The IGF-I response to very low rhGH doses is preserved in human aging.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
F Camanni
Publications and source records attributed to F Camanni.
Corticotroph and adrenal responsiveness to hCRH, hexarelin and ACTH in young and elderly subjects.
Explore the source record for details and available documents.
Adrenal Glands↗
IGF-1 levels in different conditions of low somatotrope secretion in adulthood: obesity in comparison with GH deficiency.
BACKGROUND: It is widely accepted that IGF-I synthesis and release depend on GH secretion as well as on the nutritional status and vary with age. Based on these premises, after the definition of normal IGF-I levels during lifespan, in a large population of normal subjects of both sexes, our aim was to verify IGF-I levels in large groups of adult patients with GH deficiency or obesity, a condition in which a reduced somatotrope secretion is well known. METHODS: To this goal, IGF-I levels were assayed after acid-ethanol extraction, in 326 normal subjects (NS, 98 men and 228 women, age 20-80 yrs, BMI 17.9-26.1 kg/m2), 54 patients with GH deficiency (GHD, 24 men and 30 women, age 20-80 yrs, BMI 18.2-27.1 kg/m2), and 195 patients with obesity (OB, 33 men and 162 women, age 17-71 yrs, BMI 27.7-64.9 kg/m2). In NS, IGF-I levels were similar in both sexes and showed a progressive decrease with age. No correlation was present between IGF-I and BMI in NS. Median IGF-I levels and the 3rd centile in NS when considered per decade were: III) 230 and 108.6; IV) 220 and 129.8; V) 150.5 and 72.4; VI) 163.0 and 62.4; VII) 110 and 41.6; VIII) 82 and 24.7 micrograms/l. In GHD, IGF-I levels were independent on sex and did not show reduction during lifespan. Mean IGF-I levels in GHD were lower than that in NS (64.5 +/- 5.9 vs 171.3 +/- 4.8 micrograms/l, p < 0.01) and did not correlate with age or BMI. Analyzing individual IGF-I levels, in GHD, in the III and IV decade 21/24 patients had IGF-I levels lower than 3rd centile while, up to the VIII decade, only 10/30 had IGF-I levels below normal limits. In OB, IGF-I levels were independent on sex but, like in NS, showed a progressive decrease with age and were independently, negatively correlated with BMI but not with WHR. Analyzing individual IGF-I levels, in OB, IGF-I levels were below 3rd centile in 10/77 patients in the III and IV decade and in only 8/108 patients up to the VIII decade. Mean IGF-I levels in the whole OB population (179.6 +/- 5.9 micrograms/l) were higher (p < 0.01) than those in GHD (64.5 +/- 5.9 micrograms/l) while only in the IV decade IGF-I levels in OB group were lower (p < 0.02) than those in NS (184.7 +/- 12.6 micrograms/l vs 224.0 +/- 9.2 micrograms/l). CONCLUSIONS: In conclusion, present data confirm that IGF-I levels depends on GH secretion as well as on nutritional status, being negatively and independently correlated with age and BMI. IGF-I assay is not a reliable test for the diagnosis of GH deficiency in adulthood though it gives good discrimination between GHD and normal subjects up to 40 yrs of age. In spite of low GH secretion, IGF-I levels are only slightly reduced in obesity, probably as consequence of hyperinsulinism.
Adult↗
Effects of beta-adrenergic agonists and antagonists on the growth hormone response to growth hormone-releasing hormone in anorexia nervosa.
BACKGROUND: In anorexia nervosa (AN), growth hormone (GH) hypersecretion and low insulin-like growth factor I (IGF-I) levels are present. It is unclear whether this is due to a peripheral GH resistance and a reduced IGF-I negative feedback on GH secretion or to a primary hypothalamic dysfunction. In AN, in contrast to normal subjects, cholinergic antagonists and agonists, whose action is somatostatin (SS)-mediated, have reduced and absent effects on the GH response to growth hormone-releasing hormone (GHRH). Since arginine, another substance acting via inhibition of SS, maintains its potentiating effect on GH secretion in AN, it has been hypothesized that somewhat specific alteration of the SS-mediated cholinergic influence may be present in this condition. To further clarify the neural control of AH secretion in AN, we evaluated the effects of beta-adrenergic agonists and antagonists, which are known to inhibit and increase, respectively, the GHRH-induced GH secretion in normal subjects. METHODS: We studied the effect of atenolol (ATE), a beta 1-adrenergic antagonist, and salbutamol (SALB), a beta 2-adrenergic agonist, on the GHRH-induced GH release in 10 patients with AN and in 10 normal age-matched women (NW). RESULTS: Basal GH levels were higher, whereas IGF-I were lower in AN than in NW. The GHRH-induced GH rise in AN was higher than that in NW. ATE significantly enhanced the GH response to GHRH in NW, but not in AN. The GH responses to GHRH after ATE pretreatment were similar in NW and in AN. The GH response to GHRH was inhibited by SALB in both NW and AN. The GH responses to GHRH after SALB pretreatment were similar in NW and AN. CONCLUSIONS: These data reveal an exaggerated somatotrope responsiveness to GHRH in AN that is not further increased by beta-adrenergic blockade, while is abolished by beta-adrenergic activation. This suggests that an impairment of beta-adrenergic influence on GH secretion is present in anorexia nervosa.
Adolescent↗
Growth hormone-releasing peptides and their analogs.
Growth hormone-releasing peptides (GHRPs) are a series of hepta (GHRP-1)- and hexapeptides (GHRP-2, GHRP-6, Hexarelin) that have been shown to be effective releasers of GH in animals and humans. More recently, a series of nonpeptidyl GH secretagogues (L-692,429, L-692,585, MK-0677) were discovered using GHRP-6 as a template. Some cyclic peptides as well as penta-, tetra-, and pseudotripeptides have also been described. This review summarizes recent developments in our understanding of the GHRPs, as well as the current nonpeptide pharmacologic analogs. GHRPs and their analogs have no structural homology with GHRH and act via specific receptors present at either the pituitary or the hypothalamic level. The GHRP receptor has recently been cloned and 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. Although the exact mechanism of action of GHRPs has not been fully established, there is probably a dual site of action on both the pituitary and the hypothalamus, possibly involving regulatory factors in addition to GHRH and somatostatin. Moreover, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. The marked GH-releasing activity of GHRPs is reproducible and dose-related after intravenous, subcutaneous, intranasal, and even oral administration. The GH-releasing effect of GHRPs is the same in both sexes, but undergoes age-related variations. It increases from birth to puberty and decreases in aging. The GH-releasing activity of GHRPs is synergistic with that of GHRH and not affected by opioid receptor antagonists, while it is only blunted by inhibitory influences that are known to nearly abolish the effect of GHRH, such as neurotransmitters, glucose, free fatty acids, glucocorticoids, rhGH, and even exogenous somatostatin. GHRPs maintain their GH-releasing effect in somatotrope hypersecretory states, such as acromegaly, anorexia nervosa, and hyperthyroidism. On the other hand, GHRPs and their analogs have been reported to be effective in idiopathic short stature, in some situations of GH deficiency, in obesity, and in hypothyroidism, while in patients with pituitary stalk disconnection and in Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent. A potential role in the treatment of short stature, aging, catabolic states, and dilated cardiomyopathy has been envisaged.
Animals↗
Effects of 3-month nifedipine treatment on endocrine-metabolic parameters in patients with abdominal obesity and mild hypertension.
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 vs baseline) 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.
Adult↗
Usefulness of IGF-I assay for the diagnosis of GH deficiency in adults.
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 micrograms/l) were clearly lower (p < 0.001) than those in normal subjects (170.2 +/- 4.7 micrograms/l). 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 vs 87.1 +/- 5.4 micrograms/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.
Adult↗
Diagnostic and therapeutic uses of growth hormone-releasing substances in adult and elderly subjects.
The aim of this review is to answer two questions. The first question is: is there any alternative provocative test equal to, or even better than, the insulin-tolerance test (ITT), the so-called gold standard, for the diagnosis of growth hormone deficiency (GHD) in adults and the elderly? The answer is 'yes'. In fact, when combined with arginine or pyridostigmine, growth hormone-releasing hormone (GHRH) becomes one of the most potent and reproducible tests for distinguishing patients with severe GHD from normal subjects. Owing to its tolerability and its suitability for use in the elderly, the GHRH + arginine test is the best alternative choice and is at least as sensitive as the ITT provided that appropriate cut-off limits are given. The second question is: is there any therapeutic approach alternative to recombinant human growth hormone (rhGH) for adult and elderly patients with GHD and/or for the somatopause? At present, the answer is 'no'. Growth hormone (GH)-releasing substances need the functional integrity of somatotroph cells to induce the release of growth hormone. Probably only patients with childhood-onset, isolated GHD (frequently hypothalamic-dependent) could benefit from treatment with GHRH or growth hormone secretagogues (GHS). Whenever restoration of the activity of the GH/insulin-like growth factor-1 (IGF-1) axis in the elderly would be of use, GHRH and/or GH secretagogues would be good candidates. In fact, the existence of a considerable pool of releasable growth hormone has been demonstrated in the elderly.
Adult↗
Diagnosis of GH deficiency in adults.
Within an appropriate clinical context, growth hormone deficiency (GHD) in adults must be demonstrated biochemically. The assays of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) per se do not establish the diagnosis of adult GHD. Similarly, the evaluation of spontaneous growth hormone (GH) secretion over 24 h has no diagnostic value in adulthood even when an ultra-sensitive GH assay is used. The diagnosis of adult GHD is established by provocative testing of GH secretion, and insulin-induced hypoglycaemia using the insulin tolerance test (ITT) is indicated as the test of choice. Alternative provocative tests of GH secretion have been proposed and have to be used with appropriate cut-off limits. Testing with GH releasing hormone (GHRH) alone has no diagnostic value, but when GHRH is given in combination with arginine or pyridostigmine it becomes the most potent and reproducible provocative test to evaluate the maximal secretory capacity of somatotrope cells. The potentiating effect of arginine on the GHRH-induced GH response is fully preserved while the stimulatory effect of GHRH + pyridostigmine is reduced in ageing. The GHRH + arginine test is well tolerated and reproducibly distinguishes between normal and GHD adult and elderly subjects. Thus, the GHRH + arginine test is the most promising alternative to the ITT provided that cut-off limits appropriate to its potent stimulatory effect are considered.
Adult↗
Growth hormone secretagogues as corticotrophin-releasing factors.
Explore the source record for details and available documents.
Adrenocorticotropic Hormone↗
The altered plasma amino acid pattern is responsible for the paradoxical growth hormone response to the oral glucose tolerance test in liver cirrhosis.
OBJECTIVE: An increased basal growth hormone (GH) secretion and a parodoxical GH response to the oral glucose tolerance test (OGTT) have been reported in patients with liver cirrhosis. It has been suggested that the ratio between branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) (BCAA/ AAA ratio) may determine in part the brain concentration of the AAAs, since the BCAAs compete with the AAAs for entry across the blood-brain barrier, leading to the accumulation of false neurotransmitters such as octopamine and phenylethanolamine, which are able to stimulate GH secretion (via alpha 2-adrenergic stimulation). In this study we investigated the role of amino acids, particularly the BCAA/AAA ratio, in the paradoxical response of GH to the OGTT in patients with liver cirrhosis. PATIENTS AND DESIGN: Twelve non-diabetic patients with biopsy-proven cirrhosis of the liver underwent an OGTT. Three of the five patients with a paradoxical response of GH to the OGTT underwent a second oral glucose administration associated with an infusion of BCAA solution from -30 min until 180 min. RESULTS: During the OGTT, glucose and insulin levels increased from 4.8 +/- 0.2 to 9.6 +/- 0.7 mmol/l (P < 0.001) and from 18.8 +/- 2.6 to 104.4 +/- 13.8 mU/l (P < 0.005), respectively. GH levels increased from 8.6 +/- 2.6 to 22.4 +/- 10.8 mU/l although not significantly. Five patients had a paradoxical GH response to the OGTT. A negative correlation between serum GH values and BCAA/AAA ratio in the plasma at every time point of the OGTT was found. After co-administration of glucose and BCAA in three patients the BCAA/AAAs ratio increased, abolishing the paradoxical GH secretion. CONCLUSIONS: Our data suggest that in liver cirrhosis the altered BCAA/AAA ratio may influence the altered basal GH secretion and the paradoxical GH response to the OGTT, probably by an increase of adrenergic mediators in the brain. Moreover, the increase of BCAA/AAA ratio seems to be able to abolish the GH paradoxical response to the OGTT.
Adult↗
Effects of dexamethasone and alprazolam, a benzodiazepine, on the stimulatory effect of hexarelin, a synthetic GHRP, on ACTH, cortisol and GH secretion in humans.
Hexarelin (HEX) is a synthetic GHRP which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in humans. Like other GHRPs, HEX possesses also acute ACTH and cortisol-releasing activity similar to that of hCRH. The mechanisms underlying the stimulatory effect of GHRPs on hypothalamo-pituitary-adrenal (HPA) axis are still unclear, although a CNS-mediated action has been demonstrated. In 6 normal healthy young women (26-34 years) we studied the effects on ACTH and cortisol secretion of HEX (2.0 microg/kg i.v. at 0 min) alone and preceded by dexamethasone (DEXA, 1 mg p.o. at 23.00 h on the previous night) or alprazolam (ALP, 0.02 mg/kg p.o. at -90 min), a benzodiazepine which binds to GABA receptors and possesses CRH-mediated inhibitory activity on HPA axis. ACTH and cortisol secretion after saline administration as well as the GH response to HEX alone and preceded by DEXA or ALP were also studied. HEX administration elicited an increase in ACTH (peak vs. baseline, mean +/- SEM: 28.0 +/- 6.7 vs. 11.7 +/- 2.2 pg/ml, p < 0.05) and cortisol secretion (162.6 +/- 15.0 vs. 137.7 +/- 12.6 microg/l, p < 0.05). DEXA pretreatment strongly inhibited basal ACTH (3.2 +/- 0.7 pg/ml, p < 0.01) and cortisol levels (11.3 +/- 2.5 microg/l, p < 0.001) and abolished the ACTH and cortisol responses to HEX (3.6 +/- 0.9 pg/ml, p < 0.01 and 10.7 +/- 2.0 microg/l, p < 0.001), respectively. On the other hand, ALP pretreatment did not significantly modify basal ACTH (7.9 +/- 2.0 pg/ml) and cortisol levels (127.6 +/- 14.5 microg/l) but abolished the HEX-induced ACTH and cortisol secretions (8.6 +/- 2.4 pg/ml, p < 0.05 and 111.0 +/- 6.0 microg/l, p < 0.05), respectively. ACTH and cortisol levels after HEX when preceded by ALP overlapped with those recorded during saline. HEX induced a clear GH response (peak at 15 min vs. baseline: 65.5 +/- 20.5 vs. 2.2 +/- 0.7 microg/l, p < 0.03) which was blunted by ALP (peak at 15 min: 21.5 +/- 5.5 microg/l, p < 0.05) while it was not modified by DEXA pretreatment (78.7 +/- 7.6 microg/l). In conclusion, our present data demonstrate that the ACTH- and cortisol-releasing effect of HEX is abolished by either dexamethasone or alprazolam, a benzodiazepine, which is even able to blunt the GH-releasing activity of the hexapeptide. These findings suggest that, in physiological conditions, the stimulatory effect of GHRPs on HPA axis is sensitive to the negative glucocorticoid feedback and could be mediated by GABAergic mechanisms; the latter seem also involved in the GH-releasing activity of GHRPs.
Adrenocorticotropic Hormone↗
Adrenocorticotropin and cortisol hyperresponsiveness to hexarelin in patients with Cushing's disease bearing a pituitary microadenoma, but not in those with macroadenoma.
We previously reported that in Cushing's disease (CD) the ACTH- and cortisol (F)-releasing activity of Hexarelin (HEX), a GH secretagogue, is exaggerated with respect to that in normal subjects and is higher than that of human CRH (hCRH), but it is absent in Cushing's syndrome. Our aim was to extend the study about the effects of HEX (2.0 microg/kg, iv) on ACTH and F secretion in 21 patients with CD (3 men and 18 women, 16-68 yr old). Based on magnetic resonance imaging, 15 CD patients had pituitary microadenoma, and 6 had macroadenoma. The results in CD patients were compared with those in 27 normal age-matched controls (NS; 10 men and 17 women, 24-69 yr old). Basal ACTH and F levels in CD were similar in patients with microadenom (mean+/-SEM, 78.3+/-7.2 pg/mL and 237.1+/-23.6 microg/L, respectively) and macroadenoma (57.4+/-9.0 pg/mL and 196.9+/-20.1 microg/L, respectively) and were higher (P < 0.001) than those in NS (17.7+/-2.0 pg/mL and 115.3+/-6.7 microg/L, respectively). In microadenoma CD patients, HEX induced marked ACTH and F increases (delta peak, mean+/-SEM: 261.2+/-77.6 pg/mL and 226.1+/-87.2 microg/L, respectively), which were higher (P < 0.04) than those induced by hCRH (45.6+/-16.9 pg/mL and 84.6+/-25.7 microg/L, respectively). Moreover, in microadenoma CD patients, the ACTH and F responses to HEX were higher (P < 0.001) than those in NS (18.5+/-4.0 pg/mL and 36.1+/-6.8 microg/L, respectively). In macroadenoma CD patients, HEX induced a slight, but significant increase (P < 0.02) in ACTH and F levels (33.9+/-18.0 pg/mL and 89.6+/-34.3 microg/L, respectively), which was not significantly different from that elicited by hCRH (20.0+/-7.0 pg/mL and 54.8+/-21.3 microg/L, respectively). In macroadenoma CD patients, the ACTH and F responses to HEX and hCRH were, in turn, similar to those in NS. In conclusion, our findings demonstrate that the ACTH and F hyperresponsiveness to HEX is present in Cushing's disease with micro-, but not macro- ACTH-secreting pituitary adenoma. This finding agrees with other evidence pointing toward differences in the hormonal behavior between micro- and ACTH-secreting pituitary macroadenomas.
Adenoma↗
Comparison between insulin-induced hypoglycemia and growth hormone (GH)-releasing hormone + arginine as provocative tests for the diagnosis of GH deficiency in adults.
There is now wide consensus that, within an appropriate clinical context, GH deficiency (GHD) in adults must be shown biochemically by provocative testing of GH secretion and that appropriate cut-off limits have to be defined for each provocative test. Insulin-induced hypoglycemia (ITT) is indicated as the test of choice, and severe GHD, to be treated with recombinant human GH replacement, is defined by a GH peak response to ITT of less than 3 micrograms/L. GHRH + arginine (GHRH + ARG) is one of the most promising tests in alternative to ITT. In fact, it has been reported as a potent, reproducible, and age-independent test and that it is able to distinguish between GHD and normal adults. The aim of the present study was to compare the GH response to ITT and GHRH + ARG in a large group of hypopituitary adults (n = 40; 29 male and 11 female; age: 36.4 +/- 2.1 yr). The third centile limit of the peak GH response to ITT has been reported as 5 micrograms/L, whereas in our lab, that to GHRH + ARG is 16.5 micrograms/L. In hypopituitary adults, the mean peak GH response to ITT (1.5 +/- 0.2 micrograms/L, range: 0.1-8.5 micrograms/L) was lower (P < 0.001) than that to GHRH + ARG (3.0 +/- 0.4 micrograms/L, range 0.1-12.0 micrograms/L), though there was positive correlation (r = 0.61, P < 0.001) between the GH responses to the 2 tests. The peak GH response to GHRH + ARG, but not that to ITT, was positively (though weakly) associated with insulin-like growth factor-I levels (r = 0.35, P < 0.03). Childhood and adult onset GHD patients, as well as patients with single and multiple pituitary insufficiencies, had similar peak GH responses to ITT or GHRH + ARG. Analyzing individual GH responses, 4/40 (10%) of the hypopituitary patients had GH peaks higher than 5 micrograms/L after ITT; moreover, 3 other patients (7%) had GH peaks, after ITT, higher than 3 micrograms/L. On the other hand, after GHRH + ARG, all patients had GH peaks lower than 16.5 micrograms/L, whereas 21/40 (52.5%) had GH peaks higher than 3 micrograms/L. Because 3 micrograms/L is the arbitrary cut-off for ITT, the third centile limit of which is 5 micrograms/L, we arbitrarily considered 9 micrograms/L as the cut-off point for GHRH + ARG. It is noteworthy that 37/40 (92.5%) patients had a GH peak, after GHRH + ARG, below this limit. In conclusion, our present results confirm that the ITT test is a reliable provocative test for the diagnosis of adult GHD, whereas they show that the GHRH + ARG test is, at least, as sensitive as the ITT test (provided that appropriate cut-off limits are considered). Note that even the arbitrary cut-off point below which severe GHD is demonstrated has to be appropriate to the potency of the test.
Adult↗
Orally active growth hormone secretagogues: state of the art and clinical perspectives.
Growth hormone secretagogues (GHS) are synthetic, non-natural peptidyl and nonpeptidyl molecules with potent stimulatory effect on somatotrope secretion. They have no structural homology with growth hormone-releasing hormone (GHRH) and act via a specific receptor, which has now been cloned and is present at both the pituitary and hypothalamic level. This evidence strongly suggests the existence of a still unknown natural GHS-like ligand. Several data favour the hypothesis that GHS could counteract somatostatinergic activity at both the pituitary and hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism. However, the possibility that they act via an unknown hypothalamic factor remains open. GH-releasing peptide-6 (GHRP-6) is the first hexapeptide studied extensively in humans. More recently, peptidyl superanalogues GHRP-1, GHRP-2 and hexarelin, and nonpeptidyl mimetics, such as the spiroindoline derivative MK-677, have been synthesized and their effects have been studied in humans. The GH-releasing activity of GHS is marked, dose related and reproducible after intravenous, subcutaneous, intranasal and even oral administration. The effect of GHS is partially desensitized but prolonged, intermittent oral administration increases insulin-like growth factor I (IGF-I) levels. The GH-releasing effect of GHS undergoes age-related variations; it increases from birth to puberty, remains similar in adulthood and decreases with ageing. The effect of GHS on GH release is synergistic with that of GHRH, while it is only partially refractory to inhibitory influences, which nearly abolish the effect of GHRH. GHS maintain their GH-releasing activity in some somatotrope hypersecretory states such as acromegaly, anorexia nervosa, hyperthyroidism and critical illness. The GH response to GHS has been reported clear although reduced in GH deficiency, obesity and hypothyroidism, while it is strongly reduced in patients with pituitary stalk disconnection or Cushing's syndrome. In short children, elderly subjects, critically ill patients and even in adult patients with GH deficiency an increase of IGF-I has been shown after GHS treatment. These data indicate that treatment with orally active GHS in humans enhances the activity of the GH-IGF-I axis and could be clinically useful.
Administration, Oral↗
GH response to GHRH combined with pyridostigmine or arginine in different conditions of low somatotrope secretion in adulthood: obesity and Cushing's syndrome in comparison with hypopituitarism.
BACKGROUND: Diagnosing GH deficiency in adults is difficult due to the age-related variations of GH/IGF-I axis and the influence of nutrition. Nowadays, GH replacement is allowed for patients with GH peak to provocative stimuli < 3 micrograms/L. Somatotrope insufficiency is present in hypopituitarism but also in obesity and hypercortisolism. However, to evaluate GH insufficiency in adults is difficult due to variations of GH and IGF-I levels as function of age and nutrition status. METHODS: We aimed to verify the GH response to GHRH (1 microgram/kg i.v.) combined with pyridostigmine (PD, 120 mg p.o.) or arginine (ARG, 0.5 g/kg i.v.), in 26 hypopituitaric patients (GHD), in 11 obese women (OB), in 8 women with Cushing's syndrome (CS), and in 72 control subjects (NS). RESULTS: IGF-l levels in GHD were lower than those in OB (p < 0.01) and in CS (p < 0.01) which, in turn, were lower to those in NS (p < 0.02). In NS, the GH peak responses to GHRH + PD and GHRH + ARG were similar and the minimum normal GH peak was 16.5 micrograms/L. GHD had GH responses similar, lower than those in NS (p < 0.01) and always below the normal limit. However, only 12/20 and 8/14 had peaks < 3 micrograms/L; conventionally, below this limit severe GH deficiency is shown and rhGH replacement is allowed. In OB, the GH responses to GHRH + PD and GHRH + ARG were similar, lower (p < 0.01) and higher (p < 0.01) than those in NS and GHD, respectively. Six out of 11 OB had GH peaks below the normal limits but nobody < 3 micrograms/L. In CS the GH response to GHRH + PD was lower than that to GHRH + ARG (p < 0.01); both these responses were lower than those in NS (p < 0.01) and even in OB (p < 0.01) but higher than those in GHD (p < 0.01). All and 7/8 CS had GH peaks lower than normal limits after PD + GHRH and ARG + GHRH, respectively while 6/8 showed GH peak < 3 micrograms/L after PD + GHRH but only 1 after ARG + GHRH. CONCLUSIONS: Present data demonstrate that the maximal somatotrope secretory capacity is reduced in OB and even more in CS. From a diagnostic point of view, PD + GHRH and ARG + GHRH tests distinguish OB from severe GHD. As hypercortisolism impairs the activity of cholinesterase inhibitors, only ARG + GHRH, but not PD + GHRH is a reliable test to explore the maximal somatotrope secretory capacity in CS. Notably, even with the ARG + GHRH test, in CS the maximal somatotrope secretory capacity is sometimes so reduced as to overlap with that of severe GHD.
Adult↗
IGF-I levels in different conditions of low somatotrope secretion in adulthood: obesity in comparison with GH deficiency.
BACKGROUND: It is widely accepted that IGF-I synthesis and release depend on GH secretion as well as on the nutritional status and vary with age. Based on these premises, after the definition of normal IGF-I levels during lifespan, in a large population of normal subjects of both sexes, our aim was to verify IGF-I levels in large groups of adult patients with GH deficiency or obesity, a condition in which a reduced somatotrope secretion is well known. METHODS: To this goal, IGF-I levels were assayed after acidethanol extraction, in 326 normal subjects (NS, 98 men and 228 women, age 20-80 yrs, BMI 17.9-26.1 kg/m2), 54 patients with GH deficiency (GHD), 24 men and 30 women, age 20-80 yrs, BMI 18.2-27.1 kg/m2), and 195 patients with obesity (OB, 33 men and 162 women, age 17-71 yrs, BMI 27.7-64.9 kg/m2). In NS, IGF-I levels were similar in both sexes and showed a progressive decrease with age. No correlation was present between IGF-I and BMI in NS. Median IGF-I levels and the 3rd centile in NS when considered per decade were: III) 230 and 108.6; IV) 220 and 129.8; V) 150.5 and 72.4; VI) 163.0 and 62.4; VII) 110 and 41.6; VIII) 82 and 24.7 microgram/l. In GHD, IGF-I levels were independent on sex and did not show reduction during lifespan. Mean IGF-I levels in GHD were lower than that in NS (64 +/- 5.9 vs 171.3 +/- 4.8 microgram/l, p < 0.01) and did not correlate with age or BMI. Analyzing individual IGF-I levels, in GHD, in the III and IV decade 21/24 patients had IGF-I levels lower than 3rd centile while, up to the VIII decade, only 10/30 had IGF-I levels below normal limits. In OB, IGF-I levels were independent on sex but, like in NS, showed a progressive decrease with age and were independently, negatively correlated with BMI but not with WHR. Analyzing individual IGF-I levels, in OB, IGF-I levels were below 3rd centile in 10/77 patients in the III and IV decade and in only 8/108 patients up to the VIII decade. Mean IGF-I levels in the whole OB population (179.6 +/- 5.9 microgram/l) were higher (p < 0.01) than those in GHD (64.5 +/- 5.9 microgram/l) while only in the IV decade IGF-I levels in OB group were lower (p < 0.02) than those in NS (184.7 +/- 12.6 microgram/l vs 224.0 +/- 9.2 microgram/l). CONCLUSIONS: In conclusion, present data confirm that IGF-I levels depends on GH secretion as well as on nutritional status, being negatively and independently correlated with age and BMI. IGF-I assay is not a reliable test for the diagnosis of GH deficiency in adulthood though it gives good discrimination between GHD and normal subjects up to 40 yrs of age. In spite of low GH secretion, IGF-I levels are only slightly reduced in obesity, probably as consequence of hyperinsulinism.
Adolescent↗
Effects of histaminergic antagonists on the GH-releasing activity of GHRH or hexarelin, a synthetic hexapeptide, in man.
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 micrograms/Hg iv) or Hexarelin (HEX, 2 micrograms/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 vs 2.5 +/- 1.1 micrograms/l, p < 0.02, n = 7; 34.7 +/- 7.9 vs 3.9 +/- 1.5 micrograms/l, p < 0.02, n = 6) lower (p < 0.05) than that elicited by HEX (49.1 +/- 8.5 vs 3.9 +/- 1.0 micrograms/l, p < 0.01, n = 7; 48.7 +/- 8.9 vs 3.2 +/- 0.8 micrograms/l, p < 0.01, n = 6). DPH inhibited the GH response to both GHRH (AUC: 453.9 +/- 104.7 vs 1223.7 +/- 202.6 micrograms*min/l, p < 0.05) and HEX (922.0 +/- 215.4 vs 1636.4 +/- 267.5 micrograms*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 vs 1115.3 +/- 255.6 micrograms*min/l) as well as the somatotrope responsiveness to HEX (1163.2 +/- 188.7 vs 1427.3 +/- 323.3 mg*min/l). HEX also significantly increased PRL (13.9 +/- 3.1 vs 6.5 +/- 0.8 micrograms/l, p < 0.03), ACTH (31.1 +/- 6.6 vs 16.6 +/- 2.9 pg/ml, p < 0.02) and cortisol (96.6 +/- 6.3 vs 82.2 +/- 6.2 micrograms/L, p < 0.05) levels. PRL, ACTH and cortisol responses to HEX were unaffected by DPH (536.5 +/- 85.6 vs 599.5 +/- 129.2 micrograms*min/l, 1068.5 +/- 306.0 vs 1282.8 +/- 222.0 pg*min/ml and 4277.4 +/- 588.4 vs 4738.3 +/- 355.3 micrograms*min/l, respectively) as well as by TRF (621.3 +/- 110.4 vs 530.3 +/- 131.4 micrograms*min/L, 972.4 +/- 189.6 vs 1060.2 +/- 224.7 pg*min/ml and 6203.8 +/- 1329.5 vs 5141.2 +/- 295.5 micrograms*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.
Administration, Oral↗