Treatment of tall stature in boys with somatostatin analogue 201-995: effect on final height

BACKGROUND: An optimal treatment for tall stature in boys in terms of efficacy and safety is not available. Treatment with somatostatin analogue 201-995 (SMS) has been tried with positive short-term results. METHODS: We evaluated the effect of SMS treatment on reducing adult height. Over 2 years, 16 boys presenting to our university hospital with tall stature (constitutional tall stature (n = 13), Marfan syndrome (n = 2) and tethered spinal cord (n = 1)) with a predicted final height above 197 cm were included in the study and prospectively followed until final height was reached. As one boy was lost to follow-up we have reported on 15 boys. Treatment with SMS as a single subcutaneous dose was started and continued until final height was reached. In eight boys androgens were given to induce puberty after the start of SMS and five boys were on treatment with androgens prior to SMS treatment. Effect on reduction of final height prediction, calculated with the index of potential height based on the bone age of Greulich and Pyle, was the main outcome measure. Standard anthropometric assessments were performed a year before and every 3 months during treatment. Bone age was assessed by the method of Greulich and Pyle at the start and after 6 and 12 months. RESULTS: Mean reduction in final height prediction (predicted adult height minus achieved adult height) was -0.1 cm (range -6.4 to +5.7). In three boys, asymptomatic microlithiasis of the gall bladder was diagnosed. CONCLUSIONS: We have concluded that, in spite of encouraging short-term results, long-term treatment with SMS does not reduce final height in a manner sufficient to justify SMS treatment in tall stature.     

What treatment for a child with tall stature?

Tall stature is statistically defined as a height standard deviation score (SDS) above 2 for a given age, sex and population group. The most common cause of tall stature is constitutional (often familial) tall stature. However, underlying endocrine or genetic disorders must be considered as some of them may require specific treatment or management. In constitutional tall stature, healthy children are referred to discuss treatment aiming at reducing adult height. The indications of treatment are rare and usually discussed in girls with extremely tall stature (height SDS > 4, corresponding to 185 cm in girls). The treatment options for tall children are limited and concerns have been raised about their long-term safety. Indeed, recent studies have suggested that high-dose estrogens in adolescent girls may be associated with an increased risk of infertility, as well as increased risk of cancer. Surgical epiphysiodesis has also been reported to reduce adult height but this invasive procedure in healthy children can be questionable and further data on its safety profile are required.     

Pituitary-gonadal function in boys after high dose testosterone treatment for excessively tall stature

One hundred excessively tall boys with a height prediction of 205.32 +/- 5.28 cm (mean +/- SD) were treated with 500 mg testosterone oenanthate (TE) every 14 days for a period of 14.96 +/- 5.29 months. Following therapy, the hypothalamo-pituitary-gonadal axis was evaluated, using a standardized GnRH-test at median time intervals of 14 days, 6 weeks, 13 weeks, 6 months and 16 months. Basal and stimulated LH- and FSH-values were not measurable or severely suppressed in all boys 14 days after termination of therapy. Starting at 6 weeks, normalization of pituitary-gonadal function was demonstrated in 93 boys (group 1) with follow-up periods of up to 48 months. Six boys (group 2) developed transitory hypergonadotrophic LH- and FSH-secretory patterns for up to 11 months after the last TE-injection. Testosterone and gonadotrophins were within the normal range in all 6 boys, when prospectively re-evaluated at 12 to 27 months after termination of therapy. During TE-administration, testicular volume was reduced in some, and in most boys did not show the normal enlargement occurring during puberty. However, return to normal testicular size was seen several months after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Hormonal changes during the first year of oestrogen treatment in constitutionally tall girls

OBJECTIVE: Oestrogens are used to inhibit growth in girls with constitutionally tall stature. We studied the changes in different hormones that accompany such therapy. SUBJECTS AND METHODS: In this longitudinal study we examined the levels of total insulin-like growth factor-I (IGF-I), free thyroxine (FT(4)), thyrotrophin (TSH), testosterone, dehydroepiandrosterone sulphate (DHEA-S), cortisol and prolactin in two groups of girls receiving ethinyloestradiol at a dose of either 0.1mg daily (group A, n=22) or 0.2mg daily (group B, n=36). Hormonal measurements were performed at start of therapy and after 3, 6 and 12 months. RESULTS: In both groups the levels of IGF-I, testosterone and DHEA-S were reduced while the concentrations of cortisol and prolactin were increased. The pituitary-thyroid axis was not significantly affected by this therapy. The girls receiving 0.2mg ethinyloestradiol daily had lower IGF-I levels after 12 months of therapy and had higher serum prolactin concentrations than the girls treated with 0.1mg daily. The reduction in predicted height and the advancement in bone age were similar in both groups. CONCLUSIONS: Therapy with pharmacological doses of ethinyloestradiol changes the levels of several hormones including IGF-I, testosterone, DHEA-S, prolactin and cortisol but the role of the respective changes in the inhibition of growth is not clear. The suppression of DHEA-S levels by 40% suggests that the ovaries contribute significantly to the production of this hormone in pubertal girls.     

Factors predicting adult height in girls with idiopathic central precocious puberty: implications for treatment

OBJECTIVES: To optimize the indications for treating girls with idiopathic central precocious puberty with GnRH analogues, since outcomes may vary. DESIGN: Comparison of adult heights with the data at initial evaluation and the target heights. PATIENTS: Group 1 patients (n = 43) were treated with GnRH analogue from 7.9 +/- 0.2 years to 10.8 +/- 0.1 years (bone age: 10.3 +/- 0.2 years to 12.2 +/- 0.1 years) and group 2 patients (n = 29) were monitored without treatment because their predicted adult heights were > 155 cm. The criteria for treatment were a predicted height < 155 cm and/or a LH/FSH peaks ratio of > 0.6. RESULTS: At initial evaluation, group 1 patients had greater breast development (P = 0.001) and bone age advances (2.0 +/- 0.2 years) than those of group 2 (1.3 +/- 0.2 years, P < 0.3), and higher plasma oestradiol concentrations (139 +/- 11 pmol/l vs. 62 +/- 7 pmol/l, P = 0.0001), LH peak (12.2 +/- 1.8 IU/l vs. 5.8 +/- 2.2 IU/l, P = 0.0001) and LH/FSH peaks ratio (1.3 +/- 0.2 vs. 0.5 +/- 0.1, P = 0.0001). The predicted height for group 1 at the onset of treatment (156 +/- 1.2 cm) was lower than the adult height (159.5 +/- 0.8 cm, P = 0.002), but the two were similar (164.1 +/- 1.2 cm vs. 162.7 +/- 0.9 cm) for group 2. In group 1, the difference between these heights (mean 3.4 cm) was positively correlated with the bone age advance (r = 0.51, P = 0.001), but not with chronological or bone ages, oestradiol, LH peak, LH/FSH peaks ratio before treatment or its duration. It was 5.3 +/- 1.2 cm in the 28 patients with a bone age advance of > 2 years and 0 +/- 1.3 cm in the other 15 (P < 0.02). It was 6.1 +/- 1.3 cm in the 24 patients with predicted height < 155 cm, and -0.1 +/- 1.1 cm in the other 18 (P = 0.002). The 72 patients included nine who attained an adult height over 5 cm shorter than the target height (seven treated and two untreated). The seven treated subjects included two who had retarded intrauterine growth. CONCLUSIONS: Treatment of girls with idiopathic central precocious puberty with GnRH analogues produced a mean height increase of 3.4 cm between the predicted and adult heights. The increase was greater for girls with a bone age advance of > 2 years and a predicted height < 155 cm. Adult height is spontaneously preserved in the slowly progressing form. The classical and slowly progressing forms can be distinguished by the degrees of breast development and bone age advance.     

Changes in the serum triglyceride levels following treatment with ovulation inhibitors in tall girls

The chronological course of serum triglycerides was determined in 12 girls aged 9--10 years, who have been cyclically treated with mestranol (80 microgram/d) and chlormadinonacetate during 3 1/2 years on average, because of constitutional tall stature. A significant increase of the triglycerides level from 80 to 130 mg/100 ml (0.91 to 1.49 mmol/l) could be noted, followed by normalisation within 6 months. Mechanism and metabolic risk of the reversible increase of serum triglycerides are discussed.     

The effect of a continuous infusion of a somatostatin analogue (octreotide) for two years on growth hormone secretion and height prediction in tall children

OBJECTIVE Strategies to limit the final height of tall children have centred on the use of high doses of sex steroids to advance skeletal maturation. This limits therapy to the peripubertal years whereas the greatest gain In height is in the prepubertal years. Prepubertal growth Is largely GH dependent and previous work has documented modulation of GH secretion by once or twice daily subcutaneous Injection of the somatostatin analogue octreotide. In this study we have determined the effects of a nocturnal infusion of octreotide on height prediction, GH and TSH secretion in tall children. DESIGN A patient controlled study in which height prediction and 24-hour GH and TSH secretion were compared prior to and during the course of a 2-year treatment programme with a nocturnal infusion of octreotide in a dose of 1–1.5 μg/kg body weight given subcutaneously. PATIENTS Nine tall children (4M; 5F) aged 7–14 years with final height predictions of 179 cm or greater in the girls and between 183 and 202 cm in the boys were studied. MEASUREMENTS Height prediction using the Tanner-Whltehouse system prior to and at the end of 2 years of treatment. Twenty-four-hour serum GH and TSH concentration profiles, thyroxine, IGF-I and GH responses to GHRH(1–29)NH₂ were studied prior to and at the end of the first year of therapy. RESULTS Treatment with octreotide led to a significant reduction in height prediction In 7 of the 8 children who completed treatment (median reduction 3.5 cm, range +2.8 to ?11.5; Wilcoxon, P=0.05). Twenty-four-hour mean serum GH concentration decreased by 50% (MANOVA, P=0.03) during therapy and this was accompanied by an increase In the percentage of samples giving values less than 0.5mU/1 (MANOVA, P=0.02). There was no overall change in the serum GH response to GHRH(1-29)NH₂ or serum IGF-I concentrations. Nocturnal serum TSH concentrations were reduced to levels observed during the daytime but these changes had no effect on serum thyroxine values. One patient developed gallstones during the course of therapy. CONCLUSIONS A nocturnal infusion of octreotide reduces GH secretion and height prediction in tall children. Therapy with somatostatin analogues allows a reduction In growth rate to be Instigated in the prepubertal years reducing the actual height from which will commence the pubertal growth spurt.     

The effect of large doses of ethinylestradiol on apolipoprotein levels in excessively tall prepubertal girls

Seventeen constitutionally tall prepubertal girls, aged 10 to 14 years, were treated with large doses of ethinyl estradiol (EE) to reduce their final height. The serum concentration of cholesterol, triglyceride, and apolipoproteins before and after four to 17 months of treatment were compared with the same variables in a reference group, initially matched for bone age and height. In the patients, cholesterol rose by 24% (1.1 +/- 0.8 mmol/L), triglyceride by 105% (0.97 +/- 0.70 mmol/L), LDL apo B by 48% (27 +/- 19 mg/dL), apo A-I by 45% (62 +/- 17 mg/dL), and apo A-II by 21% (12 +/- 11 mg/dL). In the reference group, none of these variables changed significantly. The ratio of LDL apo B/apo A-I remained constant in both groups.     

重组人生长激素治疗对青春发育后期女孩身高的影响

以重组人生长激素(rhGH)治疗12例青春发育后期女孩(年龄11～13岁)6个月，每日0．10～0．12IU／kg rhGH治疗提高了他们的身高生长。     

The prediction in boys and girls of the weight/height index and various skinfold measurements in adults: a two-decade follow-up study

Prediction of adiposity in adults from anthropometric measurements (arm and trunk skinfolds, weight/height) made during childhood and adolescence was assessed in a two-decade follow-up study. Weight/height showed the best correlation between childhood and adulthood values in both sexes. The child-adult correlations for skinfolds were better in males than in females and their value varied according to body site. In males, trunk skinfolds showed slightly better correlations than arm sites, and the weakest correlations were observed for the biceps. In females arm skinfolds, especially the biceps, showed a better predictive value than trunk skinfolds for which the child-adult correlation was almost nil. Trunk skinfolds, which are more often associated with metabolic complications of obesity than limb skinfolds, are predictable from childhood measurements in males and not in females. The prediction of adiposity development in different body sites may help identify children most susceptible to various pathologies in later life.     

Growth hormone secretory pattern and response to treatment in children with short stature followed to adult height

OBJECTIVE: To compare the relative utility of GH stimulation tests and assays of spontaneous GH secretion as predictors of change in height standard deviation score at the end of GH treatment in children with short stature. PATIENTS AND METHODS: We retrospectively studied 116 children (67 boys and 49 girls) with subnormal growth rates and short stature, defined as a height of more than 2SD below the mean for age and sex. The patients were classified according to their pattern of findings on baseline pharmacological GH stimulation tests and a 12-h assay of nocturnal spontaneous GH secretion. Twenty-eight patients (24%) had normal hormone levels by both methods (group I); 14 (12%) had normal levels by stimulation tests but subnormal levels by the physiological assay (group II); 48 (41%) had subnormal levels on pharmacological stimulation, with normal physiologic levels (group III); and 26 (22%) had subnormal levels by both methods (group IV). All children in groups II and IV, and 27 in group III, designated IIIb, were treated with recombinant GH at 0.7 U (0.23 mg/kg) of body weight per week. GH secretory patterns were related to final height SD scores and other growth parameters, after the patients had attained their adult stature 6.7 +/- 2.2 years (SD) after GH evaluation. RESULTS: The five groups were similar with respect to mean baseline height SD scores for chronological as well as bone age. Whether assessed as absolute or parentally adjusted (relative) values, mean gains in height SD scores were significantly greater in treated patients with physiological hormone deficiency (groups II and IV) than in those with normal hormone levels (group I, untreated controls). Relative height gains were 1.03 +/- 1.45 cm (6.6 +/- 9.28 cm) and 1.85 +/- 1.21 cm (SDS; 11.8 +/- 7.74 cm) in groups II and IV respectively, compared with only 0.11 +/- 0.42 cm (0.7 +/- 2.68 cm) in group I (P < 0.01 and P < 0.001). GH treatment failed to improve either the absolute or parentally adjusted final height of patients with GH deficiency by stimulation tests but normal levels by physiological assay. CONCLUSION: Long-term administration of GH to short children with normal spontaneous GH secretion is not associated with an appreciable increase in adult height.