Giorgio Giovannelli

Relationships between serum IGF-1, IGFBP-2, interleukin-1beta and interleukin-6 in inflammatory bowel disease.

Aims: To study the relationships between serum IGF-1, IGFBP-3 and IGFBP-2 and interleukin (IL)-1β and IL-6 in inflammatory bowel disease (IBD). Methods: Thirty-seven patients (18 males, 19 females, aged 8.8–26.1 years) with IBD (Crohn’s disease, CD, n = 17, and ulcerative colitis, UC, n = 20) were studied. Patients were in relapse or remission according to established criteria. Serum IGF-1, IGFBP-3, IGFBP-2, IL-1β and IL-6 levels were determined in patients and 15 healthy controls (aged 8.2–19.0 years). Results: IGF-1 levels were lower in patients with CD in relapse compared with controls (p < 0.05). IGFBP-2 levels were higher in CD in relapse compared with other groups (all p < 0.05). In CD and UC patients (n = 37), IGF-1 levels were inversely correlated with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). IGFBP-2 levels correlated positively with ESR and IL-1β. IL-6 levels correlated positively with ESR and CRP. IL-1β levels were elevated in CD in relapse compared to controls (p < 0.05) and were higher in UC in relapse than in other groups (all p < 0.05). In combined CD/UC patients in relapse (n = 20), IL-1β levels were higher (p < 0.05) in patients with recto-sigmoiditis (n = 5) than in other patients. Conclusions: IGF-1, IGFBP-2 levels were related to IL levels, disease activity and anatomical distribution, consistent with active inflammation modifying the IGF-IGFBP system, possibly relevant to disturbance of growth.

McCune-Albright syndrome in a male child:A clinical and endocrinologic enigma

A 6 5/12-year-old boy with polyostotic fibrous dysplasia, café-au-lait pigmentation of the skin, and precocious pubertal development was studied for two years. Parathormone, calcium, phosphorus, testosterone, cortisol, and growth hormone levels were within normal limits. Urinary 17-ketosteroids, 17-ketogenic steroids, and estrogens were at the upper limits of normal. After GnRH stimulation, there was only a very slight increase in LH and no increase in FSH. There was no increase in TSH after TRH, and plasma levels of T4 and T3 were normal. The plasma prolactin level was within normal limits, and increased after TRH stimulation (with a second, delayed upsurge). Abnormal distribution of 131I in the thyroid was evident, without clearcut evidence of hyperfunctioning areas after TSH stimulation and T3 suppression tests followed by conventional scanning and gamma camera scintiphotography. Our findings do not support the claimed, single, hypothalamic origin of the disease that is presumed to result in overproduction of releasing hormones; they are more in keeping with a pleiotropic, scattered peripheral lesion, possibly of embryonal origin.

Blood Pressure Behaviour and Control in Turner Syndrome

UNLABELLED Adult Turner syndrome (TS) patients frequently present hypertension. To clarify the pathogenesis of this hypertension we examined the blood pressure (BP) behaviour and the renin-angiotensin-aldosterone system in 31 TS patients (2-22 years of age). BP levels were occasionally elevated in 47% of the subjects and constantly elevated in 23%. Most of the patients were on estrogen replacement therapy, but 26% of them presented with elevated levels since childhood. Supine and upright plasma renin activity (PRA) values were higher in TS compared to controls and more elevated in hypertensive TS than in the normotensive ones. At Captopril challenge TS showed different PRA responses regardless of the karyotype and clinical features. Patients on estrogen therapy, however, exhibited higher increments of PRA after Captopril. CONCLUSIONS TS patients show high frequency of hypertension in pediatric age. Estrogen therapy is an outbreaking and worsening factor. An estrogen independent role of the renin-angiotensin-aldosterone system in the pathogenesis of TS hypertension is still uncertain.

Dynamics of 24-hour pulsatile cortisol, 17-hydroxyprogesterone, and androstenedione release in prepubertal patients with nonclassic 21-hydroxylase deficiency and normal prepubertal children

To assess whether the quantitative and qualitative aspects of cortisol, 17-hydroxyprogesterone (17-OHP), and androstenedione (D4A) secretion in patients with nonclassic congenital adrenal hyperplasia (NCCAH) differ from those in normal children, 24-hour serum concentrations of these steroids were measured in five prepubertal patients with NCCAH and five normal prepubertal children. Adrenal steroid profiles obtained by 30-minute sampling were analyzed by the Pulsar program. In comparison to normal children, the 24-hour quantitative parameters of 17-OHP and D4A secretion were significantly greater in NCCAH patients, but serum cortisol concentrations were similar in the two groups. When daytime and nighttime hormone releases were separately analyzed, a significant nocturnal elevation of the cortisol area under the curve above zero level (AUCo) and 12-hour mean and 17-OHP AUCo, AUC above baseline, mean peak height, amplitude, area, and 12-hour mean was detected in normal subjects only. Conversely, NCCAH patients exhibited an increased frequency and number of 17-OHP secretory peaks at night together with a reduction of the interpeak interval. No significant day/night differences in D4A concentrations were detected either in normals or in the patients. In conclusion, the results of the present study indicate that patients with NCCAH have a distinct pattern of adrenal steroid secretion characterized by a high-frequency 17-OHP release accompanied by a relative nocturnal cortisol deficiency.

Pineal Region Tumors: Endocrinological Aspects

The pineal gland and the superior cervical ganglia represent an integration center for hormonal and neural signals, and play an important role in modulating basic hormonal secretions. The prevalence of pineal tumors in the male sex and their frequent association with precocious puberty has been known for a long time. However, the rarity of ascertained cases investigated by means of direct and sensitive methods (RIA; tests applying hypothalamic releasing factors) is still preventing the proper knowledge of the endocrinological aspects of pinealomas. On the basis of the recent literature, the importance of diabetes insipidus as a very early symptom of pineal region tumors should be emphasized; in some cases, it preceded the appearance of precocious puberty of neuro-ophthalmologic signs by some years. A variable pattern of anterior pituitary impairment is also a rather common finding. In rare cases (males, with few exceptions), the precocious puberty may be explained by the presence in the pineal tumor of trophoblastic tissue secreting hCG; some of these tumors produce also alpha-fetoprotein (evidence of a yolk-sac tumor).

Pituitary TSH response to TRH: interrelationships with gonadal activity.

SummaryA TSH radioimmunoassay is described, which was used to investigate the behaviour of the TSH pituitary response (as measured by the secretory area) to TRH in groups of subjects of both sexes and different phases of gonadal activity. It is concluded that the TSH pituitary response is in no way affected by physiological variations in the plasma gonadal hormones. This independent behaviour of the TSH response, uninfluenced by gonadal activity, was apparently confirmed by the results in some pathological conditions (ovarian agenesis and primary male hypogonadism of various types) characterized by very low plasma levels of gonadal hormones.

Spontaneous Growth Hormone Secretion in Turner's Syndrome

Studies of GH secretion in patients with Turners syndrome (TS) have yielded conflicting results. A relative deficiency of GH, contributing to adult short stature, in pubertal patients with TS has been reported by some authors, but not confirmed by others. Limited and controversial data are also available on GH secretory dynamics in prepubertal girls with TS. To analyze the quantitative and qualitative aspects of GH secretion in TS further we studied 24-h GH release of 10 patients with TS and 9 short-normal children with similar auxological features. GH profiles, analyzed by the Pulsar program, indicate that a nocturnal elevation of non-pulsatile GH concentration occurs in both groups. However, only short-normal children showed a night-time increase in the sum of peak amplitudes. Patients with TS had a significantly decreased number and frequency of peaks in the night-time compared with short-normal children suggesting the possibility that an altered somatostatinergic tone modulates the activity of the somatotropes. A functional abnormality of the hypothalamic-pituitary axis is also indicated by lower GH responses to acute GHRH stimulation reported in these patients compared with normal children and by the effects on spontaneous GH secretion of chronic GHRH administration. The pathogenetic mechanisms responsible for the abnormal GH neuroregulation are not understood, although the absence of gonadal steroids is considered the principal reason. In conclusion, prepubertal girls with TS have a discrete pattern of pulsatile GH secretion suggestive of an altered somatostatinergic tone modulating GH release by the pituitary. However, the relation of the GH secretory pattern to growth in these patients is not clearly defined.

CLONIDINE TREATMENT IN CHILDREN WITH CONSTITUTIONAL GROWTH DELAY (CGO)

Ten children (9 males and 1 female; mean age 9.6 yrs)were treated with clonidide (75 μg/m2 p.os b.i.d.) for a period of 6 months. CGD diagnosis was based on the following clinical and laboratory criteria: heigth < 3rd percentile; growth velocity (GV) ≤ 5 cm/yr (4.17±0.2[Xmacr ]+ SEM); delayed bone age (BA) by 1 or more yrs and always below the age of 11; Tanner stage I; normal (> 8 ng/ml)peak serum GH responses to clonidine p.os (26±6 ng/ml) and insulin i.v.(III)(14±2.0 ng/ml); somatomedin C (SmC) levels in the normal prepubertal range (0.78±0.13 U/ml). The above mentioned parameters, in additions to OGII and baseline Cortisol (C).I4 and FT4 blood levels were examined before and after (exept ITT) 6 months of therapy. During the treatment period mean growth velocity increased (p<0.01) from 4.2 ± 0.2 to 5. 3±0.3 cm/yr although only 3/10 subjects showed a 50% increment compared to pre-therapy values. GH peak values after clonidine (30.9±5.8 ng/ml), glucose levels in response to OGII and baseline SmC, and thyroid hormone levels did not change after therapy. No significant correlation was found between GV after therapy and GH responses to provocative tests, GV, BA and chronological age before therapy in any patient. No important side effects were recorded. In conclusion, these preliminary results, indicate that clonidine might be effective in enhancing GV of some children with CGD although we were not able to differentiate responders from non responders based on clinical and laboratory parameters.

FINAL HEIGHT (F.H.) IN A GROUP OF CHILDREN WITH CONSTITUTIONAL GROWTH DELAY (CGO)

On the basis, of recent evidences, CGD seems to be a heterogeneous disorder and it has been hypothesized that some of these children could profit from different therapies. We investigated the natural outcome of a group of never treated CGD children especially in regard to their F.H..49 children (35 males and 14 females) with CGD have been followed at least yearly since prepuberty till the end of growth (bone age > 18 yrs in f.and > 19 yrs in m.). At diagnosis height was between -1 and -3 standard deviation score (SDS)(20% of the patients < 2.5 HSDS); bone age (BA)at least < 2DS for chronological age (CA)and growth velocity in the low-normal range for CA. The most important results can be summarized as follows: -mean F.H. was reached later than in normal population (17-23 yrs CA);it is always in the normal range and well correlated with the genetic target calculated on the basis of parental height (=0.68; p < 0.001). Just in 1 case F.H.was<-2DS from the target.-Height prediction (Bayley and Pinneau) is correlated with F.H. both in prepuberty and in puberty (p < 0.005);however it overestimated in both age groups (31% of cases in orepuberty and 26% in puberty).-Puberty started at 12.k yrs in f.and 13 yrs in m.and ended 3 yrs later in both sexes.In conclusion, our data confirm the fact that CGD (at least when prepubertal height is > -3DS) is a benign condition reaching all the patients normal height well correlated with the genetic target.

FASTING BLOOD GLUCOSE (BG) LEVELS IN THE LATENT PERIOD (LP) OF IDDM IN CHILDREN

We retrospectively analyzed the occasional fasting BG concentration of 21 children and OGTT of 7 subjects who developed IDDM 60-8 months later. Approaching symptomatic diabetes the fasting BG levels (72-115 mg/dl) progressively increased with a r-value of 0.68 ( p<0.005) and the peak insulin release at OGTT (40-26 uU/ml) declined in a similar linear manner (r=0.97; p<0.01). Abnormal BG elevations in response to OGTT have been noticed in all subjects at 60 min. (> 180 mg/dl)and in 3 of them also at 180 min (> 140 mg/dl); glycosuria appeared in 2 subjects. In spite of these abnormalities BG levels were not further controlled before the overt onset of IDDM. These retrospective data (rarely available in the PL of IDDM in children) confirm that the abrupt clinical onset of diabetes may be preceeded by a long period of abnormal BG levels and insulin secretory capacity. We suggest that monitoring of these parameters may constitute an effective and non-expensive measure to identify children at risk for IDDM and to admit them to immunological and genetic investigations.