Progesterone is synthesized by the cells of the oocyte-cumulus complex and is present at micromolar concentrations in the vicinity of the oocyte. Human spermatozoa generate a biphasic [Ca2+]i signal and undergo acrosome reaction upon progesterone stimulation, suggesting that the hormone acts as a secondary inducer or primer of acrosome reaction in association with the zona pellucida.
However, progesterone sensitivity of human spermatozoa is so high that many cells may undergo AR prematurely, probably compromising their ability to fertilize. Using fluorescent imaging of cells loaded with Oregon Green BAPTA-1, we have shown that exposing human spermatozoa to a progesterone gradient to mimic the stimulus encountered as sperm approach the oocyte, results in a very different response to that described in all previous reports, revealing a complexity and sophistication in the [Ca2+]i signaling of human spermatozoa that was not previously suspected. A slow rise in sperm [Ca2+]i occurs upon which, in many cells, [Ca2+]i oscillations are superimposed, which persist throughout recording (up to 1 hr). These oscillations are generated by an intracellular store in the neck region of the sperm, mobilizing in response to activation of a ryanodine-receptor (like) channel which is independent of IP3 production. Frequency of oscillations does not reflect the concentration of progesterone, which acts as a switch, the store then functioning as a semi-autonomous oscillator. Cells which generate repetitive [Ca2+]i oscillations do not show enhanced levels of acrosome reaction, but instead show an alternating pattern of flagellar activity associated with peaks and troughs of [Ca2+]i. It is proposed that; (1) acrosome reaction and flagellar beat are regulated by separate Ca2+-stores, (2) these stores are mobilized through different mechanisms by different agonists, and (3) progesterone in vivo acts as a switch for the oscillator which regulates flagellar beat mode.