0021-972x/93/7606-1505$03.

00/0
Journal of Clinical Endocrinology and Metabolism Vol. 76, No. 6
Copyright C 1993 by The Endocrine Society Prtnted III U.S.A.

Estimation of Daily Cortisol Production and Clearance

Rates in Normal Pubertal Males by Deconvolution
Analysis*
JAMES R. KERRIGAN, JOHANNES D. VELDHUIS, SANDRA A. LEYO,
AL1 IRANMANESH, AND ALAN D. ROGOL
Departments of Pediatrics (J.R.K., S.A.L., A.D.R.), Internal Medicine (J.D.V.), and Pharmacology (A.D.R.),
NSF Science and Technology Center for Biological Timing (J.R.K., J.D. V., A.D.R.), University of Virginia
Health Sciences Center, Charlottesville, Virginia 22908; and Endocrine Section (AI.), Salem Veterans
Medical Center, Salem, Virginia 24153

ABSTRACT tion, and serum cortisol half-life. A significant diurnal pattern of

To investigate daily cortisol production and clearance rates in a cortisol secretion was observed for all subjects manifest by nyctohem-
group (n = 18) of normal unstressed pubertal males, we applied decon- era1 variations in the frequency of adrenocortical secretory bursts, the
volution analysis to serum cortisol concentrations obtained every 20 amplitude (maximal rate of cortisol secretion) and the mass of cortisol
min for 24 h. Subject-specific characterization of adrenocortical secre- released per secretory episode. Maximum serum hormone concentra-
tory episodes, cortisol production rate, and serum hormone half-life for tions occurred between 0706 and 1114 h.
nine early pubertal (Tanner I or II; early) and nine late pubertal We conclude that in normal pubertal males 1) cortisol production
(Tanner IV or V; late) subjects was undertaken to assess potential roles rates as estimated by deconvolution analysis are in agreement with
of sexual maturation and changing gonadal steroid hormone concen- other recent independent isotopic estimates, but are lower than many
trations on glucocorticoid physiology. previous estimates; 2) the rise in serum gonadal steroid hormone levels
The estimated cortisol production rate for the early group [ 16.8 f is unassociated with alterations in the production rate or metabolic
1.3 kmol/m*.day (6.1 f 0.4 mg/m’. day)] was indistinguishable from clearance of cortisol; and 3) increased secretory burst frequency, in-
that of the late subjects [14.8 f 1.4 Fmol/m’. day (5.3 + 0.5 mg/m’. creased amplitude (maximal rate of cortisol secretion attained within
day)]. No differences were observed between the two pubertal groups each secretory event), and increased mass of cortisol released per
in the secretory burst frequency and half-duration, mass of cortisol adrenocortical secretory episode give rise to the normal diurnal rhythm
released per secretory episode, average maximal rate of hormone secre- of circulating cortisol. (J Clin Endocrinol Metab 76: 1505-1510, 1993)

T HE RECENT application of several novel methodologies

has resulted in better understanding
lamic-pituitary-adrenal gland (HPA) physiology.
of normal hypotha-
Stable iso-
tisol secretion rates.
Deconvolution
mathematical
analysis,
technique
or convolution
that has been utilized
modeling, is a
recently to
tope infusion combined with chromatographic/mass spectro- characterize the secretory events accompanying hormone
metric detection has permitted the accurate determination of release and the elimination rates which describe the meta-
daily cortisol production rates in children (1, 2) and adults bolic clearance of circulating hormone (8). Thus, this quan-
(3). These newly obtained estimates are markedly lower than titative tool provides an independent method by which hor-
previous determinations (4-6). Although stable isotope in- mone production rates can be determined. The application
fusion methods are not influenced by many of the inherent of this technique to the study of normal HPA physiology in
errors of previously used techniques (2, 7), some uncertainty the adult has advanced the understanding of the amplitude-
modulation and frequency changes, which characterize cir-
in the accuracy of detection may result from the episodic
cadian ACTH and glucocorticoid secretion (9, 10). Although
nature of cortisol secretion and the consequent failure to
these investigations have described the episodic and diurnal
attain true steady state conditions. Hence, assessment of
patterns of cortisol release in adults, limited data are available
cortisol production rates by independent methods is both
describing the mechanisms by which ultradian and nycto-
desirable and necessary before acceptance of the lower cor-
hemeral rhythms of adrenocortical gland secretion contribute
Received September 8, 1992. to the varying patterns of cortisol concentrations in children
Address all correspondence and requests for reprints to: James R. (11).
Kerrigan, M.D., Division of Pediatric Endocrinology, MR-4 Building/ Dynamic neuroendocrine processes occur during normal
Room 3037, Box 3, University of Virginia Health Sciences Center, human pubertal development. In particular, the secretion of
Charlottesville, Virginia 22908.
GH is markedly augmented during the later stages of puber-
*Presented in part at the Joint Meeting of the American Pediatric
Society and the Society for Pediatric Research, Baltimore, MD, May 7, tal development in both male (12) and female subjects (13),
1992. This work was supported in part by NIH Grant RR-00847 to the times when gonadal steroid hormone levels are dramatically
General Clinical Research Center of the University of Virginia, Clinical increased. The impact of sexual maturation and the associ-
Investigator Award HD-00926 (to J.R.K.), NIH RCDA lK04 HD 00634
ated rises in gonadal steroid hormones on HPA physiology,
(J.D.V.), NIH-supported Clinfo Data Reduction Systems, and the NSF
Science and Technology Center for Biological Timing (to J.R.K., J.D.V., however, has not been studied in detail. Although, in general,
S.A.L., A.D.R.), and Veterans Affairs Medical Research Fund (to A.I.). previous studies have concluded that gender- or age-associ-

1505

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1506 KERRIGAN ET AL. JCE8zM.1993
Vol76.No6

ated changes in cortisol production may be minimal (1, 5, Statistical analysis

11, 14-16), gender-related differences in HPA physiology Differences were assessed using Student’s paired t test. Mathematical
have been observed (17). No such studies, however, have relationships were appraised using linear regression analysis. The results
characterized precisely adrenocortical gland secretory epi- are presented as mean + SEM (except as noted). Statistical significance
was accepted at a P value less than 0.05.
sodesor rates of glucocorticoid elimination during the course
of puberty.
To estimate daily cortisol production and elimination rates Results
in healthy pubertal males, we have applied deconvolution
analysis to the 24-h cortisol concentration us. time series.In Clinical and biochemical parameters of study subjects
addition, we have assessedpotential puberty-related altera- The clinical characteristics of the 18 study subjects are
tions in glucocorticoid secretion and elimination and have summarized in Table 1. The average serum testosteronelevel
characterized the mechanisms by which varying adrenal was significantly greater (P = 0.0001) in the late group (23
gland secretory activity subserves the day-night rhythm of + 1.4 nmol/L) compared to the early subjects (5.1 + 1.8
cortisol release. nmol/L). Average 24-h cortisol concentrations did not differ
between the study groups, 182 + 12 vs. 188 + 14 nmol/L,
early Vs. late, respectively.
Subjects and Methods
Subjects Cortisol production and elimination rates
Eighteen healthy males were enrolled into the study after provision Representative graphs obtained by deconvolution analysis
of written informed consent by the parents and assent by the subjects. of the cortisol concentrations us. time seriesare illustrated in
The Human Investigation Committee at the University of Virginia ap-
proved the study protocol. Nine subjects (early) were of Tanner I or II Fig. 1. The results of deconvolution analysis are summarized
genital development and nine (late) were of Tanner IV or V development in Table 2.
(18). All had normal growth parameters, no known medical illnesses or Despite the differences in chronological age, sexual devel-
endocrine dysfunction, and were not receiving medications; body mass opment, and serum gonadal steroid hormone concentrations
indices were within 2 SD of age-related normal values (19). Auxologic (vide supra), no apparent differences in cortisol secretion or
measurements were normalized according to the data of Tanner and
Davies (20) and skeletal maturation and standard deviation score were
in serum cortisol half-life were observed between the early
determined according to the method of Tanner et al. (21). and late pubertal males. Detectable episodesof cortisol se-
cretion occurred with an overall average daily frequency of
12.5 f 0.6 pulses.
study protocol
When expressed as the massof cortisol produced per unit
The subjects were admitted to the General Clinical Research Center body surface area, similar total daily cortisol production rates
at the University of Virginia for two consecutive nights. Following a of 16.8 + 1.3 (6.1 + 0.5) and 14.8 + 1.4 pmol/m*.day (5.4
night of acclimatization, an indwelling venous catheter was inserted + 0.5 mg/m* . day) were obtained for the early and late males,
between 0500 and 0600 h followed by acquisition of venous blood
samples every 20 min beginning at 0800 h and continuing until 2000 h; respectively. Combined data revealed an average total daily
blood samples were then obtained every 10 min through 0800 h on day cortisol production rate for normal pubertal male subjects of
3. Urine samples for measurement of 24-h steroid metabolite excretion 15.8 + 0.9 pmol/m*.day (5.7 + 0.3 mg/m*.day).
were obtained beginning on day 2. The subjects were allowed normal
ambulatory activity and received meals at 0900, 1200, and 1730 h; a Relationship of cortisol production to urinary steroid hormone
caffeine-free snack was provided at 2100 h. Subjects were required to
be in bed with the room lights turned out from 2300-0600 h. excretion
As shown in Fig. 2, a significant positive correlation was
Assays observed between 24-h cortisol production and daily urinary
Serum cortisol concentrations were measured by RIA (Dade, Baxter- 17-hydroxycorticosteroid excretion (r = +0.68, P = 0.01).
Travenol Diagnostics, Inc. Cambridge, MA) as described previously (10,
TABLE 1. Clinical and biochemical characteristics of the normal
22). Urinary-free cortisol and 17.hydroxycorticosteroids were assayed male subjects
by the Nichols Institute (San Juan Capistrano, CA) using high perform
ante liquid chromatography and the Porter-Silber method, respectively. Early Late

Age (yr) 11.6 f 0.4 14.0 * 0.2*

Deconvolution analysis (9.9-13.0) (13.0-15.0)
Skeletal age (yr) 12.4 + 0.3 14.2 ? 0.2,
Deconvolution analysis is a mathematical technique that, when ap-
(10.2-13.2) (13.2 k 15.0)
plied to hormone concentration vs. time series, estimates subject-specific
BMI-SDS 0.2 + 0.2 0.4 + 0.3
measures of hormone production and clearance functions (8). Total daily
(-1.4-1.1) (-1.2-1.4)
production rates were derived as the sum of any determinable basal
Testosterone (nmol/L) 5.1 + 1.8 22.9 r 1.4’
secretion and the pulsatile secretion (determined as the product of
secretory burst frequency and the mass of cortisol released per secretory (<0.7-14.8) (16.5-28.2)
event). A distribution volume of 5.3 L/m* body surface area, as deter- Mean 24-h serum cortisol 182 * 12 188 * 14
mined for normal children, was used in the calculation of daily cortisol concentration (nmol/L) (110-228) (141-257)
production rates (23). The data are represented as mean + SEM; numbers in parentheses
denote the respective range of values. An asterisk (*) signifies that the
value differs significantly (P 5 0.0001) from the corresponding early
Circadian rhythmicity
value. BMI SDS, Body mass index-standard deviation score. Testos-
Diurnal rhythms of cortisol concentrations and secretory characteris- terone concentrations were measured in serum samples obtained at
tics were appraised using cosinor analysis as described previously (10). 0600 h on day 2 of the study.

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 DAILY CORTISOL PRODUCTION IN PUBERTAL MALES 1507

FIG. 1. Serum cortisol concentrations

and calculated cortisol secretory rates in
a representative subject in each of the
experimental groups, one subject in early
(two graphs on the left) and one in late
(two graphs on the right) puberty. The
vertical axes for both graphs in a given
row have identical ranges of values. The
upper panels depict the reconvolution-
fitted curves and the measured cortisol
concentration data points (shown as 30
open boxes with vertical error bars rep- Late
resenting the intra-sample SD); the de-
convolution-derived curves closely ap-
proximate the experimental data points.
The bottom panels illustrate the distinct
cortisol secretory bursts as estimated by
deconvolution analysis and are repre-
sented as secretory rate vs. time. The
small amount of basal secretion (lo-15%
of total) is not shown. 0800 08Ocl

Clock time
TABLE 2. Deconvolution analysis of cortisol secretion and
clearance as a function of pubertal stage in normal males
Early Late 30
R-O&C
Secretory burst half-duration, min” 17.9 + 4.2 22.7 + 4.3 P - 0.01
Secretory burst frequency, events/24 h 12.3 + 0.7 12.7 f 0.5 !s
Interpulse interval, min 122 + 7.7 116 + 4.9 =;: lo-
Mass of cortisol released per burst, 228 + 28 203 f 15
nmol/L WdL,)* (8.2 f 1.0) (7.4 + 0.6)
..
Amplitude of secretory bursts, 19.5 f 5.5 12.7 + 4.1
nmol/LJmin (pg/dL,. min)’ (0.71 + 0.20) (0.46 -+ 0.15)
Pulsatile cortisol production rate, 14.3 + 1.2 13.5 f 1.1 l *
pmol/m*. day (mg/m*. day) (5.2 + 0.4) (4.9 + 0.4)
Basal cortisol production rate, 2.6 f 0.5 1.4 + 0.4 0
rmol/m*. day (mg/m*. day) y; ; ;.;7) (0.50 + 0.14) 0 10 %3Bcs 30 40
Total cortisol production rate, 14.8 + 1.4 urinary
rmol/m’.day (mg/m’.day) (6:l + 0:5) (5.4 + 0.5) (wwc --my)
Cortisol half-life, min 59.0 -c 3.1 67.4 + 3.1
The data are represented as mean + SEM. No significant differences
were detected between the groups. 30
a Half-duration denotes the duration (min) of the secretory event at R - 0.43
half-maximal amplitude. P - 0.11
* L,, distribution volume. Numbers in parentheses represent values
in metric units of measurement.
c Amplitude of the secretory burst is the maximal rate of hormone
secretion attained within the event.

Circadian rhythms
Graphical representations of the 24-h variation in serum 0’
cortisol levels are illustrated in Fig. 3. The numerical data are 0 150
iEnaryh&Y
summarized in Table 3. Contributing to the diurnal variation
of cortisol concentrations were demonstrable day-night
FIG. 2. Linear regression analyses of 24-h cortisol production rates (as
rhythms of secretory burst frequency (an inverse function of estimated by deconvolution analysis) and urinary adrenal steroid hor-
interburst interval), amplitude (maximal rate of hormone mone excretion. The top panel illustrates a positive relationship be-
secretion attained within a secretory episode), and the mass tween estimated daily cortisol production rates and 24-h urinary 17-
of cortisol released per secretory burst as shown in Fig. 4. hydroxycorticosteroid (17-OHCS) excretion (normalized to urinary
creatinine). As illustrated in the bottom panel, estimated total daily
No differences were detected between the two study groups cortisol production rate does not correlate with urinary free-cortisol
in any characteristic of the diurnal rhythm of serum cortisol excretion.
levels and glucocorticoid secretion.

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1508 KERRIGAN ET AL. JCE.SM.1993
Vol76.No6

600
.
Mcror: 128 (113 142)
Amplitude: 69 (47 - 90) .
Acropbase: 2149 (2045 - 2252) . *
-. -
n .

. Amplitude:
Acrophase:
8.0 (3.6 - 12.4)
0655 (0447 0912)
. ma-

600
m

_i;
Acrophase: 0659 (0534 - 0824)

200

0
0800 2000 0800
2000
Clock time
FIG. 3. Representative graphs illustrating the 24-h variation in fre- Clock time
quently sampled serum cortisol concentrations. Cosinor analysis was FIG. 4. Diurnal rhythms of specific secretory characteristics of cortisol
utilized to appraise the presence and magnitude of day-night variations. for the combined study groups. Upper panels depict cortisol interburst
Data obtained from cosinor analysis are summarized in Table 3. interval US. time curves; the middle panels represent the amplitude, or
maximal rate of cortisol secretion attained in each burst; and the
TABLE 3. Diurnal rhythm of serum cortisol concentrations in bottom panels represent the mass of cortisol released per secretory
normal pubertal males episode as a function of clocktime. Cosinor analysis was employed to
assess diurnal rhythms (see Table 3 legend for definitions). Cortisol
Acrophase (h)” Mesor (nm~l/L)~ Amplitude (nmol/L) interburst interval is the reciprocal of secretory burst frequency. As
0910 184 + 9 122 + 5 such, diurnal rhythms of interburst interval are indicative of reciprocal
(0706-1114) changes in the frequency of cortisol secretory episodes.

“Acrophase, the time during 24 h at which the value is maximal;

numbers in parentheses represent the 95% confidence intervals. strated an effect of gender on HPA physiology. Although a
bMesor, average value (mean + SEM) about which the diurnal diurnal pattern of ACTH releasewas observed for both adult
rhythm oscillates. males and females, several notable differences were found.
c Amplitude, half the absolute difference (mean f SEM) between the More frequent ACTH pulses of greater amplitude were ob-
nadir and peak value. served throughout 24 h in the men. This physiological alter-
ation resulted in a greater average plasma concentration of
Discussion
ACTH. Taken together, these data raise the possibility that
The impact of physical maturation and sex steroid hor- alterations in HPA physiology occur with sexual develop-
mones on cortisol secretion have been investigated in a ment and the associatedrisesin sex steroid hormone levels.
limited number of studies. In general, investigators have With the exception of an investigation by Wallace et al. (ll),
reported no significant effect of age, gender, or sexual mat- none have studied the pulsatile nature of circulating cortisol
uration on HPA activity (1, 5, 11, 14-16) after the neonatal concentrations in children. Moreover, none of these investi-
period. When uncorrected for body size (surface area), how- gations have characterized the nature of cortisol secretory
ever, cortisol production rates do increase with physical episodes and the concomitantly acting processof metabolic
growth and maturation (15, 24). This observation suggestsa clearance. Therefore, here we employed deconvolution
potential interaction of physical size and adrenocortical gland analysis to assesspotential specific changesin cortisol secre-
secretory activity. Horrocks et al. (17), however, demon- tion and elimination in a group of 18 healthy malesat various

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 DAILY CORTISOL PRODUCTION IN PUBERTAL MALES 1509

stagesof sexual maturity. CRH and ACTH, as well as possibly varying adrenal respon-
A pulsatile pattern of circulating cortisol was observed in siveness to ACTH (36, 37), may then result in diurnally
our pubertal-aged male subjects. Underlying this ultradian altered cortisol secretory burst frequency and/or amplitude.
rhythm of glucocorticoid concentrations were multiple, dis- Recently, Veldhuis et al. (9) have demonstrated that nycto-
crete episodesof adrenocortical gland secretory activity. On hemeral rhythms of ACTH secretory burst amplitude, but
average, 12 cortisol secretory events were observed through- not secretory burst frequency, underly the day-night changes
out the 24-h period of observation. This estimate of cortisol in ACTH concentrations in men. Presumably these diurnal
secretory burst frequency agreeswell with that reported for alterations in ACTH secretion result from parallel changesin
normal adult males using the same methodology (22). Esti- endogenous CRH action (38). Independent oscillator systems
mates of secretory burst frequency are dependent on the have alsobeen associatedwith adrenocortical gland secretion
sampling interval and greater values may be obtained with (36, 37, 39, 40). Thus, the interplay of any, or all of these
more intensive sampling paradigms (25, 26). No effects of complex physiological rhythms may give rise to 24-h varia-
sexual development or the increased levels of serum testos- tion in adrenocortical secretory patterns.
terone on episodic cortisol secretion, total daily production In summary, a burst-like mode of cortisol secretion, with-
rates, or the metabolic degradation of the glucocorticoid were out demonstrable variation in serum hormone half-life, gives
demonstrable in our subjects. rise to episodic and nyctohemeral oscillations of circulating
The average daily cortisol production rate of 15.8 + 0.9 cortisol in the pubertal male. Sexual maturation and the
pmol/m*.day (5.7 + 0.3 mg/m2.day) is in close agreement associatedrises in gonadal steroid hormone levels have no
with independently derived values obtained recently in chil- evident effect on glucocorticoid secretion and elimination.
dren (1) and adults (3). This estimate is, however, markedly Total daily cortisol production rates as estimated by decon-
lower than earlier estimates of 12-15 mg/m2.day (5, 6, 24). volution analysis agree with results obtained recently using
These earlier investigations generally employed infusion of independent methodology, but are appreciably lower than
radioactive cortisol and measurement of radiolabeled adrenal previous measurements. These newly obtained estimates
steroid metabolites in the urine. Inability to recover all voided provide an additional basis upon which revised glucocorti-
urine and the variable nature of cortisol metabolism are coid replacement dosageregimens in children can be based.
inherent limitations in such techniques and may lead to Although some recent pediatric references suggest lower
overestimation of cortisol production (7, 27). replacement doses(41,42), others (43,44) recommend higher
Deconvolution analysis is an alternative technique that dosage regimens based on earlier estimates of cortisol pro-
appraisestonic and episodic endogenous hormone secretion duction. Excessive glucocorticoid administration during
simultaneously with metabolic clearance. Consequently, es- childhood manifests primarily as poor growth and dimin-
timation of hormone production rates by this technique does ished ultimate height (45-47). Consequently, the prescription
not require steady state conditions. In this methodology, we of appropriate amounts of glucocorticoid for children is
inferred that approximately 10-15s of total daily cortisol critical.
production could result from tonic glucocorticoid release,
whereas the majority (85-90s) was pulsatile. Basallevels of Acknowledgments
adrenocortical gland secretion have been suggested previ- We are grateful to Susan Lorek Fitzgerald for the preparation of this
ously by some (7, 22, 28), but not other (29) investigators. manuscript and to Sandra Jackson and the expert nursing staff at the
Basedon observations of varying ACTH responsivenessto University of Virginia General Clinical Research Center for their assist-
inhibitory and stimulatory factors, coexistent tonic and pul- ance with the research protocol. We kindly acknowledge the cooperation
of Nichols Institute in the measurements of urinary metabolites.
satile modesof adrenal gland secretion have been postulated
(30). Episodic glucocorticoid secretion is likely the result of
action by pulsatile ACTH secretion (9, 11, 17, 31). References
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1510 KERRIGAN ET AL. JCE & M. 1993
Vol76.No6

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