Therapy of endocrine disease: steroidogenesis enzyme inhibitors in Cushing's syndrome.Most steroidogenic enzymes are forms of cytochrome Steroidogenesis enzyme inhibitors These are oxidative enzymes, all of which have about amino acids and contain a single heme steroidogenesis enzyme inhibitors . Their inhihitors is historical: The genes are formally termed CYP genes, and a logical systematic nomenclature for these has been described http: The human genome encodes 57 cytochrome P enzymes: Whereas the acute regulation of what is the best way to take dbol is determined by the action of StAR, the chronic regulation of steroidogenesis is quantitatively determined by the production of the steroidogenic enzymesespecially Pscc . Pscc is expressed in all classic steroidogenic cell types of the adrenal, gonad, and placenta but is also expressed in the rodent  and human  fetal nervous system.
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Patients with CS suffer from a variety of comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatology.
CS is rare overall, and clinical studies of adrenal steroidogenesis inhibitors are often small and, in many cases, data are limited regarding the efficacy and safety of these treatments. Our aim was to better characterize the profiles of efficacy and safety of currently available adrenal steroidogenesis inhibitors, including drugs currently in development. We performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs.
Currently 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 Administration for CS. Therefore, there is a clear need for novel, prospectively studied agents that have greater efficacy and a low rate of adverse side effects. Efficacy and safety data of current and emerging adrenal steroidogenesis inhibitors, including osilodrostat LCI and levoketoconazole COR , show promising results that will have to be confirmed in larger-scale phase 3 studies currently ongoing.
The management of CS, and particularly CD, remains challenging. Adrenal steroidogenesis inhibitors can be of major interest to control the hypercortisolism at any time point, either before or after surgery, as discussed in this review.
Endogenous CS is rare, with an annual estimated incidence of approximately 0. Patients with CS have a mortality risk that is approximately 3. The increased mortality with CS is, in part, related to an increased risk of cardiovascular disease and coagulation disorders [ 3 — 5 ]. The risk of myocardial infarction is approximately 4. Elevated cortisol levels in patients with CS also result in a range of comorbidities, including cardiovascular e. For patients for whom disease was not controlled by initial surgery, or for patients with severe, 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 replacement and have an increased risk of adrenal crises during their lifetime [ 8 ]. There are three specific targets for medical therapy in CD, the corticotroph tumor, adrenal steroidogenesis inhibitors, and glucocorticoid receptor blockers.
Steroidogenesis inhibitors are recommended by the Endocrine Society as second-line treatment after adenomectomy in CD, depending on clinical circumstances; as first-line treatment for patients with ectopic adrenocorticotropic hormone ACTH secretion when a tumor is not detected; or as an adjunct treatment for patients with adrenocortical carcinoma [ 6 ].
Corticotropin ACTH stimulates steroidogenesis by the adrenal glands [ 9 ]. Through a variety of enzymatic reactions, cholesterol, the common steroid precursor, is converted to aldosterone, cortisol, or androstenedione Fig. Adrenal steroidogenesis inhibitors, which 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 key features of different adrenal steroidogenesis inhibitors for the treatment of CS, with particular emphasis on steroidogenesis inhibitors currently in clinical development.
Effects of 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 steps in the pathway.
Mechanisms of action of steroidogenesis inhibitors [ 21 ]. All of these drugs can induce adrenal insufficiency. However, due to liver toxicity, the approved use of ketoconazole in the United States US is restricted to the treatment of serious fungal infections with no other viable treatment options [ 7 , 12 ]. Ketoconazole is approved for the treatment of CS in the European Union [ 13 ]. Ketoconazole has also been reported to directly inhibit ACTH secretion [ 20 ], although these findings have not been confirmed [ 21 ].
In 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 ]. Similarly, in retrospective chart review, elevation of liver enzymes and severe acute liver injury were rarely observed with ketoconazole treatment [ 26 ]. Concomitant use of drugs with known hepatotoxic effects should be avoided, and acid-lowering drugs should be used with caution, as they decrease the efficacy of ketoconazole [ 24 ].
Adrenal 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 to fulfill physiologic needs [ 23 ]. Ketoconazole 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 in men patients in whom metyrapone might be more appropriate, from this point of view [ 11 , 25 ].
In the European Union, metyrapone is approved for the treatment of CS [ 13 ]. Significant reductions in urinary secretion of cortisol and aldosterone have been observed with metyrapone treatment [ 29 ].
Metyrapone has been associated with gastrointestinal adverse events and hypoadrenalism [ 6 , 30 ]. Despite the accumulation of adrenogenic and mineralocorticoid precursors associated with metyrapone treatment, 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 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 is probably a better choice for a second-line medical treatment in females for whom a long-term treatment is necessary because of hyperandrogenism [ 6 ]. Etomidate can be administered intravenously and is often used for seriously ill patients with severe hypercortisolemia who cannot take oral medication [ 6 , 21 ].
However, only a few cases of its use have been reported in the literature. Earlier studies demonstrated that inhibition of cortisol was rapidly achieved with low-dose 2.
In an emergency setting, patients with CS who received etomidate at a dose of 0. The most common side effects associated with etomidate were hypnotic effect, reduced blood pressure, myoclonus, dystonia, nausea, and vomiting [ 31 , 33 ].
Adrenal insufficiency has also been reported, which may require glucocorticoid replacement [ 31 ], thus a block-and-replace protocol is used in most cases. Etomidate is unstable in water, and is often administered in a formulation containing propylene glycol, which may increase the incidence of hemolysis and nephrotoxicity [ 33 ].
Mitotane, a synthetic derivative of the pesticide dichlorodiphenyltrichloroethane, is indicated for the treatment of adrenocortical carcinoma, but in rare cases may be used for the treatment of hypercortisolemia [ 10 , 35 ]. In patients with CS, mitotane treatment has been associated with significant reductions in cortisol and androgen levels [ 36 ]. Mitotane is associated with a number of potential side effects, including hypercholesterolemia, anorexia, gastrointestinal symptoms, decreased memory and other neurological side effects, and abnormal liver function [ 31 , 38 ]; these side effects lead to 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 and ovarian macrocysts in women receiving mitotane, which may be related to 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 [ 39 ].
Osilodrostat was initially developed as a possible treatment option for hypertension, cardiac failure, and renal disease [ 10 ]. In studies in patients with hypertension, 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 both 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, deoxycortisol and deoxycorticosterone, increased [ 41 , 42 ]. Although blood pressure decreased from baseline in the proof-of-concept study, data from the phase 2 study showed no changes in blood pressure [ 41 , 42 ].
In patients with CD, osilodrostat is also associated with an increase in ACTH 3- to 4-fold , which, due to the subsequent increase in 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 previously described. The most common adverse events in both studies were gastrointestinal adverse events e. In both studies, increased levels of testosterone were observed in female patients [ 41 , 42 ], and in the phase 2 study, symptoms of hirsutism occurred in a third of the female patients who completed the study [ 41 ].
A phase 3, double-blind, randomized withdrawal study ClinicalTrials. Patients receive osilodrostat during a week, open-label, dose-titration period weeks 1—12 , followed by a week, open-label, stable treatment period weeks 13—24 ; then patients are randomized to receive osilodrostat or a placebo during an 8-week double-blind period weeks 26—34 , and, finally, all patients receive open-label osilodrostat from weeks 35 to Levoketoconazole is the 2S,4R enantiomer of ketoconazole, purified from racemic ketoconazole [ 44 ].
In early in vitro analyses, levoketoconazole was shown to be a more potent inhibitor than the 2R,4S enantiomer of several 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 4 times lower than the 2R,4S enantiomer [ 17 — 19 ].
As an azole antifungal, levoketoconazole was screened as an inhibitor of a critical enzyme for fungal survival, CYP51A1, which also happens to be a key enzyme in cholesterol synthesis. Results of more recent analyses of the effects of racemic ketoconazole, levoketoconazole, and 2R,4S-ketoconazole on steroidogenic CYP enzymes support those of early in vitro studies [ 45 ].
Thus, a lower dose of levoketoconazole may potentially be used to achieve the same clinical effects as racemic ketoconazole; however, controlled clinical trials of different doses of levoketoconazole compared with racemic ketoconazole are needed to support these findings. In preclinical studies in rats, 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 in corticosterone were dose-dependent. Levoketoconazole treatment has not yet been evaluated in patients with CS; however, clinical results in healthy subjects and patients with type 2 diabetes 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 administration of both levoketoconazole and ketoconazole compared with placebo. Interestingly, no dose-dependent trend in the percentage change in testosterone was found with levoketoconazole administration [ 47 ]. Finally, significant decreases in low-density lipoprotein cholesterol levels were observed in diabetic patients treated with levoketoconazole [ 47 ].
Levoketoconazole treatment also resulted in nonsignificant lower serum cholesterol levels in rats than the 2R,4S enantiomer or racemic ketoconazole. This may be of particular clinical relevance for patients with CS who have a substantially increased risk of cardiovascular events [ 2 ].
In patients with type 2 diabetes, headache and nausea were the most commonly reported adverse events [ 47 ]. Although levoketoconazole treatment has not yet been evaluated in patients with CS, levoketoconazole may have a more favorable safety profile than racemic ketoconazole, which has been associated with clinically relevant drug—drug interactions and hepatotoxicity.
The pharmacokinetic profiles of levoketoconazole and the 2R,4S enantiomer suggest preferred extraction of the 2R,4S enantiomer by the liver, which may indicate a lower risk of hepatotoxicity with levoketoconazole [ 45 ]. In addition, levoketoconazole shows less potent inhibition of CYP7A1, a rate-limiting enzyme in bile acid synthesis, than the 2R,4S enantiomer [ 47 ]. Nevertheless, there has been some clinical evidence of alterations in liver function enzymes with levoketoconazole treatment [ 47 , 48 ]; further studies will be needed to clarify whether decreased hepatotoxicity is observed with levoketoconazole in patients with CS.
A single-arm, open-label, dose-titration study evaluating levoketoconazole in patients with persistent or recurrent CS, or newly diagnosed patients who are not candidates for surgery, is ongoing ClinicalTrials. The study has a variable dose-titration phase, a 6-month maintenance phase in which patients receive levoketoconazole at the therapeutic dose, and a 6-month extended evaluation phase.
Both mitotane and ketoconazole are strong inhibitors of CYP3A4 and may enhance the activity of drugs metabolized by CYP3A4, including 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 [ 51 ]. Levoketoconazole has similar effects to those of racemic ketoconazole on the CYP enzymes most relevant to drug metabolism [ 45 ].
Like ketoconazole, levoketoconazole has the potential for drug interactions with drugs metabolized via CYP3A4 e. In vitro data have also indicated that ketoconazole inhibits the cardiac potassium channel, hERG, which may result in prolongation of QT interval; thus, ketoconazole should be used with caution when used in combination with agents that also prolong QT interval or are metabolized by CYP3A4 [ 52 ]. In studies of healthy subjects, ketoconazole significantly increased QT interval [ 53 , 54 ].
A trend toward prolongation of QT interval was also reported in a study of levoketoconazole in healthy subjects [ 45 ]. While it is likely that the effect of levoketoconazole on QT interval will be similar to that of ketoconazole, additional studies are needed. Mifepristone, a glucocorticoid receptor antagonist, is also metabolized by CYP3A; thus, drugs that inhibit CYP3A, such as ketoconazole and levoketoconazole, may increase plasma mifepristone concentrations [ 55 ].
Coadministration of these drugs is rare; however, it is important to ensure an adequate wash-out when switching from one therapy to another. Steroidogenic inhibitors are typically administered as monotherapy [ 6 ]. Combination therapy may be necessary in patients who do not respond to monotherapy or who experience dose-limiting side effects [ 10 ].
In patients with severe CS, combining more than two adrenal steroidogenesis inhibitors has also been shown to be effective. Combination therapy with ketoconazole and metyrapone is relatively common, but is generally only considered for patients with more severe disease or for those who have failed to respond to monotherapy with either agent [ 10 , 30 ].