Two drugs, currently prescribed to organ transplant patients to suppress their immune system after the procedure, show great promise as birth-control medicine for men, according to a study published in the journal Science.
Cyclosporine A (also known as CsA) and FK506 (also known as tacrolimus) are currently in use with transplant recipients to reduce the risk that their body will reject the new organ. They work by inhibiting their body’s ability to synthesize a protein that mobilizes T-cells to attack. More specifically, they block the enzyme called calcineurin. And this ability is exactly what makes them promising as male birth-control.
By studying mice, researchers in Japan identified a version of calcineurin that is found only in sperm, built from a pair of shorter proteins — PPP3CC and PPP3R2. They created male mice that were unable to produce PPP3CC (and thus naturally produce less PPP3R2). Then they studied these “knockout” mice to see how they differed from their unaltered fellows.
They found that the knockout mice still had sex, but the females didn’t become pregnant. The absence of PPP3CC must be making the males infertile, the researchers figured, then set about figuring out why. The sperm got where they were needed — researchers found that sperm from the knockout mice were able to reach the part of the ovary where fertilization usually takes place. They noted that the number of sperm was lower than in regular mice, but not low enough to explain the infertility.
So they tried giving the little swimmers some help, and performed in vitro fertilization using sperm from the knockout mice. They were unable to fertilize an egg as long as the it was covered by its usual layer of cumulus cells, but it wasn’t the cumulus cells that were the problem. In further tests, the researchers found that the sperm could make their way through these cells and bind to the zona pellucida, or ZP, the membrane that surrounds the egg. But that was as far as they could go.
What kept the sperm from getting through the ZP? The knockout sperm were able to move at the about same velocity as the regular sperm, the researchers found. However, the knockout sperm were deficient at something called “hyperactivation.” This is a particular type of movement that requires the sperm’s whiplike tail to beat back and forth with extra force.
But the Japanese researchers wanted to know more. They found that the tails of the knockout sperm moved with the same frequency as those of the unaltered mice, but the part that connects the tail to the head was too rigid. This made the entire sperm cell too inflexible to move with enough force to penetrate the ZP, the researchers concluded. To make sure this was the true bottleneck, they used IVF again, to see whether knockout sperm could fertilize eggs once the ZP was gone. They could, and the fertilized eggs developed all the way to term.
Then the research team gave the immunosuppressant drugs to regular mice, to see whether their sperm would turn out like the sperm of the knockout mice. The drugs had no effect on mature sperm cells, which were just as flexible as ever, but worked better on sperm that were still developing. Regular male mice that got either CsA or FK506 for two weeks became infertile, because the middle part of their sperm was rigid. Further tests showed that it took only four days for FK506 to render the mice infertile, and five days for CsA to do the same.
When the mice stopped taking the drugs, their fertility returned after one week.
“Considering these results in mice, sperm calcineurin may be a target for reversible and rapidly acting human male contraceptives,” they concluded.