Loading…
Corticotropin Secretory Dynamics in Humans under Low Glucocorticoid Feedback
To explore the mechanisms of homeostatic adaptation of the hypothalamo-pituitary-adrenal axis to an experimental low-feedback condition, we quantitated pulsatile (ultradian), entropic (pattern-sensitive), and 24-h rhythmic (circadian) ACTH secretion during high-dose metyrapone blockade (2 g orally e...
Saved in:
Published in: | The journal of clinical endocrinology and metabolism 2001-11, Vol.86 (11), p.5554-5563 |
---|---|
Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
cited_by | cdi_FETCH-LOGICAL-c2426-9c635ee64ba824ddb2a449b8a313d46e529d781660e56e562b9c875670a9e9c03 |
---|---|
cites | cdi_FETCH-LOGICAL-c2426-9c635ee64ba824ddb2a449b8a313d46e529d781660e56e562b9c875670a9e9c03 |
container_end_page | 5563 |
container_issue | 11 |
container_start_page | 5554 |
container_title | The journal of clinical endocrinology and metabolism |
container_volume | 86 |
creator | Veldhuis, J. D. Iranmanesh, A. Naftolowitz, D. Tatham, N. Cassidy, F. Carroll, B. J. |
description | To explore the mechanisms of homeostatic adaptation of the
hypothalamo-pituitary-adrenal axis to an experimental low-feedback
condition, we quantitated pulsatile (ultradian), entropic
(pattern-sensitive), and 24-h rhythmic (circadian) ACTH secretion
during high-dose metyrapone blockade (2 g orally every 2 h for
12 h, and then 1 g every 2 h for 12 h). Plasma ACTH
and cortisol concentrations were sampled concurrently every 10 min for
24 h in nine adults. The metyrapone regimen reduced the amplitude
of nyctohemeral cortisol rhythm by 45% (P =
0.0013) and delayed the time of the cortisol maximum (acrophase) by
7.1 h (P = 0.0002). Attenuated cortisol
negative feedback stimulated a 7-fold increase in the mean (24-h)
plasma ACTH concentration, which rose from 24 ± 1.6 to 169±
31 pg/ml (ng/liter) (P < 0.0001). Augmented
ACTH output was driven by a 12-fold amplification of ACTH secretory
burst mass (integral of the underlying secretory pulse) (21 ± 3.1
to 255 ± 64 pg/ml; P < 0.0001), yielding a
higher percentage of ACTH secreted in pulses (53 ± 3.5
vs. 92 ± 1.3%; P < 0.0001).
There were minimal elevations in basal (nonpulsatile) ACTH secretion
(by 50%; P = 0.0049) and ACTH secretory burst
frequency (by 36%; P = 0.031). The estimated
half-life of ACTH (median, 22 min) and the calculated ACTH secretory
burst half-duration (pulse event duration at half-maximal amplitude)
(median, 23 min) did not change. Hypocortisolemia evoked remarkably
more orderly subordinate patterns of serial ACTH release, as
quantitated by the approximate entropy statistic (P=
0.003). This finding was explained by enhanced regularity of
successive ACTH secretory pulse mass values (P =
0.032). In contrast, there was no alteration in serial ACTH
interpulse-interval (waiting-time) regularity. At the level of 24-h
ACTH rhythmicity, cortisol withdrawal enhanced the daily rhythm in ACTH
secretory burst mass by 29-fold, elevated the mesor by 16-fold, and
delayed the acrophase by 3.4 h from 0831 h to 1154 h
(each P < 10−3).
In summary, short-term glucocorticoid feedback deprivation primarily
(>97% of effect) amplifies pulsatile ACTH secretory burst mass, while
minimally elevating basal/nonpulsatile ACTH secretion and ACTH pulse
frequency. Reduced cortisol feedback paradoxically elicits more orderly
(less entropic) patterns of ACTH release due to emergence of more
regular ACTH pulse mass sequences. Cortisol withdrawal concurrently
heightens the amplitude and mesor of 24-h rhythmic ACTH release and
delays |
doi_str_mv | 10.1210/jcem.86.11.8046 |
format | article |
fullrecord | <record><control><sourceid>endocrinepress_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1210_jcem_86_11_8046</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>10_1210_jcem_86_11_8046</sourcerecordid><originalsourceid>FETCH-LOGICAL-c2426-9c635ee64ba824ddb2a449b8a313d46e529d781660e56e562b9c875670a9e9c03</originalsourceid><addsrcrecordid>eNp1kMFKAzEURYMoWKtrt_mBmeZlMplkKdW2woALFdyFTPIKUztJSTpI_94pdevqcR-cy-UQ8gisBA5ssXM4lEqWAKViQl6RGWhRFw3o5prMGONQ6IZ_3ZK7nHeMgRB1NSPtMqZj7-IxxUMf6Du6hMeYTvT5FOzQu0yn72YcbMh0DB4TbeMPXe9HF92F7D1dIfrOuu97crO1-4wPf3dOPlcvH8tN0b6tX5dPbeG44LLQTlY1ohSdVVx433ErhO6UraDyQmLNtW8USMmwnpLknXaqqWXDrEbtWDUni0uvSzHnhFtzSP1g08kAM2cZ5izDKGkAzFnGRMgLgcFHl_qAh4Q5m10cU5im_gv-AmRxZdE</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Corticotropin Secretory Dynamics in Humans under Low Glucocorticoid Feedback</title><source>Oxford Journals Online</source><creator>Veldhuis, J. D. ; Iranmanesh, A. ; Naftolowitz, D. ; Tatham, N. ; Cassidy, F. ; Carroll, B. J.</creator><creatorcontrib>Veldhuis, J. D. ; Iranmanesh, A. ; Naftolowitz, D. ; Tatham, N. ; Cassidy, F. ; Carroll, B. J.</creatorcontrib><description>To explore the mechanisms of homeostatic adaptation of the
hypothalamo-pituitary-adrenal axis to an experimental low-feedback
condition, we quantitated pulsatile (ultradian), entropic
(pattern-sensitive), and 24-h rhythmic (circadian) ACTH secretion
during high-dose metyrapone blockade (2 g orally every 2 h for
12 h, and then 1 g every 2 h for 12 h). Plasma ACTH
and cortisol concentrations were sampled concurrently every 10 min for
24 h in nine adults. The metyrapone regimen reduced the amplitude
of nyctohemeral cortisol rhythm by 45% (P =
0.0013) and delayed the time of the cortisol maximum (acrophase) by
7.1 h (P = 0.0002). Attenuated cortisol
negative feedback stimulated a 7-fold increase in the mean (24-h)
plasma ACTH concentration, which rose from 24 ± 1.6 to 169±
31 pg/ml (ng/liter) (P < 0.0001). Augmented
ACTH output was driven by a 12-fold amplification of ACTH secretory
burst mass (integral of the underlying secretory pulse) (21 ± 3.1
to 255 ± 64 pg/ml; P < 0.0001), yielding a
higher percentage of ACTH secreted in pulses (53 ± 3.5
vs. 92 ± 1.3%; P < 0.0001).
There were minimal elevations in basal (nonpulsatile) ACTH secretion
(by 50%; P = 0.0049) and ACTH secretory burst
frequency (by 36%; P = 0.031). The estimated
half-life of ACTH (median, 22 min) and the calculated ACTH secretory
burst half-duration (pulse event duration at half-maximal amplitude)
(median, 23 min) did not change. Hypocortisolemia evoked remarkably
more orderly subordinate patterns of serial ACTH release, as
quantitated by the approximate entropy statistic (P=
0.003). This finding was explained by enhanced regularity of
successive ACTH secretory pulse mass values (P =
0.032). In contrast, there was no alteration in serial ACTH
interpulse-interval (waiting-time) regularity. At the level of 24-h
ACTH rhythmicity, cortisol withdrawal enhanced the daily rhythm in ACTH
secretory burst mass by 29-fold, elevated the mesor by 16-fold, and
delayed the acrophase by 3.4 h from 0831 h to 1154 h
(each P < 10−3).
In summary, short-term glucocorticoid feedback deprivation primarily
(>97% of effect) amplifies pulsatile ACTH secretory burst mass, while
minimally elevating basal/nonpulsatile ACTH secretion and ACTH pulse
frequency. Reduced cortisol feedback paradoxically elicits more orderly
(less entropic) patterns of ACTH release due to emergence of more
regular ACTH pulse mass sequences. Cortisol withdrawal concurrently
heightens the amplitude and mesor of 24-h rhythmic ACTH release and
delays the timing of the ACTH acrophase. In contrast, the duration of
underlying ACTH secretory episodes is not affected, which indicates
that normal pulse termination may be programmed centrally rather than
imposed by rapid negative feedback. Accordingly, we hypothesize that
adrenal glucocorticoid negative feedback controls
hypothalamo-pituitary-adrenal axis dynamics via the 3-fold distinct
mechanisms of repressing the mass of ACTH secretory bursts, reducing
the orderliness of the corticotrope release process, and modulating the
intrinsic diurnal rhythmicity of the hypothalamo-corticotrope
unit.</description><identifier>ISSN: 0021-972X</identifier><identifier>EISSN: 1945-7197</identifier><identifier>DOI: 10.1210/jcem.86.11.8046</identifier><language>eng</language><publisher>Endocrine Society</publisher><ispartof>The journal of clinical endocrinology and metabolism, 2001-11, Vol.86 (11), p.5554-5563</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2426-9c635ee64ba824ddb2a449b8a313d46e529d781660e56e562b9c875670a9e9c03</citedby><cites>FETCH-LOGICAL-c2426-9c635ee64ba824ddb2a449b8a313d46e529d781660e56e562b9c875670a9e9c03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Veldhuis, J. D.</creatorcontrib><creatorcontrib>Iranmanesh, A.</creatorcontrib><creatorcontrib>Naftolowitz, D.</creatorcontrib><creatorcontrib>Tatham, N.</creatorcontrib><creatorcontrib>Cassidy, F.</creatorcontrib><creatorcontrib>Carroll, B. J.</creatorcontrib><title>Corticotropin Secretory Dynamics in Humans under Low Glucocorticoid Feedback</title><title>The journal of clinical endocrinology and metabolism</title><description>To explore the mechanisms of homeostatic adaptation of the
hypothalamo-pituitary-adrenal axis to an experimental low-feedback
condition, we quantitated pulsatile (ultradian), entropic
(pattern-sensitive), and 24-h rhythmic (circadian) ACTH secretion
during high-dose metyrapone blockade (2 g orally every 2 h for
12 h, and then 1 g every 2 h for 12 h). Plasma ACTH
and cortisol concentrations were sampled concurrently every 10 min for
24 h in nine adults. The metyrapone regimen reduced the amplitude
of nyctohemeral cortisol rhythm by 45% (P =
0.0013) and delayed the time of the cortisol maximum (acrophase) by
7.1 h (P = 0.0002). Attenuated cortisol
negative feedback stimulated a 7-fold increase in the mean (24-h)
plasma ACTH concentration, which rose from 24 ± 1.6 to 169±
31 pg/ml (ng/liter) (P < 0.0001). Augmented
ACTH output was driven by a 12-fold amplification of ACTH secretory
burst mass (integral of the underlying secretory pulse) (21 ± 3.1
to 255 ± 64 pg/ml; P < 0.0001), yielding a
higher percentage of ACTH secreted in pulses (53 ± 3.5
vs. 92 ± 1.3%; P < 0.0001).
There were minimal elevations in basal (nonpulsatile) ACTH secretion
(by 50%; P = 0.0049) and ACTH secretory burst
frequency (by 36%; P = 0.031). The estimated
half-life of ACTH (median, 22 min) and the calculated ACTH secretory
burst half-duration (pulse event duration at half-maximal amplitude)
(median, 23 min) did not change. Hypocortisolemia evoked remarkably
more orderly subordinate patterns of serial ACTH release, as
quantitated by the approximate entropy statistic (P=
0.003). This finding was explained by enhanced regularity of
successive ACTH secretory pulse mass values (P =
0.032). In contrast, there was no alteration in serial ACTH
interpulse-interval (waiting-time) regularity. At the level of 24-h
ACTH rhythmicity, cortisol withdrawal enhanced the daily rhythm in ACTH
secretory burst mass by 29-fold, elevated the mesor by 16-fold, and
delayed the acrophase by 3.4 h from 0831 h to 1154 h
(each P < 10−3).
In summary, short-term glucocorticoid feedback deprivation primarily
(>97% of effect) amplifies pulsatile ACTH secretory burst mass, while
minimally elevating basal/nonpulsatile ACTH secretion and ACTH pulse
frequency. Reduced cortisol feedback paradoxically elicits more orderly
(less entropic) patterns of ACTH release due to emergence of more
regular ACTH pulse mass sequences. Cortisol withdrawal concurrently
heightens the amplitude and mesor of 24-h rhythmic ACTH release and
delays the timing of the ACTH acrophase. In contrast, the duration of
underlying ACTH secretory episodes is not affected, which indicates
that normal pulse termination may be programmed centrally rather than
imposed by rapid negative feedback. Accordingly, we hypothesize that
adrenal glucocorticoid negative feedback controls
hypothalamo-pituitary-adrenal axis dynamics via the 3-fold distinct
mechanisms of repressing the mass of ACTH secretory bursts, reducing
the orderliness of the corticotrope release process, and modulating the
intrinsic diurnal rhythmicity of the hypothalamo-corticotrope
unit.</description><issn>0021-972X</issn><issn>1945-7197</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><recordid>eNp1kMFKAzEURYMoWKtrt_mBmeZlMplkKdW2woALFdyFTPIKUztJSTpI_94pdevqcR-cy-UQ8gisBA5ssXM4lEqWAKViQl6RGWhRFw3o5prMGONQ6IZ_3ZK7nHeMgRB1NSPtMqZj7-IxxUMf6Du6hMeYTvT5FOzQu0yn72YcbMh0DB4TbeMPXe9HF92F7D1dIfrOuu97crO1-4wPf3dOPlcvH8tN0b6tX5dPbeG44LLQTlY1ohSdVVx433ErhO6UraDyQmLNtW8USMmwnpLknXaqqWXDrEbtWDUni0uvSzHnhFtzSP1g08kAM2cZ5izDKGkAzFnGRMgLgcFHl_qAh4Q5m10cU5im_gv-AmRxZdE</recordid><startdate>200111</startdate><enddate>200111</enddate><creator>Veldhuis, J. D.</creator><creator>Iranmanesh, A.</creator><creator>Naftolowitz, D.</creator><creator>Tatham, N.</creator><creator>Cassidy, F.</creator><creator>Carroll, B. J.</creator><general>Endocrine Society</general><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>200111</creationdate><title>Corticotropin Secretory Dynamics in Humans under Low Glucocorticoid Feedback</title><author>Veldhuis, J. D. ; Iranmanesh, A. ; Naftolowitz, D. ; Tatham, N. ; Cassidy, F. ; Carroll, B. J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2426-9c635ee64ba824ddb2a449b8a313d46e529d781660e56e562b9c875670a9e9c03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Veldhuis, J. D.</creatorcontrib><creatorcontrib>Iranmanesh, A.</creatorcontrib><creatorcontrib>Naftolowitz, D.</creatorcontrib><creatorcontrib>Tatham, N.</creatorcontrib><creatorcontrib>Cassidy, F.</creatorcontrib><creatorcontrib>Carroll, B. J.</creatorcontrib><collection>CrossRef</collection><jtitle>The journal of clinical endocrinology and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Veldhuis, J. D.</au><au>Iranmanesh, A.</au><au>Naftolowitz, D.</au><au>Tatham, N.</au><au>Cassidy, F.</au><au>Carroll, B. J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Corticotropin Secretory Dynamics in Humans under Low Glucocorticoid Feedback</atitle><jtitle>The journal of clinical endocrinology and metabolism</jtitle><date>2001-11</date><risdate>2001</risdate><volume>86</volume><issue>11</issue><spage>5554</spage><epage>5563</epage><pages>5554-5563</pages><issn>0021-972X</issn><eissn>1945-7197</eissn><abstract>To explore the mechanisms of homeostatic adaptation of the
hypothalamo-pituitary-adrenal axis to an experimental low-feedback
condition, we quantitated pulsatile (ultradian), entropic
(pattern-sensitive), and 24-h rhythmic (circadian) ACTH secretion
during high-dose metyrapone blockade (2 g orally every 2 h for
12 h, and then 1 g every 2 h for 12 h). Plasma ACTH
and cortisol concentrations were sampled concurrently every 10 min for
24 h in nine adults. The metyrapone regimen reduced the amplitude
of nyctohemeral cortisol rhythm by 45% (P =
0.0013) and delayed the time of the cortisol maximum (acrophase) by
7.1 h (P = 0.0002). Attenuated cortisol
negative feedback stimulated a 7-fold increase in the mean (24-h)
plasma ACTH concentration, which rose from 24 ± 1.6 to 169±
31 pg/ml (ng/liter) (P < 0.0001). Augmented
ACTH output was driven by a 12-fold amplification of ACTH secretory
burst mass (integral of the underlying secretory pulse) (21 ± 3.1
to 255 ± 64 pg/ml; P < 0.0001), yielding a
higher percentage of ACTH secreted in pulses (53 ± 3.5
vs. 92 ± 1.3%; P < 0.0001).
There were minimal elevations in basal (nonpulsatile) ACTH secretion
(by 50%; P = 0.0049) and ACTH secretory burst
frequency (by 36%; P = 0.031). The estimated
half-life of ACTH (median, 22 min) and the calculated ACTH secretory
burst half-duration (pulse event duration at half-maximal amplitude)
(median, 23 min) did not change. Hypocortisolemia evoked remarkably
more orderly subordinate patterns of serial ACTH release, as
quantitated by the approximate entropy statistic (P=
0.003). This finding was explained by enhanced regularity of
successive ACTH secretory pulse mass values (P =
0.032). In contrast, there was no alteration in serial ACTH
interpulse-interval (waiting-time) regularity. At the level of 24-h
ACTH rhythmicity, cortisol withdrawal enhanced the daily rhythm in ACTH
secretory burst mass by 29-fold, elevated the mesor by 16-fold, and
delayed the acrophase by 3.4 h from 0831 h to 1154 h
(each P < 10−3).
In summary, short-term glucocorticoid feedback deprivation primarily
(>97% of effect) amplifies pulsatile ACTH secretory burst mass, while
minimally elevating basal/nonpulsatile ACTH secretion and ACTH pulse
frequency. Reduced cortisol feedback paradoxically elicits more orderly
(less entropic) patterns of ACTH release due to emergence of more
regular ACTH pulse mass sequences. Cortisol withdrawal concurrently
heightens the amplitude and mesor of 24-h rhythmic ACTH release and
delays the timing of the ACTH acrophase. In contrast, the duration of
underlying ACTH secretory episodes is not affected, which indicates
that normal pulse termination may be programmed centrally rather than
imposed by rapid negative feedback. Accordingly, we hypothesize that
adrenal glucocorticoid negative feedback controls
hypothalamo-pituitary-adrenal axis dynamics via the 3-fold distinct
mechanisms of repressing the mass of ACTH secretory bursts, reducing
the orderliness of the corticotrope release process, and modulating the
intrinsic diurnal rhythmicity of the hypothalamo-corticotrope
unit.</abstract><pub>Endocrine Society</pub><doi>10.1210/jcem.86.11.8046</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0021-972X |
ispartof | The journal of clinical endocrinology and metabolism, 2001-11, Vol.86 (11), p.5554-5563 |
issn | 0021-972X 1945-7197 |
language | eng |
recordid | cdi_crossref_primary_10_1210_jcem_86_11_8046 |
source | Oxford Journals Online |
title | Corticotropin Secretory Dynamics in Humans under Low Glucocorticoid Feedback |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T19%3A16%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-endocrinepress_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Corticotropin%20Secretory%20Dynamics%20in%20Humans%20under%20Low%20Glucocorticoid%20Feedback&rft.jtitle=The%20journal%20of%20clinical%20endocrinology%20and%20metabolism&rft.au=Veldhuis,%20J.%20D.&rft.date=2001-11&rft.volume=86&rft.issue=11&rft.spage=5554&rft.epage=5563&rft.pages=5554-5563&rft.issn=0021-972X&rft.eissn=1945-7197&rft_id=info:doi/10.1210/jcem.86.11.8046&rft_dat=%3Cendocrinepress_cross%3E10_1210_jcem_86_11_8046%3C/endocrinepress_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c2426-9c635ee64ba824ddb2a449b8a313d46e529d781660e56e562b9c875670a9e9c03%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_id=info:pmid/&rfr_iscdi=true |