help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0523
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Iranmanesh, A.
Right arrow Articles by Veldhuis, J. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Iranmanesh, A.
Right arrow Articles by Veldhuis, J. D.
Related Collections
Right arrow Neuroendocrinology and Pituitary
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 9 3653-3659
Copyright © 2007 by The Endocrine Society

Putative Somatostatin Suppression Potentiates Adrenocorticotropin Secretion Driven by Ghrelin and Human Corticotropin-Releasing Hormone

Ali Iranmanesh, Paul C. Carpenter, Kristi Mielke, Cyril Y. Bowers and Johannes D. Veldhuis

Endocrine Section (A.I.), Department of Medicine, Salem Veterans Affairs Medical Center, Salem, Virginia 24153; Division of Endocrinology and Metabolism (P.C.C., K.M., J.D.V.), Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; and Endocrinology (C.Y.B.), Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Ghrelin is a 28-amino-acid Ser3-octanoylated peptide, and CRH is a 41-amino-acid peptide, both of which stimulate ACTH secretion. In principle, actions of these agonists could be subject to inhibitory modulation by hypothalamic somatostatin (SS).

Objective: Our objective was to test the hypothesis that endogenous SS restrains ghrelin and CRH-stimulated ACTH secretion, thereby linking all three, ghrelin, CRH, and SS, with ACTH secretion.

Design and Setting: We conducted a randomized, double-blind, placebo-controlled, crossover interventional study at an academic medical center.

Participants: Ten healthy postmenopausal women participated in the study.

Interventions: Interventions included iv injection of saline, ghrelin, human CRH, or both after an infusion of saline vs. L-arginine to putatively inhibit SS outflow (eight visits per subject).

Outcome Measures: ACTH concentrations quantified by repetitive blood sampling and immunochemiluminometry.

Results: Infusion of ghrelin induced peak ACTH concentrations [median (range)] of 21 (17–28) compared with 16 (11–20) ng/liter after saline (P = 0.037). CRH and L-arginine infusion evoked ACTH peaks of 23 (14–48) and 31 (21–286) ng/liter, respectively (P = 0.037 and P = 0.005 vs. saline). L-Arginine enhanced stimulation by ghrelin by 1.43-fold (P = 0.028) and that by CRH by 1.91-fold (P = 0.005). Triple stimulation with ghrelin, CRH, and L-arginine potentiated the effect of combined ghrelin/CRH by 1.45-fold (P = 0.028). Downstream cortisol responses mimicked those of ACTH but were time delayed.

Conclusions: The present outcomes indicate that the peptide ensemble comprising ghrelin, CRH, and SS (inferred by L-arginine infusion) can regulate ACTH and cortisol secretion in healthy adults.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ALTHOUGH HYPOTHALAMIC somatostatin (SS) is a major inhibitor of GH release (1, 2, 3, 4, 5), its role in regulating the secretion of other pituitary hormones, such as ACTH or proopiomelanocortin, is not well understood (6). Studies carried out in experimental systems indicate that CRH stimulates hypothalamic SS release (7, 8, 9), whereas SS blocks ACTH secretion directly via SS-receptor subtypes 2 and 5 (10, 11, 12, 13) and possibly indirectly by inhibiting CRH release (5, 6, 14). Therefore, a fundamental question arises whether withdrawal of hypothalamic SSergic outflow is necessary or sufficient to drive ACTH secretion. If SS actively restricts ACTH secretion, then a testable forecast is that acute withdrawal of SSergic inhibition should elevate ACTH concentrations, as reported in one study in the dog (15).

Other laboratory data indicate that ghrelin, a GH-releasing peptide (GHRP), can oppose certain inhibitory effects of SS in the brain and stimulate in vitro secretion of CRH and arginine vasopressin (AVP) and in vivo expression of CRH gene transcripts (3, 16, 17, 18). Nonetheless, clinical studies examining how SS, ghrelin, and CRH together control ACTH secretion are few and contradictory. One paper showed synergy between GHRP and injected CRH but not AVP, but another described no synergy between GHRP and either ACTH-releasing peptide (19, 20). Three analyses reported that systemic SS infusion does not suppress plasma ACTH or cortisol concentrations basally or when stimulated by angiotensin II, ghrelin, or CRH (21, 22, 23). In contrast, another investigation in young and older adults inferred that SS infusion paradoxically stimulates secretion of ACTH and cortisol (24). Three other studies found that SS injections in patients with Addison’s disease, Nelson’s syndrome, and Cushing’s disease reduce ACTH concentrations by about 50% (25, 26, 27). Possible unifying bases for such discrepant outcomes are that only heightened ACTH secretion is repressed by systemic SS and/or that hypothalamic SS outflow is required to mediate inhibition (6, 14).

The present study tests the proposition that muting central-neuronal SS outflow will amplify ghrelin and CRH-driven ACTH secretion in fasting adults. To this end, healthy postmenopausal women were pretreated with saline or L-arginine and then given an infusion of saline, ghrelin, CRH, or both agonists. L-Arginine provides a tool to putatively restrict hypothalamic SS outflow (28, 29). Results of this combined approach provide strong evidence for ensemble-like control of ACTH secretion by all three, ghrelin, CRH, and SS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Human subjects

Ten consenting healthy postmenopausal women enrolled in and completed all eight study sessions. The range (median) of ages was 50–69 (65) yr and body mass index 21–29 (25) kg/m2. No subject had received hormone replacement therapy for at least 6 wk before study to limit potential confounding by a variable sex-steroid milieu (30). No premenopausal women were studied. Participants provided witnessed, voluntary informed consent approved by the Mayo Institutional Review Board after the protocol was reviewed by the U.S. Food and Drug Administration under an investigator-initiated new drug number. Volunteers gave a detailed medical history, and underwent a physical examination and biochemical screening as outpatients. Indices of hepatic, renal, hematological, metabolic, and endocrine function were normal, as described in earlier studies (31). Exclusion criteria were premenopausal status or sex-hormone replacement; use of antihypertensive or psychoactive drugs that could modify hypothalamo-pituitary function; acute or chronic systemic illness including hypertension, diabetes mellitus, neoplasia, ischemic or valvular cardiac disease, pulmonary impairment, or hepatic or renal failure; transmeridian travel exceeding two time zones within the previous 5 d; weight change exceeding 2 kg in 6 wk; institutionalization; drug or alcohol abuse; hemoglobin less than 11.6 gm/dl; body mass index exceeding 30 kg/m2; and unwillingness to provide written, Institutional Review Board-approved informed consent.

Infusion paradigm

Each subject participated in eight (8) separate 4-h infusion sessions in the mornings after fasting scheduled at least 48 h apart in the Mayo General Clinical Research Center in a prospectively randomized, double-blind, placebo-controlled fashion. As described for nine women in this cohort studied earlier in a GH analysis, the iv infusion paradigms included 1) saline (20 ml/h) continuously from 0800–1200 h; 2) bolus human ghrelin (0.33 µg/kg) at 0900 h; 3) bolus human CRH (1.0 µg/kg at 0830 h) followed by constant delivery of the same dose (1 µg/kg) over 30 min; 4) combined ghrelin and CRH (above); 5) L-arginine continuously starting at 0815 (45 g delivered between 0815 and 0900 h); and 6) combined L-arginine and ghrelin; 7) combined L-arginine and CRH; and 8) all three of L-arginine, CRH, and ghrelin (32). All 10 women undertook all eight studies.

The dose selected for ghrelin was submaximally effective (33), so as to assess physiological rather than pharmacological mechanisms of ACTH control. The amount of L-arginine infused was maximal by clinical standards of efficacy, to enforce putative SS withdrawal (34). The CRH infusion schedule entailed both a bolus loading dose and constant infusion, given the rapid initial plasma half-life of human CRH of 5–9 min and delayed disappearance of 63 min (35).

Sampling schedule

To allow adaptation, volunteers spent the preceding night in the General Clinical Research Center. A vegetarian or nonvegetarian standardized meal (8 kcal/kg of 55% carbohydrate, 15% protein, and 30% fat) was served at 1800 h. Subjects then remained fasting, alcohol-abstinent, and caffeine-free until 1200 h the next day. Cannulas were placed in (contralateral) forearm veins at or before 0630 h to permit simultaneous blood sampling and peptide infusion. Blood (1.5 ml/sample) was withdrawn every 10 min for 4 h (0800–1200 h) into prechilled EDTA-containing tubes, placed on ice, centrifuged within 10 min, and frozen at –70C for later assay of ACTH and cortisol.

Hormone assays

Plasma concentrations of ACTH and cortisol were determined in singlet in each blood sample by a sensitive and specific immunochemiluminescence assay, using IMMULITE 2000 and reagents from Diagnostic Product Corp. (Los Angeles, CA), respectively. The sandwich assay for ACTH has a low-end sensitivity of 5 ng/liter with intraassay precision of 1.9–2.4% at ACTH concentrations ranging from 33–396 ng/liter. The competitive binding assay for cortisol achieves a low-end sensitivity of 0.2 µg/dl with intraassay precision of 7.5–9.8% at cortisol concentrations of 4.8–38 µg/dl. ACTH assay is highly specific with limited cross-reactivity only for the ACTH (18–39) fragment of 17%. Cortisol antibodies cross-react with prednisolone (62%), methylprednisolone (25%), prednisone (6.1%), and corticosterone (7.5%).

Analysis

Peak ACTH and cortisol concentrations were defined as the maximum of a three-point moving average of each 10-min time series. This provides model-free estimation of maximal responses.

Statistical analysis

The Kruskal-Wallis test (nonparametric ANOVA) was applied to assess median differences among ACTH and cortisol peak concentrations and times. Post hoc comparisons were made using the paired Wilcoxon signed-ranks test (36). Primary findings were confirmed by the Kolmogorov-Smirnov statistic. Data are given as the median (range).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go gives background endocrine data in the 10 volunteers. Estradiol concentrations were 5–12 pg/ml (range; multiply by 3.67 for pmol/liter). FSH concentrations were 33–109 IU/liter, thus verifying menopausal status.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Baseline subject characteristics

 
Figure 1Go depicts median ACTH and cortisol concentration time series monitored every 10 min for 4 h in each of the eight interventions in the 10 women (80 study sessions in all).


Figure 1
View larger version (19K):
[in this window]
[in a new window]

  		FIG. 1. Median (± SEM) ACTH (A) and cortisol (B) concentrations sampled every 10 min for 4 h in each of the eight secretagogue-infusion and blood-sampling sessions, as marked, in 10 postmenopausal women.

 
ACTH concentrations rose significantly in response to the infusion of L-arginine, ghrelin, and CRH (overall Kruskal-Wallis test P < 0.001), as summarized in Fig. 2Go. Post hoc analyses disclosed the following significant contrasts: 1) individual infusion of saline, L-arginine, ghrelin, and CRH induced peak ACTH concentrations (ng/liter) of 16 (11–20) with saline, 31 (21–286) with L-arginine, 21 (17–28) with ghrelin, and 23 (14–48) with CRH (0.005 < P ≤ 0.037 for each stimulus compared with saline control); 2) consecutive L-arginine/ghrelin stimulation [30 (18–111)] was more effective than ghrelin alone (P = 0.028) but not L-arginine alone; 3) combined L-arginine/CRH infusion [44 (29–122)] was 1.9-fold more effective than CRH alone (P = 0.005) but not L-arginine alone; 4) triple stimulation by L-arginine, ghrelin, and CRH induced a peak ACTH value of 45 (30–184), which exceeded that of each other stimulus (P ≤ 0.028) except combined L-arginine/CRH.


Figure 2
View larger version (23K):
[in this window]
[in a new window]

  		FIG. 2. Median peak ACTH concentrations (ng/liter) attained after secretagogue injections in the absence (saline) vs. presence of L-arginine infusion in 10 volunteers. The overall interventional effect was assessed by the Kruskall-Wallis test. Individual P values over paired columns reflect post hoc contrasts for pretreatment with L-arginine vs. saline.

 
Infusion of L-arginine, ghrelin, and CRH individually increased peak cortisol concentrations significantly compared with saline (overall Kruskal-Wallis test P < 0.001) (Fig. 3Go). In particular, peak cortisol concentrations (µg/dl) were 25 (16–36) with L-arginine, 17 (11–33) with ghrelin, and 20 (8–27) with CRH compared with saline [13 (9.7–32)] (0.005 ≤ P ≤ 0.028 for each effect). Infusion of L-arginine compared with saline augmented the effect of ghrelin by 1.42-fold (P = 0.005) and that of CRH by 1.38-fold (P = 0.007) but did not alter that of combined ghrelin/CRH [with saline, 24 (14–35), vs. with L-arginine, 29 (20–34); P > 0.10].


Figure 3
View larger version (25K):
[in this window]
[in a new window]

  		FIG. 3. Peak cortisol-concentration responses presented analogously to ACTH data in Fig. 2Go.

 
The foregoing outcomes were upheld using within-subject incremental data, wherein the response to saline was subtracted in each individual to reduce within-subject variability. Tables 2Go and 3Go report these supporting analyses for ACTH and cortisol, respectively.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Incremental ACTH concentration responses over saline

 

View this table:
[in this window]
[in a new window]

  		TABLE 3. Incremental cortisol concentration responses over saline

 
Peak ACTH concentrations occurred 85 (35–135) min [median (range)] after the onset of L-arginine infusion [P = 0.039 compared with 140 (15–225) min after saline infusion]. ACTH maxima emerged at mean intervals of 26–42 min after bolus ghrelin, 27–30 min after bolus CRH, and 40–45 min after combined bolus ghrelin/CRH infusion (P > 0.10). Further analyses indicated that prior infusion of L-arginine did not significantly alter the timing of maximal ACTH responses to ghrelin, CRH, or both.

Stimulated cortisol responses peaked 12.5 (0–25) min later than those of ACTH (P < 0.01). Analysis of the intraindividual time delays separating peak ACTH and peak cortisol concentrations disclosed that stimulation with L-arginine in the presence of CRH (but not saline or ghrelin) extended the time delay for the peak cortisol response by 20 min (P < 0.001) (Fig. 4Go).


Figure 4
View larger version (17K):
[in this window]
[in a new window]

  		FIG. 4. Median time delays (min) separating peak ACTH and cortisol concentrations under each of the eight study conditions in 10 postmenopausal women. Bars that share no common letters (e.g. C vs. AB) are significantly different (P ≤ 0.030). Bars with shared letters (e.g. AB vs. either A or BC) do not differ. P for the overall interventional effect was <0.001.

 
Ghrelin (uncommonly), CRH (occasionally), and L-arginine (commonly) elicited facial and/or neck flushing. At the dose used, L-arginine caused a metallic taste and nausea in several subjects. There were no significant (>10 mm Hg) changes in mean blood pressure during peptide infusions.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present investigation examined the hypothesis that endogenous SS restrains ghrelin- and CRH-stimulated ACTH secretion, thus introducing an ensemble of three peptides that govern ACTH and cortisol secretion. In healthy hormone-unreplaced postmenopausal women, the postulate was strongly supported by the following outcomes: 1) unequivocal stimulation of ACTH and cortisol secretion by infusion of L-arginine, a putative inhibitor of hypothalamic SS outflow; 2) augmentation of individual ghrelin- and CRH-stimulated ACTH as well as cortisol secretion by L-arginine pretreatment; 3) potentiation of combined ghrelin/CRH-driven ACTH secretion by L-arginine exposure with no further increase in cortisol output. The last outcome suggests some degree of uncoupling of ACTH and cortisol responses, possibly due to the nonlinear nature of the ACTH->cortisol dose-response function in vivo (37). The absolute ranges of peak ACTH (30–184 ng/liter) and cortisol (20–34 µg/dl) concentrations attained after combined three-peptide stimulation overlap those observed in psychological and physical stress (30). Accordingly, one may infer that ghrelin, CRH, and SS (L-arginine-responsive) pathways are able to regulate hypothalamo-pituitary-adrenal activation within the full operating range of this axis. By extension, coordinate control of ACTH and cortisol secretion by an ensemble of peptides may mediate certain stress adaptations in health and disease.

L-Arginine is believed to restrict hypothalamic SS outflow, because it consistently antagonizes autonegative feedback by GH, which is mediated via the release of periventricular-nucleus SS into hypothalamo-pituitary portal blood (2, 28, 29). There is some evidence that this action requires nitric oxide generation (38, 39, 40). Independently of the proximate neurotransmitter signal involved, L-arginine provides an indirect probe of the role of SS outflow (2, 5). Clinical dose-response studies indicate that iv delivery of 45 g L-arginine constitutes a maximally effective stimulus to GH secretion (34). The present analyses demonstrate that L-arginine is also a potent activator of ACTH release, resulting in peak ACTH concentrations of 21–286 ng/liter (compared with 11–20 ng/liter after saline). In addition, L-arginine potentiated stimulation of ACTH secretion by not only ghrelin but also CRH. Certain hypothalamic stimulatory effects of ghrelin are opposed by SS (41), whereas some central inhibitory actions of CRH are mediated via SS (7, 8). Thus, opposition to SSergic restraint could mediate the strong facilitative effects of L-arginine. In addition, the capability of ghrelin to evoke neuronal secretion of CRH might explain the lack of synergism between exogenous ghrelin and CRH reported here and recently in one study in dogs and another in humans (3, 15, 19). A recent study further affirmed that human CRH does not modify ghrelin’s stimulation of GH secretion (32), highlighting the specificity of pathways of ACTH and GH regulation.

Available literature and the present data allow one to envision potential ensemble interactions among ghrelin, CRH, and SS signaling, as schematized in Fig. 5Go. In this provisional model, ghrelin would restrict central-neural inhibition by SS, thus favoring CRH and AVP release. L-Arginine would act analogously but also reduce the secretion of hypothalamic SS into portal blood. Suppression vis-à-vis augmentation of SS outflow appears to be the most important factor in the postulated ghrelin-CRH-SS control system. A reduction in portal SS concentrations may further disinhibit corticotrope secretion, given that portal concentrations of SS normally exceed systemic values markedly (5). In this respect, muting the inhibitory influence of SS on ACTH secretion via L-arginine seems to be more important than ghrelin-induced disinhibition of CRH action. The general construct would permit the possibility that CRH, by inducing hypothalamic SS outflow, quenches its own secretion, thereby delimiting an ACTH secretory burst (42, 43). Inhibition of the latter short-feedback loop by L-arginine could explain the otherwise unexpected 20-min time delay between ACTH and cortisol maxima induced by combined administration of L-arginine only when CRH is present. The extended time delay of the cortisol response to CRH induced by L-arginine could also suggest a novel interaction between the corresponding pathways, possibly at the adrenal level.


Figure 5
View larger version (13K):
[in this window]
[in a new window]

  		FIG. 5. Hypothesized ensemble model of ACTH control that accounts for the clinical data. Not shown is a postulated negative-feedback arrow from CRH to SS, which would allow quenching of a CRH secretory burst. In principle, L-arginine could also relieve such SSergic feedback and prolong the adrenocortical response (see Discussion).

 
Caveats in interpreting these studies include, first, investigation of a relatively small cohort comprising 10 subjects, despite analyses of a total of 80 separate 4-h sampling/infusing sessions. Thus, the present outcomes need to be replicated in a larger group of volunteers. Second, implications should be evaluated further in relation to age, gender, and acute vs. chronic disease states, which jointly influence stress-adaptive pathways in the experimental animal and human (30). Among other contexts, protracted critical illness could represent an important pathophysiology in which to examine the regulation of ACTH and cortisol secretion by multiple effectors (44). Third, because interactions among secretagogues are nonlinear and concentration dependent (45, 46, 47), additional studies will be needed to quantify properties of ensemble peptidyl control more precisely.

In summary, putative muting of hypothalamic SS outflow potentiates ACTH release induced by saline, ghrelin, or CRH and combined ghrelin/CRH stimulation. The facilitative effects of presumptively reduced SSergic restraint on ACTH secretion were transmitted downstream to cortisol secretion and operated within the physiological dose-response ranges of both ACTH and cortisol production. Such observations are consistent with an ensemble concept comprising at least triple peptidyl control of corticotropin secretion in healthy postmenopausal women. The data offer a basis for assessing how additional secretagogues like AVP and other factors like sex steroids, age, and concurrent stress modulate interactive effects of ghrelin, CRH, and SS on the adrenocorticotropic axis.


   Acknowledgments
 
We thank Heidi Doe and Ashley Bryant for excellent support of manuscript preparation and graphics, the Veterans Affairs Immunochemical Laboratory for assay assistance, and the Mayo research nursing staff for conduct of the protocol.


   Footnotes
 
Disclosure: I accept responsibility for the conduct of this study, and I have seen and approve the final manuscript. No portion of this article will be published or submitted elsewhere before appearing in The Journal of Clinical Endocrinology & Metabolism. All authors have nothing to declare.

This work was supported in part via General Clinical Research Center Grant MO1 RR00585 to the Mayo Clinic and Foundation from the National Center for Research Resources (Rockville, MD) and R01 NIA AG 19695 and DK 073148 from the National Institutes of Health (Bethesda, MD).

First Published Online June 12, 2007

Abbreviations: AVP, Arginine vasopressin; GHRP, GH-releasing peptide; SS, somatostatin.

Received March 14, 2007.

Accepted June 6, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Epelbaum J 1992 Intrahypothalamic neurohormonal interactions in the control of growth hormone secretion. Ciba Found Symp 168:54–64[Medline]
  2. Giustina A, Veldhuis JD 1998 Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 19:717–797[Abstract/Free Full Text]
  3. Wren AM, Small CJ, Fribbens CV, Neary NM, Ward HL, Seal LJ, Ghatei MA, Bloom SR 2002 The hypothalamic mechanisms of the hypophysiotropic action of ghrelin. Neuroendocrinology 76:316–324[CrossRef][Medline]
  4. Bowers CY, Granda-Ayala R 1996 GHRP-2, GHRH and SRIF interrelationships during chronic administration of GHRP-2 to humans. J Pediatr Endocrinol Metab 9(Suppl 3):261–270
  5. Veldhuis JD, Roemmich JN, Richmond EJ, Bowers CY 2006 Somatotropic and gonadotropic axes linkages in infancy, childhood, and the puberty-adult transition. Endocr Rev 27:101–140[Abstract/Free Full Text]
  6. Engler D, Redei E, Kola I 1999 The corticotropin-release inhibitory factor hypothesis: a review of the evidence for the existence of inhibitory as well as stimulatory hypophysiotropic regulation of adrenocorticotropin secretion and biosynthesis. Endocr Rev 20:460–500[Abstract/Free Full Text]
  7. Peterfreund RA, Vale WW 1983 Ovine corticotropin-releasing factor stimulates somatostatin secretion from cultured brain cells. Endocrinology 112:1275–1278[Abstract/Free Full Text]
  8. Rivier C, Vale W 1985 Involvement of corticotropin-releasing factor and somatostatin in stress-induced inhibition of growth hormone secretion in the rat. Endocrinology 117:2478–2482[Abstract/Free Full Text]
  9. Aguila MC, McCann SM 1985 The influence of hGRF, CRF, TRH and LHRH on SRIF release from median eminence fragments. Brain Res 348:180–182[CrossRef][Medline]
  10. Strowski MZ, Dashkevicz MP, Parmar RM, Wilkinson H, Kohler M, Schaeffer JM, Blake AD 2002 Somatostatin receptor subtypes 2 and 5 inhibit corticotropin-releasing hormone-stimulated adrenocorticotropin secretion from AtT-20 cells. Neuroendocrinol 75:339–346[CrossRef][Medline]
  11. Hofland LJ, Van Der HJ, Feelders R, van Aken MO, Van Koetsveld PM, Waaijers M, Sprij-Mooij D, Bruns C, Weckbecker G, De Herder WW, Beckers A, Lamberts SW 2005 The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur J Endocrinol 152:645–654[Abstract/Free Full Text]
  12. Nicholson SA, Adrian TE, Gillham B, Jones MT, Bloom SR 1984 Effect of hypothalamic neuropeptides on corticotrophin release from quarters of rat anterior pituitary gland in vitro. J Endocrinol 100:219–226[Abstract/Free Full Text]
  13. Silva AP, Schoeffter P, Weckbecker G, Bruns C, Schmid HA 2005 Regulation of CRH-induced secretion of ACTH and corticosterone by SOM230 in rats. Eur J Endocrinol 153:R7–R10
  14. Brown MR, Rivier C, Vale W 1984 Central nervous system regulation of adrenocorticotropin secretion: role of somatostatins. Endocrinology 114:1546–1549[Abstract/Free Full Text]
  15. Rigamonti AE, Bonomo SM, Cella SG, Muller EE 2002 GH and cortisol rebound rise during and following a somatostatin infusion: studies in dogs with the use of a GH-releasing peptide. J Endocrinol 174:387–394[Abstract]
  16. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M, Katsuura G, Makino S, Fujino MA, Kasuga M 2001 A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology 74:143–147[CrossRef][Medline]
  17. Johnstone LE, Srisawat R, Kumarnsit E, Leng G 2005 Hypothalamic expression of NPY mRNA, vasopressin mRNA and CRF mRNA in response to food restriction and central administration of the orexigenic peptide GHRP-6. Stress 8:59–67[CrossRef][Medline]
  18. Mozid AM, Tringali G, Forsling ML, Hendricks MS, Ajodha S, Edwards R, Navarra P, Grossman AB, Korbonits M 2003 Ghrelin is released from rat hypothalamic explants and stimulates corticotrophin-releasing hormone and arginine-vasopressin. Horm Metab Res 35:455–459[CrossRef][Medline]
  19. Korbonits M, Kaltsas G, Perry LA, Putignano P, Grossman AB, Besser GM, Trainer PJ 1999 The growth hormone secretagogue hexarelin stimulates the hypothalamo-pituitary-adrenal axis via arginine vasopressin. J Clin Endocrinol Metab 84:2489–2495[Abstract/Free Full Text]
  20. Arvat E, Maccagno B, Ramunni J, Di Vito L, Broglio F, Deghenghi R, Camanni F, Ghigo E 1997 Hexarelin, a synthetic growth-hormone releasing peptide, shows no interaction with corticotropin-releasing hormone and vasopressin on adrenocorticotropin and cortisol secretion in humans. Neuroendocrinology 66:432–438[Medline]
  21. Broglio F, Arvat E, Benso A, Gottero C, Prodam F, Grottoli S, Papotti M, Muccioli G, van der Lely AJ, Deghenghi R, Ghigo E 2002 Endocrine activities of cortistatin-14 and its interaction with GHRH and ghrelin in humans. J Clin Endocrinol Metab 87:3783–3790[Abstract/Free Full Text]
  22. Volpi R, Chiodera P, Capretti L, Caiazza A, Caffarri G, Magotti MG, Boni S, Coiro V 1996 Inhibition by somatostatin of the growth hormone, but not corticotropin response to angiotensin II in normal men. Horm Res 45:269–272[Medline]
  23. Stafford PJ, Kopelman PG, Davidson K, McLoughlin L, White A, Rees LH, Besser GM, Coy DH, Grossman A 1989 The pituitary-adrenal response to CRF-41 is unaltered by intravenous somatostatin in normal subjects. Clin Endocrinol (Oxf) 30:661–666[Medline]
  24. Ambrosio MR, Campo M, Zatelli MC, Cella SG, Trasforini G, Margutti A, Rigamonti AE, Muller EE, degli Uberti EC 1998 Unexpected activation of pituitary-adrenal axis in healthy young and elderly subjects during somatostatin infusion. Neuroendocrinology 68:123–128[CrossRef][Medline]
  25. Fehm HL, Voigt KH, Lang R, Beinert KE, Raptis S, Pfeiffer EF 1976 Somatostatin: a potent inhibitor of ACTH-hypersecretion in adrenal insufficiency. Klin Wochenschr 54:173–175[CrossRef][Medline]
  26. Julesz J, Laczi F, Janaky T, Laszlo F 1980 Effects of somatostatin and bromocryptine on the plasma ACTH level in bilaterally adrenalectomized patients with Cushing’s disease. Endokrinologie 76:68–72[Medline]
  27. Tyrrell JB, Lorenzi M, Gerich JE, Forsham PH 1975 Inhibition by somatostatin of ACTH secretion in Nelson’s syndrome. J Clin Endocrinol Metab 40:1125–1127[Abstract/Free Full Text]
  28. Ghigo E, Arvat E, Valente F 1991 Arginine reinstates the somatotrope responsiveness to intermittent growth hormone-releasing hormone administration in normal adults. Neuroendocrinology 54:291–294[Medline]
  29. Alba-Roth J, Muller OA, Schopohl J, Von Werder K 1988 Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion. J Clin Endocrinol Metab 67:1186–1189[Abstract/Free Full Text]
  30. Veldhuis JD, Keenan DM, Roelfsema F, Iranmanesh A 2005 Aging-related adaptations in the corticotropic axis: modulation by gender. Endocrinol Metab Clin North Am 34:993–1014[CrossRef][Medline]
  31. Erickson D, Keenan DM, Mielke K, Bradford K, Bowers CY, Miles JM, Veldhuis JD 2004 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 89:4746–4754[Abstract/Free Full Text]
  32. Veldhuis JD, Iranmanesh A, Mielke K, Miles JM, Carpenter PC, Bowers CY 2006 Ghrelin potentiates growth hormone secretion driven by putative somatostatin withdrawal and resists inhibition by human corticotropin-releasing hormone. J Clin Endocrinol Metab 91:2441–2446[Abstract/Free Full Text]
  33. Akamizu T, Takaya K, Irako T, Hosoda H, Teramukai S, Matsuyama A, Tada H, Miura K, Shimizu A, Fukushima M, Yokode M, Tanaka K, Kangawa K 2004 Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects. Eur J Endocrinol 150:447–455[Abstract]
  34. Merimee TJ, Rabinowitz D, Fineberg SE 1969 Arginine-initiated release of human growth hormone. Factors modifying the response in normal men. N Engl J Med 281:1434–1438
  35. Schurmeyer TH, Avgerinos PC, Gold PW, Gallucci WT, Tomai TP, Cutler Jr GB, Loriaux DL, Chrousos GP 1984 Human corticotropin-releasing factor in man: pharmacokinetic properties and dose-response of plasma adrenocorticotropin and cortisol secretion. J Clin Endocrinol Metab 59:1103–1108[Abstract/Free Full Text]
  36. O’Brien PC 1983 The appropriateness of analysis of variance and multiple-comparison procedures. Biometrics 39:787–794[CrossRef][Medline]
  37. Keenan DM, Roelfsema F, Biermasz N, Veldhuis JD 2003 Physiological control of pituitary hormone secretory-burst mass, frequency and waveform: a statistical formulation and analysis. Am J Physiol 285:R664–R673
  38. Korbonits M, Trainer PJ, Fanciulli G, Oliva O, Pala A, Dettori A, Besser GM, Delitala G, Grossman AB 1996 L-Arginine is unlikely to exert neuroendocrine effects in humans via the generation of nitric oxide. Eur J Endocrinol 135:543–547[Abstract/Free Full Text]
  39. Pow DV, Crook DK 1997 Immunocytochemical analysis of the transport of arginine analogues into nitrergic neurons and other cells in the retina and pituitary. Cell Tissue Res 290:501–514[CrossRef][Medline]
  40. Bugajski J, Gadek-Michalska A, Glod R, Borycz J, Bugajski AJ 1999 Blockade of nitric oxide formation impairs adrenergic-induced ACTH and corticosterone secretion. J Physiol Pharmacol 50:327–334[Medline]
  41. Fairhall KM, Mynett A, Robinson ICAF 1995 Central effects of growth hormone-releasing hexapeptide (GHRP-6) on growth hormone release are inhibited by central somatostatin action. J Endocrinol 144:555–560[Abstract/Free Full Text]
  42. Hisano S, Daikoku S 1991 Existence of mutual synaptic relations between corticotropin-releasing factor-containing and somatostatin-containing neurons in the rat hypothalamus. Brain Res 545:265–275[CrossRef][Medline]
  43. Liposits Z, Paull WK, Setalo G, Vigh S 1985 Evidence for local corticotropin releasing factor (CRF)-immunoreactive neuronal circuits in the paraventricular nucleus of the rat hypothalamus. An electron microscopic immunohistochemical analysis. Histochemistry 83:5–16[CrossRef][Medline]
  44. Van den Berghe G 2000 Novel insights into the neuroendocrinology of critical illness. Eur J Endocrinol 143:1–13[Abstract]
  45. Keenan DM, Licinio J, Veldhuis JD 2001 A feedback-controlled ensemble model of the stress-responsive hypothalamo-pituitary-adrenal axis. Proc Natl Acad Sci USA 98:4028–4033[Abstract/Free Full Text]
  46. Keenan DM, Alexander SL, Irvine CHG, Clarke IJ, Canny BJ, Scott CJ, Tilbrook AJ, Turner AI, Veldhuis JD 2004 Reconstruction of in vivo time-evolving neuroendocrine dose-response properties unveils admixed deterministic and stochastic elements in interglandular signaling. Proc Natl Acad Sci USA 101:6740–6745[Abstract/Free Full Text]
  47. Keenan DM, Takahashi PY, Liu PY, Roebuck PD, Nehra AX, Iranmanesh A, Veldhuis JD 2006 An ensemble model of the male gonadal axis: illustrative application in aging men. Endocrinol 147:2817–2828[CrossRef][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Iranmanesh, A.
Right arrow Articles by Veldhuis, J. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Iranmanesh, A.
Right arrow Articles by Veldhuis, J. D.
Related Collections
Right arrow Neuroendocrinology and Pituitary

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