Androstenedione rhythms in saliva in congenital adrenal hyperplasia

Transcription

1 Arhives of Disese in Childhood, 1988, 63, Androstenedione rhythms in sliv in ongenitl drenl hyperplsi M C YOUNG, R F WALKER, D RIAD-FAHMY, AND I A HUGHES Deprtment of Child Helth nd Tenovus Institute, University of Wles College of Mediine, Crdiff SUMMARY Seril smples of sliv were olleted t home by 17 ptients being treted for ongenitl drenl hyperplsi to determine the irdin rhythm of ndrostenedione s n inde of therpeuti ontrol Single smples of blood for mesurement of plsm testosterone, 17H-progesterone, nd ndrostenedione onentrtions were olleted from these nd further seven ptients for omprison Plsm ndrostenedione onentrtions showed lose orreltion with plsm onentrtions of 17H-progesterone nd testosterone There ws strong orreltion between the slivry ndrostenedione profiles nd plsm testosterone onentrtions in pubertl girls Conentrtions of ndrostenedione in sliv deresed during the dy but remined rised t eh smpling time in reltion to plsm testosterone onentrtions Slivry ndrostenedione profiles re shown s nomogrms to distinguish the degree of therpeuti ontrol The onentrtion of ndrostenedione, mesured in plsm or sliv, is n lterntive mrker to monitor ontrol of tretment in ongenitl drenl hyperplsi The mesurement in sliv is useful inde of ndrogen prodution when blood smpling is diffiult Mesurements of 17H-progesterone in blood spot nd sliv re useful to monitor tretment in ptients with ongenitl drenl hyperplsi1 The mesurement of plsm ndrostenedione onentrtions hs lso been suggested2 Androstenedione is wek drenl ndrogen nd, unlike 17Hprogesterone, single mesurements re less ffeted by wide irdin vritions in plsm onentrtions This study reports the use of slivry ndrostenedione profiles to monitor tretment in ongenitl drenl hyperplsi The results re ompred with single rndom mesurements of plsm ndrostenedione, testosterone, nd 17H-progesterone s indies of the degree of ontrol Ptients nd methods Twenty four ptients ged 2 to 22 yers with ongenitl drenl hyperplsi used by 21- hydroylse defiieny, provided dt for the study Androstenedione profiles were mesured in 17 ptients 11 of whom were femle over two yer period Smples of sliv were olleted t home t 8, 12, 18, nd 22 hours, on two onseutive weekend dys A profile represents ndrostenedione onentrtions during one dy The dose of gluoortioid, given either s hydroortisone in divided doses or s demethsone one dily, ws djusted ording to linil indies of ontrol, nd single rndom mesurements of plsm 17Hprogesterone, testosterone, ndrostenedione onentrtions, nd where pproprite, plsm renin tivity Androstenedione profiles in two pubertl mle ptients were eluded from the nlysis beuse of predominnt testiulr prodution t this ge The remining 11 pubertl femle ptients nd four prepubertl hildren provided totl of 44 profiles (28 nd 16, respetively) for nlysis Dt from n dditionl 11 inomplete profiles were lso inluded in the nlysis where pproprite The result of eh slivry ndrostenedione profile ws ompred with the plsm testosterone onentrtion tht hd been mesured in morning blood smple olleted t reent lini Dt from 624 pubertl femle ptients nd prepubertl hildren were nlysed seprtely ording to the norml testosterone vlues for these ges-tht is, nmol/l nd <*5 nmol/l, respetively2-4 Plsm testosterone,5 plsm 17H-progesterone6 nd plsm nd slivry ndrostenedione7 onentrtions were mesured by rdioimmunossy The Arh Dis Child: first published s 11136/d on 1 June 1988 Downloded from on 11 November 218 by guest Proteted by opyright

2 results were nlysed by non-prmetri sttistil methods s the dt were generlly not normlly distributed The methods re stted where pproprite Results Fig 1 shows the ssoition between simultneous mesurements of plsm ndrostenedione nd testosterone onentrtions in ptients with treted ongenitl drenl hyperplsi There ws strong orreltion (r=-9, p<l1), with vlues being lowest in prepubertl hildren Fig 2 shows similr orreltion between plsm ndrostenedione nd 17H-progesterone onentrtions (r=-8, p<ooo1) There ws irdin vrition in slivry ndrostenedione onentrtions in ll 17 ptients who provided profiles The onentrtion of ndrostenedione t 8 hours ws usully greter thn 35- = 3- ' 25- ; 2- o 15-1 E 5- - oip * Plsm testosterone (nmol/l) Assoition between simultneous mesurements of Fig 1 plsm ndrostenedione nd testosterone onentrtions in ptients being treted for ongenitl drenl hyperplsi O=prepubertl ptients (n =7); *=pubertlfemle ptients (n=13); nd A=pubertl mle ptients (n=3) Tble 1 " Androstenedione rhythms in sliv in ongenitl drenl hyperplsi Z 25- to C * t 2-1 E O v i A Plsm 17H-progesterone (nmol/1) Fig 2 Assoition between simultneous mesurements of plsm ndrostenedione nd plsm 17H-progesterone in ptients being treted for ongenitl drenl hyperplsi; O=prepubertl ptients (n=7); *=pubertl femle ptients (n=13); nd A=pubertl mle ptients (n=3) 7-6- E 5 4- C j# I O- * 8 : * * t 8 A" O Time (hours) Fig 3 Conentrtions of ndrostenedione in sliv in reltion to smpling time nd rnge ofplsm testosterone onentrtions Brs= men vlues; *=plsm testosterone >2-5 nmolll; nd O=plsm testosterone <2 5 nmolll Slivry ndrostenedione nd plsm testosterone onentrtions in pubertlfemles Smpling tione (hours) * TI T2 TI T2 TI 72 TI 72 No of observtions Slivry ndrostenedione (pmol/l): Men Rnge 54( *T1-plsm testosterone onentrtion >2-5 nmol/l; T2-plsm testosterone onentrtion <2-5 nmolul,ic Arh Dis Child: first published s 11136/d on 1 June 1988 Downloded from on 11 November 218 by guest Proteted by opyright

3 626 Young, Wlker, Rid-Fhmy, nd Hughes tht t 22 hours, but onsistent fll in ndrostenedione onentrtions t eh smpling time ws seen in only one third of the profiles Fig 3 nd tble 1 show the results of slivry ndrostenedione profiles in pubertl femle ptients The profiles were subdivided ording to testosterone vlues greter or less thn 2-5 nmol/l Slivry ndrostenedione vlues in both groups grdully fell during the dy to their lowest vlues t 22 hours Inresed plsm testosterone onentrtions were generlly ssoited with high slivry ndrostenedione onentrtions t eh smpling time Although there ws some overlp in ndrostenedione vlues in the two groups, men slivry ndrostenedione onentrtions were signifintly higher t ll smpling times in those ptients with plsm testosterone vlues greter thn 2*5 nmol/l (p<1, Mnn-Whitney U test) The positive orreltion between slivry ndrostenedione vlues t 22 hours nd plsm testosterone onentrtions is shown in Fig 4 A similr ssoition ws seen t eh smpling time (tble 2) The results my be used to derive vlues for slivry ndrostenedione onentrtions tht distinguish ptients with norml or rised plsm testosterone onentrtions The nomogrm (fig 5) indites how slivry ndrostenedione profiles my be used to monitor the dequy of tretment in pubertl femles with ongenitl drenl hyperplsi Slivry ndrostenedione profiles were vilble for nlysis in only four prepubertl hildren There Z- 3 E 2- l 1* ' L) AI *: Plsm testosterone (nmol/l) Fig 4 Assoition between sliv ndrostenedione onentrtions nd plsm testosterone in pubertlfemle ptients t 22 hours Vertil line denotes plsm testosterone onentrtion of2 5 nmolll, nd horizontl interset of this nd regression line denotes ndrostenedione onentrtion in sliv tht distinguishes good nd poor ontrol ws orreltion between slivry ndrostenedione nd plsm testosterone onentrtions t every smpling time eept 12 hours (tble 3 nd fig 6) Fig 7 nd tble 3 show how slivry ndrostenedione profiles n distinguish dequte from poor ontrol Tble 2 Slivry ndrostenedione onentrtions tht differentite the degree of ontrol in pubertlfemle ptients t eh smpling time ording to plsm testosterone onentrtion of25 nmolll Smpling time (hours) (n=33) (n=38) (n=38) (n =36) Spermn's rnk orreltion oeffiient (r) p Vlue < 1 <-1 <-1 <-1 Androstenedione onentrtion (pmoli1) A- Kz F to -t 1 I -IIeV% vul =' Fig 5 Nomogrm to monitor ontrol in pubertl femle ptients with ongenitl drenl hyperplsi using ndrostenedione profiles in sliv Are lbelled "good ontrol" is ssoited with plsm testosterone onentrtions within norml rnge of3-25 nmolll Tble 3 Slivry ndrostenedione onentrtions tht differentite the degree ofontrol in prepubertl hildren t eh smpling time ording to plsm testosterone onentrtion of-5 nmolll Stnpling time (hours) (n=15) (n=16) (n=16) (n=13) Spermn's rnk orreltion oeffiient (r) ( p Vlue <()1 NS <(1 <-1 Androstenedione onentrtion (pmol/l) Arh Dis Child: first published s 11136/d on 1 June 1988 Downloded from on 11 November 218 by guest Proteted by opyright

4 5-4- ~2 O Plsm testosterone (nmol/1) Fig 6 Assoition between sliv ndrostenedione onentrtions t 8 hours () nd 18 houirs (@) nd plsm testosterone onentrtionis in prepubertl hildren? 2- CL Fig 7 Nomogrom topoor ontrol 1 V ontrol" isgsotewihood ontro Time (hours) Fig 7 Nomogrm to monitor ontrol in prepubertl hildren with ongenitl drenl hyperplsi uesing ndrostenedione profiles in sliv Are lbelled "good ontrol" is ssoited with plism- testosterone onentrtions of less thi o5 nmoll in prepubertl hildren with ongenitl drenl hyperplsi Disussion Single, rndom mesurements of steroids, prtiulrly 17H-progesterone, n be diffiult to interpret when used to monitor tretment of ongenitl drenl hyperplsi Testosterone hs been used most frequently s single mrker but in infnt nd pubertl mle ptients the onentrtion of steroid reflets testiulr rther thn drenl ndrogen prodution Mesurement of plsm ndrostenedione onentrtion hs been dvoted s Androstenedione rhythmtis in sliv in ongenitl drenl hyperplsi 627 useful lterntive2 This study onfirms the strong ssoition between simultneous mesurements of plsm testosterone, ndrostenedione, nd 17Hprogesterone onentrtions8 Korth-Shutz et!2 reported tht poor ontrol of ongenitl drenl hyperplsi ws ssoited with inresed plsm testosterone nd ndrostenedione onentrtions They onluded tht ndrostenedione onentrtions were more urte in distinguishing between ptients in good nd poor ontrol We hve shown n ssoition between slivry ndrostenedione nd plsm testosterone onentrtions There ws irdin rhythm in ndrostenedione onentrtions in treted ptients with ongenitl drenl hyperplsi irrespetive of ge, se, or stge of puberty The mgnitude of the irdin rhythm ws less thn for 17Hprogesterone' but the ury of the slivry ndrostenedione nomogrin for prediting dequy of ontrol in pubertl girls ws still 9% The nomogrm ws less disriminnt s only two groups (dequte nd poor ontrol) ould be identified Only smll number of profiles from prepubertl hildren were vilble for nlysis There ws positive orreltion between slivry ndrostenedione nd plsm testosterone onentrtions t most smpling times The nomogrm (fig 7) provides only n pproimte guide to the ontrol of tretment until the vlues for slivry ndrostenedione tht will distinguish degrees of ontrol re more preisely defined Androstenedione is wek ndrogen whih is sereted by both the drenl glnds nd the gonds Mesurement of it in ptients with ongenitl drenl hyperplsi provides useful mrker of eessive drenl ndrogen prodution, prtiulrly in pubertl mle ptients Slivry ndrostenedione profiles show irdin rhythm tht is losely ssoited with plsm testosterone onentrtions, prtiulrly in pubertl femle ptients The profiles my be used lone, or in onjuntion with 17(Hprogesterone to monitor ndrogen prodution' When the profiles of both steroids re used it is possible to hieve sensitive degree of ontrol nd n inde of ndrogen prodution in those ptients who re relutnt to hve blood smples tken Referenes Young MC Robinson JA, Red GF Rid-Fhmy D, hlughs IA 17O1H-progesterone rhythms in ongenitl drenl hyperplsi Arh Dis C hild 1988;63: Korth-Shutz S, Virdis R, Senger P Chow DM, Levin LS, New Mi Serum ndrogens s ontinuing ind of dequiy of tretment of ongenitl drenl hyperplsi J Clinz Enidorinol Metb 1978 ;46:452-8 Arh Dis Child: first published s 11136/d on 1 June 1988 Downloded from on 11 November 218 by guest Proteted by opyright

5 628 Young, Wlker, Rid-Fhmy, nd Hughes 3 Sizonenko PC, Punir L Hormonl hnges in puberty III: Correltion of plsm dehydroepindrosterone, testosterone, FSH, nd LH with stges of puberty nd bone ge in norml boys nd girls nd in ptients with Addison's disese or hypogondism or with premture or lte drenrhe J Cliit Endorinol Metb 1975;41: Duhrme JR, Forest MG, De Pertti E, Semp M, Collu R, Bertrnd J Plsm drenl nd gondl s steroids in humn pubertl development J Cliti Endorinol Metb 1976;42: Dys J, Red GF, Rid-Fhmy D A simple robust ssy for testosterone in mle plsm using n 1251-rdiolignd nd solid-phs seprtion tehniqu A tin Cliti Biohern 197;16: Dys J, Red GF, Guh-Mulik T, Hughes IA, Rid-Fhmy D A rpid ssy for 17H-progesterone in plsm, sliv nd mnioti fluid using mgnetisble solid-phse ntiserum Annt Clin Biohein 1984;21: Turkes AO, Red GF Determintion of ndrostenedione in sliv In: Red GF, Rid-Fhmy D, Wlker RF Griffiths K, eds linmunossys of steroids ini sliv Crdiff: Alph Omeg Publishing, 1982:26-7 Hughes IA, Winter JSD The reltionships hetween serum onentrtions of 17H-progesterone nd other serum nd urinry steroids in ptients with ongenitl drenl hyperplsi J Clini Endorinol Metb 1978;49:98-14 Correspondene to Dr IA Hughes, Deprtment of Child Helth, University of Wles College of Mediine, Heth Prk, Crdiff CF4 4XN Aepted 27 Otober 1987 Arh Dis Child: first published s 11136/d on 1 June 1988 Downloded from on 11 November 218 by guest Proteted by opyright