The incidence of left ventricular hypertrophy is significantly increased in post-menopausal women¹.Serum levels of 17β-estradiol and progesterone can decrease after menopause by up to 95%² and there is controversial evidence suggesting that hormone replacement therapy may be cardioprotective³.Animal studies also suggest a role for estrogens in the development of cardiac hypertrophy. For example it has been demonstrated that disrupting the expression of FKBP12.6, a protein closely associated with RyR channels, results in Ca²⁺ dysregulation in both male and female mice but only cardiac hypertrophy in males⁴.Treatment with tamoxifen, an estrogen receptor antagonist, removes this protection. To investigate whether female sex hormones can affect SR Ca²⁺ release in cardiac cells by directly modulating RyR channel function, we examined the effect of 17β-estradiol and progesterone, on the gating of RyR channels. The concentrations of hormones used in this study were close to physiological plasma levels found in pre-menopausal women².RyR from sheep hearts obtained from an abattoir were incorporated into phospholipid bilayers under voltage-clamp conditions and single-channel recordings were monitored with Ca²⁺ as the permeant ion as previously described⁵. 17β-estradiol and progesterone were dissolved in ethanol and added to the cytosolic side of the bilayer. Vehicle controls were conducted to ensure that the concentration of ethanol used did not affect channel gating.Channels were activated with ATP (1mM) and 1 µM free Ca²⁺. Our results demonstrate that the open probability (Po) of the cardiac RyR is reduced in a dose-dependent manner; the control Po (0.52±0.09) was reduced by 17±12, 50±21, and 73±10* % by 0.1, 0.5 and 1 µM progesterone respectively (mean±SEM; n=4; one-way ANOVA *P<0.001). Similarly, Po was also reduced by 17β-estradiol; 0.04 µM 17β-estradiol reduced Po to 41±15 % of control (mean±SEM; n=5; T-test P<0.05). It appears that these effects are not specific to the cardiac isoform because 0.04, 0.1 and 1 µM 17β-estradiol also reduced the Po of rabbit skeletal RyR by 63±21*, 64±18* and 81±4* % of control respectively (mean±SEM; n=5; one-way ANOVA *P<0.001).These results demonstrate that 17β-estradiol and progesterone directly inhibit RyR channel gating and suggests a potential mechanism for the protective properties of these hormones in pre-menopausal women.