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ContextFluid restriction (FR) is the recommended first-line treatment for syndrome of inappropriate antidiuresis (SIAD), despite the lack of prospective data to support its efficacy.DesignA prospective nonblinded randomized controlled trial of FR versus no treatment in chronic SIAD.Interventions and OutcomeA total of 46 patients with chronic asymptomatic SIAD were randomized to either FR (1 liter/day) or no specific hyponatremia treatment (NoTx) for 1 month. The primary endpoints were change in plasma sodium concentration (pNa) at days 4 and 30.ResultsMedian baseline pNa was similar in the 2 groups [127 mmol/L (interquartile range [IQR] 126-129) FR and 128 mmol/L (IQR 126–129) NoTx, P = 0.36]. PNa rose by 3 mmol/L (IQR 2-4) after 3 days FR, compared with 1 mmol/L (IQR 0-3) NoTx, P = 0.005. There was minimal additional rise in pNa by day 30; median pNa increased from baseline by 4 mmol/L (IQR 2-6) in FR, compared with 1 mmol/L (IQR 0-1) NoTx, P = 0.04. After 3 days, 17% of FR had a rise in pNa of ≥5 mmol/L, compared with 4% NoTx, RR 4.0 (95% CI 0.66-25.69), P = 0.35. After 3 days, 61% of FR corrected pNa to ≥130 mmol/L, compared with 39% of NoTx, RR 1.56 (95% CI 0.87-2.94), P = 0.24.ConclusionFR induces a modest early rise in pNa in patients with chronic SIAD, with minimal additional rise thereafter, and it is well-tolerated. More than one-third of patients fail to reach a pNa ≥130 mmol/L after 3 days of FR, emphasizing the clinical need for additional therapies for SIAD in some patients.

Glucocorticoid deficiency is the clinical state characterised by inadequate cortisol production. It may occur due to the primary failure of the adrenal cortex or to lack of stimulation of the adrenal cortex by adrenocorticotropic hormone. The aim of treatment of glucocorticoid deficiency is to mimic the normal physiological secretion of cortisol, in order to normalise quality of life and reverse pathological sequelae. However, the diurnal rhythm of cortisol secretion is difficult to reproduce with exogenous glucocorticoid therapy. There is wide inter- and intra-individual variability of in the dynamics of physiological glucocorticoid secretion, and glucocorticoid preparations that are currently available cannot reproduce physiological profiles. In addition, there are no reliable biomarkers to determine the adequacy of treatment. The treatment of acute glucocorticoid deficiency/ adrenal crisis involves prompt recognition and administration of parenteral hydrocortisone, rehydration, and management of electrolyte abnormalities. In the management of chronic glucocorticoid deficiency, the prevention of adrenal crisis must be balanced with avoidance of the long-term adverse effects of over-replacement. This requires close collaboration with the patient, for whom education and empowerment in the management of glucocorticoid deficiency, and the prevention of crises, are crucial.

Adrenal insufficiency (AI) is a serious condition, which can arise from pathology affecting the adrenal gland itself (primary adrenal insufficiency, PAI), hypothalamic or pituitary pathology (secondary adrenal insufficiency, SAI), or as a result of suppression of the hypothalamic-pituitaryadrenal (HPA) axis by exogenous glucocorticoid therapy (tertiary adrenal insufficiency, TAI). AI is associated with an increase in morbidity and mortality and a reduction in quality of life. In addition, the most common cause of PAI, autoimmune adrenalitis, may be associated with a variety of other autoimmune disorders. Untreated AI can present with chronic fatigue, weight loss and vulnerability to infection. The inability to cope with acute illness or infection can precipitate life-threatening adrenal crisis. It is therefore a critical diagnosis to make in a timely fashion, in order to institute appropriate management, aimed at reversing chronic ill health, preventing acute crises, and restoring quality of life. In this review, we will describe the normal physiology of the HPA axis and explain how knowledge of the physiology of this axis helps us understand the clinical presentation of AI, and forms the basis for the biochemical investigations which lead to the diagnosis of AI.

Adrenal insufficiency (AI) is associated with increased cardiovascular morbidity and mortality and reduced quality of life (QoL). Optimum glucocorticoid (GC) dosing and timing are crucial in the treatment of AI, yet the natural circadian secretion of cortisol is difficult to mimic. Furthermore, within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI due to supraphysiological GC replacement therapy, and the non-physiological pattern of current HC replacement therapy. The use of once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may address unmet clinical needs. We performed an investigator-initiated, prospective, cross-over study in 51 patients with AI [primary (PAI) and secondary (SAI)]. Patients were assessed at baseline and thereafter switched from their usual hydrocortisone (HC) regimen to a once-daily dose equivalent of DR-HC for 12 weeks. Cardiometabolic risk factors, and QoL coupled with an in-vivo assessment of tissue corticosteroid metabolism using urinary steroid metabolomics, cortisol generation curves, and adipose tissue biopsies, were assessed in the patient population before and after DR-HC and compared to age-and BMI-matched controls. After 3 months of DR-HC, the mean SBP in our study population decreased by 4.5mmHg, p=0.04 and DBP decreased by 4.2mmHg, p=0.01.There was also a significant reduction in mean weight (-1.17kg, p=0.03) and BMI (-0.3kg/m2, p=0.03). In a sub-analysis, there was a greater reduction in SBP observed in patients with SAI when compared to PAI post-DR-HC therapy (-5.8mmHg vs -4 mmHg, p=0.01). Additionally, patients reported significant improvements in QoL. In vivo analysis demonstrated that patients with AI receiving immediate-release HC (IR-HC) had a higher median 24-hour excretion of urinary cortisol compared to healthy controls [72.1µg/24hrs (IQR 43.6-124.2) vs 51.85 (35.5-72.3), p=0.02], with a lower global activity of 11β-HSD2 and higher activity of 5-alpha reductase. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary F and total GC metabolite excretion, which was most significant in the evening on diurnal urine sampling. There was an increase in global 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered post-DR-HC but there was a significant reduction in gene expression of 11β-HSD1 in subcutaneous adipose tissue Using comprehensive in-vivo techniques we have demonstrated significant abnormalities in corticosteroid metabolism in patients with primary and secondary adrenal insufficiency, driven by dysregulation in the pre-receptor enzyme activity controlling tissue-specific GC availability. Patients receiving conventional immediate-release hydrocortisone experience diurnal fluctuations in tissue cortisol exposure, which can be improved following treatment with DR-HC.

In recent years, the short Synacthen test (SS) has become the most widely used test to assess adrenal reserve. Despite its frequent use, there are still several areas related to the short Synacthen test (SST), which have no consensus including the optimum sampling times, that is, whether a 60 min post-Synacthen administration cortisol is necessary or not. Methodology We performed a retrospective data analysis of 492 SSTs performed on adult patients in a tertiary referral teaching hospital in Ireland. The SSTs were performed in the inpatient and outpatient setting and included patients across all medical disciplines and not exclusively to the endocrinology department. Results 313 patients had 0, 30 and 60 min samples available for analysis. A total of 270/313 (82%) were deemed to pass the test, that is, cortisol ≥500 nmol/L at both 30 and 60 min. Of the 313 patients, 19 (6%) patients had an indeterminate response, cortisol Conclusion Using the 30 min cortisol sample post-Synacthen administration alone identifies clinically relevant adrenal insufficiency in the majority of cases. A small subset of patients have a suboptimal response at 30 min but have a 60 min cortisol concentration above the threshold for a pass. Data regarding the long-term outcomes and management of such patients are lacking and require further study.

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 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.

Background Acute hyponatremia is a medical emergency that confers high mortality, attributed primarily to cerebral edema. Expert guidelines advocate the use of intravenous boluses of hypertonic saline rather than traditional continuous infusion to achieve a faster initial rise in plasma sodium (pNa) concentration. However, there is a limited evidence base for this recommended policy change. Methods We prospectively assessed the clinical and biochemical outcomes in patients treated for symptomatic hyponatremia caused by syndrome of inappropriate antidiuresis in response to intravenous bolus treatment with 3% saline (100 mL, repeated up to two more times) and compared the outcomes to retrospective data from patients treated with continuous intravenous infusion of low-dose (20 mL/h) 3% saline. Results Twenty-two patients were treated with bolus infusion and 28 with continuous infusion. Three percent saline bolus caused more rapid elevation of pNa at 6 hours [median (range) 6 (2 to11) vs 3 (1 to 4) mmol/L, P < 0.0001], with a concomitant improvement in Glasgow Coma Scale (GCS) [median (range) 3 (1 to 6) vs 1 (−2 to 2), P < 0.0001] at 6 hours. Median pNa concentration was similar at 24 hours in the two treatment groups. The administration of a third saline bolus was associated with greater need for dextrose/dDAVP to prevent overcorrection (OR 24; P = 0.006). There were no cases of osmotic demyelination in either group. Conclusion Three percent saline bolus produces faster initial elevation of pNa than continuous infusion with quicker restoration of GCS, and without osmotic demyelination. Frequent electrolyte monitoring, and judicious intervention with dDAVP is required to prevent overcorrection with bolus therapy.

INTRODUCTION The aldosterone/renin ratio is the initial screening test for primary hyperaldosteronism (PHA), but little data exists regarding ethnic variations in this. METHODS Following clinical observation of a high prevalence of abnormal aldosterone/renin ratio (ARR) in patients of African-origin, we retrospectively reviewed all ARR measurements in a single centre over 10 years. Rates of hypokalaemia, intraventricular septal thickness (IVS, by echocardiography) and adrenal imaging were recorded when available. RESULTS Aldosterone/renin ratio was available in 1473 patients, and abnormal in 374 (25.4%). Abnormal ARR was observed in 305/1349 (22.6%) of European-origin and 69/124 (55.6%) of African-origin patients (P

Background Glucocorticoid therapy is the most common cause of iatrogenic osteoporosis. Less is known regarding the effect of glucocorticoids when used as replacement therapy on bone remodelling in patients with adrenal insufficiency. Enhanced intracellular conversion of inactive cortisone to active cortisol, by 11 beta-hydroxysteroid dehydrogenase type 1(11β-HSD1) and other enzymes leading to alterations in glucocorticoid metabolism, may contribute to a deleterious effect on bone health in this patient group. Methods Study design: An open crossover prospective study randomizing ten hypopituitary men, with severe ACTH deficiency, to three commonly used hydrocortisone dose regimens. Measurements: Following 6 weeks of each regimen, patients underwent 24-h serum cortisol/cortisone sampling, measurement of bone turnover markers, and a 24-h urine collection for measurement of urinary steroid metabolites by gas chromatography-mass spectrometry (GC-MS). Serum cortisone and cortisol were analysed by liquid chromatography-mass spectrometry (LC-MS). Results Dose-related and circadian variations in serum cortisone were seen to parallel those for cortisol, indicating conversion of ingested hydrocortisone to cortisone. The median area under the curve (AUC) of serum cortisone was significantly higher in patients on dose A (20 mg/10 mg) [670.5 (IQR 621–809.2)] compared to those on dose C (10 mg/5 mg) [562.8 (IQR 520.1–619.6), p = 0.01]. A negative correlation was observed between serum cortisone and bone formation markers, OC [1–49] (r = − 0.42, p = 0.03), and PINP (r = − 0.49, p = 0.01). There was a negative correlation between the AUC of night-time serum cortisone levels with the bone formation marker, OC [1–49] (r = − 0.41, p = 0.03) but there were no significant correlations between day-time serum cortisone or cortisol with bone turnover markers. There was a negative correlation between total urinary cortisol metabolites and the bone formation markers, PINP (r = − 0.39, p = 0.04), and OC [1–49] (r = − 0.35, p = 0.06). Conclusion Serum cortisol and cortisone and total urinary corticosteroid metabolites are negatively associated with bone turnover markers in patients receiving replacement doses of hydrocortisone, with nocturnal glucocorticoid exposure having a potentially greater influence on bone turnover. Trial registration Irish Medicines Board Clinical Trial Number – CT900/459/1 and EudraCT Number – 2007-005018-37. Registration date: 07-09-2007.

An adrenal incidentaloma is now established as a common endocrine diagnosis that requires a multidisciplinary approach for effective management. The majority of patients can be reassured and discharged, but a personalized approach based upon image analysis, endocrine workup, and clinical symptoms and signs are required in every case. Adrenocortical carcinoma remains a real concern but is restricted to, Graphical Abstract Graphical Abstract

CONTEXT Animal data and cross-sectional human studies have established that chronic hyponatraemia predisposes to osteoporosis; the effects of acute hyponatraemia on bone turnover have not been determined. Our objective was to test the hypothesis that acute hyponatraemia leads to dynamic effects on bone turnover. DESIGN A prospective observational pilot study. METHODS Bone turnover markers [C-terminal crosslinking telopeptide of type 1 collagen (CTX-1), N-propeptide of type 1 collagen (P1NP) and osteocalcin] were measured prospectively over one week in 22 eunatraemic patients with subarachnoid haemorrhage. Patients treated with glucocorticoids were excluded. RESULTS Eight patients developed acute hyponatraemia, median nadir plasma sodium concentration 131 mmol/L (IQR 128-132), and 14 remained eunatraemic, nadir plasma sodium concentration 136 mmol/L (IQR 133-137). Significant main effects of hyponatraemia were found for P1NP (p = .02) and P1NP:CTX-1 ratio (p = .02), both fell in patients with acute hyponatraemia, with significant interaction between hyponatraemia and time from baseline for P1NP (p = .02). Significant main effects of time from baseline (p

Background Adrenal insufficiency (AI) is associated with increased cardiovascular morbidity and mortality and reduced quality of life (QoL). Optimum glucocorticoid (GC) dosing and timing are crucial in the treatment of AI, yet the natural circadian secretion of cortisol is difficult to mimic. The once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®), offers a more physiological cortisol profile and may address unmet needs. Methods An investigator-initiated, prospective, cross-over study in patients with AI. Following baseline assessment of cardiometabolic risk factors and QoL, patients switched from their usual hydrocortisone regimen to a once-daily dose equivalent of DR-HC and were reassessed after 12 weeks of treatment. Results Fifty-one patients (21 PAI/30 SAI) completed the study. Mean age was 41.6 years (s.d. 13), and 58% (n = 30) were male. The median daily HC dose before study entry was 20 mg (IQR 15–20 mg). After 3 months on DR-HC, the mean SBP decreased by 5.7 mmHg, P = 0.0019 and DBP decreased by 4.5 mmHg, P = 0.0011. There was also a significant reduction in mean body weight (−1.23 kg, P = 0.006) and BMI (−0.3 kg/m2, P = 0.003). In a sub-analysis, there was a greater reduction in SBP observed in patients with SAI when compared to PAI post-DR-HC. Patients reported significant improvements in QoL using three validated QoL questionnaires, with a greater improvement in PAI. Conclusion Dual-release hydrocortisone decreases BP, weight and BMI compared with conventional HC treatment, even at physiological GC replacement doses. Additionally, DR-HC confers significant improvements in QoL compared to immediate-release HC, particularly in patients with PAI, which is also reflected in the patient preference for DR-HC.

Glucocorticoids (GCs) are steroid hormones, which are essential for life. They are secreted by the adrenal cortex under the control of the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids are essential for the normal function of most organ systems and, in both, excess and deficiency can lead to significant adverse consequences. Adrenal insufficiency (AI) is a rare, life-threatening disorder characterized by insufficient production of corticosteroid hormones. Primary AI is defined by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids despite normal or increased adrenocorticotropin hormone (ACTH). Secondary AI is adrenal hypofunction due to insufficient amount of ACTH produced by the pituitary gland. Conventional treatment of both primary and secondary adrenal insufficiencies involves lifelong glucocorticoid replacement therapy. The role of cortisol deficiency and the impact of hydrocortisone replacement on morbidity and mortality in this patient group are under increasing scrutiny. Established glucocorticoid replacement regimens do not completely mirror endogenous hormonal production, and their monitoring to ensure optimum therapy is hampered by the lack of reliable biomarkers of hormone sufficiency. A further confounding issue is the tissue-specific regulation of glucocorticoid through the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) with research focusing on the role of this prereceptor regulation in the development of adverse metabolic features in patients. This review defines the factors influencing glucocorticoid action in patients with adrenal insufficiency receiving glucocorticoid therapy.

Background: Glucocorticoid therapy is the most common cause of iatrogenic osteoporosis. Less is known on the effect of glucocorticoids on bone remodeling when used as replacement therapy in patients with adrenal insufficiency. Enhanced intracellular conversion of cortisone to active cortisol, by 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and other enzymes leading to alterations in glucocorticoid metabolism may contribute to a deleterious effect on bone health in this patient group. Study Design: An open crossover prospective study randomizing ten hypopituitary men, with severe ACTH deficiency, to three commonly used hydrocortisone dose regimens. Measurements: Following 6 weeks of each regimen, patients underwent 24-hour serum cortisol/cortisone sampling, measurement of bone turnover markers, and a 24-hour urine collection for measurement of urinary corticosteroid metabolites by GC-MS. Serum cortisone and cortisol were analysed by LC-MS/MS. Results: Dose related and circadian variations in serum cortisone were seen to parallel those for cortisol. The median area under the curve (AUC) of serum cortisone was significantly higher in patients on dose A (20mg/10mg) [670.5 (IQR 621-809.2)] compared to those on dose C (10mg/5mg) [562.8 (IQR 520.1-619.6), p=0.01]. A negative correlation was observed between serum cortisone and bone formation markers, OC[1-49] (r=-0.42, p=0.03), and PINP (r=-0.49, p=0.01). There was a negative correlation between the AUC of night-time serum cortisone levels with the bone formation marker, OC[1-49] (r= -0.41, p=0.03) but there were no significant correlations between day-time serum cortisone or cortisol with bone turnover markers. There was a negative correlation between total urinary cortisol metabolites and the bone formation markers, PINP (r=-0.39, p=0.04), and OC[1-49] (r=-0.35, p=0.06). Conclusion: Serum cortisone and total urinary total cortisol metabolites are associated with alterations in bone turnover markers suggesting an important role of tissue-specific metabolism of glucocorticoids on bone metabolism in patients receiving HC replacement therapy.

Background : The natural history of adipsic diabetes insipidus (ADI) is not well described, and reports of recovery of thirst are rare. Design and Methods : Case histories presentation. ADI was identified by demonstrating absent thirst and arginine vasopressin (AVP) responses to hypertonic saline infusion. Results : Twelve patients with ADI were identified (craniopharyngioma 5, anterior communicating artery aneurysm (ACOM) repair 4, congenital 1, neurosarcoidosis 1, prolactinoma 1). Three patients died. Six patients had permanent ADI. Three patients had recovery of thirst, with a heterogenous pattern of recovery. In the first case, ADI had developed after clipping of an ACOM aneurysm. Ten years after surgery; he sensed the return of thirst; repeated hypertonic saline infusion showed recovery of thirst and AVP secretion. In the second case, a 41-year-old female with an intrasellar craniopharyngioma developed post-operative ADI with persistent hypernatremia. Two years post-operatively, she complained of thirst, and hypertonic saline infusion showed normalization of thirst but absent AVP responses, confirming recovery of thirst, but with persistent diabetes insipidus (DI). In the third case, a 29-year-old Caucasian had craniotomy and radiotherapy for craniopharyngioma and developed ADI post-operatively. Eight years post-op, she presented with thirst, seizures and pNa of 112 mmol/l. Hypertonic saline infusion showed persistent DI but thirst responses typical of compulsive water drinking; she has had recurrent hyponatraemia since then. Conclusions : We report that 3/12 patients with ADI recovered thirst after longstanding adipsia with heterogenous pattern of recovery. Both the mortality of 25% and the recovery rate of 25% should be considered when planning long-term surveillance.

Hyponatraemia is the most common electrolyte disturbance encountered in clinical practice. It is associated with -significant morbidity and mortality, thus appropriate investigation and treatment is essential. Hyponatraemia presents with a spectrum of clinical presentations ranging from no symptoms to life-threatening neurological sequelae. Hyponatraemia has multiple aetiologies and distinguishing the underlying aetiology facilitates appropriate treatment. This review provides an overview of the presentations and approaches to management of this common clinical condition.

Lithium is the mainstay of treatment for bipolar disorder, mania and an augmentation therapy in patients with treatment resistant depression. It has a narrow therapeutic index, with recognized adverse multi-system and endocrine side effects.To assess the impact of lithium therapy, in particular lithium toxicity, on the development of endocrine and renal disorders in a cohort of patients in a single tertiary referral centre in Ireland.A retrospective analysis was performed of the prevalence of lithium toxicity and renal, thyroid and parathyroid dysfunction in our study population.We collected laboratory data from the Clinical Chemistry department of the Adelaide and Meath Hospital incorporating the National Children's Hospital (AMNCH), Dublin, Ireland. Our study population included all patients who had at least one serum lithium measurement from January 1st 2000 to December 31st 2014 inclusive.A total of 580 patients were included in the study. Among our study group, 70 patients (12.1%) had 1 toxic lithium measurement (lithium level1.2 mmol/l). 27.8% (n 161) of patients developed stage 3 Chronic kidney Disease (CKD) or higher, which was commoner in those patients who developed toxic lithium levels (P 0.0001) and in those who developed hypernatraemia (P 0.0001). 16.2% of patients (n 94) had one serum sodium145 mmol/l during follow up. 60 patients(10.3%) had a TSH10 mU/l, while complete suppression of TSH (0.05 mU/l) was observed in 22 patients (3.8%) during follow-up. 4% (n 37) of the study population had ≥1 serum corrected calcium level2.55 mmol/l, and 4 patients had biochemical confirmation of primary hyperparathyroidism but PTH levels were only performed in 2.8% (n 16) of the studypopulation.Stage 3 CKD is common in patients receiving lithium therapy. Lithium toxicity is associated with CKD and hypernatraemia. Thyroid dysfunction and hypercalcaemia are common in patients receiving lithium therapy. Patients receiving lithium therapy require surveillance of renal, thyroid and bone biochemistry.

Summary Context and Objective Nonfunctioning pituitary adenomas (NFPAs) are the most common subtype of pituitary tumour. Hypopituitarism is observed in NFPAs due to tumour‐ or treatment‐related factors and may increase mortality risk. Here, we analysed the associations of hypopituitarism, hormone replacement and mortality in a large NFPA cohort derived from two large European centres. Design, Setting and Participants Case note review of all patients treated for NFPA in University Hospitals Birmingham and Beaumont Hospital Dublin between 1999 and 2014 was performed. Main Outcome Measures Clinical presentation, treatment strategies, pituitary function and vitality status were recorded in each patient. A multivariate Cox regression model was used to examine the association between hypopituitarism, hormone replacement and premature mortality. Results A total of 519 patients were included in the analysis. Median duration of follow‐up was 7·0 years (0·5–43). A total of 81 deaths were recorded (15·6%). On multivariate analysis, adrenocorticotropic hormone (ACTH) and gonadotropin (Gn) deficiencies were associated with an increased relative risk of death (OR 2·26, 95% CI 1·15–4·47, P = 0·01 and OR 2·56, 95% CI 1·10–5·96, P = 0·01, respectively). Increased hydrocortisone (HC) (P‐trend = 0·02) and lower levothyroxine (LT4) doses (P‐trend = 0·03) were associated with increased risk of death. Mortality increased with the degree of pituitary failure observed (P‐trend = 0·04). Conclusion ACTH and gonadotropin‐deficient patients have higher mortality rates compared to those with intact hormonal axes. Excessive HC and suboptimal LT4 replacement may also increase risk of death. Complex associations between hormone deficiency and replacement underpin the increased mortality risk in NFPA patients.

Acromegaly is a rare, chronic, progressive disease characterized by excess secretion of growth hormone (GH) and increased circulating insulin-like growth factor 1 (IGF-1) concentrations. It is caused by a pituitary adenoma in the vast majority of cases. The clinical diagnosis, based on symptoms related to GH excess, is often delayed due to the insidious nature of the disease. Consequently, patients often have established systemic complications at diagnosis with increased morbidity and premature mortality. Serum IGF-1 measurement is recommended as the initial screen for patients with suspected acromegaly. The gold standard diagnostic test remains the oral glucose tolerance test with concomitant GH measurement. Therapy for acromegaly is targeted at decreasing GH and IGF-1 levels, ameliorating patients’ symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, medical therapies (such as dopamine agonists, somatostatin receptor agonists and the GH receptor antagonist pegvisomant) and radiotherapy. A multidisciplinary approach is recommended with often a requirement for combined treatment modalities. With disease control, associated morbidity and mortality can be reduced. The recently published evidence-based guidelines by the Endocrine society addressed important clinical issues regarding the evaluation and management of acromegaly. This review discusses advances in our understanding of the pathophysiology of acromegaly, diagnosis of various forms of the disease, and focuses on current treatment modalities, and on future pharmacological therapies for patients with acromegaly.