Impaired Pituitary Axis Following Traumatic Skull Base Fracture and Associated Brain Injury

Abstract

Introduction

The pituitary gland is particularly vulnerable to head trauma due to the anatomical location. Posttraumatic hypopituitarism is an underdiagnosed consequence of traumatic brain injury (TBI), where the pituitary gland fails to produce one or more hormones due to head injury. This study aimed to evaluate the early and late changes in pituitary hormone levels after TBI and correlate them with outcomes.

Materials and Methods

This prospective study was conducted on 150 patients presenting to the Trauma Centre of Sawai Man Singh (SMS) Hospital, Jaipur, Rajasthan, India. Pituitary hormones (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], follicle-stimulating hormone [FSH], luteinizing hormone [LH], prolactin) were assessed at different intervals: immediately after trauma, on the 4th day, 21st day, and at 3-month postinjury.

Inclusion Criteria All traumatic skull base fractures (with and without brain injury) that were radiologically proven, Traumatic sella turcica or sphenoid bone fractures. History of trauma and consent.

Exclusion Criteria Nontraumatic fracture, pituitary diseases, patient with other conditions like micro- and macroadenoma that might alter pituitary hormones, nonconsenting and uncooperative patients, old traumatic fracture, and patients already on hormone therapy.

Results

It was observed that mean TSH increased from day 1 to day 4, then decreased by the 21st day and the 3rd month. Other hormones like prolactin, LH, FSH, ACTH, and GH were high on the day of admission and on the 4th day it starts to decrease and on the 21st and 90th day it starts to normalize.

Conclusion

An increase in pituitary hormone on the day of injury may be attributed to physiological adaptation to acute illness. Post-TBI pituitary dysfunction is a clinically significant entity. Secondary hypoadrenalism, hypothyroidism, and central diabetes insipidus should be treated acutely, while deficiencies in growth and gonadotrophic hormones should initially be observed. A follow-up strategy with periodic evaluation is a necessary part of the optimal care for patients with TBI.

Keywords

traumatic brain injury - hypopituitarism - head trauma - pituitary deficiency

Introduction

Traumatic brain injury (TBI) is defined as a change in brain function or other evidence of brain pathology caused by external forces and is a well-recognized public health problem worldwide. A substantial number of TBI cases are seen in emergency departments with principal causes including falls, road accidents, assaults, and sports-induced concussions. Two important risk factors for TBI are sex (males suffer from TBI three times more often than females) and age (people over 65 years old and under 14 years are particularly vulnerable).

The pituitary gland is particularly vulnerable to head trauma due to its anatomical location within the sella turcica, its fragile infundibular hypothalamic structure, and its vascular supply. Hypopituitarism is an underdiagnosed sequela of TBI. It was previously thought to be rare, comprising 0.7% of cases of hypopituitarism,[1] [2] [3] but is increasingly recognized. Understanding its true incidence is difficult as TBI is often not considered by many practitioners in the evaluation of hypopituitarism, even among endocrinologists. There is significant variability in the timing of presentation with post-TBI hypopituitarism ranging from a few days to over 40 years, though most cases present within the first year.[4]

Posttraumatic hypopituitarism (PTHP) occurs when the pituitary gland fails to produce one or more hormones due to head injury. TBI patients with PTHP may suffer from various clinical sequelae, including physical, psychological, and cognitive deficits. Symptoms can present at any time after the trauma and the signs and symptoms of hypopituitarism may be subtle, overlapping with the neurological and psychiatric sequelae of head trauma.[5] [6] [7]

Somatotropic axis insufficiency is the most common abnormality followed by hypogonadism, hypothyroidism, hypercortisolism, and diabetes insipidus. Pituitary dysfunction after a TBI is usually transient and may resolve or regain its functional abilities, but it can also present clinically or develop years after the initial TBI. TBI has been also linked to impaired quality of life, depression, and poor rehabilitation outcome.[8] [9] [10]

Much of the available data are retrospective with only a few prospective series; some combine the two methods. Prospective series also vary in latency between injury and testing. The completeness of the hypothalamic-pituitary-axis evaluation also varies among reports with some excluding certain hormones and others only measuring static hormone levels rather than combining static assessments with provocative tests.

Thus, the study aimed to evaluate the early and late changes in pituitary hormone levels after TBI and to correlate these changes with outcomes.

Materials and Methods

This prospective study was conducted on 150 patients presenting in the Trauma Centre of Sawai Man Singh (SMS) Hospital, Jaipur, Rajasthan, India, from January 1, 2023 to May 2024. The levels of hormone (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], follicle-stimulating hormone [FSH], luteinizing hormone [LH], prolactin) were assessed at different intervals: immediately after trauma, 4th day, 21days, and at 3 months postinjury. Other routine investigations and noncontrast computed tomography (CT) head scans with sellar cuts were also performed for diagnosing injury. Inclusion criteria: all traumatic skull base fractures (with and without brain injury) that were radiologically proven. Traumatic sella turcica or sphenoid bone fractures. History of trauma and consent. Exclusion criteria: nontraumatic fracture, pituitary diseases, patient with other conditions like micro- and macroadenoma that might alter pituitary hormones, nonconsenting and uncooperative patients, old traumatic fracture, and patients already on hormone therapy.

Patients with a history of trauma were clinically and radiologically evaluated for skull base injury. CT brain with sellar cuts were performed and evaluated for skull base fractures with and without brain injury or sella turcica fracture or sphenoid bone injury. Serum samples were collected immediately, on the 4th day, the 21st day, and at 3 months after TBI for analysis of GH, TSH, ACTH, FSH, LH, and prolactin. Chemiluminescence immunoassay was used for hormone estimation.

Hormonal values are described as mean ± standard deviation and when data was skewed with extreme deviation, median and range were used for analysis. IBM SPSS Statistics 26 was used for data analysis. A two-tailed Student's t-test was applied for continuous data. Skewed data were transformed into logarithmic values and statistical tests were applied to the transformed data. Correlation analyses were made using the Pearson's test for continuous data and Spearman's rho test when at least one parameter was ordinal. Factors influencing outcome were explored using logistic regression. A value of p ≤ 0.05 was considered statistically significant.

Results

In our study, the mean age of cases was 39.74 years with the majority of cases were in the age group of ≥ 51 years (30%) followed by 31 to 40 (26%). There were 15 females out of 150 cases, with the remaining 135 being males. The cause of trauma in our study was road accidents (65.3%) followed by trauma due to fall from height (24%), assaults (7.33%), and sports-related injuries (3.33%).

Mean serum TSH at admission was 2.74, followed by 3.11 on the 4th day, 2.07 on the 21st day, and 1.95 on the 90th day. On post hoc Dunn's test, we found that mean TSH increased from day 1 to day 4 (p-value = 0.0113). Later, on the 21st day, mean TSH started decreasing up to follow-up on the 90th day but this difference at 21 and 90 days was not statistically significant (p-value = 0.3417). Thus, on admission day, 4.67% had low TSH, followed by 8% on the 4th day, 9.33% on the 21st day, and 11.33% on the 90th day ([Fig. 1], [Table 1]).

Table 1 Mean TSH level.

TSH	At admission	At 4th day	21st day	90th day
Abnormal	7 (4.67%)	12 (8%)	14 (9.33%)	17 (11.33%)
Mean ± SD	2.74 ± 1.21	3.11 ± 1.23	2.07 ± 1.15	1.95 ± 1.08

Abbreviations: SD, standard deviation; TSH, thyroid-stimulating hormone.

Fig. 1 Mean TSH level.

Mean serum prolactin at admission was 33.43 followed by 31.24 on the 4th day, 30.92 on the 21st day, and 31.80 on the 90th day. On post hoc Dunn's test, we found that mean prolactin decreased from day 1 to day 4 (p = 0.0113). Later, on the 21st day, mean prolactin starts increasing up to follow-up on 90th day, but this difference at 21 and 90 days was not statistically significant (p = 0.3417). Thus, on admission day, 4.0% had low prolactin, followed by 6% on the 4th day, 6.67% on the 21st day, and 9.33% on the 90th day ([Table 2], [Fig. 2]).

Fig. 2 Mean prolactin level.

Table 2 Mean prolactin level.

Prolactin	At admission	At 4th day	21st day	90th day
Abnormal	6 (4.0%)	9 (6%)	10 (6.67%)	14 (9.33%)
Mean ± SD	33.43 ± 4.10	31.24 ± 3.23	30.92 ± 5.39	31.80 ± 5.76

Abbreviation: SD, standard deviation.

Mean serum LH and FSH at admission were 13.02 and 12.05, respectively, followed by 11.96 and 11.88 on the 4th day, 12.14 and 10.95 on the 21st day, and 12.93 and 10.12 on the 90th day. On post hoc Dunn's test, we found that mean LH and FSH were high on admission day and started decreasing on the 4th day. On follow-up on 21st and 90th days, both hormones started to reach a normal level in majority of patients. Thus, on admission day 10 and 9.33% had low LH and FSH, respectively, followed by 12.67 and 12.67% on the 4th day, 14 and 13.33% on the 21st day, and 13.33 and 12% on the 90th day ([Tables 3] and [4]; [Figs. 3] and [4]).

Fig. 3 Mean LH level.

Fig. 4 Mean FSH level.

Table 3 Mean LH level.

LH	At admission	At 4th day	21st day	90th day
Abnormal	15 (10%)	19 (12.67%)	21 (14%)	20 (13.33%)
Mean ± SD	13.02 ± 3.94	11.96 ± 3.16	12.14 ± 2.83	12.93 ± 2.52

Abbreviations: LH, luteinizing hormone; SD, standard deviation.

Table 4 Mean FSH level.

FSH	At admission	At 4th day	21st day	90th day
Abnormal	14 (9.33%)	19 (12.67%)	20 (13.33%)	18 (12%)
Mean ± SD	12.05 ± 2.81	11.88 ± 2.18	10.95 ± 2.09	10.12 ± 1.76

Abbreviations: FSH, follicle-stimulating hormone; SD, standard deviation.

We also found that mean serum ACTH and GH at admission were 35.73 and 2.37, respectively, followed by 34.20 and 1.13 on the 4th day, 32.20 and 1.16 on the 21st day, and 20.51 and 1.14 on the 90th day. On post hoc Dunn's test, we found that mean ACTH and GH was high on admission day and started decreasing on the 4th day. On follow-up on the 21st and 90th days, ACTH levels started to normalize in most patients, but GH levels remained lower. Thus, on admission day, 10 and 8.67% had low ACTH and GH, respectively, followed by 13.33 and 16% on the 4th day, 11.33 and 12% on the 21st day, and 10 and 12.67% on the 90th day ([Tables 5] and [6]; [Figs. 5] and [6]).

Fig. 5 Mean ACTH level.

Fig. 6 Mean GH level.

Table 5 Mean ACTH level.

ACTH	At admission	At 4th day	21st day	90th day
Abnormal	15 (10%)	20 (13.33%)	17 (11.33%)	15 (10%)
Mean ± SD	35.73 ± 11.08	34.20 ± 10.11	32.20 ± 10.21	20.51 ± 10.55

Abbreviations: ACTH, adrenocorticotropic hormone; SD, standard deviation.

Table 6 Mean GH level.

GH	At admission	At 4th day	21st day	90th day
Abnormal	13 (8.67%)	24 (16%)	18 (12%)	19 (12.67%)
Mean ± SD	2.37 ± 1.08	1.13 ± 1.02	1.16 ± 0.97	1.14 ± 0.97

Abbreviations: GH, growth hormone; SD, standard deviation.

Discussion

Pituitary insufficiency may have serious consequences and may aggravate the physical and neuropsychiatric morbidity observed after head injury. Patients with TBI may suffer from lethargy, muscle fatigue, and poor exercise capacity. Deficiency of GH may lead to reduced lean body mass, decreased exercise capacity, impaired cardiac function, and reduction in bone mineral density. It is found that hypopituitarism may impair recovery from TBI.[11] [12] [13] [14] Much of the available data are retrospective in nature with only a few prospective series found that majority of study done so far on endocrine manifestation of TBI are retrospective. Presently, there is paucity of prospective data on the natural history of posttraumatic neuroendocrine dysfunctions. There is need to develop appropriate guidelines for follow-up of suspected cases so that information can lead to timely and appropriate assessment and treatment of hormonal deficits. According to Agarwal et al[15], the timing of manifestation of hormonal deficiencies following TBI varies from days to years.

A large number of neuropathological studies established a frequency of 26.4 to 86% hypothalamic-pituitary lesions in patients with TBI. Several mechanisms have been suggested for this hypothalamic-pituitary dysfunction due to TBI, including hypoxic insult or direct mechanical injury to the hypothalamus, pituitary stalk, and/or pituitary gland, compression from hemorrhage, edema, or raised intracranial pressure and vascular injury to the hypothalamus or the pituitary gland. The hypophyseal vessels are anatomically vulnerable to shearing injuries, and increased intracranial pressure, anterior base of skull fractures, and pituitary ischemia or hemorrhage are described as common findings at autopsy.

It was observed that the prevalence of GH and ACTH deficiency was 8.67 and10%, respectively, on the day of TBI, which increased to 16 and 13.33% on the 4th day. After 21 days of injury, the deficiency of GH and ACTH was found in 12% each and after 3 months, the prevalence of GH and ACTH deficiency was 12.67 and 10%, respectively. Our study showed prevalence of GH deficiency similar to other studies but deficiency of ACTH was somewhat lesser in TBI patients. Agha et al[13] conducted a retrospective study in 2004 and found prevalence of GH deficiency between 8.8 and 10.7% and they reported prevalence of ACTH deficiency in 22.5%. Kelly et al[16] conducted a study on a smaller cohort of 22 patients with moderate or severe TBI. Four patients (18%) had subnormal GH responses but it was not reported how many had clinically significant deficiency. However, Kelly et al reported only one patient having adrenal deficiency. Lieberman et al[17] also reported a prevalence of 14% GH deficiency. They also reported that approximately 45% of TBI patients had morning cortisol less than normal range. Bondanelli et al[18] also conducted a small cohort study and observed that overall GH response was not significantly different among the TBI group and healthy controls. Actually, Agha et al, Kelly et al, Lieberman et al, and Bondanelli et al conducted a retrospective study in which they tried to find the deficiency of GH using glucagon stimulation test (GST) and insulin tolerance test (ITT). Adrenal deficiency was evaluated on the basis of short synacthen test (SST). According to their study, if patients failed GST and ITT or SST they were considered GH and ACTH deficient. In another study conducted by Agha et al[14] in 2005 reported 18% had GH deficiency in the acute phase, in 6 months five patients recovered function, two new deficiencies were detected in 12 months, leaving five patients (10%) with GH deficiency. Eight patients (16%) showed subnormal cortisol response in the acute phase, in 6 months four patients had recovered, and five new deficiencies were detected, and all nine patients had persistent abnormalities in 2 months. Aimaretti et al[19] conducted a study on TBI patients and evaluated the level of different hormones after 3 and 12 months and they observed that severe growth hormone deficiency (GHD) was recorded in 22.8% of the total TBI. 16% patients had GH deficiency after 3, 6, and 9 months followed by injury. Tanriverdi et al[20] observed that 9.8% had ACTH and 20.4% had GH deficiency at acute phase of TBI and after 12 months' follow-up, 19.2 and 37.7% had ACTH and GH deficiency, respectively.

In our study, we observed 4.67% had low TSH on the day of admission, followed by 8% cases on the 4th day, 9.33% cases on the 21st day, and 11.33% cases on the 90th day had low serum TSH. Agha et al observed that TSH deficiency was uncommon. The frequency of TSH deficiency with relation to other anterior pituitary hormone abnormalities is variable. Because the thyrotropes are located more medially within the adenohypophysis in the protected territory of the short hypophyseal vessels, they may be less susceptible to traumatic injury than the rest of the anterior lobe, which receives its blood supply predominantly from the more vulnerable long hypophyseal vessels. Our results are comparable with those of Kelly et al[16] who found only one patient (4.5%) with low T4 and TSH levels, who also showed a blunted response to thyrotropin releasing hormone (TRH) stimulation. In contrast, Lieberman et al found 11.6% of patients to have low free FT4 without elevated thyrotropin levels, suggesting TSH deficiency. Leal-Cerro et al[21] reported 5.8% had TSH deficiency. Tanriverdi et al[20] reported 5.8% had TSH deficiency. In the Tanriverdi et al study, initially during the acute phase of TBI 5.8% had TSH deficiency and after 12-month follow-up the same 5.8% had TSH deficiency.

In our study, we found that on the admission day 4.0% has high prolactin, followed by 6% cases on the 4th day, 6.67% cases on the 21st day, and 9.33% cases on the 90th day had high serum prolactin. In line to our results, Agha et al, Kelly et al, and Lieberman et al reported hyperprolactinemia in their study. Aimaretti et al[19] reported mild hyperprolactinemia in 4.2% of TBI.

We reported that on the admission day 10 and 9.33% had low LH and FSH, followed by 12.67 and 12.67% cases on the 4th day, 14 and 13.33% cases on the 21st day, and 13.33 and 12% cases on the 90th day had low serum LH and FSH. Leal-Cerro et al[21] reported that 17% patients had gonadotropin deficiency. Tanriverdi et al reported that 41.65 had gonadotropin deficiency at acute phase of TBI and after 12 months, 7.7% had deficiency of gonadotropin hormones.

Conclusion

An increase in pituitary hormone on day of injury may be attributed to physiological adaptation to acute illness. Post-TBI pituitary dysfunction is an entity to recognize with significant clinical relevance. Secondary hypoadrenalism, hypothyroidism, and central diabetes insipidus should be treated acutely, while deficiencies in GH and gonadotrophic hormones should be initially observed.

Our data show that posttraumatic abnormalities occur early and with high frequency, which may have significant implications for recovery and rehabilitation of TBI patients. After TBI, early neuroendocrine abnormalities are sometimes transient, whereas late abnormalities present during the course of rehabilitation. A follow-up strategy with periodic evaluation is a necessary part of the optimal care for patients with TBI.

Conflict of Interest

None declared.

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Publication History

Article published online:
18 December 2025