Pituitary function within the first year after traumatic brain injury or subarachnoid haemorrhage

Traumatic brain injury and subarachnoid haemorrhage may cause permanent physical, cognitive, behavioural and psychosocial disabilities limiting daily activities [1‐4]. With annual incidence rates from 235 to 538 cases per 100,000 inhabitants [5, 6] for TBI and of SAH from 2 to 23 cases per 100,000 inhabitants [7, 8], these injuries correspond to huge human and economic costs and offer significant challenges both with regard to acute care and follow-up.

There is accumulating evidence that specialised neurorehabilitation may enhance recovery and long-term outcome after acquired brain injury [9‐12] and also that this should start in parallel with the acute care [13] in order to prevent secondary complications and enhance functional improvement.

Several medical complications, such as infection, hydrocephalus, respiration problems (tracheostomy), nutrition problems and heterotopic ossification may interfere with the post-acute rehabilitation process [14], while this remains unclear for endocrine dysfunction. Disturbed pituitary function has recently been highlighted as one potential factor that deserves attention and potentially treatment during neurorehabilitation [15‐23]. However, until now, there is no consensus about either the prevalence, type or the clinical impact of pituitary disturbances after TBI and SAH and current recommendations for screening of pituitary function and replacement therapy are debated [24].

After TBI, some degree of post-traumatic hypopituitarism (PTHP) has been observed in 10–58 % of patients [16‐18, 23, 25‐29]. Several factors may affect the prevalence of PTHP including the time interval between TBI and evaluation of pituitary function, the severity of the injury and the diagnostic tests used [30]. In the chronic phase following TBI, growth hormone (GH), adrenocorticotrophic (ACTH), gonadotropin, and thyroidal deficiency as well as diabetes insipidus (DI) have been reported [16‐18, 23, 25‐28].

There are some corresponding studies of hormonal dysfunction after SAH and these reports on GH insufficiency, adrenal, gonadotropin, and thyroidal deficiency [19, 21, 22, 31]. The results of these are variable and even conflicting [19, 21, 22, 31‐35] probably reflecting similar factors as discussed for TBI studies [30].

We have previously reported that pituitary deficiencies occur in a substantial number of patients early after TBI and SAH [36]. The aim of the current study was to evaluate the prevalence and course of pituitary function in patients during the first year after traumatic brain injury or subarachnoid haemorrhage and also to explore the relation between pituitary function and injury variables.

This report is based on prospectively collected data from a consecutive cohort of patients, admitted to the Neurointensive care unit (NICU) at Karolinska University Hospital from 1 March 2009 until 30 June 2012 after TBI or SAH. Patients were included at the NICU and followed at the Department of Rehabilitation Medicine at Danderyd University Hospital, Stockholm Sweden, at 3, 6 and 12 months post-injury/illness. Hormone testing was performed at Department of Endocrinology, Karolinska University Hospital. Inclusion was not performed during holidays for logistic and administrative reasons. Inclusion required a moderate or severe TBI or SAH due to a ruptured aneurysm, a lowest GCS score during the first day after the event of 3–13, age ≥18 years, living in the Stockholm region and obtained informed consent. For patients, who were unconscious or otherwise unable to give informed consent, the closest relative was asked.

The study was approved by Regional Ethical Review Board in Stockholm (No: 2008/3:9 2008/1574-31/3).

In the present study, we found that although perturbations in pituitary function are frequent early after the event, they tend to wear off even though some persist or even occur later during the first year after TBI and SAH. The hormonal levels were very varying and low as well as high levels of all hormones were observed. However, in most cases, the changes in hormone levels were transient and without clinical relevance. Thus, in total, 7 out of 95 patients required hormonal replacement (4 testosterone, 1 growth hormone, 2 hydrocortisone) after 12 months while none needed treatment for hormonal hypersecretion. None of the patients had pan-hypopituitarism.

Overall, our results are mainly in accordance with the findings in some previous studies of TBI [17, 18, 23, 28]. E.g. Agha et al. [17] observed growth hormone deficiency in 13 % of 50 patients at 6 months and in 10 % at 12 months; corresponding figures for adrenal insufficiency were 18 % at 6 months and 18 % at 12 moths, respectively; for gonadotropin deficiency 23 % and 13 %, for thyroidal deficiency 2 % and 2 % at these time points, respectively. Tanriverdi et al. [18] observed hyposomatotropism, hypocortisolism, hypogonadism and hypothyroidism in 38, 19, 8 and 6 % of 52 patients at twelve months after TBI. Klose et al. [23] observed pituitary insufficiency in 76 % of 46 patients in the early phase post-injury, in 13 % at 3 months and 6 months post-injury, and in 11 % at 12 months. Bavisetty et al. [28] observed in 70 patients at 3 months and 6–9 months post-TBI major hormonal deficits in 25 % and 21 %, respectively, in the somatotroph, gonadotroph, thyrotroph, corticotroph axis.

Similarly, our findings are roughly in accordance with previous studies after SAH. Tanriverdi et al. [19]. observed GH deficiency in 36 % of 22 patients at 12 months after SAH and deficient adrenocorticotrophic hormone (ACTH) in 14 %. Furthermore, in 84 patients, Khajeh et al. [22] found gonadotropin deficiency in 20 and 5 % and GH deficiency in 10 and 5 % at 6 and 14 months, respectively, after SAH. A recent study by Kronvall et al. [21] of 60 patients at 6–12 and at 12–24 months after SAH. At these time points, they observed ACTH deficiency in 20 and 11 %, GH dysfunction in 20 and 29 %, and gonadotropin dysfunction in 2 and 11 %, respectively.

Thus, our study as well as previous studies demonstrates that pituitary perturbations are most common early after the injury but may occur in a substantial proportion of patients at later stages. Obviously, prevalence figures differ between studies and this probably reflects differences in study samples as well as with regard to definitions of pituitary hypofunction and analyse methods [23].

The most frequent pituitary insufficiency at the 1 year follow-up, observed in approximately one fourth of the patients in our study, was hypogonadotropic hypogonadism. Generally, the frequency of insufficient hormonal levels declined during follow-up and replacement was only clinically relevant in a few patients. This is in contrast to the findings in some earlier studies, reporting higher frequencies, which could be due to differences in defining pituitary hypofunction, differences in the analyses of hormones and differences in study samples.

In our study, we also observed periodic increases in hormone levels as well as high stimulated levels of cortisol after ACTH injection. The high responses to ACTH stimulation could indicate a persistent stress in these patients as also indicated by the high prolactin level seen in some patients. Of notice, high responses in the TBI group was only seen during the first three months after the event, while high responses in the SAH group was also seen 6 and 12 months after the event indicating a more persisting stress in patients with SAH.

During follow-up, the frequency of patients with perturbations in hormonal levels in our study was similar for patients with TBI or SAH, indicating that the affection of the pituitary function was not dependent on aetiology. These conditions may share some pathophysiological mechanisms such as vascular support of the pituitary [46‐48].

Although this study is subject to limitations, we believe it adds some valuable information to the existing literature and that one strength of our study is the comprehensive and long-term data collection. Consistent data now demonstrate that affection of pituitary function is most frequent in the early phase after the TBI and SAH and declines during the following months [5‐7, 10, 11]. Only a small proportion of patients with moderate or severe TBI or SAH need replacement therapy but these patients must be diagnosed and treated.

Unfortunately, we did not find an injury marker that could help identify patients at risk and thus to support a routine for selective screening of pituitary function. We investigated only a few injury markers and believe this is an important area for further studies. Recently, Zheng et al. [49] suggested that pituitary apparent diffusion coefficient (ADC) is a sensitive and independent marker of pituitary damage following TBI and others have started to investigate genetic markers [50].

However, taken together with previous reports, we find it justified to suggest that all patients with moderate or severe TBI or SAH should be routinely screened at least at one time point after the injury and that screening around 1 year after the injury may be considered a minimal obligation. However, screening of the HPA axis, TSH-thyroid axis and FSH/LH-sex hormones every third month until 12 months and of GH-IGF-1 at 12 months after the event may well be considered. Further, testing when there is clinical suspicion should be liberal. Obviously more studies are needed in order to develop evidence-based guidelines in this area. The potential impact of pituitary perturbations on the long-term outcome after TBI and SAH also need further attention.

Perturbations in pituitary function continue to occur during the first year after TBI and SAH, and low as well as high hormonal levels are seen. The changes in hormone levels are often transient and without clinical relevance. Thus, 1 year after TBI in total 7 out of 95 patients needed hormonal replacement. However, it is important to realise that a persistent hypofunction of the pituitary requiring hormonal replacement might occur in a minority after TBI or SAH. This has to be considered in the clinical management of these patients although there is still a need for more data to allow evidence-based guidelines.