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PubMed2026

Sex Hormone Receptors, HBV Integrations and Their Prognostic Predictive Value Among Hepatocellular Carcinoma Patients.

Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) infection predominantly affects males, yet few studies have investigated the association between sex hormones and HBV integrations, and their involvement in HCC prognosis. We assessed estrogen receptor alpha (ERα) and androgen receptor (AR) expression via immunohistochemistry on tissue microarrays constructed from 426 HBV-related HCC samples. HBV integration features were determined using HBV-captured sequencing data. Logistic regression models were utilized to evaluate the association between sex hormone receptor expression level and HBV integration features. Cox regression models, combined with machine learning (ML) methods, were implemented to investigate the prognostic value of sex hormone receptors and HBV integrations concerning overall survival. We found high AR expression level was significantly associated with higher HBV integration levels (adjusted odds ratio [aOR] = 1.84, 95% confidence interval [CI]: 1.09-3.11, P for trend = 0.012), TERT integration (aOR = 2.34, 95% CI: 1.16-4.74, P for trend = 0.047), intergenic integration (aOR = 2.25, 95% CI: 1.20-4.24, P for trend = 0.021), and promoter integration (aOR = 1.81, 95% CI: 1.00-3.31, P for trend = 0.034). The inclusion of sex hormone receptors and HBV integrations in the predictive models led to improvements across all performance metrics in the Cox regression analyses (AUC improvement: 0.014 [Training], 0.026 [Validation]) and the ML (AUC improvement: 0.022 [Training]), although a slight deterioration in performance was noted in the ML validation set. The results suggested a relationship between AR expression level and HBV integration events, as well as the potential utility of HBV integration biomarkers and sex hormone receptor profiles in assessing post-surgical prognosis among HCC patients.

Humans↗

PubMed1997

The GH, prolactin, ACTH and cortisol responses to Hexarelin, a synthetic hexapeptide, undergo different age-related variations.

Hexarelin (HEX) is a synthetic growth hormone-releasing peptide (GHRP) which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release in an age-dependent manner. Like other GHRPs, HEX possesses also prolactin (PRL) and ACTH/cortisol-releasing activity. similar to that of human corticotropin-releasing hormone (hCRH). The mechanisms underlying the stimulatory effect of GHRPs on lactotrope and corticotrope secretion are even less clear and the influence of age on these endocrine activities of GHRPs is unknown. To clarify this point we studied the GH, PRL, ACTH and cortisol responses to the maximal effective dose of HEX (2.0 micrograms/kg i.v.) in: 12 prepubertal children (Pre-C, 8 male, 4 female, age 5.8-12.1 years); 12 pubertal normal short children (Pub-C, 5 male, 7 female, age 9.7-15.5 years, pubertal stage II-IV); 20 normal young adults (Young, 6 males, 14 females, age 23-32 years); and in 16 normal elderly people (Elderly, 5 male, 11 female, age 66-81 years). The GH response to HEX was clear in Pre-C (0-120 min area under curve, mean +/- S.E.M. 769.5 +/- 122.2 micrograms*min/l) but strikingly increased (P < 0.001) in Pub-C (1960.2 +/- 283.5 micrograms*min/l). The HEX-induced GH rise in Young (1829.7 +/- 243.1 micrograms*min/l) persisted similar to that in Pub-C, but decreased in Elderly (951.1 +/- 232.9 micrograms*min/I, P < 0.005); the latter was, in turn, similar to that in Pre-C. HEX induced a significant PRL increase which, however, showed no age-related variations, being similar in Pre-C (512.1 +/- 88.0 micrograms*min/l), Pub-C (584.0 +/- 106.0 micrograms*min/l), Young (554.9 +/- 56.0 micrograms*min/l) and Elderly (523.9 +/- 59.6 micrograms*min/l). The ACTH-releasing activity of HEX was present in Pre-C (1356.6 +/- 204.9 pg*min/ml) and was clearly enhanced (P < 0.02) in Pub-C (2253.5 +/- 242.8 pg*min/ml). The ACTH rise after HEX in Young (1258.1 +/- 141.2pg*min/ml) was lower (P < 0.02) than that in Pub-C and similar to that in Pre-C, while the ACTH response to HEX in Elderly (1786.5 +/- 340.1 pg*min/ml) showed a further trend toward increase, being similar to that in Pub-C. On the other hand, the cortisol response to HEX showed no significant age-related variations, being not different in Pre-C (7747.2 +/- 1031.6 micrograms*min/l), Pub-C (6106.0 +/- 862.9 micrograms*min/l), Young (6827.5 +/- 509.6 micrograms*min/I) and Elderly (7950.6 +/- 658.3 micrograms*min/l). In conclusion, our present data demonstrate that in humans the GH- and ACTH-releasing activities of HEX undergo different age-related variations, while its PRL-releasing activity is not dependent on age. These finding suggest that actions at different levels and/or on different receptor subtypes mediate the different age-related hormonal effects of GHRPs.

Adolescent↗

PubMed1997

Hexarelin, a synthetic growth-hormone releasing peptide, shows no interaction with corticotropin-releasing hormone and vasopressin on adrenocorticotropin and cortisol secretion in humans.

Hexarelin (HEX) is a synthetic growth-hormone-releasing peptide (GHRP) which acts via specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in man. Like other GHRPs, HEX possesses also significant prolactin- and adrenocorticotropin (ACTH) cortisol-releasing activity, but the mechanisms underlying these effects are even less clear. To clarify the mechanisms by which HEX stimulates the pituitary-adrenal axis in man, in 7 healthy young volunteers we studied the effects of HEX (2.0 microg/kg i.v.) and/or human corticotropin-releasing hormone (hCRH; 2.0 microg/kg i.v.) and/or arginine vasopressin (AVP; 0.17 U/kg i.m.) on ACTH and cortisol secretion. The GH responses to HEX alone and combined with hCRH and/or AVP were also studied. HEX increased ACTH and cortisol secretion (peak, mean +/- SEM: 26.3 +/- 5.1 vs. 15.8 +/- 3.1 pg/ml and 145.0 +/- 11.4 vs. 131.7 +/- 11.7 microg/l, p < 0.01, respectively) to levels overlapping with those induced by AVP (27.9 +/- 6.1 vs. 13.1 +/- 3.5 pg/ml and 167.6 +/- 16.2 vs. 113.3 +/- 9.4 microg/l, p < 0.01, respectively) and similar to those elicited by hCRH (28.1 +/- 4.6 vs. 17.4 +/- 3.1 pg/ml and 182.7 +/- 22.8 vs. 114.8 +/- 12.3 microg/l, p < 0.02, respectively). The ACTH but not the cortisol response to hCRH was higher (p < 0.02) than those to HEX when evaluated as area under the curve. The co-administration of HEX and AVP had no significant interaction on ACTH and cortisol peak levels (40.7 micro 5.3 pg/ml and 168.8 +/- 13.5 microg/l, respectively). On the other hand, the co-administration of HEX and hCRH had a less than additive effect on ACTH and cortisol secretion (53.3 +/- 11.2 pg/ml and 204.0 +/- 13.7 microg/l, respectively). CRH and AVP had a true synergistic effect on ACTH (104.9 +/- 14.2 pg/ml, p < 0.01) and an additive effect on cortisol secretion (281.3 +/- 10.8 microg/l, p < 0.02). HEX did not modify the effect of CRH + AVP on both ACTH (135.5 +/- 22.0 pg/ml) and cortisol secretion (261.1 +/- 13.2 microg/l). The GH response to HEX (55.7 +/- 19.8 vs. 2.7 +/- 1.9 microg/l, p < 0.005) was unaffected by the administration of CRH alone (53.5 +/- 21.0 microg/l) and/or AVP co-administration (60.2 +/- 21.2 and 45.9 +/- 10.6 microg/l, respectively). In conclusion, the results of this study demonstrate that GHRPs, beside their well-known GH-releasing activity, possess a remarkable ACTH-releasing activity, overlapping with that of AVP and similar to that of hCRH, two neurohormones which are known to play the major role in the control of the pituitary-adrenal axis. It is noteworthy that HEX shows no synergistic effect with either AVP or hCRH which, on the other hand, truly synergize. This evidence suggests the hypothesis that the ACTH-releasing activity of GHRPs could be, at least partially, independent of both CRH- and AVP-mediated actions in humans.

Adrenocorticotropic Hormone↗

PubMed1977

Estrogen photoaffinity labels. 2. Reversible binding and covalent attachment of photosensitive hexestrol derivatives to the uterine estrogen receptor.

The ability of two radiolabeled, photoreactive estrogen analogues, [3H]hexestrol diazoketopropyl ether ([3H]Hex-DKP) and [3H]hexestrol azide ([3H]Hex-N3), to covalently label the uterine estrogen receptor is studied. Lamb uterine estrogen receptor preparations that have been partially purified (ammonium sulfate precipitation, Sephadex G-200 chromatography) and disaggregated by limited trypsinization can be electrophoresed on polyacrylamide gels under conditions where binding activity is preserved. This electrophoretic procedure was used to fractionate the proteins labeled by the two photoreactive estrogen analogues. Prior to photolysis, peaks of radioactivity indicating estrogen specific binding of [3H]-Hex-N3 and [3H]Hex-DKP are evident on the gels, although dissociation of the latter compound is extensive. When preparations of uterine estrogen receptor that contain the photoreactive derivatives are irradiated and then electrophoresed, reversibly labeled proteins can be distinguished from irreversibly labeled ones (covalently bonded), by extraction of the individual gel slices with organic solvents. While no irreversible binding to receptor appears to result from irradiation with [3H]Hex-DKP, irradiation with [3H]Hex-N3 does covalently label the estrogen receptor. The receptor covalently labeled with [3H]Hex-N3 has the same electrophoretic mobility as the unlabeled receptor; the covalent labeling process is estrogen-site specific, and the efficiency of labeling (15-20%) is consistent with the inactivation efficiency of Hex-N3, previously measured by an indirect assay. This is the first example of the labeling of a steroid hormone receptor by photoaffinity labeling.

Affinity Labels↗

PubMed1997

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↗

PubMed1997

Low hexarelin dose and pyridostigmine have additive effect and potentiate to the same extent the GHRH-induced GH response in man.

OBJECTIVES: Hexarelin (HEX) is a synthetic hexapeptide belonging to the growth hormone-releasing peptide (GHRP) family. The exact mechanism underlying the strong GH-releasing activity of GHRPs is still unclear, though it has been shown that they act both at the pituitary and the hypothalamic level, where they have specific receptors. To clarify the influence of the cholinergic system on the GH-releasing activity of GHRPs in man, we investigated the effects of pyridostigmine, a cholinergic agonist which stimulates GH secretion by inhibiting somatostatin release, on the GH response to various HEX doses. DESIGN: We studied the GH release induced by various HEX doses (0.25, 0.5 and 2.0 micrograms/kg i.v.) and pyridostigmine (PD, 120 mg po), both alone and coadministered. The interactions between the lowest HEX dose or PD and the maximally effective GHRH dose (1.0 microgram/kg i.v.) were also studied. SUBJECTS: Six normal male volunteers, aged 24-30 years, were studied. MEASUREMENTS: Serum GH was measured in duplicate by immunoradiometric assay. RESULTS: The GH response to HEX administration was dose-dependent. In fact, the GH response to 0.25 microgram/kg HEX (AUC, mean +/- SEM: 816.4 (235.6 mU/l/120 min) was lower, although not significantly, than that to 0.5 microgram/kg HEX (2154.6 +/- 491.6 mU/l/120 min), which, in turn, was lower (p < 0.05) than that after 2.0 micrograms/kg HEX (4819.2 +/- 668.0 mU/l/120 min). The GH rise after GHRH (1299.2 +/- 222.8 mU/l/120 min) was lower (P < 0.05) than that after 2.0 micrograms/kg HEX, but not different from the responses to either 0.25 or 0.5 microgram/kg HEX. PD induced a significant GH rise (559.0 +/- 129.8 mU/l/120 min, P < 0.05 vs saline), similar to that after 0.25 microgram/kg HEX, and lower than those after both 0.5 and 2.0 micrograms/kg HEX (P < 0.05 and p < 0.01, respectively) and GHRH (p < 0.05). PD pretreatment enhanced the GH response to the lowest HEX dose (1961.4 +/- 253.8 mU/l/120 min, p < 0.05) in an additive way, but failed to modify the GH response to either 0.5 or 2.0 micrograms/kg HEX (2753.6 +/- 444.6 and 5179.0 +/- 770.8 mU/l/120 min, respectively). Notably, the GH response to 0.25 microgram/kg HEX + PD was still lower (P < 0.05) than that to 2.0 micrograms/kg HEX. PD pretreatment as well as 0.25 microgram/kg HEX truly potentiated the GH response to GHRH to the same extent (4926.6 +/- 912.8 mU/l/120 min, p < 0.05 and 5958.8 +/- 750.0 mU/l/120 min, p < 0.05 respectively). The GH responses to PD + GHRH and 0.25 microgram/kg HEX + GHRH were similar to that after 2.0 micrograms/kg HEX alone. CONCLUSIONS: Our results demonstrate that pyridostigmine is able to enhance the GH response only to a very low dose Hexarelin which, in turn, potentiates the GHRH-induced GH rise to the same extent as pyridostigmine. As there is evidence that GHRPs do not inhibit hypothalamic somatostatin release, these findings are consistent with the hypothesis that they act by antagonizing somatostatin activity and/or through unknown factors. On the other hand, though there is evidence showing that GHRH activity is needed for GHRP action, our findings indicate that GHRPs act, at least partially, independently of GHRH.

Adult↗

PubMed1982

Synthesis and evaluation of catechol analogs of diethylstilbestrol on a hormone-dependent human mammary carcinoma implanted in nude mice.

3,4-Bis(3',4'-diacetoxyphenyl)hex-3-ene (5a), 4(4'-acetoxyphenyl)-3(3',4'-diacetoxyphenyl)hex-3-ene (5b), and 4(3'-acetoxyphenyl)-3(3',4'-diacetoxyphenyl)hex-3-ene (5c) were synthesized according to the method of Dodds et al. (1939). All compounds inhibited the interaction of 3H-estradiol with its receptor. The relative binding affinity (RBA) values increased in the order: 5a (1.0) less than 5c (7.6) less than 5b (21.7). In the immature mouse uterine weight bioassay, the uterotrophic activity of 5a-c was only weak. 5a and 5c, but not 5b, exhibited significant antiuterotrophic properties. All compounds significantly inhibited the growth of a postmenopausal hormone-dependent human mammary carcinoma serially implanted in nude mice.

Animals↗

PubMed2001

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.

An endogenous ligand for the GH secretagogue-receptor (GHS-receptor) has recently been isolated, from both the rat and the human stomach, and named ghrelin. It is a 28-amino-acid peptide showing a unique structure with an n-octanoyl ester at its third serine residue, which is essential for its potent stimulatory activity on somatotroph secretion. In fact, it has been demonstrated that ghrelin specifically stimulates GH secretion from both rat pituitary cells in culture and rats in vivo. The aim of the present study was to test the GH-releasing activity of ghrelin in humans and to compare it with that of GHRH and hexarelin (HEX), a nonnatural peptidyl GHS, which possesses strong GH-releasing activity but also significantly stimulates PRL, ACTH, and cortisol secretion. To clarify the mechanisms of action underlying the GH-releasing activity of ghrelin in humans, its interaction with GHRH and HEX was also studied. Seven normal young volunteers (7 men; 24-32 yr old; body mass index, 20-24 kg/m(2)) were studied. All subjects underwent the administration of ghrelin, HEX, and GHRH-29 (1.0 microg/kg i.v. at 0 min) as well as placebo (2 mL isotonic saline i.v. at 0 min). Six subjects also underwent the combined administration of ghrelin and GHRH or HEX. Blood samples were taken every 15 min from -15 up to +180 min. GH levels were assayed at each time point in all sessions; PRL, ACTH, cortisol, and aldosterone levels were also assayed after administration of ghrelin and/or HEX. Ghrelin administration induced a prompt and marked increase in circulating GH levels (Cmax, mean +/- SEM, 92.1 +/- 16.7 microg/L; area under the curve, 1894.9 +/- 347.8 microg/L.h). The GH response to ghrelin was clearly higher (P < 0.01) than the one recorded after GHRH (26.7 +/- 8.7 microg/L; 619.6 +/- 174.4 microg/L.h) and even significantly higher (P < 0.05) than after HEX (68.4 +/- 14.7 microg/L; 1546.9 +/- 380.0 microg/L x h). Ghrelin administration also induced an increase in PRL, ACTH, and cortisol levels; these responses were higher (P < 0.05) than those elicited by HEX. A significant increase in aldosterone levels was recorded after ghrelin but not after HEX. The endocrine responses to ghrelin were not modified by the coadministration of HEX. On the other hand, the coadministration of ghrelin and GHRH had a real synergistical effect (P < 0.05) on GH secretion (133.6 +/- 22.5 microg/L; 3374.3 +/- 617.3 microg/L x h). In conclusion, ghrelin, a natural ligand of GHS-receptor, exerts a strong stimulatory effect on GH secretion in humans, releasing more GH than GHRH and even more than a nonnatural GHS such as HEX. Ghrelin, as well as HEX, also stimulates lactotroph and corticotroph secretion. Ghrelin shows no interaction with HEX, whereas it has a synergistical effect with GHRH on GH secretion. Thus, ghrelin is a new hormone playing a major role in the control of somatotroph secretion in humans, and its effects are imitated by nonnatural GHS.

Adrenocorticotropic Hormone↗

PubMed1999

Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans.

Reduced cardiac mass and performances are present in GH deficiency and are counteracted by rhGH replacement. GH and IGF-I possess specific myocardial receptors and have been reported able to exert an acute inotropic effect. Synthetic GH secretagogues (GHS) possess specific pituitary and hypothalamic but even myocardial receptors. In 7 male volunteers, we studied cardiac performance by radionuclide angiocardiography after iv administration of rhGH or hexarelin (HEX), a peptidyl GHS. The administration of rhGH or HEX increased circulating GH levels to the same extent (AUC: 1594.6+/-88.1 vs 1739.3+/-262.2 microg/l/min for 90 min) while aldosterone and catecholamine levels did not change; HEX, but not rhGH, significantly increased cortisol levels. Left ventricular ejection fraction (LVEF), mean blood pressure (MBP) and heart rate (HR) were unaffected by rhGH (62.4+/-2.1 vs 62.1+/-2.3%, 90.6+/-3.4 vs 92.0+/-2.5 mm Hg, 62.3+/-1.8 vs 66.7+/-2.7 bpm). HEX increased LVEF (70.7+/-3.0 vs 64.0+/-1.5%, p<0.03) without significant changes in MBP and HR (92.8+/-4.7 vs 92.4+/-3.2 mm Hg, 63.1+/-2.1 vs 67.0+/-2.9 bpm). LVEF significantly raised at 15 min, peaked at 30 min and lasted up to 60 min after HEX. These findings suggest that in man, the acute administration of Hexarelin exerts a short-lasting, positive inotropic effect. This effect seems GH-independent and might be mediated by specific GHS myocardial receptors.

Adult↗

PubMed1999

Vasopressin and angiotensin II in blood pressure control during isoflurane anesthesia in rats.

BACKGROUND: Hormonal systems such as vasopressin (AVP) and the renin-angiotensin-aldosterone system (RAS) have been reported to become activated during anesthesia and surgery. The purpose of this study was to examine the relative importance of AVP and angiotensin II (AII) in blood pressure control during isoflurane anesthesia in rats. METHODS: Rats were given an AVP V1-receptor antagonist (AVP-a, 10 microg kg(-1)), the AII receptor antagonist saralasin (SAR, 20 microg kg(-1) min(-1)) and hexamethonium (HEX, 10 mg kg(-1)) intravenously in random order, awake or anesthetized with isoflurane. RESULTS: AVP-a had no effect on mean arterial pressure (MAP) in awake or anesthetized animals, but reduced MAP by 20.0+/-2.2% in the anesthetized rats which previously had been treated with SAR and/or HEX. SAR infusion had no effect on MAP when administered to conscious rats, but decreased MAP by 12.0+/-4.4% during anesthesia. Ganglionic blockade with HEX consistently lowered MAP in the conscious and anesthetized animals. CONCLUSION: It is concluded that AVP contributes to the maintenance of blood pressure when the autonomic nervous system (ANS) and/or RAS are blocked during isoflurane anesthesia. SAR infusion leads to hypotension during anesthesia, but not in conscious rats. These findings indicate that AII is of importance for blood pressure maintenance during isoflurane anesthesia in rats, and that apparent pressor effects of AVP come into play when RAS and/or ANS are blocked.

Anesthesia, Inhalation↗

PubMedDate not supplied

Effects of cholinergic agonists and antagonists on interleukin-2-induced corticotropin-releasing hormone release from the mediobasal hypothalamus.

In previous research we found that interleukin-2 (IL-2)-induced corticotropin-releasing hormone (CRH) release in vitro is mediated by cholinergic activation of nitric oxidergic (NOergic) neurons. The NOergic neurons release nitric oxide that stimulates CRH release. To further characterize the mechanism of IL-2-induced CRH release, the possible role of nicotinic as well as muscarinic receptors in IL-2-stimulated CRH release was evaluated. Medial hypothalamic (MH) explants from adult male rats were preincubated in Krebs-Ringer (KRB) buffer for 45 min followed by incubation for an additional 30 min in fresh KRB or KRB containing various compounds. As previously reported, acetylcholine (ACH) stimulated CRH release in a dose-related fashion. IL-2 (10(-13) M) stimulation of CRH release was unaffected by the lower concentration of ACH (10(-9) M), but surprisingly was inhibited by a 100-fold higher concentration. Atropine (ATR) (10(-7) M) blocked CRH release induced by ACH (10(-7) M) and the release of CRH induced by IL-2. The cholinergic agonist carbachol (CAR) (10(-7) M) also released CRH and this action was blocked by ATR (10(-7) M). CRH release in the presence of CAR was lowered below basal when the concentration of ATR was increased to 10(-6) M. In contrast to ACH, CAR had an additive effect to release CRH when combined with IL-2 (10(-13) M). Nicotine (10(-7) M) also stimulated CRH release and this stimulation was completely blocked by 10(-6) M but not by 10(-7) M of the nicotinic receptor blocker, hexamethonium (HEX). The lower concentration of HEX blocked the stimulatory effect of ACH (10(-7) M) and IL-2 on CRH release. Combined blockade with ATR plus HEX completely blocked the action of ACH and even reduced the CRH concentration to below basal values. Furthermore, combined blockade completely blocked the release of CRH induced by IL-2. We conclude that nicotinic as well as muscarinic receptors play an important role in CRH release, and that they both act to mediate IL-2-stimulated CRH release.

Acetylcholine↗

PubMed1998

Dopaminergic modulation of hexarelin-induced GH and PRL secretion in hyperprolactinemia.

Hexarelin (Hex), a synthetic GH-releasing peptide, has recently been found to possess a weak PRL-releasing effect in normals. The aims of this study were to investigate the effect of Hex on GH and PRL secretion in 10 hyperprolactinemic women (HPRL) and 7 controls (C). All subjects underwent stimulus testing with placebo, bromocriptine (Br) (2.5 mg po at time -60), Hex (2 micrograms/kg/bw i.v.), and Br plus Hex. During placebo, HPRL showed a higher (p < 0.01) PRL area under curve (AUC) than C. Br significantly (p < 0.01) reduced PRL AUC both in HPRL and in C. Hex was able to induce a slight but significant (p < 0.05) PRL release in both groups. PRL response to Hex was abolished (p < 0.01 vs Hex) by Br priming in HPRL, while it was only blunted (p < 0.05 vs Hex) in C. Br induced a significant (p < 0.01) GH increase in both groups. However, GH AUC after Br was significantly higher (p < 0.01) in C than HPRL. Hex induced a significant (p < 0.01) GH release both in HPRL and in C. Br priming did not modify GH response to Hex in HPRL while it slightly (p < 0.05) increased GH response to Hex in C, suggesting that neuroendocrine modifications present in HPRL might, per se, be able to impair GH response to Br plus Hex, thus giving rise to receptor competition. Hex had a weak PRL-releasing effect in both groups studied, this was only blunted by Br priming in C but was abolished in HPRL, suggesting that oversensitivity to DA-ergic agents present in HPRL could be able to antagonize completely Hex action.

Adult↗

PubMed2004

Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes.

Ghrelin exerts various metabolic activities, including regulation of glucose levels in humans. To verify whether the glucose response to ghrelin reflects a modulation of an insulin-independent hepatic phenomenon, we studied glucose output by primary porcine hepatocytes in suspension culture, after incubation with acylated ghrelin (AG), unacylated ghrelin (UAG), and hexarelin (HEX). AG induced glucose output dose dependently after 20 min of incubation (P < 0.001), whereas HEX, a GH secretagogue receptor type 1a (GHS-R1a) agonist, had no effect. UAG inhibited glucose release also dose dependently and after 20 min (P < 0.001). Moreover, UAG completely reversed AG-induced glucose output (P < 0.01). Using real-time PCR, GHS-R1a gene expression was undetectable in all the hepatocyte preparations studied. The lack of efficacy of HEX, the efficacy of UAG, and the absence of GHS-R1a expression indicate the involvement of a yet uncharacterized ghrelin receptor type. In conclusion, glucose output by primary hepatocytes is time- and dose-dependently stimulated by AG and inhibited by UAG. Moreover, UAG counteracts the stimulatory effect of AG on glucose release. These actions might be mediated by a different receptor than GHS-R1a, and apparently, we must consider AG and UAG as separate hormones that can modify each other's actions on glucose handling, at least in the liver.

Animals↗

PubMed1999

Effects of recombinant human insulin-like growth factor I administration on growth hormone (GH) secretion, both spontaneous and stimulated by GH-releasing hormone or hexarelin, a peptidyl GH secretagogue, in humans.

The negative feedback exerted by insulin-like growth factor I (IGF-I) on GH secretion occurs at the pituitary, as well as the hypothalamic level, via stimulation of SS and/or inhibition of GHRH release. In fact, recombinant human IGF-I (rhIGF-I) administration inhibits basal GH secretion, at least in fasted humans, though its effect on the GH response to GHRH is still controversial. GH secretagogues (GHS) are peptidyl and nonpeptidyl molecules that act on specific receptors at the pituitary and/or the hypothalamic level. Contrary to GHRH, the GH-releasing activity of GHS is strong, reproducible, and even partially refractory to inhibitory influences such as exogenous somatostatin. We studied the effects of rhIGF-I administration (20 microg/kg s.c. at 0 min) on GH secretion, either spontaneous or stimulated by GHRH (2 microg/kg i.v. at +180 min) or Hexarelin (HEX, 2.0 microg/kg i.v at +180 min), a GHS, in eight normal young women (age, mean +/- SEM, 28.3 +/- 1.2 yr; body mass index, 20.1 +/- 0.5 kg/m2). rhIGF-I administration increased IGF-I levels (peak vs. baseline: 420.3 +/- 30.5 vs. 274.4 +/- 25.3 microg/L, P < 0.05) within the physiological range from +120 to +300 min. No variation in glucose or insulin levels was recorded. rhIGF-I did not reduce spontaneous GH secretion [areas under curves (AUC)(0-300 min) 140.6 +/- 66.3 vs. 114.6 +/- 32.1 microg/L x h], whereas it inhibited the GH response to both GHRH (AUC(180-300 min) 447.7 +/- 159.4 vs. 715.9 +/- 104.3 microg/L x h, P < 0.05) and HEX (620.3 +/- 110.4 vs. 1705.9 +/- 328.9 microg/L x h, P < 0.03). The percent inhibitory effect of rhIGF-I on the GH response to GHRH (41.7 +/- 12.8%) was lower than that on the response to HEX (57.7 +/- 11.0%). In fact, the GH response to GHRH alone was clearly lower than that to HEX alone (P < 0.05), whereas the GH responses to GHRH and HEXwere similar after rhIGF-I. Our findings show that the sc administration of low rhIGF-I doses inhibits the GH response to GHRH and, even more, that to HEX; whereas, at least in this experimental design in fed conditions, it does not modify the spontaneous GH secretion. Because GHS generally show partial refractoriness to inhibitory inputs, including exogenous somatostatin, the present results point toward a peculiar sensitivity of GHS to the negative feedback action of IGF-I.

Adult↗

PubMed1999

Corticotropin-releasing effect of hexarelin, a peptidyl GH secretagogue, in normal subjects pretreated with metyrapone or RU-486, a glucocorticoid receptor antagonist, and in patients with Addison's disease.

GH secretagogues (GHS) are peptidyl and nonpeptidyl molecules which possess strong GH-releasing activity but also stimulatory effect on hypothalamo-pituitary-adrenal axis. The ACTH and cortisol responses to Hexarelin (HEX), a peptidyl GHS, are abolished by low-dose dexamethasone pretreatment in normal subjects but are exaggerated and higher than those after hCRH in patients with pituitary ACTH-dependent Cushing's disease, in spite of their hypercortisolism. Based on the foregoing, we studied the ACTH, cortisol and GH responses to HEX (2.0 microgram/kg i.v. at 0 min) alone and after metyrapone (2 g p.o. at 23:00 h the night before) or RU-486 (400 mg p.o. at 02:00 h), a glucocorticoid receptor antagonist, in 6 normal women (NS, age 26-34 years). The endocrine responses (mean +/- SEM) to HEX alone were also studied in 8 patients with Addison's disease (AD, 6 males, 2 females, age 30-77 years; last hydrocortisone administration the day before testing). In NS, HEX stimulated basal ACTH (peak, mean +/- SEM: 26.0 +/- 7.8 vs. 10.7 +/- 2.0 pg/ml, p < 0. 05), cortisol (163.2 +/- 18.3 vs. 137.4 +/- 15.4 microgram/l, p < 0.05) and GH (72.6 +/- 23.5 vs. 3.7 +/- 1.3 microgram/l, p < 0.01) levels. Metyrapone markedly increased basal ACTH (294.4 +/- 61.6 pg/ml, p < 0.05), reduced basal cortisol (19.6 +/- 7.2 microgram/l, p < 0.05), while it did not modify GH levels. After metyrapone pretreatment the ACTH response to HEX was clearly increased (DeltaAUC: 2,857.4 +/- 901.9 vs. 367.3 +/- 274.0 pg/ml/h, p < 0.05), while the GH response was not modified. HEX did not stimulate the low cortisol levels after metyrapone pretreatment. RU-486 significantly increased basal ACTH (76.6 +/- 12.5 pg/ml, p < 0.05) and cortisol (312.7 +/- 22.2 microgram/l, p < 0.05), while it did not modify basal GH levels. RU-486 pretreatment did not modify the ACTH, cortisol and GH responses to HEX. In AD, HEX elicited a marked ACTH response (6,619.4 +/- 3,365.8 pg/ml/h; p < 0.01), which was clearly higher (p < 0.01) than that in NS after HEX alone but not significantly different from that after HEX+MET. The GH response to HEX in AD (1,325.6 +/- 284.1 microgram/l/h) was similar to that in NS (1,519.7 +/- 483.8 microgram/l/h). In conclusion, our present data demonstrate that the ACTH-releasing activity of HEX is increased in primary hypoadrenalism as well as in normal subjects after metyrapone but not after RU-486 pretreatment. These findings indicate that in normal subjects as well as in hypocortisolemic patients the ACTH-releasing activity of GHS is enhanced by the lack of negative glucocorticoid feedback.

Addison Disease↗

PubMed1997

Hexarelin is a stronger GH-releasing peptide than GHRH in normal cycling women but not in anorexia nervosa.

Anorexia nervosa (AN) is a chronic disease in which an enhanced GH response to GHRH, a paradoxic increase after TRH and LHRH, and low IGF1 levels may be present according to the patient's clinical state. It is well known that the GH hypersecretory state commonly found in the "acute phase" of AN is restored with weight gain. The new synthetic hexapeptide, Hexarelin (HEX), which is chemically similar to GH-releasing peptide 6, has recently been shown to possess a stronger GH-releasing activity than GHRH in humans and to share a synergistic effect with GHRH when administered intravenously. Indeed, HEX shows a slight cortisol and PRL-releasing activity. The aim of the study was to evaluate the effect of i.v. administration of old (GHRH) and new (HEX) GH-releasing peptides on GH, PRL and cortisol secretion in 9 AN patients in the "recovery phase" of the disease, after partial but significant weight gain. For controls we studied 7 normal cycling women. No significant difference in GH secretion after GHRH was found between AN and controls. GHRH was not able to release cortisol or PRL either in AN or controls. HEX produced a significantly (p < 0.05) higher GH peak in controls than in AN, while GH AUC was slightly but not significantly higher. Indeed, only in controls, HEX was a stronger GH-releasing peptide than GHRH. These findings could be explained by the fact that, in AN, GH secretion is already stimulated both by reduced IGF1 levels and by increased GHRH/somatostatin ratio. As reported in the literature, the action of HEX action is only slightly influenced by variations in somatostatin tone. It therefore appears likely that the absolute or relative GHRH increase present in AN could partially mimic the unknown hypothalamic factor necessary for HEX action on the hypophisis and that, following a structural modification of pituitary HEX receptors, GHRH would become able to bind to HEX receptors on somatotropic cells. Consequently, the pituitary cells would already be over-activated and so unable to respond maximally to HEX stimulation. Indeed, in AN, GHRH might play a role of negative modulation in the control of HEX action. Finally, in our study HEX was able to produce a persistent PRL release in controls but not in AN, thus suggesting that its action could be partially dependent on the estrogen milieu, while it stimulated cortisol secretion only transiently in the patients studied.

Adolescent↗

PubMed1998

Age-related variations in the neuroendocrine control, more than impaired receptor sensitivity, cause the reduction in the GH-releasing activity of GHRPs in human aging.

The mechanisms underlying the reduction in the GH-releasing activity of GHRPs in aging are still unclear. Aim of our study was to verify in man whether age-related impairment of the neurohormonal control of GH secretion and/or receptor alterations are involved in the reduced GH response to GHRPs in aging. To this goal, in 16 normal elderly subjects (E, 66-81 yr) and 12 young controls (Y, 24-28 yr) we studied the effects of 1.0, 2.0 and 3.0 micrograms/kg i.v. Hexarelin (HEX), a synthetic hexapeptide, or GHRH, as well as the interaction among HEX (2.0 micrograms/kg), GHRH (2.0 micrograms/kg) and arginine (ARG, 0.5 gr/kg) on GH secretion. In Y the GH response to increasing doses of HEX (1.0 vs. 2.0 vs. 3.0 micrograms/kg; AUC0;v-120 +/- SEM: 1728.4 +/- 406.4 vs. 2265.9 +/- 298.4 vs. 2934.3 +/- 482.2 micrograms/L/h, p < 0.05 for 1.0 vs. 2.0 micrograms/kg) and GHRH (649.6 +/- 111.4 vs. 792.2 +/- 117.6 vs. 1402.6 +/- 363.0 micrograms/L/h) showed a progressive increase. Two micrograms/kg HEX and 1 microgram/kg GHRH were the maximal effective doses. Similarly, in E the GH response to increasing doses of HEX (336.7 +/- 50.0 vs. 742.8 +/- 157.9 vs. 1205.1 +/- 178.1 micrograms/L/h, p < 0.05 for 1.0 vs. 2 micrograms/kg, p < 0.001 for 1.0 vs. 3.0 micrograms/kg and p < 0.03 for 2.0 vs. 3.0 micrograms/kg) and GHRH (183.8 +/- 27.3 vs. 260.9 +/- 17.3 vs. 356.1 +/- 46.3 micrograms/L/h, p < 0.005 for 1.0 vs. 3.0 micrograms/kg and p < 0.05 for 2.0 vs. 3.0 micrograms/kg) showed a progressive increase. In E the GH response to 3 micrograms/kg HEX or GHRH were clearly higher than those to 2 micrograms/kg. However, at each dose the GH responses to HEX or GHRH in E were lower (p < 0.05) than those in Y. In Y the GH response to HEX + GHRH was synergistical (4259.2 +/- 308.0 micrograms/L/h, p < 0.05). ARG strikingly potentiated the GHRH-induced GH rise (2640.8 +/- 273.6 micrograms/L/h, p < 0.01) but not the HEX-induced one (2371.7 +/- 387.2 micrograms/L/h) as well as the synergistical effect of HEX and GHRH (4009.1 +/- 360.8 micrograms/L/h). In E the GH response to HEX and GHRH was still synergistical (1947.7 +/- 306.0 micrograms/L/h, p < 0.05) but these responses were lower than those in young (p < 0.01). On the other hand, in E ARG restored the GH response to GHRH (1858.9 +/- 172.8 micrograms/L/h, p < 0.01) and even those to HEX (2069.5 +/- 528.7 micrograms/L/h, p < 0.01) and HEX + GHRH (4406.0 +/- 1079.2 micrograms/L/h, p < 0.05). Our present results indicate that the impairment of GHRP and GHRH receptor activity may have a role in the reduction of the somatotrope responsiveness in aging. However, the age-related reduction in the GH-releasing activity of GHRPs seems mainly dependent on age-related variations in the neural control, i.e. concomitant GHRH hypoactivity and somatostatinergic hyperactivity.

Adult↗

PubMed1999

Tyr-Ala-Hexarelin, a synthetic octapeptide, possesses the same endocrine activities of Hexarelin and GHRP-2 in humans.

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.

Adrenocorticotropic Hormone↗