adAfterSmallInset

Introduction to How RISUG Works

When it comes to human reproduction, men have it easy. They enjoy all of the fun of procreation, but don't have to carry the baby or deliver it. When it comes to preventing pregnancy, however, the advantage lies clearly with the fairer sex. The one egg released every month by a woman makes an easy target for a variety of contraceptive interventions. As a result, women have numerous choices for contraception.

Men, on the other hand, present a greater challenge. Driven by eons of evolution involving complex processes of the endocrine and reproductive systems, men produce tens of millions of sperm per day. To prevent pregnancy, every one of those specialized cells -- think of them as DNA-packed Olympic swimmers -- must be blocked, hamstrung or killed. It's a daunting task, especially when you consider the timelines involved. It takes 75 days for sperm fashioned in the testes to mature in a tightly coiled companion structure known as the epididymis. That means an intervention that blocks sperm production won't become fully protective for two and a half months. And men who go off such an intervention would have to wait the same length of time before their fertility returns.

Because of these challenges, the search for the perfect male contraceptive -- one that's 100 percent effective, easy to use, reversible and free of side effects -- has been elusive. Condoms can fail; vasectomies are permanent and the male birth control pill hasn't materialized into a viable solution. Hope, however, may soon arrive in the form of a clear gel that's injected into the vas deferens, one of the body's main highways for sperm. The gel will be marketed in the U.S. under the name Vasalgel, but the technique is known as reversible inhibition of sperm under guidance, or RISUG. Don't bug your urologist just yet, though -- the gel still has miles to go before it receives approval from the U.S. Drug and Food Administration. Even in India, where a biomedical engineer invented the technique and has studied it for decades, RISUG still languished in phase III clinical trials as of spring 2012.

What exactly is RISUG, how does it work and how much does it cost? Is the gel safe in men who use it for years? And is it truly reversible, as its name suggests? We'll answer those questions on the following pages, but we'll begin -- in a bit of editorial foreplay -- with a story about water purification.

Guha got the inspiration for the male contraceptive RISUG when he was working on ways to fix India's water supply.

Anna Henly/The Image Bank/Getty Images

adAfterSmallInset

From Germs to Sperm: The History of RISUG

The brainchild behind RISUG is Sujoy Guha, a graduate of the Indian Institute for Technology in Kharagpur. Over his long career, Guha has brought inventive, original thinking to a variety of problems. In the 1960s, while at St. Louis University's School of Medicine, he teamed up with another researcher to develop a method for simulating the flow of blood through the human body. They tried a number of mechanical pumps, but none created the rhythmic ebb and flow of a normal circulatory system.

That led them to study the effects of a magnetic field on weak salt solutions resembling blood. The researchers made an interesting discovery: If they arranged electromagnets in the proper configuration, they could make the ions in a salt solution move in one direction. What's more, the electrically charged particles would actually pull water molecules along with them. When they assembled a prototype of a pump based on the principle, they found they could generate a jet stream of water without producing noise or vibrations. Such systems, known today as magnetohydrodynamic propulsion units, caught the attention of ship manufacturers and fiction writers. Tom Clancy based the electromagnetic "caterpillar drive" featured in "The Hunt for Red October" on Guha's ideas.

By then, the Indian researcher had moved back to his homeland -- and on to other projects. In the 1970s, he began investigating cost-effective techniques to purify rural water systems. He discovered that if he coated pipes with a common polymer called styrene maleic anhydride, he could kill bacteria lurking in the water supply. The process took advantage of an electric charge differential existing between the polymer, which was positively charged, and the bacteria cells, which carried a net negative charge. As microbes traveled through the polymer-lined pipes and encountered the strong positive charge, the attractive forces pulled them apart.

When the Indian government began worrying about its rapidly growing population, Guha wondered if the same polymer could work for male contraception. After all, the vas deferens resembled a water pipe, and sperm traveling through the narrow tubes were analogous to bacteria. Guha ran some tests and found that the procedure worked perfectly -- male rats whose reproductive plumbing received injections of the polymer didn't make any baby rats. Guha published a proof-of-concept paper in 1979, then began studying the procedure in rhesus monkeys. By the time he published the same positive results in 1985, he suspected RISUG might be a major breakthrough in the quest for better birth control. To understand its significance, it helps to understand the male reproductive system and the potential targets for contraception. That's where we're headed next.

adAfterSmallInset

Man Junk: Potential Targets for Male Contraception

If it's been a while since you took seventh-grade sex-ed, then you'll appreciate a quick refresher course. We all know about the penis, but it's nothing more than the means to an end. The real baby-making action takes place in the testes -- the organs that make male reproductive cells, or sperm. And this only because steroids from the hypothalamus and pituitary gland tell the testes to do their stuff.

The stuff begins in the seminiferous tubules, where precursor cells known as spermatogonia develop. These sperm wannabes then move to the epididymis, a structure located behind the testes. There, the cells line up and inch their way through coils and coils of ramen-noodle-like ductwork. As they make the long journey through the epididymis, they mature into the cute little tadpoles we know as sperm. From there, it's a quick jaunt, usually during sexual intimacy, along the vas deferens, to the urethra and then out the penis.

Who knew male reproduction could be so complicated? Luckily, the process provides four pivotal intervention points to foil the sperm-making machinery.

  1. First, you could manipulate hormones to stop sperm production. If you increase testosterone in a man's bloodstream (usually via intramuscular injections), the brain will stop secreting Gonadotropin-releasing hormone (GnRH), which suppresses levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thus halting sperm production.
  2. Next, you could target sperm-production sites in the seminiferous tubules. For example, spermatogonia arise from stem cells before undergoing meiosis, a special kind of cell division that results in cells with half the normal number of chromosomes (23 in humans). Drugs could derail either the stem cells or the precursor sperm cells as they undergo meiosis.
  3. Another option involves hijacking sperm in the epididymis, where the cells learn to swim like Michael Phelps and gather the enzymes necessary to penetrate an awaiting egg. You could introduce a drug that interferes with sperm motility, in essence stripping them of their backstroke. Or you could block enzymes in the sperm head, rendering it incapable of fertilizing an egg.
  4. Finally, you could let the sperm develop normally but block their exit. Filling the vas deferens with an opaque material or cutting the tube would prevent the sperm from merging with other fluids produced by the seminal vesicles, prostate and Cowper's glands. Men would still produce semen, but it wouldn't contain any egg-seeking missiles.

Over the years, researchers (and tired parents) have tried a variety of contraceptive devices, techniques and therapies that exploit one of these scenarios. Next, we'll look at a few mainstays of male contraception to understand their limitations and why scientists continue to look for a better sperm trap.

adAfterSmallInset

Pros and Con(traceptive)s: The Need for Something Better

Let's face it, females have a slew of choices when it comes to preventing pregnancy. There's the female condom, diaphragm, cervical cap, sponge and intrauterine device, as well as hormonal solutions, such as birth control pills, patches, implants and the vaginal ring. Men who want to share this burden, however, have far fewer options.

Men have used condoms made of various materials -- from animal intestines to latex -- for centuries as a barrier to prevent the escape of sperm into their partners' vaginas. They are 95 percent effective when used properly and remain one of the best solutions for preventing the spread of sexually transmitted infections. Unfortunately, they can break during intercourse or even slip off if the man using it is inexperienced. There's also withdrawal, of course, which can prevent pregnancy (but not sexually transmitted infections) and requires some skill on the user's end to be done properly.

No wonder many men choose to get a vasectomy, a surgical procedure in which each vas deferens is cut and sealed off. Although successfully tested on animals in the mid-1800s, the surgery didn't see widespread use in humans until after World War II. Today, vasectomies account for only 5 percent of all contraception, despite being 100 percent effective [source: Alexander]. One major issue is the irreversibility of the procedure. Surgery can reconnect the vas deferens of a vasectomy patient, but it's expensive and works only about 40 percent of the time [source: Encyclopædia Britannica].

Hormone therapy could solve all of these problems, but comes with its own serious side effects. For example, the World Health Organization has run trials with men who receive twice weekly injections of testosterone. As noted earlier, this has the effect of suppressing sperm production by decreasing levels of GnRH, LH and FSH. WHO scientists got good results, but they found that the frequent injections posed a commercial and psychological barrier. More troubling, high levels of circulating testosterone led to increased irritability, acne and reduced levels of good cholesterol in many test subjects.

The holy grail in male contraception is an approach that requires no surgery or hormone suppression, yet delivers 100 percent effectiveness without permanent sterilization. The most promising techniques in recent years target the vas deferens. A few scientists have been experimenting with plugs made of the same silicone material found in artificial joints. The idea is to create a roadblock in the vas deferens, blocking the exit of sperm. When a man is ready to start a family, his physician simply removes the plug.

RISUG operates in a similar fashion, but with a few key differences, which we'll explore on the next page.

Contraceptive Costs

RISUG appears to be 100 percent effective, safe and reversible. It also promises to be one of the lowest-cost contraceptives on the market. According to one source, a single RISUG injection might run about 200 Indian rupees (about $4) and would last for 10 years [source: Raina]. Now compare this to a vasectomy, which typically costs $350 to $1,000 [source: Planned Parenthood]. And forget about the female birth-control pill. A decade's worth of the pill would set a woman back about $3,600 [source: Schulman].

adAfterSmallInset

Plastic With a Punch: How RISUG Works

A vasectomy is minor surgery, but it's surgery all the same. Even silicone plugs require skilled microsurgery techniques to get them into the vas deferens and then to take them out. The advantages of RISUG become apparent when you consider the procedure. Here's how it goes.

First, the doctor numbs the skin of the scrotal sac. Then, above one testis, he creates a small hole -- one just big enough to locate the vas deferens. After he exposes a short length of the white tube, he uses a syringe to inject about 70 milligrams of styrene maleic anhydride (SMA). The doctor inserts the needle down the length of the vas, making sure the polymer fills the center opening of the tube. As soon as the needle is removed, the vas withdraws into the scrotum, and the doctor repeats the procedure on the other testis. The whole treatment takes about 15 minutes and requires no stitches -- just a small bandage over the puncture.

This ends the "surgical" aspect of RISUG, but the contraceptive compound still needs a little time before it becomes fully functional. In the minutes following the procedure, the polymer solidifies and clings to the microscopic folds making up the inner lining of the vas deferens. The gel doesn't completely block the tube, which means sperm can still make it to the urethra and exit through the penis. But the sperm aren't granted safe passage. As they swim through the plastic-coated vas deferens, the cells become neutralized by the compound's net positive charge. Their tails coil up, their bodies get bent and their cell membranes burst. What comes out in the semen is a collection of broken-down, good-for-nothing sperm totally incapable of fertilizing an egg.

Oh, yeah, and get this: The gel lasts for eight to 10 years or until a man decides he wants to become fertile again. Then it's another quick trip to the doctor, who injects a small dose of sodium bicarbonate into the vas deferens. The baking soda increases the pH inside the vas, which dissolves the polymer. Within a few days of the reversal treatment, normal, healthy sperm once again appear in the man's semen.

So why isn't RISUG more widely available? Are clinical trials uncovering hidden dangers or side effects? Up next, we'll cover the clinical reality of RISUG.

What's the Holdup?

Given the efficacy of RISUG, it's a little mystifying that the gel hasn't sailed through clinical trials and into the testes of men everywhere. One theory suggests that because RISUG isn't the product of big pharma, it's struggled against a sort of overwhelming industry inertia. After all, many drug companies are trying to develop their own versions of the male birth control pill -- a pill that would need to be taken every day for a man's entire adult life. An intervention based on a common -- and cheap -- polymer that gets applied once a decade wouldn't be viewed favorably by pharmaceutical giants hoping to earn millions of dollars a year on a contraceptive pill.

adAfterSmallInset

Trials and Tribulations: The Clinical History of RISUG

Like every (legal) drug, RISUG must still prove itself in clinical trials. A few analysts and regulatory scientists have questioned the safety of styrene maleic anhydride, which is also found in floor polishes. But so far, the gel and the procedure have proven to be safe. In fact, here's the clinical record of RISUG in India:

  • In 1993, a phase I clinical study enrolled 38 men married to women who had already received tubal ligations. Men received doses of the gel ranging from 5 to 140 milligrams. Low doses (5 to 20 milligrams) had no effect on sperm. When the men received the predicted therapeutic dose of RISUG (70 milligrams), all produced semen with no viable sperm within days after the injection. No long-term adverse effects occurred, although two subjects reported scrotal pain and enlargement.
  • In 1997, RISUG entered phase II clinical trials. This time, Guha enrolled 12 men whose wives used no other contraceptive method. He tested a fixed dose of 60 milligrams to see if pregnancy could be prevented for one year. This time, he found that sperm were inactivated immediately after the injection. No pregnancies occurred, and no adverse events were reported by the test subjects.
  • In 2001, phase III trials proved more of the same, this time with 139 men. That prompted a large-scale extension, the goal of which was to enroll 1,000 men. Unfortunately, the Indian government halted the study in 2002, citing concern over non-painful scrotal swelling. Guha and other scientists then had to produce more safety data to prove that RISUG would not harm men undergoing the procedure. Finally, after six years, experts decided the swelling was not a significant concern. Enrollment continued, and by 2011 500 Indian men had dropped their drawers in the name of science.
  • Through the years, other studies have also investigated the reversibility aspect of RISUG. Some have expressed concern that a man using the gel for a long time might not return to his pretreatment fertility after receiving the reversal injection. However, research published in 2005 provided data indicating that the testes, vas deferens and sperm of test subjects gradually returned to normal within 150 days of reversal.

Meanwhile, in February 2010, the Parsemus Foundation, an organization dedicated to funding neglected medical research, licensed the rights to develop RISUG -- as Vasalgel -- in the United States. It has since located a manufacturer to produce the polymer according to U.S. Food and Drug Administration guidelines and, in March 2012, initiated safety and efficacy studies in rabbits.

It could be years before RISUG/Vasalgel receives approval and enters the U.S. market as a readily available contraceptive -- long after it likely receives approval in India. Until then, men should hold on to their supply of condoms or decide, if they want a solution that's 100 percent effective, whether a vasectomy is right for them. And, of course, they can always take comfort knowing that the trials and tribulations of selecting a contraceptive are nothing compared to carrying and delivering a baby.

adAfterSmallInset

Author's Note

I was 41 when I had my fourth child and my one and only vasectomy. It was the right choice for an old fart like me with plenty of progeny. If RISUG lives up to its potential, it could be a great contraceptive option for men of all ages.

Sources

  • Alexander, Nancy J. "Beyond the Condom: The Future of Male Contraception." Scientific American. 1999.
  • Busse, James G. "Silent Sea Engine for Nuclear Subs." Popular Science. January 1966. Found on Modern Mechanix. (April 7, 2012) http://blog.modernmechanix.com/2011/10/27/silent-sea-engine-for-nuclear-subs/
  • Gifford, Bill. "The Revolutionary New Birth Control Method for Men." Wired. April 26, 2011. (April 7, 2012) http://www.wired.com/magazine/2011/04/ff_vasectomy/all/1
  • Guha, Sujoy. "Patent No. 5,488,075: Contraceptive for Use By a Male." Jan. 30, 1996.
  • Guha S.K., Singh G., Anand S., Ansari S., Kumar S., Koul V. "Phase I clinical trial of an injectable contraceptive for the male." Contraception. 1993 Oct;48(4):367-75.
  • Guha S.K., Singh G., Ansari S., Kumar S., Srivastava A., Koul V., Das H.C., Malhotra R.L. and Das S.K. "Phase II clinical trial of a vas deferens injectable contraceptive for the male." Contraception. 1997 Oct;56(4):245-50.
  • Kuang, Cliff. "Beyond the Male 'Pill.'" Popular Science. May 20, 2008. (April 7, 2012) http://www.popsci.com/scitech/article/2008-05/beyond-male-pill
  • Lissner, Elaine. "New male contraceptive clears hurdle." EurekAlert. March 30, 2006. (April 7, 2012) http://www.eurekalert.org/pub_releases/2006-03/mcip-nmc032906.php
  • Male Contraception Information Project. "RISUG/Vasalgel." (April 7, 2012) http://www.newmalecontraception.org/risug.htm
  • Parsemus Foundation. "Vasalgel, Multi-year contraceptive: Rabbit Study." (April 7, 2012) http://www.parsemusfoundation.org/Parsemus/New_male_contraceptives.html
  • Planned Parenthood. "Vasectomy." Health Info and Services. (April 7, 2012) http://www.plannedparenthood.org/health-topics/birth-control/vasectomy-4249.htm
  • Planned Parenthood Advocates of Arizona Blog. "Expanding Options for Male Contraception." Aug. 8, 2011. (April 7, 2012) http://blog.advocatesaz.org/2011/08/08/expanding-options-for-male-contraception/#more-2154
  • Raina, Puneet. "Male contraceptive from India on the anvil. Will it hit the shelves any sooner?" India Bioscience. (April 7, 2012) http://www.indiabioscience.org/node/241
  • Schulman, Audrey. "A new injection for men could shake up the world of contraceptives." Grist. Aug. 13, 2003. (April 7, 2012) http://grist.org/business-technology/sperminator/
  • "Vasectomy." Encyclopædia Britannica Online. Encyclopædia Britannica Inc., 2012. (April 7, 2012) http://www.britannica.com/EBchecked/topic/623770/vasectomy