Male contraceptive jab 'effective', but side effects...

"Male contraceptive injection '96% effective'," ITV News reports.

The news comes from a study looking at a new type of male contraceptive injection, which was found to be effective – but side effects like acne and mood changes were common.

The 320 healthy men involved in the study received contraceptive injections every eight weeks. Two injections were given into the buttocks: the "female" hormone progestogen and the "male" hormone testosterone.

After an initial lead-in phase to make sure the injections adequately suppressed sperm count (below 1 million/mL), the men and their partners entered a one-year test phase where they relied on the injections as a form of contraception.

The injection was effective in 98.4% of men in terms of preventing pregnancy. But the researchers found there was a high side effect rate.

For example, just under half the men reported developing acne (45.9%) and just under one in five reported mood disorders.

And around 5% of men did not recover their sperm count one year after stopping the injections.

While more than three-quarters of the men – and their partners – said they would be happy to continue to use this form of contraception, these potentially serious complications need to be addressed.

As low-tech as it may seem, the condom does have the benefit of being both 98% effective (if used correctly) and a proven method of preventing a wide range of sexually transmitted infections.

Where did the story come from?

The study was carried out by researchers from Martin Luther University and the University of Münster in Germany, as well as other international institutions.

It was funded extensively: by the United Nations Development Programme; the United Nations Population Fund; the United Nations International Children's Emergency Fund; the World Health Organization; the World Bank Special Programme of Research, Development and Research Training in Human Reproduction; and by CONRAD and Eastern Virginia Medical School using funding from the Bill and Melinda Gates Foundation and the US Agency for International Development.

The study was published in the peer-reviewed Journal of Clinical Endocrinology and Metabolism on an open access basis, so you can download the paper for free (PDF, 1.92Mb).

The UK media's reporting of the study was appropriately balanced. The potential benefits of the treatment were promoted, but the need for its side effects to be addressed was also highlighted.

What kind of research was this?

This non-randomised phase II study aimed to look at the effectiveness and safety of the male contraceptive injection.

Phase II trials are fairly early-stage studies that aim to get a better idea of the safety and effectiveness of a potential new treatment. If the findings are promising, they can move on to larger randomised controlled trials.

The researchers state that an effective form of male contraception – aside from condoms and sterilisation – is still needed.

Being able to ensure that the effects of contraception end once a man chooses to stop using it – known as reversibility – is also a pressing concern.

Early studies showed giving synthetic testosterone could suppress sperm development, although there have been potential safety concerns about this. Later study found the testosterone dose can be reduced by giving progestogen at the same time.

This study aimed to look at the contraceptive effectiveness and safety of giving muscular injections of the progestogen norethisterone enanthate (NET-EN) combined with a long-acting male hormone, testosterone undecanoate (TU).

What did the research involve?

The multicentre study was carried out at 10 centres across seven different countries: the UK, Australia, Germany, Italy, India, Indonesia and Chile.

Researchers recruited 320 healthy men aged 18 to 45 and in stable, monogamous relationships with their female partners, aged 18 to 38.

The male participants had to have a normal sperm count, with no abnormalities of shape or movement, no sexually transmitted infections, and no medical or mental health illnesses.

Female partners had to be healthy, with no desire for pregnancy within the next two years, but willing to accept a low but unknown pregnancy risk.

The study protocol included an initial suppression phase lasting 26 weeks, where men were given progestogen (NET-EN, 200mg) and testosterone injections (TU,1000mg) into the buttock muscles at the beginning of the study and then at 8, 16 and 24 weeks.

They also provided semen samples every two weeks. During this phase, couples had to use an alternative non-hormonal method of contraception, such as a condom.

When the man had produced two consecutive semen samples with sperm concentration of less than 1 million/mL, they entered the contraceptive effectiveness testing phase.

This lasted just over one year, and the men received continued to receive regular injections every eight weeks.

The couple were asked to stop using all alternative methods of contraception, and hence had to rely on the male injections.

During the testing phase, the men continued to provide semen samples at the time of each injection.

If the sperm concentration rose above 1 million/mL, they stopped the injections and entered the recovery phase of the trial, and normal contraception was resumed.

They were still regularly monitored to keep pregnancy risk to a minimum.

The main outcomes of interest were the rate of suppression of sperm during the 26-week suppression phase and the effectiveness rate during the testing phase.

Researchers also looked at the safety and reversibility of the regimen, as determined by the recovery of sperm concentration after stopping treatment. Acceptability questionnaires were also given to both partners.

What were the basic results?

Of the 320 men, 274 had achieved the required suppression by 24 weeks, with a suppression rate of 95.9 per 100 continuing users.

Eight men decided they didn't want to continue to the effectiveness phase, despite suppressed sperm production.

During the testing phase, four pregnancies occurred among the partners of the 266 continuing men, with a rate of 1.57 per 1,000 continuing users.

All pregnancies occurred in the first four months of the one-year phase. In three of these four pregnancy cases, the man's sperm count was actually below the required 1 million/mL concentration.

Six men also had "sperm rebound" during the one-year testing phase, with sperm concentrations rising to between 2 and 16.6 million/mL.

The overall failure rate when taking into account failure to suppress sperm in the suppression phase during the testing phase or pregnancy occurring was 7.5%, or a success rate of 92.5 per 100 men.

During the recovery phase, when men were tested for up to one year after stopping injections, 94.8 per 100 men had recovery of sperm concentration of 15 million/mL or more.

A total of 1,491 side effects were reported during the study, but over a third were not considered to be related to the treatment.

The most common side effects related to treatment were:

acne (46% of men reported)
increased interest in sex (38%)
injection site pain (23%)
emotional disorder (17%)
muscle aches (16%)

The study was terminated early when it was considered that the risk to the study participants in terms of side effects outweighed any benefits.

Around 88% of both men and women found the method acceptable at the start of the treatment phase, declining to around 80% at the start of the recovery phase.

How did the researchers interpret the results?

The researchers concluded that, "The study regimen led to near-complete and reversible suppression of [sperm production].

"The contraceptive efficacy was relatively good compared with other reversible methods available for men. The frequencies of mild to moderate mood disorders were relatively high."

Conclusion

This is a valuable early-stage trial that gave a good indication of the potential safety and effectiveness of the combined testosterone and progestogen male contraceptive injection.

The study has many strengths in its design, including the long overall trial duration encompassing the successive phases, comprehensive monitoring throughout, and a good sample size.

The findings show that the injection was effective in terms of adequately suppressing sperm and avoiding pregnancy in 92.5 per 100 users, or in 98.4 per 100 when only looking at failure defined as an unwanted pregnancy.

However, there are several obstacles to overcome with the method as it stands.

The men had to be continually monitored. If this treatment were ever to be licensed using this method, injection appointments and having to provide sperm samples every eight weeks may be off-putting for a lot of couples.
In three of the four accidental pregnancies, the sperm count was below the required "effective" 1 million/mL concentration – this shows that this wasn't necessarily a fail-proof and effective threshold level to aim for in all men.
One year after treatment, 94.8 per 100 men recovered their sperm concentration. Though this seems high, it certainly isn't ideal that around 5% of men would not have recovered within one year of stopping. Whether they would in the longer term is unclear.
The rate of side effects was very high and was the main reason the researchers decided to end the trial.

These findings are promising, but there's a lot of work that still needs to be done before we get any closer to a licensed contraceptive injection for men.

And important side effects, such as the potential impact on mental health, also need to be addressed.

Allan Young, professor of mood disorders at the Institute of Psychiatry, Psychology and Neuroscience at King's College London, said: "This is an interesting and important study which adds to the body of data about hormonal effects on mood, although the findings will need to be replicated.

"The adverse effects ... remind us that men, as well as women, may be subject to effects of reproductive hormones on mood.

"Mood disorders are serious neuropsychiatric conditions and should be carefully considered when reviewing the risk/benefit ratio of any treatment in this area."

Many researchers have claimed that a reliable male contraceptive drug is probably just a few years away from reaching the market. The problem is that these claims have been made for more than 40 years.

We would recommend sticking to the tried and tested condom for the time being.