Effect of growth hormone and oxandrolone treatment on glucose metabolism in Turner syndrome. A longitudinal study.

In 18 girls with Turner syndrome, glucose tolerance was studied before treatment and after 6 and 24 months of growth-promoting treatment with recombinant human growth hormone (24 IU/m(2)/week; 8 mg/m(2)/week) and oxandrolone (0.06 mg/kg/day), as well as after termination of the treatment. One girl developed an overt non-ketotic diabetes mellitus 50 months after termination of treatment. The results of the remaining 17 girls in whom the effect of treatment on glucose metabolism was reversible are presented as a group. Their median age at the beginning of the treatment was 10.4 years (range 6.9-15.9), and 15.0 years (range 12.1-19.9) at the final assessment. There was a moderate, but not significant rise in fasting glucose throughout the course of the longitudinal study. At oral glucose tolerance testing (oGTT), the area under the curve for glucose rose significantly (p = 0.013) during the period of treatment and returned to the basic value thereafter. Fasting insulin and especially the integrated insulin values (AUCi; area under the curve for insulin) during oGTT increased continuously during treatment, declined after termination of treatment but were still significantly (p = 0.04) higher than before treatment. Considering the fact that in untreated girls with Turner syndrome the fasting insulin and the AUCi increase with age, one can conclude that the insulinaemia returned to age-specific norm after termination of treatment. Thus the effect of a combined growth hormone and oxandrolone growth-promoting treatment on glucose metabolism was fully reversible in these 17 girls with Turner syndrome.

Growth promotion and Turner-specific bone age after therapy with growth hormone and in combination with oxandrolone: when should therapy be started in Turner syndrome?

The aims of this comparative multicenter study of 67 girls with Turner syndrome (TS) on three different therapeutical regimens were, first, to evaluate the effect of either recombinant human growth hormone (GH) alone or in combination with the anabolic steroid oxandrolone (Oxa) on height velocity and on Turner-specific bone age (BA'TS) and, second, to estimate the gain in final height taking the age at the onset of treatment into account. The mean advancement of BA'TS in 2 years of treatment was 2.5 years/2 years in group 1 (low dose GH: 16 IU/m2/week), 2.8 years/2 years in group 2 (high dose GH: 28 IU/m2/week) and 3.3 years/2 years in group 3 (GH: 24 IU/m2/week + Oxa: 0.06 mg/kg/day) instead of the expected 2 years/2 years advancement in untreated girls with TS. On all treatment regimens the advancement of BA'TS was more pronounced in the younger girls. In many girls with a BA'TS below 9 years at the onset of treatment the increase in height did not outweigh the advancement in BA'TS, suggesting that starting growth-promoting treatment before 9 years would not be the best way to improve final height. In our opinion, the optimal age for starting growth-promoting therapy is at 9 years. A start at a younger age might have no advantage in regard of an ultimate gain in final height. On the other hand, therapy should not be delayed much after the age of 9 years giving the girls with TS the possibility to catch up substantially before estrogen treatment is initiated.

Impact of different doses of ethinyl oestradiol on reduction of final height in constitutionally tall girls.

Fifty-two tall girls were treated for constitutionally tall stature with different ethinyl oestradiol (EE) dosages. They were divided into three different treatment groups: group B (100 micrograms EE/day; n = 11); group C (300 micrograms; n = 25) and group D (500 micrograms; n = 16) and compared with an untreated group A (n = 21) matched for age, height, bone age (BA) and height prediction. Using the height prediction method TW II, EE treatment reduced final height compared with the untreated girls in a weak dose-dependent manner, 2.3 cm (100 micrograms/day), 3.0 cm (300 micrograms/day), and 3.8 cm (500 micrograms/day). Such a dose dependency was not found on applying the Bayley-Pineau height prediction method (100 micrograms/day; 4.1 cm; 300 micrograms/day: 4.2 cm; 500 micrograms/day: 4.5 cm). However, there was a striking inverse correlation of the BA at the onset of treatment with the height reduction achieved using the TW II method (r: -0.43; P < 0.001). Importantly, girls with a BA below 12 years at the onset of treatment experienced a height reduction of more than 6 cm. CONCLUSION The EE dose used in the range of 100-500 micrograms/day is not crucial for the amount of height reduction in tall girls. In general high dose EE treatment should be given restrictively, and especially so in girls with a BA (TW2 RUS-ZH) above 12.0 years.

Adult height in constitutionally tall stature: accuracy of five different height prediction methods.

The accuracy of height predictions at various ages based on five different methods (Tanner-Whitehouse mark I; Tanner-Whitehouse mark II; index of potential height; Bayley-Pinneau; Roche-Wainer-Thissen) was compared at yearly intervals with final height achieved in 32 boys (78 predictions) and 100 girls (227 predictions) with constitutionally tall stature. The boys were initially seen at a mean (SD) chronological age of 12.5 (3) years whereas the mean chronological age in girls was 11.8 (2.1) years. In tall boys Tanner-Whitehouse mark II gives a good estimation of final height up to the bone age of 13 years with a mean overestimation of 1 cm. The overestimation of final height is higher in the bone age groups 13-14 years (2.7 cm) and 14-15 years (3.4 cm) mainly due to the tall boys with a height greater than 3 SD scores. Up to the bone age of 12 years the final height is massively overestimated by the Bayley-Pinneau method but this method give relatively accurate estimations thereafter. The estimated confidence limits are large (+/- 8 cm) for the two methods up to a bone age of 15 years. In tall girls the Tanner-Whitehouse mark II method was accurate from bone age nine to 12 years but overestimated final height in the bone age groups 12-13 years and 13-15 years by a mean of 1.8 and 1.4 cm respectively. The Bayley-Pinneau method overestimated final height in the bone age groups 12-14 years whereas the height predictions are accurate thereafter. Up to a bone age of 13 years the estimated confidence limits for the two methods are large, +/- cm, but tend to improve thereafter. It is concluded that there is no best or most accurate method for predicting adult height in tall children. There are methods of first choice differing with respect to sex and bone age. In addition, correcting factors may improve their accuracy and correct their tendency to overestimate or underestimate adult height.

Oxandrolone in constitutionally delayed growth, a longitudinal study up to final height.

Twenty-seven prepubertal boys and 9 prepubertal girls with constitutionally delayed growth were treated with the anabolic steroid oxandrolone for 12 months and followed until they reached final height. Sixteen boys were treated with a mean dose of 0.12 mg/kg.day [low dose (LD)] and 11 boys with a mean dose of 0.22 mg/kg.day [high dose (HD)]. The girls were treated with a mean dose of 0.1 mg/kg.day. Thirteen boys and 9 girls served as controls. On oxandrolone the mean height velocity increased from 4.0 to 8.6 (boys, LD), from 4.3 to 8.9 (boys, HD), and from 4.3 to 8.3 cm/yr (girls). The immediate posttreatment height velocity was significantly higher than the pretreatment height velocity (P less than 0.05), regardless of whether the patients had entered puberty. On oxandrolone the mean ratios of change in bone age/change in chronological age were 2.0 (boys, LD), 2.3 (boys, HD), and 2.0 yr/yr (girls) and continued to be accelerated during the 6 months after treatment. Height predictions at the onset of treatment and after 6 months off treatment were calculated by three different methods: Bayley-Pinneau (BP), Roche-Wainer-Thissen (RWT), and Tanner Mark II (T II). In the boys (LD) mean height predictions increased significantly by the methods of BP (3.3 cm) and RWT (2.9 cm), but not by the method of T II (0.6 cm). In the boys (HD) no significant change in height predictions was noted. In the girls mean height predictions remained unchanged by BP and RWT, but decreased significantly by T II (-2.5 cm). The difference between final height and initial height prediction was taken as a measure of the influence of the treatment on adult height. In all three treatment groups the difference between final height and initial height prediction, calculated with all three methods, did not differ from the control group. We conclude that oxandrolone treatment for 1 yr has no effect on adult height. In spite of this, the use of an anabolic steroid such as oxandrolone may still have value, as an increase in height velocity and an earlier onset of puberty may benefit short children suffering from psychological problems due to delay of growth and development.

Bromocriptine treatment in adolescent boys with familial tall stature: a pair-matched controlled study.

Recently, bromocriptine has been proposed as a novel agent for the treatment of excessively tall stature in adolescents. To further test its value, we treated nine boys, aged 10.0-15.4 yr, for 1 yr with bromocriptine (7.5 mg/day). A paradoxical plasma GH response to TRH was demonstrated in four of eight boys before and in five boys after 6 months of bromocriptine treatment. At the onset of therapy, the mean adult height prediction was 202.2 +/- 4.3 (+/- SD) cm (Bayley-Pinneau), 202.1 +/- 4.7 cm (TW Mark II), and 198.6 +/- 5.3 cm (Roche-Wainer-Thissen). After 1 yr of therapy, the mean adult height prediction had changed by -4.5 +/- 2.6 cm (Bayley-Pinneau), -3.4 +/- 2.2 cm (TW Mark II), and -2.6 +/- 1.2 cm (Roche-Wainer-Thissen). These reductions were solely due to a decrease in growth velocity and not to an increased skeletal maturation rate. To substantiate these findings, each treated boy was pair-matched with an untreated tall boy so that their chronological and skeletal ages differed by less than 1 yr. After 1 yr of follow-up, height predictions in the treated boys compared with those in the matched control boys gave significantly reduced results with the Bayley-Pinneau and the Roche-Wainer-Thissen, but not with the TW Mark II, method. Because of this discrepancy it is uncertain whether final height in tall boys will really be reduced by treatment with bromocriptine.

Effects of isolation, handling and restraint on growth of rats.

The effects of 3 environmental conditions on physical growth and skeletal maturation were assessed in pair-fed rats. Rats subjected to restraint from ages 28 to 80 days weighed less and were shorter than pair-fed like-sex controls; skeletal maturation was unaffected. The observations cannot be attributed to handling, as those animals were heavier than their controls, or to isolation, which was found to be without effect on any of the measurements. The adverse effects of restraint on physical growth are attributed to increased adrenal cortical activity, reflected in increased adrenal weight.

Effect of oral thyrotrophin-releasing hormone on serum thyroxine in growth hormone deficient and normal children.

Oral administration of synthetic TRH in a dose of 80 mg/1-73 m-2 at 0 and 12 h to normal and constitutionally small children caused a significant increase of total serum thyroxine (T4) within 6-24 h. The mean maximal T4 increment was +3-7 plus or minus 1-1 and +3-8 plus or minus 1-2 mug/dl (mean plus or minus 1 SD) respectively in the two groups. Of seventeen euthyroid GH deficient children, fifteen showed a normal and two patients a slightly subnormal response. Of fifteen hypothyroid GH deficient children nine had a prompt and normal increase of serum T4 indicating primary TRH deficiency. Two had a delayed T4 response and four had no response, even after prolonged stimulation. The localization of the primary defect in these latter subjects with severe hypothyroidism can not be made by measuring T4 only, since the thyroid gland may become unresponsive to TSH after longstanding TSH deficiency. TSH measurements are necessary in these circumstances for a clear localization of the primary defect. One GH deficient patient with hypothalamic TRH deficiency was treated with high oral TRH doses for 7 months and showed no side effects.