Background & history
After being produced in the testes and stored in the epididymis, sperm pass through a tube called the vas deferens on their way to the penis. The vas deferens is the same tube that is cut in a vasectomy. Many men throughout the world — more than half of the men in their forties in New Zealand, for example — get a vasectomy when they are finished having children (Sneyd 2001). However, vasectomy is generally permanent. Therefore, researchers have long sought a reversible alternative to vasectomy.
Aside from hormonal regimens, RISUG is the only new male contraceptive to have advanced to Phase III clinical trials–and we believe it is one of the most promising new male contraceptives.
RISUG (which is an acronym for “Reversible Inhibition of Sperm Under Guidance”) is similar to vasectomy but with several advantages, the most significant being that it is more reversible. Researchers achieve this feature by injecting a polymer (a gel) into the vas deferens, rather than cutting the vas (as is done in vasectomy). If a man wishes to restore fertility, whether after months or years, the polymer is flushed out of the vas with another injection.
RISUG is composed of powdered styrene maleic anhydride (SMA) combined with dimethyl sulfoxide (DMSO). The resulting gel is injected into the vas deferens. However, RISUG reportedly does not rely on completely blocking the vas lumen for its effectiveness. The vas is a notoriously difficult tube to block completely, since it will often stretch around a solid plug and begin to leak — or if the plug is big enough that the vas can’t stretch any farther, the vas may rupture. But apparently RISUG is not just an inert plug; the RISUG material is thought to also actively kill any sperm that come into contact with it.
Sujoy K. Guha, professor of biomedical engineering at the Indian Institute of Technology– inventor of RISUG
RISUG is injected by exposing the vas with the common “no-scalpel” method used around the world during “no-scalpel vasectomy” (NSV) (Sethi 1991). After numbing the area, the doctor pokes a hole in the scrotal skin that is so small that it doesn’t require stitches–but that makes the vas easier to see and work on. The RISUG gel is then injected into the lumen (the center opening) of each vas deferens. The injection procedure can be viewed here. The doctor then lets go of each vas deferens so it can drop back into the body, puts a band-aid-type covering over the opening, and is done. The whole procedure usually takes less than fifteen minutes from the time the man gets on the table to the time he walks away.
Within minutes of insertion, the gel solidifies and anchors itself to the microscopic folds of the inner walls of the vas deferens. As sperm come into contact with the polymer, the combination of positive and negative charges on the polymer surface reportedly causes the membranes of the sperm to burst (Chaudhury, Bhattacharyya, & Guha, 2004). The sperm are thus immotile (unable to travel) and unable to fertilize an egg.
This chemical effect appears to have another advantage: unlike a vasectomy, RISUG is effective almost immediately. This compares to a time to infertility for vasectomy of up to three months, the time it takes to reliably clear sperm out of the system (Barone 2003).
In a Phase II clinical trial in 12 men, azoospermia (absence of sperm) was found as early as five days after injection, and in the cases where any sperm were found in the first months, they were either dead or too few and too sluggish to reach an egg (Guha 1997). In a second study, sperm counts weren’t taken until at least day 13, but results were similar (Guha 1998). In a third study, six of the 25 men had zero sperm counts at one month, 15 more at two months, three more at three months, and the last one at four months. No pregnancies were reported during the six-month study (Chaki, Das, & Misro, 2003). Men are advised to wait at least three days for the polymer to fully anchor itself before having sex and to use condoms for the first ten days, but in clinical trials, there have been no pregnancies in the first months (other than in a handful of cases in which the RISUG was not injected properly) despite some subjects not following those recommendations (personal communication, Prof. S.K. Guha, Feb. 2002 and Nov. 2010).
Back-pressure on the epididymis (the coils where sperm are stored after leaving the testes) is thought to be a major factor in lowering reversal rates after vasectomy (Srivastava, Ansari, & Lohiya, 2000). If it does not completely block the vas, RISUG may cause less back-pressure than vasectomy. For example, in monkeys, the epididymis showed no appreciable signs of pressure even after 18 months (Lohiya 2005).
In animal studies, sperm recover gradually over the 1-3 months after reversal. These sperm from the second sample after reversal still show coiled tail and bent midpiece. (Lohiya 2005)
Chemical markers of prostate health are in the normal range in men using RISUG, even after eight years of RISUG use (Sharma 2001). A 2005 publication showed that accessory reproductive organs likewise remained normal (Manivannan 2005). Furthermore, unlike vasectomy, in monkey tests RISUG did not cause sperm granulomas (inflammatory reactions to sperm leakage from the reproductive tract into surrounding tissue) or an immune reaction to clean them up (Mishra 2003), eliminating the painful nodules that a small percentage of men experience after vasectomy. Finally, the inner surface of the vas deferens also returns to normal upon removing RISUG (Manivannan, Mishra, & Lohiya 1999). These all indicate that RISUG has even less impact on reproductive organs than vasectomy does.
The reversal procedure can be performed whenever a man wants, whether after days, weeks, or years of use. Since the polymer remains primarily whole, it can be flushed out by dissolving it with an injection of DMSO, a compound that is used in the medical treatment of many conditions (Santos 2003) and that is bioacceptable in the small quantities necessary (Ali 2001), or of sodium bicarbonate solution. Thus, fertility can be limited by one injection or restored by another (Misro 1979, Lohiya et al 2013). A “noninvasive” reversal is also possible (Lohiya 2005). However, many men may consider this reversal method more invasive than an injection, since it involves a combination of vibration, a low electric current, and per rectal massage to dislodge the polymer and move it through the vas deferens.
In monkey tests, researchers have injected and reversed RISUG multiple times in the same monkeys with no problems (Lohiya, Manivannan, & Mishra, 2000). Alternatively, since the polymer itself dissolves very slowly in the process, fertility could be restored by giving a smaller dose and allowing the SMA to slowly dissolve (if additional studies were first done on the safety to offspring.) Though lower doses wear off after as little as three months, the standard dose lasts at least seven years (Guha 1993; Guha 1997), and in fact the men from the early studies have been using their RISUG for 20 years now. However, no formal long-term follow-up has been published on these men. About 60 of the 139 men who got RISUG in the 2001-2002 Phase III cohort had been identified for follow-up as of 2008, and none had intact sperm (Sharma RS, personal communication 2008); the plan was to publish those results once 100 subjects had been located for follow-up, but as of 2013 publication is still awaited.
This RISUG volunteer, an army officer, seemed surprised when we asked why he chose sterilization rather than asking his wife to get it. His answer: Male sterilization is simpler and safer. Why would anybody put his wife at risk?
RISUG appears to have been safe and effective in 35 years of animal and human trials (see publications list). Studies have tested, among other things, its dosage and length of action in monkeys and men, its reversibility in rats, its reversibility multiple times in monkeys, its teratogenic potential in rats and rabbits, its toxicity in rats and monkeys, its ultrastructural effect in the vas deferens before and after removal in monkeys, its effect on seminal plasma metabolites and the prostate in men, its ultrastructural effect on sperm in monkeys, and the status of semen and accessory sex gland function in monkeys and men. The latest studies report on sperm returning to normal and safety for offspring after reversal in rats (Lohiya 2010), its reversal with DMSO in rats (Lohiya et al 2013) and on modifying it for use in females (e.g. Jha 2010).
Questions remain about the likelihood of pregnancy after reversing RISUG after long periods of use, especially since in the monkey study, cellular changes appeared in some of the sperm-producing tubules at the center of the testes after one year (Mishra 2003). However, a subsequent publication provides reassurance and additional information: the testes and vas deferens gradually returned to normal within 150 days of reversal (Lohiya 2005).
The monkey study published in 2005 reported on reversal after about 18 months of use. However, several dozen men from the first clinical trials have been using the method for 20 years or more. It would be reassuring and informative to reverse the procedure in some of those volunteers in order to determine their subsequent fertility. RISUG’s developer in India has proposed both a study of reversal after 6 months and a study of reversal in some of the men who have had it for many years. We eagerly await these studies.
Of all the methods discussed in MCIP’s previous reviews, RISUG is the one that has made the most significant progress. Researchers have completed preliminary trials in humans, and multiple hundreds of men are enrolled in larger trials; 139 in the 2001-2002 study and many more in the extension being conducted now (which is slated to enroll 1000 men). RISUG has endured many slowdowns, the most recent being trouble with syringe design, but the syringe troubles appear to be solved.
However, dedication will be required to bring RISUG to market. To gain approval in India, RISUG must maintain enough high-level support to cut through red tape.
This rural vegetable merchant travels several hours by bicycle and train to get to the wholesale market and back before dawn to support his family. He got RISUG when a Pill failure brought a surprise– a third child.
The clinical trial in India is ongoing. Men in the following cities in India can contact the following sites to see whether they are eligible for enrollment:
|Delhi||L.N.J.P. Hospital, Dr. H.C. Das 2) All India Institute of Medical Sciences, Dr. V. Seenu|
|Jaipur||University of Rajasthan, SMS Medical College, Drs. N.K. Lohiya, T.C. Sadasukhi|
|Ludhiana||Medical College, Drs. B. Shah|
|Kharagpur||Government Hospital, Dr. B. Sahoo|
|Gauhati||Gauhati Medical College Hospital, Dr. Iliyas|
|Hyderabad||Nizam Institute of Medical Sciences|
Although RISUG research is grandfathered in India because of the multi-decade track record of use in men in clinical trials with no major safety problems, to gain approval outside India for RISUG or any similar contraceptive, researchers would have to duplicate older animal safety studies on a larger scale, with state-of-the-art instruments, for a longer study period, and with extensive record-keeping. Without those animal studies, approval for human studies is unlikely. Though men are eager for this new contraceptive and would like to accelerate the process, studies must start at the beginning.
While the final clinical trial in India continues slowly but steadily enrolling men, in early 2010 a foundation focused on contraceptive research licensed the rights to develop RISUG for use outside India. Parsemus Foundation is directed by a longtime advocate of nonhormonal male contraception. The foundation began by working on RISUG, but has moved towards working on a similar but distinct product called Vasalgel, which is expected to be more cost-effective to make and which is making its way through the regulatory process necessary to bring the product to market. To learn more about polymer contraception outside India, visit the Vasalgel page.
Want to let funders know that development of new methods for men is important to you and they should make it a priority? Complete our short, no-spam survey/petition.