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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-1145
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 10 4052-4057
Copyright © 2008 by The Endocrine Society

Thyrotropin Secretion by Thyrotropinomas Is Characterized by Increased Pulse Frequency, Delayed Diurnal Rhythm, Enhanced Basal Secretion, Spikiness, and Disorderliness

Ferdinand Roelfsema, Alberto M. Pereira, Daniel M. Keenan, Johannes D. Veldhuis and Johannes A. Romijn

Department of Endocrinology and Metabolic Diseases (F.R., A.M.P., J.AR.), Leiden University Medical Center, NL2333ZA Leiden, The Netherlands; Department of Statistics (D.M.K.), University of Virginia, Charlottesville, Virginia 22904; and Endocrine Research Unit (J.D.V.), Mayo Medical and Graduate Schools, Clinical Translational Research Center, Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Ferdinand Roelfsema, Department of Endocrinology and Metabolism, Leiden University Medical Center, Albinusdreef 2, NL2333ZA Leiden, The Netherlands. E-mail: f.roelfsema{at}lumc.nl.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Hormone secretion by somatotropinomas, corticotropinomas, and prolactinomas exhibits increased pulsatility and basal secretion, accompanied by greater disorderliness.

Objective: Our objective was to evaluate TSH secretion by thyrotropinomas with up-to-date analytical and mathematical tools.

Design: Twenty-four hour blood samplings at 10-min intervals in a clinical research laboratory in five patients with a thyrotropinoma and 10 healthy age- and gender-matched controls were performed. The obtained serum TSH profiles were analyzed with a new deconvolution method, approximate entropy, Cosinor analysis, and by quantification of spikiness.

Results: TSH burst frequency and basal secretion were increased in patients compared with controls. TSH secretion patterns in patients were more irregular than in controls, but the diurnal rhythm was preserved at a higher mean in all patients, although with a 2-h phase delay.

Conclusion: TSH secretion by thyrotropinomas shares many characteristics with other pituitary hormone-secreting adenomas.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
The major regulators of TSH secretion are TRH, somatostatin and dopamine, and thyroid hormones, whereas T4 and T3 exert negative feedback at the hypothalamic and pituitary level. The interplay among these regulators governs the TSH secretion pattern, which is characterized by diurnal variation with superimposed (small) bursts (1). The 24-h secretion profile of TSH has been well described in various pathophysiological conditions, including hyperthyroidism, hypothyroidism, obesity, prolonged fasting, and in nonthyroidal illness, but not in detail in central hyperthyroidism caused by a pituitary TSH-secreting adenoma (2, 3, 4, 5, 6, 7). TSH-secreting adenoma is a rare pituitary tumor (<1% of all pituitary adenomas) and is usually diagnosed when the TSH level is inappropriately elevated in the hyperthyroid patient with increased serum T4 levels, combined with the presence of a pituitary (micro) adenoma (8). In other hormone-secreting pituitary adenomas, e.g. Cushing’s disease and prolactinoma, hormone secretion is characterized by diminished or absent diurnal amplitude, and increased basal secretion, increased pulse frequency, and diminished secretory regularity (9, 10, 11).

By analogy with the results found in other pituitary adenomas, we hypothesized that thyrotropinomas would display a changed diurnal secretion pattern, increased basal release, increased pulsatility, and decreased regularity. To this end we analyzed the TSH profiles obtained in five patients with a thyrotropinoma with up-to date analytical tools and compared the outcome of these analyses with those obtained in 10 healthy age- and gender-matched controls that were investigated in a strictly comparable way.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and controls

Five patients with central hyperthyroidism caused by a TSH-secreting adenoma were diagnosed during the last 10 yr in the Leiden University Medical Center. The diagnosis was based on an elevated serum free T4 (fT4) concentration in the presence of an inappropriate (elevated) serum TSH concentration, clinical signs of (mild) hyperthyroidism, and the presence of a pituitary adenoma on magnetic resonance imaging. The diagnosis was confirmed by positive immunostaining for TSH of the adenoma in two patients who underwent pituitary surgery because of associated acromegaly in one patients and optic chiasm compression in the other. Two patients responded favorably to octreotide treatment with improvement of clinical symptoms, normalization of the fT4 concentration, decrease in TSH concentration, and decrease in the size of the adenoma. The last patient refused any form of treatment, but T4 resistance was unlikely because of a normal genetic analysis of the β-receptor of T4. In addition, his two adult children were euthyroid, and they had normal serum fT4 and TSH concentrations. Clinical details of the patients are listed in Table 1Go. Two elderly male patients had a slightly increased serum IGF-I concentration without distinct clinical signs and symptoms of acromegaly. There were 10 healthy nonobese controls (body mass index 18–25 kg/m2) of similar sex and age range enrolled in this study, after giving written acknowledgment of informed consent for participation. The female premenopausal controls were required to have a regular menstrual cycle and not use oral contraceptives. Subjects were studied in the early follicular phase of their menstrual cycle. Chronic disease, depression (present or in history), smoking, recent transmeridional flights, night-shift work, weight change (>3 kg in 3 months), and use of medication (except for the patients) were exclusion criteria. All control subjects had an unremarkable medical history, and no abnormalities were found during physical examination, standard laboratory hematology, and blood chemistry and urine tests.


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  		TABLE 1. Clinical details of the patients and controls

 
Clinical protocol

The protocol was approved by the Medical Ethics Committee of the Leiden University Medical Center (Leiden, The Netherlands). Subjects were admitted to the Clinical Research Unit of the Department of General Internal Medicine in the early follicular stage of their menstrual cycle. None of the patients used short-acting or depot formulations of somatostatin analogs before or during the blood sampling protocol. A cannula for blood sampling was inserted into an antecubital vein. The cannula was attached to a three-way stopcock and kept patent by a continuous saline infusion. Blood samples were taken at 10-min intervals for determination of plasma TSH concentrations. Subjects remained recumbent, except for bathroom visits. No daytime naps were allowed. Meals were served according to a fixed time schedule. Lights were switched off at 2300 h. Vital signs were recorded at regular time intervals, and great care was taken not to disturb the subjects while sampling blood during their sleep (no electroencephalography sleep recording was performed).

Assays

Samples were centrifuged at 4000 rotations/min at 4 C for 20 min, within 60 min of sampling. Subsequently, plasma was divided into separate aliquots and frozen at –80 C until assays were performed. Samples of each subject were determined in the same assay run. Plasma TSH concentrations were measured with a time-resolved immunofluorometric assay (Wallac, Turku, Finland), and its standard was calibrated against the World Health Organization second standard International Reference Preparation (80/558) human TSH for immunoassays. The limit of detection was 0.05 mU/liter, and the interassay coefficient of variation was less then 5%. fT4 was estimated using an automated system (Elecsys 2010; Roche Diagnostics Nederland BV, Almere, The Netherlands). T3 was measured with Abbott Axsym (Abbott Laboratories, Abbott Park, IL).

Calculations and statistics

Deconvolution Earlier deconvolution methods in some cases yielded nonunique estimates of basal and pulsatile hormone secretion and elimination rates (12). To address this technical impasse, basal and pulsatile TSH secretion was estimated simultaneously by using a new maximum likelihood deconvolution methodology (13, 14, 15, 16). The methodology has been validated directly by analyses in the sheep and horse. The basic assumptions are that: 1) peaks in concentrations reflect the mass of hormone released in delimited secretory bursts; 2) the burst waveform (time course of instantaneous release rates) may be defined by a three-parameter generalized {gamma}-probability density; 3) combined diffusion, advection, and irreversible elimination may be represented via bi-exponential kinetics; and 4) parameter estimation is statistically conditioned on a priori estimates of pulse onset times obtained by an incremental smoothing algorithm, and then selected recursively on probabilistic grounds (17).

The Weibull renewal process is a class of random pulsing processes with variable mean frequency ({lambda}, number of pulses per 24 h) and interpulse-interval regularity ({gamma}, higher {gamma} than 1.0 denotes greater regularity than a Poisson process). Unlike the Poisson, the Weibull allows for a coefficient of variation of interburst intervals less than 100%, independently of mean frequency, thus mimicking physiological values of 20–60%.

Approximate entropy (ApEn) The ApEn statistic allows one to quantify the degree of regularity or reproducibility of subpatterns within time series. ApEn is a model-free, translation- and scale-invariant, asymptotically normally distributed statistic that distinguishes orderliness of data series of length 30 or more points. ApEn calibrates an extent of sequential interrelationships, quantifying a continuum that ranges from totally ordered to completely random. ApEn evaluates both dominant and subordinate patterns in data; notably, it will detect changes in underlying episodical behavior not reflected in peak occurrences or amplitudes. Technically, ApEn is defined as the summed logarithmic likelihood that templates (of length m) of patterns in the data that are similar (within r) remain similar (within the same tolerance r) on next (m + 1) incremental comparison. ApEn of any given time series is a single nonnegative number, with larger values corresponding to greater apparent process randomness or serial irregularity and smaller values corresponding to more instances of recognizable features or patterns in the data (18, 19). Direct empirical data show that ApEn detects unopposed feedback and decreased feedback (20).

Spikiness A subtle difference between secretory patterns between physiology and tumoral states can be acute sharp increases and decreases of serum concentrations of a hormone. We quantitated this aspect by a recently developed algorithm, which is the ratio of the SD of the first-differenced (incremental) series and the SD of the original series of serum hormone concentrations (21).

Diurnal rhythmicity Nyctohemeral variation of TSH concentrations was determined by a nonlinear unweighted least-squares cosine approximation, as reported earlier (22). Ninety-five percent statistical confidence intervals were determined for the 24-h cosine amplitude (50% of the zenith-nadir difference), mesor (rhythmic mean), and acrophase (clock time of maximal value).

Statistics

Data are presented as mean ± SEM, unless otherwise specified. The means of TSH concentration and secretion parameters of both groups were compared using the two-tailed independent Student’s t test after logarithmic transformation. Significance level was set at 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Figure 1Go depicts the serum TSH concentration profiles of two patients and two control subjects. The figure also displays the fitted concentration curve as calculated by the deconvolution analysis. At the bottom of the panels, the secretion rate during the 24-h cycle is shown, which clearly exhibits an increased burst frequency in patients compared with controls.


Figure 1
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  		FIG. 1. Serum TSH concentration profiles of two patients and controls and the fitted curves calculated with the deconvolution program are shown. At the bottom of the panels, the secretion rates are displayed.

 
In Table 2Go the results of the deconvolution analysis are shown. TSH burst frequency was increased by 1.5-fold and basal (nonpulsatile) secretion by 2.5-fold. Total and pulsatile TSH secretion, although larger in patients, did not differ significantly from controls. The Weibull {gamma}-parameter was not altered in patients compared with controls, pointing to the unchanged regularity of the distribution of the TSH pulses throughout the 24-h period.


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  		TABLE 2. Deconvolution of serum TSH concentration profiles in patients with a TSH-secreting adenoma

 
ApEn was increased in the patients, as shown in Table 3Go, pointing to the decreased regularity of hormone-concentration patterns (not necessarily pulses). Spikiness was elevated in patients to 0.4199 ± 0.2060 (mean ± SD) compared with controls 0.2378 ± 0.2060 (P = 0.016). Finally, Cosinor analysis revealed an increased mesor with unchanged amplitude in patients compared with controls. However, the rhythm showed a more than 2-h phase delay in patients (Table 4Go).


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  		TABLE 3. ApEn of serum TSH concentration profiles in TSH-secreting adenoma

 

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  		TABLE 4. Cosinor analysis of serum TSH concentration profiles in TSH-secreting adenoma

 

   Discussion
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In this case series of patients with a TSH-secreting adenoma, we established increased TSH pulse numbers with normal pulsing variability, increased basal (nonpulsatile) TSH release, decreased secretory pattern regularity, increased spikiness, and a significant phase shift in higher diurnal TSH rhythm.

Increased pulsatility is a feature common to endocrine adenomas, including somatotropinomas, prolactinomas, and corticotropinomas, as displayed in Fig. 2Go, and also hormone-secreting adrenal adenomas (9, 10, 11, 23, 24). The measurement of free {alpha}-subunit, if available, might be used to corroborate frequency acceleration in gonadotropinomas and thyrotropinomas. The diversity of tumor types suggests that the cause of increased pulsatility is probably not primarily mediated via signaling of the increased frequency of stimulatory peptides or neurotransmitters but, rather, is an intrinsic feature of the adenoma per se.


Figure 2
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  		FIG. 2. Pulse frequency and ApEn of pituitary adenomas and age- and gender-matched controls. Data for acromegaly, Cushing’s disease, and prolactinoma were recalculated from Refs. 9 10 11 .

 
Normal Weibull {gamma} indicated that frequent TSH pulses occur with normal variability in the length of interpulse intervals. Elevated Weibull {lambda} confirms the frequency increase. The other remarkable finding was the decreased regularity of secretory patterns as revealed by the increased ApEn. ApEn has been investigated in a variety of altered feed-forward and feedback states in healthy individuals, e.g. by studying the somatotropic axis in healthy subjects during GHRH or GH-releasing peptide-2 infusions and pegvisomant administration (25, 26, 27). Increased stimulation of the somatotrope by these peptides is accompanied by decreased regularity (increased ApEn), whereas decreased IGF-I feedback by blocking the GH signal with the GH-receptor blocking drug, pegvisomant, also leads to increased disorderliness of GH secretion. Thus, these studies have indicated that ApEn reflects the strength of feed-forward and feedback signaling of the studied system (20, 28). In contrast, endocrine tumors are generally not regulated by increased stimuli (with exceptions such as GHRH-secreting carcinoid tumors, or ectopic CRH-producing tumors), although diminished feedback may be present, such as observed in corticotropinomas (glucocorticoids), somatotropinoma (IGF-I), and parathyroid adenomas (calcium), which could favor irregular secretion. In addition, increased ApEn might also reflect the disorganized secretion from the tumor per se because other hormone-secreting pituitary tumors also exhibit disorderly secretion (Fig. 2Go).

One of our patients had a very active acromegalic syndrome as well. Interestingly, this patient had the lowest basal and total TSH secretion of the patient group, which might indicate that increased central somatostatin tonus also modulates TSH secretion, but obviously this observation should be confirmed in more patients.

Recent histological studies of the pituitary gland have revealed that GH-secreting cells form a large-scale network. This functional three-dimensional GH network consists of cells linked with focal adherent junctions and shows robustness across the life span despite reversible plasticity of the architecture, e.g. at puberty when GH secretion is amplified (29). Such a network can produce rapid and synchronized hormone pulses in response to physiological needs. The altered functional organization in TSH -adenoma could explain disorganized TSH secretion, as here observed with increased ApEn as well as increased spikiness, in concert with the increased burst frequency.

All our patients had a significant diurnal TSH rhythm with a mean phase delay of 2 h. Only few serum profiles have been previously reported in patients with a TSH-secreting adenoma. Samuels et al. (30) described a female patient with a TSH-secreting tumor, who showed pulsatile TSH secretion monitored by 15-min sampling for 24 h, but with an absent diurnal variation. Two other male patients were sampled at 2-h intervals. One showed a clear diurnal rhythm with a significant phase delay, as observed here, whereas the other patient had no clear rhythm (31). Finally, a male patient was described with no apparent TSH rhythm, but the rhythm was restored during treatment with bromocriptine and octreotide. Paradoxically, the mean 24-h TSH concentration increased during medical treatment (32). It should be pointed out that none of the serum TSH profiles was analyzed with currently accepted methods to confirm or reject the presence of a diurnal rhythm.

Although all patients with a TSH-secreting adenoma secrete excessive amounts of thyroid hormones, the mean TSH concentrations vary from normal to grossly elevated, in contrast with other hormone-secreting pituitary adenomas, e.g. somatotropinomas and corticotropinomas. This observation has been explained by the increased biological activity of TSH by changed glycosylation of the TSH molecule (33). Relatively intact feedback at the pituitary level cannot be excluded, although it was not studied in detail. Indeed, in our case series, only one patient had an increased mean TSH concentration, although the other patients should have had suppressed TSH levels under elevated T4 feedback. Thus, in variance with other hormone-secreting tumors, we could only establish an increased basal TSH secretion, but not pulsatile or total secretion, in the present study. It should also be noted that changed glycosylation can change hormone clearance. However, in the face of the unchanged half-life of TSH, we have no evidence yet for this notion in this limited patient cohort.

A limitation of the study is that we could only investigate patients with TSH concentrations mostly within the normal but physiologically inappropriate range. Therefore, the present conclusions cannot be extrapolated to patients with much higher TSH levels. A prediction is that such patients would also exhibit increased TSH secretory burst size.

In summary, TSH secretion by thyrotropinomas is characterized by increased pulse frequency with normal variability, enhanced nonpulsatile release, and phase resetting of the diurnal rhythm. We hypothesize that the changed secretory characteristics are caused by histological and cellular alterations of the tumoral network of thyrotrophic cells.


   Footnotes
 
Disclosure Statement: The authors have nothing to declare.

First Published Online August 5, 2008

Abbreviations: ApEn, Approximate entropy; fT4, free T4.

Received May 27, 2008.

Accepted July 24, 2008.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Morley JE 1981 Neuroendocrine control of thyrotropin secretion. Endocr Rev 2:396–436[Abstract/Free Full Text]
  2. Samuels MH, McDaniel PA 1997 Thyrotropin levels during hydrocortisone infusions that mimic fasting-induced cortisol elevations: a clinical research center study. J Clin Endocrinol Metab 82:3700–3704[Abstract/Free Full Text]
  3. Romijn JA, Adriaanse R, Brabant G, Prank K, Endert E, Wiersinga WM 1990 Pulsatile secretion of thyrotropin during fasting: a decrease of thyrotropin pulse amplitude. J Clin Endocrinol Metab 70:1631–1636[Abstract/Free Full Text]
  4. Roelfsema F, Frolich M 1991 Pulsatile thyrotropin release and thyroid function in acromegalics before and during subcutaneous octreotide infusion. J Clin Endocrinol Metab 72:77–82[Abstract/Free Full Text]
  5. Adriaanse R, Brabant G, Prank K, Endert E, Wiersinga WM 1992 Circadian changes in pulsatile TSH release in primary hypothyroidism. Clin Endocrinol (Oxf) 37:504–510[CrossRef][Medline]
  6. Adriaanse R, Brabant G, Endert E, Wiersinga WM 1994 Pulsatile thyrotropin secretion in patients with Cushing’s syndrome. Metabolism 43:782–786[CrossRef][Medline]
  7. Kok P, Roelfsema F, Frolich M, Meinders AE, Pijl H 2005 Spontaneous diurnal thyrotropin secretion is enhanced in proportion to circulating leptin in obese premenopausal women. J Clin Endocrinol Metab 90:6185–6191[Abstract/Free Full Text]
  8. Beck-Peccoz P, Brucker-Davis F, Persani L, Smallridge RC, Weintraub BD 1996 Thyrotropin-secreting pituitary tumors. Endocr Rev 17:610–638[Abstract/Free Full Text]
  9. Van Aken MO, Pereira AM, van den Berg G, Romijn JA, Veldhuis JD, Roelfsema F 2004 Profound amplification of secretory-burst mass and anomalous regularity of ACTH secretory process in patients with Nelson’s syndrome compared with Cushing’s disease. Clin Endocrinol (Oxf) 60:765–772[CrossRef][Medline]
  10. Groote Veldman R, van den Berg G, Pincus SM, Frolich M, Veldhuis JD, Roelfsema F 1999 Increased episodic release and disorderliness of prolactin secretion in both micro- and macroprolactinomas. Eur J Endocrinol 140:192–200[Abstract]
  11. Van den Berg, Frolich M, Veldhuis JD, Roelfsema F 1994 Growth hormone secretion in recently operated acromegalic patients. J Clin Endocrinol Metab 79:1706–1715[Abstract]
  12. Veldhuis JD, Evans WS, Johnson ML 1995 Complicating effects of highly correlated model variables on nonlinear least-squares estimates of unique parameter values and their statistical confidence intervals: estimating basal secretion and neurohormone half-life by deconvolution analysis. Methods Neurosci 28:130–138[CrossRef]
  13. Keenan DM, Chattopadhyay S, Veldhuis JD 2005 Composite model of time-varying appearance and disappearance of neurohormone pulse signals in blood. J Theor Biol 236:242–255[CrossRef][Medline]
  14. 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]
  15. 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]
  16. 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 Regul Integr Comp Physiol 285:R664–R673
  17. Chattopadhyay S, Veldhuis JD, Keenan DM Probabilistic recovery of pulsatile, secretory and kinetic structure: an alternating discrete and continuous schema. Q Appl Math, in press
  18. Pincus SM 1991 Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA 88:2297–2301[Abstract/Free Full Text]
  19. Pincus S, Singer BH 1996 Randomness and degrees of irregularity. Proc Natl Acad Sci USA 93:2083–2088[Abstract/Free Full Text]
  20. Veldhuis JD, Straume M, Iranmanesh A, Mulligan T, Jaffe C, Barkan A, Johnson ML, Pincus S 2001 Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans. Am J Physiol Regul Integr Comp Physiol 280:R721–R729
  21. Pincus SM, Schmidt PJ, Palladino-Negro P, Rubinow DR 2008 Differentiation of women with premenstrual dysphoric disorder, recurrent brief depression, and healthy controls by daily mood rating dynamics. J Psychiatr Res 42:337–347[CrossRef][Medline]
  22. Veldhuis JD, Iranmanesh A, Johnson ML, Lizarralde G 1990 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[Abstract/Free Full Text]
  23. Hartman ML, Veldhuis JD, Vance ML, Faria ACS, Furlanetto RW, Thorner MO 1990 Somatotropin pulse frequency and basal concentrations are increased in acromegaly and are reduced by successful therapy. J Clin Endocrinol Metab 70:1375–1384[Abstract/Free Full Text]
  24. Van Aken MO, Pereira AM, van Thiel SW, van den Berg G, Frolich M, Veldhuis JD, Romijn JA, Roelfsema F 2005 Irregular and frequent cortisol secretory episodes with preserved diurnal rhythmicity in primary adrenal Cushing’s syndrome. J Clin Endocrinol Metab 90:1570–1577[Abstract/Free Full Text]
  25. Evans WS, Anderson SM, Hull LT, Azimi PP, Bowers CY, Veldhuis JD 2001 Continuous 24-hour intravenous infusion of recombinant human growth hormone (GH)-releasing hormone-(1–44)-amide augments pulsatile, entropic, and daily rhythmic GH secretion in postmenopausal women equally in the estrogen-withdrawn and estrogen-supplemented states. J Clin Endocrinol Metab 86:700–712[Abstract/Free Full Text]
  26. Bowers CY, Granda R, Mohan S, Kuipers J, Baylink D, Veldhuis JD 2004 Sustained elevation of pulsatile growth hormone (GH) secretion and insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and IGFBP-5 concentrations during 30-day continuous subcutaneous infusion of GH-releasing peptide-2 in older men and women. J Clin Endocrinol Metab 89:2290–2300[Abstract/Free Full Text]
  27. Veldhuis JD, Bidlingmaier M, Anderson SM, Wu Z, Strasburger CJ 2001 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[Abstract/Free Full Text]
  28. Veldhuis JD, Johnson ML, Veldhuis OL, Straume M, Pincus SM 2001 Impact of pulsatility on the ensemble orderliness (approximate entropy) of neurohormone secretion. Am J Physiol Regul Integr Comp Physiol 281:R1975–R1985
  29. Bonnefont X, Lacampagne A, Sanchez-Hormigo A, Fino E, Creff A, Mathieu MN, Smallwood S, Carmignac D, Fontanaud P, Travo P, Alonso G, Courtois-Coutry N, Pincus SM, Robinson IC, Mollard P 2005 Revealing the large-scale network organization of growth hormone-secreting cells. Proc Natl Acad Sci USA 102:16880–16885[Abstract/Free Full Text]
  30. Samuels MH, Wood WM, Gordon DF, Kleinschmidt-DeMasters BK, Lillehei K, Ridgway EC 1989 Clinical and molecular studies of a thyrotropin-secreting pituitary adenoma. J Clin Endocrinol Metab 68:1211–1215[Abstract/Free Full Text]
  31. Beckers A, Abs R, Mahler C, Vandalem JL, Pirens G, Hennen G, Stevenaert A 1991 Thyrotropin-secreting pituitary adenomas: report of seven cases. J Clin Endocrinol Metab 72:477–483[Abstract/Free Full Text]
  32. Adriaanse R, Brabant G, Endert E, Bemelman FJ, Wiersinga WM 1994 Pulsatile thyrotropin and prolactin secretion in a patient with a mixed thyrotropin- and prolactin-secreting pituitary adenoma. Eur J Endocrinol 130:113–120[Abstract/Free Full Text]
  33. Beck-Peccoz P, Persani L 1994 Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol 131:331–340[Abstract/Free Full Text]



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J. D. Veldhuis, F. Roelfsema, A. Iranmanesh, B. J. Carroll, D. M. Keenan, and S. M. Pincus
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