GHRP-2

Hexarelin (HEX) and GHRP-2 are two synthetic hexapeptides, superanalogs of GHRP-6, belonging to GH secretagogue (GHS) family. GHS act via specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in humans. However, GHS also possess significant PRL- and ACTH/cortisol-releasing activity. Tyr-Ala-HEX as well as Tyr-Ala-GHRP-6 are, in turn, synthetic octapeptides generally used to perform binding studies because of their easy iodination. However, their endocrine activities have never been studied in humans. To clarify the endocrine activities of Tyr-Ala-HEX, in 7 young adult volunteers we compared the effects of the maximal effective dose of HEX (2.0 microg/kg i.v.) or GHRP-2 (2.0 microg/kg i.v.) with the same one of Tyr-Ala-HEX on GH, PRL, ACTH and cortisol levels. Basal GH, PRL, ACTH and cortisol levels in all testing sessions were similar. The administration of placebo did not modify hormonal levels. HEX and GHRP-2 administration induced the well known strong GH response (Cmax, mean+/-SE: 77.3+/-6.0 and 74.1+/-12.1 microg/l; AUC, mean+/-SE: 2596.7+/-251.1 and 2480.0+/-343.6 microg*min/l). These responses were similar to that induced by Tyr-Ala-HEX (63.7+/-18.5 microg/l; 1986.6+/-622.4 microg*min/l). Moreover, HEX, GHRP-2 and Tyr-Ala-HEX had the same significant stimulatory effect on PRL (14.9+/-2.5, 12.3+/-2.0 and 10.0+/-1.5 microg/l; 497.8+/-61.8, 480.4+/-66.9 and 415.8+/-58.5 microg*min/l), ACTH (48.0+/-10.1, 51.4+/-10.6 and 44.9+/-12.2 pg/ml; 1531.6+/-235.7, 1586.7+/-277.0 and 1338.1+/-164.5 pg*min/ml) and cortisol (179.9+/-10.0, 181.2+/-14.1 and 149.7+/-20.1 microg/l; 8465.0+/-406.6, 8689.2+/-788.1 and 6295.2+/-797.0 microg*min/l). Also the mean Tmax of the endocrine responses to HEX, GHRP-2 and Tyr-Ala-HEX were similar. In conclusion, the present results demonstrate that in humans Tyr-Ala-HEX is a GH secretagogue as potent as HEX and GHRP-2, two GHRP-6 superanalogs. Tyr-Ala-HEX also shares with HEX and GHRP-2 the same PRL- ACTH- and cortisol-releasing activity.

BACKGROUND: Sex steroids are prominent regulators of pulsatile GH secretion. HYPOTHESIS: An experimentally controlled sex-steroid milieu will permit detection of nonsteroidal factors that determine GH secretion. SUBJECTS: Eleven young (age, 24 +/- 0.99 yr) and 11 older (64 +/- 2.4 yr) men participated in the study. LOCATION: The study was conducted at a tertiary medical center. METHODS: The study consisted of GnRH-agonist down-regulation of the gonadal axis followed by fixed-dose testosterone (T) replacement (leuprolide/T clamp) and consecutive infusion of l-arginine and GHRH or GH-releasing peptide-2 (GHRP-2) to quantify peptide-secretagogue efficacies. OUTCOMES: The experimental leuprolide/T clamp yielded statistically age-comparable total, bioavailable, and free T and estradiol (E(2)) concentrations. In this controlled milieu, sequential l-arginine/GHRH infusion stimulated 1.4-fold more (P = 0.021) and l-arginine/GHRP-2 1.3-fold more (P = 0.045) GH release in young than older men. Abdominal visceral fat (AVF) correlated negatively with both GHRH (P = 0.0006; R(2) = 0.39) and GHRP-2 (R(2) = 0.29) efficacy, whereas IGF-I positively predicted the same endpoints (R(2) = 0.25 to 0.30). In multivariate analysis, AVF emerged as a dominant negative determinant of GHRH efficacy (P = 0.002; R(2) = 0.41) and IGF-I as a primary positive determinant of GHRP-2 efficacy (P = 0.007; R(2) = 0.31). CONCLUSION: During fixed T/E(2) availability, AVF contributes 41% of the GH-response variability to maximal GHRH drive, whereas IGF-I accounts for 31% of that for GHRP-2. Accordingly, a statistically equalized sex-steroid milieu permits dissection of age-independent and T/E(2)-independent modulators of GHRH and GHRP efficacy in men.

OBJECTIVE: Central hyposomatotrophism, hypothyroidism and hypogonadism are present concomitantly in men with prolonged critical illness. This study evaluated the impact of combined treatment with GH-releasing peptide-2 (GHRP-2), TRH and GnRH for 5 days compared with GHRP-2 + TRH and with GHRP-2 alone. PATIENTS AND DESIGN: Thirty-three men with prolonged critical illness participated at baseline compared to 50 age- and body mass index (BMI)-matched controls. Patients were randomly assigned to 5 days of placebo (n = 7), GHRP-2 (1 microg/kg/h; n = 9), GHRP-2 + TRH infusion (1 + 1 microg/kg/h; n = 9) or pulsatile GnRH (0.1 microg/kg every 90 min) together with GHRP-2 + TRH infusion (n = 8). MEASUREMENTS: GH, TSH and LH secretion were quantified by deconvolution analysis of serum concentration time series obtained by sampling every 20 min from 2100 to 0600 h at baseline and on nights 1 and 5 of treatment. Serum concentrations of IGF-I, IGFBPs, thyroid hormones, gonadal and adrenal steroids, proinflammatory cytokines and selected metabolic and inflammation markers were measured daily. RESULTS: Patients revealed suppressed pulsatile GH, TSH and LH secretion in the face of low serum concentrations of IGF-I, IGFBP-3 and the acid-labile subunit (ALS) (P < 0.0001 each), thyroid hormones (P < 0.0001) and total and estimated free testosterone (P < 0.0001) levels, whereas free oestradiol (E2) estimates were normal. Serum dehydroepiandrosterone sulphate (DHEAS) levels were also suppressed whereas morning cortisol was normal. Serum levels of type I procollagen (PICP) and bone alkaline phosphatase (sALP) were elevated whereas osteocalcin (OC) was low (P = 0.03). Ureagenesis (P < 0.0001) and breakdown of bone tissue (P < 0.0001) were increased. Baseline serum TNF-alpha, IL-6 and C-reactive protein level and white blood cell (WBC) count were elevated; serum lactate was normal. Only low T4 and high IGFBP-1 levels independently predicted mortality. GHRP-2 infusion reactivated GH secretion and normalized serum IGF-I, IGFBP-3 and ALS. GHRP-2 + TRH infusion reactivated both the GH axis and the thyroid axis, with normal levels of T4 and T3 reached within 1 day. Only GHRP-2 + TRH infusion combined with GnRH pulses reactivated the GH and TSH axis and at the same time increased pulsatile LH secretion compared to placebo. Only GnRH pulses together with GHRP-2 + TRH infusion increased testosterone significantly from day 2 (peak increase of + 312%) through day 5 and serum E2 with > 80% from day 1 through day 3 (all P = 0.05). Ureagenesis was reduced by GHRP-2 + TRH + GnRH (P = 0.01) and by GHRP-2 + TRH (P = 0.009) but not by GHRP-2 alone. Serum OC levels were increased only by GHRP-2 + TRH + GnRH (P = 0.03), with a trend for GHRP-2 + TRH (P = 0.09), but not by GHRP-2 alone. On day 5, serum lactate levels and WBC count were increased by GHRP-2 infused alone and in combination with TRH but not by GHRP-2 + TRH + GnRH. CONCLUSIONS: Coadministration of GHRP-2, TRH and GnRH reactivated the GH, TSH and LH axes in prolonged critically ill men and evoked beneficial metabolic effects which were absent with GHRP-2 infusion alone and only partially present with GHRP-2 + TRH. These data underline the importance of correcting the multiple hormonal deficits in patients with prolonged critical illness to counteract the hypercatabolic state.

GHRP-2 is a synthetic agonist of ghrelin, the newly-discovered gut peptide which binds to the growth hormone (GH) secretagogue receptor. Ghrelin has two major effects, stimulating both GH secretion and appetite/meal initiation. GHRP-2 has been extensively studied for its utility as a growth hormone secretagogue (GHS). Animal studies have shown its effect on food intake. However, whether GHRP-2 can also stimulate appetite in humans when administered acutely is not known. We subcutaneously infused 7 lean, healthy males with GHRP-2 (1 microg/kg/h) or saline for 270 minutes and then measured their intake of an ad libitum, buffet-style meal. Similar to what has been reported for ghrelin administration, our subjects ate 35.9 +/- 10.9% more when infused with GHRP-2 vs. saline, with every subject increasing their intake even when calculated per kg body weight (136.0 +/- 13.0 kJ/kg [32.5 +/- 3.1 kcal/kg] vs. 101.3 +/- 10.5 kJ/kg [24.2 +/- 2.5 kcal/kg], p = 0.008). The macronutrient composition of consumed food was not different between conditions. As expected, serum GH levels rose significantly during GHRP-2 infusion (AUC 5550 +/- 1090 microg/L/240 min vs. 412 +/- 161 microg/L/240 min, p = 0.003). These data are the first to demonstrate that GHRP-2, like ghrelin, increases food intake, suggesting that GHRP-2 is a valuable tool for investigating ghrelin effects on eating behavior in humans.

Because growth hormone (GH) secretion is reportedly decreased in obese patients, we examined not only the factors associated with the decreased GH secretion but also GH response to the GH-releasing peptide (GHRP)-2-load test before and after laparoscopic gastrectomy (LSG). The study comprised 28 individuals aged 19-65 years [mean body mass index (BMI), 39.4 ± 9.4 kg/m2]. In the univariate analysis, GH secretion peaks correlated negatively with BMI (r = -0.59, p = 0.001), visceral adipose tissue (r = -0.47, p = 0.005), and subcutaneous adipose tissue (r = -0.40, p = 0.04). In the two obese patients, the response to the GHRP-2-load test markedly improved by weight loss 12 months after LSG. In conclusion, GH secretion was decreased in obese patients and improved by LSG.

Performance-enhancing drugs (PEDs) marketed as "research compounds" include unregulated peptides intended to modulate the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis. The agents most commonly encountered in clinical practice and online self-administration protocols include growth hormone-releasing hormone (GHRH) analogues (e.g., sermorelin, tesamorelin, CJC-1295 with Drug Affinity Complex [DAC], CJC-1295 without DAC), growth hormone secretagogues (GHS; e.g., growth hormone-releasing peptide-2 (GHRP-2), growth hormone-releasing peptide-6 (GHRP-6), hexarelin, ipamorelin), the growth hormone (GH) fragment - AOD9604 (hGH 176-191), and insulin-like growth factor-1 (IGF-1) analogues (e.g., pegylated mechano growth factor (PEG-MGF), IGF-1 Long R3 (IGF-1 LR3)). Reported adverse effects span endocrine and metabolic disturbances (including prolactin and cortisol elevations, appetite changes, and dysglycaemia), fluid retention syndromes, musculoskeletal symptoms (myalgia/arthralgia), and injection-site reactions. Given the absence of regulatory approval for physique- or performance-related indications and the uncertainty surrounding product composition, dose, and stacking practices in unregulated supply chains, clinicians increasingly require a pragmatic framework to interpret symptoms and laboratory abnormalities in patients using these compounds. This narrative review contrasts peer-reviewed pharmacokinetic/pharmacodynamic and clinical evidence with commonly encountered online self-administration protocols, stratifying peptides into evidence tiers from regulatory-grade randomized trial data to a complete absence of human studies, and highlights the resulting uncertainty around putative performance and recomposition benefits. We summarise structural characteristics, pharmacologic effects, and commonly reported dosing patterns, and we synthesise clinically relevant adverse effects with particular attention to hormonal imbalance, endocrine-metabolic risk, and biologically plausible but unproven mitogenic concerns. Finally, we propose a clinically oriented assessment algorithm to support exposure history taking, triage of symptom domains, and risk communication without legitimising off-label peptide regimens.