Endocrine Abstracts

Endocrinologists focus on circulating and excreted cortisol for diagnosis of, and to assess severity and treatment response in, Cushing’s syndrome (Cs). However, in Cs, morbidity is mediated by excess cortisol binding to intracellular glucocorticoid (GC), mineralocorticoid (MC), and non-genomic receptors. We and others have demonstrated that 11b-hydroxysteroid dehydrogenase type 1 (HSD-1) is the source of about half of intrahepatocellular cortisol in healthy adults, patients with diabetes, and patients with mild hypercortisolism. The circulating concentration of cortisol is higher than cortisone, yet its bioavailability is limited, due to the former’s greater affinity to plasma proteins. Free circulating cortisol and cortisone concentrations are similar, the latter providing a reservoir of “inactive” GC that enters cells and is rapidly converted by HSD-1 to cortisol. Patients with severe hypercortisolism who are deficient in HSD-1 activity showed no cortisol-related morbidity. A HSD-1 inhibitor prevented the deleterious effects of prednisolone on glycemic control and osteocalcin in a Phase 1 clinical trial. Mice without the Hsd11b1 gene (which encodes HSD-1) or treated with a HSD-1 inhibitor were protected from glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, dermal atrophy, and trabecular bone loss associated with GC administration. In states of glucocorticoid excess, liver HSD-1 activity is enhanced, as assessed by the HSD-1 ratio of urinary excreted cortisol/cortisone metabolites. Administration of a HSD-1 inhibitor to such patients could reduce Cs morbidity via reduction of the cortisol (or HSD-1 metabolized medications, e.g., prednisolone) available to intracellular receptors. Furthermore, unlike current Cs treatments that are associated with substantial adrenal insufficiency risk, under full and sustained HSD-1 inhibition autonomously produced or ACTH-stimulated cortisol remains elevated in the circulatory pool, available to enter cells and act at GC, MC or non-genomic receptors at concentrations likely sufficient to prevent adrenal insufficiency. Those model predictions are under evaluation in ongoing Phase 2 clinical trials of the HSD-1 inhibitor SPI-62 in patients with ACTH-dependent Cushing’s syndrome, autonomous cortisol secretion, and (in combination with prednisolone) polymyalgia rheumatica. Until further direct experience in these conditions is gathered, we still advise caution in patients with modest autonomous cortisol secretion, who may have suppressed ACTH and atrophied normal adrenal tissue, particularly in situations where stress-dose, non-precursor GC steroids should be considered (e.g., use hydrocortisone not cortisone acetate, or prednisolone not prednisone).