Martha Suárez

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.

Peripubertal prolactinomas: clinical presentation and long-term outcome with different therapeutic approaches.

UNLABELLED The evolution of prolactinomas in children and adolescents continues to be controversial. We report on the long-term evolution (2-20 yr) of prolactinomas in 40 patients (29 F, 11 M). In females, the age for the onset of symptoms ranged between 8 and 16 yr and the age at which diagnosis was made ranged from 15 to 19 yr; in males, ages ranged from 8 to 17 yr and from 13.8 to 19 yr, respectively. In females, there was predominance of microprolactinomas (22/ 29) and the symptomatology resulted from functional disorders, whereas in males there was predominance of macroprolactinomas (8/11) and symptoms were caused by tumor mass disorders. Surgery was used as primary therapy in nine patients and as supplemental therapy in six patients. Twenty-four patients were treated primarily with bromocriptine and seven with cabergoline. Of the nine patients treated primarily with surgery, only one achieved gonadotropic axis restoration; in 25/31 patients receiving drug therapy gonadotropic function was restored to normal. Fifteen patients showed complete resolution or substantial shrinkage of tumor. CONCLUSION In pediatric and adolescent age, there seem to be age- and sex-dependent differences in the clinical presentation of prolactinomas that cannot be accounted for only in terms of time of evolution. Drug therapy can control the disease, normalize prolactin levels and achieve gonadotropic axis restoration in most patients.

Gender-related differences in urinary 6-sulfatoxymelatonin levels in obese pubertal individuals

Abstract:  The objective of this study was to measure the urinary excretion of the main melatonin metabolite 6‐sulfatoxymelatonin in obese and normal weight (wt) boys and girls. The study included 94 subjects, aged 4–15.7 yr (50 obese and 44 normal wt; 48 boys) classified as: mid‐childhood (4–7.99 yr), late‐childhood (8–12 yr) and pubertal (10.1–15.7 yr, Tanner II–IV). Normal wt subjects were children with a body mass index (BMI) between the 25th and 75th percentiles, and the group of obese subjects included children whose BMI was above the 97th percentile. A 24‐hr urine sample was collected during two intervals: (i) 18:00–08:00 hr, and (ii) 08:00–18:00 hr. Analysis of urinary 6‐sulfatoxymelatonin levels was performed by radioimmunoassay. Excretion of 6‐sulfatoxymelatonin was expressed as: (i) total amount excreted (μg); (ii) μg excreted per time interval, nocturnal or diurnal; and (iii) the difference between nocturnal and diurnal samples (μg, estimated amplitude). A factorial analysis of variance indicated that nocturnal 6‐sulfatoxymelatonin excretion and amplitude were significantly higher in the obese individuals. A significant interaction ‘BMI × age’ was detected, i.e. the effect of BMI was significant in the pubertal group only. Total, nocturnal and diurnal 6‐sulfatoxymelatonin excretion was significantly higher in girls. The increase in 6‐sulfatoxymelatonin excretion found in obesity occurred only in boys and at the pubertal age. To what extent this increase in melatonin production contributes to a delayed puberty in some pubertal obese males remains to be established.

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.

Effect of the parental origin of the X-chromosome on the clinical features, associated complications, the two-year-response to growth hormone (rhGH) and the biochemical profile in patients with turner syndrome

BackgroundIt is possible that genes on the X chromosome are expressed differently depending of its parental origin. The objective of this study was to determine the influence of the parental origin of the X-chromosome on phenotypic variability, response to rhGH and on the biochemical profile of TS patients.MethodsThis was a cross-sectional multicenter correlational study carried out over three years in six Latin-American university hospitals. Unrelated 45,X TS patients (n =  93; 18.3 ± 8.5 years )) were evaluated. A subgroup (n =  34) of the patients were prospectively treated with rhGH over two years. DNA profiles of patients and their mothers were compared to determine the parental origin of the retained X-chromosome through 10 polymorphic X-chromosome-STRs. The association with clinical features, biochemical profiles and anthropometric data at the beginning and after two years of rhGH treatment was determined.ResultsSeventy two percent of patients retained the maternal X chromosome (Xm). A trend towards significance between maternal height and patients final height (p ≤ 0.07) in 45,Xm subjects was observed. There was no correlation between paternal height and patient height. No differences were detected between both groups in regard to dysmorphic features, classical malformations or increase in the height-SDS after rhGH. There were higher levels of triglycerides, total and LDL cholesterol in patients >20 years who retained the Xm.ConclusionsThe parental origin of the retained X chromosome may influence lipid metabolism in TS patients, but its effect on growth seems to be minimal. No parental-origin-effect on the phenotypic features, associated anomalies and on the growth response to rhGH was found in 45,X TS individuals.

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.

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

ABSTRACT 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.

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 Δ 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 Δ values (p < 0.0001). Subsequent analysis showed significantly higher levels for total 6-SM, nocturnal 6-SM and nighttime-daytime Δ 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.

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.