Background:
Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the ...steroidogenesis inhibitor metyrapone for this purpose.
Objective:
The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS.
Design:
This was designed as a retrospective, multicenter study.
Setting:
Thirteen University hospitals were studied.
Patients:
We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3).
Measurements:
Measurements included biochemical parameters of activity of CS: mean serum cortisol “day-curve” (CDC) (target 150–300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC).
Results:
A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L 26.2 μg/dL vs 348.6 nmol/L 12.6 μg/dL; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L 32.0 μg/dL vs 491.1 nmol/L 17.8 μg/dL; P < .0001); and UFC (37 patients, 1483 nmol/24 h 537 μg/24 h vs 452.6 nmol/24 h 164 μg/24 h; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible.
Conclusions:
Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS.
ACROSTUDY: the first 5 years Trainer, Peter J
European journal of endocrinology,
11/2009, Volume:
161 Suppl 1
Journal Article
Peer reviewed
Open access
ACROSTUDY is an observational registry intended to collect safety and efficacy data on pegvisomant therapy. A total of 792 patients have been enrolled, of whom 83% had commenced pegvisomant prior to ...recruitment. The mean follow-up is 1.66 years with the mean duration of pegvisomant therapy 3.31 years representing 2625 patient years of treatment. About 90% of patients were on once daily pegvisomant, and 67% were on monotherapy. Disappointingly, IGF1 was normalised in <70% of patients; furthermore, in 80% of patients with an elevated IGF1, the daily dose of pegvisomant was 20 mg or less. A total of 56 serious adverse events (AEs) were reported, of which 13 were related to pegvisomant. A total of 276 AEs were reported, of which 56 were considered related to pegvisomant. The AEs most frequently attributed to pegvisomant were disturbed liver function tests and injection site reactions. Magnetic resonance imaging (MRI) was available in 684 patients. A total of 411 patients had at least one MRI on pegvisomant compared with a baseline. In 31 patients, a decrease in tumour size has been reported, of whom 20 had previously received radiotherapy. An increase in tumour size has been reported and confirmed in 22 patients. In 11 patients, there was contradictory data on tumour size, while, in six patients, central review of the films failed to confirm increase in tumour size. In conclusion, the safety data are generally reassuring, while the IGF1 normalisation rate is disappointing, which probably reflects a failure of dose titration. Further effort is needed to understand the reasons for the failure of dose titration.
Routine assessment of the hypothalamic-pituitary-adrenal axis relies on the measurement of total serum cortisol levels. However, most cortisol in serum is bound to corticosteroid-binding globulin ...(CBG) and albumin, and changes in the structure or circulating levels of binding proteins markedly affect measured total serum cortisol levels. Furthermore, high-affinity binding to CBG is predicted to affect the availability of cortisol for the glucocorticoid receptor. CBG is a substrate for activated neutrophil elastase, which cleaves the binding protein and results in the release of cortisol at sites of inflammation, enhancing its tissue-specific anti-inflammatory effects. Further tissue-specific modulation of cortisol availability is conferred by corticosteroid 11β-dehydrogenase. Direct assessment of tissue levels of bioavailable cortisol is not clinically practicable and measurement of total serum cortisol levels is of limited value in clinical conditions that alter prereceptor glucocorticoid bioavailability. Bioavailable cortisol can, however, be measured indirectly at systemic, extracellular tissue and cell levels, using novel techniques that have provided new insight into the transport, metabolism and biological action of glucocorticoids. A more physiologically informative approach is, therefore, now possible in the assessment of the hypothalamic-pituitary-adrenal axis, which could prove useful in clinical practice.
The European Registry on Cushing's syndrome (ERCUSYN) is designed to collect prospective and follow-up data at EU level on Cushing's syndrome (CS).
Baseline data on 481 CS patients (390 females, 91 ...males; mean age (±s.d.): 44±14 years) collected from 36 centres in 23 countries, including new patients from 2008 and retrospective cases since 2000. Patients were divided into four major aetiologic groups: pituitary-dependent CS (PIT-CS) (66%), adrenal-dependent CS (ADR-CS) (27%), CS from an ectopic source (ECT-CS) (5%) and CS from other aetiologies (2%).
Proportion of men in the ECT-CS group was higher than in the other groups (P<0.05). The ADR-CS group was older than the PIT-CS (P<0.05). Prevalence of hirsutism (92%) and diabetes (74%) in ECT-CS was higher than in the other groups (P<0.05 and P<0.01 respectively). PIT-CS had more skin alterations, menstrual irregularities and hirsutism than ADR-CS (P<0.01). Reduced libido was more prevalent in men than women (P<0.01). Prevalence of spine osteoporosis was higher in men than women (P<0.05), and males had more vertebral and rib fractures than females (52 vs 18% for vertebrae; P<0.001 and 34 vs 23% for ribs; P<0.05). ECT-CS consulted a diabetologist more frequently than ADR-CS (P<0.05), while a gynaecologist was consulted more often by women with PIT-CS or ADR-CS than with ECT-CS (P<0.05). Overall, weight gain was more common in women than men (P<0.01). CushingQoL and EuroQoL visual analogue scale scores did not differ between the groups.
The ERCUSYN project demonstrates a heterogeneous clinical presentation of CS at a European level, depending on gender and aetiology.
Immunoassays used for the measurement of salivary cortisol are limited by variable interference from cortisone. Salivary cortisone is a consequence of the salivary glands expressing ...11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) which converts cortisol to cortisone. We report a combined salivary cortisol and cortisone (SalF and SalE respectively) liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay to address the cortisone cross-reactivity in cortisol immunoassays and as a tool to study 11β-HSD2 activity. The method was linear up to 400
nmol/L for SalF and 200
nmol/L for SalE and the lower limits of quantitation were 0.39
nmol/L (SalF) and 0.78
nmol/L (SalE). No evidence of ion suppression was found and precision, accuracy and recovery were within internationally accepted limits. No interference was identified from 13 structurally related steroids. SalF, SalE and SalF/SalE were significantly greater in the morning than at bed-time and following stimulation of the adrenal glands. As serum cortisol increased, an exponential rise was observed in SalF and a linear increase in SalE which reached a plateau at higher SalF concentrations. We have developed a novel, robust LC–MS/MS assay for the combined measurement of SalF and SalE. Our results confirm the 11β-HSD2 activity of the salivary glands resulting in high SalE concentrations and the enzyme saturation at high substrate concentrations. This method can be used as a simple, non-invasive and highly specific tool to assess the value of salivary cortisol as a surrogate for free serum cortisol and as a potential novel way to assess 11β-HSD2 activity.
Abstract
Purpose
The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical ...control while receiving injectable somatostatin receptor ligands (SRLs).
Methods
In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 IGF-1 ≤ 1.0 × upper limit of normal ULN; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures.
Results
Mean IGF-1 measurements were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (≤ 1.0 × ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained (< 2.5 ng/mL) in 77.7% for OOC vs 30.4% for placebo (P = .0007). Median time to loss of response (IGF-1 > 1.0 or ≥ 1.3 × ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P < .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience.
Conclusions
OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs.
Neuroendocrine tumours are slow growing tumours known to secrete a variety of vasoactive peptides which give rise to symptoms of the carcinoid syndrome. The diagnosis and monitoring of patients with ...neuroendocrine tumours is undertaken in many centres using 24 h urinary measurement of 5-hydroxyindoleacetic acid. However, 5-hydroxyindoleacetic acid can also be quantified in plasma and serum.
We measured 5-hydroxyindoleacetic acid concentration in 134 paired EDTA plasma and urine samples from 108 patients with known neuroendocrine tumours and 26 healthy volunteers. We also compared 5-hydroxyindoleacetic acid concentrations in paired serum and plasma samples (n = 63), then analysed paired urine and serum samples (n = 97). Furthermore, we examined the impact of renal impairment on serum 5-hydroxyindoleacetic acid by analysing 5-hydroxyindoleacetic acid in patients without neuroendocrine tumours in different stages of chronic kidney disease, as indicated by the estimated glomerular filtration rate.
Plasma and urine 5-hydroxyindoleacetic acid had very similar diagnostic sensitivities and specificities, with areas under the curve on ROC analysis of 0.917 and 0.920, respectively. Serum and plasma 5-hydroxyindoleacetic acid values showed good correlation but serum results demonstrated a positive bias, indicating the necessity for different serum and plasma reference intervals. There was an inverse correlation between estimated glomerular filtration rate and serum 5-hydroxyindoleacetic acid concentration, with 5-hydroxyindoleacetic acid increasing once the estimated glomerular filtration rate falls below 60 mL/min/1.73 m(2).
The measurement of both serum and plasma 5-hydroxyindoleacetic acid can be used for the diagnosis and monitoring of patients with neuroendocrine tumours. Provided renal function is taken into consideration, either of these tests should be incorporated into standard practice as an alternative assay to urinary 5-hydroxyindoleacetic acid.
New causes of hypophysitis Yuen, Kevin C.J.; Popovic, Vera; Trainer, Peter J.
Best Practice & Research Clinical Endocrinology & Metabolism,
April 2019, 2019-04-00, Volume:
33, Issue:
2
Journal Article
Peer reviewed
Hypophysitis is a rare entity characterized by inflammation of the pituitary gland and its stalk that can cause hypopituitarism and/or mass effect. Etiology can be categorized as primary or secondary ...to systemic disease, but may also be classified according to anatomical and hispathological criteria. Newly recognized causes of hypophysits have been described, mainly secondary to immunomodulatory medications and IgG4-related disease. Diagnosis is based on clinical, laboratory and imaging data, whereas pituitary biopsy, though rarely indicated, may provide a definitive histological diagnosis. For the clinician, obtaining a broad clinical and drug history, and performing a thorough physical examination is essential. Management of hypophysitis includes hormone replacement therapy if hypopituitarism is present and control of the consequences of the inflammatory pituitary mass (e.g. compression of the optic chiasm) using high-dose glucocorticoids, whereas pituitary surgery is reserved for those unresponsive to medical therapy and/or have progressive disease. However, there remains an unmet need for controlled studies to inform clinical practice.
In patients with cancer, hyponatraemia is associated with increased morbidity and mortality and can delay systemic therapy.
The safety and efficacy of low-dose tolvaptan (7.5 mg) for hospitalized, ...adult patients with hyponatraemia due to Syndrome of Inappropriate Antidiuresis (SIAD), and co-existing malignancy were retrospectively evaluated in a tertiary cancer centre.
Fifty-five patients with mean baseline serum sodium (sNa) 117.9±4.6 mmol/L were included. 90.9% had severe hyponatraemia (sNa<125 mmol/L). Mean age was 65.1±9.3 years. Following an initial dose of tolvaptan 7.5 mg, median (range) increase in sNa observed at 24 hours was 9(1-19) mmol/L. Within one week, 39 patients (70.9%) reached sNa≥130 mmol/L and 48 (87.3%) had sNa rise of ≥5 mmol/L within 48 hours. No severe adverse events were reported. Thirty-three (60%) and seventeen (30.9%) patients experienced sNa rise of ≥8 and ≥12 mmol/L/24hrs, respectively. The rate of sNa correction in the first 24 hours was significantly higher among participants that continued fluid restriction after tolvaptan administration (medianquantiles: 149-16 versus 85-11 mmol/L, p=0.036). Moreover, in the over-rapid correction cohort (≥12 mmol/L/24hrs) demeclocycline was appropriately discontinued only in 60% compared to 91.7% of the remaining participants (P=0.047). Lower creatinine was predictive of higher sNa correction rate within 24 hours (p=0.01).
In the largest series to date, although low-dose tolvaptan was demonstrated to be effective in correcting hyponatraemia due to SIAD in cancer patients, a significant proportion experienced over-rapid correction. Concurrent administration of demeclocycline and/or fluid restriction must be avoided due to the increased risk of over-rapid correction.
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