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Frontiers in Endocrinology 2024Paediatric Cushing's disease (CD) is characterized by excess ACTH secretion from a pituitary adenoma, leading to hypercortisolism. It has approximately 5% of the... (Review)
Review
Paediatric Cushing's disease (CD) is characterized by excess ACTH secretion from a pituitary adenoma, leading to hypercortisolism. It has approximately 5% of the incidence of adult CD and is a rare disorder in the paediatric age range. The four most specific presenting features of hypercortisolism are: change in facial appearance, weight gain, decreased linear growth and virilisation shown by advanced pubic hair for the stage of breast development or testicular volume. The main diagnostic priority is the demonstration of hypercortisolism followed by distinction between its ACTH-dependent and ACTH-independent origin, thus leading to identification of aetiology. All treatment options aim to resolve or control hypercortisolism. Consensus favours transsphenoidal (TSS) pituitary surgery with selective removal of the corticotroph adenoma. TSS in children with CD is now well established and induces remission in 70-100% of cases. External pituitary radiotherapy and bilateral adrenalectomy are second-line therapeutic approaches in subjects not responding to TSS. Long-term medical treatment is less frequently adopted. Recurrence in paediatric CD cases is low with factors predicting relapse being higher post-TSS cortisol and ACTH levels and rapid recovery of the hypothalamic-pituitary-adrenal axis after TSS. In summary, complete excision of the microadenoma with histological and biochemical evidence for this, predicts a low rate of recurrence of CD. Due to the need for rapid diagnosis and management to avoid the burden of prolonged exposure to hypercortisolism, tertiary university centres comprising both paediatric and adult endocrinology specialists together with experienced pituitary surgery and, eventually, radiotherapy units are recommended for referral of these patients.
Topics: Adult; Humans; Child; Pituitary ACTH Hypersecretion; Hypothalamo-Hypophyseal System; Cushing Syndrome; Neoplasm Recurrence, Local; Pituitary-Adrenal System; Adenoma; Adrenocorticotropic Hormone
PubMed: 38318299
DOI: 10.3389/fendo.2024.1345174 -
Frontiers in Endocrinology 2023To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease.
OBJECTIVE
To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease.
METHODS
The multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first. Study outcomes assessed in the extension included: mean urinary free cortisol (mUFC) response rates; changes in mUFC, serum cortisol and late-night salivary cortisol (LNSC); changes in cardiovascular and metabolic-related parameters; blood pressure, waist circumference and weight; changes in physical manifestations of Cushing's disease; changes in patient-reported outcomes for health-related quality of life; changes in tumor volume; and adverse events. Results were analyzed descriptively; no formal statistical testing was performed.
RESULTS
Of 60 patients who entered, 53 completed the extension, with 29 patients receiving osilodrostat for more than 96 weeks (median osilodrostat duration: 87.1 weeks). The proportion of patients with normalized mUFC observed in the core period was maintained throughout the extension. At their end-of-trial visit, 72.4% of patients had achieved normal mUFC. Substantial reductions in serum cortisol and LNSC were also observed. Improvements in most cardiovascular and metabolic-related parameters, as well as physical manifestations of Cushing's disease, observed in the core period were maintained or continued to improve in the extension. Osilodrostat was generally well tolerated; the safety profile was consistent with previous reports.
CONCLUSION
Osilodrostat provided long-term control of cortisol secretion that was associated with sustained improvements in clinical signs and physical manifestations of hypercortisolism. Osilodrostat is an effective long-term treatment for patients with Cushing's disease.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT02180217.
Topics: Humans; Pituitary ACTH Hypersecretion; Hydrocortisone; Quality of Life; Adrenocortical Hyperfunction
PubMed: 37680892
DOI: 10.3389/fendo.2023.1236465 -
Frontiers in Endocrinology 2023This study evaluated short- and long-term efficacy and safety of the second-generation somatostatin receptor ligand pasireotide alone or in combination with dopamine...
OBJECTIVE
This study evaluated short- and long-term efficacy and safety of the second-generation somatostatin receptor ligand pasireotide alone or in combination with dopamine agonist cabergoline in patients with Cushing's disease (CD).
STUDY DESIGN
This is an open-label, multicenter, non-comparative, Phase II study comprising 35-week core phase and an optional extension phase. All patients started with pasireotide, and cabergoline was added if cortisol remained elevated. Eligible patients had active CD, with or without prior surgery, were pasireotide naïve at screening or had discontinued pasireotide for reasons other than safety. Primary endpoint was proportion of patients with a mean urinary free cortisol (mUFC) level not exceeding the upper limit of normal (ULN) at week 35 with missing data imputed using last available post-baseline assessments.
RESULTS
Of 68 patients enrolled, 26 (38.2%) received pasireotide monotherapy and 42 (61.8%) received pasireotide plus cabergoline during the core phase. Thirty-four patients (50.0%; 95% CI 37.6-62.4) achieved the primary endpoint, of whom 17 (50.0%) received pasireotide monotherapy and 17 (50.0%) received combination therapy. Proportion of patients with mUFC control remained stable during the extension phase up to week 99. Treatment with either mono or combination therapy provided sustained improvements in clinical symptoms of hypercortisolism up to week 99. Hyperglycemia and nausea (51.5% each), diarrhea (44.1%) and cholelithiasis (33.8%) were the most frequent adverse events.
CONCLUSION
Addition of cabergoline in patients with persistently elevated mUFC on maximum tolerated doses of pasireotide is an effective and well-tolerated long-term strategy for enhancing control of hypercortisolism in some CD patients.
CLINICAL TRIAL REGISTRATION
https://clinicaltrials.gov/ct2/show/NCT01915303, identifier NCT01915303.
Topics: Humans; Cabergoline; Cushing Syndrome; Hydrocortisone; Pituitary ACTH Hypersecretion; Treatment Outcome
PubMed: 37876540
DOI: 10.3389/fendo.2023.1165681 -
Reviews in Endocrine & Metabolic... Jun 2024The diagnostic approach to hypopituitarism involves many disciplines. Clinical symptoms rarely are specific. Imaging techniques are helpful but cannot prove the specific... (Review)
Review
The diagnostic approach to hypopituitarism involves many disciplines. Clinical symptoms rarely are specific. Imaging techniques are helpful but cannot prove the specific functional defects. Therefore, the definitive diagnosis of pituitary insufficiency is largely based on laboratory tests. However, also laboratory methods come with inherent limitations, and it is essential for the clinician to know and recognize typical pitfalls. Most factors potentially impairing the quality of hormone measurements are introduced in the preanalytical phase, i.e. before the hormones are measured by the laboratory. For example, the timing of blood drawing with respect to circadian rhythm, stress, and medication can have an influence on hormone concentrations. During the actual analysis of the hormones, cross-reactions with molecules present in the sample presenting the same or similar epitopes than the intended analyte may affect immunoassays. Interference can also come from heterophilic or human anti-animal antibodies. Unexpected problems can also be due to popular nutritional supplements which interfere with the measurement procedures. An important example in this respect is the interference from biotin. It became only clinically visible when the use of this vitamin became popular among patients. The extreme serum concentrations reached when patients take it as a supplement can lead to incorrect measurements in immunoassays employing the biotin-streptavidin system. To some extent, hormone analyses using liquid chromatography mass spectrometry (LCMS) can overcome problems, although availability and cost-effectiveness of this method still imposes restrictions. In the post-analytical phase, appropriateness of reference intervals and cut-offs with respect to the specific analytical method used is of outmost importance. Furthermore, for interpretation, additional biological and pharmacological factors like BMI, age and concomitant diseases must be considered to avoid misinterpretation of the measured concentrations. It is important for the clinician and the laboratory to recognize when one or more laboratory values do not match the clinical picture. In an interdisciplinary approach, the search for the underlying cause should be initiated.
Topics: Humans; Hypopituitarism; Immunoassay
PubMed: 38609701
DOI: 10.1007/s11154-024-09881-1 -
Deutsches Arzteblatt International Feb 20243% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders. (Review)
Review
BACKGROUND
3% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders.
METHODS
This review is based on publications retrieved by a selective review of the literature and on the authors' clinical experience.
RESULTS
Pituitary growth hormone deficiency is treated with recombinant growth hormone. Long-acting preparations of this type became available recently, but their long-term safety and efficacy are still unknown. Vosoritide, a CNP analogue, has also been approved for the treatment of achondroplasia, and severe primary deficiency of insulin-like growth factor 1 (IGF-1) can be treated with recombinant IGF-1. In the treatment of excessively tall stature, new information on the safety of growth-attenuating treatment and an altered perception of above-average height in society have led to a change in management.
CONCLUSION
There are new options for the treatment of rare causes of short stature, while new information on the safety of treatment strategies for excessive tallness have led to a reconsideration of surgical intervention. There is insufficient evidence on the benefits and risks of supraphysiological GH therapy and of newer treatment options for which there are as yet no robust data on adult height. Therefore, before any treatment is provided, physicians should give patients and their families detailed information and discuss their expectations from treatment and the goals that treatment can be expected to achieve.
Topics: Child; Adult; Humans; Adolescent; Insulin-Like Growth Factor I; Human Growth Hormone; Growth Disorders; Dwarfism, Pituitary; Physicians
PubMed: 38051162
DOI: 10.3238/arztebl.m2023.0247 -
CNS Neuroscience & Therapeutics May 2024Pituitary adenoma is one of the most common brain tumors. Most pituitary adenomas are benign and can be cured by surgery and/or medication. However, some pituitary... (Review)
Review
BACKGROUND
Pituitary adenoma is one of the most common brain tumors. Most pituitary adenomas are benign and can be cured by surgery and/or medication. However, some pituitary adenomas show aggressive growth with a fast growth rate and are resistant to conventional treatments such as surgery, drug therapy, and radiation therapy. These tumors, referred to as refractory pituitary adenomas, often relapse or regrow in the early postoperative period. The tumor microenvironment (TME) has recently been identified as an important factor affecting the biological manifestations of tumors and acts as the main battlefield between the tumor and the host immune system.
MAIN BODY
In this review, we focus on describing TME in pituitary adenomas and refractory pituitary adenomas. Research on the immune microenvironment of pituitary adenomas is currently focused on immune cells such as macrophages and lymphocytes, and extensive research and experimental verifications are still required regarding other components of the TME. In particular, studies are needed to determine the role of the TME in the specific biological behaviors of refractory pituitary adenomas, such as high invasion, fast recurrence rate, and high tolerance to traditional treatments and to identify the mechanisms involved.
CONCLUSION
Overall, we summarize the similarities and differences between the TME of pituitary adenomas and refractory pituitary adenomas as well as the changes in the biological behavior of pituitary adenomas that may be caused by the microenvironment. These changes greatly affect the outcome of patients.
Topics: Pituitary Neoplasms; Humans; Tumor Microenvironment; Adenoma; Animals; Treatment Outcome
PubMed: 38738958
DOI: 10.1111/cns.14729 -
Neurosurgical Review Sep 2023Recent literature demonstrates that a learning curve exists for endoscopic pituitary surgery. However, there is significant variability in the way these studies report... (Review)
Review
Recent literature demonstrates that a learning curve exists for endoscopic pituitary surgery. However, there is significant variability in the way these studies report their outcomes. This study aims to systematically review the literature regarding outcomes for endoscopic pituitary surgery and how this may be related to a surgical learning curve. An electronic search of the databases Medline, Scopus, Embase, Web of Science and Cochrane Library databases was performed and data extracted according 2020 Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) statement. Ten articles were included in the review as they examined the following: rates of gross total resection, average operative time, CSF leak rate, visual outcomes, endocrine outcomes and how these results were influenced by surgical experience. We have demonstrated that a learning curve exists for some outcome variables for endoscopic pituitary surgery. However, there is significant heterogeneity in the current body of literature which makes clear comparisons difficult.
Topics: Humans; Learning Curve; Pituitary Gland; Pituitary Diseases; Endoscopy; Databases, Factual
PubMed: 37698777
DOI: 10.1007/s10143-023-02136-8 -
Endocrine Oct 2023Non-functioning pituitary macroadenomas (NFPMs) may present with hypopituitarism. Pituitary surgery and radiotherapy pose an additional risk to pituitary function.
BACKGROUND
Non-functioning pituitary macroadenomas (NFPMs) may present with hypopituitarism. Pituitary surgery and radiotherapy pose an additional risk to pituitary function.
OBJECTIVES
To assess the incidence of hypopituitarism at presentation, the impact of treatment, and the likelihood of endocrine recovery during follow-up.
METHODS
All patients treated surgically with and without radiotherapy for NFPMs between 1987 and 2018 who had longer than six months follow-up were identified. Demographics, presentation, investigation, treatment, and outcomes were collected.
RESULTS
In total, 383 patients were identified. The median age was 57 years, with a median follow-up of 8 years. Preoperatively, 227 patients (227/375; 61%) had evidence of at least one pituitary deficiency. Anterior panhypopituitarism was more common in men (p = 0.001) and older patients (p = 0.005). Multiple hormone deficiencies were associated with large tumours (p = 0.03). Patients treated with surgery and radiotherapy had a higher incidence of all individual pituitary hormone deficiency, anterior panhypopituitarism, and significantly lower GH, ACTH, and TSH deficiencies free survival probability than those treated with surgery alone. Recovery of central hypogonadism, hypothyroidism, and anterior panhypopituitarism was also less likely to be reported in those treated with surgery and radiotherapy. Those with preoperative hypopituitarism had a higher risk of pituitary impairment at latest review than those presented with normal pituitary function (p = 0.001).
CONCLUSION
NFPMs are associated with a significant degree of hypopituitarism at time of diagnosis and post-therapy. The combination of surgery and radiotherapy is associated with a higher risk of pituitary dysfunction. Recovery of pituitary hormone deficit may occur after treatment. Patients should have regular ongoing endocrine evaluation post-treatment to assess changes in pituitary function and the need for long-term replacement therapy.
Topics: Male; Humans; Middle Aged; Retrospective Studies; Hypopituitarism; Pituitary Gland; Pituitary Neoplasms; Pituitary Hormones; Hypothyroidism
PubMed: 37389717
DOI: 10.1007/s12020-023-03434-3 -
The Pan African Medical Journal 2023Acromegaly is defined as an acquired dysmorphytic syndrome due to excessive secretion of growth hormone (GH) and consequently of insulin-like growth factor-1 (IGF-1)....
Acromegaly is defined as an acquired dysmorphytic syndrome due to excessive secretion of growth hormone (GH) and consequently of insulin-like growth factor-1 (IGF-1). This is a retrospective study of patients who were hospitalized in the Endocrinology Department of the Mohammed V Military Academic Hospital in Rabat over a period of 14 years (2008 to 2022), reporting on their clinical, paraclinical and evolutionary profiles and comparing the results with the data in the literature. Nineteen patients were included in our study. The mean age was 42.7 ± 11.6 years, with a male predominance. The clinical manifestations were dominated by a dysmorphic syndrome present in 97.4% of cases, followed by complications related to acromegaly in 88.9% of cases. The diagnosis was made when GH and IGF-1 values were elevated in 88.9% and 93.8% of cases, respectively; with a mean GH value of 25.1 μg/L. Magnetic resonance imaging (MRI) was used to diagnose the location of pituitary adenoma in all cases, 78.9% of which were macroadenomas and 21.1% microadenomas. The majority of patients (78.9%) had recourse to transsphenoidal surgery. Medical treatment was carried out in 89.5% of cases. Postoperative radiotherapy was performed in 33% of cases. Disease control was achieved in 30.1% of cases. This study shows the complex management of acromegaly. Disease control is a necessary condition in order to avoid complications, but is often difficult to obtain.
Topics: Humans; Male; Adult; Middle Aged; Female; Acromegaly; Insulin-Like Growth Factor I; Retrospective Studies; Treatment Outcome; Human Growth Hormone; Pituitary Neoplasms
PubMed: 38465009
DOI: 10.11604/pamj.2023.46.116.41952 -
European Thyroid Journal Jul 2023Central hyperthyroidism is characterized by elevated free thyroid hormone and unsuppressed thyroid-stimulating hormone (TSH), and this laboratory feature includes... (Review)
Review
BACKGROUND
Central hyperthyroidism is characterized by elevated free thyroid hormone and unsuppressed thyroid-stimulating hormone (TSH), and this laboratory feature includes TSH-secreting pituitary adenoma (TSHoma) and resistance to thyroid hormone β (RTHβ). Central hyperthyroidism combined with Graves' disease (GD) has been rarely reported.
CASE REPORT
We describe three patients with TSHoma combined with GD and one patient with GD combined with RTHβ and pituitary adenoma. These three patients with TSHoma combined with GD showed elevated thyroid hormone, while TSH level was normal or elevated, and TSH receptor antibodies were positive. After thyrotoxicosis was controlled, they all underwent transsphenoidal surgery. We also describe a patient with an initial presentation of GD who developed hypothyroidism after anti-hyperthyroidism treatment and TSH was inappropriately significantly increased. His head magnetic resonance imaging revealed a pituitary adenoma. Genetic testing confirmed a heterozygous mutation in the thyroid hormone receptor β gene c.1148G>A (p.R383H). After levothyroxine and desiccated thyroid tablet treatment, the TSH level decreased to normal.
CONCLUSION
These four cases highlight the need to consider the diagnosis of GD combined with central hyperthyroidism when faced with inconsistent thyroid function test results, illuminating the specific diagnostic and therapeutic challenges of coexisting primary and central hyperthyroidism. Finally, we propose clinical management for central hyperthyroidism combined with GD.
Topics: Humans; Pituitary Neoplasms; Hyperthyroidism; Graves Disease; Thyrotoxicosis; Research
PubMed: 37602950
DOI: 10.1530/ETJ-22-0223