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Mark Sherlock

Publications and source records attributed to Mark Sherlock.

8 recordsLinked to original sources
PubMed2007

Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 activity in vivo limits glucocorticoid exposure to human adipose tissue and decreases lipolysis.

CONTEXT: The pathophysiological importance of glucocorticoids (GCs) is exemplified by patients with Cushing's syndrome who develop hypertension, obesity, and insulin resistance. At a cellular level, availability of GCs to the glucocorticoid and mineralocorticoid receptors is controlled by the isoforms of 11beta-hydroxysteroid dehydrogenase (11beta-HSD). In liver and adipose tissue, 11beta-HSD1 converts endogenous, inactive cortisone to active cortisol but also catalyzes the bioactivation of the synthetic prednisone to prednisolone. OBJECTIVE: The objective of the study was to compare markers of 11beta-HSD1 activity and demonstrate that inhibition of 11beta-HSD1 activity limits glucocorticoid availability to adipose tissue. DESIGN AND SETTING: This was a clinical study. PATIENTS: Seven healthy male volunteers participated in the study. INTERVENTION: Intervention included carbenoxolone (CBX) single dose (100 mg) and 72 hr of continuous treatment (300 mg/d). MAIN OUTCOME MEASURES: Inhibition of 11beta-HSD1 was monitored using five different mechanistic biomarkers (serum cortisol and prednisolone generation, urinary corticosteroid metabolite analysis by gas chromatography/mass spectrometry, and adipose tissue microdialysis examining cortisol generation and glucocorticoid-mediated glycerol release). RESULTS: Each biomarker demonstrated reduced 11beta-HSD1 activity after CBX administration. After both a single dose and 72 hr of treatment with CBX, cortisol and prednisolone generation decreased as did the urinary tetrahydrocortisol+5alpha-tetrahydrocortisol to tetrahydrocortisone ratio. Using adipose tissue microdialysis, we observed decreased interstitial fluid cortisol availability with CBX treatment. Furthermore, a functional consequence of 11beta-HSD1 inhibition was observed, namely decreased prednisone-induced glycerol release into adipose tissue interstitial fluid indicative of inhibition of GC-mediated lipolysis. CONCLUSION: CBX is able to inhibit rapidly the generation of active GC in human adipose tissue. Importantly, limiting GC availability in vivo has functional consequences including decreased glycerol release.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage.

BACKGROUND: Hyponatraemia is common following subarachnoid haemorrhage (SAH) but the pathogenesis is unclear. Objective To establish the incidence, pathophysiology and consequences of hyponatraemia following SAH. METHODS: A retrospective case-note analysis of all patients with SAH admitted to Beaumont Hospital between January 2002 and September 2003. Three hundred and sixteen cases of SAH were substantiated by computed tomography (CT) scan and angiogram findings. Hyponatraemia was defined as plasma sodium < 135 mmol/l. RESULTS: One hundred and seventy-nine patients (56.6%) developed hyponatraemia and 62 (19.6%) developed significant hyponatraemia (plasma sodium < 130 mmol/l). The incidence of severe hyponatraemia following hypophysectomy was lower in the period of analysis (5/81, 6.2%, P < 0.01). Hyponatraemia was more common in patients with identified aneurysms (anterior circulation 102/168, 60.7%, posterior circulation 56/95, 60.8%) than in those with no radiological aneurysm (21/54, 38.8%, P < 0.001). Hyponatraemia was more common after aneurysmal clipping (68/103, 66%) or coiling (82/132, 62%) than after conservative treatment (29/81, 36%, P < 0.001). The aetiology of significant hyponatraemia was the syndrome of inappropriate antidiuretic hormone secretion (SIADH) 39/62 (69.2%), cerebral salt-wasting syndrome (CSWS) 4/62 (6.5%), hypovolaemic hyponatraemia 13/62 (21%), hypervolaemic hyponatraemia 3/62 (4.8%) and mixed CSW/SIADH 3/62 (4.8%). Hyponatraemia was associated with longer hospital stay (24.0 +/- 2.6 vs. 11.8 +/- 0.8 days, P < 0.001) but did not affect mortality (P = 0.07). Hyponatraemia developed more than 7 days following SAH in 21.4% and more then 7 days following intervention in 31.8%. CONCLUSIONS: Hyponatraemia is common following SAH and is associated with longer hospital stay. Clipping and coiling of aneurysms are associated with higher rates of hyponatraemia. SIADH is the commonest cause of hyponatraemia after SAH. Delayed hyponatraemia is common, and has implications for early discharge strategies.

Adolescent↗
PubMed2005

Hypothalamic-pituitary dysfunction after irradiation of nonpituitary brain tumors in adults.

CONTEXT: Hypothalamic-pituitary (HP) dysfunction is common in children treated with cranial radiotherapy (RT) for brain tumors, but there is little known about the risk of HP dysfunction in adults treated with RT for primary nonpituitary brain tumors. OBJECTIVE: The objective was to study the frequency of HP dysfunction in adults after RT for nonpituitary brain tumors. METHOD: We studied 56 adult patients who received external beam RT for primary nonpituitary brain tumors at time intervals of 12-150 months after RT. The control group consisted of 20 RT-naive patients with primary brain tumors. GH and adrenal axes were assessed using the insulin tolerance test or the glucagon stimulation test. Gonadotroph, thyrotroph, and lactotroph function were assessed using baseline blood measurements. The biological effective dose (BED) to the HP axis was calculated in the RT patients. RESULTS: Hypopituitarism was present in 41% of patients. The frequency of GH, ACTH, gonadotropin, and TSH deficiencies, and hyperprolactinemia was 32, 21, 27, 9, and 32%, respectively. Any degree of hypopituitarism and GH deficiency was significantly associated with longer time interval from RT and greater BED. However, gonadotropin deficiency and hyperprolactinemia were only related to BED, whereas ACTH deficiency was only significantly associated with the time interval from RT. One RT-naive patient was GH deficient. CONCLUSION: Adult patients treated with cranial irradiation for primary nonpituitary brain tumors are at high risk of hypopituitarism, which is time and dose dependent. Long-term surveillance and periodic evaluation are needed. We recommend that adult late effect clinics, similar to those for children, should be established.

Adrenocorticotropic Hormone↗
PubMed2005

Spontaneous recovery from posttraumatic hypopituitarism.

Hypopituitarism is an increasingly recognized complication of traumatic brain injury that can have significant potential to impair recovery and rehabilitation in affected survivors. Although posttraumatic cranial diabetes insipidus is known to be transient in many cases, recovery of established anterior pituitary hormone deficiency is thought to be a very rare event. We report the case of a 25-yr-old man who incurred severe traumatic brain injury in 1997. Sixteen months later, dynamic pituitary stimulation tests revealed severe growth hormone and adrenocorticotropin hormone deficiency. He was treated with recombinant human growth hormone and hydrocortisone. Five years after traumatic brain injury, repeat neuroendocrine assessment, prompted by an increasing serum insulin-like growth factor-1 level, showed normal growth hormone and adrenocorticotropin hormone responses. This is the first case report, to our knowledge, to show that adult posttraumatic growth hormone deficiency can be reversible. The recognition that anterior pituitary dysfunction can recover after traumatic brain injury has implications for the follow-up of patients with hypopituitarism secondary to head trauma to avoid unnecessary, expensive, and potentially harmful therapy.

Adrenocorticotropic Hormone↗
PubMed2005

The natural history of post-traumatic neurohypophysial dysfunction.

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.

Adolescent↗
PubMed2004

Attenuation of vasopressin-induced antidiuresis in poorly controlled type 2 diabetes.

Renal resistance to vasopressin has been demonstrated in type 1 diabetes and in type 2 diabetes with nephropathy. However, renal response to vasopressin in type 2 diabetes without nephropathy has not been studied. We studied 10 subjects with poorly controlled type 2 diabetes (PCDS; Hb A(1c) >9%), 10 subjects with well-controlled type 2 diabetes (WCDS; Hb A(1c) <7%), and 10 matched nondiabetic control subjects (NDCS) during a euglycemic 8-h water deprivation test. None of the subjects had nephropathy. Water deprivation caused similar rises in plasma vasopressin concentrations in all three groups, but the rise in urine osmolality in PCDS (280.3 +/- 49.7 to 594.4 +/- 88.5 mosmol/kgH(2)O) was lower than in WCDS (360.7 +/- 142.8 to 794.1 +/- 77.3 mosmol/kgH(2)O, P < 0.001) or NDCS (336.0 +/- 123.3 to 786.5 +/- 63.3 mosmol/kgH(2)O, P = 0.019). Total urine output was higher in the PCDS than in WCDS and NDCS (P < 0.05). Linear regression analysis showed that, in PCDS, the osmotic thresholds for thirst (291.9 +/- 4.6 mosmol/kgH(2)O) and vasopressin release (291.1 +/- 2.9 mosmol/kgH(2)O) were higher compared with WCDS (286.6 +/- 1.8 and 286.0 +/- 3.6 mosmol/kgH(2)O, respectively) and NDCS (286.0 +/- 2.4 and 284.1 +/- 4.7 mosmol/kgH(2)O, respectively) (between groups P < 0.001 for both variables). Under conditions of euglycemia, PCDS have impaired renal response to vasopressin and elevated osmotic threshold for thirst and vasopressin release in response to dehydration. Under conditions of chronic hyperglycemia, these abnormalities may significantly contribute to the development of dehydration in PCDS.

Aged↗
PubMed2004

Anterior pituitary dysfunction in survivors of traumatic brain injury.

Recent data suggest that anterior pituitary dysfunction after traumatic brain injury (TBI) is common. We sought to confirm the results of earlier studies in a larger cohort of patients with dynamic testing of pituitary function. We studied 102 consecutive TBI survivors (85 males; median age 28, range 15-65 yr) who had survived severe or moderate TBI (initial Glasgow Coma Scale score 3-13) at a median of 17 months (range 6-36) post event. GH and ACTH reserves were initially assessed using the glucagon stimulation test (GST). Normative data on GH and cortisol responses to the GST were obtained from 31 matched healthy controls. Patients with subnormal GH or cortisol responses were further evaluated, using the insulin tolerance test (ITT) or arginine + GHRH test for GH assessment and the ITT or 250-microg short synacthen test for the assessment of ACTH reserve. Patients were considered to be GH or ACTH deficient if they failed both the GST and the second provocative test. Baseline thyroid function, prolactin, IGF-I, gonadotropins, testosterone, or estradiol was performed in all patients and compared with local reference ranges.In controls, normal response to the GST was a stimulated GH peak of greater than 5 microg/liter and cortisol peak greater than 450 nmol/liter (16 microg/dl). Eighteen TBI patients (17.6%) had GH response to the GST less than 5 microg/liter, 11 of whom also failed the ITT or the arginine + GHRH tests. GH-deficient patients had significantly higher body mass index (P = 0.003), and lower IGF-I concentrations (P < 0.001), than GH-sufficient patients. Twenty-three patients (22.5%) had cortisol responses to GST less than 450 nmol/liter, 13 of whom also failed the ITT or short synacthen test. GH or ACTH deficiencies were not related to age, Glasgow Coma Scale score, or the presence of other pituitary hormone abnormalities (P > 0.05). Twelve patients (11.8%) had gonadotropin and one (1%) had thyrotrophin deficiencies. Twelve patients (11.8%) had hyperprolactinemia. Twenty-nine patients (28.4%) had at least one anterior pituitary hormone deficiency. This is the largest study, to date, of hypopituitarism after TBI and confirms a high prevalence of undiagnosed anterior pituitary hormone abnormalities in survivors of TBI. Hypopituitarism is a treatable cause of morbidity after TBI. In addition to conventional pituitary hormone replacement, the potential of GH treatment to enhance recovery needs to be examined in a prospective study.

Adolescent↗