Acta Neurol. Scandinav. 52, 56-62, 1975

Department of Neurology, University Hospital, Uppsala, Sweden.

HYPOTHALAMO-PITUITARY-ADRENAL FUNCTION FOLLOWING SUBARACHNOID HEMORRHAGE PEROLOFOSTERMAN ABSTRACT The endocrine function was evaluated in 50 patients a minimum of

3.5 months after a subarachnoid hemorrhage. The hypothalamopituitary-adrenal function was assessed by studying the circadian rhythm of plasma 11-hydroxycorticosteroids and with t h e metyrapone test. I n addition, screening methods were used to evaluate thyroid and gonadal functions. The results indicate that hypothalamo-pituitaryadrenal disturbances may occur i n patients surviving a subarachnoid hemorrhage. In patients who have survived a subarachnoid hemorrhage more than 3.5 months, however, frank bypopituitarism i s rare.

Lesions of the hypothalamus are commonly found in patients dying due to rupture of an intracranial aneurysm. The aneurysms which are most likely to produce hypothalamic lesions are those arising from the anterior or posterior communicating arteries (Crompfon 1963). Lesions of the hypothalamus and pituitary gland are found also in non-aneurysmal subarachnoid hemorrhages, e.g. in patients dying of intracerebral hemorrhage with extension to the subarachnoid space (Rap 1967). Jenkins et al. (1969) found a high frequency of disturbed hypothalamo-pituitary-adrenal function in patients with a ruptured aneurysm of the anterior communicating artery. Their tests were performed within 1 month of the subarachnoid hemorrhage. An improvement in the endocrine function was seen in many patients after another month. The present study was undertaken to evaluate the endocrine function in 50 patients a minimum of 3.5 months after a subarachnoid hemorrhage. The hypothalamo-pituitary-adrenal function was assessed by studying the circadian rhythm of plasma 11-hydroxycorticosteroids and with the metyrapone test. In addition, screening methods were used to evaluate thyroid and gonadal functions.

57 PATIENTS AND METHODS Fifty patients, 30 females and 20 males, were studied 3.5-26 (mean 5.3) months after a spontaneous subarachnoid hemorrhage. They were 25-65 years of age (mean 45). Angiography had demonstrated an aneurysm of the middle cerebral artery in 16 patients (all surgically treated); an aneurysm of the anterior communicating artery i n 14 patients (13 surgically treated); and a n aneurysm of the internal carotid artery i n 11 patients (all surgically treated). An additional 3 patients were operated on for an aneurysm of the pericallosal artery, of the posterior communicating artery and of the posterior spinal artery, respectively. One patient had a non-surgically treated occipital arteriovenous malformation. In 5 patients, bilateral carotid and unilateral vertebral angiograms did not dcmonstrate a bleeding source. Four patients were receiving diphenylhydantoin therapy (0.3 g daily). Otherwise no drugs were administered that could be suspected to interfere with the tests used. The circadian plasma cortisol pattern was studied by measurement of ll-hydroxycorticosteroids i n plasma every 4 h for 24 h from 8 a.m. Plasma ll-hydroxycorticosteroids were assayed by a fluorimetric method that measured non-conjugated 11-hydroxycorticosteroids (Mattinglg 1962). For characterization of a “normal” circadian cortisol pattern, the results of a previous study of a control group were used (Osterman et al. 1973). The plasma cortisol rhythm was considered normal when the difference between the highest of the two morning values ( 4 a.m. o r 8 a.m.) and the lowest of the two evening values (8 p.m. or midnight) was greater than 6.4 pg/lOO ml. The plasma cortisol level was considered normal when the average level of plasma 11-hydroxycorticosteroids for the 24-hour period was within the range 8.1-21.7 pg/lOO ml. The metyrapone test was performed i n all but one patient. Metopiron@ (Ciba) 4.5 g was given i n 4-hourly divided doses, and the urinary excretion of 17-hydroxycorticosteroids was measured for 3 days. An increase of total 17-hydroxycorticosteroids i n t h e urine of less than 7.7 mg per 24 h was regarded as a pathological response (Lundberg & Wide 1969). Thyroid function was determined i n all patients by clinical examination and the estimation of protein-bound iodine o r thyroxin, the resin uptake of 1311-labelled triiodothyronine, cholesterol and the basal metabolic rate. In one patient, who had

Table I . The results of the circadian cortisol studies and metyrapone tests in 50 patients a minimum of 3.5 months after a subarachnoid hemorrhage.

Aneurysm site

Plasma cortisol pattern

Metyrapone test

Normal

Pathological

Normal

Pathological

Middle cerebral Anterior communicating Internal carotid Pericallosal Other sites No aneurysm found

16 14 9

0 3 5

0 0 2 1 0

0

15 9 11 1 3 5

0 5 0 0 0 0

Total

47

3

44

5

58 moderate thyroid hypofunction, t h e radioiodine uptake by the thyroid was also determined. The hypothalamo-pituitary-gonadal function was assessed i n men by examination of external genitalia and h a i r distribution as well a s by questioning of sexual function. In women of fertile age, the hypothalamo-pituitary-gonadaI function was assessed by presence and type of menstrual cycle. Normal menstrual cycles were taken as an indication of normal gonadotropin levels. The normally high levels of FSH and LH i n postmenopausal women are often pathologically reduced in those with tumours of t h e sellar region ( W i d e & Lundberg, to be published). FSH and LH were therefore determined i n postmenopausal women. Immunoreactive FSH and LH i n serum were assayed by a radioimmunosorbent technique ( W i d e e t al. 1967, W i d e et al. 1973) by L. Wide, Department of Clinical Chemistry, University Hospital, Uppsala. RESULTS

The circadian cortisol pattern was normal in 47 and pathological in only 3 patients (Table 1).In 2 patients with internal carotid aneurysms, the plasma cortisol rhythm was abnormal. I n the patient with a pericallosal aneurysm, the plasma cortisol level was pathologically high. The metyrapone test was pathological in 5 of the 14 patients with anterior communicating aneurysms, and normal in the other 35 patients (Table 1 ) . Three of the 5 patients in whom the metyrapone test gave a pathological result were receiving diphenylhydantoin 0.3 g daily. I n two of these patients, the serum level of diphenylhydantoin was determined and found to be 0.4 mg/100 ml a t the time of the tests. In the patient with the occipital arteriovenous malformation, the metyrapone test was normal while the patient was on treatment with diphenylhydantoin (serum level 0.7 mg/100 m l ) . The thyroid function was normal in all patients, except one in whom moderate thyroid hypofunction was found. This patient had an anterior communicating aneurysm, a pathological result of the metyrapone test, and was receiving diphenylhydantoin. The gonadotropin levels were normal in all postmenopausal women (13 patients). All of the other women had normal menstrual cycles. There was no evidence of hypogonadism in any of the males. DISCUSSION

Endocrine disturbances, as well as radiological abnormalities and visual field defects of a type which occur with pituitary tumours, may be caused by intracranial aneurysms ( W h i t e & Ballantine 1961, Van’t Hoff et al. 1961, Kahana et al. 1962, Arseni et al. 1970, Shantharam & CZift 1974). The most common artery of origin for aneurysms that project into the sella turcica is the internal carotid. Signs of endocrine

59 disturbances are usually those of hypopituitarism but acromegaly (Girard et al. 1953, Gouazt et al. 1967) and Cushings syndrome (Hook & Norltn 1958, Arseni et al. 1970) have also been reported. Nonruptured aneurysms may cause pituitary dysfunction both by direct compression and by interfering with the vascular supply to the hypothalamus and the pituitary. Bleeding from aneurysms in the sellar region may cause frank hypopituitarism (Gerstenbrand & Weingarten 1963, Cartlidge & Shaw 1972). A high incidence of disturbed hypothalamo-pituitary-adrenal function was also found by Jenkins et al. (1969) in 18 patients with ruptured aneurysm of the anterior communicating artery. The endocrine disturbances in these cases were probably caused by hypothalamic lesions. Crompton (1963) found regions of ischemic necrosis and hemorrhages in the hypothalamus in 22 of 32 patients dying from ruptured anterior communicating aneurysms, and in 19 of 27 patients dying from ruptured posterior communicating aneurysms. He ascribed the hypothalamic lesions either to damage of the fine hypothalamic arteries in the subarachnoid space by closely adjacent aneurysms bleeding directly onto them or to distortion of the perforating vessels by severe distension of their perivascular sheaths by blood from the subarachnoid space. In some cases, massive hemorrhages were found, due to blood from an aneurysm rupturing through the hypothalamus and into the ventricles. According to R a p (1967, 1971) secondary morphological alterations may be found in the hypothalamo-hypophyseal system, not only in patients dying from subarachnoid hemorrhages, but also in patients with increased intracranial pressure of any cause. He suggested that these secondary lesions were caused by mechanical factors and disturbances in the cerebral circulation of the blood and cerebrospinal fluid. The present study was undertaken to see whether the reported frequent occurrence of a disturbed hypothalamo-pituitary-adrenal function following recent subarachnoid hemorrhage (Jenkins et al. 1969) could still be found a minimum of 3.5 months after the subarachnoid hemorrhage, and in a large series of patients with several types of aneurysms. The results indicate that disturbances of the hypothalamo-pituitary-adrenal function are uncommon in patients who have survived a subarachnoid hemorrhage for more than 3.5 months. The circadian cortisol pattern was abnormal in only 3 out of 50 patients, and the metyrapone test was pathological in only 5 out of 49 patients. In no case was the functional reduction so severe that substitution therapy was considered. Furthermore, thyroid hypo-

60 function was found in only one patient, and clinical or laboratory signs of hypogonadism were not seen. Three of the five patients in whom the metyrapone test gave a pathological result were receiving diphenylhydantoin. It has been shown that diphenylhydantoin may diminish or block the response to metyrapone (Krieger 1962, Rinne 1966). It is therefore probable that the diphenylhydantoin treatment had contributed to the pathological response in these cases. The serum level of diphenylhydantoin, however, was rather low (0.4 mg/100 ml) in two of the patients. The therapeutic range of diphenylhydantoin serum levels for control of epileptic seizures is generally considered to be 1-2 mg/100 ml (Buchthal et al. 1960, Lund 1974). Moreover, the patient whose response to metyrapone was normal had a serum diphenylhydantoin level of 0.7 mg/100 ml. It is therefore possible that the diphenylhydantoin was not the sole cause of the pathological responses to metyrapone. In addition to a pathological metyrapone test, one patient treated with diphenylhydantoin had thyroid hypofunction. The latter diagnosis was established by a lowered protein-bound iodine, high levels of cholesterol and triglycerides, and a low radioiodine uptake by the thyroid. Serum protein-bound iodine, thyroxin and triiadothyronine may be decreased during diphenylhydantoin treatment; but in patients receiving diphenylhydantoin, the radioiodine uptake by the thyroid was increased compared to that in controls ( M d h o l m Hansen e t al. 1974). Laboratory data in this case with a pathological metyrapone test, therefore, indicate that there was in fact thyroid hypofunction, and that the endocrine abnormalities were more extensive than could be explained by diphenylhydantoin alone. It is striking that the metyrapone test was pathological in 5 of 14 patients with anterior communicating aneurysms and normal in the other 35. Even if the effect of diphenylhydantoin in 3 patients is taken into consideration, it seems probable that there is a correlation between the aneurysm site and the response to the metyrapone test. The higher frequency of hypothalamic lesions observed in anterior communicating aneurysms (Crompton 1963) could explain the more frequent pathological response to the metyrapone test in these patients. All the patients with endocrine disturbances had been operated on. Endocrine disturbances may be provoked by aneurysm surgery and especially for anterior communicating aneurysms (Landolf e f al. 1972). It is therefore possible that the operative procedure also contributed to the hypothalamic lesions causing the endocrine abnormalities in some patients in the present series.

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P . 0. Osferman, M.D.

Neurologiska kliniken Akademiska sjukhuset S-750 1 4 Uppsala 1 4 Sweden

Hypothalamo-pituitary-adrenal function following subarachnoid hemorrhage.

The endocrine function was evaluated in 50 patients a minimum of 3.5 months after a subarachnoid hemorrhage. The hypothalamo-pituitary-adrenal functio...
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