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Cited by 65Hypothalamic control of reproductive hormonesHormonal and reproductive studiesAdrenal Hormones and Disorders

Proinflammatory Cytokine Infusion Attenuates LH's Feedforward on Testosterone Secretion: Modulation by Age

Open access
Veldhuis, Johannes, Yang, Rebecca, Roelfsema, Ferdinand, Takahashi, Paul·2016·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2015-3611PMC PMC4880122
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Abstract

CONTEXT: In the experimental animal, inflammatory signals quench LH's feedforward drive of testosterone (T) secretion and appear to impair GnRH-LH output. The degree to which such suppressive effects operate in the human is not known. OBJECTIVE: To test the hypothesis that IL-2 impairs LH's feedforward drive on T and T's feedback inhibition of LH secretion in healthy men. SETTING: Mayo Center for Translational Science Activities. PATIENTS OR OTHER PARTICIPANTS: A total of 35 healthy men, 17 young and 18 older. INTERVENTIONS: Randomized prospective double-blind saline-controlled study of IL-2 infusion in 2 doses with concurrent 10-minute blood sampling for 24 hours. MAIN OUTCOME MEASURES: Deconvolution analysis of LH and T secretion. RESULTS: After saline injection, older compared with young men exhibited reduced LH feedforward drive on T secretion (P < .001), and decreased T feedback inhibition of LH secretion (P < .01). After IL-2 injection, LH's feedforward onto T secretion declined markedly especially in young subjects (P < .001). Concomitantly, IL-2 potentiated T's proportional feedback on LH secretion especially in older volunteers. CONCLUSION: This investigation confirms combined feedforward and feedback deficits in older relative to young men given saline and demonstrates 1) joint mechanisms by which IL-2 enforces biochemical hypogonadism, viz, combined feedforward block and feedback amplification; and 2) unequal absolute inhibition of T and LH secretion by IL-2 in young and older men. These outcomes establish that the male gonadal axis is susceptible to dual-site suppression by a prototypic inflammatory mediator. Thus, we postulate that selected ILs might also enforce male hypogonadism in chronic systemic inflammation.

AI snapshot

Written from the paper’s full text.

TL;DR

In healthy young and older men, IL-2 infusion suppressed testosterone secretion and altered LH–testosterone coupling, with age-dependent mechanisms. IL-2 reduced LH’s feedforward drive on T in both age groups and increased T’s feedback inhibition of LH in older men, indicating dual-site suppression of the male gonadal axis.

Key findings

  • In 35 healthy men (17 young, 18 older), saline injection revealed reduced LH feedforward on T secretion in older vs young men (P < .001) and decreased T feedback inhibition of LH secretion (P < .01).
  • High-dose IL-2 vs saline suppressed T concentrations by 106 (28–183) ng/dL in young men (P = .012) and by 57 (37–76) ng/dL in older men (P < .001), with an age effect at P < .05; pooled IL-2 doses suppressed T by 93 (35–150) ng/dL in young men (P = .0049) and 55 (36–76) ng/dL in older men (P < .001).
  • IL-2 inhibited T secretory-burst mass in both young (P = .007) and older (P = .0001) men, greater in young men (P = .0001), and lowered 18-hour pulsatile T secretion in young (P = .006) and older (P = .0001) men (age effect, P = .004). IL-2 selectively suppressed basal T secretion in young men (P < .004) and T secretory-burst frequency in older men (P = .005).
  • IL-2 blunted LH’s feedforward on T in young (P < .01) and older (P < .05) men from midnight to 6 pm, and increased T feedback on LH in older men (P < .01) but not young men (age difference, P < .01).

Methods

  • Prospectively randomized, double-blind, saline-controlled crossover study in healthy men ages 18–30 and 60–80 years; each subject underwent two overnight studies with saline and either 3 million U rhIL-2 (n = 6 young, n = 6 older) or 6 million U rhIL-2 (n = 11 young, n = 12 older).
  • Blood was sampled every 10 minutes for 24 hours starting 2 hours before injection; LH and T were measured, and deconvolution analysis quantified basal and pulsatile secretion.
  • LH feedforward on T was estimated by the T-to-LH concentration ratio, and T feedback on LH by the LH-to-T ratio; analysis used ANOVA with Tukey post hoc tests, unpaired and paired t tests, with 90% power to detect a 30% effect of IL over saline on T concentrations.

Limitations

  • The paper states that more specific analytical tools are needed to confirm the inferred dual sites of IL-2 action in humans; 24-hour monitoring did not capture full T recovery, so it cannot determine whether age prolongs time to T recovery.
  • The paper states it was not powered to detect IL-2 dose effects and did not monitor 24-hour serum IL-2 or cortisol concentrations, so the extent to which varying IL-2 doses elevate cortisol or IL-2 per se and contribute to suppressed gonadal T secretion cannot be ascertained.
  • Evident from the text: dose/age strata were small (6–12 subjects each), the study used short-term IL-2 in healthy men, and feedforward/feedback were inferred from concentration ratios rather than direct GnRH measurements.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/jc.2015-3611

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 43 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Results

    Dose-pooled IL-2 compared with saline suppressed T concentrations by 55 (36-76) ng/dL in older men (P < .001).

    “and 55 (36–76) ng/dL (older, P < .001)”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    After saline injection, older compared with young men exhibited decreased T feedback inhibition of LH secretion (P < .01).

    “and decreased T feedback inhibition of LH secretion (P < .01)”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    The inhibition of T secretory-burst mass by IL-2 was greater in young than older men.

    “The main effect of IL-2 was inhibition of T secretory-burst mass (amount of T secreted per burst per unit distribution volume, ng/dL), which was significant in both young (P = .007) and older (P = .0001) men but greater in young men (P = .0001).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    Baseline FSH was higher in older than young men (9.5 ± 6.3 vs 3.3 ± 1.6 IU/L, P < .05).

    “FSH (IU/L) 3.3 ± 1.6 and 9.5 ± 6.3 (P < .05)”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Abstract

    After saline injection, older compared with young men exhibited reduced LH feedforward drive on T secretion (P < .001).

    “After saline injection, older compared with young men exhibited reduced LH feedforward drive on T secretion (P < .001)”
    Quote in the paperSubstantial claim
  • May combine two claims. 31
  • Classified as probably not a substantial claim. 16
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data
    § Results

    During the last 18 hours of the 24-hour sampling period, serum T concentrations differed by both IL-2 exposure and age.

    “During this 18-hour interval, serum T concentrations differed by both IL-2 exposure (P < .001) and by age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    There were no effects of IL-2 or age on full 24-hour LH concentration data.

    “There were no effects of IL-2 or age on full 24-hour LH concentration data.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Combined IL-2 doses blunted feedforward in young and older men from midnight to 6 pm, except 6 am to 12 pm in older men, when inhibition was nonsignificant in older men only.

    “3) combined IL-2 doses blunted feedforward in young (P < .01) and older (P < .05) men from midnight to 6 pm (P < .001 treatment effect), except 6 am to 12 pm in older men, when inhibition was nonsignificant in older men only (P < .001 vs young).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The T to LH concentration ratio is a valid surrogate dynamic measure of LH's feedforward on T secretion.

  • May combine two claims.

    Findingown data
    § Results

    Median T to LH concentration ratios differed by age and changed markedly over time after saline and IL-2 injection.

    “Figure 4, top, shows that median T to LH concentration ratios differed by age and changed markedly over time after saline and IL-2 injection.”
    Quote in the paperSubstantial claim

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

    Findingown data
    § Results

    No serious adverse events occurred, and all 35 subjects completed both 24-hour 10-minute sampling sessions.

    “No serious adverse events occurred, and all 35 subjects completed both 24-hour 10-minute sampling sessions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    LH concentrations were higher at screening in older individuals, but became similar by age over 24 hours under IL-2 stress.

    “LH concentrations were higher at screening in older individuals, but became similar by age over 24 hours under IL-2 stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    The present clinical analysis demonstrates that exogenous IL-2 suppresses both pulsatile and basal (and hence total) T secretion in young men, and inhibits principally pulsatile T secretion in older men.

    “The present clinical analysis demonstrates that exogenous IL-2 suppresses both pulsatile and basal (and hence total) T secretion in young men, and inhibits principally pulsatile T secretion in older men.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    There are age differences in IL-2's effects, defined by reduced nonpulsatile T secretion (young men), reduced T secretory burst frequency (older men), and heightened T feedback on the hypothalamopituitary unit (older men).

    “The second finding was that there are age differences in IL-2's effects, defined by reduced nonpulsatile T secretion (young men), reduced T secretory burst frequency (older men), and heightened T feedback on the hypothalamopituitary unit (older men).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    At these IL-2 doses, hematocrit, leukocyte, and platelet counts, pulse and BP were not affected.

    “At these IL-2 doses, hematocrit, leukocyte, and platelet counts, pulse and BP were not affected.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    A relatively low dose of IL-2, which induced mild and tolerable adverse reactions over saline, markedly suppressed pulsatile T secretion in young and older men.

    “The main finding was that a relatively low dose of IL-2, which induced mild and tolerable adverse reactions over saline, markedly suppressed pulsatile T secretion in young and older men.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    Headache and malaise occurred, but no oliguria, hypotension, dyspnea, or arrhythmia developed.

    “Headache and malaise occurred, but no oliguria, hypotension, dyspnea, or arrhythmia developed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    IL-2 administration selectively reduced basal (nonpulsatile) T secretion in young men and T secretory-burst frequency in older men.

    “Moreover, IL-2 administration selectively reduced basal (nonpulsatile) T secretion in young men and T secretory-burst frequency in older men.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data
    § Materials and Methods

    Total T assay correlation was R = 0.975 and slope 1.12 for linear regression on mass spectrometry.

    “Correlation was R = 0.975 and slope 1.12 for linear regression on mass spectrometry.”
    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
    § Materials and Methods

    Serum LH concentrations were assayed in duplicate using an automated 2-site monoclonal immunochemiluminescent assay with a sensitivity of 0.20 IU/L and median inter- and intraassay coefficients of variation of 5.5% and 8.5%.

    “Serum LH concentrations were assayed in duplicate using an automated 2-site monoclonal immunochemiluminescent assay with a sensitivity of 0.20 IU/L (First International Reference Preparation) and median inter- and intraassay coefficients of variation of 5.5% and 8.5%, respectively (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] 30. Veldhuis JD, Liu PY, Keenan DM, Takahashi PY. Older men exhibit reduced efficacy of and heightened potency downregulation by intravenous pulses of recombinant human LH: a study in 92 healthy men. Am J Physiol Endo Metab. 2012;302(1):E117–E122. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § Materials and Methods

    The study design was a prospectively randomized, double-blind placebo-controlled crossover study.

    “The design was a prospectively randomized, double-blind placebo-controlled crossover study”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation
    § Materials and Methods

    LH pulse detection by the automated deconvolution method was empirically validated using hypothalamo-pituitary sampling and simulated pulsatile time series, with sensitivity and specificity both exceeding 93%.

    “Pulse detection was empirically validated using hypothalamo-pituitary sampling and simulated pulsatile time series (27, 28). Sensitivity and specificity both exceed 93%.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] 27. Keenan DM, Roelfsema F, Biermasz N, Veldhuis JD. Physiological control of pituitary hormone secretory-burst mass, frequency and waveform: a statistical formulation and analysis. Am J Physiol. 2003;285(3):R664–R673. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [28] 28. Liu PY, Keenan DM, Kok P, Padmanabhan V, O'Byrne KT, Veldhuis JD. Sensitivity and specificity of pulse detection using a new deconvolution method. Am J Physiol Endo Metab. 2009;297(2):E538–E544. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Results

    Absolute full 24-hour mean T concentrations were higher in young than older men after saline injection but became similar by age after a low or high IL-2 dose.

    “Thus, absolute full 24-hour mean T concentrations were higher in young than older men after saline injection but became similar by age after a low or high IL-2 dose.”
    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
    § Materials and Methods

    Total T concentrations were assayed in duplicate by robotics-automated chemiluminescence assay with a sensitivity of 20 ng/dL and median intra- and interassay coefficients of variation of 5.2% and 8.3%.

    “Total T concentrations were assayed in duplicate by robotics-automated chemiluminescence assay. Sensitivity was 20 ng/dL (0.69 nmol/L), and median intra- and interassay coefficients of variation were 5.2% and 8.3%, respectively.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning
    § Materials and Methods

    IL-2 dose was not powered.

    “Thus, IL-2 dose was not powered.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Materials and Methods

    Subject number was powered at 90% to detect a 30% effect of IL over saline on T concentrations.

    “Subject number was powered at 90% to detect a 30% effect of IL over saline on T concentrations”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § Results

    Estimated LH feedforward on T secretion is stronger in young than older men given saline and declines more in young than older men 6-24 hours after IL-2 exposure.

    “Thus, estimated LH feedforward on T secretion is stronger in young than older men given saline and declines more in young than older men 6–24 hours after IL-2 exposure.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The T to LH concentration ratio is a valid surrogate dynamic measure of LH's feedforward on T secretion.

  • May combine two claims.

    Premisecitation
    § Abstract

    Systemic inflammation is accompanied by varying degrees of biochemical hypoandrogenemia and clinical hypogonadism in the male.

    “Systemic inflammation is accompanied by varying degrees of biochemical hypoandrogenemia and clinical hypogonadism in the male.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [1] 1. Luppa P, Munker R, Nagel D, Weber M, Engelhardt D. Serum androgens in intensive-care patients: correlations with clinical findings. Clin Endocrinol (Oxf). 1991;34(4):305–310. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [2] 2. Lephart ED, Baxter CR, Parker CR. Effect of burn trauma on adrenal and testicular steroid hormone production. J Clin Endocrinol Metab. 1987;64:842–848. [DOI] [PubMed] [Google Scholar]

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      Not checked in the free run.

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      Not checked in the free run.

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      Not checked in the free run.

    • cites [8] 8. Sundin DJ, Wolin MJ. Toxicity management in patients receiving low-dose aldesleukin therapy. Ann Pharmacother. 1998;32(12):1344–1352. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [9] 9. Sundin DJ, Wolin MJ. Aldesleukin therapy in HIV-infected patients. Am J Health Syst Pharm. 1998;55(14):1520–1523. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [10] 10. Veldhuis JD, Wilkowski MJ, Zwart AD, et al. Evidence for attenuation of hypothalamic gonadotropin-releasing hormone (GnRH) impulse strength with preservation of GnRH pulse frequency in men with chronic renal failure. J Clin Endocrinol Metab. 1993;76:648–654. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Study design and conductnone given
    § Discussion

    The data do not identify the exact site(s) of IL-2 action in the hypothalamo-pituitary unit.

    “Our data do not identify the exact site(s) of IL-2 action in the hypothalamo-pituitary unit.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Interpretationown data
    § Discussion

    The pathophysiological mechanisms of IL-2-induced hypoandrogenemia were not identical by age.

    “Additionally, the pathophysiological mechanisms of IL-2-induced hypoandrogenemia were not identical.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Study design and conductreasoning
    § Discussion

    This was the first study of its kind in nondiseased humans and therefore required FDA approval, and close FDA, Mayo IRB, and DSMB scrutiny.

    “This was the first study of its kind in nondiseased humans and therefore required FDA approval, and close FDA, Mayo IRB, and DSMB scrutiny.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Discussion

    In an analysis of 119 cancer patients, IL-2 treatment resulted in 14 patients' experiencing malaise, 5 nausea, 2 disorientation, and 2 oliguria.

    “In an analysis of 119 such patients, IL-2 treatment resulted in 14 patients' experiencing malaise, 5 nausea, 2 disorientation, and 2 oliguria (8, 9).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] 8. Sundin DJ, Wolin MJ. Toxicity management in patients receiving low-dose aldesleukin therapy. Ann Pharmacother. 1998;32(12):1344–1352. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [9] 9. Sundin DJ, Wolin MJ. Aldesleukin therapy in HIV-infected patients. Am J Health Syst Pharm. 1998;55(14):1520–1523. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Premisecitation
    § Discussion

    Capillary-leak syndrome, hypotension and tachycardia have occurred rarely at high IL-2 doses.

    “Capillary-leak syndrome, hypotension and tachycardia have occurred rarely at high IL-2 doses (31, 32).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] 31. Raab C, Weidmann E, Schmidt A, et al. The effects of interleukin-2 treatment on endothelin and the activation of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf). 1999;50(1):37–44. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

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      Not checked in the free run.

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

    Study design and conductown data
    § Discussion

    The present article reports a randomized crossover study in 17 young and 18 older men given saline and either of 2 doses of IL-2 with intensive 10-minute blood sampling over 24 hours for later measurements of LH and T and estimates of basal and pulsatile LH and T secretion by mathematical deconvolution.

    “In summary, of the complex findings, the present article reports a randomized crossover study in 17 young and 18 older men given saline and either of 2 doses of IL-2 (first 6 subjects' receiving the lower dose) with intensive 10-minute blood sampling over 24 hours for later measurements of LH and T and estimates of basal and pulsatile LH and T secretion by mathematical deconvolution.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Discussion

    In some settings, a negative association exists between inflammatory markers and total T concentrations.

    “In some settings, a negative association exists between inflammatory markers and total T concentrations (16).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] 16. Maggio M, Basaria S, Ceda GP, et al. The relationship between testosterone and molecular markers of inflammation in older men. J Endocrinol Invest. 2005;28(11 suppl proceedings):116–119. [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Interpretationreasoning
    § Discussion

    The acute T-suppressing actions of IL-2 observed here in both young and older men may have more general pathophysiologic implications under conditions of chronic inflammation.

    “Accordingly, the acute T-suppressing actions of IL-2 observed here in both young and older men may have more general pathophysiologic implications under conditions of chronic inflammation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § Discussion

    Under saline injection, older men exhibit lower T feedback on GnRH/LH than young men, as indicated by a higher LH to T ratio.

    “Thereby, we inferred that under saline injection, older men exhibit lower T feedback on GnRH/LH than young men, viz, a higher LH to T ratio.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The LH to T concentration ratio is a valid surrogate: higher LH concentrations at any given T concentration reflect reduced negative feedback by T on LH, for any given degree of GnRH drive.
    • Rests on an assumption: LH levels are determined by GnRH drive and T feedback.

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    The overall outcome is reduced T secretion even when normalized per unit LH concentration, signifying impaired testis responsiveness to LH or reduced LH bioactivity.

    “The overall outcome is reduced T secretion even when normalized per unit LH concentration, signifying impaired testis responsiveness to LH or reduced LH bioactivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Discussion

    More prolonged T deprivation occurs in men with chronic RA, systemic lupus erythematosus, metastatic cancer, HIV wasting syndrome, unstable coronary artery disease, poorly controlled DM, CKD, and in some measure normal aging.

    “More prolonged T deprivation occurs in men with chronic RA (13, 13), systemic lupus erythematosis (14), metastatic cancer (39), HIV wasting syndrome (11), unstable coronary artery disease with or without heart failure, poorly controlled DM, CKD (6), and in some measure normal aging (16).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] 13. Cutolo M, Balleari E, Giusti M, Monachesi M, Accardo S. Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotropin stimulation. Arthritis Rheum. 1988;31(10):1314–1317. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [14] 14. Köller MD, Templ E, Riedl M, et al. Pituitary function in patients with newly diagnosed untreated systemic lupus erythematosus. Ann Rheum Dis. 2004;63(12):1677–1680. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [39] 39. Viviani S, Ragni G, Santoro A, et al. Testicular dysfunction in Hodgkin's disease before and after treatment. Eur J Cancer. 1991;27(11):1389–1392. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning
    § Discussion

    The study was not a dose-response outcomes study and was appropriately powered at the higher dose.

    “The study was thus not a dose-response outcomes study, and was appropriately powered at the higher dose.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    IL-2 treatment decreased the LH to T ratio significantly in older but not young men, denoting increased T feedback on the GnRH-LH unit at the older age.

    “IL-2 treatment decreased this ratio significantly in older but not young men denoting increased T feedback on the GnRH-LH unit at the older age.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The LH to T concentration ratio is a valid surrogate: higher LH concentrations at any given T concentration reflect reduced negative feedback by T on LH, for any given degree of GnRH drive.
    • Rests on an assumption: LH levels are determined by GnRH drive and T feedback.

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

    Study design and conductreasoning
    § Discussion

    The exact extent to which varying IL-2 doses elevate cortisol or IL-2 per se and/or contribute to suppressed gonadal T secretion cannot be ascertained from this study.

    “Thus, the exact extent to which varying IL-2 doses elevate cortisol or IL-2 per se and/or contribute to suppressed gonadal T secretion cannot be ascertained from this study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data
    § Discussion

    The study was a prospectively randomized placebo-controlled within-subject crossover study in healthy young and older men exposed to saline vs rhIL-2 stress.

    “This was a prospectively randomized placebo-controlled within-subject crossover study in healthy young (median age, 24 y) and older (median age, 63 y) men exposed to saline vs rhIL-2 stress.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § Discussion

    The investigation did not monitor 24-hour serum IL-2 or cortisol concentrations.

    “Third, this investigation was not powered to detect IL-2 dose effects, and did not monitor 24-hour serum IL-2 or cortisol concentrations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    These outcomes have broad implications showing for the first time in humans a unifying mechanism by which inflammation could reduce T availability in many disease and nondisease states.

    “These outcomes have broad implications showing for the first time in humans a unifying mechanism by which inflammation could reduce T availability in many disease and nondisease states.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Discussion

    Acute and chronic illnesses are accompanied by varying degrees of biochemical hypoandrogenemia (low T).

    “Acute and chronic illnesses are accompanied by varying degrees of biochemical hypoandrogenemia (low T).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] 4. Nierman DM, Mechanick JI. Hypotestosteronemia in chronically critically ill men. Crit Care Med. 1999;27(11):2418–2421. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [37] 37. Bergendahl M, Aloi JA, Iranmanesh A, Mulligan T, Veldhuis JD. Fasting suppresses pulsatile luteinizing hormone (LH) secretion and enhances orderliness of LH release in young but not older men. J Clin Endocrinol Metab. 1998;83(6):1967–1975. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [1] 1. Luppa P, Munker R, Nagel D, Weber M, Engelhardt D. Serum androgens in intensive-care patients: correlations with clinical findings. Clin Endocrinol (Oxf). 1991;34(4):305–310. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Discussion

    Exposure to IL-2 reduces LH's feedforward drive of T secretion and augments T's feedback inhibition of LH secretion in healthy men.

    “Thereby, we show that exposure to IL-2 reduces LH's feedforward drive of T secretion and augments T's feedback inhibition of LH secretion in healthy men.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The LH to T concentration ratio is a valid surrogate: higher LH concentrations at any given T concentration reflect reduced negative feedback by T on LH, for any given degree of GnRH drive.
    • Rests on an assumption: LH levels are determined by GnRH drive and T feedback.
    • Rests on an assumption: The T to LH concentration ratio is a valid surrogate dynamic measure of LH's feedforward on T secretion.
41 of 41

  • The paper relies on this without support.

    No clinical investigations have interrogated these complementary pathophysiological mechanisms in healthy individuals subjected to a defined inflammatory stress.

    “To date, no clinical investigations have interrogated these complementary pathophysiological mechanisms in healthy individuals subjected to a defined inflammatory stress.”

  • The authors state this as an assumption.

    The LH to T concentration ratio is a valid surrogate: higher LH concentrations at any given T concentration reflect reduced negative feedback by T on LH, for any given degree of GnRH drive.

    “This ratio assumes that higher LH concentrations at any given T concentration reflect reduced negative feedback by T on LH, for any given degree of GnRH drive.”

  • The paper relies on this without support.

    LH levels are determined by GnRH drive and T feedback.

    “LH levels are determined by GnRH drive and T feedback.”

  • The paper relies on this without support.

    The T to LH concentration ratio is a valid surrogate dynamic measure of LH's feedforward on T secretion.

    “The mechanisms of IL-2's inhibition of T were further assessed using a surrogate dynamic measure of LH's feedforward on T secretion, viz, the T to LH concentration ratio.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

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.

  • Older men's overall BMI conflicts with subgroup means

    Minor

    The two older subgroups contain 6 and 12 men with mean BMIs of 27 and 28, respectively. Their combined mean is about 27.7, not the reported 30 kg/m2.

  • Overall screening testosterone means conflict with subgroup means

    Minor

    Weighting the table's screening testosterone means by subgroup size gives about 545 ng/dL for young men and 431 ng/dL for older men, rather than the reported 554 and 439 ng/dL. The differences exceed rounding of the subgroup means.

2 of 2

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Authors
Veldhuis, J., Yang, R., Roelfsema, F., & Takahashi, P.
Affiliations
Leiden University (NL)
Corresponding author
Veldhuis, Johannes
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2016-02
Volume
101
Issue
2
Pages
539-549
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2015-3611
PMC
PMC4880122
OpenAlex
W2267707996
Semantic Scholar
af5283af6afa6e1da109f3fa5ee71e2765cbe5aa
Cited by
65
References
40
Citations by year
2026: 1 · 2025: 7 · 2024: 2 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 7 · 2019: 9 · 2018: 8 · 2017: 9 · 2016: 6
FWCI
8.74
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (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 on Aging (R01AG029362, R01AG019695)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK050456)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
interleukin-2, inflammatory cytokines, luteinizing hormone, testosterone secretion, male hypogonadism, aging, gonadotropin secretion, chronic systemic inflammation
MeSH terms
Aged, Aging, Dose-Response Relationship, Drug, Double-Blind Method, Humans, Interleukin-2, Luteinizing Hormone, Male, Middle Aged, Prospective Studies, Risk Factors, Testosterone, Cytokines, Cross-Over Studies, Feedback, Physiological, Young Adult

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 2026-10-10.

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

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