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Journal of the Endocrine Society May 2019Metyrapone is an inhibitor of endogenous adrenal corticosteroid synthesis, which has been proven to be a viable option in controlling maternal serum cortisol...
CONTEXT
Metyrapone is an inhibitor of endogenous adrenal corticosteroid synthesis, which has been proven to be a viable option in controlling maternal serum cortisol concentrations during pregnancy. The infant exposure to maternally ingested metyrapone through breast milk is, however, largely unknown.
CASE DESCRIPTION
We report the excretion of metyrapone into breast milk and subsequent infant exposure from a lactating woman on 250 mg of metyrapone three times daily. Due to limited supply of breast milk, the infant was fed ∼50% breast milk and 50% formula. At steady state, the average concentrations in the studied breast milk and absolute and relative infant doses were 176 µg/L, 26.45 µg/kg/d, and 0.7%, respectively, for metyrapone, and 310 µg/L, 46.52 µg/kg/d, and 1.21% for its active metabolite metyrapol. The breastfed infant was found to have a plasma metyrapone concentration of 0.05 µg/L, with no evidence of disruption to his adrenocortical axis biochemically.
CONCLUSION
These findings indicate that maternal metyrapone use during breastfeeding did not pose a notable risk to this breastfed infant. The infants' exposure to metyrapone was further minimized by avoiding nursing for 2 to 3 hours after each metyrapone dose.
PubMed: 31041428
DOI: 10.1210/js.2018-00355 -
Neuroendocrinology 2010Active Cushing's syndrome is associated with insulin resistance induced by the high and prolonged circulating level of glucocorticoids. In endogenous Cushing's syndrome... (Review)
Review
Active Cushing's syndrome is associated with insulin resistance induced by the high and prolonged circulating level of glucocorticoids. In endogenous Cushing's syndrome the overall incidence of diabetes mellitus and insulin resistance is very likely to be under-reported as not all patients are actively investigated with glucose tolerance tests. Whilst it is common clinical experience that management of diabetes mellitus is necessary in patients with Cushing's syndrome there is a dearth of literature-based evidence to support which regimes are the most effective. Therefore, a pragmatic approach is necessary on an individualized patient basis, whereby patients are stratified according to the severity of their impaired glucose homeostasis. The most effective means of control of diabetes mellitus in a patient with active Cushing's syndrome is to lower the levels of circulating cortisol. This may initially be achieved by using adrenal steroidogenesis blockade with drugs including metyrapone, ketaconazole, or, on occasion, mitotane. The rapid action of metyrapone is particularly suitable in this circumstance. Despite this, diabetes-specific therapy is often necessary and metformin and PPAR-γ agonists may be of use, but in the acute setting insulin therapy is frequently needed. Definitive management directed against source driving Cushing's syndrome is often highly effective at either reducing the severity of diabetes, or allowing its complete resolution. Patients experiencing diabetes mellitus in the context of exogenously administered glucocorticoids may well require insulin therapy for the period that the high levels of steroids are being administered. Despite resolution of Cushing's syndrome after definitive treatment patients may continue to exhibit insulin resistance. This and other cardiovascular risk factors require ongoing and long-term attention.
Topics: Cushing Syndrome; Diabetes Mellitus; Enzyme Inhibitors; Humans; Hypoglycemic Agents; Insulin Resistance; Ketoconazole; Metformin; Metyrapone
PubMed: 20829624
DOI: 10.1159/000314316 -
AACE Clinical Case Reports 2022Cushing disease (CD) during pregnancy is a rare but serious disease that adversely impacts maternal and fetal outcomes. As the sole use of metyrapone in the management...
BACKGROUND
Cushing disease (CD) during pregnancy is a rare but serious disease that adversely impacts maternal and fetal outcomes. As the sole use of metyrapone in the management of CD has been rarely reported, we describe our experience of using it to treat a pregnant patient with CD.
CASE REPORT
A 34-year-old woman with hypertension was diagnosed with adrenocorticotropic hormone-dependent CD on the basis of a urinary free cortisol (UFC) level of 290 μg/24 h (reference range, 6-42 μg/dL) and an abnormal dexamethasone suppression test (cortisol level, 12.4 μg/dL) before becoming pregnant. She conceived naturally 12 weeks after transsphenoidal surgery and was subsequently found to have persistent disease with a UFC level of 768 μg/dL. Surgery was deemed high-risk given the proximity of the tumor to the right carotid artery and the high likelihood of residual disease. Instead, she was managed with metyrapone throughout her pregnancy and titrated to a goal UFC level of <150 μg/24 h due to the known physiologic increase in the cortisol level during gestation. The patient had diet-controlled gestational diabetes and well-controlled hypertension. She gave birth to a healthy baby boy at 37 weeks of gestation, without adrenal insufficiency in the baby or her.
DISCUSSION
This case highlights the successful use of metyrapone throughout pregnancy to manage CD in patients in whom surgery is considered high-risk or in those with a low likelihood of cure. Although metyrapone is effective, close surveillance is required for worsening hypertension, hypokalemia, and potential adrenal insufficiency. Although no fetal adverse events have been reported, this medication crosses the placenta, and the long-term effects are unknown.
CONCLUSION
We describe a case of CD during pregnancy that was successfully treated with metyrapone.
PubMed: 35415226
DOI: 10.1016/j.aace.2021.10.004 -
Pharmacology, Biochemistry, and Behavior Nov 2008For several years, our laboratory has investigated the role for the HPA axis in cocaine reinforcement. Two classes of drugs that we have studied include corticosterone...
For several years, our laboratory has investigated the role for the HPA axis in cocaine reinforcement. Two classes of drugs that we have studied include corticosterone synthesis inhibitors (e.g., metyrapone) and benzodiazepine receptor agonists (e.g., oxazepam). In the experiments described in this manuscript, we tested the effects of various doses of metyrapone and oxazepam against several doses of self-administered cocaine. Behavioral, endocrine and pharmacokinetic measures of the effects of the combination of metyrapone and oxazepam on cocaine reward are presented. Combinations of metyrapone and oxazepam at doses that produced no observable effects when administered separately significantly reduced cocaine self-administration without affecting food-maintained responding during the same sessions. Changes in pharmacokinetics or endocrine function do not appear to mediate these effects, suggesting a central mechanism of action. Therefore, although these drugs produce their effects through distinct mechanisms, an additive effect on cocaine self-administration is obtained when these drugs are administered together, suggesting that combinations of low doses of metyrapone and oxazepam may be useful in reducing cocaine seeking with a reduced incidence of unwanted side effects and a decreased potential for abuse.
Topics: Animals; Cocaine-Related Disorders; Conditioning, Operant; Corticosterone; Dose-Response Relationship, Drug; Drug Combinations; Eating; Enzyme Inhibitors; Extinction, Psychological; Hypnotics and Sedatives; Male; Metyrapone; Oxazepam; Rats; Rats, Wistar; Self Administration; Substance Abuse, Intravenous
PubMed: 18692521
DOI: 10.1016/j.pbb.2008.07.005 -
The Journal of Clinical Endocrinology... Jul 2008Our 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... (Review)
Review
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.
Topics: ACTH Syndrome, Ectopic; Adrenal Insufficiency; Adrenalectomy; Adrenocorticotropic Hormone; Cushing Syndrome; Humans; Hypophysectomy; Metyrapone; Mitotane; Nelson Syndrome
PubMed: 18413427
DOI: 10.1210/jc.2007-2734 -
Experimental and Clinical Endocrinology... Feb 2019Despite advances in diagnostic and therapeutic approach, Cushing's disease (CD) presents a challenging situation for the treating physician. (Review)
Review
BACKGROUND
Despite advances in diagnostic and therapeutic approach, Cushing's disease (CD) presents a challenging situation for the treating physician.
AIMS
To elucidate current challenges, present strengths and pitfalls of existing diagnostic tests, enlighten the need for new diagnostic approaches, appraise the effects of surgery and available pharmacological agents and identify future perspectives regarding CD.
MATERIALS AND METHODS
Systematic search to PubMed and Medline databases for publications mainly over the last five years.
RESULTS
Mutations in the ubiquitin specific peptidase 8 gene have been recently identified in functional sporadic corticotroph adenomas causing CD. Since the prevalence of obesity and metabolic syndrome is rapidly increasing, new diagnostic tests are necessary to differentiate these conditions. Next to the traditional tests, a cutoff of preoperative ACTH/cortisol ratio, an ultrasensitive late night salivary cortisol assay and the desmopressin test have been suggested as valid tools for the diagnosis and differential diagnosis of CD. Transsphenoidal surgery with variable remission and recurrence rates presents the treatment of choice for CD. Medical therapy consists of adrenal-targeted drugs e. g. ketoconazole, metyrapone, etomidate and mitotane and pituitary-targeted drugs e. g. pasireotide, cabergoline and retinoic acid.
CONCLUSIONS
CD is associated to a significant clinical burden, since numerous comorbidities persist after long-term biochemical control. These chronically ill patients show an increased mortality despite disease remission. Clinicians should treat comorbidities aggressively and seek for appropriate consultations. Structured consultation hours and expert excellence networks are needed in order to allow optimal, individualized care for affected patients, reverse increased morbidity and mortality and identify tumor recurrence early.
Topics: Comorbidity; Humans; Pituitary ACTH Hypersecretion
PubMed: 30130808
DOI: 10.1055/a-0664-7632 -
Frontiers in Endocrinology 2023Café-au-lait skin macules, Cushing syndrome (CS), hyperthyroidism, and liver and cardiac dysfunction are presenting features of neonatal McCune-Albright syndrome (MAS),...
BACKGROUND
Café-au-lait skin macules, Cushing syndrome (CS), hyperthyroidism, and liver and cardiac dysfunction are presenting features of neonatal McCune-Albright syndrome (MAS), CS being the rarest endocrine feature. Although spontaneous resolution of hypercortisolism has been reported, outcome is usually unfavorable. While a unified approach to diagnosis, treatment, and follow-up is lacking, herein successful treatment and long-term follow-up of a rare case is presented.
CLINICAL CASE
An 11-day-old girl born small for gestational age presented with deterioration of well-being and weight loss. Large hyperpigmented macules on the trunk, hypertension, hyponatremia, hyperglycemia, and elevated liver enzymes were noted. ACTH-independent CS due to MAS was diagnosed. Although metyrapone (300 mg/m/day) was started on the 25th day, complete remission could not be achieved despite increasing the dose up to 1,850 mg/m/day. At 9 months, right total and left three-quarters adrenalectomy was performed. Cortisol decreased substantially, ACTH remained suppressed, rapid tapering of hydrocortisone to physiological dose was not tolerated, and supraphysiological doses were required for 2 months. analysis from the adrenal tissue showed a pathogenic heterozygous mutation. During 34 months of follow-up, in addition to CS due to MAS, fibrous dysplasia, hypophosphatemic rickets, and peripheral precocious puberty were detected. She is still regularly screened for other endocrinopathies.
CONCLUSION
Neonatal CS due to MAS is extremely rare. Although there is no specific guideline for diagnosis, treatment, or follow-up, addressing side effects and identifying treatment outcomes will improve quality of life and survival.
Topics: Fibrous Dysplasia, Polyostotic; Cafe-au-Lait Spots; Infant, Small for Gestational Age; Humans; Female; Infant, Newborn; Adrenocorticotropic Hormone; Hydrocortisone; Cushing Syndrome
PubMed: 37560302
DOI: 10.3389/fendo.2023.1209189 -
European Journal of Endocrinology Nov 2022Symptoms of hyperandrogenism are common in patients with Cushing's disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study, we...
BACKGROUND
Symptoms of hyperandrogenism are common in patients with Cushing's disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study, we analyzed the contribution of 11-oxygenated C19 steroids (11oxC19) to hyperandrogenemia in female patients with CD.
METHODS
We assessed saliva day profiles in females with CD pre (n = 23) and post (n = 13) successful transsphenoidal surgery, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (TS), 11-ketotestosterone (11KT), as well as metabolites of classic and 11-oxygenated androgens in 24-h urine. In addition, morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol and dehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotrophic hormone in plasma in patients and controls were investigated.
RESULTS
Treatment-naïve females with CD showed a significantly elevated area under the curve of 11OHA4 and 11KT in saliva throughout the day compared to controls (11OHA4 mean rank difference (mrd) 18.13, P = 0.0002; 11KT mrd 17.42; P = 0.0005), whereas A4, TS and DHEAS were comparable to controls. Gonadotropin concentrations were normal in all patients with CD. After transsphenoidal surgery, 11oxC19 and their metabolites dropped significantly in saliva (11OHA4 P < 0.0001; 11KT P = 0.0010) and urine (11-oxo-androsterone P = 0.0011; 11-hydroxy-androsterone P < 0.0001), treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis.
CONCLUSION
Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 steroids.
Topics: Adrenocorticotropic Hormone; Androgens; Androstenedione; Androsterone; Cortisone; Dehydroepiandrosterone Sulfate; Estradiol; Female; Humans; Hydrocortisone; Hyperandrogenism; Metyrapone; Pituitary ACTH Hypersecretion; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Steroids; Testosterone
PubMed: 36074938
DOI: 10.1530/EJE-22-0320 -
American Journal of Physiology.... Jan 2020This study explored the hypothesis that late gestational reduction of corticosteroids transforms the cerebrovasculature and modulates postnatal vulnerability to mild...
This study explored the hypothesis that late gestational reduction of corticosteroids transforms the cerebrovasculature and modulates postnatal vulnerability to mild hypoxic-ischemic (HI) injury. Four groups of Sprague-Dawley neonates were studied: ) Sham-Control, ) Sham-MET, ) HI-Control, and ) HI-MET. Metyrapone (MET), a corticosteroid synthesis inhibitor, was administered via drinking water from to term. In Shams, MET administration ) decreased reactivity of the hypothalamic-pituitary-adrenal (HPA) axis to surgical trauma in (P9) pups by 37%, ) promoted cerebrovascular contractile differentiation in middle cerebral arteries (MCAs), ) decreased compliance ≤46% and increased depolarization-induced calcium mobilization in MCAs by 28%, ) mildly increased hemispheric cerebral edema by 5%, decreased neuronal degeneration by 66%, and increased astroglial and microglial activation by 10- and 4-fold, respectively, and ) increased righting reflex times by 29%. Regarding HI, metyrapone-induced fetal transformation ) diminished reactivity of the HPA axis to HI-induced stress in P9/P10 pups, ) enhanced HI-induced contractile dedifferentiation in MCAs, ) lessened the effects of HI on MCA compliance and calcium mobilization, ) decreased HI-induced neuronal injury but unmasked regional HI-induced depression of microglial activation, and ) attenuated the negative effects of HI on open-field exploration but enhanced the detrimental effects of HI on negative geotaxis responses by 79%. Overall, corticosteroids during gestation appear essential for normal cerebrovascular development and glial quiescence but induce persistent changes that in neonates manifest beneficially as preservation of postischemic contractile differentiation but detrimentally as worsened ischemic cerebrovascular compliance, increased ischemic neuronal injury, and compromised neurobehavior.
Topics: Animals; Animals, Newborn; Carotid Arteries; Cerebrovascular Disorders; Female; Hypoxia; Hypoxia-Ischemia, Brain; Ligation; Pregnancy; Prenatal Care; Pyridines; Rats; Rats, Sprague-Dawley
PubMed: 31577477
DOI: 10.1152/ajpregu.00145.2019 -
BMC Endocrine Disorders Jul 2022Ectopic ACTH-dependent Cushing syndrome is rarely caused by pheochromocytoma (PCC). Glucocorticoid-regulated positive feedback loops in ACTH and catecholamines were...
BACKGROUND
Ectopic ACTH-dependent Cushing syndrome is rarely caused by pheochromocytoma (PCC). Glucocorticoid-regulated positive feedback loops in ACTH and catecholamines were proposed in some similar cases.
CASE PRESENTATION
We present here an 80-year-old man who had previously undergone surgery for a left adrenal PCC and newly developed severe hypertension, hypokalemia, and typical Cushingoid manifestations. Investigations revealed hyperglycemia, hypokalemia, and extremely high catecholamines and their metabolites, ACTH and cortisol. Imaging modalities showed a recurrent large left adrenal mass positively visualized with I-metaiodobenzylguanidine as well as somatostatin receptor scintigraphy. Surgical interventions were not indicated; thus, metyrapone, phentolamine, and doxazocin were initiated, which successfully controlled his symptoms and biochemical conditions. With the evidence that metyrapone administration decreased ACTH and catecholamine levels, the existence of positive feedback loops was speculated. During the terminal stages of the disease, additional metyrosine treatment successfully stabilized his physiological and biochemical conditions. Upon the patient's death, pathological autopsy was performed. Immunohistochemical analysis indicated that the tumor appeared to be co-positive with tyrosine hydroxylase (TH) as well as ACTH in most tumor cells in both PCC and liver metastasis. Most cells were clearly positive for somatostatin receptor 2 staining in the membrane compartment. The dense immunostaining of ACTH, TH, dopamine-β-hydroxylase and the large tumor size with positive feedback loops may be correlated with high levels of ACTH and catecholamines in the circulation.
CONCLUSIONS
We experienced a case of severe ectopic ACTH producing the largest reported recurrent malignant left PCC with liver metastases that presented positive feedback loops in the ACTH/cortisol and catecholamine/cortisol axes. Clinicians should be aware of the paradoxical response of ACTH on metyrapone treatment and possible steroid-induced catecholamine crisis.
Topics: ACTH Syndrome, Ectopic; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Aged, 80 and over; Catecholamines; Humans; Hydrocortisone; Hypokalemia; Male; Metyrapone; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Pheochromocytoma
PubMed: 35854271
DOI: 10.1186/s12902-022-01090-8