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Poison-Tipped Arrows May Hold Secret to New Male Birth Control
Kansas Ag Connection - 07/09/2018

In springtime, many a young man's fancy will naturally turn to thoughts of love, contraception and, well ... poison-tipped arrows?

For years, women have taken on much of the responsibility when it comes to avoiding unintended pregnancies, but that may all be changing thanks to a new form of male contraception being formulated at the University of Kansas Medical Center that features a variation of an ancient poison used by African hunters and warriors on the tips of their arrows.

"There have been several studies in our country that show that men will be receptive to use contraceptives," said Gustavo Blanco, M.D., Ph.D., professor and Kathleen M. Osborn Chair of the Department of Molecular and Integrative Physiology at KU Medical Center. "While there are contraceptives for women, the development of a male contraceptive will reduce the burden of family planning that has been placed on women and will be now shared by men."

From pills to patches, sponges to IUDs, women have had far more options than men when it comes to birth control. The Food and Drug Administration approved the first female hormone pill for contraceptive use in 1960, and for the better part of six decades women have had access to a relatively safe and effective forms of birth control with the added bonus of the effects being reversible.

For men, the options have been much more limited. Basically, they can use condoms, have a vasectomy, or abstain from sex altogether. The World Health Organization (WHO) estimates that each year about 85 million pregnancies around the world are unintended, so another form of contraception may help shift some of the responsibility over to men.

Blanco's team is collaborating with researchers from the University of Minnesota, led by Gunda I. Georg, professor and chair of the Department of Medicinal Chemistry and director of the Institute for Therapeutics Discovery and Development. Their work to create a safe, reliable and reversible form of male contraception is being supported by the Contraception Branch at the National Institutes of Health, led by Branch Chief Daniel S. Johnston, Ph.D. Blanco and Georg have collaborated on several NIH-funded studies dating back to her days as a faculty member on the KU campus in Lawrence.

Blanco and Georg's teams have zeroed in on a chemical known as ouabain -- a plant extract that African warriors and hunters used as a heart-stopping poison as far back as the third century B.C. More specifically, they are looking at how an altered form of ouabain can be used to inhibit a protein in sperm cells that prevents them from swimming, which is key for male fertility.

"Several years ago we discovered that a unique form of a protein (Na,K-ATPase alpha4) that transports salt in cells is only found in sperm and is necessary for sperm to swim and fertilize the eggs," said Blanco. "A specific inhibitor that interferes with the function of these salt transporters is ouabain, a compound that at relatively high concentrations is toxic to cells."

Ouabain is found in the roots, stems, leaves, and seeds of the Acokanthera schimperi and Strophanthus gratus plants, which are native to eastern Africa. Oubain can disrupt the function of the salt-transporting proteins of heart tissue making it a deadly poison.

"The protein we found in sperm is much more sensitive to ouabain than that of the heart or of other cells," said Blanco, who has been studying ouabain as a tool to inhibit the salt transportation mechanism in cells for some time. "The high sensitivity to ouabain of the sperm salt transporter that we are studying prompted us to develop a more specific drug with the capacity to only poison sperm without affecting other types of cells."

Fertility researchers are currently following two paths when it comes to developing a male birth control pill: hormonal and non-hormonal. At this point the hormonal camp appears to have taken the lead in the race to get a product to market, but their solutions are not without drawbacks.

Scientists working with hormonal agents, such as the sex hormones progestin and testosterone, have already moved their pills into human trials, making them arguably closer to having a marketable product. But these pills have shown a variety of side effects, including weight gain, changes in libido, and lower levels of good cholesterol that could affect heart health. Generally speaking, it could be decades before the long-term effects of the hormone pills are known.

Blanco and Georg are looking at a non-hormonal approach that can naturally target mature sperm and severely limit their capacity to move, reach the egg and fertilize it. Researchers have spent the better part of the last 10 years creating versions of the ouabain molecule that bind to the transporter protein found in mature sperm. This sperm-seeking derivative of ouabain has been shown to affect sperm cells when tested on laboratory rats, decreasing the sperms' capacity to swim. Additionally, the rats have shown no ill side effects.

"One of the reasons that made us think of non-hormonal compounds for contraception is the secondary effects that sex hormones have on the human body," Blanco said. "Ouabain is specific in inhibiting salt transporters that are present in most cells. Because of this, it functions as a poison; however the modifications that we have performed and the compounds that we obtained allows them to more-specifically target only the salt transporter in sperm. Therefore, in theory, these should result in fewer secondary effects."

Just because early testing of the ouabain analog has shown promising results in laboratory rats, you won't be able to rush out and buy a non-hormonal male contraceptive pill anytime soon. Now that researchers have shown the ouabain analogs can severely reduce sperm's ability to move in test tubes and lab rats, they will need to conduct mating trials to demonstrate that a reduction in sperm motility results in real-life results.

WHO numbers suggest that a reduction in sperm motility of approximately 60 percent is enough to temporarily render a man infertile. The research team from KU Medical Center and Minnesota have their sights set on 100 percent, but they note that 80 percent would be effective.

"I believe that our strategy for male contraception using the target that we found and the compounds that we have developed has a very good chance of being successful," Blanco said.

If the mating trials prove successful, Blanco's team will begin the traditional procedure used whenever a new drug is created, including toxicological and pharmacologic studies. Their hope is to begin human trials within five years, and Blanco said those studies could take about 10 years.

So for now, the only arrows involved in humans falling in love will be the ones Cupid has at the ready in his quiver.

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