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.

Diagnostic value of urinary luteinizing hormone levels in the monitoring of precocious puberty treatment

ABSTRACT Objective To determine whether first-voided urinary LH (FV-ULH) - level measurement can adequately assess pubertal suppression as much as standard tests can. Subjects and methods The study group included patients with central precocious puberty and rapidly progressing early puberty who received up to 3 - 4 doses of GnRHa therapy monthly and did not have adequate hormonal suppression after GnRH stimulation (90-minute LH level > 4 IU/L). Design: All of the participants underwent an LHRH test just after admission to the study. According to the stimulated peak LH levels, the patients were divided into 2 groups and followed until the end of the first year of treatment. The concordance between FV-ULH and stimulated LH levels was assessed. Results The FV-ULH levels in patients with inadequate hormonal suppression were significantly high compared to patients with adequate hormonal suppression. FV-ULH levels were very strongly correlated with stimulated LH levels (r = 0.91). Its correlation with basal LH levels was significant (r = 0.65). However, this positive correlation was modestly weakened after the first year of treatment. The cutoff value for FV-ULH of 1.01 mIU/mL had the highest sensitivity (92.3%) and specificity (100%). Conclusion FV-ULH levels, using more reliable and sensitive assay methods, can be used to monitor the adequacy of GnRHa therapy.

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.

Apoplejía tumoral pituitaria / Pituitary tumor apoplexy

La apoplejía tumoral pituitaria es un síndrome infrecuente que resulta del infarto y/o hemorragia espontánea de un adenoma pituitario preexistente. Ya que el evento primario involucra el adenoma, este síndrome debe ser nombrado como apoplejía tumoral pituitaria y no como apoplejía pituitaria. El aumento súbito en la presión de los contenidos de la silla turca da como resultado una cefalea de inicio agudo (puede ser incluso una "cefalea en trueno") de intensidad severa, alteraciones visuales y compromiso en la función pituitaria. El diagnóstico se basa en una alta sospecha clínica, imagen por resonancia magnética y medición de hormonas hipofisiarias en sangre. El tratamiento se basa en medidas de soporte (líquidos intravenosos y corticoides) y en casos sin buena respuesta o con deterioro neurológico, descompresión de silla turca. A continuación presentamos el caso de un adenoma previamente no diagnosticado que debutó como apolejía tumoral pituitaria. (Acta Med Colomb 2015; 40: 249-253).

Pituitary tumor apoplexy is an infrequent condition resulting from infarction and/or spontaneous bleeding from a pre-existing pituitary adenoma. This entity requires the prior existence of an adenoma in order to be named as pituitary tumor apoplexy, otherwise, it should be named pituitary apoplexy. The sudden increase in pressure of the sella turcica's contents results in a clinical syndrome characterized by headache (which can be "thunderclap headache"), visual disturbances and hypopituitarism. Diagnosis is not always straight forward and requires high clinical suspicion in addition to magnetic resonance imaging and measurement of serum pituitary hormones. Treatment is mainly based on supportive measures (intravenous fluids and steroids) and surgical decompression in those cases with no response to medical treatment and progressive neurological impairment. We report the case of a patient with a previously unknown pituitary adenoma presenting as a tumor apoplexy. (Acta Med Colomb 2015; 40: 249-253).

Uso de agonista de GnRH para inducir ovulación en ciclos de hiperestimulación ovárica controlada: experiencia de Clínica Monteblanco, Santiago, Chile / Use of GnRH agonist to induce ovulation cycles controlled ovarian hyperstimulation: experience of Monteblanco Clinic, Santiago, Chile

Objetivo: Presentar la experiencia de la Unidad de Medicina Reproductiva de Clínica Monteblanco con el uso de análogos GnRh para la inducción final de la maduración ovocitaria. Método: Se registraron los casos de IVF/ICSI durante el año 2012 en los que se indujo la maduración final ovocitaria con análogos GnRh (Lupron®). Todos los ciclos fueron estimulados con FSHr (Puregon®) y gonadotrofina urinaria altamente purificada (Menopur®), para la prevención del alza prematura de LH, el día 5° de estimulación se agregó diariamente antagonista de GnRh. La maduración ovocitaria final se realizó con 1,25 mg de acetato de leuprolide (Lupron®), posteriormente se realizó aspiración folicular bajo guía ecográfica. Todos los embriones obtenidos fueron vitrificados y transferidos en ciclos posteriores. Resultados: Entre enero y diciembre del año 2012 se registraron 110 pacientes cuya inducción de maduración final ovocitaria se realizó con acetato de leuprolide. El promedio de ovocitos recuperados fue de 21, la proporción de ovocitos maduros fue de 72 por ciento y la frecuencia de fecundación fue de 64 por ciento. No hubo ningún caso de síndrome de hiperestimulación ovárico severo. Conclusiones: En los casos presentados de inducción de la maduración ovocitaria final con acetato de leuprolida, los resultados obtenidos son óptimos en términos de número de ovocitos en metafase II recuperados y en frecuencia de fecundación, mostrando ser una alternativa eficiente en la prevención del síndrome de hiperestimulación ovárico severo, sin alterar el pronóstico de las pacientes.

Objective: To present the experience of the Reproductive Medicine Unit of Clinica Monteblanco inducing oocyte final maturation by GnRh analogue administration. Methods: We analysed all IVF/ICSI cases performed in 2012, in which final oocyte maturation was induced by administration of GnRH analogue (Lupron®). Controlled ovarian hyperstimulation was achieved bydaily rFSH (Puregon®) and highly purified urinary gonadotropin (Menopur®) administration. In order to prevent premature LH rise, on the 5th day of stimulation daily GnRH antagonist (Orgalutran®) was added. Final oocyte maturation was induced by the administration of 1.25 mg leuprolide acetate (Lupron®). Follicular aspiration was subsequently performed under ultrasound guidance. All embryos were vitrified and transferred in a subsequent cycle. Results: We registered 110 patients. The mean number of recovered oocytes was 21; the proportion of mature oocytes was 72 percent, and the fecundation rate reached was 64 percent. No case of severe ovarian hyperstimulation syndrome (OHSS) was recorded. Conclusions: In this cohort, the use of leuprolide acetate for induce final oocyte maturation demonstrated to be an efficient alternative to induce oocyte final maturation, while preventing OHSS.

Eficacia de leuprolide 11, 25 mg para supresión de testosterona en pacientes con cáncer prostático / Leuprolide s efficacy 11, 25 mg for suppression of testosterone in patients with prostatic cancer

Introducción: Los agonistas LHRH son de elección en bloqueo androgénico por cáncer prostático. En base a pacientes castrados se considera un bloqueo adecuado una testosterona total plasmática < 50 ng/dl. Se ha sugerido controlar la testosterona total por la posibilidad de no lograr una supresión adecuada. Material y método: Entre junio de 2008 a marzo de 2009 se midió el nivel de testosterona total al tercer mes de administrada una dosis de leuprolide 11,25 mg IM. Los exámenes se realizaron en la mañana y en el mismo laboratorio. En un grupo de pacientes se estimó peso, talla e índice de masa corporal (IMC) y se evaluó su asociación con los niveles de testosterona alcanzados. Resultados: Se evaluaron 81 pacientes, la edad promedio fue 76,4 años. La testosterona total plasmática promedio fue 33,9 ng/dl. En 12/81 pacientes (14,8 por ciento) el nivel de testosterona fue menos 50 ng/dl. No se observó asociación entre la duración de hormonoterapia y los niveles de testosterona. En 40 pacientes se estimó peso, talla e IMC sin encontrarse asociación de estas variables con el nivel de testosterona. En los pacientes en que se aumentó la dosis a leuprolide 22,5 mg se obtuvo una adecuada supresión de testosterona. Conclusión: En los pacientes en tratamiento con agonistas LHRH se debe medir el nivel de testosterona plasmática dada la posibilidad de un bloqueo inadecuado. En pacientes en tratamiento con leuprolide 11,25 mg y testosterona menos 50 ng/dl el aumento de la dosis a 22,5 mg lograría un nivel de testosterona en rangos de castración quirúrgica.

Introduction: The agonistas are LHRH of election in blockage androgenic for prostatic cancer. On the basis of castrated patients considers an adequate blockage a total plasmatic testosterone < 50 ng/dl. The total testosterone for the possibility to not to achieve an adequate suppression has been suggested to control. Material and method: Between June 2008 to March 2009 leuprolide’s dose measured the level of total testosterone itself to person under administration’s third month 11.25 mg IM. The exams had done in the morning and at the same laboratory. Weight, size and index of muscle mass (IMC) were estimated in patients’ group and his association with the levels of testosterone caught up with was evaluated. Results: We evaluated 81 patients, the mean age was 76.4 years. The total testosterone the average plasmatic was 33.9 ng/dl. In 12/81 patient (14.8 percent) the level of testosterone was > 50 ng/dl. we did not observe association between hormonoterapia’s duration and the levels of testosterone. Weight, size and IMC without finding association of these variables with the level of testosterone were estimated in 40 patients. We got an adequate suppression from testosterone in the patients that 22.5 mg increased itself the dose in to leuprolide. Conclusion: LHRH must try on in the patients in treatment with agonistic the level of plasmatic testosterone once the possibility of an inadequate blockage was given. In patients in treatment with leuprolide 11.25 mg and testosterone > 50 ng/dl the increase of the dose to 22.5 mg would achieve a level of testosterone in ranges of surgical castration.

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.

Uso de meia dose de agonista do GnRH de depósito para supressão hipofisária em ciclos de fertilização in vitro / Half-dose long-acting form of GnRH agonist for pituitary suppression in cycles of in vitro fertilization

OBJETIVO: descrever a experiência de um serviço de reprodução assistida com a utilização de meia dose de agonista do GnRH de depósito para a supressão hipofisária em ciclos de fertilização in vitro (FIV). MÉTODOS: estudo prospectivo em que foram avaliados ciclos de FIV ou "intracytoplasmatic sperm injection" (ICSI) utilizando meia dose de acetato de leuprolide de depósito, iniciado na fase lútea média do ciclo menstrual, no período de agosto de 2005 a março de 2006. Foi administrado FSH recombinante para indução ovariana controlada em dose variada. O hCG era administrado quando pelo menos um folículo atingisse 19 mm de diâmetro máximo. Realizou-se FIV ou ICSI nos oócitos maduros de acordo com fator de infertilidade. Transferiram-se até quatro embriões por paciente no segundo ou terceiro dia após a captação. O uso de progesterona foi iniciado no mesmo dia da coleta oocitária. A dosagem sérica de beta-hCG foi realizada no 14° dia após a coleta dos oócitos. Foram avaliados os seguintes parâmetros: número de ciclos aspirados, ciclos cancelados e ciclos transferidos, quantidade total de FSH utilizado, número de oócitos maduros, taxa de fertilização, número de embriões transferidos, taxa de implantação embrionária e taxa de gestação clínica. RESULTADOS: 109 ciclos de FIV/ICSI utilizaram o protocolo descrito. A média de idade das pacientes foi 34,9 anos. A taxa de cancelamento foi de 1,8 por cento dos ciclos iniciados. Foram utilizadas 1.905 UI de gonadotrofina, em média, por ciclo iniciado. Um total de 86,5 por cento dos oócitos obtidos eram maduros, e a taxa de fertilização foi de 76,3 por cento. A média de embriões transferidos foi 2,7. As taxas de gestação por aspiração e por transferência foram 25,2 e 25,7 por cento, respectivamente. Um total de 26,3 por cento das gestações eram gemelares e 5,3 por cento, trigemelares. CONCLUSÃO: a administração de meia dose (1,87 mg) de acetato de leuprolide de depósito para bloqueio hipofisário pode ser...

PURPOSE: to evaluate the experience of an assisted reproduction center that uses depot administration of half-dose of GnRH agonist for pituitary suppression in assisted reproductive cycles. METHODS: prospective study that evaluated in vitro fertilization or intracytoplasmatic sperm injection (IVF/ICSI) cycles utilizing half-dose of leuprolide acetate between August 2005 and March 2006. Recombinant FSH was administered for controlled ovarian induction based on the protocol. hCG was administered when at least one follicle reached 19 mm in diameter. IVF or ICSI was performed according to infertility factor. Up to four embryos were transferred on the second or third day after oocyte retrieval. Progesterone supplementation was initiated on the same day of oocyte retrieval, and after 14 days beta-hCG was measured. The following parameters were evaluated: number of aspirated cycles, cancelled cycles, transferred cycles, total dose of FSH employed, number of mature oocytes retrieved, fertilization rate, number of transferred embryos, embryo implantation rate, and pregnancy rate. RESULTS: A hundred and nine IVF/ICSI cycles were initiated. The mean age of the patients was 34.9 years. We observed 1.8 percent of cancellation rate. The mean total dose of gonadotrophins employed was 1,905 IU per cycle. We obtained 86.5 percent of mature oocytes and the fertilization rate was 76.3 percent. The mean number of embryos transferred was 2.7. Pregnancy rates per aspiration and per transfer were 25.2 and 25.7 percent, respectively. Of those who reached pregnancy, 26.3 percent were twins and 5.3 percent were triplets. CONCLUSIONS: the half-dose of GnRH depot employed for pituitary suppression was a useful alternative for ovarian stimulation in IVF cycles because it is comfortable and practical for the patient, besides its low cost.

Prenatal testosterone treatment alters LH and testosterone responsiveness to GnRH agonist in male sheep

Although evidence is accumulating that prenatal testosterone (T) compromises reproductive function in the female, the effects of excess T in utero on the postnatal development of male reproductive function has not been studied. The aim of this study was to assess the influence of prenatal T excess on age-related changes in pituitary and gonadal responsiveness to GnRH in the male sheep. We used the GnRH agonist, leuprolide (10 µg/kg), as a pharmacologic challenge at 5, 10, 20 and 30 weeks of age. These time points correspond to early and late juvenile periods and the prepubertal and postpubertal periods of sexual development, respectively. LH and T were measured in blood samples collected before and after GnRH agonist administration. The area under the response curve (AUC) of LH increased progressively in both controls and prenatal T-treated males from 5 to 20 weeks of age (P<0.01). The LH responses in prenatal T-treated males were lower at 20 and 30 weeks of age compared to controls (P<0.05). AUC-T increased progressively in control males from 5 through 30 weeks of age and prenatal T-treated males from 5 to 20 weeks of age. The T response in prenatal T-treated males was higher at 20 weeks compared to controls of same age but similar to controls and prenatal T-treated males at 30 weeks of age (P <0.05). Our findings suggest that prenatal T treatment advances the developmental trajectory of gonadal responsiveness to GnRH in male offspring.

Efectividad de la terapia con leuprolide acetato de depósito cada tres meses en pubertad precoz central / Effectiveness of Leuprolide acetate therapy every three months in central precocious puberty

Background: Precocious puberty may reduce final adult height, and affected children may suffer social and emotional problems. The efficacy of treatment with a long acting agonist analogue of the gonadotropin releasing hormone (aLHRH) has been well demonstrated. Aim: To evaluated the efficacy of a new formulation of aLHRH (leuprolide, Lupron ®) for the suppression of gonadotropin activation and clinical signs of puberty. Material and methods: Eleven children (ten females) with idiopathic central precocious puberty, with a mean chronological age of 7.5±1.8 years and a bone age of 9.7±1.8 years were recruited. Testicular volume in the male was 15 ml. In females, Tanner stage for breast development was between 2-4 and mean ovarian volume was 2.3±0.8 ml. They were treated during 18 months with aLHRH, 11.25 mg administered intramuscularly every three months. Results: Clinical, hormonal and ultrasonographic signs of puberty regressed in all patients. The degree of suppression of LH was 87.7±5.1% at the end of the 18 months. No significant changes in bone mineral content were observed during the treatment period. Conclusions: Leuprolide (aLHRH) 11.25 mg, injected every three months, is effective for the control of central precocious puberty and allows to reduce the number of yearly injections from 12 to 4.

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.

Cáncer de próstata: bloqueo androgénico intermitente / Prostatic cancer: intermittent androgen blockade

El cáncer de próstata (CP) constituye un grave problema de salud pública. Su incidencia ha aumentado en forma considerable durante las últimas décadas, favorecido por el aumento en la supervivencia y los métodos de detección más tempranos, tales como, el uso masivo del antígeno prostático específico (APE). En los EE.UU., 1 de cada 6 varones tendrá CP en algún momento de su vida, o lo que es lo mismo, el 15 por ciento. Esta patología es la más frecuente en varones (36 por ciento) y la segunda causa de muerte por cáncer (13 por ciento) luego del cáncer de pulmón. Sin embargo, pese al gran avance que se ha observado en el diagnóstico y tratamiento, la mortalidad por CP no ha disminuido, a lo que se añade que la terapia estándar para el CP estadio D2 no se ha modificado durante las últimas cinco décadas. Las opciones terapéuticas del CP localizado en el tejido prostático o localmente avanzado son: prostatectomía radical, radioterapia, braquiterapia, crioterapia o vigilancia. Eventualmente y para fines de investigación se pueden combinar éstos tratamientos. Lamentablemente la recurrencia de enfermedad (aun bioquímica) luego de la cirugía o radioterapia con intento curativo, varía entre un 27 y un 53 por ciento. Esto implica que sólo un limitado número de pacientes está curado...

Duplicação da hipófise e da haste hipofisária: relato de um caso e revisão da literatura / Duplication of pituitary gland and stalk: case report and review of the literature

Os autores relatam um caso de uma paciente do sexo feminino, com idade cronológica de sete anos, idade óssea de 11 anos, aparecimento de mamas Tanner III bilateralmente, cuja investigação diagnóstica confirmou quadro de puberdade precoce dependente de gonadotrofinas, e a ressonância magnética da hipófise evidenciou duplicação da haste e da glândula hipofisária associada a hamartoma hipotalâmico.

The authors report a case of a female patient with chronological age of 7 years and bone age of 11 years, presenting with bilateral breast stage Tanner III and gonadotrophin-dependent precocious puberty. Magnetic resonance imaging of the sellar region demonstrated duplication of the pituitary gland and stalk associated with a hypothalamic hamartoma.

Evaluación del valor pronóstico de la respuesta atemprana de estradiol sérico, FSH y LH con el uso de acetato de leuprolide durante la hiperestimulación ovárica en reproducción asistida / Prognostic value of the early response of the serum estradiol FSH y LH action of leuprolide acetate during the folicular phase, used as an adjuvant to ovarian stimulation in IVF-ET

Objetivo: Evaluar el valor pronóstico de la respuesta temprana del estradiol sérico, FSH y LH usando acetato de leuprolide durante la fase folicular temprana, como adyuvante en ciclos de estimulación ovárica para FIV-TE. Material y métodos: Se analizaron 31 ciclos de estimulación en 26 pacientes con esterilidad primaria y secundaria. Se midió estradiol, FSH, LH del segundo al quinto día del ciclo, para establecer patrones de respuesta a la administración de GnRHa. Se compararon estos patrones de respuesta en relación con el número de ovocitos capturado, estradiol en el día de aplicación de hCG, número de embriones, y porcentaje de fertilización, realizando análisis estadístico (t-student, X2, prueba Wilcoxon). Resultados: Se observaron cuatro distintos patrones de respuesta temprana al estradiol. Patrón A: 13 ciclos, tuvieron una pronta elevación seguida por una caída del estradiol en el día 4 del ciclo. Patrón B: nueve ciclos, elevación retrasada del estradiol, seguida por una caída el día 6 del ciclo. Patrón C: siete ciclos, mostraron elevación persistente del estradiol. Patrón D: dos ciclos, ausencia de respuesta temprana del estradiol (ciclos cancelados). Se encontró diferencia significativa en nivel de estradiol al día de aplicación hCG, número de ovocitos capturados y número de embriones en el patrón A en relación con B y C. No hubo diferencia significativa en porcentaje de fertilización. Los niveles séricos de FSH y LH sin valor predictivo.Concluimos que el patrón de respuesta de estradiol al acetato de leuprolide es un buen indicador pronóstico del resultado de FIV-TE.

Valor pronóstico de la respuesta inicial de los niveles séricos de estradiol al estímulo con análogos de GnRH en fertilización in vitro / Prognostic value of initial response of estradiol serum levels to stimulation with GnRH agonists in vitro fertilization

Se estudió el valor de la respuesta del estradiol (E2) al estímulo con análogo de (GnRH) en la fase folicular temprana. Estudio retrospectivo. Se estudiaron 403 ciclos de Fertilización in vitro (FIV) de enero de 1993 a diciembre de 1995. Se agruparon en 4 patrones dependiendo de la respuesta del estradiol al estimulo de a-GnRH en la fase folicular temprana. Patrón A (n=115). B (n=22). C (n=11) y D (n=3). Se incluyeron en el estudio aquellas pacientes manejadas en fase lútea corta, (FLC) (n=153) y larga (FLL) y larga (FLL) (n=97) como grupos controles. La prueba estadística que se utilizó fue análisis de varianza ANOVA con una P< 0.05 como estadísticamente significativa. La tasa de captura ovular fue mayor en los patrones A, B, FLC, y FLL con respecto al patrón D (p=0.001). La tasa de embarazo fue superior en A, B, y FLC y FLL (25 por ciento, 19 por ciento, 22 por ciento, y 25 por ciento) respectivamente (p=0.05). La edad se encontró mayor en C y D y fase lútea con un promedio de 35 ñ 2 (p=0.05). Los patrones que tuvieron una respuesta mejor, representada por el incremento de los niveles séricos de estradiol posterior al estímulo con a-GnRG, fueron A y B, ofreciendo un mejor pronóstico para el seguimiento en FIV

Regulacion de la luteinizacion folicular por un analago de la hormona liberada de gonadotrofinas (GnRH) / Regulation of follicular luteinization by an agonist of gonadotropin-releasing hormone (GnRH)

Tratamientos prolongados con análogos de GnRH son utilizados en la clínica con el objeto de suprimir la secreción endógena de gonadotrofinas, sin embargo estos análogos ejercen un efecto directo sobre el ovario. El objetivo de este trabajo fue estudiar la acción del análogo de GnRH acetato de leuprolide (LA) sobre esteroidogénesis y apoptosis ovárica. Se inyectó LA (1 Mug/rata/día) a ratas prepúberes superovuladas con PMSG/hCG. Se aislaron los cuerpo lúteos por microdisección y se incubaron durante 3 hs con LH (10 ng/ml) o dibutiril AMPc (dAMPc 1 mM). Se midió la progesterona producida observándose una disminución en el grupo LA tanto de la producción basal como en respuesta a LH (Basales = Control C: 96,6 + 9,6; LA: 22,9 + 2,8; LH= C: 145,7 + 4,9; LA: 23,6 + 2.0 ng/ml, p<0,001). En cambio el dAMPc estimuló significativamente en ambos casos (C: 153,9 + 11,8; LA:83,15 + 8,2). El AMPc producido fue menor en cuerpos lúteos del grupo LA y no fue estimulado por LH (Basales= C: 7,29 + 1,6; LA: 1,17 + 0,6; LH = C: 13,2 + 0,4; LA: 2,5 + 0,4 ng/ml, p<0,01). El contenido proteico por cuerpo lúteo fue semejante en los dos grupos. Por otro lado, teniendo en cuenta que en cortes histológicos de ovarios de ratas tratadas con LA encontramos mayor cantidad de folículos atrésicos y menor de cuerpos lúteos, hemos determinado la cantidad de células apoptóticas. Se tomó como criterio la presencia de cuerpos apoptóticos y núcleo en medialuna, detectándose un número mayor en el grupo LA. Este resultado fue confirmado por inmunohistoquímica (TUNEL). Se concluye que LA produce en el ovario una falla en el sistema receptor de LH- adenilato ciclasa y un aumento de la apoptosis celular.