Low Dose Hexarelin and Growth Hormone (GH)-Releasing Hormone as a Diagnostic Tool for the Diagnosis of GH Deficiency in Adults: Comparison with Insulin-Induced Hypoglycemia Test1

GH deficiency (GHD) in adults must be shown by provocative testing of GH secretion. Insulin-induced hypoglycemia (ITT) is the test of choice, and severe GHD, treated with recombinant human GH replacement, is defined by a GH peak response to ITT of less than 3 μg/L. GHRH plus arginine (ARG) is a more provocative test and is as sensitive as ITT provided that appropriate cut-off limits are assumed. GH secretagogues are a family of peptidyl and nonpeptidyl GH-releasing molecules that strongly stimulate GH secretion and, even at low doses, truly synergize with GHRH. Our aim was to verify the diagnostic reliability of the hexarelin (HEX; 0.25 μg/kg, iv) and GHRH (1 μg/kg, iv) test for the diagnosis of adult GHD. To this goal, in the present study we 1) defined the normal ranges of the GH response to GHRH+HEX in a group of normal young adult volunteers (NS; n = 25; 18 men and 7 women; age, 28.5 ± 0.6 yr) and in 11 of them verified its reproducibility in a second session, and 2) compared the GH response to GHRH+HEX with that to ITT in a group of normal subjects (n = 33; 12 men and 21 women; age, 34.1 ± 1.5 yr) and hypopituitaric adults with GHD (n = 19; 10 men and 9 women; age, 39.9 ± 2.2 yr; GH peak <5 μg/L after ITT). The GH response to GHRH+ARG was also evaluated in all GHD and in 77 normal subjects (40 men and 37 women; age, 28.1 ± 0.6 yr). The mean GH peak after GHRH+HEX in NS was 83.6 ± 4.5 μg/L; the third and first percentile limits of the normal GH response were 55.5 and 51.2 μg/L, respectively). The GH response to GHRH+HEX in NS showed good intraindividual reproducibility. In GHD the mean GH peak after GHRH+HEX (2.6 ± 0.7 μg/L) was similar to that after GHRH+ARG (3.6 ± 1.0 μg/L), and both were higher (P < 0.001) than that after ITT (0.6± 0.1 μg/L); the GH responses to GHRH+HEX were positively associated with those to ITT and GHRH+ARG. Analyzing individual GH responses, 100% had severe GHD after ITT (GH peak, <3 μg/L). After GHRH+HEX all GHD had GH peaks below the third percentile limit of normality appropriate for this test (i.e. 55.5 μg/L). Thirteen of 19 (68.4%) GHD subjects had GH peaks below 3 μg/L after GHRH+HEX but all 19 (100%) had GH peaks below the first percentile limit of normality (i.e. 51.2 μg/L). The GH responses to GHRH+HEX were highly concordant with those after GHRH+ARG. In conclusion, the present results define normal limits of the GH response to stimulation with low dose HEX+GHRH in normal adults and show that this test is as sensitive as ITT for the diagnosis of adult GHD provided that appropriate cut-off limits are considered.

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Comparison between Insulin-Induced Hypoglycemia and Growth Hormone (GH)-Releasing Hormone + Arginine as Provocative Tests for the Diagnosis of GH Deficiency in Adults1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.5.4837 ◽

1998 ◽

Vol 83 (5) ◽

pp. 1615-1618 ◽

Cited By ~ 3

Author(s):

G. Aimaretti ◽

G. Corneli ◽

P. Razzore ◽

S. Bellone ◽

C. Baffoni ◽

...

Keyword(s):

Gh Deficiency ◽

Clinical Context ◽

Provocative Test ◽

Female Age ◽

Gh Secretion ◽

The Third ◽

Independent Test ◽

The Mean ◽

Normal Adults ◽

Similar Peak

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 μg/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 μg/L, whereas in our lab, that to GHRH+ARG is 16.5 μg/L. In hypopituitary adults, the mean peak GH response to ITT (1.5 ± 0.2 μg/L, range: 0.1–8.5μ g/L) was lower (P < 0.001) than that to GHRH+ARG (3.0 ± 0.4 μg/L, range 0.1–12.0 μg/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 μg/L after ITT; moreover, 3 other patients (7%) had GH peaks, after ITT, higher than 3 μg/L. On the other hand, after GHRH+ARG, all patients had GH peaks lower than 16.5 μg/L, whereas 21/40 (52.5%) had GH peaks higher than 3 μg/L. Because 3 μg/L is the arbitrary cut-off for ITT, the third centile limit of which is 5μ g/L, we arbitrarily considered 9 μg/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.

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Retesting Young Adults with Childhood-Onset Growth Hormone (GH) Deficiency with GH-Releasing-Hormone-Plus-Arginine Test1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.85.10.6858 ◽

2000 ◽

Vol 85 (10) ◽

pp. 3693-3699

Author(s):

G. Aimaretti ◽

C. Baffoni ◽

S. Bellone ◽

L. Di Vito ◽

G. Corneli ◽

...

Keyword(s):

Young Adults ◽

Gh Deficiency ◽

Statistical Significance ◽

Young Patients ◽

Normal Subjects ◽

Childhood Onset ◽

Gh Treatment ◽

Provocative Test ◽

Gh Secretion ◽

The Mean

Within an appropriate clinical context, severe GH deficiency (GHD) in adults has to be defined biochemically by provocative testing of GH secretion. Patients with childhood-onset GHD need retesting in late adolescence or young adulthood to verify whether they have to continue recombinant human GH treatment. GHRH + arginine (GHRH+ARG) is the most reliable alternative to the insulin-induced hypoglycemia test (ITT) as a provocative test for the diagnosis of GHD in adulthood, provided that appropriate cut-off limits are assumed (normal limits, 16.5 μg/L as 3rd and 9.0 μg/L as 1st centile). We studied the GH response to a single GHRH (1 μg/kg iv) + ARG (0.5 g/kg iv) test in 62 young patients who had undergone GH replacement in childhood, based on the following diagnosis: 1) organic hypopituitarism with GHD (oGHD)[ n = 18: 15 male (M), 3 female (F); age, 26.8 ± 2.2 yr; GH peak < 10 μg/L after two classical tests]; 2) idiopathic isolated GHD (iGHD) [n = 23 (15 M, 8 F); age, 23.0 ± 1.5 yr; GH peak < 10 μg/L after two classical tests]; and 3) GH neurosecretory dysfunction (GHNSD) [n = 21 (10 M, 11 F); age, 25.1 ± 1.6 yr; GH peak > 10 μg/L after classical test but mGHc < 3 μg/L]. The GH responses to GHRH+ARG in these groups were also compared with that recorded in a group of age-matched normal subjects (NS) [n = 48 (20 M, 28 F); age, 27.7 ± 0.8 yr]. Insulin-like growth factor I levels in oGHD subjects (61.5 ± 13.7μ g/L) were lower (P < 0.001) than those in iGHD subjects (117.2 ± 13.1 μg/L); the latter were lower than those in GHNSD subjects (210.2 ± 12.9 μg/L), which, in turn, were similar to those in NS (220.9 ± 7.1 μg/L). The mean GH peak after GHRH+ARG in oGHD (2.8 ± 0.8 μg/L) was lower (P < 0.001) than that in iGHD (18.6 ± 4.7μ g/L), which, in turn, was clearly lower (P < 0.001) than that in GHNSD (31.3 ± 1.6 μg/L). The GH response in GHNSD was lower than that in NS (65.9 ± 5.5 μg/L), but this difference did not attain statistical significance. With respect to the 3rd centile limit of GH response in young adults (i.e. 16.5 μg/L), retesting confirmed GHD in all oGHD, in 65.2% of iGHD, and in none of the GHNSD subjects. With respect to the 1st centile limit of GH response (i.e. 9.0 μg/L), retesting demonstrated severe GHD in 94% oGHD and in 52.1% of iGHD. All oGHD and iGHD with GH peak after GHRH+ARG lower than 9 μg/L had also GH peak lower than 3 μg/L after ITT. In the patients in whom GHD was confirmed by retesting, the mean GH peak after GHRH+ARG was higher than that after ITT (3.4 ± 0.5 vs. 1.9 ± 0.4). In conclusion, given appropriate cut-off limits, GHRH+ARG is as reliable as ITT for retesting patients who had undergone GH treatment in childhood. Among these patients, severe GHD in adulthood is generally confirmed in oGHD, is frequent in iGHD, but never occurs in GHNSD.

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Comparisons among old and new provocative tests of GH secretion in 178 normal adults

Acta Endocrinologica ◽

10.1530/eje.0.1420347 ◽

2000 ◽

pp. 347-352 ◽

Cited By ~ 69

Author(s):

G Aimaretti ◽

C Baffoni ◽

L DiVito ◽

S Bellone ◽

S Grottoli ◽

...

Keyword(s):

Low Dose ◽

Adult Population ◽

Ideal Body Weight ◽

Normative Values ◽

Gh Secretion ◽

The Third ◽

Ideal Body ◽

The Mean ◽

Age Range ◽

Normal Adults

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.

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Ghrelin test for the assessment of GH status in successfully treated patients with acromegaly

Acta Endocrinologica ◽

10.1530/eje.1.02148 ◽

2006 ◽

Vol 154 (5) ◽

pp. 659-666 ◽

Cited By ~ 9

Author(s):

S Pekic ◽

M Doknic ◽

D Miljic ◽

M Joksimovic ◽

J Glodic ◽

...

Keyword(s):

Gh Deficiency ◽

Provocation Test ◽

Tolerance Test ◽

Oral Glucose ◽

Provocative Test ◽

Gh Secretion ◽

Control Subjects ◽

Igf I ◽

Secretory Capacity ◽

Igfbp 3

Objective: Posttreatment assessment of disease activity and definition of cure of acromegaly, using measurement of GH secretion, remains problematic. Furthermore, with our efforts to achieve tight biochemical control of the disease it is foreseeable that a proportion of patients may be rendered GH deficient, thus requiring testing for GH deficiency. The aim of our study was to evaluate residual GH secretion in cured patients with acromegaly. Design and methods: At baseline, circulating GH, IGF-I, IGFBP-3, leptin and lipid (cholesterol and tri-glycerides) levels were measured in 33 acromegalic patients nine years after treatment with surgery of whom 6 were additionally irradiated. Two tests were performed: the GH suppression test - oral glucose tolerance test (OGTT) and the GH provocation test - ghrelin test (1 μg/kg i.v. bolus) and the results were compared with 11 age- and sex-matched control subjects. Results: According to the consensus criteria (normal IGF-I levels and post-OGTT GH nadir <1 μg/l), 21 treated acromegalic patients were cured, 6 had discordant IGF-I and GH nadir values during OGTT, while 6 had persistent acromegaly. After the GH provocative test with ghrelin (cut-off for severe GH deficiency is GH <3 μg/l), we detected 9 severely GH deficient patients (GHD) among 21 cured acromegalic patients. Mean GH peak (±s.e.m.) response to the ghrelin test in GHD acromegalics was significantly lower compared with acromegalics with sufficient GH secretory capacity and control subjects (1.2 ± 0.2 μg/l vs 20.1 ± 2.4 μg/l vs 31.1 ± 2.5 μg/l respectively, P<0.0001). Mean IGF-I and IGFBP-3 levels were not different between GHD and GH-sufficient cured acromegalics. Leptin levels and body mass index (BMI) were significantly higher in GHD male acromegalics compared with GH-sufficient male acromegalics. GHD female acromegalics tended to have higher BMIs while leptin levels were not different. Conclusions: The assessment of residual GH secretory capacity by the GH provocation test is necessary in the long-term follow-up of successfully treated acromegalics since a large proportion of these patients are rendered GH deficient.

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Isotope Studies in Normal and Diseased Knee Joints: 99mTc Uptake Related to Clinical Assessment and to Synovial Perfusion Measured by the 133Xe Clearance Technique

Clinical Science ◽

10.1042/cs0400327 ◽

1971 ◽

Vol 40 (4) ◽

pp. 327-336 ◽

Cited By ~ 9

Author(s):

W. C. Dick ◽

S. D. Deodhar ◽

Carol J. Provan ◽

G. Nuki ◽

W. W. Buchanan

Keyword(s):

Rheumatoid Arthritis ◽

Normal Subjects ◽

Knee Joints ◽

133Xe Clearance ◽

Normal Limits ◽

Human Volunteers ◽

Normal Human ◽

Clinical Indices ◽

Isotope Studies ◽

The Mean

1. Uptake of intravenously administered radioactive technetium (99mTc) was measured over the knee joints in normal human volunteers, in patients with osteoarthritis and in groups of synovectomized and unoperated patients with rheumatoid arthritis. The uptake was compared with clinical indices of inflammation (pain, tenderness swelling and stiffness), and the clearance rate of intra-articularly injected radioactive xenon (133Xe). The 99mTc uptakes were found to be unrelated to the isotope dose and the day-to-day reproducibility was acceptable. 2. The mean uptake of 99mTc was within normal limits in osteoarthritis. Both in synovectomized and in unoperated rheumatoid arthritis 99mTc uptake was significantly higher than in normal subjects. 3. Of the clinical indices studied significant correlation of 99mTc uptake was found with pain and swelling in all groups of patients studied. 4. Faster clearance of 133Xe in unoperated rheumatoid arthritis correlated well with the higher 99mTc uptakes. 5. The results confirm that 99mTc uptakes are raised in inflammatory arthritis but not in degenerative arthritis. The relation of 99mTc uptake to the clinical indices of inflammation and to the 133Xe clearance from the joint is discussed.

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Reproducibility of the growth hormone response to stimulation with growth hormone-releasing hormone plus arginine during lifespan

Acta Endocrinologica ◽

10.1530/eje.0.1350568 ◽

1996 ◽

Vol 135 (5) ◽

pp. 568-572 ◽

Cited By ~ 56

Author(s):

Maria Rosa Valetto ◽

Jaele Bellone ◽

Claudia Baffoni ◽

Paola Savio ◽

Gianluca Aimaretti ◽

...

Keyword(s):

Growth Hormone ◽

Gh Deficiency ◽

Normal Subjects ◽

Individual Variability ◽

Hormone Response ◽

Female Age ◽

Releasing Hormone ◽

Gh Secretion ◽

Subject Variability ◽

Within Subject Variability

Valetto MR, Bellone J, Baffoni C, Savio P, Aimaretti G, Gianotti L, Arvat E, Camanni F, Ghigo E. Reproducibility of the growth hormone response to stimulation with growth hormone-releasing hormone plus arginine during lifespan. Eur J Endocrinol 1996;135:568–72. ISSN 0804–4643 The reliability and reproducibility of provocative stimuli of growth hormone (GH) secretion in the diagnosis of GH deficiency are still controversial both in childhood and in adulthood. The combined administration of GH-releasing hormone (GHRH) and arginine (ARG), which likely acts via inhibition of hypothalamic somatostatin release, is one of the most potent stimuli known so far and has been proposed recently as the best test to explore the maximal somatotrope capacity of somatotrope cells. However, it is well known that, usually, provocative stimuli of GH secretion suffer from poor reproducibility and that of the GHRH + ARG test has still to be verified. We aimed to verify the between- and within-subject variability of the GH response to the GHRH + ARG test in normal subjects during their lifespan as well as in hypopituitaric patients with GH deficiency (GHD). In 10 normal children (C: six male and four female, age 12.3 ± 0.9 years, body mass index (BMI) = 16.6 ± 0.7 kg/m2, pubertal stages I-III), 18 normal young adults (Y: ten male and eight female, age 31.1 ± 1.3 years, BMI = 21.4 ± 0.4 kg/m2), 12 normal elderly subjects (E: two male and ten female, age 74.4 ± 1.8 years, BMI= 22.6 ± 0.6 kg/m2) and 15 panhypopituitaric GH-deficient patients (GHD: nine male and six female, age 40.9 ± 4.1 years, BMI= 22.7 ± 1.0 kg/m2), we studied the inter- and intra-individual variability of the GH response to GHRH (1 μg/kg iv) + ARG (0.5 g/kg iv) in two different sessions at least 3 days apart. The GH responses to GHRH + ARG in C (1st vs 2nd session: 61.6 ± 8.1 vs 66.5 ± 9.4 μg/l), Y (70.4 ± 10.1 vs 76.2 ± 10.7 μg/l) and E (57.9 ± 14.8 vs 52.1 ± 8.0 μg/l) were similar and reproducible in all groups. The somatotrope responsiveness to GHRH + ARG also showed a limited within-subject variability (r = 0.71, 0.90 and 0.89 and p < 0.02, 0.0005 and 0.0005 for C, Y and E, respectively). Similarly in GHD, the GH response to the GHRH + ARG test showed a good inter- (1st vs 2nd session: 2.3 ± 0.5 vs 2.2 ± 0.6 μg/l) and intra-individual reproducibility (r = 0.70, p < 0.005). The GHRH + ARG-induced GH responses in GHD were markedly lower (p < 0.0005) than those in age-matched controls and no overlap was found between GH peak responses in GHD and normal subjects. In normal subjects, the GH response to GHRH + ARG is very marked, independent of age and shows limited inter- and intra-individual variability. The GH response to the GHRH + ARG test is strikingly reduced in panhypopituitaric patients with GHD, in whom the low somatotrope responsiveness is reproducible. Thus, these findings strengthen the hypothesis that GHRH + ARG should be considered the most reliable test to evaluate the maximal secretory capacity of somatotrope cells and to distinguish normal subjects from GHD patients in adulthood. E. Ghigo, Divisione di Endocrinologia, Ospedale Molinette, C.so Dogliotti 14, 10126, Torino, Italy

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Growth hormone-releasing hormone in the diagnosis and treatment of growth hormone deficient children

Acta Endocrinologica ◽

10.1530/acta.0.112s123 ◽

1986 ◽

Vol 113 (4_Suppl) ◽

pp. S123-S129

Author(s):

R.J.M. ROSS ◽

A. GROSSMAN ◽

G.M. BESSER ◽

M.O. SAVAGE

Keyword(s):

Growth Hormone ◽

Linear Growth ◽

Gh Deficiency ◽

Venous Blood ◽

Alternative Therapy ◽

Normal Subjects ◽

Growth Hormone Releasing Hormone ◽

Releasing Hormone ◽

Gh Secretion ◽

Depot Preparations

ABSTRACT A growth hormone-releasing hormone (GHRH) has recently been extracted and synthesised, and appears to be identical to human hypothalamic GHRH. Immunoreactive GHRH is found in the venous blood of normal subjects and GH-deficient children, but is probably not hypothalamic in origin and therefore not important in GH regulation. GHRH is a potent specific stimulator of GH secretion in man, and provides a valuable diagnostic test in differentiating hypothalamic from pituitary causes of GH deficiency. Preliminary data suggests that GHRH may promote linear growth in some GH deficient children. GHRH may well prove an important alternative therapy for GH deficient children especially if depot preparations or intranasal administration prove effective.

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Mutation Analysis of the Muscarinic Cholinergic Receptor Genes in Isolated Growth Hormone Deficiency Type IB

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-0512 ◽

2009 ◽

Vol 94 (7) ◽

pp. 2565-2570 ◽

Cited By ~ 3

Author(s):

Ali Mohamadi ◽

Marco Martari ◽

Cindy D. Holladay ◽

John A. Phillips ◽

Primus E. Mullis ◽

...

Keyword(s):

Gh Deficiency ◽

Direct Sequencing ◽

Muscarinic Acetylcholine Receptor ◽

Autosomal Recessive Inheritance ◽

Normal Subjects ◽

Cholinergic Receptor ◽

Hormone Deficiency ◽

Gh Secretion ◽

Muscarinic Cholinergic ◽

Deficiency Type

Background: Isolated GH deficiency (IGHD) is familial in 5–30% of patients. The most frequent form (IGHD-IB) has autosomal recessive inheritance, and it is known that it can be caused by mutations in the GHRH receptor (GHRHR) gene or in the GH gene. However, most forms of IGHD-IB have an unknown genetic cause. In normal subjects, muscarinic cholinergic stimulation causes an increase in pituitary GH release, whereas its blockade has the opposite effect, suggesting that a muscarinic acetylcholine receptor (mAchR) is involved in stimulating GH secretion. Five types of mAchR (M1–M5) exist. A transgenic mouse in which the function of the M3 receptor was selectively ablated in the central nervous system has isolated GH deficiency similar to animals with defective GHRH or GHRHR gene. Objective: We hypothesized that mAchR mutations may cause a subset of familial IGHD. Patients/Methods: After confirming the expression of M1–M5 receptor mRNA in human hypothalamus, we analyzed the index cases of 39 families with IGHD-IB for mutations in the genes encoding for the five receptors. Coding sequences for each of the five mAchRs were subjected to direct sequencing. Results: In one family, an affected member was homozygous for a M3 change in codon 65 that replaces valine with isoleucine (V65I). The V65I receptor was expressed in CHO cells where it had normal ability to transmit methacholine signaling. Conclusion: mAchR mutations are absent or rare (less than 2.6%) in familial IGHD type IB.

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Plasma growth hormone (GH) and somatomedin C response to continuous growth hormone-releasing factor (GRF) infusion in patients with GH deficiency

Acta Endocrinologica ◽

10.1530/acta.0.1100017 ◽

1985 ◽

Vol 110 (1) ◽

pp. 17-23 ◽

Cited By ~ 4

Author(s):

Naomi Hizuka ◽

Kazue Takano ◽

Kazuo Shizume ◽

Izumi Tanaka ◽

Noriko Honda ◽

...

Keyword(s):

Growth Hormone ◽

Bolus Injection ◽

Gh Deficiency ◽

Saline Infusion ◽

Pulse Area ◽

Continuous Growth ◽

Somatomedin C ◽

Gh Secretion ◽

The Mean ◽

Plasma Gh

Abstract. Pituitary growth hormone (GH) responses during a 10-h iv infusion of saline or human GH-releasing factor (hGRF-44) at 500 ng/kg/h, followed by an iv bolus injection of hGRF-44 at 2 μg/kg body weight, were studied in 10 patients with GH deficiency. During saline infusion in 4 patients, small plasma GH increase were observed in 2 patients. However, during hGRF infusion in 6 patients, up to 4 or 13 pulses of GH secretion were observed. The mean integrated GH pulse area during hGRF infusion was 22.5 ± 5.2 (se) ng/ml × h, which was greater than that obtained during saline infusion. Plasma somatomedin C levels did not increase after hGRF infusion. After saline or hGRF infusion all patients responded to an iv bolus injection of the peptide. These results indicate that hGRF infusion augments GH secretion by increasing the number and amplitude of GH pulses and that the infusion does not cause pituitary somatotrophs to lose their capacity to respond to hGRF subsequently.

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Acylated ghrelin as a provocative test for the diagnosis of GH deficiency in adults

Acta Endocrinologica ◽

10.1530/eje-12-0584 ◽

2013 ◽

Vol 168 (1) ◽

pp. 23-30 ◽

Cited By ~ 20

Author(s):

Valentina Gasco ◽

Guglielmo Beccuti ◽

Chiara Baldini ◽

Nunzia Prencipe ◽

Stellina Di Giacomo ◽

...

Keyword(s):

Gh Deficiency ◽

Characteristic Curve ◽

Tolerance Test ◽

Acylated Ghrelin ◽

Diagnostic Reliability ◽

Provocative Test ◽

Insulin Tolerance ◽

History Of ◽

The One ◽

Overweight Subjects

ObjectiveInsulin tolerance test (ITT) is the test of reference for the diagnosis of adult GH deficiency (GHD), although GHRH in combination with arginine (ARG) or GH secretagogues are considered equally reliable tests. Testing with GH secretagogue alone is, anyway, a potent stimulus exploring the integrity of hypothalamic pathways controlling somatotropic function. We therefore aimed to determine the diagnostic reliability of testing with ghrelin, the natural GH secretagogue.MethodsWe studied the GH response (every 15 min from −15 to +120 min) to acylated ghrelin (1 μg/kg i.v. at 0 min) in 78 patients with a history of pituitary disease (49 male, 29 female; age (mean±s.d.): 52.1±18.7 years; BMI: 26.7±5.3 kg/m2). The lack of GH response to GHRH+ARG and/or ITT was considered the gold standard for the diagnosis of GHD. The best GH cut-off to ghrelin test, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using the receiver-operating characteristic curve analysis.ResultsThe best GH cut-off to ghrelin test was 7.3 μg/l in lean subjects (SE 88.2%, SP 90.9%), 2.9 μg/l in overweight subjects (SE 92.6%, SP 100%) and 0.6 μg/l in obese subjects (SE 50%, SP 100%). The diagnostic accuracy was 89.3, 94.1 and 62.5% respectively.ConclusionsOur data show that testing with acylated ghrelin represents a reliable diagnostic tool for the diagnosis of adult GHD, in lean and overweight subjects, if appropriate cut-off limits are assumed. Obesity strongly reduces GH response to ghrelin, GH weight-related cut-off limit and diagnostic reliability of the test.

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