| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Tulane University Health Sciences Center (C.Y.B., R.G.), New Orleans, Louisiana 70112; Loma Linda University, J. L. Pettit Veterans Affairs Medical Center (S.M., D.B.), Loma Linda, California 92357; and Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools, General Clinical Research Center, Mayo Clinic (J.K., J.D.V.), Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Dr. Cyril Y. Bowers, Tulane University Health Sciences Center, Box SL 53, New Orleans, Louisiana 70112. E-mail: rjabower{at}tulane.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
0.024). In the entire cohort (n = 11), GHRP-2/GHRH (1/10) stimulated GH secretion more than either GHRP-2 (1; P = 0.021) or GHRH (10; P = 0.012). The 30-d delivery of GHRP-2 (1; n = 17 subjects): 1) stimulated pulsatile, rhythmic, and entropic GH secretion by more than 3-fold on d 1 and more than 1.8-fold on d 14 and 30 (each P < 0.001 vs. saline); 2) elevated IGF-I to a stable plateau on d 1, 14, and 30 (P < 0.025 vs. baseline); and 3) increased IGFBP-3 (P < 0.01) and IGFBP-5 (P < 0.025) on d 14 and/or 30. Safety screening tests remained normal. In summary, in healthy elderly women and men: 1) acute synergy of GHRP-2 and GHRH is greater in the female; 2) 24-h combined GHRP-2 and GHRH drive is more effective than either agonist alone; and 3) 30-d stimulation with GHRP-2 sustains a physiologically activated somatotropic axis. We conclude that age, gender, stimulus duration, and secretagogue combination determine acute, intermediate, and extended responses of the somatotropic axis in the older adult. |
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Acute administration of a high dose of GHRP downregulates homologous responsiveness of the somatotropic axis in all mammalian species studied (20, 21, 22, 23, 24). However, limited indirect data suggest that continuous delivery of or repeated exposure to a low dose of GHRP can maintain elevated GH secretion and IGF-I concentrations for 12 h to 4 d (25, 26, 27, 28, 29, 30, 31). We hypothesized that constant exposure to a submaximal concentration of GHRP may mimic the physiological pattern of relatively stable systemic ghrelin concentrations (32, 33).
GH secretion and IGF-I concentrations decline significantly in healthy aging individuals. Postulated mechanisms include impaired stimulation by endogenous peptidyl secretagogues, such as GHRH and possibly ghrelin, and accentuated inhibition by hypothalamic somatostatin (34, 35, 36). We hypothesized that if relative hyposomatotropism in elderly adults arises at least in part from reduced peptidyl drive, then combined stimulation with GHRP-2 and GHRH acutely by bolus injection and over 24 h by continuous infusion should augment GH secretion more effectively than either agonist alone. In corollary, prolonged unvarying stimulation with a synthetic ghrelin analog that putatively synergizes with hypothalamic GHRH should amplify pulsatile GH secretion and elevate IGF-I concentrations. The present studies examine these interlinked postulates in healthy aging women and men.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The study cohort comprised 17 elderly subjects, nine women [age, 64 ± 3.4 yr; body mass index (BMI), 26 ± 1.2 kg/m2; IGF-I, 98 ± 11 µg/liter; mean ± SEM] and eight men (age, 64 ± 2.2 yr; BMI, 26 ± 1 kg/m2; IGF-I, 108 ± 10 µg/liter). All subjects participated in both the acute bolus protocol (see below) and the 30-d infusion study. A subset of 11 volunteers (six postmenopausal women and five older men) took part in the 24-h infusions. Seven young women (age, 25 ± 1.6 yr; BMI, 22 ± 0.7 kg/m2; IGF-I, 310 ± 52 µg/liter) and nine young men (age, 25 ± 1.7 yr; BMI 25 ± 0.7 kg/m2; IGF-I 301 ± 46 µg/liter) served as additional controls in the acute bolus paradigm. No participant was taking a glucocorticoid or an anabolic hormone. Six postmenopausal women were receiving chronic hormone replacement therapy, and three young women were taking oral contraceptives. Inclusion criteria included normal medical history, physical examination, and screening biochemical measures of hepatic, renal, metabolic, endocrine and hematological function; baseline IGF-I concentration below 125 µg/liter (in the elderly cohort); active, ambulatory, healthy, community-based living status; and, provision of witnessed, institutionally approved, written, informed consent. Exclusion criteria included use of psycho- or neuroactive drugs; substance abuse; acute or chronic illness; systemic inflammatory, cardiopulmonary, hepatic, renal, endocrine, or metabolic disease; anemia; and lack of provision of institutionally approved voluntary witnessed, written, informed consent. Protocol-specific peptide use was approved by the Food and Drug Administration and institutional review board under investigator-initiated Investigational New Drugs.
Infusion protocols
Volunteers were admitted to the General Clinical Research Center at Tulane-Charity-Louisiana State University in the evening. Blood sampling and peptide infusions were performed the next day after an overnight fast. Thrice-daily meals were provided during the 24-h infusions. There were three complementary phases of the study: 1) acute stimulation (bolus sc or iv), 2) constant 24-h sc infusion, and 3) continuous 30-d sc infusion.
In the acute bolus paradigm, GH secretion was assessed in 17 elderly and 16 young subjects in a prospectively randomized, within-subject cross-over, single-blind design on separate mornings while subjects were fasting. Studies were conducted at least 3 d apart. The protocols entailed bolus iv injection of 1) GHRH (1 µg/kg); 2/3) GHRP-2 (0.1 or 1.0 µg/kg), and 4) both GHRP-2 (0.1 µg/kg) and GHRH (1.0 µg/kg), and 5) single sc injection of GHRP-2 (10 µg/kg). Young women did not receive the maximal dose of GHRP-2. Blood was collected at –10, 0 (time of bolus), 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 135, 150, 165, 180, 210, and 240 min.
In the 24-h interventional protocol, six women and five men received each of eight separate day, randomly ordered, sc infusions of 1) saline; 2) GHRP-2 (1 µg/kg·h); 3–5) GHRH (1, 3, or 10 µg/kg·h); and 6–8) the single dose of GHRP-2 combined with one of the three doses of GHRH. Blood was sampled concurrently every 20 min for 24 h (0900–0900 h).
In the 1-month GHRP-2 infusion study, nine women and eight men each underwent blood sampling every 20 min for 24 h on four occasions; viz. d –3 (saline baseline), 1, 14, and 30. Participants began constant sc infusion of GHRP-2 (1 µg/kg·h) at 0900 h on the morning of d 1. Peptide was delivered continuously via a portable Panomat pump. The infusion site was inspected, and the pump reservoir was replenished every 3–4 d. Volunteers remained ambulatory and continued routine daily activities.
Hormone assays
GH concentrations were measured in duplicate by automated immunochemiluminescence assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) (37, 38). The assay sensitivity was 0.005 µg/liter based on 22-kDa rhGH standard, and the median inter- and intraassay coefficients of variation were 7.4% and 6.7%, respectively. No serum GH concentration fell to or below 0.020 µg/liter in this study. IGF-I and IGFBP-3 (Nichols Institute Diagnostics), cortisol and prolactin (PRL; ICN Pharmaceuticals, Inc., Costa Mesa, CA), and leptin and adiponectin (Linco Research, Inc., St. Charles, MO) were quantitated by RIA in duplicate (39, 40). IGF-II concentrations were determined by RIA using recombinant human IGF-II as standard and radioactive tracer, and a mouse monoclonal antibody against rat IGF-II (41). IGFBP-4 was determined by RIA using recombinant human IGFBP-4 as antigen, tracer, and standard, and antiserum developed in guinea pigs (42). IGFBP-5 was determined by RIA with recombinant human IGFBP-5 as antigen, tracer, and standard (43). Intra- and interassay coefficients of variation averaged 6–8% in each case. Samples from the combined cohorts were analyzed in a single batch.
Analytical methods
The burst-like secretion of GH induced by bolus iv or sc injection of secretagogues was quantitated by multiparameter deconvolution analysis, as described and validated previously (44, 45, 46, 47). The outcome is the mass (micrograms) of GH secreted per unit distribution volume (liters) above preinjection basal GH secretion corrected for biexponential GH decay (see below). Daily total (sum of pulsatile and basal) and nadir (basal) GH secretion rates during 24-h peptide infusions were computed by waveform-independent deconvolution analysis (48, 49). This methodology uses a directly measured biexponential model of 3.5 and 20.8 min for the rapid and slow half-lives of GH, wherein the longer half-life contributes to 63% of the total amplitude of plasma GH disappearance (50). GH secretion rates on d –3, 1, 14, and 30 of constant GHRP-2 infusion were calculated by the multiparameter method (44, 45, 46, 47). Outcomes are GH secretory burst frequency (number of pulses per 24 h) and mass (micrograms per liter), basal secretion rate (micrograms per liter per minute), and the slow component GH half-life (minutes), assuming a fixed rapid half-life of 3.5 min and constant fractional (0.63 slow/total) partitioning of the decay amplitude (50).
Twenty-four-hour rhythmicity of GH concentrations was assessed by cosine regression (51). Outcomes are the acrophase (time of daily maximum), amplitude (50% of the zenith-nadir difference), and mesor (regression mean) of the daily rhythm.
Approximate entropy (ApEn; 1, 20%), was used as a scale- and model-independent regularity statistic to quantitate the orderliness of GH release (52, 53, 54, 55). Higher ApEn denotes greater disorderliness of the secretion process. Mathematical models and clinical experiments establish that erosion or loss of subpattern consistency in a neuroendocrine axis signifies altered feedforward and/or feedback control with high sensitivity and specificity (both >90%) (56, 57, 58). GH ApEn is elevated in puberty compared with prepuberty and adulthood, in older compared with young individuals, and at any age in women compared with men.
Statistics
Fasting (0800 h) hormone concentrations were evaluated statistically by repeated measures ANOVA under a general linear model (SPSS, Inc., Chicago, IL). Post hoc comparisons of means were made by the Newman-Keuls statistic (59). Derived (deconvolution, cosine, and ApEn) measures were transformed logarithmically before analysis to limit dispersion of variance. Data from the 24-h and 30-d infusion studies were analyzed by one-way ANOVA within gender, followed post hoc by Tukey’s honestly significantly different test to contrast means. In view of partial analytical interdependence, outcomes generated by deconvolution or cosine analyses were compared at protected P < 0.01 (60). The a priori hypothesis that gender determines GHRP-2-stimulated pulsatile GH secretion (examined at each of the four time windows) was tested using a two-sample, two-tailed t statistic at Bonferroni protected P < 0.0125 (61). Data are cited as the mean ± SEM (and median in the case of analytically derived measures).
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
presents the time course of the cohort mean (±SEM) serum GH concentrations sampled frequently over 4 h before and after acute secretagogue injection in young adults (n = 16; Fig. 1A) and older subjects (n = 17; Fig. 1B). Data are stratified by gender. The comparison measure is the (summed) mass of GH secreted per unit distribution (micrograms per liter) after each stimulus. Salient inferences were as follows: 1) bolus iv infusion of GHRP-2 (0.1 and 1.0 µg/kg) and sc injection of GHRP-2 (10 µg/kg) stimulate GH secretion dose-dependently in both age cohorts and genders (P < 10–5); 2) each stimulus is 3- to 6-fold less effective in older than young adults (P < 0.025); 3) bolus iv injection of GHRH (1 µg/kg) elicits less GH release than the same dose of GHRP-2 in each study group (P < 0.01); 4) the combined effect of the lowest doses of GHRP-2 (0.1 µg/kg, iv) and GHRH (1 µg/kg, iv) is synergistic (supraadditive) in each cohort except young men (P < 0.01 vs. the sum of the individual secretagogue effects); 5) synergy is present, but significantly reduced in magnitude in older volunteers (P < 0.001 vs. young); and 6) the effects of the lowest dose of GHRP-2 (0.1 µg/kg) administered alone and with GHRH (1.0 µg/kg) are, respectively, 2.7-fold (P < 0.01) and 2.3-fold (P < 0.025) greater in postmenopausal women than in older men.
|
illustrates individual GH concentration profiles in one elderly man and woman sampled every 20 min for 24 h during randomly ordered, separate day, continuous sc infusion of 1) saline, 2) GHRP-2 (1 µg/kg·h), 3–5) GHRH (1, 3, or 10 µg/kg·h), and 6–8) GHRP-2 (1 µg/kg·h) combined with 3–5. IGF-I concentrations were measured at 0900 h at the beginning and end of each infusion.
|
). In men, combined stimulation with GHRP-2/GHRH (1/3) was more effectual than any one of GHRH (1; P = 0.013), GHRH (3; P = 0.019), or GHRH (10; P = 0.024), but not GHRP-2 alone (P > 0.15). Combined administration of GHRP-2/GHRH (1/10) was more effectual than any dose of GHRH (1, 3, and 10 µg/kg·h; P < 0.005), but not GHRP-2 (P = 0.067). In women, GHRP-2/GHRH (1/10) was more effective than GHRH (10 µg/kg·h; P = 0.016), but not GHRP-2 alone (P = 0.096). In the combined group of subjects (n = 11), combined GHRP-2/GHRH (1/10) was more effectual in increasing daily GH secretion than either GHRP-2 (P = 0.021) or GHRH (10; P = 0.012) alone.
|
Comparisons of deconvolution-calculated basal (nonpulsatile) GH secretion revealed that in the combined group (n = 11), only concurrent infusion of GHRP-2 and GHRH (3 or 10 µg/kg·h) elevated this measure (P = 0.0036 and P = 0.0015, respectively). The percent basal (of total) GH secretion remained less than 10% in each stimulation protocol.
The impact of constant sc infusion of GHRP-2 (1.0 µg/kg·h) on GH secretion was assessed by multiparameter deconvolution analysis, the ApEn statistic, and cosine regression. Analyses were performed at baseline (saline infusion, d –3) and on d 1, 14, and 30 of continuous GHRP-2 stimulation. Principal findings included 1) no significant alteration in the slow component half-life of GH or GH secretory burst frequency, interpulse interval, or calculated secretory burst half-duration; 2) augmentation of total (basal plus pulsatile) 24-h GH secretion (micrograms per liter per day) by 3- to 5-fold control on d 1 (P < 10–4) and by 1.8- to 2.1-fold on d 14 and 30 (P < 0.01); 3) 1.8- to 2.5-fold greater total daily GH secretion in women than men at baseline (control) and each time point during GHRP-2 stimulation (P < 0.01 each), except d 1 (Fig. 3); 4) elevation of IGF-I concentrations on d 1 to a plateau value of 180 ± 15 µg/liter, which was maintained thereafter on d 14 and 30 (P < 0.01) with no difference by sex; 5) time-dependent and gender-distinguishable stimulation of pulsatile and basal GH secretion (P < 10–4 for both measures) and the cosine mesor (regressed mean of the 24-h rhythm in GH concentrations; P < 0.001; Fig. 4); 6) elevation of GH ApEn (a feedback-sensitive regularity statistic; P < 10–4; P = 0.0019 in men and P = 0.0049 in women) on d 1, 14, and 30; and 7) 2- to 3-fold increased amplitude of 24-h rhythmic GH release (50% of the arithmetic difference between the maximum and nadir values; P < 10–5) with no change in the daily acrophase of 2340 h (clock time of the maximum).
|
|
Figure 5 summarizes fasting (0800 h) concentrations of GH, IGF-I, and IGFBP-3 and -5 on d –3, 1, 14, and 30 of continuous GHRP-2 stimulation. GH (P < 10–4) and IGF-I (P < 10–3) increased on the first day of secretagogue delivery and remained significantly elevated thereafter. IGFBP-3 (P < 0.01) and IGFBP-5 (P < 0.025) concentrations increased on d 14 and 30 and on d 1, 14, and 30, respectively. Concentrations of IGF-II, IGFBP-4, cortisol, leptin, and adiponectin were unaffected during the 30-d intervention (Table 2). PRL concentrations increased significantly, but minimally (by 
25%) in men and women on d 30 compared with baseline, but stayed within the normal range.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A key mechanistic insight of this investigation is that administration of GHRP-2 as an unvarying and submaximal stimulus will sustain physiological features of somatotropic axis activation for at least 1 month. In contrast, intermittent stimulation with a high dose of GHRP rapidly down-regulates GH secretion (see introduction). The present concept is adumbrated in short-term studies (0.5–4 d), wherein repeated or continuous submaximal GHRP administration appears to maintain elevated GH concentrations and drive pulsatile GH secretion (25, 26, 27, 28, 29, 62, 63, 64). The exact basis for the apparent resistance to down-regulation of secretagogue effects under uninterrupted and submaximal feedforward is not known. Laboratory data indicate that prolonged constant sc delivery of GHRP induces expression of the pituitary GH gene in the GHRH-depleted infantile rat (65). In addition, intragastric administration of a high dose of a nonpeptidyl mimetic of GHRP down-regulates GH and IGF-I production within 24 h, whereas daily stimulation with a minimally effective dose of the same agonist progressively increases pulsatile and entropic modes of GH secretion and IGF-I concentrations (26). In short-term clinical studies in postmenopausal women, continuous iv infusion of GHRP-2 separately or combined with GHRH for 24 h amplifies pulsatile and total GH secretion by 30- to 120-fold and elevates fasting IGF-I concentrations (27, 28, 29). The present outcomes extend such inferences in older men and women by demonstrating that unvarying sc infusion of GHRP-2 for 1 month augments pulsatile, total, 24-h rhythmic, and entropic measures of GH secretion and IGF-I, IGFBP-3, and IGFBP-5 concentrations. From a qualitative viewpoint, the foregoing specific ensemble of neuroendocrine and systemic responses is identical to that observed at the time of maximal linear growth in healthy pubertal girls and boys (66). From a quantitative vantage, continuous GHRP-2 administration for 2 and 4 wk increased the 24-h GH secretion rate in elderly adults to approximately 0.5 mg (assuming a 7% distribution volume). The latter value is approximately 50% of that attained in adolescents at peak growth velocity (66, 67, 68).
In earlier pilot studies we administered GHRP-2 and/or GHRH by bolus injection in doses ranging from 0.1–3 µg/kg, sc, and at frequencies varying from once every other day to twice daily for 1–2 wk in elderly volunteers (30, 33, 69, 70, 71). In these short-term protocols, a high dose of GHRP-2 blunted the subsequent effect of the same peptide as well as that of GHRH. On the other hand, twice (but not single) daily iv pulses of GHRH for 7 d amplified the effects of later bolus injection of either GHRP-2 or GHRH. Once daily iv pulses of GHRP-2 and GHRH together for 1 wk also maintained the responsiveness of the GH/IGF-I axis in healthy older individuals. The present analyses extend the last finding by demonstrating that continuous combined sc infusion of GHRP-2 (1 µg/kg·h) and GHRH (3 and 10 µg/kg·h in women and 10 µg/kg·h in men) for 24 h stimulates GH secretion and elevates IGF-I concentrations significantly more than either agonist alone.
The precise mechanisms that mediate the facilitative interaction between GHRP-2 and GHRH over 24 h are not established. However, GHRP impacts GHRH stimulation and somatostatin inhibition via several pathways in the experimental animal. Specifically, members of the GHRP secretagogue family stimulate pituitary GH secretion directly by 2- to 3-fold (2, 33, 72), oppose central nervous system and pituitary inhibition by somatostatin (2, 17, 73), elicit arcuate nucleus release of GHRH into portal blood (14, 15), synergize with GHRH in the hypothalamo-pituitary-intact individual (21), and induce pituitary GH gene expression during prolonged administration in vivo and possibly in vitro (65, 74). Other outcomes suggest possible modulation of synergy by currently unknown hypothalamo-pituitary factors (2, 5).
Interventional trials in children with idiopathic short stature indicate that once or repeated daily administration of a GHRP receptor agonist by intranasal, sc, or oral routes for 6 months can accelerate linear growth over the baseline rate (75, 76, 77, 78, 79). In these reports, fasting morning GH concentrations increased by 2- to 4-fold initially and then declined by about 50% to a plateau value that exceeded baseline by approximately 2-fold. In contradistinction, IGF-I concentrations rose promptly and remained equivalently elevated for at least 6 months of secretagogue delivery. We report comparable temporal dissociation between GH secretion and IGF-I concentrations during 30-d continuous GHRP-2 delivery in healthy elderly adults. The mechanistic basis for the time-dependent disparity in GH and IGF-I responses in children and adults is not known. Plausible (nonexclusive) postulates could include 1) the prominent immediate rise in mean GH concentrations, which may equal or exceed maximal stimulation of hepatic IGF-I synthesis; 2) the emergence of more effectual GH secretory patterns, which maintain systemic IGF-I production at lower GH output; 3) partial down-regulation of hypothalamo-pituitary responsiveness to unvarying GHRP drive; and/or 4) changes in concentrations of one or more IGFBPs that influence negative feedback by free and/or bound IGF-I (80, 81, 82).
Gender comparisons disclosed that acute bolus iv injection and 30-d continuous sc infusion of GHRP-2 stimulate about 2-fold greater GH secretion in hormonally replaced postmenopausal women than in elderly men. In other studies, untreated healthy pre- and postmenopausal women manifest higher amplitudes of GH concentration peaks and commensurately more pulsatile GH secretion than men of comparable age (83, 84, 85). Moreover, short-term supplementation of estradiol potentiates acute responses to synthetic GHRPs in prepubertal girls and postmenopausal women (46, 47, 86). An inferred molecular mechanism is the ability of estradiol to enhance transcriptional activity of the human GHRP receptor gene promoter in vitro (87). However, whether the latter mechanism operates in vivo or whether chronic vis-à-vis short-term estrogen replacement enhances hypothalamopituitary responsiveness to GHRP receptor agonists has not been elucidated.
The primary cause of aging-associated waning of GH and IGF-I production has not been clarified definitively (20, 21, 88). Current hypotheses include attenuation of stimulation by GHRH and possibly ghrelin and/or augmentation of inhibition by somatostatin (89). One clinical study is consistent with the idea that all three mechanisms apply, inasmuch as only combined injection of GHRH, GHRP, and L-arginine (assumed to withdraw somatostatin restraint) evoked equivalent GH release in healthy older and young adults (90). Significant two-peptide facilitation of acute and 24-h GH secretion in the current investigation would support (but not prove) the postulated diminution of GHRH and ghrelin drive, and reduced acute synergy would be consistent with excessive somatostatinergic restraint.
Constant sc delivery of GHRP-2 for 30 d increased fasting concentrations of IGF-I, IGFBP-3, and IGFBP-5, but not those of non-GH-dependent proteins, IGFBP-4 and IGF-II (91). In relation to other hormonal and metabolic markers, biochemical indexes of hepatorenal function remained normal. No clinically significant adverse events occurred. Fasting plasma glucose concentrations rose by 12% within the euglycemic range in postmenopausal women. In earlier studies, oral administration of the nonpeptidyl GHRP mimetic, MK0677, elevated glucose concentrations in elderly volunteers at 1 month of study (62). On the other hand, sc injection of hexarelin for 3 d or 4 months did not (92, 93). Whereas synthetic GHRP and ghrelin inhibit insulin secretion acutely (11, 94), continuous delivery of GHRP-2 for 1 month in the current analysis did not alter fasting insulin concentrations. Ghrelin, GHRP, and nonpeptidyl analogs evoke ACTH and cortisol secretion acutely (95). However, administration of GHRP-2 for 1 month (present study); ipamorelin for 0.5, 1, or 2 months; and hexarelin for 3 d did not increase cortisol concentrations (62, 64, 92). In one study, sc injection of hexarelin twice daily for 4 months lowered 3-h mean morning serum (but not urinary free) cortisol concentrations (93). Prolonged GHRP-2 stimulation did not change leptin or adiponectin concentrations. Leptin concentrations may decline as fat mass decreases during prolonged GH treatment in adults with organic hyposomatotropism (96). Lastly, extended GHRP-2 infusion elevated PRL concentrations in women and men by 25%. Once daily administration of ipamorelin orally for 1 month increased PRL concentrations to a similar degree, but twice daily injection of hexarelin for 3 d had no effect (62, 92). The clinical import of the foregoing increments in glucose and PRL within the normal range is not defined.
The sustained elevation of IGF-I, GH, and GH-inducible IGFBPs during 1 month of GHRP stimulation in elderly adults mimics some somatotropic axis responses to shorter-term secretagogue infusions reported in patients with protracted critical illness (97, 98, 99). A gender difference in secretagogue effectiveness is also evident in the latter context. Like aging, critical illness is marked by impaired anabolism, reduced availability of trophic hormones, and, in women, relative androgen predominance (99).
In summary, the present investigation in healthy older adults demonstrates that 1) acute (bolus) iv injection of GHRH and GHRP-2 together is more synergistic in postmenopausal women than in men of comparable age; 2) short-term (24-h) constant combined sc infusion of GHRP-2 and GHRH stimulates GH secretion and elevates IGF-I concentrations more than either peptide alone; and 3) prolonged (1-month) continuous sc delivery of GHRP-2 drives pulsatile, total, 24-h rhythmic, and entropic (feedback-adaptive) GH secretion and increases IGF-I, IGFBP-3, and IGFBP-5 concentrations. Further investigations will be required to elucidate the mechanisms that transduce the evidently sustained hypothalamo-pituitary responsiveness to unabated feedforward by GHRP.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviations: ApEn, Approximate entropy; BMI, body mass index; GHRP, GH-releasing peptide; PRL, prolactin.
Received October 15, 2003.
Accepted February 17, 2004.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  J. D. Veldhuis, D. M. Keenan, J. N. Bailey, A. Adeniji, J. M. Miles, R. Paulo, M. Cosma, and C. Soares-Welch Testosterone Supplementation in Older Men Restrains Insulin-Like Growth Factor's Dose-Dependent Feedback Inhibition of Pulsatile Growth Hormone Secretion J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 246 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Veldhuis, D. M. Keenan, and S. M. Pincus Motivations and Methods for Analyzing Pulsatile Hormone Secretion Endocr. Rev., December 1, 2008; 29(7): 823 - 864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kok, R. C. Paulo, M. Cosma, K. L. Mielke, J. M. Miles, C. Y. Bowers, and J. D. Veldhuis Estrogen Supplementation Selectively Enhances Hypothalamo-Pituitary Sensitivity to Ghrelin in Postmenopausal Women J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 4020 - 4026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Roelfsema, A. M. Pereira, D. M. Keenan, J. D. Veldhuis, and J. A. Romijn Thyrotropin Secretion by Thyrotropinomas Is Characterized by Increased Pulse Frequency, Delayed Diurnal Rhythm, Enhanced Basal Secretion, Spikiness, and Disorderliness J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 4052 - 4057. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, G. A. Reynolds, A. Iranmanesh, and C. Y. Bowers Twenty-Four Hour Continuous Ghrelin Infusion Augments Physiologically Pulsatile, Nycthemeral, and Entropic (Feedback-Regulated) Modes of Growth Hormone Secretion J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3597 - 3603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, M. Cosma, D. Erickson, R. Paulo, K. Mielke, L. S. Farhy, and C. Y. Bowers Tripartite Control of Growth Hormone Secretion in Women during Controlled Estradiol Repletion J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2336 - 2345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Farhy, C. Y. Bowers, and J. D. Veldhuis Model-projected mechanistic bases for sex differences in growth hormone regulation in humans Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1577 - R1593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, D. M. Keenan, A. Iranmanesh, K. Mielke, J. M. Miles, and C. Y. Bowers Estradiol Potentiates Ghrelin-Stimulated Pulsatile Growth Hormone Secretion in Postmenopausal Women J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3559 - 3565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, A. Iranmanesh, K. Mielke, J. M. Miles, P. C. Carpenter, and C. Y. Bowers Ghrelin Potentiates Growth Hormone Secretion Driven by Putative Somatostatin Withdrawal and Resists Inhibition by Human Corticotropin-Releasing Hormone J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2441 - 2446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, and C. Y. Bowers Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition Endocr. Rev., April 1, 2006; 27(2): 101 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D Veldhuis, J. M Patrie, K. Frick, J. Y Weltman, and A. L Weltman Administration of recombinant human GHRH-1,44-amide for 3 months reduces abdominal visceral fat mass and increases physical performance measures in postmenopausal women Eur. J. Endocrinol., November 1, 2005; 153(5): 669 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, D. Erickson, K. Mielke, L. S. Farhy, D. M. Keenan, and C. Y. Bowers Distinctive Inhibitory Mechanisms of Age and Relative Visceral Adiposity on Growth Hormone Secretion in Pre- and Postmenopausal Women Studied under a Hypogonadal Clamp J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6006 - 6013. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, A. Iranmanesh, and C. Y. Bowers Joint Mechanisms of Impaired Growth-Hormone Pulse Renewal in Aging Men J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4177 - 4183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. K. Tisi, X.-J. Liu, L. J. Wykes, C. D. Skinner, and K. G. Koski Insulin-Like Growth Factor II and Binding Proteins 1 and 3 from Second Trimester Human Amniotic Fluid Are Associated with Infant Birth Weight J. Nutr., July 1, 2005; 135(7): 1667 - 1672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Farhy and J. D. Veldhuis Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1649 - R1663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, L. Farhy, A. L. Weltman, J. Kuipers, J. Weltman, and L. Wideman Gender Modulates Sequential Suppression and Recovery of Pulsatile Growth Hormone Secretion by Physiological Feedback Signals in Young Adults J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2874 - 2881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Soares-Welch, L. Farhy, K. L. Mielke, F. H. Mahmud, J. M. Miles, C. Y. Bowers, and J. D. Veldhuis Complementary Secretagogue Pairs Unmask Prominent Gender-Related Contrasts in Mechanisms of Growth Hormone Pulse Renewal in Young Adults J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2225 - 2232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Erickson, D. M. Keenan, L. Farhy, K. Mielke, C. Y. Bowers, and J. D. Veldhuis Determinants of Dual Secretagogue Drive of Burst-Like Growth Hormone Secretion in Premenopausal Women Studied under a Selective Estradiol Clamp J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1741 - 1751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, J. T. Patrie, K. T. Brill, J. Y. Weltman, E. E. Mueller, C. Y. Bowers, and A. Weltman Contributions of Gender and Systemic Estradiol and Testosterone Concentrations to Maximal Secretagogue Drive of Burst-Like Growth Hormone Secretion in Healthy Middle-Aged and Older Adults J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6291 - 6296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Iranmanesh, C. Y. Bowers, and J. D. Veldhuis Activation of Somatostatin-Receptor Subtype-2/-5 Suppresses the Mass, Frequency, and Irregularity of Growth Hormone (GH)-Releasing Peptide-2-Stimulated GH Secretion in Men J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4581 - 4587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Erickson, D. M. Keenan, K. Mielke, K. Bradford, C. Y. Bowers, J. M. Miles, and J. D. Veldhuis Dual Secretagogue Drive of Burst-Like Growth Hormone Secretion in Postmenopausal Compared with Premenopausal Women Studied under an Experimental Estradiol Clamp J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4746 - 4754. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
