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1 Origial Paper Horm Res 2002;58: DOI: / Received: Jauary 15, 2002 Accepted after revisio: Jue 18, 2002 Icreased Adreal Adroge Levels i Patiets with Prader-Willi Sydrome Are Associated with Isuli, IGF-I, ad Lepti, but Not with Measures of Obesity Dagmar l Allemad a Urs Eiholzer a Valeti Rousso b Jürg Girard d Werer Blum e Toi Torresai c Theo Gasser b a Foudatio Growth Puberty Adolescece, Zürich, ad Departmets of b Biostatistics ad c Pediatrics, Uiversity of Zürich, Switzerlad, ad d Istitute of Pediatric Edocriology, Basel, Switzerlad; e Uiversity of Giesse, Germay Key Words Prader-Willi sydrome W Adrearche W Adreal adroges W Obesity Abstract Backgroud/Aim: Sice hyperadrogeism i simple obesity is assumed to arise from hyperisuliism ad/or icreased isuli-like growth factor I (IGF-I) or lepti levels, we examied how i patiets with Prader-Willi sydrome (PWS), the most frequet form of sydromal obesity, the accelerated adrearche ca be explaied despite hypothalamic-pituitary isufficiecy with low levels of isuli ad IGF-I. Methods: I 23 childre with PWS ad a mea age of 5.6 years, height, weight, fat mass, fastig isuli cocetratio, isuli resistace (by HOMA-R; see text), ad lepti ad IGF-I levels were determied to test whether they explai the variace of the levels of dehydroepiadrosteroe (DHEA) ad its sulfate (DHEAS), of adrosteedioe, ad of cortisol before ad durig 42 moths of therapy with growth hormoe. Results: The baselie DHEAS, DHEA, ad adrosteedioe cocetratios were icreased as compared with age-related referece values, whereas the cortisol level was always ormal. Durig growth hormoe treatmet, the DHEA cocetratio further rose, ad the cortisol level decreased sigificatly. The isuli ad IGF-I cocetratios were low before therapy, while fat mass ad lepti level were elevated. The hormoal covariates provided aloe or together betwee 24 ad 60% of the explaatio for the variace of adreal adroge levels, but the athropometric variables did ot correlate with them. Coclusios: I childre with PWS, elevated adroge levels correlate with hormoes that are usually associated with adiposity. However, the lack of direct correlatios betwee disturbed body compositio ad adroge levels as well as the icreased sesitivity to isuli ad IGF-I are abormalities specific to PWS, potetially caused by the uderlyig hypothalamic defect. Itroductio Copyright 2002 S. Karger AG, Basel Childhood obesity is geerally accompaied by accelerated growth [1] ad early sexual developmet. A recet study coducted i 17,077 US girls cofirmed that higher ABC Fax karger@karger.ch S. Karger AG, Basel /02/ $18.50/0 Accessible olie at: Dr. Urs Eiholzer Foudatio Growth Puberty Adolescece Möhrlistrasse 69 CH 8006 Zürich (Switzerlad) Tel , Fax , mail@childgrowth.org

2 body mass idex (BMI) z-scores were foud i white girls with isolated pubic hair growth [2]. Early pubarche ca result from a precocious icrease of adreal adroge levels preset i obesity [3 5]. Adreal stimulatio, i tur, may be the cosequece of hyperisuliism ad/or icreased bioavailability of isuli-like growth factor I (IGF-I) [6 8]. I additio, lepti is reported to icrease the adreal activity i prepubertal childre, e.g., via stimulatio of corticotropi-releasig hormoe [9], ad lepti also stimulates the sythesis of adreal adroges i vitro [10]. Prader-Willi sydrome (PWS) is the most frequet form of sydromal obesity. The pheotype is liked with a hypothalamic defect. To date, growth hormoe (GH) isufficiecy ad hypogoadism are well described, ad the goadal developmet at puberty is typically delayed or icomplete. Surprisigly, i this cotext, premature adrearche may be observed i childre affected by PWS [11 15], although the isuli [16] ad IGF-I [17] levels are below the ormal average due to isufficiet GH secretio [18]. The issue of accelerated adreal developmet agaist a backgroud of hypothalamic-pituitary isufficiecy i PWS has ot yet bee explaied. Although gross abormalities of adreal fuctio have ot bee reported, the itegrity of the hypothalamic-pituitaryadreal axis eeds to be cofirmed by yet more sophisticated methods [19, 20]. Therefore, it has ot yet bee specified, whether premature adrearche is the cosequece of a uderlyig hypothalamic dysfuctio or results from adiposity, as i healthy obese childre [3, 4]. I order to test the hypothesis that premature adrearche i PWS is caused by obesity ad related metabolic alteratios, idepedetly of the hypothalamic regulatio, we studied the relatios betwee adreal adroges ad body compositio parameters or associated hormoes, such as isuli, IGF-I, ad lepti, i childre with PWS ad the potetial chages iduced by treatmet with GH. The cortisol levels were documeted to assess alteratios of the adreal glucocorticoid axis. Patiets ad Methods I a prospective study, we examied a group of 23 childre, 11 girls ad 12 boys, with geetically prove PWS, i whom growth ad body compositio before ad durig log-term GH therapy (GHT) were previously described [21, 22]. At baselie, the mea age was 5.6 (rage ) years ad the boe age 6.15 (rage ) years. Four girls ad 1 boy had etered puberty at oset of therapy (breast stage 2 3 ad geital stage 3, respectively). The observatio period i 19 childre (8 female, 11 male) was log eough to otice precocious pubic hair developmet durig the critical age, but 4 adolescets were preseted after the age of 9 years, thus too late to observe precocious pubarche. Premature adrearche was defied as precocious pubic hair growth before the age of 8 years i girls ad of 9 years i boys ad elevated adreal adroge levels. The followig parameters were assessed at baselie as well as durig 12 ad 42 moths of therapy with 8 mg/m 2 /week (F0.037 mg/kg/day) recombiat GH (Pharmacia, Dübedorf, Switzerlad), admiistered by daily subcutaeous ijectios. The fat mass was measured by dual-eergy X-ray absorptiometry [22], pubertal stage, height, ad weight by stadard techiques [23], serum glucose by the stadard hexokiase method, fastig isuli by ezyme-liked immuoabsorbet assay (Tosoh, Tokyo, Japa) ad, sice 1997, by Access ultrasesitive sadwich immuoassay [Beckma, Zürich, Switzerlad; iterassay coefficiet of variatio (CV) = 3.5%], cortisol by chemilumiescece assay (Nichols Istitute, Nijmege, The Netherlads; CV = 7.1%), adrosteedioe (AD) by 125 I-RIA (DSL, Webster, Tex., USA; CV = 4.8%), dehydroepiadrosteroe (DHEA) also by 125 I-RIA (DSL; CV = 3.5%) ad its sulfate (DHEAS) by chemilumiescece assay (Nichols Istitute; CV = 9.0%), ad lepti (CV = 8.5%) [24] ad IGF- I (CV = 10.1%) [25, 26] as published by the authors. Data for subjects with PWS were judged idividually as to whether they were withi the age- ad sex-related referece rage used by the laboratory measurig the respective parameter. Examples of referece rages for boys ad girls together, age 6 9 years are give i table 1 ad 2 to facilitate the estimatio of mea values i patiets with PWS. I particular, referece data for adroges ad cortisol i US childre were provided by Edocrie Scieces (Tarzaa, Calif., USA). We recetly described [22] how lea ad fat mass were related to ormative data established i Caucasia US [27] ad i Dutch childre [28, 29]. The lepti cocetratio as well as the BMI (body weight i kilograms divided by the square of height i meters) were compared with agerelated data of healthy Germa schoolchildre, while IGF-I [25] ad Isuli [30] levels were compared with data obtaied from Swiss ad Fiish childre, respectively, as published previously [17]. The isuli resistace was assessed by homeostasis model aalysis (HOMA-R) ad compared with data of healthy adults [31]. Missig values were ot due to a specific selectio of patiets or dropouts, but to shortage of serum as a result of the difficulties ecoutered durig veipucture i childre with PWS or, i 3 patiets, to ucompleted ivestigatio itervals as a cosequece of delayed start of therapy. For the same reaso, the AD levels before therapy could ot be icluded ito the evaluatio. The patiets cotiued their eergy-reduced diets durig the study protocol [21, 22]. No additioal medicatio was admiistered besides substitutio for hypothyroidism i year-old boy (Ltyroxie 50 Ìg) ad for hypogoadism i 3 adolescets after more tha 14 moths of GHT: year-old girl receivig ethyyl estradiol 10 Ìg, year-old boy treated with testosteroe eathate 100 mg i.m., ad year-old girl receivig Triseques (2 mg estradiol, 1 mg orethisteroe acetate) [21, 22]. The study has bee approved by the Ethics Committee of the Childre s Uiversity Hospital of Zürich, ad iformed coset was obtaied from the parets. Statistical Methods All data were processed by GAS 4.1 of the Istitute for Medical Iformatics (IMI, Zürich, Switzerlad). Because most of the variables showed a skewed distributio, they were trasformed to logarithms which resulted i a approximately ormal distributio. We had to establish age-stadardized values, sice all variables, except 216 Horm Res 2002;58: l Allemad/Eiholzer/Rousso/Girard/Blum/ Torresai/Gasser

3 Table 1. Adreal serum steroids i childre with PWS (depedet variables, mea B SEM) Referece rage (6- to 9-year-old females ad males) a Before therapy 12 moths after GHT 42 moths after GHT DHEAS, mol/l!1,460 1,630B ,410B610.s. 19 3,340B710.s. 14 DHEA, mol/l B B4.5 (#) B3.5 # 15 AD, mol/l (3.3B0.83) B B Cortisol, mol/l B B30 ### B20 ## 17 a See Patiets ad Methods for further descriptio of referece data (provided by the Istitute of Pediatric Edocriology, Basel, Switzerlad). b Betwee 12 ad 42 moths of GHT, o sigificat chage of ay parameter was foud. (#), #, ##, ###,.s. p = 0.06,!0.05,!0.01,!0.001, or ot sigificat, respectively, idicate whether the residuals of the hormoes at 12 or 42 moths, corrected for age at baselie, differ sigificatly from data before therapy (tested by paired t test). Table 2. Hormoal ad athropometric covariates i childre with PWS (mea B SEM) Referece rage (6- to 9-year-old females ad males) a Before therapy 12 moths after GHT 42 moths after GHT BMI, kg/m B2.07 [24] 19.1B B1.4 ### B0.93 ### 19 Fat, kg b 5.89B4.3 [27, 29] 13.1B B4.0 # B2.0 # 13 IGF-I, g/ml 161B61 [25, 26] 101B B30 ### B38 ### 17 Lepti, g/ml 2.51B1.16 [24] 13.4B B4.0 ### 12 Isuli, mu/l 7.10B3.70 [30] 6.18B B1.40 ## B1.00 #, 16 HOMA-R c 1.48B0.46 [31] 1.30B B0.33 # B0.17.s, d 14 For defiitio of the sigificace levels see table 1. a See Patiets ad Methods for further descriptio of referece data. b Data of body compositio show i detail elsewhere [22]. c Idex of isuli resistace = Is [mu/l] / 22.5 *e lgluc[mmol/l]. d Data obtaied after 36 moths of GHT. Sigificace of differeces of the residuals at 42 moths, corrected for age at baselie, vs. data at 12 moths (tested by paired t test). for cortisol, were clearly age depedet. To do so, we calculated a least squares fit with age as explaatory variable ad the logarithm of the variable as the respose. This regressio was made idepedetly at baselie ad at 12 ad 42 moths of GH treatmet. Age-stadardized values were the defied as the residuals with respect to each fit. This stadardizatio techique is equivalet to cosiderig age as a covariate. Such stadardized variables will be deoted by the subscript res i the followig sectios of the paper. For each variable, we also compared values at baselie with values after 12 or 42 moths of GHT. I order to distiguish whether the chages observed were solely related to the icrease of age or whether they were due to the particular effect of GHT, we calculated age-stadardized values after 12 or 24 moths of GHT with respect to the baselie regressio equatio. I doig so, we were able to elimiate the age effect from all variables. We the applied paired t tests to assess ay sigificat differece betwee baselie residuals versus residuals after 12 or 42 moths, all beig age-stadardized by the same baselie equatio, hece idicatig chages due to the treatmet itself. Note that, after 12 or 42 moths of GHT, this estimate icluded the extrapolatio of age for the adolescets older tha the maximal age of 14.6 years at start. But we obtaied essetially the same results by repeatig the same calculatios without the extrapolated values. To allow for a sufficiet umber of subjects beig available for statistical calculatios, we decided to evaluate data of girls ad boys together, because iitial pubertal stages of pubic hair, breast, ad geitalia were below 3 ad because graphical represetatios did ot reveal a obvious geder differece. Adreal Adroges i PWS Horm Res 2002;58:

4 I order to ivestigate the relative cotributio of athropometric (BMI res ad fat mass res ) ad hormoal variables (lepti res, IGF- I res, fastig isuli res, or HOMA-R res ) to the levels of DHEAS res, DHEA res, AD res (this oly after 12 ad 42 moths ), ad cortisol res, we cosidered regressio models with oe or two explaatory variables. The relatioship betwee a explaatory athropometric or hormoal variable ad the respose (DHEAS res, DHEA res or cortisol res ) was characterized by the Pearso correlatio coefficiet r Pea or, equivaletly, by its square, R 2, expressed as a percetage which represets the proportio of the respose due to the explaatory variable. The relatioship betwee two explaatory variables was ivestigated i the same way. I the regressio models with two explaatory variables, we used F tests to assess the joit ifluece ad partial F tests to assess the cotributio of each explaatory variable itroduced ito the model. Throughout the aalyses, p! 0.05 was cosidered sigificat, whereas we cosidered to have a tred for p values betwee 0.05 ad Results Premature adrearche was observed i 1 girl out of 19 patiets (5.2%) before ad i 1 girl ad 1 boy (10.5%) durig GHT. Excludig youg childre below the age of 3 years, i whom the presetatio of idiopathic premature adrearche is highly improbable, the icidece would rise to 1 of 11 (9.1%) childre before ad to 2 of 11 (18.2%) childre durig therapy. High adroge levels, e.g., values exceedig the ormal rage for geder ad age, were foud i 47% of the DHEAS ad i 35% of the DHEA samples at baselie. This proportio icreased after 1 year of GHT to 53 ad 63%, respectively; after 3.5 years of GHT, agai 53% of the childre preseted with elevated DHEAS levels ad 72% with elevated DHEA levels (data ot show). Alog this lie, the mea levels of DHEAS, DHEA, ad AD were higher tha our referece rages at the baselie examiatio ad eve more distictively so after 12 ad 42 moths of GHT (table 1). However, whe the chages of variables were corrected for the effect of age, oly the icrease of DHEA was sigificat after 42 moths. I fact, the observed icrease of DHEAS was due to age. For AD we lacked a sufficiet umber of measuremets before therapy to draw ay coclusio. Thus, o average, the icrease of adreal adroges i the group was ot clearly associated with the istitutio of GH treatmet. I cotrast, the cortisol levels were well withi the ormal rage at the first examiatio ad sigificatly dropped to the lower ormal rage durig GHT. The covariates showed several abormalities, as demostrated i previous studies [17, 22, 32]. Maily the fat mass was icreased i PWS, ad the lepti levels ad the BMI were high (table 2, as a cosequece of their strog correlatio with fat mass (r = 0.85 ad r = 0.75, respectively, with both p! 0.01 ad = 16). I spite of adiposity, IGF-I, fastig isuli, ad isuli resistace (HOMA- R) were i the lower ormal rage, beig explaied by hypothalamic GH deficiecy, before therapy. Durig the GHT, the icrease i IGF-I levels was highly sigificat, ad a sigificat loss of fat mass was iduced, accompaied by a sigificat decrease of lepti ad BMI, all variables havig bee corrected for age as described i Patiets ad Methods. The isuli levels sigificatly rose after 1 year of GHT to fall slightly below baselie levels after 42 moths. Before therapy, sigificat positive correlatios were foud betwee the adreal adroges DHEAS ad DHEA as well as several hormoal parameters, but ot with athropometric variables (table 3). I the regressio models, R 2 was deduced from correlatio coefficiets (table 3) as idicated i Patiets ad Methods, ad first DHEAS as depedat variable was ivestigated. 34% of the DHEAS variace was explaied by isuli aloe, ad the bivariate model, whe isuli was already i, remaied sigificat, but substatially uchaged by the itroductio of BMI or IGF-I (38 or 39% of DHEAS variace explaied, respectively; p! 0.05, = 16). Therefore, isuli, but ot IGF-I, had the mai ifluece o DHEAS i this model. The surrogate of isuli resistace, HOMA-R, was eve more strogly liked with DHEAS: HOMA-R aloe explaied 42% of the DHEAS variability i the uivariate model deduced from r Pea (table 3), ad this relatioship remaied similar i the bivariate models additioally icludig IGF-I (R 2 = 44%, p = 0.055, = 13), fat mass (R 2 = 50%, p = 0.043, = 12), or BMI (data ot show), all by themselves ot beig sigificatly associated with DHEAS (table 3). The covariate isuli was ot sigificatly related to fat mass or body mass, ad there was oly a tred of HOMA-R to correlate with fat mass or BMI (r = 0.5 for both; p = ad = 14 ad p = ad = 15, respectively). Because of the small sample, there was oly a tred, although the correlatios were substatial. Lepti or IGF-I levels were ot associated with DHEAS, either aloe (table 3) or i ay combiatio tested (data ot show). I the uivariate model with DHEA, 24% of the variace of the adroge was explaied by lepti aloe, but i the bivariate model either the itroductio of BMI (ot sigificat) or of fat mass (36%, p = 0.087, = 14) sigificatly icreased R 2, both covariates aloe ot beig sigificatly associated with DHEA (table 3). Furthermore, 218 Horm Res 2002;58: l Allemad/Eiholzer/Rousso/Girard/Blum/ Torresai/Gasser

5 Table 3. Correlatios i childre ad adolescets with PWS before therapy 0 moths DHEAS res DHEA res Cortisol res BMI res 0.00.s s s. 16 Fat mass res 0.00.s s s. 14 IGF-I res 0.22.s s. 16 Lepti res 0.20.s s. 16 Isuli res s. 16 HOMA-R res s. 13 r = Pearso s correlatio coefficiet; p = associated sigificace; = sample size available for the aalysis of correlatio..s. = Not sigificat. Table 4. Correlatios after 12 moths of GHT 12 moths DHEAS res DHEA res AD res Cortisol res BMI res 0.10.s s s s. 18 Fat mass res 0.10.s s s IGF-I res 0.30.s s s. 17 Lepti res 0.20.s s. 9 Isuli res 0.10.s s s s. 15 HOMA-R res 0.10.s s s s. 10 r = Pearso s correlatio coefficiet; p = associated sigificace; = sample size available for the aalysis of correlatio..s. = Not sigificat. the itroductio of IGF-I ito the bivariate model with lepti slightly improved the relatioship, explaiig 40% of the variace of DHEA (p = 0.03, = 17). I the ext model, IGF-I, o its ow, sigificatly predicted 33% of the DHEA variability (table 3). IGF-I with BMI together accouted for 35% of the DHEA variace (p = 0.051, = 17). The most sigificat ad additive bivariate model was foud whe HOMA-R was icluded i additio to IGF-I, ow explaiig together 60% of the DHEA variace (p = 0.01, = 13). HOMA-R aloe accouted for 32% of the DHEA variace, ad this relatioship was ot sigificatly improved either i cojuctio with BMI or with fat mass. Isuli was ot strogly correlated with DHEA (table 3, R 2 = 22%), but the joit ifluece of isuli ad IGF-I was sigificat ad additive, accoutig for 57% of the variace of DHEA (p = 0.004, = 17). No sigificat correlatios were foud betwee cortisol ad body compositio or hormoal variables before or durig therapy (table 3, 4). After 12 moths of GH treatmet (table 4), the levels of DHEAS were o loger associated with ay idepedet variable. The levels of DHEA were ow oly explaied by lepti (table 4, R 2 = 67%), ad the regressio model remaied roughly uchaged after the additio of BMI (R 2 = 74%, p = 0.008, = 10) or isuli (R 2 = 78%, p = 0.011, = 9), but i the bivariate model o other athropometric or hormoal parameter was sigificatly associated with DHEA. Sice at this time the umber of AD measuremets was sufficiet, the regressio model could also be tested for this depedat variable: IGF-I was the oly parameter to explai the variace of AD (table 4, R 2 = 26%), ad the bivariate model was o loger sigificat whe other variables were brought i. I this coectio, it has to be poited out that i childre with Adreal Adroges i PWS Horm Res 2002;58:

6 PWS, the covariate IGF-I did ot correlate either with lea mass or with fat mass or BMI before or durig therapy. Furthermore, the lea mass did ot correlate with adreal adroges at ay time. The developmet of the cortisol levels could ot be explaied by ay idepedet variable, but there was oly a tred for fat mass to be egatively associated with the cortisol levels (table 4). After 42 moths of therapy, o sigificat explaatio was delivered by the idepedet variables to iterpret the developmet of the levels of adroges (data ot show). Discussio I summary, the mea adreal adroge levels i patiets with PWS are elevated above the ormal rage, as described i healthy obese childre [3, 4]. The icreased levels of DHEAS, DHEA, ad AD may give rise to a precocious growth of pubic hair which the is termed premature adrearche [33]. The preset study presets argumets to support the hypothesis that the dissociatio of the adreal adroge secretio from goadal maturatio i PWS is amplified by obesity ad related metabolic alteratios, idepedetly of the hypothalamic regulatio. The icrease of adreal adroge levels i PWS, before oset of therapy, is correlated with hormoes depedet o body compositio ad growth, amely isuli, lepti, ad IGF-I. The higher the isuli levels were, ad, i particular, the more isuli-resistat the subject was, the more the baselie levels of DHEAS ad DHEA were icreased. These correlatios agree with fidigs i obese childre with premature adrearche [34] or i obese hirsute wome [35]. However, isuli ad HOMA-R were i the lower ormal rage, i cotrast to simple obesity [1, 36]. Sice the isuli sesitivity is icreased i the presece of GH isufficiecy, it ca be deduced that the relatioship to adroges occurs at a lower level of isuli i patiets with PWS. IGF-I is the secod importat covariate related to DHEA at baselie ad AD durig therapy, as i healthy obese childre [8, 37] ad adolescets [38]. Most importatly, i the regressio models, isuli or HOMA-R, i additio to IGF-I, make cotributios to explai up to 60% of the variace of baselie DHEA levels. This meas that they may represet distict mechaisms to ehace levels of this adroge. This is corroborated by i vitro experimets showig that both isuli [39] ad IGFs [40] ehace the ezyme activity of steroidogeic ezymes i huma adreocortical cells. The data i patiets with PWS, showig a correlatio betwee DHEA ad lepti levels, cofirm ot oly fidigs i healthy childre [8], but also experimetal results o the stimulatio of adroge formatio via 17/20-lyase at physiological lepti levels i huma adreocortical carcioma cells [10]. A associatio betwee icreased circulatig adroge ad lepti levels has so far bee observed oly i girls with precocious pubarche [41] ad, depedet o BMI, i adult wome with polycystic ovary sydrome [42]. We suggest that i patiets with PWS, as i healthy subjects, isuli, IGF-I, ad lepti mediate the effects of icreasig adiposity to ehace the adreal adroge secretio. I fact, logitudial studies performed i healthy childre or primates have revealed that chages i BMI or related hormoes precede adrearche [43] or puberty [44] before steroid hormoes are secreted. Normally, the lepti ad IGF-I levels both icrease before puberty ad might provide the brai with iformatio o body compositio ad size to start pituitary, adreal, ad goadal maturatio [43, 44]. Durig GHT, the DHEA cocetratio sigificatly rises, potetially due to the icrease of isuli ad IGF-I levels [40]. Therefore, GHT is likely to ehace the risk of premature adrearche. However, most associatios observed previously disappeared, except for those betwee lepti ad DHEA or IGF-I ad AD. The relatioships observed at baselie may i part be offset durig therapy by the strog, direct effects of exogeous GH o IGF-I cocetratios, isuli resistace, ad isuli levels [32]. Although the elevatio of adroge levels i childre with PWS is correlated with hormoes liked with the body compositio, such as isuli, lepti ad IGF-I, o associatios are foud betwee adroge levels ad adiposity or the athropometric variables BMI, fat, or lea mass, either before or durig therapy. This observatio cotrasts results i healthy childre with ad without simple obesity, eve if the studies were carried out by similar methods [8]. I healthy childre, the pubic hair growth is advaced with icreased BMI [45], ad the serum DHEAS levels are correlated with the BMI [37, 38]. Furthermore, the steroid excretio is icreased i obese childre [46], ad the adroge excretio correlates with the lea mass [47]. The dissociatio betwee athropometric variables ad icreased adroge levels i patiets with PWS suggests that the regulatio of body mass ad body compositio is altered i PWS, as described by other authors. There is a peculiar, cetral subcutaeous fat depositio i patiets with PWS [48], but the visceral fat compartmet is relatively reduced [20] as compared with simple obesity. The reductio of the metabolically active 220 Horm Res 2002;58: l Allemad/Eiholzer/Rousso/Girard/Blum/ Torresai/Gasser

7 visceral fat is specific to PWS ad is compatible with the observatios that isuli levels i these patiets are low, eve after 3 years of GHT [32], ad that the triglyceride levels are ormal [49]. The levels of circulatig cortisol are ormal, i cotrast to adreal adroge levels, ad do ot correlate with ay other covariate, as described i healthy obese childre [50]. Sice the cortisol levels were ormal ad, durig GH treatmet, decreased withi the referece rage, idepedetly of the icrease of adreal adroges, we deduced a grossly ormal hypothalamic-pituitary regulatio of the adreal glad i PWS. However, i theory, the cortisol metabolism could be ehaced by chages iduced durig GHT, e.g., isuli icrease, but the preset outpatiet settig did ot allow for a collectio of 24-hour urie samples from the hadicapped childre. The preset study was ot desiged to examie the hypothalamic-pituitaryadreal axis exhaustively. Therefore, its fuctio i PWS will have to be assessed i further, more sophisticated studies. I coclusio, the typically delayed goadal developmet i PWS may be cotrasted by elevated adroge levels ad premature adrearche. We suggest that these represet epipheomea of hormoal chages iduced by adiposity rather tha beig the cosequece of the assumed hypothalamic defect i PWS. However, i PWS, specific alteratios chage the patter of the pubertal developmet: (1) the effects of isuli or IGF-I o circulatig adroges are exhibited at lower levels tha i subjects with itact hypothalamic fuctio; (2) the associatios betwee athropometric ad hormoal variables are disrupted, possibly by the basic defect of the regulatio of the body compositio, ad (3) the goadal developmet may be impeded due to the hypothalamic defect. Ackowledgemets We thak Mrs. Claudia Weima for her dedicated care of the patiets durig the evaluatio, for the research coordiatio, ad her techical assistace ad Prof. Jürge Zapf, Departmet of Medicie, Uiversity Zürich, for the measuremets of the IGF-I cocetratios ad the critical discussio of the mauscript. We gratefully ackowledge the support of Mr. Michael Schlumpf i aalyzig the data ad the help of Mrs. Kari Stutz i editig the Eglish mauscript. Our special thak goes to the PWS Associatio of Switzerlad ad the parets ad their PWS childre for their great commitmet ad efforts. This work was supported by the Swiss Natioal Sciece Foudatio (Grat No ) ad the Swiss Academy of Medical Scieces (Grat No. NF 455/98). Refereces 1 De Simoe M, Farello G, Palumbo M, Getile T, Ciuffreda M, Olioso P, Cique M, De Matteis F: Growth charts, growth velocity ad boe developmet i childhood obesity. 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