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The Corticotropin-Releasing Hormone Stimulation Test in White Coat Hypertension

First Department of Internal Medicine, Toho University School of Medicine, Ota-ku, Tokyo 143-0015, Japan

Address all correspondence and requests for reprints to: Yukitaka Miyachi, M.D., First Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Omorinishi Ota-ku, Tokyo 143-0015, Japan. E-mail: . miyachi{at}ma.kcom.ne.jp

Abstract

This study was undertaken to clarify the status of the ACTH and cortisol responses to CRH in patients with white coat hypertension. White coat hypertension was defined as a difference between clinic blood pressure and ambulatory blood pressure of at least 20 mm Hg for systolic blood pressure and/or 10 mm Hg for diastolic blood pressure. CRH stimulation tests were performed between 1400 and 1700 h in 11 patients with white coat hypertension (4 males and 7 females) and 11 normal subjects (4 males and 7 females). Blood pressure and heart rate were measured 15 min before, at time zero, and 15, 30, 60, and 120 min after initiation of the CRH stimulation tests. In white coat hypertension, both the mean systolic blood pressure (162 ± 15 mm Hg) and diastolic blood pressure (97 ± 10 mm Hg) were higher than in controls (P < 0.01) on 3 occasions. The mean ambulatory blood pressure for the 24-h period of the test did not differ between patients with white coat hypertension and normal subjects. Basal levels of ACTH and cortisol did not differ between patients with white coat hypertension and control subjects. However, challenge with CRH elevated ACTH (30 min) and cortisol (30, 60, and 120 min) to levels higher than those in controls, with the net increase in both ACTH and cortisol being higher than that in controls over the study period (P < 0.01). These significant responses suggest that white coat hypertension is associated with hypothalamic-pituitary-adrenal hypersensitivity to stressors.

THE USE OF 24-h ambulatory blood pressure (ABP) monitoring has resulted in an apparent increase in the incidence of white coat hypertension (WCHT) (1). The blood pressure (BP) of patients with WCHT measured in the doctor’s office [clinic blood pressure (CBP)] is higher than measurements obtained from ABP monitoring. This possibly reflects both behavioral and psychological differences in the patient in the two situation. CRH has been implicated as an important mediator in behavioral, immune, and neuroendocrine responses to stress (2). Differences in ACTH and cortisol responses to CRH have been reported in several psychiatric states (3). The CRH stimulation test was performed to evaluate the hypothalamic-pituitary-adrenal axis in WCHT patients.

Subjects and Methods

Subjects

In this study, WCHT was defined as a difference between CBP and ABP of at least 20 mm Hg for systolic blood pressure (SBP) and/or 10 mm Hg for diastolic blood pressure (DBP) (1). CBP was determined on at least three occasions by a physician, then all subjects were fitted with an ABP monitor for 24 h. A TM-2425 device (A&D Corp., Tokyo, Japan) was used in all studies and was programmed to record blood pressure every 30 min from 0600–2200 h and once per hour from 2200–0600 h the following day. This information was used to calculate the average ABP for each patient over the 24-h period.

Eleven WCHT patients (4 males and 7 females) and 11 normal subjects as controls (4 males and 7 females) were registered to take part in this study at the Toho University Hospital. The Toho University review board approved the protocol. All patients and controls signed informed consent statements and underwent a complete physical examination, blood chemistry evaluation, and endocrine history investigation. Subjects in this study did not receive any medications, such as inhaled or systemic glucocorticoids, that could affect the hypothalamic-pituitary-adrenal (HPA) axis.

CRH stimulation test

The CRH stimulation test was performed between 1400–1700 h in all WCHT patients and controls. An indwelling catheter was inserted, and 100 µg human CRH (Mitubisi Kagaku Co., Tokyo, Japan) were administered as a bolus injection. Blood samples were obtained before and 30, 60, and 120 min after the injection. Within 30 min the blood was centrifuged, and the plasma was frozen until required for assay of ACTH and cortisol. BP and heart rate (HR) were measured 15 min before, at time zero, and 15, 30, 60, and 120 min after injection of CRH.

Hormone measurement

ACTH was measured by immunoradiometric assay (Allegro ACTH kit, Nicols Co., Tokyo, Japan), and cortisol was measured by RIA (Gammacoat Cortisol, Dade Behring Ltd., Chicago, IL). Intra- and interassay coefficients of variation in ACTH and cortisol assays were 2.83% and 3.31%, and 4.16% and 6.86%, respectively.

Statistical analysis

All statistical analyses were performed using StatView software (Abacus Concepts, Inc., Berkeley, CA). Differences in BP and HR were analyzed by t test. Repeated measure one-way ANOVA was used to examine group differences in BP, HR, and ACTH and cortisol levels during the CRH stimulation testing. Each value represents the mean ± SD.

Results

Clinical characteristics

The clinical characteristics of each subject are shown in Table 1. There was no significant difference in age, height, or weight between WCHT patients and normal subjects. On three occasions the mean SBP (162 ± 15 mm Hg) and DBP (91 ± 10 mm Hg) were higher in WCHT patients than in normal subjects (P < 0.01; Table 1). In contrast, the mean ABP for the 24-h period did not differ between WCHT patients and normal subjects (Table 1). HR also did not differ between the two groups.

Before CRH administration, SBP (147 ± 18 mm Hg) was significantly higher in WCHT patients than in normal subjects and continued to be elevated during the test (Table 2). However, there was no significant difference in DBP between the groups at any time point before or after CRH administration. Basal plasma levels of ACTH were similar in WCHT patients and normal subjects at 7 ± 5 and 8 ± 3 pmol/liter, respectively (Fig. 1). In normal subjects, plasma ACTH increased to a peak level of 13 ± 5 pmol/liter 30 min after CRH administration and thereafter decreased gradually. In WCHT patients, the plasma ACTH level 30 min after CRH administration was 21 ± 5 pmol/liter, which is significantly higher than the level found in normal subjects. Basal plasma levels of cortisol were similar in WCHT patients and normal subjects at 355 ± 114 and 338 ± 141 nmol/liter, respectively (Fig. 1). In normal subjects, plasma cortisol increased to a peak of 463 ± 68 nmol/liter 30 min after CRH administration and thereafter decreased gradually. In WCHT patients plasma cortisol levels at 30, 60, and 120 min after CRH administration were 589 ± 104, 571 ± 152, and 408 ± 126 nmol/liter, respectively, which are significantly higher values than those found in normal subjects. The net increase in ACTH, calculated as the level after CRH injection minus the level before CRH injection, was 33 ± 7 pmol/liter in WCHT patients, which was significantly higher than the value of 20 ± 12 pmol/liter (P < 0.01) for normal subjects. The net increase in cortisol was 1214 ± 275 nmol/liter in WCHT patients, again significantly higher than the value of 857 ± 230 nmol/liter (P < 0.01) for normal subjects.

View larger version (13K): [in this window] [in a new window]   Figure 1. ACTH and cortisol responses to CRH in normal subjects () and WCHT patients (). *, P < 0.05; **, P < 0.01. Data are the mean ± SD.

View larger version (14K): [in this window] [in a new window]   Figure 2. Relationship between SBP (systolic CBP minus systolic ABP; upper panel) and DBP (diastolic CBP minus diastolic ABP; lower panel), and maximal ACTH (left) and cortisol (right) responses to CRH in normal subjects () and WCHT patients ().

In WCHT patients the greater increase in ACTH during the CRH stimulation test is followed by an enhanced cortisol response. The preinjection levels of ACTH and cortisol did not differ between WCHT patients and normal subjects. The significantly enhanced ACTH and cortisol responses to CRH in WCHT patients compared with the control subjects suggest that WCHT is associated with HPA hypersensitivity. Dysregulation of the HPA axis has been widely documented in depressed patients, alcoholism, and panic disorders (4, 5, 6, 7, 8). CRH injections have induced a blunted ACTH, but normal cortisol, release in depressed patients, with similar response patterns observed in patients with panic disorders or alcoholism (4). Elevated preinjection levels in patients with panic disorders might reflect greater reactivity to the preinjection environment, resulting in unintended stress responses before injection.

Recently, different findings have been reported in subgroups of depressed and panic disorder patients. Untreated patients with nondepressed panic disorder have shown ACTH and cortisol responses to CRH higher than those of control subjects (6). Patients with anxiety depression have shown significant attenuation of the ACTH response compared with patients with depression alone or normal controls (9). Negrao et al. (10) reported that strenuous exercise is a natural stressor that evokes both autonomic and HPA axis responses. They classified normal subjects into two groups: those known as high responders, who showed a significant net rise in ACTH and cortisol, and those known as low responders, who failed to show a significant net rise in ACTH and cortisol during exercise stress. The ACTH responses of high responders were higher, although not significantly so, than those of low responders during the psychological stress test. High responders had a significantly greater net integrated control response than low responders during the psychological stress test (11). Therefore, patients with WCHT resemble those with nondepressed panic disorder, chronic anxiety depression, and high responders to strenuous exercise.

As plasma ACTH and cortisol responsiveness to CRH does not differ between children and adults (12, 13), and the subjects were not receiving medication that might affect the HPA axis, the enhanced ACTH response observed in WCHT patients cannot be accounted for by age or medication. Circadian variation also does not appear to play a role, as this study was performed in the afternoon, near the trough of the cycle, and an enhanced ACTH response to CRH was still found.

SBP is higher in WCHT patients than in controls before the CRH test, although there is no relationship between SBP and basal ACTH or cortisol levels. Although the HPA axis and the sympathetic adrenomedullary system are the main neuroendocrine components of the stress response, Saito et al. (14) and Goldstein (15) reported that neither epinephrine nor norepinephrine was higher in WCHT patients than in control subjects. The mechanism of hypertension in WCHT thus remains unclear.

WCHT patients show a degree of anxiety, irritability, and hypersensitivity to external stimuli, which might produce chronic stress. Bhatnagar et al. (7) reported that rats chronically stressed by intermittent cold exposure facilitated an HPA response to the novel stimulus of restraint. Lesions in the posterior division of the paraventricular nucleus of the hypothalamus develop an increased responsiveness to stress in chronically stressed animals (7).

We hypothesize that the HPA axis responds in a similar way in WCHT and in nondepressed panic disorder, chronic anxiety depression, and high responders to strenuous exercise. The enhanced ACTH and cortisol responses to CRH in WCHT patients possibly reflect facilitation of the HPA axis by chronic stimuli.

Acknowledgments

Footnotes

Present address for I.T.: Department of Psychology and Pedagogy, Faculty of Humanities and Social Science, Meisei University, Hino, Tokyo 191-8506, Japan.

Abbreviations: ABP, Ambulatory blood pressure; BP, blood pressure; CBP, clinic blood pressure; DBP, diastolic blood pressure; HPA, hypothalamic-pituitary-adrenal; HR, heart rate; SBP, systolic blood pressure; WCHT, white coat hypertension.

Received October 31, 2001.

Accepted April 16, 2002.

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