Acthar Gel Inhibits the Activation of CD4+ and CD8+ T Cells.

Several inflammatory diseases are characterized by elevated T cell counts and high pro-inflammatory cytokine levels. Inhibiting T cell activity may reduce tissue damage associated with these diseases. Acthar® Gel has potent anti-inflammatory properties, yet little is known about its effect on T cells. This study compared the effects of Acthar, synthetic adrenocorticotropic hormone 1-24 (ACTH1-24) depot, and prednisolone in a murine model of T cell activation. Assessments of CD4+ helper and CD8+ cytotoxic T cells and plasma concentrations of interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α) were made following anti-CD3-activation. Acthar significantly reduced the number of activated CD4+ and CD8+ T cells at amounts comparable to synthetic ACTH1-24 depot or prednisolone. However, Acthar reduced production of IFN-γ, IL-2, and TNF-α significantly more than the other drugs, suggesting that the in vivo immunomodulatory effects of Acthar on T cells are distinct from synthetic ACTH1-24 depot or prednisolone.

Perinatal Stress in Immature Foals May Lead to Subclinical Adrenocortical Dysregulation in Adult Horses: Pilot Study.

The persistent endocrinological effects of perinatal stress due to gestational immaturity in horses are unknown, although effects have been reported in other livestock species. This pilot study tested the hypothesis that persistent adrenocortical dysregulation is present in horses that were gestationally immature at birth by assessing the salivary cortisol response to exogenous ACTH. Case horses (n = 10) were recruited with histories of gestation length < 315 d or dysmaturity observable through neonatal signs. Positive controls (n = 7) and negative controls (n = 5) were recruited where possible from related horses at the same locations. Cases and positive controls received an intramuscular, low-dose (0.1 ug/kg) of synthetic ACTH (Tetracosactrin 250 mg/mL, Synacthen); negative controls received no ACTH. Saliva samples were collected from all horses at baseline T = 0 and at 30 min intervals post injection from T = 30 to T = 150. These were assayed for salivary cortisol concentration (SCC) using a commercially available ELISA kit (Salimetrics). All baseline values (T = 0) were within normal published ranges. Peak and AUC values (corrected for baseline) for case horses were significantly different (ANOVA P < .001) to positive controls, with either higher (H-cases) or lower (L-cases) SCC values, outside the 95% Confidence Interval of the reference population. There was no significant effect of breed, age, sex, test month, or location on results. The results suggest that gestational immaturity may lead to subclinical adrenocortical dysregulation, with affected horses presenting an elevated or blunted response to a low-dose ACTH stimulation, despite normal basal levels.

Basal serum cortisol levels predict a normal response to the Synacthen stimulation test in hospitalised patients.

BACKGROUND: The short Synacthen test (SST) is widely used to assess the hypothalamus-pituitary-adrenal axis in the outpatient setting. However, in the inpatient setting, technical difficulties to adhere to the protocol may pose a challenge for using this test. AIMS: To find the most suitable basal serum cortisol (BSC) cut-off for predicting an adequate response to the SST in non-critically inpatients without conducting the actual test. METHODS: Information was retrieved retrospectively from medical files of 197 patients who had had a 250 µg SST between the years 2000 and 2016 at the Shaare Zedek Medical Center. BSC, electrolytes, creatinine, thyroid-stimulating hormone, blood counts and blood pressure values were evaluated for a correlation with the results of the SST. RESULTS: A BSC cut-off of 280 nmol/L provides a negative predictive value of 94% for adrenal insufficiency (AI). Using a cut-off of 380 nmol/L increases the sensitivity to 96% and yields a negative predictive value of 95.8%. CONCLUSIONS: In this study, we found two suitable BSC cut-offs for predicting an adequate response to the SST in hospitalised patients. We suggest using the lower cut-off (280 nmol/L) for patients with a low level of suspicion for AI and using the higher cut-off (380 nmol/L) for patients with a higher level of suspicion. A BSC above this cut-off makes the diagnosis of AI very unlikely and precludes the need for a Synacthen test.

Pharmacokinetics and Pharmacodynamics of Repository Corticotropin Injection Compared With Synthetic ACTH1-24 Depot and Methylprednisolone in Healthy Subjects.

Repository corticotropin injection (RCI; Acthar Gel) is a naturally sourced complex mixture of adrenocorticotropic hormone (ACTH) analogs and other pituitary peptides. This phase 1, single-center, open-label, randomized parallel study directly compared the pharmacokinetics and pharmacodynamics of RCI and synthetic ACTH1-24 depot. Methylprednisolone was included to estimate the steroidogenic exposure of RCI and synthetic ACTH1-24 depot when used to treat nephrotic syndrome. A total of 48 healthy subjects aged 18 to 50 years were randomly assigned 1:1:1 to RCI (80 IU subcutaneously twice weekly on study days 1 and 4), synthetic ACTH1-24 depot (1 mg subcutaneously twice weekly on study days 1 and 4), or methylprednisolone (32 mg orally once daily on study days 1 through 6). After 2 doses, RCI induced about 5-fold lower free cortisol exposure and an estimated 4-fold lower steroidogenic exposure than synthetic ACTH1-24 depot. The lower endogenous cortisol response of RCI was achieved despite higher observed mean plasma concentrations of N25-deamidated porcine ACTH1-39 (the pharmacokinetic marker for RCI) than of ACTH1-24 . The different pharmacodynamic properties demonstrated by RCI and synthetic ACTH1-24 depot in this study suggest that these products in the ACTH class are not interchangeable.

ACTH Stimulation Maximizes the Accuracy of Peripheral Steroid Profiling in Primary Aldosteronism Subtyping.

CONTEXT: Adrenocorticotropic hormone (ACTH) can contribute to aldosterone excess in primary aldosteronism (PA) via increased melanocortin type 2 receptor expression. Dynamic manipulation of the hypothalamic-pituitary-adrenal (HPA) axis could assist PA subtyping, but a direct comparison of dynamic tests is lacking. OBJECTIVE: To investigate plasma steroid differences between aldosterone-producing adenoma (APA) and bilateral PA (BPA) relative to ACTH variations. METHODS: We conducted comprehensive dynamic testing in 80 patients: 40 with APA and 40 with BPA. Peripheral plasma was collected from each patient at 6 time points: morning; midnight; after 1 mg dexamethasone suppression; and 15, 30, and 60 minutes after ACTH stimulation. We quantified 17 steroids by mass spectrometry in response to ACTH variations in all patients and compared their discriminative power between the 2 PA subtypes. RESULTS: Patients with APA had higher morning and midnight concentrations of 18-hydroxycortisol, 18-oxocortisol, aldosterone, and 18-hydroxycorticosterone than those with BPA (P < 0.001 for all). In response to cosyntropin stimulation, the APA group had larger increments of aldosterone, 18-oxocortisol, 11-deoxycorticosterone, corticosterone, and 11-deoxycortisol (P < 0.05 for all). Following dexamethasone suppression, the APA group had larger decrements of aldosterone, 18-hydroxycortisol, and 18-oxocortisol (P < 0.05 for all), but their concentrations remained higher than in the BPA group (P < 0.01 for all). The highest discriminatory performance between the PA subtypes was achieved using steroids measured 15 minutes post-ACTH stimulation (area under receiver operating characteristic curve 0.957). CONCLUSION: Steroid differences between APA and BPA are enhanced by dynamic HPA testing; such noninvasive tests could circumvent the need for adrenal vein sampling in a subset of patients with PA.

Synacthen Stimulation Test Following Unilateral Adrenalectomy Needs to Be Interpreted With Caution.

Background: Cortisol levels in response to stress are highly variable. Baseline and stimulated cortisol levels are commonly used to determine adrenal function following unilateral adrenalectomy. We report the results of synacthen stimulation testing following unilateral adrenalectomy in a tertiary referral center. Methods: Data were collected retrospectively for 36 patients who underwent synacthen stimulation testing one day post unilateral adrenalectomy. None of the patients had clinical signs of hypercortisolism preoperatively. No patient received pre- or intraoperative steroids. Patients with overt Cushing's syndrome were excluded. Results: The median age was 58 (31-79) years. Preoperatively, 16 (44%) patients had a diagnosis of pheochromocytoma, 12 (33%) patients had primary aldosteronism and 8 (22%) patients had non-functioning adenomas with indeterminate/atypical imaging characteristics necessitating surgery. Preoperative overnight dexamethasone suppression test results revealed that 6 of 29 patients failed to suppress cortisol to <50 nmol/L. Twenty (56%) patients achieved a stimulated cortisol ≥450 nmol/L at 30 minutes and 28 (78%) at 60 minutes. None of the patients developed clinical adrenal insufficiency necessitating steroid replacement. Conclusions: Synacthen stimulation testing following unilateral adrenalectomy using standard stimulated cortisol cut-off values would wrongly label many patients adrenally insufficient and may lead to inappropriate prescriptions of steroids to patients who do not need them.

Comparison of Steroidogenic Exposure Following the Administration of Repository Corticotropin Injection With a Synthetic ACTH1-24 Depot and Methylprednisolone in Healthy Subjects.

The pharmacokinetics (PK) and pharmacodynamics (PD) of clinically relevant doses of repository corticotropin injection (Acthar Gel) and synthetic ACTH1-24 depot have not been fully characterized. We compared the steroidogenic exposure of repository corticotropin injection and synthetic ACTH1-24 depot in healthy adults at therapeutic doses using data from 2 separate phase 1 studies. Subjects were randomly assigned to repository corticotropin injection 40 or 80 IU subcutaneously twice weekly or 80 IU subcutaneously 3 times weekly for 15 days or to daily synthetic ACTH1-24 depot doses of 0.5 mg subcutaneously, 0.75 mg subcutaneously, 1 mg subcutaneously, or 1 mg intramuscularly for 5 days. A population PK/PD model was developed to simulate the free cortisol exposure of a clinically relevant dose of synthetic ACTH1-24 depot (1 mg subcutaneously twice weekly). Study drug doses were converted to methylprednisolone-equivalent doses using the steroidogenic exposure of methylprednisolone 16 mg daily as a conversion factor. Doses were also converted to prednisone equivalents using a coefficient of 1.25. These analyses revealed that the steroidogenic exposure of repository corticotropin injection at clinically relevant doses was substantially lower than that for synthetic ACTH1-24 depot. The 3 repository corticotropin injection regimens were equivalent to approximately 5, 8, and 16 mg of daily prednisone, respectively. On the basis of simulated free cortisol exposure, synthetic ACTH1-24 depot 1 mg subcutaneously twice weekly was comparable to 57 mg of daily prednisone. These results suggest that repository corticotropin injection has pharmacological effects that cannot be considered identical to synthetic ACTH1-24 depot.

Effect of cosyntropin during adrenal venous sampling on subtype of primary aldosteronism: analysis of surgical outcome.

OBJECTIVES: We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA). DESIGN: Multicenter retrospective study by Japan PA study. METHOD: We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI <2 with ACTH-stimulated LI ≥4 (Bilateral (B) to U group, n = 15); and basal LI ≥2 with ACTH-stimulated LI <4 (U to B group, n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria. RESULTS: Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI. CONCLUSIONS: Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group.

Long acting porcine sequence ACTH in the diagnosis of adrenal insufficiency.

OBJECTIVES: Injectable tetracosactide hexa-acetate, ACTH 1-24 (Synacthen), is not marketed in many countries including India, whereas Injectable long acting porcine sequence, ACTH 1-39 (Acton Prolongatum®) is easily available and much cheaper. This study aimed to find the diagnostic accuracy of ACTH stimulation test using i.m. Acton Prolongatum® (acton prolongatum stimulation test, APST) in comparison with Synacthen (short synacthen test, SST) for the diagnosis of glucocorticoid insufficiency. METHODS: Subjects with a suspicion of adrenal insufficiency based on clinical features underwent a SST with 250 µg Synacthen followed by APST using 30 units of Acton Prolongatum®. Serum cortisol levels were measured at 60 and 120 min following injection of Acton Prolongatum®. Stimulated peak cortisol of less than 18 µg/dL on SST was considered as adrenal insufficiency. RESULTS: Forty seven patients with mean age of 36.7 ± 14.4 years were enrolled for the study. Based on SST, twenty (n = 20) persons were classified as having adrenal insufficiency, whereas twenty-seven (n = 27) were found to be normal. Area under the curve of APST (at 120 min) was 0.986 when compared to SST, thus proving its high accuracy. A serum cortisol cut off value of 19.5 µg/dL at 120-min following stimulation with Acton Prolongatum® showed a sensitivity of 100% and specificity of 88%. CONCLUSION: ACTH stimulation test using Acton Prolongatum® is an economical and accurate alternative to the short Synacthen test.

Pitfalls in the interpretation of the cosyntropin stimulation test for the diagnosis of adrenal insufficiency.

PURPOSE OF REVIEW: Adrenal insufficiency is a rare disease characterized by cortisol deficiency. The evaluation of patients suspected of having adrenal insufficiency can be challenging because of the rarity of the disease and limitations in the biochemical assessment of the cortisol status by either basal or dynamic testing [adrenocorticotropic hormone (ACTH) stimulation test]. Prompt and adequate diagnosis is of paramount importance to avoid adverse outcomes. We aimed to summarize the recent developments in the conduction and interpretation of the ACTH stimulation test for the diagnosis of adrenal insufficiency. RECENT FINDINGS: The ACTH stimulation test is commonly performed in patients suspected of having adrenal insufficiency when the basal serum cortisol levels are inconclusive. Recent literature has evaluated the impact of technical aspects such as time of the day the test is performed, type of assay and sample source used for cortisol measurement on the clinical value of this test, as well as the feasibility of reliable low dose ACTH testing. SUMMARY: Clinicians evaluating patients with suspected adrenal insufficiency should take into consideration the clinical presentation (likelihood of adrenal insufficiency before testing) when interpreting the results of the ACTH stimulation test and be aware of clinical and technical factors that can affect cortisol values and diagnostic accuracy of this test.

Performance of low-dose cosyntropin stimulation test in the afternoon.

BACKGROUND: Earlier research on 1 µg low-dose test (LDT) performed using 20.3 cm plastic IV tubing on healthy volunteers, has shown that afternoon testing was associated with a sevenfold increased likelihood of failing the test. Nevertheless, it has been claimed that subnormal cortisol response using plastic tubes might have resulted from cosyntropin adherence to the tube and, thus, loss of the delivered dosage. Following from our previous study, which showed that using a short (2.5 cm) plastic tube does not alter in-vitro-cosyntropin dosage delivery or healthy-volunteers' morning cortisol responses, we predicted that, when using the same short plastic tube, LDT would show comparable morning and afternoon cortisol stimulation. The current study was designed to investigate this prediction by comparing morning and afternoon cortisol responses in healthy volunteers during LDT, using a short plastic tube. METHODS: Thirteen healthy adult volunteers were recruited for the study. Each subject underwent morning and afternoon LDT via 25 mm plastic intravenous line tube. Baseline serum cortisol (SC) in addition to SC and salivary free cortisol (SFC) 30-minute responses were determined. RESULTS: Mean baseline morning SC concentration was higher in the morning than in the afternoon (13.63±3.42 and 9.18±2.78 µg/dL, respectively; P<0.001); however, mean absolute SC-concentration increment between baseline and 30-minute time point was higher in the afternoon than in the morning (11.89±3.50 and 7.71±3.12 µg/dL, respectively; P=0.002). Subsequently, LDT resulted in comparable morning and afternoon 30-minute SC (21.33±3.08 and 21.08±3.43 µg/dL, respectively; P=0.782) and SFC concentration (0.939±0.256 and 1.036±0.372 µg/dL, respectively; P=0.463). CONCLUSIONS: In healthy volunteers, using a 2.5 cm plastic tube, LDT provides comparable morning and afternoon 30-minute stimulated SC and SFC concentration.

Low-dose ACTH stimulation testing in dogs suspected of hypoadrenocorticism.

BACKGROUND: Low-dose ACTH stimulation testing would lower cost and may increase sensitivity for identification of partial ACTH deficiency. HYPOTHESIS: (1) The low-dose ACTH stimulation test will provide comparable results to the standard-dose ACTH stimulation test in dogs suspected of hypoadrenocorticism and (2) partial ACTH deficiency exists in dogs and can result in chronic, intermittent gastrointestinal signs. ANIMALS: Thirty-one client-owned dogs suspected of having hypoadrenocorticism. METHODS: Prospective study. Dogs suspected of having hypoadrenocorticism received 1 µg/kg cosyntropin IV for the first ACTH stimulation test; the second test was performed 4 h later and dogs received 5 µg/kg cosyntropin IV. Blood samples were obtained pre-ACTH and 1 hour post-ACTH for each dose (4 measurements total). Samples for endogenous ACTH measurement were obtained at the time of initial blood collection. RESULTS: No significant difference was observed in the basal cortisol concentration before administration of a 1 µg/kg versus before a 5 µg/kg dose of cosyntropin (P = .544). For dogs suspected of having hypoadrenocorticism, the ACTH-stimulated cortisol concentrations in response to both doses of ACTH were equivalent (90% confidence interval [CI], 80.5-97.2%; P = .04). No cases with partial ACTH deficiency were identified conclusively. CONCLUSIONS AND CLINICAL IMPORTANCE: A 1 µg/kg dose of cosyntropin is equivalent to a 5 µg/kg dose of cosyntropin for screening dogs suspected of hypoadrenocorticism. The existence of partial ACTH deficiency was not identified in this small group of dogs.

Role of sampling times and serum cortisol cut-off concentrations on the routine assessment of adrenal function using the standard cosyntropin test in an academic hospital from Spain: a retrospective chart review.

OBJECTIVES: Aiming to validate the use of a single poststimulus sampling protocol for cosyntropin test short standard high-dose test (SST) in our institution, our primary objectives were (1) to determine the concordance between 30 and 60 min serum cortisol (SC) measurements during SST; and (2) to evaluate the diagnostic agreement between both sampling times when using classic or assay-specific and sex-specific SC cut-off values. The secondary objectives included (1) estimating the specificity and positive predictive value of 30 and 60 min sampling times while considering the suspected origin of adrenal insufficiency (AI); and (2) obtaining assay-specific cut-off values for SC after SST in a group of subjects with normal hypothalamic-pituitary-adrenal (HPA) axis. DESIGN AND SETTING: This is a retrospective chart review study conducted at a Spanish academic hospital from 2011 to 2015. PARTICIPANTS AND INTERVENTIONS: Two groups were evaluated: (1) a main study group including 370 patients in whom SC was measured at 30 and 60 min during SST; and (2) a confirmative group that included 150 women presenting with a normal HPA axis in whom SST was conducted to rule out late-onset congenital adrenal hyperplasia. Diagnostic agreement between both sampling times was assessed by considering both classic (500 nmol/L) and assay-specific SC cut-off concentrations. RESULTS: Diagnostic agreement between both sampling times was greater when applying sex-specific and assay-specific cut-off values instead of the classic cut-off values. For suspected primary AI, 30 min SC determination was enough to establish a diagnosis in over 95% of cases, without missing any necessary treatment. When central AI is suspected, 60 min SC measurement was more specific, establishing a diagnosis in over 97% of cases. CONCLUSIONS: Sex-specific and assay-specific SC cut-off values improve the diagnostic accuracy of SST. For primary disease, a subnormal SC response at 30 min is a reliable marker of adrenal dysfunction. On the contrary, when central AI is suspected, 60 min SC measurement improves the diagnostic accuracy of the test.

Retrospective review of Synacthen testing in infants.

BACKGROUND: A subnormal cortisol response (30 min level (C30min)<550 nmol/L) to synthetic adrenocorticotrophic hormone/Synacthen test (SDST) in all infants does not necessarily indicate underlying or persistent hypothalamic-pituitary-adrenal axis pathology. METHODS: We retrospectively evaluated the diagnoses and outcomes in 68 infants who had a SDST at age <6 months from 2011 to 2014. RESULTS: 29 (43%) infants had a subnormal SDST. Causative pathology was identified in 9/29 (31%). In 20/29 (69%) with no identified pathology, repeat SDST was normal in 18/20 (90%) at median age 0.6 (range 0.1-3.2) years but persistently subnormal in 2. Those with a transient abnormality were more likely to be small for gestational age (P=0.03) and had higher initial SDST C30min (390 nmol/L vs 181 nmol/L, P=0.01) than those with pathology. CONCLUSION: Specific aetiology can be identified in a third of infants with a subnormal SDST. When the aetiology remains elusive, adrenal function should be reassessed as the problem can be transient.

Subtyping of primary aldosteronism with adrenal vein sampling: Hormone- and side-specific effects of cosyntropin and metoclopramide.

BACKGROUND: Cosyntropin and metoclopramide can affect the subtyping of primary aldosteronism when used with adrenal vein sampling by exerting hormone- and side-specific effects on cortisol and aldosterone secretion. We investigated how these stimuli affect the selectivity index, the relative aldosterone secretion index, and the lateralization index in consecutive primary aldosteronism patients submitted to adrenal vein sampling. METHODS: We recruited 171 patients; of these, 149 underwent adrenal vein sampling before and after stimulation with cosyntropin (250 µg intravenous bolus, n= 53, 73% with an aldosterone-producing adenoma) or with metoclopramide (10 mg intravenous bolus, n= 96, 65% aldosterone-producing adenoma), and 32 with an aldosterone-producing adenoma were investigated for the relative gene expression of dopamine, melanocortin 2, and 5-hydroxytryptamine (serotonin) 4 receptor with microarrays. Cosyntropin increased the selectivity index similarly on both sides; metoclopramide did not. Cosyntropin decreased relative aldosterone secretion index on the aldosterone-producing adenoma side but not contralaterally. Metoclopramide did not affect the selectivity index, but increased the relative aldosterone secretion index similarly on both sides. Because of these changes, cosyntropin decreased the lateralization index, while metoclopramide did not affect it. The relative gene expression of melanocortin 2, albeit heterogeneous across tumors, was 35% less (P<.0001) in aldosterone-producing adenoma than in the normal adrenal cortex, while dopamine receptor D2 and 5-hydroxytryptamine (serotonin) 4 receptors did not differ between tissues. CONCLUSION: Cosyntropin, while facilitating ascertainment of selectivity, lessens the lateralization, likely because of a blunted melanocortin 2 expression in aldosterone-producing adenoma. The similar expression of dopamine and 5-hydroxytryptamine (serotonin) 4 receptors in aldosterone-producing adenoma and the normal adrenal cortex can explain why metoclopramide increased the relative aldosterone secretion index on both sides and, therefore, failed to increase the lateralization index.

Total and free cortisol levels during 1 µg, 25 µg, and 250 µg cosyntropin stimulation tests compared to insulin tolerance test: results of a randomized, prospective, pilot study.

PURPOSE: The appropriate cosyntropin dose during cosyntropin stimulation tests remains uncertain. We conducted a prospective, randomized pilot study to compare 1 µg IV low dose cosyntropin test, 25 µg IM medium dose cosyntropin test, and 250 µg IM standard dose cosyntropin test to evaluate secondary adrenal insufficiency. Insulin tolerance test was used as the gold standard. METHOD: The study included patients with hypothalamic/pituitary disease (n = 10) with at least one pituitary axis deficiency other than ACTH deficiency and controls (n = 12). All tests were done in random order. Sensitivity and specificity were calculated for total cortisol and serum free cortisol cut-off levels during cosyntropin stimulation tests. RESULTS: The median (range) age and F/M sex ratios for patients and controls were 54 years (23-62), 2/8, and 33 years (21-51), 6/6, respectively. The best total cortisol cut-off during low dose cosyntropin test, medium dose cosyntropin test, 30 min and 60 min standard dose cosyntropin test were 14.6 µg/dL (100% sensitivity & specificity), 18.7 µg/dL (100% sensitivity, 88% specificity), 16.1 (100% sensitivity & specificity), and 19.5 µg/dL (100% sensitivity & specificity), respectively. There was no difference in the ROC curve for cortisol values between the cosyntropin stimulation tests (p > 0.41). Using a cortisol cut-off of 18 µg/dL during cosyntropin stimulation tests, only cortisol level at 30 min during standard dose cosyntropin test provided discrimination similar to insulin tolerance test. The best peak free cortisol cut-off levels were 1 µg/dL for insulin tolerance test, 0.9 µg/dL for low dose cosyntropin test, 0.9 µg/dL for medium dose cosyntropin test, and 0.9 µg/dL and 1.3 µg/dL for 30 min and 60 min standard dose cosyntropin test, respectively. CONCLUSION: All cosyntropin stimulation tests had excellent correlations with insulin tolerance test, when appropriate cut-offs were used. This pilot study does not suggest an advantage in using 25 µg cosyntropin dose during the cosyntropin stimulation test. A serum free cortisol cut-off of 0.9 µg/dL may be used as pass criterion during low dose cosyntropin test, standard dose cosyntropin test cosyntropin test, and 30 min standard dose cosyntropin test.

Subtype Diagnosis of Primary Aldosteronism: Is Adrenal Vein Sampling Always Necessary?

Aldosterone producing adenoma and bilateral adrenal hyperplasia are the two most common subtypes of primary aldosteronism (PA) that require targeted and distinct therapeutic approaches: unilateral adrenalectomy or lifelong medical therapy with mineralocorticoid receptor antagonists. According to the 2016 Endocrine Society Guideline, adrenal venous sampling (AVS) is the gold standard test to distinguish between unilateral and bilateral aldosterone overproduction and therefore, to safely refer patients with PA to surgery. Despite significant advances in the optimization of the AVS procedure and the interpretation of hormonal data, a standardized protocol across centers is still lacking. Alternative methods are sought to either localize an aldosterone producing adenoma or to predict the presence of unilateral disease and thereby substantially reduce the number of patients with PA who proceed to AVS. In this review, we summarize the recent advances in subtyping PA for the diagnosis of unilateral and bilateral disease. We focus on the developments in the AVS procedure, the interpretation criteria, and comparisons of the performance of AVS with the alternative methods that are currently available.

Optimization of left adrenal vein sampling in primary aldosteronism: Coping with asymmetrical cortisol secretion.

We evaluated the influence of catheter sampling position and size on left adrenal venous sampling (AVS) in patients with primary aldosteronism (PA) and analyzed their relationship to cortisol secretion. This retrospective study included 111 patients with a diagnosis of primary aldosteronism who underwent tetracosactide-stimulated AVS. Left AVS was obtained from two catheter positions - the central adrenal vein (CAV) and the common trunk. For common trunk sampling, 5-French catheters were used in 51 patients, and microcatheters were used in 60 patients. Autonomous cortisol secretion was evaluated with a low-dose dexamethasone suppression test in 87 patients. The adrenal/inferior vena cava cortisol concentration ratio [selectivity index (SI)] was significantly lower in samples from the left common trunk than those of the left CAV and right adrenal veins, but this difference was reduced when a microcatheter was used for common trunk sampling. Sample dilution in the common trunk of the left adrenal vein can be decreased by limiting sampling speed with the use of a microcatheter. Meanwhile, there was no significant difference in SI between the left CAV and right adrenal veins. Laterality, determined according to aldosterone/cortisol ratio (A/C ratio) based criteria, showed good reproducibility regardless of sampling position, unlike the absolute aldosterone value based criteria. However, in 11 cases with autonomous cortisol co-secretion, the cortisol hypersecreting side tended to be underestimated when using A/C ratio based criteria. Left CAV sampling enables symmetrical sampling, and may be essential when using absolute aldosterone value based criteria in cases where symmetrical cortisol secretion is uncertain.