Context:
Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release ...tablet with a more physiological exposure-time cortisol profile.
Objective:
The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets.
Design and Setting:
We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers.
Patients:
The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM).
Intervention:
The same daily dose of hydrocortisone was administered as OD dual-release or TID.
Main Outcome Measure:
We evaluated cortisol pharmacokinetics.
Results:
Compared with conventional TID, OD provided a sustained serum cortisol profile 0–4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = −0.7 kg, P = 0.005), systolic blood pressure (difference = −5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: −2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = −0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004).
Conclusion:
The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.
Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result ...from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.
Current management of Cushing's disease Tritos, N. A.; Biller, B. M. K.
Journal of internal medicine,
November 2019, Letnik:
286, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Cushing's disease (CD) is caused by a pituitary tumour that secretes adrenocorticotropin (ACTH) autonomously, leading to excess cortisol secretion from the adrenal glands. The condition is associated ...with increased morbidity and mortality that can be mitigated by treatments that result in sustained endocrine remission. Transsphenoidal pituitary surgery (TSS) remains the mainstay of treatment for CD but requires considerable neurosurgical expertise and experience in order to optimize patient outcomes. Up to 90% of patients with microadenomas (tumour below 1 cm in largest diameter) and 65% of patients with macroadenomas (tumour at or above 1 cm in greatest diameter) achieve endocrine remission after TSS by an experienced surgeon. Patients who are not in remission postoperatively or those who relapse may benefit from undergoing a second pituitary operation. Alternatively, radiation therapy to the sella with interim medical therapy, or bilateral adrenalectomy, can be effective as definitive treatments of CD. Medical therapy is currently adjunctive in most patients with CD and is generally prescribed to patients who are about to receive radiation therapy and will be awaiting its salutary effects to occur. Available treatment options include steroidogenesis inhibitors, centrally acting agents and glucocorticoid receptor antagonists. Several novel agents are in clinical trials and may eventually constitute additional treatment options for this serious condition.
Objective: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing’s syndrome, because there is no recent consensus on ...the management of this rare disorder.
Participants: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing’s syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing’s disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing’s disease, and 5) management of ectopic ACTH syndrome, Nelson’s syndrome, and special patient populations.
Evidence: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking.
Consensus Process: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority.
Conclusions: ACTH-dependent Cushing’s syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing’s syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing’s disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing’s syndrome, early diagnosis and prompt therapy are warranted.
ABSTRACT
Stellar multiplicity is believed to influence planetary formation and evolution, although the precise nature and extent of this role remain ambiguous. We present a study aimed at testing the ...role of stellar multiplicity in the formation and/or evolution of the most massive, close-in planetary and substellar companions. Using past and new direct imaging observations, as well as the Gaia DR2 catalogue, we searched for wide binary companions to 38 stars hosting massive giant planets or brown dwarfs (M > 7 MJup) on orbits shorter than ∼1 au. We report the discovery of a new component in the WASP-14 system, and present an independent confirmation of a comoving companion to WASP-18. From a robust Bayesian statistical analysis, we derived a binary fraction of $79.0^{+13.2}_{-14.7}$ per cent between 20 and 10 000 au for our sample, twice as high as for field stars with a 3σ significance. This binary frequency was found to be larger than for lower-mass planets on similar orbits, and we observed a marginally higher binary rate for inner companions with periods shorter than 10 d. These results demonstrate that stellar companions greatly influence the formation and/or evolution of these systems, suggesting that the role played by binary companions becomes more important for higher-mass planets, and that this trend may be enhanced for systems with tighter orbits. Our analysis also revealed a peak in binary separation at 250 au, highlighting a shortfall of close binaries among our sample. This indicates that the mechanisms affecting planet and brown dwarf formation or evolution in binaries must operate from wide separations, although we found that the Kozai–Lidov mechanism is unlikely to be the dominant underlying process. We conclude that binarity plays a crucial role in the existence of very massive short-period giant planets and brown dwarf desert inhabitants, which are almost exclusively observed in multiple systems.
Context: Pasireotide (SOM230) is a novel multireceptor ligand somatostatin analog with affinity for somatostatin receptor subtypes sst1–3 and sst5. Because most GH-secreting pituitary adenomas ...express sst2 and sst5, pasireotide has the potential to be more effective than the sst2-preferential somatostatin analogs octreotide and lanreotide.
Objective: Our objective was to evaluate the efficacy and safety of three different doses of pasireotide in patients with acromegaly.
Design: We conducted a phase II, randomized, multicenter, open-label, three-way, crossover study.
Patients: Sixty patients with acromegaly, defined by a 2-h five-point mean GH level higher than 5 μg/liter, lack of suppression of GH to less than 1 μg/liter after oral glucose tolerance test, and elevated IGF-I for age- and sex-matched controls. Patients could have had previous surgery, radiotherapy, and/or medical therapy or no previous treatment.
Intervention: After treatment with octreotide 100 μg sc three times daily for 28 d, each patient received pasireotide 200, 400, and 600 μg sc twice daily in random order for 28 d.
Main Outcome Measure: A biochemical response was defined as a reduction in GH to no more than 2.5 μg/liter and normalization of IGF-I to age- and sex-matched controls.
Results: After 4 wk of octreotide, 9% of patients achieved a biochemical response. After 4 wk of pasireotide 200–600 μg sc bid, 19% of patients achieved a biochemical response, which increased to 27% after 3 months of pasireotide; 39% of patients had a more than 20% reduction in pituitary tumor volume. Pasireotide was generally well tolerated.
Conclusions: Pasireotide is a promising treatment for acromegaly. Larger studies of longer duration evaluating the efficacy and safety of pasireotide in patients with acromegaly are ongoing.
Results from this phase II study demonstrate that pasireotide is a promising novel treatment for patients with acromegaly.
Summary
Objective
Twenty‐four‐hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushing's syndrome. Because there are few data on UFC variability in patients with active ...Cushing's disease, we analysed baseline UFC in a large patient cohort with moderate‐to‐severe Cushing's disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data.
Design
Observational study (enrolment phase of Phase III study).
Methods
Patients (n = 152) with persistent/recurrent or de novo Cushing's disease and mean UFC (mUFC) ≥1·5×ULN (normal: 30–145 nmol/24 h) were included. Mean UFC level was calculated from four 24‐h urine samples collected over 2 weeks.
Results
Over 600 24‐h UFC samples were analysed. The mUFC levels of samples 1 and 2 and samples 3 and 4 were 1000 nmol/24 h (SD 1872) and 940 nmol/24 h (SD 2148), respectively; intrapatient coefficient of variation (CV) was 38% for mUFC. The intrapatient CV using all four samples was 52% (95% CI: 48–56). The intrapatient CV was 51% (95% CI: 44–58) for samples 1 and 2, 49% (95% CI: 43–56) for samples 3 and 4 and 54% (95% CI: 49–59) for samples 1, 2 and 3. Variability in mUFC increased as UFC levels increased. There were no correlations between UFC and clinical features of hypercortisolism.
Conclusions
There is intrapatient variability of approximately 50% in 24‐h UFC measurements, which is relevant to targets set to estimate any treatment effect. Analysing more than two 24‐h collection periods in individual patients does not result in a relevant decrease in variability. Interestingly, UFC levels did not correlate with hypercortisolism severity.
Context: There is currently no medical therapy for Cushing’s disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the ...management of this disorder.
Objective: Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushing’s disease.
Design: We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study.
Patients: Thirty-nine patients with either de novo Cushing’s disease who were candidates for pituitary surgery or with persistent or recurrent Cushing’s disease after surgery without having received prior pituitary irradiation.
Intervention: Patients self-administered sc pasireotide 600 μg twice daily for 15 d.
Main Outcome Measure: Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure.
Results: Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders.
Conclusions: Pasireotide produced a decrease in UFC levels in 76% of patients with Cushing’s disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.
Results from this phase II study show pasireotide to be a promising pituitary-directed medical therapy for patients with Cushing’s disease.
Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH ...Research Society (GRS) concluded that ‘for approved indications, GH is safe’; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.
Context. The consortium of the Spectro-Polarimetric High-contrast Exoplanet REsearch installed at the Very Large Telescope (SPHERE/VLT) has been operating its guaranteed observation time (260 nights ...over five years) since February 2015. The main part of this time (200 nights) is dedicated to the detection and characterization of young and giant exoplanets on wide orbits. Aims. The large amount of data must be uniformly processed so that accurate and homogeneous measurements of photometry and astrometry can be obtained for any source in the field. Methods. To complement the European Southern Observatory pipeline, the SPHERE consortium developed a dedicated piece of software to process the data. First, the software corrects for instrumental artifacts. Then, it uses the speckle calibration tool (SpeCal) to minimize the stellar light halo that prevents us from detecting faint sources like exoplanets or circumstellar disks. SpeCal is meant to extract the astrometry and photometry of detected point-like sources (exoplanets, brown dwarfs, or background sources). SpeCal was intensively tested to ensure the consistency of all reduced images (cADI, Loci, TLoci, PCA, and others) for any SPHERE observing strategy (ADI, SDI, ASDI as well as the accuracy of the astrometry and photometry of detected point-like sources. Results. SpeCal is robust, user friendly, and efficient at detecting and characterizing point-like sources in high contrast images. It is used to process all SPHERE data systematically, and its outputs have been used for most of the SPHERE consortium papers to date. SpeCal is also a useful framework to compare different algorithms using various sets of data (different observing modes and conditions). Finally, our tests show that the extracted astrometry and photometry are accurate and not biased.
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