Endogenous Cortisol and Lung Damage in a

Predominantly Smoking Population

KIMBERLEY D. CLARK, NIGEL WARDROBE-WONG, and PHILLIP D. SNASHALL
Department of Medicine, School of Clinical Medical Sciences, University of Newcastle upon Tyne; and Departments of
Cardio-respiratory Medicine and Radiology, North Tees General Hospital, Stockton on Tees, Cleveland, United Kingdom

We examined the association of endogenous corticosteroid status with lung structure and function in
a cross-sectional and longitudinal study in response to a recent finding of a relationship between
plasma cortisol and rate of annual decline in airway function. We recruited 74 cigarette-smoking and
20 never-smoking volunteers 35 to 65 yr of age after publicity in local media. Exclusion criteria were
FEV1 , 1.5 L or a history of airway disease. We performed spirometry and a high resolution CT lung
scan and measured CO transfer, serum cortisol, and 24-h urinary cortisol excretion. There were no
differences in serum or urinary cortisol between those with and those without low FEV1, low KCO, or
high resolution CT (HRCT) emphysema, except that urinary cortisol was 19% higher in subjects with
HRCT emphysema (p 5 0.05). Log urinary cortisol/body weight was negatively correlated with KCO
(p 5 0.000) and KCO was lower in the highest tertile of urinary cortisol (p 5 0.001). Subjects were re-
studied after 520 6 69 d. Changes in FEV1 and KCO showed no significant correlations with serum or
urinary cortisol. We conclude that airway function does not relate to serum or urinary cortisol, but
there may be a relationship between cortisol excretion and emphysema. Clark KD, Wardrobe-
Wong N, Snashall PD. Endogenous cortisol and lung damage in a predominantly smoking
population. AM J RESPIR CRIT CARE MED 1999;159:755–759.

An analysis of longitudinal data from the Normative Aging METHODS

Study showed an inverse relationship between rate of decline
of FEV1 and plasma cortisol concentration in smoking, ex-
smoking, and nonsmoking men (1). In men in the lower third
of the cortisol range the rate of decline of FEV1 was on aver-
age eight times greater than in those in the upper third, but de-
spite this striking difference baseline FEV1 did not differ sig-
nificantly between cortisol tertiles.
Therapeutic doses of systemically administered corticoste-
riods may stabilize airway function in COPD (2), perhaps by
suppressing inflammatory changes that lead to damage (3),
but studies of basal plasma cortisol in COPD have shown no
significant differences from normal (4–7).
We have reexamined the association between endogenous
corticosteroid status and lung disease in a cross-sectional and
longitudinal study of a predominantly smoking population of
both sexes, excluding subjects with known obstructive lung
disease. We have looked at the relationship of aspects of lung
structure and function to serum cortisol concentration and uri-
nary cortisol excretion.
(Received in original form September 22, 1997 and in revised form August 31, 1998)
Supported in part by a grant from the Northern & Yorkshire Region NHS Execu-
tive.
Correspondence and requests for reprints should be addressed to Professor P. D.
Snashall, Department of Medicine, North Tees General Hospital, Stockton on
Tees, Cleveland TS19 8PE, UK.
Am J Respir Crit Care Med Vol 159. pp 755–759, 1999
Internet address: www.atsjournals.org
Subjects
Seventy-four current cigarette smokers (5 or more cigarettes/d) aged
35 to 65 yr of age (mean age, 51.3 6 7.5 yr; M 38, F 36) and 20 lifetime
nonsmoking control subjects (mean age, 50.7 6 8.1 yr; M 7, F 13) were
recruited after publicity in local media. All subjects were white. Ex-
clusion criteria were a FEV1 , 1.5 L, history of asthma, bronchodila-
tor or corticosteroid medication, and use of other tobacco products.
The study was approved by the North Tees Local Research Ethics
Committee. Subjects were recruited after reading a description of the
study and possible risks. Consent was written. Subjects were informed
of their results and encouraged to stop smoking.
Lung Function
Forced spirometry and CO transfer were measured seated using auto-
mated apparatus (Model TTUSA; PK Morgan, Chatham, Kent, UK).
Expiratory flow-volume curves were recorded from a computerized
dry rolling-seal spirometer. The forced expiratory maneuver was re-
peated until duplicate estimates of FVC and FEV1 were within 5% of
each other; we accepted the highest value. CO transfer was measured
by the single-breath method (8) using a 9-s breathhold time. Duplicate
measurements were accepted where estimates of TLCO and effective
alveolar volume (VA) were within 5%; CO transfer coefficient (KCO)
was derived (5 TLCO/VA). Hemoglobin was measured, and in all cases
was within the normal range.
Predicted lung function values used were from Roberts and col-
leagues (9) based on a similar white, urban, nonsmoking population.
Lung Structure
High resolution CT (HRCT) scanning was performed using an IGE
Sytec 3000i CT scanner. Three 1-mm cuts from the upper, middle, and
lower zones of the right lung were taken at TLC. Images were ana-
756 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 159 1999

TABLE 1 ear regression were used to examine the relationships of lung functional
CHARACTERISTICS OF THE CROSS-SECTIONAL STUDY SAMPLE* and structural variables to cortisol. A p value , 0.05 was accepted as
significant. In line with this, for the lower limit of normality of FEV1
Characteristic Smokers Nonsmokers p Value Total Group and KCO, we adopted (mean, 1.645 SD). Values below this will occur
by chance on 5% of occasions in a normal population (9).
Number 74 20 — 94
Age, yr 51.3 (7.5) 50.7 (8.11) 0.76 51.2 (7.58)
Serum cortisol, nmol/ml 371.7 (87.6) 337.7 (69.3) 0.11 364.5 (84.9) RESULTS
Urinary cortisol, nmol/24 h 170.4 (61.4) 191.6 (45.7) 0.17 175.1 (58.7)
Cross-Sectional Study
FEV1, L 3.01 (0.87) 3.43 (0.63) 0.05 3.1 (0.84)
FVC, L 4.0 (0.98) 4.18 (0.87) 0.46 4.04 (0.96) Lung function and HRCT findings. The lung function vari-
KCO, kPa/s 1.41 (0.28) 1.63 (0.27) 0.01 1.46 (0.30) ables FEV1 and KCO were significantly reduced in the smoking
FEV1, % pred 93.9 (15.1) 108.2 (10.8) 0.00 97.0 (15.4) group (Table 1). In 10 smokers FEV1 was abnormally low, one
FVC, % pred 96.8 (10.6) 101.9 (10.3) 0.06 97.9 (10.7)
of whom also had a low KCO; KCO was low in a further nine
KCO, % pred 86.8 (17.7) 100.4 (16.8) 0.01 89.9 (18.3)
smokers. HRCT scanning demonstrated mild emphysema (in-
* Values in parentheses are standard deviations. The p values are for the differences volving , 25% of the lung parenchyma) in 18 smokers, severe
between smoking and nonsmoking groups.
emphysema (involving . 75% of parenchyma) in one. Six em-
physematous smokers had a low KCO. Lung function and
structure was normal in the nonsmoking volunteers.
Effect of smoking on cortisol. Mean serum cortisol, ad-
lyzed independently by two radiologists using the criteria of Remy- justed for age and sex, and urinary cortisol, adjusted for age,
Jardin and colleagues (10). sex, and body weight did not differ significantly between
smoking and nonsmoking subjects (Table 1).
Serum Cortisol
Cortisol levels with lung damage. There were no significant
Measurements of serum cortisol were made (three measurements in differences in adjusted serum cortisol concentration between
70, two in 15, and one in nine) on separate days. Subjects attended the subjects with and without low FEV1, low KCO or HRCT em-
laboratory between 8:15 and 9:00 A.M. after an overnight fast and an
abstinence from smoking of at least 8 h. Subjects lay supine for 30 min
physema (Table 2). Serum cortisol tended to be higher in sub-
before venepuncture. Blood samples were centrifuged immediately, jects with a low FEV1 (p 5 0.09). Adjusted urinary cortisol
and serum was frozen at 2208 C until determination of cortisol con- was 19% higher in subjects with HRCT emphysema (p 5
centration. Serum cortisol was measured by enzyme-immunological 0.05); otherwise there were no significant differences of uri-
assay using a Boehringer Mannheim ES 300 immunoassay analyser nary cortisol between groups, but there were tendencies for
(Boehringer Mannheim Immunodiagnostics, Lewes, Sussex, UK). urinary cortisol to be higher in subjects with low KCO (p 5
0.09). The mean coefficient of variation of repeat serum corti-
24-Hour Urinary Cortisol sol measurements was 12.8%.
Eighty-six subjects (19 nonsmokers, 67 smokers) successfully col- Correlations of cortisol with FEV1 and KCO. In multiple lin-
lected their urine for 24 h. Urinary volume was measured and the con- ear regression (with age, sex, and smoking status) log urinary
centration of cortisol ascertained by means of a cortisol-125I radioim- cortisol/body weight showed a significant negative correlation
munoassay (Orion Diagnostica, Espoo, Finland).
with KCO (p 5 0.000) (Table 3). The correlation was similarly
Longitudinal Study significant with urinary cortisol and log urinary cortisol. Oth-
erwise neither lung function variable showed any significant
Fifty-seven subjects (M/F 5 26⁄31; 39 smokers, 18 nonsmokers) at-
tended for repeat measurement of lung function after a mean interval relationship to serum or urinary cortisol.
of 520 6 69 d. FEV1 and KCO by tertile of serum and urinary cortisol.
There were no significant differences in lung function between
Statistics tertiles of serum cortisol (Table 4). However, a significant dif-
The data were analyzed using a statistical package (SPSS Inc., Chi- ference was seen in KCO between tertiles of urinary cortisol/
cago, IL). Unadjusted data from smokers and nonsmokers were com- body weight, KCO being 21% lower in the highest tertile than
pared using an unpaired t test. Analysis of covariance and multiple lin- in the lowest.

TABLE 2
ADJUSTED MEAN SERUM* AND URINARY† CORTISOL CONCENTRATION BY CIGARETTE
SMOKING STATUS, WITH AND WITHOUT LUNG DAMAGE

Serum Cortisol Urinary Cortisol

(nmol/ml) (nmol/24 h)

Smoking Subjects Subjects

Status (n) Mean SE p Value (n) Mean SE p Value

Nonsmoker 74 336 15.5 67 195 10.5

0.08 0.08
Smoker 20 373 10.2 19 167 7.5
FEV1, normal 83 361 9.2 77 175 6.7
0.09 0.87
FEV1, low 10 410 27.4 9 172 20.3
HRCT, normal 75 380 10.0 68 164 6.8
0.13 0.05
HRCT, emphysema 19 344 18.3 18 195 15.8
KCO, normal 81 361 9.6 74 170 7.1
0.43 0.09
KCO, low 10 384 26.3 9 184 13.0

* Adjusted for age, sex, and (except for smoker/nonsmoker comparison) smoking.
†
Adjusted for age, sex, weight, and (except for smoker/nonsmoker comparison) smoking.
Clark, Wardrobe-Wong, and Snashall: Endogenous Cortisol and Lung Damage 757

TABLE 3
RESULTS OF LINEAR REGRESSION MODELS RELATING LEVELS OF
FEV1 AND TO SELECTED COVARIATES (n 5 94)

FEV1 KCO
(L) (kPa/s)

Regression Regression
Independent Variables Coefficient SE p Value Coefficient SE p Value

Age, yr 20.040 0.007 0.000 20.004 0.004 0.342

Height, m 3.856 1.013 0.000 21.460 0.560 0.011
Sex 0.525 0.192 0.008 0.173 0.106 0.107
Smoking status 20.428 0.141 0.003 20.302 0.078 0.000
Log serum cortisol, nmol/ml 0.082 0.530 0.878 20.154 0.293 0.601
Log urinary cortisol/body weight, nmol/24 h/kg 20.262 0.343 0.447 20.716 0.190 0.000
Constant 21.789 2.223 0.423 4.633 1.230 0.000

Longitudinal Study
Decline of lung function and cortisol. On multiple linear re-
gression (Table 5) there were no significant relationships be-
tween decline of FEV1 or KCO, and either serum or urinary
cortisol. There were no significant differences in rate of de-
cline of FEV1 (adjusted for height, age, sex, smoking status,
and initial FEV1) or of rate of decline of KCO (adjusted for
age, sex, smoking status, and initial KCO) between tertiles of
serum or urinary cortisol (Table 6).
DISCUSSION
We have failed to demonstrate any relationship between se-
rum cortisol and lung function. Specifically, we have not con-
firmed the previous observation (1) that FEV1 declines more
rapidly in subjects with low normal serum cortisol, nor could
we demonstrate an effect of cortisol on baseline FEV1. Our
findings are therefore in line with studies showing normal
plasma cortisol concentrations in COPD (4–7).
We have to consider why our study and that of Sparrow
and colleagues (1) have come to such different conclusions.
Volunteers for both studies were obtained by media advertise-
ment, and may therefore not be typical of their populations.
Our advertisements stated that we were studying the effects of
smoking on the lung, and this may have encouraged participa-
tion of subjects who were concerned about their respiratory
health, and it is therefore possible that our study population
was enriched with smokers with incipient COPD. It is unclear
whether selection bias of a comparable nature applied to
Sparrow’s volunteers. The study of Sparrow and colleagues
was on smoking (25%), ex-smoking (42%), and never-smoking
(33%) men, excluding subjects with chronic diseases, including
bronchitis and asthma. Sparrow and colleagues (1) were also
at pains to establish the normality of volunteers’ endocrine
and gonadal systems. We studied smokers (79%) and never-
smokers (21%) of both sexes. We excluded ex-smokers and
subjects with a diagnosis of asthma or COPD or receiving
medication for these conditions, and subjects with a FEV1 be-
low 1.5 L. We made no selection on the basis of endocrine sta-
tus. Mean age of subjects in the two studies were similar, and
FEV1 values were almost identical.
It is not stated whether any of the men in the study of Spar-
row and colleagues had abnormally low lung function results.
In our population, despite exclusion criteria, we found 10
smokers with an abnormally low FEV1. Plasma cortisol tended
to be higher in those with reduced FEV1 (p 5 0.09), the re-
verse of what would be expected from the data of Sparrow
and colleagues.
Although Sparrow and colleagues (1) describe their study
as prospective, it is part of a wider study on gonadal function
performed 18 yr prior to publication (11). They do not state
whether they set out with the hypothesis that serum cortisol is
a factor determining rate of FEV1 decline or whether the rela-
tionship emerged fortuitously from their analysis. This is very
relevant to the statistical interpretation of their finding.
Sparrow and colleagues suggest that the rate of decline of
FEV1 in subjects in the lowest tertile of serum cortisol concen-
tration is 71.6 ml/yr faster than in subjects in the highest ter-
tile. They measured this over a 4.7-yr period, but clearly such a
difference would have to operate for longer to produce signifi-
cant airflow obstruction. If we make the modest assumption
that this difference has been maintained in the study group for

TABLE 4
ADJUSTED* MEAN LEVELS OF PULMONARY FUNCTION BY TERTILE OF SERUM
CORTISOL AND BY TERTILE OF URINARY CORTISOL/BODY WEIGHT

FEV1 (L) KCO (kPa/s)

n Mean SE p Value Mean SE p Value

Tertile of serum cortisol concentration, nmol/ml

I (172.3–319.7) 31 3.14 0.16 1.47 0.05
II (320–395) 32 3.03 0.14 NS 1.43 0.06 0.475
III (397.5–598.3) 31 3.14 0.15 1.53 0.06
Tertile of urinary cortisol/body weight, nmol/24 h/kg
I (0.74–2.08) 29 3.18 0.17 1.63 0.07
II (2.1–2.74) 28 3.14 0.17 NS 1.39 0.05 0.001
III (2.77–4.23) 29 3.07 0.14 1.35 0.05

* FEV1 adjusted for age, height, smoking, and sex; KCO adjusted for age, sex, and smoking status.
758 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 159 1999

TABLE 5
RESULTS OF LINEAR REGRESSION MODELS RELATING MEAN ANNUAL
CHANGE IN FEV1 AND KCO TO SELECTED COVARIATES

DFEV1 (L) DKCO (kPa/s)

Regression Regression
Independent Variable Coefficient SE p Value Coefficient SE p Value

Age, yr 0.002 0.002 0.41 20.002 0.002 0.27

Sex 20.21 0.039 0.60 20.002 0.032 0.93
Smoking status 20.058 0.030 0.061 20.086 0.033 0.01
Height, M 0.401 0.218 0.073
Initial pulmonary function* 0.004 0.021 0.836 0.005 7.92 204 0.00
Log10 serum cortisol, ng/ml 0.208 0.125 0.105 0.002 0.155 0.99
Log10 urinary cortisol, nmol/24 h/kg 0.025 0.095 0.794 0.170 0.120 0.17
Constant 21.111 0.520 0.039 20.662 0.467 0.16

* Initial FEV1 (L) or initial KCO (kPa/s).

10 yr we would expect to see a 715-ml difference between ter-
tiles in the cross-sectional study. With the standard deviation
of adjusted FEV1 (700 ml) we have a 90% chance of detecting
the difference at the 1% level of significance with 31 subjects
in each tertile. Our observed difference was 0 ml. The likeli-
hood of a Type II error is low. By the same token Sparrow and
colleagues should have observed a significant difference be-
tween tertiles in their cross-sectional study. Their observed
difference was 240 ml (p 5 0.08) but some of this arose be-
cause their cross-sectional data were gleaned from both first
and second lung function measurements (depending on which
measurement was temporally closest to the cortisol measure-
ment). Thus, their cross-sectional data include measurements
affected by the rapid change observed in the longitudinal study.
Clearly their cross-sectional data are not compatible with a sub-
stantial difference in rate of decline being maintained for more
than a few years.
By comparison with the previous study (1) our longitudinal
study lacks statistical power because we were not able to ex-
tend follow-up as long as we would have wished. The short in-
terval between measurements has meant a larger standard de-
viation of the adjusted change in FEV1 compared with the
study of Sparrow and colleagues. We calculate that there was
an 85% chance of finding a difference of the magnitude that
Sparrow and colleagues found at the 0.05 level of significance.
Our observed difference between tertiles was 21 ml/yr (higher
in the lowest cortisol tertile). The difference was nonsignifi-
cant, but clearly there is a real possibility of a Type II error.
Urinary cortisol gives a better indication of the biologically
active free cortisol (12) despite intersubject differences in the
renal tubular handling of cortisol. We were unable to show
any significant relationship between cortisol excretion and
FEV1 in either cross-sectional or longitudinal parts of the
study. Unexpectedly, we have demonstrated an inverse rela-
tionship between urinary cortisol excretion and KCO; low KCO
is associated with the highest tertile of urinary cortisol excre-
tion. Although highly statistically significant (p 5 0.001), the
finding needs to be treated with caution since we had no prior
hypothesis in this area. We assume that emphysema was the
main cause of reduced KCO in this population; urinary cortisol
excretion seemed to be significantly elevated in smokers with
HRCT emphysema (p 5 0.05), but a higher level of signifi-
cance is required since we made multiple statistical compari-
sons of cortisol with smoking, lung function, and structure.
With one exception, smokers with emphysema were asymp-
tomatic, and it is therefore unlikely that cortisol excretion was
increased by the stress of illness. Because there was a trend for
urinary cortisol to be lower in smokers, it is unlikely that the
relationship with emphysema is due to smoking.
No coherent pattern has emerged from the literature on
the effect of smoking on serum or urinary cortisol. We found
no significant differences in serum or urinary cortisol between
smokers and nonsmokers. Others have found serum/plasma
cortisol to be elevated (13–15) or lowered (16) or unchanged
(1) in smokers, whereas urinary cortisol was found to be higher
in smokers (17). Smoking induces oxidative mechanisms re-
sponsible for cortisol metabolism, but excretion of 6-b-hydroxy-
cortisol was the same in smokers and nonsmokers (18).

TABLE 6
ADJUSTED* MEAN ANNUAL CHANGE IN PULMONARY FUNCTION BY TERTILE OF SERUM CORTISOL
CONCENTRATION AND BY TERTILE OF URINARY CORTISOL/BODY WEIGHT

DFEV1 (L) Adjusted for Covariates DKCO (kPa/s) Adjusted for Covariates

n Mean SE p Value Mean SE p Value

Tertile of serum cortisol concentration, ng/ml

I (172–318) 19 0.055 0.03 0.088 0.03
II (319–383) 19 0.050 0.02 0.89 0.053 0.03 0.57
III (386–519) 19 0.034 0.03 0.079 0.03
Tertile of urinary cortisol/body weight,
nmol/24 h/kg
I (1.16–2.27) 16 0.063 0.03 0.041 0.04
II (2.29–2.72) 17 0.001 0.02 0.21 0.092 0.03 0.40
III (2.77–4.17) 17 0.072 0.03 0.073 0.02

* FEV1 adjusted for height, age, sex, smoking status, and initial FEV1; KCO adjusted for age, sex, smoking status, and initial KCO.
Clark, Wardrobe-Wong, and Snashall: Endogenous Cortisol and Lung Damage
In conclusion, we have failed to confirm the findings of
Sparrow and colleagues (1), but we have demonstrated a ten-
dency for urinary cortisol excretion to be higher in smokers
with emphysema and in subjects with reduced KCO.
References
1. Sparrow, D., G. T. O’Connor, B. Rosner, D. Demolles, and S. T. Weiss.
1993. A longitudinal study of plasma cortisol concentration and pul-
monary function decline in men. Am. Rev. Respir. Dis. 147:1345–1348.
2. Postma, D. S., I. Peters, E. J. Steenhuis, and H. J. Sluiter. 1988. Moder-
ately severe chronic airflow obstruction: can corticosteroids slow
down obstruction? Eur. Respir. J. 1:22–26.
3. Wright, J. L., L. M. Lawson, P. D. Pare, B. J. Wiggs, S. Kennedy, and
J. C. Hogg. 1983. Morphology of peripheral airways in current smok-
ers and ex-smokers. Am. Rev. Respir. Dis. 127:474–477.
4. Voisin, C., P. Fossati, F. Wattel, J. LeFebvre, M. Racadot, A. B. Tonnel,
and J. C. LeLeu. 1970. La reponse cortico-surrenalienne au cours des
episodes de decompensation survenant chez l’insuffisant respiratoire
chronique. Lille Med. 15:1367–1374.
5. Cornil, A., D. Glinoer, R. Leclercq, and G. Copinschi. 1975. Adrenocor-
tical and somatotrophic secretions in acute and chronic respiratory in-
sufficiency. Am. Rev. Respir. Dis. 112:77–81.
6. Semple, P.d’A., G. H. Beastall, W. S. Watson, and R. Hume. 1981. Hy-
pothalamic-pituitary dysfunction in respiratory hypoxia. Thorax 36:
605–609.
7. Gimenez, M., T. Mohan-Kumar, J. C. Humbert, N. De Talances, M.
Teboul, J. L. Ponz, and J. M. Polu. 1987. Haematological and hor-
monal responses to dynamic exercise in patients with chronic airway
obstruction. Eur. J. Clin. Invest. 17:75–80.
8. Ogilvie, C. M., R. E. Forster, and W. S. Blakemore. 1957. A standardized
breath holding technique for the clinical measurement of the diffusing
capacity of the lung for carbon monoxide. J. Clin. Invest. 36:1–17.
9. Roberts, C. M., K. D. MacRae, A. J. Winning, L. Adams, and W. A.
759
Seed. 1991. Reference values and prediction equations for normal lung
function in a non-smoking white urban population. Thorax 46:643–650.
10. Remy-Jardin, M., J. Remy, C. Boulenguez, A. Sobaszek, A. J.-L. Edme,
and D. Furon. 1993. Morphologic effects of cigarette smoking on air-
ways and pulmonary parenchyma in healthy adult volunteers: CT
evaluation and correlation with pulmonary function tests. Radiology
186:107–115.
11. Sparrow, D., R. Bosse, and J. W. Rowe. 1980. The influence of age, alco-
hol consumption and body build on gonadal function in men. J. Clin.
Endocrinol. Metab. 51:508–512.
12. Williams, G. H., and R. G. Dluhy. 1994. Diseases of the adrenal cortex.
In K. J. Isselbacher, E. Braunwald, J. D. Wilson, J. B. Martin, A. S.
Fauci, and D. L. Kasper, editors. Harrison’s Principles of Internal
Medicine. McGraw-Hill, New York. 1953–1955.
13. Field, A., G. Colditz, W. Willett, C. Longcope, and J. B. McKinlay. 1994.
The relation of smoking, age, relative weight, and dietary intake to se-
rum adrenal steriods, sex hormones, and sex hormone-binding globu-
lin in middle-aged men. J. Clin. Endocrinol. Metab. 79:1310–1316.
14. Baron, J., R. J. Comi, V. Cryns, T. Brinck-Johnsen, and N. G. Mercer.
1995. The effect of cigarette smoking on adrenal cortical hormones. J.
Pharmacol. Exp. Ther. 272:151–155.
15. Kirschbaum, C., E. Gonzalez Bono, N. Rohleder, C. Gessener, K. M.
Pirke, A. Salvador, and D. H. Hellhammer. 1987. Effects of fasting
and glucose load on free cortisol responses to stress and nicotine. J.
Clin. Endocrinol. Metab. 82:1101–1105.
16. Handa, K., S. Kono, H. Ishii, K. Shinchi, K. Imanishi, and K. Arakawa.
1994. Relationship of alcohol consumption and smoking to plasma
cortisol and blood pressure. J. Hum. Hypertens. 8:891–894.
17. Eliasson, M., E. Hagg, D. Lundblad, R. Karlsson, and E. Bucht. 1993. In-
fluence of smoking and snuff use on electrolytes, adrenal and calcium
regulating hormones. Acta Endocrinol. (Copenh.) 128:35–40.
18. Vestal, R., B. J. Cusack, G. D. Mercer, G. W. Dawson, and B. K. Park.
1987. Aging and drug interactions: I. Effect of cimetidine and smoking
on the oxidation of theophylline and cortisol in healthy men. J. Phar-
macol. Exp. Ther. 241:488–500.