Cornell University scientists have taken a major step toward developing a safe, reversible, long-acting and 100% effective nonhormonal male contraceptive, considered the holy grail of male contraception.
A proof of principle study in mice, six years in the making, shows how targeting a natural checkpoint in meiosis, the process by which sex cells reproduce, safely stopped sperm production.
The study published Tuesday in the Proceedings of the National Academy of Sciences.
The researchers made use of JQ1, a small molecule inhibitor that was developed as a research tool to study cancer and inflammatory disease. Because of its neurological side effects, it wasn’t a viable therapy for disease, or as a final contraceptive, but it’s known to disrupt a stage of meiosis called prophase 1. This enabled Cornell researchers to provide the first proof of principle that meiosis – and sperm production – can be targeted safely and reversibly.
“We’re practically the only the group that’s pushing the idea that contraception targets in the testis are a feasible way to stop sperm production,” said Paula Cohen, professor of genetics and director of the Cornell Reproductive Sciences Center.
“Our study shows that mostly we recover normal meiosis and complete sperm function, and more importantly, that the offspring are completely normal,” Cohen said.
Currently, male contraceptives include condoms and vasectomies. Many men are wary of vasectomies, the only long-acting option for men, and they are technically reversible through subsequent surgery. Researchers have been especially reluctant to develop a hormonal contraceptive, as such treatments have proven potentially dangerous in women.
Cohen and colleagues decided to target meiosis, as opposed to other stages, in order to fully stop sperm production in a manner that was reversible and that left males otherwise fully functional.
“We didn’t want to impact the spermatogonial stem cells, because if you kill those, a man will never become fertile again,” Cohen said. Also, once sperm entered spermiogenesis, there was a potential for viable sperm to leak out and fertilize an egg.
JQ1 disrupts meiosis by killing cells during a stage called prophase 1, and it cuts off the onset of gene expression required for spermiogenesis.
In the study, the researchers administered JQ1 in male mice for three weeks. They found that the mice produced no sperm, and that all the molecular parameters of meiosis were disrupted, including chromosomal behavior during prophase 1.
Then they stopped delivering JQ1, and within six weeks, most of the healthy parameters of prophase 1 returned, along with normal sperm production. They then bred those mice and found they were all fertile, and bred the pups to show that they too were fertile, yielding healthy offspring.
“It shows that we recover complete meiosis, complete sperm function, and more importantly, that the offspring are completely normal,” Cohen said.
A male contraceptive would likely start in the form of an injection taken every three months, or possibly a patch, to ensure effectiveness, Cohen said.
