Structured Assessment of Hypopituitarism after Traumatic Brain Injury and Aneurysmal Subarachnoid Hemorrhage in 1242 Patients: The German Interdisciplinary Database

Abstract

Clinical studies have demonstrated that traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH) are frequent causes of long-term disturbances of hypothalamo-pituitary function. This study aimed to assess the prevalence and associated factors of post-traumatic hypopituitarism in a large national registry of patients with TBI and SAH. Data were collected from 14 centers in Germany and Austria treating patients for TBI or SAH and performing endocrine assessments. Data were collected using a structured, internet-based study sheet, obtaining information on clinical, radiological, and hormonal parameters. A total of 1242 patients (825 TBI, age 43.5±19.7 years; 417 SAH, age 49.7±11.8 years) were included. We studied the prevalence of hypopituitarism reported based on different definitions of laboratory values and stimulation tests. Stimulation tests for the corticotropic and somatotropic axes were performed in 26% and 22% of the patients, respectively. The prevalence of hypopituitarism in the chronic phase (at least 5 months after the event) by laboratory values, physician diagnoses, and stimulation tests, was 35%, 36%, and 70%, respectively. Hypopituitarism was less common in the acute phase. According to the frequency of endocrine dysfunction, pituitary hormone secretion was impaired in the following sequence: ACTH, LH/FSH, GH, and TSH. TBI patients with abnormal stimulation tests had suffered from more severe TBI than patients with normal stimulation tests. In conclusion, our data confirm that hypopituitarism is a common complication of TBI and SAH. It is possible that patients with a higher likelihood of hypopituitarism were selected for endocrine stimulation tests.

Introduction

T raumatic brain injury (TBI) is the leading cause of death and disability in young adults, affecting 235 per 100,000 persons per year. Aneurysmal subarachnoid hemorrhage (SAH) occurs in 6–10 per 100,000 inhabitants each year. Survivors of both TBI and SAH often suffer significant chronic adverse physical and psychological impairments due to the trauma (Schneider et al., 2007b).

Several studies from the last decade have shown that TBI and/or SAH put patients at substantial risk of subsequent hypopituitarism (Agha et al., 2004a, 2004b, 2005a, 2005b; Aimaretti et al., 2005; Bondanelli et al., 2004; Herrmann et al., 2006; Kelly et al., 2000; Klose et al. 2007a,2007b; Kreitschmann-Andermahr et al., 2004; Leal-Cerro et al., 2005; Lieberman et al., 2001; Popovic et al., 2004; Schneider et al., 2006; Tanriverdi et al., 2006). In a systematic review of the literature analyzing published data on 911 patients in the chronic stage after TBI or SAH, the prevalence of any type of hypopituitarism and of multiple hormone deficiencies was 30% and 8%, respectively (Schneider et al., 2007b). These were clinical studies with fixed protocols and predefined inclusion and exclusion criteria.

However, to date it is not clear if these findings also extend to everyday practice and how relevant this is to routine treatment of patients with these brain pathologies. To address this question, we launched an interdisciplinary database, the German Database on Hypopituitarism after Traumatic Brain Injury and Aneurysmal Subarachnoid Hemorrhage. This allows each participating center to enter data on clinical and endocrine function in patients with TBI and SAH in structured form. In this article, we describe the results of the prevalence and associated covariates of hypopituitarism in this database.

Methods

The study complied with the Declaration of Helsinki and was approved by the ethics committee of the Bavarian Chamber of Physicians. All patients gave written informed consent.

Data were collected using a structured, internet-based study sheet, obtaining information on clinical, radiological, and hormonal parameters. We collected data on the type and severity of the brain trauma and on endocrine function. Participating centers were asked to provide clinical and endocrine information as completely as possible. However, the database was designed to be as open as possible. Therefore we did not preclude patients from being added to the database if only a minimal amount of information was present. Details on the methodology and a description of the population have been published elsewhere (Kreitschmann-Andermahr et al., 2011).

At the close on November 20, 2008 13 centers in Germany and one center in Austria had included a total of 1242 patients with TBI (n=825) or SAH (n=417) in the database for whom clinical data and basal hormone values were available.

Hormone levels were measured in the laboratories of the participating centers and recorded in the study sheets. We used different definitions of hormone deficiencies, depending on the quality of reporting:

Luteinizing hormone/follicle-stimulating hormone (LH/FSH) deficiency in men: testosterone <10.4 nmol/L (<3.0 μg/L); LH/FSH deficiency in women <50 years of age: amenorrhea; LH/FSH deficiency in women ≥50 years of age: LH <14 U/L; thyroid-stimulating hormone (TSH) deficiency: free thyroxine (T₄) <11 pmol/L and no history of previous thyroid disease as indicated by thyroid hormone replacement before TBI or SAH; adrenocorticotropic hormone (ACTH) deficiency: peak cortisol in stimulation test <500 nmol/L (<180 μg/L), or basal cortisol <100 nmol/L (<36μg/L) if no stimulation test was performed; growth hormone (GH) deficiency: peak GH below the predefined cutoff of the stimulation test or insulin-like growth factor-1 (IGF-1) levels below the local age- and sex-specific reference value if no stimulation test was performed. We allowed the following stimulation tests for assessment of the ACTH axis: insulin tolerance test (ITT), short ACTH test, and glucagon test (all with a cutoff of <500 nmol/L [<180 μg/L]). For assessment of the GH axis we allowed the ITT and the glucagon test using a GH cutoff of <3 μg/L, and the growth-hormone-releasing hormone (GHRH) + arginine test using body mass index (BMI)-dependent cutoffs (BMI <25, 25–29.9, and ≥30 kg/m²: GH <11.5 μg/L, <8 μg/L, and <4 μg/L, respectively; Ho et al., 2007).

Additionally, the treating physicians who were entering the data were asked to rate each pituitary axis as sufficient or deficient, based on local reference ranges, additional information, and clinical judgment. We analyzed these physician evaluations separately.

Statistical analysis

Data were analyzed separately for patients in the acute (<5 months) and in the chronic phase (>5 months). Descriptive statistics were used to summarize the data. Descriptive statistics of interval measured data are expressed as mean±standard deviation (SD). Missing variables were treated missing at random. We used the Mann-Whitney U test to compare differences in proportions, and analysis of variance (ANOVA) and the t-test for comparisons of means. A two-sided p value of <0.05 was considered clinically significant. All analyses were performed with SAS software (SAS Institute Inc., Cary, NC).

Results

Prevalence of hypopituitarism

Table 1 displays the baseline characteristics of all patients. Data on the severity by initial Glasgow Coma Scale (GCS) score or Hunt and Hess Scale (H&H) score, Glasgow Outcome Scale (GOS) score, and BMI data were available for 725, 1042, and 639 of the 1242 patients, respectively.

Table 1.

Baseline Characteristics

	n	TBI	n	SAH
Age, mean (SD)	821	45.1 (29.1)	415	50.2 (11.6)
% Male/female	822	73.5/26.5	414	33.3/66.7
% Acute/chronic	807	51.9/48.1	412	43.7/56.3
Body mass index, mean (SD)	379	25.3 (4.8)	260	27.2 (9.8)
Initial Glasgow Coma Scale score, median (IQR)	346	13.0 (10.0)
Initial Hunt and Hess score, median (IQR)			379	2.0 (2.0)
Glasgow Outcome Scale score, median (IQR)	687	4.0 (1.0)	355	4.0(1.0)

n=numbers of available data for each parameter.

SD, standard deviation; IQR, interquartile range; TBI, traumatic brain injury; SAH, subarachnoid hemorrhage.

To take into account differences in data quality, we used different definitions of hypopituitarism with numbers of studied subjects varying according to the completeness of endocrine data: A: Subjects with basal laboratory values: free T₄, cortisol, and testosterone in men, and IGF-1 (n=914); B: Subjects with the treating physician's evaluation of pituitary function (n=859); and C: subjects with stimulation tests for both ACTH and GH secretion in addition to basal endocrine evaluation (n=158).

Since acute illness may influence hormonal values, we analyzed patients in the acute (<5 months) and chronic phase (≥5 months) after TBI or SAH separately, using an arbitrary cutoff of 5 months as described previously (Schneider et al., 2007a). Even though changes in pituitary function have been observed even later than 12 months after TBI (Tanriverdi et al., 2008), we used this cutoff point for practicability. In a minority of patients, data on the time after the event were missing. These patients were excluded from the analyses. Therefore, the sums of patients reported below differ slightly from the numbers of patients reported for the definitions for A, B, and C above.

In the acute phase, the prevalence of any hypopituitarism among TBI and SAH patients were 39% and 23% by basal laboratory values, and 17% and 15% by physician diagnoses, respectively. In the chronic phase, the prevalence of any hypopituitarism among TBI and SAH patients were 38% and 32% by laboratory values, and 37% and 35% by physician diagnoses, respectively. Table 2 shows the prevalence of any, isolated, and multiple hypopituitarism by the different definitions. The prevalence of any hypopituitarism in the chronic phase by laboratory values, physician diagnoses, and stimulation tests was 35%, 36%, and 70%, respectively.

Table 2.

Prevalence of Hypopituitarism in Percent by Different Definitions

	Acute			Chronic
Definition	Any deficiency	Single deficiencies	Multiple deficiencies	Any deficiency	Single deficiencies	Multiple deficiencies
A (n=914)	35	32	3	35	30	5
B (n=859)	16	12	5	36	28	9
C (n=158)	70	45	25	60	49	11

A: basal laboratory values; B: physician diagnoses; C: stimulation tests.

Table 3 shows the prevalence of hormone deficiencies by axes. In the chronic phase, according to both laboratory values and treating physician evaluations, ACTH deficiency was most common, followed by LH/FSH deficiency, and GH deficiency. However, according to the stimulation tests, GH deficiency was the most common.

Table 3.

Prevalence of Hypopituitarism in Percent by Pituitary Axes and by Different Definitions

	Acute				Chronic
Definition	ACTH	LH/FSH	TSH	GH	ACTH	LH/FSH	TSH	GH
A (n=914)	3	1	1	2	13	9	5	6
B (n=859)	4	8	4	5	17	15	7	8
C (n=158)	15	15	5	60	27	16	1	31

A: basal laboratory values; B: physician diagnoses; C: stimulation tests.

ACTH, adrenocorticotropic hormone; LH/FSH, Luteinizing hormone/follicle-stimulating hormone; TSH, thyroid-stimulating hormone; GH, growth hormone.

Factors associated with hypopituitarism

We analyzed if there were differences in age, BMI, or GOS, GCS, or H&H scores between subjects with 0, 1, or at least 2 endocrine deficiencies as defined by basal hormone values (definition A). There were no differences in BMI, or GOS, GCS, or H&H scores. However, subjects with multiple hypopituitarism were significantly younger than subjects without hypopituitarism (mean age±SD: no hypopituitarism 44.2±17.5 years; multiple deficiencies 36.9±17.6 years; p=0.034).

We additionally analyzed whether any of the above-mentioned factors was associated with hypopituitarism if only subjects with stimulation tests for the GH and ACTH axes were studied (definition C). Here there were no significant associations in the total group. However, TBI patients with hypopituitarism had lower GCS scores (mean GCS±SD: no hypopituitarism 12.3±2.7; single deficiency 7.5±4.9; multiple deficiencies 4.0±1.2; p=0.021).

TBI patients in the chronic phase with stimulation tests for the ACTH or GH axes with deficiencies of the ACTH or GH axis had worse GOS scores than patients without deficiencies of these axes (mean GOS±SD: no deficiencies 4.6±0.6; deficiencies 4.4±0.8; p=0.032). These differences were no longer significant if GH or ACTH deficiency was analyzed alone. There were also no significant differences for GOS among SAH patients.

Discussion

To our knowledge this is the largest database to date assessing endocrine function in survivors of TBI and SAH. In our analysis, we found that one-third of all patients with TBI or SAH were affected by pituitary dysfunction. The prevalences found were comparable among TBI and SAH patients. In the acute phase relative to the chronic phase, lower prevalences of hypopituitarism were reported. If only subjects with stimulation tests for the corticotropic and somatotropic axes were included, the prevalence of hypopituitarism reached 70%. Hypopituitarism was associated with higher severity of TBI and with worse outcome in TBI patients with stimulation tests, but not in other patients.

The prevalence of post-traumatic hypopituitarism we found is in accord with previous publications showing similar prevalences (Agha et al., 2004a, 2004b, 2005a, 2005b; Aimaretti et al., 2005; Bondanelli et al., 2004, Herrmann et al., 2006; Kelly et al., 2000; Klose et al., 2007a,2007b; Kreitschmann-Andermahr et al., 2004; Leal-Cerro et al., 2005; Lieberman et al., 2001; Popovic et al., 2004; Schneider et al., 2006,2007b; Tanriverdi et al., 2006). However, more recent studies reported lower prevalences of hypopituitarism in patients with TBI (van der Eerden et al., 2010) and SAH (Klose et al., 2010), with prevalences of 1% and 0% after TBI and SAH, respectively. Several reasons may account for these discrepant findings.

First, the patients studied by van der Eerden and colleagues (2010) were consecutive patients from an emergency unit presenting with any degree of TBI. Therefore the majority of these patients had mild TBI. The patients included in this database, on the other hand, as well as most patients studied in previous reports, mainly represent patients with prolonged hospitalization and thus a much higher degree of TBI severity (Agha et al., 2004a, 2004b, 2005a, 2005b; Aimaretti et al., 2005; Bondanelli et al., 2004; Herrmann et al., 2006; Kelly et al., 2000; Klose et al., 2007a,2007b; Kreitschmann-Andermahr et al., 2004; Leal-Cerro et al., 2005; Lieberman et al., 2001; Popovic et al., 2004; Schneider et al., 2006,2007a; Tanriverdi et al., 2006).

Furthermore, in the studies by van der Eerden and associates (2010) and Klose and colleagues (2010), abnormal screening results required a confirmation test. The open and exploratory design of our database did not allow requiring confirmation tests in our patients. It is possible that the number of pituitary deficiencies was overestimated if confirmation testing was not performed in patients with abnormal test results, or that normalization of pituitary function occurred between the first and second tests. On the other hand, it is also possible that the screening tests did not detect all cases of hypopituitarism, causing an underestimation of the true prevalence.

Finally, it is also possible that simple chance or other unknown differences in the characteristics of the cohorts caused the discrepant findings found between the reports of van der Eerden and associates (2010) and Klose and colleagues (2010) and the much larger database we present here.

It is of note that the prevalence of suspected hypopituitarism was even higher if only patients with stimulation tests were analyzed. This most likely reflects the fact that patients with a higher suspicion of hypopituitarism were selected for stimulation testing by their treating physicians. Even though here GH deficiency was less common in the chronic than in the acute phase, a substantial number of patients presented with ACTH deficiency in the chronic phase. This is particularly striking since unrecognized ACTH deficiency can be a life-threatening condition. In the study by van der Eerden and associates (2010), the one confirmed case of hypopituitarism also had ACTH deficiency. Even if not all cases of ACTH deficiency could be confirmed, these results underscore the importance of actively searching for ACTH deficiency in patients with TBI and SAH.

Our study confirms the findings of previous studies that hypopituitarism is a common complication of TBI and SAH, and that the severity of TBI is a risk factor for post-traumatic hypopituitarism. Our study extends these findings to a much larger and less restricted population. However, it must be kept in mind that most patients included here were from centers treating patients with more severe forms of brain injury. Therefore the prevalences found here cannot be generalized to all subjects with brain injury.

Some as yet unresolved questions remain that cannot be comprehensively answered by our study or previous reports. First, it is still unclear if all patients with signs of endocrine dysfunction actually have worse outcomes than patients without hypopituitarism. And second, we do not know if all patients with endocrine dysfunction will benefit from hormone replacement.

We found that TBI patients with abnormal stimulation tests had a worse outcome than patients with normal stimulation tests. This suggests that the outcome might be affected by the presence of hypopituitarism. However, these findings were not present in SAH patients, and we cannot exclude with certainty that both worse outcomes and hypopituitarism were due to more severe TBI. Also data in the literature are discrepant. While some studies described worse outcomes in patients with hypopituitarism (Bondanelli et al., 2007; Kelly et al., 2006; Klose et al., 2007b; Popovic et al., 2004), this was not confirmed in another study (Pavlovic et al., 2010).

A pilot study showed improvement of cognitive function in patients with post-traumatic GH deficiency if treated with GH (High et al., 2010). Further placebo-controlled studies of hormone replacement are needed to confirm these preliminary findings and to assess the effects of other hormones in patients with post-traumatic hypopituitarism.

Our study has several strengths and limitations. A major strength is the size of our study population and the open design, which allowed a naturalistic view of post-traumatic hypopituitarism.

Our study was designed to be as open as possible to any center that treats patients with TBI and SAH and assesses hormone levels. Therefore we did not measure hormones centrally. This might cause different classifications of endocrine function if different assays but the same cutoffs are being used. However, the fact that the prevalence of hypopituitarism we found was similar if general cutoffs for hormone levels were used or if physician diagnoses were used indicates that this caused only minor bias.

Additionally, since we aimed at including as many patients as possible, we tried to use as few criteria as possible for the definitions of hormone deficiencies by basal laboratory values. Therefore we did not require gonadotropin measurement to define hypogonadism in women younger than 50 years of age, and in men and we did not require TSH measurement to define TSH deficiency. The prevalence of primary hypogonadism in men is low. Therefore we do not believe that this affected the prevalence of male hypogonadism to a large extent. However, we cannot rule out that the prevalence of male hypogonadism was slightly overestimated by measurement of basal laboratory values. Similarly, some patients with pre-existing primary hypothyroidism might have been misclassified as TSH deficient, even though we tried to exclude this by excluding patients with known thyroid disease before the trauma. In premensopausal women hormone levels are often indiscriminative, and estradiol levels can vary depending on the stage of the menstrual cycle, whereas amenorrhea is a clear sign of gonadotropic dysfunction (Schneider et al., 2007b).

Moreover, our study is limited by the heterogeneity of data quality as in any database with this type of open design. Potentially, though speculative, more homogeneous criteria for hormone deficiency and data quality might have yielded more clear-cut associations between hypopituitarism, severity of injury, and outcomes. Also, our study was only designed to screen for hormonal abnormalities without confirmation testing. We cannot rule out with certainty that confirmation testing would have yielded lower prevalences of hypopituitarism. And finally, as in most previous studies in this field, our study was limited by the lack of a control group for the establishment of suitable reference values specific for this population. This was not possible due to the open design and lack of central laboratory values in our study, and this might have introduced bias. We strongly believe that adequate control groups should be included in future studies addressing the prevalence of hypopituitarism after brain injury.

In summary, our data confirm in a large database that hypopituitarism is a common problem after TBI and SAH, and that higher severity of TBI is a risk factor for hypopituitarism. Particular attention should be paid to the detection of ACTH deficiency. Further studies are needed to advance our knowledge of the relationship between post-traumatic hypopituitarism and the effects of hormone replacement.

Footnotes

Acknowledgments

The authors are grateful to all the centers who contributed patient data to the registry. The database is supported by an independent investigator grant from Pfizer Pharma GmbH. Data storage and statistical analyses were performed by Elmar Beck, Anfomed, Germany. The members of the advisory board of the database were: Prof. Günther-Karl Stalla, Prof. Ilonka Kreitschmann-Andermahr, Prof. Eberhard König, Prof. Michael Buchfelder, and Prof. Eberhard Uhl. The following investigators recruited more than one patient to the database: Dr. Kreitschmann-Andermahr, RWTH Aachen; Dr. Stalla, MPI München; Dr. König/Dr. Schneider, Bad Aibling; Dr. Tuschy, Helios-Kliniken Erfurt; Dr. Steube, Neurol. Kl. Bad Neustadt; Dr. Buchfelder/Dr. Kreutzer, Kopfklinik Erlangen; Dr. Sudhoff, Fachklinik Enzensberg; Dr. Faust, Universität Köln; Dr. Lange, VS Schwenningen; Dr. Oertel, Universität Giessen; Dr. Renner, Universität Leipzig; Dr. Fleck/Dr. Wallaschofski, University Greifswald; Dr. Berg, Uni Essen; and Dr. Uhl, Klagenfurt.

Author Disclosure Statement

H.J.S. received research grants from Pfizer, travel grants from Novartis, Pfizer, and Lilly, speaker fees from Novo Nordisk, Pfizer, and Lilly, and is a member of the German KIMS (Pfizer International Metabolic Survey) board. M.S. received research grants and travel grants from Pfizer and Novo Nordisk. I.K.A. received research grants form Pfizer and Novo Nordisk, and travel grants from Pfizer, Novo Nordisk, and Novartis, and is a member of the German KIMS (Pfizer International Metabolic Survey) board. H.W. received research grants, speaker fees, and travel grants from Pfizer and Novo Nordisc, and is a member of the German KIMS (Pfizer International Metabolic Survey) board. S.F. received travel grants from Novo Nordisk and Pfizer. M.F. is a member of the German KIMS (Pfizer International Metabolic Survey) board. A.K. received travel grants from Pfizer. B.S. is an employee of Pfizer Global Pharmaceuticals. M.B. received research grants, speaker fees, and travel grants from Pfizer, Novo Nordisk, and Novartis, and is a member of the German KIMS (Pfizer International Metabolic Survey) board. M.J. is an employee of Clinsupport, Erlangen. G.K.S. received research grants, speaker fees, and travel grants from Pfizer, Novo Nordisk, and Novartis. C.I.E.R., and U.T. report no conflicts of interest.

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