Key to male infertility

Yousef Al-Abed, PhD, and his colleagues at The Feinstein Institute for Medical Research have isolated an immune substance called macrophage migration inhibitory factor (MIF) in semen samples from infertile and reproductively healthy men. MIF is key to helping sperm mature, which is necessary for its union with an egg. The finding could lead to a diagnostic test to determine fertility status.

The study appears in the latest issue of Molecular Medicine. The semen samples were collected from men three to five days after a period of sexual abstinence. The scientists had no idea when analyzing levels of MIF whether the sample came from any of the 68 men who had problems conceiving or from the 27 healthy controls. The findings have a Goldilocks kind of quality: Those with infertility problems had MIF levels that were either too high or too low. Those who had no problems conceiving had levels that were just right.

When the scientists added MIF into lab dishes filled with healthy sperm, it decreased the count and impaired their motility.

If MIF has a role in infertility, Dr. Al-Abed and his colleagues are wondering whether it might just work as a form of male contraception. In the meantime, the scientists have a patent on an assay that can be used to analyze MIF levels to help determine whether a man will have problems conceiving. About 15 percent of couples attempting to get pregnant for the first time have problems conceiving. About 40 percent of infertility problems are due to disorders in the male.

MIF is a key player of the immune system. MIF was identified 40 years ago but it was only recently that scientists discovered its role as a pro-inflammatory substance. MIF has now been linked to many autoimmune and inflammatory diseases – such as diabetes and sepsis – and Al-Abed, an organic chemist by training, has been trying to identify and design small molecules that would block MIF activity.

The Feinstein researchers recently identified a critical area on the MIF protein surface that is crucial for the inflammatory response. Such a substance designed to target this area could be used to treat a variety of conditions, including septic shock, sepsis, rheumatoid arthritis and diabetes. The team designed a specific inhibitor called ISO-1 to fit into this pro-inflammatory site. In an animal model of sepsis, ISO-1 abolishes MIF’s potent inflammatory abilities and the animals respond dramatically. They lived through the once-fatal sepsis.

In patients in the throes of sepsis – an over-reactive and potentially fatal immune response to a bacterial infection – MIF concentrations are 10 to 20 times higher than normal. If MIF goes down, the chance that patients will survive sepsis is increased dramatically. “The idea is to suppress inflammation so that cells stop producing MIF,” said Dr. Al-Abed.

Every year, 215,000 Americans die of sepsis, a systemic inflammatory reaction to infection. Another 500,000 survive the infection, and scientists are still trying to figure out why these patients survive and others don’t. There are no treatments for this massive all-out war on the body. Those who survive often face serious cardiovascular problems. Scientists examining cardiac function during sepsis have identified macrophage migration inhibitory factor (MIF) as a key factor in heart damage. And antibodies targeted to MIF, so-called anti-MIF antibodies, significantly improves cardiac performance during septic shock.

MIF levels are also two times higher in autoimmune diseases like rheumatoid arthritis and diabetes. In the laboratory, Al-Abed and his colleagues found that having MIF on board in high amounts in animals prone to diabetes set the disease process in motion weeks earlier than expected. The team is now trying to design a clinical study to look at MIF levels in type 1, or juvenile, diabetes.

One thing has become clear about the MIF molecule: It needs a network. To act as a pro-inflammatory soldier, it relies on other substances to help. “MIF on its own is not toxic,” Dr. Al-Abed said. They are now trying to figure out what substances MIF partners with to do its dirty work.