Reassessing the role of progesterone in fertilization—compartmentalized calcium signalling in human spermatozoa?

Progesterone is present at micromolar concentrations in the vicinity of the oocyte. Human spermatozoa generate a biphasic rise in intracellular calcium concentration ([Ca(2+)](i)) and undergo the acrosome reaction upon progesterone stimulation, suggesting that the hormone acts as a secondary inducer or 'primer' of the acrosome reaction in association with the zona pellucida. However, the sensitivity of human spermatozoa to progesterone is such that many cells may undergo the acrosome reaction prematurely, compromising their ability to fertilize. We have shown that exposing human spermatozoa to a progesterone gradient, simulating the stimulus encountered as sperm approach the oocyte, results in a novel response. A slow rise in [Ca(2+)](i) occurs, upon which, in many cells, [Ca(2+)](i) oscillations are superimposed. Cells showing this pattern of response do not undergo the acrosome reaction, but instead show an alternating pattern of flagellar activity associated with peaks and troughs of [Ca(2+)](i). A Ca(2+) store in the rear of the sperm head apparently generates this complex signal, functioning as an '[Ca(2+)](i) oscillator'. We propose that: (i) the acrosome reaction and flagellar beat are regulated by separate Ca(2+) stores; (ii) these stores are mobilized through different mechanisms by different agonists; and (iii) progesterone in vivo acts as a switch for the oscillator which regulates the flagellar beat mode.