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Cited by 7Stress Responses and CortisolAdrenal Hormones and DisordersNeuropeptides and Animal Physiology

Regulation of Pulsatile and Entropic ACTH Secretion Under Fixed Exogenous Secretagogue Clamps

Open access
Roelfsema, Ferdinand, Aoun, Paul, Takahashi, Paul Y., Erickson, Dana, Yang, Rebecca, Veldhuis, Johannes D.·2017·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2017-00115PMC PMC5505204
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Abstract

Background: Adrenocorticotropic hormone (ACTH) secretion is controlled by unobservable hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) pulses. Clamping exogenous CRH or AVP input could allow indirect quantification of the impact of the endogenous heterotypic hormone. Methods: We conducted a randomized, double-blind, placebo-controlled, crossover study in 28 healthy adults (16 men). Volunteers underwent a sex-steroid clamp and a cortisol clamp. ACTH was measured over 10 hours by 10-minute sampling during each of four randomized intravenous (IV) secretagogue clamps (i.e., continuous IV CRH, AVP, both peptides, or saline). Desensitization was tested by bolus injection of the noninfused peptide. Results: Mean ± standard error of the mean 10-hour ACTH concentrations (ng/L) in the sex-combined analysis were: saline, 32 ± 4.6; AVP, 29 ± 4.6; CRH, 67 ± 6.2; and CRH-AVP, 67 ± 8.8 (any CRH vs AVP or saline, P < 0.0001). CRH and AVP increased approximate entropy (relative randomness) of ACTH release (P < 0.0001). Bolus AVP injection after CRH infusion yielded a 2.5-hour ACTH concentration of 46 ± 4.3, exceeding that seen after bolus CRH or saline injection (26 ± 3.3 and 24 ± 3.6, respectively; P = 0.002 and 0.001). Sex hormone clamps did not influence ACTH levels. Conclusions: A CRH, but not AVP, clamp yields sustained pulsatile ACTH secretion with high ACTH secretory-burst mass and randomness. After 10-hour CRH infusion, bolus AVP but not CRH, evoked marked ACTH release, likely caused by heterotypic sensitization of corticotropes by CRH. Similar interactions might underlie chronic stress states.

Integrity signals

Registry

Crossref · 10.1210/jc.2017-00115

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

6 of 18 cited sources checked · 3 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    In healthy subjects ACTH ApEn is age, body mass index, and sex independent, unless the glucocorticoid receptor is blocked experimentally.

    “Indeed, in healthy subjects ACTH ApEn is age, body mass index, and sex independent, unless the glucocorticoid receptor is blocked experimentally (31).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] 2016, Pulsatile cortisol feedback on ACTH secretion is mediated by the glucocorticoid receptor and modulated by gender, J Clin Endocrinol Metab source
  • Premisecitation

    Pulsatile cortisol feedback in brain and subcutaneous tissue follows intravascular cortisol pulsatility.

    “Persistence of cortisol pulsatility in the study setting is physiologically important because cortisol pulsatility in brain and subcutaneous tissue follows intravascular cortisol pulsatility (25,26).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [25] 2012, Circadian and ultradian rhythms of free glucocorticoid hormone are highly synchronized between the blood, the subcutaneous tissue, and the brain, Endocrinology source

      The opening summary (p. 4346) and Discussion report that free corticosterone pulses in rats are synchronized between blood, subcutaneous tissue, and brain, supporting the claim’s central point. The study measured corticosterone rather than cortisol and did not measure feedback, so those aspects are not established by this source. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [26] 2008, Corticosterone levels in the brain show a distinct ultradian rhythm but a delayed response to forced swim stress, Endocrinology source
  • Findingown data

    During the first 4 hours of peptide infusions, linear regressions of mean ACTH on serum E2 were significant only during AVP administration (R2=0.52 and 0.64 for the first 2 hours and for the second 2 hours respectively; P=0.008 and 0.002, respectively; and b=0.019±0.006 and 0.067±0.016, respectively).

    “During the first 4 hours of peptide infusions (divided into blocks of 2 hours), linear regressions of mean ACTH on serum E 2 were significant only during AVP administration (R 2 = 0.52 and 0.64 for the first 2 hours and for the second 2 hours respectively; P = 0.008 and 0.002, respectively; and b = 0.019 6 0.006 and 0.067 6 0.016, respectively).”
    Quote in the paperSubstantial claim
  • Findingown data

    An initial difference between AVP (less) and CRH (greater) associated cortisol concentrations disappeared over the last 4 hours.

    “An initial difference between AVP (less) and CRH (greater) associated cortisol concentrations disappeared over the last 4 hours.”
    Quote in the paperNot a substantial claim
  • Findingown data

    During the first 2 hours of the peptide-secretagogue infusions, AVP and CRH achieved prominent synergy over either peptide alone.

    “However, during the first 2 hours of the peptide-secretagogue infusions, AVP and CRH achieved prominent synergy over either peptide alone, confirming the expected two-peptide potentiation of ACTH secretion, at least acutely.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 18
  • May combine two claims. 41

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In their model, ACTH pulsatility and cortisol pulsatility emerged when the CRH signal was large and unchanged when the CRH signal strength was small.

    “In their model, ACTH pulsatility and cortisol pulsatility emerged when the CRH signal was large and unchanged when the CRH signal strength was small.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] 2010, Origin of ultradian pulsatility in the hypothalamic-pituitary-adrenal axis, Proc Biol Sci source

      The Results and discussion state that only intermediate CRH drive produced ACTH and CORT pulses; high and low drive both produced constant levels. The claim matches the low-drive result but reverses the reported result for high drive. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In an earlier analysis using a comparable protocol, measured cortisol-binding globulin concentrations remained higher, and calculated free cortisol concentrations remained lower, in women than in men.

    “On the other hand, in an earlier analysis using a comparable protocol of ketoconazole blockade and cortisol addback, measured cortisol-binding globulin concentrations remained higher, and calculated free cortisol concentrations remained lower, in women than in men (14).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] 2014, Estradiol, but not testosterone, heightens cortisol-mediated negative feedback on pulsatile ACTH secretion and ACTH approximate entropy in unstressed older men and women, Am J Physiol Regul Integr Comp Physiol source

  • Classified as probably not a substantial claim.

    Premisecitation

    Walker et al. proposed that cortisol oscillations per se can maintain pulsatile ACTH secretion.

    “Walker et al. (24), using a theoretical model of the hypothalamicpituitary-adrenal axis, proposed that cortisol oscillations per se can maintain pulsatile ACTH secretion.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] 2010, Origin of ultradian pulsatility in the hypothalamic-pituitary-adrenal axis, Proc Biol Sci source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The consideration that ACTH pulsatility requires pulsatile feedback by cortisol has been illustrated by mathematical modeling.

    “The consideration that ACTH pulsatility requires pulsatile feedback by cortisol has been illustrated mathematical modeling (24).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] 2010, Origin of ultradian pulsatility in the hypothalamic-pituitary-adrenal axis, Proc Biol Sci source

      The Introduction (page unavailable) describes a mathematical model with negative cortisol feedback on ACTH, and the Results and discussion report that it produces pulses in both ACTH and cortisol under constant CRH drive. The paper shows that these feedback interactions can generate pulsatility; it does not establish the stronger claim that ACTH pulses require pulsatile cortisol feedback. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    During infusions, successive 2-hour mean ACTH concentrations rose significantly (P<0.0001) under distinct secretagogues (P<0.0001).

    “During infusions, successive 2-hour mean ACTH concentrations rose significantly (P , 0.0001) under distinct secretagogues (P , 0.0001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pulsatile, but not basal, ACTH secretion differed among the four infusion types, being 1.5- to 2.1-fold greater during continuous IV infusion of CRH-AVP and CRH, respectively (ANOVA P<0.0001 versus saline or AVP).

    “Pulsatile, but not basal, ACTH secretion differed among the four infusion types, being 1.5to 2.1-fold greater during continuous IV infusion of CRH-AVP and CRH, respectively (analysis of variance P , 0.0001 versus saline or AVP).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The relationship between E2 and ACTH secretion was strong (R2 > 0.5) for AVP but was not evident during saline, CRH, or CRH-AVP administration.

    “This relationship was strong (R 2 .0.5) for AVP but was not evident during saline, CRH, or CRH-AVP administration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither sex nor the administration of sex hormones altered ACTH ApEn.

    “Neither sex nor the administration of sex hormones altered ACTH ApEn (Supplemental Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In healthy adults under sex-steroid and cortisol clamps, mean 10-hour ACTH concentrations were saline 32±4.6 ng/L, AVP 29±4.6 ng/L, CRH 67±6.2 ng/L, and CRH-AVP 67±8.8 ng/L, with any CRH higher than AVP or saline (P<0.0001).

    “Mean 6 standard error of the mean 10-hour ACTH concentrations (ng/L) in the sexcombined analysis were: saline, 32 6 4.6; AVP, 29 6 4.6; CRH, 67 6 6.2; and CRH-AVP, 67 6 8.8 (any CRH vs AVP or saline, P , 0.0001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Basal (nonpulsatile), rather than pulsatile, cortisol secretion was stimulated weakly by infused AVP/CRH and inferably inhibited by ketoconazole.

    “Basal (nonpulsatile), rather than pulsatile, cortisol secretion was stimulated weakly by infused AVP/CRH and inferably inhibited by ketoconazole.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Bolus AVP injection after 10-hour CRH infusion yielded a 2.5-hour ACTH concentration of 46±4.3 ng/L, exceeding that after bolus CRH or saline injection (26±3.3 and 24±3.6 ng/L; P=0.002 and 0.001).

    “Bolus AVP injection after CRH infusion yielded a 2.5-hour ACTH concentration of 46 6 4.3, exceeding that seen after bolus CRH or saline injection (26 6 3.3 and 24 6 3.6, respectively; P = 0.002 and 0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was a detectable cortisol rise in response to 10-hour hCRH or combined hCRH and AVP infusion, but not saline or AVP, indicating some adrenal secretory breakthrough (P<0.05).

    “There was a detectable cortisol rise in response to 10-hour hCRH or combined hCRH and AVP infusion (but not saline or AVP), indicating some adrenal secretory breakthrough (P , 0.05) (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ACTH levels during AVP and saline infusion were similar, except during the first (P=0.023) and the last (P=0.001) 2 hours of infusion.

    “Additionally, ACTH levels during AVP and saline infusion were similar, except during the first (P = 0.023) and the last (P = 0.001) 2 hours of infusion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cortisol levels, although strictly within normal levels (highest absolute 2-hour mean, 13.4±0.6 mg/dL), depended on the infused ACTH secretagogue and on sex, being consistently higher in women than men.

    “However, cortisol levels, although strictly within normal levels (highest absolute 2-hour mean, 13.4 6 0.6 mg/dL), depended on the infused ACTH secretagogue and on sex, being consistently higher in women than men.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was no effect of sex (P=0.90) or addback of sex hormones (P=0.50) on 2-hour mean ACTH concentrations during infusions.

    “However, there was no effect of sex (P = 0.90) or addback of sex hormones (P = 0.50).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The increase in pulsatile ACTH secretion was due principally to amplification of ACTH secretory-burst mass (P<0.0001), with a small increase in burst frequency during CRH infusion (P=0.001).

    “This was due principally to amplification of ACTH secretory-burst mass (P , 0.0001), with a small increase in burst frequency during CRH infusion (P = 0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No correlations were present during continuation of the peptide infusions, and no relations between T and mean ACTH were found in men.

    “No correlations were present during continuation of the peptide infusions, and no relations between T and mean ACTH were found in men.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cortisol concentrations in 2-hour blocks depended on time (P<0.0001), infused secretagogue type (CRH infusions greater than AVP or saline alone) (P<0.0001), and sex (women greater than men) (P<0.0001).

    “Cortisol concentrations in 2-hour blocks depended on time (P , 0.0001), infused secretagogue type (CRH infusions .AVP or saline alone) (P , 0.0001), and sex (women .men) (P , 0.0001) (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the sex-combined analysis, mean 10-hour ACTH concentrations and ACTH secretion rates rose significantly and similarly during CRH and combined CRH-AVP infusions over AVP or saline.

    “In the sex-combined analysis (allowable statistically in the absence of a sex effect), mean 10-hour ACTH concentrations and ACTH secretion rates rose significantly and similarly during CRH and combined CRH-AVP infusions over AVP or saline”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Under these conditions, no influences of sex, sex hormone addback, or sex hormone concentrations were present.

    “Under these conditions, no influences of sex, sex hormone addback, or sex hormone concentrations were present.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Sex (P≥0.45) and the addback of sex steroids (P>0.11) were not significant categorical variables under the GLM analysis, using cortisol concentrations as the covariate.

    “Sex (P $ 0.45) and the addback of sex steroids (P .0.11) were not significant categorical variables under the GLM analysis, using cortisol concentrations as the covariate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Secretory-burst mode and interburst regularity were not influenced by infused secretagogue type (P=0.74).

    “Secretory-burst mode and interburst regularity were not influenced by infused secretagogue type (P = 0.74).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    10-hour ACTH concentrations and ACTH secretion rates rose significantly and similarly during CRH and combined CRH-AVP infusions over AVP or saline infusion.

    “10-hour ACTH concentrations and ACTH secretion rates rose significantly and similarly during CRH and combined CRH-AVP infusions over AVP or saline infusion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In deconvolution analysis of cortisol profiles, basal (and total) secretion was amplified, but pulsatile secretion was not.

    “The results of deconvolution analysis of the cortisol profiles are displayed in Table 4. Basal (and total) secretion was amplified, but pulsatile secretion was not.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During the first 2 hours of peptide infusions, the mean ACTH concentration during combined CRH and AVP infusion was 48.4±4.3 ng/L, which exceeded that during CRH alone (29.7±2.5 ng/L; P=0.005) and AVP alone (P<0.001).

    “The mean ACTH concentration during combined CRH and AVP infusion was 48.4 6 4.3 ng/L, which exceeded that during CRH alone (29.7 6 2.5 ng/L; P = 0.005) and AVP alone (P , 0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    After 10-hour CRH infusion, bolus AVP but not CRH evoked marked ACTH release, likely caused by heterotypic sensitization of corticotropes by CRH.

    “After 10-hour CRH infusion, bolus AVP but not CRH, evoked marked ACTH release, likely caused by heterotypic sensitization of corticotropes by CRH.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Volunteers underwent a sex-steroid clamp and a cortisol clamp.

    “Volunteers underwent a sex-steroid clamp and a cortisol clamp.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Study design and conductnone given

    Pulsatile cortisol feedback was maintained during the experiments.

    “For our experiments, it was crucial that pulsatile cortisol feedback was maintained.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Higher ApEn denotes increased autonomy of feedforward over feedback control, as reflected here by strong exogenous stimulation of corticotropes and weak inhibition by cortisol feedback.

    “Higher ApEn denotes increased autonomy of feedforward over feedback control, as reflected here by strong exogenous stimulation of corticotropes (feedforward) and weak inhibition by cortisol feedback.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Estradiol concentrations were mean (range) 12.9 (5.9 to 19.0) pg/mL in sex-steroid deplete women and 681 (112 to 1700) pg/mL in E2-replete women.

    “Estradiol concentrations were mean (range) 12.9 (5.9 to 19.0) pg/mL in sex-steroid deplete women and 681 (112 to 1700) pg/mL in E 2 -replete women.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Time-varying plasma concentrations of ACTH drive pulsatile adrenal production of cortisol.

    “Time-varying plasma concentrations of ACTH drive pulsatile adrenal production of cortisol, which associates with plasma proteins (e.g., albumin and cortisol-binding globulin) (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] 2004, Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women, J Clin Endocrinol Metab source

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

    Study design and conductown data

    The study was a randomized, double-blind, placebo-controlled, crossover study in 28 healthy adults (16 men).

    “We conducted a randomized, double-blind, placebo-controlled, crossover study in 28 healthy adults (16 men).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    This outcome favors the notion of cortisol-driven pulsatility but does not exclude unknown pulsatility inputs from other hypothalamic sources.

    “This outcome favors the notion of cortisol-driven pulsatility but does not exclude unknown pulsatility inputs from other hypothalamic sources.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All subjects completed the studies, and no adverse events were noted.

    “All subjects completed the studies, and no adverse events were noted.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The variable-waveform deconvolution analysis used a Matlab-based adaptive-mesh multiparameter-search algorithm that was cross-validated previously.

    “The analysis implements a Matlab-based adaptive-mesh multiparameter-search algorithm that was cross-validated previously (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] 2009, Sensitivity and specificity of pulse detection using a new deconvolution method, Am J Physiol Endocrinol Metab source

  • May combine two claims.

    Study design and conductown data

    No statistically significant differences in basal levels between subjects randomized to receive sex steroids and those who did not receive replacement were found with the unpaired Student's t test except for estradiol in women of the placebo group, which consisted exclusively of postmenopausal women.

    “No statistically significant differences in basal levels between subjects randomized to receive sex steroids and those who did not receive replacement were found with the unpaired Student's t test except for estradiol in women of the placebo group, which consisted exclusively of postmenopausal women.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Sex hormone addback resulted in pharmacologic to high-normal young-adult values in hormone-replete subjects and very low levels in the leuprolide-suppressed nonreplaced subjects.

    “Sex hormone addback resulted in pharmacologic to high-normal youngadult values in hormone-replete subjects and very low levels in the leuprolide-suppressed nonreplaced subjects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    A CRH, but not AVP, clamp yields sustained pulsatile ACTH secretion with high ACTH secretory-burst mass and randomness.

    “A CRH, but not AVP, clamp yields sustained pulsatile ACTH secretion with high ACTH secretory-burst mass and randomness.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cortisol feedback restrains neuronal secretion of AVP, CRH, and ACTH and antagonizes pituitary actions of AVP and CRH by activating selective signaling pathways, including nuclear type I and II glucocorticoid receptors.

    “In turn, cortisol feedback restrains neuronal secretion of AVP, CRH, and ACTH and antagonizes pituitary actions of AVP and CRH by activating selective signaling pathways, including nuclear (type I and II) glucocorticoid receptors (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] 2009, The ultradian and circadian rhythms of free corticosterone in the brain are not affected by gender: an in vivo microdialysis study in Wistar rats, J Neuroendocrinol source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Approximate entropy provides a sensitive (>90%), model-free, and scale-invariant measure of relative randomness due to loss of feedback control within a network.

    “ApEn provides a sensitive (.90%), model-free, and scale-invariant measure of relative randomness due to loss of feedback control within a network.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] 2001, Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans, Am J Physiol Regul Integr Comp Physiol source

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

    Premisecitation

    CRH and AVP both individually and synergistically trigger exocytotic discharge of ACTH-containing secretory granules and promote de novo biosynthesis and accumulation of ACTH in corticotrope cells.

    “CRH and AVP both individually and synergistically trigger exocytotic discharge of adrenocorticotropic hormone (ACTH)-containing secretory granules and promote de novo biosynthesis and accumulation of ACTH in corticotrope cells (9,10).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] 1983, Effects of synthetic ovine corticotropin-releasing factor, glucocorticoids, catecholamines, neurohypophysial peptides, and other substances on cultured corticotropic cells, Endocrinology source
    • cites [10] 1988, Role of endogenous arginine vasopressin in potentiating corticotropin-releasing hormone-stimulated corticotropin secretion in man, J Clin Endocrinol Metab source

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    In the statistical analyses of ACTH secretion, the mean cortisol concentration of each subject in each time period was used as a covariate.

    “Therefore, in the statistical analyses of ACTH secretion, the mean cortisol concentration of each subject in each time period was used as a covariate.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Plasma ACTH was assayed via a sensitive and specific solid-phase immunochemiluminescent assay with intraassay coefficients of variation of 6.4, 2.7, and 3.2% at 5.7, 28, and 402 ng/L.

    “Plasma ACTH was assayed in each 10-minute sample via sensitive and specific solid-phase immunochemiluminescent assay (Siemens Health Care Diagnostics, Deerfield, IL).The detection threshold was 5 ng/L (divide by 4.5 for pmol/L).Intraassay coefficients of variation were 6.4, 2.7, and 3.2% at 5.7, 28, and 402 ng/L, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Testosterone concentrations were 17.2 (7.4 to 44.0) ng/dL in T-deplete men and 1670 (1208 to 2138) ng/dL in T-replete men.

    “concentrations were 17.2 (7.4 to 44.0) ng/dL in T-deplete men and 1670 (1208 to 2138) ng/dL in T-replete men Table 1.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Neurotransmitter inputs from the cerebral cortex, hippocampolimbic system, and brainstem stimulate or inhibit recurrent burst-like secretion of hypothalamic CRH and AVP into hypothalamo-pituitary portal blood.

    “For example, neurotransmitter inputs from the cerebral cortex, hippocampolimbic system, and brainstem stimulate or inhibit recurrent burst-like secretion of hypothalamic corticotropinreleasing hormone (CRH) and arginine vasopressin (AVP) into hypothalamo-pituitary portal blood (5)(6)(7)(8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (5)(6)(7)(8)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Physiological (free) glucocorticoid levels in the brain are extremely important in negative feedback on hypothalamic neurons but appear comparable by sex in animal models.

    “Physiological (free) glucocorticoid levels in the brain are extremely important in negative feedback signal on hypothalamic neurons but appear to be comparable by sex in animal models (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] 2009, The ultradian and circadian rhythms of free corticosterone in the brain are not affected by gender: an in vivo microdialysis study in Wistar rats, J Neuroendocrinol source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In vitro studies of corticotrope secretion allow for both homologous and heterologous desensitization.

    “In vitro studies of corticotrope secretion also allow for both homologous and heterologous desensitization (9,23).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] 1983, Effects of synthetic ovine corticotropin-releasing factor, glucocorticoids, catecholamines, neurohypophysial peptides, and other substances on cultured corticotropic cells, Endocrinology source
    • cites [23] 1987, Detailed kinetic analysis of adrenocorticotropin secretion by dispersed rat anterior pituitary cells in a microperifusion system: effects of ovine corticotropin-releasing factor and arginine vasopressin, Endocrinology source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The complex interactions between AVP and CRH inferred here both acutely (2 hours) and over a longer interval (10 hours) provide a possible framework for developing hypotheses to explain the potentially puzzling effects of different stressor environments and medications on ACTH secretion.

    “The complex interactions between AVP and CRH inferred here both acutely (2 hours) and over a longer interval (10 hours) provide an possible framework for developing hypotheses to explain the potentially puzzling effects of different stressor environments and medications on ACTH secretion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Caveats of the study include the relatively short duration; the pharmacologic nature of the peptide, cortisol, E2, and T clamps; and the partial escape of adrenal cortisol secretion.

    “Caveats of the study in the current study include the relatively short duration; the pharmacologic nature of the peptide, cortisol, E 2 , and T clamps; and the partial escape of adrenal cortisol secretion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In this setting, the impact of sex hormones on ACTH secretion was explained by total cortisol concentrations and inferable potentiation of endogenously driven and exogenous AVP-stimulated ACTH secretion by systemic E2 concentrations.

    “In this setting, the impact of sex hormones on ACTH secretion was explained by total cortisol concentrations and inferable potentiation of endogenously driven and exogenous AVP-stimulated ACTH secretion by systemic E 2 concentrations.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Total cortisol concentrations adequately reflect glucocorticoid negative feedback on ACTH secretion in this setting.

  • May combine two claims.

    Interpretationown data

    The present mechanistic investigation reveals an inhibitory effect of sustained AVP exposure on acute CRH drive and a potentiating effect of sustained CRH exposure on acute AVP stimulation.

    “The present mechanistic investigation of regulated ACTH secretion in men and women under partially controlled cortisol feedback reveals an inhibitory effect of sustained AVP exposure on acute CRH drive and a potentiating effect of sustained CRH exposure on acute AVP stimulation.”
    Quote in the paperSubstantial claim
51 of 51

  • The paper relies on this without support.

    Time-dependent changes in endogenous CRH and AVP have not been observed.

    “However, more detailed study of the complex interrelations among AVP, CRH, ACTH, and cortisol is not straightforward because time-dependent changes in endogenous CRH and AVP have not been observed.”

  • The paper relies on this without support.

    Total cortisol concentrations adequately reflect glucocorticoid negative feedback on ACTH secretion in this setting.

    “The current study did not repeat such measurements, using covariate analysis instead to parse the contribution of unequal total cortisol concentrations by sex.”
2 of 2

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.

  • The stated cortisol-infusion duration does not match its clock times

    Major

    The specified interval from 10:00 AM to noon is two hours, not 14 hours. This also places the stated cortisol infusion after most of the overnight secretagogue clamp.

    Reported 14 · recomputed 2

  • Burst frequency is described as both unchanged and increased

    Minor

    The discussion says burst frequency was essentially the same with and without infused secretagogues, whereas the results report an increase during CRH infusion with P = 0.001.

  • The stated maximum two-hour cortisol mean is below a ten-hour mean

    Minor

    The discussion calls 13.4 mg/dL the highest two-hour mean, but Table 2 reports a ten-hour mean of 18.2 mg/dL for women receiving CRH-AVP. At least one two-hour segment of that ten-hour period must have a mean of at least 18.2 mg/dL.

3 of 3

Cites

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Cited by

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Related

Authors
Roelfsema, F., Aoun, P., Takahashi, P. Y., Erickson, D., Yang, R., & Veldhuis, J. D.
Affiliations
  • Leiden University Medical Center (NL)
  • Mayo Clinic (US)
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2017-03-28
Volume
102
Issue
7
Pages
2611-2619
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2017-00115
PMC
PMC5505204
OpenAlex
W2606594137
Cited by
7
References
32
Citations by year
2026: 1 · 2025: 1 · 2022: 4 · 2019: 1
FWCI
0.15
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
Funders
  • National Institutes of Health (UL1TR000135)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK050456, R01DK073148)
  • National Center for Advancing Translational Sciences (TR000135)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
ACTH secretion, pulsatile hormone secretion, approximate entropy, corticotropin-releasing factor, vasopressin, hypothalamic-pituitary-adrenal axis, desensitization, chronic stress
MeSH terms
Adrenocorticotropic Hormone, Aged, Arginine Vasopressin, Constriction, Corticotropin-Releasing Hormone, Double-Blind Method, Female, Follow-Up Studies, Humans, Hydrocortisone, Infusions, Intravenous, Male, Middle Aged, Reference Values, Gonadal Steroid Hormones, Time Factors, Leuprolide, Cross-Over Studies

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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