Hipogonadismo masculino secundario a macroprolactinoma / Men with hypogonadism secondary to macroprolactinoma / Hipogonadismo masculino secundário a macroprolactinoma

Los prolactinomas son los tumores funcionantes de hipófisis más frecuentes. Se clasifican según su tamaño en microprolactinomas (menores a 1 cm) y macroprolactinomas (mayor o igual a 1 cm). Estos últimos tienen mayor frecuencia en hombres y en general se diagnostican más tardíamente, cuando aparecen síntomas compresivos. La hiperprolactinemia interfiere con la secreción pulsátil de la hormona liberadora de gonadotropinas (GnRH), lo que genera la inhibición de secreción de hormona luteinizante (LH) y de hormona foliculoestimulante (FSH), y en consecuencia produce hipogonadismo hipogonadotrófico. El presente artículo reporta un caso clínico de un paciente de 26 años, de sexo masculino, en el que se realiza el diagnóstico de hipogonadismo hipogonadotrófico secundario a un macroprolactinoma, en el contexto de una pubertad detenida.

Prolactinomas are the most common functioning pituitary tumors. According to size, they are classified into microprolactinomas (smaller than 1 cm) and macroprolactinomas (larger than or equal to 1 cm). The latter are more frequent among men and in general of late diagnosis upon compressive symptoms. Hyperprolactinemia interferes with the pulsatile secretion of the gonadotrophin releasing hormone (GnRH)) what results in inhibition of the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), what consequently produces hypogonadotrophic hypogonadism. The study reports the clinical case of a 26-year-old male who was diagnosed with hypogonadotrophic hypogonadism secondary to macroprolactinoma, within the context of detained puberty.

Os prolactinomas são os tumores hipofisários funcionantes mais comuns. São classificados de acordo com seu tamanho em microprolactinomas (menos de 1 cm) e macroprolactinomas (maior ou igual a 1 cm). Estas últimas são mais frequentes em homens e geralmente são diagnosticadas mais tarde, quando aparecem sintomas compressivos. A hiperprolactinemia interfere na secreção pulsátil do hormônio liberador de gonadotropina (GnRH), levando à inibição da secreção do hormônio luteinizante (LH) e do hormônio folículo-estimulante (FSH) e, consequentemente, hipogonadismo hipogonadotrófico. Este artigo relata o caso clínico de um paciente do sexo masculino de 26 anos, no qual é feito o diagnóstico de hipogonadismo hipogonadotrófico secundário a um macroprolactinoma, no contexto de puberdade interrompida.

Considerations when treating male pubertal delay pharmacologically.

INTRODUCTION: Delayed puberty , usually affects psychosocial well-being. Patients and their parents show concern about genital development and stature. The condition is transient in most of the patients; nonetheless, the opportunity should not be missed to diagnose an underlying illness. AREAS COVERED: The etiologies of pubertal delay in males and their specific pharmacological therapies are discussed in this review. EXPERT OPINION: High-quality evidence addressing the best pharmacological therapy approach for each etiology of delayed puberty in males is scarce, and most of the current practice is based on small case series or unpublished experience. Male teenagers seeking attention for pubertal delay most probably benefit from medical treatment to avoid psychosocial distress. While watchful waiting is appropriate in 12- to 14-year-old boys when constitutional delay of growth and puberty (CGDP) is suspected, hormone replacement should not be delayed beyond the age of 14 years . When hypogonadism is diagnosed, hormone replacement should be proposed by the age of 12 years . Testosterone replacement has been used for decades and is fairly standardized. Aromatase inhibitors have arisen as an interesting alternative . Gonadotrophin therapy seems more physiological in patients with central hypogonadism, but its efficacy and timing still need to be established.

Delayed Puberty Phenotype Observed in Noonan Syndrome Is More Pronounced in Girls than Boys.

INTRODUCTION: Pubertal delay is described as one of the clinical features in Noonan syndrome (NS) and it may be one of the factors causing short adult height in those patients. The present study aimed at characterizing pubertal development in NS and identifying pubertal delay predictors. METHODS: We analyzed 133 individuals with a molecular diagnosis of NS and clinical puberty evaluation. We characterized delayed puberty as pubertal onset after 12 years in girls and 13.5 years in boys, according to parameters of the Brazilian population. To investigate its predictors, we correlated the age at onset of puberty with several characteristics and genotype in a multilevel regression model. For comprehending pubertal development in NS, we assessed age and anthropometric measures at each Tanner stage and adult age. RESULTS: The mean age at puberty onset for girls was 11.9 ± 1.9 years and for boys, 12.5 ± 1.7 years, significantly later than the Brazilian population (p = 0.025; p < 0.001). Girls (49.1%) presented delayed puberty more frequently than boys (27.9%, p = 0.031). Body mass index standard deviation scores (SDS) and insulin growth factor 1 SDS at puberty onset significantly predicted later puberty entry. Height gain from the onset of puberty to adult height was lower in children with pubertal delay. CONCLUSION: Pubertal delay is characteristically found in children with NS, more frequently in females. The low weight of patients with NS could modulate the age of puberty, just as the increase in overweight/obesity in the general population has shown an effect on reducing the age of onset of puberty.

The role of acid-labile subunit (ALS) in the modulation of GH-IGF-I action.

Acid-labile subunit (ALS) deficiency (ACLSD) constitutes the first monogenic defect involving a member of the Insulin-like Growth Factor (IGF) binding protein system. The lack of ALS completely disrupts the circulating IGF system. Autocrine/paracrine action of local produced IGF-I could explain the mild effect on growth. In the present work we have revised the more relevant clinical and biochemical consequences of complete ACLSD in 61 reported subjects from 31 families. Low birth weight and/or length, reduced head circumference, height between -2 and -3 SD, pubertal delay and insulin resistance are commonly observed. Partial ACLSD could be present in children initially labeled as idiopathic short stature, presenting low IGF-I levels, suggesting that one functional IGFALS allele is insufficient to stabilize ternary complexes. Dysfunction of the GH-IGF axis observed in ACLSD may eventually result in increased risk for type-2 diabetes and tumor progression. Consequently, long term surveillance is recommended in these patients.

Clinical and Genetic Characterization of a Constitutional Delay of Growth and Puberty Cohort.

INTRODUCTION: Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. Family history of delayed puberty (2 or more affected members in a family) has been evidenced in 50-75% of patients with CDGP and the inheritance is often consistent with autosomal dominant pattern, with or without complete penetrance. However, the molecular basis of CDGP is not completely understood. OBJECTIVE: To characterize the clinical and genetic features of a CDGP cohort. METHODS: Fifty-nine patients with CDGP (48 boys and 11 girls) underwent careful and long-term clinical evaluation. Genetic analysis was performed using a custom DNA target enrichment panel designed to capture 36 known and candidate genes implicated with pubertal development. RESULTS: All patients had spontaneous or induced pubertal development (transient hormonal therapy) prior to 18 years of age. The mean clinical follow-up time was 46 ± 28 months. Male predominance (81%), short stature (91%), and family history of delayed puberty (59%) were the main clinical features of this CDGP -cohort. Genetic analyses revealed 15 rare heterozygous missense variants in 15 patients with CDGP (25%) in seven different genes (IGSF10, GHSR, CHD7, SPRY4, WDR11, SEMA3A,and IL17RD). IGSF10 and GHSR were the most prevalent affected genes in this group. CONCLUSIONS: Several rare dominant variants in genes implicated with GnRH migration and metabolism were identified in a quarter of the patients with familial or sporadic CDGP, suggesting genetic heterogeneity in this frequent pediatric condition.

Influence of sexual maturation status on the relationship between body adiposity indicators and age: a cross-sectional study.

OBJECTIVES: To determine the influence of sexual maturation status on adiposity indicators of children and adolescents. RESULTS: 2412 individuals participated, 1285 (47.4%) males and 1408 (52.6%) females. There was moderate to weak correlation between age and adiposity indicators for both sexes. By analyzing the relationship between age and body fat indexes adjusted for Sexual Maturation Status, several changes were observed, mainly in girls. Precocious maturation was associated with increased adiposity indicators in girls, whereas late maturation was associated with decreased adiposity indicators in both sexes. Precocious maturation was associated with increased adiposity indicators in girls, whereas late maturation was associated with decreased adiposity indicators in both sexes.

Pubertad. Inicio. Pubertad precoz. Pubertad retardada / Puberty. Initiation. Precocious puberty. Delayed puberty

Se hace una revisión sobre los mecanismos moleculares implicados en la iniciación de la pubertad incluyendo la leptina y las kisspeptinas. La leptina es un péptido producido en el tejido adiposo e implicado en la regulación del apetito. Además este péptido interactúa con otros a nivel central e interfiere con la función del eje reproductivo, en especial la proopiomelanocortina (POMC) y el neuropéptido Y (NPY). La restricción de alimento retrasa la pubertad y el exceso de leptina la acelera. La señalización a través de neuronas productoras de kisspeptina es importante para la iniciación de la pubertad y la unión con su receptor activa una cascada de señalización sobre la producción de GnRH. Se han descrito otras vías implicadas en el comienzo de la pubertad que aún se encuentran en estudio. Se estima que gran parte de la variación del momento de la pubertad en humanos tiene que ver con factores genéticos.

A review is done about the molecular mechanisms implicated in puberty beginning, including leptin and kisspeptins. Leptin is a peptide produced in adipose tissue and implicated in appetite regulation. This peptide interacts with other peptides in central level and interferes with reproductive axis functioning, especially with proopiomelanocortin (POMC) and Neuropeptide Y (NPY). Food intake restriction delays puberty while leptin excess accelerates it. Signaling through kisspeptin producing neurons is important for initiation of puberty and union with its receptor activates a signaling cascade over GnRH production. Other paths implicated in puberty initiation have been described but are still being studied. It is estimated that great part of variations in the moment of puberty in humans are related to genetic factors.

Clinical and cytogenetic features of 516 patients with suspected Turner syndrome - a single-center experience.

BACKGROUND: Clinical suspicion of Turner syndrome (TS) may be challenging. Short stature and absent puberty are not mandatory and the dysmorphic picture is widely variable. The aim of the study was to describe a representative sample of patients with suspected TS in a single center and to verify which set of features may help discriminate those with TS. METHODS: This was a retrospective study of patients with suspected TS evaluated between 1989 and 2012 with the same clinical and cytogenetic protocols. Data regarding reason for referral, age and height at diagnosis, birth data, pubertal features and dysmorphisms were analyzed. RESULTS: TS was diagnosed in 36% of 516 patients; structural chromosome anomalies predominated (42%). Short stature was the main reason for referral of patients with and without TS. The mean age of patients at first visit, with TS or without TS was similar (11.89 and 11.35 years, respectively), however, infants and adolescents predominated in the TS group. The mean full-term birth weight was lower in patients with TS as well as height at diagnosis, but normal height z-score was found in 17% of patients. Spontaneous puberty occurred in 30% of TS patients aged 13 years or more, but most had pubertal delay. Residual lymphedema, webbed neck, cubitus valgus, hyperconvex nails, shield chest, abnormal nipples, pigmented nevi, short fourth metacarpal and shorter height were the best discriminators for girls with TS. CONCLUSIONS: Though short stature, pubertal delay and typical stigmata should prompt investigation of TS, lack of one of these features should not exclude this hypothesis. Dysmorphisms other than those considered "typical" should be sought on physical examination.

Alteraciones puberales en adolescentes con leucemia en fase de vigilancia.

OBJECTIVE: To evaluate which factors are associated with alterations in pubertal development in pediatric patients with leukemia in the surveillance phase. METHOD: A case-control study was carried out, including patients aged 8-14 years with diagnosis of acute lymphoblastic leukemia under surveillance. Demographic data were collected, age at diagnosis, type of leukemia, risk of leukemia, duration and type of treatment received, time of surveillance phase; and pubertal development was assessed by Tanner stage, bone age, pelvic ultrasound for women, and LH levels. Fisher's exact test and Mann-Whitney U-test were used. RESULTS: Twenty-five pediatric patients with a diagnosis of acute lymphoblastic leukemia between 8 and 14 years of age with a median of 8 were included, only 4 (16%) presented pubertal alterations, 1 had pubertal delay and 3 advanced puberty. The history of radiotherapy was related to pubertal alterations (p = 0.03). CONCLUSIONS: The antecedent of having received radiotherapy as part of the treatment in patients with acute lymphoblastic leukemia is a risk factor for developing pubertal abnormalities.

Evaluation of Delayed Puberty in Adolescents With Cleft Lip/Palate.

OBJECTIVE: To assess the frequency of delayed puberty in adolescents with cleft lip and/or cleft palate (CL/P). DESIGN: This was a cross-sectional study of 203 patients with CL/P and no associated syndromes treated at the Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, Brazil. We evaluated boys aged 14-19 years and girls aged 13-18 years. The patients were classified according to Tanner stages of sexual development. The age of menarche was recorded. Patients were assigned to three groups according to cleft type: isolated cleft lip (CL), cleft lip and palate (CLP), and isolated cleft palate (CP). The results were expressed as frequencies and averages and compared with pubertal changes described for typically developing adolescents as reported in the literature. RESULTS: Subjects were 115 boys and 88 girls. All boys in the CL group and the CP group had already started puberty, and two boys in the CLP group (2.3%) had delayed puberty. All girls had started puberty. The average age at menarche was 12.3 years in the CL group, 12.1 years in the CLP group, and 12.5 years in the CP group. CONCLUSIONS: The frequency of delayed puberty and the average age at menarche in adolescents with CL/P and no associated genetic syndromes or anomalies were within the expected range for typically developing adolescents (i.e., those without CL/P) in the same age group.

Retraso Puberal. Reporte de caso / Delayed Puberty. Case Report

La pubertad ocurre generalmente entre los 7 y 13 años de edad en las niñas, y entre los 9 y 15 años en los niños, se considera retraso puberal cuando no ha comenzado su desarrollo luego de esta edad. El crecimiento es el proceso fisioló- gico más característico de la infancia y la adoles- cencia, determinado genéticamente en algunos casos y en otros dependerá de la compleja interacción de factores ambientales; un retraso en el diagnóstico puede ocasionar el detrimen- to no solo de la talla y maduración sexual final sino de su salud integral por la falta de un trata- miento oportuno. El presente caso trató de un paciente masculino de 18 años de edad con antecedente de desnutrición y diarrea crónica más síndrome convulsivo secundaria a hipona- tremia, por el cual fue referido; sin embargo desde el punto de vista de crecimiento y desa- rrollo presentaba peso, talla e IMC por debajo del percentil 3 para su edad y características sexuales secundarias no desarrolladas, durante su hospitalización se realizó pruebas hormona- les LH:1.49 mlU/ml, FSH: 8.51 mlU/ml, Testoste- rona: 0.22 ng/ml, Factor de Crecimiento insulini- co tipo 1: 87.30 ng/ml e imágenes Rx de mano y muñeca izquierda que mostró edad ósea de 12 años con 2 meses +/- 2 años DE, los cuales fueron necesarios para definir la enfermedad de base, el diagnóstico clínico de un hipogonadis- mo y retraso puberal en el adulto no son habi- tuales en la práctica médica, hecho en el cual radica la relevancia del caso presentado...(AU)

Accuracy of Endocrine Tests for Detecting Hypogonadotropic Hypogonadism in Girls.

OBJECTIVE: To assess the accuracy of inhibin B and the gonadotropin releasing hormone agonist test for the diagnosis of hypogonadotropic hypogonadism (HH). STUDY DESIGN: We performed a retrospective analysis of data collected 2009-2014 using a strict clinical protocol. All prepubertal nonunderweight girls, aged 13-17.5 years with Tanner breast stage B1/B2 and low estradiol levels, were tested and re-examined at 6-month intervals (n = 21). Constitutional delay of growth and puberty was defined by spontaneous menarche; HH was identified by association with specific causes of HH or no spontaneous progress of puberty during follow-up. Inhibin B was measured using enzyme-linked immunosorbent assay, and follicle-stimulating hormone and luteinizing hormone (basal and stimulated by triptorelin) were measured using a chemiluminescence immunoassay. RESULTS: The cohort comprised 12 girls with constitutional delay of growth and puberty and 9 girls with HH. The causes of HH included hypopituitarism (n = 3), Prader-Willi syndrome, chromosomal aberration, intellectual disability syndrome with ataxia, and idiopathic causes (n = 2). Each measurement, basal inhibin B <20 pg/mL or stimulated follicle-stimulating hormone (4 hours) <11 IU/L, demonstrated a sensitivity and a specificity of 100% for the detection of HH. Stimulated luteinizing hormone (4 hours) <9 IU/L showed 100% sensitivity but only 83% specificity. CONCLUSIONS: Inhibin B seems to be the ideal measurement for detecting HH in girls. The gonadotropin releasing hormone agonist test is an alternative diagnostic modality, although this approach is more invasive and laborious.

Alteraciones del olfato asociadas a hipogonadismo hipogonadotrófico. Su importancia en la detección precoz / Changes associated with the smell hypogonadotropic hypogonadism. It’s importance in the early detection / Alterações associadas à hipogonadismo cheiro hypogonadotropic. Sua importância no detecção precoce alterações associadas à hipogonadismo cheiro hypogonadotropic. Sua importância na detecção precoce

Introducción: El hipogonadismo hipogonadotrófico asociado a alteraciones del olfato (HHAAO), esuna variante de hipogonadismo hipogonadotrófico, que se asocian a un defecto en la hipófisis o en elhipotálamo, obedeciendo a una falta de hormonas que en condiciones normales estimulan a los ovarioso los testículos.Casos clínicos: Este protocolo se originó a partir de pacientes que consultaron por alteraciones del olfato, desde octubre de 2013 hasta octubre de 2014, de30 pacientes entre 6 a 16 años, se detectaron 3 mujeres menores de 15 años de edad; que presentaron anosmia constatada por olfatometría y ausencia debulbos olfatorios en resonancia magnética nuclear. Una paciente presentó hipoacusia...

Introduction: The hypogonadotropic hypogonadism associated with disturbances of smell (HHAAO),is a variant of hypogonadotropic hypogonadism, which are associated to a defect in thepituitary or hypothalamus, obeying a lack of hormonesthat normally stimulate the ovaries or thetesticles. Clinical case: This originated from patients who consulted for disorders of smell, from October 2013to October 2014, 30 patients aged 6-16 years were detected, 3 women under 15 years of age; they hadanosmia proven by olfactometry and absence of olfactory bulbs in Nuclear Magnetic Resonance. Onepatient had hearing lost...

Introdução: O hipogonadismo hipogonadotrófico associada a distúrbios do olfato (HHAAO), é uma variante de hipogonadismo hipogonadotrófico, que estão associados a um defeito na hipófise ou hipotálamo,obedecendo a uma falta de hormônios que normalmente estimulam os ovários ou os testículos.Caso clínico: Este provenientes de pacientes que consultaram para distúrbios do olfato, a partir de outubro 2013 a outubro de 2014, 30 pacientes comida de entre 6-16 anos foram detectados, três mulheres com menos de 15 anos de idade; eles tinha manosmia comprovada por olfatometria e ausência de bulbos olfatórios em Ressonância Magnética Nuclear.Um paciente apresentou perda auditiva...

Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay.

OBJECTIVE: To analyze the GNRHR in patients with normosmic isolated hypogonadotropic hypogonadism (IHH) and constitutional delay of growth and puberty (CDGP). DESIGN: Molecular analysis and in vitro experiments correlated with phenotype. SETTING: Academic medical center. PATIENT(S): A total of 110 individuals with normosmic IHH (74 male patients) and 50 with CDGP. INTERVENTION(S): GNRHR coding region was amplified and sequenced. MAIN OUTCOME MEASURE(S): Novel variants were submitted to in vitro analysis. Frequency of mutations and genotype-phenotype correlation were analyzed. Microsatellite markers flanking GNRHR were examined in patients carrying the same mutation to investigate a possible founder effect. RESULT(S): Eleven IHH patients (10%) carried biallelic GNRHR mutations. In vitro analysis of novel variants (p.Y283H and p.V134G) demonstrated complete inactivation. The founder effect study revealed that Brazilian patients carrying the p.R139H mutation shared the same haplotype. Phenotypic spectrum in patients with GNRHR mutations varied from complete GnRH deficiency to partial and reversible IHH, with a relatively good genotype-phenotype correlation. One boy with CDGP was heterozygous for the p.Q106R variant, which was not considered to be pathogenic. CONCLUSION(S): GNRHR mutations are a frequent cause of congenital normosmic IHH and should be the first candidate gene for genetic screening in this condition, especially in autosomal recessive familial cases. The founder effect study suggested that the p.R139H mutation arises from a common ancestor in the Brazilian population. Finally, mutations in GNRHR do not appear to be involved in the pathogenesis of CDGP.