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》

Carbohydrate metabolism during long-term growth hormone (GH) treatment and after discontinuation of GH treatment in girls with Turner syndrome participating in a randomized dose-response study. Dutch Advisory Group on Growth Hormone.

To assess possible side-effects of GH treatment with supraphysiological doses on carbohydrate (CH) metabolism in girls with Turner syndrome (TS) during long term GH treatment and after discontinuation of GH treatment, the results of oral glucose tolerance tests and hemoglobin A1c measurements were analyzed in 68 girls with TS participating in a randomized dose-response trial. These previously untreated girls, aged 2-11 yr, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m2 x day (-0.045 mg/kg x day); group B, first year ,4 IU/m2 day; thereafter, 6 IU/m2 x day (approximately 0.0675 mg/kg x day); group C, first year, 4 IU/m2 x day; second year, 6 IU/m2 x day; thereafter, 8 IU/m2 x day (approximately 0.090 mg/kg x day). After the first 4 yr, girls 12 yr of age or older started with 5 microg/kg BW-day 17beta-estradiol for induction of puberty. To assess the effects of long term high dose GH treatment on CH metabolism, the 7-yr data from the oral glucose tolerance tests in 9 girls of group C were evaluated (group C1). To determine whether the changes in CH metabolism during GH treatment would persist after discontinuation of GH treatment, the data for 28 girls who had reached adult height (group A, n = 9; group B, n = 10; group C, n = 9) were evaluated at baseline, after 4 yr of GH treatment, and 6 months after discontinuation of GH. Seven-year data for group C1 showed that glucose levels did not significantly change during GH treatment, whereas fasting insulin levels as well as glucose-induced insulin levels increased significantly. The data for the 28 girls who were treated with GH for a mean (SD) period of 85.3 (13.3) months demonstrated that the GH-induced higher insulin levels decreased to values close to or equal to pretreatment values after discontinuation of GH treatment. Changes in CH variables were not significantly related to the GH dose. Hemoglobin A1c levels never showed an abnormal value. The prevalence of impaired glucose tolerance was low, and none of the girls developed diabetes mellitus. In conclusion, long term GH treatment with dosages up to 8 IU/m2 x day in girls with TS has no adverse effects on glucose levels, but induced higher levels of insulin, indicating relative insulin resistance. The increased insulin levels during long term GH treatment decreased after discontinuation of GH treatment to values close to or equal to pretreatment values. Although the reversibility of the effects of long term GH is reassuring, the consequence of long term hyperinsulinism is still unknown.

Sas TC ，de Muinck Keizer-Schrama SM ，Stijnen T ，Aanstoot HJ ，Drop SL ... -  《JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM》

Effect of discontinuation of long-term growth hormone treatment on carbohydrate metabolism and risk factors for cardiovascular disease in girls with Turner syndrome.

GH treatment increases insulin levels in girls with Turner syndrome (TS), who are already predisposed to develop diabetes mellitus and other risk factors for developing cardiovascular disease. Therefore, in the present study, we investigated carbohydrate metabolism and several other risk factors that may predict development of cardiovascular disease in girls with TS after discontinuation of long-term GH treatment. Fifty-six girls, participating in a randomized dose-response study, were examined before, during, and 6 months after discontinuing long-term GH treatment with doses of 4 IU/m(2).d ( approximately 0.045 mg/kg.d), 6 IU/m(2).d, or 8 IU/m(2).d. After a minimum of 4 yr of GH treatment, low-dose micronized 17beta-estradiol was given orally. Mean (SD) age at 6 months after discontinuation of GH treatment was 15.8 (0.9) yr. Mean duration of GH treatment was 8.8 (1.7) yr. Six months after discontinuation of GH treatment, fasting glucose levels decreased and returned to pretreatment levels. The area under the curve for glucose decreased to levels even lower than pretreatment level (P < 0.001). Fasting insulin levels and the area under the curve for insulin decreased to levels just above pretreatment level (P < 0.001 for both), although being not significantly different from the control group. No dose-dependent differences among GH dosage groups were found. At 6 months after discontinuation, impaired glucose tolerance was present in 1 of 53 girls (2%), and none of the girls developed diabetes mellitus type 1 or 2. Compared with pretreatment, the body mass index SD-score had increased (P < 0.001), and the systolic and diastolic blood pressure SD-score had decreased significantly at 6 months after discontinuation of GH treatment (P < 0.001 for both) although remaining above zero (P < 0.001, P < 0.05, and P < 0.005, respectively). Compared with pretreatment, total cholesterol (TC) did not change after discontinuation of GH treatment, whereas the atherogenic index [AI = TC/high-density lipoprotein cholesterol (TC/HDL-c)] and low-density lipoprotein cholesterol (LDL-c) had decreased; and both HDL-c and triglyceride levels increased (P < 0.001 for AI, LDL-c, and HDL-c; P < 0.05 for triglyceride). Compared with the control group, AI, serum TC, and LDL-c levels were significantly lower (P < 0.001 for all), whereas HDL-c levels were significantly higher (P < 0.05). In conclusion, after discontinuation of long-term GH treatment in girls with TS, the GH-induced insulin resistance disappeared, blood pressure decreased but remained higher than in the normal population, and lipid levels and the AI changed to more cardio-protective values.

Van Pareren YK ，De Muinck Keizer-Schrama SM ，Stijnen T ，Sas TC ，Drop SL ... -  《JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM》

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》