Animal data indicate beneficial effects of hormone replacement therapy (HRT) on cognition and cortical spinogenesis, but results from clinical trials are inconsistent. The authors mimicked, in female monkeys, the timing and composition of HRT regimens used in humans. Neither continuous delivery of oestrogen with or without progesterone nor cyclic delivery of combined oestrogen and progesterone increased the number of spines in the dorsolateral prefrontal cortex. The authors conclude that standard HRT regimens are unlikely to provide the cognitive enhancement — shown in animal models — associated with cyclic oestrogen delivery only.