Long-term results of GnRH analogue (Buserelin) treatment in girls with central precocious puberty

The GnRH analogue Buserelin was given for one year to six girls with central precocious puberty in a daily subcutaneous dose of 20 micrograms/kg/day. A decrease of plasma estradiol and vaginal maturation index to prepubertal values was obtained in 5 out of 6 cases. Bone maturation decreased and final predicted adult height improved significantly. This analogue of GnRH appears to be an effective medication for gonadotropin dependent precocious puberty in girls.     

Predictive factors for the effect of gonadotrophin releasing hormone analogue therapy on the height of girls with idiopathic central precocious puberty

The factors influencing the final height of central precocious puberty patients treated with gonadotrophin releasing hormone (GnRH) analogues remain a critical issue. This study compares the predicted final height before and after GnRH analogue therapy to identify predictive factors for final height. Fourteen girls with idiopathic central precocious puberty were treated with a GnRH analogue. All had an active non-regressive form before therapy, full and permanent suppression of oestrogenic activity during therapy (duration >2 years, 3.1±0.3 years, mean ±SEM), and the pubertal pituitary-ovarian axis had normalized in all of them 1 year after the cessation of therapy. The mean predicted final height increased from 152±1.8 cm before therapy to 162.2±1.2 cm (P<0.01) at the last evaluation performed 4.5±0.3 years after the onset of therapy. The mean gain in predicted final height between the onset of therapy and the last evaluation was 10.2±1.1 cm. It was correlated with the following data recorded at the onset of therapy: bone age advance over chronological age (r=0.66,P<0.02), predicted final height at the onset of therapy (r=–0.76,P<0.001), and the difference between the target height and the predicted height at onset of therapy (r=0.76,P<0.001). We conclude that GnRH analogue therapy is more likely to improve final height prognosis in girls who initially present with a markedly advanced bone age and a great difference between their target and predicted heights. Both these parameters reflect the severity of the disease at diagnosis.This work was presented in part at the international symposium on GnRH analogues in cancer and human reproduction, Geneva, November 1990. Abstract, Gynecol Endocrinol 4 [Suppl 2]:101 (1990)     

Weight evolution in girls treated for idiopathic central precocious puberty with GnRH analogues

Data concerning the effects of GnRHa on weight gain are scarce. OBJECTIVE: To assess the variation of the body mass index (BMI) in girls during GnRHa treatment for idiopathic central precocious puberty (CPP). PATIENTS AND METHODS: Semestral anthropometric data from 176 girls treated with goserelin or leuprorelin were analyzed. RESULTS: BMI z-score increased from 1.5 +/- 0.1 SD before treatment (n = 176) to 1.7 +/- 0.2 SD after 24 months (n = 61, p = 0.008). In girls with normal weight before treatment, this variation was greater (n = 112, 0.2 +/- 0.1 SD, p = 0.01) than in those who were overweight (n = 63, -0.9 +/- 0.2 SD, p = 0.7). In the goserelin group the weight change adjusted for bone age was greater (n = 28, 0.4 +/- 0.1 SD) than in the leuprorelin group (n = 5, 0.04 +/- 0.1 SD, p = 0.05). CONCLUSIONS: A slight increase in BMI was noted, mainly in girls with normal weight before treatment. The influence of different GnRHa on weight must be further investigated.     

促性腺激素释放激素类似物联合重组人生长激素对中枢性性早熟女童身高的影响

目的 研究促性腺激素释放激素类似物（GnRHa）与重组人生长激素（rhGh）联合治疗以及GnRHa单用对骨龄≥10岁的特发性中枢性性早熟（ICPP）女童成年身高的改善情况。方法 将6个医学中心确诊为ICPP符合研究条件的80例女童（年龄9.0±0.7岁,骨龄≥10岁）根据治疗方法分为GnRHa与rhGh联合治疗组（31例）及GnRHa单用组（49例）。观察治疗前后的预测成年身高、接近成年身高和身高净获等各项指标的变化。结果 两组在治疗后按骨龄的身高标准差分值均较治疗前有显著改善（P<0.01）,其中GnRHa与rhGh联合治疗组明显优于GnRHa单用组（P<0.01）。联合用药组接近成年身高（157±6 cm vs 157±4 cm）、身高净获（4.68 cm vs 3.89 cm）、停药时预测成年身高（161±5 cm vs 158±5 cm）、接近成年身高与遗传靶身高差值等指标均略高于GnRHa单用组,但差异无统计学意义（均P >0.05）。结论 GnRHa与rhGh联合治疗或GnRHa单用组均能改善骨龄≥10岁ICCP女童的成年身高,但两药联用优势不明显。对ICPP患儿预测成年身高的评估需要慎重,停药时的预测值偏高。     

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.     

GnRHa治疗女性中枢性性早熟疗效及不良反应观察

目的观察促性腺激素释放激素类似物(GnRHa)治疗特发性中枢性性早熟对改善患者终身高的确切疗效,探讨GnRHa治疗的不良反应。方法23例女性特发性中枢性性早熟(ICPP)终止GnRHa治疗后随访(45.0±14.2)个月,观察终身高、月经初潮时间、月经规则程度、体质指数(BMI),比较了G-P图谱、TW3和身高曲线图三种方法预测终身高的精确度。结果GnRHa治疗(24.3±13.1)个月,平均终身高为(160.3±4.2)cm,与靶身高比较,从治疗前预测身高-1.58±2.02SD增加到-0.01±1.53SD。停止治疗后(11.5±5.5)个月出现或复现月经初潮,月经周期均规则。达终身高时BMI为20.81±2.08。停止治疗时G-P图谱和TW3预测值与实际终身高比较差异无统计学意义,均明显高于曲线法的预测值。结论GnRHa治疗ICPP能有效改善终身高,经随访无不良反应。     

Treatment of central precocious puberty with an intranasal analogue of GnRH (Buserelin)

One boy and 13 girls with central precocious puberty were treated for 1 year using Buserelin, a GnRH analogue, given intranasally (0.3 mg, four times a day). After 1, 3 and 12 months of therapy, the gonadotropin responses to GnRH were abolished in all the patients whereas mean basal serum concentrations of luteinizing hormone (LH) remained similar to those of pubertal controls. During Buserelin treatment, genital development in the boy and breast development in the girls showed no further progress or some regression. In the boy, serum testosterone levels returned to prepubertal values. In the girls, serum oestradiol levels were variable and, in four of them, vaginal smears showed the persistence of a slight oestrogenic effect during therapy. Pelvic ultrasonography did not show any significant variation in ovarian and uterine lengths. Among the 14 patients, 3 had some progression of pubic hair development, irrespective of serum dehydroepiandrosterone sulphate (DHEAS) levels. In eight patients previously treated with cyproterone, elevated prolactin levels were observed before and during the first month of Buserelin administration. During treatment, mean height velocity was markedly reduced from 11.6 to 6.1 cm/year and mean bone age velocity (±1 SD) was 0.85±0.38 year/year. After 1 year of treatment, the differences in predicted adult height ranged between −0.74 and +1.04 SDS (standard deviation score). These differences were inversely related (r=−0.72) to the prognosis of adult height calculated before treatment. We conclude that, in central precocious puberty, intranasal administration of Buserelin, 1.2 mg/day, may arrest sexual development and reduce height velocity and bone maturation. Improvement of adult height prognosis may occur, especially when it was markedly impaired before treatment.     

醋酸亮丙瑞林缓释剂对中枢性性早熟女童生长和成年终身高预测的影响

目的：观察醋酸亮丙瑞林缓释剂(GnRH a)对中枢性性早熟女童生长和成年终身高指标的影响。方法：对13例中枢性性早熟女童给予GnRH a 50～80 μg/kg,4周注射1次,治疗6～15个月(平均治疗9.6个月)+适量有氧运动和/或生长激素(r hGh)。对比治疗前后身高、骨龄、预测身高及促黄体生成素(LH),雌二醇(E2)促卵泡激素(FSH)等指标变化。结果：身高由(137.64±9.35) cm增至(148.0±6.1) cm (P0.05)。最高身高预测值从(149.53±4.66) cm增至(157.2±1.98) cm (P<0.01)。LH,FSH较治疗前明显降低(P<0.05)。结论：GnRH a可明显抑制第二性征发育使骨龄的生长延缓,辅以适量的有氧运动和/或r hGh,能有效改善终身高。     

Long-acting GnRH analogue triptorelin therapy in central isosexual precocious puberty

OBJECTIVE: To evaluate the efficacy of long acting GnRH analogue in improving the auxological outcome of patients with central isosexual precocious puberty (CIPP) and to determine the factors influencing the response. METHODS: Thirty-five patients (30 girls, 5 boys) with CIPP were treated with a long acting GnRH analogue, triptorelin. Final height outcomes and factors affecting treatment were analyzed. RESULTS: Treatment was started at the chronological age (CA) of 6.5 1.8 years in girls and 4.4 1.5 years in boys and continued for a period of 3.7 1.8 years in girls and 6 1.8 years in boys. Follow-up period after discontinuation of treatment was 2.2 0.5 years in girls and 2.6 0.3 years in boys. Treatment led to regression of precocious puberty and reversal of secondary sexual characteristics. There was decline in growth rate reflected by a fall in heightSD of 0.8 0.8 in girls and 2.3 0.9 in boys (p = 0.014), an even greater retardation in bone age (BA) advancement with a decrease in BA-CA of 1.7 1 years in girls and 2.7 1 years in boys and a fall in heightSDBA of 1.5 1.1 in girls and 2.1 1.6 in boys. Final height (149.8 6.9 cm in girls and 161.9 3.9 cm in boys) exceeded projected height at the onset of treatment (143.4 8.3 cm in girls and 154.3 2.7 cm in boys) by 6.4 2.4 cm in girls and 7.6 1.5 cm in boys ( p < 0.001 in both the groups). Factors influencing height gain included age at start of therapy (r = 0.715), BA-CA at the time of initiation of treatment (r = 0.734), heightSDBA at the onset of treatment ( r = 0.566) and the duration of treatment (r = 0.711). Girls treated at an age of less than 6 years (n = 9) had a greater height gain (8.7 1.6 cm versus 5.3 1.9 cm, p < 0.001) and achieved similar final height (148.7 8 cm versus 150.2 6.6 cm) in those treated after this age (n = 21). No side effects of GnRH therapy were observed in the study. CONCLUSION: Long acting GnRH therapy is effective in improving the auxological outcome of patients with CIPP. Maximum benefit is observed in girls with greater bone age advancement treated at a younger age and for a longer duration of treatment. These girls had lower bone age advance at discontinuation of treatment.     

Hormonal changes during GnRH analogue therapy in children with central precocious puberty

Gonadotropin releasing hormone analogues (GnRHa) have been used for treatment of central precocious puberty (CPP) for more than 15 years. They are generally considered safe although data on potential long-term side effects are scarce. However, GnRHa therapy has profound effects on both the hypothalamopituitary-gonadal axis as well as on growth hormone (GH) secretion. Gonadal activity is increased in children with CPP; during GnRHa therapy secretion of gonadal hormones is suppressed as reflected by measurements of LH, FSH, and estradiol/testosterone. More recently, studies of levels of inhibin A and B as well as markers of androgen action such as SHBG and prostate specific antigen have demonstrated marked suppression of gonadal function possibly to infra-physiological levels. The possible long-term consequences of these observations have yet to be determined. Detailed analyses of the GH-IGF-I axis have revealed a decrease in levels of free, biologically active IGF-I during GnRHa treatment. These findings are in accord with the observed decrease in height velocity in children with CPP under treatment with GnRHa, and may also play a role in the relatively small gain in final height in most patients.     

正常青春期少女及特发性中枢性性早熟女孩生长激素结合蛋白、性激素与生长

本文对41例青春期女孩及30例特发性中枢性性早熟(ICPP)女孩。观察其身高、体重、身高增长速度、骨龄与生长激素结合蛋白(GHBP)、雌二醇(E_2)的相关关系,结果示GHBP在青春各期间无显著差异,GHBP与身高生长速度(GV)、身高标准差分(HtsDs)、体重指数(BMI)呈正相关,GHBP与E_2、年龄(CA)、骨龄(BA)无相关关系。正常青春少女与ICPP女孩相应青春期血清GHBP无明显差异,ICPP女孩GHBP与HtsDs及BMI呈正相关关系,与E_2、CA及BA无相关关系。提示正常青春少女及ICPP女孩的生长,在GH轴调控途径上,至少在生长激素受体(GHR)/GHBP水平是相同的。GHBP受营养的正性影响,不受年龄、骨龄影响。     

Reversible inhibition of central precocious puberty with a long acting GnRH analogue.

A 7 year old girl with precocious puberty was treated with buserelin, a long acting analogue of gonadotrophin releasing hormone. Spontaneous and stimulated gonadotrophin secretion became prepubertal but returned to pubertal values when buserelin was withdrawn, suggesting that normal sexual maturation should follow cessation of treatment.     

促性腺激素释放激素类似物(曲普瑞林)治疗女童特发性中枢性性早熟23例疗效观察

目的观察促性腺激素释放激素类似物(曲普瑞林)治疗女童特发性中枢性性早熟(ICPP)的临床疗效。方法应用曲普瑞林治疗23例ICPP女童6个月,观察治疗前后第二性征、子宫、卵巢、骨龄(BA)、血清雌二醇(E2)、促性腺激素释放激素(GnRH)激发试验激素水平、预测成人终身高的变化及药物副反应。结果治疗后患儿乳房、子宫、卵巢体积均有缩小,E2、促黄体生成激素(LH)、卵泡刺激素(FSH)峰值均显著降低,骨龄成熟延迟,骨龄/实际生活年龄(BA/CA)值下降,预测成人终身高治疗前为(155.5±0.81)cm,治疗后为(157.0±0.81)cm,较治疗前有改善,差异具有统计学意义(P<0.01)。结论曲普瑞林治疗ICPP能够抑制性腺轴及性腺发育,延缓BA成熟,最终对改善成人终身高有意义。     

Final height after combined growth hormone and GnRH analogue treatment in adopted girls with early puberty

Background: Girls adopted from developing countries often have early or precocious puberty, requiring treatment with gonadotrophin-releasing hormone (GnRH) analogues. During such treatment, decreased growth velocity is frequent. Aim: To study whether the addition of growth hormone (GH) to GnRH analogue treatment improves final height in girls with early or precocious puberty. Methods: Forty-six girls with early or precocious puberty (age ≤9.5 y) adopted from developing countries were randomized for treatment for 2-4 y with GnRH analogue, or with a combination of GH and GnRH analogue. Results: During treatment, the mean growth velocity in the GH/GnRH analogue group was significantly higher compared to the control group. Combined GH/GnRH analogue treatment resulted in a higher final height: 158.9 cm compared to 155.8 cm in the GnRH analogue-treated group. Three out of 24 girls (13%) in the combined group and nine of the 22 girls (41%) treated with GnRH analogue alone attained a final height below -2 standard deviation scores (SDS).

Conclusion: The difference between the two groups is statistically significant, and possibly of clinical importance. A future challenge is to identify a subgroup with clinically significant advantage of GH addition to GnRH analogue treatment. Being very short on arrival in Sweden and being short and young at start of treatment are possible indicators.     

联合应用促性腺激素类似物和生长激素治疗女性初潮后特发性中枢性性早熟

我们于2001年7月—2004年7月对一组就诊时已有月经初潮、具有严重生长潜能受损的特发性中枢性性早熟（ICPP）患儿,联合应用促性腺激素类似物（GnRHa）和生长激素（GH）治疗,观察其对身高增长和预测成年身高的影响。     

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.     

The effect of gonadotrophin releasing hormone analogue on height prognosis in growth hormone deficiency and normal puberty

We have treated seven pubertal children, five (three female, two male) with growth hormone deficiency and two (one female, one male) with constitutional short stature with intranasal (D-Serine⁶) gonadotrophin releasing hormone (GnRH) analogue (Buserelin) for a mean of 0.84 years (range, 0.5–1.3). Treatment was successful in arresting pubertal development but there was no improvement in final height prognosis.Abbreviations GnRH gonadotrophin releasing hormone - GH growth hormone     

Effect of combined treatment with gonadotropin releasing hormone analogue and growth hormone in patients with central precocious puberty who had subnormal growth velocity and impaired height prognosis

Growth hormone-insulin-like growth factor-I status and response to growth hormone therapy (0.6 IU/kg/week sc, six times a week for 12 months) were evaluated in 12 girls (chronological age 9.4 ± 1.6 years) suffering from central precocious puberty with growth velocity less than 4 cm/year and no substantial increase or decrease in predicted adult height during gonadotropin releasing hormone (Gn-RH) analogue treatment (D-Trp⁶-LH-RH, 60 μg/kg im/28 days). At baseline, large variations were observed in nocturnal growth hormone (GH) means (pathological values (< 3.6μg/l) 33.3%), stimulated levodopa GH peaks (pathological values (<10.0 μg/I) 28.6%) and serum insulin-like growth factor-I (IGF-I) levels. Neither GH nor IGF-I levels were correlated with growth velocity. During recombinant GH therapy, growth velocity increased significantly (baseline 3.0 ± 0.9 cm/year; 6 months 6.4 ± 1.9cm/year, p < 0.001 versus baseline; 12 months 6.0 ± 1.3cm/year, p < 0.001 versus baseline). There was a significant increase in height SDS for bone age (baseline –1.6 ±0.5 SDS; 12 months -1.04 ± 0.6SDS; p < 0.002) and in predicted adult height (baseline 152.0 ± 3.6cm; 12 months 155.9 ± 3.4cm; p < 0.002). Our results suggest that combined therapy with Gn-RH analogues and recombinant GH can improve growth velocity and predicted adult height in girls with central precocious puberty and impaired height prognosis during Gn-RH analogue treatment.     

Reduction of bone density: An effect of gonadotropin releasing hormone analogue treatment in central precocious puberty

Gonadal steroids drive the significant bone mineral increase that occurs at puberty. Oestrogen deprivation in women results in bone loss. We investigated bone mineralization by single photon absorptiometry in girls with central precocious puberty (n=13, age 3.8–8.5 years) before and during 1 year of treatment with gonadotropin releasing hormone analogue (GnRH-a=longacting D-Trp⁶-GnRH, 60 g i.m. every 28 days). Before GnRH-a therapy, bone mineral density (BMD) was significantly higher in patients than in ten control girls matched for chronological age (patients 0.575±0.097 g/cm², controls 0.433±0.049 g/cm²,P<0.001). Patient BMD was not significantly different from that of ten control girls matched according to patient bone age (0.550±0.046 g/cm²,P=NS). During GnRH-a treatment, pituitary-gonadal axis was suppressed and patient BMD significantly decreased (6 months: –6.0%,P<0.002 vs baseline; 12 months: –8.0%,P<0.001 vs baseline). We conclade that in girls with precocious puberty the activation of gonadal steroid secretion induces an increase in bone mineralization and that oestrogen deprivation by GnRH-a treatment caused a significant decrease in BMD.