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|Year : 2012 | Volume
| Issue : 4 | Page : 390-394
Pituitary dysfunction in survivors of spontaneous subarachnoid hemorrhage of anterior communicating artery and middle cerebral artery aneurysms: A comparative study
Pinaki Dutta1, Kanchan K Mukherjee2, Prashant K Chaudhary2, Shriq Rashid Masoodi3, Srinivasan Anand4, Ashis Pathak2, Viral N Shah1, Suresh Narain Mathuriya2
1 Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Endocrinology, Sher-e-Kashmir Institute, Jammu & Kashmir, Department of Neurosurgery, PGIMER, Chandigarh, India
4 Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||30-May-2012|
|Date of Decision||21-Jun-2012|
|Date of Acceptance||28-Jul-2012|
|Date of Web Publication||6-Sep-2012|
Kanchan K Mukherjee
Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
Background: The data on incidence of hypopituitarism after SAH are conflicting. Furthermore, it is still not known whether there is any difference in hormonal deficiencies between SAH due to anterior communicating artery (A-com) and middle cerebral artery (MCA) aneurysms. Materials and Methods: This study includes both retrospective and prospective arms. The data collected included baseline demographic profile, clinical severity on admission to the hospital by the Hunt and Hess grading system and World Federation of Neurological Surgeons (WFNS) grading, radiological severity of bleed by the Fisher's classification, and treatment details. All the patients underwent detailed hormonal evaluation at baseline and 6 months in prospective group while at the end of 1 year in the retrospective group. Hormonal deficiencies between patients with A-com and MCA aneurysmal SAH were compared using appropriate statistical tests. Results: Of 60 patients studied, 47 patients (A-com: 28 and MCA: 19) were in the retrospective group, while 13 patients (A-com-9, MCA-4) were in the prospective group. The baseline data were comparable between the two groups. At or after 6 months follow-up, 19 (31.6%) patients, 10 patients with A-com and 9 patients with MCA aneurysmal SAH, had some form of hormone deficiency. Furthermore, there was no difference in endocrine dysfunctions between the two groups. There was no correlation between the severity of hormonal deficiency and the clinical severity of SAH grade by Hunt and Hess and radiological grade of SAH by Fisher's grade. Conclusion: Hormonal deficiencies are not uncommon in patients with SAH. There is no difference in hormonal deficiencies and severity of hypopituitarism in patients with SAH due to A-com and MCA bleed.
Keywords: Aneurysm, subarachnoid hemorrhage, hypopituitarism
|How to cite this article:|
Dutta P, Mukherjee KK, Chaudhary PK, Masoodi SR, Anand S, Pathak A, Shah VN, Mathuriya SN. Pituitary dysfunction in survivors of spontaneous subarachnoid hemorrhage of anterior communicating artery and middle cerebral artery aneurysms: A comparative study. Neurol India 2012;60:390-4
|How to cite this URL:|
Dutta P, Mukherjee KK, Chaudhary PK, Masoodi SR, Anand S, Pathak A, Shah VN, Mathuriya SN. Pituitary dysfunction in survivors of spontaneous subarachnoid hemorrhage of anterior communicating artery and middle cerebral artery aneurysms: A comparative study. Neurol India [serial online] 2012 [cited 2019 Sep 17];60:390-4. Available from: http://www.neurologyindia.com/text.asp?2012/60/4/390/100729
| » Introduction|| |
The incidence of spontaneous subarachnoid hemorrhage (SAH) is 6 per 100,000 patients with the age peak between fourth to sixth to decade; however, there are no studies in India to determine that whether incidence is similar to the developed nations. , Anterior communicating artery (A-com) aneurysms are the commonest aneurysm and ruptured aneurysms accounts for nearly 85% of SAH.  Mortality reported with aneurysmal SAH (aSAH) is about 50% and furthermore, survivors of aSAH are left with high morbidity. , aSAH also pose risk for hypothalamo-pituitary dysfunctions as a result of proximity of hypothalmo-pituitary structure to the circle of Willis. Over the last few years, number of studies has been carried out to determine hypothalamo-pituitary dysfunction in survivor of aSAH. ,,,,,,, Hypopituitarism is not an uncommon complication of aSAH and reported frequency of endocrine dysfunction in most of the studies varied between 11% and 50%. ,,, However, most of these studies were retrospective and have some methodological limitations. Recent prospective study with robust methodology by Klose and colleagues  failed to demonstrate chronic hypopituitarism in the survivors of aSAH. Endocrine disturbances may be the result of either compression of the hypothalamic-pituitary complex by the aneurysm itself or post hemorrhagic local tissue pressure changes or toxic effects of the extravasated blood, ischemia caused by vasospasm, elevated intracranial pressure, hydrocephalus, or local injury during surgery. , Theoretically, all these complications should be true for aneurysms of the A-com as portions of hypothalamus get blood supply from arteries derived from A-com artery. Thus, we hypothesize that SAH secondary to rupture of A-com aneurysms should have more endocrine dysfunctions than SAH secondary to rupture of middle cerebral artery (MCA) aneurysms. However, till date none of the studies have tested this hypothesis. Considering these lacunae in the literature, we aimed to analyze the incidence of endocrine dysfunction in patients with SAH and to compare their occurrence and severity between SAH due to A-com and MCA aneurysms.
| » Materials and Methods|| |
This study was carried out in the departments of Neurosurgery and Endocrinology at Postgraduate Institute of Medical Education and Research, Chandigarh, India, and has the approval of the Institutional Ethics committee. The study included 60 patients, 47 in the retrospective group and 13 in the prospective group. The retrospective group included 47 patients with aSAH (A-com; 28 and MCA; 19) and had ictus at least 1 year ago. Records of survivors of SAH secondary to A-com and MCA aneurysmal rupture were traced from Central Record Department (CRD) of the institute. The addresses and/or telephone numbers mentioned in their records were noted. Then letters were sent to all of them for follow-up visits in the outpatient clinic. Direct telephonic communications were made with 57 patients and total 47 patients gave written informed consent to participate in the study. The prospective group included 13 patients who presented within 72 h of ictus. A baseline hormonal profile was done before surgery and a follow-up hormonal analysis was carried out at 6 months or later of ictus. Clinical, biochemical investigations, management, and outcome data were recorded in all the patients. Complete pituitary hormone profile was assessed along with the clinical and biochemical profiles for patients with SAH from A-com and MCA aneurysms. The patients with a known history of diabetes mellitus, thyroid disorders or other pituitary dysfunctions, other systemic diseases, uncontrolled hypertension, patients with multiple aneurysms, and patients who refused to give consent to participate in the study were excluded from the study. The following variables were recorded in all the patients: age, sex, clinical severity on admission to the hospital by Hunt and Hess  and World Federation of Neurological Surgeons (WFNS) grading, radiological severity by Fisher grade,  aneurysm location, treatment modality, and SAH-related complications, such as vasospasm, intraoperative rupture, hydrocephalus, rebleeding, high intracranial pressure, or epileptic seizures, were recorded.
Evaluation of anterior pituitary functions was carried out in all the patients. Samples for all the hormones were taken between 0800 and 0900 h as per the departmental protocol in EDTA vial and were sent to the laboratory immediately for analysis. Serum T4 (normal range: 4.8-12.7 μg/dl), luteinizing hormone (LH) (men: 1.7-8.6 mIU/ml and women: 2.4-12.6 mIU/ml), follicle stimulating hormone (FSH) (men: 1.5-12.4 mIU/ml and women: 3.5-12.5 mIU/ml, postmenopausal >30 mIU/L), prolactin (men: 4.0-15.2 ng/ml and women: 4.79-23.3 ng/ ml), testosterone (9.9-27.8 nmol/L), estradiol (12.5-166 pg/ ml), and cortisol (0800 h: 171-536 nmol/L) were estimated by immunochemiluminiscence (Elecys2010, Roche Diagnostic, Germany). Insulin like growth factor-1 (IGF-1) was estimated by enzyme immuno assay method (DRG international, EIA-2947, Germany) and for IGF-1 age and gender-specific normative data as provided by the manufacturer kit was used. Urine (500-850 mosmol/kg) and serum (275-300 mosmol/kg) osmolality were assessed by freezing point depression method (Fiske micro sample osmometer, USA).
Endocrine abnormalities definitions
Criteria used to define pituitary hormone deficiency or excess were as follow: secondary hypothyroidism was diagnosed when T 4 level was less than 4.8 μg/dl with low or normal thyroid stimulating hormone (TSH) level. Central hypogonadism in men was defined as serum testosterone < 9 nmol/L in the presence of low or normal levels of LH and in women, it was defined as 17 β estradiol levels < 12 pg/ml in presence of low or normal gonadotropins, while in postmenopausal women low or inappropriately normal gonadotropins for age was considered diagnostic (FSH < 30 mIU/L). Prolactin levels below 5 ng/ml in both sex were considered to be low.
The statistical analysis was carried out using SPSS 11. Data were represented as mean ± SD unless specified. The normality of the variables was checked by Kolmogorov-Simrnov test. The parametric tests used for continuous data were independent student "t0" test for unpaired samples and paired "t" test for paired variables. The nonparametric tests used were Wilcoxon-signed rank test for paired samples and Man-Whitney U test for unpaired variables. Correlation for nonparametric data was assessed by Spearman correlation test. P < 0.05 was considered as significant.
| » Results|| |
A total of 158 individuals with aSAH were screened and finally, 60 patients (37 male) with the mean age of 44.9 ± 13.1 years were evaluable [Figure 1]. Of the 23 women, 12 were postmenopausal. Of the 60 patients with aSAH, 23 had SAH from MCA aneurysm rupture, while 37 patients had SAH resulting from A-com aneurysm rupture; 47 patients (A-com: 28 and MCA: 19) were in the retrospective group, while 13 patients were (A-com: 9 and MCA: 4) in the prospective group.
In the prospectively studied patients, growth hormone (GH) status depicted as mean IGF-1 values was normal (149.00 ± 16.30 ng/dl) at ictus, but it decreased to 96.10 ± 56.35 ng/ml at 6 months (P = 0.05). Eight patients had hypogonadism at ictus and at 6 months of follow-up, only four had hypogonadism and all these four patients had new onset hypogonadism. Similarly seven patients were GH deficient at ictus as depicted by lower age and gender matched IGF-1 values. At the end of 6 months, five patients were GH deficient, out of these two had new onset GH deficiency and three continued to have GH deficiency since ictus. Three patients had central hypothyroidism as defined by low T4; two of them recovered and only one had persistent hypothyroidism at 6 months. One patient had diabetes insipidus which recovered on follow- up. Two patients developed new onset chronic persistent hyponatremia.
Since there was no difference in clinical, radiological, and hormonal profile between retrospective and prospective groups at or after 6 months follow-up, these patients were analyzed together for endocrine dysfunctions [supplementary Table 1]. [Additional file 1] None of the patients in retrospective group or prospective group had history of hormone replacement therapy, clinical features of pre-ictal hormonal deficiency, and no structural abnormalities of hypothalamous or pituitary on imaging. Overall, 19 (31.6%) patients had one or more hormonal deficiency at 6 months following aSAH, with central hypogonadism being the most common hormone deficiency (36.6%), followed by GH deficiency (15%). Seven patients in A-com group had one hormone deficiency and three had two or more hormone deficiencies, while in the MCA group eight patients had one hormone deficiency and one had two hormone deficiencies. Two patients in each group had diabetes inspidus, while syndrome of inappropriate antidiuretic hormone secretion was noted in two patients in the A-com group. These pituitary dysfunctions between the two groups remained statistically nonsignificant except for prolactin deficiency and SIADH, being more common in patients with A-com aSAH [Table 1]. There was no correlation between the clinical and radiological severity of SAH graded by Hunt and Hess and Fisher's grade, respectively, with that of severity of hormone deficiency supplementary.
|Table 1: Clinical and hormonal differences between patients|
with A-com SAH and MCA SAH at 6 months
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| » Discussion|| |
In this study, the incidence of hyopituitarism was 31.6% at or after 6 months in survivors with aSAH. The clinical and radiological severity of aSAH did not correlate with the degree of endocrine dysfunction. There was no difference in hormonal outcome according to site of aneurysmal bleed. Endocrine dysfunctions as a complication of aSAH may improve or new hormonal deficiencies may appear with time.
The frequency of any hormone deficiency in patients with aSAH at 6 months was 30% in our study. This finding is in concordance with most other studies but not with some studies. ,,,,,, The differences in the results of these studies are related to different inclusion criteria, study design and variable definition for hypopituitarism, and difference in assay cut-off for various hormones.
In most of the previous studies, most common hormone deficiency was GH deficiency followed by gonadotrophins, adrenocorticotrophic hormone (ACTH), and TSH.  However, in our study, we found gonadotrophin deficiency as commonest. A study by Klose et al. found ACTH as the commonest hormone deficiency in patients with aSAH.  The differences in age, gender, and severity of global health impairment might have also influenced the results. The Hunt and Hess, and Fisher's grades are of limited utility for global assessment. In our study, glucocorticoid deficiency was found only in one subject in the long run; however, approximately one third of the patients had poor glucocorticoid reserve requiring sick day guideline. Again, these differences in the results may be due to different tests used, different assays, and different cut-offs used to define deficiencies. In the present study, new onset hormone deficiency was observed between 6 and 12 months and most of these were single hormone deficiency. The early deficiencies in the prospective group were mostly transient and recovered during follow-up. A few new deficiencies developed in patients who had absolutely normal function at baseline. Therefore, repeat hormonal evaluation is warranted at 6-12 months in all patients to find out late onset deficiency.
Acute hormonal deficiencies may be the result of bleed, pressure effects, vasospasm, or ischemia, ,,,, which may be reversible with treatment, and hence, some of the hormonal deficiencies recover over the period of time. However, later on due to infarct or structural damage to hypothalamo-pituitary axis, new hormone deficiency develops or becomes permanent. These may be the reason for recovery or appearance of new hormone deficiency, as seen in our prospective cohort of SAH.
The endocrine disturbances in aSAH may be the result of any of the causes mentioned above. , This may be particularly true for aneurysms of the A-com artery. Hypothalamic area gets perforators from proximal portion of stem of anterior cerebral, carotid, and posterior communicating arteries. The perforating arteries lie in the floor of third ventricle and vulnerable to vasospasm. The seminal autopsy data by Crompton in 1983 substantiated this hypothesis. In that study, hypothalamic lesions were found in 69% and 42 % of patients with SAH from A-com and MCA aneurysms, respectively.  Considering the above facts, it is expected that patients with SAH from A-com aneurysm should have more prevalent and severe hormonal insufficiency as compared to patients with SAH from MCA aneurysms. In our study, there was no significant difference in patients with SAH from A-com aneurysms versus MCA aneurysms. This may suggest that hormonal deficiency may not correlate well with the with the site of aneurysms. SAH from either A-com or MCA aneurysm is usually diffuse around hypothalamo-pituitary structure and may result in similar hormonal deficiencies as observed in our study. This hypothesis is further substantiated by the findings of our study; of the 60 patients, 49 patients had Fisher's grade 3 or more SAH on imaging.
In our study, there was no correlation between the severity of hormonal deficiency and clinical stage at admission as assessed by Hunt and Hess scale and radiological severity as assessed by Fisher's grade. This observation is similar to the findings in the other studies. , We believe that some global health impairment scoring system like acute physiology and chronic health evaluation (APACHE) or sequential organ failure assessment (SOFA) score would have been better tools than that of Hunt and Hess or Fisher's grade. However, this has not been examined in any clinical trial till date. Clinical severity of SAH does not help to discriminate between patients at high and low risk of developing hypopituitarism, and hence, we recommend that all the patients should be subjected to endocrine evaluation not only at baseline but after 6-12 months too. Another striking observation in our study was more number of patients was in poor Hunt and Hess grade than poor WFNS grade. This could be explained by the fact that patients with confusion (drowsiness) would be categorized into Hunt and Hess grade 3; however, the Glasgow Coma Scale score in these patients would be 13 or 14, and thus, these patients would be categorized into WFNS grade 2, which is a good grade SAH. There were 13 such patients in this study.
The limitations of our study are small sample size in the prospective group, not performing dynamic tests, lack of control group with other neurological illness having same global health score, and temporary clipping time.
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