Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies

Existing Reviews

Please note, new claims can take a short while to show up.

No claims yet.

Annotation Summary

Term Occurence Count Dictionary
testosterone 4 endocrinologydiseasesdrugs
atorvastatin 2 endocrinologydiseasesdrugs
diabetes mellitus 1 endocrinologydiseases
hyperandrogenism 1 endocrinologydiseases
hypokalemia 5 endocrinologydiseases
mitotane 12 endocrinologydiseasesdrugs
osteoporosis 1 endocrinologydiseases
adrenal insufficiency 3 endocrinologydiseases
cabergoline 2 endocrinologydiseasesdrugs
cortisol 47 endocrinologydiseasesdrugs
hypogonadism 1 endocrinologydiseases

Graph of close proximity drug and disease terms (within 200 characters).

Note: If this graph is empty, then there are no terms that meet the proximity constraint.

Review

Having read the paper, please pick a pair of statements from the paper to indicate that a drug and disease are related.

Select Drug Character Offset Drug Term Instance
atorvastatin 24923 levoketoconazole has the potential for drug interactions with drugs metabolized via CYP3A4 (e.g., felodipine and atorvastatin ) [[45]]. In drug interaction studies, exposure of felodipine was increased 10-fold with coadministration
atorvastatin 25080 exposure of felodipine was increased 10-fold with coadministration of levoketoconazole, while exposure to atorvastatin was increased by ~30 % when coadministered with levoketoconazole (compared with a ~50 % increase with
cabergoline 27772 steroidogenesis inhibitors has also been shown to be effective. Combination therapy with ketoconazole and cabergoline normalized UFC in 79 % of patients with CD; however, based on late-night salivary cortisol levels,
cabergoline 28049 this combination [[56]]. In a study of 17 patients with CD, treatment with a regimen of pasireotide, cabergoline , and ketoconazole normalized UFC levels in 88 % of patients by day 80; reductions in UFC levels of
cortisol 372 /2016AbstractPurposeEndogenous Cushing’s syndrome (CS) is a rare disease that results from exposure to high levels of cortisol ; Cushing’s disease (CD) is the most frequent form of CS. Patients with CS suffer from a variety of
cortisol 858 with CD, have recurrent disease. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatology. CS is rare overall, and clinical studies of adrenal steroidogenesis
cortisol 2190 remains challenging. Adrenal steroidogenesis inhibitors can be of major interest to control the hyper cortisol ism at any time point, either before or after surgery, as discussed in this review.IntroductionCushing’s
cortisol 2379 review.IntroductionCushing’s syndrome (CS) is a potentially fatal disease associated with chronic hyper cortisol emia [[1]]. Endogenous CS is rare, with an annual estimated incidence of approximately 0.7–2.4 cases
cortisol 3017 approximately 20.6 times higher in patients with CS compared with the general population [[2]]. Elevated cortisol levels in patients with CS also result in a range of comorbidities, including cardiovascular (e.g.,
cortisol 3477 musculoskeletal (e.g., muscle weakness) symptoms [[1]].Treatment options that directly address the hyper cortisol emia include surgery (pituitary, adrenal, or ectopic tumor resection), medical treatment, and/or radiotherapy
cortisol 4103 first line of treatment, unless surgery is contraindicated or unlikely to successfully reduce excess cortisol levels [[6]]. For patients for whom disease was not controlled by initial surgery, or for patients with
cortisol 5429 variety of enzymatic reactions, cholesterol, the common steroid precursor, is converted to aldosterone, cortisol , or androstenedione (Fig. 1). Adrenal steroidogenesis inhibitors, which act by blocking various steps
cortisol 5612 act by blocking various steps in the steroid biosynthesis pathway resulting in reduced production of cortisol and other steroids, are a cornerstone of medical treatment of CS [[10]]. This review summarizes the
cortisol 6099 detail below and summarized in Table 1.Fig. 1Effects of adrenal steroidogenesis inhibitors on the cortisol synthesis pathway [[9]]. The enzymatic pathways in cortisol synthesis are represented schematically.
cortisol 6159 adrenal steroidogenesis inhibitors on the cortisol synthesis pathway [[9]]. The enzymatic pathways in cortisol synthesis are represented schematically. Inhibitors are depicted in purple boxes and may inhibit multiple
cortisol 8802 patients with CS, ketoconazole treatment has been associated with significant decreases in urinary free cortisol (UFC) and urinary levels of cortisol and androgen metabolites [[22]]. A retrospective study of 200 patients
cortisol 8839 has been associated with significant decreases in urinary free cortisol (UFC) and urinary levels of cortisol and androgen metabolites [[22]]. A retrospective study of 200 patients receiving single-agent ketoconazole
cortisol 10402 insufficiency is rare, except when the treatment is given as a block-and-replace strategy (a regimen in which cortisol production is completely inhibited by steroidogenesis inhibitors and glucocorticoids are administered
cortisol 11272 CYP11B1, but also inhibits the activity of CYP11B2 [[28]]. Significant reductions in urinary secretion of cortisol and aldosterone have been observed with metyrapone treatment [[29]]. In a retrospective study of 164
cortisol 11479 164 patients with CS who received metyrapone monotherapy, 43–76 % of patients achieved control of cortisol levels (defined by prespecified values of mean serum cortisol day-curve, 24-hour UFC, and 09.00 h cortisol)
cortisol 11541 43–76 % of patients achieved control of cortisol levels (defined by prespecified values of mean serum cortisol day-curve, 24-hour UFC, and 09.00 h cortisol) [[30]]. No escape was reported, and 83 % of the patients
cortisol 11587 levels (defined by prespecified values of mean serum cortisol day-curve, 24-hour UFC, and 09.00 h cortisol ) [[30]]. No escape was reported, and 83 % of the patients treated for more than 12 months (mean = 22 months)
cortisol 12845 Etomidate can be administered intravenously and is often used for seriously ill patients with severe hyper cortisol emia who cannot take oral medication [[6], [21]]. However, only a few cases of its use have been reported
cortisol 13025 cases of its use have been reported in the literature.Earlier studies demonstrated that inhibition of cortisol was rapidly achieved with low-dose (2.5 mg/h) etomidate in patients with hypercortisolism and was distinct
cortisol 13113 inhibition of cortisol was rapidly achieved with low-dose (2.5 mg/h) etomidate in patients with hyper cortisol ism and was distinct from the sedative effects of the drug [[33]]. In patients with CS, etomidate treatment
cortisol 13274 drug [[33]]. In patients with CS, etomidate treatment resulted in significant suppression of serum cortisol levels within 11 h of infusion [[34]]. In an emergency setting, patients with CS who received etomidate
cortisol 13472 received etomidate at a dose of 0.1 mg/kg per hour exhibited rapid and prolonged suppression of serum cortisol levels [[34]]. The most common side effects associated with etomidate were hypnotic effect, reduced
cortisol 14192 the treatment of adrenocortical carcinoma, but in rare cases may be used for the treatment of hyper cortisol emia [[10], [35]]. Mitotane inhibits CYP11A1, CYP11B1, CYP11B2, and 5α-reductase [[7], [10]]. In patients
cortisol 14386 [[7], [10]]. In patients with CS, mitotane treatment has been associated with significant reductions in cortisol and androgen levels [[36]]. In the largest study (76 patients) reported to date on the use of mitotane
cortisol 14516 [[36]]. In the largest study (76 patients) reported to date on the use of mitotane in CD, control of cortisol hypersecretion was observed in 72 % of the patients after a median time of 6.7 months; the mitotane
cortisol 16619 significant and dose-dependent decreases in urine and plasma levels of aldosterone and a blunting of the cortisol response to synthetic ACTH were observed [[10]].In a 10-week, proof-of-concept study in patients with
cortisol 17241 22-week, phase 2 study of osilodrostat in patients with CD with UFC levels above the ULN, normalization of cortisol levels was achieved in 84 % of patients by week 10 and 79 % by the end of the study [[41]]. In both
cortisol 17458 studies, patients achieved normal UFC within a month of starting treatment [[41], [42]]. Plasma levels of cortisol and aldosterone were decreased in both studies, while levels of their precursors, 11-deoxycortisol and
cortisol 17557 cortisol and aldosterone were decreased in both studies, while levels of their precursors, 11-deoxy cortisol and 11-deoxycorticosterone, increased [[41], [42]]. Although blood pressure decreased from baseline
cortisol 19851 enzymes in the steroidogenic pathway, including CYP11B1, a key enzyme in the final step of adrenal cortisol synthesis; levoketoconazole had a half maximal inhibitory concentration for CYP11B1 that was approximately
cortisol 21493 support preclinical results showing suppression of corticosterone by levoketoconazole. In an analysis of cortisol levels over time in healthy subjects, the mean area under the curve (AUC) for cortisol was lower following
cortisol 21580 analysis of cortisol levels over time in healthy subjects, the mean area under the curve (AUC) for cortisol was lower following administration of both levoketoconazole and ketoconazole compared with placebo.
cortisol 21793 study in patients with type 2 diabetes, nonsignificant mean reductions in 12-hour overnight plasma cortisol AUC were observed with both ketoconazole and levoketoconazole after 14 days of dosing [[47]]. Interestingly,
cortisol 27867 and cabergoline normalized UFC in 79 % of patients with CD; however, based on late-night salivary cortisol levels, subclinical hypercortisolism persisted in patients treated with this combination [[56]]. In
cortisol 27901 79 % of patients with CD; however, based on late-night salivary cortisol levels, subclinical hyper cortisol ism persisted in patients treated with this combination [[56]]. In a study of 17 patients with CD, treatment
cortisol 28716 inhibitor may be used during the first several months of treatment [[10]]. In patients with severe hyper cortisol ism (UFC >5 times ULN) related to ectopic ACTH syndrome or adrenal carcinoma, the combination of metyrapone
cortisol 29119 hypokalemia, hypertension, and diabetes [[58]]. Similarly, in a study of 11 patients with severe hyper cortisol ism and significant comorbidities that precluded surgical intervention, who were administered metyrapone
cortisol 30045 however, based on the in vitro data, it is hypothesized that the greater potency of levoketoconazole for cortisol suppression relative to ketoconazole, along with its potentially favorable hepatic tolerability profile,
cortisol 30892 of comorbidities [[61]]. In a retrospective study of 16 patients who received adequate presurgical cortisol suppression therapy with ketoconazole or metyrapone prior to undergoing transsphenoidal surgery, postoperative
cortisol 31012 therapy with ketoconazole or metyrapone prior to undergoing transsphenoidal surgery, postoperative cortisol suppression was observed and, surprisingly, long-term remission was significantly increased compared
cortisol 31166 long-term remission was significantly increased compared with patients with borderline or inadequate cortisol suppression pretreatment [[62]]. However, a retrospective study of previously untreated patients who
cortisol 32107 medical treatment [[63]].Subclinical adrenal CSThough controversial, subclinical CS or mild adrenal hyper cortisol ism is defined as a subtle hypersecretion of cortisol that does not fully manifest in a clinical phenotype
cortisol 32160 controversial, subclinical CS or mild adrenal hypercortisolism is defined as a subtle hypersecretion of cortisol that does not fully manifest in a clinical phenotype [[64]]. However, subclinical CS may be associated
cortisol 32429 hypertension, type 2 diabetes, osteoporosis, dyslipidemia, or coronary heart disease as a result of chronic cortisol elevation, but this association has not been conclusively demonstrated. As a result of the sparse data
cortisol 33629 recurrence following surgery. Adrenal steroidogenesis inhibitors are associated with high rates of cortisol normalization and clinical improvements. Combination therapies of well-studied drugs might allow for
cortisol 34039 agents with improved tolerability and potency are needed. In phase 2 studies, osilodrostat provided cortisol normalization in almost 80 % of patients with no short-term escape. Based on preclinical and early
mitotane 1508 drugs.ResultsCurrently available adrenal steroidogenesis inhibitors, including ketoconazole, metyrapone, etomidate, and mitotane , have variable efficacy and significant side effects, and none are approved by the US Food and Drug
mitotane 14316 [35]]. Mitotane inhibits CYP11A1, CYP11B1, CYP11B2, and 5α-reductase [[7], [10]]. In patients with CS, mitotane treatment has been associated with significant reductions in cortisol and androgen levels [[36]]. In
mitotane 14489 cortisol and androgen levels [[36]]. In the largest study (76 patients) reported to date on the use of mitotane in CD, control of cortisol hypersecretion was observed in 72 % of the patients after a median time
mitotane 14618 cortisol hypersecretion was observed in 72 % of the patients after a median time of 6.7 months; the mitotane level necessary to obtain control was lower than the level recommended for the treatment of adrenal
mitotane 15549 discontinuation of treatment in approximately a quarter of patients and require close monitoring of plasma mitotane levels [[6]]. A recent study of premenopausal women demonstrated a high incidence of menstrual disorders
mitotane 15705 women demonstrated a high incidence of menstrual disorders and ovarian macrocysts in women receiving mitotane , which may be related to elevated levels of luteinizing hormone, follicle-stimulating hormone, and estrogen
mitotane 15842 elevated levels of luteinizing hormone, follicle-stimulating hormone, and estrogen as a consequence of mitotane alleviating the negative feedback normally exerted by the ovaries on the production of those hormones
mitotane 24310 inhibitors have the potential for drug interactions with drugs metabolized by CYP enzymes (Table 2). Both mitotane and ketoconazole are strong inhibitors of CYP3A4 and may enhance the activity of drugs metabolized by
mitotane 24539 oral anticoagulants, statins, cyclosporine, and tacrolimus [[49]–[51]]. The inhibitory effects of mitotane treatment on CYP3A4 are long lasting and have been observed several months after therapy is discontinued
mitotane 28547 respond to monotherapy with either agent [[10], [30]]. Due to the relatively slow onset of action of mitotane , combination therapy with a rapid-onset steroidogenesis inhibitor may be used during the first several
mitotane 28883 adrenal carcinoma, the combination of metyrapone and ketoconazole (and in some patients, subsequent mitotane ) resulted in normal UFC values in 73 % of patients (n = 22) and a concomitant improvement of clinical
mitotane 29261 that precluded surgical intervention, who were administered metyrapone and ketoconazole followed by mitotane maintenance therapy, UFC was normalized in all patients receiving combination therapy and remained below
testosterone 10588 glucocorticoids are administered to fulfill physiologic needs) [[23]]. Ketoconazole may also affect gonadal testosterone synthesis, resulting in decreased androgen levels and subsequent hypogonadism and gynecomastia in male
testosterone 18579 syncope) led to dose reductions of osilodrostat [[41], [42]]. In both studies, increased levels of testosterone were observed in female patients [[41], [42]], and in the phase 2 study, symptoms of hirsutism occurred
testosterone 21080 levoketoconazole had a greater potency for decreasing corticosterone (the main glucocorticoid in rats [[46]]) and testosterone levels than the 2R,4S enantiomer or racemic ketoconazole [[45]]. Levoketoconazole-mediated decreases
testosterone 21964 after 14 days of dosing [[47]]. Interestingly, no dose-dependent trend in the percentage change in testosterone was found with levoketoconazole administration [[47]]. Finally, significant decreases in low-density
Select Disease Character Offset Disease Term Instance
adrenal insufficiency 4327 life-threatening disease, bilateral adrenalectomy is also an option [[6]]. However, as a result of the adrenal insufficiency (AI) induced by bilateral adrenalectomy, patients undergoing the procedure will require hydrocortisone
adrenal insufficiency 7408 during pregnancyCYP, cytochrome P450; AE, adverse event; NR, not reported. All of these drugs can induce adrenal insufficiency aIn patients with diabetes mellitusAdrenal steroidogenesis inhibitors currently in clinical useKetoconazoleKetoconazole,
adrenal insufficiency 18391 studies were gastrointestinal adverse events (e.g., nausea, diarrhea); adverse events associated with adrenal insufficiency (i.e., fatigue, dizziness, nausea, muscle spasms, hypotension, and syncope) led to dose reductions of
diabetes mellitus 7447 adverse event; NR, not reported. All of these drugs can induce adrenal insufficiencyaIn patients with diabetes mellitus Adrenal steroidogenesis inhibitors currently in clinical useKetoconazoleKetoconazole, a synthetic imidazole
hyperandrogenism 12523 for a second-line medical treatment in females for whom a long-term treatment is necessary because of hyperandrogenism [[6]].EtomidateEtomidate, an imidazole derivative, is used for the induction of anesthesia and is also
hypogonadism 10666 may also affect gonadal testosterone synthesis, resulting in decreased androgen levels and subsequent hypogonadism and gynecomastia in male patients; therefore, it is generally used as a second-line medical therapy
hypokalemia 9161 “uncontrolled” patients had a ≥50 % decrease in UFC; concurrent improvements in hypertension, diabetes, and hypokalemia were also observed [[23]]. Escape from ketoconazole-mediated control occurred in some patients (7 %)
hypokalemia 12083 incidence of metyrapone-related hirsutism, acne, and edema were rare, albeit not prospectively studied, and hypokalemia was reported but manageable with replacement [[30]]. Of note, some patients were initially treated with
hypokalemia 12281 initially treated with antialdosterone drugs, which might have led to an underestimation of worsening of hypokalemia and hypertension. Although no clear recommendation has been made on this specific point, metyrapone
hypokalemia 18010 11-deoxycorticosterone, may be associated with the development of certain side effects (worsening of hypokalemia , increased blood pressure levels) [[10]]. These side effects were not specifically reported in the studies
hypokalemia 29017 values in 73 % of patients (n = 22) and a concomitant improvement of clinical symptoms, including hypokalemia , hypertension, and diabetes [[58]]. Similarly, in a study of 11 patients with severe hypercortisolism
osteoporosis 32352 CS may be associated with an increased risk of comorbidities, such as hypertension, type 2 diabetes, osteoporosis , dyslipidemia, or coronary heart disease as a result of chronic cortisol elevation, but this association

You must be authorized to submit a review.