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Demographic Data of the Healthy Volunteers at the Baseline Visit
SAT-401 Estimation of Endogenous Heterotypic Peptidyl Stimulation of ACTH Secretion under an Exogenous Secretagogue Clamp Authors: Ferdinand Roelfsema 1 M.D., Ph.D., Paul Aoun 2 M.D. , Paul Takahashi, M.D.3; Rebecca J. Yang, R.N., B.S.N.4, Johannes D. Veldhuis, M.D.4 1 Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, The Netherlands, 2 Palm Beach Diabetes & Endocrine Specialists, West Palm Beach, FL, USA, 3 3Primary Care Internal Medicine, Mayo Clinic, 4Rochester, MN, USA, Endocrine Research Unit, Mayo Clinic, Rochester, MN. The authors have nothing to disclose. Funding: Supported in part via R01 DK (JDV) and P30 DK (Metabolic Studies Core of the Minnesota Obesity Center) from the National Institutes of Health (Bethesda MD) and by UL1 TR from the National Center for Advancing Translational Sciences . • Studies on ACTH secretion are hampered by unobservable hypothalamic CRH and AVP pulses. • Clamping of one of the secretagogues by an exogenous infusion of the same could allow indirect quantification of the impact of the endogenous heterotypic hormone. • The aim of the study was to explore the individual and joint contributions of AVP and CRH to pulsatile ACTH secretion under nominal pharmacologically imposed cortisol-feedback and sex-steroid clamps in men and women. Background Table 1 • ACTH secretagogue clamps yield continued pulsatile ACTH secretion, putatively driven by noninfused endogenous peptides. • Infusions of ACTH secretagogues induce higher ACTH secretory burst mass and randomness. • AVP infusion fails to sustain increased ACTH secretion, approaching saline infusion. • Combined infusion of CRH and AVP results in a temporary potentiation of ACTH secretion, leveling off after 2 hours. • After sustained CRH administration, bolus AVP injection induces marked ACTH release, much larger than CRH injection after AVP infusion. • Sex and sex-steroid addback in leuprolide-clamped older volunteers were not significant variables after taking into account the higher cortisol levels in women. Summary Table 2 Table 3 PPT Scientific Poster_4x6 Blue Template.ppt Demographic Data of the Healthy Volunteers at the Baseline Visit Women Men E2 (+) E2 (-) T (+) T (-) Number of volunteers 8 4 9 7 Age (yr) 59 ± 3.9 54 ± 2.8 56 ± 2.2 58 ± 4.0 BMI (kg/m2) 25.0 ± 1.0 24.3 ± 1.6 28.4 ± 0.6 26.7 ± 0.7 TSH (mU/L) 1.6 ± 0.4 3.8 ± 1.4 2.3 ± 0.5 2.5 ± 0.4 Estradiol (pg/mL) 104 ± 50 18.2 ± 5.9* 28.0 ± 3.4 29.8 ± 3.4 Testosterone (ng/dL) 21.0 ± 3.3 12.7 ± 1.4 408 ± 40 502 ± 76 Cortisol (µg/dL) 12.4 ± 1.1 11.5 ± 1.1 12.0 ± 0.8 13.6 ± 1.4 Estradiol after Leuprolide (pg/mL) 681 ± 190 12.9 ± 2.7 57 ± 4.2 2.7 ± 0.4 Testosterone after Leuprolide (ng/dl) 6.9 ± 0.8 6.7 ± 1.2 1670 ± 103 17.2 ± 5.1 SHBG (nmol/L) 76.9 ± 9.7 57.7 ± 9.2 24.4 ± 1.6 30.6 ± 6.9 Data are mean ± SEM. *: P : 0.01. ACTH and Cortisol Responses during Hormone Infusion and after Bolus Injection Deconvolution Analysis of the 10-hour ACTH Profiles Infusion CRH CRH&AVP AVP Saline GLM Contrasts Burst number 11.7±0.3 9.9±0.4 9.4±0.5 10.3±0.4 0.001 Slow half-life (min) 19.3±0.3 17.5±0.6 17.3±0.9 19.7±0.2 Burst mode (min) 11.3±1.0 13.5±0.8 10.6±0.9 10.7±1.0 0.08 Basal secretion (ng/L/10 h) 734±109 1243±124 363±42 279±49 0.11 Pulse secretion (ng/L/10 h) 1287±167 931±171 583±123 814±145 <0.0001 CRH>AVP,saline and CRH/AVP. AVP<saline and CRH/AVP. Total secretion (ng/L/10 h) 2021±186 2174±258 946±137 1093±157 CRH>AVP and saline CRH/AVP>AVP Mean burst mass (ng/L) 110±14 93±17 64±14 82±15 CRH>AVP AVP<CRH/AVP Bursting regularity 2.57±0.16 2.25±0.18 2.36±0.23 2.44±0.13 0.74 CRH CRH/AVP AVP Saline GLM P-values Mean 10 h ACTH ng/L Men 81.4 ± 9.8 3 63.2 ± 34.5 ± 7.5 2 40.3 ± 7.5 <0.001 Sex 0.88 Women 53.5 ± 5.0 3 78.4 ± 24.0 ± 5.0 2 31.3 ± 5.9 Sex steroidse:0.46 Mean 10 h cortisol µg/dL 10.3 ± 14.1 ± 8.6 ± 6.5 ± 0.34 Sex <0.001 12.9 ± 18.2 ± 10.6 ± 8.2 ± 0.36 Sex steroids 0.26 ApEn ACTH 10 h infusion 0.699±0.031A 0.789 ± 0.038A 0.789 ± 0.048A 0.545 ± 0.035B Sex:0.67, sex hormone: 0.55 Cross-ApEn cortisol→ACTH 1.020±0.058A 1.099±0.067A 0.947±0.058A 0.8781±0.070A 0.039 Sex:0.61, sex steroids 0.60 Burst mass ng/L After bolus 188±29A 835±18.4B 410±67C 177±30AC Sex 0.82, sex steroids 0.43 Mean ACTH ng/L 26.1±3.3A 86.2±16.8B 45.9±4.3AB 23.5±3.6A Sex:0.48,sex steroids 0.33 Δ ACTH ng/L 19.4±2.0A 124±19.9B 75.6±9.1C -42.8±7.4D Sex 0.12, sex steroids 0.50 _ • Study design: Prospective double-blind, placebo-controlled partial within-subject crossover study in 16 men and 12 women aged between yr. The outline of the study is illustrated in Fig 1. • Blood samples were obtained every 10 min during 14 h for measurement of ACTH and cortisol.. • The infused dose of CRH between and h was 1 µg/kg/h and that of AVP 10.5 IU/m2 (near maximal doses). Bolus injections at h in men: AVP 0.67 IU/m2, CRH 1 µg/kg, in women AVP 0.5 IU/m2 and CRH 0.67 µg/kg. Methods P-values: 1: vs Saline<0.001; 2:vs CRH and CRH/AVP <0.001;3: vs Saline <0.001; 4 vs Saline Different alphabetic superscripts denote P<0.05 by post hoc comparisons. Shared superscripts denote P>0.05. Data are mean ± SEM. Sex and sex hormone addback were not significant Figure 1 Figure 3 • 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. • This paradigm generates a framework for investigating AVP’s putative desensitization of CRH action , and CRH’s inferred potentiation of AVP action. • These interactions may explain unexpected effects of certain neuropsychiatric stressors, which release CRH and/or AVP. Conclusions Figure 2 ACTH and Cortisol Concentrations after Administration of CRH, AVP, AVP&CRH and Saline ______ ACTH and Cortisol Response after Bolus Injection of the Non-infused ACTH Secretagogue Analyses The upper panels show mean ACTH and cortisol concentrations during the complete 14-h blood sampling period. The interrupted vertical lines reflect the start of the ACTH secretagogue and the end of the continuous infusion and the bolus injection of the non-infused hormone. In the lower 2 panels the concentrations are averaged over six 2-h bins. Height of the bars indicates mean values with SEM. Statistical evaluation of ACTH responses were done with the GLM procedure with sex and sex steroid addback as variables, and mean cortisol concentration after the bolus injection with the ACTH secretagogue as covariate, because levels were higher in women (right upper panel). The lower right panel shows the ACTH Approximate Entropy (ApEn) during the 10 h infusion. ApEn measures the regularity of circulating hormone concentrations, and reflects the balance between forward drive and feedback. • Demographics are reported with means and SEM (Table 1). • General Linear Model (GLM) was used for the analyses of the ACTH deconvolution data of the 10-h infusion period, mean 10-h concentrations of ACTH and cortisol, that of the infusion period split into 2-h bins and hormone levels after the bolus injection of the ACTH secretagogues. P values less than were considered significant. Multiple comparisons were corrected with the Sidak procedure. • Approximate Entropy, a metric which quantitates the balance between feedforward and feedback strength, was applied to the 10-h ACTH profiles. High numbers reflect increased irregularity associated with diminished feedback. We thank Jill Smith for support of poster preparation and graphics; the Mayo Immunochemical Laboratory for assay assistance; and the Mayo research nursing staff for implementing the protocol. Supported in part via R01 DK073148, and P30 DK (Metabolic Studies Core of the Minnesota Obesity Center) from the National Institutes of Health (Bethesda, MD) and by UL1 TR from the National Center for Advancing Translational Sciences (NCATS). Acknowledgments
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