Ghrelin and Growth Hormone:
Human Growth hormone pulsed release is regulated through the intermittent non-secretion of somatostatin while the amplitude of GH release is determined by GHRH. Ghrelin stimulates GH secretion independent of these pathways. Growth Hormone secretagogues act through specific G-protein coupled receptors that are distinct from that of GHRH. J Clin Endocrinol Metab. 2002 Jun;87(6):2988 Ghrelin administration in rats produces a peak GH response at 5-15 minutes with return to basal levels within an hour. The GH response elicited is about 2-3 times that evoked by GHRH alone. Eur J Endocrinol. 2000 Nov;143(5):R7-9.Simultaneous administration of Ghrelin and GHRH has a synergistic effect on GH release. J Clin Endocrinol Metab. 2001 Sep;86(9):4552 Ghrelin administration in humans also elicits a stronger GH secretion response than with GHRH. J Clin Endocrinol Metab. 2000 Dec;85(12):4908-11. But despite initial theories, Ghrelin is no longer thought to be a major regulator of GH secretion in vivo in humans due to many reasons. GH secretion occurs normally in the absence of Ghrelin. Ghrelin knocked-out mice attained normal size with normal GH levels. Suppression of GH secretion by GHRH antagonist did not alter Ghrelin concentration profiles in acromegalic humans. GH treatment in GH deficient mice did not change Ghrelin levels. Insulin tolerance test failed to change Ghrelin levels despite producing increases in GH. Further, despite a 50 fold rise in Ghrelin levels in a case of pancreatic Ghrelinoma, no associated rise in GH or IGF1 was evident. J Clin Endocrinol Metab. 2003 Jul;88(7):3117-20 Studies showed no coincidence of GH and Ghrelin pulses. But a study in 8 healthy men sampling at 20 minute intervals for 12 hours has demonstrated a relationship between Ghrelin and GH pulsatility. Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E506-12 While this might show co-secretion of the two, no direct regulatory role for Ghrelin on GH secretion has been demonstrated. In that study, although GHRH failed to increase Ghrelin, the combination of GHRH and arginine increased Ghrelin levels suggesting the role of somatostatin inhibition in Ghrelin release.
Ghrelin and Growth
Ghrelin and Newborns:
Plasma Ghrelin estimation in 54 cord blood samples (gestational age 37 - 41.6 wk; birth weight, 2206-4326 g) and 47 neonatal blood samples ( postnatal d 3-8) revealed that plasma Ghrelin concentrations in cord blood ranged from 110.6-446.1 pmol/liter, which were equal to or higher than those in normal weight adults.J Clin Endocrinol Metab. 2003 Nov;88(11):5473-7) These values were significantly and inversely correlated with birth weight, birth length, placental weight, and IGF-I concentration , but were not significantly correlated with the GH concentration ( P = 0.12). The Ghrelin concentrations in small for gestational age newborn were significantly higher than those in appropriate for gestational age newborns. The Ghrelin concentrations in the vein were significantly higher than those in the artery in 8 cord blood samples , suggesting that the placenta is an important source of fetal Ghrelin. In neonates, the Ghrelin concentrations ranged from 133.0-481.7 pmol/liter (median, 268.3 pmol/liter), which were significantly higher than those in cord blood. Lower cord Ghrelin levels in term infants are associated with slower weight gain from birth to 3 months of age J Clin Endocrinol Metab. 2004 Aug;89(8):3847-50 while lower Ghrelin levels have been related to slower growth in small for gestational age infants. Caesarean section has been found to result in lower Ghrelin levels in the new born compared to normal delivery with no correlation of Ghrelin with age gender insulin glucose or growth hormone in (93 full term healthy) newborns. J Endocrinol Invest. 2003 Apr;26(4):RC9-11
Catch up weight gain in small for gestational age babies has been shown to correlate with 10 minute post IV glucose Ghrelin levels but not fasting glucose levels, although Ghrelin suppression with IV glucose was similar in both small and adequate- for- gestational age babies. Higher Ghrelin levels (lower suppression post IV glucose) was associated with better catch up weight gain. J Clin Endocrinol Metab. 2002 Dec;87(12):5830-3
Pre-pubertal children have higher Ghrelin concentrations than those in puberty [218 pg/ml (n = 42) and 157 pg/ml (n = 79), P < 0.001], with significant negative correlations between Ghrelin and age . The decrease in Ghrelin with advancing pubertal stage/age was more marked in boys than girls. In the whole group, Ghrelin was negatively correlated to BMI. Ghrelin was also negatively correlated to IGF-I, IGFBP-3 and Leptin but not IGF-II. It was positively related to IGFBP-1. This data may suggest that it is not a direct growth-promoting hormone. But the inverse relationship with IGF-I and the positive relationship with IGFBP-1, could suggest that decreasing Ghrelin levels might trigger or facilitate growth acceleration over puberty. Clin Endocrinol (Oxf). 2003 Nov;59(5):649-54.
Ghrelin levels after overnight fasting in prepubertal and pubertal children are similar to those in young adults. But food intake does not suppress Ghrelin levels in pre pubertal children. J Clin Endocrinol Metab. 2004 Apr;89(4):1662-5
Ghrelin and Ageing
Normal (healthy) ageing is associated with a decrease in appetite and energy intake, NHANES 1988–1991. Am J Clin Nutr 62(Suppl):1072S–1080S. with resultant weight loss in the elderly predominantly due to protein loss from muscles. Am J Epidemiology. 147, Issue 8 755-763. Growth hormone decreases with age as does testosterone levels, all of which could have a relationship to Ghrelin secretion or sensitivity.
Normal ageing has been shown to be associated with lower Ghrelin levels. Ghrelin levels were lower by 35% in older normal weight patients (n=7)compared to younger normal weight patients (n=12). J Endocrinol. 2002 Oct;175(1):R1-5. Another study demonstrated a 20% lower mean Ghrelin levels at baseline in well nourished older subjects compared to healthy younger subjects. J Clin Endocrinol Metab. 2003 Aug;88(8):3747-55. In that study, a mixed meal produced less Ghrelin suppression in the older healthy subjects. Both older groups in both studies had higher BMI which could explain the lower Ghrelin levels found. Normal age related trend in Ghrelin levels in older healthy people, independent of body composition, needs to be elucidated.
A study in 18 young and 16 elderly subjects showed that the GH-releasing effect of Ghrelin undergoes age-related decline. The effects of Ghrelin on ACTH and PRL secretion was similar in young and elderly. J Clin Endocrinol Metab. 2003 Apr;88(4):1537-42
Plasma Ghrelin levels have been shown to be significantly lower in hypogonadal men than in BMI matched eugonadal controls. J Clin Endocrinol Metab. 2003 Sep;88(9):4139-43 Testosterone levels tend to decrease with age and this might be a cause (or effect) of associated Ghrelin reductions in the elderly. Testosterone replacement increases Ghrelin levels suggesting the former explanation.
Human Growth hormone pulsed release is regulated through the intermittent non-secretion of somatostatin while the amplitude of GH release is determined by GHRH. Ghrelin stimulates GH secretion independent of these pathways. Growth Hormone secretagogues act through specific G-protein coupled receptors that are distinct from that of GHRH. J Clin Endocrinol Metab. 2002 Jun;87(6):2988 Ghrelin administration in rats produces a peak GH response at 5-15 minutes with return to basal levels within an hour. The GH response elicited is about 2-3 times that evoked by GHRH alone. Eur J Endocrinol. 2000 Nov;143(5):R7-9.Simultaneous administration of Ghrelin and GHRH has a synergistic effect on GH release. J Clin Endocrinol Metab. 2001 Sep;86(9):4552 Ghrelin administration in humans also elicits a stronger GH secretion response than with GHRH. J Clin Endocrinol Metab. 2000 Dec;85(12):4908-11. But despite initial theories, Ghrelin is no longer thought to be a major regulator of GH secretion in vivo in humans due to many reasons. GH secretion occurs normally in the absence of Ghrelin. Ghrelin knocked-out mice attained normal size with normal GH levels. Suppression of GH secretion by GHRH antagonist did not alter Ghrelin concentration profiles in acromegalic humans. GH treatment in GH deficient mice did not change Ghrelin levels. Insulin tolerance test failed to change Ghrelin levels despite producing increases in GH. Further, despite a 50 fold rise in Ghrelin levels in a case of pancreatic Ghrelinoma, no associated rise in GH or IGF1 was evident. J Clin Endocrinol Metab. 2003 Jul;88(7):3117-20 Studies showed no coincidence of GH and Ghrelin pulses. But a study in 8 healthy men sampling at 20 minute intervals for 12 hours has demonstrated a relationship between Ghrelin and GH pulsatility. Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E506-12 While this might show co-secretion of the two, no direct regulatory role for Ghrelin on GH secretion has been demonstrated. In that study, although GHRH failed to increase Ghrelin, the combination of GHRH and arginine increased Ghrelin levels suggesting the role of somatostatin inhibition in Ghrelin release.
Ghrelin and Growth
Ghrelin and Newborns:
Plasma Ghrelin estimation in 54 cord blood samples (gestational age 37 - 41.6 wk; birth weight, 2206-4326 g) and 47 neonatal blood samples ( postnatal d 3-8) revealed that plasma Ghrelin concentrations in cord blood ranged from 110.6-446.1 pmol/liter, which were equal to or higher than those in normal weight adults.J Clin Endocrinol Metab. 2003 Nov;88(11):5473-7) These values were significantly and inversely correlated with birth weight, birth length, placental weight, and IGF-I concentration , but were not significantly correlated with the GH concentration ( P = 0.12). The Ghrelin concentrations in small for gestational age newborn were significantly higher than those in appropriate for gestational age newborns. The Ghrelin concentrations in the vein were significantly higher than those in the artery in 8 cord blood samples , suggesting that the placenta is an important source of fetal Ghrelin. In neonates, the Ghrelin concentrations ranged from 133.0-481.7 pmol/liter (median, 268.3 pmol/liter), which were significantly higher than those in cord blood. Lower cord Ghrelin levels in term infants are associated with slower weight gain from birth to 3 months of age J Clin Endocrinol Metab. 2004 Aug;89(8):3847-50 while lower Ghrelin levels have been related to slower growth in small for gestational age infants. Caesarean section has been found to result in lower Ghrelin levels in the new born compared to normal delivery with no correlation of Ghrelin with age gender insulin glucose or growth hormone in (93 full term healthy) newborns. J Endocrinol Invest. 2003 Apr;26(4):RC9-11
Catch up weight gain in small for gestational age babies has been shown to correlate with 10 minute post IV glucose Ghrelin levels but not fasting glucose levels, although Ghrelin suppression with IV glucose was similar in both small and adequate- for- gestational age babies. Higher Ghrelin levels (lower suppression post IV glucose) was associated with better catch up weight gain. J Clin Endocrinol Metab. 2002 Dec;87(12):5830-3
Pre-pubertal children have higher Ghrelin concentrations than those in puberty [218 pg/ml (n = 42) and 157 pg/ml (n = 79), P < 0.001], with significant negative correlations between Ghrelin and age . The decrease in Ghrelin with advancing pubertal stage/age was more marked in boys than girls. In the whole group, Ghrelin was negatively correlated to BMI. Ghrelin was also negatively correlated to IGF-I, IGFBP-3 and Leptin but not IGF-II. It was positively related to IGFBP-1. This data may suggest that it is not a direct growth-promoting hormone. But the inverse relationship with IGF-I and the positive relationship with IGFBP-1, could suggest that decreasing Ghrelin levels might trigger or facilitate growth acceleration over puberty. Clin Endocrinol (Oxf). 2003 Nov;59(5):649-54.
Ghrelin levels after overnight fasting in prepubertal and pubertal children are similar to those in young adults. But food intake does not suppress Ghrelin levels in pre pubertal children. J Clin Endocrinol Metab. 2004 Apr;89(4):1662-5
Ghrelin and Ageing
Normal (healthy) ageing is associated with a decrease in appetite and energy intake, NHANES 1988–1991. Am J Clin Nutr 62(Suppl):1072S–1080S. with resultant weight loss in the elderly predominantly due to protein loss from muscles. Am J Epidemiology. 147, Issue 8 755-763. Growth hormone decreases with age as does testosterone levels, all of which could have a relationship to Ghrelin secretion or sensitivity.
Normal ageing has been shown to be associated with lower Ghrelin levels. Ghrelin levels were lower by 35% in older normal weight patients (n=7)compared to younger normal weight patients (n=12). J Endocrinol. 2002 Oct;175(1):R1-5. Another study demonstrated a 20% lower mean Ghrelin levels at baseline in well nourished older subjects compared to healthy younger subjects. J Clin Endocrinol Metab. 2003 Aug;88(8):3747-55. In that study, a mixed meal produced less Ghrelin suppression in the older healthy subjects. Both older groups in both studies had higher BMI which could explain the lower Ghrelin levels found. Normal age related trend in Ghrelin levels in older healthy people, independent of body composition, needs to be elucidated.
A study in 18 young and 16 elderly subjects showed that the GH-releasing effect of Ghrelin undergoes age-related decline. The effects of Ghrelin on ACTH and PRL secretion was similar in young and elderly. J Clin Endocrinol Metab. 2003 Apr;88(4):1537-42
Plasma Ghrelin levels have been shown to be significantly lower in hypogonadal men than in BMI matched eugonadal controls. J Clin Endocrinol Metab. 2003 Sep;88(9):4139-43 Testosterone levels tend to decrease with age and this might be a cause (or effect) of associated Ghrelin reductions in the elderly. Testosterone replacement increases Ghrelin levels suggesting the former explanation.