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Pituitary Oct 2022Cushing's disease (CD), caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, is the most common form of Cushing's syndrome (CS), accounting for... (Review)
Review
Cushing's disease (CD), caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, is the most common form of Cushing's syndrome (CS), accounting for approximately 70% of cases. CD requires a prompt diagnosis, an adequate treatment selection, and long-term management to limit hypercortisolism duration and long-term complications and improve patient outcomes. Pituitary surgery is the first-line option, which is non-curative in one third of patients, therefore requiring additional treatments. Medical therapy has recently acquired an emerging role, with the availability of several drugs with different therapeutic targets, efficacy and safety profiles. The current review focuses on efficacy and safety of steroidogenesis inhibitors, and particularly the historical drugs, ketoconazole and metyrapone, and the novel drugs levoketoconazole and osilodrostat, which seem to offer a rapid, sustained, and effective disease control. Ketoconazole should be preferred in females and in patients without severe liver disease; levoketoconazole may offer an alternative to classical ketoconazole, appearing characterized by a higher potency and potential lower hepatotoxicity compared to ketoconazole. Metyrapone should be preferred in males and in patients without severe or uncontrolled hypokalemia. Both ketoconazole and metyrapone may be preferred for short-term more than for long-term treatment. Osilodrostat may represent the best choice for long-term treatment, in patients with poor compliance to the multiple daily administration schedule, and in patients without severe or uncontrolled hypokalemia. Steroidogenesis inhibitors may be used alone or in combination, and associated with pituitary directed drugs, to improve the efficacy of the single drugs, allowing a potential use of lower doses for each drug, and hypothetically reducing the rate of adverse events associated with the single drugs. Clinicians may tailor medical therapy on the specific clinical scenario, considering disease history together with patients' characteristics and hypercortisolism's degree, addressing the needs of each patient in order to improve the therapeutic outcome and to reduce the burden of illness, particularly in patients with persistent or recurrent CD.
Topics: Male; Female; Humans; Pituitary ACTH Hypersecretion; Cushing Syndrome; Metyrapone; Ketoconazole; Hypokalemia; Steroid Synthesis Inhibitors; Pituitary Neoplasms; Adrenocorticotropic Hormone
PubMed: 36036308
DOI: 10.1007/s11102-022-01262-8 -
Frontiers in Endocrinology 2022Twenty-four-hour urinary free cortisol (24h-UFC) is the most used test for follow-up decision-making in patients with Cushing syndrome (CS) under medical treatment....
INTRODUCTION
Twenty-four-hour urinary free cortisol (24h-UFC) is the most used test for follow-up decision-making in patients with Cushing syndrome (CS) under medical treatment. However, 24h-UFC determinations by immunoassays (IA) are commonly overestimated because of steroid metabolites' cross-reaction. It is still uncertain how ketoconazole (KTZ)- and metyrapone (MTP)-induced changes on the urinary steroid metabolites can alter the 24h-UFC*IA determinations' reliability.
METHODS
24h-UFC was analyzed by IA and gas chromatography-mass spectrometry (GC-MS) in 193 samples (81 before treatment, 73 during KTZ, and 39 during MTP) from 34 CS patients. In addition, urinary steroidome was analyzed by GC-MS on each patient before and during treatment.
RESULTS
Before treatment, 24h-UFC*IA determinations were overestimated by a factor of 1.75 (95% CI 1.60-1.94) compared to those by GC-MS. However, during KTZ treatment, 24h-UFC*IA results were similar (0.98:1) to those by GC-MS (95% CI, 0.83-1.20). In patients taking MTP, IA bias only decreased 0.55, resulting in persistence of an overestimation factor of 1.33:1 (95% CI, 1.09-1.76). High method agreement between GC-MS and IA before treatment ( = 0.954) declined in patients under KTZ ( = 0.632) but not in MTP ( = 0.917). Upper limit normal (ULN) reductions in patients taking KTZ were 27% larger when using 24h-UFC*IA compared to 24h-UFC*GC-MS, which resulted in higher false efficacy and misleading biochemical classification of 15% of patients. Urinary excretion changes of 22 urinary steroid metabolites explained 86% of the 24h-UFC*IA interference. Larger urinary excretion reductions of 6β-hydroxy-cortisol, 20α-dihydrocortisol, and 18-hydroxy-cortisol in patients with KTZ elucidated the higher 24h-UFC*IA bias decrement compared to MTP-treated patients.
CONCLUSION
KTZ and MTP alter the urinary excretion of IA cross-reactive steroid metabolites, thus decreasing the cross-reactive interference of 24h-UFC*IA determinations present before treatment. Consequently, this interference reduction in 24h-UFC*IA leads to loss of method agreement with GC-MS and high risk of overestimating the biochemical impact of KTZ and MTP in controlling CS because of poor reliability of reference ranges and ULN.
Topics: Cushing Syndrome; Humans; Hydrocortisone; Immunoassay; Ketoconazole; Metyrapone; Reproducibility of Results; Steroids
PubMed: 35282465
DOI: 10.3389/fendo.2022.833644 -
Journal of Neuroendocrinology Dec 2022The ventromedial prefrontal cortex (vmPFC) regulates fear acquisition, fear extinction, mood, and HPA axis function. Multiple brain regions exhibit time-of-day dependent...
The ventromedial prefrontal cortex (vmPFC) regulates fear acquisition, fear extinction, mood, and HPA axis function. Multiple brain regions exhibit time-of-day dependent variations in learning, long term potentiation (LTP), and dendritic morphology. Glucocorticoids have been implicated in the regulation of dendritic structure in the context of stress. Glucocorticoids are also known to regulate molecular clock entrainment via upregulation of Per1 transcription. In the present study, C57BL/6 N mice were sacrificed at three distinct times of day (ZT3, ZT12, and ZT16, lights off at ZT12) and Per1 mRNA expression was measured in the infralimbic and prelimbic vmPFC subregions using droplet digital (dd) PCR after recovering from adrenalectomy or sham surgery for 10 days. Sham mice showed Per1 rhythmicity in both infralimbic (IL) and prelimbic (PL) cortex, with peak expression occurring at ZT12. Adrenalectomized mice showed reductions in Per1 amplitude at ZT12 in both IL and PL, suggesting that the vmPFC molecular clock is entrained by diurnal glucocorticoid oscillations. Thy1-eGFP mice were used to visualize and quantify dendritic spine density on deep layer pyramidal dendrites at ZT 3, 12, and 16. Spine density in both PL and IL exhibited changes between the light (inactive) and dark (active) phases, with peak spine density observed at ZT16 and trough spine density observed at ZT3. These changes in spine density were restricted to changes in long thin and stubby type spines. To determine if changes in spine density is regulated by glucocorticoid oscillations, the 11β-hydroxylase inhibitor metyrapone was administered 2 h prior to the onset of the active phase (ZT10) daily for 7 days. Metyrapone administration blocked both the diurnal peak of plasma corticosterone and peak spine densities in the IL and PL at ZT16. These results suggest that vmPFC molecular clock gene and dendritic spine diurnal rhythms depend on intact diurnal glucocorticoid oscillations.
Topics: Animals; Mice; Circadian Rhythm; Extinction, Psychological; Fear; Glucocorticoids; Hypothalamo-Hypophyseal System; Metyrapone; Mice, Inbred C57BL; Pituitary-Adrenal System; Prefrontal Cortex
PubMed: 36426781
DOI: 10.1111/jne.13212 -
Molecular and Cellular Endocrinology Mar 2020Adrenal-derived glucocorticoids mediate the physiological response to stress. Chronic disturbances in glucocorticoid homeostasis, i.e. in Addison's and Cushing's disease... (Review)
Review
Adrenal-derived glucocorticoids mediate the physiological response to stress. Chronic disturbances in glucocorticoid homeostasis, i.e. in Addison's and Cushing's disease patients, predispose to the development of atherosclerotic cardiovascular disease. Here we review preclinical and clinical findings regarding the relation between changes in plasma glucocorticoid levels and the atherosclerosis extent. It appears that, although the altered glucocorticoid function can in most cases be restored in the different patient groups, current therapies do not necessarily reverse the associated risk for atherosclerotic cardiovascular disease. In our opinion much attention should therefore be given to the development of a Cushing's disease mouse model that can (1) effectively replicate the effect of hypercortisolemia on atherosclerosis outcome observed in humans and (2) be used to investigate, in a preclinical setting, the relative impact on atherosclerosis susceptibility of already available (e.g. metyrapone) and potentially novel (i.e. SR-BI activity modulators) therapeutic agents that target the adrenal glucocorticoid output.
Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Disease Models, Animal; Glucocorticoids; Humans; Mice; Molecular Targeted Therapy
PubMed: 31968221
DOI: 10.1016/j.mce.2020.110728 -
Neurologia Medico-chirurgica 2014The treatment of functioning pituitary adenoma (FPA) must achieve endocrinological remission as well as tumor size reduction. The first-line treatment of FPA except... (Review)
Review
The treatment of functioning pituitary adenoma (FPA) must achieve endocrinological remission as well as tumor size reduction. The first-line treatment of FPA except prolactinoma is transsphenoidal surgery (TSS). Medical treatments and/or radiation will be applied as adjuvant therapies succeeding to TSS. In patients with prolactinoma, dopamine agonists, especially cabergoline, are quite efficient. Dopamine agonists decrease plasma prolactin levels and induce shrinkage in most patients and can be ceased in some of them. In patients with acromegaly, dopamine agonists, somatostatin analogues, and growth hormone receptor antagonist have been used as a monotherapy or the combination, and the high remission rate can be achieved. Pasireotide having high affinity to type 5 somatostatin receptors will be available for the patients presenting resistance against type 2 receptor agonists, such as octreotide and lanreotide. The preceding treatment with somatostatin analogues is beneficial for improving the success rate of TSS. The chimera compounds of somatostatin analogues and dopamine agonists have been investigated. The medical treatments of Cushing's disease are challenging, if TSS is not successful. To suppress ACTH secretion, dopamine agonists and somatostatin analogues have been examined, but neither came to show a sufficient effect. Pasireotide reduces urinary cortisol excretion with a high remission rate. Adrenal enzyme inhibitors (AEIs), such as metyrapone, can inhibit cortisol synthesis form adrenal glands promptly and sufficiently in most of patients. LCI699, a newly developed AEI, is more potent than metyrapone and will be available. We should use available medical treatments for improving the prognosis and quality of life.
Topics: Adenoma; Combined Modality Therapy; Pituitary Hormones; Pituitary Neoplasms
PubMed: 25446388
DOI: 10.2176/nmc.ra.2014-0239 -
Animals : An Open Access Journal From... Dec 2022Cortisol concentration in fish scales is a novel and reliable indicator of chronic stress. However, until now cortisol in scales has been considered to be accumulated...
Cortisol concentration in fish scales is a novel and reliable indicator of chronic stress. However, until now cortisol in scales has been considered to be accumulated through the circulation and it has not yet been studied whether it can be de novo produced from cells found in the scales. In the current study, scales of European sea bass, , were stimulated in-vitro with a range of concentrations of adrenocorticotropic hormone (ACTH) to investigate if they can produce and release cortisol. Moreover, scales were exposed to a combination of ACTH and metyrapone, an inhibitor of cortisol production, to examine whether cortisol was actually produced in the scales. Results from ACTH administration showed that scales increased their cortisol release in a dose-dependent manner. This effect was reversed when scales were co-incubated with ACTH and metyrapone, indicating that cortisol was produced de novo and not released only upon stimulation with ACTH.
PubMed: 36552430
DOI: 10.3390/ani12243510 -
Pediatric Endocrinology, Diabetes, and... 2022The purpose of this work was to present the current state of knowledge on the effects of frequently used therapeutic forms, selected pharmacotherapy (including... (Review)
Review
The purpose of this work was to present the current state of knowledge on the effects of frequently used therapeutic forms, selected pharmacotherapy (including glucocorticosteroids, immune checkpoint inhibitors, mitotane, metyrapone, aminoglutetimide, etomidate, ketoconazole, fluconazole), but also radiation therapy on the functioning of the hypothalamic-pituitary-adrenal axis in children and adolescent during and after oncological treatment. The most common pediatric cancers, where complications of adrenal insufficiency occur, are presented. Moreover, current recommendations how to diagnose the function of the adrenal axis in oncological pediatric patients, as well during oncological treatment as after it, including patients treated with steroids and also patients in severe stages, are reported. The rules of the treatment of adrenal dysfunction in those patients are presented. This understanding is of key importance for oncologists and endocrinologists in the process of diagnosing, treating and developing patient health care, as well as during therapy as after it, offering safety and improving the quality of life.
Topics: Adolescent; Adrenal Glands; Child; Etomidate; Fluconazole; Humans; Hypothalamo-Hypophyseal System; Immune Checkpoint Inhibitors; Ketoconazole; Metyrapone; Mitotane; Pituitary-Adrenal System; Quality of Life
PubMed: 36134674
DOI: 10.5114/pedm.2022.118319 -
Frontiers in Endocrinology 2023
Topics: Humans; Adrenal Insufficiency; Hydrocortisone
PubMed: 37124742
DOI: 10.3389/fendo.2023.1180264 -
Psychoneuroendocrinology Feb 2018Disturbed sleep is a core feature of posttraumatic stress disorder (PTSD), characterized in part by decreased delta power sleep that may result from stress-related...
Disturbed sleep is a core feature of posttraumatic stress disorder (PTSD), characterized in part by decreased delta power sleep that may result from stress-related alterations in corticotropin releasing factor (CRF), hypothalamic pituitary adrenal axis (HPA) regulation and glucocorticoid signaling. Overnight HPA axis response mediating sleep disturbances in men and women with PTSD was examined using a metyrapone challenge. Metyrapone blocks cortisol synthesis, removing negative feedback, and increases the release of hypothalamic CRF and pituitary adrenocorticotropic hormone (ACTH). Laboratory-based polysomnography was used to monitor the sleep of 66 medically healthy, medication-free men and pre-menopausal follicular phase women including 33 with chronic PTSD (16 women and 17 men) and 33 age- and sex-matched controls (14 women and 19 men) over 3 consecutive nights. Participants completed an overnight metyrapone challenge after an adaptation and baseline night of sleep and ACTH was obtained by repeated blood sampling. Metyrapone resulted in a greater increase in ACTH and greater decreases in cortisol and delta spectral power sleep in PTSD subjects compared to controls, and a greater increase in ACTH in women compared to men. There was no sex difference in metyrapone effects on delta power sleep, and no significant metyrapone by PTSD by sex interactions with either ACTH or delta power sleep. Regression analyses indicated that a greater increase in ACTH response was associated with a greater decrease in delta power sleep response in PTSD subjects, but no such relationship was found in controls. The PTSD group difference was similar in men and women. These results suggest that stress-related alterations of the HPA axis in PTSD may contribute to sleep difficulties. Therapeutics that target the HPA axis may offer promise as a potential future treatment for PTSD and related sleep difficulties.
Topics: Adrenocorticotropic Hormone; Adult; Corticotropin-Releasing Hormone; Cross-Sectional Studies; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Metyrapone; Pituitary-Adrenal System; Polysomnography; Sleep; Sleep Wake Disorders; Stress Disorders, Post-Traumatic
PubMed: 29268182
DOI: 10.1016/j.psyneuen.2017.12.002