Prevalence of hypopituitarism and quality of life in survivors of post‐traumatic brain injury

Abstract Background Hypopituitarism is a recognized sequela of traumatic brain injury (TBI) and may worsen the quality of life (QoL) in survivors. Aims To assess the prevalence of post‐traumatic hypopituitarism (PTHP) and growth hormone deficiency (GHD), and determine their correlation with QoL. Methods Survivors of moderate to severe TBI were recruited from two Algerian centres. At 3 and 12 months, pituitary function was evaluated using insulin tolerance test (ITT), QoL by growth hormone deficiency in adults’ questionnaire (QoL‐AGHDA), and 36‐item short‐form (SF‐36) health survey. Results Of 133 (M: 128; F: 5) patients aged 18‐65 years, PTHP and GHD were present at 3 and 12 months in 59 (44.4%) and 23 (17.29%), 41/116 (35.3%) and 18 (15.5%). Thirteen patients with GHD at 3 months tested normally at 12 months, while 9 had become GHD at 12 months. At 3 and 12 months, peak cortisol was < 500 nmol/L) in 39 (29.3%) and 29 (25%) patients, but <300 nmol/L in only five and seven. Prevalence for gonadotrophin deficiency was 6.8/8.6%, hypo‐ and hyperprolactinaemia 6.8/3.8% and 5.2/8.6%, and thyrotrophin deficiency 1.5/0.9%. Mean scores for QoL‐AGHDA were higher in patients with PTHP at 3 and 12 months: 7.07 vs 3.62 (P = .001) and in patients with GHD at 12 months: 8.72 vs 4.09 (P = .015). Mean SF‐36 scores were significantly lower for PTHP at 3 months. Conclusion Prevalence of PTHP and GHD changes with time. AGHDA measures QoL in GHD more specifically than SF‐36. Full pituitary evaluation and QoL‐AGHDA 12 months after TBI are recommended.

than 20 prospective and retrospective studies have been published and reported an overall prevalence for post-traumatic pituitary insufficiency of 30%.  Growth hormone (GH) deficiency is the most frequently reported endocrine consequence of TBI 31 and results in the adult GH deficiency syndrome. This well-recognized and distinctive clinical condition comprises lack of energy and fatigue, social isolation, disturbed emotional reactions and social behaviour, poor general health, lack of self-control, anxiety, decreased vitality, and impaired mood and sense of well-being as well as problems with sexual relationships. 32,33 However, these symptoms are also frequently reported by patients who have sustained TBI. The question therefore arises-are such symptoms in TBI survivors related to GH deficiency/PTHP or to the damage caused by the head injury itself? The aim of this study therefore was measure the prevalence of PTHP in

| PATIENTS AND ME THODS
This prospective study was conducted to evaluate the endocrine and QoL outcome in victims of moderate to severe TBI who had been ad- sheets of the patients. Of note, high-dose steroids were not normally given to survivors of TBI in the acute phase in our units, given previous work showing that this may worsen outcome. 34 Acute cortisol evaluation has been presented in a previous publication. 35 Patients with cortisol < 83 nmol/L in the acute phase or at 3 and 12 months post-TBI were treated with replacement hydrocortisone, and those with cortisol between 83 and 200 nmol/L were treated if symptomatic and those with cortisol between 200 and 550 nmol/L were counselled and prescribed treatment in the event of major stress. In patients receiving hydrocortisone replacement, treatment was stopped 24 hours before ITT at 3 and 12 months, to avoid any interference with the cortisol assay.
Brain imaging status was classified according to Marshall stratification 36 as follows: diffuse injury I (no visible pathology); diffuse injury II (midline shift of 0-5 mm but basal cisterns remain visible, no high or mixed density lesions > 25 cm 3 ; diffuse injury III (midline shift of 0-5 mm, basal cisterns compressed or effaced, but no lesions > 25 cm 3 ); diffuse injury IV (midline shift > 5 mm but no lesions > 25 cm 3 ); evacuated mass lesion V (any lesion evacuated surgically) and non-evacuated mass lesion VI (high or mixed density lesions > 25 cm 3 , not surgically evacuated). Marshall stage VI was compared at 3 and 12 months in patients with and without anterior pituitary hormone deficiency.

| Hormonal measurements and assays
In the absence of contraindications, for example history of seizures, the insulin tolerance test (ITT) was performed according to consensus guidelines 37,38 3 and 12 months after TBI. Insulin was given in the dosage of 0.1 units/kg, taking a glucose nadir of <2.2 mmol/L as representing adequate hypoglycaemia. Sampling was carried out at baseline, 15, 30, 45, 60, 90 and 120 minutes for growth hormone and cortisol, while luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), free thyroxine (FT4), testosterone, estradiol, insulin growth factor one (IGF1), adrenocorticotrophic hormone (ACTH) and prolactin were measured at baseline (Table 1).
Growth hormone, IGF-1, cortisol, estradiol, testosterone, prolactin, thyroxine, TSH and prolactin were assayed using Cis-bio RIA. LH and FSH were assayed using RIA-MP Biomedicals. Growth hormone deficiency (GHD+) during ITT was defined as a peak value of <3 µg/L (9 mIU/L). IGF-1 levels were recorded as low if below the age-related reference range and frankly subnormal if <84 ng/mL (10.97 nmol//L) at any age.
Inter-assay intervals for cortisol were 5.7-8 and 1-6.7, intra-assay intervals were 5.3-3.6 and 6-3.7 for an inferior limit of detection of 3.0 nmol/L. An adequate stimulus for cortisol secretion was taken as ITT-induced hypoglcaemia of <2.2 mmol/L. The chosen cut-off for defining adrenal insufficiency (AI) was a cortisol level of <500 nmol/L, in keeping with international recommendation and guidelines. 39,40 In males, gonadotrophin deficiency was defined as serum testosterone < 8 nmol/L, consistent with our laboratory reference range of 8.2-34.6 nmol/L and with <8 nmol/L cut-off recommended by guidelines. 41,42 In females, gonadotrophin deficiency was defined as estradiol < 60 pmol/L in non-menopausal women with normal/ low gonadotrophins. Measurement of sex hormone-binding globulin (SHBG) was not available in our laboratory. Hypoprolactinaemia was defined as prolactin < 3.65 µg/L and hyperprolactinaemia as prolactin > 23.7 µg/L in men and >25 µg/L in women, and thyrotrophin deficiency as free thyroxine < 8.25 pmol/L with normal or low TSH.
PTHP was considered if the patient had at least one pituitary axis deficiency.

| Quality of life assessment
Assessment with QoL-AGHDA and SF-36 was performed 3 and  44 In the present study, QoL scores between patients with and without PTHP and GHD were compared, and the number of patients with PTHP and GHD whose scores ex-   45 Differences between patients with and without PTHP and GHD were compared, and the number of patients with PTHP and GHD at each time point scoring < 1 SD less for each component were recorded.
All the patients were able to answer both questionnaires despite any neurological sequelae from their TBI.

| Statistical analysis
This was performed using Student's t test of CHI tests for between group comparisons. Comparison of means was with ANOVA or Krusal-Wallis test, and Pearson coefficient was used for analysing quantitative variables. Cross-tabulation with chi-squared test was applied to determine differences in Marshall stage stratification between patients with and without PTHP. Data were analysed using SPSS version 21.

| Ethical aspects
The Scientific and Ethics Committees of the central hospital of Army and the Medical Faculty of Algiers approved this study. Consent for recruitment during the acute phase of the study, including sampling for serum cortisol, was obtained from all 277 families on behalf of the patients. Consent for dynamic testing and questionnaire in the survivors at 3 and 12 months was obtained from the patients and their families.

| RE SULTS
Between November 2009 and December 2013, 277 patients with moderate or severe TBI who were seen during the acute phase in the two hospitals were enrolled into the study. Of these, 98 patients died, leaving 179 survivors. Sixteen of the survivors were unable to respond to the questionnaire, and 17 could respond to the questionnaire but either could not be tested by ITT or refused dynamic testing, while 13 were lost to follow-up.
RTA was the most frequent cause, occurring in 48% of patients.
Thirty-five (26.3%) of the patients had multiple injuries and 66 (42%) TA B L E 1 Pituitary evaluation of survivors of moderate to severe traumatic brain injury at 3 and 12 mo after the initial event. Peak growth hormone and cortisol levels were recorded during the insulin tolerance test, thyroid stimulating hormone, thyroid hormones, gonadotrophins, testosterone and estradiol, and prolactin were recorded at baseline. Post-traumatic hypopituitarism was defined as the presence of at least one pituitary hormone deficiency

| Data relating to pituitary function 3 and 12
months after injury (see Table 1 and Figure 1) Table 1 and Figure 1 show the prevalence of pituitary hormone defi-
Ten patients had GHD both at 3 and 12 months. However, 13 of the patients with peak GH < 3 µg/L at 3 months tested normally at 12 months, while nine who had tested normally at 3 months had become GHD at 12 months. Of the 18 patients with GHD at 12 months, AI was found in nine, gonadotrophin deficiency in two and at least one other pituitary deficiency in 15.
Only one patient received GH replacement therapy after 12 months. Figure 2A

| Other pituitary hormone deficiencies
Gonadotrophin deficiency was present in 10 (8.6%) male patients and no females at 12 months and TSH deficiency in only one patient.
Prolactin levels were subnormal in 10 and elevated in six patients at 12 months. No TBI survivor had diabetes insipidus.
3.5 | Factors predicting post-traumatic hypopituitarism at 3 and 12 months (see Figure 3A,B) Predictive factors of PTHP in bivariate analysis at 3 months were skull base fracture, duration of intubation and initial traumatic imaging according to Marshall stratification, with a significant correlation between the presence and absence of PTHP according to Marshall

stages.
At 12 months, duration of intubation and coma, and multiple injuries predicted PTHP. However, the correlation with Marshal stage stratification was no longer present ( Figure 3B).
Severity of brain injury as evaluated by GCS, anaemia, hypotension, papillary status and acute phase surgery did not predict the occurrence of PTHP at either 3 or 12 months after injury. Table 2 shows that QoL-AGHDA scores at 3 months were significantly higher in patients with PTHP than those without (P = .0012) but not between GHD and non-GHD patients (P = .65).

| D ISCUSS I ON
TBI is an important public health problem and remains the leading cause of handicap and disability in young adults. 1 Victims are usually young adult males, with RTA and falls being the most frequent causes. 2 The prevalence of TBI in Algeria is unknown, but its frequency of RTA is ranked among the top five countries in the world, with 3000 deaths and 25.700 injured during 2016. 46 The outcome in severe TBI is generally poor, and the presence of neuroendocrine complications may further worsen the prognosis. 1 PTHP is now well-recognized as a complication of TBI but, as shown in Table 3, the reported prevalence varies widely between 1% and 83%.  In the current study, a PTHP prevalence of 44.4% was found at 3 months, falling to 34.3% at 12 months. Our 3-month data are in keeping with the studies of Bavisetty, 19 Aimaretti 12 and Schneider. 13 Reasons for the relatively high frequency of PTHP in our study com- Of note, we excluded patients with mild TBI (GCS > 13) because we considered that this population is at low risk of developing PTHP.
The 12-month prevalence of PTPH in this study is close to that reported by Schneider, 13 Popovic 8 and Agha. 6 The wide range of prevalence of 11%-56% reported in other studies 9,10,13,19 could reflect a combination of confounding variables such as: inclusion/ exclusion criteria, timing of evaluation, TBI severity, type of stimulation tests used for evaluating corticotrophin and somatrophin functions and the selected hormone cut-offs. Such confounders limit the analytical power of meta-analysis and reviews. 47 For this reason, it is not possible at present to give a 'true' prevalence figure for PTHP. For this to be achieved, international consensus would be required in order to agree the thresholds used to define anterior pituitary insufficiency, the type of tests and assay methods used, CT findings, GCS threshold, and the interval(s) between

TBI and assessment.
As with other studies, we found that individual patients with PTHP at 3 months can show resolution by 12 months, attributable to resolution of the initial vascular and ischaemic insults to the pituitary. 48 In keeping with this, we found a significant correlation between Marshall stratification and PTHP at 3 months, whereas this was no longer present at 12 months, consistent with pituitary recovery in some patients. Additionally, we show that some patients with normal pituitary function at 3 months may develop PTHP, attributable to progressive damage through mechanisms such as autoimmune post-traumatic hypophysitis. 49 The differences in GHD and AI prevalence at 3 and 12 months could also reflect the confounding influence of variable intra-patient reproducibility of the ITT, even though this is the gold standard for assessment of the somatotroph and corticotroph axes.
The prevalence of AI in our study 3 and 12 months post-TBI is relatively high at 31.6% and 25% but these figures conceal much   In our study, SF-36 data show significant differences in physical function, social function and emotional health in patients with and without PTHP at 3 months after TBI, but not for GHD. By 12 months, these differences were no longer evident except for Vitality scores, which were lower in the GHD group. It is noteworthy that scores for Physical Function and Vitality were higher than the general population at 12 months (see Figure 4B), explicable in terms of the marked physical improvement in our younger patients with moderate TBI.

TA B L E 3 Prevalence of post-traumatic hypopituitarism (PTHP) reported in the literature between 2000 and 2018
Other studies have used SF-36 to assess QoL in TBI survivors with and without PTHP, including Kelly, Bavisetty, Nourollahi, Wachter and Kokshoorn who used others scales. 17,19,22,56,56 Nouroullahi et al found differences, particularly concerning limitation in physical activity, vitality, social and emotional activities and general health 57 while Kokshoorn et al found a difference in the general health perception score (P = .0016), depression (P = .05), social isolation (P = .02) and decreased activity (P = .027) with post-traumatic PTHP. 22 Our findings indicate that SF-36 assessment 3 months after TBI may be too soon in the recovery period, with some aspects being influenced by pituitary dysfunction which may then resolve, and also by non-endocrine factors related to the traumatic event, which may also resolve.
Further work is needed in this difficult field, to tease out the effects of GHD and PTHP as opposed to non-endocrine factors on QoL after TBI, and long term follow-up is needed to confirm this association. One avenue for future study is to compare QoL in GHtreated patients with GHD and patients with GHD who remain untreated, and it is our intention to continue monitoring our Algerian cohort of patients.
From a practical point of view, we recommend evaluating pituitary function 3 months after TBI by analysing basal hormones rather than carrying out dynamic testing. At 12 months, full pituitary evaluation should be performed, using the ITT where possible, with QoL-AGHDA assessment at 12 months, offering GH replacement to patients with GHD and high QoL scores at this stage. SF-36 assessment at 12 months, although not specific to PTHP, is a valuable tool in the global monitoring of progress in all cases of moderate to severe TBI.

ACK N OWLED G M ENTS
The authors thank the doctors and the nurses of neurosurgery and critical care medicine departments of Salim Zemirli hospital and central hospital of army in Algiers. We also thank the patients and their families.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data from which this study was written up form part of the MD thesis of the first author, Professor Meriem Bensalah. Access to these data may be requested from the first author, with the proviso that data affecting patient confidentiality will be restricted.