Impact of progestins on estradiol potentiation of the glutamate calcium response

One mechanism by which estrogen may modulate cognitive function is through potentiation of glutamate-mediated rises in intracellular calcium ([Ca²⁺]_i) with resultant effects on neuronal morphology and signaling. Since progesterone is a component of hormone replacement therapy (HRT), we sought to determine whether therapeutically relevant progestins attenuated or blocked estrogen potentiation of glutamate-induced [Ca²⁺]_i rises. 17β-estradiol and progesterone, alone or in combination, significantly potentiated the rise in [Ca²⁺]_i. When co-administered, progesterone attenuated the estrogen response to the level seen with progesterone alone. In contrast, medroxyprogesterone acetate (MPA) had no effect when administered alone and completely blocked the 17β-estradiol-induced potentiation when co-administered. These results may have important implications for effective use of HRT to maintain cognitive function during menopause and aging.