Evaluation and Treatment of Tall Statured Girls
Evaluation and Treatment of Tall Statured Girls
Objective

 To evaluate the phenotypic characteristics and diagnoses in a large cohort of 304 consecutive
 girls referred due to tall stature. Furthermore, to evaluate the effect of oral
 administration of 17β-estradiol on predicted adult height in constitutionally tall statured
 girls.

 Design

 A single-centre retrospective observational study of 304 girls evaluated due to tall stature
 between 1993 and 2013.

 Setting

 Tertiary referral centre for pediatric endocrinology.

 Participants

 A total of 304 girls were evaluated for tall stature of whom 39 (13%) were excluded due to
 missing data, reclassification, overgrowth syndromes or associated comorbidities. Another 58
 (19%) girls did not fulfil auxological criteria for constitutionally tall stature (CTS),
 resulting in a total of 207 (68%) girls eligible for analysis.

 Main Outcome Measures

 The effect of oral treatment with 17β-estradiol on height, predicted adult height (PAH),
 final height and circulating hormones in constitutional tall statured girls.
17α-ethinylestradiol (EE2) treatment of extreme tall stature has become increasingly debated
 and controversial. In Sweden, percutaneous epiphysiodesis operation is suggested as an
 alternative to EE2 treatment. An alternative clinical practise was introduced 20 years ago,
 when early treatment with oral administration of natural estrogens (17β-estradiol (E2)) was
 introduced in order to initiate or ensure rapid progression of puberty (and epiphyseal
 closure) in tall statured girls.

 A retrospective 20-year single center experience included evaluation of 304 tall statured
 girls and the possible clinical effects of oral administration of E2.

 Subjects and methods

 Patients

 The patient population consisted of girls who were referred with tall stature or overgrowth
 syndromes (ICD10 34.4, and ICD10 DE874, DQ970, DQ873A, DQ873B) to the Department of Growth
 and Reproduction at Rigshospitalet in Copenhagen, Denmark, during a 20-years period (between
 1993 and 2013). A total of 304 patients were identified, and the diagnoses were re-evaluated
 as part of the present study.

 Clinical data and medical history

 Medical history was obtained using a structured review of patient record files. Clinical data
 on pubertal development were obtained from each patient visit. Puberty was evaluated by
 inspection and palpation of the breasts and s pubic hair according to Marshall and Tanner. A
 wall-mounted stadiometer (Holtain Ltd., Crymych, United Kingdom) was used to measure standing
 height to the nearest 0.1 cm. The girls were weighed on a digital electronic scale (Seca
 delta, model 707; Seca, Hamburg, Germany) with a precision of 0.1 kg while wearing light
 clothing and no shoes. BMI was calculated as weight (kg) divided by height (m2). The Danish
 growth references published by Tinggaard et al. was used in this study. Boneage (BA) was
 calculated according to the methods of Greulich and Pyle (GP) using manual readings between
 1993-2008 (n=368), and automated BA estimation from 2008-2013 (n=378) . Target height was
 calculated as the sum of the mother's and father's heights (cm) minus 13 cm, divided by 2.
 Predicted Adult Height (PAH) was calculated using BoneXpert .

 17β-Estradiol treatment

 The decision to initiate treatment with E2 was determined individually, and made by the
 physician together with the patient and her parents, depending on height SDS, age, PAH and
 target height. Oral E2 was administered in increasing doses depending on age and pubertal
 stage. The starting doses ranged between 0.2 mg E2 to 4 mg E2. The speed of dose increment
 depended on the individual girl (age, bone BA, maturity, pubertal stage and PAH). The
 treatment consisted of 17β-estradiol supplemented with norethisteronacetat after 1-2 years of
 E2, or after the first menstrual bleeding. Oral E2 treatment was administered in the form of
 Trisekvens® (Novo Nordisk Scandinavia AB, Copenhagen, Denmark), Trisekvens Forte® (Novo
 Nordisk Scandinavia AB, Copenhagen, Denmark) and/or Femanest® (Sandoz A/S, Copenhagen,
 Denmark). Clinical and biochemical values were recorded at baseline and at each year
 thereafter. The treatment was generally terminated when the X-ray showed closed epiphyseal
 lines at final or near-final (<2 cm/year) height.

 Laboratory analysis

 Blood samples were drawn from the antecubital vein between 8 AM and 1 PM in the non-fasting
 state. Blood samples were clotted and centrifuged, and serum was stored at -20° Celsius until
 hormone analyses were performed. Serum follicle-stimulating hormone (FSH) and luteinising
 hormone (LH) were measured by time-resolved immunofluorometric assays (Delfia, Wallac, Turku,
 Finland). The detection limits (dL) for FSH and LH were 0.06 and 0.05 IU/l, respectively.
 Intra- and interassay coefficients of variation (CV) were < 5% in both gonadotropin assays.
 Testosterone was measured by radioimmunoassay (RIA) (Coat-a-count, Diagnostic Products
 Corporation, Los Angeles, CA) with a dL of 0.23 nmol/L and intra- and interassay CV both <
 10%. Serum sex hormone-binding globulin (SHBG) was measured by time-resolved
 immunofluorometric assays (Delfia, Wallac, Turku, Finland) with a dL of 0.20 nmol/l, and
 intra- and interassay CVs of 5.8% and 6.4%, respectively. Serum insulin-like growth factor I
 (IGF-I) was measured using a highly sensitive in-house RIA as previously described by Juul et
 al. The intra- and interassay CV were 3.9% and 8.7%, respectively. From 2008 IGF-I levels
 were determined by conventional immunoassays (IMMULITE 2000 IGF-1; Siemens Healthcare
 Diagnostics, Los Angeles, CA, USA) on automated IMMULITE 2000 (Siemens). The CV were less
 than 4% and 9%, respectively. Serum insulin-like growth factor-binding protein 3 (IGFBP-3)
 was measured by RIA, as previously described by Blum et al. The intraassay CV was 2.4% and
 the interassay CV was 10.7%. Between 1993 and 2013, serum inhibin B was measured using one of
 two double antibody enzyme immunometric assays (Inhibin B DSL or Oxford Bio-Innovation
 Inhibin B), both with a dL of 20 pg/ml and intra- and interassay CV < 16%. Estradiol was
 measured by RIA (Pantex, Santa Monica, CA; before 1998 distributed by Immuno Diagnostic
 Systems, Bolton, UK) with a dL of 18 pmol/L, and intra- and interassay CVs < 8% and <13%,
 respectively. Only assays for IGF-I changed during the 20-year study period, and we compared
 the two assays rigorously and ensured that they yielded similar results before changing the
 assay.

 Statistical analysis

 Data are displayed as the median with interquartile range (25th;75th percentiles) and/or the
 range (min - max). Results of treatment effect and IGF-I (SD) are displayed as the mean ± SD.
 Hormone values below the dL of the assay were assigned a value corresponding to the dL/2. The
 Mann-Whitney U test and student's test was used to determine significance when comparing
 clinical, auxological, and laboratory data between groups, and student's t-test was used when
 comparing the effect of treatment within the group of girls treated with oral E2. All
 statistical analyses were performed using SPSS software (IBM Corporation, Armonk, NY, version
 22).
Inclusion Criteria:

 -  tall stature (height > 2 SD)

 Exclusion Criteria:

 -  none