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Summary OBJECTIVE Increased levels of free thyroid hormones have been previously described in prepubertal blind subjects and have been thought to be a consequence of a partial target organ refractoriness due to the early and prolonged lack of light perception. The aim of this study was to clarify whether this abnormality is permanent or transient and the interrelationships between melatonin and thyroid hormone secretion. MEASUREMENTS Total and free thyroid hormones, TSH, thyroxine-binding globulin (TBG), reverse trilodothyronine (rT3) and melatonin were measured In plasma samples obtained at 0800 h (two hours after lights-on) In a group of 11 totally (group 1) and 16 partially (group 2) blind adult patients and in 10 age-matched healthy subjects. RESULTS Both totally and partially blind patients showed melatonin levels higher than in controls (330 ± 106 pmol/l, group 1 and 361 ± 159 pmol/l, group 2, respectively; controls: 53 ± 12 pmol/l, P < 0.001 vs both groups), but fT4, fT3, T4, T3 TSH, rT3 and TBG concentrations showed no significant differences from controls. CONCLUSIONS A possible resetting of pltuitary-thyroid axis regulation can occur in blindness after puberty; variations of melatonin secretion could play a role in this. The inhibitory effect of melatonin on thyroid gland function found in animals does not seem to occur in humans. Elevated melatonin levels, both in patients with total blindness and in those with light perception only, suggest that more complex mechanisms other than light signalling are involved in the changes of melatonin secretion in blindness.

To clarify the occurrence of circannual GH, TSH, T4 and T3 rhythms in prepuberty we have been studying, for a four year period, 150 healthy subjects, aged 6-10, by cross-sectional design. Plasma samples were taken at 0800 h and all hormones were measured by RIA. The occurrence of any circannual rhythm was statistically investigated by the cosinor method. A significant rhythm was validated (P = 0.02) only in TSH secretion, with annual crest time in December; GH, T4, T3 did not show a circannual rhythm. Our results seem to strengthen the hypothesis that the thyroid hormones, at least before puberty, do not play an important role in the regulation of circannual TSH periodicity.

The aim of this study was to determine if changes in LH, FSH, PRL, and testosterone (T) secretion occur in blind prepubertal boys. Eight blind and six normal boys, aged 7-10 yr, living at an institute for blind subjects in Naples, Italy, were studied. Each had a combined GnRH (100 micrograms) and TRH (200 micrograms) test at 0800 h after nocturnal rest. Plasma LH, FSH, PRL, and T levels were measured by RIA. The blind boys had basal plasma LH, FSH, and T levels significantly lower than those in the normal boys (P less than 0.01 for all three); plasma PRL basal levels were similar to those in the normal boys. The blind boys, moreover, had lower peak LH, FSH, and PRL (P less than 0.01 for all three peaks) levels in response to GnRH-TRH. Our results, similar to those found by others in patients with delayed puberty or with hypogonadotropic hypogonadism, suggest that light stimuli influence neuroendocrine-gonadal activity in humans, as in other mammals; and in blind prepubertal boys, impaired hormone secretion could cause a delay of pubertal development or more severe hypogonadism.

No appreciable changes in plasma GH levels after TRH stimulation have been observed in normal subjects, whereas acute GH release has been reported in primary hypothyroidism and other pathophysiological states. To evaluate the effect of the T4 replacement therapy on TRH-induced GH release, 28 patient volunteers with primary congenital hypothyroidism (PCH), were studied before (11 subjects), after 1 month (nine subjects) and after long-term T4 replacement therapy (eight subjects). All patients underwent a TRH test with measurement of TSH, PRL and GH levels, and were compared to 28 age-matched normal subjects. An increase of plasma GH after TRH was found in 46% of patients without any therapy, in 67% of patients after one month of T4 administration and in 75% of patients after long-term therapy. No changes were observed in plasma GH levels in controls. The TSH response to TRH was inhibited and the response of PRL was reduced step by step by T4 replacement therapy in our patients with PCH. Our results suggest that: (i) Replacement T4 therapy in PCH does not abolish the paradoxical GH response to TRH, in spite of inhibiting the TSH response and reducing the exaggerated PRL response; (ii) the GH response to TRH in PCH seems to be unrelated to low thyroid hormone levels and/or to high TSH levels, but it could be due to changes in hypothalamic-pituitary regulation which are not improved by T4 replacement therapy.

We investigated the melatonin (MT) circadian rhythm before and after somatostatin (octreotide) acute administration in ten subjects (4 M, 6 F. 23-52 yr old) with active acromegaly due to pituitary microadenoma. Blood samples were drawn every 2 hours over a 48-h span; after 24-h basal blood collection, octreotide (Sandostatin, Sandoz) 100 micrograms sc/8 h was administered. As control, 7 healthy adult subjects (3M, 4F; 26-50 yr old) were studied in basal condition over a 24-h span. Plasma MT and GH levels were measured by RIA in each sample, IGF-1 levels were measured by immunoradiometric assay in basal and after octreotide morning samples. The comparisons were made by Mann-U-Withney and Wilcoxon test as appropriate; the existence of a MT circadian rhythm was validated by cosinor analysis; GH and MT values were correlated by Pearson's correlation coefficient. All of 7 control subjects and 2 of 10 acromegalics had significant 24-h MT rhythm. The area under curve (AUC), mesor and amplitude of the MT rhythms in acromegalics were significantly lower than in the controls (p0.001, 0.002 and 0.0006, respectively), with an earlier acrophase (median value: 22:14 vs 02:08 h of controls). Basal plasma IGF-1 levels and circadian GH concentrations were significantly increased in acromegalics in comparison with the control group. Octreotide administration significantly reduced GH, restoring a circadian MT rhythm in 5 of 10 acromegalics, with MT mean mesor and AUC not different from controls. Mean amplitude still remained lower than controls (p0.0006), with an earlier acrophase (median 00:01 h). No significant correlation was found between individual GH and MT levels. Our data indicate a reduction of MT circadian secretion in acromegaly, due especially to a blunted nocturnal increase with earlier MT peak; moreover, acute octreotide administration increase MT levels without modifying amplitude and phase of night-time secretion significantly. These findings suggest a negative interrelationship between GH and MT secretions or a facilitatory influence of somatostatin on daytime MT release only. This partial recovery of pineal secretion after octreotide in acromegalics could be a clinically significant contribution to improve their quality of life, considering that MT is involved in the regulation of several important functions.

The aim of this study was to determine if changes in IGF-1 levels and in final stature occur in blind adult subjects. Eighteen subjects (4 females and 14 males) with total blindness (Group 1) and 26 subjects (5 females and 21 males) with only light perception (Group 2), living at an Institute for blind adult subjects in Naples, Italy, were studied. Their height and weight were compared to British standards. Plasma morning IGF-1 levels, measured by IRMA method were compared to those of 18 normal controls (6 females and 12 males) matched for age and weight. A high prevalence of short stature was demonstrated especially in Group 1 (p = 0.00005 by chi-square for trend test) but was also present in Group 2 (p = 0.02). No alterations in weight distribution were observed in both groups. Basal IGF-I levels in both Group 1 and Group 2 were similar to those of controls: IGF-1 (M +/- SE), 30.9 +/- 2.9 nmol/L and 37.9 +/- 2.7 nmol/L, respectively, vs 33.3 +/- 2.9 nmol/L, NS. High prevalence of final short stature in both groups confirms a negative influence of total or partial blindness on growth. These complex mechanisms appear to involve more than alterations in GH and IGF-I secretion.

Background. Renal transplant recipients often show various metabolic abnormalities including reduced glucose tolerance, impaired insulin sensitivity and altered lipid metabolism. However, the acute effects of carbohydrate ingestion on substrate utilization and energy expenditure have not been fully elucidated. Methods. We evaluated: (i) basal energy expenditure (EE) and substrate utilization, (ii) metabolic fate of an oral glucose load, and (iii) substrate-induced thermogenesis in: (a) 15 non-diabetic renal transplant recipients (Tx) (BMI 25 ± 1) on triple immunosuppressive therapy, (b) 11 patients with primary glomerulonephritis (BMI 25 ± 1) (Cort) receiving prednisone treatment, and (c) 12 healthy subjects (BMI 26 ± 1) (N). Continuous indirect calorimetry was performed in the basal post-absorptive state for 60 min and continued for an additional 180 min following an oral glucose load (75 g). Results. In the basal state, EE was similar in the three study groups. It averaged 14.6 ± 0.7, 15.7 ± 1.3, and 14.1 ± 0.8 cal/kg/min in Tx, Cort, and N respectively. Glucose oxidation was higher in N (1.3 ± 0.2 mg/kg/min) than in Tx (0.7 ± 0.2) and Cort (1.0 ± 0.2) (P

Idiopathic Addison's disease is a chronic organ-specific autoimmune disorder with a long subclinical period characterized only by the presence of adrenal autoantibodies (AA) with or without adrenal function failure. The aim of this longitudinal study was to evaluate the behavior of AA using, an indirect fluorescence method, and adrenal function in 20 AA-positive and 50 AA-negative patients screened by an investigation of a large population of organ-specific autoimmune disease patients without clinical Addison's disease. As controls, 100 normal age-matched subjects were tested only once. In the 20 AA-positive and 50 negative patients, AA and adrenal functional tests were evaluated every 4 months for 5 yr. The AA-positive patients were grouped into 5 adrenal functional stages, specifically: stage 0, normal adrenal function; stage 1, high PRA and low (or normal) aldosterone levels alone; stage 2, along with impaired cortisol response to ACTH, stage 3, along with increased ACTH levels; and stage 4, clinically overt Addison's disease. On the basis of the behavior of AA, the 20 positive patients were grouped as follows: group A, 11 patients with AA titer of 1:8 or higher at the first observation and persistently AA positive in subsequent observations, with titers ranging from 1:8 to 1:64; group B, 6 patients with initial AA titers of 1:8 or lower and AA disappearance in subsequent observations; and group C, 3 patients with AA titer of 1:32 or higher, undergoing corticosteroid therapy after the start of the study and showing AA disappearance in subsequent observations. With respect to adrenal function in group A, 2 patients initially in stage 1 and 1 patient initially in stage 2 did not progress to the upper stages, whereas 5 patients initially in stage 0 and 3 initially in stage 1 progressed subsequently to the upper stages, in 2 cases reaching overt clinical Addison's disease (stage 4). On the other hand, all of the patients of group B showed both a spontaneous disappearance of AA and recovery of adrenal function during the study span. Also, the 3 patients of group C showed disappearance of AA after corticosteroid therapy with recovery of adrenal function. None of the 50 patients who were initially AA negative became AA positive subsequently or showed impairment of adrenal function. We reached the following conclusions. 1) AA, even if present initially in some subjects without clinical Addison's disease, can subsequently disappear. 2) Restoration of adrenal function after disappearance of AA indicates that a spontaneous remission of subclinical adrenocortical failure can occur.(ABSTRACT TRUNCATED AT 400 WORDS)

Male pseudohermaphroditism in a 6 month old boy, due to congenital 3β-hydroxysteroid dehydrogenase deficiency, associated with atrial septal defect, is reported. At 2 weeks he required therapy for severe dehydration and projectile vomiting. The parents were first cousins and one female sibling had died suddenly at 2 months. The patient presented with melanoderma, perineal hypospadias with testicles in a bifid scrotum and atrial septal defect (ostium secundum). Complete cytogenetic studies showed a 46,XY karyotype. Serum sodium ranged from 129 to 140 mEq/l and serum potassium from 5.1 to 4.6 mEq/l. Basal plasma hormonal studies showed normal androstenedione (Δ4A), decreased cortisol (F), slightly elevated ACTH, 17-hydroxy-progesterone (17-OH-P) and testosterone (T), and highly increased dehydroepiandrosterone-sulphate (DHEA-S) levels. ACTH stimulation increased and DXM suppression decreased the plasma levels of DHEA-S, 17-OH-P and T but not that of F; hCG stimulation during cortisone therapy did not change the levels of DHEA-S and T. Corticosteroid therapy normalized electrolyte levels and reduced melanoderma and hormonal hypersecretion. Moderately elevated plasma levels of 17-OH-P and T suggest a partial testicular 3β-HSD deficiency. The multifactorial inheritance and the relatively high prevalence of atrial septal defect vs the rarity of adrenal enzymatic defect suggest a causal association even if a common genetic factor cannot be excluded.

To clarify the influence of primary testicular failure upon circannual hormone rhythmicity we have been studying, by cross-sectional design, 93 adult patients with Klinefelter's syndrome (KS) and 64 adult healthy males to look for evidence of circannual rhythms in testosterone (T), LH, FSH and PRL plasma concentrations. Plasma samples were taken from 08.00 to 09.00 h and all hormones were measured by radioimmunoassay. The data were assessed by the single cosinor method in order to obtain evidence for any significant rhythm and to estimate its parameters mesor, amplitude and acrophase. In the controls, annual rhythms were validated for the secretion of T (annual crest time in September), LH (annual crest time in February) and FSH (annual crest time in January), whereas PRL did not show a significant annual rhythm. In KS, significant circannual rhythms were validated for the secretion of T (annual crest time in April) and FSH (annual crest time in September), but not for LH and PRL secretion. Our results suggest that in KS the circannual hormone rhythmicity may be influenced by seminiferous tubule dysgenesis.

Authors report on a rare case of thyroid involvement by histiocytosis X. A 27-yr-old man with diabetes insipidus and lung bullous disease of 2 yr duration was found to have thyroid gland infiltration by differentiated histiocytosis X. This was based on cytological findings consistent with the diagnosis, obtained by fine needle aspiration biopsy. Endocrine studies revealed altered hypothalamic-pituitary function accounted for by a hypothalamic lesion.

The aim of this study was to explore the occurrence of abnormalities in the circannual thyrotropin (TSH) rhythm in Klinefelter's syndrome (KS). For 3 years, 69 healthy adult males and 73 patients with KS, usually living in Sardinia, were studied by a cross-sectional design. Plasma samples were taken between 08.00 and 09.00 h and TSH was radioimmunoassayed. First, the mean (+/- SD) of the data, grouped for each month of the year, was estimated to seek any macroscopic annual variation. Then, a cosine function was fitted to the single serially independent data by the single cosinor method in order to test for any statistically significant rhythm and, if the no-rhythm assumption is rejected, to describe the circannual parameters. Our patients showed circannual mean TSH concentrations lower than controls (p less than 0.001) without any statistically significant circannual rhythm, which was instead apparent in normal subjects with the annual crest time in December (95% CL November-February). Our results support the hypothesis that in KS the impaired TSH secretion may be related to abnormalities in the hypothalamic-pituitary coordination of the circannual rhythmicity of this hormone.

A virilization syndrome in a normally menstruated 20--year-old woman, due to adrenocortical tumor, is reported. Preoperative basal hormonal study showed normal plasma gonadotropins, androstenedione (A) and cortisol, slightly elevated testosterone (T), markedly increased urinary 17 ketosteroids (17KS) excretion and plasma dehydroepiandrosterone-sulfate (DHEA-S) levels. Thus DHEA-S was the major constituent of the androgen excess. Urinary 17KS and plasma DHEA-S did not change after ACTH, whereas increased after dexamethasone (DXM)-hCG administration. PRL and LH responses to TRH and LHRH tests were exaggerated. Echotomography, pneumoperitoneum radiography and selective adrenal venous angiography showed a tumor in the left adrenal gland. After the tumor removal all abnormalities were corrected. Light and electron microscopy showed well differentiation of the tumoral cells with typical ultrastructural characteristics of androgen-secreting tissue. It is concluded that the absence of amenorrhea and of LH suppression does not exclude the possibility of an androgen-secreting tumor. Moreover, the unusual finding of slightly elevated T value may be reported to enzymatic defect at the neoplastic cellular level. Furthermore the paradoxical DXM-hCG androgen response may be due to spontaneous variations in hormone secretion by the tumor or to cell receptors alteration.

Plasma hGH response to provocative tests (insulin-induced hypoglycaemia and arginine infusion) appears normal in Turner's syndrome. Two cases are reported of the chromatin positive variety of ovarian dysgenesis (XO/XX mosaicism) with unusual absence of plasms hGH response to provocative tests (arginine infusion, insulin-induced hypoglycaemia). Study of other pituitary functions supports the view that a hypothalamic-pituitary impairment is present in these cases. In fact, in these cases we observed low values of gonadotrophin excretion and limited responses of plasma ACTH and plasma corticosteroids to provocative tests (insulin-induced hypoglycaemia, metopyrone). Moreover, markedly abnormal plasma TSH response to TRF was observed in Case 2. The results are discussed with reference to the significance of this rare association.

The paper reports on precocious puberty and galactorrhoea in a 4 8/12 year old boy. Roentgenograms of the skull showed slight lateral bulging of sella floor and pneumoencephalography indicated a pituitary adenoma with a suprasellar extension. Pre-operative study of anterior pituitary function was normal except for increased values of LH (900 mIU/ml), testosterone (2000 ng/ml) and prolactin (215 ng/ml). After removal of a chromophobe pituitary adenoma by transfrontal surgery the galactorrhoea disappeared within 10 days. Post-operative endocrine evaluation showed immediate normalization of LH, testosterone and prolactin values.

Plasma TSH responses after an i.v. injection of 100 mg of L-dopa were evaluated by radioimmunoassay in 4 normal euthyroid subjects and in 8 patients with primary hypothyroidism. In agreement with previous results, no variations to plasma TSH levels were observed in the euthyroid subjects. In contrast, in primary hypothyroidism L-dopa induced a biphasic response in plasma TSH. In fact, we observed a transitory increase witha maximum at 30 min (mean plus or minus SEM equals 54 plus or minus 18%) followed by a decrease reading a minimum level of plasma TSH basal values at 90 min (mean plus or minus SEM equals 15 plus or minus 6%). Thesefindings demonstrate that the plasma TSH response to L-dopa in primary hypothyroidism is time-dependent . Some speculation on the possible mechanism of this action is presented.

Findings on thyroid function in blind subjects are lacking. The aim of this study was to investigate the thyroid hormonal pattern in prepubertal blind subjects. Six healthy and 8 blind males, aged 7-10 yr, in Tanner stage one puberty, living at Institute "Martuscelli" for blind young subjects, Napoli, Italy, were studied. Each had a TRH (200 micrograms) test at 08:00 h after nocturnal rest. Plasma TSH, T4, T3, free T4(FT4), free T3(FT3) and cortisol (F) were measured by RIA. Our blind subjects show levels of TSH (basal values and absolute peak after TRH), T4, T3 and F normal but FT4 levels significantly higher than controls (39 pg/ml +/- 4.7 vs 12 +/- 0.6, p less than 0.001; 14 pg/ml +/- 1.3 vs 4.7 +/- 0.2, p less than 0.001, respectively). Our results, similar to those found in some patients with euthyroid hyperthyroxinemia, suggest that the prolonged inability to receive light signal could influence the metabolism of thyroid hormones and/or cause a tissue resistance to their action, even if this hypothesis must be verified by future more extensive investigations.

Summary OBJECTIVE Cytoplasmic autoantibodies to vasopressin cells (AVP) have been detected in patients with idiopathic central diabetes insipidus and only in one patient with endocrine autoimmune diseases without clinical diabetes insipidus. The aim of this study was to look for AVP cell antibodies (AVP-cell-Ab) in human sera of a large population of autoimmune endocrine disease patients without diabetes insipidus and to test whether an occurrence of these antibodies in some patients can be associated with partial impairment of posterior pituitary function. MEASUREMENT Sera from 410 patients (310 females, 100 males, age range 10–46 years) with autoimmune endocrine disorders (260 with thyroid autoimmune disease, and 150 with insulin dependent diabetes mellitus) without clinical diabetes insipidus, and from 100 normal subjects, were investigated for hypothalamic autoantibodies by an indirect immunofluorescence method. Positive sera were subsequently tested with specific rabbit anti AVP serum. RESULTS None of controls, but five out of 410 patients (1–2%) were AVP-cell-Ab positive. All positive and nine negative from the 410 screened patients were tested for posterior pituitary function. Two out of five AVP-cell-Ab positive patients showed partial diabetes Insipidus. CONCLUSION AVP cell antibodies can be shown in some patients with endocrine autoimmune disease without diabetes insipidus and can sometimes be associated with findings of partial posterior pituitary dysfunction. This suggests that clinical diabetes insipidus could be preceded by a long subclinical period characterized only by the occurrence of AVP-cell-Ab in the sera associated or followed by alterations in functional tests. Longitudinal studies are needed to confirm this hypothesis.

For a period of four years we have been studying 106 healthy males and 66 healthy females, aged 6-10, by cross-sectional design, to look for evidence of a circannual rhythm in LH, FSH, testosterone, PRL, and cortisol secretion. Plasma samples were taken at 0800 h and all hormones were measured by RIA. A cosine function was fitted to the single data to indicate any significant circannual (about 1 year) rhythm and to estimate its parameters: mesor, amplitude, and acrophase. Annual changes were validated in the secretion of: LH (annual crest time in January in both sexes), testosterone (studied only in males, annual crest time in July), and PRL (significant rhythm only in females with annual crest time in March). FSH and cortisol did not show an annual rhythm in both sexes. Our data suggest that sex influences the circannual hormonal rhythms from prepuberty onwards.