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

Purpose

Endogenous 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 comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. However, some patients may not be eligible for surgery due to comorbidities, and approximately 25 % of patients, especially those 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 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.

Methods

We performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs.

Results

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 (LCI699) and levoketoconazole (COR-003), show promising results that will have to be confirmed in larger-scale phase 3 studies (currently ongoing).

Conclusions

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.

     

Pituitary Society Delphi Survey: An international perspective on endocrine management of patients undergoing transsphenoidal surgery for pituitary adenomas

Pituitary - In adults and children, transsphenoidal surgery (TSS) represents the cornerstone of management for most large or functioning sellar lesions with the exception of prolactinomas....     

Remission rate after transsphenoidal surgery in patients with pathologically confirmed Cushing’s disease, the role of cortisol, ACTH assessment and immediate reoperation: a large single center experience

Postoperative serum cortisol is used as an indicator of Cushing’s disease (CD) remission following transsphenoidal surgery (TSS) and guides (controversially) the need for immediate adjuvant treatment for CD. We investigated postoperative cortisol and adrenocorticotropic hormone (ACTH) levels as predictors of remission/recurrence in CD in a large retrospective cohort of patients with pathologically confirmed CD, over 6 years at a single institution. Midnight and morning cortisol, and ACTH at 24–48 h postoperatively (>24 h after last hydrocortisone dose) were measured. Remission was defined as normal 24-h urine free cortisol, normal midnight salivary cortisol, a normal dexamethasone-corticotropin releasing hormone (CRH) test or continued need for hydrocortisone, assessed periodically. Statistical analysis was performed using PASW 18. Follow up data was available for 52 patients (38 females and 14 males), median follow up was 16.5 month (range 2–143 months), median age was 45 years (range 21–72 years), 28 tumors were microadenomas and 16 were macroadenomas, and in eight cases no tumor was observed on magnetic resonance imaging. No patient with postoperative cortisol levels >10 mcg/dl were found to be in remission. Ten of the 52 patients with cortisol >10 mcg/dl by postoperative day 1–2 underwent a second TSS within 7 days. Forty-three patients (82.7 %) achieved CD remission (36 after one TSS and 7 after a second early TSS) and six patients suffered disease recurrence (mean 39.2 ± 52.4 months). An immediate second TSS induced additional hormonal deficiencies (diabetes insipidus) in three patients with no surgical complications. Persistent disease was noted in nine patients despite three patients having an immediate second TSS. Positive predictive value for remission of cortisol <2 mcg/dl and ACTH <5 pg/ml was 100 %. Cortisol and ACTH levels (at all postoperative time points and at 2 months) were correlated (r = 0.37, P < 0.001). Nadir serum cortisol of ≤2 mcg/dl and ACTH <5 pg/ml predicted remission (P < 0.005), but no level predicted lack of recurrence. Immediate postoperative ACTH/cortisol did not predict length of remission. No patients with postoperative cortisol >10 mcg/dl were observed to have delayed remission; all required additional treatment. There was no significant difference in age, body mass index, tumor size and length of follow-up between postoperative cortisol groups: cortisol ≤2 mcg/dl, cortisol >5 mcg/dl and cortisol >10 mcg/dl. Immediate postoperative cortisol levels should routinely be obtained in CD patients post TSS, until better tools to identify early remission are available. Immediate repeat TSS could be beneficial in patients with cortisol >10 mcg/dl and positive CD pathology: our combined (micro- and macroadenomas) remission rate with this approach was 82.7 %. ACTH measurements correlate well with cortisol. However, because no single cortisol or ACTH cutoff value excludes all recurrences, patients require long-term clinical and biochemical follow-up. Further research is needed in this area.     

Predictors of silent corticotroph adenoma recurrence; a large retrospective single center study and systematic literature review

Purpose

Silent corticotroph adenomas (SCAs) are clinically silent and non-secreting, but exhibit positive adrenocorticotropic hormone (ACTH) immunostaining. We characterized a single center cohort of SCA patients, compared the SCAs to silent gonadotroph adenomas (SGAs), identified predictors of recurrence, and reviewed and compared the cohort to previously published SCAs cases.

Methods

Retrospective review of SCA and SGA surgically resected patients over 10 years and 6 years, respectively. Definitions; SCA—no clinical or biochemical evidence of Cushing’s syndrome and ACTH positive immunostaining, and SGA—steroidogenic factor (SF-1) positive immunostaining. A systematic literature search was undertaken using Pubmed and Scopus.

Results

Review revealed 814 pituitary surgeries, 39 (4.8%) were SCAs. Mean follow-up was 6.4 years (range 0.5–23.8 years). Pre-operative magnetic resonance imaging demonstrated sphenoid and/or cavernous sinus invasion in 44%, 33% were >?50% cystic, and 28% had high ACTH levels pre-operatively. Compared to SGAs (n?=?70), SCAs were of similar size and invasiveness (2.5 vs. 2.9 cm, p?=?0.2; 44 vs. 41%, p?=?0.8, respectively), but recurrence rate was higher (36 vs. 10%, p?=?0.001) and more patients received radiation therapy (18 vs. 3%, p?=?0.006). Less cystic tumors (0 vs. 50%, p?<?0.001) and higher pre-operative ACTH levels (54 vs. 28 pg/ml, p?=?0.04) were predictors of recurrence for SCAs.

Conclusion

This review is unique; a strict definition of SCA was used, and single center SCAs were compared with SGAs and with SCAs literature reviewed cases. We show that SCAs are aggressive and identify predictors of recurrence. Accurate initial diagnosis, close imaging and biochemical follow up are warranted.

     

Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience

Acromegaly is associated with serious morbidity and mortality, if not well controlled. Approved somatostatin receptor ligands (SRLs) are a mainstay of medical therapy and exhibit preferential affinity for somatostatin receptor (SSTR) subtype 2. Our objective was to assess whether characteristic features of individual growth hormone (GH)-secreting adenomas at diagnosis, correlated with SRL sensitivity, using defined tumor markers. A retrospective review of 86 consecutive acromegaly surgeries (70 patients) performed between January 2006 and December 2011 was undertaken. Patients with any preoperative medical treatment were excluded. Response to SRL therapy was defined as normalization of insulin-like growth factor 1 (IGF1) and random GH < 1.0 ng/dl. Immunohistochemical staining pattern: sparsely granulated, densely granulated, mixed growth hormone-prolactin (GH/PRL) and SSRT2 positivity (+) were correlated with clinicopathologic features, adenoma recurrence, and SRL treatment response. Two-tailed t test, univariate ANOVA, Kruskal–Wallis and bivariate correlation were performed using PAWS 18. The cohort eligible for analysis comprised 59 patients (41 female and 18 male). Based on pre-surgery adenoma imaging dimensions, 81.3 % (48) were macroadenomas and average maximum tumor diameter was 18.1 ± 9.9 mm. Patients on SRLs were followed for 13.4 ± 15.8 (mean ± SD) months. Sparsely granulated adenomas were significantly larger at diagnosis, exhibited lower SSTR2 positivity and had a lower rate of biochemical normalization to SRLs. Densely granulated adenomas were highly responsive to SRLs. Overall, patients with SSTR2A+ adenomas responded more favorably to SRL treatment than those with SSTR2A? adenomas. Eighty-one percent of patients with SSTR2A+ adenomas were biochemically controlled (both GH and IGF1) on SRL treatment, e.g. a much higher normalization rate than that reported in the unselected acromegaly population (20–30 %). Detailed knowledge of adenoma GH granularity and the immunohistochemical SSTR2A+ status is a predictor of SRL response. These immunoreactive markers should be assessed routinely on surgical specimens to assess subsequent SRL responsiveness and potential need for adjunctive therapy after surgery.     

Failure of successful renal transplant to produce appropriate levels of 1,25-dihydroxyvitamin D

Introduction Bone metabolism disturbances following renal transplantation (RT) are complex and multifactorial in origin. Abnormalities in 1,25-dihydroxyvitamin D levels in RT patients under treatment at our Bone Center prompted this retrospective study. Methods Parameters of vitamin D metabolism were compared in RT patients and a cohort of patients with primary hyperparathyroidism (PHTP) who mimicked the hyperparathyroid state of the RT patients. Thirty-one RT recipients (from 300 reviewed) matched our inclusion criteria with a stable graft function for more than 1 year and a glomerular filtration rate (GFR) >50 mL/min per 1.73 m² (Group A); these were compared with 42 consecutive patients with PHTP who had been referred to the same Bone Center for treatment for over 1 month (Group B). Statistical analysis included the chi-square or Fisher’s exact tests for categorical data and the Wilcoxon rank sum test for quantitative measures. Results The mean (±SD) 1,25-dihydroxyvitamin D level was significantly lower (p < 0.001) in Group A patients (29.8 ± 16.2) than in Group B patients (70.2 ± 25.9) despite non-significant differences in the levels of parathyroid hormone (PTH) (mean: 184.0 vs.101.1;p < 0.29), phosphorus (mean: 3.2 vs. 3.1; p < 0.3) and 1,25-vitamin D (mean: 19.5 vs. 25.2; p < 0.06). Group A patients had lower levels (p < 0.05) of mean serum calcium and calculated GFR (9.3 mg/dL, 65.7 mL/min) than Group B patients (10.6 mg/dL, 97.6 mL/min). 1,25-Dihydroxyvitamin D significantly correlated with calcium (p < 0.001), 25-vitamin D (p < 0.005) and GFR (p < 0.001) in both groups, but there was a notable lack of association between 1,25-dihydroxyvitamin D and PTH (p < 0.64) or phosphorus (p < 0.26) in Group A patients. In this group, 1,25-dihydroxyvitamin D was not influenced by the type of immunosuppresion regimen (p < 0.06), use of biphosphonates (p < 0.73), presence of diabetes (p < 0.59), menopause in women (p < 0.08), season (p < 0.43) or race (p < 0.31). Our data indicate that 1,25-dihydroxyvitamin D metabolism remains disturbed for a considerable time after successful RT, with the result that the level of 1,25-dihydroxyvitamin D in RT patients is lower despite physiological signals that should stimulate its production. Our analysis of many clinical variables was unable to elucidate the underlying mechanism(s) for this disturbance. Conclusion Successful RT may not produce appropriate levels of 1,25-dihydroxyvitamin D commensurate to the elevated levels of PTH. This abnormality along with sustained hyperparathyroidism may contribute to bone loss following transplantation.     

Extended treatment of Cushing’s disease with pasireotide: results from a 2-year,Phase II study

In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing’s disease (core study), treatment with pasireotide 600 μg sc bid reduced urinary free cortisol (UFC) levels in 76 % of patients and normalized UFC in 17 %. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open-ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged ≥18 years with Cushing’s disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56 % of the 18 patients had lower UFC than at core baseline and 22 % had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing’s disease.