The differential diagnosis and treatment of Cushing's syndrome

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Unrecognized cavernous sinus (CS) invasion by adenomas is a major factor in surgical failure and recurrence of Cushing disease (CD), and pituitary adenomas. Exploration of the CS during trans-sphenoidal surgery (TSS) and resection of the involved medial wall of CS (medial wall of the CS) can achieve apparent gross total resection. Of 315 consecutive transsphenoidal procedures, 50 patients had CS exploration because of preoperative MRI findings (n = 37) or intraoperative findings (n = 13). Adenoma adherence (n = 18, 36%) or invasion (n = 32, 64%) of the medial wall was observed. Thirteen patients with subtotal resection were recommended for radiation. Among 37 patients with gross total resection, 12 (29.7%) received radiotherapy because of elevated postoperative hormone levels, including persistent hypercortisolemia (n = 5), elevated normalized early postoperative ACTH (n = 5), or cortisol (n = 5). No recurrence occurred in these 12 patients. This integrated strategy, using intraoperative findings and postoperative biochemical monitoring, may guide effective adjuvant therapy in CD. We aimed to identify predictors of treatment success and hepatotoxicity during rapid titration of ketoconazole (KTZ) and metyrapone (MET) in patients with ACTH-dependent Cushing syndrome and to assess differences in blood pressure or potassium. KTZ achieved target morning cortisol <12 ug/dL in 39% of patients, compared to 74% on MET. Lower baseline cortisol predicted success only with MET. Among KTZ responders, maximal effect occurred by 2 days after a dose increase. LFTs worsened with KTZ and improved with MET. A similar proportion of patients had an LFT reach or exceed 3ULN with KTZ (22%) and MET (25%). Higher doses of KTZ, but not MET, predicted this. Blood pressure and hypokalemia improved with KTZ but did not change with MET. Based on this retrospective review, hypercortisolism can likely be controlled faster with rapid titration of KTZ or MET than is currently done. LFT abnormalities increased with KTZ but were common with MET treatment, likely reflecting underlying liver pathology in CS. Identification of tumors causing ectopic ACTH syndrome (EAS) is challenging. We prospectively compared DOTATATE, F-DOPA and conventional imaging modalities in 24 patients with ectopic ACTH syndrome caused by neuroendocrine tumors confirmed by pathology and/or biochemical cure. Among the functional scans, the sensitivity (Se) for F-DOPA was higher than Octreoscan (Se 88%, 95%CI 67% - 97% vs 31%, 95%CI 10% - 61%) and overlapped DOTATATE (Se 79%, 95%CI 57-92%). Among structural modalities, CT had the highest Se (96%, 95%CI 76-100%) when interpreted knowing results of functional scans; Se was 57% (95%CI 35-76%) without those data. Cardiac CT/MRI had the 100 positive predictive value (PPV). Combinations of CT/MRI plus DOTATATE and/or F-DOPA provided high PPVs (89-100%) with Se 64-87%. Combined CT and MRI without functional scans provided PPV 79% with Se 55%.DOTA and DOPA improve tumor detection in EAS by increasing Se of structural scans and PPV of detected lesions. The two scans are complementary and should be integral to imaging strategies for EAS. However, DOPA is not currently FDA-approved for this indication. Hypogonadism may be caused by Cushing syndrome and may intensify its adverse consequences. We retrospectively determined the frequency of male hypogonadism before and after curative surgery for CS, and its cause. 36 of 44 men had baseline hypogonadism (total T 205 ± 28 ng/dL and suppressed or low LH). LH, total and free T, and sex hormone-binding globulin increased at 6 and 12 months post curative surgery, but hypogonadism persisted in 51% at 6 months and in 26% at 12 months. Mean LH and LH pulse frequency increased after surgery without changes in LH pulse amplitude, mean FSH, or peak gonadotropin response to GnRH, suggesting that hypogonadism is mediated through suppression of hypothalamic GnRH secretion. We also provided guidance regarding the evaluation and treatment of ectopic ACTH syndrome as well as commentary on the use of weighted evening doses of medical treatment (ie “chronotherapy”) for Cushing syndrome. Ongoing work evaluates the utility of the ACTH antagonist atumelnant in the treatment of ACTH-dependent Cushing syndrome.