A potential new male contraceptive drug has just undergone its first tests in human volunteers. The results give the first indication that the drug, which does not use artificial hormones or affect testosterone production by the testes, may be safe in humans.
Author
- Susan Walker
Associate Professor in Contraception, Reproductive and Sexual Health, Anglia Ruskin University
While previous attempts have been made to develop a male contraceptive in the past, these largely failed to pass clinical trials due to their unacceptable side-effects. But this newest contraceptive works differently from past attempts, which means it doesn't require surgery and is much less likely to cause hormonal side-effects - problems that have helped stop previous attempts from reaching the market.
The study showed the drug was well tolerated in a small group of healthy young men and did not appear to cause any serious side-effects at the doses used. Further research will be needed to demonstrate precisely how effective it is as a contraceptive.
The new method uses a specially-designed chemical known as YCT-529 to target a specific cell receptor in the testes called retinoic acid receptor-alpha.
Similar, but less specific compounds, had been shown to reduce sperm production in humans previously. But these compounds also had unwanted side-effects - such as feeling ill when drinking alcohol , altering salt levels in the bloodstream and not being fully reversible in all men. This made them unsuitable for contraceptive use.
But in animal studies , YCT-529 was shown to produce fully reversible, temporary infertility without any significant side-effects. A study in mice also found that those who went on to father babies after stopping the drug produce normal, healthy offspring.
Based on these results, the drug then entered into phase one trials in humans. This is the first stage of human testing, where a small group of healthy volunteers are recruited to test safety, tolerability and possible side-effects.
This small trial involved 16 male volunteers who took the drug twice at increasing doses - either 10mg to 30mg or 90mg to 180mg. Some men took placebo pills for comparison.
The participants were monitored for 15 days for any effects on normal hormone levels, inflammation (signs of cell damage), kidney and liver function, abnormal heart rhythms, sexual desire and mood.
No changes were detected in the natural hormones in the body. There were also no lasting effects on liver and kidney function and no signs of cell damage. No dangerous abnormalities of heart rhythm were detected, and the participants reported no changes in mood or sexual desire.
However, participants only took two doses of the drug and were only followed up for 15 days. The authors say in the paper that a larger phase two trial is underway which will test the drug in a greater number of men.
This will then be followed by phase three trials in hundreds of men where the effectiveness, reversibility and side-effects of longer term use of the drug will be assessed. These are the hurdles which have prevented other approaches from being made widely available.
Why past male contraceptives have failed
At present there are no commercially available contraceptive methods for men that are not only safe and effective at preventing pregnancy, but which also allow sperm production to be turned off and on again at will.
While condoms have few side-effects and are used at will, they have a relatively high failure rate (resulting in pregnancy around 12%-18% of the time with typical use).
A vasectomy, which severs the tube connecting the sperm-producing testes to the rest of the male reproductive organs, is very effective (more than 99%) and safe - but it's not easily reversible and requires a minor operation.
There have been previous attempts (and some ongoing) at producing a reversible method of contraception for men. Some have proven to be effective at stopping sperm production or preventing sperm from exiting the male reproductive tract. However, they haven't moved to the stage of commercial production, often because of unwanted side-effects.
Most of these attempts used one of two main approaches to prevent pregnancy.
One method involves injecting a substance into the vas deferens (a tube leading from the testes to the urethra). This substance filters out and damages sperm during ejaculation. This substance can be flushed out through a minor procedure if the man wishes to become fertile again.
The drawback of this method is that it requires a minor surgical procedure (an injection into the scrotum) and that the man has to have a further procedure to reverse its effects.
The second route involves stopping sperm production altogether by lowering the hormones that cause sperm to be made in the testes.
The most successful of these trials used an injectable progestogen (a synthetic version of the sex hormone progesterone). This injectable signalled the brain to stop producing follicular stimulating hormone (FSH) and lutenising hormone (LH), which normally signal the testes to produce sperm and testosterone.
However, suppressing LH also turned off the testosterone in the testes that is needed for normal, healthy function in men. To counteract the loss of testosterone, this contraceptive approach required men to take an "add back" testosterone - either as a tablet or a gel applied to the skin.
But a major trial testing this method was stopped early because of the hormonal side-effects participants experienced, including mood swings, acne and changes to sex drive.
There's a long way to go before the new drug can be considered suitable for use as a male contraceptive. But this new approach shows a lot of promise because it avoids upsetting hormonal balance and can be taken orally - rather than requiring an invasive procedure.
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Susan Walker has previously received funding from Bayer PLC who manufacture contraceptive devices.
