A longitudinal study on bone mineral density until adulthood in girls with Turner's syndrome participating in a growth hormone injection frequency-response trial.

OBJECTIVE:The aim of this study was to assess the volumetric bone mineral density (BMD) in girls with Turner's syndrome (TS) before and during growth hormone (GH) treatment in combination with low dose oestrogens as well as three years after discontinuation of GH treatment. DESIGN:In a prospective, randomized injection frequency-response study, the effect of GH treatment in combination with low dose ethinyl oestradiol (starting with 0.05 microgram/kg/day), on BMD was evaluated, comparing twice daily (BID) with once daily (OD) injections of a total GH dose of 6 IU/m2/day until adult height was reached. After discontinuation of GH treatment, the dosage of oestrogens was further increased to adult supplementation levels. PATIENTS:Nineteen untreated girls with TS, mean (SD) baseline pretreatment age 13.3 (1.7) (range 11.0-17.6) year. MEASUREMENTS:Before and during GH treatment, measurements of volumetric BMD were performed using phalangeal radiographic absorptiometry. In addition, the BMD measurements were repeated three years after discontinuation of GH treatment. BMD results were adjusted for bone age and sex, and expressed as SD-scores (SDS) using reference values of healthy Dutch girls. RESULTS:At baseline, most individual BMD values of cortical bone as well as those of trabecular bone were within the normal range of healthy girls. However, the mean BMD SDS of the trabecular bone was significantly lower than zero. During treatment, the BMD SDS showed a significant increment to values equal or higher than zero after mean (SD) GH treatment period of 36.6 (7.5) months. The increase in BMD of the cortical bone was significantly higher in the OD group than in the BID group. The BMD SDS in the last year of GH treatment was not significant different between the two injection frequency groups. Three years after discontinuation of GH treatment, the BMD values had increased further similar as in healthy girls, resulting in BMD values all within normal range or even higher. CONCLUSIONS:Most untreated girls with Turner syndrome, age >/= 11 years, have a normal volumetric BMD of the cortical, as well as of the trabecular bone compared to healthy girls. During GH treatment with 6 IU/m2/day in combination with low dose oestrogens, the BMD SDS increases significantly. After discontinuation of GH treatment and the use of oestrogens in an adult dosage, the BMD was as high as in young healthy women.

Sass TC ，De Muinck Keizer-Schrama SM ，Stijnen T ，Asarfi A ，Van Leeuwen WJ ，Van Teunenbroek A ，Van Rijn RR ，Drop SL ... -  《CLINICAL ENDOCRINOLOGY》

Bone mineral density assessed by phalangeal radiographic absorptiometry before and during long-term growth hormone treatment in girls with Turner's syndrome participating in a randomized dose-response study.

Sas TC ，de Muinck Keizer-Schrama SM ，Stijnen T ，van Teunenbroek A ，van Leeuwen WJ ，Asarfi A ，van Rijn RR ，Drop SL ，Dutch Advisory Group on Growth Hormone ... -  《PEDIATRIC RESEARCH》

Final height in girls with Turner's syndrome treated with once or twice daily growth hormone injections. Dutch Advisory Group on Growth Hormone.

Sas TC ，de Muinck Keizer-Schrama SM ，Stijnen T ，van Teunenbroek A ，Hokken-Koelega AC ，Waelkens JJ ，Massa GG ，Vulsma T ，Gerver WJ ，Reeser HM ，Delemarre-van de Waal HE ，Jansen M ，Drop SL ... -  《-》

Carbohydrate metabolism during growth hormone treatment and after discontinuation of growth hormone treatment in girls with Turner syndrome treated with once or twice daily growth hormone injections.

To assess possible side-effects of treatment with supraphysiological GH dosages on carbohydrate (CH) metabolism in girls with Turner syndrome (TS) during GH treatment until adult height is reached as well as after discontinuation of GH treatment. In a prospective, randomized injection frequency-response study, the effect of GH treatment in combination with low dose ethinyl oestradiol on CH metabolism was evaluated, comparing twice daily (BID) with once daily (OD) injections of a total GH dose of 6 U/m2/day until adult height was reached. Nineteen untreated girls with TS, mean (SD) pretreatment age 13.3 (1.7) (range 11.0-17.6) year. Glucose and insulin concentrations during oral glucose tolerance tests (OGTT) were measured before and during GH treatment, as well as at 6 months after discontinuation of GH treatment. GH treatment was discontinued after a mean of 43 (range 27-57) months. In one of the 19 girls, a different girl at each time point before, during and after discontinuation of GH treatment, the glucose response to OGTT after 120 minutes was above 7.8 mmol/l but below 11.1 mmol/l, indicating impaired glucose tolerance. None of the girls developed diabetes mellitus. Fasting glucose levels did not significantly change during, or after discontinuation of GH treatment. The 3 h area under the curve for time-concentration adjusted for fasting levels during the OGTT for glucose showed a significant decrease during GH treatment. In contrast to the glucose levels, GH treatment induced considerably higher insulin levels compared to pretreatment values. After discontinuation of GH insulin levels decreased to values comparable with pretreatment levels. None of these observed changes were different between the GH injection frequency groups. The changes in CH variables during and after discontinuation of GH were not related to changes in body mass index. GH treatment with 6 U/m2/day in combination with low dose ethinyl oestradiol in girls with Turner syndrome aged > or =11 years did not negatively influence glucose levels, but induced higher levels of insulin indicating relative insulin resistance. These changes in insulin levels were independent of the frequency of the GH injections (once vs. twice daily). After discontinuation of GH treatment, insulin values decreased to baseline levels.

Sas T ，de Muinck Keizer-Schrama S ，Aanstoot HJ ，Stijnen T ，Drop S ... -  《CLINICAL ENDOCRINOLOGY》

Growth response and levels of growth factors after two years growth hormone treatment are similar for a once and twice daily injection regimen in girls with Turner syndrome. (Dutch Working Group on Growth Hormone).

GH is known to improve height velocity in girls with Turner syndrome (TS) but the optimal dosage regimen has yet to be defined. We attempted to improve the growth response by trying to mimic normal pulsatile GH secretion more closely. In a 2-year study the effect of fractionated twice daily (BID) was compared with once daily (OD) s.c. injections of a total GH dose of 6 IU/m2/day. BID injections were administered as two-thirds at bedtime and one-third in the morning. The subjects concurrently received low dose ethinyl oestradiol (0.05 mg/kg/day, orally). Nineteen girls with TS aged 11 years or over, who were previously involved in a 10-week GH cross-over study. Height and bone age were evaluated in relation to untreated Turner reference data. Final height (FH) was predicted using the Bayley and Pinneau (BP) method, the modified index of Potential Height (mIPHRUS), and a recently developed Turner-specific method (PTSRUS) based on regression coefficients for height (H), chronological age (CA) and bone age (BA). Plasma levels of GH, GHBP, IGF-1, and IGFBP-3 were determined by RIA. After 2 years treatment the growth response expressed as HV, HVSDS, the change in HSDSCA, the gain in height over estimated untreated values and in FH prediction all showed significant improvements. Although mean values tended to be higher with OD injections, significant differences between groups were not found. Bone maturation was similar between groups and compared with untreated estimated values. Independent of treatment group, the change in HSDSCA after 2 years of GH treatment was related negatively to the baseline CA and HSDSCA, and positively to BA delay at baseline. After 18 months of GH treatment the significant decrease in GHBP plasma levels observed after 6 months was no longer significant. In contrast, IGF-1 and IGFBP-3 plasma levels and the IGF-1 to IGFBP-3 ratio increased significantly during 18 months GH therapy. None of these growth related factors showed a difference between groups in their 18 months change. Relevant side-effects were not observed during the first 2 years of GH treatment. The present growth data are in conformity with the data of the earlier 24-hour GH profiles. The growth response and plasma levels of growth related factors after 2 years GH on a total dose of 6 IU/m2/day in combination with low-dose oestrogens were not significantly different between the once daily and the twice daily GH injection regimen.

van Teunenbroek A ，de Muinck Keizer-Schrama S ，Stijnen T ，Waelkens J ，Wit JM ，Vulsma T ，Gerver WJ ，Reeser H ，Delemarre-van de Waal H ，Jansen M ，Drop S ... -  《CLINICAL ENDOCRINOLOGY》