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In the literature, few studies analyze the effect of GH therapy on height, preferring a more indirect approach, where factors influencing the total pubertal and pre-pubertal growth in GH-deficient patients are evaluated and subsequently used to estimate the overall effect at the end of the therapy; unfortunately, this approach does not quantify the real growth gain in treated patients. Using a non-parametric Empirical Bayes approach, our study analyzes the growth response to GH treatment in a homogeneous cohort of 317 patients with pituitary GH deficiency who were enrolled during their pre-pubertal stage in the GH Piedmont Registry (Italy), between January 2000–October 2008, and have at least 2 yr of follow-up. To estimate the growth curve for males and females, a non-parametric regression model was fitted, applying Empirical Bayes techniques. A validation of the model was also performed. Improvement was evident in both genders, since both males and females mean growth curve, which started below the 3rdpercentile at the beginning of the therapy, reached the 10thpercentile of the Tanner curve at the end of observation (17 yr old for males and 14 yr old for females); the estimation procedure achieved a good precision. The methodological approach allows for fitting a model able to evaluate longitudinally the response to GH treatment, by means of estimating the overall growth curve, even in presence of sparse information about children heights.

Objective: The aim of this study is to estimate the annual incidence and prevalence rate of the GH treatment exposure in patients under the age of 18 treated for hypopituitarism or isolated GH deficiency (GHD) in Piedmont, during the period January 1, 2002 to December 31, 2004. Methods: The selection criteria for recombinant human GH (rhGH) treatment in childhood were approved by the Ministry of Health in Italy in the yr 1998. The present analysis is based on data from the Registry of subjects receiving GH therapy (GH Registry) made up of the 918 pediatric patients (age <18 yr) with a diagnosis of GHD (excluding Prader-Willi and Turner syndromes and other conditions), diagnosed in the period January 1, 2002–December 31, 2004. The case series has been described as regards the number of cases per year of diagnosis; the prevalence and incidence rates, calculated per 10,000 (?) inhabitants, are given for each year of the study period. Results: The prevalence rate increases slightly from 8.62? in 2002 to 9.44? in 2004 and the incidence rates estimated were 2.49?, 1.86? and 1.97? in the yr 2002, 2003 and 2004, respectively. Conclusion: The Piedmont GH Registry represents the first database available in Italy and could set an example for the other Italian regions as well.

The diagnosis of GH deficiency (GHD) in adults is established by laboratory testing in patients with an appropriate clinical history of hypothalamic pituitary disease. As the measurement of IGF-I and IGFBP-3 levels as well as the spontaneous GH secretion are not considered reliable parameters, the diagnosis of GHD in adults may be established by GH provocative tests, provided that a reproducible test with clear normative limits is available. The insulin tolerance test (ITT) is a reliable diagnostic test in adults, but is contraindicated in several clinical conditions which are often observed in adult patients with suspected GHD. The other classic GH provocative tests, except the glucagon test, have a poor diagnostic utility and should be abandoned. GHRH combined with arginine or GH secretagogues represent a potent, safe, reproducible and reliable test which should be preferable to the ITT as a first-choice diagnostic test for GHD.

To verify if the entity of the peak GH responses to the GHRH+arginine (ARG) test is able to show different degree forms of GH deficiency (GHD), we linked these responses with the number of other anterior pituitary deficits. These anterior pituitary deficits were also related with IGF-I levels. To this purpose, we studied a large cohort of lean patients with pituitary disease of different etiologies [86 males and 68 females; age: mean±SEM 41.5±1.2 yr, body mass index (BMI) <25 kg/m2]. The patients were subdivided into 4 groups according to the increasing number of hormone deficiencies: isolated GHD (HYPO1, no.=28) or GHD plus one, two or three additional hormones (gonadotrophin, ACTH, and TSH) deficiencies (HYPO2, no.=20; HYPO3, no.=15; HYPO4, no.=91). Peak GH responses to the GHRH+ARG test and IGF-I levels showed a clear difference among the groups (p<0.01 and p<0.001, respectively). A significant difference was found between HYPO1 and HYPO4 for IGF-I levels (p<0.05), and between HYPO1 and HYPO4 and between HYPO2 and HYPO4 for the GHRH+ARG test (p<0.005). Considering only the patients who underwent both GHRH+ARG test and insulin tolerance test (ITT) (no.=70), the pattern of the peak GH responses to the GHRH+ARG test was the same of the whole group of patients, while no statistical difference was found with ITT. Our data show that the peak GH responses to the GHRH+ARG test and the IGF-I levels are linked to the severity of hypopituitarism, expressed by the number of increasing anterior pituitary deficits. This association is lost if the evaluation of the GH status is performed by the ITT. In all, the GHRH+ARG test and measurement of IGF-I are able to evidence different degrees of GHD in adult patients with pituitary disease.

Unlike normal subjects, in patients with anorexia nervosa (AN) the GH response to GHRH is refractory to the increasing and inhibitory effect of cholinergic agonists and antagonists, respectively. This cholinergic impairment could reflect malnutrition-induced exhaustion of acetylcholine (Ach) precursors. We studied whether treatment with glycerophosphocholine (GLY), an Ach precursor, could disclose the potentiating effect of pyridostigmine (PD) on the GH response to GHRH in AN. In 6 young women with AN (AW) we studied the GH response to iv GHRH (1.0 μg/kg) alone and combined with oral PD (120 mg) before and after 1 month of oral treatment with GLY (400 mg thrice daily). Eight age-matched normal women (NW) were studied as controls. Before GLY, basal GH levels in AW were higher (p<0.05) than in NW. The GH response to GHRH in AW was higher (p<0.05) than in NW. PD failed to modify the GHRH-induced GH rise in AW, while it enhanced it in NW (p<0.05). One month treatment with GLY in AW did not modify the GH response to GHRH either alone or combined with PD. This study shows the existence of a derangement in the cholinergic control of somatotroph function in AN and indicates that treatment with Ach precursors does not exert any effect on this impairment. This could reflect primary alterations of cholinergic neurons, though the effectiveness of more prolonged treatment and/or higher doses of cholinergic precursors needs to be verified.

The diagnosis of acromegaly, in an appropriate clinical context, usually relies on lack of GH suppression below 1 μg/l during OGTT coupled with elevated IGF-I levels. On the other hand, in normal subjects glucose-induced inhibition of GH secretory bursts without any further decrease of interpulse GH levels had already been shown. Based on the foregoing, we aimed to compare the diagnostic reliability of OGTT-induced GH nadir with that recorded during 3-h spontaneous GH secretion. In 59 acromegalic patients (17 male and 42 female, age, mean±SE 51.5±1.9, range 21–76 yr) and in 82 normal subjects (43 male and 39 female, age, mean±SE 35.7±1.5, range 15–72 yr) GH secretion was evaluated every 30 min from 0 to 180 min during slow saline infusion or OGTT (75 g at 0 min). A nadir GH concentration below 1 μg/l was recorded in all normal subjects either during OGTT or saline infusion if GH secretion was evaluated over 180 min. In contrast in acromegalic patients a nadir GH concentration below 1 μg/l never occurred in both conditions. This study shows that a 3-h spontaneous GH profile is as reliable as OGTT in the diagnosis of active acromegaly.

It is widely accepted that the classical dose of 250.0 μg ACTH (1–24) (tetracosactin) is clearly supra-maximal while 1.0 and 0.03 μg have been shown as the maximal and the lowest stimulatory ACTH doses for cortisol (F) secretion in normal young subjects. Testing with low ACTH dose would better evaluate adrenal sensitivity to corticotropin. The aims of the present study were: a) to clarify the adrenal sensitivity to ACTH in patients with different duration of corticotroph insufficiency by testing with low and very low tetracosactin doses; and b) to evaluate diagnostic implication regarding the ability of ACTH tests to distinguish patients with corticotroph insufficiency from normal subjects. In 24 hypopituitaric patients (HYPOPIT, 15 male and 9 female, age 22–50 yr, BMI: 22–26 kg/m2) with corticotrophin deficiency we studied the F, DHEA and aldosterone (A) responses to challenges with low ACTH doses (0.06 or 0.5 μg iv at 0 min) followed by 250 μg iv (at +60 min). The results in HYPOPIT were compared with those recorded in 12 normal controls (NS, 6 male and 6 female, age 22–34 yr, BMI: 20–25 kg/m2). Basal F and DHEA levels in HYPOPIT were lower than in NS, while A levels were similar in both groups. The F responses to ACTH in HYPOPIT were dose-independent and markedly lower (p<0.0001) than in NS. After the 0.06 and 0.5 μg ACTH dose, 16% of HYPOPIT patients showed δF peak within the range of normal response. No HYPOPIT showed δF peak within the normal range after 250 μg ACTH. The DHEA responses to ACTH in HYPOPIT were dose-independent and markedly lower than in NS (p<0.0001). Overlap between individual DHEA responses in HYPOPIT and NS was present after 0.06 μg and 0.5 μg but not after 250 μg tetracosactin. The A responses in HYPOPIT were dose-dependent and overlapped with those in NS. The adrenal responses to ACTH in HYPOPIT were not associated with the duration of the disease. In conclusion, the present study shows that the mean F and DHEA but not the A responses to ACTH (1–24) are markedly impaired in hypopituitaric patients with corticotroph insufficiency independently of the duration of the disease. The impaired F and DHEA response to ACTH is also independent of the dose, suggesting the existence of relatively enhanced sensitivity of the fasciculata and reticularis adrenal zone to ACTH but meantime remarkable impairment of the adrenal function due to corticotrophin deficiency. In the present study, testing with submaximal ACTH doses did not distinguish patients with secondary adrenal insufficiency from normal subjects.

Alprazolam (AL), a benzodiazepine which activates gamma-amino butyrric acid (GA-BA)-ergic receptors, exerts a clear inhibitory effect on the activity of the hypothalamo-pitu-itary-adrenal (HPA) axis and is able to markedly reduce the ACTH response to metyrapone-induced inhibition of glucocorticoid feedback. It has been suggested that its inhibitory action could be regulated by CRH or AVP mediated mechanisms. However, the effect of benzodi-azepines on the HPA response to CRH or AVP is contradictory. It has been shown that benzodi-azepines have specific receptors on the adrenal gland but it is unclear if they mediate biological effects in humans. In order to further clarify the mechanisms underlying the inhibitory effect of benzodiazepine on HPA axis in humans, we studied the effect of AL (0.02 mg/kg po at -90 min) or placebo in 7 healthy young volunteers (7 female, age: 26–34 yr; wt: 50–58 kg, BMI 20–22 kg/m2) on: 1) the ACTH and cortisol responses to hCRH (2.0 µg/kg iv at 0 min) or AVP (0.17 U/kg im at 0 min); 2) the cortisol, aldosterone and DHEA responses to ACTH 1–24 (0.06 and 250 µg iv at 0 and 60 min, respectively). After placebo, the ACTH and cortisol responses to hCRH (peaks, mean±SE: 29.8± 4.4 pg/ml and 199.3±19.6 µg/l) were similar to those recorded after AVP (31.7±6.5 pg/ml and 164.8±18.0 µg/l); the cortisol response to 0.06 µg ACTH (190.4±11.8 µg/l) was similar to that recorded after hCRH and AVP but lower (p<0.01) than that after 250 µg ACTH (260.6±17.4 µg/l). AL did not modify the ACTH response to both hCRH (42.5±7.1 pg/ml) and AVP (33.3±2.7 pg/ml), which even showed a trend toward increase. AL also failed to significantly modify the cortisol response to both hCRH (156.3±12.7 µg/l) and AVP (119.4±14.5 µg/l), which, on the other hand, showed a trend toward decrease. The cortisol peaks after 0.06 µg ACTH were significantly reduced (p<0.02) by AL pre-treatment (115.0±7.7 µg/l) which, in turn, did not modify the cortisol response to the subsequent ACTH bolus (214.7±16.6 µg/l). The DHEA and aldos-terone responses to all the ACTH doses were not significantly modified by AL. In conclusion, these data show that the HPA response to AVP as well as to hCRH is refractory to the inhibitory effect of AL which, in turn, blunts the cortisol response to low ACTH dose. These findings suggest that both CRH- and AVP-mediated mechanisms could underlie the CNS-mediated inhibitory effect of AL on HPA axis; in the meantime, these results suggest that benzodiazepines could also act on adrenal gland by blunting the sensitivity of the fasciculata zone to ACTH.

Acromegaly is frequently associated with the presence of thyroid disorders, however the exact prevalence is still controversial. An Italian multicenter study was performed on 258 patients with active acromegaly (high levels of IGF-I and lack of suppression of serum GH levels below 2 µg/l after an OGTT). The control group was represented by 150 patients affected by non-functioning and PRL-secreting pituitary adenomas. Two hundred and two out of 258 acromegalic patients (78%) were affected by thyroid disorders with a significantly higher prevalence with respect to the control group (27%, p<0.0001). One hundred and three patients presented (39.9%) non-toxic nodular goiter, 46 (17.8%) non-toxic diffuse goiter, 37 (14.3%) toxic nodular goiter, 1 toxic diffuse goiter (0.4%), 12 (4.6%) Hashimoto’s thyroiditis, 3 (1.2%) thyroid cancer. Two patients presented a co-secreting TSH pituitary adenoma. Thirty-six patients had been previously treated for various thyroid abnormalities. Among the 222 acromegalic patients never treated for thyroid disorders thyroid ultrasonography was performed on 194 subjects. Thyroid volume in patients with thyroid abnormalities was 28±17.5 ml (median 23) while it was 10.8±3.6 ml (median 10) in patients without thyroid disorders (p<0.0001). Thyroid volume was correlated with the estimated duration of acromegaly (r=0.7, p<000.1), but not with age or with serum GH, IGF-I and TSH concentrations. Thyroid volume was higher in acromegalic patients than in the above control population (23.5±16.9 ml vs 13.9±12.8 ml, p<0.0001). In 62 acromegalic patients 101 fine-needle biopsies of thyroid nodules were performed; 7 nodules were suspicious and the patients were submitted to thyroid surgery: papillary thyroid carcinoma was found in 3 patients. In conclusion, in a large series of acromegalic patients an increased prevalence of thyroid disorders (78%), particularly non-toxic nodular goiter, has been observed. Thyroid volume, evaluated by ultrasonography, was correlated to the estimated duration of acromegaly. Finally, the prevalence of thyroid carcinoma was slightly increased than in the general population.

OBJECTIVE: Adults with severe GH deficiency (GHD) need recombinant human growth hormone (rhGH) replacement to restore body composition, structure functions and metabolic abnormalities. The optimal rhGH dose for replacement has been progressively reduced to avoid side effects. The aim of the present study was to define the minimal rhGH dose able to increase both IGF-I and IGF binding protein (BP)-3 levels in GHD and to verify the possible change in GH sensitivity. DESIGN AND PATIENTS: To this goal, we studied the effect of 4-day treatment with 3 rhGH doses (1.25, 2.5 and 5.0 microg/kg/day) on IGF-I and IGFBP-3 levels in 25 panhypopituitary adults with severe GHD (12 males and 13 females, age: 44.5+/-3.0 years, body mass index (BMI): 27.0+/-0.9 kg/m(2)) and 21 normal young adult volunteers (NV, 12 males and 9 females, age: 30.5+/-2.0 years, BMI: 20.8+/-0.5 kg/m(2)). RESULTS: Basal IGF-I and IGFBP-3 levels in GHD were lower (P<0.001) than in NV. In NV the 1.25 microg/kg dose of rhGH did not modify IGF-I levels. The dose of 2.5 microg/kg rhGH significantly increased IGF-I levels in men (P<0.001) but not in women, while the 5.0 microg/kg dose increased IGF-I levels in both sexes (P<0.001). IGFBP-3 levels were not modified by any of the administered rhGH doses. In GHD patients, all rhGH doses increased IGF-I levels 12 h after both the first (P<0.01) and the fourth rhGH dose (P<0.001). At the end of treatment percentage increases in IGF-I were higher (P<0.001) in GHD patients than in NV. In contrast with NV, in GHD patients the IGF-I response to short-term stimulation with rhGH was independent of gender. Moreover, GHD patients showed increases in IGFBP-3 after the fourth administration of both 2.5 and 5.0 microg/kg rhGH. CONCLUSION: The results of the present study demonstrate that the minimal rhGH dose able to increase IGF-I and IGFBP-3 levels in GHD patients is lower than in normal subjects, at least after a very short treatment. This evidence suggests an enhanced peripheral GH sensitivity in GH deprivation.

OBJECTIVE: Glucagon administration stimulates both somatotroph and corticotroph secretion in humans, although this happens only if glucagon is administered by the intramuscular route and not by the intravenous route. On the other hand, GH secretagogues (GHS) strongly stimulate GH and also possess ACTH-releasing activity. DESIGN AND METHODS: To clarify the mechanisms underlying the stimulatory effects of both glucagon and GHS on somatotroph and corticotroph secretion, we studied the GH, ACTH and cortisol responses to glucagon (GLU, 0.017 mg/kg i.m.) and Hexarelin, a peptidyl GHS (HEX, 2.0 microg/kg i.v.) given alone or in combination in 6 normal young volunteers (females, aged 26-32 years, body mass index 19.7-22.5 kg/m). RESULTS: GLU administration elicited a clear increase in GH (peak vs baseline, mean+/-S.E.M.: 11.6+/-3.4 vs 3. 3+/-0.7 microg/l, P<0.02), ACTH (11.6+/-3.3 vs 4.1+/-0.3 pmol/l, P<0. 02) and cortisol (613.5+/-65.6 vs 436.9+/-19.3 nmol/l, P<0.05) levels. HEX induced a marked increase in GH levels (55.7+/-19.8 vs 3. 7+/-1.9 microg/l, P<0.005) and also significant ACTH (5.7+/-1.1 vs 3. 4+/-0.6 pmol/l, P<0.01) and cortisol (400.2+/-31.4 vs 363.4+/-32.2 nmol/l, P<0.05) responses. The GH area under the curve (AUC) after HEX was clearly higher than after GLU (1637.3+/-494.0 vs 479.1+/-115. 7 microg/l/120 min, P<0.04) while HEX and GLU coadministration had a true synergistic effect on GH release (3243.8+/-687.5 microg/l/120 min, P<0.02). The ACTH and cortisol AUCs after HEX were lower (P<0. 02) than those after GLU (208.3+/-41.3 vs 426.3+/-80.9 pmol/l/120 min and 18 874.5+/-1626.1 vs 28 338.5+/-2430.7 nmol/l/120 min respectively). The combined administration of HEX and GLU had an effect which was less than additive on both ACTH (564.02+/-76.5 pmol/l/120 min) and cortisol (35 424.6+/-5548.1 nmol/l/120 min) secretion. CONCLUSIONS: These results show that the intramuscular administration of glucagon releases less GH but more ACTH and cortisol than Hexarelin. The combined administration of glucagon and Hexarelin has a true synergistic effect on somatotroph secretion but a less than additive effect on corticotroph secretion; these findings suggest that these stimuli act via different mechanisms to stimulate somatotrophs while they could have a common action on the hypothalamo-pituitary-adrenal axis.

Well-nourished patients with dilated cardiomyopathy (DCM) show slight reduction of mean basal IGF-I levels which, however, display a response to a rhGH dose as low as 5.0 µg/kg/day similar to that of age-matched control subjects (CS). To further investigate peripheral GH sensitivity, we studied the IGF-I and IGFBP-3 responses to 4-day sc 2.5 µg/kg/day rhGH administration, the lowest effective dose able to increase IGF-I levels in normal subjects, in 10 DCM patients [age (mean±SE): 57.6±1.0 yr, body mass index (BMI): 24.0±1.2 kg/m2, left ventricular ejection fraction: 26.2±3.2%, NYHA (New York Heart Association): I/0, II/4, III/4, IV/2] and in 9 age-matched healthy CS (age: 55.3±1.2 yr, BMI: 23.7±1.8 kg/m2). Basal IGF-I levels in DCM were lower though not significantly than those in CS (147.7±9.8 vs174.7±17.0 µg/l). Basal IGFBP-3 levels in DCM were similar to those in CS (3.1±0.3 vs2.7±0.2 mg/l). In CS 4-day rhGH increased IGF-I levels (222.4±14.9 µg/l; p<0.01 vsbaseline) but did not modify IGFBP-3 levels (3.0±0.2 mg/l). In DCM IGF-I levels were increased by 4-day rhGH administration (175.7±11.0 µg/l; p<0.05 vsbaseline) with a similar percent extent than in CS. On the other hand, in DCM, but not in CS, 4-day rhGH significantly increased IGFBP-3 levels (3.5±0.3 mg/l; p<0.05 vsbaseline). Therefore, in conclusion, testing with the lowest effective rhGH dose further suggest that peripheral GH sensitivity in well-nourished DCM is preserved. On the other hand, DCM patients show enhanced IGFBP-3 sensitivity to stimulation by rhGH.

OBJECTIVE: It is known that glucagon administration elicits ACTH and cortisol responses in humans, although this effect takes place after intramuscular or subcutaneous but not after the intravenous route of administration. The mechanisms underlying this stimulatory effect on corticotroph secretion are unknown but they are unrelated to glucose variations and stress-mediated actions. DESIGN AND METHODS: To throw further light on the stimulatory effect of i.m. glucagon on the pituitary-adrenal axis, using six normal young female volunteers (26-32 years, body mass index 19.7-22.5 kg/m(2)) we studied the interaction between glucagon (GLU; 0.017 mg/kg i.m.) and human corticotropin-releasing hormone (hCRH; 2.0 microg/kg i.v.) or vasopressin (AVP; 0.17 U/kg i.m.). The interactions between hCRH and AVP on the hypothalamo-pituitary-adrenal (HPA) axis and the GH response to GLU alone or combined with hCRH or AVP were also studied. RESULTS: GLU i.m. administration elicited a clear increase in ACTH (peak vs baseline, means+/-s.e.m.: 11.6+/-3.3 vs 4.2+/-0.3 pmol/l, P<0.05), cortisol (613.5+/-65.6 vs 436.9+/-19.3 nmol/l, P<0.05) and GH levels (11.6+/-3.4 vs 3.3+/-0.7 microg/l, P<0.05). The ACTH response to GLU (area under the curve: 426.4+/-80.9 pmol/l per 120 min) was higher than that to AVP (206.3+/-38.8 pmol/l per 120 min, P<0.02) and that to hCRH (299.8+/-39.8 pmol/l per 120 min) although this latter difference did not attain statistical significance. The GLU-induced cortisol response (28336.9+/-2430.7 nmol/l per 120 min) was similar to those after hCRH (24099.2+/-2075.2 nmol/l per 120 min) and AVP (21808.7+/-1948.2 nmol/l per 120 min). GLU and hCRH had an additive effect on ACTH (964.9+/-106.6 pmol/l per 120 min, P<0.02) and a less than additive effect on cortisol levels (35542.5+/-2720. 2 nmol/l per 120 min). Similarly, GLU and AVP had an additive effect on ACTH (825.6+/-139.6 pmol/l per 120 min, P<0.02) and an effect less than additive on cortisol levels (33059.2+/-1965.3 nmol/l per 120 min). The effects of GLU co-administered with hCRH or AVP were similar to those of the combined administration of hCRH and AVP on ACTH (906. 0+/-152.7 pmol/l per 120 min) and cortisol (34383.5+/-1669.2 nmol/l per 120min) levels. The GH response to GLU was not modified by hCRH or AVP. CONCLUSIONS: These results show that i.m. glucagon administration is a provocative stimulus of ACTH and cortisol secretion, at least as potent as hCRH and AVP. The ACTH-releasing effect of i.m. glucagon is not mediated by selective CRH or AVP stimulation but the possibility that both neurohormones play a role could be hypothesized.

Classical provocative stimuli of GH secretion such as insulin-induced hypoglycaemia, arginine, clonidine, glucagon and levodopa have been widely used in clinical practice for approximately 30 years. On the other hand, in the last 10 years new potent stimuli of GH secretion have been proposed, but an extensive comparison with the classical ones has rarely been performed, at least in adults. In order to compare the GH-releasing activity of old and new provocative stimuli of GH secretion, and to define the normative values of the GH response, in 178 normal adults (95 males, 83 females; age range: 20-50 years, all within +/-15% of their ideal body weight), we studied the GH response to: insulin-induced hypoglycaemia (ITT, 0.1IU/kg i.v.), arginine (ARG, 0.5g/kg i.v.), clonidine (CLO, 300 microg/kg p.o.), glucagon (GLU, 1mg i.m.), pyridostigmine (PD, 120mg p.o.), galanin (GAL, 80pmol/kg per min), GH-releasing hormone (GHRH, 1 microg/kg i.v.), GHRH+ARG, GHRH+PD, hexarelin, a GH-releasing protein (HEX, 2 microg/kg i.v.) and GHRH+HEX (0.25 microg/kg i.v.). The mean (+/-s.e.m.) peak GH response to ITT (21.8+/-2.8, range: 3.0-84.0 microg/l) was similar to those to ARG (18.0+/-1.6, range: 2.9-39.5 microg/l) or GLU (20. 5+/-2.2, range: 10.6-36.9 microg/l) which, in turn, were higher (P<0. 001) than those to CLO (8.2+/-1.6, range: 0.3-21.5 microg/l), PD (9. 6+/-1.1, range: 2.2-33.0 microg/l) and GAL (9.3+/-1.1, range: 3.9-18. 3 microg/l). The GH response to GHRH (19.1+/-1.5, range: 2.7-55.0 microg/l) was similar to those after ITT, ARG or GLU but clearly lower than those after GHRH+ARG (65.9+/-5.5, range: 13.8-171.0 microg/l) and GHRH+PD (50.2+/-4.6, range: 17.7-134.5 microg/l) which, in turn, were similar. The GH response to HEX (55.3+/-5.5, range: 13.9-163.5 microg/l) was similar to those after GHRH+ARG and GHRH+PD but lower (P<0.001) than that after GHRH+HEX (86.0+/-4.3, range: 49. 0-125.0 microg/l) which was the most potent stimulus of GH secretion. In this adult population the third centile limits of peak GH response to various stimuli were the following: ITT: 5.3; ARG: 2.9; CLO: 1.5; GLU: 7.6; PD: 2.2; GAL: 4.0; GHRH: 5.0; GHRH+ARG: 17.8; GHRH+PD: 17.9; HEX: 21.6; GHRH+HEX: 57.1. These results confirm that, among classical provocative tests of GH secretion, ITT followed by ARG and GLU are the most potent ones and possess clear limits of normality. GHRH+ARG or PD and HEX are strong stimuli of GH secretion which, however, is maximally stimulated by a combination of GHRH and a low dose of HEX. It is recommended that each test is used with appropriate cut-off limits.

Recently, a new long-acting form of bromocriptine (Parlodel LA, Sandoz) has been developed and it has already been found to be effective in lowering plasma PRL levels in normal volunteers and postpartum women. This work reports the clinical, hormonal and radiological effects of a single 50 mg dose of long-acting bromocriptine in 10 patients with tumorous hyperprolactinemia (2 microprolactinomas, 6 macroprolactinomas, 1 acromegaly and 1 nonsecreting macroadenoma). A rapid and long-lasting (28 days) normalization of PRL levels was observed in patients with microprolactinoma, acromegaly and nonsecreting adenoma. None of the 6 patients with macroprolactinoma underwent normalization of plasma PRL, but the latter was markedly reduced (61–80% of basal levels). A second injection of the drug in 5 macroprolactinoma patients induced a further reduction of plasma PRL levels in 2 of them. No changes in the tumor size were observed either after the first or the second injection of long-acting bromocriptine in any of the patients. This injectable form of bromocriptine induced nausea and/or mild hypotension Jasting a few h in 4 of the 10 patients and was better tolerated than the oral form as regards both the duration and intensity of the side effects. Thus, as this drug has proved to be efficacious and well tolerated by the patients, this long-acting form of bromocriptine may be a valid therapeutical approach for initiating medical treatment of patients with prolactinoma.

Growth hormone‐releasing peptides (GHRPs) are synthetic molecules with strong, dose‐related and reproducible growth hormone (GH)‐releasing activity in humans. GHRPs act at both the pituitary and the hypothalamic level, where specific receptors have been located. In adults, GHRPs release more GH than does GH‐releasing hormone (GHRH), whilst their co‐administration has a synergistic effect, indicating that they have, at least partially, different mechanisms of action. However, normal activity of GHRH‐secreting neurones is needed to achieve the full GH‐releasing effect of GHRPs. In contrast to GHRH, the GH‐releasing activity of GHRPs is not further increased by substances acting via inhibition of hypothalamic somatostatin, and is only blunted by substances that stimulate hypothalamic somatostatin release. Even free fatty acids and exogenous somatostatin, which act directly on somatotrophs, do no more than blunt the effect of GHRPs. Thus, the GH‐releasing activity of GHRPs is partially refractory to inhibitory influences. GHRPs act, at least in part, by antagonism of somatostatin activity, both at the pituitary and the hypothalamic level. The GH‐releasing effect of GHRPs is not dependent on gender, but undergoes age‐related variations. Gonadal steroids seem to influence the activity of GHRPs only in childhood. The reduced GH response to GHRPs in the elderly is probably due mainly to concomitant GHRH hypoactivity and somatostatinergic hyperactivity. A preserved GH‐releasing effect of GHRPs has been reported in acromegaly, anorexia nervosa, hyperthyroidism and in critically ill patients. GHRPs have also been found to increase GH release in children with idiopathic short stature, in GH deficiency and in obese patients, in whom there is a well‐known reduction of somatotroph function. The GH response to GHRPs is markedly reduced in hypothyroidism and Cushing's syndrome. □ Growth hormone, growth hormone‐releasing hormone, growth hormone‐releasing peptides, growth hormone secretagogues, ageing

The diagnosis of growth hormone (GH) deficiency (GHD) is currently based on failure to increase plasma GH levels to an arbitrary cutoff point of 7 or 10 μg/l in response to two provocative stimuli. False negative responses to these tests, however, frequently occur thus reducing their diagnostic reliability. The aim of this study was to assess a combination of pyridostigmine (PD) and GH-releasing hormone (GHRH) (60 mg oral PD 60 min before 1 μg/Kg GHRH iv) as a reliable test probing pituitary somatotropic function. In fact PD, an acetylcholinesterase inhibitor, strikingly potentiates GH response to GHRH likely by inhibiting somatostatin release. The combination PD + GHRH was tested in normal children and adolescents (NS, n = 27) and in a large group of short children classified as having familial short stature (FSS, n = 24), constitutional growth delay (CGD, n = 34) and GH deficiency (organic, oGHD, n = 6; idiopathic, iGHD, n = 10). In all groups results obtained by PD + GHRH were compared with those obtained by testing with GHRH, Clonidine (CLON) and PD alone and by studying spontaneous nocturnal GH secretion over 8 hours. Assuming 7 μg/l as minimum normal GH peak, a positive response occurred in only 18/24, 11/12 and 12/13 NS for GHRH, CLON, and PD, respectively. In contrast even assuming a minimum normal GH peak as high as 20 μg/l, PD + GHRH induced a positive response in 27/27 NS all having a nocturnal GH mean concentration (MC) ≥ 3 ug/l. Therefore PD + GHRH test gave no false negative responses and this was true not only in NS but even in all FSS and CGD having a GH MC ≥ 3 μg/l. On the other hand, PD + GHRH induced a negative GH response in all oGHD and in 8/10 iGHD patients. In the remaining two iGHD patients, PD + GHRH demonstrated a normal pituitary GH reserve in spite of a GH MC < 3 μg/l and low IGF-I level, thus pointing to a hypothalamic pathogenesis for the GHD. Considering FSS and CGD children having a GH MC < 3 μg/l, PD + GHRH showed a primary pituitary GH deficiency in 3/12 CGD with low plasma IGF-I levels. In conclusion, in slowly growing children PD + GHRH test is the most reliable provocative test for the diagnosis of primary pituitary GH deficiency being capable to discriminate between an unequivocally normal and impaired somatotropic function. The study of spontaneous GH secretion is mandatory only for those patients having low height velocity but a normal GH response to PD + GHRH in order to look for the existence of a GHD due to hypothalamic dysfunction.

In man the GH response to GHRH is highly variable and some normal subjects may be completely unresponsive to the neuropeptide. On the other hand, the potentiation of cholinergic activity by pyridostigmine (PD), a cholinesterase inhibitor, increases the GH response to GHRH, probably by inhibiting somatostatin release. The aim of this study was to assess the existence of intrain-dividual variability in the GH response to GHRH and verify the effects of PD treatment on inter- and intraindividual variability. Twenty normal adults (17 M and 3 F) and 10 normal prepubertal children (9 M and 1 F) underwent 2–5 administrations of 1 µg/kg GHRH on different days. Seven adults and all children also underwent 1–5 other tests in which GHRH was preceded (60 min before) by oral PD (120 mg in adults and 60 mg in children). The GH responses to GHRH were highly variable, not only within subjects but also in the same subject on different occasions (peak range; adults: 0.4–49.0 ng/ml; children: 2.4–50.0 ng/ml). PD always markedly increased the GH response to GHRH, even unmasking this response in 3 adults and 4 children hyporesponsive to the neuropeptide alone. However the variability in the GH response was still present (adults: 27.2–108.5 ng/ml; children: 25.0–144.0 ng/ml), though reduced (adults: p= 0.0005; children: p= 0.0204). These data indicate that: i. A great inter- and intraindividual variability in the GH response to GHRH is present. ii. PD always potentiates this response, reducing the variability and abolishing false negative responses. The variability in the GH response to GHRH may be due, at least in part, to a different somatostatinergic tone that can be blunted by the enhancement of the cholinergic function.

Dopaminergic system seems to influence the regulation of insulin secretion, although in man conflicting data are reported. Furthermore, bromocriptine (BRC), a dopaminergic agonist, has been recently found to inhibit the seasonally occurring hyperinsulinemia and the increase in body weight in the hamster. On this basis, we investigated the effect of BRC on spontaneous and stimulated insulin secretion in human obesity. Six obese (BMI: 33.2±1.6 Kg/m2) underwent the administration of: 1) arginine (ARG, 0.5 g/Kg iv in 30 min), 2) BRC (2.5 mg po), 3) ARG + BRC. In each test plasma glucose and serum insulin, growth hormone (GH) and prolactin levels were determined. BRC did not significantly reduce spontaneous and ARG-induced insulin release. Baseline and stimulated glucose levels were also unchanged. BRC determined an increase in GH levels (3.7±1.3 vs0.5±0.3 μg/l, p<0.05), but failed to modify the somatotrope responsiveness to ARG. On the other hand, both spontaneous and stimulated PRL secretion were reduced by BRC (2.5±0.4 vs6.7±1.1 μg/l, p<0.05 and 0.8±1.9 vs11.0±2.1 μg/l, p<0.05, respectively). Our results show that in obese patients the acute activation of dopaminergic receptors by bromocriptine fails to modify both basal and ARG-induced insulin release, while inhibits spontaneous and stimulated PRL secretion. Our data also show that the low GH response to arginine in obesity is not improved by the coadministration of bromocriptine, in agreement with the hypothesis that both substances act by the same mechanism, i.e. inhibition of endogenous somatostatin release.

The effects of a 0.5 g/kg body weight arginine infusion on plasma inorganic phosphate and potassium were examined in 15 normal subjects, and 6 recently diagnosed insulinopenic diabetics. Plasma phosphorus displayed a highly significant (p<0.001) fall in normal subjects, with a maximum fall below the baseline of 1.11 ± 0.15 mg/100 ml or 33 ± 3% (mean ± SE). In addition, there was a highly significant correlation (p<0.01) between these falls and the insulin peaks induced by arginine. Plasma potassium levels, on the other hand, displayed a distinct and significant increase in 7 of the 8 subjects studied in this connection. The maximum increase over the baseline was 1.23 ± 0.17 meq/l or 33 ± 6% (p<0.01 ). In diabetic patients, arginine too led to a fall in phosphorus. While this was still significant, it was clearly less than in normal subjects: maximum fall = 0.64 ± 0.09 mg/100 ml or 15 ±3%. Plasma potassium increased to a greater extent than in normal subjects: maximum increase = 1.63 ± 0.21 meq/l or 42 ± 6%. These findings show that arginine is responsible for a fall in plasma phosphorus that may well be partly related to the insulin response, and an increase in plasma potassium of clinical significance, whose mechanism(s), however, are still obscure.

The effect of the somatostatin analog (GHRIH-A) D-Trp8, D-Cys14on plasma levels of growth hormone, pancreatic glucagon, insulin and glucose was studied in four acromegalic patients and in four maturity-onset mild diabetics. Acromegalics received a bolus iv injection of 25 μg of GHRIH-A, followed by a continuous infusion of 25 μg in saline over an hour. Mild diabetics were submitted in two different days to two tests: arginine (30 g in 30 min) ± GHRIH-A (bolus iv injection of 25 μg followed by an infusion of 25 μg/h over 120 min) and arginine + saline. GHRIH-A lead to a significant (2 p<0.01) fall in GH basal secretion in acromegalics, and significantly reduced the GH response to arginine in maturity-onset diabetics. The inhibitory effect of insulin secretion was less impressive, but significative in both groups. No significant changes in plasma pancreatic glucagon values were noted. In mild diabetics, GHRIH-A infusion induced a small but significant increase in the blood glucose increment due to arginine. Our data suggest that this somatostatin analog may be potentially useful only when GH suppression is the main therapeutic goal to be reached, as in acromegaly and in severe diabetic retinopathy, but not in metabolic control of mild diabetic patients with a good residual insulin secretion.

We evaluated the efficacy of different doses of methimazole (MMI) as the initial therapy for Graves’ disease. Fourteen patients were treated with 15 mg/die of the drug (group A) and 14 with 30 mg/die (group B). Blood samples for T3, T4, FT3 and FT4 were obtained before beginning therapy, every 48 h during the first 12 days and on the 45th day of treatment. All these hormonal parameters fell significantly from the 2nd day of therapy in both groups. All the patients, except for one in group B, had normal or subnormal levels of thyroidal hormones on the 45th day of treatment. The comparison between the two groups of regression coefficients over the first 12 days showed no significant differences. The absolute decrease of each examined parameter on day 12 was positively correlated with the relevant pretreatment value. These results demonstrate that doses of MMI (15 mg/die) much lower than those commonly recommended are able to rapidly control thyroidal overproduction as effectively as 30 mg/die.

Parasympathetic nervous system is known to affect insulin secretion in animal and man and there is evidence that it is involved in the outcome of spontaneous and stimulated insulin hypersecretion observed in animal obesity. In human obesity, there are contradictory data. We studied the effect of 150 mg orally administered pirenzepine (PNZ), a muscarinic receptor antagonist, on the insulin response to glucose (75 g po or 0.33 g/kg i.b.w. iv) or arginine (0.5 g/kg infused in 30 min) in 18 obese subjects normotolerant to glucose. PNZ did not modify basal serum insulin and the hormone response to either intravenous glucose (AUC: 5221.6±1177.6 vs5309.8±1534.8 mU/L.min) or arginine load (4257.9±832.7 vs3952.8±549.3 mU/L.min). Calculated as AUC the insulin response to oral glucose load was unaffected by PNZ (6601.5±1218.6 vs8614.3±1095.2 mU/L-min). Actually, the insulin rises at +30 min after oral glucose load was significantly blunted by PNZ (37.0±3.4 vs81.6±16.9 mU/L; p<0.03). However, after statistical evaluation by ANCOVA assuming basal insulin and +30 min glucose levels as covariates, this significance disappeared. Our present data do not agree with the hypothesis that the cholinergic system plays a role in the exaggerated insulin secretion of obesity. Nevertheless, these findings confirm that acetylcholine positively influences insulin secretion in humans, likely viaindirect mechanisms.

Arginine has well-known stimulatory effects on GH, PRL and insulin secretion in man but the mechanisms underlying these effects are still unclear. More recently, it has been demonstrated that arginine is the precursor of nitric oxide (NO) which mediates its vasodilatator effect. Thus, it has been hypothesized that NO could also mediate the hormonal effects of arginine. To clarify this point, in seven normal young volunteers (7 normal male subjects, age 26–35 yr) we compared the effects of arginine hydrochloride (ARG, 0.5 g/kg iv over 30 min) on GH, PRL, insulin and glucose levels as well as on blood pressure, with those of isosorbide dinitrate (ISDN, 5 mg po) and molsidomine (MOLS, 4 mg po), two NO donors which possess well-known vasodilatatory effects. ARG infusion elicited a clear-cut GH increase (peak vsbaseline 17.6±4.7 vs2.7±0.8 (g/L, p<0.01), PRL (20.6±2.8 vs6.9±0.5 (g/L, p<0.01) and insulin levels (31.4±5.7 vs4.5±2.1 (U/L, p<0.01) while induced a biphasic variation of plasma glucose levels with early increase (p<0.01), followed by late decrease below basal values (p<0.01). On the other hand, blood pressure was decreased by ARG (nadir vsbaseline; systolic: 103±6 vs112±3, p<0.02 and diastolic 61 ±4 vs72±2 mmHg, p<0.02, respectively). ISDN and MOLS did not modify basal GH, PRL and insulin as well as glucose levels while induced a clear reduction in blood pressure (ISDN: nadir vsbaseline; systolic: 94±4 vs112±2, p<0.02; diastolic 69±3 vs80±2, p<0.02; MOLS: systolic: 94±3 vs113±2 p<0.02; diastolic 63±4 vs72±2, p<0.02). The lowering effect of both ISDN and MOLS on both systolic and diastolic blood pressure levels was higher than that induced by ARG. The effect of the latter was, in turn, significantly different from that of placebo on diastolic levels only. In conclusion, our present date are against the hypothesis that NO mediates the stimulatory effects of arginine on GH, PRL and insulin secretion. On the other hand, our findings agree with the hypothesis that ARG has NO-mediated vasodilatatory effect able to decrease blood pressure in man.

Beta adrenergic receptors mediate the inhibitory influence of catecholamines on GH secretion in man, likely via stimulation of hypothalamic somatostatin release. To further clarify the role of β adrenergic receptors in the neural control of GH secretion, in 7 normal females (age 21–27 yr) we studied the interaction of salbutamol (SAL 0.08 mg/kg orally), a β2-adrenergic agonist, with GHRH (1 μg/kg iv) and/or galanin (GAL 15 μg/kg iv), a neuropeptide endowed with a GH-releasing effect which is likely mediated by concomitant stimulation of GHRH- and inhibition of somatostatin-secreting neurons. SAL inhibited the GH response to GHRH (AUC: 282.6 ±102.7 vs 1083.6 ±176.5 μg/l/h, p< 0.05) and, although not significantly, that to GAL (263.9 ±103.7 vs 418.4 ±70.4 μg/l/h). GAL enhanced the GHRH-induced GH rise (2129.5 ±362.2 μg/l/h, p< 0.05) but SAL pretreatment inhibited this effect (1249.8 ±257.1 μg/l/h, p<0.02) so that the GH response to the combined administration of GHRH, GAL and SAL overlapped with that to the neurohormone alone. In conclusion, our results show that the inhibitory influence of β adrenergic activation on GH secretion overrides the stimulatory one of galanin. They strenghten the view that in man β-adrenergic receptors and galanin modulate GH secretion having opposite influences aimed to balance the function of the GH-IGF-I axis.

Beta-adrenergic receptors mediate the inhibitory influence of cathecolamines on GH secretion, probably via the stimulation of hypothalamic somatostatin release. Accordingly, beta-adrenergic agonists and antagonists inhibit and increase, respectively, the GH response to many stimuli, including GHRH, in man. Aim of the present study was to verify the effect, if any, of beta-adrenergic drugs on the GH response to Hexarelin, a synthetic GH-releasing hexapeptide. Interestingly, the GH-releasing effect of Hexarelin has been reported to be partially refractory to neuroendocrine manipulations known to strongly enhance or abolish the GHRH-induced GH release. In 6 normal male volunteers (aged 22–27 yr) we studied the interaction of the maximally effective iv dose of Hexarelin (HEX, 2 μg/kg iv at 0 min) with atenolol (100 mg po at −60 min) or salbutamol (0.08 mg/kg po at - 60 min), which are beta-adrenergic antagonist and agonist, respectively. HEX induced a marked GH rise(AUC, mean ± SE: 4573.2±588.8 μg.min/L), which was unchanged by atenolol (4706.2±928.2 μg.min/L) but blunted by salbutamol (2792.8±618.0 μg.min/L, p<0.03). In conclusion, present data show that, in man, the GH-releasing effect of Hexarelin is not enhanced by beta-adrenergic blockade while is only blunted by the activation of beta receptors. According to other data, these results indicate that the potent GH-releasing activity of Hexarelin is, at least partially, refractory to beta-adrenergic-mediated manipulations of somatostatinergic activity.

It is widely accepted that, in man, galanin, a neuropeptide, has a clear GH releasing effect while its stimulatory influence on PRL secretion is matter of debate. To clarify this point, in 6 normal young women (23–35 yr) in their early follicular phase, we studied the effect of galanin (pGAL, 80 pmol/kg. min infused iv over 60 min) on both basal and arginine (ARG, 0.5 g/kg iv in 30 min), TRH (400 μg iv as a bolus at 0 min) or metoclopramide (MCP, 10 mg iv as a bolus at 0 min)-stimulated PRL secretion. GAL infusion failed to significantly increase basal PRL levels (peak vsbaseline: 12.2±3.6 vs8.7±1.2 μg/L) but counteracted the spontaneous PRL decrease observed during saline infusion (AUG: 1216.6±282.1 vs672.0±94.5 μg.min/L; p<0.05). GAL infusion clearly enhanced the PRL response to TRH (AUC: 5806.3±743.0 vs3952.1 ±423.9 μg.min/L, p<0.05) and ARG (AUC: 3676.8±382.6 us 2638.9 ± 287.0 μg.min/L, p<0.05), respectively. On the other hand, GAL failed to modify the MCP-induced PRL response (AUC: 15409.5±2085.3 vs14787.9±2045.5 μg.min/L). The PRL response to MCP was higher than that to TRH (p<0.01 ) which, in turn, was higher than that to ARG (p<0.01). During GAL infusion, the PRL response to TRH or ARG remained lower (p<0.01) than that after MCP administration. Thus, in conclusion, present data demonstrate that in normal women galanin enhances the PRL response to ARG and TRH but fails to modify that induced by dopamine receptor blockade with metoclopramide. Based on evidence that the inhibition of central dopaminergic activity inhibits the lactotrope responsiveness to dopaminergic antagonists or TRH, it is unlikely that galanin influences PRL secretion viainhibition of dopaminergic tone.

The effect of dopamine on thyrotropin (TSH) and prolactin (PRL) levels was studied in 5 normal subjects, 7 women with galactorrhea, 9 acromegalics and 4 patients with primary hypothyroidism. Dopamine infused at the rate of 280 μg/min produced significant decrease in plasma TSH and PRL levels in all four groups, though a lower fall in TSH was noted in acromegalics. A similar reduction in PRL was also noted after 28 μg/min dopamine. Phentolamine infusion (0.5 mg/min) had no effect on PRL response to dopamine. These results indicate that a dopaminergic stimulation led to an inhibition of TSH and PRL secretion. Since the high polarity of dopamine impedes its passage through the blood-brain barrier, its site of action should be outside this barrier, probably in the pituitary.

Aim of the present study was to verify the maximal secretory capacity of somatotrope cells in patients with pathological hyperprolactinemia (HPRL) comparing it with that in normal age-matched women (NW). To this goal in 12 HPRL normal weight patients (age 28.6±2.6 yr, BMI 23.1 ±1.1 kg/m2) and 8 NW (27.2±0.8 yr, 22.8±0.8 kg/m2) we studied the GH response to GHRH (1µg/kg iv), GHRH plus arginine (ARG, 0.5 g/kg iv), an amino acid probably acting at the hypothalamic level inhibiting somatostatin release, and Hexarelin (HEX, 2 µg/kg iv), a synthetic hexapeptide belonging to GHRP family, which acts concomitantly at the pituitary and the hypothalamic level. IGF-I levels in HPRL were similar to those in NW (179.2±16.5 µg/l and 218.5±30.8 µg/l). In NW the GH response to GHRH (AUC: 1299.5±186.9 µg.90 min/l) was lower (p<0.02) than those to GHRH+ARG (5252.7±846.3 µg.90 min/l) and HEX (3216.6±462.3 µg.90 min/l) which, in turn, were similar. In HPRL the GH response to GHRH (894.7±242.4 µg.90 min/l) was lower (p<0.03) than that to HEX (1586.5±251.3 µg.90 min/l) and both were lower (p<0.03) than that to GHRH+ARG (4468.8±941.7 µg.90 min/l). In HPRL the GH responses to GHRH and HEX were lower than those that in NW (p<0.03) while that to GHRH+ARG was similar in both groups. These results demonstrate that the somatotrope responsiveness to GHRH and HEX is clearly reduced in patients with pathological hyperprolactinemia. On the other hand, in this condition the GH response to GHRH+ARG is normal. As arginine likely acts via inhibition of hypothalamic somatostatin release, these findings show that the maximal secretory capacity of somatotrope cells in hyperprolactinemia is preserved and indicate that partial refractoriness of somatotrope cells to GHRH and HEX could be due to somatostatinergic hyperactivity.

The role of histamine in the neural control of GH secretion in man is still unclear, although a stimulatory influence has been hypothesized in man. To clarify this point, in 7 normal young women (23–28 yr) in their early follicular phase, we studied the effect of the histaminergic blockade by diphenhydramine (DPH, 80 mg os at −60 min) on the GH response to GHRH (2 μg/Hg iv) or Hexarelin (HEX, 2 μg/kg iv), a synthetic hexapeptide with strong GH-releasing effect. In 6 of the 7 women the effect of terfenadine (TRF, 120 mg os at −60 min), another H1-receptor antagonist, on the GH response to GHRH or HEX was also studied. As HEX has also PRL- and ACTH-releasing activity and histamine has been shown to have a stimulatory role in the neural control of these hormones, the effects of DPH or TRF on the HEX-induced PRL, ACTH and Cortisol release were also studied. GHRH induced a GH rise (peak, mean±SEM: 35.4±6.5 vs2.5±1.1 μ/l, p<0.02, n=7; 34.7±7.9 vs3.9±5 μg/l, p<0.02, n=6) lower (p<0.05) than that elicited by HEX (49.1±8.5 vs3.9±1.0 μg/l, p<0.01, n=7; 48.7±8.9 vs3.2±0.8 μg/l, p<0.01, n=6). DPH inhibited the GH response to both GHRH (AUG: 453.9±104.7 vs1223.7±202.6 μg*min/l, p<0.05) and HEX (922.0±215.4 vs1636.4±267.5 μg*min/l, p<0.05), although the HEX-induced GH rise persisted higher than that induced by GHRH (p<0.05). TRF did not modify the GHRH-induced GH rise (950.5±369.2 mg*min/l vs1115.3±255.6 μg*min/l) as well as the somatotrope responsiveness to HEX (1163.2±188.7 vs1427.3±323.3 mg*min/l). HEX also significantly increased PRL (13.9±3.1 vs6.5±0.8 μg/l, p<0.03), ACTH (31.1 ±6.6 vs16.6±2.9 µg/ml, p<0.02) and Cortisol (96.6±6.3 vs822<62 μg/L, p<0.05)’levels. PRL, ACTH and Cortisol responses to HEX were unaffected by DPH (536.5±85.6 vs599.5±129.2 μg*min/l, 1068.5±306.0 vs1282.8±222.0 µg*min/ml and 4277.4±588.4 vs4738.3±355.3 μg*min/l, respectively) as well as by TRF (621.3±110.4 vs530.3±131.4 μg*min/L, 972.4±189.6 vs1060.2±224.7 µg*min/ml and 6203.8±1329.5 vs5141.2±295.5 μg*min/l, respectively). In conclusion, our findings are against the hypothesis of a major role of H1-receptor-mediated histaminergic influence on GH secretion in humans. In fact, the H1-histaminergic blockade by TRF does not affect the GH response to GHRH or HEX; the inhibitory effect of DPH may probably be due to its intrinsic anticholinergic activity. Our data also confirm that Hexarelin releases more GH than GHRH and demonstrate that its effect on GH, PRL and ACTH release is not mediated by H1-receptors.

A hypothalamic pathogenesis for the reduced GH secretion in aging has been reported for both animal and man. To further address this issue we studied in 31 elderly normal subjects (6 males and 25 females, aged 66–90 yr) and in 22 young healthy controls (13 males and 9 females, aged 20–35 yr) the GH responses to GHRH test (GHRH29, 1 μg/kg iv as a bolus at 0 min) alone and combined with pyridostigmine, a cholinesterase inhibitor (PD, 120 mg po 60 min before GHRH), or with arginine (ARG, 30 g in 100 ml infused from 0 to 30 min). Serum IGF-I levels were lower in elderly than in young subjects (mean±SE: 86.9±7.2 vs 288.7±22.1 μg/L, p<0.01). The GHRH-induced GH increase was lower in elderly than in young subjects (p<0.01). PD increased the GH response to GHRH in both groups (p<0.001), but in elderly subjects this response persisted lower (p<0.0001) than that ob-served in young adults. Also ARG coadministration potentiated the GHRH-induced GH release in both groups (p<0.0001) but in this case the elderly’s responses overlapped with the young’s. The GH in-crease observed after combined administration of ARG and GHRH was higher (p<0.0001) than that elicited by PD plus GHRH in elderly but not in young subjects. Analyzing individual GH responses, a GH peak below the limit of normality for young adults was observed in 19 (61.3%) elderly subjects after PD plus GHRH administration while ARG plus GHRH test elicited a normal GH peak in all but one. Taking into account that the GH-releasing effect of both PD and ARG is likely mediated by inhibition of hypothalamic somatostatin release, our data show that in elderly subjects the acutely releasable GH pool is preserved and give support to the hypothesis that a somatostatin hypertone underlies the reduced GH secretion of aged individuals. PD but not ARG fails to potentiate the GH response to GHRH in about 60% of aged subjects. These findings are suggestive for an impairment of the hypothalamic cholinergic system which, in turn, would be responsible for somatostatin hyperactivity and GH hyposecretion.

Ghigo E, Ceda GP, Valcavi R, Goffi S, Zini M, Mucci M, Valenti G, Muller EE, Camanni F. Effect of 15-day treatment with growth hormone-releasing hormone alone or combined with different doses of arginine on the reduced somatotrope responsiveness to the neurohormone in normal aging. Eur J Endocrinol 1995;132:32–6. ISSN 0804–4643It is well known that both spontaneous and growth hormone-releasing hormone (GHRH)-stimulated GH secretion undergo an age-related decrease; in addition, there is supportive evidence that the GH hyposecretory state of aging is of hypothalamic origin. The aims of the study in 35 normal elderly subjects (20 males and 15 females aged 65–89 years) were to verify whether the low somatotrope responsiveness to GHRH (1 μg/kg) can be primed by a daily GHRH treatment and whether the potentiating effect of both high intravenous (0.5 g/kg) and low oral (8 g) doses of arginine (ARG) on GH response to GHRH is maintained with time. In group A (N = 14) the GH response to GHRH on day 1 (AUC: 373.5 ± 78.5 μg·1−1·h−1) was unchanged after 7 (3720 ± 38 μg·1−1·h−1) and 15 days (377.9 ± 63.8 μg·1−1·h−1) of daily GHRH administration. In group B (N = 6) the GH response to GHRH co-administered with iv ARG on day 1 (1614.2 ± 146.2 μg · 1−1· h−1) was higher (p < 0.05) than that of GHRH alone (group A) and persisted unchanged after 7 (1514.7±366.5 μg·1−1·h−1) and 15 days (1631.7 ± 379.1 μg · 1−1· h−1) of treatment. In group C (N = 15) the GH response to GHRH co-administered with oral ARG on day 1 (950.6 ± 219.4 μg·1−1· h−1) was higher (p < 0.03) than that of GHRH alone (group A) but lower (p < 0.05) than that to GHRH plus iv ARG (group B). It was unchanged after 7 (816.2 ± 208.5 μg·1−1· h−1) and 15 days (760.4 ± 165.0 μg · 1−1· h−1) of treatment; these responses were still higher (p < 0.05) than that to GHRH alone. Insulin-like growth factor I levels were not modified by any of the treatments. In conclusion, our results demonstrate that in normal aging the low somatotrope responsiveness to GHRH is not improved by prolonged treatment with the neurohormone but it is enhanced by the combined treatment with ARG and this effect does not vanish after a 15-day treatment period. The effect of ARG is present even after a low oral dose, although less markedly than after a high intravenous dose.F Camanni, Divisione di Endocrinologia, Ospedale Molinette, C. so Dogliotti 14, 10126 Torino, Italy

The effect of 100 mg im sulpiride on plasma Prl levels was studied in 10 normal females, 21 patients with galactorrhoea and normal plasma Prl, 10 women with puerperal hyperprolactinaemia and 27 patients with amenorrhoea-galactorrhoea and high plasma Prl levels.The response to sulpiride in patients with galactorrhoea but normal Prl was slightly higher (P< 0.05) than that observed in normal women, but only if expressed in per cent.Women with puerperal hyperprolactinaemia respond to the drug with a marked increase in Prl (mean ± sem: 563.0 ± 142.8%), even though their baseline values are already very high (mean ± sem: 133.6 ± 23.8 ng/ml).By contrast, there is a lower or no response to sulpiride in 13 women with pituitary tumour.The same was true in 11 patients with hyperprolactinaemia of uncertain aetiology but also 10 of these subjects presented signs suggestive of a tumour.In the last 3 patients with pathological hyperprolactinaemia in whom a consistent Prl increase after sulpiride was observed, hyperprolactinaemia was probably not of tumourous origin.On the basis of these results, the sulpiride test appears promising for discriminating between organic and 'functional' cases of enhanced Prl secretion.

A cohort of brain neurotransmitters, especially catecholamines and acetylcholine, play a crucial role in the control of neurosecretory growth hormone-releasing hormone (GH-RH)- and somatostatin (SS)-producing neurons, and hence growth hormone (GH) secretion. Stimulation of α2-adrenoceptors or of muscarinic cholinergic receptors in the hypothalamus stimulates GH release, probably via stimulation of GH-RH and inhibition of somatostatin release, respectively. Additionally, stimulation of dopamine receptors is stimulatory to GH release, while activation of β-receptors inhibits GH release via stimulation of hypothalamic somatostatin function. As a corollary, in GH deficiency states drugs affecting catecholaminergic and cholinergic functions may be exploited for diagnostic and/or therapeutic purposes, and may be useful for a better understanding of the underlying pathophysiology. Levodopa (L-dopa) [125 to 500mg orally], the physiological precursor of the catecholamines, administered either alone or in combination with carbidopa (50mg orally), to prevent its peripheral decarboxylation to dopamine, and/or the β-adrenoceptor antagonist propranolol (0.75 mg/ kg orally), and the α2-adrenoceptor agonist clonidine (0.15 mg/m2orally), are a fairly reliable stimulus of GH release. In normal subjects, however, false-negative GH responses and wide inter-individual variability may occur with these drugs. Additionally, the GH secretory response to these provocation tests is a poor predictor of endogenous 24-hour GH secretion, since levodopa or clonidine may elicit a response within normal limits in children of short stature with reduced 24-hour GH secretion and good responsiveness to GH therapy. The availability of GH-RH, a direct probe of pituitary somatotrophs, held out promise of unravelling the hypothalamic or pituitary origin of GH secretory disturbance. It soon became apparent, however, that this was not the case, because of the wide inter- and intraindividual variation in the GH response. However, the coadministration of GH-RH and muscarinic cholinergic agonists, for example pyridostigmine (which deprive the pituitary of hypothalamic SS inhibitory influences), is a useful diagnostic probe. In a large group of normal children and adolescents who received an intravenous injection of GH-RH, preceded by oral administration of pyridostigmine (60mg orally), none gave a false-negative response; this was also true for a group of short children with different forms of GH disturbances, in whom 8-hour nocturnal GH secretion was within normal limits. However, some false-negative responses occurred in children following testing with GH-RH, clonidine or pyridostigmine alone. Interestingly, the cut-off point for normality following pyridostigmine + GH-RH was as high as 20 ng/ml, while for the other provocation tests it is only 5 to 10 ng/ml. Responses lower than 20 ng/ml were present in all children with organic and most of the children with idiopathic GH deficiency. The fact that in most subjects with GH deficiency and/or short stature GH-RH evokes variable but unequivocal rises in plasma GH levels points to a dysfunction of hypothalamic regulation; the dysfunction would primarily affect neurotransmitter and not hypophysiotropic neurosecretory neurons. In children with isolated GH deficiency (IGHD), 6 months of oral administration of levodopa (60 mg/kg) or bromocriptine (2.5mg) increased growth velocity, basal GH levels and in some of the children serum somatomedin-C levels. Similarly, clonidine (0.1 mg/m2orally) given for 3 months to 1 year to children with isolated GH deficiency or constitutional delay of growth (CGD) induced in some of them a clearcut stimulation of linear growth. After 2 months of treatment in a group of children with constitutional delay of growth, clonidine increased the 24-hour GH concentration and the mean GH pulse amplitude. In contrast, pyridostigmine (60 to 180mg orally) does not have growth-promoting therapeutic potential, probably because it fails to potentiate the GH-RH-induced rise in GH at night. A GH hyposecretory dysfunction is also present in obese children and adults. In these patients acute pretreatment with pyridostigmine significantly increased baseline GH levels and the GH response to GH-RH, these indices becoming similar to those of lean control subjects receiving GH-RH alone. However, combined administration of pyridostigmine and GH-RH elicited a higher GH response in lean control subjects than in obese subjects. Decreases in GH pulse amplitude and frequency and marked blunting of the GH response to various secretagogues occurs in both animals and humans during aging. The mechanism of these changes is unclear but studies in aged animals have shown that passive immunisation with antisomatostatin serum or treatment with pilocarpine or clonidine stimulates GH release.

It is widely accepted that abdominal obesity presents with exaggerated insulin secretion, insulin resistance and a trend toward glucose intolerance. Hypertension is frequently associated to abdominal obesity, and hyperinsulinism could play a role in its pathogenesis. Some studies reported that Ca-antagonists positively influence insulin sensitivity and glucose tolerance in obese patients with normal or elevated blood pressure. However, other studies reported worsening of metabolic balance during treatment with Ca-antagonists in hypertensive non-insulin-dependent diabetes mellitus (NIDDM) patients and in normal subjects. We studied 19 patients with abdominal obesity, mild hypertension and insulin resistance on balanced, mild hypocaloric diet (1400 Kcal), to verify the effects of the Ca-antagonist nifedipine on both basal and oral glucose tolerance test (OGTT)-induced glucose and insulin levels as well as on IGF-I basal and DHEA-S levels and fat mass (FM). To achieve this goal, 10 hypertensive obese subjects (HOB-NIFE, 3 males, 7 females, mean age±SD 44.6±1.7 yr; body mass index (BMI) 37.1±2.5 Kg/m2, WHR 0.95±0.02) received 3-month treatment with nifedipine (Adalat Crono 30 Bayer, 1 tab daily) while other 9 hypertensive obese (HOB, 3 males, 6 females, 42±2.4 yr, BMI 35.8±1.8 Kg/m2, WHR 0.91±0.03) were studied during diet only. The same parameters were studied also in 8 normotensive obese patients (OB: 3 males, 5 females, 48.1±2.1 yr, BMI 35.8±2.4 Kg/m2, WHR 0.90±0.03) on the same balanced hypocaloric diet. Basal systolic (SBP) and diastolic (DBP) blood pressure levels in HOB-NIFE and HOB were similar. At baseline, all groups had similar basal and OGTT-induced glucose, insulin and glucose insulin ratio (GIR) levels as well as IGF-I and DHEA-S levels. After 3 months BMI fell to the same extent in all groups (p<0.05 vsbaseline) while WHR and FFM/FM ratio did not change. SBP and DBP decreased HOB-NIFE (p<0.02) but also during diet alone in both HOB and OB, though to a lesser extent (p<0.05). Both basal and OGTT-stimulated glucose and insulin levels as well as IGF-I and DHEA-S levels were not modified in HOB-NIFE as well as in HOB and OB. In conclusion, our data indicate that nifedipine treatment does not modify glucose tolerance as well as insulin secretion and sensitivity, IGF-I and DHEA-S levels in hypertensive abdominal obese patients. Thus, nifedipine treatment has no detrimental effects on endocrine-metabolic balance in hypertensive obese patients.

IGF-I is the best marker of GH secretory status but it also depends on the nutritional status and peripheral hormones such as insulin, glucocorticoids, thyroid hormones and gonadal steroids. Though monitoring IGF-I levels is the best way for evaluating appropriate GH replacement, the usefulness of IGF-I assay in the diagnosis of adult GH deficiency (GHD) is still matter of debate. To clarify this point in a large population of GHD adults (no.=135, 61 women and 74 men; age, mean±SE: 43.8±1.4 yr, range 20–80 yr) we studied IGF-I levels, their reproducibility and association to peak GH response to GHRH+arginine (GHRH+ARG) test and insulin tolerance test (ITT). The results in GHD were compared with those in a large population of normal subjects (no.=336, 233 women and 103 men, aged 20–80 yr). Mean IGF-I levels in GHD (77.8±4.9 µg/l) were clearly lower (p<0.001) than those in normal subjects (170.2±4.7 µg/I). In Childhood Onset GHD (CO-GHD; no.=40; age, mean±SE: 27.8±1.5 yr) IGF-I levels were lower than those in Adult Onset GHD (AO-GHD; no.=95, age, mean±SE: 50.7±1.4 yr) (56.6±9.7 vs87.1 ±5.4 µg/l, p<0.0003). In both GHD and normal subjects IGF-I levels showed good, reproducibility (r=0.92, p<0.00001 and r=0.62, p<0.00001, respectively). In GHD, but not in normal subjects, IGF-I levels were positively associated to peak GH responses to GHRH+ARG (r=0.57, p<0.00001); on the other hand, the GH peak after ITT was not associated to IGF-I in GHD. In normal subjects, but not in GHD, IGF-I levels were negatively associated to age (r=−0.60, p<0.00001). Considering individual IGF-I levels there was a clear overlap between GHD and normal subjects. However, this overlap was strongly dependent on age. In fact, in the third and fourth decade of life 83.6% of GHD had IGF-I levels below the 3rd centile of normal values; on the other hand, in the fifth-sixth decade and in ageing 47% and only 12% of GHD, respectively, had IGF-I levels low for age. In conclusion, our results demonstrate that IGF-I levels represent a reproducible marker of GH status and are reduced more in CO-GHD than in AO-GHD adults. An overlap exists between GHD and normal subjects, however this is small up to the 4th decade of life. Thus, though normal IGF-I levels do not rule out the existence of GHD, up to 40 yr low IGF-I levels strongly point to GHD if malnutrition and liver disease have been ruled out.

Summary Sulpiride, an antipsychotic drug of the benzamide class, reportedly displaces stereospecifically [3H]-butyrophenones from putative dopamine (DA) binding sites in rat striatum. To evaluate if sulpiride displays the same stereospecificity in the inhibition of pituitary DA receptors, the effect of the two (-)- and (+)-sulpiride isomers was tested with regard to their ability to stimulate prolactin (PRL) secretion in rats and man and to displace [3H]-spiroperidol bound to rat anterior pituitary receptors.

Growth hormone-releasing peptides (GHRPs) are synthetic, non-natural peptides endowed with potent stimulatory effects on somatotrope secretion in animals and humans. They have no structural homology with GHRH and act via specific receptors present either at the pituitary or the hypothalamic level both in animals and in humans. The GHRP receptor has recently been cloned and, interestingly, it does not show sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-like ligand which, however, has not yet been found. The mechanisms underlying the GHRP effect are still unclear. At present, several data favor the hypothesis that GHRPs could act by counteracting somatostatinergic activity both at the pituitary and the hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism. However, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. GHRP-6 was the first hexapeptide to be extensively studied in humans. More recently, a heptapeptide, GHRP-1, and two other hexapeptides, GHRP-2 and Hexarelin, have been synthesized and are now available for human studies. Moreover, non-peptidyl GHRP mimetics have been developed which act via GHRP receptors and their effects have been clearly demonstrated in animals and in humans in vivo. Among non-peptidyl GHRPs, MK-0677 seems the most interesting molecule. The GH-releasing activity of GHRPs is marked and dose-related after intravenous, subcutaneous, intranasal and even oral administration. The effect of GHRPs is reproducible and undergoes partial desensitization, more during continuous infusion, less during intermittent administration; in fact, prolonged administration of GHRPs increases IGF-I levels both in animals and in humans. The GH-releasing effect of GHRPs does not depend on sex but undergoes age-related variations. It increases from birth to puberty, persists at a similar level in adulthood and decreases thereafter. By the sixth decade of life, the activity of GHRPs is reduced but it is still marked and higher than that of GHRH. The GH-releasing activity of GHRPs is synergistic with that of GHRH, is not affected by opioid receptor antagonists, such as naloxone, and is only blunted by inhibitory influences, including neurotransmitters, glucose, free fatty acids, glucocorticoids, recombinant human GH and even exogenous somatostatin, which are known to almost abolish the effect of GHRH. GHRPs maintain their GH-releasing effect in somatotrope hypersecretory states such as in acromegaly, anorexia nervosa and hyperthyroidism. On the other hand, their good GH-releasing activity has been shown in some but not in other somatotrope hyposecretory states. In fact, reduced GH responses after GHRP administration have been reported in idiopathic GH deficiency as well as in idiopathic short stature, in obesity and in hypothyroidism, while in patients with pituitary stalk disconnection or Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent. In short children an increase in height velocity has also been reported during chronic GHRP treatment.Thus, based on their marked GH-releasing effect even after oral administration, GHRPs offer their own clinical usefulness for treatment of some GH hyposecretory states.European Journal of Endocrinology136445–460

Hexarelin (HEX), a synthetic hexapeptide, has a strong and reproducible GH-releasing activity in man after intravenous, subcutaneous, intranasal and oral administration. Its effect undergoes age-related variations, being reduced in elderly subjects. In spite of evidence in animals showing that the activity of GH-releasing peptides (GHRPs) is positively influenced by oestrogens, in young adults no sex-related difference has been found in the GH response to HEX or to other GHRPs. We aimed to clarify the influence of the menopause and oestrogens on the GH-releasing activity of HEX. We studied the GH response to the acute administration of the maximal effective dose of HEX (2 μg/kgi.v.) in 24 young women (YW, age: 27·3±0·5 years; body mass index (BMI): 20·7±0·3 kg/m2). 14 post-menopausal women (PW, age: 52·9±1·2 years; BMI: 23·2±0·9 kg/m2) and 14 aged women (AW, age: 68·9±1·5 years; BMI: 21·7±0·7 kg/m2). In 10 post-menopausal women the GH response to HEX was also studied after 3 months of transdermal oestradiol treatment (delivery 50 μg/die). Basal oestrogen and GH levels in PW were lower than those in YW (oestrogen: 4·8±3·6 vs 42·0±3·4 pg/ml (mean±s.e.m.), P< 0·001; GH: 1·5±0·5 vs 2·9±0·6 μg/l, P< 0·02) and similar to those in AW (oestrogen: 1·3±0·4 pg/ml; GH: 0·9±0·2 μg/l). IGF-I levels in PW were not different from those in YW (174·4±11·9 vs 195·5±14·9 μg/l) and higher than those in AW (109·8±15·8 μg/l, P<0·01). The GH response to HEX in PW (areas under the curve±s.e.m.: 453·6±56·0 μg.min/l) was lower (P<0·002) than that in YW (1630·4±259·7 μg.min/l) while it did not differ from that in AW (781·8±189·3 μg.min/l). In PW 3-month oestrogen administration increased oestradiol levels (38·3±5·9 vs 0·8±0·4 pg/ml, p<0·001) making them similar to those recorded in YW, while it failed to modify both basal GH and IGF-I levels (GH: 1·8±0·6 vs 1·5±0·7 μg/l; IGF-I: 164·6±14·3 vs 175·0±12·3 μg/l). Also the GH response to HEX was not modified by oestradiol treatment (518·4±125·6 vs 425·4±69·3 μg.min/l). In conclusion, present data confirm the strong GH-releasing effect of Hexarelin in humans and demonstrate that its activity is already reduced in post-menopausal women to an extent overlapping that in elderly women. Moreover, oestrogen treatment is not able to restore it. Thus, the lack of oestrogens does not seem to account for the reduced somatotroph responsiveness to GHRPs in the post-menopausal period.European Journal of Endocrinology136483–487

Ghigo E, Arvat E, Rizzi G, Goffi S, Grottoli S, Mucci M, Boghen MF, Camanni F. Growth hormonereleasing activity of growth hormone-releasing peptide-6 is maintained after short-term oral pretreatment with the hexapeptide in normal aging. Eur J Endocrinol 1994;131:499–503. ISSN 0804–4643The reduced activity of the growth hormone (GH)–insulin-like growth factor I (IGF-I) axis in aging may contribute to changes in body composition. As this GH insufficiency is due to hypothalamic pathogenesis, the availability of GH-releasing peptides (GHRPs), such as GHRP-6 (His-d-Trp-Ala-Trp-d-Phe-Lys-NH2) which is active even after oral administration, might be useful to restore it. The aim of our study was to verify the effectiveness of oral administration of GHRP-6 in normal elderly subjects and to investigate whether its GH-releasing activity is maintained or vanishes after short-term oral treatment. Seven normal elderly women (aged 65–82 years) were studied. The effect of oral administration of 300 μg/kg GHRP-6 on GH secretion was investigated before and after 4 days of treatment with the hexapeptide given twice daily. The GH response to the maximal effective dose of GHRH (1 μg/kg iv) also was studied. Before treatment, oral administration of 300 μg/kg GHRP-6 elicited a clear GH rise (peak 10.7 ± 3.3 μg/l; AUC 353.1 ± 90.6 μg·l−1·h−1). which was significantly higher (p < 0.01) than that induced by intravenous GHRH (peak 5.1 ± 1.5 μg/l; AUC 106.5 ±43.9 μg · l−1·h−1). After 4 days of treatment with GHRP-6, the GH response to the hexapeptide was maintained, with a trend towards an increase (peak 16.8 ± 2.9 μg/l; AUC 499.8 ± 107.2 μg·l−1·h−1). The IGF-I levels were not increased significantly after treatment (77.1 ± 8.4 vs 84.1 ± 12.2 μg/l). In conclusion, our results demonstrate that, in aging, oral GHRP-6 administration elicits a GH response that is higher than the maximal effective dose of intravenous GHRH and that the effect of the hexapeptide does not vanish after short-term treatment. More prolonged treatment and/or more frequent administrations of GHRP-6 are likely needed to increase IGF-I levels.F Camanni, Division of Endocrinology, Department of Pathophysiology, Ospedale Molinette, C.so Dogliotti 14, 10126 Torino, Italy

To better understand the state of dopamine (DA) neurotransmission in the tuberoinfundibular DA system (TIDA), monoiodotyrosine (3-iodo-L-tyrosine, MIT), a potent inhibitor of DA synthesis, was acutely administered to 8 normal women, 7 postpartum women, 8 women with pathological hyperprolactinemia and 5 women after successful removal of a prolactinoma. The effects on plasma prolactin (PRL) and thyrotropin (TSH) were compared to those induced in the same subjects by the DA receptor antagonist domperidone (DOM). MIT (1 g po) and DOM (10 mg iv) induced qualitatively similar hormonal responses, although the PRL-and TSH-releasing effects of DOM were always greater than those of MIT. In control subjects, MIT treatment induced a consistent rise in plasma PRL (peak increment 45.2 ± 13 ng/ml at 120 min); in the same subjects DOM induced a prompter and higher PRL response, (peak increment 147.8 ± 26 ng/ml at 30 min). MIT failed to alter plasma TSH levels, while DOM induced a significant rise in plasma TSH. In postpartum women MIT induced a prompter and higher PRL rise than that occurring in controls (peak increment 180.3 ± 20 ng/ml at 90 min), though also in this instance DOM proved to be a more potent PRL releaser (peak increment 345.7 ± 88 ng/ml at 30 min) than MIT. MIT was unable to stimulate TSH secretion, while DOM induced a significant rise in plasma TSH. In women with pathological hyperprolactinemia MIT failed to alter baseline PRL levels while DOM slightly increased them (peak increment 14.7 ± 3 ng/ml at 30 min). Both compounds increased significantly plasma TSH levels, again the effect of DOM being greater than that of MIT. Finally, postsurgery assessment evidenced a normal PRL response to MIT and DOM in only one out of the 5 patients successfully cured. These data indicate that: i) in postpartum women TIDA function is normal or even increased; ii) a loss of dopaminergic control of PRL secretion is present in pathological hyperprolactinemia and persists after successful removal of the prolactinoma; iii) an opposite pattern of TSH and PRL responsiveness to inhibition of DA function is present in postpartum women and subjects with pathological hyperprolactinemia.