Controversies in the Definition and Treatment of Idiopathic Short Stature (ISS)

The term idiopathic short stature (ISS) refers to short children with no identifiable disorder of the growth hormone (GH)/insulin like growth factor (IGF) axis and no other endocrine, genetic or organ system disorder. This heterogeneous group of short children without GH deficiency (GHD) includes children with constitutional delay of growth and puberty, familial short stature, or both, as well as those with subtle cartilage and bone dysplasias. In rare cases, ISS is due to IGF molecular abnormalities. In this review we tackle the major challenges in the definition and treatment of ISS.     

重组人生长激素治疗不同生长激素分泌状态青春前期矮小患儿追赶性生长模式分析

目的 比较不同生长激素(GH)分泌状态矮小患儿重组人生长激素(rhGH)治疗后的初始追赶性生长模式,初步探讨其机制.方法 回顾性分析62例青春前期不同GH分泌状态矮小患儿对rhGH治疗1年半的追赶性生长模式并定期监测体格指标、促生长素轴的血清指标和骨龄.结果 各组在初始追赶性生长的幅度相似,特发性矮小(ISS)组比完全性生长激素缺乏症(GHD)组更早出现生长减速,并与生长激素结合蛋白(GHBP)水平降低和胰岛素样生长因子结合蛋白3的标准差分数(SDS)增值较小显著相关.GH激发峰值(Ghmax)>7μg/L的部分性GHD组与ISS组有类同的生长追赶的模式.结论 GH受体的降调节和受体后效应的降低可能是ISS组较早出现生长减速的机制.以Ghmaxμg/L作为GHD诊断的界值并相应选择rhGH治疗剂量有更充分的依据和临床意义.     

Acute ghrelin response to intravenous dexamethasone administration in idiopathic short stature or isolated idiopathic growth hormone-deficient children

Acylated ghrelin has been originally described for its potent GH-releasing activity mediated by the activation of the GH secretagogue receptor type 1a. More recently, ghrelin has been reported to exert several other GH-independent biological actions, among which in the modulation of metabolic functions. Glucocorticoids are well known to exert important metabolic functions but also to modulate GH secretion, although through mechanisms that have not been fully clarified so far. Interestingly, the existence of a feedback link between glucocorticoids and ghrelin system has already been reported. The aim of our study was to evaluate the acute GH and ghrelin responses to dexamethasone (DEX) administration in children with idiopathic short stature (ISS) or isolated idiopathic GH deficiency (GHD). Eight children with ISS (age: 9.5+/-1.2 yr) and 7 with GHD (12.1+/-1.4 yr) underwent iv DEX administration (0.3 mg/body surface area at 0 min). IGF-I, GH, and ghrelin levels were assayed at baseline and every 30 min from 120 up to 240 min after DEX. Compared to baseline levels DEX decreased ghrelin in ISS at 120 min and 240 min (p<0.04). On the other hand DEX did not modify ghrelin levels in GHD. After DEX, ghrelin was reduced in ISS compared to GHD (p<0.02). DEX increased GH in ISS but not in GHD (peak: 11.1+/-1.2 vs 7.6+/-0.9 microg/l). Basal, as well as after-DEX ghrelin levels negatively correlated with IGF-I in GHD (p<0.03) and with height SD score (HSDS) in ISS (p<0.02). Acute DEX administration is able to decrease ghrelin in ISS, but not in GHD children. Both basal and after-DEX ghrelin levels negatively correlate with IGF-I and HSDS. All these data suggest the existence of a feedback link among ghrelin, glucocorticoids and the GH/IGF-I axis.     

Antipituitary antibodies recognizing growth hormone (GH)-producing cells in children with idiopathic GH deficiency and in children with idiopathic short stature

CONTEXT: Antipituitary antibodies (APA) recognizing GH-secreting cells may indicate an autoimmune pituitary involvement in adults with idiopathic GH deficiency (IGHD). OBJECTIVE: We aimed 1) to investigate the presence of APA in prepubertal children with IGHD or idiopathic short stature (ISS), identifying the pituitary hormone-producing cells targeted by APA; and 2) to verify whether in patients with ISS the presence of APA could predict the development of GHD. DESIGN: We performed a cross-sectional and partially longitudinal cohort study. SETTING: The study was performed at the Endocrinology Unit and Pediatric Unit of the Second University and University Federico II of Naples, respectively. PATIENTS: Twenty-six children with IGHD (group 1), 60 children with ISS (group 2), 33 children with GHD caused by lesions/abnormalities of the hypothalamus or pituitary (group 3), and 40 controls participated in the study. Nineteen children of group 2 were reevaluated after 2 yr. MAIN OUTCOME MEASURES: IGF-I levels, GH secretion, and APA (by indirect immunofluorescence) were evaluated in all participants. RESULTS: At study entry, APA recognizing GH-producing cells were detected in seven of 26 children in group 1 and in 14 of 60 in group 2. Two years later, all eight initially APA-positive and all 11 APA-negative of the 19 reevaluated patients persisted positive and negative, respectively. The reevaluation of GH secretion in these patients revealed the development of GHD in all but one of the APA-positive children but in none of the APA-negative ones. CONCLUSIONS: IGHD in children can be frequently associated with APA targeting GH-secreting cells; thus, the detection of APA in children with ISS could identify those prone to develop GHD.     

The use of insulin-like growth factor 1 reference values for the diagnosis of growth hormone deficiency in prepubertal children

OBJECTIVE: This study was done to determine whether the use of reference values obtained in children with idiopathic short stature (ISS) improved the clinical value of serum insulin-like growth factor I (IGF-1) as a tool for diagnosing GH deficiency (GHD) in prepubertal children. PATIENTS AND METHODS: Serum IGF-1 was measured with a new IRMA kit (IGFI-RIA CT, Cis Bio, Gif sur Yvette, France) in 168 prepubertal normal children and in prepubertal children with ISS (n = 68), organic GHD due to a craniopharyngioma (oGHD, n = 15) and permanent idiopathic GHD (iGHD, n = 28). RESULTS: IGF-1 was lower (P < 0.001) in iGHD than in either ISS or oGHD and was below the fifth percentile of the normal range in 29/68 ISS (43%), 8/15 oGHD (53%) and 28/28 (100%) iGHD patients. Three oGHD (20%) and two iGHD (7%) patients had a serum IGF-1 below the fifth percentile of the normal group but above the fifth percentile of the ISS group. Thus, a serum IGF-1 below the fifth percentile of the normal group distinguished between normal children and iGHD with 100% sensitivity, between normal and oGHD with 53% sensitivity and between normal and all GHD (idiopathic + organic) with 84% sensitivity; the overall specificity was only 57%. Conversely, a serum IGF-1 below the fifth percentile of the ISS population distinguished between ISS and iGHD with 93% sensitivity, between ISS and oGHD with 33% sensitivity and between ISS and all GHD with 72% sensitivity; the overall specificity was then 95%. CONCLUSIONS: A serum IGF-1 within the normal range virtually excludes idiopathic GHD but does not rule out organic GHD, whereas an IGF-1 below the ISS range is strongly in favour of GHD, after exclusion of poor nutritional status and/or liver disease. An IGF-1 below the normal range but in the idiopathic short stature range gives no definitive conclusion even when it is associated with a low GH peak. Thus, whereas reference values obtained in normal children must be used to interpret serum IGF-1 in short prepubertal children, reference data obtained in idiopathic short stature children should also be taken into account.     

Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues

BACKGROUND AND OBJECTIVE Growth hormone treatment In children with Idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long-term effect of GH therapy in children with Idiopathic short stature. DESIGN We have treated 27 prepubertal children with ISS with recombinant human GH (rhGH) in an initial dosage of 2 IU/m² body surface/day subcutaneously, which was doubled either after the first year if the height velocity increment was less than 2 cm/year, or thereafter if height velocity fell below the P50 for bone age. Growth and bone maturation of the treatment group (ISS group, n= 21) were compared to those of an untreated control group with ISS (ISS controls, n= 27) and of a group of rhGH treated children with isolated GH deficiency (GHD group, n= 7). RESULTS In 9 patients of the ISS group still on treatment, height standard deviation score (HSDS) for chronological age increased from ?3.8±0.7 to ?2.3±0.9 (mean±standard deviation) over 6 years, while in matched ISS controls HSDS for age did not change. HSDS for age in the GHD group increased from ?3.9±0.6 to ?1.8±0.7 after 4 years, significantly more than the ISS group. Bone maturation was accelerated In the ISS and GHD groups. HSDS for bone age and predicted adult height did not change in either group. Final height in 12 children of the ISS group was ?2.6±1.0 SDS. In the untreated controls final height was similar. A low integrated GH concentration over 24 hours, a low GH peak to provocative stimuli, and minimal initial BA delay predicted a favourable outcome. CONCLUSION rhGH treatment In this group of children with Idiopathic short stature did not increase average final height. Part of the heterogeneity of the response can be attributed to the variation in endogenous GH secretion and initial bone age delay.     

Serum leptin levels are not influenced by arginine and insulin infusion and by acute changes of GH

The aim of this study was to evaluate the relationship between GH and leptin in a group of short children and adolescents. Leptin and GH serum levels were measured before and during pharmacological stimulation tests (arginine and insulin) in a group of 45 children (30 male, 15 female), mean age 8.6+/-3.9 yr, affected by idiopathic isolated GH deficiency (GHD), and in a group of 27 children (15 male, 12 female), age 10.9+/-3.3 yr, with constitutional growth delay. Results showed that basal and peak leptin levels as well as the AUC were significantly higher in GHD patients compared to controls (p<0.05) and correlated with BMI SDS (p<0.0001) in GHD patients. No change in leptin serum levels was observed during either stimulation test. No correlation was found, however, between basal leptin serum levels and basal, peak and the AUC of GH during the tests. Moreover, no correlation was found between the acute changes of serum GH concentration during both stimulation tests and leptin serum levels. The results suggest that leptin and GH secretion is not correlated and that leptin serum levels mainly reflect the amount of fat tissue, which is higher in GHD patients.     

Melatonin levels decrease in type 2 diabetic patients with cardiac autonomic neuropathy

The present study has been designed to determine melatonin levels in type 2 diabetic patients and test the relationship between the autonomic nervous system and melatonin dynamics. Thirty-six type 2 diabetic patients and 13 age-matched healthy subjects were recruited for the study. Circadian rhythm of melatonin secretion was assessed by measuring serum melatonin concentrations between 02:00-04:00 and 16:00-18:00 hr. Melatonin dynamics were re-evaluated with respect to autonomic nervous system in diabetic patients with autonomic neuropathy who were diagnosed by the cardiovascular reflex tests, heart rate variability (HRV), and 24-hr blood pressure monitoring. Nocturnal melatonin levels and the nocturnal melatonin surge were low in the diabetic group (P = 0.027 and 0.008 respectively). Patients with autonomic neuropathy revealed decreased melatonin levels both at night and during day when compared with healthy controls (P < 0.001 and 0.004 respectively) while the melatonin dynamics were similar to controls in patients without autonomic neuropathy. Nocturnal melatonin level was positively correlated with nocturnal high and low frequency components of HRV (P = 0.005 and 0.011 respectively) and systolic and diastolic blood pressures at night (P = 0.002 and 0.004 respectively) in patients with autonomic neuropathy. We found a negative correlation between nocturnal melatonin levels and the degree of systolic blood pressure decrease at night (r = -0.478, P = 0.045). As a conclusion this study has shown that circadian rhythm of melatonin secretion is blunted in type 2 diabetic patients and there is a complex relationship between various components of autonomic nervous system and melatonin secretion at night. Among the patients with autonomic neuropathy those with more preserved HRV and the systolic nondippers (<10% reduction in blood pressure during the night relative to daytime values) have more pronounced melatonin surge at night.     

Serum melatonin circadian profiles in women suffering from cervical cancer

Although there is an increasing evidence that the pineal gland may play a role in human malignancy, the studies on melatonin concentrations in different types of malignant tumors brought about controversial results. However, changes in melatonin concentrations have been observed in some types of human malignant tumors. Therefore, we decided to study the circadian melatonin rhythm in patients suffering from cervical cancer in different stages of progression and to compare them with those in subjects free from neoplastic disease. A total of 45 women were analyzed in this study. The subjects were divided into two groups. The first group consisted of 31 patients [mean age 52.1 +/- 1.8 yr (mean +/- S.E.M.), range 32-77 yr] with cervical cancer in various stages of the disease. The second group consisted of 14 healthy volunteers [mean age 53.5 +/- 2.0 yr (mean +/- S.E.M.), range 42-63] who served as the control group. Blood samples were collected at 08:00, 12:00, 16:00, 20:00, 22:00, 24:00, 02:00, 04:00, 06:00, and 08:00 hours. Melatonin concentration was measured by immunoenzymatic method. There were significant differences in circadian melatonin profiles as well as in the area under curve among the two studied groups. Melatonin concentrations were significantly lower in cancer patients in comparison with healthy individuals. Taking into consideration stage of the cervical cancer significantly lower melatonin secretion has been found in all subgroups of patients in comparison with that of tumor-free control group. Additionally, nocturnal melatonin concentrations as well as area under curve were significantly lower in advanced stage of cancer (stages 3 and 4) in comparison with patients with preinvasive cancer (stage 0) at 24:00, 02:00, and 04:00 hours and patients with stage 1 disease at 02:00 and 04:00 hours. The results of the present study indicate that the presence of cervical cancer influences melatonin levels in women. Moreover, stage dependence in reduction of melatonin concentrations has been found.     

重组人生长激素治疗单纯性生长激素缺乏症和特发性矮小症患儿血清C型利钠肽氨基末端浓度与生长速率的变化

目的 探讨单纯性生长激素缺乏症(isolated growth hormone deficiency,IGHD)以及特发性矮小症(idiopathic short stature,ISS)患儿经重组人生长激素(recombinant human growth hormone,rhGH)治疗后,血清C型利钠肽氨基末端(NTproCNP)浓度的变化及其与生长速率(growth velocity,GV)的关系.方法 共有48例青春期前的患儿纳入研究(IGHD 25例,ISS 23例),并给予rhGH治疗1年.治疗前及治疗后6个月分别测血清胰岛素样生长因子-Ⅰ (IGF-Ⅰ)和NTproCNP的浓度.治疗1年后,计算所有患儿的GV、身高Z积分(HTSDS)以及身高Z积分的变化值(△HTSDS).结果 IGHD组中,治疗前后IGF-I Z积分的变化值(△IGF-ISDS)、NTproCNP浓度的变化值(△NTproCNP)与治疗1年中GV呈正相关(r=0.407,P=0.044;r=0.490,P=0.013);治疗前生长激素(CH)峰值也与治疗前IGF-ISDS、NTproCNP浓度(r=0.558,P=0.004;r=0.630,P=0.001)以及治疗后△IGF-ISDS与△NTproCNP呈正相关(r=0.466,P=0.019).而在ISS患儿中,治疗1年中GV只与治疗后△NTproCNP相关(r=0.845,P＜0.01).结论 在IGHD和ISS患儿应用rhGH的促生长治疗中,NTproCNP水平随着生长速率的增加而增加.因此除了IGF-I,NTproCNP作为一种新的生化标记物,也可用于评估和预测这两类患儿在rhGH治疗后的GV变化.     

Do growth hormone (GH) serial sampling,insulin‐like growth factor‐I (IGF‐I) or auxological measurements have an advantage over GH stimulation testing in predicting the linear growth response to GH therapy?

OBJECTIVE: To compare the relative utility of GH secretion via pharmacological stimulation, overnight serial sampling, IGF-I levels and auxological variables as predictors of change in height standard deviation score (deltaHt SDS) during GH treatment. DESIGN: A multicentre observational study. PATIENTS: Prepubertal children (n = 825) with idiopathic growth failure who were subsequently treated with GH were divided into two groups, based on their maximum GH response to pharmacological stimulation testing: (1) idiopathic GH deficiency (IGHD), defined by a maximum GH response < 10 microg/l (n = 300); and (2) idiopathic short stature (ISS), with a maximum GH response > or = 10 microg/l (n = 525) (GH conversion factor: 3 IU = 1 mg). MEASUREMENTS: Overnight spontaneous GH secretion was measured in all patients. The following characteristics of spontaneous GH secretion were studied: maximum or peak GH, mean peak GH, number of GH peaks, pooled GH, mean GH, and approximate entropy of GH secretion. RESULTS: Although children with IGHD had lower indices of spontaneous GH secretion, there were no differences between IGHD and ISS groups in baseline Ht SDS, growth rate or IGF-I level. The dose and duration of GH therapy were similar. There was no statistically significant difference in the mean (+/- SD) change in Ht SDS (deltaHt SDS) in the two groups (IGHD 1.3 +/- 0.9 and ISS 1.2 +/- 0.8). Measures of spontaneous secretion, such as peak GH, mean of GH peaks, mean area under GH peaks, and mean GH, as well as IGF-I concentrations, were all statistically significantly correlated with deltaHt SDS in IGHD children (P < 0.0001). A significant correlation was also observed for pooled GH (P = 0.002) and approximate entropy (P = 0.01). Children with the most severe ISS (Ht SDS < -3.33) demonstrated a more disorganized pattern of GH secretion compared to children who were not as short (Ht SDS -2.33 to -1.64), as indicated by a higher approximate entropy (0.673 +/- 0.193 vs. 0.607 +/- 0.161, P < 0.004). This increased disorder in GH secretion was accompanied by lower IGF-I levels (104 +/- 99 microg/l vs. 137 +/- 74 microg/l, P < 0.001), even though pooled GH concentrations were indistinguishable between the two groups (2.2 +/- 1.3 microg/l vs. 2.0 +/- 1.0 microg/l). Children with IGHD demonstrated lower approximate entropy than did those with ISS (0.551 +/- 0.235 vs. 0.631 +/- 0.182, P < 0.0001). Duration of GH treatment, height deficit and genetic potential (midparental Ht SDS) were the most important variables influencing deltaHt SDS in children receiving GH therapy. Maximum stimulated GH, IGF-I and indices of spontaneous GH secretion also correlated with deltaHt SDS, but their relative importance varied among diagnostic groups. CONCLUSIONS: Patients with GH deficiency demonstrate a reduced capacity for GH secretion, while those with idiopathic short stature exhibit a more disorderly and less functional secretory pattern. Although effective in predicting a response to GH treatment in patients with severe GH deficiency, overnight serial sampling is less practical than other methods currently available. In addition, serial sampling was less useful as a predictor of growth response to exogenous GH in patients with idiopathic short stature.     

Effect of melatonin treatment on 24-hour rhythms of serum ACTH, growth hormone, prolactin, luteinizing hormone and insulin in rats injected with Freund''s adjuvant

The effect of melatonin injection on Freund's adjuvant-induced changes in levels and 24-hr rhythms of circulating ACTH, growth hormone (GH), prolactin (PRL), luteinizing hormone (LH), and insulin was assessed in rats. Animals received subcutaneous (s.c.) injections of melatonin (30 microg) or vehicle, 1 hr before lights off for 12 days. Ten days after melatonin treatment, they were injected with Freund's complete adjuvant or its vehicle s.c., and after 3 days, rats were killed at six different time intervals throughout a 24-hr cycle to measure the different hormones by radioimmunoassay (RIA). Following Freund's adjuvant injection, an increase in serum ACTH, with maintenance of ACTH diurnal rhythm was found. Acrophases of the ACTH rhythm varied from 13:39 to 17:12 hr and the amplitude of rhythm was augmented after immunization. In immunized rats, melatonin treatment increased the amplitude of serum ACTH rhythm. For GH, a depressive effect of immunization on circulating levels, together with absence of diurnal rhythmicity were found. Immunization augmented circulating PRL, while conserving its diurnal rhythmicity. Melatonin-injected rats showed significant diurnal variations of serum PRL after immunization only. Acrophases of the serum PRL rhythm varied from 19:37 to 22:04 hr. Immunization decreased circulating LH and suppressed its 24-hr rhythmicity pattern. The effect of immunization on LH was counteracted by melatonin injection. Acrophases of serum LH rhythm varied from 00:44 to 03:53 hr. Significant effects of immunization and time of day on circulating insulin were detected; immunization increased serum insulin levels with a shift in acrophase from early afternoon to midnight. The data indicate that several early changes in levels and 24-hr rhythms of circulating ACTH, PRL, and LH in Freund's adjuvant-injected rats were sensitive to treatment with pharmacological amounts of melatonin.     

Can exaggerated response to a GH provocative test identify patients with partial GH insensitivity syndrome?

OBJECTIVES: In the majority of children with short stature, the etiology is unknown. Mutations of the GH receptor (GHR) have been reported in a few children with apparent idiopathic short stature (ISS). These patients had low IGF-I, IGF-binding protein-3 (IGFBP-3) and GH-binding protein (GHBP), but a normal or exaggerated GH response to provocative stimuli, suggestive of partial GH insensitivity (GHI). We attempted to identify children with partial GHI syndrome, based on their response to GH provocative stimuli and other parameters of the GH-IGF-I axis. SUBJECTS AND METHODS: One hundred and sixty-four pre-pubertal children (97 boys, 67 girls) aged 7.2 (0.5-16.75) years were studied. All had short stature with height <3rd centile. The weight, bone age (BA) and body mass index (BMI) of the subjects, as well as the parents' heights and mid parental height (MPH) were assessed. Basal blood samples were taken for IGF-I, IGFBP-3 and GHBP. All subjects underwent a GH provocative test with either clonidine, arginine or insulin. The subjects were divided into three groups: (A) patients with peak GH concentration <18 mIU/l in two different provocative tests (GH deficiency - GHD, n=33); (B) patients with peak GH between 18.2 and 39.8 mIU/l (normal response, n=78); (C) patients with peak GH >40 mIU/l (exaggerated GH response, n=53). RESULTS: No significant differences were found in age, height (standard deviation score (SDS)), parental height (SDS) and the difference between chronological age and bone age (DeltaBA) between the groups. Patients with GHD were heavier (P=0.039) and had significantly higher BMI (SDS) (P=0.001) than the other groups. MPH (SDS) was lower in the group of exaggerated responders (P=0.04) compared with the other groups. No significant differences were found between the groups for the biochemical parameters when expressed nominally or in SDS, except for IGFBP-3 (SDS), which was lower in the GHD group (P=0.005). The GHBP levels were not lower in the group of exaggerated GH response to provocative stimuli. Height (SDS) correlated negatively with basal GH values in pooled data of all the subjects (r=-0.358, P<0.0001), in normal responders (r=-0.45, P<0.0001) and in the exaggerated responders (r=-0.341, P<0.0001), but not in the GHD group. CONCLUSION: Exaggerated GH response to provocative tests alone does not appear to be useful in identifying children with GHI.     

Decreased nocturnal synthesis of melatonin in patients with coronary artery disease

In human beings, cardiovascular activity has a distinct circadian variation: Heart rate, blood pressure, and vascular tone decrease at night. Nocturnal cardiovascular blunting is at least partially linked to the autonomic activity and increased risk of cardiac and cerebral events. To assess whether decreased nocturnal melatonin synthesis and secretion in coronary artery disease (CAD), we investigated nocturnal secretion pattern of melatonin in patients with CAD and healthy subjects. The present study performed in 16 patients with angiographically documented CAD (aged 46-71 years) and in nine healthy controls (aged 36-66 years). Blood samples were collected every 2 h between 22:00 and 08:00 h. Melatonin levels were measured with a commercially available radioimmunoassay kit. We found large interindividual variation in the pattern of melatonin secretion in both groups. Patients with CAD secreted less nocturnal melatonin at 02:00, 04:00 and 08:00 h than control subjects (P=0.014, P=0.04 and P=0.025, respectively). Peak and Delta melatonin (peak-lowest melatonin) were found lower in patients with CAD (48.6 [19.1-75.4] vs. 131.4 [67.8-137.2] pg/ml, P=0.006 and 43 [10.5-68.5] vs. 107.6 [55.7-113.1] pg/ml, P=0.002, respectively). Peak time of melatonin secretion was observed earlier in patients with CAD (02:00 h [23:00-02:00 h] vs. 03:45 h [02:00-05:00 h], P=0.04). Our study provides useful and preliminary information about decreased nocturnal melatonin synthesis and release in patients with CAD might help physicians in managing these patients.     

Seasonality of psychopathology and circannual melatonin rhythm

The association of seasonal changes in health and disease has been known for centuries. The prevalence of psychopathological symptoms with seasonal fluctuations and the use of melatonin as a biological marker of circadian and circannual rhythms is well documented. The aim of this work was to study the variability of melatonin secretion between summer and winter in our geographical area (28 degrees N, 16 degrees W) and relate the changes to the level of psychopathology. Ten drug-free, nonsmoker, healthy subjects were studied in summer (August) and winter (December). Blood samples for melatonin assays were collected every hour at night for 5 hr, from 22:00 to 02:00 hr, and next day at noon. Melatonin was assayed by an ELISA technique. Psychopathology was evaluated by means of the 28-item version of the General Health Questionnaire (GHQ-28). All subjects had a circadian rhythm of melatonin secretion in summer and winter. There was a seasonal rhythm with melatonin levels being significantly higher at night in winter than in summer. Melatonin levels at 22:00, 23:00, 24:00 and 01:00 hr and mean melatonin area under the curve (AUC) were significantly higher in winter than in summer. Melatonin AUC increased 80% in winter compared with summer. The GHQ-28 somatic and anxiety subscales and the total GHQ-28 score were significantly higher in winter than summer. Psychopathology scores were significantly and negatively correlated with melatonin production in summer and winter. Our data strongly suggest that melatonin production and psychopathology levels present seasonal fluctuations and these variations should be taken into account when conducting research in this field.     

Growth hormone secretion in adult patients with thalassaemia

BACKGROUND AND OBJECTIVES: Growth retardation and short stature are frequent clinical features of patients with beta-thalassaemia major. Dysfunction of the GH-IGF-1 axis has been described in many thalassaemic children and adolescents with short stature and reduced growth velocity. Several studies have demonstrated that recombinant GH treatment improves growth velocity in these patients, although response to the treatment is variable and not predictable. A reassessment of the GH-IGF-1 axis must be performed in young adults with childhood-onset GH deficiency (GHD), after attainment of final height, to select those who are candidates for replacement therapy as adults. To our knowledge there are no data available on retesting the GH-IGF-1 axis in adult thalassaemic patients with childhood-onset GHD. The aim of our study was to investigate GH secretion in adult thalassaemic patients with childhood-onset GHD. DESIGN: We reassessed GH secretion in a group of adult thalassaemic patients in whom partial GHD had been diagnosed during childhood. PATIENTS AND METHODS: We performed an arginine plus GH-releasing hormone (GHRH) stimulation test in 16 thalassaemic patients (10 males, six females) with a mean age of 24.8 +/- 3.6 years. The cut-off level for GH response was set at 9 microg/l, according to the literature. Ferritin, IGF-1, liver enzymes and lipid levels were also determined. RESULTS: We found persisting GHD in three patients, one patient had borderline values (GH peak = 10.4 microg/l), whereas the others had a normal response. These results are in accordance with the data on GH retesting in adult patients with idiopathic partial childhood-onset GHD. CONCLUSION: We conclude that GH status should be retested in adult thalassaemic patients with childhood-onset GHD. If the diagnosis of adult GHD is established, GH treatment may be considered as it could contribute to improve heart function and bone mineral density, which are frequently impaired in adult thalassaemic patients.     

Metabolic benefits of growth hormone therapy in idiopathic short stature

The US Food and Drug Administration approved use of recombinant human growth hormone (GH) for the treatment of idiopathic short stature (ISS) in children; however, few studies have evaluated metabolic outcomes. This article addresses whether children with ISS treated with GH experience the same metabolic benefits as children with GH deficiency (GHD) treated with GH. A systematic review of all published studies of GH treatment in children with ISS that included data on metabolic outcomes identified five studies. No meta-analysis has been performed.Studies show a metabolic response to GH treatment in children with ISS similar to that observed in children with GHD; effects include a transient decrease in insulin sensitivity and a dose-dependent increase in insulin-like growth factor I. However, no increase in the risk of diabetes was found. Children with ISS seem to benefit from GH treatment in terms of height gain without any severe negative metabolic outcomes.     

A test of the coincidence and duration models of melatonin action in Siberian hamsters: the effects of 1-hr melatonin infusions on testicular development in intact and pinealectomized prepubertal Phodopus sungorus

The pineal hormone melatonin is known to play an important role in mediating photoperiodic messages to the reproductive system in seasonal breeding animals. Our goal was to test, in a single experimental paradigm, two hypotheses that have been forwarded to describe how the circadian rhythm of pineal melatonin transmits photoperiodic information to the reproductive system: 1) induction, i.e., a short-day effect, occurs when secreted melatonin and a circadian rhythm of sensitivity to melatonin coincide in time; 2) induction occurs following exposure to elevated circulating melatonin levels for a prescribed duration. In order to determine the relative validity of these hypotheses, we investigated the testicular maturation response to 1-hr daily infusions of 10, 25, and 50 ng of melatonin in pinealectomized intact and prepubertal Siberian hamsters (Phodopus sungorus). Animals received, beginning on day 15 of life, programmed subcutaneous infusions of melatonin or vehicle at one of five time points (19:00-20:00, 20:00-21:00, 21:00-22:00, 24:00-01:00, and 03:00-04:00 hr) for 15 days. In animals gestated and raised in a long photoperiod (LD16:8 = 16L, where L is the duration of light in hours, and D that of dark), melatonin infusion right after lights off (20:00-21:00 hr) significantly retarded gonadal maturation; this dose was ineffective at other times tested. Doses of 10 and 25 ng melatonin were ineffective at all time points. Identical results were obtained in prepubertal hamsters gestated in a short photoperiod (LD10:14 = 10L) and raised in 16L; these results were independent of the presence or absence of the pineal gland. In animals gestated and raised in 10L, melatonin infusions failed to suppress testicular development beyond that induced by the photoperiod; testicular development was maximally suppressed in all groups. The results of these investigations are best explained under the experimental conditions employed here: 1) the photoperiodic gonadal response in juvenile Siberian hamsters is regulated by the coincidence in time of exogenously administered melatonin with an intrinsic rhythm of sensitivity to melatonin, which, under the constraints imposed by our experimental design, occurred at 20:00-21:00 hr; and 2) the duration of the melatonin signal alone, equal in all groups, cannot explain the results.     

Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians

Melatonin secretion is an endogenous synchronizer, and it may possess some anti-aging properties. Thus we examined melatonin levels in physiological aging, in extreme senescence and in senile dementia. In healthy old (age 66-94 yr) and young subjects (age 23-39 yr) and in demented patients (age 68-91 yr) plasma melatonin was measured by radioimmunoassay in eight serial blood samples. In centenarians (age 100-107 yr) melatonin levels were estimated by assaying urinary 6-hydroxymelatonin sulfate (aMT6s) in two different urine samples collected from 08:00 to 20:00 hours and from 20:00 to 08:00 hours. These data were compared with the aMT6s excretion of old and young controls. Elderly subjects, demented or not, exhibited a flattened circadian profile of plasma melatonin, because of the suppression of the nocturnal peak. An age-related decline of the circadian amplitude of the melatonin rhythm occurred in old subjects, especially in demented individuals. Furthermore, the melatonin nocturnal peak was significantly correlated with the severity of the cognitive impairment. aMT6s urinary excretion also declined with age. However, as in young controls, in centenarians the aMT6s excretion was significantly higher at night than during the day. In conclusion, pineal melatonin secretion is affected by age and by the degree of cognitive impairment. In centenarians the maintenance of the circadian organization of melatonin secretion may suggest that the amplitude of the nocturnal peak and/or the persistence of a prevalent nocturnal secretion may be an important marker of biological age and of health status.     

Effects of a one-hour light pulse on the timing of the circadian rhythm in melatonin secretion in rams

Abstract: The effects of a 1-hr light pulse on the timing of the circadian rhythm in the blood plasma concentration of melatonin were documented in Soay rams. Groups of 5 to 6 animals were transferred from short days (LD 8: 16) to constant dim red light (DD) for 6 days, and were exposed to a 1-hr light pulse at one of 16 different times throughout 24 hr on day 3. Blood samples were collected hourly for 30 hr before (day 2–3) and after the light pulse (day 5–6), and the plasma concentrations of melatonin were measured by radioimmunoassay. The animals were allocated to experimental groups based on the circadian time (CT) when the light pulse was given using two hourly blocks through the circadian day; the onset of enhanced melatonin secretion (melatonin peak) was designated as CT 12. Under DD there was a clearly defined plasma melatonin rhythm in all animals. The mean duration of the melatonin peak was 13.24 ± 0.16 hr (n = 91) and the mean period between the onset of successive melatonin peaks was 23.55 ± 0.10 hr (n = 21). The effect of the 1-hr light pulse on the time of onset of the melatonin peak varied significantly with the circadian time when the light pulse was given (ANOVA, P= 0.031). Light-induced significant (pre- vs post-pulse onset, Students t-test, P < 0.05) phase delays in the onset of the melatonin peak in the early subjective day at CT 2.5 hrs (mean ø: -1.9 hr), and in the early subjective night at CT 12.5 and 14.5 (mean ø: -2.0 hrs), but not at other times. The light pulse never induced significant phase advances. The effects of the light pulse on the offset of plasma melatonin peak did not vary significantly with the time of the light pulse (ANOVA, P= 0.780), although significant differences in the pre- and post-pulse offset occurred at CT 14.5 and 18.5 (mean ø: -1.5 hr). The differential changes in the onset and the offset of the melatonin peak resulted in changes in the duration of the peak (maximum difference between means: 3.8 hr). The results indicate that entrainment occurs under natural 24 hr LD cycles when light impinges on the early subjective night and induces a net phase delay, thus extending the period of the melatonin rhythm to 24 hr. This causes a close phase relationship between the end of the light period and the onset of the melatonin peak as occurs in sheep under natural cycles. The results are also consistent with a multiple oscillator governing melatonin secretion, and that differential entrainment of the component oscillators by light affects the duration of the melatonin peak.