Expanding Men's Birth Control; Introducing Six Promising Options.

Key Takeaways:

• With birth control, the focus has always been on female methods, like oral contraceptive pills, IUDs, contraceptive implants, etc. And in contrast, men have two options- condoms and vasectomy. And there have been reports of latex allergy by men who use condoms as their only method of contraception, and there is the fear of the non-reversal of vasectomy, coupled with the exorbitant cost of getting a vasectomy done.
• Clearly, there is a great need for safer, reversible, cost-effective, accessible, and efficient methods of birth control that are male-focused and acceptable to the intended demographic. And for this reason, this article would explore all the newer options of male birth control, and when they would be available for individual use.

INTRODUCTION

121 million unintended pregnancies occur globally, despite over 16 methods of available contraceptives. And the world’s population is predicted to hit a new high of 8 billion people by September 2022, as hypothesized by the United Nations.

Because historically, most family planning methods focus on female methods of birth control, and while they are effective in preventing unintended pregnancies, many women have reported serious side effects, including migraines, blood clots, depression, high blood pressure, etc. And because of these side effects, they leave many couples and families without appropriate and effective birth control methods.

And recently, several multicultural surveys, spanning four continents reveals that a majority of men expressed willingness to share the responsibility of birth control with their female partners, and use more birth control options that are male-specific, reversible, and adjacent to the female methods.

Until now, men have limited options for birth control: condoms (which are considered uncomfortable by some, largely due to latex allergy, and some other reasons), and vasectomy (which is a permanent invasive method, because of the unpredictable success of reversal surgery). And despite these methods of birth control for men, male methods account for approximately 14% of birth control worldwide, while this percentage increases to 30% in developed countries.

Why male birth control?

Male birth control, also known as male contraceptives, is any method of preventing pregnancy that exclusively involves male physiology.

The greatest perceived benefit of male birth control was increased pregnancy prevention, according to a 2018 survey, where over 31% of the men responded that they would feel more in control of their reproductive health. Also, birth control prevents the transmission of sexually transmitted infections, and helps to curb the increasing crisis of overpopulation.

How do male contraceptives work?

Male contraceptive methods are classified into three broad categories, based on their mode of action, and this guides the development of novel contraceptives:

1. Methods that suppress sperm production.
2. Methods that obstruct the transport of sperms in the female reproductive system
3. Methods that disrupt the fertilizing ability of sperms, such that they can’t fertilize a woman’s eggs.

What are the current methods of male birth control and how did they come into existence?

• ?Condom

The male condom which is worn over an erect penis during sex was created to prevent unintended pregnancy and STIs(sexually transmitted infections), and it dates back to the 18th century when a certain “Dr condom” supplied a king with animal-tissue sheaths to keep him from fathering illegitimate children, and subsequently, condoms were made from linen, silk or plants. And in the 1860s, the earliest form of latex condoms was developed.

Presently,? 5.7% of couples worldwide use condoms as contraceptive methods, with the percentage being higher in developed countries: 20% in the US, 25% in Germany, and 80% in Japan.

Though efficient as a barrier, physically blocking semen from being released into the vagina, millions of men around the world protested that male condoms diminish sexual pleasure. But the major disadvantage of male condom use is its high failure rate of 13%, which can be attributed to human error, rushed use, misuse, or non-use, rather than mechanical failure(breakage or slippage). And in the case of latex allergy (which often goes undiagnosed and unreported), non-rubber(polyurethane, natural membrane) condoms can be substituted; but even with this development, the condom is only moderately effective in preventing pregnancy. Because in theory, condoms are 98% effective if used perfectly. However, with typical real-life use, condoms are only around 85% effective

• Vasectomy

Vasectomy, which is a surgical procedure that prevents sperm from leaving a man’s body, permanently, is performed under local anaesthesia wherein the small tubes in the scrotum that carry sperms are cut and removed.

The first ever vasectomy was performed in 1894 in Britain, to relieve a patient’s swollen, hardened prostate gland. And a few years later, many men who sought vasectomy as a family planning method were denied unless they were at least 35 years and had at least 3 children, such that by 1960, only 45,000 American men had had vasectomies voluntarily. However, as of this writing, the prevalence of vasectomy in Africa is 0.0%, with less than 100,000 men have accessed it, and the highest rates of vasectomy in Africa were reported in South Africa (0.7%) and Namibia(0.4%), which is much lower than the global average of 2.4%( 12% in the USA and Canada combined, and 11% in Oceania and Northern Europe).

The major disadvantage of vasectomy is the possibility of non-reversal and the high costs of vasovasostomy-the surgical procedure that reverses vasectomy- which costs about $6000- $25000 in most United States hospitals. Besides these, short-term complications include but are not limited to haematoma (collection of blood inside the scrotum), infection, and excruciating pain in the testicles. Also, vasectomy is not effective immediately following the surgery.

“Although new sperms won’t be able to get into the semen, it takes a while to get rid of lingering live sperm, following vasectomy. So, it’s imperative to perform sperm analysis to confirm azoospermia(absence of sperms in a man’s ejaculate) before having sex without birth control, to avoid getting someone pregnant post-vasectomy” said Stanton Honig, MD, director of Men’s Health at Yale Medicine Urology, U.S.A.

Before developing new contraceptive methods, there are certain things to be considered, and this guides the development process.

An ideal contraceptive for men should fulfill the following criteria:

1. ?Be readily available and affordable.
2. ?Be acceptable to both partners?
3. ?Be at least as effective as the corresponding female contraceptive methods.
4. ?Have immediate results.
5. ?Be reversible
6. Have no side effects, especially concerning virility, sex drive, and erectile function.

Undoubtedly, male condoms and vasectomy are limited, in that they do not fulfill all the above criteria. And this calls for new contraceptive methods.

So, what are the new methods of male birth control?

1.Male contraceptive gel

A.NES/T???

NES/T, a hormonal male contraceptive gel, which combines progestin(aka nestoterone) and testosterone(male sex hormone that regulates sex drive, bone and muscle mass, and sperm production), is developed by the Population Council, and funded by the National Institute of Health(NIH).

The birth control gel is applied topically to the back and shoulders and absorbed through the skin. The progestin in the gel prevents the production of natural testosterone, thereby decreasing sperm production to less than one million sperm in every milliliter of ejaculation( which is just 0.5% of a normal sperm count)while the testosterone in the gel replaces this effect, and helps to maintain normal sex drive and other functions that the hormone exert.

So far, NES/T gel has been well received in humans, as it is currently in phase 2 clinical trial, and is estimated to be completed by December 2024, when a Phase 3 clinical trial would begin. And in 5 years, it might be commercially available, said Professor Christian Wang, Professor of Medicine at Los Angeles Biomedical Research Institute, and the lead investigator of the clinical trials.

While NES/T has been successfully tested in 420 monogamous couples at 15 sites around the world, and a recent report stated that up to 89% of men who enrolled in the clinical trial at the University of Washington, one of the 15 sites, saw their sperm concentrations reduce to less than one million sperm per milliliter, which is ideal for achieving birth control,

“People have expressed skepticism towards new methods of male contraception, owing to an inherent belief that men would not use the male contraceptive frequently, thereby putting their female partners at risk of unintended pregnancy and that their female partners would not trust them”, says Professor Wang.

Although the contraceptive gel offers reversibility, which is the goal of an ideal male contraceptive; side effects, including rash and increased risk of sunburn at the site of application, have been noted, and are considered acceptable by most people in the clinical trial.

“I have experienced no change in mood, but I’ve got a few small spots on my back, but they are already clearing up. And I have an increased sex drive, and I’ve put on maybe 1kg (in weight) but that’s probably because of the beer if I’m quite honest,” said James- one of the participants in the clinical trial- in a BBC interview.

B. RISUG

Reversible Inhibition of Sperm Under Guidance, or RISUG- developed in the 1970s by Professor Sujoy Guha, a biomedical engineer at the School of Medicine and Technology, India- is a nonsurgical vasectomy procedure, that involves injecting a polymer gel made from styrene maleic anhydride (SMA) and dimethyl sulfoxide (DMSO)- into the vas deferens (a narrow tube in the testes that stores sperm). Normally when a man is sexually aroused, sperm travels from the testes through the vas deferens for ejaculation from the urethra and is launched through the penis. The gel, which is positively charged, attacks sperms (negatively charged) traveling through the vas deferens, thereby rendering the sperms infertile.????

As the name suggests, RISUG is completely reversible: a mixture of water and baking soda is injected into the vas deferens, to flush out the gel.??

Currently, in phase 3 clinical trial, the RISUG gel has been reported to suppress sperm production in 98% of the over 500 men taking part in the clinical trials, and there have been no reports of pregnancy in their partners for close to 13 years. However, slight swelling of the testes, without associated pain, has been observed in a few participants; which resolves within 15 days.

“This would be a world-class contraceptive for men. It is reliable, effective, and long-acting. It is expected to be approved for public usage in the near future,” says RS Sharma, a reproductive biologist at the Delhii-based Indian Council of Medical Research and the contraceptive’s lead researcher.

The commercialization of RISUG gel might take a few more years because the contraceptive has not gained traction beyond India, and for a drug or contraceptive to be received globally, it has to be funded by pharmaceuticals and non-profit organizations; get approved by the Food and Drug Administration, United States of America and get licensed by regulatory bodies. But the good news is that a non-profit organization, Parsemus Foundation has acquired the rights to take RISUG to the American market, and a similar version of RISUG- Vasalgel- has been tested in Rhesus monkeys, and found to be effective in suppressing pregnancy. Human clinical trials are underway.

C. ADAM

ADAM, dubbed “IUD (intrauterine device)" for men, is a water-based gel implant. And like RISUG, it is also non-hormonal, reversible, and long-lasting.

Developed by Contraline, a medical device company; ADAM is designed to provide birth control in men for 12 months. It is a minimally invasive procedure, where the gel is injected into the vas deferens, thereby obstructing the flow of sperms without affecting ejaculation or sexual performance. After the 12 months of its installment, the water-based gel liquefies, restoring sperm's ability to exit the vas deferens, thereby reversing its contraceptive effects.

The first human clinical trial began in April 2022 and is expected to be completed by 2025.?

Contraline has since secured over $10.7 million to finance the trials since 2021, and over 2000 men indicated interest to participate in the clinical trials, as declared by Keven Eisenfrants, co-founder and CEO of Contraline.

2. Male contraceptive device

A.COSO

COSO,” an ultrasound-based, reversible and hormone-free” contraceptive device for men, was invented by a German inventor, Rebecca Weiss, and it is designed for home use.

After years of trying out different hormonal contraceptives, Rebecca Weiss was diagnosed with cancer of the cervix- the aftermath of long-term use of hormonal contraceptives-and this prompted her to develop an alternative method of birth control.

“When my partner and I were looking for an alternative method, we realized the lack of male contraceptives,” she remarked.

COSO, “the testicle-bath” device uses ultrasound(a procedure that sends out sound waves into the body, and in this case-the testicles) to temporarily halt sperm production, therefore, achieving contraception.

And according to a 2012 study done to test the efficacy of ultrasound treatment as a reversible male contraceptive in rhesus monkeys, Dr. Fahim and his colleagues demonstrated that “exposure of the testicles to low-intensity ultrasound resulted in complete and prolonged cessation of sperm production without affecting circulating levels of testosterone.” And it is worthy of note that the rates of sperm production in rhesus monkeys are synonymous with the average rates of sperm production in proven-fertile men.

COSO has since been tested on animals, and clinical trials on humans are right around the corner. The device needs to be filled up with water up to a designated mark, which is assigned by a doctor according to individual testicle size, and then the water is automatically heated up to an operating temperature, and the user sits with legs spread apart to place the testicles in the device for a few minutes, and the remaining time is monitored on the COSO app.

??According to Rebecca, COSO should become effective within 2 weeks and last for at least 2 months. And fertility would return to normal 6 months after the last treatment.

3. Male contraceptive pill

A. DMAU

DMAU, which stands for Dimethandrolone undecanoate, is a hormonal contraceptive pill, taken orally, once daily; and has passed the first round of clinical trials, and is currently being developed as a long-acting injection.

Regarding how the male birth control pill works, it reduces testosterone by suppressing two male hormones- follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-and ultimately results in reduced sperm production.

However, DMAU’s ability to reduce testosterone levels and sperm production has been linked to side effects like acne, headaches, lowered libido, and weight gain. But these symptoms are synonymous with those experienced by millions of women on hormonal birth control pills.

Despite the setback, due to reports of side effects,100 healthy men, ages 18 to 50 in the clinical trial took a daily dose(100mg to 400 mg)of DMAU and after 28 days, expected contraception was achieved.

B. YCT529

YCT529 is a non-hormonal male birth control pill, which works by blocking a protein called the retinoic acid receptor alpha (RAR-a) that binds to a type of vitamin A; retinoic acid(which plays a pivotal role in sperm formation). So once this protein is targeted, it reduces sperm production without interfering with other functions of vitamin A (like cell growth, development of a fetus, etc)) and mitigates side effects.

“YCT529 will begin testing in human clinical trials in the third or fourth quarter of 2022,” said Gunda George, Ph.D., University of Minnesota.

“When given orally to male mice for 4 weeks, YCT529 dramatically reduces sperm counts and is 99% effective in preventing pregnancy without any noticeable side effects. The mice could father pups again 4-6 weeks after they stopped receiving the compound,” said Md Abdullah al-Noman, one of the researchers working on YCT529, at the University of Minnesota.

Taking all of this into account, why are these methods of male birth control not available for public use?

The challenges of getting novel male contraceptives into the market are innumerable. And these barriers include, but are not limited to:

• Male reproductive system

The first challenge to introducing novel male contraceptives is the biological architecture of men. “The male produces hundreds of millions of sperms every day and when the ejaculate comes out, there are 250 million sperm,” said Michael Skinner, a reproductive Biologist at Washington State University, U.S.A. This challenge poses difficulty in achieving contraception by suppressing these millions of sperms in men, in comparison to the relative ease of halting the production of one or two eggs per month in women.

David Sakal, chair and director of the Male Contraceptive Initiative (MCI) says that while small doses of hormones can inhibit a woman’s ovulation- thereby achieving birth control- the male body would have to be flooded with hormones before the testes stop producing sperm.

• Funding

The contraceptive market is predominantly female because historically, birth control has been framed as a “woman’s issue,” and in 2015 alone, the National Institute of Health (NIH), U.S. A spent $424 million on family planning, but much of it went to research in female contraception and reproduction. And there have been concerns about whether the market revenue from male contraceptives would offset the investment necessary to get approval from regulatory bodies and get distributed for commercial use.

• Side Effects

Confounding double standards when it comes to acceptable side effects for men vs women has also contributed to bringing new male contraceptives to the market. And this is evident in the series of terminated research and development of new male contraceptives over the years.?

For instance, in 2016, it was widely reported in several upsetting headlines from different news outlets around the world, that a clinical trial of birth control for men was halted after the participants reported side effects including severe mood changes, increased libido, pain at the injection site and acne. Which to be frank, these side effects are only a fraction of the side effects that women who rely on hormonal birth control experience.

• Regulatory approval

The development of promising contraceptives can be hindered by a complex regulatory process.

“There is an extensive process for new drugs to reach the market, and for contraceptives, it takes about 25 years, which encompass getting it through three clinical trial stages, passing regulatory requirements, and ultimately bringing it to market,” says John Townsend, the chairperson of the Population Council’s ethical review board, United States.

In Conclusion,

Contraception is a basic human right, and the high failure rate of condoms and the unreliability of vasectomy reversals demonstrate the need for alternative, effective male contraceptive options. And the development and the instauration of additional methods of birth control for men would result in a revolutionary change in societal gender dynamics, thereby improving reproductive health for men all over the world, and reducing the burden of unintended pregnancies on marginalized communities.

But in order to achieve this change, there has to be a collaboration between the government, regulatory bodies, pharmaceuticals, public and private health sectors, non-government organizations, and members of the society.

At the current pace of drug development, regulatory approval for new male birth control might take another decade, but this timeline could potentially be shortened with increased resources channeled into the development pipeline. And also schools and community health programs should incorporate information about male birth control into their sex education programs, and there should be awareness on different social media platforms and traditional mediums of communication- to reach marginalized communities- about various available contraceptive methods and updates about the novel options in development.?

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Images Credits:

Getty Images.The Lily (Birth Control) Rebecca Weiss (COSO). Population Council(NES/T)

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