Advances in the management of traumatic brain injury, subarachnoid haemorrhage and intracranial tumours have led to improved survival rates and an increased focus on quality of life of survivors. Endocrine sequelae of the acute brain insult and subsequent neurosurgery, peri-operative fluid administration and/or cranial irradiation are now well described. Unrecognised acute hypopituitarism, particularly ACTH/cortisol deficiency and diabetes insipidus, can be life threatening. Although hypopituitarism may be transient, up to 30% of survivors of TBI have chronic hypopituitarism, which can diminish quality of life and hamper rehabilitation. Patients who survive SAH may also develop hypopituitarism, though it is less common than after TBI. The growth hormone axis is most frequently affected. There is also accumulating evidence that survivors of intracranial malignancy, who have required cranial irradiation, may develop hypopituitarism. The time course of the development of hormone deficits is varied, and predictors of pituitary dysfunction are unreliable. Furthermore, diagnosis of GH and ACTH deficiency require dynamic testing that can be resource intensive. Thus the surveillance and management of neuroendocrine dysfunction in neurosurgical patients poses significant logistic challenges to endocrine services. However, diagnosis and management of pituitary dysfunction can be rewarding. Appropriate hormone replacement can improve quality of life, prevent complications such as muscle atrophy, infection and osteoporosis and improve engagement with physiotherapy and rehabilitation.
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Aoife Garrahy, Mark Sherlock, and Christopher J Thompson
Amar Agha, Mark Sherlock, Jack Phillips, William Tormey, and Christopher J Thompson
Background and objectives: Posterior pituitary function remains poorly investigated after traumatic brain injury (TBI). We report the results of a study designed to prospectively define the natural history of post-traumatic diabetes insipidus (DI) and syndrome of inappropriate antidiuretic hormone secretion (SIADH) using standard reliable methodology.
Design and methods: 50 consecutive patients with severe or moderate TBI (initial Glasgow Coma Scale (GCS) score 3/15–13/15) were prospectively studied on three occasions: at the acute phase and at 6 months and at 12 months following TBI. In the acute phase, DI was diagnosed either by the presence of hypernatraemia in association with hypotonic polyuria or by the water-deprivation test (WDT) and, at 6 and 12 months by the WDT in all patients. Normative data on response to the WDT were obtained from healthy matched volunteers. Functional outcome was assessed using the Glasgow Outcome Scale (GOS).
Results: 13 patients (26%) had DI in the acute post-TBI phase, of whom nine patients recovered by 6 months and one additional patient recovered by 12 months. Of the remaining three patients with permanent DI, two had partial vasopressin deficiency. Acute-phase peak plasma osmolality correlated negatively with the initial GCS scores (r = −0.39, P = 0.005) and with the GOS scores (r = −0.45, P = 0.001). Seven patients had SIADH in the acute phase of TBI but none did at 6 or 12 months. No new cases of DI or SIADH were noted after the acute phase.
Conclusion: This prospective study shows that posterior pituitary dysfunction is common following TBI. Most cases recover completely but there is an appreciable frequency of long-term DI which can be subtle and should be recognized and managed appropriately.
Lucy-Ann Behan, David Carmody, Bairbre Rogers, Mark J Hannon, Colin Davenport, William Tormey, Diarmuid Smith, Christopher J Thompson, Alice Stanton, and Amar Agha
Increased cardiovascular and cerebrovascular morbidity and mortality in hypopituitary subjects may be linked to inappropriate glucocorticoid exposure; however, the pathophysiology remains unclear. We aimed to examine the effect of three commonly prescribed hydrocortisone (HC) regimens on vascular risk factors.
An open crossover study randomising ten hypopituitary men with severe adrenocorticotrophic hormone deficiency to three HC dose regimens: dose A (20mg mane and 10mg tarde), dose B (10mg mane and 10mg tarde) and dose C (10mg mane and 5mg tarde).
Following 6 weeks on each regimen, participants underwent 24-h serum cortisol sampling, 24-h ambulatory blood pressure (BP) measurements, calculation of the Ambulatory Arterial Stiffness Index (AASI), oral glucose tolerance testing and fasting serum osteoprotegerin (OPG) sampling.
There were no differences in 24-h BP between dose regimens and controls; however, low-dose HC replacement (dose C) was associated with the lowest AASI, indicating a less stiff arterial tree (P<0.05) compared with the other dose regimens. Loss of the physiologic nocturnal BP dip was more common in higher HC replacement regimens, although only significant for dose B compared with dose C (P=0.03). Twenty per cent of patients had abnormal glucose tolerance, but this was unrelated to dose regimen. OPG correlated strongly with 24-h BP in those on dose A only (r=0.65, P=0.04).
Currently prescribed HC replacement doses do not result in significant differences in absolute BP levels or improvements in insulin sensitivity. However, lower HC doses may result in lower arterial stiffness and a more physiological nocturnal BP dip. Long-term studies are required to confirm these findings and evaluate their impact on vascular morbidity in this patient group.
Lucy-Ann Behan, Grainne Kelleher, Mark J Hannon, Jennifer J Brady, Bairbre Rogers, William Tormey, D Smith, Christopher J Thompson, Malachi J McKenna, and Amar Agha
Glucocorticoid (GC) therapy is associated with adverse effects on bone metabolism, yet the effects of different GC physiological replacement regimens in hypopituitarism are not well characterised. We aimed to assess the effect of three hydrocortisone (HC) replacement dose regimens on bone turnover.
An open cross-over study randomising ten hypopituitary men with severe ACTH deficiency to three commonly used HC dose regimens: dose A (20 mg mane and 10 mg tarde), dose B (10 mg mane and 10 mg tarde) and dose C (10 mg mane and 5 mg tarde).
Following 6 weeks of each regimen, the participants underwent 24-h serum cortisol sampling and measurement of bone turnover markers: bone-specific alkaline phosphatase, procollagen type I N-propeptide (PINP), intact osteocalcin (OC(1–49)), C-terminal cross-linking telopeptide (CTX-I) and tartrate-resistant acid phosphatase 5b (TRACP5b). Bone remodelling balance was estimated as an absolute ratio (PINP:CTX-I) and as an index using standardised scores derived from the matched controls.
There were significant increases in the concentrations of the formation markers PINP (P=0.045) and OC(1–49) (P=0.006) and in the PINP:CTX-I ratio (P=0.015), and a more positive bone remodelling balance index (P=0.03) was observed in patients on the lowest dose C than in those on the highest dose A. Mean 24-h cortisol concentrations correlated negatively with CTX-I (r=−0.66 and P=0.04) and TRACP5b (r=−0.74 and P=0.01) in patients on dose B and with OC(1–49) (r=−0.66 and P=0.04) and CTX-I (r=−0.81 and P<0.01) in patients on dose C. In patients receiving the lower-dose regimen, trough cortisol concentrations correlated with increased bone formation and resorption.
Low-dose HC replacement (10 mg mane and 5 mg tarde) is associated with increased bone formation and a positive bone remodelling balance. This may have a long-term beneficial effect on bone health.
Carlo L Acerini, Robert C Tasker, Simonetta Bellone, Gianni Bona, Christopher J Thompson, and Martin O Savage
Pituitary dysfunction is now well recognised after traumatic brain injury (TBI) in adults; however, little except anecdotal evidence is known about this potential complication in childhood and adolescence. Histopathological evidence exists for both hypothalamic and pituitary damage, but few data specific to children have been published. We review the available paediatric data, which shows that after both mild and severe TBI, hypopituitarism may occur, with GH and gonadotrophin deficiencies appearing to be most common. Precocious puberty has also been documented. Road-traffic accidents, falls, sport and child abuse are the most common aetiological factors for paediatric TBI. There are no published data on the incidence or prevalence, neither within a population of children with TBI, of hypopituitarism, nor on its natural history or response to hormone replacement. We urge paediatric endocrinologists, in collaboration with adult endocrinologists, to perform formal prospective research studies in patients suffering from TBI to clarify these questions.
Anne Marie Hannon, Triona O’Shea, Claire A Thompson, Mark J Hannon, Rosemary Dineen, Aftab Khattak, James Gibney, Domhnall J O’Halloran, Steven Hunter, Christopher J Thompson, and Mark Sherlock
Pregnancy is rarely reported in acromegaly. Many patients are diagnosed in later life and younger patients may have subfertility due to hypopituitarism. We present a case series of 17 pregnancies in 12 women with acromegaly.
Twelve women with acromegaly who completed pregnancy were identified from centres involved in the Irish Pituitary Study. Eleven women had pituitary macroadenomas and one woman had a microadenoma. Only 5/17 pregnancies had optimal biochemical control of acromegaly preconception, as defined by IGF-1 concentration in the age-related reference level and plasma GH concentration of <2 μg/L. In 6/17 pregnancies, dopamine agonist treatment was continued during pregnancy; all other acromegaly treatments were discontinued during pregnancy.
Effect of pregnancy on acromegaly: No patient developed new visual field abnormalities, or symptoms suggestive of tumour expansion during pregnancy. In 9/12 patients, plasma IGF-1 concentrations that were elevated preconception normalised during pregnancy. There was a reduction in plasma IGF-1 concentrations, though not into the normal range, in a further two pregnancies.
Effect of acromegaly on pregnancy: 15 healthy babies were born at term; one patient underwent emergency C-section at 32 weeks for pre-eclampsia, and one twin pregnancy had an elective C-section at 35 weeks’ gestation. Blood pressure remained within normal limits in the remainder of the pregnancies. Gestational diabetes did not develop in any pregnancy.
Our data suggests that pregnancy in women with acromegaly is generally safe, from a maternal and foetal perspective. Furthermore, biochemical control tends to improve despite the withdrawal of somatostatin analogue therapy during pregnancy.
Colin Davenport, Wan A Mahmood, Hannah Forde, David T Ashley, Amar Agha, John McDermott, Seamus Sreenan, Christopher J Thompson, Frank McGrath, Brendan McAdam, Philip M Cummins, and Diarmuid Smith
Vascular calcification (VC) is inhibited by the glycoprotein osteoprotegerin (OPG). It is unclear whether treatments for type 2 diabetes are capable of promoting or inhibiting VC. The present study examined the effects of insulin and liraglutide on i) the production of OPG and ii) the emergence of VC, both in vitro in human aortic smooth muscle cells (HASMCs) and in vivo in type 2 diabetes.
HASMCs were exposed to insulin glargine or liraglutide, after which OPG production, alkaline phosphatase (ALP) activity and levels of Runx2, ALP and bone sialoprotein (BSP) mRNA were measured. A prospective, nonrandomised human subject study was also conducted, in which OPG levels and coronary artery calcification (CAC) were measured in a type 2 diabetes population before and 16 months after the commencement of either insulin or liraglutide treatment and in a control group that took oral hypoglycemics only.
Exposure to insulin glargine, but not liraglutide, was associated with significantly decreased OPG production (11 913±1409 pg/104 cells vs 282±13 pg/104 cells, control vs 10 nmol/l insulin, P<0.0001), increased ALP activity (0.82±0.06 IU/104 cells vs 2.40±0.16 IU/104 cells, control vs 10 nmol/l insulin, P<0.0001) and increased osteogenic gene expression by HASMCs. In the clinical study (n=101), insulin treatment was associated with a significant reduction in OPG levels and, despite not achieving full statistical significance, a trend towards increased CAC in patients.
Exogenous insulin down-regulated OPG in vitro and in vivo and promoted VC in vitro. Although neither insulin nor liraglutide significantly affected CAC in the present pilot study, these data support the establishment of randomised trials to investigate medications and VC in diabetes.
Mark Sherlock, Lucy Ann Behan, Mark J Hannon, Aurora Aragon Alonso, Christopher J Thompson, Robert D Murray, Nicola Crabtree, Beverly A Hughes, Wiebke Arlt, Amar Agha, Andrew A Toogood, and Paul M Stewart
Patients with hypopituitarism have increased morbidity and mortality. There is ongoing debate about the optimum glucocorticoid (GC) replacement therapy.
To assess the effect of GC replacement in hypopituitarism on corticosteroid metabolism and its impact on body composition.
Design and patients
We assessed the urinary corticosteroid metabolite profile (using gas chromatography/mass spectrometry) and body composition (clinical parameters and full body DXA) of 53 patients (19 female, median age 46 years) with hypopituitarism (33 ACTH-deficient/20 ACTH-replete) (study A). The corticosteroid metabolite profile of ten patients with ACTH deficiency was then assessed prospectively in a cross over study using three hydrocortisone (HC) dosing regimens (20/10 mg, 10/10 mg and 10/5 mg) (study B) each for 6 weeks. 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity was assessed by urinary THF+5α-THF/THE.
Endocrine Centres within University Teaching Hospitals in the UK and Ireland.
Main outcome measures
Urinary corticosteroid metabolite profile and body composition assessment.
In study A, when patients were divided into three groups – patients not receiving HC and patients receiving HC≤20 mg/day or HC>20 mg/day – patients in the group receiving the highest daily dose of HC had significantly higher waist-to-hip ratio (WHR) than the ACTH replete group. They also had significantly elevated THF+5α-THF/THE (P=0.0002) and total cortisol metabolites (P=0.015). In study B, patients on the highest HC dose had significantly elevated total cortisol metabolites and all patients on HC had elevated THF+5α-THF/THE ratios when compared to controls.
In ACTH-deficient patients daily HC doses of >20 mg/day have increased WHR, THF+5α-THF/THE ratios and total cortisol metabolites. GC metabolism and induction of 11β-HSD1 may play a pivitol role in the development of the metabolically adverse hypopituitary phenotype.