Expanding the use of salivary cortisol as a non-invasive outpatient test in the dynamic evaluation of suspected adrenal insufficiency.

Background: Adrenal insufficiency (AI) is potentially life-threatening, and accurate diagnosis is crucial. The first-line diagnostic test, the adrenocorticotrophic hormone (ACTH) stimulation test, measures serum total cortisol. However, this is affected in states of altered albumin or cortisol-binding globulin levels, limiting reliability. Salivary cortisol reflects free bioactive cortisol levels and is a promising alternative. However, few studies are available, and heterogenous methodologies limit applicability. Methods: This study prospectively recruited 42 outpatients undergoing evaluation for AI, excluding participants with altered cortisol-binding states. Serum (immunoassay) and salivary (liquid chromatography tandem mass spectrometry) cortisol levels were sampled at baseline, 30 min, and 60 min following 250 µg synacthen administration. AI was defined as a peak serum cortisol level <500 nmol/L in accordance with guidelines. Results: The study recruited 21 (50%) participants with AI and 21 without AI. There were no significant differences in baseline characteristics, blood pressure, or sodium levels between groups. Following synacthen stimulation, serum and salivary cortisol levels showed good correlation at all timepoints (R2 = 0.74, P < 0.001), at peak levels (R2 = 0.72, P < 0.001), and at 60 min (R2 = 0.72, P < 0.001). A salivary cortisol cut-off of 16.0 nmol/L had a sensitivity of 90.5% and a specificity of 76.2% for the diagnosis of AI. Conclusion: This study demonstrates a good correlation between serum and salivary cortisol levels during the 250 µg synacthen test. A peak salivary cortisol cut-off of 16.0 nmol/L can be used for the diagnosis of AI. It is a less invasive alternative to evaluate patients with suspected AI. Its potential utility in the diagnosis of AI in patients with altered cortisol-binding states should be further studied.

Acromegaly: pathogenesis, diagnosis, and management.

Growth hormone-secreting pituitary adenomas that cause acromegaly arise as monoclonal expansions of differentiated somatotroph cells and are usually sporadic. They are almost invariably benign, yet they can be locally invasive and show progressive growth despite treatment. Persistent excess of both growth hormone and its target hormone insulin-like growth factor 1 (IGF-1) results in a wide array of cardiovascular, respiratory, metabolic, musculoskeletal, neurological, and neoplastic comorbidities that might not be reversible with disease control. Normalisation of IGF-1 and growth hormone are the primary therapeutic aims; additional treatment goals include tumour shrinkage, relieving symptoms, managing complications, reducing excess morbidity, and improving quality of life. A multimodal approach with surgery, medical therapy, and (more rarely) radiation therapy is required to achieve these goals. In this Review, we examine the epidemiology, pathogenesis, diagnosis, complications, and treatment of acromegaly, with an emphasis on the importance of tailoring management strategies to each patient to optimise outcomes.

Personalized Medical Treatment of Patients With Acromegaly: A Review.

Acromegaly is associated with significant morbidity and mortality if it is not appropriately treated. In addition to insulin-like growth factor 1 and growth hormone normalization as well as tumor shrinkage, the treatment goals include relieving symptoms, managing complications, and improving patients' quality of life. Surgical resection is a first-line treatment option for most patients, with few being pretreated preoperatively with medications. Somatostatin receptor ligands (SRLs), injectable and, more recently, oral capsules, have been the cornerstone of first-line medical therapy for persistent disease. However, several factors, including sparsely granulated adenomas, absent or low somatostatin receptor status, T2-hyperintensity imaging, young age, and aryl hydrocarbon receptor-interacting protein mutations, can predict first-generation SRL resistance. Patients with these characteristics may be better candidates for the growth hormone receptor antagonist pegvisomant, or in cases of large tumors, the second-generation SRL pasireotide. Combination therapy should be further pursued in patients who remain biochemically uncontrolled or have a high remnant tumor after monotherapy. An efficacious and cost-effective pegvisomant dose-sparing effect of SRLs when used in combination has been demonstrated. With such a wide array of medical treatment options, it is becoming increasingly important to tailor treatment to patients' unique characteristics and preferences, with a goal of personalizing management to achieve high-quality outcomes.

Cystic appearance on magnetic resonance imaging in bihormonal growth hormone and prolactin tumors in acromegaly.

PURPOSE: To investigate demographic, imaging and laboratory characteristics, and treatment outcomes of acromegaly patients who have bihormonal (BA) growth hormone (GH) and prolactin (PRL) immunoreactive adenomas compared to patients who have densely granulated GH adenomas (DGA) and sparsely granulated GH adenomas (SGA). METHODS: Retrospective review of single-center surgically treated acromegaly patients; pathology was analyzed by a single neuropathologist using 2017 WHO criteria. Preoperative magnetic resonance imaging was assessed to evaluate tumor size, cystic component, invasion and T2 signal intensity. RESULTS: Seventy-seven patients; 19 BA (9 mammosomatotroph and 10 mixed GH and PRL adenomas) were compared with 30 DGA, and 28 SGA. Patients with BA were older than SGA (49.6 vs 38.5 years, p = 0.035), had a higher IGF-1 index (3.3 vs 2.3, p = 0.040) and tumors were less frequently invasive (15.8% vs 57.1%, p = 0.005). BA more frequently had a cystic component on MRI than both SGA and DGA (52.6% vs 14.3%, and 22%, p = 0.005 and 0.033, respectively). When all histological types were combined, biochemical remission postoperatively was more common in non-cystic than cystic tumors (50% vs 22.5%, p = 0.042). Somatostatin receptor ligand response rate was 66.7%, 90.9% and 37.5% in BA, DGA and SGA patients, respectively (p = 0.053). CONCLUSION: Imaging characteristics are an increasingly important adenoma behavior determinant. An adenoma cystic component may suggest that a GH adenoma is a BA. Cystic tumors exhibited lower rates of surgical remission in this series; therefore, optimized individual patient treatment is needed, as patients could be candidates for primary medical treatment.

High prevalence of adrenal insufficiency at diagnosis and headache recovery in surgically resected Rathke's cleft cysts-a large retrospective single center study.

BACKGROUND: Rathke's cleft cysts (RCC) are lesions that arise from Rathke's pouch. Though frequently incidental, resulting symptoms in a minority of cases are indicators for surgical resection, which may prove beneficial. OBJECTIVE: To characterize a cohort of surgically-resected RCC cases at Oregon Health & Science University; tabulate associated hormonal imbalances and symptoms, possible symptom reversal with surgery, determine recurrence risk; identify predictors of recurrence and headache improvement. METHOD: Electronic records of all RCC resected cases (from 2006-2016; 11 years) were retrospectively reviewed. Patients had been evaluated by one neuroendocrinologist using a uniform protocol. RESULTS: A pathological RCC diagnosis was established in 73 of 814 (9%) surgical pituitary cases. The RCC cohort was 77% (n = 56/73) female, mean age was 39.5 ± 14.9 years at first surgery, and at presentation headache was reported in 88% and visual defects/diplopia in 18% of patients. Initial RCC maximum diameter was 1.3 ± 0.7 cm. The most frequent hormonal deficit was cortisol; 24% of patients had a new adrenal insufficiency (AI) diagnosis, however, 36% also had AI at 3 months post-operatively. Mean follow up was 4.0 ± 4.5 years. Two-thirds of patients (41/62) had headache improvement 3 months post-operatively. Post-operative imaging revealed no residual cyst in 58% (38/65). In those patients with no residual RCC, 29% had recurrence and 71% had long lasting cure. From the 42% (27/65) of patients with residual cyst on post-operative imaging; 59% (16/27) remained stable, 26% (7/27) progressed and 15% (4/27) regressed. CONCLUSION: Symptomatic RCC present mostly in women, with a high proportion reporting headaches. Prevalence of AI at diagnosis is high. Surgery may not achieve adrenal axis recovery, but renders a high percentage of headache improvement. Approximately 25% of RCC will recur by 4 years postoperatively. Clinicians should cautiously screen patients with symptomatic RCC, regardless of lesion size for AI.

Factors Associated with Resolution of Hypertension after Adrenalectomy in Patients with Primary Aldosteronism.

BACKGROUND: The aim of this study was to investigate the factors associated with resolution of hypertension after adrenalectomy in patients with primary aldosteronism. A secondary aim was to describe our use of the contralateral ratio in adrenal venous sampling (AVS) in the setting of suboptimal successful cannulation rates. METHODS: A retrospective review of patients who underwent AVS followed by unilateral adrenalectomy for primary aldosteronism was performed. RESULTS: Complete resolution of hypertension and hypokalemia was seen in 17 of 40 patients (42.5%), while a clinical improvement in hypertension was seen in 38 of 40 (95%). Shorter duration of hypertension, mean aldosteronoma resolution score (ARS), and a high ARS of 3 to 5 were associated with resolution of hypertension after adrenalectomy (P=0.02, P=0.02, and P=0.004, respectively). Of the individual components of ARS, only a duration of hypertension of ≤6 years was associated with resolution of hypertension after adrenalectomy (P=0.03). CONCLUSION: A shorter duration of hypertension was significantly associated with resolution of hypertension after adrenalectomy in patients with primary aldosteronism.

Hypercoagulability and Risk of Venous Thromboembolic Events in Endogenous Cushing's Syndrome: A Systematic Meta-Analysis.

Background: Hypercortisolism has been implicated in the development of venous thromboembolic events (VTE). We aimed to characterize VTE risk in endogenous Cushing's syndrome (CS) patients, compare that risk to other pathologies, and determine if there are any associated coagulation factor changes. Methods: Medline and Scopus search for "hypercortisolism" and "thromboembolic disease" from January 1980 to April 2017 to include studies that reported VTE rates and/or coagulation profile of CS patients. A systematic review and meta-analysis were performed. Results: Forty-eight studies met inclusion criteria. There were 7,142 CS patients, average age was 42 years and 77.7% female. Odds ratio of spontaneous VTE in CS is 17.82 (95%CI 15.24-20.85, p < 0.00001) when comparing to a healthy population. For CS patients undergoing surgery, the odds ratio (both with / without anticoagulation) of spontaneous VTE is 0.26 (95%CI 0.07-0.11, p < 0.00001)/0.34 (0.19-0.36, p < 0.00001) when compared to patients undergoing hip fracture surgery who were not treated with anticoagulants. Coagulation profiles in patients with CS showed statistically significant differences compared to controls, as reflected by increases in von Willebrand factor (180.11 vs. 112.53 IU/dL, p < 0.01), as well as decreases in activated partial thromboplastin time (aPTT; 26.91 vs. 30.65, p < 0.001) and increases in factor VIII (169 vs. 137 IU/dL, p < 0.05). Conclusion: CS is associated with significantly increased VTE odds vs. general population, but lower than in patients undergoing major orthopedic surgery. Although exact timing, type, and dose of anticoagulation medication remains to be established, clinicians might consider monitoring vWF, PTT, and factor VIII when evaluating CS patients and balance advantages of thromboprophylaxis with risk of bleeding.

Predictors of silent corticotroph adenoma recurrence; a large retrospective single center study and systematic literature review.

PURPOSE: Silent corticotroph adenomas (SCAs) are clinically silent and non-secreting, but exhibit positive adrenocorticotropic hormone (ACTH) immunostaining. We characterized a single center cohort of SCA patients, compared the SCAs to silent gonadotroph adenomas (SGAs), identified predictors of recurrence, and reviewed and compared the cohort to previously published SCAs cases. METHODS: Retrospective review of SCA and SGA surgically resected patients over 10 years and 6 years, respectively. Definitions; SCA-no clinical or biochemical evidence of Cushing's syndrome and ACTH positive immunostaining, and SGA-steroidogenic factor (SF-1) positive immunostaining. A systematic literature search was undertaken using Pubmed and Scopus. RESULTS: Review revealed 814 pituitary surgeries, 39 (4.8%) were SCAs. Mean follow-up was 6.4 years (range 0.5-23.8 years). Pre-operative magnetic resonance imaging demonstrated sphenoid and/or cavernous sinus invasion in 44%, 33% were > 50% cystic, and 28% had high ACTH levels pre-operatively. Compared to SGAs (n = 70), SCAs were of similar size and invasiveness (2.5 vs. 2.9 cm, p = 0.2; 44 vs. 41%, p = 0.8, respectively), but recurrence rate was higher (36 vs. 10%, p = 0.001) and more patients received radiation therapy (18 vs. 3%, p = 0.006). Less cystic tumors (0 vs. 50%, p < 0.001) and higher pre-operative ACTH levels (54 vs. 28 pg/ml, p = 0.04) were predictors of recurrence for SCAs. CONCLUSION: This review is unique; a strict definition of SCA was used, and single center SCAs were compared with SGAs and with SCAs literature reviewed cases. We show that SCAs are aggressive and identify predictors of recurrence. Accurate initial diagnosis, close imaging and biochemical follow up are warranted.

Clinical profile of silent growth hormone pituitary adenomas; higher recurrence rate compared to silent gonadotroph pituitary tumors, a large single center experience.

PURPOSE: Study and comparison of characteristics of silent growth hormone adenomas (SGHA), silent corticotroph adenomas (SCA), and silent gonadotroph adenomas (SGA) in a single institution cohort of surgically treated pituitary adenomas. METHODS: Retrospective analysis of SGHA surgically resected over 10 years: SGHA was defined as no clinical or biochemical evidence of acromegaly and positive GH immunostaining. RESULTS: Of 814 pituitary surgeries; 2.1% (n = 17) were SGHA, 4.5% (n = 37) SCA, and 18.9% (n = 70/371; 2011-2016) SGA. Mean age at SGHA diagnosis was 43 years, with a large female predominance (82%). Mean tumor size and cavernous/sphenoid sinus invasiveness for SGHA, SCA, and SGA were 1.5 ± 1.0 cm and 25%, 2.5 ± 1.2 cm and 43%, 2.9 ± 2.0 cm and 41%, respectively (tumor size p = 0.009, SGHA vs. SGA, and invasion p; not-significant). During mean follow-up of 3.9 years, two patients (11%) developed elevated insulin-like growth factor-1 and five patients (29%) required a second surgery for tumor recurrence. Rate of surgical reintervention was similar to SCA (31%), but higher than SGA (10%) (p = 0.035, SGHA vs. SGA), and 18% underwent radiation therapy, similar to SCA (19%, p; not-significant) but higher than SGA (2.9%, p = 0.018). CONCLUSION: This is the largest single center study characterizing SGHA behavior with SGA and SCA control groups in a cohort of surgically resected pituitary adenomas. SGHA present mostly in young females, and should be closely followed due to their higher likelihood of recurrence and potential of progression to clinical acromegaly. We propose that a complete hormonal staining panel be routinely performed for all pituitary adenomas.

The role of combination medical therapy in the treatment of acromegaly.

PURPOSE: Uncontrolled acromegaly results in approximately 2-fold excess mortality. Pituitary surgery is first-line therapy, and medical treatment is indicated for persistent disease. While cabergoline and pegvisomant are used in select patients, somatostatin receptor ligands (SRLs) remain the cornerstone of medical treatment. Management of patients poorly responsive to SRLs is therefore, challenging. The purpose of this review is to highlight the options for combination medical therapy in the treatment of acromegaly, with an emphasis on efficacy and safety. METHODS: All original articles/abstracts detailing combination medical therapy in acromegaly were identified from a PubMed search. RESULTS: Studies reviewed included retrospective and open-label prospective studies. While the combination of SRL and cabergoline was generally well tolerated, a lower baseline insulin-like growth factor-1 (IGF-1) level was the best predictor of efficacy; this combination may be most effective in patients with mildly elevated IGF-1. SRL-pegvisomant combination normalized IGF-1 in the majority of patients; continued efficacy despite individual drug dosing reduction was also reported. The risk of significant liver enzyme elevation was, however, higher than that reported with SRL monotherapy; close monitoring is recommended. Data on pegvisomant-cabergoline combination is limited, but this may be an option in the setting of SRL intolerance. Reports on temozolomide used in combination with other medical therapies in patients with aggressive GH-secreting tumors are also summarized. CONCLUSION: While more prospective, randomized controlled trials on long-term efficacy and safety are needed, combination medical therapy remains a treatment strategy that should be considered for acromegaly patients poorly responsive to SRLs.

Update on medical treatment for Cushing's disease.

Cushing's disease (CD) is the most common cause of endogenous Cushing's syndrome (CS). The goal of treatment is to rapidly control cortisol excess and achieve long-term remission, to reverse the clinical features and reduce long-term complications associated with increased mortality. While pituitary surgery remains first line therapy, pituitary radiotherapy and bilateral adrenalectomy have traditionally been seen as second-line therapies for persistent hypercortisolism. Medical therapy is now recognized to play a key role in the control of cortisol excess. In this review, all currently available medical therapies are summarized, and novel medical therapies in phase 3 clinical trials, such as osilodrostat and levoketoconazole are discussed, with an emphasis on indications, efficacy and safety. Emerging data suggests increased efficacy and better tolerability with these novel therapies and combination treatment strategies, and potentially increases the therapeutic options for treatment of CD. New insights into the pathophysiology of CD are highlighted, along with potential therapeutic applications. Future treatments on the horizon such as R-roscovitine, retinoic acid, epidermal growth factor receptor inhibitors and somatostatin-dopamine chimeric compounds are also described, with a focus on potential clinical utility.

Prevalence and patterns of bone loss in the first year after renal transplant in South East Asian patients.

BACKGROUND: Limited data are available regarding patterns of bone loss in South East Asian renal transplant patients. We aimed to determine the prevalence of low bone density and factors contributing to bone loss in Singaporean patients in the first year after renal transplant. METHODS: Seventy-nine consecutive patients who underwent renal transplant were evaluated. Bone mineral density (BMD) was evaluated at 0 (baseline), and at 6 and 12 months after transplant. Baseline parathyroid hormone and vitamin D levels were also assessed. Multivariate regression models were used to investigate the relationship between the different variables and BMD. RESULTS: Thirty-six patients (45.6%) had low BMD at baseline. Factors correlating with the low BMD were older age, postmenopausal status, and tertiary hyperparathyroidism (P<0.0005, 0.009, and 0.027, respectively). There was a linear decrease in total hip and lumbar spine BMD from baseline to 12 months, the decrease from baseline to 6 months being significant (P=0.019 for total hip and P<0.0005 for lumbar spine). Patients with tertiary hyperparathyroidism had a greater risk of decrease in BMD at 6 months compared with patients with secondary hyperparathyroidism (odds ratio=13.5, confidence interval: 1.3, 144.4) and with those who had parathyroidectomy (odds ratio=34.9; confidence interval: 2.0, 598.8). CONCLUSIONS: The prevalence of low BMD in this population of renal transplant recipients was high. Parathyroid status was the only independent factor that correlated with low BMD at baseline and subsequent bone loss highlighting the critical role of this hormone in bone metabolism after renal transplant.