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Glucocorticoids (GC), commonly prescribed for their anti-inflammatory actions, have adverse metabolic and bone effects. 5a-reductase inhibitors (5aRI) inhibit the metabolism of cortisol to its active metabolites and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors inhibit the re-activation of cortisol from the inactive cortisone. Two clinical studies were performed to investigate how coadministration of prednisolone with a 5aRI and prednisolone with an 11ß-HSD1 inhibitor affects the GC-induced metabolic effects in healthy volunteers. The FindIt2 clinical study is a prospective randomized study. 19 healthy male volunteers were recruited and underwent detailed metabolic assessment before and after administration of prednisolone (10mg daily) or prednisolone (10mg daily) and a 5aRI (finasteride 5 mg daily or dutasteride 0.5 mg daily) for 7 days. The results showed that 5aRIs can exacerbate the adverse effects of prednisolone such as hepatic, peripheral and adipose tissue insulin resistance. This study has significant translational implications, including the need to consider GC dose adjustments, but also the necessity for increased vigilance for the development of adverse effects. The TICSI study is a randomized, double-blind, placebo-controlled study. 32 healthy male volunteers were recruited, of which 30 were eligible for analysis. They were randomized to receive prednisolone + placebo or prednisolone + AZD4017 for 7 days. They also, underwent detailed metabolic assessment before and after treatment. The results showed that co-administration of 11ß-HSD1 inhibition limits the adverse metabolic and bone effects of prednisolone. 11ß-HSD1 inhibition provides a potential strategy for selectively limiting the adverse side effects of prescribed GC. The outcomes of these two clinical studies suggest that pre-receptor metabolism plays a fundamental role in the effect of GCs in metabolic tissues. Assessment of prereceptor enzyme activity could be used to predict response, as well as risk of sideeffects, in patients requiring treatment with GCs.