March 16, 2021
An extract of an herb used in traditional Chinese medicine works as a reversible oral contraceptive in male mice and monkeys, researchers say.
Triptonide, extracted from the herb Tripterygium wilfordii Hook F, did not appear to cause any side effects in the animals, said Wei Yan, MD, PhD, an investigator at the Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California.
"This is the tenth or eleventh compound we tested," Yan told Medscape Medical News, "and right away I realized this is it. Bingo. We got it."
Yan and his colleagues are now seeking funding to complete pharmacology and toxicology studies on triptonide. If those are promising, they plan to start human clinical trials. Their study was published in Nature Communications.
If triptonide finds its way to market, it will hit a target that researchers have been missing for decades.
Worldwide, half of all pregnancies are unintended, and half of unplanned pregnancies end in abortion, suggesting that current methods of contraception are falling short, Yan said.
Although there are many alternatives for women, including oral drugs, men have only condoms, vasectomy, withdrawal, and the avoidance of penetration, which have varying degrees of efficacy.
"I don't think it's fair to ask women to take pills, and men cause the trouble and don't take responsibility," Yan said.
Researchers have had difficulty finding pharmaceutical means to control the male half of the reproductive process. Female oral contraceptives use hormones to mimic pregnancy, which is a time during which women are naturally infertile. No such phase exists for men. And although women release one egg a month, men produce a thousand sperm every second, any one of which can fertilize the egg.
It has proved very hard to kill all those sperm without hurting the man who makes them, Yan said. So he hit on the idea of crippling the sperm instead.
Disrupting Sperm Development
Searching for compounds that might achieve this goal, he came across literature on T wilfordii Hook F, commonly known as lei gong teng, or thunder god vine. Practitioners of traditional Chinese medicine use it to treat rheumatoid arthritis and other autoimmune and inflammatory diseases. He said that with more than 3 months of use, it can cause male infertility. It appears to interrupt the development of the sperm, causes malformations, and lowers sperm counts and motility.
In the 1980s, studies of two compounds isolated from the herb, triptolide and tripchlorolide, caused such severe liver toxicity in rats that researchers abandoned those investigations.
Focusing instead on a less abundant compound in the herb, triptonide, Yan and his colleagues got much better results.
In an initial study to determine the best dose in mice, they found that a dose of 0.8 mg/kg body weight per day produced sperm with heads bent backward. Such sperm are not able to travel to find an egg, they determined. The drug didn't cause any measurable ill effects on the mice.
They fed the drug to 12 male mice for 4 weeks, then mated each of these males to two fertile female mice. Although the mice copulated, none of the female mice became pregnant. After a washout period, the male mice were able to impregnate female mice.
The researchers ran a similar series of studies in macaque monkeys. They found that a dose of 0.1 mg/kg body weight per day caused deformations in more than 95% of the sperm in these monkeys. The researchers treated four male monkeys for up to 126 weeks. None of them showed any major health effects.
Yet, the treated male monkeys were unable to impregnate fertile female monkeys. After the researchers stopped treating the male monkeys for about 40 days, the animals' sperm returned to their normal shapes, and the monkeys were again able to impregnate female monkeys.
Sperm counts were lower in the treated monkeys than in the control monkeys, but the difference was not statistically significant.
"I'm excited about the paper," said John Amory, MD, MPH, a professor of medicine at the University of Washington, Seattle, Washington. "We've struggled, those of us interested in developing a male contraceptive."
Research has shown that most women would trust their partners to use an oral contraceptive, he said. "And men account for 30% of contraception now, so they're using the contraceptives they have available," he said.
Amory emphasized that the triptonide research is still in early stages. He and his colleagues continue to work on a hormonal approach to male contraception.
Yan and Amory have disclosed no relevant financial relationships.
Nat Commun. Published online February 23, 2021. Full text
Laird Harrison writes about science, health and culture. His work has appeared in national magazines, in newspapers, on public radio and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at www.lairdharrison.com or follow him on Twitter: @LairdH.