Pituitary tumours without distinct lineage differentiation express stem cell marker SOX2.

CONTEXT: The recent WHO 2022 Classification of pituitary tumours identified a novel group of 'plurihormonal tumours without distinct lineage differentiation (WDLD)'. By definition, these express multiple combinations of lineage commitment transcription factors, in a monomorphous population of cells. OBJECTIVES: To determine the expression of stem cell markers (SOX2, Nestin, CD133) within tumours WDLD, immature PIT-1 lineage and acidophil stem cell tumours, compared with committed cell lineage tumours. METHODS: Retrospective evaluation of surgically resected pituitary tumours from St Vincent's Hospital, Sydney. Patients were selected to cover a range of tumour types, based on transcription factor and hormone immunohistochemistry. Clinical data was collected from patient files. Radiology reports were reviewed for size and invasion. Samples were analysed by immunohistochemistry and RT-qPCR for SF-1, PIT-1, T-PIT, SOX2, Nestin and CD133. Stem cell markers were compared between tumours WDLD and those with classically "mature" types. RESULTS: On immunohistochemistry, SOX2 was positive in a higher proportion of tumours WDLD compared with those meeting WHO lineage criteria, 7/10 v 10/42 (70 v 23.4%, p = 0.005). CD133 was positive in 2/10 tumours WDLD but 0/41 meeting lineage criteria, P = 0.003. On RT-qPCR, there was no significant difference in relative expression of stem cell markers (SOX2, CD133, Nestin) between tumours with and WDLD. CONCLUSIONS: Our study is the first to biologically characterise pituitary tumours WDLD. We demonstrate that these tumours exhibit a higher expression of the stem cell marker SOX2 compared with other lineage-differentiated tumours, suggesting possible involvement of stem cells in their development.

Elevated insulin-like growth factor-1 in patients without clinical evidence of acromegaly.

OBJECTIVES: To (1) identify the frequency of IGF-1 elevation in a cohort of patients without clinically suspected GH excess, in a state-based reference laboratory over a 24-month period, and (2) to examine potential differences in comorbidities and relevant medications between people with an elevated IGF-1 compared to a matched control group. DESIGN: All IGF-1 measurements at Pathology Queensland between 1/12/2018-1/12/2020 were identified. The medical records of those with IGF-1 ≥1.1x the upper limit of the reference range were appraised to determine: (1) documentation of acromegalic features, (2) relevant comorbidities and medication use, and (3) further investigations to exclude pathological GH excess. PATIENTS AND MEASUREMENTS: There were 2759 IGF-1 samples measured in 1963 people ≥18 years, over the specified period. Of these, 204 had IGF-1 ≥1.1x the upper limit of the age-matched reference range; 102 cases (61M, 41F) met inclusion criteria, and were matched to 102 controls with a normal IGF-1 based on age, sex, gonadal status and pituitary anatomy on MRI. RESULTS: There were significant differences in the frequency of dopamine agonist use (19/102 cases vs. 6/102 controls, OR = 3.66, 95% confidence interval [CI]: 1.45-9.29, p = .009) and chronic kidney disease (CKD) (14/102 cases vs. 4/102 controls, OR = 3.90, 95% CI: 1.28-11.14, p = .024). CONCLUSIONS: Out of 1963 patients having IGF-1 measured, 102 (5.2%) had an elevated IGF-1 where there was no known acromegaly, GH replacement or endogenous glucocorticoid excess. Intraindividual biological variability, assay imprecision and physiological factors are known contributors to falsely elevated IGF-1, dopamine agonist therapy and CKD should also be considered.

Treatment of Prolactinoma.

Prolactinomas are the commonest form of pituitary neuroendocrine tumor (PitNET), representing approximately half of such tumors. Dopamine agonists (DAs) have traditionally been the primary treatment for the majority of prolactinomas, with surgery considered the second line. The aim of this review is to examine the historical and modern management of prolactinomas, including medical therapy with DAs, transsphenoidal surgery, and multimodality therapy for the treatment of aggressive prolactinomas and metastatic PitNETs, with an emphasis on the efficacy, safety, and future directions of current therapeutic modalities. DAs have been the mainstay of prolactinoma management since the 1970s, initially with bromocriptine and more recently with cabergoline. Cabergoline normalizes prolactin in up to 85% of patients and causes tumor shrinkage in up to 80%. Primary surgical resection of microprolactinomas and enclosed macroprolactinomas performed by experienced pituitary neurosurgeons have similar remission rates to cabergoline. Aggressive prolactinomas and metastatic PitNETS should receive multimodality therapy including high dose cabergoline, surgery, radiation therapy (preferably using stereotactic radiosurgery where suitable), and temozolomide. DAs remain a reliable mode of therapy for most prolactinomas but results from transsphenoidal surgery in expert hands have improved considerably over the last one to two decades. Surgery should be strongly considered as primary therapy, particularly in the setting of microprolactinomas, non-invasive macroprolactinomas, or prior to attempting pregnancy, and has an important role in the management of DA resistant and aggressive prolactinomas.

Towards precision medicine for clinically non-functioning pituitary tumours.

OBJECTIVE: Clinically non-functioning pituitary tumours (NFPT) are a heterogenous group of neoplasms with diverse outcomes. The purpose of this narrative review was to summarize available data on predictive factors, both in routine practice and research settings. DESIGN: A literature review was conducted for papers published in peer-reviewed journals, investigating clinical, radiological, pathological and genetic predictive factors in NFPT. RESULTS: Several clinical and radiological factors have been associated with NFPT recurrence and/or aggressiveness, including larger size and pre-/post-operative growth rates. Application of transcription factor immunohistochemistry has given rise to improved subtype identification, including 'higher-risk' subtypes, in routine clinical practice. Numerous other pathological and genetic biomarkers have demonstrated promise for prognostication in the research setting. CONCLUSION: NFPT are a heterogenous group of tumours, characterized by diverse presentation, pathogenesis and outcomes. Ongoing refinements in understanding of tumour biology are likely to pave the way to improved integrative prognostication and precision medicine for NFPT.

The relationship between early post-operative ACTH / cortisol following pituitary surgery and long-term glucocorticoid requirement - Do ultradian rhythms matter?

OBJECTIVE: To determine whether early (4-8h) post-operative ACTH after trans-sphenoidal surgery (TSS) predicts long-term hypothalamic-pituitary-adrenal (HPA) axis function and to investigate early morning day 1 ACTH/cortisol variability using rapid sampling. DESIGN: Prospective observational study. METHODS: Participants undergoing TSS were included; those treated with glucocorticoids pre-operatively received 100 mg intravenous hydrocortisone on anaesthetic induction. ACTH and cortisol were measured post-operatively at + 4h and + 8h after induction and on day 1 every 10 minutes between 0700h and 0900h. PRIMARY OUTCOME: glucocorticoid requirement at 6 months. RESULTS: Nineteen participants (10F, 9M): 6/19 (32%) were treated with replacement glucocorticoids pre-operatively; 4 had ceased by 6 weeks post-operatively. One patient developed new hypopituitarism post-operatively meaning 3/19 (16%) required glucocorticoids at 6 months. Post-operative + 4h ACTH < 14.3 pmol/L (65 ng/L) predicted secondary adrenal insufficiency (SAI) (sensitivity 100%, specificity 75%), whilst no participant with a post-operative + 4h ACTH ≥ 14.3 pmol/L (65 ng/L) required glucocorticoids at 6 months. Day 1 ACTH and cortisol showed a significant circadian fall between 0700h-0900h; ACTH 4.2 pmol/L (IQR 2.9-5.9) to 3.7 pmol/L (IQR 2.9-5.1) P = .006 and cortisol 549 nmol/L (IQR 337-618) to 439 nmol/L (IQR 315-606) P < .001, with clinically insignificant ultradian secretory pulses. CONCLUSIONS: No participant with a post-operative + 4h ACTH ≥ 14.3 pmol/L (65 ng/L) required glucocorticoids at 6 months; however, given only 3/19 participants had the primary outcome of interest, this must be confirmed in a larger cohort. The timing of a day 1 morning cortisol between 0700h and 0900h influences the accuracy of a single cut-off to diagnose SAI after pituitary surgery.

Copeptin is increased by nausea and vomiting during hypertonic saline infusion in healthy individuals.

OBJECTIVE: Measurement of hypertonic saline-stimulated copeptin has recently been described for the differentiation of polyuria-polydipsia syndrome. This study aims to determine the copeptin response to intravenous 3% hypertonic saline, including evaluation of adverse effects, in a local cohort of healthy adults >18 years in Australia. DESIGN: Prospective clinical study. METHODS: Twenty healthy volunteers (10 males and 10 females) were recruited. Participants underwent infusion of 3% hypertonic saline via a previously described standardized protocol, until the plasma sodium was ≥150 mmol/L, with measurement of plasma copeptin. RESULTS: Mean peak sodium was 152 mmol/L ± SD 1.4 with osmolality 315 mmol/kg ± SD 3.9. Median volume of hypertonic saline infused to reach target sodium ≥ 150 mmol/L was 1536 mL (IQR 1362, 1992). Mean rate of plasma sodium rise was 5.9 mmol/L/hour ± SD 1.5. Hypertonic saline-stimulated copeptin had non-parametrical distribution with median of 33.8 pmol/L (IQR 27.6, 63.6). Overall median symptom burden was 6/10 (range 3/10-9/10). Copeptin was significantly higher for those who experienced nausea and/or vomiting (n = 13) (median 39.0 pmol/L; IQR 32.5, 90), compared to those participants who did not experience either (median 20.0 pmol/L; IQR 13.0, 31.0) (P = 0.003). There were no serious adverse events. CONCLUSION: Hypertonic saline-stimulated copeptin measurements were similar in our population compared with previously reported reference intervals in healthy volunteers. There is a wide range of stimulated copeptin measurements in the healthy population. Nausea and vomiting are common adverse effects which enhance the copeptin response.

Impact of subclinical hypothyroidism on health-related quality of life: a narrative review.

A biochemical diagnosis of subclinical hypothyroidism (SCH) is defined by an elevated serum thyroid-stimulating hormone (TSH) with a normal serum free thyroxine (FT4). This paper discusses SCH in the Australian population, the impact of SCH on health-related quality of life (HRQoL), and the evidence for thyroid hormone therapy as well as exercise therapy to improve HRQoL in SCH. The prevalence of SCH in Australia is approximately 4-5% and is higher in females and the elderly. Current evidence suggests thyroid hormone therapy is not associated with an improvement in HRQoL. However, there does appear to be a subgroup of those with SCH that experience an impairment in HRQoL who may potentially benefit from treatment. Because the majority of research to date has been done in elderly, largely asymptomatic individuals, this may not be representative of the entire SCH population. In addition, alternative treatments, such as exercise therapy, have not been well explored in the literature, despite exercise therapy's effects on HRQoL in other populations. Further research is required to define clearly which individuals with SCH are likely to experience an impaired HRQoL, as well as explore the effects of thyroid hormone therapy and exercise therapy in these individuals.

Elevated insulin-like growth factor-1 in Cushing's disease.

OBJECTIVE: To determine if patients with untreated Cushing's disease have higher serum insulin-like growth factor-1 (IGF-1) compared to matched controls, and if IGF-1 decreases following remission of Cushing's disease. DESIGN: Retrospective case-control study matching Cushing's disease cases to control patients for adenoma size, age, sex, diabetic and gonadal status, body mass index and serum IGF-1 measured within one year. Paired analysis of pre-operative (untreated) and >3 months post-operative (remission) serum IGF-1 for cases. PATIENTS AND MEASUREMENTS: All patients were investigated at the Princess Alexandra Hospital Endocrine Unit between 2005 and 2017. Serum IGF-1 was measured in 25 cases and 49 controls, 23 case-control pairs and 13 cases pre- and post-operatively. RESULTS: Mean serum IGF-1 in cases was significantly higher compared to controls-32 ± 12 nmol/L compared to 25 ± 8 nmol/L, (P = 0.005). The proportion of cases with elevated serum IGF-1 above an age-adjusted reference range was higher compared to 1:1 matched controls (8/23 (35%) vs 1/23 (4%), P = 0.02). In 13 cases in remission post-operatively, serum IGF-1 decreased significantly from 31 (IQR 29-40.5) nmol/L to 23 (IQR 15-28.5) nmol/L, (P < 0.001), despite no difference in the prevalence of pre- vs post-operative pituitary hormone dysfunction (P = 0.47). CONCLUSION: Patients with untreated Cushing's disease may have elevated IGF-1, which decreases following remission. Mildly elevated IGF-1 in Cushing's disease does not imply pathological growth hormone (GH) excess.

Urea treatment in fluid restriction-refractory hyponatraemia.

OBJECTIVE: Hyponatraemia in hospitalized patients is common and associated with increased mortality. International guidelines give conflicting advice regarding the role of urea in the treatment of SIADH. We hypothesized that urea is a safe, effective treatment for fluid restriction-refractory hyponatraemia. DESIGN: Review of urea for the treatment of hyponatraemia in patients admitted to a tertiary hospital during 2016-2017. Primary end-point: proportion of patients achieving a serum sodium ≥130 mmol/L at 72 hours. PATIENTS: Urea was used on 78 occasions in 69 patients. The median age was 67 (IQR 52-76), 41% were female. Seventy (89.7%) had hyponatraemia due to SIADH-CNS pathology (64.3%) was the most common cause. The duration was acute in 32 (41%), chronic in 35 (44.9%) and unknown in the rest. RESULTS: The median nadir serum sodium was 122 mmol/L (IQR 118-126). Fluid restriction was first-line treatment in 65.4%. Urea was used first line in 21.8% and second line in 78.2%. Fifty treatment episodes (64.1%) resulted in serum sodium ≥130 mmol/L at 72 hours. In 56 patients who received other prior treatment, the mean sodium change at 72 hours (6.9 ± 4.8 mmol/L) was greater than with the preceding treatments (-1.0 ± 4.7 mmol/L; P < 0.001). Seventeen patients (22.7%) had side effects (principally distaste), none were severe. No patients developed hypernatraemia, overcorrection (>10 mmol/L in 24 hours or >18 mmol/L in 48 hours), or died. CONCLUSIONS: Urea is safe and effective in fluid restriction-refractory hyponatraemia. We recommend urea with a starting dose of ≥30 g/d, in patients with SIADH and moderate to profound hyponatraemia who are unable to undergo, or have failed fluid restriction.

The effect of glucocorticoids on Thrombospondin-1, Osteocalcin and the Thrombospondin-1:Osteocalcin ratio in humans.

OBJECTIVE: Thrombospondin-1 (TSP1), a matricellular protein, and Osteocalcin (OCN), a noncollagenous protein secreted by osteoblasts, are known to be up- and down-regulated, respectively, by glucocorticoids. The aim of this study was to determine whether a ratio between TSP1:OCN was altered by changes in glucocorticoid activity in humans. DESIGN: Prospective observational study. SETTING: Tertiary university hospital in Queensland, Australia. PATIENTS AND MEASUREMENTS: Patients with Cushing's syndrome (CS, n = 19), asthma or giant cell arteritis on chronic prednisolone treatment (PRED, n = 13), adrenal insufficiency (AI, n = 16) and healthy volunteers (HV, n = 20). Plasma TSP1 and serum total OCN were measured by immunoassay at 0800h, 1200h and 1600h in patients with CS, patients with AI taking replacement glucocorticoids, HV before and after 4 mg dexamethasone and PRED patients predose at 800 and 4 hours post-dose at 1200 hours. RESULTS: Plasma TSP1 in CS was higher (P < .0001), and serum OCN was lower (P < .0001) than HV. The TSP1:OCN ratio in HV increased significantly after 4 mg dexamethasone (P < .0001) and in AI after taking their hydrocortisone replacement therapy (P < .001). PRED patients had a higher TSP1:OCN ratio compared with HV at both 800 and 1200 hours (both P < .001), but no significant change occurred from pre- to post-dose. A TSP1:OCN ratio of >73 at 800 hours differentiated CS from HV with a sensitivity of 95% and a specificity of 100%. CONCLUSIONS: The TSP1:OCN ratio is elevated in patients on prednisolone and in patients with CS compared with healthy volunteers. It may be a useful biomarker of total body glucocorticoid activity in humans.

Testosterone therapy to prevent type 2 diabetes mellitus in at-risk men (T4DM): Design and implementation of a double-blind randomized controlled trial.

BACKGROUND: Low circulating testosterone is associated with an increased risk of developing type 2 diabetes (T2DM) in overweight men with impaired glucose tolerance (IGT). AIMS: To determine in a multi-centre, double-blinded placebo-controlled randomized trial whether testosterone treatment combined with lifestyle intervention (Weight Watchers) relative to lifestyle intervention alone reduces T2DM incidence and improves glucose tolerance at 2 years. STUDY POPULATION: Overweight or obese men aged 50-74 years with a serum testosterone of ≤14 nmol/L and IGT or newly diagnosed T2DM established by an oral glucose tolerance test (OGTT). SETTING, DRUG AND PROTOCOL: Six Australian capital city-based tertiary care centres. Participants were randomized 1:1 and injected with testosterone undecanoate (1000 mg/4 mL) or vehicle (4 mL castor oil), at baseline, 6 weeks and 3-monthly thereafter. PRIMARY ENDPOINTS: (a) Proportion of participants with 2-hour OGTT ≥11.1 mmol/L at 2 years, and (b) a difference at 2 years ≥0.6 mmol/L in the mean 2-hour OGTT glucose between treatments. SECONDARY ENDPOINTS: Fasting insulin, HbA1c, body composition, maximal handgrip strength; sexual function and lower urinary tract symptoms; serum sex steroids and sex hormone binding globulin; mood and psychosocial function; adherence to lifestyle intervention; and healthcare utilization and costs. SAFETY: Overseen by an Independent Data Safety Monitoring Committee. Haematocrit, lipids and prostate-specific antigen (PSA) are assessed 6-monthly and information relating to haematological, urological and cardiovascular adverse events from each clinic visit. SUB-STUDIES: (a) Changes in bone density and micro-architecture, (b) motivation and behaviour, (c) telomere length, (d) extended treatment up to 4 years, and (e) hypothalamo-pituitary testicular axis recovery at treatment end.

A high-volume, low-cost approach to participant screening and enrolment: Experiences from the T4DM diabetes prevention trial.

BACKGROUND/AIMS: Participant recruitment to diabetes prevention randomised controlled trials is challenging and expensive. The T4DM study, a multicentre, Australia-based, Phase IIIb randomised controlled trial of testosterone to prevent Type 2 diabetes in men aged 50-74 years, faced the challenge of screening a large number of prospective participants at a small number of sites, with few staff, and a limited budget for screening activities. This article evaluates a high-volume, low-cost, semi-automated approach to screen and enrol T4DM study participants. METHODS: We developed a sequential multi-step screening process: (1) web-based pre-screening, (2) laboratory screening through a network of third-party pathology centres, and (3) final on-site screening, using online data collection, computer-driven eligibility checking, and automated, email-based communication with prospective participants. Phone- and mail-based data collection and communication options were available to participants at their request. The screening process was administered by the central coordinating centre through a central data management system. RESULTS: Screening activities required staffing of approximately 1.6 full-time equivalents over 4 years. Of 19,022 participants pre-screened, 13,108 attended a third-party pathology collection centre for laboratory screening, 1217 received final, on-site screening, and 1007 were randomised. In total, 95% of the participants opted for online pre-screening over phone-based pre-screening. Screening costs, including both direct and staffing costs, totalled AUD1,420,909 (AUD75 per subject screened and AUD1411 per randomised participant). CONCLUSION: A multi-step, semi-automated screening process with web-based pre-screening facilitated low-cost, high-volume participant enrolment to this large, multicentre randomised controlled trial. Centralisation and automation of screening activities resulted in substantial savings compared to previous, similar studies. Our screening approach could be adapted to other randomised controlled trial settings to minimise the cost of screening large numbers of participants.

Seasonality of hip fracture and vitamin D deficiency persists in a sub-tropical climate.

Both hip fractures and vitamin D (25-hydroxyvitamin D (25-OHD)) deficiency are more common in winter in regions with temperate climates, but few data exist for a sub-tropical climate. In a South East Queensland tertiary hospital over a 7-year period, there were significantly more hip fractures in winter than the other three seasons (analysis of variance P = 0.003), with associated higher frequency of 25-OHD deficiency - 42.5% in winter compared to 28.5% in summer, odds ratio 1.86 (95% confidence interval 1.35-2.56), P = 0.0001. Seasonality of hip fracture and 25-OHD deficiency occurs even in a sub-tropical climate.

Higher risk of phaeochromocytoma/paraganglioma (Phaeo-Pgl) in SDHD than SDHB carriers: an Australian cohort study.

Carriers of succinate dehydrogenase (SDHx) mutations are at risk of developing phaeochromocytomas, catecholamine secreting extra-adrenal paragangliomas and non-secretory head and neck paragangliomas and require lifelong surveillance. There is no current consensus on the optimal surveillance strategy. This study describes the outcomes of a cohort of 50 SDHx mutation carriers followed at a tertiary Australian hospital using a surveillance protocol involving annual clinical review with plasma/urine metanephrines and biennial magnetic resonance imaging from skull base to pelvis.

Radioiodine treatment for graves' disease: a 10-year Australian cohort study.

BACKGROUND: Radioactive iodine (I131) is a common definitive treatment for Graves' Disease. Potential complications include worsening, or new development of Graves' eye disease and development of a radiation thyroiditis. The purpose of the present study was to assess outcomes of patients treated with I131 in an Australian tertiary centre over 10 years. METHODS: Data from 101 consecutive patients treated with I131 for a diagnosis of Graves' disease between 2005 to 2015 was collected and reviewed retrospectively. Baseline TSH receptor antibody titre, pre-treatment free thyroxine (FT4), technetium scan uptake, initial treatment, duration of treatment, reason for definitive therapy, complications, and time to remission (defined as euthyroidism or hypothyroidism after 12 months) were recorded. RESULTS: Of the 92 patients with adequate outcome data, 73 (79.3%) patients achieved remission with a single dose of I131. Of the remaining 19 patients, 12 had a second dose and became hypothyroid. TSH receptor antibody titre at diagnosis was significantly lower in the group that achieved remission with the first dose compared with those who did not (P = 0.0071). There was no difference in technetium uptake, I131 dose, duration of therapy or pre-treatment free thyroxine (FT4). I131 was complicated by development of eye disease in 3 patients and 1 (of 11 with pre-existing eye disease) had worsening eye disease. A clinically apparent flare of hyperthyroidism following I131 was evident in 8 patients (8.6%). CONCLUSION: Radioiodine is an effective therapy for Graves' Disease with few complications. The majority of patients achieve remission with a single dose. Those who require a second dose are more likely to have higher TSH receptor antibody titres at diagnosis. To the best of our knowledge, this is the first study to report outcomes from radioiodine treatment for Graves' disease in an Australian population.

Investigation and management of moderate to severe inpatient hyponatraemia in an Australian tertiary hospital.

BACKGROUND: Hyponatraemia is the most common electrolyte disturbance amongst hospitalised patients. Both American and European guidelines recommend fluid restriction as first line treatment for SIADH, however differ on second line recommendations. The objective of this study was to examine investigation and management of hyponatraemia in hospitalised patients in an Australian tertiary hospital. METHODS: A retrospective audit was conducted of electronic medical records and laboratory data of inpatients with serum sodium (Na) ≤125 mmol/L, admitted over a 3 month period to the Princess Alexandra Hospital, Brisbane, Australia. The main outcomes measured included: demographic characteristics, investigations, accuracy of diagnosis, management strategy, change in Na and patient outcomes. RESULTS: The working clinical diagnosis was considered accurate in only 37.5% of cases. Urine Na and osmolality were requested in 72 of 152 patients (47.4%) and in 43 of 70 euvolaemic patients (61.4%). Thyroid function tests (67.1%) and morning cortisol (45.7%) were underutilized in the euvolaemic group. In the SIADH cohort, fluid restriction resulted in a median (IQR) 7.5 mmol/L (4-10.5) increase in Na after 3 days; no treatment resulted in a median 0 mmol/L (- 0.5-1.5) change. Oral urea was utilized in 5 SIADH patients where Na failed to increase with fluid restriction alone. This resulted in a median 10.5 mmol/L (3.5-13) increase in Na from baseline to day 3. There were no cases of osmotic demyelination. The median length of stay was 8 days (4-18.5). Mortality was 11.2% (17 patients). There was a weak but significant correlation between nadir serum Na and mortality (R = 0.18, P = 0.031). CONCLUSION: Inpatient hyponatraemia is often inadequately investigated, causing errors in diagnosis. Treatment is heterogeneous and often incorrect. In cases with hyponatraemia refractory to fluid restriction, oral urea presents an effective alternative treatment.

Polyuria-polydipsia syndrome: a diagnostic challenge.

The main determinants for the maintenance of water homeostasis are the hormone arginine vasopressin (AVP) and thirst. Disturbances in these regulatory mechanisms can lead to polyuria-polydipsia syndrome, which comprises of three different conditions: central diabetes insipidus (DI) due to insufficient secretion of AVP, nephrogenic DI caused by renal insensitivity to AVP action and primary polydipsia due to excessive fluid intake and consequent physiological suppression of AVP. It is crucial to determine the exact diagnosis because treatment strategies vary substantially. To differentiate between the causes of the polyuria-polydipsia syndrome, a water deprivation test combined with desmopressin administration is the diagnostic 'gold standard'. Thereby, AVP activity is indirectly evaluated through the measurement of urine osmolality after prolonged dehydration. However, this test has several limitations and may fail to distinguish precisely between patients with primary polydipsia and mild forms of central and nephrogenic DI. The direct measurement of AVP during the water deprivation test, which was reported in the 1980s, has not been widely adopted due to availability, assay issues and diagnostic performance. Recently, copeptin, the c-terminal portion of the larger precursor peptide of AVP, has been evaluated in the setting of polyuria-polydipsia syndrome and appears to be a useful candidate biomarker for the differential diagnosis. A standardised method for the water deprivation test is presented as part of a joint initiative of the Endocrine Society of Australia, the Australasian Association of Clinical Biochemists and the Royal College of Pathologists of Australasia to harmonise dynamic endocrine tests across Australia.

A will and a way to fund medicines for rare diseases: the story of human growth hormone replacement for adults with growth hormone deficiency.

Growth hormone (GH) replacement therapy was recently recommended by the Pharmaceutical Benefits Advisory Committee (PBAC) for listing on the Pharmaceutical Benefits Scheme for adults with severe GH deficiency and impaired quality of life. This approval was significant for two reasons. First, the application was initiated and coordinated by a health professional working group, who prepared a 'public interest' submission to PBAC. Second, it resulted in a recommendation to subsidise therapy for a rare disease after two prior rejections on the basis of uncertainty about efficacy and cost effectiveness. There are important lessons to learn about the power of professional groups to drive health policy and attain funding for rare diseases.

Prospective evaluation of a week one overnight metyrapone test with subsequent dynamic assessments of hypothalamic-pituitary-adrenal axis function after pituitary surgery.

OBJECTIVE: To determine whether an overnight metyrapone test (OMT) within the first week postpituitary surgery can definitively assess the hypothalamic-pituitary-adrenal (HPA) axis, compared with subsequent dynamic tests and glucocorticoid requirement at 6 months. DESIGN: Prospective study measuring morning cortisol levels on days 3 and 4 post-operatively, OMT day 5-7 and week 6, week 6 250 µg short Synacthen test (SST) and week 7 insulin tolerance test (ITT). PATIENTS AND MEASUREMENTS: Forty participants who underwent pituitary surgery at a single centre (Cushing's disease excluded) were followed for at least 6 months. 46% had pre-operative adrenal insufficiency. PRIMARY OUTCOME: week 1 OMT compared to glucocorticoid requirement at 6 months. SECONDARY OUTCOMES: the performance of ITT as a "definitive" test and all tests compared to glucocorticoid requirement at 6 months. RESULTS: Week 1 OMT showed concordance with ITT at week 7 of 78% and glucocorticoid requirement at 6 months of 81% respectively which was not significantly different from post-operative morning cortisol levels; 37% of participants with an abnormal OMT on day 6 had a normal OMT at week 6. All HPA axis tests showed similar concordance with glucocorticoid requirement at 6 months of 80%-85%. CONCLUSIONS: Overnight metyrapone test within the first week after pituitary surgery was no better than an early morning cortisol level at predicting glucocorticoid requirement at 6 months. OMT at week 6 demonstrated recovery of HPA axis in a substantial proportion of participants who failed earlier assessments; thus, definitive testing should be delayed until 6 weeks post-operatively.

Younger age is a risk factor for regrowth and recurrence of nonfunctioning pituitary macroadenomas: Results from a single Australian centre.

OBJECTIVE: The natural history of nonfunctioning pituitary macroadenomas (NFPMA) after surgical resection is variable, with guidelines unable to define the duration of radiological follow-up. In this first Australian series, we identify risk factors for regrowth/recurrence of NFPMA to assist with guiding recommendations for long-term follow-up. DESIGN: Retrospective analysis of all radiotherapy-naïve cases with NFPMA resected between 1995 and 2013. PATIENTS: One hundred and twenty-three cases had both ≥2 postoperative scans and ≥12-month follow-up. MEASUREMENTS: Regrowth was defined as any sustained increase in diameter of residual adenoma or recurrence as any new adenoma occurring post complete resection on serial pituitary MRI. RESULTS: Median follow-up time was 48 months (interquartile range [IQR]: 31-86). Overall regrowth/recurrence occurred in 29% (36/123). Regrowth occurred in 40% (30/76) at a median time of 44.5 months (IQR 22-80) compared to recurrence of 12.5% (6/48; P=.003), occurring at a median time of 48 months (IQR 12-96; P=.7). Further treatment was required in 66.7% and 56.7%, respectively (=1.0). Risk factors for regrowth/recurrence by multivariate analysis were presence of residual disease and younger age at presentation. The longest time for regrowth was 168 months (14 years) and recurrence 156 months (13 years). CONCLUSIONS: Presence of postoperative residual adenoma and younger age at presentation are the main predictors of regrowth/recurrence in NFPMA. Long-term serial imaging is required to detect regrowth and recurrence in younger patients and those with residual disease. Most regrowth/recurrences will occur within 10 years of follow-up.