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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 12 4015-4019
Copyright © 1997 by The Endocrine Society

Original Studies

Seasonal Variation in Glucocorticoid Activity in Healthy Men1

Brian R. Walker2, Ruth Best, Joseph P. Noon, Graham C. M. Watt and David J. Webb

University of Edinburgh, Department of Medicine, Western General Hospital (B.R.W., R.B., J.P.N., D.J.W.), Edinburgh EH4 2XU; and University of Glasgow, Department of General Practice, Woodside Health Centre (G.C.M.W.), Glasgow G20 7LR, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Brian R. Walker, British Heart Foundation Senior Research Fellow, University of Edinburgh, Department of Medicine, Western General Hospital, Edinburgh EH4 2XU, Scotland, United Kingdom. E-mail: B.Walker{at}ed.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Many endocrine systems are subject to seasonal variation. However, studies of the hypothalamic-pituitary-adrenal axis in man have been limited to patients with psychiatric illness with conflicting results. We studied 105 healthy men, age 24–33 yr, during a 15-month period that included two winters. We measured cortisol and its metabolites by gas chromatography/mass spectrometry in plasma and urine and the intensity of dermal blanching after overnight topical application of beclomethasone dipropionate.

There were no differences between subjects studied during the two winter periods, but marked differences between subjects studied in winter and summer. In winter, 0900-h plasma cortisol concentrations were higher (73 ± 10 ng/mL, n = 41 vs. 35 ± 4, n = 25 in summer; P < 0.01), total cortisol metabolite excretion was lower (678 ± 67 µg/mmol creatinine vs. 900 ± 98; P < 0.05), the ratio of metabolites of cortisol to those of cortisone was higher (3.0 ± 0.2 vs. 2.1 ± 0.1; P < 0.01), and dermal glucocorticoid sensitivity was higher (7.2 ± 0.4 arbitrary units vs. 5.6 ± 0.5; P < 0.02). Although blood pressure and fasting insulin/glucose relationships were not measurably different between seasons, these correlated with dermal vasoconstriction and cortisol metabolite excretion rate.

We conclude that plasma cortisol and tissue sensitivity to glucocorticoids are higher in winter, but cortisol production rate is reduced. This could be explained by a reduction in cortisol clearance rate: urinary free cortisol/cortisone ratios were not different but A-ring-reduced metabolites of cortisol were higher in winter, suggesting that conversion of cortisone to cortisol by hepatic 11ß-hydroxysteroid dehydrogenase 1 is enhanced. It is an intriguing possibility that increased glucocorticoid activity contributes to the increased prevalence of disease during the winter.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CUSHING’S syndrome, caused by excess secretion of the principal glucocorticoid hormone cortisol, is associated with immunosuppression, depression, and risk factors for cardiovascular disease, including hypertension and glucose intolerance. More subtle variations in cortisol activity within the normal physiological range have been implicated in the pathophysiology of these abnormalities in patients who do not have Cushing’s syndrome (1, 2, 3). Infectious diseases, depression, and cardiovascular disease are subject to seasonal variation, being more common in winter (4, 5). This report concerns the possibility that the activity of cortisol also varies between seasons and might therefore contribute to seasonal variation in glucocorticoid-dependent illness.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The studies were performed in Edinburgh, Scotland at a latitude of 55 degrees N. The study began in October and was completed 15 months later. Hours of daylight vary from a nadir of 7.0 h/day in winter to a peak of 18.3/per day in summer. Mean daytime air temperatures for each month were obtained from the Scottish Meteorological Office, which has a recording station 1 km from our hospital (Table 1Go). Lothian Health Ethical Committee approval and written informed consent were obtained.


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  		Table 1. Subject characteristics and biochemistry

 
We studied 105 male white Caucasians, age 24–33 yr, who were selected at random from a cohort of normal subjects in whom contrasting predisposition to high blood pressure has been characterized on the basis of their own blood pressure and the blood pressures of their parents (6). Subjects were invited to attend for study on any convenient date, resulting in a random distribution throughout the year (Table 1Go). A greater number of subjects were studied during the winter because the study lasted 15 months and included two winter periods. Subjects on regular medication were excluded. Subjects collected urine for 24 h and attended for investigation at 0900 h having abstained from food, alcohol, and cigarettes from 2200 h on the previous evening and proprietary medication for a week. Blood was withdrawn after 30 min of lying supine, and blood pressure measured on three occasions over 15 min with a Hawksley random zero sphygmomanometer (Hawksley and Sons Ltd., West Sussex, UK).

Dermal glucocorticoid sensitivity was measured as previously described (7, 8, 9, 10). In brief, 50 µL beclomethasone dipropionate (Sigma Chemical Co., Poole, UK) at 0, 1, 5, 10, 100, or 1000 µg/mL in 95% ethanol was applied in random order to circles of 14 mm diameter on the volar surface of the nondominant forearm. After occlusion under polyethylene wrap for 16–18 h, the intensity of blanching was assessed the following morning in a room with fluorescent lighting first on a visual scale from 0–3 by an observer who was blind to the order of application and to all other data and second using a reflectance spectrophotometer (Erythemameter, Diastron Ltd., Hampshire, UK). This device measures the ratio of red/green light reflected from the skin surface, called the erythema index. Because red reflects oxyhemoglobin concentrations, and green reflects melanin concentrations, the erythema index corrects for variations in skin color between individuals. The erythema index for each test site was subtracted from the erythema index for the site treated with vehicle alone to produce a blanching index (10). The blanching index corrects for the nonspecific variations in skin color that occur in different environments in the same individual. For correlations with other variables, and for the data in the abstract, the visual scores are summarized as areas under the dose-response curve (i.e. the sum of scores for all treated circles).

Laboratory analyses were performed at the end of the study, using samples stored at -20 C (urine) or -70 C (plasma). We measured plasma glucose and electrolytes on a Beckman CX-3 autoanalyzer (Beckman Instruments, High Wycombe, UK), renin activity by RIA for angiotensin I generation using the Rianen kit (Dupont, Stevenage, UK), aldosterone by RIA (Coat-a-Count Diagnostics, Los Angeles, CA), and insulin using a microparticle enzyme immunoassay on an Abbott Labs. IMX analyzer (Abbott Labs. Ltd., Maidenhead, UK). Insulin sensitivity was estimated using the homeostasis model of assessment (HOMA) (11). Cortisol and its metabolites were measured by electron impact gas chromatography/mass spectrometry following Sep-pak C18 extraction (Waters Ltd., Edinburgh, UK), hydrolysis with ß-glucuronidase, and formation of the methoxime-trimethylsilyl derivatives (12, 13). Epi-cortisol and epi-tetrahydrocortisol were used as internal standards. Total cortisol metabolite excretion was calculated as tetrahydrocortisols + tetrahydrocortisone + cortols + cortolones (14).

Statistical analyses

Results were grouped into four seasons: winter (November-January); spring (February-April); summer (May-July); and fall (August-October). Results are expressed as mean ± SEM and were compared by ANOVA followed by probability of least squares difference tests when P < 0.05, except for the concentration-response curves of visual scores of dermal blanching, which were compared by Friedman nonparametric ANOVA.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
To identify any tendency for measurements to drift with time independently of the seasons, results were compared between the first (n = 26) and second (n = 15) winter periods. No differences were observed (data not shown). Data for both winter periods were combined for further analyses.

Results are shown in Table 1Go and Figs. 1Go and 2Go. Consistent differences were observed between summer and winter, with more variable results in spring and fall. In winter, plasma cortisol concentrations were higher, but total cortisol metabolite excretion was reduced. Although plasma cortisone concentrations were also higher in winter, and there was no difference between seasons in cortisol/cortisone ratios in plasma or urine, the ratio of the urinary A-ring-reduced metabolites of cortisol (5{alpha}- and 5ß- tetrahydrocortisol) to those of cortisone (tetrahydrocortisone) was increased in winter.



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  		Figure 1. Seasonal variation in plasma and urinary corticosteroids. Bars, Mean ± SEM. THF, Tetrahydrocortisol; THE, tetrahydrocortisone. *, P < 0.05; **, P < 0.01 vs. winter.

 


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  		Figure 2. Seasonal variation in dermal vasoconstrictor sensitivity to beclomethasone dipropionate. Bars, Mean ± SEM. Results are shown for intensity of blanching measured either on a visual scale (a), or by reflectance spectrophotometry (b). •, winter; {square}, spring; {circ}, summer; {blacktriangleup}, fall. ANOVA for visual scale showed an interaction between season and dose response (P < 0.01) that was significant between summer and winter (P < 0.01) or spring (P < 0.05) and between fall and spring (P < 0.02). ANOVA for reflectance spectrophotometry showed an interaction between season and dose response (P < 0.02) that was significant between winter and summer (P < 0.01) or spring (P < 0.01).

 
The intensity of dermal vasoconstriction to glucocorticoids was increased in winter, using either visual scoring or reflectance spectrophotometry. This was attributable both to increased sensitivity [most obvious with visual scoring, which is more precise in the lower part of the concentration-response curve (10)] and maximum response [more obvious with reflectance spectrophotometry, which is more precise at higher concentrations of beclomethasone dipropionate (10)]. In addition, erythema indices for skin treated with vehicle alone did not differ between summer and winter, indicating that the difference in blanching cannot be accounted for by differences in basal skin color (Table 1Go).

These variations in cortisol activity were not accompanied by measurable differences between seasons in blood pressure or fasting insulin/glucose relationships. However, both total cortisol metabolite excretion and the area under the curve of dermal glucocorticoid sensitivity correlated with fasting glucose concentration (r = +0.20, P < 0.05; and r = +0.19, P < 0.05, respectively) and HOMA insulin resistance index (r = +0.37, P < 0.001; and r = +0.20, P < 0.05). Relationships with mean arterial blood pressure did not reach statistical significance (r = +0.18, P < 0.07; and r = +0.18, P < 0.07, respectively). There were no differences in indices of renal mineralocorticoid receptor activation, including plasma renin activity and aldosterone.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Many endocrine systems in man exhibit differences between summer and winter. Seasonal variation in the hypothalamic-pituitary-adrenal axis has been described in primates (15), rodents (16), reptiles (17, 18), and fish (19). However, studies of seasonal variation in glucocorticoid activity in man have been limited to measurements of plasma cortisol concentrations and have provided contradictory results. Thus, in healthy volunteers some investigators report higher 0900-h plasma cortisol concentrations in winter (20), whereas others found no difference between seasons (21, 22). By contrast, in patients with psychiatric disease, including major depression, 0900-h plasma cortisol concentrations were not different between seasons, but plasma cortisol after an overnight dexamethasone suppression test was lower in winter (23, 24, 25). This suggests that depressed patients are either more sensitive to dexamethasone or have impaired metabolic clearance of dexamethasone in winter. Finally, studies of the glucocorticoid receptor in healthy human leukocytes also provide contradictory data. One group found no difference in dexamethasone binding between seasons (26), but a recent study suggests that the affinity and capacity of binding is decreased in winter (27).

The current study is the first to compare both plasma and urinary cortisol metabolites and in vivo sensitivity to glucocorticoids in man in different seasons. The data confirm that plasma cortisol is higher in winter, but this is accompanied by a paradoxical reduction in excretion of cortisol metabolites, an index of cortisol secretion rate (14). This combination cannot be explained by alterations in corticosteroid binding globulin, especially because there is a similar elevation of plasma cortisone concentrations in winter, and this steroid is not bound by corticosteroid binding globulin. Rather, the combination of higher plasma cortisol and reduced cortisol metabolite excretion suggests that the metabolic clearance rate of cortisol is reduced in winter, resulting in a slower decay of the early morning peak of plasma cortisol concentration. Alternatively, the morning peak of cortisol secretion could be delayed in winter, perhaps because of altered sleeping patterns associated with later sunrise. However, in the temperate climate in Edinburgh, people do not vary their working schedules between summer and winter and therefore wake at the same time independently of the season. Moreover, the seasonal difference in timing of dawn is ameliorated by a change of 1 h between Greenwich Mean Time (winter) and British Summer Time (summer). Also, plasma cortisone concentrations do not display a diurnal rhythm (28), so that the higher plasma cortisone levels in winter cannot be explained by altered sleep patterns.

A difference in cortisol metabolism in winter is also suggested by the elevated ratio of the A-ring-reduced metabolites of cortisol to those of cortisone in urine. Conversion of cortisol to cortisone is catalyzed in the kidney by 11ß-hydroxysteroid dehydrogenase (HSD) type 2. The reverse conversion of cortisone to cortisol is catalyzed in the liver by 11ß-HSD type 1 (28, 29). Inhibition of renal 11ß-HSD2 results in higher ratios of free cortisol/cortisone in urine (13, 30) and suppression of plasma renin activity and aldosterone, which we did not observe in winter. Therefore, it seems more likely that cortisol clearance is impaired in winter because of enhanced 11ß-HSD1 activity, which influences the intrahepatic cortisol/cortisone ratio and affects the ratios of A-ring-reduced metabolites. 11ß-HSD1 also converts 11-dehydrodexamethasone to dexamethasone, so that the same phenomenon could account for enhanced dexamethasone suppressibility in depressed patients in the winter (12).

Dermal glucocorticoid sensitivity is a measure of in vivo glucocorticoid sensitivity which, unlike dexamethasone suppression testing, is not influenced by systemic metabolic clearance rates. The skin response is mediated by glucocorticoid receptors (31) and reflects, at least in part, sensitivity to glucocorticoids in nonvascular peripheral tissues because it correlates with the bronchodilator response to prednisolone in asthmatics (8). Glucocorticoid-induced skin blanching was more intense in winter than in summer. This observation was confirmed by reflectance spectrophotometry (10), which showed that there was no difference in the degree of apparent blanching in areas treated with vehicle alone between summer and winter. Thus, variable dermal blanching is not explained by differences in skin color between seasons, and is unlikely to be explained by differences in skin temperature. Glucocorticoid receptor expression is down-regulated by elevated cortisol concentrations. One possible explanation for the enhanced skin response in winter is that there is a lower level of tonic down-regulation of dermal glucocorticoid receptors by endogenous cortisol. Like the abnormalities of urinary cortisol metabolites, this might also result from enhanced 11ß-HSD1 activity, which converts cortisol to cortisone in vessels and thereby modulates glucocorticoid receptor activation (7, 9).

At present we can only speculate on the mechanisms that mediate the differences in cortisol metabolism between summer and winter. 11ß-HSD1 is regulated by glucocorticoids, ACTH, thyroid hormones, sex steroids, GH, and insulin (29), all of which may be subject to seasonal variation. In addition, the physiological responses to changes in daylight and environmental temperature are poorly characterized. In this study design, it is not possible to distinguish seasonal differences that are dependent on light or temperature. Intriguingly, plasma cortisol is lowered by phototherapy for seasonal affective disorder (32), although it is a moot point whether this is a cause or consequence of the improvement in mood. Finally, it is possible that cortisol metabolism is influenced by cytokines, because the 11ß-HSD1 gene has promoter sequences that are regulated by CEBP-ß (33), the second messenger for the acute-phase cytokine interleukin-6. Infections might cause up-regulation of 11ß-HSD1, as has been observed in patients with active pulmonary tuberculosis (3). Therefore, the increased prevalence of other more common infections in winter might account for our observations.

These results suggest that cortisol concentrations are elevated for at least some of the day during the winter, particularly in sites where 11ß-HSD1 converts cortisone to cortisol, and that tissue sensitivity to glucocorticoids is enhanced in winter. We might expect this to affect glucocorticoid-dependent variables, such as blood pressure, bone mass [interacting with seasonal variation in vitamin D levels (34)], and mood [perhaps contributing to seasonal affective disorder (32)]. Our study did not demonstrate seasonal variation in blood pressure (35) and insulin sensitivity, but it may have had insufficient statistical power to do so, and there was a relationship between cortisol secretion/sensitivity and these variables. We have suggested that enhanced glucocorticoid secretion and sensitivity makes an important contribution to the pathophysiology of cardiovascular risk factors (1). Both the risk factors for, and prevalence of, myocardial infarction and stroke are increased in winter (4, 5). It is an intriguing possibility that enhanced glucocorticoid sensitivity is a mediator of these seasonal variations in cardiovascular disease.


   Acknowledgments
 
We are grateful to Drs. David Holton and Hugh Edwards who assisted with recruitment of subjects, and to the Scottish Meteorological Office for providing temperature data.


   Footnotes
 
1 This work was supported by a grant from the Scottish Home and Health Department. Back

2 A British Heart Foundation Senior Research Fellow. Back

Received May 12, 1997.

Revised June 30, 1997.

Accepted August 13, 1997.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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