He stared back at me, his face blank. He didn’t like my answer. We had examined the known genetic causes of azoospermia and had come up dry. “I really don’t know why you’re azoospermic, but I’d say it’s still very likely to be genetic, but currently undefined.” Not much to work with, but it’s where we are at the moment.
“Unexplained male infertility” is when the evaluation reveals nothing to explain the problem. Everything, including the semen analysis, is stone cold normal. But, when the semen analysis shows no sperm and similarly, all medical, hormonal and genetic testing comes up clean, then this is called “unexplained azoospermia.” In this case, the Y chromosome testing looks fine and the rest of the chromosomes look pristine.
Here’s what’s on the slate for explaining cases of azoospermia in the future:
- Look in other places. Our genetic testing focuses heavily on the Y chromosome, which makes sense since it’s the male chromosome and it harbors a bunch of male fertility genes. Believe it or not though, the girlish X chromosome could harbor just as many male fertility genes!
- Look at the beginning. The testicle develops within the early fetus when sperm precursor stem cells migrate to what will become the testicle proper and populate it. Failure of this migration caused by faulty developmental genes could leave the house “empty” of sperm as an adult.
- Look at the path. The quality control process in the sperm making business is intense. Maybe that’s why every sperm is sacred. Our studies show that important quality checkpoints are present when chromosomes mix and match (recombination) during meiosis. If these molecular “dances” do not go well, infertility could result
- Look at other paths. Changing the DNA sequence of a gene is called a “genetic mutation.” But what is it called when you alter a gene without causing a mutation? Epigenetics. Yes, I am getting technical here but these stealth genomic changes are fascinating and have recently been associated with male infertility. Not only that, they may be inherited from one generation to the next.
So, men are a lot more complicated than they appear. I’ll admit that saying that azoospermia is “genetic but undefined” is an excuse for now, but stay tuned as this science is sizzling.