16 August 2012
There may be new hope in the search for “the Pill” for men, a male contraceptive that would be more effective than condoms and more easily reversible than a vasectomy. A compound called JQ1, which was originally developed as a cancer therapy, can also cause reversible infertility in male mice without apparent side effects for the rodents or their offspring, researchers report today. The compound isn’t ready for testing in healthy men, but it offers a promising lead in the quest for an improved male contraceptive. “I’m delighted to see a new potential approach,” says reproductive biologist William Bremner of the University of Washington School of Medicine in Seattle, who was not involved in the study.
Scientists have struggled for decades to find ways to reversibly and safely block male fertility. Bremner says several key challenges stand in the way: First, men generate millions of sperm per day compared to the typical single egg a woman produces each month. Second, there is a “blood-testis barrier” that blocks many blood-borne compounds from reaching the area where sperm are produced. Finally, any potential drug must be extremely safe and not cause any lasting genetic damage to sperm or their precursor cells.
JQ1 was originally developed as an anticancer agent, says James Bradner, a chemical biologist at Dana-Farber Cancer Institute in Boston and one of the paper’s authors. It was designed to inhibit a protein called BRD4, which helps regulate cell division and is known to be involved in a type of aggressive skin cancer. Bradner has high hopes that BRD4 inhibitors such as JQ1 will become cancer therapies, but he and his colleagues knew that BRD4 is also closely related to a protein called BRDT, which helps control cell division in the testis. So they collaborated with Martin Matzuk, a reproductive biologist of Baylor College of Medicine in Houston, Texas, to test JQ1 as a potential contraceptive in mice.
The researchers report today in Cell that after 6 weeks of daily injections of JQ1 the animals’ sperm counts were reduced by nearly 90%. Only 5% of the remaining sperm were able to swim properly, compared with 85% of sperm in control mice. After 3 months of treatment, none of the mice were able to sire offspring, although their mating behavior was otherwise normal. The compound had no apparent effect on the production of testosterone or other hormones made by the testes. The researchers also showed that the effect is reversible. A month or two after treatment stopped, all of the mice were again able to father as many pups as control mice, and the animals’ testis size and sperm counts returned to normal levels between 1 and 3 months after treatment stopped. The treatment caused no obvious side effects in the mice, and the offspring of the treated animals showed no abnormalities.
The compound seems to target developing sperm both before and after meiosis, the special cell-division process that forms sperm and eggs, Matzuk says. That means that there are fewer sperm precursor cells in the testis, and few of those go on to produce functional sperm.
Bradner, the father of 18-month-old twins, jokes that he has been taking “a gram a day” of JQ1 recently. But both he and Matzuk caution that researchers need to find a new compound that interacts with only the testis protein BRDT—and doesn’t affect BRD4 or related proteins that are present in most of the body’s cells—before clinical tests can begin. “We need a compound that is exquisitely specific,” Bradner says. Matzuk says that the crystal structure of BRDT interacting with JQ1, which colleagues at the University of Oxford have worked out, will provide valuable clues.
Debra Wolgemuth, a reproductive biologist at Columbia University Medical Center who has studied BRDT, agrees. “If you’re taking healthy people in their twenties and giving them a drug, you want to be very sure it doesn’t affect anything else,” she says. “The bar for safety and efficacy is as high as you can get.” She and her colleagues have been testing compounds that interrupt vitamin A metabolism, which have also shown promise as male contraceptives. However, she notes that the lifespans of mice aren’t sufficient to test the possible long-term effects of drugs that people might want to be able to take for decades. Primate experiments, meanwhile, are prohibitively expensive, and funding is scarce. “I’m very excited when any new developments come along for a field that has been dreadfully overlooked for far too long,” she says. “The more targets we have to pursue, the better.”