Clinical and laboratory parameters of gonadotropin-releasing hormone analog treatment effectiveness in children with precocious puberty

OBJECTIVE: There are no doubts about the clinical benefits of treatment with GnRH analogs for patients diagnosed with central precocious puberty (CPP). However, laboratory monitoring of CPP is still a matter of considerable controversy in the literature. Therefore, the main objective of this study was to evaluate the cut-off values of stimulated LH that determine gonadotrophic suppression. METHODS: Twenty-four girls, on treatment with leuprorelin acetate (LA) at 3.75 mg IM every 28 days, were studied. The clinical parameters used to indicate clinical effectiveness were regression or maintenance of sexual characteristics according to the Tanner stage, growth velocity reduction, reduction or maintenance of the difference between bone age and chronological age and maintenance or improvement of the final height prediction. For the laboratory effectiveness test, basal estradiol, LH, and FSH levels were collected before and 1 and 2 h after the administration of 3.75 mg LA. RESULTS: Eleven girls showed improvement in all clinical parameters, and their effectiveness tests were compared to those of the other patients to calculate the cut-off values, which were ≤3.64 IU/L (p=0.004*) for LH after 1 h and ≤6.10 IU/L (p<0.001*) for LH after 2 h. CONCLUSION: The LH response after the LA stimulation test, associated with clinical data and within a context of CPP, constitutes a reliable and feasible resource and can assist in monitoring the effectiveness of treatment.

Advanced bone age as an indicator facilitates the diagnosis of precocious puberty / Idade óssea avançada como um indicador de facilitação do diagnóstico de puberdade precoce

Abstract Objective: Diagnosis of central precocious puberty has always been challenging in clinical practice. As an important method in the diagnosis of central precocious puberty, luteinizing hormone-releasing hormone stimulation test is complex and time-consuming. In many cases, clinical traits are inconsistent with luteinizing hormone-releasing hormone stimulation test results, therefore not reliable for diagnosis. In this study, the authors intended to find an indicator that predicts the results of the luteinizing hormone-releasing hormone stimulation test among subjects with early pubertal signs. Methods: Cases of 382 girls with early breast development before 8 years old and luteinizing hormone-releasing hormone stimulation test before 9 years old were included and underwent follow-up tests. Patients with peak luteinizing hormone level ≥5 IU/L were considered positive in the luteinizing hormone-releasing hormone stimulation test. Anthropometric data, body mass index, bone age evaluation, blood hormones levels of luteinizing hormone, estradiol, follicle-stimulating hormone, and uterine and ovarian volumes were analyzed. Results: Subjects with positive results in the initial test demonstrated early bone maturation, accelerated growth, and elevated basal blood luteinizing hormone, estradiol, and follicle-stimulating hormone levels, when compared with subjects with negative results in the initial test. Subjects with positive results in the follow-up test presented a more advanced bone age and more accelerated linear growth, when compared with subjects with negative results in the follow-up test. Conclusions: According to the statistical analysis, advanced bone age is the most effective predictor of the result of luteinizing hormone-releasing hormone stimulation test.

Resumo Objetivo: O diagnóstico da puberdade precoce central sempre foi complicado na prática clínica. Como um importante método no diagnóstico de puberdade precoce central, o teste de estimulação do hormônio liberador do hormônio luteinizante é complexo e demorado. Em muitos casos, as características clínicas são incompatíveis com os resultados do teste de estimulação do hormônio liberador do hormônio luteinizante e, assim, não são confiáveis para o diagnóstico. Neste estudo, visamos constatar um indicador que previsse os resultados do teste de estimulação do hormônio liberador do hormônio luteinizante entre indivíduos com sinais puberais precoces. Métodos: Foram incluídos casos de 382 meninas com desenvolvimento precoce das mamas antes dos 8 anos de idade e teste de estimulação do hormônio liberador do hormônio luteinizanteantes dos 9 anos e elas foram submetidas a testes de acompanhamento. Os resultados das pacientes com nível máximo de hormônio luteinizante ≥ 5 IU/L foram consideradas positivos no teste de estimulação do hormônio liberador do hormônio luteinizante. Foi feita uma análise dos dados antropométricos, do índice de massa corporal, da avaliação da idade óssea, dos níveis sanguíneos de hormônio luteinizante, volumes uterinos e ovarianos de estradiol (E2) e do hormônio folículo-estimulante. Resultados: Os indivíduos com resultado positive no teste inicial demonstraram maturação precoce do osso, crescimento acelerado e níveis sanguíneos elevados de hormônio luteinizante, estradiol e hormônio folículo-estimulante, em comparação aos indivíduos com resultados negativos no teste inicial. Os indivíduos com resultados positivos no teste de acompanhamento apresentaram um maior avanço na idade óssea e crescimento linear mais acelerado, em comparação aos indivíduos com resultados negativos no teste de acompanhamento. Conclusões: De acordo com a análise estatística, a idade óssea avançada é o indicador mais efetivo do resultado do teste de estimulação do hormônio liberador do hormônio luteinizante.

Pubertad precoz y temprana: evaluación y tratamiento / Early puberty: evaluation and treatment

El autor de este artículo repasa las características clínicas de la pubertad precoz y la pubertad temprana, las pruebas diagnósticas indicadas en la evaluación de los pacientes que la presentan y las recomendaciones actuales de tratamiento. (AU)

The author of this article reviews the clinical features of early puberty, the diagnostic tests for the patients ́ evaluation andthe current treatment recommendations. (AU)

Evaluation of central precocious puberty treatment with GnRH analogue at the Triangulo Mineiro Federal University (UFTM)

Objective To report our experience of treating central precocious puberty (CPP) with a GnRH analogue with respect to the final heights (FH) attained in patients who completed treatment. Subjects and methods Among 105 records of children diagnosed with precocious puberty, 62 cases (54 girls and 8 boys), who were treated with leuprolide acetate/3.75 mg/monthly, were selected, and divided into 4 groups: group 1 (G1), 25 girls who attained FH; group 2 (G2), 18 girls who completed treatment but did not reach FH; group 3 (G3), 11 girls still under treatment; and group 4 (G4), 8 boys, 5 of which attained FH. Treatment was concluded at a bone age of 12 years, and follow-up continued until FH was achieved. Results In both G1 and G2 groups, height standard deviation score (SDS), weight-SDS and percentile of body mass index (PBMI) did not show intra/intergroup differences at the beginning and at interruption of treatment, but when added, G1+G2, height-SDS and weight-SDS differed significantly (p = 0.002 and 0.0001, respectively). In G1, 19 of 25 cases attained TH, and average height gain was 16.7 cm (7.7- 27.1); there was significant difference between FH and prediction of FH at the start (PFH at start) (p = 0.0001), as well as between PFH at interruption vs TH and vs FH (p = 0.007) with FH higher than TH (p = 0.004). Significant correlation was identified between FH and height gain after treatment. Conclusion As shown by some studies, GnRH analogue treatment was effective in children with CPP reaching FH near the genetic target.

Serum Kisspeptin Levels in Korean Girls with Central Precocious Puberty

Central precocious puberty (CPP) is caused by premature activation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin and G-protein coupled receptor-54 system is the essential gatekeeper of the reproductive system, playing a key role in the activation of the gonadotropic axis at puberty. We aimed to determine whether serum kisspeptin may function as a marker for CPP by investigating serum kisspeptin levels in Korean girls with CPP and their prepubertal controls. Serum kisspeptin levels of Korean girls with CPP (n = 30) and age-matched healthy prepubertal controls (n = 30) were measured with a competitive enzyme immunoassay. Serum kisspeptin levels were significantly higher in CPP group than in control group (4.61 +/- 1.78 vs 2.15 +/- 1.52 pM/L, P < 0.001). Serum kisspeptin was positively correlated with peak luteinizing hormone (LH), peak/basal LH ratio and peak LH/follicular-stimulating hormone (FSH) ratio during GnRH stimulation test. CPP is supposed to be triggered by premature increase of kisspeptin. Serum kisspeptin may be used as a marker of CPP. Further studies on KISS1 gene polymorphisms leading to higher risk of premature increase of kisspeptin and upstream regulator of kisspeptin are also needed.

Gonadotropin-releasing Hormone Stimulation Test for Precocious Puberty / 대한진단검사의학회지

BACKGROUND: Gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard to identify central precocious puberty (CPP). This test requires multiple blood samples at different time points to measure gonadotropin levels, and is therefore expensive, time-consuming, and uncomfortable for patients. We aimed to simplify the GnRH stimulation test to require fewer blood samples. METHODS: A study of 166 girls with precocious puberty was undertaken. Blood samples were obtained at 0, 15, 30, 45, 60, 90, and 120 min after GnRH administration, and the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured. For each parameter, the sensitivities and specificities were estimated and ROC curves were constructed. RESULTS: One hundred and twenty-eight patients (77.1%) were diagnosed for CPP. Peak LH levels were achieved 30 min after GnRH stimulation in patients with CPP. Further, 98.4% of the 45-min samples were diagnostic for CPP, and the cumulative frequency of LH values of > or =5 IU/L was 100% at 45 min. Using this cut-off value for LH, the ROC curve for LH at 45 min showed the highest sensitivity (98.4%) and specificity (100%) in the diagnosis of CPP. CONCLUSIONS: Values of LH measured from a single blood sample obtained at 45 min in the GnRH stimulation test may be adequate for the diagnosis of CPP. Two samples, taken at 30 and 45 min after stimulation, were able to accurately diagnose CPP in 100% of the patients in this study.

Premature thelarche: clinical and laboratorial assessment by immunochemiluminescent assay

In order to establish cut-off limits and to distinguish isolated premature thelarche (IPT) from precocious puberty (PP), we evaluated data from 79 girls with premature thelarche, comparing basal and stimulated LH and FSH serum concentrations with those from 91 healthy girls. A GnRH stimulation test was performed in 10 normal girls and in 42 with premature thelarche. Comparison among groups was performed by Kruskal-Wallis and Dunn’s tests. LH values were significantly greater in girls with IPT than in control groups. Basal gonadotropin concentrations were higher in patients with PP than in controls, but not different from patients with IPT. Peak LH levels after GnRH stimulation distinguished those two groups, with a cut-off value of 4.0 IU/L, but still with minimal overlap. In conclusion, a girl with premature thelarche and LH peak value above 4.5 IU/L has, indeed, PP, but values between 3.5 and 4.5 IU/L point to careful follow-up.

Com o objetivo de estabelecer o valor de corte e distinguir telarca precoce isolada (TPI) de puberdade precoce (PP), avaliamos 79 meninas com telarca precoce, comparando as dosagens basais e pós-estímulo de LH e FSH com grupo-controle. O teste de estímulo com GnRH foi realizado em 10 meninas normais e em 42 com telarca precoce. Os testes de Kruskal-Wallis and Dunn foram usados na comparação dos grupos. Os níveis de LH foram significativamente mais elevados no grupo com TPI, quando comparados com controles. As gonadotrofinas basais foram mais elevadas naquelas com PP que nos controles, mas não diferiram do grupo com TPI. O pico de LH após GnRH distinguiu estes dois grupos, com valor de corte de 4,0 UI/L, apesar de pequena sobreposição. Concluímos que uma menina com telarca precoce e LH pós-estímulo acima de 4,5 UI/L apresenta PP, mas valores entre 3,5 e 4,5 UI/L requerem seguimento cuidadoso.

Basal luteinizing hormone/follicle stimulating hormone ratio in diagnosis of central precocious puberty.

BACKGROUND: Precocious puberty is characterized by breast development in girls prior to 8 years old and may have acne, adult odor, growth spurt and menstruation. Conventionally, gonadotropin releasing hormone (GnRH) stimulation test is a gold standard for diagnosis of central precocious puberty but it is a time-comsuming procedure that is not practical on an out patient basis. OBJECTIVE: To evaluate the basal luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio in diagnosis of central precocious puberty in order to save time and cost. SUBJECTS AND METHOD: The GnRH stimulation tests were performed on 51 girls with breast development before 8 years old. The 51 girls were divided into 2 groups, 24 girls with central precocious puberty (CPP) and 27 girls with premature thelarche (PT), and the clinical data and GnRH stimulation tests data were compared between the 2 groups. The authors also compared the clinical data and GnRH stimulation tests data between 13 girls with PT and 12 girls with thelarche variants (TV) who developed puberty approximately 1 year later as confirmed by GnRH stimulation test. RESULTS: Girls with CPP had a large bone age and chronological age ratio and advancement of breast staging. Girls with TV had a greater level of basal luteinizing hormone (LH), peak LH and 120 min estradiol than girls with PT. Basal luteinizing hormone and follicle stimulating hormone (FSH) ratio greater than 0.2 can be used to diagnose CPP with 75 per cent sensitivity, 85 per cent specificity, 82 per cent positive predictive value (PPV) and 82 per cent negative predictive value (NPV). CONCLUSION: Girls with CPP have a basal LH/FSH ratio greater than 0.2 and this can be used as a cut-off point for the diagnosis CPP.

Telarquia prematura: aumento de la actividad estrogénica total en el plasma / Premature thelarche: increased of total estrogenic activity in the serum

Con el propósito de estudiar las causas de la telarquia prematura, se comparó el perfil hormonal y las características de los genitales internos mediante ultrasonografía pelvians en 41 niñas afectadas, de 21,15 ñ 9,74 meses de edad y e 31 controles de la misma edad y nivel socioeconómico y se buscó contaminación de los alimentos con zearalenona y dietilbestrol por cromatografía en capa delgada. La actividad estrogénica total en el plasma de las niñas, así como plasma y tejidos de pollo, se midió por el método de radiorreceptor. Las concentraciones basales de LH, FSH, prolactina y estradiol eran similares en pacientes y controles. La actividad estrogénica total fue significativamente mayor en las niñas con telarquia (201 ñ 102 vs 78 ñ 20 pg E2 equivalente) y descendió a niveles similares que en los controles (75 ñ 8 pg E2) al desaparecer la telarquia. La respuesta a LHRH en pacientes con telarquia fue mayor para FSH (28,7 ñ 17,5 Uµ/ml) que para LH (5,01 ñ 2,7 Uµ/ml). El tamaño del útero y la maduración ósea fueron similares en ambos grupos, pero el volumen ovárico medio fue mayor en pacientes con telarquia. No se detectaron contaminantes exógenos en la sangre de las niñasy los tejidos de 25 pollos. La actividad estrogénica en el plasma de las aves cumplía las recomendaciones internacionales (FAO). La respuesta de FSH al factor liberador, el mayor volumen ovárico y el aumento de la actividad estrogénica sugieren activación parcial del eje hipotálamo-hipofisiario-gonadal de predominio FSH en las niñas con telarquia prematura

Hypothalamic hamartomas and precocious puberty.

Ten children, five boys and five girls with true precocious puberty at an early age were found to have hypothalamic hamartomas on brain imaging. Very early onset of puberty, varying from a few weeks to three years of age, and rapid progression were characteristic. Accelerated growth velocity and markedly advanced bone age were evident in all. Gonadotropin and gonadal hormone levels were elevated above the prepubertal range. Six children had associated developmental delay or hyperactivity.

Puberdade precoce central por tumor hipotalâmico / Central precocious puberty by hypothalamic tumors

Descrevemos o caso de um menino com três anos de idade e puberdade precoce central por tumor hipotalâmico (hamartoma). O diagnóstico de processo expansivo do sistema nervoso central foi estabelecido pela tomografia computadorizada e ressonância magnética de crânio. As alteraçöes hormonais mais importantes na investigaçäo foram a elevaçäo do nível sérico de testosterona e a resposta das gonadotrofinas ao hormônio liberador das gonadotrofinas (GnRH). O tratamento com o agonista do GnRH, após a cirurgia, tornou-se útil para bloquear a progressäo da precocidade central.