50 Years of Research and Still No Male Contraceptive Pill?

Written by Swathi Kumar, edited by Daniele Guido and Ryan Khan.

What’s taking so long?

Condoms and vasectomies are the main methods that come to mind when considering male contraception. Conversely, female birth control methods, such as oral contraceptive pills and intrauterine devices (IUDs), have long since dominated the market due to a combination of cultural, religious, and socioeconomic factors. Research has come a long way since Ancient Egyptians used honey and lemon as a spermicide in 3500 BC, with a whopping 257 female contraceptive pills available on the market today. In stark comparison to major growth in the female contraceptive industry over the past century, the stagnation of the male contraceptive pill market is rather surprising (Figure 1).

When developing the ideal contraceptive, there are several boxes to tick:

• Easy to use and rapidly effective
• Favourable safety and tolerability profiles
• Reversible
• Acceptable to both partners and does not affect libido
• Inexpensive and readily available

Hundreds of female contraceptive drugs have managed to pass this checklist, yet the situation is quite the opposite for male contraceptive alternatives despite our modern-day scientific knowledge of the male reproductive system. To understand the position of the male contraceptive industry, scientific research, public opinion, global potential and cost effectiveness must all be considered.

The Research Pipeline

There are four categories of male contraceptive methods undergoing clinical trials: male birth control pills, male contraceptive gels, nonhormonal options and vas-occlusive contraception.

1. Male birth control pills work similarly to their female counterparts in that they both target molecular receptors to manipulate hormonal activity. Dimethandrolone Undecanoate (DMAU) and 11β-Methyl Nortestosterone (11β-MNT) both bind to androgen and progesterone receptors. Daily oral DMAU, Injectable DMAU and 11β-MNT are currently under evaluation in  Phase I clinical trials.
2. The daily male contraceptive Nestorone (NES) and Testosterone (T) (NES/T) combination gel works quite differently. The gel is applied to the shoulders and upper arms for 4 hours every day and reduces sperm concentration from the normal level of < 15 million/mL to < 1 million/mL.
3. Nonhormonal drugs target genes and proteins essential for male fertility. One such example is a soluble adenylyl cyclase (sAC) inhibitor that inhibits a molecule called ADCY10 found only in male germ cells. Another nonhormonal male contraceptive target is the Epididymal Protease Inhibitor (Eppin), which binds to a protein in the semen called semenogelin. Developing a small organic compound that binds to Eppin and mimics the effects of semenogelin would result in a rapid decrease in sperm intracellular pH and calcium levels, and ultimately prevent sperm motility.
4. Vas-occlusive contraception blocks sperm transport in the vas deferens. The front-runner in the male contraceptive alternative industry, RISUG (Reversible Inhibition of Sperm Under Guidance), falls under this category. RISUG is a gel-based polymer which coats the inner walls of the vas deferens (the tube that carries sperm to the urethra) and affects sperm mobility, whilst still allowing fluid to pass through.

The Professor Who Spent 40 Years Developing a Male Contraceptive Injection

A new drug takes between 10–15 years to become commercially available. Professor Sujoy Guha spent over double the amount of time – his entire career – developing the world’s first male contraceptive injection RISUG. He published his first paper on RISUG in 1979 and completed clinical trials in 2019 – a whole 40 years later. So, what took so long? In 1993, someone reported that the individual chemicals styrene and maleic anhydride in the injection were carcinogenic, causing clinical trials to halt for 3 years. However, the injection contains the compound styrene maleic anhydride (SMA), which is in fact, not carcinogenic. Combining SMA with dimethyl sulphoxide (DMSO) causes the formation of an ionic film that neutralises sperm within the vas  deferens. As RISUG’s name describes, the contraceptive effect can be reversed using two injections which dissolve the film. RISUG can last up to 10–15 years. Unfortunately for Professor Guha, history repeated itself in 2002 when another case was made against RISUG’s toxicity, just 6 months before the injection was due to become commercially available in India. At present, RISUG is the only male contraceptive procedure currently in an extended Phase III clinical trial and is waiting for approval for mass production in India.

The Feasibility of Male Contraceptive Alternatives

The effect of RISUG is localised, lasts for up to 15 years and is easily reversible with minor side effects. But how many men would opt to use it? A US survey from 30 years ago revealed that only 78% of men believed that contraception is a shared responsibility. Many societies have since developed a more modern outlook on contraception compared to the 1990’s when circulating information on contraception in the US was illegal. But internationally, is the idea of the male contraceptive alternative a reality? An average of 55% of men expressed interest in using alternative male contraception in a 2002 global survey across 9 countries (Figure 2). The highest percentage of men willing and men disapproving to use a new male fertility control were seen in Spain and Argentina, respectively. Indonesia was the only country to have a higher percentage of disapproving than willing views. The result of this survey provides some insight on which regions of the world may be more receptive to a male contraceptive alternative than others. Increased communication to the general public about the advantages of alternative male contraception will certainly help normalise what can already be a sensitive topic.

The global potential of a male contraceptive drug is enormous, even though the COVID-19 pandemic has delayed family planning for many. Unintended pregnancy rates are substantially higher in low-GDP countries than in high-GDP countries. Poor contraceptive use is listed as one of the various causes of overpopulation, with only 43% of women in developing countries being reported to use at least one form of contraceptive (Figure 3). The global average fertility level, or the average number of children per woman, is 2.68. In contrast, Niger has the world’s highest fertility level at 6.9. The UN’s 2020 report on World Fertility and Family Planning quotes “If the rise in contraceptive use accelerates, fertility levels may fall faster than expected”. Therefore, if 50% of men in developing countries were to take a contraceptive drug, it would theoretically make up for the remaining half of the population and majorly influence the global fertility level. This is key to tackling overpopulation and achieving the UN’s sustainability goals.

A 2018 UK survey suggested 33% of British men would be open to trying hormonal contraception, but as of August 2021, there is still no male contraceptive alternative on the market. If it were, the most effective arrangement would be for the NHS to offer contraceptive alternatives for free to men, just as female contraceptive pills are free for women. If male contraceptive alternatives were purchased privately, the cost would still be far cheaper than a £500 vasectomy at the same private healthcare provider. Keeping in mind the global potential of an alternative male contraceptive, the willingness to try it and the various ongoing clinical trials, alternative male contraceptive solutions should eventually revolutionise family planning and the notion of contraception as a whole.

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