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.     

Luteinizing hormone-releasing hormone analogue (Buserelin) treatment for central precocious puberty: A multi-centre trial

Abstract A multi-centre open trial of Buserelin, a luteinizing hormone-releasing hormone (LHRH) analogue, was conducted in 13 children with central precocious puberty. Eleven children (eight girls and three boys), aged 3.4–10.2 years at commencement, completed the required 12 month period of treatment. Initially all patients received the drug by intranasal spray in a dose of 1200 μg/day, but by the end of the 12 month period two were having daily subcutaneous injections and three were receiving an increased dose intranasally. The first month of treatment was associated in one boy with increased aggression and masturbation, and in the girls with an increase in the prevalence of vaginal bleeding. Thereafter, however, both behavioural abnormalities and menstruation were suppressed. Median bone age increased significantly during the study, but without any significant change in the ratio of height age to bone age. The median predicted adult height for the group therefore did not alter significantly over the twelve months of the study. Buserelin treatment caused a reduction in the peak luteinizing hormone and follicle-stimulating hormone (FSH) responses to LHRH, mostly to prepubertal levels, and also suppressed basal FSH. In the first weeks of treatment, the girls' serum oestradiol levels rose significantly and then fell to prepubertal or early pubertal levels. A similar pattern was seen for serum testosterone levels. Serum somatomedin-C levels, however, showed little fluctuation over the course of the study. Buserelin treatment was safe and well accepted, and offers the promise of improved linear growth potential in precocious puberty.     

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。     

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.     

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.     

Growth, growth hormone and sex steroid secretion in girls with central precocious puberty treated with a gonadotrophin releasing hormone (GnRH) analogue

We have treated 14 girls with central precocious puberty for a mean period of 2.3 years (range, 0.5-3.9) with intranasal (D-Ser6) GnRH analogue administered in a mean dose of 28 micrograms/kg/day (range, 15-56). With the onset of treatment there was an initial increase in sitting height compared to subischial leg length, but overall there was no significant change in height standard deviation score for bone age. In this respect our results were indistinguishable from untreated children with central precocious puberty. There was a decrease in physiological GH secretion, associated with decreased sex steroid secretion, which probably accounts for the growth deceleration which has been described during GnRH analogue therapy. The effect of this growth deceleration combined with slowing of the rate of epiphyseal maturation may explain the absence of alteration in height prognosis.     

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.     

Near final height after GnRH agonist treatment in central precocious puberty

The impact of treatment of central precocious puberty (CPP) with gonadotropin-releasing hormone agonists (GnRHa) on final height remains controversial. We analyzed the long term results of 23 girls with CPP treated with triptorelin or leuprolide. Their "near final height" (NFH) assessed at a bone age of at least 14 years and expressed as SDS, was compared either with predicted height before treatment (PAH) or with parental height (TH). We also compared NFH of 12 girls treated before 8 years of age (7.0 +/- 0.5 yr) with NFH of 11 girls treated after 8 years old (8.5 +/- 0.3 yr). The NFH of the 23 girls (-0.9 +/- 1.0 SDS) was not different either from PAH (-0.85 +/- 1.5 SDS) or from TH (-0.5 +/0.6 SDS). Earlier treated girls reached a NFH (-0.97 +/- 1.0 SDS) not different from later treated girls (-0.91 +/- 1.0 SDS; p = ns) and both groups reached parental height (NFH - TH = -0.44 +/- 1 and -0.09 +/- 0.83 SDS, respectively). In conclusion, our patients, treated either earlier or later, reached a near final height comparable to predicted height and familial target; however, these results might still improve further because the girls have not yet reached their final adult height.     

Leptin concentrations in precocious puberty or untimely puberty with and without GnRH analogue therapy

Nutritional status and body composition influence the development and maintenance of reproductive competence in mammals. It has been suggested that leptin concentrations communicate nutritional status to the neuroendocrine reproductive axis. To determine the interrelationship between circulating gonadotropin and leptin concentrations, leptin concentrations were measured in 39 children treated for GnRH dependent precocious or untimely puberty. Leptin concentrations were obtained during pubertal suppression with GnRH analogue therapy and during spontaneous pubertal gonadotropin secretion. The status of gonadotropin secretion (suppressed vs not suppressed) was verified by simultaneous GnRH stimulation tests and sex steroid concentrations. Leptin concentrations were similar at both time-points and correlated only with body mass index. Thus, no relationship was apparent between circulating concentrations of gonadotropins, sex steroids, and leptin.     

Efficacy of Zoladex LA (goserelin) in the treatment of girls with central precocious or early puberty

OBJECTIVE: To assess the efficacy of a longer acting preparation of the gonadotrophin releasing hormone (GnRH) analogue goserelin (Zoladex LA, 10.8 mg) in 12 girls with central precocious or early puberty. METHODS: Two girls started treatment de novo; the remainder had been on suppressive treatment for a median duration of 1.5 (range, 0.2-5.6) years. Assessment comprising auxology, pubertal staging, and pelvic ultrasound examination was carried out at weeks 0, 4, 8, 10, and 12 (first cycle) and weeks 8, 10, and 12 (second cycle) to evaluate the required injection frequency. Thereafter, assessment was performed on the day of injection. Zoladex LA was given every 12 weeks unless pubertal progression occurred. RESULTS: Satisfactory control was achieved in eight patients using this regimen, and three patients required more frequent injections. One girl was removed from the study because of clinical progression and extreme mood swings. No serious adverse effects occurred. Mean height velocity during the study period was 4.5 cm/year (range, 3.1-6.6) compared with 6.5 cm/year (range, 3.8-9.6) before treatment in nine patients for whom data were available. CONCLUSIONS: Zoladex LA was effective in controlling precocious puberty in girls when given at intervals of 9-12 weeks and it is recommended that an initial assessment is made eight weeks after beginning treatment.     

Treatment of precocious puberty using an intranasal luteinizing hormone-releasing hormone analogue: Buserelin

Abstract Fourteen patients with precocious puberty were treated for 1-3 years with 900-1800 μg/day of intranasal (i.n.) Buserelin. The peak luteinizing hormone and follicle-stimulating hormone responses to intravenous luteinizing hormone-releasing hormone were reduced significantly 4 weeks after starting treatment and remained suppressed while the patients were on treatment. Two patients were withdrawn because of drug non-compliance. Three patients showed regression of pubertal changes, four patients showed no progression and five patients showed progression of breast size or pubic hair staging after 1.5-2 years of treatment.
Treatment was changed to the subcutaneous route in two patients because of hormonal escape and accelerated skeletal maturation. The mean growth velocity decreased from 10.78 cm/year (s.e.m. = 0.64) to 7.06 cm/year (s.e.m. = 0.85) after 1 year of treatment ( P < 0.005). After an increase in dosage (from 900 μg/day to 1800 μg/day) in most patients, further significant falls in growth velocity to 5.29 cm/year (s.e.m. = 0.45), 4.63 cm/year (s.e.m. = 0.8) and 5.06 cm/year (s.e.m. = 0.5) were observed at 18, 24 and 30 months, respectively, compared with the pretreatment value ( P < 0.001). With treatment, the increased rate of skeletal maturation normalized. In 10 patients who had completed 2 years of treatment, the height standard deviation score for bone age improved from a pretreatment value of -2.42 ± 0.42 to -1.6 ± 0.42 after 2 years of treatment ( P < 0.01), indicating an improvement in height prognosis. It is concluded that i.n. Buserelin at a dose of 1800 μg/day is effective in the treatment of most but not all patients with precocious puberty.     

Treatment of precocious puberty using an intranasal luteinizing hormone-releasing hormone analogue: Buserelin

Fourteen patients with precocious puberty were treated for 1-3 years with 900-1800 micrograms/day of intranasal (i.n.) Buserelin. The peak luteinizing hormone and follicle-stimulating hormone responses to intravenous luteinizing hormone-releasing hormone were reduced significantly 4 weeks after starting treatment and remained suppressed while the patients were on treatment. Two patients were withdrawn because of drug non-compliance. Three patients showed regression of pubertal changes, four patients showed no progression and five patients showed progression of breast size or pubic hair staging after 1.5-2 years of treatment. Treatment was changed to the subcutaneous route in two patients because of hormonal escape and accelerated skeletal maturation. The mean growth velocity decreased from 10.78 cm/year (s.e.m. = 0.64) to 7.06 cm/year (s.e.m. = 0.85) after 1 year of treatment (P less than 0.005). After an increase in dosage (from 900 micrograms/day to 1800 micrograms/day) in most patients, further significant falls in growth velocity to 5.29 cm/year (s.e.m. = 0.45), 4.63 cm/year (s.e.m. = 0.8) and 5.06 cm/year (s.e.m. = 0.5) were observed at 18, 24 and 30 months, respectively, compared with the pretreatment value (P less than 0.001). With treatment, the increased rate of skeletal maturation normalized. In 10 patients who had completed 2 years of treatment, the height standard deviation score for bone age improved from a pretreatment value of -2.42 +/- 0.42 to -1.6 +/- 0.42 after 2 years of treatment (P less than 0.01), indicating an improvement in height prognosis. It is concluded that i.n. Buserelin at a dose of 1800 micrograms/day is effective in the treatment of most but not all patients with precocious puberty.     

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。     

Idiopathic central precocious puberty in girls: presentation factors

Background  

It is sometimes difficult to distinguish between premature thelarche and precocious puberty in girls who develop breasts before the age of 8 years. We evaluated the frequencies of the signs associated with breast development and the factors influencing the presentation of girls with idiopathic central precocious puberty (CPP).     

Long-term treatment of central precocious puberty with an intranasal LHRH analogue: control of pituitary function by urinary gonadotropins

Daily subcutaneous doses of luteinizing hormonereleasing hormone (LHRH) analogues are a well-established therapy for gonadotropin-dependent precocious puberty. Reports on intranasally administered analogues, however, are controversial. We studied the effect of intranasal d-Ser (TBU)⁶-LHRH (BUS) on growth rate, skeletal maturation, and urinary gonadotropins in five girls and one boy with central precocious puberty (CPP) who had been treated for 1.4–2.3 years (mean 1.9). Because of the potential antifertility effects of LHRH analogues, testicular histology was analysed in the boy. In the five children with accelerated growth, the bone age-related velocity of heigh gain decreased from 10.58 ±2.77 to 5.82±1.8 cm/year (means±SD, P<0.01), and the ratio of change in bone age to change in chronological age fell below 1. Basal luteinizing hormone (LH), and LHRH-stimulated LH and follicle stimulating-hormone, at pubertal levels before treatment, decreased significantly in all children, normalizing in four (P<0.04). During therapy, pituitary function was best controlled by urinary LH, which correlated with clinical data. After 13 months of therapy, testicular histology showed degenerated Sertoli cells, and absence of B-and Ap-spermatogonia and of primary spermatocytes in the boy. We conclude that: (1) Efficient long-term suppression of central precocious puberty — including accelerated growth and skeletal maturation — can be maintained by intranasal dosage of BUS. (2) Urinary LH reflects pituitary function and proves to be a reliable guide to adjustment of the LHRH-analogue dose regimen. (3) Testicular atrophy after 1 year of continuous therapy with high doses of BUS raises the question of potential infertility in boys with precocious puberty treated with potent analogues of the LHRH.Abbreviations CPP central precocious puberty - LH luteinizing hormone - FSH tollicle-stimulating hormone - LHRH luteinizing hormone-releasing hormone - LHRH_A LHRH analogue - BUS the analogue d-Ser[TBU]⁶-LHRH (Buserelin), HOE 766) - BA bone age - BA/ CA ratio of change in bone age to change in chronological age - SDS standard deviation score - T urinary testosterone - E2 urinary oestradiol