urinary 17-ketogenic steroids are said to show a high correlation with actual Cortisol secretion rates than to Porter-Silber chromagens. The plasma Cortisol level is an important index of adrenocortical activity and measures the 17-hydroxycorticoid steroids of the plasma. Approximately 85 % of the material in human plasma reacts with phenylhydrazine in sulphuric acid as Cortisol. In normal subjects the normal concentration ranges from 5-20 micrograms per 100 milliliters. Plasma Cortisol shows diurnal fluctuations, the highest values being found at (i-9 A.M. with a slow decline thereafter to a minimum between midnight and 2 A.M. Alteration in the diurnal pattern may be important in interpreting the physiologic significance of plasma hormone levels. It is clear that the concentration of plasma Cortisol does not always reflect the rate of secretion by the adrenal cortex. A normal plasma level in the presence of a decreased rate of disposal suggests decreased secretion of steroid while a normal level and the presence of an increased rate of degradation suggests increased secretion. In order to resolve such uncertainties isotopic Cortisol can be utilized to obtain a more quantitative measure of adrenal cortical secretion (Peterson 1959) (34), (Tait 1963) (35). Cortisol production rate in normal adults is 16±6 mgms. per 24/hrs. Isotopic methods of estimating actual production rates of steroids are very informative and specific diagnostic techniques. Aldosterone: Plasma levels of aldosterone are so low as to he of limited practical value. Urinary aldosterone determinations are presently used and constitute the three oxometabolites which are measured. This represents about 10 <7c of the aldosterone secreted daily. Normal values range from 5-20 micrograms per day. Accuracy in the measurement of this small moiety has been greatly enhanced by using the double isotope derivative dilution technique of Kliman and Peterson (36) (1960). It is important to remember that sodium depletion stimulates an increased secretion of aldosterone and thus evaluation requires circumstances with a normal salt intake. Testosterone: The most potent natural occuring androgen is testosterone from the testis. However, in certain virilizing disorders significant quantities of this hormone or its immediate precursors which can be converted to testosterone in the liver are secreted from the adrenal. Methods involving gas liquid chromatography (l)orfman and Shipley) (37) or double isotope derivative dilution (Riondel et al. 1963) (38) are available for the measurement of testosterone in plasma or urine. The plasma concentration appears to be the most useful method because urinary values may be deceptive because of the conversion of steroids to urinary conjugates of testosterone. Plasma testosterone in the normal adult male ranges from .3-1 microgram per 100 milliliters. Urinary values for testosterone glucuronide vary with the methodology employed but most authors have found 30-150 micrograms per 24 hours in adult males and only 4-15 -micrograms per 24 hours in normal females. Adrenal cortical stimulation: T h e response to corticotrophin is a specific test of adrenocortical reserve function. ACTH is given intravenously 20-40 USP units of lyophilized hormone in a 6-8 hour infusion. It may be given intramuscularly 60-80 units of ACTH Gel. Normal subjects show the following responses to an 8 hour infusion of ACTH: Urinary 17-ketogenic steroids increased to a level of 30-55 mgms. per 24 hours, 17-liydroxycorticosteroids rise to 15-30 micrograms per 100 ml. A rapid screening test can be done using plasma Cortisol values before and after a 1-2 hour infusion of ACTH: The values rise to 30-40 micrograms per 100 ml. Adrenocortical suppression: Elevated levels of plasma Cortisol suppressed pituitary secretion of corticotrophin and adrenocortical function falls to a low level. T h e administration of very potent synthetic glucocorticoids inhibits adrenal activity but will not contribute significantly to the results of corticosteroid measurement. Dexamethazone is usually used since its ACTH suppressing activity is approximately 30 times that of Cortisol. The dosage is .5 mgm. orally every 6 hours for 2-3 days. Normally the urinary 17-ketogenic. steroids decline to less than 6 mgms. per 24 hours, the 17-hydroxycorticoids fall below 3 mgms. for 24 hours and plasma Cortisol to a level under 5 micrograms per 100 ml. A more rapid procedure consists of 1 mgm. of dexamethazone given orally at midnight, plasma Cortisol is drawn the following morning and is normally less than 10 micrograms per 100 ml and usually less than 3 micrograms per 100 ml. F r o m the foregoing facts an understanding of the underlying biochemistry in hyperplasia, adenoma and carcinoma of the adrenal cortex is greatly increased. By means of the foregoing laboratory measurements differentiation of these conditions in the clinic is accomplished. Hyperadrenocorticism is a state of increased adrenocortical hyperfunction w h i c h may be caused by hyperplasia, adenoma or carcinoma. A variety of clinical syndromes may result from each of these lesions. * * * Hyperadrenocorticism or Increased Adrenal Cortical Hyperfunction: The adrenal cortex secretes Cortisol, aldosterone and other cortico steroids, androgens, estrogens and progesterone. In different clinical disorders the gland may secrete an excess of one or more of these compounds. A variety of clinical syndromes may occur as a result of different lesions such as bilateral cortical hyperplasia, benign tumor or malignant tumor. ** * CUSHING'S SYNDROME: Cushing's Syndrome properly defined refers to the clinical picture described in 1932 by Harvey Cushing. The disease is comparatively rare, occurs mostly in young adults and is 3-5 times more common in females than males. T h e clinical features of this syndrome reflect the metabolic phenomena resulting from excessive levels of Cortisol. Pathogenesis: In 75 % of patients having Cushing's Syndrome no adrenal neoplasma is present but hyperfunction of the adrenal cortex occurs as a result of hyperplasia. Cushing postulated that in these cases the disorder rose from a pituitary basophilic adenoma. At the same time he recognized the fact that adrenal tumors could cause the identical clinical picture and stated that when the same features characterized the syndrome of basophile adenoma tliey in all probability are secondarily ascribable to a hypersecretory influence of the adrenal cortex even in the absence of any histologically appreciable abnormality. Subsequent studies failed to confirm the pituitary basophilic tumors as the important cause of the disease and opinion swung so the view that the adrenocortical hyperplasia could be primary. However, it is now clear that the anterior pituitary gland is indeed importantly involved. There are cases of basophilic pituitary adenomas found but more often a chromophobe tumor is encountered leading to the suggestion that the apparent chromophobe cells are very actively secreting cells of chromophilic origin. In 25 % of cases an adrenocortical neoplasm is found. Somewhat more than one half of these tumors are benign. Benign tumors may or may not be independent of corticotrophic control. Malignant tumors are usually autonomous. Rarely an adrenal rest tumor arises in ectopic adrenocortical tissue, most commonly located in the perinephric area but also found near the celiac axis, ovaries, testis, or elsewhere. When an adrenal tumor is the primary source of excess Cortisol, pituitary ACTH output is suppressed and non-tumorous adrenal tissue is atrophic. In 1967 Liddle (39) has showed direct and indirect evidence that the majority of patients with Cushing's Syndrome due to adrenocortical hyperplasia had increased secretion of ACTH. In most cases plasma corticotropin levels are moderately elevated, in others the concentration is in the upper normal range. Patients with Cushing's disease do not show a normal decline in plasma c o r t i c o t r o p i n late in the day, explaining a lack of diurnal variation in plasma Cortisol excretion. It would appear to be an increased pituitary production of ACTH that leads to adrenocortical hyperplasia and increased secretion of Cortisol in hyperadrenocorticism. It has been shown that reduction in Cortisol output by adrenalectomy results in further elevation of ACTH while the administration of additional Cortisol produces a fall in plasma ACTH. Therefore it has been suggested that the primary defect in Cushing's disease may reside in the hypothalamus whereby the center controlling corticotrophin releasing factor is reset so that higher than normal levels of plasma Cortisol are required to inhibit CRF output. Para endocrine tumors such as oat-cell bronchogenic carcinoma, carcinoma of the liver, carcinoma of the prostate, carcinoma of the breast may be responsible for hyperadrenocorticism simulating Cushing's Syndrome. These patients have elevated plasma levels of a material which is biologically, chemically and immunologically indistinguishable from ACTH. The source of this substance is the malignant tumor; pituitary corticotrophin is suppressed. The adrenal lesion is adrenocortical hyperplasia. Signs and Symptoms: Cusliing described the syndrome including a truncal type of obesity, amenorrhea in females or impotence in males, hypertrichosis in females, purplish cutaneous striae, plethora, hypertension, muscular weakness, a buffalo hump due to cervical kyphosis osteoporosis, glycosuria, erythemia, edema, proteinuria and a marked susceptibility to infection. The obesity produces classic moon fascies and prominent fat deposits in the dorso-cervical,, supraclavicular and subscapular areas. Suppression of gonadal function is common and hirsutism occurs in many females but true virilization is unusual. Hypertension is frequently present and sometimes persists in long standing cases despite cure of other signs and symptoms. The effects of excess Cortisol produces muscle weakness, osteoporosis with decalcification of the bones, easy bruisability and ecchymoses. Purplish striae are found in about 2/3 of the patients. Mental disturbances ranging from emotional lability to major psychoses usually of a depressive or paranoid type appear frequently. Laboratory Findings: Circulating eosinophils are below 100 cells per cu. ml in 90 % of patients and moderate neutrophilic leucocytosis is often found. The hematocrit is usually within normal range but mild elevation is occasionally present particularly in those patients producing excessive androgens. Hypokalemia sometimes accompanied by hypochloremia and metabolic alkalosis is usually restricted to those with severe disease. Three fourths of the patients exhibit intermittent glycosuria but overt diabetes occurs in a much smaller number. There is an increased incidence of nephrolithiasis as a result of the enhanced urinary calcium excretion secondary to progressive osteporosis. Occasionally hyperuricemia and uric acid calculi are found. Osteoporosis is most marked in the spine and pelvis but in severe long standing cases even the skull may be involved and fractures of vertebrae, ribs and pelvis caii occur from mild trauma. Diagnosis: The diagnosis of Cushing's Syndrome may be confirmed bv measurement of an increase in adrenocortical production of Cortisol. It is desirable to obtain information concerning the underlying lesionbilateral adrenocortical hyperplasia or neoplasia. Direct measurement of Cortisol by isotope dilution of Cortisol production rate is preferably accomplished with urinary metabolite method. The value exceeds 30 rag. per day in most patients with Cushing's syndrome. The chromatographic isolation of free Cortisol in urine and quantitation by the PorterSilber procedure gives values in excess of 150 rag. per day. Measurement of the 24 hour excretion of 17-ketogenic steroids or 17-hydroxycorticoids shows levels are increased in the majority of patients but in mild cases borderline or normal results may be encountered. Plasma Cortisol concentrations are usually elevated but in some patients are only in the upper range of normal. The best evidence in favor of the diagnosis comes from a demonstration that the feedback control of adrenocortical function is abnormal: a. The diurnal variation of plasma Cortisol levels is lost so that morning and evening values fall within the same range b. A single oral dose of dexamethasone (1.0 nig.) given at midnight, fails to elicit the normal degree of pituitarv-adrenocortical suppression; plasma Cortisol measured the following morning is above 10 micrograms per 100 ml and often above 20 micrograms per 100 ml. c. While Cortisol production is regularly suppressed in normal subjects given small doses of dexamethasone (0.5 nigra, every 6 hours for 48 hours) little or no suppression occurs in patients with Cushing's syndrome (Liddle et al, I960) (40). A normal response is a decrease of urinary 17-hydroxycorticoids to less than 3 mgms. per day or of urinary 17-ketogenic steroids to less than 6 mgms. per day, demonstrating that the hypokalemic tiuitary system responds appropriately to an increase in plasma glucocorticoid levels. Lack of suprression in patients with adrenal hyperplasia appears to indicate that the hypothalamic pituitary axis is reset to a higher threshold. Determination of the type of causative adrenal lesion is accomplished by pharmacologic tests: a. pituitary adrenal suppression with dexamethasone. b. adrenocortical stimulation by ACTH and c. pituitary activation by metyrapone. Suppression of urinary corticoid excretion values to less than half the baseline can be demonstrated in patients with adrenal hyperplasia. Patients with adrenal neoplasms either benign or malignant ordinarily fail to show a significant fall of plasma or urinary steroids even with large doses of dexamethasone. Patients with adrenocortical hyperplasia usually demonstrate increased reactivity to exogenous adrenocorticotrophic hormone. Following a standard 8-hour intravenous infusion of corticotrophin a hyperactive response is evidenced by an excessive rise in plasma Cortisol and urinary 17-hydroxycorticosteroids or 17-ketogenic steroids. The response of benign adenomas is variable. Adrenal carcinoma is usually resistant to stimulation reflecting the autonomy of the tumor tissue and atrophy of the contralateral gland 'Laidlaw 1955) (41). Patients with adrenal hyperplasia demonstrate a hyperactive response to metyrapone reflected by an excessive rise in urinary 17-hydroxycorticoids or 17-ketogenic steroids. In contrast patients with benign or malignant adrenocortical tumors show a failure of the urinary steroids to rise because after the administration of metyrapone corticotrophin is not released in the normal manner. Very high levels of urinary corticosteroids and 17-ketosteroids suggest the presence of an adrenocortical tumor. Gross increase in dehvdroepiandrosterone occurs in most of these cases. In the case of nonendocrine tumors producing corticotropin or ACTH like peptides baseline plasma Cortisol and urinary steroid values are often markedly elevated. These are difficult to differentiate from hyperplasia of the adrenal cortex. These patients usually exhibit responsiveness to ACTH unless endogenous ACTH secretion by the tumor approaches the level at which maximal adrenocortical activation occurs but no suppression with dexamethasone, even in high dosage levels. No increase in urinary corticosteroids follows metyrapone administration. Plasma ACTH levels are also significantly elevated. The major difficulty in differential diagnosis arises in patients with obesity, hypertension and diabetes mellitus, especially in females with these disorders accompanied by hirsutism. Extreme obesity is uncommon in Cushing's syndrome and in exogenous obesity the distribution of excess fat is generalized and not truncal. The baseline urinary steroid values in exogenous obesity are oftent moderately elevated but the diurnal variation is intact. Very obese patients may show a hyperactive response to ACTH but dexamethasone suppression occurs normally. Patients with chronic active hepatic disease or carcinoma of the liver may exhibit clinical changes reminiscent of Cushing's syndrome probably because of an impaired ability to metabolize Cortisol. Plasma Cortisol secretion rates are within the normal range. Hyperpigmentation in patients with Cushing's syndrome points tc an extra adrenal neoplasm producing excessive quantities of corticotropin. The responsible lesion may be a pituitary tumor most commonly a chromophobe adenoma. The sella turcica may be enlarged depending upon the size of the lesion. In some cases these tumors have actually been invasive producing severe headaches and visual disturbances including ophthalmoplegia. Hyperpigmentation occurs in paraendocrine lesions producing corticotropin-like polypeptides. These tumors may be bronchogenic in origin, the adrenal medulla, thymus, pancreas, liver, ovary, thyroid, parotid gland, prostate and other organs also have been involved. Obesity is usually absent in these patients and hypokalemic alkalosis is often severe. Techniques for Visualization of the Adrenal Glands: Radiologic evidence of adrenal tumors should be sought initially on the plain film of the avdomen followed by excretory urography. A greatly increased yield will be obtained by combining excretory urography with tomography or laminography. The insufflation of air or gas with tomography is no longer necessary. In fact, evidence now points to the fact that erroneous conclusions have been drawn more often from pneumograms than not. Fifty-eight deaths due to gas embolism have been reported, thirty-four from perinephric injection and twenty-four from presacral injection. All the deaths have occurred with air, oxygen or helium whereas none have occurred with carbon dioxide or nitrous oxide because of the latters high solubility. Adrenal angiography, both arterial and venous, have added the most active radiologic visualization of the adrenal glands and have furnished the most accurate visual differentiation of hyperplasia, adenoma and carcinoma. The refined selective characterization of the arteries and veins of the adrenal gland have furnished not only more accurate visualization but also the possibility of carrying out biochemical measurements of steroids in the venous effluent. Great care must be taken during venography because of the fragility of the gland and the possibility of hemorrhage and rupture. Increasing experience is being obtained by the radiologist in the characterization of the vessels of both the kidney and the adrenal. The biochemical measurements of the venous effluent are becoming increasingly accurate and add immeasurably to the radiographic visualization attained simultaneously. Preoperative utilization of these studies are being increasingly used with good results. Surgical exploration constitutes the final diagnostic procedure. It permits the direct visualization of a tumor, of aberrant adrenal lesions and the differentiation of hyperplasia and tumor is easily made at the operating table with confirmation of the preoperative biochemical and pharmacologic studies. Unless the surgeon has had extensive experience with adrenocortical lesions in his training he should not undertake the exploration of these cases. However, such training is not always available and the necessity for exploration by the inexperienced should be preceded with all of the preoperative diagnostic parameters which have been outlined. The recognition of adrenocortical hyperplasia may be difficult at the operating table but knowledge regarding the preoperative tests will always reinforce the operative findings and serve as a guide to the surgical decisions. Repeatedly we have had to reoperate patients who had previously been operated and adrenal glands found without tumor and no tissue had been removed. Perpetuation of hyperadrenocorticism had existed and demanded the reoperation with bilateral total adrenalectomy. On the other hand we have seen patients who have had bilateral total adrenalectomy when their primary lesion was either an ovarian tumor or the Stein-Leventhal polycystic ovary lesion. Preoperative decisions concerning treatment should be based on a specific diagnosis established on the basis of studies of pituitary adrenocortical function. At times it is impossible to differentiate between adenoma and hyperplasia preoperatively and exploration is the final step. In mild cases without enlargement of the sella turcica and no radiologic evidence of a suprarenal mass but showing a defective suppression of urinary corticoids by dexamethasone and significant elevation of these by ACTH stimulation or by metyrapone, pituitary irradiation may be indicated as the initial treatment. It is emphasized that transitory improvement after pituitary irradiation may occur when the causative adrenal process is either hyperplasia or adenoma. The five-year mortality of the untreated Cushing's disease approaches 50 % (Plotz et al, 1952) (42). It is to be emphasized that the management of Cushing's syndrome involves procedures of considerable magnitude entailing some risk. Many patients are converted from a state of hyperadrenocorticism to a state of permanent adrenal insufficiency. The latter however can be adequately and intelligently controlled by the administration of hydrocortisone, cortisone acetate and fluorohydrocortisone. Nonetheless, it is hazardous to make a diagnosis of Cushing's syndrome when it does not exist. Patients with adrenocortical hyperplasia having enlargement of the sella turcica have usually been treated with irradiation using a telecobalt source to deliver 4000 to 4500 r to the pituitary through multiple ports; with alpha particles delivered by linear accelerator, it is possible to deliver >S000 r to the pituitary gland with reasonable safety (Lawrence et al, 1961) (43). Internal pituitary irradiation has also been employed using stereotaxic implantation of Yttrium-90 by the transphenoidal route; use of this procedure is limited by potential deletorious effects of irradiation on perisellar structures. Tumors exhibiting progressive expansion and producing visual field defects and other signs should be surgically removed. When sellar enlargement is only moderate and signs are limited, the surgical procedure of choice may well be transphenoidal cryohypophysectomy. With more extensive involvement the transfrontal approach should be employed. These patients require not only adrenocortical substitution therapy but gonadal and thyroid replacement treatment as well. Patients without sellar enlargement have been treated in the past by subtotal bilateral adrenalectomy. However, subtotal adrenalectomy entailed certain serious disadvantages; eventual relapse can be expected in 30 % or more patients; and the statuts and the fate of the adrenal remnant are often problematic, as demonstrated by the eventual occurrence of adrenal insufficiency in approximately 50 % of the patients. Intercurrent stress may precipitate adrenal crisis in patients who have only sufficient adrenal tissue to meet the hormone requirements for normal existence. Total bilateral adrenalectomy is the surest method of controlling Cushing's syndrome (Harrison et al., 1953) (44). The procedure is indicated in those patients who have severe disease with advancing hypertension, diabetes, progressive osteoporosis, psychosis, or other potentially serious complications. The procedure is also indicated in those patients who have not responded to treatment aimed at the pituitary gland. Patients having a mild degree of Cushing's syndrome may have a subtotal adrenalectomy followed by very close surveillance in the future. Total adrenalectomy has been performed during the last 18 years in the treatment of Cushing's syndrome. During this time an unexpected complication in 10-15 % of patients has been the appearance of a pituitary tumor. All of these tumors that have been reported were chromophobe adenomas. One cannot always be certain that they were not present prior to the adrenalectomy but it is possible that some have occurred subsequent to it. ADRENAL TUMORS: The treatment of a primary adrenocortical tumor is complete surgical resection. In most cases the condition is unilateral so that the involved adrenal gland can be removed and the contralateral atrophic gland left intact. The ultimate recovery of normal adrenocortical function in the remaining gland eliminates the need for hormone replacement therapy. Bilateral aldosterone adenomas have been found infrequently. The preparation of the patient must adhere to the usual principles of gaining maximal preoperative renal and cardiorespiratory function. If the patient has congestive heart failure, profound potassium depletion, or infection appropriate measures must be taken to deal with these complications before surgery is undertaken. Once surgical treatment has been elected, whether the diagnosis is tumor or hyperplasia, the following consideration are fundamental: 1. All patients must be adequately prepared preoperatively and firmly supported postoperatively by adrenal hormone replacement. Full scale hormone treatment should be employed irrespective of the extent of adrenal resection since the incidence of complication attributable to proper hormone therapy has been almost negligible. Adequate quantities of cotisol are necessary during and following surgery. 2. Water soluble preparations of Cortisol can be given intravenously, intramuscularly or subcutaneouslv, 100 mgms. every 8 hours beginning with preoperative medication and continuig for 24 hours postoperatively. 3. During the ensuing 7-10 days the dosage is gradually decreased towards physiologic levels. 4. When a large tumor has been localized unilateral adrenal resection is carried out through a posterolateral incision with resection of the 11th rib for a subdiaphragmatic extrapleural extraperitoneal approach. 5. If the tumor is very large a transthoracic exposure by a thoracoabdominal incision is judicious because it facilitates exposure and makes the operation much more safe. 6. If the tumor has not been localized a decision must be made concerning an approach through an anterior incision across the epigastrium or a bilateral posterior approach simultaneously with resection of the 11th rib on each side. The abdominal approach gives the added advantage of further exploration with regards to ectopic tissue. With increasing experience it is the author's feeling that the approach should be determined by the size of the tumor, the physical attributes of the patient as well as the basic pathologic process present. Hyperaldosteronism demands bilateral exploration in most cases. The anterior approach is less desirable in cases of marked obesity. Osteoporosis with or without multiple vertebral compression fractures makes the posterolateral approach more hazardous. When simultaneous bilateral posterolateral incisions are to be employed exploration of the left adrenal is usually undertaken first since the surgical hazards are less on this side (the vena cava and liver being on the right). In the presence of obvious adrenocortical atrophy a hyperfunctioning tumor or. the opposite side is highly probably. If both adrenal glands appear atrophic the likelihood of aberrant hyperexcreting adrenal cortical tissue is high. 7. Postoperatively, the patient is maintained on dosage of Cortisol sufficient to prevent symptoms of adrenocortical insufficiency. Recovers- of the remaining adrenal gland can be facilitated by the intramuscular administration of corticotropin 20-40 units daily for a few weeks. This has seldom been necessary. Ordinarily hormone treatment can be withdrawn completely in less than three months. Many malignant tumors can be completely resected and their management is then identical with benign adenoma. If total resection of an adrenal carcinoma cannot be accomplished subtotal removal should be performed and subsequently chemotherapy carried out. In one patient reoperation has yielded a more complete removal after the lapse of several months because of biologic encapsulation of the residual tumor. Chemotherapy of adrenal cortical carcinoma will be discussed in further detail later. PRIMARY ALDOSTERONISM : In 1952 the isolation and identification of electrocortin or aldosterone was accomplished by a group working at the University of Basle and the University of London in a cooperative effort. These were Simpson-Tait, Wettstein, Neher, von Euler and Reichstein. In 1955 a new clinical syndrome was described by Jeroin Conn at the University of Michigan which was characterized by benign arterial hypertension, hypokalemia, alkalosis, muscle weakness and vasopressin resistant polyuria. The first aldosterone producing adenoma was removed by Baum a the University of Michigan. The majority of cases reported to date have resulted from an antonomons aldosterone adrenal secreting adenoma. Three-fourths of these tumors have measured less than 3 cm diameter and have weighed less than 6 grams. In some cases the diameter has been 1 cm or less and the weight below 2 grams. These tumors have been much more common on the left than on the right and in more than 90 /c of cases there has been a single tumor; in the remainder multiple tumors have been found usually in only one gland but rarely both adrenals have been involved. In a small number of patients an adrenal carcinoma has been encountered but the true incidence is not krown. 80 % of the patients have been between the ages of 30-60 and there have been twice as many females as males. In an increasing number of reports all of the typical clinical findings have been present but at operation adrenal hyperplasia or normal appearing adrenal glands have been found. In 1961 Conn (45) suggested that this might represent a separate category of juvenile aldosteronism. In contrast to the usual syndrome these patients were young, usually male and often presented with malignant hypertension and frequently gave a history of polyuria and polydipsia beginning in childhood. It is now clear that a significant number of adult patients who fulfill all accepted diagnostic criteria for primary aldosteronism no adrenal tumor is present. Many of these cases may be a secondary type of aldosteronism. In a series of 38 adult patients, 2/3 of whom were females, a typical solitary cortical adenoma was found in 26 while in 5 the tumor was associated with multiple microadenomata. In 7 patients no tumor was found; adrenocortical hyperplasia was present in 6 and no abnormality could be identified in the remaining glands. When nodular or diffuse cortical hyperplasia is present it is possible that all zona glomerulosa cells have undergone a primary metabolic derangement leading to autonomous oversecretion of aldosterone but, in view of the pathophysiology of other known adrenocortical disorders this is unlikely. It seems more reasonable to postulate that the glomerulosa is responding to an abnormal trophic stimulus since Cortisol production is normal and plasma renin levels were low it is unlikely that either ACTH or angiotensin are involved in these cases. Secondary aldosteronism of unknown etiology may prove to be a more suitable description of such cases. c Pathophysiology of Aldosteronism: Aldosterone in excess increases the distal renal tubular reabsorption of sodium and the excretion of potassium, hydrogen, ammonium, and magnesium ions. Sodium retention leads to expansion of extracellular and plasma volumes followed by increase in glomerular filtration rate, renal plasma flow, and concomitantly decrease in renin production. Eventually the kidney escapes from the sodium retaining action but not from the effects on potassium secretion. As a result a progressive depletion of total body intracellular potassium ensues. The decreased intracellular action is partially compensated by a vovement into cells of hydrogen ions leading to systemic alkalosis. The latter, particularly in the presence of hypokalemia, may cause paresthesias and even tetany. Mild weakness progressing to frank paralysis may occur from this potassium loss. Poor concentrating ability of the kidney and a reduced capacity to acidify the urine results from the kaliopenic tubular nephropathy. The urine is alkaline and contains a high content of ammonia. There may be an exaggeration of the normal postural sodium diuresis secondary to and expanded extracellular fluid volume in the presence of hypertension, and in soma patients a marked sodium diuresis and nocturia occurs. The exact mechanism by which excess aldosterone causes hypertension is not defined but it appears to be secondary to changes in sodium metabolism since salt restriction prevents the rise in blood pressure. The administration of aldosterone and salt decreases plasma renin levels which indicates that a mechanism other than the renin angiotensin system is involved. Tobian (46) (1960) has suggested that increased sodium and water content of the arteriolar wall which followed mineral corticoid administration may increase peripheral vascular resistance thereby raising the blood pressure. Symptoms and Signs: The incidence of symptoms in the first 145 cases reported in the literature have been summarized by Conn 1964 (47) and are recorded in the table below: Symptoms in Primary .. 73 % Nocturia, polyuria . . . . . 72 % .. 51 % 46 % ... . 24 % Muscle weakness Polydipsia Paresthesias Aldosteronism Visual disturbances . . . . Intermittent paralysis . . . Tetany Muscle discomfort (Asymptomatic) .... . . 21 % 21 % 21 % 16 % 6 % Physical findings in 145 cases summarized by Conn are listed in the following table: Signs Hypertension in Primary 100 % Aldosteronism Positive Trousseau 17 % Retinopathy 50 % Tetany 9 % Cardiomegaly 41 % Paralysis 4 % Laboratory Findings: The following table lists the major biochemical abnormalities encountered in hyperaldosteronis. Laboratory Abnormalities in Primary A. Blood 1. Hypokalemia 1. 2. Hypernatremia 3. Hypomagnesemia 2. 3. 4. Alkalosis 4. 5. Increased plasma volume 5. Aldosteronism B. Urine Decreased concentrating ability' Decreased ability to acidify Increased potassium excretion (high urine potassium at low plasma potassium levels) Normal 17-OHCS, 17-KGS and 17-KS Increased aldosterone excretion secretion rate G. Increased plasma aldosterone 7. Decreased plasma renin It is to be emphasized that these biochemical abnormalities may be psychical and in early cases the serum potassium concentration will be consistently normal but diminished with potassium deprivation and increased with potassium administration. There exists a renal-adrenal mechanism for the normal maintenance of sodium balance and systemic renal perfusion pressure. Through this mechanism the kidney releases renin when its perfusion is threatened, and renin generates angiotensin. Angiotensin stimulates aldosterone secretion which causes retention of sodium and tends to restore renal perfusion. In 1964 Conn suggested that this system, functioning through feedback mechanisms, might result in subnormal plasma renin activity in primary aldosteronism and that this finding could provide an additional diagnostic criterion. It has now been confirmed that when aldosterone is secreted the mechanisms normally involved in aldosterone stimulation are suppressed and plasma renin activity is low. Furthermore, procedures which are known to elicit a significant rise in plasma renin levels in normal subjects (the maintenance of upright posture and sodium deprivation) are usually much less effective in patients with primary aldosteronism. Diagnosis: The autonomous secretion of aldosterone by an adrenal adenoma is indicated by an elevated secretion rate in plasma and urine of aldosterone. At the same time the excess hormone suppresses renal production of renin. An increase of aldosterone output while the patient receives a liberal salt intake, and a decrease in plasma renin in the face of salt deprivation, are two changes which provide the major criteria for the diagnosis of primary aldosteronism (Conn, 1964). The present major criteria for the diagnosis of primary aldosteronism are: a. Hypertension which is not malignant; b. Hypokalemia which tends to imprpve with sodium restriction, gets worse with sodium loading and which is not the result of diuretic therapy; c. Increased aldosterone output which persists despite high sodium intake or mineralacorticoid administration; d. Suppressed plasma renin levels which fail to rise normally during the maintenance of the upright position and the restricted sodium intake. Improved techniques of renal-adrenal tomography, selective adrenal angiography and venography have delineated some lesions as small as 1-2 cms in diameter. Conn, Sutton and Egdahl have all reported on the successful use of adrenal phlebography in demonstrating these tumors. The measurement of aldosterone in the adrenal venous effluent has been successful in reports by Conn (48) and Egdahl (49). Differential Diagnosis: In the differential diagnosis of primary aldosteronism one must consider all those conditions causing hypertension, hypokalemia and any condition which causes elevation of aldosterone output. Among these conditions are patients with hypertension or primary aldosteronism, secondary aldosteronism due to malignant hypertension, diuretic therapy of hypertension, genital defects in the biosynthesis of corticoids resulting in a mineral corticoid excess, Cushing's syndrome, malignancies causing ACTH increase, pseudoaldosteronism and licorice ingestion. In the normotensive states in the differential diagnosis the syndrome of juxtaglomerular hyperplasia of Bartter (50), renal tubular acidosis and familial periodic paralysis must be considered. Treatment: The cause of primary aldosteronism is an aldosteroneproducing adrenocortical adenoma, the proper treatment of which is surgical removal. The minimal criteria before adrenal exploration are hypertension, elevated aldosterone output which is not suppressed by sodium loading, or mineralacorticoid administration; low plasma renin levels which do not rise normally in response to sodium restriction and the upright posture. Even with these requirements fulfilled. 10-15 of the patients explored will have diffuse or nodular bilateral adrenocortical hyperplasia rather than a tumor; the source of the stimulus responsible for the hyperplasia is not now known, but these patients are considered to have a form of secondary aldosteronism and their response to adrenalectomy is not reliably predictable. Finally, in an occasional patient bilateral tumors will be found. When x-rays and the studies of the venous effluent from the two adrenal glands localize the tumor one may be satisfied temporarily at least with only exploration and removal of the tumor on that side. Usually the approach has been bilateral and the simultaneous bilateral posterior approach is the approach of choice. Some have preferred an anterior transverse and upper abdominal incision with oblique extension downard toward the iliac crest in thin subjects. The morbidity is considered to be lower through the bilateral posterior approach, in all but heavily muscular individuals. Preoperative management centers around correction of the potassium deficit using supplemental potassium chloride in doses of 40-120 mEq. per day. A low sodium diet will aid potassium repletion and in severe cases aldosterone antagonists (spironolactones) or agents which interfere with renal tubular ion transport (triamterene) may be helpful. When a tumor is found it should be removed by unilateral adrenalectomy; this is in contrast to the policy of those who favor discrete resection of the tumor by partial adrenalectomy. Because of their small size the tumors will not be immediately apparent in some cases, but by very careful palpation and complete surgical exposure very small adenomata can be identified. Nodular hyperplasia may simulate a single adenoma; at times it has not been identified correctly except by histologic examination. If no tumor is found at exploration of one gland the opposite gland must be explored. In patients with adrenocortical hyperplasia the p r o c e d u r e of choice is controversial. Subtotal adrena lectomy is p r e f e r r e d by most authors in an e f f o r t to interrupt the c y c l e of aldosterone overproduction. H o w e v e r , the chance that a small adenoma w i l l be left in the remnant indicates that total adrenalectomy may be the m o r e desirable procedure. Simultaneous renal biopsy is carried out in order to measure the extent of renal damage. Postoperatively, there is an expected urinary diuresis of sodium, potassium is retained and carbon d i o x i d e content and p H of the blood return to normal. P o l y u r i a and p o l y d i p s i a usually disappear p r o m p t l y but the biochemical shifts are not complete until the second or third postoperative week. At times patients w i l l develop azotemia, hvponatremia and hyperkalemia during the immediate postoperative p e r i o d r e f l e c t i n g a transient aldosterone d e f i c i e n c y . In such instances, replacement therapy w i t h f l u o r o h y d r o c o r t i s o n e w i l l be required temporarily. In patients w i t h extensive renal disease azotemia may persist i n d e f i n i tely. In Conn's experience about 15 % of the patients show only a t e m p o r a r y decline in pressure and a subsequent gradual rise to preoperative levels. In 85 % of patients blood pressure either returns to normal w i t h i n 4 months f o l l o w i n g the operation or significantly declines but does not reach the normal level. T h i s has occured even in patients in w h o m all defects of electrolyte metabolism have been completelyobliterated making it appear that in some patients the hypertension is f i x e d , presumably on a renal basis. T h e studies in most clinics w o u l d indicate that hyperaldosteronism is not a common cause of hypertension. T h i s is in contradistinction to the f i n d i n g s of Conn and his group at the University of Michigan. ADRENOGENITAL SYNDROME: T h e adrenogenital syndrome includes all cases of sexual p r e c o c i t y and heterosexual abnormalities due to adrenocortical dysfunction. Except f o r the relatively rare f e m i n i z i n g tumors in males, the clinical features of the disorder are the result of an excessive adrenal production of androgens, p r o d u c i n g heterosexual v i r i l i z i n g changes in females and isosexual p r e c o c i t y in males. The adrenogenital syndrome classification 1. Prenatal (congenital v i r i l i z i n g adrenocortical Pseudohermaphroditism in females Macrogenitosomia praecox in males hyperplasia) 2. Postnatal (adrenocortical hyperplasia or tumor) Prepubertal: Heterosexual p r e c o c i t y in females Isosexual p r e c o c i t y in males Postpuberal: V i r i l i s m in females Feminization in males T h e p r o b l e m of heterosexual development in infants or small children us that of d i f f e r e n t i a t i n g cases due to genetic intrauterine influence f r o m cases due to abnormal secretion of sex hormones by the fetal endocrine system, including the adrenal cortex. T h e f o r m e r include true hermaphroditism in w h i c h both ovarian and testicular tissue are present; male pseudohermaphroditism, in w h i c h the gonads are testes but the genital ducts, urogenital sinus, and external genitalia exhibit ambisexual d i f f e r e n t i a t i o n ; and the female pseudohermaphroditism due to maternal masculinizing hormones (e.g. virilizing ovarian tumor). It is important to note that in true hermaphroditism, and male pseudohermaphoditism secondary sexual characteristics do not develop p r i o r to the normal time of puberty, and once initiated, development of the external genitalia and genital ducts is largely unpredictable and may or may not correspond to the sex of the gonads. In contrast, heterosexual abnormalities of adrenal origin are often prepubertal in onset and sexual differentiation occurs along a fairly predictable pattern, for example, in female pseudohermaphroditism development of the genital tubercle is masculine, while the genital ducts are always feminine. T h e principal objective in dealing with problems of isosexual precocity, such as macrogenitosomia p r a c o x is to establish the source of the stimulus and, i.e. whether the development of secondary sex characteristics is the result of adrenal or gonadal hormones. The disturbance may arise in a primary tumor of adrenal or gonad or result secondarily from precocious pituitary-adrenal or pituitary-gonadal activation. Congenital virilizing adrenal hyperplasia: T h i s is the most common disorder of adrenocortical function in childhood. F o u r clinical types of virilizing adrenal hyperplasia have been identified as a. simple virilism; b. virilism and sodium loss; c. virilism and hypertension; and d. the 3B hydroxysteroid dehydrogenase defect; e. a fifth congenital disorder involving the 17-hydroxylation system has been described. 60 % of the patients show simple virilism alone and one-third have exhibited salt loss, but the actual occurence of this form may be higher since, in some cases, patients can die undiagnosed. Approximately 5 % have developed hypertension and the 3B hydroxysteroid dehydrogenase defect is apparently very rare. Three times as many females as males have been described w i t h this disorder. In all four types of the disorder virilism results from the excessive production of adrenal androgens. The primary fact is a deficiency of one or more specific enzymes necessary for the biosynthesis of Cortisol. The decrease in Cortisol output activates the mechanism regulating the hypothalmic-pituitary-adrenocortical function, and increased" quantities of ACTH are released. Stimulation by this corticotropin brings about adrenal hyperplasia and accelerates the synthesis of adrenal steroids. As a result, Cortisol production approaches normal levels but precursors of Cortisol accumulate behind the enzyme block and are secreted. The pathways leading to androgen production are not impeded, and androgen secretion rises. The most common form of the disease is due to a relative deficiency of 21-Hydroxylase and results in simple virilism. T h e major urinary metabolites of progesterone are pregnanolone and pregnanediol; of 17-hydroxyprogesterone, 17-hydroxypregnanolone and pregnanetriol; of 21-deoxycortisol, they are 11-hydroxypregnanetriol and 11-ketopregnanetriol. The demonstration of significantly increased quantities of these metabolites in the urine identifies the site of the partial enzymatic deficiency. Pregnanetriol is most conveniently measured and provides a simple key to the diagnosis. Increased quantities of dehydroepiandrosterone sulfate are excreted directly into the urine; delta 4 androstenedione is converted in the adrenal or in the liver into testosterone. When the disorder is severe, aldosterone synthesis is also materially impaired, as demonstrated by an inadequate rise in aldosterone production rate in response to sodium restriction. In addition to virilization, significant sodium loss occurs in these patients. With the C - l l - H y d r o x y l a s e defect the key urinary metabolites are tetrahydrodeoxycorticosterone and tetrahydro-S. T h e unblocked andro- gen pathway again produces excessive quantities of delta 4-androstenedione, resulting in increased testosterone and 17-ketosteroid production. Aldosterone synthesis is depressed but abnormal sodium loss does not occur Decause of the accumulation of 11-deoxycorticosterone which also may account for the hypertension. The enzymatic defect is due to a non sex-linked recessive mutant gene which is expressed clinically only in the homozygous offspring. Multiple cases occur in one generation, and the affected siblings always have the same form of the disease; the parents show no evidence of endocrine dysfunction. Signs and Symptoms: In the female infant congenital virilizing adrenal hyperplasia is manifested as pseudohermaphroditism. The gonads are ovaries and the mullerian ducts differentiate normally into the uterus, oviduct and vagina; the urogenital sinus persists and excessive development of the genital tubercle occurs. One ordinarily encounters at birth a large clitoris resembling a hypospadiac penis, hypertrophic labia majora, atrophic labia minora, and a urogenital sinus opening at the base of the clitoris. On rectal examination the uterus may be palpable but prostatic tissue is absent. Endoscopy reveals both urethra and vagina opening into a common passage, a uterine cervix, but absence of the verumontanum and ejaculatory ducts. Pubic and axillary hair usually appear by the age of 3-4 years. Skeletal and muscular growth are accelerated. Acne may occur and the voice deepens. Menstruation and breast development do not occur at puberty. In the male infant, premature virilization occurs but the patient may reach 2-4 years before genital growth becomes abnormal. Pubic, axillary and eventually facial hair develop. Acne appears and enlargement of the larynx accompanies deepening of the voice. It is important to note that the testes typically remain small. Penile and prostatic size reach adult proportions in late childhood. Rarely do testes become enlarged and regression occurs with suppressive steroid treatment which indicates that the scrotum contains aberrant adrenocortical tissue. The most common cause of female pseudohermaphroditism and isosexual precocity in males is congenital adrenocortical hyperplasia. The diagnosis should be considered in all infants exhibiting vomiting, dehydration or other signs of acute adrenal insufficiency. It is important in the differential diagnosis of hypertension in children having sustained hypertension. One must document the elevation of urinary 17-ketosteroids and of the abnormal urinary metabolites. It is essential to show that the excretion of urinary 17-ketosteroids and of the urinary metabolites is suppressed by the administration of dexamethazone. The suppression tests indicate the basic pathologic process is adrenal hyperplasia and not neoplasia. Virilizing adrenal tumors produce large amounts of urinary 17-ketosteroids mainly 17-dehydroepiandrosterone sulfate and the administration of dexamethazone does not return the values to normal. The principle of therapy of congenital adrenal hyperplasia is suppression of adrenocortical activity by supplying Cortisol or other glucocorticoids, inhibiting corticotropin output and preventing the secretion of adrenal androgens. Intramuscular administration is more effective than oral administration. Inaccurate dosage has been responsible for failure of suppression and restoration to a normal pattern of growth and development. Initial doses are 10-20 mgins. of Cortisol per day for infants; 20-40 mgms. per day of Cortisol for older children and 60- 80 mgms. per day for adolescents or adults. The necessary maintenance dosage must be measured specifically in individual cases using the level of urinary 17-ketosteroids or specific urinary metabolites such as pregnanetriol as a guide. The results are measured in terms of growth rate and osseous development. With inadequate suppression of adrenal function bone age advances and leads to premature epiphyseal fusion. Failure to suppress may result in adrenocortical hyperplasia persisting for many years that may result in neoplasia. Therefore continued suppressive therapy must be maintained-both in females and males. Postnatal Adrenogenital Syndrome: Postnatal adrenal virilism in females prior to puberty may result from adrenal hyperplasia but is usually due to adrenal tumor. Tumors have been discovered in the first six months of life, or in the postpuberal period. When a neoplasm is causative the external genitalia are normal at birth but virilization is usually progressive; pubic and axillary hair develop and the clitoris enlarges. Excessive somatic development in growth is accelerated. The output of urinary 17-ketosteroids is high and the urinary dehvdroepiandrosterone sulfate is usually elevated. The diagnosis depends upon the exclusion of congenital adrenal hyperplasia by failure of dexamethasone inhibition. Pyelography and tomography are valuable in the preoperative localization of the tumor. Arteriography and measurement of the hormones in the venous effluent of the adrenal represent refined coordinated advances in diagnosis. The adrenogenital syndrome in adult females occurs before the menopause and either hyperplasia or tumor may be responsible but tumor is unfortunately more often the cause. The earliest event is the appearance of hirsutism of the face and extremities and the conversion of the pubic hair line into a male pattern. Hair of the scalp becomes thin and actual baldness ensues with temple recession being common. Menses become scanty and cease. Libido is diminished and the breasts, ovaries and uterus diminish in size as the clitoris undergoes hypertrophy. The voice deepens as the larynx enlarges and the musculature of the body until body configuration may approach the male form. High levels of urinary 17-ketosteroids are measured. Syndromes with characteristics of Cushing's and the adrenogenital syndrome may be caused by either hyperplasia or tumor but the latter should always be suspected. In the differential diagnosis polycystic disease of the ovaries, arrhenoblastomas, and luteinizing granulosa cell tumors must be considered. Pelvic exi^loration may be necessary to establish the presence or absence of primary ovarian pathology. Differentiation between bilateral adrenocortical hyperplasia and adrenocortical tumors is essential. A plain film of the abdomen, adrenal tomography with excretory urography and selective angiography both arterial and venous may serve to localize the tumor. Venography is not without hazard and must bo done with the greatest care. Dexamethasone suppression will cause a fall in the urinary metabolites when adrenocortical hyperplasia is the cause of their increase. This will not occur when a malignant tumor is the cause. Some adenomas do show suppression and also an elevation in response to ACTH stimulation. The treatment of virilizing adrenal tumor is immediate removal. When the tumor has been localized preoperatively, the approach is determined very much by its size and direction of growth. When the predominant growth seems to be interiorly down into the abdomen transverse abdominal incision extending down to the iliac crest is a very a d e q u a t e exposure. T u m o r s of less great size m a y be a p p r o a c h e d t h r o u g h the classical f l a n k i n c i s i o n w i t h r e s e c t i o n of the 11th rib. T h i s is an e x t r a p l e u r a l , s u b d i a p h r a g m a t i c a p p r o a c h . When the tumors are quite large a p o s t e r o l a t e r a l t h o r a c o a b d o m i n a l a p p r o a c h is definitely t h e p r o c e d u r e of choice. W h e n t h e t u m o r h a s not been a c c u r a t e l y localized t r a n s a b d o m i n a l a p p r o a c h by a t r a n s v e r s e i n c i s i o n w i t h oblique extensions as n e c e s s a r y i n f e r i o r l y is p r e f e r a b l e , t h o u g h b i l a t e r a l f l a n k incisions may be used but do not o f f e r as w i d e e x p o s u r e w h e n d o n e in the prone position. Feminizing Adrenogenital Syndrome in Males: T h e f e m i n i z i n g a d r e nogenital s y n d r o m e in males is nearly a l w a y s d u e to t u m o r . Feminization h a s not been d e s c r i b e d as the p r e s e n t i n g p i c t u r e in congenital a d r e n o c o r t i c a l h y p e r p l a s i a . F e m i n i z a t i o n a p p e a r i n g in the adult male a l w a y s raises t h e question of m a l i g n a n t a d r e n o c o r t i c a l n e o p l a s m . In 1965 Gabrilove r e v i e w e d 52 cases of f e m i n i z i n g a d r e n o c o r t i c a l t u m o r s . T h e y o c c u r between t h e ages of 25-50. G y n e c o m a s t i a is the most f r e q u e n t c h a n g e a n d is usually bilateral. D i m i n i s h e d libido and testic u l a r a t r o p h y o c c u r in one-half of t h e p a t i e n t s . Oligospermia, obesity, feminine hair distribution, penile atrophy, arterial hypertension and e d e m a m a y also be occasionally f o u n d . Some p a t i e n t s h a v e s h o w n m o o n face, c u t a n e o u s striae, osteoporosis a n d steroid d i a b e t e s s i m i l a r to Gushing's s y n d r o m e . T h e s e t u m o r s a r e t y p i c a l l y large a n d p a l p a b l e in m o r e t h a n 50 % of t h e p a t i e n t s . In most cases d e a t h o c c u r s w i t h i n t w o y e a r s f o l l o w i n g t h e onset of s y m p t o m s . Metastases a p p e a r in t h e liver, lungs, a n d p a n c r e a s by direct extension. E s t r o g e n i c e x c r e t i o n is m u c h g r e a t e r in m a l i g n a n t t u m o r s t h a n w i t h a d e n o m a s . E s t r o n e , estradiol a n d estriol a r e s i m i l a r to the d i s t r i b u t i o n f o u n d in n o r m a l males. Very high values f o r 17-ketosteroids a n d u r i n a r y estrogens a r e f o u n d . R a d i c a l o p e r a t i o n f o r c a n c e r is necessary, r e m o v i n g all p e r i a d r e n a l fat, fascia a n d l y m p h a t i c s . T h e k i d n e y is o f t e n i n v a d e d a n d must be r e m o v e d on that side. In a d d i t i o n , the spleen a n d tail of t h e p a n c r e a s h a v e been involved in some cases a n d r e q u i r e d removal. If the t u m o r can be r e m o v e d , g y n e c o m a s t i a regresses, libido r e t u r n s , a n d the testes i n c r e a s e in size. E x c e s s i v e e x c r e t i o n of u r i n a r y estrogens, 17-ketosteroids a n d 1 7 - h v d r o x y c o r t i c o i d s fall. P e r s i s t e n c e of s y m p t o m s a n d elevated steroid levels a r e an i n d i c a t i o n of f u n c t i o n i n g metastases. T h e a d m i n i s t r a t i o n of o p 1)1)1) h a s r e d u c e d steroid o u t p u t in some cases but not in all. Functional Tumors of the Adrenal: Adenoma: Adrenocortical tumors a r e f o u n d in a p p r o x i m a t e l y o n e - f o u r t h of p a t i e n t s w i t h Cushing's syndrome, a n d about one-half of these n e o p l a s m s a r e benign. Tumors v e i g h i n g over 200 gm. h a v e been r e p o r t e d as t r u e a d e n o m a s but usually the a d e n o m a is a small lesion. T h e d i f f e r e n t i a t i o n b e t w e e n a d e n o m a a n d c a r c i n o m a in these large t u m o r s m a y be quite d i f f i c u l t histologically. T h e benign t u m o r s usually p r o d u c e t h e h y p e r g l u c o c o r t i c o i d state in c o n t r a s t to t h e state of virilization or f e m i n i z a t i o n . Primary a l d o s t e r o n i s m is d u e to an a d e n o m a usually t h o u g h in a few i n s t a n c e s carcinoma has occurred. C a r c i n o m a of t h e a d r e n a l cortex is a r a r e m a l i g n a n c y , a c c o u n t i n g for less t h a n 0.2 %• of d e a t h s f r o m all c a n c e r . It o c c u r s at a n y age but the highest i n c i d e n c e is b e t w e e n the ages of 20-50. A significant n u m b e r of cases have o c c u r r e d b e f o r e the age of 10. Virilization in females w i t h a n d w i t h o u t Cushing's s y n d r o m e a n d a l d o s t e r o n i s m a r e p r o d u c e d by c a r c i n o m a a n d e m p h a s i z e t h e i r t e n d e n c y to p r o d u c e a m i x e d p i c t u r e or i n t e r g r a d e t y p e of lesion. In a d d i t i o n to surgical removal the treatment has involved reoperation after radiation therapy of metastases and chemotherapy as well, ó p DDD has been effective in causing inhibition of growth of adrenocortical carcinoma. Te compound ó p DDD has the chemical formula 1, 1-dichloro2 (O-Chlorophenyl) - 2 (p-chlorophenyl) - ethane and has been shown to produce a marked decrease in the secretion of steroids by the adrenal cortex, often associated with focal degenerative lesions of the zona reticularis and the zona fasciculata. Recently Hutter and Kayhoe (51) 1966 summarrized the results of ó p DDD treatment of 138 patients with adrenal carcinoma. Initial dosage for adults is 2-6 grams in divided doses and subsequently the level is increased until toxicity becomes a limiting factor. Maximum daily dose in most patients is 8-10 gms. Unfortunately toxic side effects are noted in 90 % of patients. Drug reactions predominantly involve the gastrointestinal tract, neuromuscular system, and the skin. Anorexia, nausea, vomiting and diarrhea are the gastrointestinal disturbances. Central nervous system depression manifested as lethargy and somnolence occurs in about one-fourth of the treated patients but is usually reversible with reduction of dosage. Dizziness, vertigo, muscle tremors, headache, and confusion have occured. Cutaneous eruptions appear in 15 % of the patients and art; not always dose related. Bone marrow depression and liver damage have not been noted. In 70 % of patients urinary steroid values are decreased during treatment. It may 3-4 weeks before any fall is noted. 35 % of treated patients may be expected to show objective signs of tumor regression including the reduction in the size of palpable masses, disappearance of pulmonary metastatic lesions, a decrease in the intensity of hormone-induced effects, diminished pain and improved strength. Survival for as long as 3 years has occured in the presence of hepatic metastases following removal of a large adrenocortical carcinoma when chemotherapy has been utilized in the above mentioned form. Recently, a new agent has been introduced for the control of metabolic derangements resulting from steroid producing lesions. This compound is aminoglutethimide, originally used as an anticonvulsant. In vitro and in vivo studies indicate that the drug inhibits adrenal steroid synthesis by interfering with the conversion of cholesterol to pregnenolone. The adrenal cortex undergoes hypertrophy through increased corticotropin secretion by the feedback system. The usefulness seems to be the management of pituitary-dependent adrenocortical hyperplasia. However, the drug has produced favorable responses in patients with metastatic adrenocortical carcinoma. Dosage of 75 to 2 gm. per day. At dose levels of 1.2 gm. per day or less, minimal side effects occur but doses of 1.5 gms. per day cause anorexia, somnolence, fever, vomiting, ataxia and skin rashes. These untoward effects have disappeared following withdrawal of the drug. CONCLUSIONS Great progress has been made in the study and care of disorders of the adrenal cortex since Addison's first publication in 1855. Parallel progress has been made in advances with regards to the adrenal medulla. The synthesis of cortisone, the demonstration of its life saving substitutional effects, the discovery of ACTH and desoxvcorticosterone acetate as well as the synthetic mineralacortlcoids such as fluorohydrocortisone followed by the isolation and synthesis of electrocortin and Conn's description of aldosteronism constitute the chief advances in the biochemistry and physiology of the adrenal cortex. The striking improvements in radiography of the adrenal and the simultaneous improvements in anesthesiology and surgical technique all add up to great progress in the management of surgery of the adrenals in the last nineteen years. RESUME De grands progrès ont été faits dans l'étude et le traitement des perturbations du cortex surrénal depuis la première publication d'Addison en 1851. Des progrès parallèles ont été faits en ce qui concerne la partie médullaire. La synthèse de la cortisone, la démonstration de son effet salutaire sur la vie, la découverte de l'acétate de désoxycorticostérone et de l'hormone adréno-corticotrophique suivis de l'isolation et de la synthèse de l'électrocortine et la description par Conn de l'aldostéronisme constituent les principaux progrès dans la biochimie et la physiologie du cortex surrénal. Les aspects des tableaux cliniques causés par l'hyperadrénalinisme dû à l'hyperplasie et au néoplasme du cortex surrénal seront décrits et illustrés. Le changement important du métabolisme organique et inorganique dans cet hyperfonctionnement sera décrit en détail avec ses effets sur les cellules, l'hématologie et la sexualité. Les tests de stimulation et de suppression du lobe antérieur de l'hypophyse seront étudiés. Le diagnostic clinique, biochimique, pharmacologique et radiologique sera discuté en relation avec l'hvpertrophie et la tumeur de la surrénale. On étudiera le diagnostic différentiel des tumeurs du cortex surrénal en incluant l'adénome. Les améliorations frappantes en radiographie ont été de paire avec celles de la chirurgie. Ces techniques seront discutées et illustrées. Un résumé des résultats du traitement chirurgical sera donné. ZUSAMMENFASSUNG Grosse Fortschritte wurden seit der ersten Publikation von Addison im Jahre 1851 bei Untersuchung und Behandlung der Nebennierenrindenperturbationen gemacht. Gleiche Fortschritte wurden bezüglich des Markanteiles gemacht. Die Synthese des Cortisons, der Beweis seiner heilsamen Wirkung auf das Leben, die Entdeckung des Desoxycorticosteronacetats und des adrenocorticotrophen Hormons, gefolgt von der Isolierung und der Synthese des Elektrocortins und der Beschreibung des Aldosteronismus durch Conn stellen die wichtigsten Fortschritte in der Biochemie und Physiologie der Nebennierenrinde dar. Die Aspekte der klinischen Bilder, die durch den Hyperadrenalismus auf Grund der Hyperplasie und eines Neoplasmas der Nebennierenrinde entstehen, werden beschrieben lind illustriert. Der wichtige W e c h s e l des anorganischen und organischen Metabolismus bei dieser Ueberfunktion wird im Einzelnen beschrieben mit seiner W i r k u n g auf die Zellen, die Hämatologie und Sexualität. Diese Teste zur Stimulation und Suppression des vorderen Hypophysenlappens werden bearbeitet. Die klinische, b i o c h e m i s c h e , p h a r m a k o l o g i s c h e und radiologische Diagnostik w i r d diskutiert in Beziehung zur Hypertrophie und zum T u m o r der Nebenniere. Die Differentialdiagnostik der N e b e n n i e r e n r i n d e einschliesslich des Adenoms werden untersucht. Die frappierenden Verbesserungen auf dem Gebiete der Radiographie gingen mit denen der Chirurgie parallel. Diese T e c h n i k e n werden besprochen und illustriert. E i n e Zusammenfassung der c h i r u r g i s c h e n Behandlung wird noch gegeben. RESUMEN A p a r t i r de la p r i m e r a p u b l i c a c i ó n de Addison en 1851, se han realizado grandes progresos en el estudio y tratamiento de los trastornos de la corteza suprarrenal. P a r e c i d o s progresos se lian hecho en lo que c o n c i e r n e a la parte medular. La síntesis de la cortisona, la demostración de su efecto beneficioso, el descubrimiento del acetato de oxicorticosterona y de la hormona a d r e n o - c o r t i c o t r o p a seguido del aislamiento y síntesis de la e l e c t r o c o r t i n a v la d e s c r i p c i ó n p o r Conn del aldosteronismo constituyen los progresos más importantes en la b i o q u í m i c a y fisiología de la corteza suprarrenal. Los aspectos de los cuadros c l í n i c o s provocados por hiperadrenalismo debido a la hiperplasia y a neoplasias de la corteza suprarrenal serán descritos e ilustrados. El c a m b i o importante del metabolismo orgánico e i n o r g á n i c o en esta h i p e r f u n c i o n será descrita detalladamente con sus efectos celulares, hematologicos y sexuales. Los tests de estimulación y supresión del lobulo anterior de la hipófisis serán estudiados. El diagnostico clínico, bioquímico, farmacologico y radíólogico será discutido en relación con la hipertrofia y el tumor suprarrenal incluyendo el adenoma. Los sorprendentes avances radiologicos corren pareja con los quirúrgicos. Estas t é c n i c a s quirúrgicas serán discutidas e ilustrafas, además se expondrá un resumen de los resultados del tratamiento quirúrgico. RIASSUNTO Dei grandi progressi sono stati fatti nello studio e nella terapia delle perturbazioni cortico-surrenali dopo la p r i m a pubblicazione di Addison nel 1851. Progressi paralleli sono stati inoltre fatti a n c h e rispetto alla sostanza midollare. La sintesi del cortisone, la dimostrazione dei suoi effetti salutari sulla vita, la scoperta dell'acetato di desossicorticosterone e dell'ormone adreno - cortico - trofico seguita dall'isolamento e dalla sintesi della elettrocortina e dalla descrizione fatta da Conn dell'aldosterinismo costituiscono i p r i n c i p a l i progressi nella b i o c h i m i c a e nella fisiologia della c o r t e c c i a surrenale. L'aspetto dei quadri c l i n i c i causati dall'iperadrenalismo dovuto ad iperplasia o neoplasia della c o r t e c c i a surrenale sono descritti e illustrati. Il cambiamento importante del metabolismo organico ed inorganico che si rivela in questa iperfunzione è descritto particolareggiatamente coi suoi efl'etti sulle cellule, sulla emtologia e la sessualità. Sono altresì studiati i test di stimolazione e di soppressione del lobo anteriore ipofisario. La diagnosi clinica, b i o c h i m i c a , f a r m a c o l o g i c a e radiologica è discussa in relazione all'ipertrofìa o al tumore della surrenale. Viene studiata a n c h e la disgnostica differenziale dei tumori della c o r t e c c i a surrenale adenoma incluso. I meravigliosi miglioramenti constatati a mezzo della radiografia sono sovrapponibili a quelli ottenuti con la chirurgia. La varie teclin i c h e sono discusse e illustrate. E ' altresì illustrato un riassunto sui risultati degli interventi c h i r u r g i c i . BIBLIOGRAPHY (1) ADDISON, T. — On t h e C o n s t i t u t i o n a l a n d Local E f f e c t s of Disease of t h e S u p r a r e n a l C a p s u l e s . L o n d o n , D. H i g h l e y , 1885. (2) OLIVER, (3) CANNON, G. a n d S C H A E F E R , A.E. — P h y s i o l o g i c a l Effects of A d r e n a l E x t r a c t s . Journal of Physiology. London. 18:230, 1895. W . 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In Eisenstein A.B.: The Adrena' Cortex, Boston, Little Brown & Company, 1967, p. 523. ( 4 0 ) L I D D L E , G . W . — Test of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome. J. Clin. Endocr. X Metab. 20:1539, 1960. HARRISON, J.H., THORN, ( 4 1 ) L A I D L A W , J . C . , G O E T Z , F . C . , J E N K I N S , 1)., M Ü N S O N , P . L . , H A R R I S O N , J . H . a n d T H O R N , G . W . — 17-Ketosteroid and Androgen Excretion in Orchiec- tomized, Adrenalectomized Patients. ,/. Clin. Endocrinol. 12:971, 1952 and RAGAN, C . The natural history of Cushing's syndrome. Am. J. Med. 13:597, 1952. ( 4 2 ) P L Ö T Z , C . M . , KNOVVLTON, A . I . , C.A. and Climat. Assoc. 73:17«, 1961. ( 4 3 ) L A W R E N C E , J . H . , TOBIAS, BORN, J . L . — Acromegaly. Tr. Am. Clin. — F u r t h e r Observations of bilateral adrenalectomy in man. Am. A. Genito-Urin. Surg. 44:85 1952. ( 4 5 ) CONN, J . W . and CONN, E . S . — Primary aldosterone versus hypertensive disease with secondary aldosteronism. Recent Progr. Hormone lies. 17:389, 1961. ( 4 6 ) TOBIAN, L. — Interrelationships of electrolytes, j u x t a g l o m e r u l a r cells and hypertension. Physiol Ken. 40:280, I960. ( 4 7 ) CONN, J . W . , K N O P F , R . F . and N E S B I T , R. — P r i m a r y Aldosteronism: present evaluation of its clinical characteristics and of the results of surgery. In Baulieu, E.E. and Robel, P.: Aldosterone. Philadelphia, F.A. Davis Co. 1964, p. 327. (48) CONN, J.W., C O H E N , E.L. and R O V N E R , D . R . — Suppression of plasma renin activity in p r i m a r y aldosteronism. Distinguishing primary f r o m secondary aldosteronism in hypertensive disease. J.A.I\1..4. 190:213, 1964. ( 4 9 ) EGDAHL, R I C H A R D H „ M.I).. Paul C. KAHN and J a m e s C. MELBY, M.I). Role of Angiography in Surgery of the Adrenal. Am. J. Surgery 117:480-484] 1969. ( 5 0 ) B A R T T E R , F . C . , P R O N O V E , P . , G I L L , J.R., Jr. and M C C A R D L E , R . C . — Hyperplasia of the j u x t a g l o m e r u l a r complex with hvperaldosteronism and hypokalemic alkalosis. Am. .J. med. 33:811, 1962. (51) H I T T E R , A.M. and KAYHOE, D.E. — Adrenal cortical carcinoma. Results of t r e a t m e n t with o p DDD in 138 patients. Am. J. Med. 41:581, 1966. ( 4 4 ) H A R R I S O N , J . H . , T H O R N , G . W . & J E N K I N S , I). EFECTOS DE LA SUPRARRENALECTOMIA EN LAS NEFROESCLEROSIS C O N HIPERTENSION por ARMANDO E. TRABUCCO Profesor de Urologìa en la Universidad de Buenos Aires. Escuela de Medicina. República Argentina (*) Extracto La intima relación existente entre suprarrenal y riñon se pone de manifiesto cuando alguna de las glándulas se altera. En los casos de nefroesclerosis, muestra la suprarrenal modificaciones notorias en su estructura y aunque las manifestaciones clínicas expresadas por los análisis de la secreción suprarrenal no sean de máxima claridad, en cambio son muy evidentes las alteraciones morfológicas de la capa glomerular de la zona cortical y de las estructuras de la ona medular ; esto último en especial cuando se trata de casos con franca hipertensión. La adrenalectomia unilateral mejora el estado clínico de un apreciable número de casos de nefroesclerosis. Por numerosos trabajos e investigaciones sabemos del poder fibroplástico de los mineral-corticoides ; también sabemos que estos elementos secretados por la zona cortical de la suprarrenal, tienen un valor my importante en la etiopatogenia de las hipertensiones. Por otra parte, también conocemos la acción hipertensiva de los elementos secretados por la zona medular de las adrenales. Lo que se discute aún es la relación o mecanismo de interacción entre los elementos elaborados en la zona cortical y los producidos en la zona medular. Del equilibro de estos elementos depende el mantenimiento de la vida normal ; su desarmonía producirá alteraciones, una de las cuales podría ser la enfermedad esclero-hipertensiva. Si a esto le agregamos un estado de esclerosis renal, ya sea como consecuencia o como causa de las alteraciones suprarrenales, tendremos completado el cuadro de ínter-acción reno-suprarrenal. Teniendo en cuenta la reflexión anterior, hemos planeado la investigación del estado anatómico de las suprarrenales en aquellos casos de nefroesclerosis con o sin hipertensión unilateral de la glándula. (*) Este t r a b a j o ha sido lieeto en colaboración con los l)ics. Márquez, l'.R. y Borzone, R.J. MATERIAL Y MÉTODO Llevamos actualmente en estudio 37 enfermos la mayoría con graves insuficiencias renales en los cuales los tratamientos médicos han sido incapaces de detener la marcha del proceso. Los enfermos estudiados se encontraban en distintos periodas evolutivos predominando sin embargo lo que se considera el periodo terminal de la insuficiencia renal. Es prudente hacer el análisis de los casos estudiados. Dividiremos et relato en : Estudio clínico analizando suscintamente ; el estado hipertensivo, la función renal, la función suprarrenal, los métodos de investigación radiológica y radioisotópica. Luego relataremos la preparación preoperatoria, el método quirúrgico utilizado (discusión del lado) y el tratamiento postoperatorio inmediato y mediato. Terminada esta primera parte expondremos los resultados : 1") Anatomopatologia de la glándula suprarrenal ; 2") Evolución de los casos y ; 3 ) Discusión de teorías. Casos estudiados. — En nuestra estadística figuran más de 50 casos estudiados y adrenalectomizados por patología hipertensiva pero, como nuestra intención es relacionar la patología hipertensiva aparentemente renal, con anormalidades funcionales de la suprarrenal, tenemos que limitar este estudio a solo 37 casos, donde además de la evidente enfermedad renal encontramos también una evidente alteración de la anatomía de la suprarrenal que hemos extirpado y lo que más interés tiene es la consecusión de los resultados clínicos sumanente alentadores, con mejorías que persisten hasto ahora por más de -0 años de volución postoperatoria. Edad. — La edad de los pacientes estudiados y operados ha oscilado entre 24 años el más joven y 58 años el más viejo estando la mayoría de los casos elegidos en la tercera y cuarta década. Sexo. — Tocante al sexo podemos decir que 22 enfermos han sido del sexo femenino y 15 del masculino. No nos ánimos a dar valor a esta estadística, pero habrá que tenerlo en cuenta, sobre todo porque la preponderacia de mujeres estaba en el predominio de las lesiones pielonefriticas. Estudio de los enfermos. — De los 37 casos estudiados, 13 tenían diagnóstico de glomerulonefritis crónica, de los cuales tan solo 3 eran de evolución benigna con respecto a insuficiencia renal, los otros eran marcadamente graves, tanto en su estado clínico como en las comprobaciones funcionales. Los otros 24 casos estaban formados por estados pielonefríticos genuinos salvo uno. Desechamos por el momento toda pielonefritis secundaria a alteraciones renales, como hidronefrosis, litiasis, tumores, etc. De todos estos casos de pielonefritis solamente 4 no tenian lesiones graves generales, secundarias a la hipertensión o a la insuficiencia renal ; los 20 restantes debemos considerarlos como casos graves por su estado y por su pronóstico. Desde el punto de vista patológico hemos estudiado únicamente aquellos casos en que el estado renal entraba dentro del campo de las nefritis y de las pielonefritis ; incluímos solamente un caso de poliquistosis renal con pielonefritis doble ; por su naturaleza anatóo mica deberíamos excluirlo, pero, el estado anatomo-patológico de las suprarrenales post-morten fué tan extraordinariamente interesante, que permitió hilar una serie de estados anatómicos observados en otros casos, pero que en este se presentaron simultáneamente dando unidad deductiva a las conclusiones sobre la morfología patológica de la glándula. Si tomamos en conjunto a los 37 casos podemos decir que ; desde el punto de vista de la insuficiencia renal, en 29 de ellos la insuficiencia renal era manifiestamente grave. En ostros 5 enfermos las pruebas funcionales de riñon fueron discretas y en otros 3 no había manifestaciones de insuficiencia urinaria, salvo que le exigiéramos funciones de tolerancia máxima reveladas por valores iguales extraídos de analisis repetidos en condiciones distintas de vida, esfuerzos, etc. Con respecto a la hipertensión : de los 37 casos, 33 eran marcadamente hipertensos, del tipo de hipertensión sostenida crónica con Mx. por arriba de 20 era. de Ilg. y con mínima siempre elevada. Varios casos llegaban a limites superiores a 27 cm. de Hg. De los 37 casos solamente 4 no teñían manifestaciones hipertensivas graves, pero su máxima estaba aún en las mejores condiciones, por arriba de 14-15 cm. de Hg. ; la mínima siempre tendía a manifestarse elevada. Para valorar el estado arterial general de los casos hemos recurrido en forma sistemática al estudio de fondo de ojo; podemos decir que hemos encontrado solo 8 caso en donde las arterias de fondo de ojo eran del tipo de hilo de cobre y con exudados retiñíanos. En 12 enfermos se encontró signo de Gura, grado 3. En 12 enfermos, grado 2. En 8 enfermos grado 1 o insinuándose una muy discreta compreción vascular. Para valorar el estado funcional de los ríñones se han utilizado las pruebas de depuración ureica, de depuración de creatinina y de depuración iòdica, así como la elimitación de Sulfofenalftaleína 6 mlgr. en una hora. Además, en muchos de ellos se ha medido la eliminación del iodo-hipurato marcado. Como dijimos más arriba solamente 4 dieron pruebas suficientes ; los restantes estaban dentro de los límites de insuficiencia grave o mediana predominando en gran número las primeras. En algunos casos liemos practicado también el estudio de las arterias renales mediante la aortografía con arteriograma total y con arteriografía renal selectiva, constatando en los casos graves de esclerosis las características arterias rígidas de los ríñones en ese estado. Las venas renales las hemos etudiado en 2 casos mediante flebografía selectiva. Estos exámenes de morfología vascular renal, no nos grada hacerlos rutinariamente, sino en casos muy seleccionados. Consideramos estas maniobras demasiado riesgosas, sobre lodo cuando son hechas en enfermos de grave insuficiencia renal ; hemos tenido agravaciones muy marcadas del estado de los enfermos e inclusive una muerte a consecuencia de este tipo de examen diagnóstico. Figura 1. INVESTIGACIÓN DEL ESTADO FUNCIONAL DE LAS SUPRARRENALES Hemos tratado, en la mayoría de los enfermos operados, de investigar el estado anatómico y funcional de las suprarrenales, siempre en busca de una orientación quirúrgica o de un estado funcional que nos proporcione datos analíticos claros y constantes que puedan revelar una disfunción fisiológica de las glándulas suprarrenales. Desgraciadamente tenemos que manifestar la enorme dificultad en obtener determinación fidedigna y la gran variabilidad de los valores funcionales aún en el mismo individuo. Las pruebas funcionales de la suprarrenal a que hemos recurrido han sido. La determinación de 17 liidroxicortisoles y de 17 cetoesteroides en sangre y en orina. Investigación de la aldosterona en sangre y en orina. La investigación y relación de las miliequivalencias de Na. y K, la prueba de Ekton-Ross, la prueba de eosinopenia provocada con A.C.T.H. y el Dosaje urinario y sanguíneo de Acido Vinil-mandélico. T" HL JL üf* Fio. 1 Nefroesclerosis hipertensiva, angiografia del riñon izquierdo. Suprarrenograma Fig. 2 angiográfico del caso anterior. Todas las pruebas mencionadas más arriba se han practicado, como dijimos, en la mayoría de los enfermos. En algunos se hizo imposible por deficiencias técnicas. En 4 de ellos las muestras de sangre fueron recogidos directamente de la aorta en la zona del riñon y de la vena renal izquierda simultáneamente. Debemos dejar ya establecido que hemos descartado todos acquellos casos en donde la mostración de feo-cromocitomas se hacia evidente, ya sea por las cifras del ácido vinil-mandélico exageradamente alta, ya sea por las manifestaciones hipertensivas clínicas o ya sea por el descubrimiento de tumores suprarrenales feocromocitómicos, dejando bien establecido que los que más nos interasaba eran los casos de nefroesclerosis en su relación con la suprarrenal. Los resultados de las investigaciones sobre las funciones que podrían revelar patologiá de la glándula han sido, en realidad, muy pobres. Las cifras del ácido vinil-mandélico eran normales a sobrepasaban discretemente a la normalidad; no obstante, en algumas ocasiones estaban marcadamente altas, aunque oscilantes en los distintos análisis. Las evidencias de aldosteronismo primario han sido muy pobres, pero creemos que podrían deberse a fallas en la técnica de su deterNa minación. El desequilibro iónico fué algunas veces evidente y K estuvo de acuerdo con los resultados anatómicos. Los 17 Hidroxicorticoides y los 17 Cetosteroides fueron generalmente normales. Las pruebas de Ekton-Ross han sido normales o aproximadamente. La Eosinopenia provocada, normal. Estas evidencias funcionales químicas a nuestro alcance no expresaban la realidad anatomo-patológica que, como veremos, se mostró muy evidente. INVESTIGATIÓN DEL ESTADO MORFOLÓGICO DE LAS SUPRARRENALES La investigación de la morfología de las suprarrenales la hemos practicado mediante distintas técnicas radiológicas pero, como la supprarrenal es muy difficil de evidenciarla con radiografías directas, hemos debido emplear métodos de artificio para hacer resaltar su imagen. Utilizamos la infiltración de gas en la atmósfera perirrenal y la inyección de sustancia opaca por sus arterias. Entre los métodos empleados para evidenciar la glándula rodeándola con un gas inerte, hemos empleado el método de Ruiz-Rivas, por el cual se introduce gas carbónico por vía presacra y el método de Carelli en el que la infiltración gaseosa se hace directamente en la atmósfera perirrenal. Cuando el volumen de la suprarrenal es lo suficientemente grande, la infiltracióne con gas carbónico o con aire delimita al órgano poniéndolo en evidencia dentro de una zona transparente a los rayos. Sin embargo, en nuestros casos, tanto el método que utiliza la inyección gaseosa por la escotadur sacro-coxigea como aquel que inyecta directamente en la celda renal, 110 nos han dado resultados satisfactorios y muchas veces se han confundido masas grasas, de forma más o menos triangular, con las suprarrenales ; claro está que en todos nuestros casos, si bien la glándula estaba aumentada discretamente de tamaño, no era lo suficiente para que fuera puesta de manifiesto en forma inobjetable. Angiografia suprarrenal. En vista de las dificultades diagnósticas con los métodos comunes, hemos intentado exidenciar la glándula con la angiografia selectiva, procedimiento difícil, sobre todo por la multiplicidad de vasos arteriales que irrigan la glándula ; 110 obstante, inyectando substancia iododa en la arteria renal, puede llenarse a veces la arteria suprarrenal inferior que parte de la renal y que es indudablemente la mayor de las arterias nutricias. La inyección de substancia opaca sirve además para hacer el diagnóstico de lesión vascular renal. Hemos empleado la arteriografiá suprarrenal porqué el perineumo reno-suprarrenal es una investigación falaz : Utilizamos la arteriografia selectiva de las suprarrenales en 5 casos pudiendo detectar la glándula sin inconvenientes ; esta investigación diagnóstica, la consideramos riesgosa porque se trabaja con enfermos en pobres condiciones biológicas y como la inyección de iodo, por más atóxico que sea el compuesto inyectable, siempre es en cantidad respetable, despertando inconvenientes después del exàmen, con malestar general, con desequilibrio vago-simpático y en un caso anuria. No obstante, la investigación radiológica con inyección de substancia de contraste en las arterias renales puede dar imágenes muy aceptables de la glándula suprarrenal verdaderos suprarrenogramas, que fijan con una verdadera y positiva imagen, el sitio y el tamaño de la glándula examinada. Este exámen no siempre es factible y se necesita mano especializada para conseguir resultados satisfactorios. La imagen más común es la que presenta en forma contrastada a la arteria suprarrenal inferior saliendo de la arteria renal ; generalmente es menos difícil en el lado izquierdo. La substancia opaca entrando por la arteria renal se introduce en la suprarrenal inferior y recorre un trayecto que algunas veces parece exagerado, para luego echarse en una laguna sanguinea, adoptando una imagen de apariencia algodonosa, en cierto modo parecida a la -, imagen que presentan las radiografías contrastadas de los tumores macizos de riñon, esta difusión de tipo algodonoso de la substancia opaca en la suprarrenal debe de estar dada, a nuestro entender, por el sistema cisternal que tiene la glándula, verdaderas cavidades de almacenamiento que pasan desapercividas en los órganos normales, pero que en nuestros casos, como veremos más adelante, se muestran muy evidentes y que generalmente están situadas en la zona de conjunción de la cortical con la medular. En la figura adjunta puede verse la impregnación iòdica que debemos interpretar que está situada en la medular, en su unión con la cortical. Las capas más superficiales de la cortical 110 se evidencian, pero el conjunto general de la imagen tiene, sin lugar a dudas, la forma carcterística del órgano en estudio. Agreguemos que la impregnación es rápida pero no lo suficiente como para impedir registrar su imagen. Figura 2. TRATAMIENTO Prepacación del enfermo : El enfermo ha sido preparado tratando de mantener su equilibrio sanguíneo lo más apropiado posible. Después de algunos ensayos, hemos encontrado que la administración de cortisona no es necesario hacerla en gran cantidad. Tan solo 50 mg. durante 2 días antes de la intervención ha sido suficiente. No hemos encontrado inconveniente en la administración de Na. Suprarrenalectomía : Con respecto a la intervención quirúrgica podemos decir : De la experiencia que tuvimos con la suprarrenalectomía total o subtotal hecha en otra serie de casos de hipertensión a r t e r i a l , así como en las p a r c t i c a d a s en e n f e r m o s p o r c á n c e r de p r ó s t a t a , liemos s a c a d o en c o n s e c u e n c i a que los b e n e f i c i o s de las s u p r a r r e n a l e c t o m í a s b i l a t e r a l e s son m u y escasos en r e l a c i ó n al p e r j u i c i o p r o v o c a d o p o r los s í n t o m a s a d r e n o p r i v o s que, a d e m á s de ser serios y graves, no son fáciles de c o m p e n s a r . P o r lo tanto, en 36 de los 37 casos de esta serie de e n f e r m o s h e m o s p r a c t i c a d o la a d r e n a l e c t o m í a u n i l a t e r a l , eligiendo g e n e r a l m e n t e la g l á n d u l a i z q u i e r d a . Se h i c i e r o n c u a t r o a d r e n a l e c t o m í a s d e r e c h a s p o r q u e f u é n e c e s a r i o i n v e s t i g a r el estado del p e d í c u l o r e n a l y del r i ñ o n d e r e c h o en sendos casos de h i p e r t e n s i ó n . N u e s t r a p r e f e r e n c i a p o r el lado i z q u i e r d o estriba en que la a d r e n a l i z q u i e r d a es a n a t ó m i c a m e n t e m á s g r a n d e , e s t a n d o a d e m á s c o l o c a d a m á s b a j o en la región l u m b a r y sus p e d í c u l o s son m u c h o m á s accesibles, s o b r e todo la vena central, que se p u e d e ligar sin d i f i c u l t a d ; no así la d e r e c h a que algunas veces es t a n corta que p a r e c e no d e j a r espacio ligable e n t r e la s u p r a r r e n a l y la vena cava. La vía de a b o r d a j e p a r a la a d r e n a l e c t o m í a h a sido la lateral epic o s t o l u m b a r 12a. p r o l o n g a d a 5 cm. en la p a r e d e n t e r i o r del a b d o m e n . Este a b o r d a j e es s u m a m e n t e fácil y r á p i d o y p e r m i t e no solo u n gran c a m p o q u i r ú r g i c o , sino t a m b i é n una e x p l o r a c i ó n a m p l i a del r i ñ ó n y demás tejidos para-adrenales y para-aórticos. La a t e n c i ó n o p e r a t o r i a debe ser c u i d a d o s a a causa de las sorp r e s a s que p u e d e n d a r las r e a c c i o n e s d e p e n d i e n t e s del m o n o s e o de la glándula. E n general no h e m o s t e n i d o i n c o n v e n i e n t e s d e n t r o de la fase o p e r a t o r i a , p e r o sí h e m o s visto a l g u n a s crisis h i p e r t e n s i v a s , s o b r e todo c u a n d o la vena c e n t r a l de la glándula se halla m u y p r o f u n d a o es m u y corta, e s p e c i a l m e n t e en el lado d e r e c h o . Bajas s u s t a n c i a l e s de la p r e s i ó n a r t e r i a l , como o b s e r v á b a m o s c u a n d o p r a c t i c á b a m o s la extirp a c i ó n de a m b a s glándulas, no las h e m o s visto m á s y las p e q u e ñ a s c a í d a s de tensión son r á p i d a m e n t e s u b s a n a b l e s con la a d m i n i s t r a c i ó n de e p i n e f r i n a . Tratamiento postoperatorio : Más i m p o r t a n t e es tal vez el t r a t a m i e n t o i n m e d i a t o p o s t o p e r a t o r i o . Como regla g e n e r a l i n s t i t u i m o s el d í a de la o p e r a c i ó n y los 3 días subsiguientes, la a d m i n i s t r a c i ó n d i a r i a de 100 mg. de c o r t i s o n a d e p a r t i d a s en 25 mg. c a d a 6 h o r a s p o r vía p a r e n t e r a l . Luego d i s m i n u i m o s p a u l a t i n a m e n t e la dosis, p a r a estar en solo 25 mg. d i a r i o s a los 15 días y r e t i r a m o s la m e d i c a c i ó n a los 20 días de o p e r a d o . En el p o s t o p e r a t o r i o i n m e d i a t o d a m o s t a m b i é n D.O.C.A. 10 mg. d u r a n t e los p r i m e r o s diez días. No h e m o s e n c o n t r a d o i n c o n v e n i e n t e s en la a d m i n i s t r a c i ó n de suero fisiológico salino normal. Es e x t r a o r d i n a r i a la t o l e r a n c i a que t i e n e n estos e n f e r m o s c r ó n i c o s a u n a i n t e r v e n c i ó n que p a r e c e r í a t e n e r que ser m á s c h o c a n t e . Si el e n f e r m o está bien p r e p a r a d o , si el a r t e o p e r a t o r i o es limpio y r á p i d o y el p o s t o p e r a t o r i o es el q u e h e m o s i n d i c a d o , la t o l e r a n c i a es p e r f e c t a , no p r e s e n t á n d o s e signos de i n s u f i c i e n c i a i n m e d i a t a . No obstante, d e b e m o s l a m e n t a r la p é r d i d a de 2 e n f e r m o s en el p e r í o d o i n m e d i a t o , m u r i e n d o u n o de u n p r o c e s o c a r d i a c o agudo a los 3 días de o p e r a d o , y otro de i n s u f i c i e n c i a s u p r a r r e n a l , con v ó m i t o s y fiebre, que no p u d i m o s c o m p e n s a r , d u r a n d o s o l a m e n t e 10 días. RESULTADOS Normalmente, las glándulas suprarrenales cuando se les ha eliminado todo el tejido periglandular, tienen un peso aproximado de 3 gr. a 3.500 gr. La izquierda, siempre más voluminosa alcanza algunas veces a 3.800 gr. pero difícilmente más. En los 37 casos estudiados, el peso de las suprarrenales extraídas y limpias de todo elemento conjuntivo periglandular, variaba entre ios 4 grs. y los 9 grs. pudiéndose agrupar de la siguiente manera : Entre 4 y 5 gr. 8 glándulas Entre 5 y 6 gr. 8 » Entre (i y 7 gr. 10 » Entre 7 y 8 gr. 3 Entre 8 y 9 gr. 2 Arriba de 9 gr. De estas dos últimas, una pesaba 9 gr. y la otra 9.300 gr. Si comparamos el peso de estas glándulas con el estado clínico de estos enfermos, podemos decir con seguridad, que, en las nefroesclerosis hipertensivas graves, cualquiera que sea su origen etiológico, las suprarrenales tienen 1111 mayor peso, llegando en dos de ellos arriba de los 9 gr. En las 4 suprarrenales que pertenecían a esclerosis renales sin hipertensión, los pesos correspondían a valores inferiores de 5 gr. Con respecto a estos resultados en relación con los análisis de la función suprarrenal, podemos decir que : cuando los análisis clínicos revelaban aumento de catecolominas o de Vinil-mandélico, existía, sin ninguna duda, hiperplasia de la zona medular y de las formaciones venosas que describiremos más adelante. Una suprarrenal de 7.200 gr., llevaba un nervio apreciable, en contacto y dentro de la cortical. Otra suprarrenal de 6.800 gr. tenia, adosado en una de sus caras, un pequeño tumor hiperplásico de la capa glomerular de la zona cortical. Color de las suprarrenales : Si bien el color de las suprarrenales normales es amarillo oro, en todas las suprarrenales extraídas, hecho ya observado en el acto quirúrgico, el color era más bien amarillo grisáceo y algunas veces grisáceo directamente. En cuanto a la forma, tamaño y espesor, es tan variable en las normales, que 110 podemos decir que en estas suprarrenales haya habido variaciones marcadas ; tan sólo diremos que erran todas más grandes, pero podríamos decir que, apreciativamente en las formas hipertensivas eran generalmente de mayor espesor. Hasta ahora 110 encontramos verdaderos tumores macroscópicamente muy evidentes. Recorde raos que hemos descartado de exprofeso todo caso que muestre evidencia de feocromocitomas clínicamente demostrable. HISTOLOGIA Resultados : La investigación h i s t o p a t o l ó g i c a es lo que m á s evidentemente m u e s t r a la i n t e r r e l a c i ó n s u p r a r r e n a l con el r i ñ o n . Las lesiones e n c o n t r a d a s son bien c l a r a s y n e t a m e n t e d i f e r e n t e s en r e l a c i ó n a las g l á n d u l a s n o r m a l e s y p e r m i t e n i n t e r p r e t a r los h e c h o s clínicos d a n d o base p a r a la e x p l i c a c i ó n de las m e j o r í a s c o n s e g u i d a s con la ablación de la g l á n d u l a s u p r a r r e n a l en estos casos d e n e f r o e s c l e r o s i s con o sin hipertensión. Antes de detallar lo e n c o n t r a d o h i s t o l ó g i c a m e n t e , q u e r e m o s e x p o n e r n u e s t r o s c o n c e p t o s s o b r e la e s t r u c t u r a n o r m a l de la glándula. En g e n e r a l , la división de la s u p r a r r e n a l en dos zonas, c o r t i c a l y m e d u l a r no p u e d e de n i n g ú n m o d o negarse, p e r o es n e c e s a r i o ser m á s e s p e c i f i c o c o n r e s p e c t o a las e s t r u c t u r a s n o r m a l e s de estas zonas, y d e t e n e r n o s a d e m á s a p e n s a r sobre el valor fisiológico de la zona de u n i ó n que se e s t a b l e c e c u a n d o t o m a n c o n t r a c t o la c o r t i c a l y la m e d u l a r . P o r de p r o n t o a la zona c o r t i c a l debe agregársele otra c a p a que a d q u i e r e especial i m p o r t a n c i a c u a n d o la g l á n d u l a es c r ó n i c a m e n t e e x c i t a d o y así, a las c a p a s g l o m e r u l a r , r e t i c u l a r y f a s c i c u l a r se debe a g r e g a r otra, la germinativa. Los c o m p o n e n t e s c e l u l a r e s que f o r m a n la c a p a g e r m i n a t i v a están c o l o c a d a s en c o n t a c t o i n m e d i a t o con la cápsula c o n j u n t i v a del ó r g a n o , son las que r e c i b e n de i n m e d i a t o el sistema nutricio s a n g u í n e o en base a c a p i l a r e s y p e q u e ñ a s a r t e r i o l a s ; no es u n a c a p á c o n t i n u a y m á s bien sus células están a g r u p a d a s en c o n j u n t o s d e 3, -1 o m á s elementos, sin e s t r u c t u r a s a r q u i t e c t ó n i c a s p r o p i a s . Se ed 3, -1 o más elementos, sin f o r m a n la g l o m e r u l a r p o r q u e la a r q u i t u e c t u r a de esta última es, c o m o v e r e m o s m á s adelante, m u y bien d e f i n i d a . Las células g e r m i n a t i v a s en sí a d o p t a n la f o r m a c o m ú n de t o d o s los elementos epiteliales ; en p r i n c i p i o d e b e n c o n s i d e r a r s e como e l e m e n t o s r e d o n d o s p e r o , p o r la c o m p r e s i ó n de los vecinos, están en f o r m a s p o l i é d r i c a s diversas. Son células m e d i a n a s , de p r o t o p l a s m a t e ñ i d o con los colores ácido, m á s t e ñ i d o s que los de la c a p a glomer u l a r y m u c h o m á s que los de la f a s c i c u l a r , a u n q u e , en general, en su o r i g e n se p a r e z c a n . El c o n t e n i d o p r o t o p l a s m á t i c o está c o n s t i t u i d o p o r los elementos c o m u n e s d i s c e r n i b l e s p o r las c o l o r a c i o n e s citológicas. El núcleo de las células g e r m i n a t i v a s es de t a m a ñ o m e d i a n o , r e d o n d e a d o y está colocado m á s bien h a c i a la base e x t e r n a celular. E v i d e n t e m e n t e p a r e c e ser ést el g r u p o celular de c a r á c t e r p r o d u c t i v o ; a u n q u e no t e n e m o s aún e v i d e n c i a neta de su f u n c i ó n , p a r e c e r e g i r la p r o d u c c i ó n e i n i c i a c i ó n del ciclo celular cortical. En c u a n t o a las d e m á s c a p a s de la zona c o r t i c a l n o r m a l , no hablar e m o s p o r estar de a c u e r d o con los c o n o c i m i e n t o s actuales. Con r e s p e c t o a la zona de u n i ó n de la c o r t i c a l con la m e d u l a r , si bien está el c o n c e p t o general de neta división e n t r e estos g r u p o s emb r i o l ó g i c a m e n t e n e t a m e n t e d i f e r e n t e s , d é b e n o s p e n s a r que la i n t e r r e lación fisiológica e n t r e ellos es m u c h o m á s i m p o r t a n t e que lo q u e p u e d e p a r e c e r a s i m p l e vista. P o r de p r o n t o es en esa zona en d o n d e se ven las p r i m e r a s m a n i f e s t a c i o n e s c i s t e r n a l e s que c o l e c c i o n a r á n los p r o ductos de secreción' celular y que n o r m a l m e n t e p a r e c e r í a n no existir p e r o que v e r e m o s e v i d e n c i a r en los estados patológicos. R e p i t i e n d o lo que d i j i m o s más a r r i b a , el resto de la zona m e d u l a r t a m p o c o e n t r a r á en discusión p o r c o n s i d e r a r l o , h a s t a a h o r a , d e n t r o d e los c o n o c i m i e n t o s clásicos. PATOLOGIA SUPRARRENAL Habiendo dado nuestro punto de vista sobre la histología normal de las suprarrenales, expondremos inmediatamente lo encontrado en esta investigación. Este capítulo representa el punto más importante de este trabajo. Las modificiaciones anatomo-histológicas de las suprarrenales en los casos de esclerosis renal maligna, cualquiera que sea su origen inicial o su patología, muestran características y variaciones que consideramos de interés fisiopatológco y que podrían explicar algunos estados evolutivos cuya marcha fatal inexorable podría ser retardada o detenida con tratamiento apropiado. La metódica empleada para el estudio de estas suprarrenales ha sido la usual en histología patológica. Se ha tenido especial cuidado en fijar las glándulas en forma inmediata después de su extirpación quirúrgica. Los fijadores usados han sido : formol al 10%, formol bicromatado y formol picroacétio de Rouin. Inclusión en parafina ; cortes de las mismas y cortes por congelación. Las coloraciones empleadas han sido : Hematoxilina-Eosina, Tricrómico de Masson, Tricrómico de Mallory, coloraciones argénticas de Del Río-Ortega, coloración de Gomorri y de Bielchanzky para sistema nervioso. Zona cortical : Sus alteraciones : Tanto en las nefroesclerosis con hipertensión como en las que no presentaban hipertensión, las lesiones fueron similares. Prácticamente en todas las glándulas examinadas hemos encontrado alteraciones de las estructuras normales. Estas alteraciones podemos catalogarlas de la siguiente manera : Capa germinativa : La capa germinativa se hace en general más evidente. Figura 3. Esta capa que en condiciones normales está constituida por pequeños grupos de 3 a 4 células situadas aisladamente debajo de la cápsula conjunctiva de la suprarrenal, se hace, en estos procesos, mucho más espesa aumentado su número a 6, 8 o más elementos, formando algunas veces, por la continuidad de sus agrupaciones, una verdadera capa continua que abarca casi toda la periferia glandular ; muéstrase activa aunque no hemos observado divisiones celulares como se pueden observar en otras capas de células germinativas del organismo. Los grupos celulares germinativos suelen penetrar profundamente en el espesor de la zona cortical llegando en muchas circunstancias hasta la reticular. Capa glomerular : La capa glomerular es la que muestra más alteraciones en su estructura, todas en forma de hiperplasia. Así hemos hallado : a) Hiperplasia glomerular difusa, donde todos los elementos de la capa glomerular y aún parte de la fascicular se encuentran aumentados en número, pero sin alteración de la armonía de su estructura c salvo en algunos casos en que la capa glomerular adquiere tal espesor que dezplaza manifiestamente al resto de las células fasciculares y a toda la capa reticular, quedando reducidas aparentemente estas dos últimas capas a la mitad de su área habitual. No creemos en realidad, que sea una reducción real de elementos fasciculares y reticulares ; podría ser una imagen aparente producida por el aumento indudable del espesor de la capa glomerular. Figura 4. FIG. 4 Hiperplasia glomerular difusa. I)) Hiperplasia glomerular nodular. En algunos casos hemos podido observar que la capa glomerular, si bien siempre presenta un aumento de su área, muestra además verdaderos estados hiperplásicos localizados en forma de nodulos, algunas veces visibles macroscópicamente. Estos nodulos están bien limitados por el resto de las células de la zona cortical y pueden colocarse en cualquier sitio de ella, ya sea cerca de la cápsula o ya sea más profundamente en plena capa reticular. El tamaño de estos nodulos hiperplásicos es variable pero, generalmente son pequeños. Con respecto a su número, habitualmente son nodulos solitarios, por lo menos en el exámen de una preparación pero, en el exámen total de la glándula, se puede constatar su multiplicidad. Figura 5. c) Hiperplasia glomerular adenomatoide. En general la hiperplasia glomerular adenomatoide la hemos observado en pocas circunstancias pero, la hemos visto muy especialmente en una nefroesclerosis terminal provocada por una poliquistosis renal. Se mostraba como una hiperplasia nodular pero con cavidades colectoras que la hacían parecer a una verdadera glándula. Es propable que sea una imagen dada por el acumulo de secretiones almacenadas en los intersticios y en los capilares intercelulares. Figura (i. d) Hernias tisurales. Hemos observado también en casos de esclerosis terminal hipertensiva, una situación muy curiosa. La cápsula fibroconjuntiva de la suprarrenal mostraba soluciones de continuidad o efracciones y, saliendo a través de tales efracciones, se podia ver masas celulares pertenecientes a la capa glomerular, mostrando un volumen apreciable, en situación extraglandular y unidas a la glándula por un puente celular a través de la efracción. Las células herniadas estaban perfectamente conservadas y se había elaborado alrededor de la masa saliente, una seudocápsula continente que aseguraba indudablemente la vitalidad y los intercambios celulares. Figura 7. Fio. 5 Hiperplasia glomerular nodular. Fie. 7 Hernia tisural. e) Tumores corticales anexos a la glándula principal. En dos de los casos de nefroesclerosis por nefritis crónica, hemos observado un verdadero tumorcito, al parecer aislado, situado al lado de la glándula y (le un tamaño lo suficientemente apreciable como para observarse a pequeño aumento. Este tumorcito estaba formado por células corticales, evidentemente de la capa más superficial y era probablemente del tipo glomerular. El origen de estos tumorcit.os a d l á t e r e a la glándula, p u e d e e x p l i c a r s e f á c i l m e n t e si nos a t e n e m o s a la e x i s t e n c i a de las soluciones de c o n t i n u i d a d que h e m o s visto en la cápsula p r o p i a a d r e n a l . E] t u m o r h a l l a d o tenía todo el aspecto de estar aislado del resto de la glándula, p e r o su o r i g e n p o d r í a ser m u y bien g l a n d u l a r inicial, p o r q u e al p r o v o c a r s e u n a h e r n i a celular en la cápsula, p e r m i t e ésta la f o r m a c i ó n de u n a t u m a r a c i ó n , no i m p o r t a n d o su t a m a ñ o . Luega la c á p s u l a p r o p i a , al c i c a t r i z a r s e y r e c u p e r a r su c o n t i n u i d a d deja, de esta m a n e r a , aislado al t u m o r n e o f o r m a d o . El m a n t e n i m i e n t o m e t a b ó l i c o de las células en su nueva s i t u a c i ó n , p u e d e h a c e r s e p e r f e c t a m e n t e m e d i a n t e el sistema de i n j e r t o en el t e j i d o v á s c u l o - c o n j u n t i v o p e r i s u p r a r r e n a l . F i g u r a 8. Capas fascicular y reticular : Las c a p a s f a s c i c u l a r y r e t i c u l a r se e n c u e n t r a n , algunas veces, en estado de alteración e s t r u c t u r a l , p e r o sus v a r i a c i o n e s se deben m á s al d e s p l a z a m i e n t o que s o p o r t a n p o r el a g r a n d a m i e n t o de la glonierular, que p o r lesiones p r o p i a s , s i e n d o sus situaciones a n o r m a l e s , al p a r e c e r , de escasa i m p o r t a n c i a . Zona medular : En las n e f r o e s c l e r o s i s con h i p e r t e n s i ó n o sin ella, se o b s e r v a n algunas a l t e r a c i o n e s de la e s t r u c t u r a n o r m a l de la zona m e d u l a r de las s u p r a r r e n a l e s . Estas a l t e r a c i o n e s t i e n e n p o c o s i g n i f i c a d o en los casos de esclerosis sin h i p e r t e n s i ó n ; p e r o , en todos aquellos casos que p r e s e n t a r o n h i p e r t e n s i ó n severa, h e m o s o b s e r v a d o a l t e r a c i o n e s sumam e n t e i m p o r t a n t e s y que nos l l a m a r o n m a r c a d a m e n t e la a t e n c i ó n . C o n s i d e r a n d o las m o d i f i c a c i o n e s e s t r u c t u r a l e s o b s e r v a d a s , p o d r í a m o s d e c i r que ellas se p r e s e n t a n en general, en s e n t i d o de a u m e n t o de n ú m e r o de células, de tipo h i p e r p l á s i c o y en m o d i f i c a c i o n e s de los sistemas de e v a c u a c i ó n s e c r e t o r i a , así c o m o de a l t e r a c i o n e s de tipo neurales. P a r a seguir la m e t ó d i c a de exposición e m p l e a d a p o d e m o s d e c i r q u e las a l t e r a c i o n e s e n c o n t r a d a s son : anteriormente, a) H i p e r p l a s i a de la zona m e d u l a r . P r a t i c a m e n t e h e m o s o b s e r v a d o la h i p e r p l a s i a d e la zona m e d u l a r en t o d a s las g l á n d u l a s s u p r a r r e n a l e s e x t r a í d a s , p e r o , muy p o c o m a r c a d a en los casos sin h i p e r t e n s i ó n y en cambio, m u y e v i d e n t e en todos los casos que p r e s e n t a b a n h i p e r tensión. E n este a u m e n t o de n ú m e r o de los elementos celulares, estos no m o s t r a b a n signos de desviación m a l i g n a ni m u t a c i o n e s y t e n í a n sus células un aspecto p r á c t i c a m e n t e ormal. Con algunas c o l o r a c i o n e s especiales se p o n í a , sin e m b a r g o , de m a n i f i e s t o 1111 p o l i c r o m a t i s m a que i n d i c a b a , p r o b a b l e m e n t e , d i f e r e n t e s estados f u n c i o n a l e s , p e r o , t a n t o en f o r m a como en t a m a ñ o y en a c t i v i d a d n u c l e a r no d i f e r í a n de lo que se e n c u e n t r a en las m e d u l a r e s de las s u p r a r r e n a l e s n o r m a l e s . La h i p e r p l a s i a p u e d e m a n i f e s t a r s e en f o r m a total, e s t a n d o toda la zona m e d u l a r de los distintos sectores de la glándula en estado de h i p e r p l a s i a , p e r o t a m b i é n p u e d e m a n i festarse m á s i n t e n s a m e n t e en c i e r t a s zonas en especial. En general, la p a r t e m á s h i p e r p l á s i c a suele ser la zona c e n t r a l de la glándula p e r o , eso 110 es óbice p a r a que en las b a n d e l e t a s de la g l á n d u l a se vean zonas de a u m e n t o e s t r u c t u r a l que llegan, a veces, a ser v e r d a d e r a s h i p e r p l a s i a s totales. F i g u r a s !) y 10. FIG. 9 Hiperplasia medular en la orejuela. FIG. 10 Hiperplasia medular central. b) Incremento de los espacios intercelulares. También es frecuente la observación del aumento de tamaño y de número de los espacios cavitarios intercelulares y, en especial, en las zonas de la medular que está situada en las extremidades de las bandeletas y que toman contacto directo con la zona cortical, produciendo una verdadera zona intermedia. Esas cavidades intercelulares podrían ser capilares llenos de secrección pero, si bien algunas veces llega a observarse un endatelio limitante, en general no existe tal endotelio y se forma entonces un verdadero sistema lacunar intercelular ; Estas cavidades confluyen en definitiva hacia la parte central de la zona medular. Figura 11. c) Aumento de las cavidades venosas. Ea confluencia de los espacios intercelulares, mencionado más arriba, termina por constituir una gran cavidad venosa que formará, más adelante, la vena central de la glándula. Normalmente las venas que surcan la zona medular, están formadas por paredes finas, delgadas y son de muy baja participación muscular ; son, si pudiéramos decir, como cisternas colectoras. Figura 11. d) Modificationes de las paredes venosas. En los casos observados por nosotros, hemos encontrado notables cambios en las estructuras que constituyen la pared venosa ; las describiremos con cierto detalle porque es necesario darles todo el significado fisiológico que requieren. Así hemos visto : 1" Alteraciones en la endovena. Las modificaciones en la pared interna del vaso, están constituidas por grupos celulares con todas las características de los elementos leyomiomatosos. Estas formaciones pueden ser de diverso tamaño y se establecen como pequeños tumorcitos endoparietales que pueden llegar a ser, algunas veces, relativamente grandes y ocupar un espacio endovenoso apreciable. Figura 12. 2" Hemos observado también que, en algunas ocasiones, esas formaciones endoparietales con características gang'lionares, están en contacto íntimo con la terminación nerviosa de un nervio que puede tener apreciable diámetro. Las coloraciones para sistema nervioso marcan un retículo de lipo gliar que, naciendo del tumor, toma contacto con algún nervio situado en un extremo de esta formación. Figura 13. Estas formaciones pueden ser únicas o múltiples. 3" Alteraciones de la pared venosa en situación intermedia. Llama también la atención ciertas formaciones de estructuras neuromuscular, situadas aisladamente en plena pared venosa. El tamaño de las mismas puede ser muy diverso, pero, siempre Fio. 11 Sistema cisternal y vena colectora. Fie. 12 Tumor leiomatoso intravenoso. están situadas en plena pared y son, generalmente, nodulares, redondeadas, bien precisas y como encapsuladas. Las coloraciones selectivas muestran que estas forcaciones están constituidas por fibras musculares lisas y elementos muy semejantes a las sélulas ganglionares nerviosas. Se diferencian estas formaciones, muy netamente, de las enteriormente descriptas en situación endovenosa, porque aquellas 110 tienen fibras musculares y éstas, situadas en plena pared, tienen fibras musculares predominantemente. Figura 14. Fio. 13 Formaciones paraganglionares intravenosas con su nervio correspondiente. Fio. 14 Leiomiomas nodulares de la pared venosa, 4" Alteraciones de toda la pared venosa. En las grandes cavidades venosas liemos encontrado modificaciones de la estructura muscular ; así, parcticamente en todas las glándulas suprarre- nales extraídas y, en especial en las de los casos con hipertensión, hemos podido observar modificaciones netas de las paredes venosas, mostrando éstas, marcadas hipertrofias en sentido circular. Estas alteraciones están limitadas, formando como verdaderos manguitos circundando una cavidad : Histológicamente están formados por elementos musculares lisos hiperplasiados e hipertrofiados y también por estructuras neuroganglionares. Estas formaciones determinan marcados estrechamientos de la cavidad vascular central, pareciendo actuar como verdaderos esfínteres, teniendo por arriba y por abajo de ellos, cavidades donde la vena se halla con sus paredes normales finas y sin alteración de ninguna especie. Figuras 15 y lfi. Fio. 15 Pseudoesfínter venoso. ''' Pseudoesfínter en vénula. 5° Otra situación que es necesario describir, es la de la existencia de estructuras muy similares a los ganglios nerviosos que están situadas por fuera de la pared venosa pero, por un extremo, en contacto con dichas paredes ; la que se puede ver en la Figura 17, parece ser un pequeño ganglio nervioso con el cuerpo ganglionar situado libremente en pleno tejido medular y con sus terminaciones entrando dentro de la pared venosa, en su trayecto extraganglionar. (5 Hipertrofia total de la vena central. En general el exámen histológico de la vena central de todas las suprarrenales estudiadas, deja ver algunas alteraciones estructurales traducidas por aumento de las capas musculares. La hipertrofia de las capas musculares fué especialmente observada en un caso de hipertensión en una poliquistosis renal : La estructura muscular tenía, en ese caso, una marcado reacción hipertrófica, tanto que el espesor de sus paredes era mucho mayor que la cavidad que formaban dichas paredes, determinando un aparente estrechamiento de su luz. o Zona intermedia : Lo que llamamos zona intermedia, es decir el espacio donde toma contacto la zona cortical con la medular, si bien no tiene características propias definidas, suele tener modificaciones en su estructura arquitectónica que es necesario poner de relieve ; lo que más llama la atención en las suprarrenales de estos enfermos de nefroesclerosis con y sin hipertensión, es el desarrollo de un sistema cisternal que se pone marcadamente de manifiesto, sobre todo en las nefroesclerosis hipertensivas. No sabemos si el sistema cisternal pasa a ser un hecho defensivo sirviendo de acumulación del exceso de secreciones químicas celulares y actuando como lago regulador o sí, en realidad, es un sistema de ataque cuando se produce bruscamente la eliminación de los elementos secretados, que producirá reacciones violentas generales del tipo hipertensinógeno o esclerógeno. Figura 17. En la zona intermedia suelen observarse también algunas formaciones nerviosas, representadas por nervios de apreciable diámetro, que desparraman sus terminaciones en dicha zona. Figura 18. Fio. 17 Ganglio nervioso en relación con la pared venosa. FIG. 18 Grueso tronco nervioso penetrando hasta la zona intermedia. También es dable observar pequeños grupos celulares medulares que se sitúan rodeando a vasos venosos centrales y, en contreparte, algunas masas celulares de la cortical, que incursionan dentro de la zona medular. Sisteman complementarios : Aparte de las alteraciones encontradas en la estructura parenquimatosa y de sostén de la propia glándula suprarrenal, hay también algunas alteraciones en lo que podríamos llamar sistemas complementarios de la glándula y, aquí podemos mencionar ciertas formaciones nerviosas que hemos encontrado en 4 casos de nefroesclerosis con hipertensión. En uno de ellos, especialmente, perteneciente a una glomerulonefritis hipertensiva grave, pudimos observar formaciones nerviosas de tipo tumoral, verdaderos neuromas de tipo benigno cuyo espesor era prácticamente igual al de una de las lengütas de a suprarrenal, a la que estaba adosado. Este tumor se encontraba situado en un repliegue del órgano y en relación con arteriolas y venas. El conjunto parecía representar un verdadero pedículo vasculonerviosp en anomalía. Pero lo más interesante no estaba en la formación tumoral en si, sino en sus relaciones con la glándula. Junto al neuroma había nervios de apreciable diámetro que penetraban en la cortical de la suprarrenal y después de recorrer 1111 corto trayector se distribuían en abanico por los espacios intersticiales Figura 19. Estas alteraciones de la distribucción nerviosa en la suprarrenal las hemos visto repetidas en varias glándulas, tanto que, en una de ellas, un tronco nervioso penetraba indiviso hasta la zona medular tomando contracta directo con las grandes formaciones vasculocisternales. Fie. 19 Neuroma paraglandular. EVOLUTION CLINICA No podemos dejar de considerar la evolución clínica de 36 de los 37 casos estudiados y tratados con adrenalectomia unilateral. Repetimos que el trigésimo séptimo caso pertenecía a una esclerosis renal por poliquistosis y ha sido incluido en esta estadística porque la suprarrenal extraída postmorten fué muy interesante. En los 36 casos, si bien nuestra principal atención estaba orientada hacia el estudio de la relación suprarrenal-riñón, no dejábamos de tener esperanzas sobre el resultado clínico favorable con la extirpación de la glándula. Teníamos, por de pronto, en nuestro pensamiento, la base fisiológica de la acción fibroplástica de las suprarrenales mediante los mineralcorticoides ; teníamos además la acción fisiológica indiscutida de los elementos secretados por la medular y /también por lo Aldosterona, sobre la tensión arterial. De manera que la adrenalectomia tendría que ser, desde todo punto de vista, una intervención médicamente favorable. Y los resultados clínicos han sido todo lo satisfactorio que se podría esperar. Nunca hemos pensado, al hacer la adrenalectomia, en curaciones definitivas de la esclerosis renal, ni hemos pensado tampoco en retrocesos totales de dichas lesiones. Consideramos que las esclerosis renales son estados de repercusión general ; por la tanto, no era nuestra pretensión curar lesiones establecidas e irreversibles, pero sí tener la esperanza de detener la gravedad progresiva y mantener al enfermo en estado de compensación functional, evitando, con la adrenalectomia, que el proceso avance en forma inexorable como siempre lo hace. Pues bien, como dijimos, los resultados han sido alentadores y hemos conseguido restituir a más de la mitad de los enfermos tratados, a las actividades sociales, trabajo, etc. que cumplían anteriormente. Es interesante hacer 11 estudio a distancia de los enfermos sometidos a esta intervención analizando la sobrevida mediata, el estado clínico general y sobre todo la evolución de latensión arterial, las modificaciones que pueden haber surgido deste el punto de vista de la función renal y también considerar su reintegración a la vida de relación cotidiana y su capacidad para valerse por sí mismo. Análisis de lo. sobrevida postoperatoria : Ya hemos dejado señalado que la mortalidad postoperatoria inherente a la intervención ha sido (fe 3 enfermos de los cuales solamente una fué causada por insuficiencia aguda suprarrenal, las otras dos fueron debidas una a un infarto pulmonar y otra a un estado cardíaco agudo, estos dos últimos casos desgraciadamente deben ser considerados como riesgos imprevisibles ; en cuanto al caso de insuficiencia suprarrenal aguda, es probable que se haya tratado de una glándula única ; con todo, ese hecho no es óbice para la sobrevida, en realidad se trataba de un enfermo con una nefroesclerosis terminal, en muy mal estado, con franca uremia y que no se pudo llevar a un post-operatorio sin riesgos. En cuanto a ia sobrevida mediata podemos decir que 3 de los operados fallecieron antes de terminar el año de la intervención uno de un infarto de miocardio, y 2 de trombosis cerebral. Otros dos enfermos fallecieron dentro de los 2 años de operados, también por fenómenos angiocerebrales y los restantes todos han vivido más de 3 años estando aún vivos 8 enfermos que hace más de 10 años hemos operado. Evolución de la presión arterial en los casos de hipertensión : De los 37 casos operados, 33 eran liipertensos, la mayor parte graves ; con lesiones angeticas en fondo de ojo y con estado general muy comprometido. De estos 33 enfermos debemos descartar los 3 óbitos postoperatorios ; los 30 restantes presentaron en forma inmediata una baja fanca de las cifras tensionales sobre todo de la Mx. ; esto puede ser imputado al desequilibrio operatorio, pero es interesante consignar que más de la mitad han permanecido con tensión arterial dentro de los límites normales y que aquellos que volvieron a hacerse liipertensos han podido controlar su hipertensión mucho más fácilmente y con menos cantidad de drogas hipotensoras. De los enfermos con más de 10 años de vida postoperatoria, prácticamente todos están con límites tensionales normales o muy ligeramente excedidas. Función renal : La función renal es la que menos se ha modificado. En realidad ningún enfermo entró en normalidad de depuración renal, esto es fácilmente compresible, porque no podemos pensar en involución de un estado esclerósico renal, pero sí podemos decir que la gran mayoría de los enfermos han detenido por asi decir, el agravamiento continuo de su insuficiencia renal ; algunos han mejorado hasta en forma notable, Pensamos que evitando la evolución esclerogénica prodría haberse producido una hipertrofia por necesidad de los nefrones que hasta ese momento no estaban afectados. Como argumento de importancia para explicar el buen estado funcional depurador que presentan algunos enfermos, debemos pensar que al estar frenada la tendencia esclerogénica, los demás órganos depuradores, incluida especialmente la piel, han aumentado la capacidad de rendimiento equilibrando la aliminación de toxinas orgánicas. Estado qeneral desde el punto de vista social : Todos los enfermos que hemos considerado en este trabajo eran seres en condiciones muy inferiores para valerse por si mismos, incluido muchos de ellos podián considerarse como afectados a mantenimiento social p o r la comunidad. La adrenalectomía, al normalizar en muchos la tensión arterial y la regulación de su función depuradora, los ha mejorado de tal manera que de carga social se han transformado en seres que se han valido por si solos p a r a su ulterior subsistencia, volviendo a trabajar y a prestar utilidad social, aunque en cierto modo limitada p a r a los excesos. Siempre han sido útiles en condiciones normales de vida, manteniendo indudablemente ciertas precauciones en un mejor equilibrio vital. Los resultados de los 37 casos operados se pueden resumir la siguiente manera : de Muy mejorados 18 : Mejorados 11 : Sin resultados <S. Consideramos muy mejorados a aquellos cuya evolución postoperatoria alejada lia sido muy buena, con nomalización de la tensión arterial, mejoría del estado general, restitución a sus funciones sociales y bienestar general. Dejamos aclarado que, si bien en algunos enfermos hemos tenido gran mejoría en la función renal, nunca hemos visto esta función normalizada en forma absoluta. Consideramos mejorados a todos aquellos enfermos que, subjetivamente, han sentido bienestar pero, en los que la tensión arterial no se ha normalizado como era de desear y en los que la función renal ha permanecido invariable. Consideramos sin resultados aquellos casos en que no ha habido modificaciones objectivas o subjetivas de mejoría. INTERPRETACION Si nos atenemos a la estricta observación de los hechos, especialmente a los resultados anatomo-patolágicos debemos sacar en consecuencia : 1" En la nefroesclerosis, cualquiera que sea su etiología, existen siempre alteraciones en la zona cortical y, en especial, en las capas germinal, glomerular y parte de la fascicular. Estas alteraciones son hiperplasias y ocupan un mayor espacio glandular que lo que ocupan dichas capas normalmente. Su importancia en la proliferación celular llega desde la hiperplasia simple hasta la de los tipos nodular y adenomatoide. 2" En la nefroesclerosis con hipertensión, cualquiera que sea su origen, existen las alteraciones de la zona cortical mencionadas y, además, marcadas modificaciones alterativas de la zona medular tales como ; hiperplasia del tejido medular ; formaciones ganglionares en la p a r e d venosa, algunas veces con relación nerviosa troncular bien manifiesta ; formaciones neuromusculares seudo-esfinterianas ; lagos cisternales que se intercomunican mediante seudo-esfínteres, y existen las alteraciones de la zona cortical, pero la medular está poco alterada. 3" También se observa que, en las nefroesclerosis sin hipertensión por último, formaciones tumorales nerviosas diversas. De estos hechos se puede deducir, por lo tanto que, por existir una hiperplasia glomerular, se p r o d u c i r á un aumenta de mineral- corticoides, elemento fibroplástico por excelencia, que podrían no solo mantener la actividad esclerósica en el riñon, sino también iniciar hipotéticamente el establecimiento de la ffbrosis renal. El aumento de la tensión sanguínea podría estar relacionado con aldosteronismo pero también podemos pensar que la hipertensión puede estar provocada o mantenida por el particular estado en que se encuentra la zona medular. Una hiperplasia medular puede mantener un tenor de producción catecolamínica más sostenido que en estado normal. Además la existencia de cavidades cisternales con elementos de excitación ganglionar, así como el establecimiento de esfínteres interseccionales, puede explicar las descargas de catecolaminas en el estado anormal hipertensivo. Si a ésto agregamos las evidencias neurales, tendríamos aclareció el proceso patológico de las nefroesclerosis con y sin hipertensión. DISCUSION Teniendo en nuestras manos las constancias de las alteraciones de las suprarrenales en los estados de nefroesclerosis y siendo estas alteraciones prácticamente iguales, cualquiera que sa la etiología, cabe la discusión de los hechos encontrados : Podemos considerar, entonces, a estos hechos desde tres puntos de vista a saber : 1" Las alteraciones de la suprarrenal responden a una primitiva alteración del riñon y es entonces una consecuencia patológica o ; 2 La suprarrenal, primitivamente alterada, modifica la estructura renal produciendo su estado nefroesclerótico y la hipertensión, y ; 3 Puede haber una interrelación de ambas glándulas y afectarse éstas reciprocamente, estableciéndose 1111 verdadero círculo vicioso, cualquiera que sea el punto de partida de esta patología adrenorenal. 1" Consideramos el primer punto : Las alteraciones de suprarrenal responden a una primera patología renal. Esquema I. Las investigaciones practicadas hasta ahora permiten, por deducción clínica, explicar estas alteraciones estructurales encontradas en la suprarrenal en los casos de nefroesclerosis con o sin hipertensión. Así, si partimos de la base de una esclerosis renal primitiva, podemos decir, de acuerdo con los trabajos de Davis y col., de Murrow y Gannon, de Larragh y col. 19(50, etc. que el riñon isquémico excita la produción de Aldssterona, siendo el mecanismo más convincente el de la producción exagerada de Renina-Angiotensina 11 que, en condiciones de isquemia y de alteración renal, es producida por el aparato juxtaglomerular de Goomartigli. Es evidente y está demostrado, que el aumento de Angiotensina Ií produce Aldosteronismo y aumento de los mineralcorticoides ; esta acción excitante, si es sostenida, deberá producir un cambio en el estado histológico normal de la corteza suprarrenal y este cambio será la hiperplasia funcionante de la glándula suprarrenal en su situación cortical glomerular que irá desde la hiperplasia funcionante hasta la producción de verdaderos adenomas secretantes. L1 aumento total de mineralcorticoides producirá, a su vez, esclerosis renal. o o El hiperaldosteronismo occulto o manifiesto influirá sobre la presión arterial, produciendo hipertensión. Partiendo siempre de un estado de nefroesclerosis primitiva, aparte del hecho considerado más arriba, tenemos también las propias ISQUEMIA RENAL MIPER FUNCION DEL APARATO T U X T A G I O H E R U U AUriEHTO « IE VOLEMIA ESQUEMA I Hipótesis considerando al riñon como agente primitivo. alteraciones imputables a la insuficiencia renal, como ser la absorción de K. y un aumento de H. en la sangre que conducirán ambos a un aldosteronismo defensivo produciendo, de esta menera, la retención de Na. y pérdida tubular renal de K. y H., hechos que conducen también a la hipertensión por aumento de la volemia sanguínea. Este aumento de la volemia producirá la consabida excitación esplácnica, no solo para aumentar la diuresis, sino que también excitará a la medular suprarrenal que, a su vez, provocará hipertensión. 2 Si nos colocamos en una situación patológica diametralmente opuesta a la enterior pensando que las alteraciones renales son una consecuencia de alteración primitiva de la suprarrenal, también podemos explicar este hecho apoyándonos en investigaciones fisiopatológicas conocidas. Esquema II. Por trabajos de Farrell (1959), Powell y Hookes (1956), Conn ,1955/56 y 57), Droud y col. (1956), et., podíamos decir que una excitación permanente de la corteza suprarrenal producida primitivamente por un aumento de la volemia sanguínea o también por un o aumento de h o r m o n a e x c i t a d o r a c o r t i c o a d r e n a l , tal como la hormona pineo-hipotalámica-adrenotropa de F a r r e l l , se p r o d u c i r á por esta excitación, constante y sostenida, un estado histológico de hiperfunción c o r t i c o - s u p r a r r e n a l traducido en hiperplasia de distintas formas histológicas pero, todas ellas en situación c o r t i c a l p r i m i t i v a . Esta situación c o n d u c i r á a un aumento oculto o visible en las cantidades sanguíneas y u r i n a r i a s de m i n e r a l c o r t i c o i d e s , en especial de Aldosterona. Este estado p r o d u c i r á un aumento de Na. en la sangre con pérdida de K. v de H. A.C.T.H MORMORA DE FARREL MIHERALCORTICOIDE ALDOSTERONA AUMENTO DISMINUCION NA [S AUMENTO DE VOLEMIA t EXCITACION ESPLACNICA REN1NA AN6I0TENSINA J L CATECO L A M I ÑAS HIPERTENSION HIPERTENSION ESQUEMA II Hipótesis considerando a la s u p r a r r e n a l como agente primitivo. La retención de Na. p r o d u c i r á un aumento de la volemia sanguínea ; con ello se p r o d u c i r á no solo un estado de hipertensión dependiente del aldosteronismo, sino también una verdadera e x c i t a c i ó n simpática que, p o r intermedio de los esplácnicos, tratará de forzar la diuresis ; además, e x c i t a r á por esa vía esplácnica, la zona medular suprerrenal con aumenta de catecolaminas, cuyo doble fin será actuar sobre la diuresis ( R i c h a r d ) y sostener la tensión arterial para forzar la eliminación de los fluidos orgánicos. Este estado de e x c i t a c i ó n nerviosa medular suprarrenal conduce a la h i p e r p l a s i a de sus células y a las modificationes vasculonerviosas que hemos descrito en el transcurso de este trabajo. Si por otra parte, consideramos que el estado de e x c i t a c i ó n adrenal producido por la h o r m o n a de F a r r e l l o por cualquier otro m e c a n i s m o que aumente el total de m i n e r a l c o r t i c o i d e s , éstos inducirán a la fibrosis general y,, en c i r c u n s t a n c i a s de o b r a r en un organismo con une alteración r e n a l p o r i n f e c c i ó n o por estados de sensibilización, la respuestra será indudablemente por nefroesclerosis. Aquí también se c e r r a r á el c i r c u l o vicioso con p r o d u c c i ó n renal de Angiotensina II que llevará a un aldsteronismo secundario con sus con sus c o n o c i d a s consecuencias. 3" Hemos visto escuetamente c|iie, tanto en la situación primera, es decir de patología renal primitiva como en la segunda de irritación corticoadrenal primitiva, no puede establecerse la primacía de ninguna de las dos en forma absoluta. I'or otra parte, el estado de interrelación mutua salta a la vista. Cualquiera que sean las circunstancias así empiece la enfermedad ya sea en la suprarrenal o ya sea en el riñon, siempre se establecerá un círculo vicioso que aumentará indefectiblemente la gravedad del proceso, conduciéndolo a la malignidad en la función renal, sea ésta con hipertensión o sin ella. La única solución terapéutica repetimos, está en cortar el círculo vicioso. En estos casos el acto terapéutico menos grave y menos agresivo es la adrenalectomía unilateral. Con respecto al ¿ porqué ? la ablación de una suprarrenal puede producir mejoría podemos decir que, según trabajos de investigación clínica y en especial los de Pezzuoli, la eliminación de una glándula produce, por carencia parcial de controles hipofisiarios, una mayor producción de estimulantes corticoides hipofisiarios que, al actuar sobre la otra glándula o sobre algunas aberrancias corticales, producirá un notable aumento de glucocorticoides, frenando, por asi decir, la producción de mineralcorticoides, cortando de esta manera eí círculo vicioso en que el estado reno-suprarrenal se había colocado. La mejoría subjetiva se p r o d u c i r á prácticamente en forma inmediata y aunque la cantidad de órgano renal destruido difícilmente será recuperable, el tejido renal remanente, sin la acción fibroplástica del exceso de mineralcorticoides, podrá recuperar gran p a r t e de su función perdida, normalizándose dentro de lo relativo. Las modificaciones observadas en la zona medular en los enfermos con nefroesclerosis hipertensiva, creemos que tienen real importancia. No estamos en condiciones de afirmar ni de discriminar si estas modificaciones anatomo-histológicas son causa o consecuencia del estado renal y de la hipertensión ; lo que si podemos suponer es que, la mayor cantidad de elementos productores y reguladores de catecolaminas puede determinar una cause de mantenimiento y agravación del estado hipertensivo. Parece claro que el sistema cisternal de la suprarrenal, tanto el intercelular como el venoso cavitario, pueda estar normalmente regulado por formaciones esfinterianas de poca importancia, dependientes del sistema nervioso mantenedor del equilibrio fisiológico. Ante un hecho como es el aumento de la producción cortical de Aldosterona o de la excitabilidad nerviosa trasmitida p o r los esplácnicos y mantenida por la cronicidad, la consecuencia lógica será el desarrollo marcado de dichas formaciones neuromusculares y de la hiperplasia medular, así como de la manifestación de los ganglios simpáticos endovenosos. Estos aumentos de los factores nerviosos y de las formaciones anatómicas por ellos estimuladas, pueden p r o d u c i r y mantener el estado hipertensivo aún sin grandes alteraciones sanguíneas de las catecolaminas o de su producto de desintegración, el Acido Vi nilman délico. Dicho sea de paso, siempre hemos encontrado a estos últimos productos en valores moderadamente elevados. De ahí la importancia de la hiperplasia así como el aumento de las cavidades reservorios y demás elementos encontrados en todos estos casos de nefroesclerosis hipertensivas. RÉSUMÉ D après les nombreuses études effectuées sur la fonction des glande« surrénal es, on est arrivé à des conclusions bien claires que quelques'-' unes des 40 hormones jusqu'à aujourd'hui découvertes ont, les unes une action hbroplastique et les autres une action sur la tension artérielle. On a aussi constaté qu'il existe une action réciproque entre d'autres organes et les surrénales. En nous appuyant sur ce fait, nous avons entrepris une investigation clinique chez l'homme, avec l'intention de voir quelles sont les relations qui pourraient exister entre la surrénale et le rein et, réciproquement, entre le rein et la surrénale. En plus nous avons pratiquement obtenu des bénéfices thérapeutiques en interrompant 1 action reciproque réno-surrénale, par l'extirpation d'une des glandes surrénales. Le présent travail se base sur l'étude de 37 cas choisis de malades avec nephrosclérose dont l'origine est due à diverses causes mais, plus spécialement a des néphrites ou à des pvélonéphrites. On a pratiqué, comme condition clinique fondamentale, les études fonctionnelles et morphologiques des reins et des glandes surrénales. Nous avons étudié la fonction du rein en utilisant les épreuves de dépuration uréique, de la créatinine et de la sulphorphénolphtaleïne. En plus, dans un certain nombre de cas, on a aussi utilisé la méthode d'étude des courbes d'élimination du iode-liipurate radioisotopique. Quant à la morphologie rénale, on a employé, pour son étude, la classique radiographie avec substance de contraste par voie endoveineuse aussi bien que les angiographies par voie aortique totales et sélectives. Ces dernières investigations offrent, dans notre opinion, des avantages, mais elles peuvent aussi présenter des sérieux inconvénients. D'après les études fonctionnelles et morphologiques des reins on a choisi les cas avec des lésions bien évidentes. Pour les surrénales, on a investigué les fonctions corticales par le dosage de l'Aldostérone, par l'épreuve d'Ekton-Ross et par le dosage et la détermination de cortisoles et de 17 cétostéroïdes. Quant à la fonction médullaire, on a fait le dosage des catecolamines sanguines et. plus spécialement, de l'acide vinyl-mandélique dans le sang aussi bien que dans l'urine. On doit bien faire remarquer que, dans trois cas nous avons obtenu du sang artériel directement de l'artère rénale gauche et du sang veineux directement extrait de la cave dans la zone de sortie de la veine centrale de la glande surrénale, a fin d'investiguer les éléments sécrétés par la glande. Les résultats obtenus par ces preuves analytiques n'ont, presque jamais, été convaincants. En général, nous pouvons dire que les fonctions qui appartiennent à la couche fasciculaire et à la couche réticulaire de la zone corticale, ne montrent pas des changements substantiels. En échange, nous avons pu apprécier que la quantité de minéral-corticoïdes est, en général, dans les limites supérieures normales ou légèrement augmentée, surtout en ce qui concerne l'Aldostérone. La fonction de la zone médullaire, représentée par l'élimination de l'acide vinyl-mandélique urinaire, s'est aussi montrée, dans tous les cas de malades avec hypertension, dans les limites supérieures normales ou légèrement augmentée. L'étude morphologique des glandes surrénales a été basée sur des pneumographies périglandulaires pratiquées soit par la voie présacrée, soit par la voie locale. On a aussi effectué les angiographies sélectives dont les résultats ont été relativement satisfaisants. Nous voulons spécialement établir le fait que, pour choisir les 37 cas de malades traités, nous avons absolument exclu tout cas où il pourrail s'agir de Phéocromocitomes. Pour la surrénalectomie nous avons préféré la technique unilatérale, et, pour des raisons anatomiques, nous avons pratiqué de préférence la surrénalectomie du côté gauche. Notre expérience antérieure dans plus de 50 cas de surrénalectomies bilatérales nous a démontrée que l'extirpation totale est dangereuse et la subsistance biologique très difficile à mener. Comme voie chirugicale nous avons pratiqué la voie épicostale en sacrifiant la 12° côte et en prolongeant l'incision vers l'abdomen. Cette voie nous permet de faire une exploration parfaite de la glande surrénale, du rein, de l'aorte et des ganglions sympathiques para-vertébraux. Quant aux résultats de cette investigation clinique, nous allons faire d'abord le rapport sur les très intéressantes modifications anatomopathologiques des surrénales et après nous exposerons les résultats cliniques obtenus. Examen Anatomopathoiogique. Le poids des surrénales extirpées était, en général, augmenté en comparaison au poids normal. Deux pesaient plus de 9 grammes. Les altérations structurales se trouvaient dans les zones corticale, médullaire et dans la zone d'union entre les deux zones mentionnées. Dans la zone corticale nous avons trouvé des hyperplasies de la couche germinale. La couche glomérulaire présentait aussi des hyperplasies des types diffus, nodulaire et adénomatoïde. Les couches fasciculaire et réticulaire de la glande ne montraient pas d'altérations fondamentales, sauf le naturel déplacement à cause de l'agrandissement des couches glomérulaire et germinative. Dans la zone d'union on a rencontré des espaces très dilatés entre les cellules, lesquels constituaient des vraies cisternes. Les hyperplasies diffuses et nodulaires prédominaient dans la zone médullaire. On a aussi vu des modifications très importantes des structures vasculaires. Ces modifications étaient constituées par des formations para-ganglionnaires endoveineuses en relation directe avec des grands troncs nerveux. On a aussi vu des changements dans la structure musculaire de la paroi vasculaire, modifications en forme de leiomyomes et de pseudo-sphincters. On doit interpréter ces pseudo-sphinters comme le mécanisme (le régulation hormonale qui aurait à sa charge soit la rétention, soit l'élimination des hormones sécrétées par la glande et accumulées dans les cisternes décrites. Nous complétons ce résumé d'observations anatomopathologiques en ajoutant que, on a aussi vu des neurones périglandulaires, des hernies capsulaires de la corticale et des petites tumeurs isolées adossées à la glande, formées par des cellules glomérulaires et nourries par depédicules indépendants. Résultats cliniques. Ils ont été aussi satisfaisants que l'on aurait pu le désirer. Quand nous avons pratiqué les surrénalectomies, nous n'avons jamais prétendu la guérison définitive de la sclérose rénale, comme nous n'avons non plus pensé à une rétrocession totale du processus sclérogène. Notre espoir était celui de pouvoir arrêter le dangereux et progressif cours de la maladie et de pouvoir maintenir le patient dans un bon état de compensation fonctionnelle en évitant, au moyen de la surrénalectomie, la progession d'un processus sans réversion. " Survie postopératoire. 36 cas opérés : trois décédés avant une annee, deux avant les deux années. Le reste a vécu plus de trois ans et, de ce reste, dix patients ont déjà une survie de dix années depuis 1 opération. Evolution de la tension artérielle. Nous avons 33 malades avec hypertension et presque tous sont des cas graves. On a observé tout de suite une franche diminution des chiffres tensionnels. On pourrait peut-être attribuer ce fait au déséquilibre postopératoire mais, il est très intéressant de remarquer que, dans plus de la moitié des cas opérés, les tensions artérielles sont restées dans les chiffres inférieurs à ceux d'avant l'opération. Dans les cas où la tension s'éleva de nouveau, elle put être parfaitement contrôlée avec des drogues spéciales pour bloquer la glande surrénale. Fonction rénale. La fonction rénale a été très peu modifiée ; ce fait est parfaitement compréhensible ; dans certains cas elle a été considérablement améliorée. Pour expliquer l'excellent état général d'un nombre de malades opérés, nous devons penser que, à cause de la faute d'excitation sclérogène de la surrénale, les autres organes dépurateurs auraient possiblement augmenté leur effet en produisant ainsi l'équilibre de l'élimination de toxines. Nous résumons le résultat général comme il se suit : très améliorés 18, améliorés 11, sans résultats 8. Comme ce n'est pas facile de résumer la discussion des faits investigués, nous dirons que : 1° Les altérations de la surrénale peuvent être une conséquence de la pathologie rénale primitive. 2° La surrénale, primitivement altérée, produira, sur un terrain propice, les néphroscléroses et les hypertensions. 3° Comme un raisonnement éclectique, nous devons considérer la relation réciproque des deux glandes, en établissant ainsi un vrai cercle vicieux qui affecterait toutes les deux. Nous conseillons au lecteur de se rapporter aux cadres ci-joints, dans lesquels on pourra parfaitement suivre les actions pathologiques réciproques des deux glandes. Pour avoir plus d'information, voir dans le rapport les références utilisées. 1 SUMMARY Several studies have been carried out on the function of the adrenal gland and the conclusion has been that, some of the 40 hormones chemically discovered so far have sclerotic or hypertensive action. The inter-relation between the adrenals and other organs has also been proved. Taking this into account, we have started a clinical investigation in patients, with the purpose of observing the relations that could exist between the adrenal glands and the kidney, and viceversa. The results obtained have shown significant alterations in the morphology of the adrenals. Besides, we have practically obtained therapeutical benefits when interrupting the adrenal-kidnev inter-relation by resecting one of the adrenal glands. This work is based on the study of 37 selected patients with nephrosclerosis of different etiologies, especially nephritis and pyelonephritis. The functional and morphological studies of the kidneys and adrenals have been considered as the main clinical conditions. We have studied the renal function by means of urea and chrealinine clearances and sulfophenolphtalein test. Besides, in certain cases, the curve of elimination of radioisotopic iodine-hippurate was also performed. The renal morphology was studied with the classical intravenous pyelogram and with total and selective aortic angiographies. From our standpoint, these latter investigations offer advantages but may also cause serious inconveniences. We have only included in the study those cases with marked functional and morphological kidney alterations. The functions of the adrenal cortex were studied by means of aldosterone determinations, Ekton-Boss tests and Cortisols and 17 ketosteroids dosage and determinations. Function of the medullar zone was studied using serum-catecholamines dosage and investigation, and especially by serum and urinary vanillyl-mandelic acid determinations. On three occasions, with the purpose of determining the elements secreted by the gland, arterial blood was obtained directly from the left renal artery and venous blood from the vena cava in the area where I he central adrenal vein joins it. The results of these analytic tests of the adrenal function have never been fully convincing. In general, we may say that the function corresponding to the reticularis and fasciculata zones of the adrenal cortex do not show substantial variations. We did find, however, that ths amount of mineral-corticoids, especially aldosterone, were generally slightly above their normal values. The urinary excretion of vanillylmandelic acid, that represents the medullar zone's function, was found to be above or in the upper limit of its normal values in all the cases with hypertension. The morphological study of the adrenal glands was carried out by means of periglandular neumographies with presacral or local approach selective angiographies with moderately satisfactory results have also been performed. We wish to emphasize that none of the 37 patients were cases of feochromositoma. We prefer a unilateral adrenalectomy and for anatomical reasons, the left gland. Our previous experience with more than 50 cases has shown us that bilateral adrenalectomies are risky, and that biological balance is difficult to maintain. We employ the epicostal surgical approach with total resection of the twelfth rib, extending the incision toward the abdomen. This approach is excellent and allows a full exploration of the gland, kidney, aorta and paravertebral sympathetic ganglia. We will first express the interesting anatomopathological modifications that we have found in the adrenals and later the clinical results that have been obtained. Anatomopathological study. Almost all the adrenal glands were heavier than normal; two of them even weighed more than 9 gm. The structural alterations were present in the adrenal cortex, in the medullar zone and in the intermediate area. In the cortical zone we found hyperplasia of the germinal layer and glomerulosa. Hyperplastic zones, in the latter area, presented diffuse, nodular and adenomatoid patterns. The fasciculata and reticularis did not show structural alterations except the displacement caused by the enlargement of the glomerulosa and germinal layers. Enlarged intercellular spaces forming true cisternas were found in the intermediate zone. Diffuse and nodular hyperplasia predominated in the medullar zone and remarkable modifications were observed in its vascular elements. The latter consisted of endovenous formations with the characteristics of nervous ganglia in close contact with gross nervous fibers. These modifications were also seen in the muscular layer of the vascular wall forming leiomyomas and pseudo-sphincters. The presence of these pseudo-sphincters elements can be explained as a normal regulatory mechanism sometimes retaining and sometimes discharging the hormonal secretion of the gland, accumulated in the described cisternas. To complete this summary of anatomopathological observations we should also mention the following alterations: periglandular neuromas, tissular hernias of the cortical zone through the adrenal capsule and small, isolated tumors situated close lo the gland, formed by cells belonging to the glomerulosa and supplied by independent pedicles. Clinical results. The clinical results have been satisfactory as expected. We have never thought of a definite cure for nephrosclerosis by means of adrenalectomy, neither of a complete improvement of the sclerotic lesions. We had the hope of stopping the progressive derangement and to keep the patient functionally compensated, detaining with the adrenalectomy, the inexorable progression of an irreversible process. Postoperative lifespan. Three of the 36 operated patients died before one year and two within two years. The rest of the patients have survived more than three years and eight of them more than ten years. Evolution of arterial pressure. 33 were hypertensive patients, most of them with severe hypertension. An evident and inmediate lowering of the blood pressure values was observed. Actually, this could be due to the postoperative unbalance, but it is worth noting that more than half the patients have maintained their blood pressure values markedly beneath the pre-operative ones. Those who return to the previous elevated values were more easily controlled using blockading drugs. Renal function. As can be perfectly understood, the renal function was the less modified. However, in some patients it markedly improved. The good general conditions of some patients could be well explained by the improved efficiency of the rest of the depurative organs now that the sclerotic action of the adrenals has ceased, thus equilibrating the toxin excretion. We summarize the results as follows: 18 very improved, 11 improved and 8 unimproved patients. As it is not easy to summarize the discussion of the mentioned findings we can say that: I The adrenal's alterations can be a consequence of the primary renal pathology. 2° The adrenal gland, first affected, will induce nephrosclerosis and hypertension. 3° From an eclectic point of view we must consider that both the kidney and the adrenal are inter-related and affect each other, thus creating a vicious circle. We submit the reader to the enclosed graphs in which the pathological interaction between both glands can be observed. Further information can be found in the references listed in the study. o ZUSAMMENFASSUNG Aus den zahlreichen Studien die zur Frage der Nebennierendrüssenfunktion gemacht wurden geht mit Klarheit hervor, dass einige aus den 40 bisher chemisch erfassten Hormone fibroplastische, andere aber eine blutdruchsteigernde Wirkung fordern. Man hat dabei eine starke Wechselwirkung beider Nebennieren mit anderen Organsystemen deutlich festgestellt. Anhand dessen, haben wir bei Menschen klinische Untersuchungen unternommen, um uns über die Beziehung zwischen der Nebenniere und der Niere, oder umgekehrt^ zwischen der Niere und der Nebenniere, neue Erkenntnisse zu erscliliessen. Die Ergebnisse Hessen im Hinblick auf die Morphologie der Nebenniere auf substanzielle Veränderungen scliliessen. Ausserdem, haben wir praktisch therapeutische Begünstigung, bei Unterbrechung der renosuprarenalen Vorgänge durch Exstirpation einer der beiden Nebennierendrüssen, erziehlt. Zur Auswertung dieser Untersuchung kam das Krankengut von 37 Fällen zur frage, die unter Patienten mit Nephrosklerose verschiedener Ursache, meistens aber durch Nephritis und Pyelonephritis bedingt, ausgesucht wurden. Als grundlegende klinische Bedingung waren die funktionnelle und morphologische Studien der Niere und der Nebenniere, massgebend. Zur Untersuchung der Nierenfunktion haben wir die Proben der Harndepuration, des Kreatinins und des Sulphophenolphtaleins durchgeführt. In einer Anzahl von Fällen haben wir eigens die Ausscheidungskurven des radio-isotopischen Johypurats studiert. Was die Nierenmorphologie anbetrifft, wurde die klassische Radiographie mit endovenös eingeführten Kontrastsubstanz und die selektive und totale Angiographie der arteria aortica, benützt. Der angiographische Nachweis ergibt, unserer Meinung nach, einige Vorteile, gestalltet sich aber mitunter schlecht und kann dabei manchmal gewisse Schwierigkeiten verursachen. Aus der funktionellen und morphologischen Untersuchungen der Niere haben wir diejenige Befunde gewält, bei denen sichtbare Läsionen eindeutig objektiviert werden konnten. Hinsichtlich den Nebenniere, wurde die Kortikalfunktion untersucht, gestützt auf Aldosteron, die Ekton-Ross Probe, die Dosierung und die Bestimmung der Kortizole und 17 Ketosteroide. Was die Medularfunktion anbetrifft, wurden Katekolamine im Blut, insbesondere aber die Vynylmandelsäure im Blut und Harn, untersucht und bestimmt. Es sei noch zu vermerken, dass dreimal die Arterialblutproben gelegentlich aus der linken arteria der Niere und die venösen Blutproben aus dem intracava Raum des Ausgangs der Nebennierenzentralvene, extrahiert wurden. Die Ergebnisse der analytischen Proben der Nebennierenfunktion waren leider nie überzeugend. Im allgemeinen kann aber gesagt werden, dass die dem Kortikalbereicli entsprechende Funktionen der faszicular und Retikularschichten, keine grundgehende Veränderungen aufwiessen; dem gegenüber, findet man Häufig einen allgemeinen Anstieg der Mineralkortikoidmenge, die das Normalwert übersteigt und, besonders im Bezug auf das Aldosteron, über die Grenze gering zunimmt. Die Funktion der Medularzone - durch die Ausscheidung der im Harn befindlichen Vinylmandelsaüre representiert - nimmt auch hier in allen Hypertensionsfällen leicht über den Normalwert zu. Das morphologische Studium der Nebennierendrüsse wurde mittels periglandulären Neumographie lokal oder via pressacra durchgeführt. Ausserdem haben wir einschlägige selektive Angiographie, mit relativ befriedigenden Ergebnissen, angewandt. Es muss besonders vermerkt werden, dass es in keinem der 37 Fälle sich um Feokromozitome handelte. Für die Adrenektomie haben wir die unilaterale Technik verwendet und aus anatomischen Gründen die linke Drusse bevorzugt. Unsere frühere Erfahrung von über 50 Fällen der beiderseitigen Adrenektomie liess uns die totale Exstirpation als bedenklich erscheinen, da sie nur schwer biologisch aufrechtzuerhalten ist. Der chirurgische Eingriff Erfolgte epikostal mit totaler Resektion der zwölften Rippe und wurde dann abdominal verlängert. Somit wurde ein optimalbreites Feld offen, der eine äussert günstige Erforschung der Driisse, der Niere, der aorta und der Ganglia paravertebrale sympathicorum, ermöglichte. Im Hinblick auf die klinische Untersuchungsbefunde sei vorerst aul die höchst interessante anatomopathologische Veränderungen der Nebenniere liingewiessen. Abschliessend werden wir in die Besprechung der klinischen Ergebnisse eingehen. Anatomopathologisches Studium. Bei den entfernten Nebennieren wurde ein Gewitchtsanstieg gegenüber dem Normalgewicht verzeichnet; in zwei Fällen wogen die Nebennieren bis auf 9 gr. Die strukturellen Veränderungen zeigten sich in der Kortikal und Medularzone und im Zwischenraum. Im Kortikalraum findet man Hyperplasien der germinalen Schicht. Ahnlicherweise, zeigte sich die glomerulare Schicht hyperplasiert und man erkannte diffuse Hyperplasien, Nodulare und Adenomatoide. Die faszikulare und Retikularschichten des Organs wiessen, ausser der Verlagerung durch die Dilatation der glomerulare und germinative» Schichten bedingt, keine wesentliche Veränderungen auf. Im Zwischenraum erkannte man interzelluläre Raüme, die zu Wölbungen sich vergrössert hatten und regelrechte Zisternen bildeten. Im Medularraum dominierten diffuse Hyperplasien und Nodulare. Es wurden ausserdem äusserst wichtige Veränderungen der Vaskulärstruktur beobachtet, die zu paraganglionären endovenösen Gebilden führten und in direkten Beziehung zu den dicken nervösen Stammen standen. Es wurden, ausserdem, Veränderungen in der Muskelstruktur der Gefässwande, in Form von Leiomyome oder pseudo Sphinkter, erkannt. Diese letzteren dürften als eine Art Mechanismus der hormonellen Regulation betrachtet werden, die aufladend oder entladend die abgesonderten Hormone der Drüsse in die obengenannte Zisternen aufspeichern. Zur Ergänzung dieser anatomisch-pathologischen Erscheinungen soll noch gesagt werden, dass man ausserdem periglanduläre Neurome, kapsuläre Rindenbrüche und kleine einzelne Tumore erkannt hatte, die, an der Drüsse anhaftend, sich durch glomerulare Zellen auszeichneten und durch eigene unabgängige Stiele versorgt werden. Klinische Befunde. Die klinische Befunde erwiessen sich im ganzen, so weit man es erwarten konnte, als befriedigend. Nie haben wir der Adrenektomie an eine endgültige Heilung der Nephrosklerose gedacht, noch haben wir einen totalen Rückgang der sklerotischen Schädigungen erwartet. Wir haben lediglich gehofft in das progresive Geschehen einschreiten zu können, den Kranken durch die Adrenektomie in ein funktionelles Kompensationszustand zu versetzen und so den unvermeidlichen Ablauf eines irreversiblen Prozesses zu vermeiden. Postoperative Sterblichkeits-Rate. Bei 36 operierten 3 verstarben innerhalb des ersten Jahres; 2 innerhalb von 2 Jahren. Die restlichen überlebten reichlich das dritte Jahr und 8 leben schon 10 Jahre seit der Operation. Entwicklung des Arteriendruckes. 33 Kranken zeigten meitens eine schwere Hypertension. Es wurde eine scharfe Senkung der Druckziffern beobachtet, was auf das post-operativ gestörte Gleichgewicht zurückzuführen sein dürfte; jedenfalls ist es interessant zu vermerken, dass über die hälfte der Fälle einen Arteriendruck besassen der viel niedriger war der den sie vor der Operation gehabt hatten; in den jenigen Fällen bei denen der Druck wieder anstieg, konnte man es mit blockierenden Mitteln viel leichter kontrollieren. Nierenfunktion. Diese hatte sich am wenigstens verändert, was auch verständlich ist, obwohl in manchen Fällen eine erstaunliche Besserung eintrat. Die hohe Erfolgsquote und der gute Allgemeinzustand einiger Patienten ergeben als Argument, dass bei Abwesenheit der sklerogenetischen Excitation der Nebenniere, andere Organsysteme durch seine erhöhte Leistungsfähigkeit die Ausscheidung der Toxine ausgeglichen haben konnten. Anschliessend könnten unsere Ergebnisse folgenderweise erfasst werden; ausgeprägte Besserung, 18; guter Intervall der Besserung, 11; ohne Erfolg, 8. Da es keine leichte Sache ist die erzielilte Ergebnisse in eine Diskussionsform zusammenzufassen, wollen wir folgendes sagen : 1° Die Veränderungen der Nebenniere dürfte offensichtlich die Konsequenz einer primärer Nephropathologie sein. 2° Die primären Veränderungen der Nebenniere werden unter günstigen Bedingungen eins Nephrosklerose und Hypertension verursachen. 3° Als eklektische Schlussfolgerung müssen wir die Wechselwirkung beider Driissen in betracht ziehen, die sich zu einer Kreisbewegung schliesst und beide Driissen gegenseitig schädigt. Zur Verfolgung der patologischen Wechselwirkung beider Driissen, wird dem Leser die Benutzung der Abbildungen und Tabellen empfohlen; als Informationsquelle vermittelt die Literaturausswahl ein Schrifftum, der sich von selbst emfiehlt. BIASSUNTO Dopo numerosi studi sulla funzione delle surrenali si è giunti a conclusioni più precise nel senso che qualcuno dei 40 ormoni sino ad oggi scoperti hanno azione fibroplastica e altri sulla pressione arteriosa. Si è anche constatato che esiste una reciproca azione fra gli altri organi e le surrenali. Tenendo conto di questo fatto noi abbiamo intrapreso uno studio clinico sull'uomo per vedere quali relazioni reciproche ci potessero essere fra surrenale e rene fra rene e surrenale. In più noi abbiamo potuto ottenere alcuni benefici terapeutici interrompendo l'azione specifica reno-surrenale con l'asportazione di una sola ghiandola. Questo lavoro si basa sullo studio di 37 casi scelti f r a coloro che presentavano una nefrosclerosi dovuta per le più a nefriti o pielonefriti. Abbiamo praticato, come condizioni fondamentale, gli studi funzionali e morfologici dei reni e delle surrenali. Abbiamo studiato la funzione renale con le prove di depurazione ureica, della creatinina e della ftaleina. In più, in alcuni casi, abbiamo utilizzato la nefrografia con radio-isotopi. Per quanto riguarda la morfologia renale ei siamo serviti sia della classica urografia, quanto della angiografìa sia aortica che selettiva. Questi ultimi esami, secondo noi, offrono certo dei vantaggi ma possono anche dar luogo a seri inconvenienti. Abbiamo sempre scelto casi con lesioni ben evidenti. Per quanto riguarda le surrenali abbiamo studiato le funzioni corticali col dosaggio dell'Aldosterone, con la prova di Ekton-Ross e col dosaggio e la determinazione dei cortisoli e dei 17 chetorteroidi. Quanto alla funzione midollare abbiamo dosato le catecolamine del sangue ma specialmente l'acido vinil-mandelico sia nel sangue che nell'orina. Dobbiamo specialmente far notare che in tre casi noi abbiamo ricavato sangue arterioso direttamente dall'arteria renale sinistra e sangue venoso dalla cava nel punto di emergenza della vena centrale surrenale per poter ottenere elementi secreti dalla ghiandola. I risultati ottenuti per queste prove analitiche non sono quasi mai risultati convincenti. In generale moi possiamo dire le funzioni devolute sia alla zona fascicolata che a quella reticolare della parte corticale non mostrano mai cambiamenti sostanziali. In cambio noi abbiamo potuto precisare che la quantità di minerale cortidoide è, in generale, nei limiti superiori normali o leggermente aumentata soprattutto per l'Aldosterone. La funzione midollare, rappresentata attraverso l'eliminazione del acido vinil-mandelico urinario si è anche dimostrata, in tutti gli ipertesi, nei limiti normali superiori o leggermente aumentata. Lo studio morfologico delle surrenali è stato eseguito con delle pneumografie perighian dolari sia per via presacrale che per via locale. Abbiamo anche praticato angiografìe selettive con risultati relativamente sofdisfacenti. Abbiamo altresì scartato tutti i casi in cui si poteva sospettare un feocromocitoma. Per la surrenalectomia noi abbiamo preferito la tecnica unilaterale e soprattutto dal Iato sinistro. La nostra anteriore esperienza in più di 50 casi di surrenalectomia bilaterale ci ha dimostrato che questo comportamento è pericoloso perchè è molto difficile controllare l'equilibrio biologico. Come via chirurgica noi seguiamo quella epicostale sacrificando la 12a. costola e prolungando l'incisione addominale : questa via permette una perfetta esplorazione della surrenale, del rene, dell'aorta e dei gangli simpatici para-vertebrali. Per quanto riguarda i risultati di questa ricerca clinica noi riporteremo successivamente le interessanti modificazioni anatomo-patologiche delle surrenali e poi esporremo i risultati clinici. Esame anatomo-patologico. Il peso delle surrenali asportate era in generale aumentato. Due pesavano più di 9 grammi. Le alterazioni strutturali si trovavano tanto nella corticale che nella midollare e anche nella zona di unione. Nella corticale iperplasica della zona germinale, iperplasia di topo diffuso, nodulare e adenomatoide nella zona glomerulare, mentre lo stato fascicolare e reticolare non mostravano lesioni fondamentali salvo la naturale dislocazione dovuta alle cause di cui sopra. Nella zona di unione si è constatato l'esistenza di spazi assai dilatati fra le cellule quasi a costituire delle vere cisterne. La iperplasia diffuse e nodulari predominavano nella zona midollare, mentre si son viste anche importanti modificazioni delle strutture vascolari, costituite da formazioni para-ganglionari endovenose in relazione diretta coi tronchi nervosi e da modificazioni hella struttura muscolare della parete vascolare come leiomiomi o pseudosfìnteri. Questi peuso-sfinteri si devono interpretare come fattori maccnici di regolazione ormonale che presiede sia la ritenzione, sia l'eliminazione degli ormoni secreti dalla ghiandola e accumulati nelle già descritte cisterne. Noi vogliamo completare questo riassunto anatomo-patologico, aggiungendo che abbiamo visto sia dei neuroni perigliiandolari, sia delle ernie capsulari della corticale sia dei piccoli tumori isolati addossati alla ghiandola formati da cellule glomerulari nutrite da peduncoli indipendenti. Risultali clinici. Sono stati soddisfacenti secondo le speranze desiderate. Con la surrenalectomia non abbiamo mai avuto la pretesa di guarire la sclerosi renale nè di far regredire il processos sclerogeno. Le nostre aperanze erano quelle di arrestare la progressione pericolosa della malattia e di poter mantenere il malato in uno stato di acquisito compenso funzionale stabile. Sopravvivenza post-operatoria. 36 casi operati, 3 morti entro l'anno, 2 prima di due anni. I rimanenti vivono da più di tre anni mentre 10 vivono già da 10 anni. Evoluzione della pressione arteriosa. Noi abbiamo 33 malati con ipertensione e in grave stato : in lutti abbiamo osservato una netta caduta della pressione. Si potrebbe attribuire questo fatto ad uno squilibrio post-operatorio, ma è interessante far notare che in più della metà dei casi operati le pressioni arteriose sono sempre rimaste su valori inferiori a quelli pre-operatorie. Nei casi in cui la pressione si era ancora elevata essa ha potuto essere più facilmente controllata con medicamenti speciali atti a bloccare la surrenale. Funzione renale. La funzione renale è stata poco modificata e ciò è perfettamente comprensibile. In certi casi però essa è stata considerevolmente migliorata. Per spiegare l'eccellente stato generale di un certo numerodi operati noi possiamo pensare che, tolta l'eccitazione sclerogena della surrenale, gli altri organi depuratori avranno potuto aumentare la loro funzione reiquilibrando l'eliminazione delle tossine. Noi riassumiamo i risultati generali : molto migliorati 18 - migliorati 11 - senza risultati 8. Non essendo facile riassumere le discussioni dei fatti studiati, noi diremo che : 1° Le alterazioni delle surrenali possono essere conseguenza della patologia renale primitiva. 2° La surrenale, primitivamente alterata, produrrà, su terreno predisposto, la nefrosclerosi e l'ipertensione. 3° Secundo un ragionamento eclettico noi dobbiamo considerare una relazione reciproca fra le due ghiandole tale da creare un circolo vizioso interessante entrambe. Noi consigliamo al lettore di consultare le tavole della relazione, dalle quali appariranno le azioni patologiche reciproche delle due ghiandole. Per maggiori dati informativi consultare la bibliografia riportata. BIBLIOGRAFIA and N E L S O N , D.H. : The dual action of aldosterone of renal sodium reabsorption in normal subject. Clin. Res. 7 : 274, 1959. AUGUST, J . T . , NELSON D . H . and T H O H N , G . W . : Aldosterone. New Engl. J. Med. 259 : 917, 1958. AUGUST, J . T . , N E L S O N D . H . and T H O R N , G . W . : Aldosterone. New Engl. J. Med. 259 : 9Í57, 1958. BAUDINO, C., BAUDINO, G.H., SONZINI, 0. and OSAKAR, E.M. : Primary aldosteronism caused by adrenal adenoma. A case with severe hypertension. Sem. Med. 121 : 1323, 1962. B A U E R , H.G. : Endocrine and other clinical manifestations of hypothalamic disease; survey of 60 cases with autopsies. J. Clin. Endocr. 14 : 13, 1954. BOHZONE, B . J . : Fisiología suprarrenal aplicada a la clínica. IV Jornadas Rioplatenses de Urología. P. 298, 1967. CONN, J . W . : Primary aldosteronism, new clinical syndrome. J. Lab. Clin. Med. 45 : 3, 1955. CONN, J . W . : Diagnosis and management of primary aldosteronism. Fourth Pan American Congress of Endocrinology, 1957. CONN, J . W . : Aldosteronism and hypertension. Primary aldosteronism versus hypertensisive disease with secondary aldosteronism. Arch. Intern. Med. 107 : 813, 1961. CONN, J . W . : Plasma renin activity in primary aldosteronism. Importance in differential diagnosis and in research of essential hipertensión. J.A.M.A. CONN, J . W . and Louis, L.H. : Production of endogenous « salt active » corticoids as reflected in concentrations of sodium and chloride of thermal sweat. J. Clin. Endocrin. 10 : 12, 1950. CONN, J . W . , R O V N E R , D.R. and C O H E N , E.L. : Normal and altered function of the renin angiotensin-aldosterone system in m a n : applications in clinical and research medicine. Ann. Intern. Med. 63 : 266, 1965. CRANE, M . G . , H A R R I S , J . J . and H E R U E R , R . : Primary aldosteronism due to an adrenal carcinoma. Ann. Intern. Med. 63 : 494, 1965. AUGUST, J . T . DAVIS, O . J . , YANKOPOULUS, N . A . , LIEBERMAN, F . , HOLMAN, J . a n d B A H N , R . C . : The role of the anterior pituitary in the control of aldosterone secretion in experimental secondary hyperaldosteronism. J. Clin. Invest. 39 : 765, 1960. DUSTAN, H . P . , CORCORAN, A . C . and PAGE, I . H . : Renal function in prumary' aldosteronism. J. Clin. Invest. 35 : 2357, 1957. ELLISON, E.H. : Anterior transabdominal adrenalectomy for endocrine disease. Amer. J. Surg. 99 : 497, 1960. F A R R E L , G . : The physiological factors which inflence the secretion of aldosterone. jRec. Prog. Horm. Res. 15 : 275, 1959. F A R R E L , G . : Steroidogenic properties of extracts of beef diencephalon. Endocrinology, 65 : 29, 1959. F A R R E L , G . L . , BAUSCHKOLB, E . W . and KOLETSKY, S. : Secretion of aldosterone by hypophysectomized dogs. J. Clin. Endocr. Metab. 15 . 1852, 1955. F I N E , D„ MEISELAS, L.E. and AUERBACH, T. : The effect of acute hypovolemia Oil the release of aldosterone and on the renal excretion of sodium. J. Clin Invest., 37 : 232, 1958. GOI.DENBERG, M. : Adrenal medullary function. Amer J. Med. 10 : 627, 1951. H E T Z E L , B.S. and H I Ñ E , D . C . : Adrenal cortical function in hypertension. J. Clin. Endocr. 12 : 296, 1952. : The role of aldosterone in man. Evidence for regulation of electrolyte balance and arterial pressure by a renal-adrenal system which may be involved in malignant hypertension. J.A.M.A. 174 : 293, 1960. LARAÜH, J . H . : Interrelationship between angiotensin, norepinephrine, epinephrine, aldosterone secretion and electrolyte in man. Circulation, 25 : 203 1962. MARQUEZ, F. : Clínica quirúrfica de la glándula suprarrenal. IV Jornadas Rioplatenses de Urología, p. 308, 1967. MAHQUEZY, R.A., B R I C A I R E , H . , P H I L B E R T , M . and LAUDAT, M.A. : Tumeur de la Surrénale avec syndrome d'hyperproduction d'hormone minérale. Ann. D'Endocrino/. 26 : 72, 1965. LAHAUH, J . H . MCCAA, C . S . , RICHARDSON, T . Q . , MCCAA, R . E . , SULYA, L . L . a n d GUYTON, A . C . : Aldosterone secretion by dogs during the development phase of Goldblat hypertension. J. Endocrin. 33 : 97, 1965. MILLS, L.C. and M O V E R , J . H . : I n f l a m m a t i o n and diseases of Connective Tissues. Philadelphia : W.B. Saunders Co., 1961. M U L R O W , P . J . , GANONG, W . F . , CERA, G . and K U L J I A N , A . : The nature of aldosterone stimulating fector in dog kidneys. J. Clin. Invest. 41 : 505, 1962. P E Z Z U O L I , G . , M O N T O R S I , W . , G H I R I G H E L L I , C . and T U S I N O , G . : Tentative d'interprétation de l'action de la surrénalectomie dans la thromboangiose. L'hypertrophie surrénalienne « dysarmonique ». Presse Med. 664 : 693, 1956. TRABUCCO, A., MARQUEZ, F.J. y B O R Z O N E , R. : Comentarios sobre siete casos de adrenalectomias por trastornos nefro-hipertensivos. Rev. Argent. Urol. 21 : 210, 1952. TRABUCCO, A., MARQUEZ, F.J. y B O R Z O N E , R.J. : La suprarrenal desde el punto de vista clínico-quirúrgico. IV Jornadas Rioplatenses de Urologia., pag. 286, 1967. TRABUCCO, A. : Reseña del valor quirúrgico de las suprarrenales en medicina operatoria. IV Jornadas Rioplatenses de Urologia., p. 317 : 1967. TRABUCCO, A., MARQUEZ, F . J . and B O R Z O N E , R . J . : Adrenalectomy in cases of severe renal sclerosis. Transactions of the american association of Genito-Urinary Surgeons. 60 : 138, 1968. T R O N C H E T T I , F . , ROMANELLI, R . , MATEZZI, I . F . , SALVETTI, A . a n d CELLA, P . L . : La fonction cortico-surrénaliène dans l'hypertension essentielle et réno-vasculaire. Corrélation entre la surrénale et rein. Ann. Endocr. 26 : 233, 1965. W O L F E R T H , C . C . , J E F F E R S , W . A . , HAFKENSCHIEL, J . H . and H I L L S , A . G . : Effects of subtotal adrenalectomy alone and combined with sympatectomy upon blood pressure levels and complications of severe arterial hypertension. Bull. N.Y. Acad. Med. 29 : 115, 1953. TABLE DES MATIERES 1. - LES RÉSULTATS ÉLOIGNÉS DE LA CHIRURGIE DES CALCULS CORALLIFORMES J.-M. G I L - V E R N E T : L a cinigia intrasinusal de los cálculos coraliformes 11 K.-F. A L B R E C H T : Langfristige Ergebnisse in der Chirurgie korallenförmiger Steine. Operationstechnick, Operationsfolgen und-ergebnisse, Verhütung von Rezidiven 57 P. A B O U L K E R et Et. B E R N A R D : L a lithiase coralliforme phosphatique primitive femme, avec infection urinaire gram-négative de la 71 M. A R D U I N I : I risultati a distanza della chirurgia della calcolosi coralliforme sotto il profilo anamnestico, clinico ed anatomocliirurgico 95 2. - LE REFLUX VÉSICO-URÉTÉRAL A. Chez l'enfant W. G R E G O I R : L e mécanisme du reflux congénital et acquis 143 W. L E A D B E T T E R : R a p p o r t non parvenu D. I N N E S W I L L I A M S : Vesico-ureteric reflux in children : pathology and natural history 180 181 B. Chez l'adulte J . G L E E N and J.H. GRIMES : The problem of vesicoureteral reflux in adults 229 R. LOPEZ E N G E L K I N G Reflujo vesico-ureteral en el adulto 244 3. - LA CHIRURGIE DES GLANDES SURRÉNALES S. SHISHITO : Post-operative course and treatment in adrenal surgery . . 319 W.-M. Z I E G L E R und G. MAYOR : Die chirurgie der Nebennieren 347 J.-H. HARRISON and D. J E N K I N S : Disorders of the adrenal cortex ; their medical and surgical management 359 A.E. TRABUCCO : Effectos de la suprarrenalectomia en las nefroesclerosis con hipertensión 389 G. et R. J O L Y Imprimeurs 1 9, rue des S t s - P è r e s P A R I S ( V I ' )