AJP - Endo Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 286: E25-E30, 2004. First published September 23, 2003; doi:10.1152/ajpendo.00230.2003
0193-1849/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
286/1/E25    most recent
00230.2003v1
Right arrow Alert me when this article is cited
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 ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Biermasz, N. R.
Right arrow Articles by Roelfsema, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Biermasz, N. R.
Right arrow Articles by Roelfsema, F.

Octreotide represses secretory-burst mass and nonpulsatile secretion but does not restore event frequency or orderly GH secretion in acromegaly

Nienke R. Biermasz,1 Alberto M. Pereira,1 Marijke Frölich,2 Johannes A. Romijn,1 Johannes D. Veldhuis,3 and Ferdinand Roelfsema1

1Department of Metabolism and Endocrinology and 2Department of Clinical Chemistry, Leiden University Medical Center, 2333ZA Leiden, The Netherlands; and 3Department of Endocrinology/Metabolism and Internal Medicine, Mayo Medical School, Mayo Clinic and Foundation, Rochester, Minnesota 55905

Submitted 31 May 2003 ; accepted in final form 28 August 2003


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 DISCLOSURES
 REFERENCES
 
Octreotide is a potent somatostatin analog that inhibits growth hormone (GH) release and restricts somatotrope cell growth. The long-acting octreotide formulation Sandostatin LAR is effective clinically in ~60% of patients with acromegaly. Tumoral GH secretion in this disorder is characterized by increases in pulse amplitude and frequency, nonpulsatile (basal) release, and irregularity. Whether sustained blockade by octreotide can restore physiological secretion patterns in this setting is unknown. To address this question, we studied seven patients with GH-secreting tumors during chronic receptor agonism. Responses were monitored by sampling blood at 10-min intervals for 24 h, followed by analyses of secretion and regularity by multiparameter deconvolution and approximate entropy (ApEn). The somatostatin agonist suppressed GH secretory-burst mass, nonpulsatile (basal) GH release, and pulsatile secretion, thereby decreasing total GH secretion by 86% (range 70-96%). ApEn decreased from 1.203 ± 0.129 to 0.804 ± 0.141 (P = 0.032), denoting greater regularity. None of GH pulse frequency, basal GH secretion rates, or ApEn normalized. In summary, chronic somatostatin agonism is able to repress amplitude-dependent measures of excessive GH secretion in acromegaly. Presumptive tumoral autonomy is inferred by continued elevations of event frequency, overall pattern disruption (irregularity), and nonsuppressible basal GH secretion.

growth hormone; human; deconvolution analysis; diurnal rhythm

GROWTH HORMONE (GH) is secreted in a pulsatile fashion in healthy individuals. In the daytime and fed state, GH is released in diminutive bursts, whereas in fasting and during sleep, GH outflow unfolds in volley-like episodes. Primary secretagogues are hypothalamic GH-releasing hormone (GHRH) and, possibly, ghrelin. Autoinhibition is imposed by somatostatin, which mediates central feedback actions of GH and IGF-I. GHRH and somatostatin also influence somatotrope cell growth chronically (17). Acromegaly is a disease of excessive and autonomous GH secretion, associated with an increased mass (number and size) of somatotrope cells. Most often, a pituitary adenoma can be visualized and removed surgically. Investigations of tumoral GH secretion in active acromegaly have revealed increases in pulse-event frequency, basal (nonpulsatile) secretion, irregularity, and (absolute) diurnal rhythmicity (19-21, 44). In patients with noninvasive adenomas, transsphenoidal surgery can normalize each attribute (43, 45).

Octreotide is a potent somatostatin agonist that effectually suppresses GH hypersecretion in ~60% of patients with active acromegaly. The rationale for using this agent is to block GH release and limit somatotrope cell growth specifically, without the risk implicit in radiotherapy of inducing subsequent pituitary insufficiency (11, 13, 28, 32, 42). Octreotide therapy is used when curative surgery is not attainable. The basis of repression of mean serum GH concentrations by these agents is not clear (40). However, somatostatin agonists strongly suppress GH burst mass and nonpulsatile GH release and enforce regularity in normal young men and women, older men, and postmenopausal women (8-10, 31). We tested the clinical postulate that prolonged receptor occupancy achieved by the depot form of octreotide could reverse selected facets of autonomous tumoral GH secretion in patients with active acromegalic disease.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 DISCLOSURES
 REFERENCES
 
Patients and Control Subjects

Seven patients (4 men and 3 women, mean age 55 yr, range 39-75 yr), with clinically active acromegaly, and 18 healthy control subjects (9 males and 9 females, mean age 51 yr, range 39-69 yr) were recruited for this study. Body mass index (wt/ht2) was comparable at 25.6 ± 1.5 kg/m2 in patients and 23.9 ± 0.72 kg/m2 in control subjects. The diagnosis of acromegaly was based on progressive acral growth, incomplete suppression of GH during oral glucose loading (nadir concentration >5 mU/l), and an elevated serum IGF-I concentration interpreted by age. Five patients had previous transsphenoidal surgery without normalization of GH excess.

Patients were studied before and during sustained octreotide treatment (20-mg injections of Sandostatin LAR at 4-wk intervals). They were selected from 11 acromegalics on the basis of clinical responsiveness to octreotide and normal IGF-I concentration. None of the patients had clinical signs or biochemical evidence of hypopituitarism. The study was approved by the ethical committee of the Leiden University Medical Center, and written informed consent was obtained from all patients and control subjects.

Sampling Protocol

Patients were hospitalized on the evening before sampling. On the following morning, an indwelling intravenous cannula was inserted in a forearm vein. Blood samples were withdrawn at 10-min intervals for 24 h starting at 0900. Serum was stored at -20°C until assayed. A slow intravenous infusion of heparin (1 U/ml) was used to maintain access. Patients were free to move about but not to sleep during daytime. Meals were served at 0800, 1230, and 1730. Lights were turned off between 2200 and 2400. No sleep monitoring was carried out.

GH was measured in samples collected every 10 min, and octreotide in sera was obtained every hour. At the start of the protocol (0900, fasting), an extra blood sample was obtained for screening safety data and measurements of IGF-I, IGF-binding protein-3, free thyroxine, cortisol, testosterone, estradiol, and LH.

Sampling was carried out 12-16 days after intramuscular injection with octreotide and after the patients had received injections for >=3 mo (range 3-18, median 12). At that time IGF-I had normalized, and this measure remained stable during subsequent follow-up at the same dosing schedule.

Assays

GH concentrations were measured with a sensitive time-resolved fluoroimmunoassay (Wallac, Turku, Finland) specific for the 22-kDa GH protein. The assay uses recombinant human (rh)GH as standard (Genotropin; Pharmacia & Upjohn, Uppsala, Sweden), which is calibrated against the World Health Organization First International Reference Preparation (no. 80-505). The limit of detection is 0.03 mU/l, or 0.01 µg/l. Intra-assay coefficients of variation (CVs) were 1.6-8.4% in the concentration range of 0.26-47 mU/l.

The total serum IGF-I concentration was determined by RIA after extraction and purification on ODS-silica columns (Incstar, Stillwater, MN). The interassay CV was <11%. The detection limit was 11 µg/l. Age-related normative data were determined in the same laboratory.

Serum octreotide concentrations were measured by RIA in the research laboratory of Novartis Pharma (Basel, Switzerland). The limit of detection was 50 pg/ml, and intra-assay CVs were 6-10%.

Analyses

Deconvolution analysis. Multiparameter deconvolution analysis was used to quantitate basal and pulsatile GH secretion and the GH half-life (50). This waveform-specific technique estimates the rate of basal release, the number and mass of randomly ordered secretory bursts, and the subject-specific (monoexponential) half-life (48). The daily pulsatile GH secretion rate is the product of secretory-burst frequency and the mean mass of GH released per event. Total GH secretion is the sum of basal and pulsatile secretion (48, 50).

Approximate entropy. Approximate entropy (ApEn) was used as a scale- and model-independent regularity statistic to quantitate the orderliness or regularity of serial GH concentrations over 24 h. Normalized ApEn parameters of m = 1 (test range) and r = 20% (threshold) of the intraseries SD were used, as described previously (31). Hence, this member of the ApEn family is designated ApEn(1, 20%). The ApEn metric evaluates the consistency of recurrent subordinate (nonpulsatile) patterns in a time series and thus yields information distinct from and complementary to cosinor and deconvolution (pulse) analyses (51). Higher absolute ApEn values denote greater relative randomness of hormone patterns, such as observed for tumoral secretion of ACTH, GH, and prolactin (18, 20, 44). Data are presented as absolute ApEn values and normalized ApEn ratios, defined by the mean ratio of absolute ApEn to that of 1,000 randomly shuffled versions of the same series (51).

Nyctohemeral (24-h) rhythmicity. Diurnal variations in GH and octreotide concentrations were appraised by cosinor analysis, as reported earlier (47). Ninety-five percent statistical confidence intervals were determined for the 24-h cosine amplitude (50% of the zenith-nadir difference), mesor (mean), and acrophase (time of the maximal value).

Statistical Analysis

Data are presented as means ± SE, unless otherwise noted. Statistical analyses were carried out via ANOVA and linear regression. Logarithmic transformation was used to limit heterogeneity of variance. P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 DISCLOSURES
 REFERENCES
 
Biochemical and Clinical Outcomes

During octreotide intervention, IGF-I concentrations decreased from 424 ± 76 to 143 ± 7.6 µg/l (range 122-168 µg/l) and normalized in each subject (P = 0.01). All patients experienced clinical improvement concurrently. Illustrative GH time series are shown in Fig. 1.



View larger version (27K):
[in this window]
[in a new window]
  		Fig. 1. Serum growth hormone (GH) concentration time series in 7 acromegalic patients before (A) and during sustained octreotide therapy (B). Data reflect sampling of blood every 10 min for 24 h. y-Axis scales are logarithmic and differ before and during intervention to aid in visualization.

 

Deconvolution Analysis

Octreotide inhibited basal GH secretion by more than ninefold and pulsatile secretion by sevenfold. The latter was explained by a sixfold fall in burst mass, with no reduction in event frequency or GH half-life (Table 1). However, octreotide did not normalize either basal secretion rate or burst frequency. The fraction of basal to total GH secretion also remained elevated (P < 0.001). Octreotide significantly repressed the sum of pulsatile and basal GH secretion (total daily GH production) by 86 ± 3% (range 70-96%) (Fig. 2).


View this table:
[in this window]
[in a new window]
  		Table 1. Deconvolution analysis of daily GH concentration time series

 


View larger version (16K):
[in this window]
[in a new window]
  		Fig. 2. Twenty-four-hour GH secretion rates in 7 acromegalic patients before and during chronic octreotide treatment and in 18 healthy sex- and age-matched control subjects. Daily GH secretion is partitioned analytically into basal (nonpulsatile), pulsatile, and total (sum of basal and pulsatile) secretion. P values denote the effect of octreotide (patients) and the contrast with normal volunteers (controls).

 

Diurnal GH Characteristics

Cosinor data are depicted in Table 2. Octreotide lowered the mesor (mean 24-h GH concentration about which the calculated rhythm varies) and amplitude (50% of nadir to zenith difference) sixfold. The acrophase (time of maximum) occurred ~3 h after midnight in both the patient and control cohorts and was unaffected by suppressive therapy.


View this table:
[in this window]
[in a new window]
  		Table 2. Cosinor analysis of the 24-h GH concentrations in acromegalic patients before and during intervention with octreotide

 

Octreotide and GH

Octreotide concentrations did not vary significantly over 24 h. The overall mean 24-h concentration (pg/ml) was 900 (range 530-1,540) pg/ml, and the coefficient of variation was 13% (range 10-17.2%).

ApEn

The octreotide intervention reduced ApEn of the GH concentration time series significantly (P = 0.032). A decrease denotes feedback repression (45). However, values failed to normalize (P = 0.003; Fig. 3). The latter distinction was not attributable to amplitude differences, because the normalized ApEn ratio (ratio in ApEn of observed to randomly shuffled cognate series) exhibited comparable changes (P = 0.014 vs. control).



View larger version (9K):
[in this window]
[in a new window]
  		Fig. 3. Approximate entropy (ApEn) of GH concentration time series in 7 acromegalic patients before and during octreotide therapy and 18 sex- and age-matched controls. A: absolute ApEn (1, 20%), the right normalized ApEn ratios (observed to random). An ApEn ratio of 1.0 is not distinguishable from that of randomly shuffled data series. P values are represented as described in Fig. 2.

 


   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 DISCLOSURES
 REFERENCES
 
Sustained (>=3 mo) exposure to a potent and selective somatostatin receptor agonist (octreotide) significantly repressed basal, pulsatile, and more irregular patterns of GH secretion by somatotrope tumors. Comparable response mechanisms are inferrable in healthy individuals exposed to somatostatin (9, 17, 31). In contradistinction, octreotide failed to normalize the elevated GH secretion, the more disorderly GH release patterns, and the increased GH pulse frequency associated with tumoral GH secretion. Biomathematical simulation studies indicate that accelerated pulse frequency, but not elevated interpulse hormone concentrations, contribute statistically to heightened irregularity (27). Some, but not all, surgical series report normalization of rapid GH pulsatility after surgery (23). Discrepancies among studies may reflect choice of GH assay, definitions of cure, patient selection, sampling frequency, and duration and peak-detection methods (19-21, 43, 45). Radiotherapy tends to normalize total IGF-I and glucose-suppressed GH concentrations (7, 39) but not dynamic secretory characteristics. For example, irregular patterns of GH release (elevated ApEn), rapid event frequency, and high basal GH secretion may persist after irradiation (35). The pathophysiology of anomalous GH-secretory control in the latter setting could include hypothalamic or pituitary injury due to prior therapeutic radiation and/or partially nonsuppressible continuing secretion by residual tumoral cells (4, 35). Normal somatotropes would predictively secrete little if any GH under the profound inhibitory effects of octreotide (17).

An unexplained discrepancy is recognized between the degree of therapy-induced inhibition of GH and IGF-I concentrations (1, 5, 6, 14, 34). Transgenic hepatic IGF-I gene-silencing experiments establish that the majority of blood-borne IGF-I is of hepatic origin (namely, 70-80%) (29, 41, 53). Other analyses in the rat and human indicate that a continuous basal-like mode of GH secretion (or experimental delivery) preferentially drives hepatic IGF-I synthesis (16, 26). Thus the relative admixture of pulsatile and basal GH secretion appears to determine IGF-I concentrations at any mean GH concentration (17, 20). In addition, there is variable sensitivity to GH among individuals based on age, gender, and estrogen availability (12, 23, 25, 33, 38, 54). In this regard, during octreotide intervention, two patients maintained slightly elevated GH concentrations and normal IGF-I concentrations.

Clinical observations support the hypothesis that GH-producing adenomas arise from mutations within the anterior pituitary gland, resulting in variable degrees of secretory autonomy. However, somatostatin and other feedback signals may continue to direct GH secretion in some measure in untreated acromegalic individuals. For example, fasting augments GH release in some patients with this disease (as in healthy subjects) but paradoxically diminishes GH secretion in others despite a fall in IGF-I concentration (22). Conversely, in one study, infusion of rhIGF-I lowered integrated GH concentrations by 25%, consistent with some sensitivity to IGF-I feedback (24). GHRH and GH-releasing peptides stimulate tumoral GH release both acutely and over 24 h (2, 15, 30, 38). The present responses to constant octreotide suppression are consistent with significant negative feedback on amplitude-specific measures such as GH secretory-burst mass and daily pulsatile GH secretion. The basis for only partial normalization of basal GH release, GH burst frequency, and irregular GH secretion patterns is not known. We hypothesize that these three facets of GH-secretory control are more proximate markers of somatotrope tumoral transformation.

Before octreotide treatment, acromegalic patients maintained a significant diurnal variation of GH release with a normal acrophase. Mechanisms that drive such rhythmicity in normal individuals include activity, food intake, sleep, and internal circadian inputs (17). Octreotide concentrations varied by 13% over 24 h within the target therapeutic range. Under these conditions, octreotide abolished detectable GH rhythmicity in two of seven subjects.

Sample-by-sample regularity (ApEn) mirrors the relative strength of feedback and feedforward signaling in complicated integrated systems, such as neuroendocrine axes. In normal subjects, infusion of somatostatin decreases ApEn, indicating more regular GH release, as expected for an effectual feedback signal on theoretical grounds (49). However, the somatostatin analog failed to restore the control degree of orderly GH release. From a mechanistic point of view, octreotide reduces IGF-I availability for feedback, which could elevate GH secretory irregularity in proportion to the extent of feedback withdrawal (46). On the other hand, a presumptive secondary rise in endogenous GHRH release in response to lower IGF-I concentrations would further drive irregular secretion (46, 52). Most plausibly, by analogy with other benign endocrine tumors (18, 20, 44), properties of transformed somatotrope cells may contribute to irregular (less coordinated) patterns of GH release, as observed here. In this regard, surgical removal of the somatotropinoma normalizes GH ApEn in 70% of patients with operable acromegaly (45).

In conclusion, constant octreotide delivery in patients with acromegaly lowers 24-h GH secretion by 86% through combined inhibition of the mass of individual GH-secretory events and the basal secretion rate. This mode of medical therapy does not normalize accentuated basal secretion, elevated pulse frequency, or disorderly GH release.


   GRANTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
DISCLOSURES
 REFERENCES
 
The study was supported in part by National Center for Research Resources (Rockville, MD) and General Clinical Research Center Grant RR-M01-00585 to the Mayo Clinic and Foundation.


   DISCLOSURES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 DISCLOSURES
REFERENCES
 
Financial support for measurements of octreotide was kindly provided by Novartis Pharma BV, Arnhem, The Netherlands, and technical assistance was provided by M. Rouilly, Novartis Pharma AG, Preclinical Safety Europe, Bioanalytics and Pharmacokinetics, Basel, Switzerland.


   FOOTNOTES
 

Address for reprint requests and other correspondence: F. Roelfsema, Dept. of Metabolism and Endocrinology, Leiden Univ. Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands (E-mail: f.roelfsema{at}lumc.nl).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 DISCLOSURES
 REFERENCES
 

  1. Abosch A, Tyrell B, Lamborn K, Hannegan LT, Applebury CB, and Wilson CB. Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab 83: 3411-3418, 1998.[Abstract/Free Full Text]
  2. Alster DK, Bowers CY, Jaffe CA, Ho PJ, and Barkan AL. The growth hormone (GH) response to GH-releasing peptide (His-DTrp-Ala- Trp-DPhe-Lys-NH2), GH-releasing hormone, and thyrotropin-releasing hormone in acromegaly. J Clin Endocrinol Metab 77: 842-845, 1993.[Abstract]
  3. Attanasio R, Barausse M, and Cozzi R. Raloxifene lowers IGF-I levels in acromegalic women. Eur J Endocrinol 148: 443-448, 2003.[Abstract]
  4. Barkan AL, Halasz I, Dornfeld KJ, Jaffe CA, Friberg RD, Chandler WF, and Sandler HM. Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly. J Clin Endocrinol Metab 82: 3187-3191, 1997.[Abstract/Free Full Text]
  5. Bates AS, Evans AJ, Jones P, and Clayton RN. Assessment of GH status in acromegaly using serum growth hormone, serum insulin-like growth factor-I and urinary growth hormone secretion. Clin Endocrinol 42: 417-423, 1995.[Medline]
  6. Biermasz NR, van Dulken H, and Roelfsema F. Ten-year follow-up results of transsphenoidal microsurgery in acromegaly. J Clin Endocrinol Metab 85: 4596-4602, 2000.[Abstract/Free Full Text]
  7. Biermasz NR, van Dulken H, and Roelfsema F. Long-term follow-up results of postoperative radiotherapy in 36 patients with acromegaly. J Clin Endocrinol Metab 85: 2476-2482, 2000.[Abstract/Free Full Text]
  8. Bray MJ, Vick TM, Shah N, Anderson SM, Rice LM, Iranmanesh A, Evans WS, and Veldhuis JD. Short-term estradiol replacement in postmenopausal women selectively mutes somatostatin's dose-dependent inhibition of fasting growth hormone secretion. J Clin Endocrinol Metab 86: 3143-3149, 2001.[Abstract/Free Full Text]
  9. Calabresi E, Ishikawa E, Bartolini L, Delitala G, Fanciulli G, Oliva O, Veldhuis JD, and Serio M. Somatostatin infusion suppresses GH secretory burst frequency and mass in normal men. Am J Physiol Endocrinol Metab 270: E975-E979, 1996.[Abstract/Free Full Text]
  10. Dimaraki EV, Jaffe CA, DeMott-Friberg R, Russell-Aulet M, Bowers CY, Marbach P, and Barkan AL. Generation of growth hormone pulsatility in women: evidence against somatostatin withdrawal as pulse initiator. Am J Physiol Endocrinol Metab 280: E489-E495, 2001.[Abstract/Free Full Text]
  11. Ezzat S, Snyder PJ, Young WF, Bayaiy LD, Newman C, Klibanski A, Molitch ME, Boyd AE, Sheeler L, and Cook DM. Octreotide treatment of acromegaly. A randomized, multicenter study. Ann Intern Med 117: 711-718, 1992.[CrossRef][ISI][Medline]
  12. Faria AC, Bekenstein LW, Booth RA Jr, Vaccaro VA, Asplin CM, Veldhuis JD, Thorner MO, and Evans WS. Pulsatile growth hormone release in normal women during the menstrual cycle. Clin Endocrinol 36: 591-596, 1992.[Medline]
  13. Flogstad AK, Halse J, Bakke S, Lancranjan I, Marbach P, Bruns C, and Jervell J. Sandostatin LAR in acromegalic patients: long-term treatment. J Clin Endocrinol Metab 82: 23-28, 1997.[Abstract/Free Full Text]
  14. Freda PU, Post KD, Powell JS, and Wardlaw SL. Evaluation of disease status with sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly. J Clin Endocrinol Metab 83: 3808-3816, 1998.[Abstract/Free Full Text]
  15. Gelato MC, Oldfield E, Loriaux DL, and Merriam GR. Pulsatile growth hormone secretion in patients with acromegaly and normal men: the effects of growth hormone-releasing hormone infusion. J Clin Endocrinol Metab 71: 585-590, 1990.[Abstract]
  16. Gevers EF, Wit JM, and Robinson ICAF. Growth, growth hormone (GH)-binding protein and GH-receptors are differentially regulated by peak and trough components of the GH secretory pattern in the rat. Endocrinology 137: 1013-1018, 1996.[Abstract]
  17. Giustina A and Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 19: 717-797, 1998.[Abstract/Free Full Text]
  18. Groote Veldman R, van den Berg G, Pincus SM, Frölich M, Veldhuis JD, and Roelfsema F. Increased episodic release and disorderliness of prolactin secretion in both micro- and macroprolactinomas. Eur J Endocrinol 140: 192-200, 1999.[Abstract]
  19. Hartman ML, Pincus SM, Johnson ML, Matthews DH, Faunt LM, Vance ML, Thorner MO, and Veldhuis JD. Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release. J Clin Invest 94: 1277-1288, 1994.[ISI][Medline]
  20. Hartman ML, Veldhuis JD, Vance ML, Faria AC, Furlanetto RW, and Thorner MO. Somatotropin pulse frequency and basal concentrations are increased in acromegaly and are reduced by successful therapy. J Clin Endocrinol Metab 70: 1375-1384, 1990.[Abstract]
  21. Ho KY and Weissberger AJ. Characterization of 24-hour growth hormone secretion in acromegaly: implications for diagnosis and therapy. Clin Endocrinol (Oxf) 41: 75-83, 1994.[Medline]
  22. Ho PJ, Friberg RD, and Barkan AL. Regulation of pulsatile growth hormone secretion by fasting in normal subjects and patients with acromegaly. J Clin Endocrinol Metab 75: 812-819, 1992.[Abstract]
  23. Ho PJ, Jaffe CA, Friberg RD, Chandler WF, and Barkan AL. Persistence of rapid growth hormone (GH) pulsatility after successful removal of GH-producing pituitary tumors. J Clin Endocrinol Metab 78: 1403-1410, 1994.[Abstract]
  24. Jaffe CA, Pan W, Brown MB, DeMott-Friberg R, and Barkan AL. Regulation of GH secretion in acromegaly: reproducibility of daily GH profiles and attenuated negative feedback by IGF-I. J Clin Endocrinol Metab 86: 4364-4370, 2001.[Abstract/Free Full Text]
  25. Janssen YJH, Frölich M, and Roelfsema F. A low starting dose of Genotropin in growth hormone-deficient adults. J Clin Endocrinol Metab 82: 129-135, 1997.[Abstract/Free Full Text]
  26. Jørgensen JOL, Møller N, Lauritzen T, and Christiansen JS. Pulsatile versus continuous intravenous administration of growth hormone (GH) in GH-deficient patients: effects on circulating insulin-like growth factor-I and metabolic indices. J Clin Endocrinol Metab 70: 1616-1623, 1990.[Abstract]
  27. Keenan DM and Veldhuis JD. Hypothesis testing of the aging male gonadal axis via a biomathematical construct. Am J Physiol Regul Integr Comp Physiol 280: R1755-R1771, 2001.[Abstract/Free Full Text]
  28. Lancranjan I and Atkinson AB. Results of a European Multicentre Study with Sandostatin LAR in acromegalic patients. Pituitary 1: 105-114, 1999.[CrossRef][Medline]
  29. Liu JL, Yakar S, and LeRoith D. Mice deficient in liver production of insulin-like growth factor I display sexual dimorphism in growth hormone-stimulated postnatal growth. Endocrinology 141: 4436-4441, 2000.[Abstract/Free Full Text]
  30. Losa M, Chiodini PG, and Liuzzi A. Growth hormone-releasing infusion in patients with active acromegaly. J Clin Endocrinol Metab 63: 88-93, 1986.[Abstract]
  31. Mulligan T, Jaen-Vinuales A, Godschalk M, Iranmanesh A, and Veldhuis JD. Synthetic somatostatin analog (octreotide) suppresses daytime growth hormone secretion equivalently in young and older men: preserved pituitary responsiveness to somatostatin's inhibition in aging. J Am Geriatr Soc 47: 1422-1424, 1999.[ISI][Medline]
  32. Newman CB, Melmed S, Snyder PJ, Young WF, Bayaiy LD, Levy R, Stewart WN, Molitch ME, and Gagel RF. Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients—a clinical research center study. J Clin Endocrinol Metab 80: 2768-2775, 1995.[Abstract]
  33. Parkinson C, Renehan AG, Ryder WDJ, O'Dwyer ST, Shalet SM, Trainer PJ. Gender and age influence the relationship between serum GH and IGF-I in patients with acromegaly. Clin Endocrinol 57: 59-64, 2002.[CrossRef][Medline]
  34. Parkinson C, Ryder WDJ, and Trainer PJ. The relationship between serum GH and serum IGF-I in acromegaly is gender-specific. J Clin Endocrinol Metab 86: 5240-5244, 2001.[Abstract/Free Full Text]
  35. Peacey SR, Toogood AA, Veldhuis JD, Thorner MO, and Shalet SM. The relationship between 24-hour growth hormone secretion and insulin-like growth factor I in patients with successfully treated acromegaly: impact of surgery or radiotherapy. J Clin Endocrinol Metab 86: 259-266, 2001.[Abstract/Free Full Text]
  36. Pellegrini E, Carmignac DF, Bluet-Pajot MT, Mounier F, Bennett P, Epelbaum J, and Robinson IC. Intrahypothalamic growth hormone feedback: from dwarfism to acromegaly in the rat. Endocrinology 138: 4543-4551, 1997.[Abstract/Free Full Text]
  37. Pincus SM. Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA 88: 2297-2301, 1991.[Abstract/Free Full Text]
  38. Popovic V, Damjanovic S, Micic D, Petakov M, Dieguez C, and Casanueva FF. Growth hormone (GH) secretion in active acromegaly after combined administration of GH-releasing hormone and GH-releasing peptide-6. J Clin Endocrinol Metab 79: 456-460, 1994.[Abstract]
  39. Powell JS, Wardlaw SL, Post KD, and Freda PU. Outcome of radiotherapy for acromegaly using normalization of insulin-like growth factor I to define cure. J Clin Endocrinol Metab 85: 2068-2071, 2000.[Abstract/Free Full Text]
  40. Roelfsema F, de Boer H, and Frölich M. The influence of octreotide treatment on pulsatile growth hormone release in acromegaly. Clin Endocrinol (Oxf) 33: 297-306, 1990.[Medline]
  41. Sjögren K, Liu JL, Blad K, Skrtic S, Vidal O, Wallenius V, LeRoith D, Törnell J, Isaksson OGP, Jansson JO, and Ohlson C. Liver-derived insulin-like growth factor-I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci USA 96: 7088-7092, 1999.[Abstract/Free Full Text]
  42. Vance ML and Harris AG. Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide. Results of the International Multicenter Acromegaly Study Group. Arch Intern Med 151: 1573-1578, 1991.[Abstract]
  43. Van den Berg G, Frölich M, Veldhuis JD, and Roelfsema F. Growth hormone secretion in recently operated acromegalic patients. J Clin Endocrinol Metab 79: 1706-1715, 1994.[Abstract]
  44. Van den Berg G, Pincus SM, Veldhuis JD, Frölich M, and Roelfsema F. Greater disorderliness of ACTH and cortisol release accompanies pituitary-dependent Cushing's disease. Eur J Endocrinol 136: 394-400, 1997.[Abstract]
  45. Van den Berg G, Pincus SM, Frölich M, Veldhuis JD, and Roelfsema F. Reduced disorderliness of growth hormone release in biochemically inactive acromegaly after pituitary surgery. Eur J Endocrinol 138: 164-169, 1998.[Abstract]
  46. Veldhuis JD, Bidlingmaier M, Anderson SM, Wu Z, and Strasburger CJ. Lowering total plasma insulin-like growth factor I concentrations by way of a novel, potent, and selective growth hormone (GH) receptor antagonist, pegvisomant (B2036-peg), augments the amplitude of GH secretory bursts and elevates basal/nonpulsatile GH release in healthy women and men. J Clin Endocrinol Metab 86: 3304-3310, 2001.[Abstract/Free Full Text]
  47. Veldhuis JD, Iranmanesh A, Johnson ML, and Lizarralde G. Twenty-four-hour rhythms in plasma concentrations of adenohypophyseal hormones are generated by distinct amplitude and/or frequency modulation of underlying pituitary secretory bursts. J Clin Endocrinol Metab 71: 1616-1623, 1990.[Abstract]
  48. Veldhuis JD and Johnson ML. Specific methodological approaches to selected contemporary issues in deconvolution analysis of pulsatile neuroendocrine data. Methods Neurosci 28: 25-92, 1995.
  49. Veldhuis JD, Johnson ML, Veldhuis OL, Straume M, and Pincus SM. Impact of pulsatility on the ensemble orderliness (approximate entropy) of neurohormone secretion. Am J Physiol Regul Integr Comp Physiol 281: R1975-R1985, 2001.[Abstract/Free Full Text]
  50. Veldhuis JD, Moorman J, and Johnson ML. Deconvolution analysis of neuroendocrine data: waveform-independent methods and application. Methods Neurosci 20: 279-325, 1994.
  51. Veldhuis JD and Pincus SM. Orderliness of hormone release patterns: a complementary measure to conventional pulsatile and circadian analyses. Eur J Endocrinol 138: 358-362, 1998.[CrossRef][ISI][Medline]
  52. Veldhuis JD, Straume M, Iranmanesh A, Mulligan T, Jaffe CA, Barkan AL, Johnson ML, and Pincus SM. Secretory process regularity monitors neuroendocrine feedforward signaling strength in humans. Am J Physiol Regul Integr Comp Physiol 280: R721-R729, 2001.[Abstract/Free Full Text]
  53. Wallenius K, Sjögren K, Peng XD, Park S, Wallenius V, Liu JL, Umaerus M, Wennbo H, Isaksson O, Frohman L, Kineman R, Ohlson C, and Jansson JO. Liver-derived IGF-I regulates GH secretion at the pituitary level in mice. Endocrinology 142: 4762-4770, 2001.[Abstract/Free Full Text]
  54. Wolthers T, Hoffman DM, Nugent AG, Duncan MW, Umpleby M, and Ho KKY. Oral estrogen antagonizes the metabolic actions of growth hormone in growth hormone-deficient women. Am J Physiol Endocrinol Metab 281: E1191-E1196, 2001.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Eur J EndocrinolHome page
S W van Thiel, J J Bax, N R Biermasz, E R Holman, D Poldermans, F Roelfsema, H J Lamb, E E van der Wall, J W A Smit, J A Romijn, et al.
Persistent diastolic dysfunction despite successful long-term octreotide treatment in acromegaly
Eur. J. Endocrinol., August 1, 2005; 153(2): 231 - 238.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
H. H. Van Vugt, H. J.M. Swarts, B. J.M. Van de Heijning, and E. M. Van der Beek
Centrally Applied Somatostatin Inhibits the Estrogen-Induced Luteinizing Hormone Surge via Hypothalamic Gonadotropin-Releasing Hormone Cell Activation in Female Rats
Biol Reprod, September 1, 2004; 71(3): 813 - 819.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
286/1/E25    most recent
00230.2003v1
Right arrow Alert me when this article is cited
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 ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Biermasz, N. R.
Right arrow Articles by Roelfsema, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Biermasz, N. R.
Right arrow Articles by Roelfsema, F.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.