Clinical Signs Of Hypercortisolism Research Articles

THU041 Clinical Improvements In Patients With Cushing’s Disease Treated With Osilodrostat According To Urinary And Late-night Salivary Cortisol Levels: Pooled Analysis From LINC 3 And LINC 4

Abstract Disclosure: B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Research Investigator; Self; served on the LINC 3 steering committee. M. Fleseriu: Consulting Fee; Self; HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Research Investigator; Self; served on the LINC 3 steering committee. R. Pivonello: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Pfizer, Inc., Bresmed Health Solutions, Damor farmaceutici, S&R Farmaceutici SpA, Organon Italia Srl, Siunergos Pharma, Biohealth Italia Srl. Research Investigator; Self; Novartis Pharmaceuticals, Recordati, Xeris Pharmaceuticals (Strongbridge), Corcept Therapeutics, Takeda, Neurocrine Biosciences, Camurus AB, Pfizer, Inc., Merk Serono, Ibsa. R. Feelders: Consulting Fee; Self; HRA Pharmaceuticals, Recordati. Grant Recipient; Self; Corcept Therapeutics. M. Gadelha: Advisory Board Member; Self; Novo Nordisk, Recordati, Crinetics Pharmaceuticals. Speaker; Self; Recordati, Ipsen, Pfizer, Inc., Crinetics, Novo Nordisk. A. Lacroix: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Ipsen, Novo Nordisk. Grant Recipient; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Ipsen, Novo Nordisk. P. Witek: Grant Recipient; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly. Speaker; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly. A.P. Heaney: Advisory Board Member; Self; Xeris Pharmaceuticals (Strongbridge), Novo Nordisk, Lundbeck Pharma. Speaker; Self; Chiasma, Ipsen. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. J. Newell-Price: Consulting Fee; Self; Crinetics, Diurnal, HRA Pharmaceuticals, Recordati Rare Diseases. Grant Recipient; Self; Crinetics, Diurnal, HRA Pharmaceuticals, Recordati Rare Diseases. Introduction: In two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734), osilodrostat, a potent oral 11β-hydroxylase inhibitor, led to rapid, sustained reductions in mean urinary free cortisol (mUFC) and late-night salivary cortisol (LNSC), as well as improvements in clinical signs of hypercortisolism and health-related quality of life (HRQoL), in patients (pts) with Cushing’s disease (CD). mUFC and LNSC are recommended for monitoring treatment response. Objective: We assessed if pts with control of both mUFC and LNSC experienced greater improvements in clinical signs of hypercortisolism and HRQoL, compared to control of mUFC alone. Methods: LINC 3 comprised a 48-week (W) core phase, including an 8W randomized-withdrawal period. LINC 4 included a 12W, double-blind, placebo-controlled period followed by 36W of open-label osilodrostat. Both studies had an optional extension. mUFC (mean of 2–3 samples; normal range [NR] 11–138 nmol/24h [4–50 µg/24h]) and LNSC (one sample; NR ≤2.5 nmol/L [≤0.9 µg/L]) were measured by liquid chromatography-tandem mass spectrometry. Changes in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism and HRQoL were assessed in the pooled population according to mUFC and LNSC control status: both controlled (C) mUFC + LNSC (mUFC ≤ULN + LNSC ≤ULN), C-mUFC (mUFC ≤ULN + LNSC >ULN) and uncontrolled (UC) mUFC + LNSC (mUFC >ULN + LNSC >ULN). Pts with C-LNSC (mUFC >ULN + LNSC ≤ULN) were not analyzed as very few pts had control of LNSC without UFC control. This analysis includes pts in core and extension phases with both mUFC and LNSC assessments available. Periods where pts received placebo were excluded. Results: 136 (85.0%) of 160 pts with available assessments had UC mUFC + LNSC at baseline (BL). At W48 (n=133) and W72 (n=111), respectively, 59 (44.4%) and 54 (48.6%) pts had C mUFC + LNSC, 49 (36.8%) and 44 (39.6%) had C-mUFC, and 19 (14.3%) and 11 (9.9%) had UC mUFC + LNSC. Pts with C mUFC + LNSC had greater percentage improvements from BL to W72 in cardiovascular/metabolic-related parameters than pts with C-mUFC or UC mUFC + LNSC, respectively: fasting plasma glucose, –5.0%, –4.8%, 1.9%; glycated hemoglobin, –5.1%, –4.8%, –1.3%; weight, –6.5%, –6.5%, –4.5%; waist circumference, –7.2%, –6.3%, –4.9%. Physical manifestations of hypercortisolism generally improved from BL to W72 regardless of mUFC/LNSC control. Pts with C mUFC + LNSC or C-mUFC had the greatest improvement from BL to W72 in HRQoL. Conclusions: The greatest improvements in cardiovascular/metabolic-related parameters and HRQoL were observed in pts with C mUFC + LNSC or C-mUFC, compared to pts with UC mUFC + LNSC. Improvements in most physical manifestations of hypercortisolism were observed regardless of mUFC/LNSC control. Data are limited by small patient numbers in some groups. Normalization of both mUFC and LNSC can improve long-term treatment outcomes in pts with CD. Presentation: Thursday, June 15, 2023

PMON160 Improvements in Clinical Signs of Hypercortisolism and Quality of Life According to Urinary and Late-Night Salivary Cortisol Levels in Patients with Cushing's Disease Treated with Osilodrostat

Abstract Objective Cushing's disease (CD) is a debilitating disorder of chronic hypercortisolism. Assessment of 24h mean urinary free cortisol (mUFC) and late-night salivary cortisol (LNSC) is recommended for screening and monitoring treatment response. In the published core period of the Phase III, LINC 3 study (NCT02180217), osilodrostat therapy (a potent oral 11β-hydroxylase inhibitor) produced rapid, sustained reductions in both mUFC and LNSC alongside improvements in clinical signs of hypercortisolism and health-related quality of life (HRQoL) in patients with CD. Here we explored cardiovascular/metabolic-related parameters, physical features and HRQoL according to mUFC and/or LNSC control. Methods LINC 3 (core period) enrolled 137 adults with CD and mUFC >1.5x upper limit of normal (ULN), who received open-label osilodrostat up to 48-week (W) (starting dose: 2 mg twice daily [bid]; maximum: 30 mg bid); eligible patients were randomized in an 8W placebo-controlled, withdrawal period (W26–34). mUFC (three sample average; normal 11–138 nmol/24h [4–‍50 µg/24h]) and LNSC (single sample; normal ≤2.5 nmol/L) were assessed centrally by liquid chromatography-tandem mass spectrometry. Cardiovascular/metabolic-related parameters, physical features (rating: 0=absent;1=mild;2=moderate;3=severe), CushingQoL and Beck Depression Inventory-II (BDI-II) scores were also evaluated. Data were recorded at baseline, regularly throughout, and at W48. Analyses are presented for patients with both mUFC and LNSC assessments, defined as: both mUFC+LNSC controlled (mUFC≤ULN+LNSC≤ULN), only mUFC controlled (mUFC≤ULN+LNSC>ULN), only LNSC controlled (mUFC>ULN+LNSC≤ULN) and both mUFC+LNSC uncontrolled (mUFC>ULN+LNSC>ULN). Results Of evaluable patients at baseline (n=87), 74 (85.1%) had both mUFC+LNSC uncontrolled. At W48, 38 patients (54.3%) had both mUFC+LNSC controlled, 21 (30.0%) had only mUFC controlled, 3 (4.3%) had only LNSC controlled, and 8 (11.4%) had both mUFC+LNSC uncontrolled. Patients with both mUFC+LNSC controlled had generally greater mean improvements from baseline to W48 in cardiovascular/metabolic-related parameters than those with only mUFC or LNSC controlled or both mUFC+LNSC uncontrolled, respectively: weight, –5.9, –3.3, –2.2 and –‍3.8 kg; systolic blood pressure, –14.4, –8.0, –7.4, –3.0 mmHg; diastolic blood pressure, –‍8.6, –4.8, –8.2, –4.0 mmHg; fasting plasma glucose, –16.9, –4.8, –15.0, –11.0 mg/dL; and HbA1c, –0.4, –0.3, –0.9, –0.0%. CushingQoL/BDI-II scores improved from baseline to W48 irrespective of mUFC and/or LNSC control. The proportion of patients with improved physical manifestations of hypercortisolism (facial rubor, striae, fat pads, bruising, hirsutism [females], muscle atrophy) was greatest in patients with both mUFC+LNSC controlled or only mUFC controlled. Discussion At W48, over half the evaluable patients had both mUFC+LNSC controlled following osilodrostat treatment. Improvements in clinical signs of hypercortisolism and HRQoL occurred irrespective of mUFC and/or LNSC control; however, for some clinical outcomes, improvements were greater in patients with both mUFC+LNSC controlled. Findings are limited by small patient numbers in some groups. mUFC and LNSC are complementary parameters used to assess disease control and patients with both mUFC+LNSC controlled have better outcomes. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Impact of urinary and late-night salivary cortisol levels on clinical signs of hypercortisolism and quality of life in patients with Cushing's disease treated with osilodrostat

Impact of urinary and late-night salivary cortisol levels on clinical signs of hypercortisolism and quality of life in patients with Cushing's disease treated with osilodrostat

Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase

The authors report the outcomes from the pivotal phase 3 trial in patients with Cushing’s disease of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, [mitochondrial 11β-hydroxylase]). Twice-daily osilodrostat rapidly reduced mean 24-h urine free cortisol (UFC) and sustained this reduction alongside improvements in clinical signs of hypercortisolism.

Long-Term Control of Urinary Free Cortisol With Osilodrostat in Patients With Cushing’s Disease: Final Results From the LINC 2 Study

Introduction: During the 22-week core LINC 2 study, the oral 11β-hydroxylase inhibitor osilodrostat normalized mean urinary free cortisol (mUFC) in 79% (15/19) of patients with Cushing’s disease. This report describes long-term LINC 2 efficacy and safety results following an optional extension. Methods: Patients receiving clinical benefit at week 22 could enter the extension (that ran until Oct 22, 2019), continuing the same osilodrostat dose; dose adjustments were permitted based on efficacy and safety. Response rate (mUFC ≤ULN [controlled] or mUFC >ULN but ≥50% decrease from baseline [BL; partially controlled]) was assessed over time. Efficacy/safety were assessed for all patients from core BL until study end. Results: Of 19 enrolled patients (female:male 14:5; mean [SD] age 36.8 years [8.4]), 16 entered the optional extension and 8 of them remained on treatment until study end. Median (range) osilodrostat exposure was 282 weeks (2-351). Mean mUFC decreased from BL (9.9 x ULN) to ≤ULN by week 4 and remained stable throughout the study. All 19 patients achieved mUFC ≤ULN at least once during the study. At each assessment up to month 70 of the extension phase, 50-88% of ongoing patients were controlled, and up to 18% were partially controlled. Mean percentage change in clinical signs from BL (mean [SD]) to last assessment were: fasting plasma glucose, -10.8% (22.1) (from BL: 105.6 mg/dL [49.2]); HbA1c, -2.1% (9.0) (from BL: 5.7% [0.7]); systolic BP, -3.3% (12.6) (from BL: 132.6 mmHg [11.6]); diastolic BP, -2.0% (10.4) (from BL: 85.0 mmHg [6.5]); BMI, -5.9% (8.8) (from BL: 30.7 kg/m2 [7.0]). Overall, 9 patients discontinued treatment (n=2 core and n=7 extension), mostly because of AEs or no longer requiring treatment (n=3 each). The most common AEs during the entire treatment period were nausea (n=10), adrenal insufficiency, and headache (both n=9). AEs related to hypocortisolism and adrenal hormone precursor accumulation occurred in 11 (mostly adrenal insufficiency, n=9) and 12 patients (mostly hypertension, n=4), respectively; most were grade 1/2 and managed with dose adjustment/interruption and/or concomitant medication. Mean (SD) plasma ACTH increased from 1.8 x ULN (0.9) at BL to 7.1 x ULN (12.3) at week 22 and 6.9 x ULN (12.6) at last assessment. Mean (SD) 11-deoxycortisol increased from 1.2 x ULN (1.3) at BL to 13.6 x ULN (12.2) at week 22 and 3.6 x ULN (4.2) at last assessment. In females, mean (SD) testosterone increased from 0.8 x ULN (0.4) at BL to 2.4 x ULN (2.1) at week 22 and 1.0 x ULN (0.9) at last assessment. Two patients, both female, reported an AE of hirsutism. Conclusions: Rapid reductions in mUFC were sustained for up to 6 years of osilodrostat treatment and were accompanied by improvements in clinical signs of hypercortisolism. Osilodrostat was well tolerated, with no new safety signals during long-term treatment.

Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase

Cushing's disease is a rare endocrine disorder characterised by cortisol overproduction with severe complications. Therapies for cortisol reduction are often necessary. Here we report the outcomes from the pivotal phase III study of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, mitochondrial [11β-hydroxylase]; Novartis Pharma AG, Basel, Switzerland) in patients with Cushing's disease. LINC 3 was a prospective, multicentre, open-label, phase III study with a double-blind randomised withdrawal period, that comprised four periods. Patients aged 18-75 years, with confirmed persistent or recurrent Cushing's disease (defined as mean 24-h urinary free cortisol [UFC] concentration >1·5 times the upper limit of normal [ULN] and morning plasma adrenocorticotropic hormone above the lower limit of normal) who had previously had pituitary surgery or irradiation, or were newly diagnosed and who refused surgery or were not surgical candidates, were recruited from 66 hospital sites and private clinical practices in 19 countries. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks (1-30 mg twice daily; film-coated tablets for oral administration) on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, weeks 13-24, osilodrostat was continued at the therapeutic dose determined during period 1. In period 3, beginning at week 26, participants who had a mean 24-h UFC concentration of less than or equal to the ULN at week 24, without up-titration after week 12, were randomly assigned (1:1), via an interactive-response technology, stratified by osilodrostat dose at week 24 and history of pituitary irradiation, to continue osilodrostat or switch to placebo for 8 weeks. Participants and investigators were masked to treatment assignment. Ineligible participants continued open-label osilodrostat. In period 4, weeks 35-48, all participants were given open-label osilodrostat until core-study end. The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3. The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (ie, mean 24-h UFC concentration of ≤ULN) at the end of the randomised withdrawal period (week 34), without up-titration during this period. The key secondary endpoint was the proportion of participants with a complete response at the end of the single-arm, open-label period (ie, period 2, week 24) without up-titration during weeks 13-24. Analysis was by intention-to-treat for all patients who received at least one dose of osilodrostat (full analysis set; key secondary endpoint) or randomised treatment (randomised analysis set; primary endpoint) and safety was assessed in all enrolled patients who received at least one dose of osilodrostat and had at least one post-baseline safety assessment. LINC 3 is registered with ClinicalTrials.gov, NCT02180217, and is now complete. Between Nov 12, 2014, and March 22, 2017, 202 patients were screened and 137 were enrolled. The median age was 40·0 years (31·0-49·0) and 106 (77%) participants were female. 72 (53%) participants were eligible for randomisation during the withdrawal phase, of whom 36 were assigned to continue osilodrostat and 35 were assigned to placebo; one patient was not randomly assigned due to investigator decision and continued open-label osilodrostat. More patients maintained a complete response with osilodrostat versus with placebo at week 34 (31 [86%] vs ten [29%]; odds ratio 13·7 [95% CI 3·7-53·4]; p<0·0001). At week 24, 72 (53%; 95% CI 43·9-61·1) of 137 patients maintained a complete response without up-titration after week 12. Most common adverse events (ie, occurred in >25% of participants) were nausea (57 [42%]), headache (46 [34%]), fatigue (39 [28%]), and adrenal insufficiency (38 [28%]). Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase. Twice-daily osilodrostat rapidly reduced mean 24-h UFC and sustained this reduction alongside improvements in clinical signs of hypercortisolism; it was also generally well tolerated. Osilodrostat is an effective new treatment option that is approved in Europe for the treatment of endogenous Cushing's syndrome and in the USA for Cushing's disease. Novartis Pharma AG.

Cushing syndrome in pregnancy, diagnosed after delivery

Cushing syndrome (CS) is rare in pregnancy, and few cases have been reported to date. Women with untreated CS rarely become pregnant because of the ovulatory dysfunction induced by hypercortisolism. It is difficult to diagnose CS in pregnancy because of its very low incidence, the overlap between the clinical signs of hypercortisolism and the physiological changes that occur during pregnancy and the changes in hypothalamus-pituitary-adrenal axis activity that occur during pregnancy and limit the value of standard diagnostic testing. However, CS in pregnancy is associated with poor maternal and fetal outcomes; therefore, its early diagnosis and treatment are important. Here, we report two patients with CS that was not diagnosed during pregnancy, in whom maternal and fetal morbidity developed because of hypercortisolism.

Spontaneous Resolution of Primary Hypercortisolism of Cushing Disease After Pituitary Hemorrhage

To describe a case of spontaneous resolution of primary hypercortisolism from Cushing disease (CD) due to pituitary apoplexy (PA). Clinical, laboratory, and pathologic information are described. A 59-year-old female presented with a headache, a 2.3 cm sellar mass with a questionable hemorrhagic component, and clinical signs of hypercortisolism. On further evaluation, she had an increased 24-hour urine free cortisol, abnormal serum cortisol during a low dose dexamethasone suppression test, and an elevated plasma adrenocorticotropic hormone (ACTH), consistent with pituitary CD. As she was being prepared for surgical resection, she was noted to have spontaneous biochemical remission associated with resolution of her symptoms of hypercortisolism, and a repeat magnetic resonance imaging scan showed shrinkage of the sellar mass. She has been managed conservatively since and remains in clinical/biochemical remission until present time, 18 months following her initial presentation. We report a case of spontaneous resolution of CD from symptomatic hemorrhage within an ACTH-secreting pituitary adenoma, or PA. This has been rarely reported in the medical literature. The fact that she did not pass through a phase of adrenal withdrawal, makes us suspect a residual functional adenoma within or around the sella which may eventually grow, causing her disease to recur, as has been reported. Hence, continued monitoring will be required.

ARMC5 mutation in a Portuguese family with primary bilateral macronodular adrenal hyperplasia (PBMAH).

SummaryPBMAH is a rare etiology of Cushing syndrome (CS). Familial clustering suggested a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene. A 70-year-old female patient was admitted due to left femoral neck fracture in May 2014, in Orthopedics Department. During hospitalization, hypertension (HTA) and hypokalemia were diagnosed. She presented with clinical signs of hypercortisolism and was transferred to the Endocrinology ward for suspected CS. Laboratory workup revealed: ACTH <5 pg/mL; urinary free cortisol (UFC), 532 µg/24 h (normal range: 20–90); failure to suppress the low-dose dexamethasone test (0.5 mg every 6 h for 48 h): cortisol 21 µg/dL. Abdominal magnetic resonance imaging (MRI) showed enlarged nodular adrenals (right, 55 × 54 × 30 mm; left, 85 × 53 × 35 mm), and she was submitted to bilateral adrenalectomy. In 2006, this patient’s 39-year-old daughter had been treated by one of the authors. She presented with severe clinical and biological hypercortisolism. Computed tomography (CT) scan showed massively enlarged nodular adrenals with maximal axis of 15 cm for both. Bilateral adrenalectomy was performed. In this familial context of PBMAH, genetic study was performed. Leucocyte DNA genotyping identified in both patients the same germline heterozygous ARMC5 mutation in exon 1 c.172_173insA p.I58Nfs*45. The clinical cases herein described have an identical phenotype with severe hypercortisolism and huge adrenal glands, but different ages at the time of diagnosis. Current knowledge of inheritance of this disease, its insidious nature and the well-known deleterious effect of hypercortisolism favor genetic study to timely identify and treat these patients.Learning points:PBMAH is a rare etiology of CS, characterized by functioning adrenal macronodules and variable cortisol secretion.The asymmetric/asynchronous involvement of only one adrenal gland can also occur, making disease diagnosis a challenge.Familial clustering suggests a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene.The insidious nature of this disease and the well-known deleterious effect of hypercortisolism favor genetic study of other family members, to diagnose and treat these patients timely.As ARMC5 is expressed in many organs and recent findings suggest an association of PBMAH and meningioma, a watchful follow-up is required.

Assessment of glucocorticoid therapy with salivary cortisol in secondary adrenal insufficiency

Appropriate glucocorticoid replacement therapy in adrenal insufficiency (AI) is crucial, given the risks of chronic under- or overtreatment, particularly in patients on multiple medications. Salivary sampling allows for non-invasive, stress-free cortisol measurement. To determine whether salivary cortisol measurement is helpful in assessing the adequacy of glucocorticoid therapy with cortisone acetate (CA) in patients with secondary AI. A prospective cohort study at the Endocrinology Unit of Padua University Hospital. Six samples of salivary cortisol were collected from 28 patients with secondary AI on CA treatment and from 36 healthy volunteers at fixed times of the day, and used to calculate salivary cortisol levels at each time point and the area under the curve (AUC) across the different sampling times. Salivary cortisol levels were lower in patients than in controls in the morning but no differences were found in the afternoon or at night before resting. Salivary cortisol levels were higher in patients immediately following CA administration. Ten patients showed an AUC above the 97.5th percentile of controls, without clinical signs of hypercortisolism, and salivary cortisol levels 90 min after each dose of CA predict the AUC. All patients had severe GH deficiency and there were no differences in salivary cortisol levels or AUC between patients treated or not with GH. Two salivary cortisol determinations, able to predict the daily AUC, may allow for assessing the adequacy of glucocorticoid replacement therapy in secondary AI and for identifying cases of over- or undertreatment.

Concurrent primary aldosteronism and subclinical cortisol hypersecretion

Primary aldosteronism is the most frequent cause of secondary hypertension and is responsible for an increased risk of cardiometabolic complications. A concomitant subtle cortisol hyperproduction could enhance cardiovascular risk. We prospectively estimated the occurrence of subclinical hypercortisolism in primary aldosteronism patients. In a large population of hypertensive patients without clinical signs of hypercortisolism, 76 consecutive patients with primary aldosteronism were investigated. Differential diagnosis between unilateral and bilateral aldosterone hypersecretion was made by computed tomography/MRI and/or adrenal venous sampling (AVS). Subclinical hypercortisolism was defined as failure to suppress plasma cortisol to less than 50 nmol/l after 1 mg-overnight dexamethasone, used as screening test, and at least one of two other abnormal hormonal parameters, that is, adrenocorticotrophin (ACTH) less than 2 pmol/l and urinary cortisol more than 694 nmol/24 h. Three out of 76 patients had postdexamethasone plasma cortisol more than 50 nmol/l. Only one also showed low-normal ACTH and mildly elevated urinary cortisol. The patient had a right 4 cm adrenal mass. Laparoscopic adrenalectomy was followed by short-term steroid replacement to prevent adrenal insufficiency. In-situ hybridization showed CYP11B1 expression exclusively in tumoral tissue, whereas CYP11B2 was expressed only in a peritumoral region composed of zona glomerulosa-like cells, suggesting the co-existence of a cortisol-producing adenoma and an aldosterone-producing hyperplasia in the same adrenal. The restoration of hormone abnormalities to normal levels was confirmed at 12 months of follow-up. Concurrent aldosterone and subclinical cortisol hypersecretion seems to be a rare event in primary aldosteronism patients; however, its detection by appropriate testing is important to avoid AVS misinterpretation.

Computed tomography and low-field magnetic resonance imaging of the pituitary gland in dogs with pituitary-dependent hyperadrenocorticism: 11 cases (2001–2003)

To compare the results of computed tomography (CT) and magnetic resonance imaging (MRI) of the pituitary gland in dogs with pituitary-dependent hyperadrenocorticism (PDH) caused by histologically confirmed pituitary adenoma. Retrospective case series. 11 dogs with PDH that underwent transsphenoidal hypophysectomy. Medical records of dogs examined between January 2001 and March 2003 were reviewed. Dogs were included in this study if they had clinical signs of hypercortisolism at the time of admission (for which PDH was diagnosed) and underwent transsphenoidal hypophysectomy. Pre- and postcontrast CT and low-field MRI (0.2-Tesla magnet) were performed on the same day as surgery for each dog. An abnormal pituitary gland was found in 7 dogs by use of MRI and in the same 7 dogs by use of CT. Significant differences were found between postcontrast CT and MR images for height, width, and length of the pituitary gland; brain area; and thickness of the sphenoid bone. However, the pituitary gland height-to-brain area ratio determined from postcontrast CT and MR images was not significantly different. The signal-to-noise ratio and contrast-to-noise ratio of pre- and postcontrast MR images were significantly higher than those of the CT images. Low-field MRI and dynamic CT imaging of the pituitary gland provided comparable information on the presence of pituitary adenomas in dogs with PDH.

Adrenal incidentaloma: an overview of hormonal data from the National Italian Study Group.

Adrenal masses are more and more frequently detected by adrenal ultrasound, computed tomography or nuclear magnetic resonance carried out for a reason other than the suspicion of adrenal disease (incidentalomas). The findings of an incidentaloma still leaves many diagnostic and therapeutic questions open. We report the results of a multicentric retrospective evaluation of patients with adrenal incidentalomas, performed by a Study Group of the Italian Society of Endocrinology. According to the definition of incidentaloma, exclusion criteria a priori were: severe or paroxysmal hypertension, frank hypokalemia and clinical signs of hypercortisolism or hyperandrogenism. 29 centers participated in the study and the data obtained by questionnaire were collected in 2 centers for final elaboration. Center 1 carried out the epidemiological and clinical evaluation. Basal and dynamic hormonal evaluation of 786 among the 1013 cases recruited were performed in our center (center 2). Functional studies included: diurnal rhythm of cortisol, urinary free cortisol (UFC), ACTH, DHEAS, 17-OH progesterone, testosterone, androstenedione, supine and upright plasma renin activity (PRA) and aldosterone, urinary aldosterone, urinary catecholamines and VMA. The hormonal dynamic evaluation included the overnight dexamethasone suppression test (1 mg), CRH test and ACTH test. In our study, 89% (702 patients) of adrenal incidentalomas were non-hypersecretory masses; 6.2% (49 patients) showed a preclinical Cushing's syndrome (PCS) (at least two altered parameters of pituitary-adrenal axis); 3.4% (27 patients) were pheochromocytomas; 0.89% (7 patients) were aldosteronomas. One tumor was a masculinizing adrenocortical carcinoma. Two hundred sixty patients underwent surgical exploration and the histological diagnosis showed: 138 adenomas (53%), 32 carcinomas (12%), 26 pheochromocytomas (10%). 16 myelolipomas (8%), 13 cystic lesions (5.5%), 7 tumors of neuronal lineage (3%). 12 metastases (4%), 13 others (5%). The 138 patients with adenomas had the following hormonal diagnosis: 103 nonfunctional adenomas (74%), 31 PCS (23%) and 4 cases of hyperaldosteronism (3%). In the patients with PCS an abnormal dexamethasone suppression test was found in 86% of cases (37/41 patients). Values for ACTH were low in 78% (32/41 patients). UFC was elevated in 64% of patients, the diurnal rhythm of cortisol evaluated in 14 patients was absent in 7. Only in 50% of cases DHEAS values (12/24 patients) were decreased, whereas they were normal in the other 50%. Interestingly, 8 patients with normal DHEAS and normal UFC showed nonsuppressible cortisol by dexamethasone test (1 mg). Blunted ACTH response to CRH was detected in 9 of 14 patients (64%). Thus our data suggest that the best parameter for evaluating subclinical hypercortisolism seems to be the overnight dexamethasone suppression test. In 27 patients with pheochromocytoma 24-hour urinary catecholamine and VMA levels were elevated in 86 and 46% of cases respectively. In 7 patients with hyperaldosteronism upright PRA was suppressed in 100% of cases and aldosterone plasma levels were elevated in 6 patients (86%); serum potassium level was slightly decreased in 60% of cases. In 86 of 138 histologically proven adenomas, DHEAS levels were: normal in 59% of patients, decreased in 36% and elevated in 4.6%, whereas in 22 of 32 cortical carcinomas evaluated. DHEAS levels were normal in 63% of cases, decreased in 18% and elevated 18%. Post-ACTH 17-OH progesterone levels were elevated in 52% (62/118 patients) of non-functioning adenomas and in 2 of 4 carcinomas. Not enough data are yet available postoperatively. In summary, endocrine evaluation can lead to the identification of a nonnegligible number of cases of clinically unsuspected pheochromocytomas and subtle hypercortisolism (about 3.4 and 6.2%, respectively of all adrenal incidentalomas), while cases of primary subclinical aldosteronism are rarely found. (ABSTRACT TRUNCATED)

SPONTANEOUS GH SECRETION IN AN EIGHT YEARS OLD BOY WITH ACTH-PROOUCING PITUITARY TUMOR

An 8y.old boy(bone age:6y.)developed early onset of pubic hair, testes vol.3ml, height at 25th c., blood pressure normal. Weight was at 97th c., but rapid increase was reported(4/88:21.5kg/118cm and 9/89:34.5kg/126cm). Endocrinol. findings:cortisol profile, 2mg dexameth test, 170HP were normal. Testosterone(5.0nmol/l) and prolactin(650mU/l were slightly elevated. CT scan of pit.area and adrenals showed no abnormalities. Cyproteronacetate(100mg/d)was given until age 11y. Growth curve followed exactly 25th c.during next 2y. Between age 10y. and 11y.3m.(bone age:11y.)growth decelerated dramatically. Normal spontaneous cortisol were found repeatedly. At age 11y.(8/92)testing by 2mg dexameth. :ACTH:21.2-10.6pmol/l, cortisol :629-451nmol/l, but by 8mg dexameth. :ACTH:22.9-6.2 pmol/l, cortisol :941-72 nmol/l. Testosterone(3.5nmol/l)and prolactin(336mU/l)were normal. MRT showed 20x23x8mm pituit, tumor. Overnight GH secretion was measured before operation. Complete transsphenoidal tumor exstirpation was performed, immunol. investigation visualized ACTH storage. To elucidate the mechanism of impaired growth, overnight GH secretion will be retested 2months after operation. Conclusions: 1)Coincidence of early puberty and clinical signs of hypercortisolism must carefully followed even in cases with normal cortisol and CT scan. 2)Rapid bone maturation could mask detrimental effects of cortisol on growth. 3)Measurement of spontaneous GH secretion may contribute to clarify mechanisms of impaired growth in Cushings disease.

A case of pseudo-Nelson’s syndrome: cure of ACTH hypersecretion by removal of a bronchial carcinoid tumor responsible for Cushing’s syndrome

It may sometimes be difficult to distinguish Cushing's disease from ectopic ACTH syndrome. A case is described here of a patient with a Cushing's syndrome and diagnostic difficulties. Initial features were consistent with a Cushing's disease (in particular metopirone test was positive). Because of relapse of hypercortisolism after mitotane therapy, total adrenalectomy was performed. Thereafter features occurred that evoked Nelson's syndrome, including high plasma ACTH levels and a pituitary mass syndrome. Pituitary reserve testings by vasopressin or corticotropin-releasing factor were positive, although inconstantly, in that plasma ACTH increased. A lung tumor was discovered about 20 yr after the first clinical signs of hypercortisolism. Its removal led to the discovery of a bronchial carcinoid tumor and was followed by normalization of plasma ACTH levels. An analysis of proopiomelanocortin-related peptides was performed postoperatively on the blood drawn before and after the tumor resection and on the tumor; the results of this study would have been contributive to the diagnosis of occult ectopic ACTH tumor. In conclusion this case demonstrates the limitations of the conventional procedures in the diagnosis of the ectopic ACTH syndrome. At contrast the newer biochemical procedures may be very useful in determining the type of hypercortisolism.

Different therapeutic efficacy of ketoconazole in patients with Cushing's syndrome

The property of ketoconazole to inhibit adrenal biosynthesis of cortisol was used in a clinical study of 14 patients with Cushing's syndrome (pituitary-dependent Cushing's disease, n = 10; adrenocortical adenoma, n = 2; adrenocortical carcinoma, n = 1; ectopic ACTH syndrome, n = 1). Five patients were treated in a short-term manner (1000 mg over 24 h) and nine patients for a longer period (600 mg/die from 1 week up to 12 months). After short-term administration of ketoconazole, serum cortisol levels fell distinctly only in the patient with adrenocortical adenoma, but not at all or only slightly in the other patients, whereas serum levels of progesterone and 11-deoxy-compounds increased markedly in all patients, with the exception of the patient with adrenocortical carcinoma. Plasma ACTH levels increased in the patients with Cushing's disease but not in the patients with tumor. After long-term treatment of three patients with Cushing's disease over 3, 10, and 12 months, the clinical signs of hypercortisolism persisted or were only slightly ameliorated. In these three patients as well as in three other patients with Cushing's disease treated for a shorter period of 1 to 4 weeks, serum and urinary cortisol levels decreased, but were not normalized, whereas plasma ACTH levels increased variably. Only in one patient with Cushing's disease, in the second patient with adrenocortical adenoma, and in the patient with ectopic ACTH syndrome, serum and urinary cortisol levels returned to normal. We conclude from our data, that the antimycotic drug inhibits biosynthesis of cortisol by blocking adrenal 11 beta- and 17 alpha-hydroxylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

DISSOCIATION BETWEEN PLASMA ADRENAL ANDROGENS AND CORTISOL IN CUSHING'S DISEASE AND ECTOPIC ACTH-PRODUCING TUMOUR: RELATION TO ADRENARCHE

To assess the effect of chronic hypersecretion of corticotropin (ACTH) and other peptides derived from proopiomelanocortin, and of cortisol, on plasma adrenal androgen concentration, plasma dehydroepiandrosterone sulphate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione (Δ4A), and cortisol were measured in 14 children and adolescents with Cushing's disease, a 9-year-old boy with an ectopic ACTH-producing tumour, and a group of normal, age-related individuals. The plasma DHEA-S concentration was normal for chronological age in 9 of 12 patients and for bone age in 7 of 10 patients. The plasma DHEA level was normal for chronological age in 12 of 14 patients and for bone age in 8 of 10 patients. In contrast, the concentration of plasma Δ4 A was raised for chronological age in 6 of 13 patients and for bone age in 7 of 10 patients. All patients had raised plasma cortisol levels in the afternoon and other laboratory and clinical signs of hypercortisolism. In the boy with an ectopic ACTH-producing tumour, plasma DHEA-S was moderately raised, plasma DHEA was normal, and plasma Δ4 A was very high. This patient's plasma ACTH levels ranged from 1340 to 1520 pg/ml and the cortisol levels from 51 to 95 μg/dl. The findings suggest that a factor other than ACTH is also required for adrenal androgen secretion. Since the other proopiomelanocortin-related peptides—ie, the N-terminal peptide (1-76), β-endorphin (β-EP), β-lipotropin (β-LPH), and γ-lipotropin (γ-LPH)—are raised in the plasma of patients with Cushing's disease, one of these is unlikely to be that putative factor.

Hypermineralocorticoidism: the sole clinical manifestation of an adrenal cortical carcinoma.

SummaryAn adrenocortical carcinoma in a 54 year old female patient is reported. Arterial hypertension, muscular weakness, hypokalemic alkalosis and urinary potassium loss were the prominent features. Although plasma corticol was increased, there were no clinical signs of hypercortisolism. Surgical removal of the tumor appeared to be impossible; o p ’ DDD therapy achieved to normalize temporarily the urinary excretion not only of 17 hydroxycorticoids and of 17 ketosteroids but also of tetrahydroaldosterone.The pathogenesis of the mineralocorticoid syndrome and the influence of o p ’ DDD on the adrenocortical aldosterone production are discussed.