An Adrenocortical Tumor Secreting Weak Mineralocorticoids

Transcription

1 Endocrol. Jpon. 1987, 34 (1), An Adrenocorticl Tumor Secretg Wek Merlocorticoids KAZUHIKO MAKINO1, KEIGO YASUDA1, MAKIO OKUYAMA2, MOTOKO OJIMA3, NOBUAKI SASANO4 AND KIYOSHI MIURA1 1 The Third Deprtment Internl Medice, Gifu University School Medice, Gifu500, Jpn 2The Deprtment Internl Medice, Chubu Rosi Hospitl, Ngoy, 455, Jpn 3The Third Deprtment Internl Medice, Fukushim Medicl College, Fukushim960, Jpn 4The Second Deprtment Pthology, Tohoku University School Medice, Sendi980, Jpn Abstrct An drenocorticl crcom (15.5g) secretg excessive mounts steroids wek merlocorticoid ctivity 25-yer-old womn ws studied prticulr reference to its vivo vitro secretions steroids. Severe hypertension, occsionl low serum potssium suppressed PRA mjor clicl fdgs, improved removl. In preopertive stge, plsm levels 11-deoxycorticosterone, 18-hydroxy-11- deoxycorticosterone, corticosterone 18-hydroxycorticosterone ll cresed. However, plsm level ldosterone ws repetedly norml. Although plsm levels pregnenolone, 17-hydroxypregnenolone, progesterone 17-hydroxyprogesterone very high, those or lte step steroids, i.e. 11-deoxycortisol, cortisol, dehydroepirosterone, rostenedione testosterone lmost norml. From se fdgs, mjor etiologicl role wek merlocorticoids such s 11-deoxycorticosterone, 18-hydroxycorticosterone corticosterone her hypertension ws suggested. Pregnenolone 17-hydroxypregnenolone tissue cresed, but 11-deoxycorticosterone, corticosterone, ldosterone, cortisol drenl rogens such s dehydroepirosterone, rostenedione testosterone below norml or low norml. In vitro production 11-deoxycorticosterone, ldosterone or cortisol by tissue slices ws very low scrcely responded to syntic ACTH. An drenl clicl signs merlocorticoid excess but no evidence ldosterone hypersecretion is very rre. Only Received July9, 1986 This work ws supported by grnt from Mistry Helth Welfre "Disorders Adrenl hormones" "Disorders Hypothlmo-pituitry Gl" Reserch Committees, Jpn. spordic cse reports drenocorticl crcom hypersecretion 11-deoxycorticosterone (DOC)(Powell-Jckson et l., 1974; Devies et l., 1980) or corticosterone (B)(Frser et l., 1968) denom excessively producg DOC (Kondo et l., 1976) or B (Mills et l., 1980) documented. The present pper concerns vivo vitro studies steroidogenesis cse hypertension cused by n drenocorticl crcom producg exces-

2 MAKENO 66 sive mounts DOC, 18-hydroxy-DOC, 18-hydroxy-B. B Cse Report A25-yer-old Jpnese womn ws dmitted to Gifu University Hospitl June, 1978becuse hypertension. Five yers before dmission hypertension (220/ 150mmHg) ws first noted. On dmission, her blood pressure ws190/124mmhg, but or physicl exmtion results negtive. Lbortory dt s follows: ECG showed left ventriculr hypertrophy U wves leds V2-V4. Serum sodium rnged140to144meq/1 (men 142, 12estimtions), potssium3.4to 4.1mEq/1 (men3.7, 12estimtions) chloride ws103meq/1. Potssium clernce ws norml (12.0ml/m) but cresed to33.2ml/m fter n trve- smll typicl Histology rrnged drenocorticl n crcom: lveolr mitotic or figure Endocrol. Februry1987 et l. Jpon. nous dmistrtion sodium thiosulfte (norml; below30ml/m (Abe, 1964)). Arteril ph showed mild lklosis (ph7.45) bse excess ws+2.8meq/1. Bsl PRA ws low (0.1ng/ml/h; norml rnge 0.3to3.2) filed to respond to2h upright posture fter n trvenous dmistrtion 1mg/kg furosemide (0.2 ng/ml/h; norml rnge1.4to8.3). PRA responded slightly from0.1to2.2ng/ml/h to severe stimultion tests such s combtion 2h upright position fter n trvenous dmistrtion 1mg/kg furosemide under sodium restriction (N below30meq/dy) orl dmistrtion 40mg furosemide dy for3dys. Plsm levels ldosterone lwys norml, but those wek merlocorticoids cludg DOC mrkedly elevted. These dt will be described lter detil. Adrenl sctiscnng dexmethsone pretretment demonstrted n enlrged left Prt ribbon (Hemtoxyl pttern. nodulr Insert eos prolifertion is high st, ~40& ~160). power typicl view

3 Vol.34 No.1 drenl mss. veled WEAK Computed round left mss drenl Plsm 1,900ng/dl, upper ven cv, fdgs, On left Her blood becme PRA 2h she observble grnulr is cellulr The nodulr drk bsl normlly present, well from vsculr ws norml cpsulr tubulo-vesiculr vsion. vsion ws Tumor predomnt criste hve irregulrly elongted smooth-surfced not evident dignosis crcom. (Fig.2), little drencorticl n smll Hemorrhge, Histologicl differentited nuclei figures. re nucler observed. composed Electronmicroscopiclly : reticulum Slight ws Spordic hyperchromtic but fely rrnged structures. termgled. mly pleomorphism conspicuous, His- ws lveolr lesions yelseverl lesion. which mitotic necrosis 7yers fdgs ( ~5,600). to fibrotic surfce, conted medium-sized occsionl trvenous centrl oper- cut color, cytoplsm cler n endoplsmic mitochondri re composed Jnury, opertion, Electronmicroscopic rough-surfced se wek The (Fig.1), removed. (1mg/kg) At Sphericl reticul furosemide opertion, tologiclly potssium fter fter 1.8to3.9ng/ml/h. fter serum responded position dmistrtion nodules norml mesured3.5 ~3.0 ~3.5cm weighed15.5g. trbeculr ws fter recovered upright brown (4.6mEq/l). lowish 67 CARCINOMA (130/86mmHg) 260 ve, on 6weeks In3months potssium ferior secretg performed pressure pressure serum ws suggested. drenl norml tion. Bsed ws left renl ADRENAL blood The ve right prts drenl lprotomy lower merlocorticoids 1979, renl respectively. mrg ws260ng/dl, re- smooth left it 140ng/dl, (3.5 ~3.0 ~3.5cm). while PRODUCING tomogrphy region DOC ng/dl MINERALOCORTICOIDS shped nucleus mitochondri. endoplsmic

4 68 MAKINO et l. Endocrol. Februry1987 Jpon. possessed lrge round or ovoid nuclei well developed nucleoli. Drk irregulr shpe high, homogenous electron densities occsionlly conted filmentous structures. Mitochondri numerous generlly round or tubulr shpe poorly developed criste. Lrge, round mitochondri well developed lmellr criste rrely detected. Ribosomes well developed scttered smooth-surfced endoplsmic reticul seen. Golgi pprtus, lipid droplets dense bodies less. Mterils Methods Steroid hormone ssy plsm: Plsm levels followg15steroids, i. e. pregnenolone, progesterone, DOC, B, 18-hydroxy-DOC, 18-hydroxy-B, ldosterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol, dehydroepirosterone (DHEA), rostenedione, testosterone estrdiol mesured by previously reported specific rdioimmunossys (Ojim, 1974; Ojim et l., 1975; et l., 1980). Briefly, n liquot ml plsm ws dded to tube contg tritited steroids (bout30,000dpm), extrcted dichloromethne, dried pplied to Sephdex LH-20column. The column size solvent system (v/v) s follows: 0.7 ~6.0 cm column ws used for pregnenolone, 17- hydroxypregnenolone, progesterone, 17-hydroxyprogesterone (benzene95: methnol5), estrdiol (benzene85: methnol15), DHEA, rostenedione testosterone (hexne80: benzene10: methnol10), 1 ~20cm column for cortisol, B, 11-deoxycortisol (dichloromethne99: ethnol 1), 1 ~55cm column for DOC, ldosterone, 18-hydroxy-DOC 18-hydroxy-B (distilled wter). The pproprite eluted frctions collected n liquot m ws counted for estimtion recovery, or liquot ws nlyzed for steroid content by rdioimmunossy. The plsm concentrtions DOC, ldosterone cortisol mrked s Tbles12 mesured by method Tochigi et l.(1976), rdioimmunossy kits usg125i-ldosterone (Commissrit l'energie Atomique, Frnce) or125i-cortisol (Diichi RI Lbortory, Tokyo, Jpn), respectively. Steroid concentrtion tissue: A portion tissue ws fely sliced homogenized Krebs-Rger bicrbonte buffer (ph7.4) loose-fittg Teflon glss homogenizer. Steroids homogente extrcted 10vol dichloromethne, mesured by rdioimmunossy s mentioned bove. The norml drenocorticl tissues surgiclly resected for tretment three ptients brest cncer used for control. In vitro steroid production by tissue: Fely sliced tissues, weighg bout100 to200mg, suspended totl volume 30-50ml Krebs-Rger bicrbonte buffer (ph7.4) contg200mg/dl glucose, cubted or out10-8m syntic 5% CO2gs mixture. After cubtion, ldosterone, DOC cortisol relesed medium mesured by rdioimmunossy fter extrction dichloromethne. Similr vitro studies performed on drenl cortex djcent to, control drenl cortices obted from six ptients brest cncer. Results A. In vivo steroid study Preopertive stge (Tble1, A)) Plsm levels pregnenolone, DOC, 18-hydroxy-DOC, B 18-hydroxy-B mrkedly higher thn those norml subjects. Plsm levels ldosterone repetedly norml. Plsm concentrtions progesterone 17-hydroxyprogesterone clerly elevted. Plsm levels 11- deoxycortisol cortisol norml rnge. Urry excretions 17- OHCS lso norml (4.8mg/di; norml rnge2.9to9.8). An orl dmistrtion 1mg dexmethsone t2100h lod plsm cortisol level from5.5to2.7Đg/ dl t0900 h next dy. Plsm DHEA, rostenedione, testosterone estrdiol ll norml rnge. Urry excretions 17-KS lso norml (3.7 mg/dy; norml rnge3.0to16.0). An

5 Vol.34 No.1 WEAK MINERALOCORTICOIDS PRODUCING ADRENAL CARCINOMA 69 Concentrtions vrious steroids plsm tissue A) Preopertive stge (): norml rnges steroids control plsm or steroids content control drenl tissues obted from ptients brest cncer n: number control drenl tissues *:,ƒêg/dl,**:ƒêg/g tissue, : See method text trmusculr jection 1mg/dy1-24 ACTH-Z for3dys duced rise plsm levels cortisol from10.5to32.5 but scrce ldosterone response from 11.0to15.0ng/dl. Plsm DOC mesured by method Tochigi et l.(1976) cresed from79to269ng/dl on morng 3rd dy, but result did not clerly demonstrte tht chnge is dependent on ACTH becuse mrked dily fluctution bsl plsm DOC levels rnged from37to244ng/dl (men128 ng/dl, 6estimtions). Postopertive stge (Tble1, B)) The bsl level plsm DOC or ldosterone3months fter opertion ws low norml (1.0ng/dl) or low (2.3ng/dl), both scrcely responded to n trmusculr iection 1 mg/dy syntic for3dys (DOC: 7.0ng/dl, ldosterone: 4.9ng/dl). The bsl level (13.1ƒÊg/di) response to ACTH (33.0ƒÊg/di) plsm cortisol ws norml, s preopertive period. B. Steroid concentrtions tissue (Tble1) Concentrtions pregnenolone 17- hydroxypregnenolone mrkedly high, but those progesterone 17-hydroxyprogesterone s well s DOC, B ldosterone cortisol mrkedly or modertely

6 70 MAKINO et l. Endocrol. Februry1987 Jpon. Releses ldosterone, DOC cortisol by drenl tissue, djcent ACTH (-): out ACTH ACTH (+): ACTH n: number control drenl tissues obted from ptients brest cncer low comprison those control drenl cortices. DHEA ws modertely low, rostenedione testosterone mrkedly low. drenl cortex control drenl cortices ir responses to10-8m syntic1-24acth C. Steroid production by tissue (Tble 2) Bsl production ldosterone, DOC cortisol by slices ws mrkedly lower thn tht by control drenl cortices slightly responded to phrmcologicl dose syntic1-24acth (10-8M). Production se steroids before fter ACTH stimultion by drenl cortex djcent to ws much higher thn tht from tissue, but lower thn tht by norml drenl cortices. Discussion The present weighg15.5g ws histologiclly terpreted s differentited drenocorticl crcom bsed on fdg nodulr lesions compressg surroundg tissue. The lesions composed smll cresed bsophili rrnged irregulr solid nests occsionl mitotic figures vsculr vsion. The removl djcent tissue resulted restortion norml blood pressure serum potssium. Susted low or low norml levels ldosterone or DOC ir poor response to ACTH even3months fter opertion suggested suppressed preopertive secretion se steroids by contrlterl drenl. Norml suppressibility plsm cortisol by dexmethsone suggested tht cortisol ws secreted normlly even preopertive period mly from contrlterl drenl gl /or from djcent tissue surroundg. The norml plsm ldosterone level preopertive period this cse is le fdgs lmost norml preopertive plsm ldosterone levels observed DOC (Powell-Jckson et l., 1974; Kondo et l., 1976; Dvies et l., 1980) or B (Frser et l., 1968; Mills et l., 1980) producg drenl reported previously. We could not exme ldosterone content /or histologicl view djcent drenl tissue, but bsl ldosterone relese from it this cse ws much less thn tht control drenl tissue, lthough it ws fr more thn tht tissue. This is comprble low postopertive bsl plsm ldosterone level, suggests tht preopertive norml ldosterone level would be mly due to ldosterone production from. Concerng responsiveness ldosterone relese to ACTH slice experiment on djcent tissue, slight response ws observed, lthough it ws much less thn

7 Vol.34 No.1 WEAK MINERALOCORTICOIDS PRODUCING ADRENAL CARCINOMA 71 tht control drenl tissue. Generlly zon glomerulos tissue djcent to n ldosterone producg denom, even when it shows morphologiclly hyperplsi, is not ctive respect to ldosterone secretion (Neville et l., 1982). In fct, ldosterone response to ngiotens II tissue djcent to n ldosterone producg denom ws negligible or bsent fce considerble response ldosterone relese to ACTH (Brown et l., 1980). Thus, ptient's hypertension occsionl mild hypopotssemi suppressed PRA found to be duced by excessive mounts merlocorticoids or thn ldosterone secreted by drenl crcom, s judged from known reltive potencies mong se wek merlocorticoids, DOC my ply primry role symptoms. However, it is still possible tht ldosterone, even though norml rnge, might prticipte prt se symptoms. Cses drenl crcom hypermerlocorticoidism re usully ssocited concomitnt hypersecretion or drenocorticl hormones such s glucocorticoids rogens, y should be considered to be mixed hypercorticoidism rr thn pure hypermerlocorticoidism. Adrenocorticl s producg DOC (Powell-Jckson et l., 1974; Dvies et l., 1980; Kondo et l., 1976) or B (Frser et l., 1968; Mills et l., 1980), eir mlignnt (Powell-Jckson et l., 1974; Dvies et l., 1980; Frser et l., 1968) or benign (Kondo et l., 1976; Mills et l., 1980), hve been documented s hypermerlocorticoidism or thn hyperldosteronism. All se ptients hd severe hypertension hypopotssemi. A ptient n drenl crcom high plsm level DOC lone mong merlocorticoids reported by Powell-Jckson et l.(1974) excreted lrge mounts urry17-kgs. In B producg drenl crcom reported by Frser et l.(1968), preoperetive studies on drenl rogens DOC not performed. In benign DOC producg drenl reported by Kondo et l. (1976), plsm B 18-hydroxy-B not mesured. In present cse, hypersecretion DOC, 18-hydroxy-DOC, B 18-hydroxy-B norml levels plsm cortisol, urry17-ohcs, plsm drenl rogens urry17-ks confirmed dignosis rre form pure hyperwek merlocorticoidism. In our cse, results slice experiments did not lwys support vivo dt. We cnnot dequtely expl this discrepncy: i. e. why progesterone, 17-hydroxyprogesterone DOC levels low, why ws DOC production by slice decresed condition high levels se steroids plsm. Low efficcy steroid production which is well known chrcteristics drenocorticl crcom, reltively lrge size, my hve prt contributed to low vitro steroid concentrtions high plsm levels, respectively. In ddition, becuse drenl corticl crcoms rrely uniform ir structure generl, this would be relted to fct tht only portion tissue ws used for slice experiments. Furr study similr cses is required. References Abe, S;1964). The effect sodium thio-sulfte lodg on potssium clernce prticulr reference to its dignostic vlue for primry ldosteronism. Jp. J. Nephrology6, (In Jpnese). Brown, G., J. Dougls E. Brvo (1980). Angiotens II receptors vitro ldosterone responses ldosterone-producg denoms, djcent nonous tissue, norml humn drenl glomerulos. J. Cl. Endocrol. Metb. 51, Dvies, D., W. F. Kelly, I. Lg, M. J. O'Hre S. Loizou (1980). Docoms; An drenl crcom secretg deoxycorticosterone but not ldosterone. Act Endocrol. [suppl.]

8 72 MAKINO et l. Endocrol. Februry1987 Jpon. (copenh.) 243, 133. Frser, R., V. H. T. Jmes, J. London, W. S. Pert, A. Rwson, C. A. Gilles A. M. Mcky (1968). Clicl biochemicl studies ptient corticosterone secretg drenocorticl. Lncet II Kondo, K., T. Srut, I. Sito, R. Yoshid, H. Mruym S. Mtsuki (1976). Benign deoxycorticosterone-producg drenl. J. A. M. A. 236, Mills, I. H., R. F. Cook, J. M. Glley, O. M. Edwrds A. D. Tit (1980). Corticosteronesecretg s: out renl rtery stenosis. Cl. Endocrol.(Oxf.) 13, Neville, A. M. M. J. O'Hre (1982). The humn drenl cortex. Pthology Biology tegrted pproch. Sprger-Verlg, New York. Ojim, M.(1974). Simultneous determtion plsm ldosterone 11-deoxycorticosterone (DOC). Foli Endocrol. Jp. 50, (In Jpnese). Ojim, M., S. Li, K. Miur A. Kmbegw (1975). Simultneous determtion plsm progesterone 17-hydroxyprogesterone its ppliction. Horumon to Rsho23, (In Jpnese). Ojim, M. A. Kmbegw (1980). Plsm concentrtions 18-hydroxy-11-deoxycorticosterone 18-hydroxy-corticosterone simultneously mesured norml subjects drenocorticl disorders. Tohoku J. Exp. Med. 132, Powell-Jckson, J. D., A. Gl, R. Frser, R. Grhm, P. Msson, G. A. Missen, P. R. Powell-Jckson A. Wilson (1974). Excess deoxycorticosterone secretion from drenocorticl crcom. Br. Med. J. 2, Tochigi, B., M. Tomit, T. Yoshid, S. Tkgi, T. Mko A. Kmbegw (1976). Rdioimmunossy plsm11-deoxycorticosterone (DOC) Horumon to Rsho24, (In Jpnese).