GH deficiency during the transition period: clinical characteristics before and after GH replacement therapy in two different subgroups of patients.

OBJECTIVE: To study two subsets of patients with GH deficiency (GHD) during the transition period: childhood onset GHD (CO-GHD) and patients who develop GHD during the transition phase (TO-GHD) before and after GH replacement. PATIENTS AND MEASUREMENTS: In 1340 GHD subjects from KIMS (Pfizer International Metabolic Database), CO (n=586) or TO (n=754), background characteristics, anthropometric measurements, IGF-1, lipids and quality of life (QoL) were evaluated at baseline and after 3 years of GH replacement. RESULTS: Both groups responded similarly to GH treatment. Changes of clinical outcomes were mainly determined by their value at baseline. Onset of the disease in childhood or transition period did not appear to be a significant predictor of response in any of the clinical outcomes. CONCLUSIONS: Age at GHD diagnosis was a significant predictor for many outcomes at baseline, but disease onset did not appear as an independent predictor concerning changes after 3 years of GH treatment. The results suggest that GH replacement during the transition period should be considered independently of the onset of the deficiency.

Confirmation of neonatal screening: reference intervals and evaluation of methodological changes in TSH measurement.

Neonatal reference values for serum thyrotropin are scarce and comprise only small numbers of patients. During 2006, changes were made in IMMULITE kits for TSH measurement. To validate methodological changes, 80 serum samples from patients were evaluated and to establish reference intervals, 334 neonates and infants were analyzed (divided into 4 groups). Group 1 (G1) (48-72 h of life) (n=153), group 2A (G2A) (7-10 days of life) (n=65), group 2B (G2B) (11-14 days of life) (n=35), group 3 (G3) (28-40 days of life) (n=81). Current kits overestimate TSH results by 26 to 37%; TSH (mIU/L) reference intervals (percentile 2.5-97.5) were G1 (1.1-12.7), G2A (1.8-9.8), G2B (1.1-7.1) (p < 0.03 vs. G2A), G3 (1.2-6.9). We suggest that during the second week of life, reference values should be divided into an early stage and a late stage, at least, for there to be an adequate interpretation of borderline measurements in newborn thyroid screening.

Male-female differences in 6-sulfatoxymelatonin excretion in hypopituitary patients.

OBJECTIVE: To evaluate melatonin secretion in adult hypopituitary patients with Growth Hormone deficiency (AGHD) on and off replacement therapy. SUBJECTS AND METHODS: We studied 48 subjects: 12 (6 males) untreated AGHD (AGHDnt), 20 (10 males) treated AGHD (AGHDt) and 16 healthy subjects (8 males) as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24 h samples), nocturnal (6-SMn): 1800-0800 and diurnal samples (6-SMd): 0800-1800. RESULTS: Significant differences were observed among the 3 groups of male subjects, in total 6-SM (p < 0.05), nocturnal 6-SM (p < 0.02) and nighttime-daytime delta values (p < 0.003). CG had significantly higher values than the AGHDnt in total 6-SM (p < 0.01), nocturnal 6-SM (p < 0.05) and nighttime-daytime delta values (p < 0.01). AGHDt patients showed significantly higher levels in nighttime-daytime delta values than AGHDnt patients (p < 0.05). In females, no significant differences were found among the 3 groups studied in total, nocturnal, diurnal or nighttime-daytime delta values. In males, significant correlations were found among total 6-SM (r = 0.58; p = 0.029), nocturnal 6-SM (r = 0.70; p = 0.006) and nighttime-daytime delta values (r = 0.71; p = 0.004) vs. serum IGF-1 levels in subjects evaluated. In females, significant correlations were found among total 6-SM (r = 0.57; p = 0.02) vs. serum IGF-1 levels in subjects evaluated. A tendency towards a significant correlation was found in diurnal 6-SM (r = 0.48; p = 0.07). CONCLUSIONS: Our findings show a sexual dimorphism in 6-SM excretion in AGHD patients and provide an interesting approach to a further understanding of some chronobiological disorders involved in GH deficiency.

Burden of Growth Hormone Deficiency and Excess in Children.

Longitudinal growth results from multifactorial and complex processes that take place in the context of different genetic traits and environmental influences. Thus, in view of the difficulties in comprehension of the physiological mechanisms involved in the achievement of normal height, our ability to make a definitive diagnosis of GH impairment still remains limited. There is a myriad of controversial aspects in relation to GH deficiency, mainly related to diagnostic controversies and advances in molecular biology. This might explain the diversity in therapeutic responses and may also serve as a rationale for new "nonclassical" treatment indications for GH. It is necessary to acquire more effective tools to reach an adequate evaluation, particularly while considering the long-term implications of a correct diagnosis, the cost, and safety of treatments. On the other hand, overgrowth constitutes a heterogeneous group of different pathophysiological situations including excessive somatic and visceral growth. There are overlaps in clinical and molecular features among overgrowth syndromes, which constitute the real burden for an accurate diagnosis. In conclusion, both GH deficiency and overgrowth are a great dilemma, still not completely solved. In this chapter, we review the most burdensome aspects related to short stature, GH deficiency, and excess in children, avoiding any details about well-known issues that have been extensively discussed in the literature.

Decreased 6-Sulfatoxymelatonin Excretion in Male GH-Deficient Children and Adolescents.

AIM: To evaluate melatonin secretion in a group of untreated and treated male growth hormone (GH)-deficient children and adolescents. METHODS: We studied 44 male subjects: 8 untreated GH-deficient patients (GHDnt), 16 treated GH-deficient patients (GHDt) and 20 healthy children and adolescents as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24-hour samples), nocturnal (18.00-8.00 h) and diurnal samples (8.00-18.00 h). Levels of 6-SM were expressed as micrograms excreted per time interval and x0394; values (difference between nighttime and daytime values). RESULTS: Significant differences were observed among the 3 groups of pediatric subjects studied for total 6-SM (p < 0.0001), nocturnal 6-SM (p < 0.0001) and x0394; values (p < 0.0001). Subsequent analysis showed significantly higher levels for total 6-SM, nocturnal 6-SM and nighttime-daytime x0394; in the CG versus the GHDnt (p < 0.01) and in the CG versus the GHDt group (p < 0.01). No significant correlations were found between 6-SM excretion and insulin-like growth factor-1 values in the children and adolescents studied. CONCLUSIONS: GH-deficient patients showed lower levels of 6-SM. Our findings provide a different insight to a further understanding of some chronobiological disorders involved in GH deficiency in children.

Evaluation of diagnostic accuracy of insulin-like growth factor (IGF)-I and IGF-binding protein-3 in growth hormone-deficient children and adults using ROC plot analysis.

We critically evaluated the diagnostic value of IGF-I and IGF-binding protein-3 (IGFBP-3) in GH deficiency (GHD) in children and adults using receiver operating characteristic (ROC) plot analysis. Sixty-six children (chronological age, 1.3-15 yr) were studied: 34 GHD and 32 idiopathic short stature (ISS). Ninety-two adults (chronological age, 18-70 yr) were also evaluated: 72 GHD, 34 of childhood onset (AGHD-CO), and 38 of adult onset (AGHD-AO); and 20 healthy volunteers. The SD score (SDS) for IGF-I was calculated from 596 normal subjects (212 children and 384 adults), and the SDS for IGFBP-3 was calculated from 350 normal subjects (212 children and 138 adults). The ROC plot showed that the best IGF-I SDS cut-off line was -1.65 for children [sensitivity (S), 68%; specificity (Sp), 97%, diagnostic efficiency (DEf), 81%], the cut-off line for AGHD was -1.65 for AGHD-CO (S, 91%; Sp, 100%; DEf, 94%), and the cut-off line for AGHD-AO was -1.80 (S, 81%; Sp, 100%; DEf, 88%). For IGFBP-3 SDS, the best cut-off line was -1.80 for children (S, 90%; Sp, 60%; DEf, 78%); it was -1.45 for AGHD-CO (S, 90%; Sp, 75%; DEf, 82%) and -0.90 for AGHD-AO (S, 90%; Sp, 68%; DEf, 77%). An accurate diagnosis was obtained using IGF-I SDS alone in GHD children 65%; ISS, 97%; AGHD-CO, 92%; AGHD-AO, 86%, with IGFBP-3 SDS alone in GHD children 60%; ISS, 90%; AGHD-CO, 75%; AGHD-AO, 68%. Considering both, an accurate diagnosis was obtained in GHD children 60%; ISS, 87%; AGHD-CO, 71%; AGHD-AO, 64%. In conclusion, our findings support the need to use cut-off lines expressed in SDS obtained using an appropriate statistical methodology for better characterization of the various clinical presentations. IGF-I proved to be more useful because of its good diagnostic efficiency and accuracy in both children and adults, whereas IGFBP-3 did not significantly contribute to the diagnosis of GHD.

Basal ultrasensitive LH assay: a useful tool in the early diagnosis of male pubertal delay?

The aim of this study was to evaluate the usefulness of basal measurements of gonadotropins in distinguishing between constitutionally delayed puberty (DP) and hypogonadotropic hypogonadism (HH), comparing its diagnostic efficiency with that of the dynamic GnRH infusion test (0.83 microg/min during 120 min). We studied 20 males, chronological age (CA) 14-18 years, with a final diagnosis of DP (n = 8), partial HH (n = 5) and complete HH (n = 7), confirmed by follow-up. We also evaluated basal samples of ultrasensitive LH and FSH in 117 healthy control males (CA 2-19 yr), classified according to Tanner stage. In the control group, ROC plot analysis showed a cutoff to differentiate prepuberty from puberty of 0.65 IU/l for LH (sensitivity: 91%, specificity: 98%). Differences were found (p < 0.05) in basal LH and in maximal responses to GnRH in complete HH in relation to DP and partial HH. The diagnostic efficiency of the GnRH infusion test was 85%. For basal LH, a cut-off limit of 0.65 IU/l showed a diagnostic efficiency of 85% for complete HH and 100% for partial HH and DP. We conclude that, in our experience, basal LH levels above 0.65 IU/l measured by ultrasensitive assay would rule out a complete deficiency. It was not possible to differentiate DP from partial HH, either in basal samples or with the infusion test.

Tumoral versus non-tumoral hyperprolactinemia in children and adolescents: possible usefulness of the domperidone test.

UNLABELLED: The aim of this study was to evaluate the usefulness of the domperidone test for the difficult diagnosis between functional and tumoral hyperprolactinemia. We evaluated 36 patients, aged 5-18 years, 14 (12 F, 2 M) with hyperprolactinemia (non-tumoral: 10; pituitary adenoma: 4) and 22 individuals as a control group (prepubertal: 5 F, 8 M; pubertal: 4 F, 5 M). Basal prolactin (PRL) (IRMA-DPC), T4 and TSH and PRL 30 min post-domperidone (0.2 mg/kg b. wt i.v.) were measured. Non-tumoral hyperprolactinemic females showed basal PRL: 45 (29-80) (median and range) ng/ml; post-domperidone: 208 (116-290) ng/ml; delta PRL (PRL 30' - PRL 0'): 167 (77-252) ng/ml; and PRL ratio (PRL 30'/PRL 0'): 3.9 (2.3-7.6). Females with pituitary adenoma showed basal PRL: 129 (125-660) ng/ml; post-domperidone: 202 (150-535) ng/ml; delta PRL: 73 (25-135) ng/ml; and ratio: 1.2 (0.8-1.6). Two males, one with a non-tumoral hyperprolactinemia and the other one with a pituitary adenoma, presented, respectively, PRL 0':45, 160; PRL 30':130, 173; delta: 85, 13; ratio: 2.9, 1.1. All non-tumoral patients showed a PRL ratio (30'/0') > 2.3, while no patient with pituitary adenoma had a ratio > 1.6. CONCLUSIONS: PRL response to domperidone allowed us to characterize hyperprolactinemias, although the presence of a blunted response should be confirmed in a larger number of patients with tumors with 'low' PRL levels (dependence on etiology or basal PRL level?).

Prolactin excess: treatment and toxicity.

Dopamine agonists provide highly effective therapy for the treatment of hyperprolactinemia. As a result of their efficacy and tolerability, these agents are considered to be the initial therapy of choice in children, adolescents and adults with idiopathic hyperprolactinemia and prolactinomas. The four dopamine agonists, bromocriptine, pergolide, cabergoline and quinagolide, share a similar mechanism of action and side effect profile. Although studies of cabergoline have demonstrated the highest treatment efficacy and tolerability, all four of these agents are safe, effective and tolerable in children and adolescents. When fertility is desired, bromocriptine is generally preferable, but cabergoline is also likely safe; pergolide and quinagolide should not be used in this setting.

Inhibidores de tirosina cinasa y disfunción tiroidea / Tyrosine kinase inhibitors and thyroid dysfunction

Los inhibidores de la tirosina cinasa son utilizados para el tratamiento de diversas neoplasias interfiriendo en múltiples vías de proliferación celular y angiogénesis tumoral. Estos fármacos presentan efectos adversos de clase, destacándose entre ellos la afectación de la función tiroidea. Existen diferentes mecanismos propuestos por los cuales estos agentes orales llevan tanto al hipotiroidismo como a la tirotoxicosis. Aún no existe consenso sobre el seguimiento y tratamiento ante la aparición de estos efectos.

Tyrosine kinase inhibitors are used for the treatment of different types of tumours, interfering in various cell proliferation pathways, and tumour angiogenesis. These oral agents have side effects, thyroid dysfunction outstanding among them. There are different mechanisms through which these agents lead to hypothyroidism, as well as thyrotoxicosis. There is still no consensus on the treatment and follow-up of the above mentioned effects.

Male-female differences in 6-sulfatoxymelatonin excretion in hypopituitary patients

ABSTRACT Objective To evaluate melatonin secretion in adult hypopituitary patients with Growth Hormone deficiency (AGHD) on and off replacement therapy. Subjects and methods We studied 48 subjects: 12 (6 males) untreated AGHD (AGHDnt), 20 (10 males) treated AGHD (AGHDt) and 16 healthy subjects (8 males) as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24 h samples), nocturnal (6-SMn): 1800-0800 and diurnal samples (6-SMd): 0800-1800. Results Significant differences were observed among the 3 groups of male subjects, in total 6-SM (p < 0.05), nocturnal 6-SM (p < 0.02) and nighttime-daytime delta values (p < 0.003). CG had significantly higher values than the AGHDnt in total 6-SM (p < 0.01), nocturnal 6-SM (p < 0.05) and nighttime-daytime delta values (p < 0.01). AGHDt patients showed significantly higher levels in nighttime-daytime delta values than AGHDnt patients (p < 0.05). In females, no significant differences were found among the 3 groups studied in total, nocturnal, diurnal or nighttime-daytime delta values. In males, significant correlations were found among total 6-SM (r = 0.58; p = 0.029), nocturnal 6-SM (r = 0.70; p = 0.006) and nighttime-daytime delta values (r = 0.71; p = 0.004) vs. serum IGF-1 levels in subjects evaluated. In females, significant correlations were found among total 6-SM (r = 0.57; p = 0.02) vs. serum IGF-1 levels in subjects evaluated. A tendency towards a significant correlation was found in diurnal 6-SM (r = 0.48; p = 0.07). Conclusions Our findings show a sexual dimorphism in 6-SM excretion in AGHD patients and provide an interesting approach to a further understanding of some chronobiological disorders involved in GH deficiency.

Enfermedad de Graves infanto-juvenil: tratamiento alternativo con 131I / Graves disease in childhood and youth: alternative treatment with 131I

Entre 1982 y 1988 se realizó tratamiento y seguimiento de 22 pacientes con enfermedad de Graves infanto-juvenil (13f y 90m). Las edades de comienzo de la enfermedad oscilaron entre 4 y 17 años (x12 a 10m). En todos los casos se efectuó tratamiento con metimazol (MMI) y una vez alcanzado el eutiroidismo, conMMI + hormona tiroidea, con una duración de 1 a 2 meses (m) a 6 años (a). Siete pacientes remitieron con esta terapéutica, 3 abandonaron la consulta, 6 continúan en tratamiento y en 7 se administró una dosis terapéutica (DT) de I (3). En estos últimos (4f y 3m), la edad al recibir la DT oscilaba entre 15 y 20 a.(x17a. 1m.). En 4 casos se indicó el I por remisión luego de administrar MMI por lapsos mayores a 4 años, en 1 caso por recidiva al año de suspender el MMI y en 2 por no ccumplimiento del tratamiento. Las DT variaron entre 4 y 15 mCi (x7,322). Cuatro pacientes remitieron con la 1ra. dosis, 2 requirieron una 2§ DT y en 1 caso fue necesario suministrar una 3ra. Con un seguimiento de 10m. a 2 a. 1 m., 3 pacientes permanecen eutiroideos y 4 presentan hipotiroidismo, que se manifstó entre 2 y 10 m. post DT. No se observaron alteraciones hematológicas, nódulos tiroideos ni aparición o agravamiento de oftalmopatía preexistente. Consideramos que la DT de I(3) constituye un recurso alternativo de alta eficacia en los pacientes infanto-juveniles en quienes ha fracasado la terapéutica antitiroidea, en aquellos en que no se logra la continuidad del tratamiento o ante la aparición de efectos colaterales graves

Reproducibility and variability of the arginine test in normal adults: comparison between sexes

The biochemical diagnosis of growth hormone deficiency in adults (AGHD) remains controversial, mainly as regards stimulation tests and suggested cut-off lines. The insulin tolerance test proved to be the most effective growth hormone (GH) secretagogue in normal males, but a poor intra-individual reproducibility has been reported. Given the safety of the arginine (AST), we decided to evaluate the incidence of false negatives (non responder normal subjects), its reproducibility and variability. Twenty five healthy non-obese volunteers (16 males, 9 females) with a chronological age range between 19 and 40 years, (mean: 29.8) were evaluated. AST was performed (0.5 g/kg IV infusion for 30 min), measuring GH (IRMA) at baseline (B), 30, 60 and 90 minutes, and it was repeated in the same subject 7 to 30 days later; in females both tests were performed in the early follicular phase. Results (median and range) were: 1st test B: 0.61 (0.35-22.60) mug/L; maximal response (Mx Resp) 10.00 (0.48-48.80 mug/L 2nd test B:0.50 (0.38-27.0) mug/L; Mx Resp 11.00 (0.50-47.70) mug/L. The statistical evaluation (Wilcoxon signed rank test) showed no differences between B vs. B and Mx Resp vs Mx Resp. Separated by Sex, males showed: 1st test: B 0.45 (0.35-4.30) mug/L; Mx Resp 6.30 (0.48-48.80) mug/L. 2nd test B 0.46 (0.38-8.80) mug/L; Mx Resp 10.90 (0.50-47.70) mug/L, while females showed 1st test: B 5.20 (0.50-22.60) mug/L; mx Resp 14.00 (3.50-36.70) mug/L 2nd test B 3.60 (0.75-27.00) mug/L; Mx Resp 13.00 (3.70-28.10) mug/L. The statistical comparison (Mann Whitney test) showed significant differences between both sexes in basal values of the first and second test (p<0.001), and in the naximal response of the first test (p<0.03). The statistical analysis did not show significant differences in delta increases between males and females, neither in the first AST nor in the second one. Considering GH values =3 mug/L as a positive response, 4 males exhibited insufficient responses in both tests and other 2 males showed discordant results between tests 1 and 2. All females evaluated produced responses above 3 mug/L in both tests. The results of the present study demonstrate that, particularly in men, AST has no clear limit of normality while it shows good intra-individual reproducibility. In conclusion, at present the biochemical diagnosis of AGHD requires a clear and precise standardization which includes all variables that can modify the GH response to the stimulus used.