Características clínicas y etiología de la ginecomastia en pacientes en edad prepuberal / Clinical features and etiology of gynecomastia in patients at prepubertal age

La ginecomastia es la proliferación benigna del tejido glandular mamario del varón, generalmente aparece en ciertos periodos de la vida como la época neonatal, puberal o senil, siendo la expresión de cierto disbalance en la acción de estrógenos y andrógenos en la glándula mamaria. Es poco frecuente durante la prepubertad y se debe investigar exhaustivamente el origen de la misma. Objetivo: evaluar las características clínicas y poder definir la etiología en un grupo de pacientes con ginecomastia prepuberal, Materiales y métodos: es un estudio retrospectivo, descriptivo y multicéntrico. Se recolectaron datos de antecedentes familiares, personales, examen físico, laboratorio, evolución, conducta terapéutica y se determinaron las posibles etiologías. Resultados: Fueron evaluados 53 pacientes con ginecomastia, con edad media de 8,4 años (0,88-13,72 años), se encontró mayor prevalencia en niños mayores de 7 años (79,2 %). La presentación bilateral fue la más frecuente en el 73,5 %, 17 (32 %) presentaron obesidad, siendo en 7 (13,7 %) severa (IMC ≥ 3 SDS). En 34 pacientes (64,1 %) no se encontró la etiología; en 12 pacientes (23,5 %) se constató fuente exógena de estrógeno; 2 pacientes con exceso de aromatasa; 1 con neurofibromatosis tipo I y glíoma del nervio óptico; 1 niño con tumor suprarrenal izquierdo productor de estrógenos y 1 paciente con síndrome de Peutz-Jeghers. Conclusión: La ginecomastia prepuberal es poco común, en esta población el mayor porcentaje fue idiopática o por exposición a estrógenos exógenos, pero es una señal de alarma que obliga a descartar la presencia de un trastorno endocrinológico importante.

Gynecomastia is the benign proliferation of male breast glandular tissue. The occurrence of gynecomastia at prepubertal ages is very uncommon and can be a sign of severe endocrine or systemic disease. The main underlying mechanism for the development of gynecomastia appears to be the imbalance between estrogen and androgen action. Objective: to assess clinical characteristics, etiology and course of prepubertal gynecomastia in a group of patients regularly followed at the endocrinology clinic. We performed a retrospective, descriptive, multicenter study. Materials and methods: data on family history, past history of the disease, physical examination, and clinical course were collected. Results: 53 prepubertal patients were included. Median age at presentation was 8.4 years (0.88-13.72 years). An increased prevalence was observed in children > 7 years (79.2 %). Bilateral gynecomastia was the most common form of presentation, (73.5 %). Seventeen patients (32 %) were obese, 7 (13.7 %) with a BMI above 3 SDS. In 34 patients (64.1 %) the etiology of gynecomastia could not be identified (idiopathic). In 12 patients (23.5 %) estrogen exposure was detected; 2 patients suffered from aromatase excess syndrome, 1 had neurofibromatosis type I and optic glioma, 1 had a feminizing adrenocortical tumor and 1 had Peutz-Jeghers syndrome. Conclusion: Prepubertal gynecomastia is rare. In this cohort of 53 children, the most common etiologies were idiopathic or exogenous estrogens exposure. Although gynecomastia may be due to benign causes, in the majority of patients evaluations should be performed to rule out a severe underlying systemic or endocrine disease.

La hormona de crecimiento durante el período de transición

La etapa de transición ha sido definida como el período de la vida que comienza hacia el fin de la pubertad y finaliza cuando se adquiere la maduración adulta completa. Esta fase dura aproximadamente 6 a 8 años y durante la misma se producen una serie de modificaciones cuantitativas y cualitativas en la esfera física y psíquica, caracterizadas por la adquisición de la talla y composición corporal adulta, del pico de masa ósea, la obtención de una plena capacidad fértil y, finalmente, de las características psicosociales propias del adulto. Deben recordarse los efectos que la hormona de crecimiento (GH) ejerce a lo largo de toda la vida del sujeto sobre el metabolismo, función y estructura cardíaca, hueso, composición corporal y calidad de vida. Sin embargo, hay datos conflictivos sobre la necesidad de continuar, sin interrupción, con la terapia de GH durante la etapa de transición. Se debe tener en cuenta, también, que existe un grupo de pacientes que adquieren la insuficiencia de GH durante el período de transición. Si bien existen claras evidencias que indican no discontinuar el tratamiento luego de haber finalizado la etapa de crecimiento, los pacientes deben ser reevaluados previamente para constatar si el déficit es suficientemente severo como para justificar mantener la terapéutica con GH. La respuesta a gran parte de estas dudas podrá resolverse con estudios randomizados y observacionales a largo plazo, desarrollados por equipos multidisciplinarios especializados.

Transition phase has been defined as the period of life starting in late puberty and ending with full adult maturation. This phase extends over approximately 6 to 8 years. A number of quantitative and qualitative changes occur during this phase both in physical and psychic aspects, which are characterized by attainment of adult height and body composition, peak bone mass, full reproductive potential and, finally, psychosocial characteristics inherent to adults. We should remember the effects exerted by growth hormone (GH) throughout the life of a subject on metabolism, cardiac function and structure, bone, body composition and quality of life. However, there are controversial data on the need to continue GH therapy during the transition period with no discontinuation. We should also take into account that there is a group of patients who develop GH deficiency during the transition period. Even if there is clear evidence against discontinuation of therapy after completion of the growth period, patients should be previously reevaluated to confirm if GH deficiency is severe enough to warrant continuation of GH therapy. The response to many of these issues may be obtained from long-term randomized and observational studies conducted by specialized multidisciplinary teams.

Cosecretion of glycosylated prolactin and non-glycosylated prolactin from childhood to the end of puberty.

BACKGROUND: Glycosylated prolactin (G-PRL) is considered as the major post-translational modification of prolactin (PRL) showing reduced lactotropic and mitogenic activities compared to non-glycosylated prolactin (NG-PRL). AIM: To evaluate the evolution of G-PRL in normoprolactinemic children and adolescents and to analyze possible variations in glycosylated/total prolactin (T-PRL) ratios. METHODS: T-PRL, G-PRL and NG-PRL were evaluated in 111 healthy female and male children and adolescents (4.1-18 years), classified as group 1 (Tanner I), group 2 (Tanner II-III) and group 3 (Tanner IV-V). G-PRL and NG-PRL were identified by chromatography on concanavalin-A-Sepharose. RESULTS: G-PRL/T-PRL (median-range): females, group 1: 0.59 (0.17-0.77), group 2: 0.56 (0.31-0.78), group 3: 0.60 (0.38-0.79); males, group 1: 0.64 (0.39-0.80), group 2: 0.61 (0.24-0.79), group 3: 0.62 (0.35-0.90); the p value is not significant among the different groups in both genders. G-PRL/T-PRL ratios do not change when comparing low (first quartile) versus high (third quartile) T-PRL levels in the different groups. CONCLUSION: Our study would appear to support cosecretion of G-PRL and NG-PRL from childhood to the end of puberty. Such cosecretion would not be dependent on sex steroid levels. It is important to point out that puberty does not change the proportions of G-PRL and NG-PRL.

Melatonina y deficiencia de hormona de crecimiento: contribucin a la evaluacin de los desrdenes neuroendocrinos / Melatonin and growth hormone deficiency: a contribution to the evaluation of neuroendocrine disorders

La melatonina constituye un integrante fundamental del denominado "reloj biolgico" y las alteraciones hormonales sueo-dependientes. Siendo la secrecin fisiolgica de GH, predominantemente nocturna, evaluamos en un grupo de nios y adultos deficitarios de GH (GHD) sin y con tratamiento sustitutivo, la secrecin nocturna de melatonina. Estudiamos 44 pacientes GHD: Grupo a (Ga): Nios sin tratamiento; Grupo b (Gb): Nios con tratamiento con GH (0.16 mg/Kg/semana, dosis estable por mnimo de 6 meses); Grupo c (Gc): Adultos sin tratamiento y Grupo d (Gd): Adultos con tratamiento con GH (0.1- 0.8 mg/da, para mantener IGF1 entre 0 y +2 SDS, dosis estable por mnimo de 6 meses). Todos los pacientes con dficits hormonales asociados estaban adecuadamente sustituidos. La produccin de melatonina fue evaluada a travs de la medicin de su principal metabolito urinario: 6-Sulfatoximelatonina (6-SM), dosado por radioinmunoensayo, en muestras nocturnas (6PM a 8AM). Los niveles de 6-SM nocturna expresados como μg/unidad de tiempo fueron (media SEM) para el grupo peditrico: Ga = 6.50 ( 5.10) y Gb = 8.21 ( 5.31) (Test de Mann-Whitney, p = 0.82). Para los adultos fueron: Gc = 2.99 ( 1.17) y Gd = 6.60 ( 2.00) (Test de Mann-Whitney, p = 0.35). En algunas alteraciones hipotlamo-hipofisarias han sido descriptas modificaciones del patrn secretorio de melatonina, pero no se han caracterizado en forma completa an, las posibles variaciones en pacientes con GHD. Si bien en las condiciones de este estudio, no hallamos diferencias en la excrecin nocturna de 6-SM entre los GHD no tratados y los tratados en ambos grupos, ello no invalida la existencia de posibles diferencias que podran detectarse estudiando la secrecin diurna de melatonina y su diferencia con la secrecin nocturna. Todo ello podr contribuir al conocimiento de los posibles desrdenes cronobiolgicos involucrados en la deficiencia de GH.

Melatonin, a hormone secreted by the pineal gland, constitutes a landmark in neuroendocrine integration. The relationship between melatonin and different pituitary hormones and sex steroids has been studied; however, the relationship between growth hormone (GH) and melatonin remains unclear. Considering that melatonin is an essential component of the so-called "biological clock", related to circadian rhythm, day-night cycle, and sleep-dependent hormonal alterations, and knowing that physiological GH secretion occurs predominantly at night, we decided to evaluate nocturnal melatonin secretion in a group of GH-deficient children and adults on and off replacement therapy. Patients and Methods: We studied 44 patients with GH deficiency (GHD), duly confirmed by pharmacological tests, divided into 4 groups: Group a (Ga ): untreated GHD children; Group b (Gb): GHD children on GH replacement therapy (0.16 mg/Kg/week, stable dose for at least 6 months); Group c (Gc): untreated GHD adults and Group d (Gd): GHD adults on GH replacement therapy (0.1- 0.8 mg/day, to maintain IGF1 between 0 and +2 SDS, stable dose for at least 6 months). All associated hormonal deficits were adequately replaced. Melatonin production was evaluated by measuring the excretion of its major urinary metabolite: 6-Sulphatoxymelatonin (6-SM). Urinary 6-SM was measured (radioimmunoassay, Stockgrand Ltd, Guildford, UK) in nocturnal samples (6PM to 8AM) in all patients. Results: Nocturnal 6-SM levels expressed as μg/unit of time were (mean SEM) for the pediatric group: Ga = 6.50 ( 5.10) and Gb = 8.21 ( 5.31) (Mann Whitney test, p = 0.82). For adults: Gc = 2.99 ( 1.17) and Gd = 6.60 ( 2.00) (Mann Whitney test, p = 0.35). Discussion and Conclusions: It is difficult to characterize the relationship between melatonin and GH in healthy individuals; however, the administration of intravenous melatonin stimulates GH secretion in normal adults. In some hypothalamic-pituitary alterations, changes in the secretory pattern of melatonin have been reported, but possible variations in GHD patients have not been thoroughly characterized yet. This led us to evaluate 6-SM concentrations in GH deficient children and adults on and off adequate replacement therapy. One of the major aspects of this study has been the evaluation of baseline 6-SM concentrations, with no physiological or pharmacological stimulation. Even if under the conditions of this study we found no differences in nocturnal excretion of 6-SM between untreated and treated GHD individuals in both groups, this does not rule out the potential existence of differences that might be detected by studying diurnal melatonin secretion and its difference with nocturnal secretion. Such studies may contribute to an understanding of potential chronobiological disorders involved in GH deficiency.

Insuficiencia ovárica primaria familiar asociada a una translocación X;autosoma / Familial primary ovarian insuffciency associated with X;autosomal translocation

La insuficiencia ovárica primaria (IOP) es una condición clínica que describe un estado de disfunción ovárica que se presenta antes de los 40 años. En el 8-9 % de las pacientes se han descripto anomalías del cromosoma X, tanto familiares como esporádicas. Estas incluyen anomalías numéricas como la monosomía o trisomía X, aneuploidías parciales como deleciones o isocromosomas, y anomalías estructurales como las translocaciones X;autosoma (TXA). Presentamos una paciente con diagnóstico de hipogonadismo hipergonadotrófico efectuado a los 18 años, en la que el estudio citogenético reveló un cariotipo 46,X,t(X;11)(q23;q22), interpretándose como una translocación X;autosoma balanceada con punto de ruptura en la región crítica para la función ovárica normal. A los 25 años de edad, bajo tratamiento hormonal sustitutivo cursó un embarazo. Nació una niña con crecimiento y desarrollo normales, con telarca y pubarca a los 11 años. A los 13 años y 3 meses, debido a una detención en el desarrollo puberal, se le diagnosticó un hipogonadismo hipergonadotrófico. El estudio citogenético detectó la traslocación X;autosoma balanceada heredada de su madre. Las mujeres con translocaciones X;autosoma balanceadas frecuentemente desarrollan falla ovárica prematura por interrupción de la región crítica del cromosoma X que se extiende entre Xq13 a Xq27. En conclusión, presentamos dos pacientes (madre e hija) con diagnóstico de una TXA balanceada, y discutimos los aspectos vinculados con las alteraciones de los segmentos del cromosoma X involucrados en el funcionamiento ovárico, así como las consecuencias para su eventual descendencia.

Primary Ovarian Insufficiency (POI) is a clinical condition characterized by ovarian dysfunction before 40 years of age. In 8-9 % of patients, both familial and sporadic chromosome abnormalities have been reported. These include numerical abnormalities such as monosomy or trisomy X, partial aneuploidies, such as deletions or isochromosomes, and structural abnormalities such as X;autosomal translocation (XAT). We report the case of a patient diagnosed with hypergonadotropic hypogonadism at the age of 18, whose cytogenetic study revealed a formula 46,X,t(X;11)(q23;q22), interpreted as an X;autosome balanced translocation with breakpoint in the critical region for normal ovarian differentiation. At the age of 25, under hormone replacement therapy, the patient became pregnant. She gave birth to a girl with normal growth and development, with thelarche and menarche at 11 years old. At the age of 13 years and 3 months, because of an arrest of pubertal development, she was diagnosed with hypergonadotropic hypogonadism. The cytogenetic study detected the X;autosome balanced translocation inherited from her mother. Women with X;autosome balanced translocation frequently develop premature ovarian failure because of breakpoints in the critical region of the X chromosome from Xq13 to Xq27. In conclusion, we report the case of two patients (mother and daughter) with a diagnosis of XAT, and discuss molecular genetics issues related to alterations of X chromosome segments involved in ovarian function, as well as the consequences for potential offspring.

Prolactinoma in children and adolescents.

The evolution of prolactinomas in children and adolescents continues to be controversial. Girls have more prevalence of microprolactinomas and their signs and symptoms are related to hyperprolactinemia and the resulting hypogonadotrophic hypogonadism. In males, the greater incidence of macroadenomas results in the presence of neuro-ophthalmologic signs. The larger prevalence of macroadenomas in males is consistent with findings in adults and would not be related to a later diagnosis. In patients with asymptomatic hyperprolactinemia, the presence of altered proportions of PRL isoforms should be evaluated. The diagnosis of prolactinoma requires both radiographic evidence of pituitary adenoma and laboratory analysis documenting the presence of sustained hyperprolactinemia. Because of their effectiveness and tolerance, dopaminergic agonists are the initial therapy of choice in pediatric age patients. Finally, molecular biology and genetic studies have brought new insights into the pathogenesis, clinical behavior and different therapeutic responses.

Hiperprolactinemia en la población infantojuvenil: un tema vigente / Hyperprolactinaemia in child an adolescent population: a current issue

La hiperprolactinemia constituye la altelaración endocrina más común del eje hipotálamo-hipofisario, aunque su prevalencia en la población infantojuvenil no está aún claramente definida. Además de la Prolactina (PRL) nativa (23Kda), se han descripto numerosas variantes moleculares, algunas de ellas con menor o ausente actividad biológica. Todo proceso que interrumpa la secreción de dopamina, interfiera con su liberación hacia los vasos portales hipofisarios o bloquee los receptores dopaminérgicos de las células lactotróficas, puede causar hiperprolactinemia. Si bien la patología tumoral constituye el diagnóstico de mayor relevancia, los prolactinomas son poco frecuentes en nios y adolescentes, aunque tienen en general una particular presentación clínica: de acuerdo con nuestra experiencia, el retraso puberal puede observarse en aproximadamente el 50% de las pacientes de sexo femenino. En pacientes con hiperprolactinemia asintomática debe evaluarse la presencia de proporciones alteradas de isoformas de PRL. La cromatografía en columna con sephadex G100, la precipitación con suspención de proteína A o con PEG y la ultracentrifugación constituyen los métodos más frecuentemente empleados para la detección de las distintas isoformas de PRL. En nuestra experiencia la B PRL constituyó el 6,6 - 32,6% de la PRL total y la BB PRL contituyó el 40 y el 72% de çesta en este gruo de pacientes. En cuanto al tratamiento por su efectividad y tolerancia, los agonistas dopaminérgicos constituyen la terapia inicial de elección en pacientes en edad pediátrica. La bromocriptina y la cabergolina han sido empleadas y con resultados similares a los de los pacientes adultos.

[Subcutaneous and intranasal use of a LH-RH analog in the treatment of girls with central precocious puberty]. / Utilización de un análogo de LH-RH subcutáneo e intranasal en el tratamiento de niñas con pubertad precoz central.

Luteinizing hormone-releasing hormone analogues (LH-RHa) offer a novel approach for non-steroidal manipulation of the reproductive endocrine axis. LH-RH agonists are now employed in the management of central precocious puberty (CPP). The aim of the present work is to show the results of one of the first experiences in our country in the therapeutics of this pathology with LH-RHa (Buserelin) both subcutaneously (SC) and intranasally (IN). Five girls with CPP, aged 1.3 to 6.8 years, were selected (Table 1). The doses employed were: 25 micrograms/kg/day in 2 SC applications followed by 1200 micrograms/day IN. In case 4 IN route only was used because she presented an allergic cutaneous reaction to the SC injection and in case 3 only the SC route was employed because of her chronological age. The period of treatment oscillated between 3 and 21 months. In 2 girls 150 mg of medroxyprogesterone was administered before the analogue therapy and it was maintained during a week. In 4 patients a regression of breast development was observed to Tanner's I or II incipient grades and in case 1 only partial involution was noted. In 4 of the 5 patients, annual growth velocity could be evaluated, showing in 3 of them a reduction between 40 and 55% VS pretreatment associated with a desacceleration of the skeletal maturation (Figs. 1, 2). The prediction of adult height increased 2 cm in one case and 4.5 cm in 2 cases; 4/5 girls showed a reduction of FSH, LH and estradiol levels to prepubertal values after 3 months of treatment and in one patient after 6 months of therapy (Fig. 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Utilización de un análogo de LH-RH subcutáneo e intranasal en el tratamiento de niñas con pubertad precoz central. / [Subcutaneous and intranasal use of a LH-RH analog in the treatment of girls with central precocious puberty]

Luteinizing hormone-releasing hormone analogues (LH-RHa) offer a novel approach for non-steroidal manipulation of the reproductive endocrine axis. LH-RH agonists are now employed in the management of central precocious puberty (CPP). The aim of the present work is to show the results of one of the first experiences in our country in the therapeutics of this pathology with LH-RHa (Buserelin) both subcutaneously (SC) and intranasally (IN). Five girls with CPP, aged 1.3 to 6.8 years, were selected (Table 1). The doses employed were: 25 micrograms/kg/day in 2 SC applications followed by 1200 micrograms/day IN. In case 4 IN route only was used because she presented an allergic cutaneous reaction to the SC injection and in case 3 only the SC route was employed because of her chronological age. The period of treatment oscillated between 3 and 21 months. In 2 girls 150 mg of medroxyprogesterone was administered before the analogue therapy and it was maintained during a week. In 4 patients a regression of breast development was observed to Tanners I or II incipient grades and in case 1 only partial involution was noted. In 4 of the 5 patients, annual growth velocity could be evaluated, showing in 3 of them a reduction between 40 and 55

VS pretreatment associated with a desacceleration of the skeletal maturation (Figs. 1, 2). The prediction of adult height increased 2 cm in one case and 4.5 cm in 2 cases; 4/5 girls showed a reduction of FSH, LH and estradiol levels to prepubertal values after 3 months of treatment and in one patient after 6 months of therapy (Fig. 3).(ABSTRACT TRUNCATED AT 250 WORDS)