Endocrine Abstracts

Fluasterone (16-α-fluoro-5-androsten-17-one) is a structural analogue of dehydroepiandrosterone (DHEA) that retains DHEA clinical properties without its androgenic effects. In animal models, fluasterone exhibits DHEA-like effects, including anti-inflammatory, anti-proliferative, and anti-diabetic properties but is consistently more potent than DHEA. An orphan-drug designation for fluasterone has been granted by the FDA for treatment of Cushing’s syndrome (CS), including hyperglycemia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatosis (NAS). Oral DHEA was shown to produce remission of hyperglycemia in mice. Oral fluasterone was shown to be superior to control in reduction of plasma glucose levels and while DHEA is highly androgenic, producing 25-fold increase in plasma testosterone levels and a dose-related increase in seminal vesicle weights, these findings were not present in mice treated with fluasterone. The mechanism of the anti-glucocorticoid effect of fluasterone has not been established. Fluasterone prevents thymic involution induced by treatment with pharmacological doses of dexamethasone in mice, which indicates marked anti-glucocorticoid action independent of any changes in endogenous glucocorticoid levels. In mice, fluasterone, when injected subcutaneously at 5 mg/kg, decreased plasma corticosterone levels, and this was correlated with lowering of fasting plasma glucose. As the dose of fluasterone was increased, corticosterone and fasting plasma glucose levels both rebounded due to increased corticotropin. In mice that develop NAFLD, 8-wk treatment with fluasterone lowered inflammation and NAS fibrosis. In humans, a total of 105 adults have received one or more oral or buccal doses of fluasterone during seven phase-1 and phase-2 trials. Because oral fluasterone underwent extensive first-pass metabolism, oral dosing was discontinued. Nevertheless, oral studies showed efficacy in patients having either rheumatoid arthritis or hypertriglyceridemia. Buccal fluasterone was then investigated in a phase 1/2 study of 24 adults with metabolic syndrome who received an 8-wk, once-daily buccal tablet of fluasterone or placebo. The triglyceride levels in the 80 mg fluasterone group declined from baseline by 34% at week 2, 4, 6, and 8 and by 35% at week 8. In the placebo group, at the corresponding time points the triglyceride levels increased by 6% and 7%, respectively. The decline in triglyceride level from baseline in the 80 mg buccal fluasterone group was significantly greater than that in the placebo group with no adverse events reported. Thus, we propose a double-blind, placebo-controlled, crossover pilot study of the efficacy and safety of buccal Fluasterone in the control of hyperglycemia in adults with CS.