Acute administration of hexarelin stimulates GH secretion during day and night in normal men

1 Mar 1997

Acute administration of hexarelin stimulates GH secretion during day and night in normal men / Sandro Loche, Annamaria Colao, Marco Cappa, Diego Ferone, Bartolomeo  Merola, Antonell Faedda, Bruno P. Imbimbo, Romano Deghenghi, Gaetano Lombardi

  • Clinical Endocrinology 45 (1997 3 (March); p. 275-279
  • PMID: 9156035
  • DOI: 10.1046/j.1365-2265.1997.1240940.x


Abstract

Objective: Hexarelin is a synthetic hexapeptide with potent GH-releasing activity in both animals and men. The aim of this study was to investigate the effect of a bolus injection of hexarelin given in the morning during wakefulness and during nocturnal sleep in a group of normal adult men.

Design and subjects: Eight normal men, aged 21-33 years, of normal height and within 10% of ideal body weight were studied. All subjects received in random order saline or hexarelin (2 micrograms/kg) in the morning between 0800 and 0900 h after they had fasted overnight. The same experiments were performed during nocturnal sleep in the same subjects. Saline or hexarelin were injected within 30 minutes after the onset of sleep between 2300 and 2400 h. Sleep was recorded by visual inspection.

Measurements: In all four test sessions blood samples were taken 30, 15 minutes and immediately before the injection of saline or hexarelin and then every 15 minutes for 2 hours. GH was measured by an immunoradiometric assay. All values are expressed as peak GH levels or as area under the curve (AUC) calculated by trapezoidal integration.

Results: Mean peak GH concentrations after hexarelin during the morning (58.2 +/- 4.7 micrograms/l) (GH micrograms/l l x 2 = mU/l) were not different from those observed during sleep (61.2 +/- 4.3 micrograms/l). The rate of disappearance of GH from plasma was slower during sleep (t1/2 = 64.9 +/- 14.8 min) than during morning hours (t1/2 = 24.9 +/- 1.4 min, P < 0.01). Mean AUC responses to hexarelin during sleep (1466 +/- 145 micrograms.min/l) were significantly higher than during morning hours (903 +/- 94 micrograms.min/l, P < 0.001).

Conclusions: These results show that GH responsiveness to a growth hormone releasing peptide is preserved during the night. This could be exploited for diagnostic and/or therapeutic purposes.

The growth hormone response to hexarelin in patients with different hypothalamic-pituitary abnormalities

1 Nov 1998

The growth hormone response to hexarelin in patients with different hypothalamic-pituitary abnormalities / M. Maghnie, V. Spica-Russotto, M. Cappa, M. Autelli, C. Tinelli, P. Civolani, R. Deghenghi, F. Severi, S. Loche

  • Journal of Clinical Endocrinology & Metabolism 83 (1998) 11 (1 November); p. 3886–3889
  • PMID: 9814463
  • DOI: 10.1210/jcem.83.11.5242


Abstract

We evaluated the GH-releasing effect of hexarelin (Hex; 2 microg/kg, i.v.) and GHRH (1 microg/kg, i.v.) in 18 patients (11 males and 7 females, aged 2.5-20.4 yr) with GH deficiency (GHD) whose hypothalamic pituitary abnormalities had been previously characterized by dynamic magnetic resonance imaging (MRI). Ten patients had isolated GHD, and 8 had multiple pituitary hormone deficiency. All patients were receiving appropriate hormone replacement therapy. Twenty-four prepubertal short normal children (11 boys and 13 girls, aged 5.9-13 yr, body weight within +/-10% of ideal weight) served as controls. MRI studies revealed an ectopic posterior pituitary at the infundibular recess in all patients. A residual vascular component of the pituitary stalk was visualized in 8 patients with isolated GHD (group 1), whereas MRI showed the absence of the pituitary stalk (vascular and neural components) in the remaining 10 patients (group 2), of whom 8 had multiple pituitary hormone deficiency and 2 had isolated GHD. In the short normal children, the mean peak GH response to GHRH (24.8 +/- 4.4 microg/L) was significantly lower than that observed after Hex treatment (48.1 +/- 4.9 microg/L; P < 0.0001). In the GHD patients of group 2, the mean peak GH responses to GHRH (1.4 +/- 0.3 microg/L) and Hex (0.9 +/- 0.3 microg/L) were similar and markedly low. In the patients of group 1, the GH responses to GHRH (8.7 +/- 1.3 microg/L) and Hex (7.0 +/- 1.3 microg/L) were also similar, but were significantly higher that those observed in group 2 (P < 0.0001). In the whole group of patients, a significant correlation was found between the GH peaks after Hex and those after GHRH (r = 0.746; P < 0.0001). In this study we have confirmed that the integrity of the hypothalamic pituitary connections is essential for Hex to express its full GH-releasing activity and that Hex is able to stimulate GH secretion in patients with GHD but with a residual vascular component of the pituitary stalk.

Biologic activities of growth hormone secretagogues in humans

1 Feb 2001

Biologic activities of growth hormone secretagogues in humans / E. Ghigo, E. Arvat, R. Giordano, F. Broglio, L. Gianotti, M. Maccario, G. Bisi, A. Graziani, M. Papotti, G. Muccioli, R. Deghenghi, F. Camanni

  • Endocrine 14 (2001) 1 (Feb); p. 87-93
  • PMID: 11322506
  • DOI: 10.1385/ENDO:14:1:087


Abstract

Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules with strong, dose-dependent, and reproducible growth hormone (GH)-releasing activity even after oral administration. GHSs release GH via actions on specific receptors (GHS-R) at the pituitary and, mainly, at the hypothalamic levels. GHSs likely act as functional somatostatin antagonists and meantime enhance the activity of GH-releasing hormone (GHRH)-secreting neurons. The GH-releasing effect of GHSs is independent of gender but undergoes marked age-related variations. Estrogens play a major role in enhancing the GH response to GHSs at puberty, which GHRH hypoactivity, somatostatinergic hyperactivity and impaired activity of the putative GHS-like ligand and receptors probably explain the reduced GH-releasing effect of GHSs in aging. The activity of GHSs is not fully specific for GH. Their slight prolactin-releasing activity probably comes from direct pituitary action. In physiological conditions, the ACTH-releasing activity of GHSs is dependent on central actions; a direct action on GHS-R in pituitary ACTH-secreting tumors likely explains the peculiar ACTH and cortisol hyperresponsiveness to GHSs in Cushing disease. GHSs have specific receptor subtypes in other central and peripheral endocrine and nonendocrine tissues mediating GH-independent biologic activities. GHSs influence sleep pattern, stimulate food intake, and have cardiovascular activities. GHs have specific binding in normal and neoplastic follicular derived human thyroid tissue and inhibit the proliferation of follicular-derived neoplastic cell lines. The discovery of ghrelin, a 28 amino acid peptide synthesized in the stomach but also in other tissues, has opened new fascinating perspectives of research in this field.

Growth hormone-releasing peptides and their analogs

1 Jan 1998

Growth hormone-releasing peptides and their analogs / F. Camanni, E. Ghigo, E. Arvat

  • Frontiers in neuroendocrinology 19 (1998) 1 (January); p. 47-72
  • PMID: 9465289
  • DOI: 10.1006/frne.1997.0158


Abstract

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.

Identification of the growth-hormone-releasing peptide-2 (GHRP-2) in a nutritional supplement

26 Feb 2010

Identification of the growth-hormone-releasing peptide-2 (GHRP-2) in a nutritional supplement / Andreas Thomas, Maxie Kohler, Joachim Mester, Hans Geyer, Wilhelm Schänzer, Michael Petrou, Mario Thevis

  • Drug Testing and Analysis 2 (2010) 3 (March); p. 144-148
  • PMID: 20878896
  • DOI: 10.1002/dta.120


Abstract

Black market products of a pharmaceutical nature and nutritional supplements have received substantial and increasing attention because of potential performance enhancement in elite and non-professional sports. In addition, improved general health is claimed for non-competing individuals. The risks and foreseeable dangers of the uncontrolled use of highly potent and non-approved pharmaceutical compounds in healthy individuals are of considerable concern. In the present case report, the emerging drug candidate GHRP-2 with verified growth-hormone-releasing properties was identified and quantified in tablets offered as an over-the-counter nutritional supplement. The impact of this orally active peptide on the hGH/IGF-axis has been established for several years and its illicit use in elite sports has been assumed. As a releasing factor for hGH, GHRP-2 belongs to the list of substances prohibited by the World Anti-Doping Agency (WADA). Unfortunately, to date there is no routinely performed assay for the determination of these peptides potentially occurring in biological fluids of competing athletes, but the present data will facilitate the implementation by providing principle analytical information on liquid chromatographic and mass spectrometric behaviour. Qualitative identification of the target analyte after extraction from the tablet matrix was performed by high resolution/high accuracy mass spectrometry after liquid chromatographic separation under consideration of the accurate masses and the ratios of the protonated molecules and their fragment ions derived from their collisionally induced dissociation. Quantitative results were obtained by means of liquid chromatography coupled to a triple quadrupole mass spectrometer and linear regression using an external calibration curve (with GHRP-2 reference compound) adjusted via internal standard (Hexarelin). Hereby, the content of GHRP-2 was determined with approximately 50 µg per tablet.

Doping in the recombinant era: strategies and counterstrategies

9 Nov 2005

Doping in the recombinant era : strategies and counterstrategies / Hassan M.E. Azzazy, Mai M.H. Mansour, Robert H. Christenson

  • Clinical Biochemistry 38 (2005) 11 (November); p. 959-965
  • PMID: 16286094
  • DOI: 10.1016/j.clinbiochem.2005.09.007
  • Comment in:
    • Doping in the recombinant era / Gary Green
    • PMID: 17200034
    • DOI: 10.1016/j.clinbiochem.2006.11.002


Abstract

Advances in recombinant DNA technology have created one of the most powerful weapons in the current doping arsenal: recombinant proteins [Sweeney HL. Gene doping. Sci Am 2004;291:62-9; Unal M, Ozer Unal D. Gene doping in sports. Sports Med 2004;34:357-62]. Recombinant erythropoietin (EPO) and human growth hormone (hGH) are currently being abused but are fortunately detectable either directly by employing isoelectric focusing and immunoassays or indirectly by assessing changes in selected hematopoietic parameters. The detection is technically demanding due to the extent of similarity between the recombinant proteins and their endogenous counterparts. Another issue facing detection efforts is the speed and conditions at which blood samples are collected and analyzed in a sports setting. Recently, gene doping, which stemmed out of legitimate gene therapy trials, has emerged as the next level of doping. Erythropoietin (EPO), human growth hormone (hGH), insulin-like growth factor-1 (IGF-1), peroxisome proliferator-activated receptor-delta (PPAR delta), and myostatin inhibitor genes have been identified as primary targets for doping. Sports clinical scientists today are racing against the clock because assuring the continued integrity of sports competition depends on their ability to outpace the efforts of dopers by developing new detection strategies.

Gene therapy, genetic doping and sport: fundaments and implications for the future

1 Dec 2021

Gene therapy, genetic doping and sport : fundaments
and implications for the future / Guilherme Giannini Artioli, Rosário Dominguez Crespo Hirata, Antonio Herbert Lancha Junior

  • Revista Brasileira de Medicina do Esporte 13 (2007) 5; p. 349-354
  • DOI: 10.1590/s1517-86922007000500013


Abstract

Optimal performance has been constantly sought for in high level competitive sport. To achieve this goal, many athletes use illicit drugs and methods, which could have important side effects. Gene therapy is a very recent therapeutic modality, whose results have shown to be efficient in the treatment of severe diseases so far. The basis of gene therapy is a vectorial transfer of genetic materials to target-cells in order to supply the products of an abnormal gene in the patient's genome. Recently, the potential for misuse of gene therapy among athletes has called attention of scientists and sports regulating organs. The transfer of genes that could improve athletic performance, a method prohibited by COI in 2003, was named gene doping. The most important candidate genes for gene doping are the ones which codify for the following proteins: GH, IGH-1, miostatin blockers, VEGF, endorfins and enkefalins, eritropoetin, leptin and PPAR-delta. Once inserted in the athlete genome, the gene would be expressed and produce an endogenous product capable of improving performance. Thus, current doping detection methods are not sensitive enough to detect gene doping, which in turn could stimulate its use among athletes. Moreover, gene therapy still presents known application problems, such as inflammatory response and lack of control of gene activation. It is probable that such problems would be even more important in healthy individuals, since there would be excessive product of the transferred gene. Moreover, other unknown risks specific for each gene are present. Therefore, debate on gene doping should be carried on in the academic as well as sports field, in order to study prevention, control and detection measures of gene doping, avoiding hence, future problems regarding the misuse of this promising therapy.

TJD-AD 2018-128 Disciplinary Decision - Football

13 Dec 2018

In January 2018 the Brazilian Doping Control Authority (ABCD) reported an anti-doping rule violation against the football player after his A and B samples tested positive for the prohibited substance Fenoterol. After notification a provisional suspension was ordered ant the Athlete filed a statement in his defence.

The Athlete admitted the violation and explained with medical evidence that on the day of the sample collection he suffered from an asthma attack and had used medication as treatment that contained the prohibited substance.

The Athlete argued the he was unaware that his medication was prohibited, while he was tested before without issues. He requested to lift the provisional suspension and for a reduced sanction.

ABCD contended that the Athlete had acted negligently with his medication because he had failed to inform his football club about his asthma. Prior he had not applied for a TUE, nor applied for a TUE after the positive test result. Rather he had used the substance deliberately and intentionally for sport.

The Rapporteur finds that the presence of a prohibited substance has been established in the Athlete's samples and accordingly that he had committed an anti-doping rule violation.

The Rapporteur accepts that the violation was not intentional and the result of the Athlete's use of his medication. In view of the Athlete's conduct the Rapporteur deems that he had acted with a degree of negligence. Further the substantial delays in the proceedings were considered not attributed to the Athlete.

Therefore the TJD-AD decides on 13 December 2018 to impose a 12 month period of ineligibility on the Athlete, starting on the date of the sample collection, i.e. on 26 November 2017.

TJD-AD 2018-123 Disciplinary Decision - Bodybuilding

13 Jan 2019

In February 2018 the Brazilian Doping Control Authority (ABCD) reported an anti-doping rule violation against the bodybuilder Refusal or failure to submit to sample collection during a competition in december 2017. After notification a provisional suspension was ordered.

The TJD-AD Rapporteur establishes that the Athlete had signed the notification, yet thereupon intentionally failed to submit to sample collection. Further the Athlete failed to demonstrate that the violation was not intentional, nor grounds for a reduced sanction.

Therefore the TJD-AD decides on 13 January 2019 to impose a 4 year period of ineligibility on the Athlete starting on the date of the provisional suspension, i.e. on 11 June 2018.

TJD-AD 2018-111 Disciplinary Decision - Football

20 Nov 2018

In September 2017 the Brazilian Doping Control Authority (ABCD) has reported an anti-doping rule violation against the football player after his A and B sample tested positive for the prohibited substance Hydrochlorothiazide.

After notification a provisional suspension was ordered and the Athlete filed a statement in his defence. The Athlete denied the intentional use of the substance and could not explain how the substance entered his system. Also analysis of his supplements in a the Rio de Janeiro Lab revealed no prohibited substances.

The Rapporteur finds that the presence of a prohibited substance has been established in the Athlete's samples and accordingly that he committed an anti-doping rule violation.

The Rapporteur considers that the Athlete failed to demonstrate that the violation was not intentional nor grounds for a reduced sanction. Further the Rapporteur holds that there were substantial delays in the proceedings not attributed to the Athlete.

Therefore the TJD-AD decides on 20 November 2018 to impose a 2 year period of ineligibility on the Athlete, starting on the date of the sample collection, i.e. on 8 May 2017.

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