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  • Are Adolescent Boys with Klinefelter Syndrome AndrogenDeficient? A Longitudinal Study of Finnish 47,XXY Boys


    Hospital for Children and Adolescents [A.M.W., L.D., S.W., T.R.], Helsinki University Central Hospital, University of Helsinki, 00029Helsinki, Finland; Department of Pediatrics [L.D.], Kuopio University Hospital, University of Kuopio, 70211 Kuopio, Finland; GoteborgPediatric Growth Research Center [E.N., C.A.-L.], Institute for Health of Women and Children, The Sahlgrenska Academy at Goteborg

    University, 41685 Goteborg, Sweden

    ABSTRACT: Testosterone (T)-substitution therapy is widely usedin adult patients with Klinefelter syndrome (KS) to prevent symp-toms and sequels of androgen deficiency, but it is currently unknownif adolescent boys with KS benefit from early T therapy. To evaluatethe optimal age to start T substitution, we searched for signs ofandrogen deficiency in pubertal boys with KS. 14 nonmosaic47,XXY boys, aged 1013.9 y, were followed up for 437 mo withstaging of puberty and frequent reproductive hormone measurements.Furthermore, indices reflecting androgen action (serum SHBG, lep-tin, and prostate-specific antigen (PSA) levels) were studied. Bothonset and progression of puberty according to Tanner stages werenormal in boys with KS. Consistently, serum T concentrations in-creased as expected and remained normal throughout follow-up.Changes in the indices of androgen action (decreases in serum SHBGand leptin, and increase in serum PSA concentrations) occurrednormally, except that average leptin levels were higher in the boyswith KS (KS boys 11.8 7.0 g/L; controls 7.6 4.7 g/L; p 0.033). Despite normal T concentrations, the KS boys displayed fromthe age of 13 y elevated serum FSH and LH levels, and exaggeratedgonadotropin responses to gonadotropin-releasing hormone. Thesedata do not demonstrate an unequivocal androgen deficiency inadolescent boys with KS that would necessitate androgen supple-mentation therapy during early puberty. (Pediatr Res 59: 854859,2006)

    KS with its estimated prevalence of 152 per 100,000 malesis a common form of male hypogonadism (1). Onlysubtle physical signs, such as an increase in height velocity,long-leggedness, slightly lower than normal testicular volumeand a tendency to central obesity may be evident beforepuberty (2,3). Prepubertal boys with KS often have delayedspeech development and learning disabilities, difficulties inrelationships with peers and siblings, and have quiet andunassured manner (3). All these symptoms have been relatedto androgen deficiency.

    Testes of adult KS males are characterized by hyalinizationand fibrosis of the seminiferous tubules, and hyperplasia of theLeydig cells (4). The mechanisms leading to degeneration ofthe seminiferous tubules are unknown, but this process seemsto accelerate at the onset of puberty (5). Prepubertal boys withthe 47,XXY karyotype have only slightly reduced testicularvolume (6,7), and the hypergonadotropism typical of adult KSpatients cannot be detected before midpuberty (5,8,9). Boyswith KS do not typically display delayed onset of puberty andtheir serum testosterone (T) levels usually remain within thelow normal range throughout puberty (5,8,9). Serum LHlevels usually further increase from midpuberty onwards,probably reflecting a compensatory feedback mechanism tomaintain sufficient Leydig cell function (5,8,9). After pubertalmaturation, these compensatory efforts may fail to maintainsufficient circulating T levels, and subsequently T substitutiontherapy is widely used in adult KS patients to avoid symptomsand sequels of androgen deficiency (2,10).

    It has been proposed that adolescent boys with KS maybenefit from early T therapy (1115). Reports, however, arelacking that verify hypoandrogenism in 47,XXY boys duringpuberty or examine their androgen status before the start oftreatment (1115). Consequently, the optimal age for initiat-ing androgen therapy remains unclear. Our aim was thereforeto use clinical and laboratory data from a longitudinal obser-vation period of 14 adolescent nonmosaic 47,XXY boys todetermine whether they displayed signs of androgen defi-ciency during early puberty.


    Subjects. Fourteen nonmosaic 47,XXY boys (KS group) were followed upprospectively for 425 mo (median, 18). In addition, data from routineclinical visits prior and after the systematic surveillance period were collectedfrom patient records. None of the subjects was or had previously been onandrogen therapy. At the start of the systematic prospective follow-up, their

    Received November 15, 2005; accepted January 16, 2006.Correspondence: Anne Wikstrom, M.D., HUCH, Hospital for Children and Adoles-

    cents, PO Box 281, 00029 Helsinki, Finland; e-mail: anne.wikstrom@fimnet.fiSupported by grants from the Medical Society of Finland (Finska Lakaresallskapet)

    (AW), the Finnish Medical Foundation (AW, TR), the Finnish Cultural Foundation (TR),the Foundation for Pediatric Research (TR), and the Hospital District of Helsinki andUusimaa.

    DOI: 10.1203/01.pdr.0000219386.31398.c3

    Abbreviations: BA, bone age; CDP, constitutional delay of puberty; CV,coefficient of variation; E2, 17-estradiol; GnRH, gonadotropin-releasinghormone; KS, Klinefelter syndrome; PSA, prostate-specific antigen; SHBG,sex hormone-binding globulin T, testosterone

    0031-3998/06/5906-0854PEDIATRIC RESEARCH Vol. 59, No. 6, 2006Copyright 2006 International Pediatric Research Foundation, Inc. Printed in U.S.A.


  • median age was 11.5 y (range, 10.013.9), and their median BA, according tothe method of Greulich and Pyle (16), also 11.5 y (range, 7.514.5). Some ofthe clinical and hormonal data have already been published (5).

    The boys visited the Hospital for Children and Adolescents in Helsinkievery fourth to sixth month. At each visit, puberty was staged according toTanner (17), and sera were taken for hormone measurements. The venousblood samples were drawn between 0730 and 1530 h. Body mass indices(BMI) were calculated as weight (kg) divided by the square of height (m2).Width and length of the testes were measured with a ruler to the nearestmillimeter; testicular volume was calculated by the formula 0.52 length width2 (18). BA was assessed annually, and GnRH stimulation test per-formed: serum FSH was measured at 0 (before), 30, 60, and 90 min., andserum LH at 0 (before), 20, 30, and 60 min following an intravenous injectionof GnRH (Relefact, Hoechst Marion Roussel, Frankfurt, Germany) 3.5 g/kg;maximum 100 g. The parents of each boy gave their informed consent forparticipation in this study approved by the ethics committee for pediatrics,adolescent medicine and psychiatry of the Hospital District of Helsinki andUusimaa.

    For comparison of serum T and E2 levels in KS boys to values in healthyadolescent boys, we used recently published reference values from 55 healthySwedish boys (19,20). These boys, aged 5.018.6 y, had undergone serialsampling for 24-h serum T and E2 profiles once or repeatedly during pubertaldevelopment; their venous blood samples were drawn six times during 24 h.

    Furthermore, we investigated in KS boys longitudinal changes in serumconcentrations of SHBG, PSA, leptin, FSH, LH, and inhibin B levels andcompared these to values in 25 healthy, untreated Finnish boys with CDPpreviously followed up in our unit (21,22). For assessment of laboratoryvalues for the CDP group, when compared with the KS group, BA rather thanchronological age (CA) was used, since BA in the CDP group were delayed[difference from CA (mean SD) 2.40 0.67 y during follow-up]. Forassessment of laboratory values in KS boys CA were used, because differ-ences between BA and CA in these boys during the study period were small(mean difference 0.36 1.11 y).

    Biochemical measurements. Venous blood samples were allowed to clot;serum was separated by centrifugation and stored at 20 C or 70 C.

    To allow direct comparison between serum T and E2 concentrations inthe KS boys and the healthy Swedish boys, serum T and E2 levels in bothgroups were measured in the same laboratory. For serum T, an ultrasensitive(sensitivity, 0.03 nmol/L) modified RIA was used (Spectria testosterone,Orion Diagnostica, Espoo, Finland) (23). The intra-assay CV was 11% at0.2 nmol/L, and 7% at concentrations 0.9 nmol/L; the correspondinginterassay CV were 15% and 10%, respectively. Serum E2 concentrationswere measured with a modified RIA (Spectria estradiol, Orion Diagnostica,Espoo, Finland) after diethyl ether extraction (20,24). The assay detectionlimit was 4.5 pmol/L, intra-assay CV was 13% at 19 pmol/L, and interassayCV 12% at 22 pmol/L.

    Serum SHBG concentrations were measured by time-resolved fluoroim-munoassay (Perkin-Elmer Life Sciences, Turku, Finland) with inter- andintra-assay CVs both less than 5% according to the manufacturer. Serumleptin was quantitated with a commercially available RIA from Linco Re-search Inc., St. Charles, MO. The detection limit of this assay is 0.5 g/L.Interassay CV was 7% (concentration range, 525 g/L).

    Serum PSA was quantitated with a time-resolved immunofluorometricassay (Prostatus PSA EQM DELFIA, Wallac, Turku, Finland). The detectionlimit for PSA was 0.02 g/L. Interassay CV was 4% at PSA concentrations0.2 to 100 g/L.

    Serum FSH and LH levels were measured by ultrasensitive immunoflu-orometric assays, as described (25). FSH and LH concentrations 0.1 IU/Lwere treated as 0.1 IU/L. For FSH, interassay CV was 3.3% and intra-assayCV 4.4%; for LH 4.4% and 4.1%. Serum inhibin B levels weremeasured by a commercially available immunoenzymometric assay accordingto manufacturers instructions (Serotec, Oxford, UK). The detection limit was15.6 pg/mL. The interassay CV was 15% and the intra-assay CV 5%.



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