Oxandrolone in Girls with Turner's Syndrome

Twenty-six one-year treatment periods on oxandrolone (0.1 mg/kg/day) were studied in 20 patients with Turner's syndrome. Control patients with Turner's syndrome were matched by using the following criteria: difference in bone age being not greater than 0.S years and difference in the Bayley-Pinneau height prediction not greater than 3 cm. Height and height velocity were compared with standards of girls with Turner's syndrome (10) and expressed in standard deviation scores (SDS). On oxandrolone height velocity increased significantly from −0.3 SDS to +3.0 SDS. The increase in height velocity was negatively correlated to the bone age at onset of treatment ( r = 0.62, p<0.01). Height SDS improved by 0.45 SDS in the treated patients whereas it did not change in the control patients. The bone age velocity during the treatment period (including a six-month period after treatment) was 0.75 year/year in the treated, compared to 0.66 year/year in the control patients (NS). 15 of the 20 patients have reached final height. The difference in final height minus predicted height (Bayley-Pinneau) at onset of treatment was taken as a measure of "gain in final height". Seven of those (mean bone age 12.1 years at onset of treatment) were treated for one year only and had–compared to the matched controls–a mean net gain in final height of 2.5 cm (NS). Eight patients (mean bone age 10.1 years at onset of treatment) were treated for two one-year periods and had a significant mean net gain in final height of 5.2 cm. Height predictions calculated by the method of Lenko (14) gave an identical mean net gain in final height (5.1 cm)     

Standards for Growth and Final Height in Turner's Syndrome

ABSTRACT. Data on birth, growth and final height were collected retrospectively for 78 women with Turner's syndrome born 1955-66. Seventy-one had received estrogen treatment from a mean age of 17.7 years (SD=2.0 years), while 7 were spontaneously menstruating. At birth Turner girls were 440 g lighter (p<0.001) and 1.4 cm shorter (p<0.001) than 46, XX girls. Standards for untreated growth were established for the age period 6.5-17.5 years, while growth after 17.5 years was described in both untreated and estrogen treated women. Analysis of growth pattern showed that though no pubertal growth sport was present, the steady decrease of height velocity (HV) was interrupted at the age of 9 years. HV was then constant until 12 years of age, whereafter it slowly decreased. Mean final height (FH) was 146.8 cm (SD=5.8 cm, n=76) compared to 166.8 cm in the general female population. No difference was found between 45, X women and women with other karyotypes (p>0.7). Correlations between FH and parental heights, birthweight and birthlength were similar to those reported for normal women (19). FH varied with age at diagnosis. Those diagnosed after 17 years of age had a mean FH=151.3 cm, while those diagnosed before had a mean FH=145.8 cm (p<0.001).     

Prediction of Final Height in Turner's Syndrome A Comparative Study

ABSTRACT. Various methods are used for prediction of final height in girls with Turner's syndrome (TS), but their accuracy has not been systematically investigated or compared. We have compared predictions of final height made with the most commonly used methods in 20 Turner girls at ages 9.5–18 years. Growth standards based on growth and final height of 78 Danish Turner women were used for calculation of standard deviation scores (SDS). In order to provide the necessary basis for "index of potential height" (IPH) method, bone age development was determined from 74 X-rays of 38 untreated Turner girls aged 5.2-19 years. This method was further modified and improved for use in TS. Prediction methods based only on height and chronological age (CA) showed little difference from methods including bone age. The IPH method in our modification was more accurate than those of Bayley-Pinneau and Tanner. At younger ages the IPH method showed better results when using Tanner-Whitehouse 2 (TW2) bone age than when using Greulich-Pyle bone age. Accuracy of predictions were considerably improved by combining methods with and without allowance for bone age. Combinations including the IPH method based on TW2 bone age appeared to be the most accurate. Predictions of final height in Turner's syndrome should therefore be made by combining the IPH method and one of the methods based on height and CA.     

Spontaneous Growth in Turner's Syndrome

Growth in Turner's syndrome can be divided into four phases: intrauterine growth is slightly retarded, normal growth occurs up to a hone age of about 3 years, with a tendency to compensate for the loss in growth during intrauterine life, stunting of growth is severe during childhood, after a hone age of about 10 years — the time when puberty normally starts - the growth phase is prolonged, hut total height gain is not essentially reduced. Based on a study of 150 patients with Turner's syndrome whose spontaneous growth was observed, standards of height and height velocity (means and SDs) were calculated to allow mathematical analysis of the spontaneous growth and growth during treatment in these patients. The auxological characteristics in Turner's syndrome do not support the assumption that GH deficiency playsa primary role in the pathogenesis of the growth disorder.     

What More Can Be Done for Girls and Women with Turner's Syndrome and Their Parents?

Nielsen, J. (Cytogenetic Laboratory, Aarhus Psychiatric Hospital, Risskov, Denmark). What more can be done for girls and women with Turner's syndrome and their parents? Acta Paediatr Scand [Suppl] 356: 93, 1989.
More should be done for Turner's girls/women and their parents. There is a need for early diagnosis, provision of information to Turner's parents, girls and women, provision of a support system in the form of Turner's contact groups, relevant treatment of all Turner's related disorders and problems at the appropriate age. More information is needed, including information given by physicians and Turner's women in journals, radio and television. This has been happening in Denmark during recent years. Turner's contact groups should be available in all countries, and all Turner's girls and women and their parents should be encouraged to join such groups. More research should be undertaken concerning growth, growth stimulating treatment, oestrogen treatment and in vitro fertilization in Turner's syndrome; more social-psychological studies are also needed.     

Standards for Growth and Growth Velocity in Turner's Syndrome

Turner-specific natural growth and growth velocity curves based on the retrospectively surveyed growth data of 704 Japanese patients in a mixed cross-sectional and longitudinal mode are reported. There was no significant difference in growth between the patients with karyotype 45,X and non-45,X. Twenty-three patients had a history of genital bleeding between the ages of 11 and 14 years (12 years ± 9 months). The mean height of the patients with genital bleeding did not differ significantly from that without bleeding from birth until 1 year 3 months of age but thereafter the former were always significantly taller than the latter. The former ceased growing after 18 years; on the other hand the latter were still growing after 18 years and then the final height of each group of patients became almost the same (139.6 ± 3.5 cm in the former and 139.1 ± 5.6 cm in the latter). A slight and gentle growth spurt was observed during the expected adolescent period in both groups, with and without genital bleeding. However, the mean height of peak (1.3 ± 0.95 cm/year) and the mean peak velocity (5.2 ± 1.1 cm/year) in the patients with genital bleeding were significantly higher than those (0.7 ± 0.36 and 3.8 ± 0.6 cm/year, respectively) in the patients without genital bleeding.     

Effect of Recombinant Human Growth Hormone Therapy on Bone and Clinical Parameters in Girls with Turner's Syndrome

Ferrández, A., Mayayo, E., Arnal, J.M., Garcia, C., Buduel, C., Lasarte, J.J., Anton, R., hyuelo P., and The Spanish Collaborative Group (Endocrine Unit, Children's Hospital, Miguel Servet, Zaragoza, Spain). Effect of recombinant human growth hormone therapy on bone and clinical parameters in girls with Turner's syndrome. Acta Paediatr Scand [Suppl] 356: 87, 1989.
Forty-eight girls with Turner's syndrome were assigned to one of three treatments; recombinant human growth hormone (rhGH) alone, rhGH plus oxandrolone, and rhGH plus ethinyloestradiol. Treatment with rhGH alone or in combination with oxandrolone induced catch-up growth. Older girls treated with rhGH plus ethinyloestradiol showed less marked improvement. The gain in height was associated with a gain in bone diameter and cortical thickness (reflecting increased bone mass). There was a rapid loss of subcutaneous fat. These effects of growth hormone are similar to those observed in patients with growth hormone deficiency.     

Variable effect of growth hormone on growth and final adult height in Scottish patients with Turner's syndrome

The aim of this work was to assess the outcome of recombinant growth hormone (rGH) therapy in a large unselected group (72) of patients with Turner's syndrome (TS), 26 of whom have reached final height. Growth data were collected from Scottish patients with TS and outcome was assessed in three ways: response to therapy in the first year, response in subsequent years and final height. Phenotypic, auxological, genetic and biochemical factors, all of which may have affected the first-year response, were investigated. Fifty-one percent of the cohort had a clinically "good" first-year response to therapy and 49% had a "poor" response; a "good" response was defined as a change in the TS standard deviation score (SDS) of +0.5 or more and a "poor" response as a change in the TS SDS of less than +0.5. The percentage of children showing a positive change in TS SDS after 2, 3 and 4 years of therapy declined (88%, 78%, 41%). Mean (range) final height was 142.6 (133.4–153.6) cm, mean (range) pretreatment TS SDS was -0.27 (-2.1 to +1.09) and mean (range) final TS SDS was -0.05 (-1.4 to +1.59). Thirteen (50%) patients attained a final height that was greater than projected, eleven did not attain their projected final height and two achieved their exact projected final height. Short girls with TS appear to benefit more from rGH supplementation than tall girls, but otherwise there was no significant correlation between any of the parameters studied and the response to treatment. It is concluded that large-scale prospective studies are still required to assess the impact of rGH on final height in TS and to identify factors responsible for the variability in response.     

Growth in Infancy and Childhood in Girls with Turner's Syndrome

ABSTRACT. We describe spontaneous longitudinal growth in girls with Turner's syndrome (TS), using the infancy-childhood-puberty (ICP) growth model. Lenght/height during the first 12 years of life was studied in 58 Swedish girls with TS. Their mean length at birth was 47.8 cm (SDS –1.4) and mean height at 12.0 years of age 127.3 cm (SDS –3.0). A clear age-dependent subnormality was observed in the change in length-height SDS (ΔSDS). Mean ΔSDS values at ages 0.0 to 0.5 and 3.0 to 6.0 years were normal. In contrast, the mean ΔSDS at ages 0.5 to 3.0 and 6.0 to 12.0 years were subnormal. The onset of the childhood growth component (normally located between 0.5 and 1.0 year of age) was, on the average, delayed by 0.28 year. This accounts for the subnormality of ΔSDS at 0.5 to 3.0 years of age. About 50% of the variation in height at 12.0 years of age, as determined by a multiple linear regression analysis, was significantly explained by length at 0.5 year of age, age at the onset of the childhood component, and ΔSDS at 6.0 to 12.0 years of age.     

Growth Hormone Treatment in Turner's Syndrome

ABSTRACT. A total of 21 patients with Turner's syndrome were treated with pituitary hGH and/or somatrem for 1–2 years. Plasma non-esterified fatty acid increased significantly from 0.52 ± 0.06 to 1.30 ± 0.09 mEq/litre at 4 hours after injection of hGH, 4 IU (mean ± SEM, p < 0.001). Basal plasma IGF-1 levels were within the normal range; however, they increased significantly at 24 hours after the first three daily injections of hGH, 4 IU (basal, 0.92 ± 0.14 units/ml; 24 hours, 1.39 ± 0.16 units/ml; 48 hours, 1.68 ± 0.19 units/ml; 72 hours, 1.91 ± 0.22 units/ml; p < 0.001). For long-term treatment, patients were given hGH, 4–16 IU for 1–2 years. Their height velocity increased to 5.5 ± 1.2 cm/year and 5.1 ± 0.6 cm/year in the first and second year of the treatment, respectively. These values were greater than the pretreatment value of 3.6 ± 0.8 cm/year (p < 0.001). Antibody against hGH was observed in 60% of the patients at the end of 12 months of somatrem treatment. Otherwise there were no significant changes in physical, blood or urine examinations. These results indicate that hGH treatment is useful for the acceleration of growth velocity in patients with Turner's syndrome.     

Treatment of Turner's Syndrome with Recombinant Human Growth Hormone (Somatrem)

This report extends to 3 years the prospective study of the effects of somatrem alone or in combination with oxandrolone on growth in Turner's syndrome. Sixty-seven patients completed the 1-year study period during which all treatment groups had statistically increased height velocities as compared to the control group. Oral glucose tolerance and insulin responses remained unchanged after 1 year of somatrem treatment. The group Receiving oxandrolone experienced an increase in integrated glucose response and the group receiving combined therapy an increase in both integrated glucose and insulin responses. During the second and third years the somatrem group remained on the same dose and treatment schedule and grew at mean velocities of 5.4 ± 1.1 and 4.6 ± 1.4 cmiyear. The dose of oxandrolone was reduced by 50% during the second and third years for the combination group. The somatrem dnse remained unchanged. This group had height velocities of 7.4 ± 1.4 cm and 6.1 ± 1.5 cm/year. The control group and the group treated with oxandrolone alone were converted to combined therapy at the lowered oxandrolone dose. Their growth rates during the second year were 8.3 ± 1.2 and 7.1 ± 1.6 cm/year, respectively. Using bone age determinations and the methods of Bayley and Pinneau, allgroups currently show predicted increases in final adult height.     

Molecular Genetics of Turner's Syndrome

Connor, J.M. and Loughlin, S.A.R. (University Department of Medical Genetics, Duncan Guthrie Institute, Yorkhill, Glasgow G3 8SJ, UK). Molecular genetics of Turner's syndrome. Acta Paediatr Scand [Suppl] 356: 77, 1989.
Recombinant DNA technology now allows an analysis of sex chromosomal abnormalities at the molecular level. X chromosomes differ in respect of their pattern of cutting sites for particular restriction enzymes; these differences can be used to determine which X chromosomes or which part of an X chromosome has been inherited from a parent. Furthermore, these techniques can be used to define the presence or absence of particular regions of the X chromosomes with a higher level of resolution than it is possible to achieve using light microscopy. Thirty-eight families in which there was a child or fetus with Turner's syndrome were studied using a series of DNA probes that detect differences (restriction fragment length polymorphisms) among X chromosomes. Analysis of the origin of the normal X chromosome was possible in 27 families. In 14 families with 45,X the observed X was maternal in each, whereas in 13 children with other karyotypes (46,X,i(Xq); 45,X/46,X,i(Xq); 45,X/46,XX; 45,X/46,X,r(X)) the origin of the normal X was paternal in six and maternal in seven patients. In two other families, mosaicism, which was unsuspected at chromosomal analysis, was revealed. DNA probes studied in the remaining nine families were uninformative. These results suggest that different pathogenic mechanisms operate for pure 45,X when compared with the other karyotypes associated with Turner's syndrome. The presence of unsuspected mosaicism in some of these families has clinical implications in relation to prognosis and management.     

A regression method including chronological and bone age for predicting final height in Turner's syndrome, with a comparison of existing methods

A total of 235 measurement points of 57 Dutch women with Turner's syndrome (TS), including women with spontaneous menarche and oestrogen treatment, served to develop a new Turner-specific final height (FH) prediction method (PTS). Analogous to the Tanner and Whitehouse mark 2 method (TW) for normal children, smoothed regression coefficients are tabulated for PTS for height (H), chronological age (CA) and bone age (BA), both TW RUS and Greulich and Pyle (GP). Comparison between all methods on 40 measurement points of 21 Danish TS women showed small mean prediction errors (predicted minus observed FH) and corresponding standard deviation (ESD) of both PTS_RUS and PTS_GP, in particular at the "younger" ages. Comparison between existing methods on the Dutch data indicated a tendency to overpredict FH. Before the CA of 9 years the mean prediction errors of the Bayley and Pinneau and TW methods were markedly higher compared with the other methods. Overall, the simplest methods—projected height (PAH) and its modification (mPAH)—were remarkably good at most ages. Although the validity of PTS_RUS and PTS_GP remains to be tested below the age of 6 years, both gave small mean prediction errors and a high accuracy. FH prediction in TS is important in the consideration of growth-promoting therapy or in the evaluation of its effects.     

Early Initiation of Growth Hormone Treatment: Influence on Final Height

Vanderschueren-Lodeweyckx, M., Van den Broeck, J., Wolter, R. and Malvaux, P. (Department of Paediatric and Adolescent Endocrinology, University of Leuven, Department of Paediatrics, University of Brussels and Department of Paediatrics, University of Louvain, Belgium). Early initiation of growth hormone treatment: influence on final height. Acta Paediatr Scand [Suppl] 337:4, 1987.
Retrospective growth data for 34 hGH deficient patients who had been treated for at least 3 years with hGH were analysed in a Belgian multicentre study. Final height was related to target height and was usually below it, hut it was not determined by chronological or bone ages, bone age delay, height velocity before or during therapy, nor by duration of treatment. Total height gain during long-term substitution with hGH is inversely related to chronological and hone ages at the start of therapy, and is positively related to the duration of therapy. Early diagnosis of hGH deficiency is thus important, as it allows catch-up growth to optimal height before puberty, which in turn results in a good pubertal growth spurt.     

Improved final height in Turner's syndrome following growth-promoting treatment at a single centre

AIMS: To examine the final height (FH) outcome of girls with Turner's syndrome (TS) treated at a single Scottish centre (Glasgow group), to compare it with an earlier national analysis (Scottish group) and to suggest reasons for any change. METHODS: Retrospective growth and treatment data for 29 Glasgow patients were compared with those of 26 Scottish patients. RESULTS: Age at GH start (mean +/- SD) was 10.1 +/- 2.6 vs 12.1 +/- 1.7 y (p < 0.01) in the Glasgow versus Scottish groups, with overall duration of treatment 6.2 +/- 2.4 vs 3.7 +/- 1.1 y (p < 0.001) and years of GH treatment before pubertal induction 2.7 +/- 2.8 vs 0.3 +/- 0.8 y (p < 0.001), respectively. Pubertal induction was at a similar age: 12.7 +/- 1.8 vs 12.8 +/- 1.8 y (ns). FH was 151.1 +/- 4.6 cm in the Glasgow group compared with 142.6 +/- 5.6 cm in the Scottish group (p < 0.001), with FH - projected adult height (PAH) 5.7 +/- 4.6 cm vs 0.6 +/- 3.6 cm (p < 0.001), respectively. Univariate analysis of the Glasgow group's FH - PAH with a number of growth and treatment variables identified no statistically significant relationships. CONCLUSION: This group's improved FH and FH - PAH, relative to an earlier sample, are attributed to the introduction of GH treatment from a younger age and for longer, overall and before pubertal induction. In addition, the authors believe that compliance with treatment has been enhanced by this single centre's dedicated Turner clinic and the efforts of its established "growth team". These data demonstrate that a favourable FH can be achieved using a safe and financially viable dose of GH, while inducing puberty at a "normal" age.     

Hormonal Changes during Development in Turner's Syndrome

The hormonal changes observed during infancy, childhood and adolescence in patients with Turner's syndrome are reviewed, with particular emphasis on gonadotrophins and GH. The relative roles of gonadal insufficiency, maturation of the CNS and disturbed body composition (i.e. obesity) are discussed with respect to the endocrine findings.     

Effect of growth hormone treatment on craniofacial growth in Turner's syndrome

A cephalometric study was performed in 19 patients with Turner's syndrome, aged 8.7–16.5 years. A lateral roentgencephalogram was taken before and after two years of treatment with biosynthetic growth hormone in a dose of 24 IU/m²/week. During two years of growth hormone treatment, the mandibular length increased mainly due to vertical growth. The initially posteriorly rotated mandible showed an anterior rotation, although the normal position was not reached. The other linear measurements and angles did not change during treatment. No indications were found for an increase in the disproportionate growth or for excessive chin growth as a sign of acromegaly during growth hormone treatment. In conclusion, growth hormone treatment in patients with Turner's syndrome resulted in an increase in mandibular length, mainly due to vertical growth of the ramus and in the anterior rotation of the mandible.     

Turner Syndrome: Effect of Hormone Therapies on Height Velocity and Adult Height

ABSTRACT. 76 patients with Turner syndrome received estrogen alone, androgen and estrogen started simultaneously or, after preceding androgen therapy, estrogen with or without androgen. Six patients had spontaneous pubertal development and received no estrogen. Two patients received human growth hormone with androgen during >2.0 years. Height velocity increased during all therapies to mean SD scores of 7.6 during androgen-estrogen started simultaneously, 4.6 during androgen alone, 4.2 during androgen-estrogen after preceding androgen, 2.7 during estrogen alone, and 0.6 during estrogen after preceding androgen. Adult height was measured in all cases, it was 145.5±5.7 (mean ± SD) for the whole series without significant differences between the groups. It correlated strongly with midparent height, and was greater for patients with the 45,X karyotype than for the others combined.     

Oestrogen Therapy in Turner's Syndrome

Oestradiol stimulates growth and development in Turner's syndrome. Previous results with low-dose oestradiol on growth rate are reviewed. The effect of oestradiol in low concentrations on somatomedin generation, GH secretion and directly on osseous tissue, may explain the growth response. The observations presented here of 35 girls treated with 17-β-oestradiol demonstrated a definite increase in growth rate in the first year of therapy. Bone maturation was accelerated, but a reduction in final height was not found.