Tratamiento con análogos de la hormona liberadora de gonadotrofinas (aGnRH) en niñas, niños y adolescentes / Treatment with gonadotropin-releasing hormone analogs (GnRHa) in childhood and adolescence

Desde hace varias décadas, los análogos de la hormona liberadora de gonadotrofinas (aGnRH) son el tratamiento de elección en la pubertad precoz central (PPC) en niñas y en niños. Causan una inhibición del eje hipotálamo-hipófiso-gonadal, disminuyen la secreción de gonadotrofinas, estradiol y testosterona; como consecuencia, producen una regresión de los caracteres sexuales secundarios durante el tratamiento. En los últimos años, estos análogos también se utilizan en adolescentes transgénero, en adolescentes y adultas jóvenes con enfermedades oncológicas, en algunas situaciones muy particulares en niños y niñas con talla baja, y en pacientes con trastornos del neurodesarrollo. En Argentina, los más utilizados son el acetato de triptorelina y el acetato de leuprolide en sus formas de depósito. Estos medicamentos han demostrado eficacia y seguridad. El objetivo de esta publicación es realizar una revisión y actualización del uso de los aGnRH en niños, niñas y adolescentes.

For several decades, gonadotropin releasing hormone analogs (GnRHa) are the medical treatment selected for central precocious puberty (CPP) in girls and boys. They generate an inhibition of the hypothalamus-pituitarygonadal axis decreasing LH, FSH, estradiol and testosterone secretion and, in this way, they produce a regression of secondary sexual characters under treatment. In the last years, these analogs are also used in trans adolescents, in adolescents and young adults with oncological diseases, in some very particular situations in children with short stature and in patients with neurodevelopmental disorders. In Argentina the most commonly used formulations are triptorelin and leuprolide acetate depot forms. These analogs have proven both their efficacy and their safety. The aim of this paper is to review and update about the use of GnRHa in children and adolescents.

Efficacy of Leuprorelide acetate (Eligard®) in daily practice in Brazil: a retrospective study with depot formulations in patients with prostate cancer

ABSTRACT Introduction: Androgen deprivation therapy (ADT) is the mainstay of therapy for advanced prostate cancer. Studies addressing the efficacy of different depot formulations of long acting luteinizing hormone releasing hormone agonists in the Brazilian population are lacking. We aimed to compare the efficacy of three schedules of leuprolide acetate in lowering PSA in a real world population. Materials and Methods: We reviewed the medical records of patients with prostate cancer seen at our institution between January 2007 and July 2018. We analyzed patients treated with long-acting leuprolide acetate and grouped these patients into three strata according to the administration of ADT every 1, 3 or 6 months. The primary outcome was the serum prostate specific antigen (PSA) levels at 6 and 12 months after treatment initiation. We used Friedman test to compare the distribution of PSA levels at baseline and at 6 and 12 months within each treatment stratum. We considered two-sided P values <0.05 as statistically significant. We analyzed toxicity descriptively. Results: We analyzed a total of 932 patients, with a median age of 72 years and a median time since diagnosis of prostate cancer of 8.5 months. ADT was administered monthly in 115 patients, quarterly in 637, and semiannually in 180. Nearly half of the patients had locally advanced disease. In comparison with baseline, median serum PSA levels were reduced at 12 months by at least 99.7% in the three strata (P <0.001 in all cases). Sexual impotence and hot flashes were the most frequently reported toxicities. Conclusion: To our knowledge, this is the largest assessment of real-world data on alternative schedules of leuprolide in a Brazilian population. Our study suggests that PSA levels can be effectively be reduced in most patients treated with monthly, quarterly, or semiannual injections of long-acting leuprolide acetate.

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.

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.

GnRH Agonist Therapy in a Patient with Recurrent Ovarian Granulosa Cell Tumors

A 65-yr-old woman presented 17 yr status post-hysterectomy with bilateral ovarian salpingo-oophorectomy, attributable to ovarian cancer. She was admitted to our hospital, with multiple cystic liver masses and multiple large seeded masses in her abdomen and pelvic cavity. Histological examination of the pelvic masses demonstrated granulosa cell tumors. After two courses of systemic combination chemotherapy, with paclitaxel and carboplatin, the masses in the abdomen and pelvic cavity increased, and debulking surgery also failed because of peritoneal dissemination with severe adhesion. Finally, she underwent palliative radiotherapy for only the pelvic masses obstructing the urinary and GI tracts, and monthly hormonal therapy with a gonadotrophin-releasing hormone agonist; leuprorelin 3.75 mg IM. Subsequently, multiple masses beyond the range of the radiation as well as those within the radiotherapy field partially decreased. This partial response had been maintained for more than 8 months as of the last follow-up visit. Owing to its long and indolent course and the low metabolic rate of the tumors, advanced or recurrent granulosa cell tumor (GCT) requires treatment options beyond chemotherapy, surgery, and radiotherapy. Hormonal agents may provide another treatment option for advanced or recurrent GCT in those who are not candidates for surgery, chemotherapy, or radiotherapy.

Fatores determinantes do ganho na altura em meninas com puberdade precoce central idiopática tratadas com análogo de GnRH / Predictive factors for height gain in idiopathic central precocious puberty treated with GnRH analogues

OBJETIVO: avaliar fatores determinantes de maior ganho na estatura como resultado do tratamento com GnRHa. MÉTODOS: estudo retrospectivo de 33 meninas com puberdade precoce central idiopática tratadas com GnRHa. Foram avaliadas: idade no início dos sintomas e no início do tratamento, tempo decorrido entre o início de aparecimento dos caracteres puberais e o início do tratamento, idade óssea, avanço da idade óssea, duração do tratamento com GnRHa, altura real e escore Z, altura predita e escore Z e dosagens hormonais de FSH e LH após estímulo com GnRH, que foram correlacionadas com o ganho de altura no final do tratamento, calculada pela diferença entre altura predita no final e início do tratamento. Para análise estatística foi utilizada a correlação linear de Pearson, além da regressão linear múltipla. RESULTADOS: a média de idade no início do tratamento foi 7,8±1,3 anos, com idade óssea média de 10,1±1,6 anos. O avanço da idade óssea era de 2,3±1,1 anos e foi controlado com o tratamento. O ganho em altura predita foi de 2,5±1,3 cm e foi correlacionado positivamente com o tempo decorrido entre o início dos sintomas e o início do tratamento e com o avanço da idade óssea, além de se correlacionar negativamente com o escore Z da altura no início do tratamento e com a altura predita no início do tratamento, sendo este último o principal fator determinante do ganho obtido com o tratamento. CONCLUSÕES: meninas com maior comprometimento da altura predita para a idade adulta, visualizado pelo maior desvio em relação à população (escore Z) e pelo maior avanço na idade óssea foram as que obtiveram maior benefício com o tratamento com GnRHa, não devendo ser excluídas do grupo a ser tratado.

PURPOSE: to evaluate predictive factors of response to GnRHa treatment in girls with idiopathic central precocious puberty. METHODS: a retrospective cohort study was conducted involving 33 girls diagnosed with idiopathic central precocious puberty and treated with GnRHa. The following independent variables were assessed: age at the beginning of therapy and at the onset of symptoms, time elapsed since the appearance of pubertal characteristics and the beginning of treatment, bone age, bone age advance, duration of GnRHa treatment, actual height and Z-score, predicted height and Z-score and hormone measurements of FSH and LH after GnRH stimulation, which were correlated with gain in height as a dependent variable at treatment discontinuation, calculated by the difference between the predicted height at the end and beginning of treatment. For statistical analysis, Pearson's linear correlation was used, in addition to multiple linear regression analysis. RESULTS: the mean age at the beginning of treatment was 7.8±1.3 years, with a mean bone age of 10.1±1.6 years. Bone age advance was 2.3±1.1 years and was controlled during the treatment period. Gain in predicted height was 2.5±1.3cm. It was positively correlated with time elapsed since the beginning of symptoms and the beginning of treatment and with bone age advance, while negatively correlated with the Z-score of height at the beginning of treatment and predicted height at the beginning of treatment, and the latter was the main factor determining gain from treatment. CONCLUSIONS: girls who had the most significant compromise of predicted adult height, as detected by a larger deviation from the population (Z-score) and the most considerable advance in bone age, received benefit from GnRHa therapy, and they must not be excluded from the group to be treated.

Comparison of Clinical Efficacy between a Single Administration of Long-Acting Gonadotrophin-Releasing Hormone Agonist (GnRHa) and Daily Administrations of Short-Acting GnRHa in In Vitro Fertilization-Embryo Transfer Cycles

This study was aimed to evaluate the efficacy of a single administration of long-acting gonadotrophin-releasing hormone agonist (GnRHa) as compared with daily administrations of short-acting GnRHa in controlled ovarian hyperstimulation (COH) for in vitro fertilization and embryo transfer (IVF-ET) cycles. The mean dosage of recombinant follicle-stimulating hormone (rFSH) required for COH (2,354.5+/-244.2 vs. 2,012.5+/-626.1 IU) and the rFSH dosage per retrieved oocyte (336.7+/-230.4 vs. 292.1+/-540.4 IU) were significantly higher in the long-acting GnRHa group (N= 22) than those in the short-acting GnRHa group (N=28) (p<0.05). However, the mean number of visit to the hospital that was required before ovum pick-up (3.3+/-0.5 vs. 22.2+/-2.0) and the frequency of injecting GnRHa and rFSH (12.8+/-1.2 vs. 33.5+/- 3.5) were significantly decreased in the long-acting GnRHa group (p<0.0001). The clinical pregnancy rate, implantation rate, and early pregnancy loss rate were not significantly different between the 2 groups. So, we suggest that a single administration of long-acting GnRHa is a useful alternative for improving patient's convenience with clinical outcomes comparable to daily administrations of short-acting GnRHa in COH for IVF-ET cycles.

Response to the gonadotropin releasing hormone agonist leuprolide in immature female sheep androgenized in utero

Similar to women with Polycystic Ovary Syndrome (PCOS), female sheep treated prenatally with testosterone (T-females) are hypergonadotropic, exhibit neuroendocrine defects, multifollicular ovarian morphology, hyperinsulinemia and cycle defects. Hypergonadotropism and multifollicular morphology may in part be due to developmentally regulated increase in pituitary responsiveness to GnRH and may culminate in increased ovarian estradiol production. In this study, we utilized a GnRH agonist, leuprolide, to determine the developmental impact of prenatal testosterone exposure on pituitary-gonadal function and to establish if prenatal exposure produces changes in the reproductive axis similar to those described for women with PCOS. Eight control and eight T-females were injected intravenously with 0.1 mg of leuprolide acetate per kilogram of body weight at 5, 10 and 20 weeks of age. Blood samples were collected by means of an indwelling jugular vein catheter at 0, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 hours after leuprolide. Area under the curve (AUC) of LH response to leuprolide increased progressively between the three ages studied (P<0.05). AUC of LH in T-females was higher than in control females of the same age at 5 and 10 weeks of age (P<0.05), but similar at 20 weeks of age. AUC of estradiol response was lower at 10 but higher at 20 weeks of age in T-females compared to controls of the same age (P<0.05). Our findings suggest that prenatal T treatment alters the pituitary and ovarian responsiveness in a manner comparable to that observed in women with PCOS.

Adnexal torsion following gonadotropin-releasing hormone analog therapy: a case report

Torção anexial pode ocorrer em crianças e adolescentes do sexo feminino. Frequentemente está associada com doenças ovarianas que resultam em crescimento da gônada. A torção anexial pode comprometer os ovários isoladamente, as tubas uterinas ou ambos e o sintoma principal é dor pélvica aguda. Descrevemos um caso de dor pélvica aguda em uma menina de 8 anos de idade, com diagnóstico prévio de puberdade precoce e que estava em tratamento com análogo de GnRH. O exame ultra-sonográfico demonstrava útero de tamanho normal com ovários aumentados bilateralmente e múltiplos cistos. Na laparotomia foi encontrado torção completa do anexo direito. O exame histológico demonstrou edema maciço de ovário associado com múltiplos cistos antrais e redução da reserva folicular.

Embarazo obtenido con ovodonación y fertilización in vitro en pacientes de 50 años de edad / Pregnancy obtained with embryon donation and in vitro fertilization in 50 years old women

Se presenta un caso exitoso de ovodonación para conseguir un embarazo en una paciente de 50 años. Las indicaciones y técnicas se describen y los aspectos éticos

Tratamiento de la endometriosis con análogos de GnRH y estudio comparativo / Treatment of endometriosis with GnRH analogues: a comparative study

Objetivo. Evaluar la efectividad del tratamiento de la endometriosis con análogos de GnRH. Material y método. Se estudió a 100 mujeres divididas aleatoriamente en dos grupos: uno tratado con danazol (testigo) y uno con GnRH (experimental). Todas las mujeres contaban con un estudio laparoscópico y al término del tratamiento fueron sometidas a una segunda intervención. Resultados: La remisión de los síntomas y las lesiones endometriósicas fueron similares en ambos grupos, al igual que la tasa de embarazos, con la ventaja de que los efectos secundarios fueron menores en el grupo experimental. Conclusión. Los análogos de GnRH son una buena alternativa en las mujeres con intolerancia al danazol

Informe preliminar con análogos del GnRh de depósito y cirugía en el tratamiento de la endometrosis / Preliminary report with analogous of the GnRh of depot and surgery in the treatment of the endometriosis

El objetivo de este informe es mostrar nuestra experiencia preliminar en el tratamiento sucesivo y combinado quirúrgico y médico con análogos del GnRh de depósito (Lupron 3.75) e hiperestimulación ovárica controlada con gonadotrofinas (H.M.G.H.C.G.) en el tratamiento de la endometrosis. Se evaluó un grupo de 61 pacientes que consultaron por infertilidad en el Instituto de Ginecología y Fertilidad de Bs. As. entre el 1 de octubre de 1992 y el 31 de mayo de 1994. En todas ellas se realizó una laparoscopia para diagnóstico y estadificación de la endometrosis según la clasificación revizada de la Sociedad Americana de Fertilidad, realizándose en el mismo acto los procedimientos quirúrgicos (coagulación, lisis, quistectomia, etc.) según fuera necesario. Todas las pacientes fueron medicadas con Lupron 3.75 una ampolla mensual durante un período de 6 meses posteriores a la cirugía. Del total de 61 pacientes 24 (39,3 por ciento) se embarazaron, de las cuales 15 lo logró en forma espontánea, 13 (54.1 por ciento) en el primer semestre postratamiento 2 (8.3 por ciento) en el segundo semestre. 25 pacientes fueron estimuladas con gonadotrofinas, a partir del 6to. mes de finalizado el Lupron por un período de tres meses y 9 (37.5 por ciento) de ellas lograron el embarazo. En conclusión los resultados obtenidos sugieren que el tratamiento quirúrgico y médico con análogos del Gn-Rh y gonadotrofinas son útiles en el tratamiento de la endometrosis, permitiendo acortar el período en que se obtiene el embarazo logrando además una adecuada tolerancia y aceptación por parte de la paciente

Endometriose: tratamento com agonista do GnRH a partir de lesäo induzida em ratas / Endometriosis: treatment with agonist of the GnRH from lesion induced in female rats

Os autores procuram demonstrar a eficácia do tratamento com análogo do GnRH (acetato de leuprolide) na endometriose experimental induzida em ratas. A induçao foi realizada em 80 fêmeas. OS animais do grupo tratado tiveram suas lesoes avaliadas com quatro, sete, nove e 12 semanas de tratamento. O volume de tecido endometrial sofreu uma diminuiçao significativa com o uso de droga. Conclui-se, assim, que o acetato de leuprolide faz reduçao das lesoes de forma significativa e que a técnica utilizada para a induçao da endometriose é eficaz.

Uso de análogos GnRH en cirugía histeroscópica / Use of GnRH analogs in hysteroscopic surgery

El manejo de la cirugía histeroscópica, especialmente en la ablación endometrial y miomectomías, esta adquiriendo cada vez más importancia en la práctica clínica de los ginecólogos, siendo por tanto una opción válida frente al sangrado uterino anormal, la presencia de miomas submucosos, así como otra cirugía uterina. En este sentido se ha visto el valor de inhibir el crecimiento endometrial y modificar su patrón de vascularización, previo al procedimiento, facilitando así los resultados de ésta cirugía endoscópica. La literatura muestra a varios autores que recomiendan el uso de diversos inhibidores sobre el endometrio. Los análogos de hormonas liberadoras de gonadotrofinas GnRH, han encontrado aquí una importante indicación, pues se ha visto que tienen buenos resultados en la preparación del endometrio para ser sometido a ablación endometrial y a miomectomías, los resultados en relación a metroplastia y otra cirugía sobre el útero no es concluyente o muestra ser ineficaz. Se han utilizado otros medicamentos como progestágenos o danazol, sin obtener tan buenos resultados en cuanto a modificar las características del endometrio, o reducir el volumen de miomas uterinos en un 30 a 35 por ciento promedio. Se presenta una revisión de la literatura al respecto. Se expone una experiencia local y se discuten los beneficios de la cirugía endoscópica

Análogos GnRH, Acetato de Leuprolide / GNRH analogues, Leyprolide Acetate

El acetato de leuprolide es una nonapéptido sintético, D-leucina 6 etilamida, agonista de la hormona natural liberadora de gonadotropinas (GnHR o LN-RH). Posee mayor potencia que la hormona natural. Su nombre químico es acetato de 5-Oxo-L-proli-L-histidil-L-triptofi-L-seril-L-tirosil-D-leusil-L-leusil-L-leusil-L-Leusil-L-arginil-N-etil-L-prolinamida. Su ingreso,más o menos reciente, al armamentarium terapéutico ha causado cierto revuelo ante la posibilidad de tratar por métodos no quirúrgicos la leiomiomatosis y la endometriosis al igual que ciertas formas de infertilidad. En esta guía se establece las indicaciones y los límites racionales del uso de este nuevo medicamento.

Utilidad de los agonistas de GnRH en el tratamiento preoperatorio de la miomatosis uterina complicada: caso clínico / Utility of the GnRH agonists in the presurgical treatment of complicated uterine myomatosis

Los agonistas de GnRH de uso prolongado producen un hipogonadismo hipogonadotrópicoreversible, por lo que han sido utilizados en el tratamiento preoperatorio de miomas uterinos logrando amenorrea y disminución del tamaño de ellos. Se presenta el caso de una paciente de 43 años, portadora de una miomatosis uterina asociada a metrorragia que ingresa por un cuadro de trombosis venosa profunda extensa con indicación absoluta de anticoagulación, dado el riesgo de exacerbación de la metrorragia por los anticoagulantes y considerando al alta morbilidad asociada a una hiosterectomía de urgencia en ella; se decide tratamiento médico con un agonista de GnRH de depósito (acetato de leuprolide 3,75 mg IM mensual). Se obtiene el cese de la metrorragia en 3 días y una significativa disminución del tamaño uterino permitiendo mantener tratamiento anticoagulante y proceder a una histerectomía total electiva 3 meses después. Se analizan las características de los análogos de GnRH, mecanismo de acción, efectos adversos y otras indicaciones en medicina