Determinants of dual secretagogue drive of burst-like growth hormone secretion in premenopausal women studied under a selective estradiol clamp

Erickson, Dana; Keenan, Daniel M.; Farhy, Leon; Mielke, Kristi; Bowers, Cyril Y.; Veldhuis, Johannes D.

doi:10.1210/jc.2004-1621

Cited by 21Growth Hormone and Insulin-like Growth FactorsHypothalamic control of reproductive hormonesPituitary Gland Disorders and Treatments

Determinants of dual secretagogue drive of burst-like growth hormone secretion in premenopausal women studied under a selective estradiol clamp

Open access

Erickson, Dana, Keenan, Daniel M., Farhy, Leon, Mielke, Kristi, Bowers, Cyril Y., Veldhuis, Johannes D.·2005·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jc.2004-1621PMC PMC1236972

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Abstract

The present study tests the hypothesis that estradiol (E(2)), compared with placebo (Pl), amplifies combined-secretagogue stimulation of GH secretion in premenopausal women studied at comparable IGF-I and testosterone concentrations. To this end, 13 women underwent GnRH agonist-induced gonadal down-regulation followed by graded transdermal addback of E(2) or Pl and randomly ordered iv infusions of saline or paired secretagogues on separate morning fasting. GH secretion was assessed by frequent blood sampling, immunochemiluminometry, and variable-waveform deconvolution analysis. Two-way ANOVA revealed that specific secretagogue combination (P < 0.001), E(2) status (P = 0.012), and their interaction (P = 0.038) jointly determined GH secretory-burst mass. Compared with Pl, the E(2)-clamped milieu elevated mean fasting GH concentrations (P = 0.032), the mass of GH secreted in bursts (P = 0.037), and maximal stimulation by paired l-arginine/GH-releasing peptide (GHRP)-2 (P = 0.028). E(2) also markedly accelerated the initial release of GH induced by GHRH/GHRP-2 (P < 0.001) and l-arginine/GHRH (P < 0.01). By linear regression analysis, E(2) concentrations positively forecast 41% of intersubject variability in GH secretion stimulated by combined l-arginine/GHRP-2 (P = 0.018), whereas abdominal visceral-fat mass negatively predicted 49% of that due to l-arginine/GHRH (P = 0.012). These data indicate that pulsatile GH secretion in young women studied at constant IGF-I and testosterone concentrations is dictated 3-fold jointly by secretagogue pair, E(2) availability, and intraabdominal adiposity. Moreover, the rapidity of GH release is controlled 2-fold jointly by E(2) and GHRH.

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Cites

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Claims the paper makes

8 of 47 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

Study design and conductcitation
The present mathematical structure for the first time allows direct statistical verification of maximum-likelihood estimates.
“The present mathematical structure for the first time allows direct statistical verification of maximum-likelihood estimates, as validated empirically by in vivo experiments in the horse and sheep (38, 56).”
Quote in the paperSubstantial claim2 of 2 sources checked
- cites [38] Keenan, 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 source
  Appendix F (page unavailable) describes maximum-likelihood estimation and explicitly computed parameter variances and covariances. The Discussion (page unavailable) calls for statistical verification of the model form and direct experimental validation of parameter estimates; it does not say the structure allows direct statistical verification of maximum-likelihood estimates for the first time. (LLM, conf=0.82)
  Experimental — accuracy not yet measured
- cites [56] Keenan, 2001, A feedback-controlled ensemble model of the stress-responsive hypothalamo-pituitary-adrenal axis., Proc Natl Acad Sci USA source
  The Discussion (page unavailable) says the model allows estimation of ACTH and cortisol secretion rates and supports computer-assisted predictions and hypothesis testing. Searches for maximum-likelihood estimates and direct statistical verification found no passage establishing that the structure permits such verification for the first time. (LLM, conf=0.72)
  Experimental — accuracy not yet measured
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Interpretationcitation
E2 may upregulate receptor-dependent actions of GHRP.
“Laboratory data are consistent with a unifying notion that E 2 may upregulate receptor-dependent actions of GHRP.”
Quote in the paperSubstantial claim2 of 3 sources checked
- cites [23] Shuto, 2002, Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity., J Clin Invest source
- cites [54] Horikawa, 2000, Regulation of pituitary growth hormone-secretagogue and growth hormone-releasing hormone receptor RNA expression in young Dwarf rats, Endocr J source
  The Abstract and RNA analysis section report substantially higher pituitary GHSR RNA in female than male dwarf rats and suggest sex-steroid regulation. They do not test E2 or show that it upregulates receptor-dependent responses to GHRP; the measured outcome was receptor RNA expression, not GHRP action. (LLM, conf=0.78)
  Experimental — accuracy not yet measured
- cites [55] Kamegai, 1999, Growth hormone-releasing hormone receptor (GHRH-R) and growth hormone secretagogue receptor (GHS-R) mRNA levels during postnatal development in male and female rats., J Neuroendocrinol source
Premisecitation
E2 induces transcription of the human GHRP receptor gene in vitro.
“and E 2 induces transcription of the human GHRP receptor gene in vitro (23,54,55).”
Quote in the paperSubstantial claim2 of 3 sources checked
- cites [23] Shuto, 2002, Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity., J Clin Invest source
- cites [54] Horikawa, 2000, Regulation of pituitary growth hormone-secretagogue and growth hormone-releasing hormone receptor RNA expression in young Dwarf rats, Endocr J source
  The Abstract and RNA analysis discuss GHSR RNA expression in dwarf-rat pituitaries, including differences between males and females and suppression after GH treatment. A search for E2 or estradiol-induced transcription of the human GHRP receptor gene in vitro found no passage addressing that claim; the rat findings do not establish or contradict it. Page numbers were not available in our copy. (LLM, conf=0.75)
  Experimental — accuracy not yet measured
- cites [55] Kamegai, 1999, Growth hormone-releasing hormone receptor (GHRH-R) and growth hormone secretagogue receptor (GHS-R) mRNA levels during postnatal development in male and female rats., J Neuroendocrinol source
  The Abstract reports that pituitary GHS-R mRNA levels in rats are associated with changes in the gonadal steroid environment, and suggests that gonadal steroids mediate GHS-R expression. It does not establish that E2 induces transcription of the human GHRP receptor gene in vitro; the species, experimental setting, and causal claim exceed what this paper reports. (LLM, conf=0.83)
  Experimental — accuracy not yet measured
Premisecitation
Gene transcripts encoding the pituitary GHRP receptor are 2- to 10-fold more abundant in the adult female than male rodent pituitary.
“gene transcripts encoding the pituitary GHRP receptor are 2to 10-fold more abundant in the adult female than male rodent pituitary”
Quote in the paperNot a substantial claim2 of 3 sources checked
- cites [23] Shuto, 2002, Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity., J Clin Invest source
- cites [54] Horikawa, 2000, Regulation of pituitary growth hormone-secretagogue and growth hormone-releasing hormone receptor RNA expression in young Dwarf rats, Endocr J source
  The RNA analysis reports about tenfold higher pituitary GHSR RNA in female than male spontaneous dwarf rats; the study examined young rats at day 40, not adults. The Discussion also reports that GHSR expression became higher in males in normal rats at day 45. The source therefore does not support the claim’s generalization to adult rodents or its 2-to-10-fold range. (LLM, conf=0.88)
  Experimental — accuracy not yet measured
- cites [55] Kamegai, 1999, Growth hormone-releasing hormone receptor (GHRH-R) and growth hormone secretagogue receptor (GHS-R) mRNA levels during postnatal development in male and female rats., J Neuroendocrinol source
  The Results report higher pituitary GHS-R mRNA in adult female rats than in males. The reported differences are 89% per whole pituitary and 64% per somatotrope—about 1.9-fold and 1.6-fold—not the claimed 2- to 10-fold range. Page numbers are unavailable in our copy. (LLM, conf=0.90)
  Experimental — accuracy not yet measured
Findingown data
In healthy premenopausal women, E2 administration compared with placebo reduced FSH concentrations 4.8-fold.
“FSH concentrations were 4.8-fold lower after E 2 than Pl administration.”
Quote in the paperSubstantial claim

Findingown data
Each secretagogue combination stimulated GH secretion more than saline.
“Each secretagogue combination stimulated GH secretion more than saline (P Ͻ 0.005).”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
E2 did not influence the variability of intersecretory-burst intervals.
“E 2 did not influence the mean intersecretory-burst interval, defined as the reciprocal of lambda, or the variability, defined by gamma of intersecretory-burst intervals (Fig. 3).”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
E2 did not affect basal GH secretion.
“which was due to greater total (2.1-fold,P ϭ 0.038) and pulsatile (2.2-fold, P ϭ 0.037) but not basal GH secretion.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
GH secretion in E2-treated women exceeded that in placebo-treated subjects after l-arginine/GHRP-2 by 2.2-fold.
“and after l-arginine/GHRP-2 by 2.2-fold (P ϭ 0.028).”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
In women receiving placebo, GHRH/GHRP-2 infusion prolonged by 1.3-fold the time to maximal GH secretion compared with saline or l-arginine/GHRH.
“In women receiving Pl, larginine/GHRP-2 infusion abbreviated by 1.7-fold (P Ͻ 0.001), whereas GHRH/GHRP-2 infusion prolonged by 1.3fold (P Ͻ 0.01), the time to maximal GH secretion, compared with either saline or l-arginine/GHRH.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
In premenopausal women given E2 vs placebo, E2 maintained significantly higher mean GH concentrations (2.4-fold).
“volunteers given E 2 , compared with Pl, maintained significantly higher mean GH concentrations (2.4-fold, P ϭ 0.032)”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
Total IGF-I concentrations did not differ by estrogen status in the two cohorts.
“Total IGF-I concentrations did not differ by estrogen status.”
Quote in the paperNot a substantial claim
Findingown data
E2 did not alter GH responses to GHRH/GHRP-2.
“E 2 did not alter responses to l-arginine/GHRH or GHRH/GHRP-2.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
E2 did not alter GH responses to l-arginine/GHRH.
“E 2 did not alter responses to l-arginine/GHRH or GHRH/GHRP-2.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
E2 concentrations positively predict 41% of the GH-response variability to l-arginine/GHRP-2.
“Regression analyses disclosed that E 2 concentrations positively predict 41% of the GH-response variability to l-arginine/GHRP-2”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
GH secretion in E2-treated women exceeded that in placebo-treated subjects after saline by 2.3-fold.
“GH secretion in E 2 -treated women exceeded that in Pltreated subjects after infusion of saline by 2.3-fold (P ϭ 0.041)”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
In women receiving placebo, l-arginine/GHRP-2 infusion abbreviated by 1.7-fold the time to maximal GH secretion compared with saline or l-arginine/GHRH.
“In women receiving Pl, larginine/GHRP-2 infusion abbreviated by 1.7-fold (P Ͻ 0.001), whereas GHRH/GHRP-2 infusion prolonged by 1.3fold (P Ͻ 0.01), the time to maximal GH secretion, compared with either saline or l-arginine/GHRH.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
The higher mean GH concentrations in E2 vs placebo were due to greater total GH secretion (2.1-fold).
“which was due to greater total (2.1-fold,P ϭ 0.038) and pulsatile (2.2-fold, P ϭ 0.037) but not basal GH secretion.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
E2 did not influence the mean intersecretory-burst interval.
“E 2 did not influence the mean intersecretory-burst interval, defined as the reciprocal of lambda, or the variability, defined by gamma of intersecretory-burst intervals (Fig. 3).”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
E2 increased pulsatile GH secretion 2.2-fold compared with placebo.
“which was due to greater total (2.1-fold,P ϭ 0.038) and pulsatile (2.2-fold, P ϭ 0.037) but not basal GH secretion.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
In healthy premenopausal women, E2 administration compared with placebo produced 7.8-fold higher serum E2 concentrations.
“E 2 concentrations were 7.8-fold higher (P Ͻ 0.001)”
Quote in the paperSubstantial claim
Findingown data
Two-way ANOVA revealed significant interventional effects of secretagogue type, E2 supplementation, and their interaction on summed mass of GH secreted in pulses.
“Twoway ANOVA with repeated measures revealed significant interventional effects of secretagogue type (P Ͻ 0.001), E 2 supplementation (P ϭ 0.012), and their interaction (P ϭ 0.038).”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
Abdominal visceral-fat mass negatively determines 49% of the response variability to l-arginine/GHRH infusion.
“whereas abdominal visceral-fat mass negatively determines 49% of the response variability to l-arginine/GHRH infu-”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
In healthy premenopausal women, LH and Te concentrations were reduced to equivalent values in both E2 and placebo cohorts.
“LH and Te concentrations were reduced to equivalent values in both cohorts [absolute maxima in all subjects 1.1 IU/liter and 22 ng/dl (0.76 nmol/ liter), respectively].”
Quote in the paperSubstantial claim
Findingown data
After E2, relative efficacy of the three secretagogue pairs was l-arginine/GHRP-2 = GHRH/GHRP-2 = l-arginine/GHRH.
“and after E 2 , l-arginine/GHRP-2 ϭ GHRH/GHRP-2 ϭ l-arginine/GHRH.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
Compared with Pl, the E2-clamped milieu elevated mean fasting GH concentrations.
“Compared with Pl, the E 2 -clamped milieu elevated mean fasting GH concentrations (P ‫؍‬ 0.032), the mass of GH secreted in bursts (P ‫؍‬ 0.037), and maximal stimulation by paired L- arginine/GH-releasing peptide (GHRP)-2 (P ‫؍‬ 0.028).”
- Also stated in: § Discussion · plain
  “E 2 addback in premenopausal women with controlled IGF-I and Te concentrations elevated fasting 6-h mean GH concentrations (micrograms per liter) and both pulsatile (burst-like) and total (basal plus pulsatile) GH secretion (micrograms per liter per 6 h).”
Quote in the paperSubstantial claim
Findingown data
Deconvolution analysis disclosed comparable mean values and variability of GH interburst intervals in the two estrogenic extremes.
“Deconvolution analysis disclosed comparable mean values and variability of GH interburst intervals and similar basal GH secretion rates in the two estrogenic extremes.”
Quote in the paperSubstantial claim
Findingown data
In this sex steroid-clamped paradigm, E2 compared with Pl doubles burst-like GH release driven by L-arginine/GHRP-2.
“In this sex steroidclamped paradigm, E 2 , compared with Pl, doubles burst-like GH release driven by l-arginine/GHRP-2 and accelerates the attainment of maximal GH secretion induced by GHRH/ GHRP-2.”
Quote in the paperSubstantial claim
Findingown data
Deconvolution analysis disclosed similar basal GH secretion rates in the two estrogenic extremes.
“Deconvolution analysis disclosed comparable mean values and variability of GH interburst intervals and similar basal GH secretion rates in the two estrogenic extremes.”
Quote in the paperSubstantial claim
Findingreasoning
E2 prolongs the latency to maximal GH secretion induced by combined l-arginine/GHRP-2.
“and conversely, prolongs the latency to maximal GH secretion induced by combined l-arginine/GHRP-2.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
Specific secretagogue combination, E2 status, and their interaction jointly determined GH secretory-burst mass.
“Two-way ANOVA revealed that specific secretagogue combination (P < 0.001), E 2 status (P ‫؍‬ 0.012), and their interaction (P ‫؍‬ 0.038) jointly determined GH secretory-burst mass.”
Quote in the paperSubstantial claim
Findingown data
E2 markedly accelerated the initial release of GH induced by GHRH/GHRP-2.
“E 2 also markedly accelerated the initial release of GH induced by GHRH/GHRP-2 (P < 0.001) and L-arginine/GHRH (P < 0.01).”
Quote in the paperSubstantial claim
Findingown data
In young women, E2 concentrations positively forecast 41% of intersubject variability in GH secretion stimulated by combined L-arginine/GHRP-2.
“In contradistinction, E 2 positively determines the stimulatory impact of l-arginine/GHRP-2.”
- Also stated in: § Discussion · plain
  “By linear regression analysis, E 2 concentrations positively forecast 41% of intersubject variability in GH secretion stimulated by combined L-arginine/GHRP-2 (P ‫؍‬ 0.018), whereas abdominal visceral-fat mass negatively predicted 49% of that due to L-arginine/GHRH (P ‫؍‬ 0.012).”
- Also stated in: § Discussion · plain
  “By regression analyses, E 2 concentrations determine two fifths of the variability of l-arginine/GHRP-2 feedforward, whereas abdominal visceral-fat mass predicts half of the variability associated with l-arginine/GHRH stimulation.”
Quote in the paperSubstantial claim
Findingown data
In young women, abdominal visceral-fat mass negatively predicts about half (49%) of the variability in GH secretion stimulated by L-arginine/GHRH.
“The current analyses offer further mechanistic insights into the basis of this relationship by demonstrating a strongly negative association (R 2 ϭ 0.49) between the stimulatory effect of l-arginine/GHRH on GH release and visceral-fat mass in young women.”
- Also stated in: § Discussion · plain
  “By linear regression analysis, E 2 concentrations positively forecast 41% of intersubject variability in GH secretion stimulated by combined L-arginine/GHRP-2 (P ‫؍‬ 0.018), whereas abdominal visceral-fat mass negatively predicted 49% of that due to L-arginine/GHRH (P ‫؍‬ 0.012).”
- Also stated in: § Discussion · plain
  “By regression analyses, E 2 concentrations determine two fifths of the variability of l-arginine/GHRP-2 feedforward, whereas abdominal visceral-fat mass predicts half of the variability associated with l-arginine/GHRH stimulation.”
Quote in the paperSubstantial claim
Findingown data
In the estradiol clamp, testosterone concentrations did not differ significantly between placebo and estradiol groups.
“Testosterone (ng/dl) b | 17 Ϯ 4.7 | 19 Ϯ 2.1 | NS”
Quote in the paperNot a substantial claim
Findingown data
In the estradiol clamp, IGF-I concentrations did not differ significantly between placebo and estradiol groups.
“IGF-I (g/liter) | 249 Ϯ 20 | 308 Ϯ 40 | NS”
Quote in the paperNot a substantial claim
Findingown data
In the estradiol clamp, estradiol concentrations were higher in the estradiol group than in the placebo group.
“Estradiol (pg/ml) a | 18 Ϯ 4.1 | 141 Ϯ 11 | Ͻ0.001”
Quote in the paperSubstantial claim
Findingown data
E2 markedly accelerated the initial release of GH induced by L-arginine/GHRH.
“E 2 also markedly accelerated the initial release of GH induced by GHRH/GHRP-2 (P < 0.001) and L-arginine/GHRH (P < 0.01).”
Quote in the paperSubstantial claim
Findingown data
In this sex steroid-clamped paradigm, E2 compared with Pl accelerates the attainment of maximal GH secretion induced by GHRH/GHRP-2.
“In this sex steroidclamped paradigm, E 2 , compared with Pl, doubles burst-like GH release driven by l-arginine/GHRP-2 and accelerates the attainment of maximal GH secretion induced by GHRH/ GHRP-2.”
Quote in the paperSubstantial claim
Findingown data
E2 accelerates the initial rate of GH release stimulated by GHRH/GHRP-2 and l-arginine/GHRH.
“In particular, E 2 accelerates the initial rate of GH release stimulated by GHRH/ GHRP-2 and l-arginine/GHRH”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Findingown data
Compared with Pl, the E2-clamped milieu elevated the mass of GH secreted in bursts.
“Compared with Pl, the E 2 -clamped milieu elevated mean fasting GH concentrations (P ‫؍‬ 0.032), the mass of GH secreted in bursts (P ‫؍‬ 0.037), and maximal stimulation by paired L- arginine/GH-releasing peptide (GHRP)-2 (P ‫؍‬ 0.028).”
- Also stated in: § Discussion · plain
  “E 2 addback in premenopausal women with controlled IGF-I and Te concentrations elevated fasting 6-h mean GH concentrations (micrograms per liter) and both pulsatile (burst-like) and total (basal plus pulsatile) GH secretion (micrograms per liter per 6 h).”
Quote in the paperSubstantial claim
Findingown data
E2 addback in premenopausal women with controlled IGF-I and Te concentrations elevated total (basal plus pulsatile) GH secretion.
“E 2 addback in premenopausal women with controlled IGF-I and Te concentrations elevated fasting 6-h mean GH concentrations (micrograms per liter) and both pulsatile (burst-like) and total (basal plus pulsatile) GH secretion (micrograms per liter per 6 h).”
Quote in the paperSubstantial claim
Findingown data
Compared with Pl, the E2-clamped milieu elevated maximal stimulation by paired L-arginine/GHRP-2.
“Compared with Pl, the E 2 -clamped milieu elevated mean fasting GH concentrations (P ‫؍‬ 0.032), the mass of GH secreted in bursts (P ‫؍‬ 0.037), and maximal stimulation by paired L- arginine/GH-releasing peptide (GHRP)-2 (P ‫؍‬ 0.028).”
Quote in the paperSubstantial claim
Premisecitation
§ Determinants of Dual Secretagogue Drive of Burst-Like Growth Hormone Secretion in Premenopausal Women Studied under a Selective Estradiol Clamp
Clamping any two inputs by maximal exogenous stimulation or putative withdrawal of endogenous inhibition allows indirect inferences about the third unmanipulated signal.
“Clamping any two inputs by maximal exogenous stimulation (using GHRH and GHRP-2) or putative with-drawal of endogenous inhibition (infusing l-arginine to limit SS outflow) allows indirect inferences about the third unmanipulated signal.”
Quote in the paperSubstantial claim0 of 5 sources checked
- cites [28] Farhy, 2003, Joint pituitary-hypothalamic and intrahypothalamic autofeedback construct of pulsatile growth hormone secretion, Am J Physiol Regul Integr Comp Physiol source
- cites [29] Farhy, 2004, Putative GH pulse renewal: periventricular somatostatinergic control of an arcuate-nuclear somatostatin and GH-releasing hormone oscillator, Am J Physiol source
- cites [30] Farhy, 2004 source
- cites [31] Veldhuis, 2002, Impact of estradiol supplementation on dual peptidyl drive of growth-hormone secretion in postmenopausal women., J Clin Endocrinol Metab source
- cites [32] Erickson, 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 source
Premisecitation
Earlier deconvolution methods in some cases yield nonunique estimates of basal hormone secretion and elimination rates.
“Earlier deconvolution methods in some cases yield nonunique estimates of basal hormone secretion and elimination rates (34).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [34] Veldhuis, 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 source
Interpretationreasoning
Based on a three-peptide feedback model, a plausible unifying inference is that E2 facilitates hypothalamopituitary stimulation by GHRP.
“Based on a three-peptide feedback model of GH control, a plausible unifying inference is that E 2 facilitates hypothalamopituitary stimulation by GHRP”
Quote in the paperSubstantial claim
Interpretationreasoning
E2 can augment spontaneous and l-arginine/GHRP-2-stimulated GH secretion by central effects on the hypothalamopituitary unit rather than exclusively by depleting total serum IGF-I concentrations.
“a plausible inference is that E 2 can augment spontaneous and l-arginine/GHRP-2-stimulated GH secretion by central effects on the hypothalamopituitary unit rather than exclusively by depleting total serum IGF-I concentrations.”
Quote in the paperSubstantial claim
Premisecitation
§ Determinants of Dual Secretagogue Drive of Burst-Like Growth Hormone Secretion in Premenopausal Women Studied under a Selective Estradiol Clamp
Sex steroids increase pulsatile and thereby total GH secretion by augmenting the mass of GH secreted in each burst.
“Sex steroids increase pulsatile and thereby total GH secretion by augmenting the mass of GH secreted in each burst (3,7,16,17).”
Quote in the paperSubstantial claim0 of 4 sources checked
- cites [3] Mauras, 1987, Augmentation of growth hormone secretion during puberty: evidence for a pulse amplitude-modulated phenomenon., J Clin Endocrinol Metab source
- cites [7] Gentili, 2002, Unequal impact of short-term testosterone repletion on the somatotropic axis of young and older men., J Clin Endocrinol Metab source
- cites [16] Mauras, 1990, Increased hGH production rate after low-dose estrogen therapy in prepubertal girls with Turner’s syndrome., Pediatr Res source
- cites [17] Shah, 1999, Actions of estrogen on the pulsatile, nyctohemeral, and entropic modes of growth hormone secretion, Am J Physiol source
Interpretationreasoning
Similar Te concentrations in the two cohorts point to sex steroid selectivity of E2 action.
“In corollary, similar Te concentrations in the two cohorts would point to sex steroid selectivity of E 2 action.”
Quote in the paperSubstantial claim
Interpretationown data
Analytical modeling was consistent most parsimoniously with estrogenic enhancement of the central actions of GHRP.
“Analytical modeling was consistent most parsimoniously with estrogenic enhancement of the central actions of GHRP (Fig. 8).”
Quote in the paperSubstantial claim
Interpretationown data
Relative visceral adiposity inhibits pituitary stimulation by GHRH.
“whereas relative visceral adiposity inhibits pituitary stimulation by GHRH.”
Quote in the paperSubstantial claim
Interpretationreasoning
The lack of estrogenic augmentation of responses to l-arginine/GHRH or GHRH/GHRP-2 corroborates the selectivity of the control pathways affected by E2.
“The lack of estrogenic augmentation of responses to l-arginine/GHRH or GHRH/GHRP-2 corroborates the selectivity of the control pathways affected by E 2 .”
Quote in the paperSubstantial claim
Interpretationreasoning
The foregoing outcomes may be unified under the most frugal hypothesis that E2 potentiates the combined hypothalamopituitary actions of GHRP.
“According to a minimal analytical model of reciprocal interactions among GHRH, GHRP, and SS, the foregoing outcomes may be unified under the most frugal hypothesis that E 2 potentiates the combined hypothalamopituitary actions of GHRP.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: The minimal analytical model of reciprocal interactions among GHRH, GHRP, and SS is a valid representation of the hypothalamopituitary system.
Interpretationreasoning
E2 can either facilitate or retard exocytotic release of presynthesized GH stores, depending on the nature of the two-peptide stimulus.
“E 2 can either facilitate or retard exocytotic release of presynthesized GH stores, depending on the nature of the two-peptide stimulus.”
Quote in the paperSubstantial claim
Interpretationown data
The rapidity of GH release is controlled 2-fold jointly by E2 and GHRH.
“Moreover, the rapidity of GH release is controlled 2-fold jointly by E 2 and GHRH.”
Quote in the paperSubstantial claim
Interpretationreasoning
The effects of E2 on GH concentrations should reflect changes in GH secretion.
“Thus, the effects of E 2 on GH concentrations should reflect changes in GH secretion.”
Quote in the paperSubstantial claim
Interpretationreasoning
The different outcomes point to signal specificity of GH regulation.
“The different outcomes point to signal specificity of GH regulation.”
Quote in the paperSubstantial claim
Premisecitation
The daily GH secretion rate varies inversely with estimated abdominal visceral-fat mass in middle-aged men and women.
“The daily GH secretion rate varies inversely with estimated abdominal visceral-fat mass in middle-aged men and women (60).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [60] Vahl, 1997, Abdominal adiposity rather than age and sex predicts the mass and patterned regularity of growth hormone secretion in mid-life healthy adults, Am J Physiol source
Interpretationown data
E2 is not a primary determinant of nonpulsatile GH secretion in the human.
“Equivalent basal GH secretion in a low and high E 2 milieu indicates that E 2 is not a primary determinant of nonpulsatile GH secretion in the human (1,39).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [1] Giustina, 1998, Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human., Endocr Rev source
- cites [39] Veldhuis, 2004, Estradiol supplementation modulates growth hormone (GH) secretory-burst waveform and recombinant human insulin-like growth factor-I-enforced suppression of endogenously driven GH release in postmenopausal women., J Clin Endocrinol Metab source
Interpretationown data
Relative intraabdominal adiposity attenuates GHRH efficacy in a putatively SS-withdrawn context.
“The selectivity of this outcome would suggest that relative intraabdominal adiposity in some manner attenuates GHRH efficacy in a putatively SS-withdrawn context.”
Quote in the paperSubstantial claim
Interpretationown data
Pulsatile GH secretion in young women studied at constant IGF-I and testosterone concentrations is dictated 3-fold jointly by secretagogue pair, E2 availability, and intraabdominal adiposity.
“These data indicate that pulsatile GH secretion in young women studied at constant IGF-I and testosterone concentrations is dictated 3-fold jointly by secretagogue pair, E 2 availability, and intraabdominal adiposity.”
Quote in the paperSubstantial claim
Premisecitation
The measured distribution volume of GH does not differ significantly among young women and men; pre-, mid-, and postpubertal boys; and postmenopausal women receiving estradiol and placebo.
“The measured distribution volume of GH does not differ significantly among young women and men; pre-, mid-, and postpubertal boys; and postmenopausal women receiving estradiol and placebo (46,61,62).”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites [46] Anderson, 2001, Estradiol supplementation selectively relieves GH’s autonegative feedback on GH-releasing peptide-2-stimulated GH secretion., J Clin Endocrinol Metab source
- cites [61] Shah, 1999, Time-mode of growth hormone (GH) entry into the bloodstream and steady-state plasma GH concentrations rather than sex, estradiol, or menstrual-cycle stage primarily determine the GH elimination rate in healthy young women and men., J Clin Endocrinol Metab
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [62] Richmond, 2002, Accelerated escape from GH autonegative feedback in midpuberty in males: evidence for time-delimited GH-induced somatostatinergic outflow in adolescent boys., J Clin Endocrinol Metab source
Interpretationcitation
A stable GH secretory burst-renewal process under E2 drive is consistent with reported uniformity of GH pulse frequency at different stages of puberty, across the menstrual cycle, and in men and women.
“The inference of a stable GH secretory burst-renewal process under E 2 drive would agree with the reported uniformity of GH pulse frequency at different stages of puberty, across the menstrual cycle, and in men and women (3, 7, 17, 57-59).”
Quote in the paperNot a substantial claim0 of 6 sources checked
- cites [3] Mauras, 1987, Augmentation of growth hormone secretion during puberty: evidence for a pulse amplitude-modulated phenomenon., J Clin Endocrinol Metab source
- cites [7] Gentili, 2002, Unequal impact of short-term testosterone repletion on the somatotropic axis of young and older men., J Clin Endocrinol Metab source
- cites [17] Shah, 1999, Actions of estrogen on the pulsatile, nyctohemeral, and entropic modes of growth hormone secretion, Am J Physiol source
- cites [57] Martha Jr, 1992, Endogenous growth hormone secretion and clearance rates in normal boys as determined by deconvolution analysis: relationship to age, pubertal status and body mass., J Clin Endocrinol Metab source
- cites [58] Berg, 1996, An amplitude-specific divergence in the pulsatile mode of GH secretion underlies the gender difference in mean GH concentrations in men and premenopausal women., J Clin Endocrinol Metab source
- cites [59] Veldhuis, 2000, Gender and sexual maturation-dependent contrasts in the neuroregulation of growth hormone secretion in prepubertal and late adolescent males and females—a general clinical research center-based study., J Clin Endocrinol Metab
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims. 6
Classified as probably not a substantial claim. 7

May combine two claims.
Findingown data
After placebo, relative efficacy of the three secretagogue pairs was GHRH/GHRP-2 = l-arginine/GHRH > l-arginine/GHRP-2.
“Relative efficacy of the three secretagogue pairs after Pl was GHRH/GHRP-2 ϭ l-arginine/GHRH Ͼ l-arginine/GHRP-2 (P Ͻ 0.05)”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Classified as probably not a substantial claim.
Premisecitation
The peptide doses were chosen as maximally stimulatory in dose-response analyses in women.
“The foregoing peptide doses were chosen as maximally stimulatory in dose-response analyzes in women (31,33).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [31] Veldhuis, 2002, Impact of estradiol supplementation on dual peptidyl drive of growth-hormone secretion in postmenopausal women., J Clin Endocrinol Metab source
- cites [33] Veldhuis, 2003, Estradiol supplementation enhances submaximal feed-forward drive of growth hormone (GH) secretion by recombinant human GH-releasing hormone-1,44-amide in a putatively somatostatin-withdrawn milieu., J Clin Endocrinol Metab source
Probably not a substantial claim: may not pass S4 (based).
Premisecitation
§ Determinants of Dual Secretagogue Drive of Burst-Like Growth Hormone Secretion in Premenopausal Women Studied under a Selective Estradiol Clamp
GHRH, SS, and ghrelin constitute a minimal set of regulators to pituitary somatotropes.
“The idea is that GHRH, SS, and ghrelin constitute a minimal set of regulators to pituitary somatotropes.”
Quote in the paperNot a substantial claim0 of 3 sources checked
- cites [1] Giustina, 1998, Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human., Endocr Rev source
- cites [2] Veldhuis, 2003, Three-peptide control of pulsatile and entropic feedback-sensitive modes of growth hormone secretion: modulation by estrogen and aromatizable androgen, J Pediatr Endocrinol Metab
  Not checked in the free run.
- cites [20] Veldhuis, Endocr Rev source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone given
The order of saline and secretagogue infusions was randomized, placebo controlled, and patient blinded within cohort.
“The order of saline and secretagogue infusions was also randomized, Pl controlled, and patient blinded within cohort.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data
The study was a randomized parallel-cohort design.
“The study was a randomized parallel-cohort design (n ϭ 8 women given E 2 ; n ϭ 5 administered Pl).”
Quote in the paperNot a substantial claim
May combine two claims.
Premisecitation
§ Determinants of Dual Secretagogue Drive of Burst-Like Growth Hormone Secretion in Premenopausal Women Studied under a Selective Estradiol Clamp
Infusion of IGF-I suppresses and experimental reduction of IGF-I concentrations stimulates pulsatile GH secretion by approximately 2-fold.
“infusion of IGF-I suppresses and experimental reduction of IGF-I concentrations stimulates pulsatile GH secretion by approximately 2-fold (26,27).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [26] Veldhuis, 2002, Impact of experimental blockade of peripheral growth hormone (GH) receptors on the kinetics of endogenous and exogenous GH removal in healthy women and men., J Clin Endocrinol Metab source
- cites [27] Keenan, 2003, Cortisol feedback state governs adrenocorticotropin secretory-burst shape, frequency and mass in a dual-waveform construct: time-of-day dependent regulation, Am J Physiol source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Continuous sc GHRP-2 infusion for 1 month stimulates GH secretion by 2-fold more in older estrogen-replaced women than comparably aged men.
“continuous sc GHRP-2 infusion for 1 month stimulates GH secretion by 2-fold more in older estrogen-replaced women than comparably aged men (63).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [63] Bowers, 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 source
May combine two claims.
Study design and conductreasoning
The new analytical platform was developed to permit potentially asymmetric secretory bursts and ensure valid discrimination among simultaneous and highly correlated contributions to a hormone-concentration profile.
“Specifically, the new analytical platform was developed to permit potentially asymmetric (rather than exclusively Gaussian) secretory bursts and ensure valid discrimination among simultaneous and highly correlated contributions to a hormone-concentration profile.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
L-arginine inhibits SS release in the experimental animal and inferentially in the human.
“although l-arginine inhibits SS release in the experimental animal and inferentially in the human (1)”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [1] Giustina, 1998, Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human., Endocr Rev source
May combine two claims.
Premisecitation
E2 supplementation in postmenopausal women augments stimulation by GHRP-2 and submaximal drive by GHRH.
“clinical investigations indicate that E 2 supplementation in postmenopausal women augments stimulation by GHRP-2 and submaximal drive by GHRH”
Quote in the paperNot a substantial claim0 of 5 sources checked
- cites [33] Veldhuis, 2003, Estradiol supplementation enhances submaximal feed-forward drive of growth hormone (GH) secretion by recombinant human GH-releasing hormone-1,44-amide in a putatively somatostatin-withdrawn milieu., J Clin Endocrinol Metab source
- cites [39] Veldhuis, 2004, Estradiol supplementation modulates growth hormone (GH) secretory-burst waveform and recombinant human insulin-like growth factor-I-enforced suppression of endogenously driven GH release in postmenopausal women., J Clin Endocrinol Metab source
- cites [44] Anderson, 2001, Short-term estradiol supplementation augments growth hormone (GH) secretory responsiveness to dose-varying GH-releasing peptide infusions in healthy postmenopausal women., J Clin Endocrinol Metab
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [45] Bray, 2001, Short-term estradiol replacement in postmenopausal women selectively mutes somatostatin’s dose-dependent inhibition of fasting growth hormone secretion., J Clin Endocrinol Metab
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [46] Anderson, 2001, Estradiol supplementation selectively relieves GH’s autonegative feedback on GH-releasing peptide-2-stimulated GH secretion., J Clin Endocrinol Metab source
May combine two claims.
Interpretationown data
The present methodology predicts that physiological compared with low concentrations of E2 determine not only the mass of GH secretory bursts but also their inferred waveform.
“The resultant methodology predicts that physiological compared with low concentrations of E 2 determine not only the mass of GH secretory bursts but also their inferred waveform (Fig. 6).”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
- The authors state this as an assumption: Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
- The authors state this as an assumption: The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
The present analyses do not address the effects of prolonged dual-secretagogue stimulation under E2-clamped conditions.
“First, the present analyses do not address the effects of prolonged dualsecretagogue stimulation under E 2 -clamped conditions.”
Quote in the paperNot a substantial claim

12 of 12

The authors state this as an assumption.
Observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density).
“The basic assumptions are that observed concentration peaks reflect the mass contained in a flexible secretory-burst waveform (three-parameter generalized gamma probability density);”
The authors state this as an assumption.
Combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics.
“combined diffusion, advection, and irreversible elimination proceed via biexponential kinetics;”
The authors state this as an assumption.
The deconvolution solution is statistically conditioned on a priori estimates of pulse-onset times.
“and the solution is statistically conditioned on a priori estimates of pulse-onset times, as previously described”
The authors state this as an assumption.
The minimal analytical model of reciprocal interactions among GHRH, GHRP, and SS is a valid representation of the hypothalamopituitary system.
“According to a minimal analytical model of reciprocal interactions among GHRH, GHRP, and SS, the foregoing outcomes may be unified under the most frugal hypothesis that E 2 potentiates the combined hypothalamopituitary actions of GHRP.”

4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

Placebo testosterone variability exceeds the stated maximum
Minor
For five placebo subjects with a mean testosterone concentration of 17 ng/dl and no value above 22 ng/dl, the reported standard error of 4.7 ng/dl is impossible. Even if concentrations could be zero, the largest possible standard error is about 4.3 ng/dl.
Placebo LH variability exceeds the stated maximum
Minor
Among five placebo subjects, a mean LH concentration of 0.37 IU/liter with no value above 1.1 IU/liter cannot have a standard error of 0.38. Even allowing values down to zero, the largest possible standard error is about 0.23 IU/liter.

2 of 2

Pathophysiology of the Neuroregulation of Growth Hormone Secretion in Experimental Animals and the Human*
Giustina, A., & Veldhuis, J. D. (1998) · Endocrine Reviews · doi:10.1210/edrv.19.6.0353 · Cited by 1,253 · see citing works
Self-citation
Pathophysiology of the Neuroregulation of Growth Hormone Secretion in Experimental Animals and the Human
Giustina, A. (1998) · Endocrine Reviews · doi:10.1210/er.19.6.717 · Cited by 489 · see citing works
Effects of Estrogen and Sex Difference on Secretion of Human Growth Hormone1
FRANTZ, A. G., & RABKIN, M. T. (1965) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-25-11-1470 · Cited by 467 · see citing works
Endocrine Control of Body Composition in Infancy, Childhood, and Puberty
Veldhuis, J. D., Roemmich, J. N., Richmond, E. J., Rogol, A. D., Lovejoy, J. C., Sheffield-Moore, M., Mauras, N., & Bowers, C. Y. (2005) · Endocrine Reviews · doi:10.1210/er.2003-0038 · Cited by 452 · see citing works
Self-citation
Augmentation of growth hormone secretion during puberty: evidence for a pulse amplitude-modulated phenomenon.
MAURAS, N., BLIZZARD, R. M., LINK, K., JOHNSON, M. L., ROGOL, A. D., & VELDHUIS, J. D. (1987) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-64-3-596 · Cited by 300 · see citing works
Self-citation
An amplitude-specific divergence in the pulsatile mode of growth hormone (GH) secretion underlies the gender difference in mean GH concentrations in men and premenopausal women.
van den Berg, G., Veldhuis, J. D., Frölich, M., & Roelfsema, F. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.7.8675561 · Cited by 293 · see citing works
Self-citation
Endogenous growth hormone secretion and clearance rates in normal boys, as determined by deconvolution analysis: relationship to age, pubertal status, and body mass.
Martha, P. M., Gorman, K. M., Blizzard, R. M., Rogol, A. D., & Veldhuis, J. D. (1992) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.74.2.1730812 · Cited by 268 · see citing works
Self-citation
Regulatory mechanisms of growth hormone secretion are sexually dimorphic.
Jaffe, C. A., Ocampo-Lim, B., Guo, W., Krueger, K., Sugahara, I., DeMott-Friberg, R., Bermann, M., & Barkan, A. L. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2908 · Cited by 236 · see citing works
Estrogen and Testosterone, But Not a Nonaromatizable Androgen, Direct Network Integration of the Hypothalamo-Somatotrope (Growth Hormone)-Insulin-Like Growth Factor I Axis in the Human: Evidence from Pubertal Pathophysiology and Sex-Steroid Hormone Replacement1
Veldhuis, J. D., Metzger, D. L., MARTHA, P. M., Mauras, N., Kerrigan, J. R., Keenan, B. S., Rogol, A. D., & Pincus, S. M. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.10.4317 · Cited by 225 · see citing works
Self-citation
Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity.
Shuto, Y., Shibasaki, T., Otagiri, A., Kuriyama, H., Ohata, H., Tamura, H., Kamegai, J., Sugihara, H., Oikawa, S., & Wakabayashi, I. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0213300 · Cited by 220 · see citing works
Androgen-stimulated pubertal growth: the effects of testosterone and dihydrotestosterone on growth hormone and insulin-like growth factor-I in the treatment of short stature and delayed puberty
Keenan, B. S., Richards, G. E., Ponder, S. W., Dallas, J. S., Nagamani, M., & Smith, E. R. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.76.4.8473416 · Cited by 207 · see citing works
Both oral and transdermal estrogen increase growth hormone release in postmenopausal women--a clinical research center study
Friend, K. E., Hartman, M. L., Pezzoli, S. S., Clasey, J. L., & Thorner, M. O. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.6.8964860 · Cited by 189 · see citing works
Activation of the somatotropic axis by testosterone in adult males: evidence for the role of aromatization
Weissberger, A. J., & Ho, K. K. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.76.6.8501143 · Cited by 185 · see citing works
Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults
Vahl, N., Jorgensen, J. O., Skjaerbaek, C., Veldhuis, J. D., Orskov, H., & Christiansen, J. S. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.272.6.e1108 · Cited by 178 · see citing works
Self-citation
Somatostatin receptor subtype 2 knockout mice are refractory to growth hormone-negative feedback on arcuate neurons.
Zheng, H., Bailey, A., Jiang, M.-H., Honda, K., Chen, H. Y., Trumbauer, M. E., Van der Ploeg, L. H. T., Schaeffer, J. M., Leng, G., & Smith, R. G. (1997) · Molecular Endocrinology · doi:10.1210/mend.11.11.0016 · Cited by 169 · see citing works
Growth hormone (GH)-releasing hormone secretion is stimulated by a new GH-releasing hexapeptide in sheep.
Guillaume, V, Magnan, E., Cataldi, M., Dutour, A., Sauze, N., Renard, M., Razafindraibe, H., Conte-Devolx, B., Deghenghi, R., & Lenaerts, V (1994) · Endocrinology · doi:10.1210/endo.135.3.7915227 · Cited by 166 · see citing works
Somatostatin is required for masculinization of growth hormone-regulated hepatic gene expression but not of somatic growth.
Low, M. J., Otero-Corchon, V., Parlow, A. F., Ramirez, J. L., Kumar, U., Patel, Y. C., & Rubinstein, M. (2001) · Journal of Clinical Investigation · doi:10.1172/jci11941 · Cited by 163 · see citing works
Gender and Sexual Maturation-Dependent Contrasts in the Neuroregulation of Growth Hormone Secretion in Prepubertal and Late Adolescent Males and Females--A General Clinical Research Center-Based Study
Veldhuis, J. D., Roemmich, J. N., & Rogol, A. D. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.7.6697 · Cited by 155 · see citing works
Self-citation
Estrogen receptor blockade with tamoxifen diminishes growth hormone secretion in boys: evidence for a stimulatory role of endogenous estrogens during male adolescence.
Metzger, D. L., & Kerrigan, J. R. (1994) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.79.2.8045971 · Cited by 152 · see citing works
A feedback-controlled ensemble model of the stress-responsive hypothalamo-pituitary-adrenal axis.
Keenan, D. M., Licinio, J., & Veldhuis, J. D. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051624198 · Cited by 145 · see citing works
Self-citation
Biostatistics: A Methodology for the Health Sciences.
Fisher, L. D., & van Belle, G. (1997) · Biometrics · doi:10.2307/2533583 · Cited by 134 · see citing works
Estrogen and Testosterone, But Not a Nonaromatizable Androgen, Direct Network Integration of the Hypothalamo-Somatotrope (Growth Hormone)-Insulin-Like Growth Factor I Axis in the Human: Evidence from Pubertal Pathophysiology and Sex-Steroid Hormone Replacement
Veldhuis, J. D. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.82.10.3414 · Cited by 132 · see citing works
Self-citation
Increased hGH production rate after low-dose estrogen therapy in prepubertal girls with Turner’s syndrome.
Mauras, N., Rogol, A. D., & Veldhuis, J. D. (1990) · Pediatric Research · doi:10.1203/00006450-199012000-00018 · Cited by 127 · see citing works
Self-citation
The Dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene.
Baumann, G., & Maheshwari, H. (1997) · Acta Paediatrica · doi:10.1111/j.1651-2227.1997.tb18366.x · Cited by 111 · see citing works
Growth hormone (GH) secretion in patients with an inactivating defect of the GH-releasing hormone (GHRH) receptor is pulsatile: evidence for a role for non-GHRH inputs into the generation of GH pulses.
Roelfsema, F., Biermasz, N. R., Veldman, R. G., Veldhuis, J. D., Frölich, M., Stokvis-Brantsma, W. H., & Wit, J.-M. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.6.7536 · Cited by 106 · see citing works
Self-citation
Maturation of the Regulation of Growth Hormone Secretion in Young Males with Hypogonadotropic Hypogonadism Pharmacologically Exposed to Progressive Increments in Serum Testosterone1
Giustina, A., Scalvini, T., Tassi, C., Desenzani, P., Poiesi, C., Wehrenberg, W. B., Rogol, A. D., & Veldhuis, J. D. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.4.3871 · Cited by 99 · see citing works
Self-citation
The role of sexual steroids in the modulation of growth hormone (GH) secretion in humans.
Devesa, J., Lois, N., Arce, V., Diaz, M. J., Lima, L., & Tresguerres, J. A. F. (1991) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(91)90179-9 · Cited by 98 · see citing works
Unequal impact of short-term testosterone repletion on the somatotropic axis of young and older men.
Gentili, A., Mulligan, T., Godschalk, M., Clore, J., Patrie, J., Iranmanesh, A., & Veldhuis, J. D. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.2.8222 · Cited by 98 · see citing works
Self-citation
Physiological control of pituitary hormone secretory-burst mass, frequency, and waveform: a statistical formulation and analysis
Keenan, D. M., Roelfsema, F., Biermasz, N. R., & Veldhuis, J. D. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00195.2003 · Cited by 96 · see citing works
Self-citation
The effect of one-year cross-sex hormonal treatment on bone metabolism and serum insulin-like growth factor-1 in transsexuals
van Kesteren, P. J. M., Lips, P. T. A. M., Devillé, W. L. J. M., Popp‐Snijders, C., Asscheman, H., Megens, J. A. J., & Gooren, L. J. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.6.8964856 · Cited by 94 · see citing works
The GH-releasing effect of ghrelin, a natural GH secretagogue, is only blunted by the infusion of exogenous somatostatin in humans.
Di Vito, L., Broglio, F., Benso, A., Gottero, C., Prodam, F., Papotti, M., Muccioli, G., Dieguez, C., Casanueva, F. F., Deghenghi, R., et al. (2002) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2002.01530.x · Cited by 83 · see citing works
Short-Term Estradiol Supplementation Augments Growth Hormone (GH) Secretory Responsiveness to Dose-Varying GH-Releasing Peptide Infusions in Healthy Postmenopausal Women
Anderson, S. M., Shah, N., Evans, W. S., Patrie, J. T., Bowers, C. Y., & Veldhuis, J. D. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.2.7240 · Cited by 83 · see citing works
Actions of estrogen on pulsatile, nyctohemeral, and entropic modes of growth hormone secretion
Shah, N., Evans, W. S., & Veldhuis, J. D. (1999) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1999.276.5.r1351 · Cited by 82 · see citing works
Self-citation
Androgen receptor blockade with flutamide enhances growth hormone secretion in late pubertal males: evidence for independent actions of estrogen and androgen.
Metzger, D. L., & Kerrigan, J. R. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.76.5.8496305 · Cited by 77 · see citing works
Growth Hormone‐Releasing Hormone Receptor (GNRH‐R) and Growth Hormone Secretagogue Receptor (GHS‐R) mRNA Levels During Postnatal Development in Male and Female Rats
Kamegai, Wakabayashi, Kineman, & Frohman (1999) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.1999.00330.x · Cited by 74 · see citing works
Maturation of the Regulation of Growth Hormone Secretion in Young Males with Hypogonadotropic Hypogonadism Pharmacologically Exposed to Progressive Increments in Serum Testosterone
Giustina, A. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.82.4.1210 · Cited by 74 · see citing works
A construct of interactive feedback control of the GH axis in the male
Farhy, L. S., Straume, M., Johnson, M. L., Kovatchev, B. P., & Veldhuis, J. D. (2001) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.281.1.r38 · Cited by 70 · see citing works
Self-citation
Reconstruction of <i>in vivo</i> time-evolving neuroendocrine dose–response properties unveils admixed deterministic and stochastic elements
Keenan, D. M., Alexander, S., Irvine, C. H. G., Clarke, I., Scott, C., Turner, A., Tilbrook, A. J., Canny, B. J., & Veldhuis, J. D. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0300619101 · Cited by 70 · see citing works
Self-citation
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 Men1
Veldhuis, J. D., Bidlingmaier, M., Anderson, S. M., Wu, Z., & Strasburger, C. J. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.7.7656 · Cited by 68 · see citing works
Self-citation
Short-Term Modulation of the Androgen Milieu Alters Pulsatile, But Not Exercise- or Growth Hormone (GH)-Releasing Hormone-Stimulated GH Secretion in Healthy Men: Impact of Gonadal Steroid and GH Secretory Changes on Metabolic Outcomes<sup>1</sup>
Fryburg, D. A., Weltman, A., Jahn, L. A., Weltman, J. Y., Samojlik, E., Hintz, R. L., & Veldhuis, J. D. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.11.4379 · Cited by 64 · see citing works
Self-citation
Growth hormone-releasing hormone and somatostatin concentrations in the hypophysial portal blood of conscious sheep during the infusion of growth hormone-releasing peptide-6
Fletcher, T. P., Thomas, G. B., & Clarke, I. J. (1996) · Domestic Animal Endocrinology · doi:10.1016/0739-7240(96)00017-3 · Cited by 62 · see citing works
Impact of experimental blockade of peripheral growth hormone (GH) receptors on the kinetics of endogenous and exogenous GH removal in healthy women and men.
Veldhuis, J. D., Bidlingmaier, M., Anderson, S. M., Evans, W. S., Wu, Z., & Strasburger, C. J. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2001-011885 · Cited by 61 · see citing works
Self-citation
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.
Bowers, C. Y., Granda, R., Mohan, S., Kuipers, J., Baylink, D., & Veldhuis, J. D. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031799 · Cited by 57 · see citing works
Self-citation
Joint recovery of pulsatile and basal hormone secretion by stochastic nonlinear random-effects analysis
Keenan, D. M., Veldhuis, J. D., & Yang, R. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.275.6.r1939 · Cited by 56 · see citing works
Self-citation
Short-Term Estradiol Replacement in Postmenopausal Women Selectively Mutes Somatostatin’s Dose-Dependent Inhibition of Fasting Growth Hormone Secretion1
Bray, M. J., Vick, T. M., Shah, N., Anderson, S. M., Rice, L., Iranmanesh, A., Evans, W. S., & Veldhuis, J. D. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.7.7647 · Cited by 56 · see citing works
Self-citation
Putative GH pulse renewal: periventricular somatostatinergic control of an arcuate-nuclear somatostatin and GH-releasing hormone oscillator
Farhy, L. S., & Veldhuis, J. D. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00473.2003 · Cited by 55 · see citing works
Self-citation
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.
Veldhuis, J. D., Evans, W. S., & Johnson, M. L. (1995) · Methods in Neurosciences · doi:10.1016/s1043-9471(06)80031-5 · Cited by 54 · see citing works
Self-citation
Stochastic model of admixed basal and pulsatile hormone secretion as modulated by a deterministic oscillator
Keenan, D. M., & Veldhuis, J. D. (1997) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1997.273.3.r1182 · Cited by 51 · see citing works
Self-citation
E2 Supplementation Selectively Relieves GH’s Autonegative Feedback on GH-Releasing Peptide-2-Stimulated GH Secretion
Anderson, S. M., Wideman, L., Patrie, J. T., Weltman, A., Bowers, C. Y., & Veldhuis, J. D. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.12.8076 · Cited by 50 · see citing works
Self-citation
Joint pituitary-hypothalamic and intrahypothalamic autofeedback construct of pulsatile growth hormone secretion
Farhy, L. S., & Veldhuis, J. D. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00086.2003 · Cited by 50 · see citing works
Self-citation
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
Veldhuis, J. D. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.7.3304 · Cited by 50 · see citing works
Self-citation
Unequal autonegative feedback by GH models the sexual dimorphism in GH secretory dynamics
Farhy, L. S., Straume, M., Johnson, M. L., Kovatchev, B. P., & Veldhuis, J. D. (2002) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00407.2001 · Cited by 49 · see citing works
Self-citation
The impact of dose and route of estrogen administration on the somatotropic axis in normal women.
Lissett, C. A., & Shalet, S. M. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-022036 · Cited by 48 · see citing works
Estradiol supplementation enhances submaximal feed-forward drive of growth hormone (GH) secretion by recombinant human GH-releasing hormone-1,44-amide in a putatively somatostatin-withdrawn milieu.
Veldhuis, J. D., Evans, W. S., & Bowers, C. Y. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030410 · Cited by 46 · see citing works
Self-citation
Time Mode of Growth Hormone (GH) Entry into the Bloodstream and Steady-State Plasma GH Concentrations, Rather Than Sex, Estradiol, or Menstrual Cycle Stage, Primarily Determine the GH Elimination Rate in Healthy Young Women and Men1
Shah, N., Aloi, J., Evans, W. S., & Veldhuis, J. D. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.8.5881 · Cited by 46 · see citing works
Self-citation
Attenuation of the growth hormone secretagogue induction of Fos protein in the rat arcuate nucleus by central somatostatin action.
Dickson, S. L., Viltart, O., Bailey, A. R. T., & Leng, G. (2008) · Neuroendocrinology · doi:10.1159/000127237 · Cited by 42 · see citing works
Cortisol feedback state governs adrenocorticotropin secretory-burst shape, frequency, and mass in a dual-waveform construct: time of day-dependent regulation
Keenan, D. M., & Veldhuis, J. D. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00299.2003 · Cited by 41 · cited 1× · see citing works
“The latter need arises because infusion of IGF-I suppresses and experimental reduction of IGF-I concentrations stimulates pulsatile GH secretion by approximately 2-fold (26,27).”
BackgroundSelf-citation
Short-Term Estradiol Replacement in Postmenopausal Women Selectively Mutes Somatostatin's Dose-Dependent Inhibition of Fasting Growth Hormone Secretion
Bray, M. J. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.7.3143 · Cited by 40 · see citing works
Impact of Estradiol Supplementation on Dual Peptidyl Drive of GH Secretion in Postmenopausal Women
Veldhuis, J. D., Evans, W. S., & Bowers, C. Y. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.2.8251 · Cited by 36 · see citing works
Self-citation
Untitled work
(2003) · PubMed · Cited by 35 · see citing works
Self-citation
Estradiol supplementation modulates growth hormone (GH) secretory-burst waveform and recombinant human insulin-like growth factor-I-enforced suppression of endogenously driven GH release in postmenopausal women.
Veldhuis, J. D., Anderson, S. M., Kok, P., Iranmanesh, A., Frystyk, J., Ørskov, H., & Keenan, D. M. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031482 · Cited by 34 · see citing works
Self-citation
Time Mode of Growth Hormone (GH) Entry into the Bloodstream and Steady-State Plasma GH Concentrations, Rather Than Sex, Estradiol, or Menstrual Cycle Stage, Primarily Determine the GH Elimination Rate in Healthy Young Women and Men
Shah, N. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.84.8.2862 · Cited by 29 · see citing works
Dual secretagogue drive of burst-like growth hormone secretion in postmenopausal compared with premenopausal women studied under an experimental estradiol clamp.
Erickson, D., Keenan, D. M., Mielke, K., Bradford, K., Bowers, C. Y., Miles, J. M., & Veldhuis, J. D. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0424 · Cited by 26 · see citing works
Self-citation
Split Plot Designs
McGee, D. (2005) · Encyclopedia of Biostatistics · doi:10.1002/0470011815.b2a16073 · Cited by 24 · see citing works
Accelerated escape from GH autonegative feedback in midpuberty in males: evidence for time-delimited GH-induced somatostatinergic outflow in adolescent boys.
Richmond, E., Rogol, A. D., Basdemir, D., Veldhuis, O. L., Clarke, W., Bowers, C. Y., & Veldhuis, J. D. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.8.8770 · Cited by 19 · see citing works
Self-citation
Regulation of pituitary growth hormone-secretagogue and growth hormone-releasing hormone receptor RNA expression in young Dwarf rats
HORIKAWA, R., TACHIBANA, T., KATSUMATA, N., ISHIKAWA, H., & TANAKA, T. (2000) · Endocrine Journal · doi:10.1507/endocrj.47.supplmarch_s53 · Cited by 16 · see citing works
Short-Term Testosterone Supplementation Relieves Growth Hormone Autonegative Feedback in Men
Veldhuis, J. D., Evans, W. S., Iranmanesh, A., WELTMAN, A. L., & Bowers, C. Y. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031017 · Cited by 16 · see citing works
Self-citation
Activation of somatostatin-receptor subtype-2/-5 suppresses the mass, frequency, and irregularity of growth hormone (GH)-releasing peptide-2-stimulated GH secretion in men.
Iranmanesh, A., Bowers, C. Y., & Veldhuis, J. D. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0205 · Cited by 10 · see citing works
Self-citation
Descriptive Statistics.
Kalton, G., & Conway, F. (1963) · Journal of the Royal Statistical Society Series C (Applied Statistics) · doi:10.2307/2985799 · Cited by 3 · see citing works
Both oral and transdermal estrogen increase growth hormone release in postmenopausal women--a clinical research center study
Friend, K. E. (1996) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.81.6.2250
The effect of one-year cross-sex hormonal treatment on bone metabolism and serum insulin-like growth factor-1 in transsexuals
van Kesteren, P. (1996) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.81.6.2227
Androgen-stimulated pubertal growth: the effects of testosterone and dihydrotestosterone on growth hormone and insulin-like growth factor-I in the treatment of short stature and delayed puberty
Keenan, B. S. (1993) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.76.4.996
Gender and Sexual Maturation-Dependent Contrasts in the Neuroregulation of Growth Hormone Secretion in Prepubertal and Late Adolescent Males and Females--A General Clinical Research Center-Based Study
Veldhuis, J. D. (2000) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.85.7.2385
Self-citation
Short-Term Estradiol Supplementation Augments Growth Hormone (GH) Secretory Responsiveness to Dose-Varying GH-Releasing Peptide Infusions in Healthy Postmenopausal Women
Anderson, S. M. (2001) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.2.551

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Fryburg, 1997, Short-term modulation of the androgen milieu alters pulsatile but not exercise or GHRH-stimulated GH secretion in healthy men., J Clin Endocrinol Metab, 82, 3710

Sorted by citations

Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition
Veldhuis, J. D., Roemmich, J. N., Richmond, E. J., & Bowers, C. Y. (2006) · Endocrine Reviews · doi:10.1210/er.2005-0006 · Cited by 235 · see citing works
Self-citation
Aging and hormones of the hypothalamo-pituitary axis: Gonadotropic axis in men and somatotropic axes in men and women
Veldhuis, J. D. (2008) · Ageing Research Reviews · doi:10.1016/j.arr.2007.12.005 · Cited by 98 · see citing works
“A recent clinical model employs a transdermal estrogen clamp imposed by gonadotropin downregulation and E2 addback to mimic steady-state physiology (Erickson et al., 2004, 2005).”
InfluentialSelf-citation
The effect of caloric restriction interventions on growth hormone secretion in nonobese men and women
Redman, L. M., Veldhuis, J. D., Rood, J. C., Smith, S. R., Williamson, D., Ravussin, É., & for the Pennington CALERIE Team (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00530.x · Cited by 61 · see citing works
“The strongest correlates of the age-related decline in GH are increased abdominal visceral fat and sex-steroid depletion (Weltman et al., 1994; Iranmanesh et al., 1998; Erickson et al., 2005; Veldhuis et al., 2005a,b).”
BackgroundSelf-citation
The Role of the Growth Hormone/Insulin-Like Growth Factor System in Visceral Adiposity
LEWITT, M. S. (2017) · Biochemistry Insights · doi:10.1177/1178626417703995 · Cited by 46 · see citing works
Increases in IGF-1 After Anti–TNF-α Therapy Are Associated With Bone and Muscle Accrual in Pediatric Crohn Disease
DeBoer, M. D., Lee, A. M., Herbert, K., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-01916 · Cited by 38 · see citing works
Estrogen supplementation selectively enhances hypothalamo-pituitary sensitivity to ghrelin in postmenopausal women
Kok, P., Paulo, R. C., Cosma, M., Mielke, K. L., Miles, J. M., Bowers, C. Y., & Veldhuis, J. D. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0522 · Cited by 35 · see citing works
“Volunteers had a single-slice computerized tomogram (CT) of the abdomen at L3–4 to quantify sc and visceral adipose tissue, as described earlier (24).”
MethodSelf-citation
GH peak response to GHRH‐arginine: relationship to insulin resistance and other cardiovascular risk factors in a population of adults aged 50–90
Carmichael, J. D., Danoff, A., Milani, D., Roubenoff, R., LESSER, M. L., Livote, E. E., Reitz, R. E., Ferris, S. H., & Kleinberg, D. L. (2006) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2006.02569.x · Cited by 34 · see citing works
Estradiol Potentiates Ghrelin-Stimulated Pulsatile Growth Hormone Secretion in Postmenopausal Women
Veldhuis, J. D., Keenan, D. M., Iranmanesh, A., Mielke, K. L., Miles, J. M., & Bowers, C. Y. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-0948 · Cited by 34 · see citing works
Self-citation
Glucagon Stimulation Test for Childhood Growth Hormone Deficiency: Timing of the Peak is Important
Strich, D., Terespolsky, N., & Gillis, D. (2008) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2008.08.044 · Cited by 25 · see citing works
Pituitary and/or Peripheral Estrogen-Receptor α Regulates Follicle-Stimulating Hormone Secretion, Whereas Central Estrogenic Pathways Direct Growth Hormone and Prolactin Secretion in Postmenopausal Women
Cosma, M., Bailey, J. N., Miles, J. M., Bowers, C. Y., & Veldhuis, J. D. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1322 · Cited by 25 · see citing works
Self-citation
Distinctive Inhibitory Mechanisms of Age and Relative Visceral Adiposity on Growth Hormone Secretion in Pre- and Postmenopausal Women Studied under a Hypogonadal Clamp
Veldhuis, J. D., Erickson, D. Z., Mielke, K. L., Farhy, L. S., Keenan, D. M., & Bowers, C. Y. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0854 · Cited by 26 · see citing works
Self-citation
Pre-VersusPostmenopausal Age, Estradiol, and Peptide-Secretagogue Type Determine Pulsatile Growth Hormone Secretion in Healthy Women: Studies Using Submaximal Agonist Drive and an Estrogen Clamp
Hudson, S. B. A., Schroeder, D. R., Bailey, J. N., Mielke, K. L., Erickson, D. Z., Miles, J. M., Bowers, C. Y., & Veldhuis, J. D. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1769 · Cited by 18 · see citing works
Self-citation
Growth hormone and prolactin response to ghrelin during the normal menstrual cycle
Messini, C. I., Dafopoulos, K. C., CHALVATZAS, N., Georgoulias, P., & Messinis, I. E. (2008) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2008.03505.x · Cited by 18 · see citing works
Relative effects of estrogen, age, and visceral fat on pulsatile growth hormone secretion in healthy women
Veldhuis, J. D., Hudson, S. B. A., Erickson, D. Z., Bailey, J. N., Reynolds, G. A., & Bowers, C. Y. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00230.2009 · Cited by 18 · see citing works
Self-citation
Gender, Sex-Steroid, and Secretagogue-Selective Recovery from Growth Hormone-Induced Feedback in Older Women and Men
Veldhuis, J. D., Erickson, D. Z., Wigham, J. R., Weist, S., Miles, J. M., & Bowers, C. Y. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0298 · Cited by 11 · see citing works
Self-citation
Tripartite Control of Growth Hormone Secretion in Women during Controlled Estradiol Repletion
Veldhuis, J. D., Cosma, M., Erickson, D. Z., Paulo, R., Mielke, K. L., Farhy, L. S., & Bowers, C. Y. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0043 · Cited by 6 · see citing works
Self-citation
Secretagogues govern GH secretory-burst waveform and mass in healthy eugonadal and short-term hypogonadal men
Veldhuis, J. D., & Keenan, D. M. (2008) · European Journal of Endocrinology · doi:10.1530/eje-08-0414 · Cited by 6 · see citing works
“Similar variability was estimated for the GH-pulsing mechanism in young women ( 14 ), but markedly less variability was inferred for GH in postmenopausal women (g 2.2‐2.4) and LH in men (2.5‐3.7) and women (2.4‐5.4) (12, 29, 30).”
BackgroundInfluentialSelf-citation
Gonadal Status and Body Mass Index Jointly Determine Growth Hormone (GH)-Releasing Hormone/GH-Releasing Peptide Synergy in Healthy Men
Paulo, R., Cosma, M., Soares-Welch, C. V., Bailey, J. N., Mielke, K. L., Miles, J. M., Bowers, C. Y., & Veldhuis, J. D. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1388 · Cited by 5 · see citing works
“Caveats include the need to conduct similar studies in other age groups, and, to the degree practicable, after longer intervals andvariabledegreesofgonadalsuppression.Thegonadaldownregulation paradigm could be combined with transdermal supplementation of sex steroids, as performed recently in women (28, 29 ), and eval…”
MethodSelf-citation
Peripheral estrogen receptor-α selectively modulates the waveform of GH secretory bursts in healthy women
Veldhuis, J. D., Keenan, D. M., & Bowers, C. Y. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00438.2007 · Cited by 5 · see citing works
“secretion via GHRP and/or GHRH receptors ( 12 ; 42; 43).”
BackgroundMethodSelf-citation
Regulation of basal, pulsatile, and entropic (patterned) modes of GH secretion in a putatively low-somatostatin milieu in women
Veldhuis, J. D., Hudson, S. A., Bailey, J. N., & Erickson, D. Z. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00136.2009 · Cited by 1 · see citing works
“Total IGF-I, IGFbinding protein (IGFBP)-1, and IGFBP-3 concentrations were assayed by immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX) as presented (9, 10, 41).”
BackgroundMethodSelf-citation
Current World Literature
(2006) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/01.med.0000202323.44809.4f

Dual secretagogue drive of burst-like growth hormone secretion in postmenopausal compared with premenopausal women studied under an experimental estradiol clamp.
Erickson, D., Keenan, D. M., Mielke, K., Bradford, K., Bowers, C. Y., Miles, J. M., & Veldhuis, J. D. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0424 · Cited by 26 · see citing works
Self-citation
Estradiol regulates GH-releasing peptide's interactions with GH-releasing hormone and somatostatin in postmenopausal women
Norman, C., ROLLENE, N. L., Erickson, D. Z., Miles, J. M., Bowers, C. Y., & Veldhuis, J. D. (2013) · European Journal of Endocrinology · doi:10.1530/eje-13-0733 · Cited by 15 · see citing works
Self-citation
Estradiol Potentiates Ghrelin-Stimulated Pulsatile Growth Hormone Secretion in Postmenopausal Women
Veldhuis, J. D., Keenan, D. M., Iranmanesh, A., Mielke, K. L., Miles, J. M., & Bowers, C. Y. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-0948 · Cited by 34 · see citing works
Self-citation
Impact of Estradiol Supplementation on Dual Peptidyl Drive of GH Secretion in Postmenopausal Women
Veldhuis, J. D., Evans, W. S., & Bowers, C. Y. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.2.8251 · Cited by 36 · see citing works
Self-citation
Contributions of gender and systemic estradiol and testosterone concentrations to maximal secretagogue drive of burst-like growth hormone secretion in healthy middle-aged and older adults
Veldhuis, J. D., Patrie, J. T., Brill, K. T., Weltman, J. Y., Mueller, E. E., Bowers, C. Y., & Weltman, A. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0644 · Cited by 25 · see citing works
Self-citation

Authors: Erickson, D., Keenan, D. M., Farhy, L., Mielke, K., Bowers, C. Y., & Veldhuis, J. D.
Affiliations: Mayo Clinic (US)
University of Virginia (US)
Tulane University (US)
ORCID: Erickson, Dana
Farhy, Leon
Veldhuis, Johannes D.
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 2005-03-01
Volume: 90
Issue: 3
Pages: 1741-1751
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jc.2004-1621
PMC: PMC1236972
OpenAlex: W1990803534
Cited by: 21
References: 92
Citations by year: 2018: 1 · 2017: 1
FWCI: 2.90
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Mayo Clinic (RR00585)
National Institutes of Health (RR-00585)
National Institute on Aging (RR00585, R01AG014799)
National Center for Research Resources (RR-00585, M01RR000585)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (K25HD001474)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
Keywords: growth hormone secretion, estradiol, premenopausal women, secretagogues, L-arginine, GHRP-2, growth hormone-releasing hormone, visceral fat, GnRH agonist, insulin-like growth factor I, testosterone
MeSH terms: Administration, Cutaneous, Adult, Endocrine System, Estradiol, Female, Humans, Insulin-Like Growth Factor I, Pulsatile Flow, Growth Hormone-Releasing Hormone, Premenopause, Human Growth Hormone

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Determinants of dual secretagogue drive of burst-like growth hormone secretion in premenopausal women studied under a selective estradiol clamp

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