Combined therapy with GnRH analog plus growth hormone in central precocious puberty

GnRH analogues (GnRHa) arrest pubertal development, and slow growth velocity (GV) and bone maturation, thus improving adult height in central precocious puberty (CPP). In some patients, however, GV decreases to such an extent that it compromises the improvement in predicted adult height (PAH) and therefore the addition of GH is suggested. Of 20 patients with idiopathic CPP (treated with GnRHa [depot-triptorelin] at a dose of 100 microg/kg every 21 days i.m. for at least 2-3 yr) whose GV fell below the 25th percentile for chronological age (CA), ten received, in addition to the GnRHa, GH at a dose of 0.3 mg/kg/wk, s.c. 6 days weekly, for 2-4 yr. Ten patients matched for BA, CA, and duration of GnRHa treatment who showed the same growth pattern but refused GH treatment, served to evaluate the efficacy of the addition of GH. No patient showed classical GH deficiency. Both groups discontinued treatment at a comparable BA (mean +/- SEM): 13.2 +/- 0.2 yr in GnRHa + GH vs 13.0 +/- 0.1 yr in the control group. At the conclusion of the study all the patients had achieved adult height. Adult height was considered to be attained when the growth during the preceding year was less than 1 cm, with a BA of over 15 yr. Patients of the group treated with GH + GnRHa showed an adult height significantly higher (p<0.001) than pretreatment PAH (160.6 +/- 1.3 vs 152.7 +/- 1.7 cm). Height SDS for BA significantly increased from -1.5 +/- 0.2 at start of GnRHa to -0.21 +/- 0.2 at adult height (p<0.001). Target height was significantly exceeded. The GnRH alone treated group reached an adult height not significantly higher than pretreatment PAH (157.1 +/- 2.5 vs 155.5 +/- 1.9 cm). Height SDS for BA did not change (from -1.0 +/- 0.3 at start of GnRHa to -0.7 +/- 0.4 at adult height). Target height was just reached but not significantly exceeded. The gain in centimeters obtained calculated between pretreatment PAH and final height was 7.9 +/- 1.1 cm in patients treated with GH combined with GnRH analogue while in patients treated with GnRH analogue alone the gain was just 1.6 cm +/- 1.2 (p=0.001). Furthermore, no side effects, bone age progression, or ovarian cysts, were observed in GnRHa + GH treated patients. In conclusion, a gain of 7.9 cm in adult height represents a significant improvement which justifies the addition of GH for 2-3 yr to conventional treatment with GnRH analogues in patients with central precocious puberty, and with a decrease in growth velocity so marked as to impair predicted adult height to below the third percentile.     

Catch-up growth in severe juvenile hypothyroidism: treatment with a GnRH analog

Anecdotal reports suggest that the addition of a gonadotropin releasing hormone (GnRH) analog (GnRHa) in addition to L-thyroxine (LT4) replacement may increase adult stature in children with severe longstanding hypothyroidism by prolonging the pubertal growth period. This retrospective chart review compares the height outcome and body mass index in 33 children (21 treated with LT4 alone and 12 treated with LT4 + GnRHa) with severe longstanding hypothyroidism and bone age delay. Seventeen controls and six GnRHa-treated patients were followed to adult height (BA >14 yr [F]/16 yr [M] and/or growth velocity < 2 cm/yr). At diagnosis, GnRHa-treated patients were 1) older and shorter for chronological age, and 2) more advanced in puberty and bone age. Despite these differences, at adult height, both groups had similar improvements in height Z scores, similar height deficits, and comparable adult heights. Changes in BMI Z score were similar for both groups. Our study suggests that the addition of GnRHa to LT4 may improve interval growth without imposing a risk of obesity in children with longstanding severe hypothyroidism.     

Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution

Out of 35 girls with idiopathic central precocious puberty (CPP) treated with gonadotropin-releasing hormone agonist (GnRHa) (depot-triptorelin) at a dose of 100 microg/kg every 21 days i.m. for at least 2-3 years whose growth velocity fell below the 25th percentile for chronological age (CA), 17 received growth hormone (GH) in addition at a dose of 0.3 mg/kg/week, s.c., 6 days per week, for 2-4 years. The other 18, matched for bone age (BA), CA and duration of GnRHa treatment, who showed the same growth pattern but refused GH treatment, remained on GnRHa alone, and were used as a control group to evaluate GH efficacy. No patient was GH deficient. Both groups discontinued treatment at a comparable BA (mean +/- SD): BA 13.4 +/- 0.6 in GnRHa plus GH group vs 13.0 +/- 0.5 years in the GnRHa alone group. The 35 patients have reached adult height (i.e. growth during the preceding year was less than 1 cm, with a BA of over 15 years). Patients of the group treated with GH plus GnRHa showed an adult height (161.2 +/- 4.8 cm) significantly higher (p < 0.001) than pre-treatment predicted adult height (PAH) calculated according to tables either for accelerated girls (153.2 +/- 5.0 cm) or for average girls (148.6 +/- 4.3 cm). The adult height of the GnRH alone treated group (156.6 +/- 5.7) was not significantly higher than pre-treatment PAH if calculated on Bayley and Pinneau tables for accelerated girls (153.9 +/- 3.8 cm), whilst it remained significantly higher if calculated on tables for average girls (149.6 +/- 4.0 cm) (p < 0.001). The gain between pre-treatment PAH and final height was 8.2 +/- 4.8 cm according to tables for accelerated girls and 12.7 +/- 4.8 cm according to tables for average girls in patients treated with GH plus GnRHa; while in patients treated with GnRH alone the gain calculated between pre-treatment PAH for accelerated girls was just 2.3 +/- 2.9 cm and 7.1 +/- 2.7 cm greater than pre-treatment PAH for average girls. The difference between the gain obtained in the two groups (about 6 cm) remained the same, however PAH was calculated. The addition of GH to GnRHa in a larger cohort of patients with CPP with a longer follow-up confirms the safety of the combined treatment and the still significant but more variable gain in the group with the combined treatment, probably due to the larger number of patients analyzed. Caution is advised in using such an invasive and expensive treatment, and there is need for further studies before widespread clinical use outside a research setting.     

Sufficiently long-term treatment with combined growth hormone and gonadotropin-releasing hormone analog can improve adult height in short children with isolated growth hormone deficiency (GHD) and in non-GHD short children

GnRHa treatment can decelerate the bone age advancement and delay the epiphyseal closure, and GH can compensate the decreased pubertal height velocity by suppressing sex steroid hormones. It is reasonably concluded from long-term controlled studies that combined GH and GnRHa treatment does effectively increase total pubertal growth and improve adult height in short children with isolated GHD and non-GHD who enter puberty at short stature when the additional GnRHa treatment is continued for more than three years, although there a proper large randomized control trial is necessary to confirm surely the efficacy of combined GH and GnRHa treatment.     

Efficacy of combined treatment with growth hormone and gonadotropin releasing hormone analogue in children with poor prognosis of adult height

OBJECTIVE: This study was conducted to study the role of combination therapy of growth hormone and Gonadotropin-releasing hormone (GnRH) analogues in girls with idiopathic central precocious puberty (CPP) or idiopathic short stature (ISS). METHODS: Five girls with CPP (median age 9.1 y, pubertal stage 2-3) (3 of them previously treated with GnRH analogue (GnRHa) for 16.2 +/- 0.3 months) and 8 girls with ISS (median age 11.4 y, pubertal stage 2-3) (previously treated with GH for 10.95 +/- 1.42 months), were treated with recombinant human GH (0.33 mg/kg/week) and GnRHa (3.75 mg/28 days) for 22 months. RESULTS: Height of girls with CPP improved from - 1.3 to - 0.2 SDS and height for BA from - 2.1 to - 0.6 SDS (P = 0.042). Predicted adult height (PAH) improved from - 3.1 to - 0.6 SDS (P = 0.042). In girls with ISS only PAH improved from - 3.0 to - 1.5 SDS (P = 0.025). CONCLUSION: Combined treatment improves height and PAH in CPP. Height in ISS is also improved however not significantly.     

GnRHa治疗中枢性性早熟女童对终身高的影响

目的：观察促性腺激素释放激素类似物（GnRHa）对治疗中枢性性早熟（central precocious puberty,CPP）女童终身高的作用及相关因素。方法：对26例CPP女童应用GnRHa治疗前后预测身高、骨龄的标准差分值［HtSDS(BA)］、终身高、体重指数（BMI）、初潮情况等进行评价,分析它们与终身高的相关性。结果：治疗前预测身高为151.5±5.7 cm;停药时预测身高为158.4±5.2 cm;终身高为158.0±4.0 cm,高于靶身高155.3±4.4 cm (P<0.01)。终身高与初始身高、预测身高、HtSDS(BA)正相关。治疗前BMI为17.1±2.1、治疗后BMI为19.9±3.2,两者呈正相关。停药后平均13.2±6.1个月后初潮,平均初潮年龄为12.2±0.7岁。结论：GnRHa治疗CPP可有效地改善终身高,终身高与治疗前身高及预测身高等密切相关,停药后患儿青春发育与正常儿童相似。［中国当代儿科杂志,2009,11（5）：374-376］     

Management of puberty in growth hormone deficient children

The pubertal growth spurt accounts for approximately one-eighth of adult height and is regulated by complex hormonal interactions involving the somatotropic and gonadal axes. The observation that children with growth hormone deficiency (GHD) may fail to achieve an appropriate pubertal growth spurt led to the development of strategies to optimize GH therapy during puberty. In one strategy the dosage of GH is increased during puberty to support pubertal growth and in keeping with the physiological increase in serum levels of the hormone seen at that age. A different approach is to combine a GnRH analog (GnRHa) to GH to stop pubertal development, delaying epiphyseal fusion and prolonging peripubertal growth. Both strategies require caution. As regards the first strategy, too high doses of GH may shorten the pubertal time for growth; we found a small, nonsignificant, improvement in final height by increasing the dose by less than half. Preliminary results on the second strategy are more encouraging. However, manipulation of puberty should be limited to selected patients who show a statural height SDS for bone age unfavorable in terms of height prognosis.     

Final height after gonadotrophin releasing hormone agonist treatment for central precocious puberty: the Dutch experience

Final height (FH) data of 96 children (87 girls) treated with GnRH agonist for central precocious puberty were studied. In girls mean FH exceeded initial height prediction by 7.4 (5.7) cm (p < 0.001); FH was significantly lower than target height, but still in the genetic target range. When treatment started < 6 years of age, height gain was significantly higher than when started > 8 years of age. Bone age (BA) and chronological age (CA) at start of treatment, as well as BA advance at cessation of treatment, were the most important variables influencing height gain in multiple regression analysis. BA advance at start of treatment was most important in simple correlation. In girls, GnRHa treatment seems to restore FH into the target range. A younger age and advanced bone age at start of treatment are associated with more height gain from GnRHa treatment.     

Treatment of central precocious puberty: lessons from a 15 years prospective trial. German Decapeptyl Study Group

There is still controversy about the auxological outcome of GnRH agonist treatment in patients with CPP and about the favorable age and auxological characteristics at start of treatment for achieving a normal final height (FH) or for preserving height potential. We analyzed the FH data of 52 young women from a prospective multicentric trial which was started in 1985. The aim of this analysis was to determine factors that may predict a favorable FH or a good height gain. Chronological age (CA) was 5.2 +/- 2.1 yr (+/- SD) at start of puberty, 6.2 +/- 2.0 yr at start of triptorelin depot treatment, 11.1 +/- 1.1 yr at end of treatment, and 16.7 +/- 2.6 yr at FH evaluation. After 4.8 +/- 2.2 yr (1.1-9.9 yr) of treatment duration, FH was 160.6 +/- 8.0 cm (vs 154.9 +/- 9.6 cm of initial height prediction [PAH], p<0.05). A FH within TH range or in excess of mean TH was achieved by 78% or 41% of patients. FH was above the 3rd percentile of the normal German population in 29% of patients (63% had an initial PAH < 156 cm). The group of patients with start of puberty at age < or = 6 yr (Group 1) showed a significantly higher height gain (FH - initial PAH) and lower height deficit compared to TH than older patients (Group 2). Furthermore, the percentage of patients from Group 1 reaching TH range or mean TH showed a significant increase with GnRH agonist treatment whereas this was not the case in Group 2. Stepwise regression analysis showed that height SDS at end of treatment, age at menarche, bone age (BA) at start of treatment, and BA advancement at end of treatment were determinants of FH (r2=0.923). Initial BA advancement and treatment duration were the factors that explained 68% of the variability of height gain. Although BA advancement at initiation of treatment was negatively associated with FH it was a positive predictor of height gain. In addition, height gain correlated significantly with CA and BA at start of treatment (r= -0.430, p=0.004 and r=0.359, p=0.018). Growth after interruption of treatment had no significant predictive effect on FH. It is concluded that a higher percentage of patients below 6 yr of age at start of puberty do profit from GnRH agonist treatment with respect to achieving a normal FH. BA, BA advancement, and height SDS at treatment start are important factors for determining outcome.     

Effect of GnRH analogue on height potential in patients with severe growth hormone insensitivity syndrome treated with IGF-I

Children with growth hormone insensitivity syndrome (GHIS) who receive insulin-like growth factor 1 (IGF-1) treatment and enter puberty with inadequate height gain are unlikely to reach adult height within the normal range. Final height standard deviation score (SDS) in most treated children is < or = -5. Combining IGF-1 with gonadotrophin-releasing hormone analogue (GnRHa) therapy may help to improve their final height. Three patients on IGF-1 treatment, two with primary GHI and one with secondary GHI, were started on GnRHa therapy at the onset of puberty. Their ages ranged from 6.4 years to 12.9 years at the start of IGF-1 therapy (120 microg/kg twice daily by subcutaneous injection). Gains in height/bone age SDSs under GnRHa therapy ranged from 0 to 0.9. Growth velocity on GnRHa therapy ranged from 4 cm/year to 4.8 cm/year. Bone maturation (measured as change in bone age divided by change in chronological age, deltaBA/deltaCA) decreased after the start of GnRHa therapy. Predicted adult height (PAH) improved in two patients and was maintained in one. Bone mineral density showed gradual improvement from baseline. Treatment with GnRHa resulted in a gain in PAH. Final height results will provide the definite answer on the effectiveness of this combined treatment.     

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.     

Puberty and growth development in patients with a 21-hydroxylase defect

Twenty six females suffering from congenital adrenal hyperplasia due to 21-hydroxylase-deficiency with and without salt wasting were evaluated to determine their growth patterns with special regard to their pubertal growth spurt. 17 patients have been substituted with hydrocortisone 20-25 mg/m2 and if necessary with 9 alpha-fluoro-cortisol 0.025-0.15 mg (group 1), 9 patients have got an additional cyproterone-acetate-therapy during their pubertal development (group 2). Group 1: A pubertal growth spurt was found in 14 females (82.4%) with a peak height velocity of 6.2 +/- 1.6 (SD) cm/yr. At the beginning of puberty the early treated girls showed a progressing retardation of bone age. Therefore the peak height velocity based on advancing bone age was elevated up to 8.7 +/- 1.4 (SD) cm/yr bone age (p = 0.01). Salt wasting (n = 10) did not seem to influence the pubertal growth velocity and the pubertal growth spurt (p = 0.1, p greater than 0.1), but the growth until cessation which was found to be markedly decreased (p less than 0.1). Group 2: Cyproterone-acetate suppressed symptoms of puberty but did not extinguish growth spurt. During 6.3 +/- 1.3 (SD) yrs of treatment bone age advanced only 4.2 +/- 0.7 (SD) yrs. However, in this period height increased by 20.8 +/- 6.4 (SD) cm which corresponds to a mean height velocity of 3.3 +/- 0.8 (SD) cm/yr, and 4.9 +/- 0.8 (SD) cm/yr bone age. Furthermore at puberty peak height velocity results in 4.5 +/- 0.7 (SD) cm/yr and in 10.4 +/- 4.6 (SD) cm/yr bone age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Accelerated versus slowly progressive forms of puberty in girls with precocious and early puberty. Gonadotropin suppressive effect and final height obtained with two different analogs

OBJECTIVES: To distinguish which children with precocious puberty (PP) and early puberty (EP) should be treated and which followed without therapy. To determine the effect of GnRH analog treatment on the final height of treated patients and compare the effect of two different analogs on gonadotropin suppression and final height. STUDY DESIGN: Sixteen females with PP or EP with a mean chronological age (CA) of 8.8 +/- 1.4 years and a mean bone age (BA) of 10.8 +/- 1.3 years were treated for a mean of 2.7 +/- 1.0 years with a GnRH analog (triptorelin or leuprolide acetate; group A), while 21 girls with a mean CA of 8.5 +/- 1.0 years, a mean BA of 9.7 +/- 1.4 years and a predicted adult height of >155 cm were followed without therapy (group B). Criteria for treatment were one of: a. predicted adult height (PAH) of <155 cm initially or at any time during follow up; b. PAH over 155 cm with a dramatic decrease in PAH over a 6-month follow-up period; c. advanced and rapidly progressing breast development for age (Tanner 3 before the age of 9 years). RESULTS: GnRHa therapy suppressed gonadotropins in group A, while gonadotropins increased gradually in group B. Height velocity (HV) decreased in group A, while it remained accelerated in group B; BA increased a mean of 1.7 +/- 0.5 years in group A and 3.2 +/- 0.3 years in group B. This resulted in a height increase in group A from a baseline PAH of 153.7 +/- 1.2 cm to a final height (FH) of 160.9 +/- 4.0 cm (p <0.001), clearly above their target height (TH) of 157.7 +/- 4.2 cm. The height of group B children did not change over time (164.1 +/- 4.1 cm before therapy and 166.0 +/- 6.0 cm at FH), both above their TH. The mean leuprolide acetate dose utilized in this study decreased during treatment, while both the initial and final triptorelin dose remained unchanged. Adequate gonadotropin suppression (peak level of LH and FSH of <2 IU/l after i.v. GnRH stimulation) was noted with both leuprolide acetate and triptorelin, although LH suppression was slightly more pronounced with triptorelin. BA advanced 1.8 +/- 0.4 years during leuprolide acetate treatment and 1.5 +/- 0.3 years with triptorelin, so that FH increased a mean of 5.5 +/- 1.3 cm with leuprolide acetate and 8.7 +/- 2.2 cm with triptorelin. CONCLUSIONS: PAH of <155 cm before or during therapy, PAH of >155 cm with a dramatic decrease in predicted height over a 6-month follow-up period and/or advanced and rapidly progressing breast development in girls with PP or EP were useful parameters in deciding which patients to treat. GnRHa therapy suppressed gonadotropins, HV and bone maturation in children with an accelerated form of PP or EP, resulting in a significant height increase. Final height remained stable over time in untreated patients. Adequate gonadotropin suppression was noted with both analogs, although with the doses of analog used in our study, LH and BA suppression were more pronounced with triptorelin, resulting in a larger height gain.     

Factors influencing final/near-final height in 12 boys with central precocious puberty treated with gonadotrophin-releasing hormone agonists. Italian Study Group of Physiopathology of Puberty

Gonadotrophin-releasing hormone agonists (GnRHa) have been demonstrated as the therapy of choice for central precocious puberty (CPP). Few studies have provided male patients' adult height data. In our multicenter study we evaluated long-term effects of different GnRHa preparations and final/near-final height (FH) in 12 boys with CPP and analyzed the factors influencing FH. Patients' mean chronological age at the time of diagnosis was 7.6 +/- 0.9 yr. Three patients were treated only with triptorelin at a mean dose of 90 microg/kg i.m. every 28 days. Nine patients initially received buserelin (at a mean initial dose of 53.4 microg/kg/day i.n. divided into 3-6 equal doses) or buserelin (at a mean dose of 36.7 microg/kg/day s.c.) and were subsequently switched to triptorelin. The GnRHa therapy was continued for 4.1 +/- 0.6 yr (range 2.9-5.4). The mean predicted adult height increased from 169.9 +/- 4.2 cm at diagnosis to 180.7 +/- 6.0 cm at the end of treatment. Mean FH was 176.1 +/- 6.1 cm (170.1-190.7), corresponding to mean SDS(CA) 0.4 +/- 0.8 (-0.6/2.5), mean SDSBA 0.2 +/- 0.9 (-0.6/2.4) and mean corrected SDS for target height of 0.4 +/- 0.6 (-0.8/1.2). Multiple regression analysis revealed that FH was mainly influenced by target height and height at discontinuation of GnRHa therapy. The present data indicate that GnRHa therapy significantly improves growth prognosis in boys with CPP and fully restores genetic height potential.     

Growth response, pubertal growth and final height in Greek children with growth hormone (GH) deficiency on long-term GH therapy and factors affecting outcome

The growth data of 156 children (100 boys, 56 girls) with growth hormone deficiency (GHD), treated with human growth hormone (GH) for 5.7+/-3.7 years, from 1970-1997, were retrospectively analyzed to assess the efficacy of GH treatment and the factors involved. 62.2% of the studied population had idiopathic GHD (IGHD) and 35.2% had organic GHD (OGHD). At initiation of treatment, chronological age (CA) was 10.1+/-4.0 years in children with IGHD and 9.7+/-4.0 years in those with OGHD, while bone age (BA) was 7.0+/-3.7 and 7.7+/-3.2 years, respectively. The SDS of the growth velocity during the first year of therapy (GV1) was negatively related to CA at start of therapy (r = -0.53, p = 0.01). 109 children have reached final height (FH): 67 boys (FH = 165.3+/-6.3 cm) and 42 girls (FH = 153.9+/-5.4 cm). FH SDS was not significantly different from target height (TH) SDS. In the total group, FH SDS was positively related to height SDS for CA and BA at start of therapy (p = 0.01, p = 0.001, respectively), to TH SDS (r = 0.40, p = 0.001), and to GV1 (r = 0.33, p = 0.001). TH SDS was not different between the IGHD and OGHD groups (-1.02+/-0.8 vs. -0.94+/-6.9). The height gain at puberty did not differ between the groups with induced or spontaneous puberty in boys (23.7+/-8.6 vs. 25.4+/-6.9, not significant), while in girls it was higher in the group with spontaneous puberty (12.7+/-7.3 vs. 20.0+/-9.0, p = 0.008). The age and height at start of puberty was higher in girls and boys with induced puberty. In the total group, the FH SDS of children with induced puberty was higher in comparison with those with spontaneous puberty (-1.0+/-0.8 vs. -1.7+/-0.9, p = 0.001) and it was positively related to the height at start of puberty. When the two sexes were analyzed separately, the difference reached significance only in boys. In conclusion, children with GHD on GH treatment achieved a final height which was comparable to their genetic potential. The FH of children with OGHD was not different from those with IGHD. The age and height at start of puberty were the most significant determining factors for FH. Hence, a better FH might be expected by delaying or arresting puberty.     

Third-generation Aromatase Inhibitor Improved Adult Height in a Japanese Boy with Testotoxicosis

In this study, we report a Japanese boy with testotoxicosis due to a heterozygous mutation [p. A572V] in the LH/CGR gene, who was the first boy treated with a third-generation aromatase inhibitor (AI) and reached his adult height in Japan. He showed accelerated growth and rapid penile growth from 3 yr of age and was diagnosed as having testotoxicosis. Combined treatment with anastrozole and spironolactone was started when he was 7 yr old and 145.8 cm (+4.45 SD) tall, at which point his bone age (BA) was 13.5 yr. His predicted adult height (PAH) was estimated to be 158.3 cm. The combined treatment was continued until he was 13 yr old and 166.5 cm tall, with his BA being 15.5 yr. He reached his adult height of 166.9 cm at 15 yr of age. Combined treatment with anastrozole and spironolactone successfully decelerated BA advancement, prolonged pubertal period and improved adult height.     

Do all girls with apparent idiopathic precocious puberty require gonadotropin-releasing hormone agonist treatment?

OBJECTIVE: To evaluate prospectively pubertal and predicted adult height progression until final height (FH) or near FH in girls with apparent idiopathic precocious puberty who were not treated. STUDY DESIGN: The decision not to treat at the time of initial evaluation was based on evidence of slowly progressive puberty as shown by bone age (BA) advancement <2 years above the chronologic age, whatever the hypothalamic pituitary ovarian axis activation, or no evidence of hypothalamic pituitary ovarian axis activation, whatever the BA advancement. During follow-up, patients who showed a significant decrease in predicted FH were treated with gonadotropin-releasing hormone agonist. RESULTS: Twenty-six girls with idiopathic precocious puberty were studied at a mean chronologic age of 7.4 +/- 0.9 years during a follow-up period of 6.6 +/- 2.2 years until FH or near FH. During the first 2 years of follow-up, most of the patients (group 1, n = 17; 65% of the cases) showed no substantial changes in predicted FH. They never required treatment, and menarche occurred at a mean chronologic age of 11.9 +/- 0.6 years. Their mean FH (or near FH) at 160.7 +/- 5.7 cm was close to their target height (161.3 +/- 4.7 cm). On the other hand, after a mean follow-up period of 1.4 +/- 0.8 years, 9 patients (group 2) had acceleration of bone maturation and deterioration of their predicted FH (from 162.1 +/- 6. 2 cm to 155.3 +/- 5.6 cm; P <.01), which was at that time significantly lower than their target height (P <.05) (mean target height = 159.8 +/- 4.6 cm). They received a gonadotropin-releasing hormone agonist for 2.1 +/- 0.7 years, resulting in a restoration of growth prognosis (mean FH or near FH = 160.2 +/- 6.7 cm). CONCLUSIONS: This study demonstrates that not all patients with apparent idiopathic precocious puberty require medical treatment, notably when there is no evidence of hypothalamo-pituitary ovarian activation or no significantly advanced BA to impair height potential. Most show a slowly progressing puberty. However, careful follow-up of these patients is necessary up to at least 9 years of age, because until then height prediction may deteriorate, necessitating gonadotropin-releasing hormone agonist treatment in one third of the cases.     

Height prognosis of children with true precocious puberty and growth hormone deficiency: effect of combination therapy with gonadotropin releasing hormone agonist and growth hormone.

We evaluated height prognosis and therapeutic efficacy of long-term, combination therapy with gonadotropin releasing-hormone agonist and growth hormone (GH) in five children (three girls) with coexistent precocious puberty and GH deficiency. Their clinical characteristics and growth response were compared with those of 12 girls with idiopathic true precocious puberty and eight prepubertal GH-deficient children (one girl). Precocious GH-deficient subjects were older than the precocious GH-sufficient children (9.5 +/- 1.8 years vs 6.5 +/- 1.3 years; mean +/- SD), but bone ages were comparable (12 +/- 3.7 years vs 10 +/- 0.9 years); their chronologic age was similar to that of the prepubertal GH-deficient children (9.6 +/- 2.1 years), but bone age was significantly more advanced (6.9 +/- 2.3 years). The mean height velocity of the prepubertal GH-deficient children (3.8 +/- 1.5 cm/yr) was lower than that of the precocious GH-deficient subjects (6.7 +/- 1.6 cm/yr) and the precocious GH-sufficient children (9.5 +/- 2.9 cm/yr). Baseline adult height prediction z scores were significantly lower in the precocious GH-deficient children (-3.7 +/- 1.0) than in either the precocious GH-sufficient children (-2.2 +/- 1.0) or the prepubertal GH-deficient subjects (-1.5 +/- 0.8). During therapy with gonadotropin releasing-hormone agonist, growth rates slowed to an average of 3.7 cm/yr in the precocious GH-deficient children but increased after the addition of GH to 7.4 cm during the first year of combination therapy. After 2 to 3 years of combination therapy, height predictions increased an average of 10 cm, compared with an increase of 2.8 cm in the precocious GH-sufficient group treated with gonadotropin releasing-hormone agonist alone. We conclude that combination treatment with gonadotropin releasing-hormone agonist and GH improves the height prognosis of children with coexistent true precocious puberty and GH deficiency, but falls short of achieving normal adult height potential.     

下丘脑-垂体-性腺轴抑制程度对中枢性性早熟女童成年预测身高的影响

目的 研究促性腺激素释放激素类似物(GnRHa)治疗过程中下丘脑-垂体-性腺轴(HPGA)抑制程度与中枢性性早熟(CPP)女童成年预测身高(PAH)的关系,以指导临床个体化调节GnRHa 治疗剂量。方法 收集75 例CPP 女童的临床资料,记录GnRHa 治疗的不同时间点身高、骨龄(BA)、子宫卵巢容积及LH、FSH 峰值、E2 水平,计算各时间点PAH,分析PAH 改善(ΔPAH=PAH-靶身高)的情况及其与HPGA 抑制的关系,并采用阈值效应分析寻找ΔPAH 的最佳HPGA 抑制范围。结果 GnRHa 治疗后PAH 较治疗初期有明显改善。ΔPAH 与ΔBA 呈负相关;治疗24 月时ΔPAH 与LH 呈负相关。将子宫容积控制在2.3~3.0 mL 之间,LH 控制在0.8 IU/L 以下,FSH 控制在2.4 IU/L 以下对延缓BA 的增长及改善PAH 有利。结论 GnRHa 治疗能改善CPP 女童的PAH。选择合适的GnRHa 治疗剂量,将子宫容积、LH、FSH 控制在一定范围内,有利于延缓BA 及改善PAH。     

Short-term therapy with recombinant growth hormone in polytransfused thalassaemia major patients with growth deficiency

Growth failure is commonly described in polytransfused thalassaemia major patients (Th) with or without growth hormone (GH) releasing hormone-GH axis impairment. We have investigated the efficacy of short-term recombinant GH (rhGH) therapy (Saizen [Serono] 0.1 IU/kg/day 6 evenings/week administered s.c. for 12 months) on growth and predicted final height in 28 (19M, 9F) regularly transfused Th with growth deficiency (aged 14.8 +/- 2.0 yr) on long term desferrioxamine s.c. therapy. All Th had no evidence of congestive heart failure, hypothyroidism or impaired glucose tolerance; in all patients the GH peak (evaluated during both insulin and clonidine test) was < or = 20 mIU/l; hypergonadotropic hypogonadism was excluded in Th with delayed puberty. At the start of therapy height age (HA)/bone age (BA) ratio was 0.92 +/- 0.12. Bone age delay was positively correlated to chronological age (CA), serum ferritin levels (mean of the last three years), the age at the start of chelation therapy, growth velocity calculated for CA during the last year; a positive correlation was also found between circulating IGF-I levels and age at the start of chelation therapy. After 1 year on rhGH therapy there was a significant increase of height calculated for CA (not for BA), of growth velocity calculated for both CA and BA and of circulating IGF-I levels; the HA variation/BA variation ratio was 1.85 +/- 1.71, without any significant difference between predicted final height at the start (-1.08 +/- 1.28 SDS) and at the end of rhGH therapy (-0.88 +/- 1.13). The variation of height calculated for CA was positively correlated to both CA and growth velocity during the last year before rhGH therapy (calculated for CA) and negatively to the height at the start (calculated for CA). There were no side effects and haematological parameters did not show significant changes. In conclusion, our data, obtained in a relatively large group of Th, confirm the emerging results of short-term (12 months) rhGH therapy on growth, as shown by the increase of both growth velocity and height calculated for CA. With regard to final height, although the mean variation of HA/variation of BA ratio was 1.85, no significant increase of the predicted final height was found between the start and the end of rhGH therapy. We are evaluating the effect of long-term rhGH therapy on growth in these patients.