BACKGROUND Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional regimens fail to mimic normal hormone profiles over 24 hours.OBJECTIVE To investigate the metabolic consequences of conventional hormone replacement in hypopituitary adults by measuring circulating levels of the major fuels, glucose, non‐esterified fatty acids (NEFA), glycerol and 3‐hydroxybutyrate (3‐OHB) over 24 hours in hypopituitary subjects and controls.SUBJECTS Ten GH and adrenocorticotrophin deficient hypopituitary adults on conventional replacement and 13 controls matched for age, sex and body mass index were studied. The patients received replacement with hydrocortisone twice daily (at 0730 and 1730 h; mean (range) daily dose 22 (10–30) mg/24 h) but not with GH. Other hormones were replaced as clinically necessary.MEASUREMENTS Circulating glucose, NEFA, glycerol and 3‐OHB levels were measured over 24 hours together with concentrations of cortisol (total and free), GH and insulin, and urinary free cortisol.RESULTS Levels of glucose, NEFA and 3‐OHB were lower in patients than controls (mean ± SEM) (4.3 ± 0.1vs5.3 ± 0.1 mmol/l,P = 0.0001; 291 ± 46vs448 ± 48 μmol/l,P = 0.015; 78 ± 8vs136 ± 24 μmol/l,P = 0.035, respectively) before breakfast. This decrease in glucose, NEFA and 3‐OHB was observed in the patient group throughout the night, from midnight to breakfast. For NEFA, the decrease persisted throughout the 24 hours. Glycerol did not differ significantly in patients and controls. Integrated levels of total and free plasma cortisol, and 24‐hour urine cortisol excretion, were normal in patients but total and free plasma cortisol concentrations overnight were markedly decreased (overnight area under the curve (AUC) of total cortisol: 440 ± 154vs1593 ± 267 nmol/l h,P = 0.0024; overnight AUC of free cortisol: 24 ± 8vs161 ± 26 nmol/l h,P = 0.0001). GH levels were low throughout the whole 24 hours in the patient group (24‐hour AUC: 10.6 ± 5.1vs74.6 ± 19.6 mU/l h,P = 0.008).CONCLUSIONS Hypopituitary adults on conventional hormone replacement regimens have low concentrations of metabolic fuels, glucose, non‐esterified fatty acids and 3‐hydroxybutyrate throughout the night, possibly related to GH deficiency or to decreased overnight circulating cortisol levels. This overnight fuel deficiency may und