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INTRODUCTION: Cushing's syndrome (CS) constitutes one of the most challenging diagnostic assessments for paediatric endocrinologists. The clinical presentation of some children with exogenous obesity overlaps with those observed in hypercortisolism states. Accurate, non-invasive first-line tests are necessary to avoid false-positive results in the obese. We aimed to evaluate the diagnostic accuracy of salivary cortisol to assess endogenous hypercortisolism in children with obesity and clinical overlapping signs of Cushing's syndrome. METHODS: Case-control study that included children aged 2-18 years, BMI-SDS ≥ 2.0 and a follow-up >2 years. Patients were assigned to three categories: Group A, features strongly indicative of paediatric CS (growth failure combined with increasing weight); Group B, features suggestive of CS (e.g. moon face and striae); and Group C, less specific features overlapping with CS (e.g. hypertension, hirsutism, insulin resistance). Children in categories A and B formed the control group. Ten patients with confirmed CS were the case group. All children collected saliva samples on the same day in the morning between 7 to 8 am (morning salivary cortisol: mSC) and at 11 pm (nocturnal salivary cortisol: nSC). The mSC and nSC results were used to calculate the percentage decrease of cortisol at night (%D). Main outcomes by ROC for nSC and the %D were sensitivity, specificity, positive (P) and Negative (N) predictive values (PV) and their corresponding 95%IC. Salivary cortisol was measured by electrochemiluminiscence assay (lower limit of quantification: 2.0 nmol/L). RESULTS: 75/112 children met the inclusion criteria, whereas 22/75 children were eligible for the control group. Only controls decreased nSC [median and interquartile range: 2.0 (2.0-2.5) nmol/L] compared to mSC [6.9 (4.8-10.4) nmol/L], p< 0.0001. A cut-off for nSC ≥8 nmol/L confirmed CS within a sensitivity: 1.0 (0.69 to 1.0), specificity: 1.0 (0.85 to 1.0), PPV: 1.0 (0.69 to 0.99) and NPV: 1.0(0.85 to 0.99), achieving a diagnostic efficiency of 100%. The cut-off obtained for %D was 50%. No child with CS had a %D ≥50%, but 6/22 children in the control group had a %D below the cut-off, resulting in a lower overall diagnostic accuracy of 81% compared to nSC. CONCLUSION: Salivary cortisol at 11 pm is an accurate, feasible and non-invasive first-line test to assess endogenous hypercortisolism in children with obesity and clinical suspicion of Cushing's syndrome. The nSC was also useful in showing that the circadian rhythm of cortisol was preserved in children with exogenous obesity. In patients with nSC ≥8.0 nmol/L, other biochemical assessments and imaging studies are needed to further confirm the aetiology.
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BACKGROUND: Abdominal obesity is an important cardiovascular disease risk factor. Plasma fatty acids display a complex network of both pro and antiatherogenic effects. High density lipoproteins (HDL) carry out the antiatherogenic pathway called reverse cholesterol transport (RCT), which involves cellular cholesterol efflux (CCE), and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities. OBJECTIVES: Our aim was to characterize RCT and its relation to fatty acids present in plasma in pediatric abdominal obesity. METHODS: Seventeen children and adolescents with abdominal obesity and 17 healthy controls were studied. Anthropometric parameters were registered. Glucose, insulin, lipid levels, CCE employing THP-1 cells, LCAT and CETP activities, plus fatty acids in apo B-depleted plasma were measured. RESULTS: The obese group showed a more atherogenic lipid profile, plus lower CCE (Mean±Standard Deviation) (6 ± 2 vs. 7 ± 2%; P < 0.05) and LCAT activity (11 ± 3 vs. 15 ±5 umol/dL.h; P < 0.05). With respect to fatty acids, the obese group showed higher myristic (1.1 ± 0.3 vs. 0.7 ± 0.3; P < 0.01) and palmitic acids (21.5 ± 2.8 vs. 19.6 ± 1.9; P < 0.05) in addition to lower linoleic acid (26.4 ± 3.3 vs. 29.9 ± 2.6; P < 0.01). Arachidonic acid correlated with CCE (r = 0.37; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05), palmitioleic acid with CCE (r = -0.35; P < 0.05), linoleic acid with CCE (r = 0.37; P < 0.05), lauric acid with LCAT (r = 0.49; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05) ecoisatrienoic acid with CCE (r = 0.40; P < 0.05) and lignoseric acid with LCAT (r = -0.5; P < 0.01). CONCLUSIONS: Children and adolescents with abdominal obesity presented impaired RCT, which was associated with modifications in proinflammatory fatty acids, such as palmitoleic and myristic, thus contributing to increased cardiovascular disease risk.
Subject(s)
Cardiovascular Diseases , Fatty Acids , Humans , Adolescent , Child , Obesity, Abdominal , Obesity , Cholesterol/metabolism , Linoleic Acids , Myristic AcidsABSTRACT
INTRODUCTION: The prevalence of polycystic ovarian syndrome (PCOS) in adolescent girls is between 1 and 4.3%. It remains controversial whether women with a history of idiopathic central precocious puberty (ICPP) are at increased risk for PCOS. Our objective was to assess the prevalence of PCOS in adolescents with a history of ICPP compared with healthy adolescents and the prevalence of PCOS among ICPP girls who have received or not gonadotropin-releasing hormone analogue (GnRHa) treatment. METHODS: We assessed post-menarcheal girls with a history of ICPP. Girls were evaluated at gynecological age ≥2.5 years. Data collected were age at menarche, menstrual cycle characteristics, BMI, clinical hyperandrogenism (HA), total and free testosterone levels. PCOS diagnosis was defined by criteria for adolescents. Subjects were also analyzed regarding whether or not they had received GnRHa treatment. RESULTS: Ninety-four subjects were assessed, and 63 had been treated with GnRHa. Menstrual disorders were found in 29%, clinical HA in 36%, and biochemical HA in 23%. Twelve percent met the diagnostic criteria for PCOS. There was no difference in BMI or in the incidence of menstrual dysfunction or hyperandrogenemia between treated and untreated patients. A higher proportion of clinical HA was found in untreated patients when compared to treated girls. The relative risk (RR) of developing PCOS in ICPP girls was 2.5 compared to a population of healthy adolescents. This RR was not higher in patients who received treatment with GnRHa than in those who did not. CONCLUSION: Adolescent girls with a history of ICPP have an increased risk of PCOS. This risk seems not to be related to GnRHa treatment.
Subject(s)
Hyperandrogenism , Polycystic Ovary Syndrome , Puberty, Precocious , Adolescent , Female , Humans , Child, Preschool , Polycystic Ovary Syndrome/complications , Polycystic Ovary Syndrome/epidemiology , Puberty, Precocious/drug therapy , Prevalence , Hyperandrogenism/complications , Hyperandrogenism/epidemiology , MenarcheABSTRACT
INTRODUCTION: Assessment of the hypothalamic-pituitary-adrenal (HPA) axis is necessary after prolonged glucocorticoid therapy withdrawal. Salivary cortisol reflects 65% of the free circulating cortisol fraction. Saliva collection is non-invasive and child friendly. OBJECTIVE: We aimed to evaluate the diagnostic accuracy of morning salivary cortisol (mSAF) to determine HPA recovery after prolonged corticosteroid therapy in children. METHODS: We conducted a prospective, validation study in 171 paediatric patients (mean ± SD age: 13.0 ± 4.4 years) who received glucocorticoids for >4 weeks (median and interquartile range: 11 [7-14] months) and were referred for therapy withdrawal. Serum and saliva samples were collected between 8 and 9 a.m. on the same day. Cortisol was measured by an electrochemiluminescence immunoassay (ECLIA) 48 h after cessation of glucocorticoid therapy. Serum cortisol ≥193 nmol/L was used as the reference cut-off value for HPA recovery after glucocorticoid withdrawal and mSAF as the index test. RESULTS: The cut-off concentration obtained by ROC for mSAF was ≥5.0 nmol/L. True positive and true negative results were observed in 85/171 and 40/171 children, respectively. The false-positive rate was low (3/171, 1.7%); however, false-negative results were observed in 43/171 (25%) children. The main ROC results (95% CI) were area under curve: 0.98 (0.96-0.99), sensitivity: 0.66 (0.57-0.75), specificity: 0.93 (0.81-0.99), positive predictive value: 0.97 (0.90-0.99), negative predictive value: 0.48 (0.37-0.59), LR+: 9.5, and diagnostic accuracy: 73.1%. CONCLUSION: The present study supports that mSAF ≥5.0 nmol/L by ECLIA is a non-invasive biomarker for the assessment of HPA recovery after prolonged glucocorticoid therapy in paediatric patients, with a positive predictive value of 97%. This proposed cut-off should be further validated using gold standard techniques for steroid quantification such as liquid chromatography-tandem mass spectrometry.
Subject(s)
Glucocorticoids , Hydrocortisone , Humans , Child , Adolescent , Hydrocortisone/analysis , Prospective Studies , Hypothalamo-Hypophyseal System , Pituitary-Adrenal System , Saliva/chemistryABSTRACT
Hypopituitarism, or the failure to secrete hormones produced by the anterior pituitary (adenohypophysis) and/or to release hormones from the posterior pituitary (neurohypophysis), can be congenital or acquired. When more than one pituitary hormone axis is impaired, the condition is known as combined pituitary hormone deficiency (CPHD). The deficiency may be primarily due to a hypothalamic or to a pituitary disorder, or concomitantly both, and has a negative impact on target organ function. This review focuses on the pathophysiology, diagnosis and management of anterior pituitary hormone deficiency in the pediatric age. Congenital hypopituitarism is generally due to genetic disorders and requires early medical attention. Exposure to toxicants or intrauterine infections should also be considered as potential etiologies. The molecular mechanisms underlying the fetal development of the hypothalamus and the pituitary are well characterized, and variants in the genes involved therein may explain the pathophysiology of congenital hypopituitarism: mutations in the genes expressed in the earliest stages are usually associated with syndromic forms whereas variants in genes involved in later stages of pituitary development result in non-syndromic forms with more specific hormone deficiencies. Tumors or lesions of the (peri)sellar region, cranial radiation therapy, traumatic brain injury and, more rarely, other inflammatory or infectious lesions represent the etiologies of acquired hypopituitarism. Hormone replacement is the general strategy, with critical periods of postnatal life requiring specific attention.
Subject(s)
Hypopituitarism , Humans , Hypopituitarism/diagnosis , Hypopituitarism/therapy , Child , Pituitary Hormones, Anterior/deficiency , Pituitary Hormones, Anterior/metabolismABSTRACT
Introduction: Hematopoietic malignancies are the most frequent type of cancer in childhood. Recent advances in cancer treatment have significantly improved survival until adulthood. There is an extensive literature on the effects of cancer treatment on the gonadal axis in adult survivors of childhood cancer mainly focused on sperm production, but scarce information exists on the immediate impact of cancer and its treatment in boys. Objectives: In this work, we determined the status of the hypothalamic-pituitary-testicular (HPT) axis function at diagnosis and the immediate impact of chemotherapy at the start of treatment in children and adolescents with hematopoietic malignancies. Subjects and methods: In a prospective study of 94 boys and adolescents with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or non-Hodgkin lymphoma (NHL), we determined serum AMH, inhibin B and FSH to assess the gonadotrophin-Sertoli cell component of the HPT axis, and testosterone and LH to evaluate the gonadotrophin-Leydig cell component, at diagnosis and after 3 months of chemotherapy. Secondarily, the general health state was evaluated. Results: In prepubertal boys, at diagnosis, AMH, inhibin B and FSH were lower compared to the reference population, reflecting an FSH-Sertoli cell axis dysfunction. After 3 months of chemotherapy, all hormone concentrations increased. At pubertal age, at diagnosis, AMH and inhibin B were lower compared to the reference population for Tanner stage, with inappropriately normal FSH, suggesting a primary Sertoli cell dysfunction with insufficient gonadotrophin compensation. The LH-Leydig cell axis was mildly disrupted. After 3 months of chemotherapy, inhibin B and AMH were unchanged while median FSH levels rose to values that exceeded the reference range, indicating a significant impairment of Sertoli cell function. Testosterone normalized concomitantly with an abnormal LH elevation reflecting a compensated Leydig cell impairment. General health biomarkers were impaired at diagnosis and improved after 3 months. Conclusion: The HPT axis function is impaired in boys with hematopoietic malignancies before the initiation of chemotherapy. There is a primary testicular dysfunction and a concomitant functional central hypogonadism that could be due to an impaired overall health. The HPT axis function improves during the initial 3 months of chemotherapy concomitantly with the general health state. However, in pubertal boys the dysfunction persists as shown by elevated gonadotropin levels after 3 months.
Subject(s)
Hematologic Neoplasms , Neoplasms , Adult , Humans , Male , Child , Adolescent , Follicle Stimulating Hormone , Prospective Studies , Semen , Testosterone , Hematologic Neoplasms/drug therapyABSTRACT
BACKGROUND: The most frequent monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I (IGF1) and the acid-labile subunit (IGFALS). GHI is characterized by a continuum of mild to severe post-natal growth failure. OBJECTIVE: To characterize the molecular defect in a patient with short stature and partial GHI. PATIENT AND METHODS: The boy was born at term adequate for gestational age from non-consanguineous normal-stature parents. At 2.2â¯years, he presented proportionate short stature (height -2.77 SDS), wide forehead and normal mental development. Whole-exome analysis and functional characterization (site-directed mutagenesis, dual luciferase reporter assay, immunofluorescence and western immunoblot) were performed. RESULTS: Biochemical and endocrinological evaluation revealed partial GH insensitivity with normal stimulated GH peak (7.8â¯ng/mL), undetectable IGF1 and low IGFBP3 levels. Two heterozygous variants in the GH-signaling pathway were found: a novel heterozygous STAT5B variant (c.1896G>T, p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W). Functional in vitro characterization demonstrated that p.K632N-STAT5b is an inactivating variant that impairs STAT5b activity through abolished phosphorylation. Remarkably, the patient's immunological evaluation displayed only a mild hypogammaglobulinemia, while a major characteristic of STAT5b deficient patients is severe immunodeficiency. CONCLUSIONS: We reported a novel pathogenic inactivating STAT5b variant, which may be associated with partial GH insensitivity and can present without severe immunological complications in heterozygous state. Our results contribute to expand the spectrum of phenotypes associated to GHI.
Subject(s)
Agammaglobulinemia/genetics , Laron Syndrome/genetics , STAT5 Transcription Factor/genetics , Agammaglobulinemia/immunology , Child, Preschool , Heterozygote , Human Growth Hormone/metabolism , Humans , Insulin-Like Growth Factor Binding Protein 3/metabolism , Insulin-Like Growth Factor I/metabolism , Laron Syndrome/immunology , Laron Syndrome/metabolism , Laron Syndrome/physiopathology , Male , Pituitary Function Tests , Point Mutation , Severity of Illness IndexABSTRACT
Introduction: Practice guidelines cannot recommend establishing a diagnosis of growth hormone deficiency (GHD) without performing growth hormone stimulation tests (GHST) in children with risk factors, due to the lack of sufficient evidence. Objective: Our goal was to generate an evidence-based prediction rule to diagnose GHD in children with growth failure and clinically identifiable risk factors. Methods: We studied a cohort of children with growth failure to build the prediction model, and a second, independent cohort to validate the prediction rule. To this end, we assessed the existence of: pituitary dysgenesis, midline abnormalities, (supra)sellar tumor/surgery, CNS infection, traumatic brain injury, cranial radiotherapy, chemotherapy, genetic GHD, pituitary hormone deficiencies, and neonatal hypoglycemia, cholestasis, or hypogenitalism. Selection of variables for model building was performed using artificial intelligence protocols. Specificity of the prediction rule was the main outcome measure in the validation set. Results: In the first cohort (n=770), the resulting prediction rule stated that a patient would have GHD if (s)he had: pituitary dysgenesis, or two or more anterior pituitary deficiencies, or one anterior pituitary deficiency plus: neonatal hypoglycemia or hypogenitalism, or diabetes insipidus, or midline abnormalities, or (supra)sellar tumor/surgery, or cranial radiotherapy ≥18 Gy. In the validation cohort (n=161), the specificity of the prediction rule was 99.2% (95% CI: 95.6-100%). Conclusions: This clinical rule predicts the existence of GHD with high specificity in children with growth disorders and clinically identifiable risk factors, thus providing compelling evidence to recommend that GHD can be safely diagnosed without recurring to GHST in neonates and children with growth failure and specific comorbidities.
Subject(s)
Algorithms , Body Height/physiology , Human Growth Hormone/deficiency , Machine Learning/standards , Brain/diagnostic imaging , Brain/metabolism , Child , Child, Preschool , Cohort Studies , Dwarfism, Pituitary/blood , Dwarfism, Pituitary/diagnostic imaging , Female , Humans , Male , Practice Guidelines as Topic/standards , Predictive Value of Tests , Reproducibility of Results , Risk FactorsABSTRACT
BACKGROUND: IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation. RESULTS: We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from -1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth. CONCLUSION: The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.
Subject(s)
Growth Disorders/genetics , Hearing Loss, Sensorineural/genetics , Insulin-Like Growth Factor I/deficiency , Mutation, Missense/genetics , Abnormalities, Multiple/genetics , Cell Proliferation , Computational Biology , Computer Simulation , Fetal Growth Retardation/genetics , HEK293 Cells , Homozygote , Humans , Infant , Insulin-Like Growth Factor I/genetics , Male , Pedigree , Polymorphism, Single Nucleotide/genetics , Receptor, IGF Type 1 , Receptors, Somatomedin/genetics , Tyrosine/geneticsABSTRACT
El crecimiento y la maduración física del niño y del adolescente transcurre por diversas etapas observándose cambios en la talla y velocidad de crecimiento característicos que son consecuencia entre otros factores, de cambios hormonales en el sistema o eje de la hormona de crecimiento (GH). Los principales componentes de este eje con utilidad clínica en la etapa infanto-juvenil son la GH, el factor de crecimiento insulino símil tipo I (IGF-I) y las proteínas de transporte. La GH es secretada por la hipófisis en forma de pulsos a la circulación y esto es uno de los principales factores que condicionan su utilidad como marcador de deficiencia de GH. La medición de GH en condiciones basales únicamente tiene valor diagnóstico cuando se obtiene en hipoglucemia y especialmente si se trata de un neonato. Es necesario entonces, en el resto de los casos, evaluar la capacidad de secreción de GH mediante pruebas funcionales de estímulo estandarizadas. Los factores dependientes de GH son considerados biomarcadores fidedignos de la acción de GH. Sin embargo, su concentración varía ampliamente durante la etapa pediátrica obligando su interpretación en el contexto de valores de referencia establecidos según la edad, sexo y desarrollo puberal. El presente trabajo revela los profundos cambios fisiológicos en los componentes del sistema de la GH que ocurren en la etapa pediátrica y los recaudos que deben tenerse en cuenta cuando se utilizan en el diagnóstico de la deficiencia de GH
Among other factors, the postnatal growth and physical maturation of children and adolescents (characterized by changes in the size and growth velocity rates) are influenced by components of the growth hormone (GH) system. GH, the type I insulin-like growth factor (IGF-I) and their transport proteins constitute the more relevant biochemical tools for the GH deficiency (GHD) diagnosis in pediatrics. The GH is secreted by the pituitary gland into the circulation in pulses and this pulsatility limits its usefulness, with the exception of a random basal GH in neonates under hypoglycaemia. Therefore, it is necessary to evaluate GH secretion status in standardized functional tests. IGF-I and IGFBP-3 are considered reliable biomarkers of GH action. However, these GH-dependant biomarkers widely vary in the paediatric period, forcing their interpretation in the context of confident reference values according to age, sex and pubertal development. The present revision reveals the profound physiological changes in the components of the GH system throughout the whole pediatric period and the situations that must be taken into account when they are used in the diagnosis of GHD
Subject(s)
Humans , Growth Hormone , Growth , Pediatrics , Growth and Development , EndocrinologyABSTRACT
OBJECTIVE: To investigate the occurrence of abnormally elevated values of biomarkers of growth hormone (GH) action in short children on recombinant human GH (rhGH) therapy. METHODS: Sixty-three prepubertal short children were examined: 31 with GH deficiency (GHD), 25 small for gestational age (SGA), and 9 with Turner syndrome (TS). The main outcomes were the following: standard deviation score (SDS) values of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio before, at the 1st and at the 2nd year on rhGH and Δheight (Ht)-SDS to evaluate GH treatment efficacy (adequate 1st-year ΔHt SDS: >0.4 SDS for GHD and >0.3 SDS for non-GHD). RESULTS: Seventy-eight percent of GHD, 78% of SGA and 55% of TS children had adequate 1st-year ΔHt SDS. In GHD, 88% of IGF-I SDS and IGFBP-3 SDS that were ≤-2.0 SDS at baseline normalized on treatment. Abnormal IGF-I values >+2.0 SDS were observed in 52% of SGA and in 55% of TS patients on rhGH. Within each group, the IGF-I/IGFBP-3 molar ratio increased significantly from pretreatment and throughout therapy, remaining within normal range for most patients. ΔIGF-I/IGFBP-3 molar ratio SDS were significantly higher in children with an adequate response (p < 0.01). CONCLUSION: Non-GHD groups presented markedly elevated concentrations of GH biomarkers on rhGH and normal IGF-I/IGFBP-3 molar ratio in most patients. Since there is a lack of consensus regarding the molar ratio usefulness, we think that interventions towards a more physiological IGF-I serum profile should be implemented.
Subject(s)
Body Height/drug effects , Growth Disorders/drug therapy , Human Growth Hormone/therapeutic use , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/metabolism , Recombinant Proteins/therapeutic use , Adolescent , Body Height/physiology , Child , Child, Preschool , Female , Growth Disorders/blood , Human Growth Hormone/pharmacology , Humans , Infant , Male , Recombinant Proteins/pharmacology , Retrospective Studies , Treatment OutcomeSubject(s)
Endocrinology/organization & administration , Pediatrics/organization & administration , Societies, Medical/organization & administration , Argentina , Child , Child, Preschool , Congresses as Topic , Humans , Hypopituitarism/congenital , Hypopituitarism/therapy , Latin America , Prader-Willi Syndrome/therapy , Thyroid Diseases/therapyABSTRACT
INTRODUCTION: Androstenedione (A4) is an adrenal and gonadal steroid biomarker, useful in the assessment of children in whom steroidogenic disorders are suspected. The first key step in the evaluation of a diagnostic test resides on confident reference intervals (RI). The lack of updated A4-RI with current methods in pediatrics may mislead A4 results and limit its diagnosis accuracy. AIM: To provide A4 reference ranges in healthy children. METHODS: Prospective, descriptive study. 283 children aged 4 days to 18 years were included. In children < 1 yr, A4 was measured directly in serum (NE-A4) and postorganic solvent extraction (E-A4) for the assessment of interfering steroids. The influence of chronological age (CA), gender, and Tanner stage (T) were investigated. RESULTS: In the neonatal period, E-A4 was significantly lower than NE-A4; boys had higher NE-A4; sexual dimorphism disappeared after extraction procedure. In children older than 4 months, A4 concentration remained low until the age of 5 years. Thereafter, A4 increased significantly in association with CA and T (r2 = 0.65; p < 0.001), obtaining the highest concentrations in children within pubertal ages without sexual dimorphism. CONCLUSION: We recommend to perform solvent extraction in neonates and to take into account age and sexual development to properly interpret A4 results in childhood.
Subject(s)
Androstenedione/blood , Adolescent , Androstenedione/standards , Biomarkers/blood , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , MaleABSTRACT
BACKGROUND: Estradiol at baseline or after a classical gonadotropin-releasing hormone test did not reflect ovarian steroidogenesis in central precocious puberty (CPP) girls. AIMS: To evaluate estradiol response to depot triptorelin, both at start and during therapy to determine how active ovarian steroidogenesis is at pubertal stage and under therapy. METHODS: A prospective study was performed in 43 CPP girls. Serum luteinizing hormone and follicle-stimulating hormone at 3 h (LH-3h, FSH-3h) and estradiol at 24 h (E2-24h) after injection of depot triptorelin 3.75 mg were measured, at first dose and at 3, 6, 12, 18 and 24 months of treatment. RESULTS: E2-24h after depot triptorelin was >100 pg/ml after the first dose. Estradiol response (E2-24h) fell to levels <14 pg/ml in 78 out of 82 follow-up visits along 2 years of therapy. Concomitantly, LH-3h and FSH-3h were <4.0 and <6.3 IU/l, respectively. In 4 patients with inadequate treatment, E2-24h, LH-3h and FSH-3h rose to pubertal values similar to those observed at first dose. CONCLUSION: Estradiol (<14 pg/ml) assessment 24 h after depot triptorelin administration is a reliable and simple manner to confirm ovarian suppression in CPP girls during treatment.
Subject(s)
Estradiol/blood , Puberty, Precocious/blood , Puberty, Precocious/drug therapy , Triptorelin Pamoate/administration & dosage , Child , Female , Follow-Up Studies , Humans , Prospective StudiesABSTRACT
BACKGROUND: Combined pituitary hormone deficiency (CPHD) presents a wide spectrum of pituitary gland disorders. The postnatal gonadotropic surge provides a useful period to explore the gonadotropic axis for assessing the presence of congenital hypogonadotropic hypogonadism (CHH). AIM: To explore the functioning of the hypothalamic-pituitary-gonadal axis in the postnatal gonadotropic surge for an early diagnosis of CHH in newborns or infants suspected of having CPHD. SUBJECTS AND METHODS: A cohort of 27 boys under 6 months and 19 girls under 24 months of age with suspected hypopituitarism was studied. Serum concentrations of LH, FSH, testosterone, inhibin B, anti-Müllerian hormone (AMH) and estradiol were measured, and male external genitalia were characterized as normal or abnormal (micropenis, microorchidism and/or cryptorchidism). RESULTS: CPHD was confirmed in 36 out of 46 patients. Low LH and testosterone levels were found in 66% of the hypopituitary males, in significant association with the presence of abnormal external genitalia. This abnormality had a positive predictive value of 93% for CHH. No significant association was observed between serum FSH, AMH and inhibin B and the patient's external genitalia. CONCLUSION: In newborn or infant boys with CPHD, LH and testosterone concentrations measured throughout the postnatal gonadotropic surge, together with a detailed evaluation of the external genital phenotype, facilitate the diagnosis of CHH at an early stage.
Subject(s)
Hypogonadism/diagnosis , Hypogonadism/therapy , Hypopituitarism/congenital , Hypopituitarism/complications , Anti-Mullerian Hormone/blood , Brain/pathology , Female , Follicle Stimulating Hormone/blood , Genitalia, Male/abnormalities , Gonadal Steroid Hormones/blood , Humans , Hydrocortisone/blood , Hydrocortisone/deficiency , Hypogonadism/etiology , Infant , Inhibins/blood , Luteinizing Hormone/blood , Magnetic Resonance Imaging , Male , Sex Characteristics , Testosterone/bloodABSTRACT
BACKGROUND AND AIMS: Hypocalcemia after thyroidectomy is caused by parathyroid trauma. There are no studies regarding the usefulness of intact parathyroid hormone (PTH) as a monitor of postoperative hypoparathyroidism tool in pediatrics. We evaluated the diagnostic accuracy of intra- and postoperative PTH to predict the risk of developing post thyroidectomy hypocalcemia in children. METHODS: A prospective longitudinal cohort study was conducted in 32 pediatric patients (3.2-17.6 years old) undergoing total thyroidectomy. Intact PTH measured by the assays (Immulite Immunoassay System [ICMA] or electrochemioluminescence assay [ECLIA]) at 5 (PTH-5) and 60 (PTH-60) minutes after thyroid removal were considered as predicting variables. The postoperative outcome was hypocalcemia (endpoint variable). Patients were clinically and biochemically monitored regularly for 48 hours after surgery. RESULTS: Of the patients, 47% developed hypocalcemia (15% symptomatic). An ICMA PTH-5 of ≤14 pg/mL or an ECLIA PTH-5 of ≤16 pg/mL predicted hypocalcemia with a sensitivity of 80%, specificity of 100%, positive predictive value (PPV) of 100%, and diagnostic efficiency (DE) of 91%. Using the same cutoff values, PTH-60 presented a sensitivity of 93%, specificity of 82%, PPV of 81%, and DE of 87%. Adjusting for variation in the assays and combining intra- and postoperative PTH determinations, we developed an algorithm that improved sensitivity, specificity, and DE. CONCLUSION: PTH is useful for predicting hypocalcemia after total thyroidectomy in children. The use of our proposed strategy should be considered to (a) initiate preventive treatment in patients identified at high risk for hypocalcemia, (b) shorten the duration of hospitalization, and (c) reduce the clinical and biochemical controls in those who remained normocalcemic.
Subject(s)
Decision Support Techniques , Hypocalcemia/diagnosis , Hypoparathyroidism/diagnosis , Parathyroid Hormone/blood , Postoperative Complications/diagnosis , Thyroidectomy , Adolescent , Algorithms , Biomarkers/blood , Calcium/blood , Calcium/deficiency , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Hypocalcemia/blood , Hypocalcemia/etiology , Hypoparathyroidism/blood , Hypoparathyroidism/etiology , Intraoperative Period , Male , Outcome Assessment, Health Care , Parathyroid Hormone/deficiency , Postoperative Complications/blood , Postoperative Complications/etiology , Postoperative Period , Predictive Value of Tests , Prospective Studies , Risk Assessment , Sensitivity and SpecificityABSTRACT
In early fetal development, the testis secretes - independent of pituitary gonadotropins - androgens and anti-Müllerian hormone (AMH) that are essential for male sex differentiation. In the second half of fetal life, the hypothalamic-pituitary axis gains control of testicular hormone secretion. Follicle-stimulating hormone (FSH) controls Sertoli cell proliferation, responsible for testis volume increase and AMH and inhibin B secretion, whereas luteinizing hormone (LH) regulates Leydig cell androgen and INSL3 secretion, involved in the growth and trophism of male external genitalia and in testis descent. This differential regulation of testicular function between early and late fetal periods underlies the distinct clinical presentations of fetal-onset hypogonadism in the newborn male: primary hypogonadism results in ambiguous or female genitalia when early fetal-onset, whereas it becomes clinically undistinguishable from central hypogonadism when established later in fetal life. The assessment of the hypothalamic-pituitary-gonadal axis in male has classically relied on the measurement of gonadotropin and testosterone levels in serum. These hormone levels normally decline 3-6 months after birth, thus constraining the clinical evaluation window for diagnosing male hypogonadism. The advent of new markers of gonadal function has spread this clinical window beyond the first 6 months of life. In this review, we discuss the advantages and limitations of old and new markers used for the functional assessment of the hypothalamic-pituitary-testicular axis in boys suspected of fetal-onset hypogonadism.
ABSTRACT
BACKGROUND: Reference intervals (RI) of serum 17α- hydroxyprogesterone (17OHP) are useful to confirm congenital adrenal hyperplasia (CAH) in neonates with abnormal screening results and nonclassical forms of CAH in symptomatic children. We aimed to establish serum 17OHP RI in normal children and adolescents using a current 17OHP radioimmunoassay (RIA). METHODS: Serum 17OHP was measured via a current RIA (Diasource) in children, i.e. 111 infants aged <1 year [before (NE-17OHP) and after extraction (E-17OHP)] and 216 children aged 1-17 years. Forty NE serum samples from subjects aged >1 year, covering the whole analytical range, were simultaneously measured to compare 17OHP RIA from Diagnostic System Laboratories (DSL) (withdrawn) and Diasource by Passing Bablok linear regression and ratio plot. The equation obtained was used to correct our own previous RI (DSL RIA) for infancy for the Diasource RIA. Samples from infants aged <1 year were used to verify the calculated RI with evaluator protocol C28-A3. The influence of age, gender, and Tanner's classification (T) was assessed in children aged >1 year by ANOVA. RESULTS: E-17OHP as measured via the Diasource RIA was significantly lower than NE-17OHP in infants aged <1 year (p < 0.0001). The 17OHP measurement from the Diasource RIA was negatively biased compared to the value obtained using the DSL RIA (Diasource (ng/ml) = 0.85 DSL (ng/ml) -0.32 ng/ml, r = 0.952). Most infants (93%) had age- and gender-adjusted NE-17OHP and E-17OHP levels within the recalculated RI. Serum 17OHP significantly increased throughout prepuberty (p < 0.001). Sexual dimorphism was only observed at T IV-V. CONCLUSION: When evaluating 17OHP during childhood, we recommend taking into account the extraction procedure in neonates, the method used, age, and the Tanner's stage.
Subject(s)
17-alpha-Hydroxyprogesterone/blood , Aging/blood , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Linear Models , Male , Radioimmunoassay/methods , Reference ValuesABSTRACT
OBJECTIVE: To investigate the possible association of circulating components of GH-IGFs-IGFBPs system with the GHR-exon 3 genotype in normal and idiopathic short stature (ISS) children. DESIGN: Descriptive, cross-sectional study in normal and ISS children. SUBJECTS AND METHODS: 192 normal and 81 ISS children (age: 5-17 years) were included. Serum IGF-I, IGFBP3, ALS and GHBP levels were measured. GHR-exon 3 polymorphism (GHRd3) was analyzed by multiplex PCR assay. Normal and ISS children were divided according to GHR-exon 3 genotype: homozygous for the full-length GHR isoform (GHRfl) and carriers of one or two copies of the GHRd3 allele. RESULTS: GHRd3 genotype distribution (fl:fl/fl:d3/d3:d3,%) in normal (60:34:6) and ISS (64:32:4) was similar and reached Hardy-Weinberg equilibrium. ISS children had significantly reduced levels of GHBP and GH-dependent factors as compared to controls (p<0.0001). Within the normal group, homozygous carriers of the GHRfl allele had significantly higher GHBP serum levels than those with one or two copies of the GHRd3 allele (Mean ± SEM; GHRfl: 3.2 ± 0.2 vs GHRd3: 2.7 ± 0.2 nmol/L, p = 0.04). No other significant association with GHR exon 3 polymorphism was found in either the normal or the ISS groups. CONCLUSIONS: GHR exon 3 polymorphism is distributed similarly in normal and ISS children, however only normal homozygous children for GHRfl allele showed higher GHBP levels. The lack of association between GHBP and GHR polymorphism in ISS children might be related to the heterogeneity of this group, where potential defects in GH receptor action may result in partial GH insensitivity.
Subject(s)
Carrier Proteins/genetics , Dwarfism/blood , Dwarfism/genetics , Exons/genetics , Human Growth Hormone/blood , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/metabolism , Polymorphism, Genetic/genetics , Adolescent , Carrier Proteins/blood , Case-Control Studies , Child , Child, Preschool , Cross-Sectional Studies , Female , Follow-Up Studies , Genotype , Humans , Male , Polymerase Chain Reaction , Protein Isoforms , RadioimmunoassayABSTRACT
CONTEXT: The GnRH test is the gold standard to confirm the diagnosis of central precocious puberty (CPP); however, this compound is not always readily available. Diagnostic accuracy of subcutaneous GnRH analogues tests compared to classical GnRH test has not been reported. OBJECTIVE: To evaluate the diagnostic accuracy of Triptorelin test (index test) compared to the GnRH test (reference test) in girls with suspicion of CPP. DESIGN: A prospective, case-control, randomized clinical trial was performed. CPP or precocious thelarche (PT) was diagnosed according to maximal LH response to GnRH test and clinical characteristics during follow-up. PATIENTS AND INTERVENTIONS: Forty-six girls with premature breast development randomly underwent two tests: (i) intravenous GnRH 100 µg, (ii) subcutaneous Triptorelin acetate (0.1 mg/m(2), to a maximum of 0.1 mg) with blood sampling at 0, 3 and 24 h for LH, FSH and estradiol ascertainment. MEASUREMENTS: Gonadotrophins and estradiol responses to Triptorelin test were measured by ultrasensitive assays. RESULTS: Clinical features were similar between CPP (n = 33) and PT (n = 13) groups. Using receiver operating characteristic curves, maximal LH response (LH-3 h) under Triptorelin test ≥ 7 IU/l by immunofluorometric assay (IFMA) or ≥ 8 IU/l by electrochemiluminescence immunoassay (ECLIA) confirmed the diagnosis of CPP with specificity of 1.00 (95% CI: 0.75-1.00) and sensitivity 0.76 (95% CI: 0.58-0.89). Considering either LH-3 h or maximal estradiol response at 24 h (cut-off value, 295 pm), maintaining the specificity at 1.00, the test sensitivity increased to 0.94 (95% CI: 0.80-0.99) and the diagnostic efficiency to 96%. CONCLUSION: The Triptorelin test had high accuracy for the differential diagnosis of CPP vs PT in girls providing a valid alternative to the classical GnRH test. This test also allowed a comprehensive evaluation of the pituitary-ovarian axis.