Sympathoadrenal Counterregulation in Patients with Hypothalamic Craniopharyngioma

Abstract

In humans, the role of hypothalamic centers for activation of counterregulatory release of catecholamines and glucagon during hypoglycemia is unclear. To address this question, we investigated the counterregulatory response to acute insulin-induced hypoglycemia of glucagon, epinephrine, and norepi-nephrine in eight patients who had undergone transcranial surgery for a craniopharyngioma extending to the hypotha-lamic region. We compared the patients' responses with those of four patients suffering from hypopituitarism and of six healthy subjects. After the iv injection of 0.1 U of human insulin per kg of body weight in the patients or 0.15 U in healthy subjects, the plasma glucose concentrations decreased to similar minimum levels within 30 min in all three groups. All subjects recovered spontaneously from hypoglycemia within 2 h. In five of eight craniopharyngioma patients, only a small counterregulatory rise in plasma epinephrine (<2-fold) and norepinephrine could be observed (P < 0.05 for epinephrine and P 0.22 for norepinephrine vs. healthy controls). During hypoglycemia, virtually no adrenergic symptoms (tremor, heart pounding, and anxiety) were reported by these five patients , and changes in the heart rate were diminished. In three craniopharyngioma patients, the counterregulatory increase in catecholamines was unimpaired, adrenergic symptoms were reported and a rise in heart rate was observed during hypoglycemia. In all craniopharyngioma patients, the coun-terregulatory glucagon response to hypoglycemia was preserved and orthostasis increased both catecholamines and the heart rate similar to in the patients with hypopituitarism as well as in the healthy controls. Our results demonstrate selective impairment of counterregulatory sympathoadrenal activation in patients who had undergone surgery for a cra-niopharyngioma extending to the hypothalamic region. This strongly suggests the involvement of hypothalamic centers in hypoglycemia-induced activation of the sympathoadrenal axis in humans. It remains unclear as to whether hypoglyce-mia-induced glucagon secretion is also controlled by the hy-pothalamus. However, a common hypothalamic center controlling both counterregulatory catecholamine and glucagon release is unlikely, and sympathoadrenal activation is not required for hypoglycemia-induced glucagon secretion in humans. (J Clin Endocrinol Metab 87: 624-629, 2002) A DECREASE IN blood glucose stimulates the secretion of several counterregulatory hormones such as glu-cagon, catecholamines, cortisol, and GH (1, 2). These hormones act in concert to prevent or correct hypoglycemia. The role and contribution of the individual counterregulatory hormones in the correction of hypoglycemia is relatively well understood (1, 2). The mechanisms, however, and the loci responsible for activation of counterregulatory hormone release are less well defined. In various animal models, conflicting results were reported concerning the tissues that sense hypoglycemia and those which coordinate the coun-terregulatory endocrine responses (3-12). More recent studies in rats suggested that nuclei in the ventromedial hypo-thalamus are involved in the activation of counterregulatory glucagon and catecholamine secretion (13, 14). In humans, however, the role of hypothalamic centers for activation of counterregulatory release of catecholamines and glucagon during hypoglycemia is poorly understood. Evidence that the hypothalamus is involved stems from a patient who suffered from neurosarcoidosis and infiltration of the hypo-thalamus, and who had a complete loss of the counterregu-latory response to hypoglycemia (15). To further explore this question, we investigated the counterregulatory response of glucagon, epinephrine, and norepinephrine in patients who had undergone transcranial surgery for a craniopharyngi-oma extending to the hypothalamic region. We compared them to a group of patients suffering from hypopituitarism and to a group of normal subjects. Subjects and Methods Subjects Eight patients who received transcranial surgery for a craniophar-yngioma extending to the hypothalamic region (group A), four patients with hypopituitarism (group B), and six healthy volunteers (group C) were studied. Group A: Patients with craniopharyngioma (six males and two females) who were aged 18-46 yr (mean sem 34 3.5 yr) and had a body mass index (BMI) of 19-38 kg/m 2 (mean sem 28.3 1.8 kg/m 2). Transcranial surgery was performed 1-16 yr (mean sem 4 2 yr) before this study. Postoperatively, the patients required standard replacement therapy for hypopituitarism (hydrocortisone, levothyroxine, and sexual hormones), and diabetes insipidus (desmopressin). According to their adrenergic counterregulatory response, the patients were divided into groups A1 and A2 (see Results). The BMI of patients in group A1 was 26.6 2 kg/m 2 (mean sem, n 5), and in the patients of group A2 it was 31.1 3.6 kg/m 2 (n 3). Five craniopharyngioma patients suffered from postoperative weight gain (four in group A1 and one in group A2). Group B: Patients with hypopituitarism (three males and one female) were aged 34-48 yr (mean sem 41 3.2 yr) and had a BMI of 24-28 kg/m 2 (mean sem 25.6 1 kg/m 2). Causes of the hypopituitarism in these patients were due to transsphenoidal surgery of a chromophobe pituitary adenoma (1 patient), autoimmune hypophysitis (one patient), and empty sella syndrome (two patients). All patients received standard replacement therapy for hypopituitarism (hydrocortisone, levothyrox-ine, and sexual hormones). Abbreviation: BMI, Body mass index.