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Role of ghrelin in regulation of growth hormone secretion by Ghrelin-pituitary-GH axis linkage.

Introduction

Ghrelin is the endogenous ligand of the growth hormone secretagogue receptor (GHSR) and is the first hormone linking gastrointestinal-pituitary axis. [1-4] In collaboration with GHRH and somatostatin, ghrelin may well be the third peptidergic factor involved in GH regulation. [5] Ghrelin exerts pleiotropic actions, consistent with the widespread distribution of ghrelin and GHS-R expression in central and peripheral tissues. [6] In mammals, ghrelin has been shown to exhibit a range of actions on cardiovascular, gastrointestinal, and pancreatic functions, as well as lipogenic and glucogenic actions. [7-9] In mammals, it is suggested that the main physiological function of ghrelin is to stimulate growth hormone release from the pituitary and increase food intake. [10] Actions of ghrelin on GH secretion provide a strong force for envisioning that one of the major role of ghrelin could be the regulation of secretion of GH. This review addresses the timely topic on a gut hormone ghrelin and its role in the regulation of growth hormone secretion and we intend to explore the intriguing dimensions on the possible physiological role of the Ghrelin /GH system. The review has put forth the findings of the effect of human ghrelin as well as Growth Hormone Releasing Hormone (GHRH) and synthetic Ghrelin on GH secretion. This study is to comprehensively review the existing literature on the effects of ghrelin on secretion of growth hormone.

Materials and Methods

Criteria for considering studies for this review:

* Types of studies: Randomised controlled trials or nonrandomised trials were included in the review that evaluated one or both the outcome measures.

* Types of participants: Participants were healthy adult male volunteers.

* Types of interventions: The active intervention was Ghrelin, marketed under any brand name. The review included trials comparing the effect of Ghrelin in different doses and different types. Also trials comparing the effect of ghrelin vs GHRH on the release of growth hormone were included in the review.

* Types of outcome measures: (i) Primary outcomes: Secretion of growth hormone; (ii) Secondary outcomes: Change in body weight.

Search methods for identification of studies: Searches were not conducted for trials before 1999 because ghrelin was discovered in 1999. We searched the following electronic databases: The Cochrane Library; MEDLINE; Pub Med; Science Citation Index; BIOSIS, EMBASE, CINAHL. The references of all identified studies were inspected for further randomized controlled trials. No language restrictions were applied. A manual search was performed for medical journals. Experts, authors and manufacturers were contacted to seek clarifications and asked to contribute published and unpublished material.

Data collection and analysis: Selection of studies: Two reviewers independently screened the title and abstracts from searches on electronic databases to identify those articles relevant to this review. Full articles were retrieved for further assessment. All full text articles were read independently by two reviewers to make a decision on inclusion. Disagreements were resolved by discussion and by seeking the opinion of the third reviewer.

Data extraction and management: A data extraction form was designed to include: design, details of the participants (age, BMI), Intervention (intervention groups, dosage, duration and mode of administration of the intervention), outcome measures as detailed above and adverse events. Data were extracted by two reviewers independently. Additional unpublished data were also obtained by contacting the authors of the paper

Analysis issues: As the trials were not carried out according to a common protocol and there were variations in clinical settings, dosage; etc. Meta-analysis could not be performed.

Results

The literature searches identified 15 references that described 10 potentially relevant trials. Eight publications were excluded because they varied in participant characteristics and intervention strategy. Seven trials (Table 1) involving 83 participants met the inclusion criteria and were included in this review. These trials are described in the characteristics of included studies table. Three trials were done in Japan and one each in Italy, USA, Austria and Yugoslavia. All the trials were randomized. Trial size ranged from 6 to 32 participants. Six trials administered ghrelin and one trial administered anamorelin. The daily dose used in these trials ranged between 0.08 to 5 [micro]g/kg. Reported outcomes included amount of/ change in release of growth hormone, change in body weight and adverse effects of ghrelin. Mean age of the included patients in each trial ranged from 25 to 40 years.

Effects of interventions: Three studies (Peino et al, Maier et al, Tokoyo et al) studied the effect of different doses of ghrelin on secretion of growth hormone. Ghrelin at the dose of 0.08, 0.25, 0.5 and 1.0 [micro]g/kg elicited a peak GH secretion that was not significantly different than placebo group. The trials found that Ghrelin is a potent releaser of GH in normal individuals, with a dose-response pattern of operation. Takaya et al studied the time course of serum GH levels after various doses of ghrelin. All doses (0.2 [micro]g/kg, 1.0 [micro]g/kg and 5.0 [micro]g/kg) produced monophasic responses and reached the peak values at 30 min. After administration of 0.2 [micro]g/kg and 1.0 [micro]g/kg of ghrelin, GH levels returned to basal values by 180 min while 5.0 [micro]g/kg dose of ghrelin, the value was still higher than the basal level.

Two trials (Avat et al and Micic et al) compared the potencies of ghrelin with GHRH, GHRP and synthetic ghrelin like Hexarelin (HEX) for secretion of GH and also the effect of co-administration of these peptides. They found that the GH response to ghrelin was higher (P < 0. 01) than GHRH and even significantly higher (P < 0.05) than that after HEX. In Arvat's trial; GH response to ghrelin plus HEX was similar to that recorded after ghrelin alone ; i.e the endocrine responses to ghrelin were not modified by the co-administration with HEX while in Hataya's trial, mean GH response of two peptide combinations were more than the summed mean GH response values of each peptide alone (P < 0.05). Micic's study found that on clinical grounds, GHRP-6 is less potent but more efficacious at releasing GH and that on molar basis the order of potency is ghrelin > GHRH> GHRP-6. Also, the study showed that a previous injection of saturating doses of GHRP-6 partially, but not totally, desensitized the ghrelin-mediated GH secretion.

Garcia studied the effect of different doses of Anamorelin on GH levels and body weight and found that Anamorelin significantly increases GH levels in dose-related pattern and also increases body weight with good tolerability and selectivity. Maier studied the effect of autonomic system on the ghrelin and found that atropine alone significantly reduced fasting ghrelin levels, whereas under pyridostigmine alone did not alter ghrelin levels. Ghrelin in combination with atropine induced significantly reduced GH concentrations compared with ghrelin administration alone for both ghrelin doses, whereas ghrelin-induced GH peak concentrations were not enhanced by pyridostigmine treatment.

No side effects were reported in three studies while three studies noted adverse effects of transient facial flushing, warm sensation in upper trunk and/or bowel movements for few minutes.

Discussion

Ghrelin appears to be highly potent, probably being the strongest GH secretagogue when administered alone. [18] The results of the studies show that, in humans, ghrelin releases more GH than GHRH, GHRP-6 and even than a non-natural GHS, such as HEX. [19] It is not yet established if this is due to a higher affinity for the GHS-receptor or to prolonged plasma half-life. The endocrine responses to ghrelin are not modified by its co-administration with HEX which indicates the reproducibility of somatotroph responsiveness to ghrelin. Along with GHRH, ghrelin has a synergistically effect on GH secretion which agrees with the synergism between non-natural GHS and GHRH [20] and indicates that these peptides act, at least partially, via different mechanisms. In normal individuals, ghrelin is partially resistant to a previous administration of GHRP-6 and to the ensuing GH rise for which two types of cellular responses have been proposed: the homologous desensitization effects and the cross-talk observed between the GHRH receptor and the GHS receptor. Homologous desensitization has been described in vivo for GHRH-mediated GH secretion, wherein; a first administration of GHRH leads to a reduced or absent GH response to a second GHRH dose, provided that the two challenges are separated by few hours. [21] The basis of the homologous desensitization phenomenon is most probably a down-regulation of the cell membrane receptor, internalized after activation, and requires more than 2 h before being recycled towards the membrane again. Previous administration of GHSs such as hexarelin or GHRP-6 leads, 2 h later, to a near complete blockade of GHRH-mediated GH secretion, a finding called heterologous desensitization. [22]

Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl compounds that are believed to stimulate the release of GH by a direct effect on the pituitary somatotroph and by stimulation of growth hormone-releasing hormone (GHRH) release and/or via functional antagonism of somatostatin (SRIH) tone. [24] They also binds and activate hypothalamic GHS-R. Maier's study shows that cholinergic blockade with ATR suppresses ghrelin plasma concentrations and modulation of the cholinergic system with ATR, but not PD, influences the ability of different ghrelin dosages to induce GH release. The main influence of PD on GH release is via lowering somatostatinergic tone in the median eminence of the hypothalamus. [24] The non-additive effect of ghrelin and PD could be attributed to the fact that both substances act on the same pathway. The study provides evidence that interplay exists between ghrelin and the cholinergic system in humans. The adverse effects reported in the trials were mild, infrequent, and transient thereby indicating that ghrelin is well tolerated and can be used therapeutically. Limitations of our review pertain to the potential incompleteness of the reviewed evidence. We aimed to identify all RCTs on the topic. However, only a few studies provided data on our primary outcome variable and we could not find trials after 2009. We did not restrict our searches by publication language, and are therefore confident that our strategy minimised bias. We only included data from clinical trials that were randomised. Nevertheless, the extent of methodological rigor varied among trials.

Conclusion

The best evidence that is available suggests that ghrelin significantly increases GH, compared with placebo, GHRH and HEX and can be used as an adjunctive treatment. Reported adverse events were infrequent, mild, and transient. Future trials should report clinical as well as physiological outcomes. The role of ghrelin in the regulation of GH and its clinical implication needs further assessment.

References

[1.] Mear Y, Enjalbert A, Thirion S. GHS-R1a constitutive activity and its physiological relevance. Front Neurosci 2013;7:87.

[2.] Pradhan G, Samson SL, Sun Y. Ghrelin: much more than a hunger hormone. Curr Opin Clin Nutr Metab Care 2013;16(6):619-24.

[3.] Albarran-Zeckler RG, Smith RG. The ghrelin receptors (GHS-R1a and GHS-R1b). Endocr Dev 2013;25:5-15.

[4.] Muller TD, Tschop MH. Ghrelin--a key pleiotropic hormone-regulating systemic energy metabolism.Endocr Dev 2013;25:91-100.

[5.] Carreira MC, Crujeiras AB, Andrade S, Monteiro MP, Casanueva FF.Ghrelin as a GH-releasing factor. Endocr Dev 2013;25:49-58.

[6.] Bowers CY. History to the discovery of ghrelin. Methods Enzymol 2012;514:3-32.

[7.] Rizzo M, Rizvi AA, Sudar E, Soskic S, Obradovic M, Montalto G, et al. A review of the cardiovascular and anti-atherogenic effects of ghrelin. Isenovic ER.Curr Pharm Des 2013;19(27):4953-63.

[8.] Chen CY, Tsai CY. Ghrelin and motilin in the gastrointestinal system. Curr Pharm Des 2012;18(31):4755-65.

[9.] Granata R, Ghigo E. Products of the ghrelin gene, the pancreatic ([beta]-cell and the adipocyte. Endocr Dev 2013; 25:144-56.

[10.] Verhulst PJ, Depoortere I. Ghrelin's second life: from appetite stimulator to glucose regulator. World J Gastroenterol 2012;18(25):3183-95.

[11.] Peino R, Baldelli R, Rodriguez-Garcia J, Rodriguez-Segade S, Kojima M, Kangawa K, et al. Ghrelin-induced growth hormone secretion in humans. Eur J Endocrinol 2000;143(6):R11-4.

[12.] Arvat E, Maccario M, Vito L, Broglio F, Benso A, Gottero C, et al. Endocrine Activities of Ghrelin, a Natural Growth Hormone Secretagogue (GHS), in Humans: Comparison and Interactions with Hexarelin, a Nonnatural Peptidyl GHS, and GH-Releasing Hormone, J Clin Endocrinol Metab 2001;86(3):1169-74.

[13.] Garcia JM, Polvino WJ. Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormonesecretagogue in healthy volunteers. Growth Horm IGF Res 2009;19(3):267-73.

[14.] Maier C, Schaller G, Buranyi B, Nowotny P, Geyer G, Wolzt M, et al. The Cholinergic System Controls Ghrelin Release and Ghrelin-Induced Growth Hormone Release in Humans. J Clin Endocrinol Metab 2004;89(9):4729-33.

[15.] Hataya Y, Akamizu T, Takaya K, Kanamoto N, Ariyasu H, Saijo M, et al. A Low Dose of Ghrelin Stimulates Growth Hormone (GH) Release Synergistically with GH-Releasing Hormone in Humans. J Clin Endocrinol Metab 2001;86(9):4552.

[16.] Micic D, Macut D, Sumarac-Dumanovic M, Kendereski A, Popovic V, Deghenghi R, et al. Ghrelin-induced GH secretion in normal subjects is partially resistant to homologous desensitization by GH-releasing peptide-6. Eur J Endocrinol. 2002 Dec;147(6):761-6.

[17.] Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, et al. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 2000;85(12):4908-11.

[18.] Allas S, Abribat T. Clinical perspectives for ghrelin-derived therapeutic products. Endocr Dev 2013;25:157-66.

[19.] Carreira MC, Crujeiras AB, Andrade S, Monteiro MP, Casanueva FF. Ghrelin as a GH-releasing factor. Endocr Dev 2013;25:49-58.

[20.] Schellekens H, Dinan TG, Cryan JF. Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward. Front Neurosci 2013;7:148.

[21.] Corazzini V, Salvatori R. Molecular and clinical aspects of GHRH receptor mutations. Endocr Dev 2013;24:106-17.

[22.] Berlanga J, Cibrian D, Guevara L, Dominguez H, Alba JS, Seralena A, et al. Growth-hormone-releasing peptide 6 (GHRP6) prevents oxidant cytotoxicity and reduces myocardial necrosis in a model of acute myocardial infarction. Clin Sci (Lond) 2007;112(4):241-50.

[23.] Liantonio A, Gramegna G, Carbonara G, Sblendorio VT, Pierno S, Fraysse B, et al. Growth hormone secretagogues exert differential effects on skeletal muscle calcium homeostasis in male rats depending on the peptidyl/nonpeptidyl structure. Endocrinology 2013;154(10):3764-75.

[24.] Maier C, Schaller G, Buranyi B, Nowotny P, Geyer G, Wolzt M, et al. The Cholinergic System Controls Ghrelin Release and Ghrelin-Induced Growth Hormone Release in humans. J Clin Endocrinol Metab 2004;89(9):4729-33.

Source of Support: Nil

Conflict of interest: None declared

Mahalaqua Nazli Khatib (1), Shilpa Gaidhane (2), Abhay Gaidhane (3), Quazi Syed Zahiruddin (3)

(1) Department of Physiology, JN Medical College, Datta Meghe Institute of Medical Sciences, Sawangi Meghe, Wardha, Maharashtra, India

(2) Department of Medicine, JN Medical College, Datta Meghe Institute of Medical Sciences, Sawangi Meghe, Wardha, Maharashtra, India

(3) Department of Community Medicine, JN Medical College, Datta Meghe Institute of Medical Sciences, Sawangi Meghe, Wardha, Maharashtra, India

Correspondence to: Mahalaqua Nazli Khatib (nazli.786@rediffmail.com)

DOI: 10.5455/ijmsph.2014.250120141

Received Date: 17.01.2014

Accepted Date: 25.03.2014
Table-1: Characteristics and finding of the included studies

Country &    Peino et al (2000)   Japan. Randomized
Type of
study        Arvat (2001)         Italy. Randomized, single blind

             Garcia (2009)        USA. Randomized, double-blind,
                                  placebo-controlled

             Maier (2004)         Austria. Randomized, double-blind,
                                  placebo-controlled, crossover study

             Hataya (2001)        Japan. Randomized

             Micic (2002)         Yugoslavia. Randomized

             Takaya (2000)        Japan. Randomized

Partici-     Peino et al (2000)   12 normal, healthy male volunteers;
pants                             Age: 26.2 [+ or -] 1:1 years; BMI:
                                  24.0 [+ or -] 0.4 kg/[m.sup.2]

             Arvat (2001)         7 healthy male volunteers; Age:
                                  28.6 [+ or -] 2.9 years (mean [+ or
                                  -] SEM); BMI: 22.1 [+ or -] 0.8 kg/
                                  [m.sup.2]

             Garcia (2009)        32 healthy normal volunteers

             Maier (2004)         12 healthy male volunteers; Age:
                                  27.6 [+ or -] 1.1 years (mean [+ or
                                  -] SEM); BMI: 24.0 [+ or -] 0.5 kg/
                                  [m.sup.2]

             Hataya (2001)        8 healthy male volunteers; Age:
                                  28-46 years; BMI: 22.8 [+ or -] 2.3
                                  kg/[m.sup.2]

             Micic (2002)         6 healthy male volunteers; Age: 32
                                  [+ or -] 3 years

             Takaya (2000)        6 healthy male volunteers; Age:
                                  28-37 years; BMI: 22.6 [+ or -] 2.8
                                  kg/[m.sup.2]

Interve-     Peino et al (2000)   6 subjects: ghrelin at four
ntion                             different doses, 0 (placebo), 0.25,
                                  0.5 and 1.0 mg/kg on four different
                                  days. 6 different subjects were
                                  tested with ghrelin at either 3.3
                                  mg/kg or 6.6 mg/kg on two different
                                  occasions.

             Arvat (2001)         All subjects underwent 4 sessions,
                                  3 days apart: (1) Placebo (2 mL
                                  isotonic saline iv at 0 min); (2)
                                  Ghrelin (1.0 [micro]g/kg iv at 0
                                  min); (3) HEX (1.0 [micro]g/kg iv
                                  at 0 min); and (4) GHRH/29 (1.0
                                  [micro]g/kg iv at 0 min).

                                  6 subjects also underwent two
                                  further sessions in which they were
                                  administered: (1) Ghrelin and HEX
                                  or (2) Ghrelin and GHRH.

             Garcia (2009)        Administered escalating doses of
                                  anamorelin (25, 50, and 75 mg
                                  daily) vs. placebo.

                                  For all subjects, 6 study days
                                  (A-F) with 3-d intervals were
                                  scheduled in randomized order:

                                  Day A: PD at -60 and placebo
                                  (isotonic saline) iv at time point
                                  0;

                                  Day B: ATR, 1 mg iv at time point 0
                                  and placebo iv at time point 0;

             Maier (2004)         Day C: PD at -60 and ghrelin 0.25
                                  [micro]g/ kg BW at 0;

                                  Day D: ATR at 0 and ghrelin 0.25
                                  [micro]g/kg BW at 0; Day E: PD at
                                  -60 and ghrelin 1 [micro]g/kg BW at
                                  0;

                                  Day F: ATR at 0 and ghrelin 1
                                  [micro]g/kg BW at 0.

                                  6 of the 12 subjects were also
                                  tested with the two doses (0.25 and
                                  1 [micro]g/kg, respectively) of
                                  ghrelin alone

             Hataya (2001)        3 different doses of combinations
                                  of ghrelin (0.08, 0.2, 1.0
                                  [micro]g/kg + fixed doses of GHRH
                                  (1.0 [micro]g/kg) were administered
                                  to 3 groups of 4 subjects

                                  On each day, subjects were
                                  challenged

                                  twice with different GH stimulants:
                                  each subject served as his own
                                  control.

             Micic (2002)         Day 1: Saline at 0 min and at 120
                                  min ghrelin iv 1.0 [micro]g/kg

                                  Day 2: GHRH at a dose of 1.0
                                  [micro]g/kg at 0 min and at 120 min
                                  ghrelin at a dose of 1.0
                                  [micro]g/kg

                                  Day 3: GHRP-6 at a dose of 1.0
                                  [micro]g/kg at 0 min followed at
                                  120 min by ghrelin at a dose of 1.0
                                  [micro]g/kg

             Takaya (2000)        2-3 doses of ghrelin randomly
                                  allocated 7 days apart among 6
                                  subjects

                                  Synthetic ghrelin administered 0.2,
                                  1.0 or 5 [micro]g/kg iv

Result       Peino et al (2000)   Ghrelin at the dose of 0.25, 0.5
                                  and 1.0 [micro]g/kg elicited a peak
                                  GH secretion of 0.5 [+ or -] 0.007;
                                  0.6 [+ or -] 0.09 and 6.5 [+ or -]
                                  2.6 [micro]g/l resp that was not
                                  significantly different than
                                  placebo group (0.6 [+ or -] 0.08
                                  [micro]g/kg). These higher ghrelin
                                  doses elicited a robust GH release
                                  significantly higher than the
                                  placebo (P<0.005) and then the
                                  1|ig/kg dose (P<0.005).

             Arvat (2001)         Basal GH levels were similar in all
                                  sessions. Ghrelin induced a prompt
                                  and marked increase in circulating
                                  GH levels. The GH response to
                                  ghrelin was higher (P < 0.01) than
                                  GHRH (Cmax, 26.7 [+ or -] 8.7
                                  [micro]g/L; AUC, 619.6 [+ or -]
                                  174.4 [micro]g/L-h; Tmax, 25.7 [+
                                  or -]  4.3 min) and even
                                  significantly higher (P < 0.05)
                                  than that after HEX (Cmax, 68.4 [+
                                  or -] 14.7 [micro]g/ L; AUC, 1546.9
                                  [+ or -] 380.0 [micro] g/L-h; Tmax,
                                  30.0 [+ or -] 3.3 min). The
                                  endocrine responses to ghrelin were
                                  not modified by the
                                  co-administration with HEX. GH
                                  response to ghrelin plus HEX was
                                  similar to that recorded after
                                  ghrelin alone (Cmax, 99.7 [+ or -]
                                  12.9 vs. 100.3 [+ or -] 17.3
                                  [micro]g/L; AUC, 2265.9 [+ or -]
                                  201.8 vs. 2066.0 [+ or -]
                                  358.3[micro] g/L-h

             Garcia (2009)        Anamorelin significantly increased
                                  GH levels at all doses (p<or=0.01).
                                  Significant dose-related increases
                                  in body weight were recorded.
                                  Changes in body weight directly
                                  correlated with changes in IGF-1
                                  levels.

             Maier (2004)         ATR alone significantly reduced
                                  fasting ghrelin levels by 25%. PD
                                  alone did not alter ghrelin levels
                                  and did not enhance Ghrelin-induced
                                  GH peak concentrations. Ghrelin +
                                  ATR: Significantly reduced GH
                                  concentrations compared with
                                  ghrelin administration alone for
                                  both ghrelin doses. Ghrelin at 0.25
                                  [micro]g/ kg increased circulating
                                  ghrelin conc. with peak values of
                                  634 [+ or -] 22.6 fmol/ml. Higher
                                  ghrelin dosage (1 [micro]g/ kg)
                                  induced peak values of 1959.4 [+ or
                                  -] 163.5 fmol/ml.

             Hataya (2001)        At small doses of 0.08 and 0.2
                                  [micro]g/kg ghrelin, combined
                                  administration of the two peptides
                                  significantly stimulated GH release
                                  in a synergistic manner. Mean GH
                                  response of two peptide
                                  combinations were more than the
                                  summed mean GH response values of
                                  each peptide alone (P < 0.05). At
                                  1.0 [micro]g/kg ghrelin, the
                                  tendency of the synergistic effect
                                  was observed

             Micic (2002)         Saline-ghrelin test: Saline did not
                                  modify GH basal levels; mean GH
                                  peak: 1.5 [+ or -] 0.6mg/l. Ghrelin
                                  at 120 min elicited a significant
                                  GH mean peak of 39:9 [+ or -] 2:8
                                  mg/l. GHRH -ghrelin test: the GH
                                  secretion elicited by GHRH was
                                  rather erratic with a mean GH peak
                                  of 9.4 [+ or -] 2.8mg/l; and when
                                  ghrelin was administered 120 min
                                  later the GH mean peak was 26.8 [+
                                  or -] 4.7mg/l. GHRP-6-ghrelin test:
                                  GHRP-6 induced a mean GH peak of
                                  18:4 [+ or -] 5:9mg/l; while
                                  ghrelin at 120 min induced a GH
                                  mean peak of 19:8 [+ or -] 2:9mg/l.

Side         Peino et al (2000)   No relevant side effects were
effects                           observed with ghrelin No changes in
             Arvat (2001)         heart rate and blood pressure were
                                  recorded after ghrelin
                                  administration. 3 out of seven
                                  subjects were hungry at the end of
                                  the ghrelin testing session.
                                  Transient facial flushing in 2 out
                                  of seven subjects after HEX
                                  administration. Co-administration
                                  of ghrelin and HEX or ghrelin and
                                  GHRH did not modify the side
                                  effects recorded after the
                                  administration of various peptides
                                  alone.

             Garcia (2009)        Anamorelin was well tolerated.

             Hataya (2001)        Ghrelin + GHRH produced bowel
                                  movement in 3 out of 4 subjects.
                                  GHRH-6 produced facial flushing in
                                  all the subjects for 1-3 min.

             Micic (2002)         No significant change in heart rate
                                  and blood pressure. No side-effects
                                  were reported in any stimulation
                                  test

             Takaya (2000)        2-4 sujects with 1.0 or 5.0
                                  [micro]g/kg reported warm sensation
                                  in upper trunk and/or bowel
                                  movements for few minutes. No other
                                  side effects.

Conclusion   Peino et al (2000)   Ghrelin is a potent releaser of GH
                                  in normal individuals, with a
                                  dose-response pattern of operation.
                                  No saturating dose was observed.

             Arvat (2001)         Ghrelin is important in the control
                                  of somatotroph function in humans.
                                  Non-natural GHSs imitate its
                                  GH-releasing effect.

             Garcia (2009)        Anamorelin increases GH, IGF-1,
                                  IGFBP-3 and body weight with good
                                  tolerability and selectivity

             Maier (2004)         In humans, fasting ghrelin
                                  concentrations might be under
                                  cholinergic control and that the
                                  cholinergic system appears to
                                  modulate ghrelin-induced GH
                                  release.

             Hataya (2001)        Ghrelin acts synergistically with
                                  GHRH in humans

             Micic (2002)         Ghrelin is a more potent releaser
                                  of GH. On molar basis the order of
                                  potency is ghrelin > GHRH> GHRP- 6

                                  On clinical grounds, GHRP-6 is less
                                  potent but more efficacious at
                                  releasing GH.

BW: Body weight; PD: Pyridostigmine, ATR: Atropinum sulfuricum
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Title Annotation:RESEARCH ARTICLE
Author:Khatib, Mahalaqua Nazli; Gaidhane, Shilpa; Gaidhane, Abhay; Zahiruddin, Quazi Syed
Publication:International Journal of Medical Science and Public Health
Article Type:Report
Date:Apr 1, 2014
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