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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1734-1738
Copyright © 1997 by The Endocrine Society

Pediatric Endocrinology

Blood Pressure in Children and Adolescents with Cushing’s Syndrome before and after Surgical Cure

Maria Alexandra Magiakou1, George Mastorakos1, Keith Zachman and George P. Chrousos

Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: George P. Chrousos, M.D., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Room 10N262, Bethesda, Maryland 20892.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Approximately half of children and adolescents with Cushing’s syndrome develop hypertension. To examine the role of hypercortisolism in the pathogenesis of hypertension in young patients and to establish its reversibility, we studied 31 hypertensive children and adolescents with Cushing’s syndrome (systolic, diastolic, and/or mean blood pressure more than 2 SD U for age and sex) from a total of 63 patients before, and for a period of 1 yr after surgical cure. Preoperatively, 93.5%, 42%, and 45% of these patients presented with an increase of the systolic, diastolic, and mean blood pressure, respectively. The systolic blood pressure remained increased in 30.7%, 15.8%, and 5.5% of patients at 3, 6, and 12 months after surgical cure, respectively. The diastolic and mean blood pressure completely normalized by 3 months after surgical cure. A significant, positive correlation was observed between the systolic blood pressure and the duration of the disease, but no correlation was seen with the 24-h urinary free cortisol values and/or the patients’ body mass indices. The lack of correlation between 24-h urinary free cortisol values and blood pressure suggests that hypercortisolism influences blood pressure through multiple pathways. The positive correlation between the systolic blood pressure and the duration of the disease points towards the deleterious effects of prolonged hypercortisolism and the significance of early diagnosis and treatment. The fact that the blood pressure normalized within a year from the correction of hypercortisolism suggests that, as a rule, young patients with hypercortisolism do not develop essential hypertension.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HYPERTENSION among pediatric patients with Cushing’s syndrome has been reported to be frequent; however, its prevalence has not been established (1). Rates ranging from 13–77% have been reported, based on small series of 15 patients or less. Persistence of hypertension has been suggested as an independent predictor of mortality in adults with Cushing’s syndrome (2). In a large series of 59 children and adolescents with Cushing’s syndrome, hypertension (mainly systolic) was present in 47% of the patients (3). Thus, the prevalence of hypertension, although lower than that found in adult patients with Cushing’s syndrome (4, 5, 6, 7, 8, 9, 10, 11, 12), is undoubtedly one of the hallmarks of this condition in children and adolescents.

Glucocorticoids cause hypertension through several mechanisms: activation of the renin-angiotensin system (13, 14); enhancement of cardiovascular inotropic and pressor reactivity to vasoactive substances, including catecholamines and/or vasopressin and angiotensin II (15, 16, 17, 18); suppression of the vasodilatory systems, including the nitric oxide synthase, prostacyclin, and kinin-kallikrein systems (19); and through their intrinsic mineralocorticoid activity (20). In addition, glucocorticoids may exert some hypertensive effects on cardiovascular regulation through the central nervous system via both glucocorticoid and mineralocorticoid receptors (21, 22, 23, 24, 25). In patients with ACTH-dependent Cushing’s syndrome, hypersecretion of steroid biosynthesis intermediates with sodium-retaining activity, such as corticosterone and deoxycorticosterone, contributes to hypertension (26).

To examine the involvement of endogenous hypercortisolism on the pathogenesis of hypertension of Cushing’s syndrome and to define the outcome of hypertension after surgical cure, we studied the arterial blood pressure of hypertensive children and adolescents with Cushing’s syndrome before, and for a period of 1 yr after correction of hypercortisolism.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Thirty-one children and adolescents (20 female, 11 male, 13.5 ± 0.8 yr old, mean ± SE) with Cushing’s syndrome (23 with pituitary adenomas, 5 with primary adrenal disease, and 3 with ectopic ACTH secretion), who had been hypertensive (systolic and/or diastolic and/or mean blood pressure > 2 SD units (SDU) for age and sex) during the hypercortisolemic state, were included in the study. These patients had been hypercortisolemic for a mean period of 26.2 ± 3.4 months (mean ± SE). All patients were evaluated and treated at the National Institutes of Health. Their clinical profile is summarized in Table 1Go. These patients were selected from an original series of 63 patients with Cushing’s syndrome, for presence of hypertension (Fig. 1Go) (3). The biochemical documentation of endogenous hypercortisolism was based on measurements of 24-h urine free cortisol (UFC) excretion, and on the lack of circadian rhythmicity in plasma cortisol concentrations.


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  		Table 1. Patient clinical profile

 


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  		Figure 1. Systolic, diastolic, and mean blood pressure of 63 children and adolescents with Cushing’s syndrome during the hypercortisolemic state. The black lines represent the mean values and the grey areas, the SE.

 
All patients with pituitary adenomas underwent successful transsphenoidal surgery. Of the five patients with primary adrenal disease, four had micronodular adrenal disease and underwent bilateral adrenalectomy, and one had an adrenal adenoma and underwent surgical excision of the tumor. Of the three patients with ectopic ACTH secretion, one had a thymoma, and one a thymic carcinoma, and both had a total thymectomy. The third patient also had a thymectomy, on the basis of an ACTH gradient on thymic-vein sampling. No tumor was found, however, and a bilateral adrenalectomy was performed 1 month later. This patient was recently diagnosed with carcinoid tumorlets of the lung, which were excised.

All patients were cured after surgical excision of the tumor and were monitored for at least a year after surgical cure (at 3, 6, and 12 months postoperatively). They were considered cured if urinary cortisol values were less than 10 ug per 24 h (<28 nmol/day) and morning (0700–0900 h) plasma cortisol values were less than 1 ug/dL (<28 nmol/L) the third day after surgery (36 h after temporary discontinuation of glucocorticoid coverage). Postoperatively, they were treated with replacement hydrocortisone (12–15 mg/m2·day) given in the morning for a period of 6–12 months, i.e. until the complete recovery of their hypothalamic-pituitary-adrenal (HPA) axis. The postoperative recovery of the HPA axis was evaluated periodically with serial standard ACTH tests (250 ug Cortrosyn given as an iv bolus) and was confirmed by a plasma cortisol value greater than or equal to 18 µg/dL (500 nmol/L), 60 min after the administration of ACTH.

Methods

Protocol. All patients had been admitted at the NIH, at first, for a complete clinical and laboratory evaluation and surgical treatment of Cushing’s syndrome, and subsequently, for follow-up at 3, 6, and 12 months after surgical cure. At all time points, a detailed medical history was obtained, and a complete physical examination was performed, including measurements of weight, height by stadiometer, systemic blood pressure, and staging of sexual development, according to the method of Tanner (27, 28). Systemic blood pressure was taken in all patients twice a day (0700 h and 1900 h) using appropriate size cuffs and mercury-based manometers. Preoperatively, for each patient, at least 5 measurements of 24-h UFC were averaged to determine the mean urinary cortisol excretion per square meter of body surface area (29). Preoperatively, and 3, 6, and 12 months after surgical cure, serum electrolytes and cholesterol values were measured.

Methods. The mean blood pressure was estimated using the formula diastolic blood pressure + pulse pressure/3" (pulse pressure = systolic - diastolic) (30). Systolic, diastolic, and mean blood pressure values were expressed in SDU for age and sex (31). Body mass indices (BMI) were calculated using the formula weight (kilograms)/height2 (square meters). The severity of the disease was estimated as the product of duration of the disease in months x UFC values. Twenty-four-hour urinary free cortisol excretion was measured by direct RIA (32). The intraassay and interassay coefficients of variation were 5% and 10%, respectively.

Statistical analysis. Systolic, diastolic, and mean blood pressure values in SDU for age and sex are expressed as mean ± SE. Group differences at different time points were examined by ANOVA, repeated measures), followed by Bonferroni-corrected Student’s t tests. Correlations were attempted between UFC, duration and severity of the disease, BMI, and serum electrolyte or cholesterol concentrations and blood pressure. Statistical significance was set at less than 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Blood pressure values in children and adolescents with Cushing’s syndrome

Before surgery. The SDU of the systolic, diastolic, and mean blood pressure of 63 children and adolescents with Cushing’s syndrome during the hypercortisolemic state are shown in Fig. 1Go. The clinical profile of these patients was discussed in detail in a previous report (3). Thirty of 63 (47%), 13/63 (21%), and 14/63 (22%) of these patients presented with systolic, diastolic, and mean blood pressure, respectively, and more than 2 SDU for age and sex) and were included in the present study.

Preoperatively, 93.5%, 42%, and 45% of the 31 hypertensive patients presented with an increase more than 2 SDU for age and sex in the systolic, diastolic, and mean blood pressure, respectively (Table 1Go). The mean ± SE systolic, diastolic, and mean blood pressure values expressed in SDU were 2.9 ± 0.2, 1.7 ± 0.2, and 2.2 ± 0.2, respectively (Fig. 2Go).



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  		Figure 2. Mean ± SE values of the systolic, diastolic, and mean blood pressure of 31 hypertensive children and adolescents with Cushing’s syndrome, preoperatively (preop) and 3, 6, and 12 months after surgical cure (*, P < 0.05 systolic, diastolic, and mean preop vs. 3, 6, and 12 months postoperatively; +, P < 0.05, diastolic and mean 3 months vs. 12 months postoperatively; #, P < 0.05 mean 6 months vs. 12 months postoperatively, ANOVA repeated measures followed by Bonferroni corrected Student’s t test).

 
All patients had been obese during the hypercortisolemic state (BMI - SDU = 3.3 ± 0.6).

Postoperatively. The systolic blood pressure remained increased in 30.7%, 15.8%, and 3.2% of patients at 3, 6, and 12 months after surgical cure, respectively, whereas the diastolic and mean blood pressure normalized in all patients 3 months after surgical cure.

The mean ± SE values of the systolic, diastolic, and mean blood pressure in SDU are depicted in Fig. 2Go. The systolic blood pressure decreased from 2.9 ± 0.2 SDU preoperatively, to 1.1 ± 0.3, 0.7 ± 0.3, and 0.3 ± 0.2 at 3, 6, and 12 months after surgical cure, respectively. The diastolic blood pressure decreased from 1.7 ± 0.2 SDS preoperatively, to 0.8 ± 0.2, 0.07 ± 0.2, and -0.25 ± 0.2 at the same time points, respectively. A decrease was observed in diastolic blood pressure between 3 and 12 months postoperatively. The mean blood pressure decreased from 2.2 ± 0.2 SDU preoperatively, to 0.9 ± 0.2, 0.4 ± 0.1, and -0.06 ± 0.2 at the same time points, respectively. A decrease was observed in mean blood pressure, both between 3 and 12 months and between 6 and 12 months postoperatively (P < 0.05, ANOVA, Fig. 2Go).

The BMIs of the patients normalized by the end of the first year after surgical cure (BMI - SDU = 0.94 ± 0.3).

Statistical correlations. Preoperatively, a positive correlation was observed between systolic blood pressure and the duration of the disease (P = 0.04) but not between diastolic or mean blood pressure and the same parameter. No significant correlations were found between systolic, diastolic, or mean blood pressure and 24-h urinary free cortisol excretion values, severity of the disease, BMI, and serum electrolyte or cholesterol values.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
During the hypercortisolemic state, hypertension in our patients was mostly systolic. This suggests that our patients had increased cardiac output via enhanced cardiac sensitivity to catecholamines, probably secondary to glucocorticoid-mediated suppression of norepinephrine metabolism and increases in adrenergic receptor density and/or coupling and effect (26, 33). Excessive mineralocorticoid activity, with distal exchange of sodium against potassium or proton ions and subsequent volume expansion was proposed as a pathophysiologic mechanism of hypertension of Cushing’s syndrome (4, 33), and hypokalemic alkalosis was considered characteristic of childhood Cushing’s syndrome (34). However, recent determinations of total exchangeable sodium, performed in adult patients with the disorder, suggested that the role of sodium retention was minor (33). The low prevalence of hypokalemia and alkalosis (2 and 7%, respectively) reported in our series supports this conclusion (3).

Because our patients were followed for at least 1 yr after surgical cure, we had the opportunity to study their blood pressure longitudinally, after the correction of hypercortisolism. We found that the mean values of systolic, diastolic, and mean blood pressure of hypertensive children and adolescents with Cushing’s syndrome decreased towards the normal range by 3 months after the correction of hypercortisolism and that blood pressure values continued to decrease for at least 1 yr. This finding is in accordance with the alleviation of cortisol excess effects on other human biological systems. Thus, the HPA axis recovers completely by about 6–12 months after surgical cure of patients with Cushing’s disease, and similarly, growth function is resumed early during the first postoperative year (35, 36, 37). Similarly, the skin manifestations of Cushing’s syndrome resolve within 12 months after surgical cure (38).

A significant positive correlation was observed between the systolic (but not diastolic or mean blood pressure) and the duration of the disease in our patients. The correlation between obesity and hypertension is well documented bibliographically (39, 40, 41, 42, 43, 44, 45, 46). However, although all of our patients had been obese during the hypercortisolemic state and their BMIs normalized by the end of the first year after surgical cure, we found no correlation between blood pressure and BMI values before or after cure. These findings suggest that, unlike the direct correlation of BMI with essential hypertension, the hypertension of patients with Cushing’s syndrome depends on the direct and/or indirect effects of increased cortisol concentrations on multiple biochemical pathways, whose activity is determined by different sets of genes expressed differently in each individual patient. These include not only potentiation of vasopressor systems, but also inhibition of vasodepressor systems, and to a lesser extent, salt retention. The positive correlation between the systolic blood pressure and the duration of the disease points towards the deleterious effects of prolonged hypercortisolism and the significance of early diagnosis and treatment. That the blood pressure normalized in all patients within a year from the correction of hypercortisolism suggests that young patients with hypercortisolism do not develop permanent microvessel remodeling leading to irreversible essential hypertension (47). We speculate that glucocorticoids, through their antigrowth factor and anticytokine effects (including blockade of the AP1 (cjun-cfos) and NF-kB transcription factors (48)), may protect the blood vessels from the detrimental effects of prolonged hypertension. Alternatively, the young age of the patients may be the explanation for this phenomenon.


   Footnotes
 
1 New addresses: Maria Alexandra Magiakou, M.D., Aglaia Kyriakou Children’s Hospital, University of Athens, Greece 11527; George Mastorakos, M.D., Endocrine Unit, Evgenidion Hospital, University of Athens, Greece 11527. Back

Received December 19, 1996.

Revised February 11, 1997.

Accepted February 24, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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