Cardiovascular Risk Markers in Adults With Adrenal Incidentaloma and Mild Autonomous Cortisol Secretion.

CONTEXT: Many adrenal adenomas exhibit mild autonomous cortisol secretion (MACS). Although MACS is associated with increased cardiovascular mortality, the underlying mechanisms are not fully defined. OBJECTIVE: To investigate mechanisms that may link MACS and cardiovascular mortality in adults with adrenal adenoma. DESIGN: Cross-sectional study. PATIENTS: Twenty adults with adrenal adenoma and MACS and 20 controls with nonfunctioning adrenal adenoma. METHODS: Reactive hyperemia index (RHI) was measured by peripheral artery tonometry and 24-hour ambulatory blood pressure monitoring (24h AMBP) was performed. Indices of insulin secretion and sensitivity were estimated by measuring glucose and insulin fasting and following a mixed meal. MAIN OUTCOME MEASURE: The primary outcome was the difference in RHI between participants with MACS vs nonfunctioning adrenal adenoma. RESULTS: The average cortisol after 1-mg dexamethasone and urinary free cortisol were higher in patients with MACS. There was no significant difference in fasting RHI (2.0 [interquartile range (IQR) 1.6-2.4] vs 2.0 [IQR 1.7-2.2, P = .72), but postprandial RHI was higher in patients with MACS (2.2 [1.8-2.7] vs 1.8 [1.5-2.2], P = .04). 24-hour ambulatory blood pressure monitoring and Matsuda index were not significantly different in the groups. Fasting glucose and glucose area under the curve after the mixed meal were higher and insulinogenic index was lower in participants with MACS. CONCLUSION: Adults with adrenal adenoma and MACS do not have fasting endothelial dysfunction and postprandial endothelial function may be better. These patients have fasting and postprandial hyperglycemia with lower insulin secretion, which may underlie the association between MACS and increased cardiovascular mortality.

The physiology of growth hormone (GH) in adults: translational journey to GH replacement therapy.

The fact that growth hormone (GH) plays an important role in health after the cessation of growth requiring replacement therapy in adult life has only been recognised in the last three decades. This has only been made possible by recombinant technology providing GH supplies required to undertake investigations in the physiology of GH action and the benefits of replacement therapy in patients identified by rigorously validated diagnostic tests for GH deficiency (GHD). Human studies have revealed important regulatory roles in substrate metabolism, sodium homeostasis, body composition, and physical function. GH-induced anabolism is achieved by stimulating amino acid incorporation into protein while reducing oxidative loss simultaneously enhancing lipid utilisation by stimulating fatty acid oxidation and reducing lipid storage. Sodium and fluid retention are enhanced by activating the renin-angiotensin system and distal renal tubular reabsorption. GH stimulates the aerobic and anaerobic energy systems that underpin muscle and cardiovascular function. These pleiotropic actions explain the clinical picture of increased adiposity, reduced lean mass, and impaired physical and psychological function in the GHD adult, all of which are reversed when GH is replaced. Women require a greater replacement dose of GH than men. This is because androgens enhance while oestrogens attenuate GH action. The oestrogen effect is route-dependent, occurring with oral delivery blunting the liver-mediated actions of GH by directly inhibiting GH receptor signalling, global experience spanning over 30 years has attested to the safety, efficacy, and benefits of replacement therapy for adults with GHD.

Cardio-metabolic pathophysiology in mild glucocorticoid excess: Potential implications for management of adrenal incidentaloma.

Adrenal adenomas are incidentally identified in up to 5% of computer tomography scans performed for unrelated indications. A proportion of these adrenal incidentalomas are found to autonomously secrete cortisol based on definitions in current guidelines. Epidemiological studies suggest that chronic exposure to mild glucocorticoid excess from adrenal incidentalomas is associated with significantly increased cardiometabolic risk. However, current management guidelines adopt a conservative approach as no large prospective randomized studies have demonstrated that these patients benefit from surgery. This narrative review examines the epidemiological and mechanistic studies related to three common clinical settings of mild glucocorticoid excess to gain further insight into the potential benefits of treating patients with adrenal incidentaloma and possible autonomous cortisol secretion.

Insulin sensitivity, cardiovascular function and bone health in women with early stage breast cancer before and after cancer treatment.

BACKGROUND: Cardiovascular disease is a leading cause of death in breast cancer survivors, but the underlying cause is not fully characterised. AIMS: To determine whether insulin sensitivity, cardiovascular risk markers and body composition were perturbed in women treated with chemotherapy for early stage breast cancer and whether perturbations occurred before or after cancer treatment. METHODS: Sixteen women with breast cancer and 17 control subjects were studied. Twelve breast cancer patients returned for a second visit following cancer treatment comprising chemotherapy (n = 2), or chemotherapy and radiotherapy (n = 10). The Matsuda index to estimate insulin sensitivity, fasting lipids, pulse wave velocity (PWV), reactive hyperaemia index (RHI) and body composition by dual energy X-ray absorptiometry were measured. RESULTS: There were no significant differences in age (53 ± 9 vs 54 ± 11 years; P = 0.82) or body mass index (28 ± 7 vs 28 ± 6; P = 0.97) between patients with breast cancer and controls. Patients with breast cancer had higher triglycerides than controls (1.2 ± 0.1 vs 0.8 ± 0.1 mmol/L; P = 0.03), but there were no significant differences in the Matsuda index, PWV and RHI. Following cancer treatment, there was a lower Matsuda index (6.3 ± 1.2 vs 5.2 ± 1.0; P = 0.01), but this was not associated with a significant change in vascular function. Bone mass fell by 3% from 2.27 ± 0.11 to 2.20 ± 0.10 kg after cancer treatment (P = 0.03). CONCLUSIONS: Patients with breast cancer had higher triglycerides before treatment and a reduction in insulin sensitivity and bone mass following cancer treatment. Future larger and longer-term studies should characterise the effect of reduced insulin sensitivity on rates of diabetes, cardiovascular disease, cancer outcomes and fracture. TRIAL REGISTRATION: ACTRN12614001055695.

Vasculogenic hyperprolactinemia: severe prolactin excess in association with internal carotid artery aneurysms.

PURPOSE: Internal carotid artery (ICA) aneurysms have rarely been found in association with marked hyperprolactinemia in the absence of prolactinoma; the cause of hyperprolactinemia has never been investigated. We aimed to determine if the observed hyperprolactinemia is due to a vascular-derived or known prolactin secretagogue from the injured ICA, analogous to pregnancy-associated hyperprolactinemia putatively due to placental factors. METHODS: We conducted a case series and literature review of individuals with severe hyperprolactinemia in association with ICA aneurysms. In two affected patients at our institutions, we performed RT-PCR and ELISA of prolactin secretagogues that are produced by vascular tissue and/or upregulated in pregnancy: AGT (encoding angiotensinogen), TAC1 (encoding substance P), HDC (encoding the enzyme responsible for conversion of histidine to histamine), and prolactin-releasing hormone (PRLH). Patient blood samples were compared to pregnancy blood samples (positive controls) and middle-aged male blood samples (negative controls). RESULTS: Two men presented with serum prolactin >100-fold normal associated with cavernous ICA aneurysms and no pituitary adenoma. Aneurysm stenting in one man more than halved his serum prolactin. In both men, dopamine agonist therapy markedly reduced serum prolactin. RT-PCR and ELISA showed no differences between patients and controls in AGT, TAC1 or HDC expression or PRLH titre, respectively. Literature review revealed 11 similar cases. CONCLUSIONS: We propose the term 'vasculogenic hyperprolactinemia' to encompass the hyperprolactinemia associated with ICA aneurysms. This may be mediated by an endothelial factor capable of paracrine stimulation of lactotrophs; however, angiotensin II, substance P, histamine and PRLH appear unlikely to be causative.

Relationship between Vitamin D Status and Autonomic Nervous System Activity.

Vitamin D deficiency is associated with increased arterial stiffness. However, the mechanisms underlying this association have not been clarified. The aim was to investigate whether changes in autonomic nervous system activity could underlie an association between 25 hydroxy vitamin D and arterial stiffness. A total of 49 subjects (age = 60 ± 8 years, body mass index = 26.7 ± 4.6 kg/m², 25 hydroxy vitamin D = 69 ± 22 nmol/L) underwent measurements of pulse wave velocity (PWV) and augmentation index (AIx), spontaneous baroreflex sensitivity, plasma metanephrines and 25 hydroxy vitamin D. Subjects with 25 hydroxy vitamin D ≤ 50 nmol/L were restudied after 200,000 International Units 25 hydroxy vitamin D. Plasma metanephrine was positively associated with AIx (p = 0.02) independent of age, sex, smoking and cholesterol and negatively associated with 25 hydroxy vitamin D (p = 0.002) independent of age, sex and season. In contrast, there was no association between baroreflex sensitivity and 25 hydroxy vitamin D (p = 0.54). Treatment with vitamin D increased 25 hydroxy vitamin D from 43 ± 5 to 96 ± 24 nmol/L (p < 0.0001) but there was no significant change in plasma metanephrine (115 ± 25 vs. 99 ± 39 pmol/L, p = 0.12). We conclude that as plasma metanephrine was negatively associated with 25 hydroxy vitamin D and positively with AIx, it could mediate an association between these two variables. This hypothesis should be tested in larger interventional studies.

Acute effect of increasing glucocorticoid replacement dose on cardiovascular risk and insulin sensitivity in patients with adrenocorticotrophin deficiency.

CONTEXT: Higher hydrocortisone doses are associated with increased overall and cardiovascular mortality in ACTH-deficient patients. The mechanisms underlying this association have not been fully defined. OBJECTIVE: The aim of the study was to determine whether increasing hydrocortisone (or equivalent) to 30 mg/d in ACTH-deficient patients increased cardiovascular risk and whether a reduction in insulin sensitivity and attenuation of insulin's hemodynamic effects was responsible for this effect. DESIGN: We conducted an open interventional study between 2011 and 2013. SETTING: The study was performed in the Endocrine Research Unit, Repatriation General Hospital, Adelaide, Australia. PATIENTS: Seventeen ACTH-deficient subjects taking hydrocortisone (≤20 mg/d) for at least 6 months were studied. INTERVENTION: Subjects were studied before and after a 7-day increase in hydrocortisone to 30 mg/d. MAIN OUTCOME MEASURE: The primary outcome was the change in pulse wave velocity, both fasting and after a 75-g oral glucose load. RESULTS: Fasting and post-glucose load pulse wave velocities were not significantly different on the higher glucocorticoid dose. Fasting augmentation index (24.9 ± 2.7 vs 22.6 ± 2.6%; P = .04) and reactive hyperemia index (2.3 ± 0.2 vs 2.0 ± 0.2; P = 0.04) were lower on the higher glucocorticoid dose, with no significant difference in the post-glucose load changes in these variables. There were no significant changes in insulin sensitivity or secretion on the higher glucocorticoid dose. CONCLUSIONS: Endothelial dysfunction may contribute to the increased cardiovascular mortality associated with higher glucocorticoid doses. This may be a direct glucocorticoid effect, not mediated by insulin resistance. ACTH-deficient patients should thus be prescribed the lowest safe glucocorticoid replacement dose.

Free and total plasma cortisol measured by immunoassay and mass spectrometry following ACTH1₋24 stimulation in the assessment of pituitary patients.

CONTEXT: Measurement of plasma cortisol by immunoassay after ACTH1₋24 stimulation is used to assess the hypothalamic-pituitary-adrenal (HPA) axis. Liquid chromatography-tandem mass spectrometry (LCMS) has greater analytical specificity than immunoassay and equilibrium dialysis allows measurement of free plasma cortisol. OBJECTIVE: We investigated the use of measuring total and free plasma cortisol by LCMS and total cortisol by immunoassay during an ACTH1₋24 stimulation test to define HPA status in pituitary patients. DESIGN AND SETTING: This was a case control study conducted in a clinical research facility. PARTICIPANTS: We studied 60 controls and 21 patients with pituitary disease in whom HPA sufficiency (n = 8) or deficiency (n = 13) had been previously defined. INTERVENTION: Participants underwent 1 µg ACTH(1-24) intravenous and 250 µg ACTH1₋24 intramuscular ACTH1₋24 stimulation tests. MAIN OUTCOME MEASURES: Concordance of ACTH1₋24-stimulated total and free plasma cortisol with previous HPA assessment. RESULTS: Total cortisol was 12% lower when measured by immunoassay than by LCMS. Female sex and older age were positively correlated with ACTH1₋24-stimulated total and free cortisol, respectively. Measurements of total cortisol by immunoassay and LCMS and free cortisol 30 minutes after 1 µg and 30 and 60 minutes after 250 µg ACTH1₋24 were concordant with previous HPA axis assessment in most pituitary patients. However, free cortisol had greater separation from the diagnostic cutoff than total cortisol. CONCLUSIONS: Categorization of HPA status by immunoassay and LCMS after ACTH1₋24 stimulation was concordant with previous assessment in most pituitary patients. Free cortisol may have greater clinical use in patients near the diagnostic threshold.

Screening for diabetes in patients with inflammatory rheumatological disease administered long-term prednisolone: a cross-sectional study.

OBJECTIVE: The aim of the study was to assess the effect of long-term prednisolone on fasting and post-glucose load glucose concentration in patients with inflammatory rheumatological disease. We hypothesized that prednisolone would predominantly increase post-glucose load glucose concentration and that fasting glucose would have poor sensitivity as a screening test for diabetes in patients receiving chronic prednisolone therapy. METHODS: In a cross-sectional study of subjects with inflammatory rheumatological disease but without known diabetes, 60 subjects [age = 70 (±10) years, 62% female] who were receiving chronic (>6 months) prednisolone [6.5 (±2.1) mg/day] (Group 1) and 58 controls [age = 70 (±11) years, 62% female] who had not received oral glucocorticoids for at least 6 months (Group 2) underwent an oral glucose tolerance test. RESULTS: Fasting glucose was significantly lower [5.0 (±0.1) vs. 5.3 (±0.1) mmol/l, P = 0.02) and post-glucose load glucose concentration significantly higher [8.0 (±0.4) vs. 6.8 (±0.3) mmol/l, P = 0.02] in Group 1 than in Group 2. In a multiple regression analysis, glucocorticoid use (P = 0.004) and log CRP (P = 0.02) were independently associated with fasting glucose, while waist circumference (P = 0.01), but not glucocorticoid use, was independently associated with post-glucose load glucose concentration. A fasting glucose ≥5.6 mmol/l had 33 and 83% sensitivity for diabetes in Groups 1 and 2, respectively. CONCLUSION: There is discordance between a reduced fasting and increased post-glucose load glucose concentration in rheumatological patients on long-term prednisolone. Therefore fasting glucose has poor sensitivity to screen for diabetes in prednisolone-treated patients. Treatment of prednisolone-induced hyperglycaemia should be directed at the postprandial period. Trial registration. Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au/, ACTRN12607000540415.

Low O6-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours.

CONTEXT: Recent case reports detail the successful use of temozolomide in the management of aggressive pituitary tumours. O(6)-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that counteracts the effect of temozolomide. OBJECTIVE: To study MGMT expression in pituitary tumours and consider whether MGMT expression is associated with response to temozolomide therapy in aggressive pituitary tumours. PATIENTS: We report two patients with aggressive pituitary tumours treated with temozolomide, one who responded to temozolomide and the other who did not. MGMT expression was assessed in a further 88 archived pituitary tumour samples. DESIGN: MGMT expression was assessed by immunohistochemistry. MGMT promoter methylation was studied by methylation-specific polymerase chain reaction (MSP), sequencing of MGMT was performed and loss of heterozygosity (LOH) analysis undertaken. RESULTS: Low MGMT expression and MGMT promoter methylation were found in the pituitary tumour of the patient who responded to temozolomide. Conversely, high MGMT expression was seen in the patient demonstrating a poor response to temozolomide. Eleven out of 88 archived tumour samples (13%) had low MGMT expression. Prolactinomas were more likely to have low MGMT expression compared with other pituitary tumour subtypes (P < 0.001). There was no significant difference in MGMT expression between invasive and noninvasive tumours, or between recurrent and nonrecurrent tumours. A significant inverse correlation was found between MGMT expression and promoter methylation (P = 0.012). CONCLUSION: MGMT expression as assessed by immunohistochemistry may predict response to temozolomide therapy in patients with aggressive pituitary tumours. MGMT promoter methylation is likely to explain low MGMT expression in some, but not all, pituitary tumours.

Comparison of efficacy and tolerability of somatostatin analogs and other therapies for acromegaly.

Medical therapy plays an important role in the management of acromegaly. Dopamine agonists and somatostatin analogs are two classes of drugs approved for this purpose worldwide. Pegvisomant, a growth hormone receptor antagonist, has recently been evaluated in clinical trials. Somatostatin analogs have been the mainstay of medical treatment during the last 10 yr with their acceptability enhanced by the development of depot preparations. Somatostatin analogs improve symptoms and signs of acromegaly in the majority, normalize IGF- 1 in up to 60%, and result in tumor shrinkage in up to half of patients. Dopamine agonists have modest efficacy and limited tolerability. They are more effective in mixed GH/prolactin-secreting tumors. Newer agonists with D2 receptor specificity have fewer side effects but are less efficacious than somatostatin analogs. The addition of a dopamine agonist to somatostatin analog therapy can result in greater biochemical control than with individual agents. Pegvisomant is the most effective drug treatment for acromegaly, but it is likely to have a major adjuvant role as its mechanism of action is not directed at the tumor. The availability of more effective and better tolerated drug therapies offers greater flexibility and individualization of therapy that will lead to improved patient care and disease control.

Xanthomatous pituitary lesions: a report of two cases and review of the literature.

We describe two young men with cystic pituitary enlargement on magnetic resonance imaging (MRI) causing hypopituitarism. The first patient presented acutely unwell with headache and vomiting associated with anterior and posterior pituitary dysfunction. The second patient presented with hypopituitarism after a long history of hypogonadism. In both cases yellow/brown fluid was found at surgery and histological examination revealed inflammatory infiltrate with foamy histiocytes, lymphocytes and multinucleated giant cells containing cholesterol clefts. Full recovery of pituitary function occurred after surgery in the first but not the second patient. The first case is the first documented case of xanthomatous hypophysitis with recovery of pituitary function following surgery. The cases differed in duration of disease, as indicated by the long history of symptoms, the histological finding of marked fibrosis and the lack of recovery of pituitary function in the second. Xanthomatous pituitary lesions categorized in the literature as xanthomatous hypophysitis, xanthogranulomatous hypophysitis and xanthogranuloma of the sellar region have overlapping histological features. Our two cases revealed histological features that do not fit completely into any of the categories but share features of all three. These findings suggest that the various xanthomatous lesions of the sellar region may be a spectrum of a common inflammatory process rather than distinct pathological entities.