RISUG (which is an acronym for “Reversible Inhibition of Sperm Under Guidance”), called Vasalgel™ in the U.S., is similar to vasectomy but with one significant advantage: it is more easily 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). The polymer then coats the inside walls of the vas deferens and kills sperm as they go by. If a man wishes to restore fertility, whether after months or years, the polymer is flushed out of the vas with another injection. This method could thus be ideal for men who think they are finished having children but would like the chance to change their minds in case of remarriage or the death of a child—and it could possibly even be appropriate for men who want child-spacing or young men who want to complete their schooling before having children.
|RISUG is a clear gel.|
RISUG is in advanced clinical trials in India; some of the men have been using it for more than 15 years. Right now, only local men near the study sites in India are eligible for the trials, though there could be a limited market release in 2012/2013 for Indian men. But there’s good news for men outside India: RISUG may be on its way to the rest of the world! In early 2010, a small foundation that grew out of the Male Contraception Information Project purchased rights to begin studying RISUG in the U.S. and developing it for the rest of the world. The goal is to have it on the market as an alternative to vasectomy as early as 2015, with clinical trials beginning in 2012. Its new name is Vasalgel™. The foundation is moving fast on getting the first steps done, but won’t have enough money to finish the project; if you want to show larger funders that there’s demand and that they should partner on finishing the job, add your voice to MCIP’s short, no-spam petition to funders.
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 the most promising new male contraceptive. However, much remains to be done to prepare RISUG for U.S. or European regulatory approval so that men outside India can have access to it too.
RISUG (which is an acronym for “Reversible Inhibition of Sperm Under Guidancer”) 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). The polymer then coats the inside walls of the vas deferens and kills sperm as they go by. 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, for which the method was previously named) combined with dimethyl sulfoxide (DMSO). Just enough of the resulting gel is injected into the vas deferens to coat the walls of the vas deferens and mostly block the lumen (passageway). However, RISUG 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 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 RISUG is not just an inert plug; the RISUG material also actively kills any sperm that come near it. Therefore a smaller amount can be injected without worrying that leakage will make the method less effective. In fact, a small amount of leakage is actually a significant advantage, as it can reduce the pressure buildup that occurs with complete blockage.
|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 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 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 has 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 beginning to be seen as a major factor in lowering reversal rates after vasectomy (Srivastava, Ansari, & Lohiya, 2000). Because it does not always 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 does 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). 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.
|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 has been safe and effective in 25 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) 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, but the studies are still in the approvals process. We anxiously await approval of 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 will eventually enroll 1000 men). RISUG has endured many slowdowns, the most recent being trouble with syringe design, but the syringe troubles appear to be solved, investigators are being re-trained, and as of May 2011 the clinical trials are resuming full-speed enrollment of men.
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. For the moment RISUG has this support, but it is essential for RISUG’s progress that RISUG be seen as a technology eagerly awaited by the world. Publicity and public pressure for research can help.
To gain approval outside India, supporters must 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.
|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.
Luckily, this is now finally happening. 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. The foundation is directed by a longtime advocate of nonhormonal male contraception. The foundation has interviewed and evaluated contract manufacturers to produce RISUG, a winner has been chosen, and the product has been renamed “Vasalgel.” The steps for Vasalgel development are:
- Winter 2010/2011: Analyzing RISUG from India (DONE)
- Early 2011: Developing streamlined production processes; analyzing purity and quality (DONE)
- Spring 2011: Cross-checking with RISUG’s developer; analysis to make sure the new product matches the specifications of the old
- Summer 2011: Scaling up the manufacturing process; Preparing the Vasalgel produced for preclinical tests
- 2011 and 2012: International Organization for Standardization (ISO) testing for biocompatibility, tissue irritation, etc.; abbreviated preclinical efficacy study
If all goes well with these preliminary steps, the next steps would be formal toxicology studies. Then within 2012, there could be clinical trials of Vasalgel for United States men. Vasalgel could be on the U.S. market as early as 2015, although initially just as an alternative to vasectomy (later studies would be conducted to support reversibility rather than delaying initial rollout as a vasectomy alternative). The developers will then pursue approvals and affordable availability in countries around the world.
But this will only be possible with public awareness and support. The foundation is too small to fund the entire $5 million development process. After proof of concept (confirming that Vasalgel works and is safe), the foundation hopes to turn the project over to a dynamic new nonprofit called WomanCare Global, which specializes in finishing development on reproductive health products and getting them to market. WomanCare Global recently scored a coup by negotiating a public sector price that will make nonsurgical female sterilization affordable to women outside the U.S. for the first time. The key variable, though, is whether WomanCare Global has enough funding in a year or two, despite the economic downturn, to be able to take on this new project. We are hopeful that current large-foundation funders will stick with WomanCare Global, and that new angel funders will appear who care enough about Vasalgel to specifically fund its development.
If you live outside of India and wish to voice support for Vasalgel development in your country, complete our short, no-spam survey/petition.
To become an angel investor for the development and introduction of RISUG in the United States, contact the Parsemus Foundation.
|If you live in India, are healthy, between the ages of 25-40 and have two or more children,
you may already be able to get RISUG in one of the following cities:
1) L.N.J.P. Hospital, Dr. H.C. Das
|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|
Next section: Heat Methods of Male Contraception
A small amount of RISUG can provide
Prof. Guha consults with the surgical team.
Untreated sperm head.
Sperm head after RISUG treatment.
Koel Chaudhury (a postdoctoral fellow at the time) presenting
Graduate student Shivani Sharma presenting RISUG at the 2004
Dr. R.S. Sharma is in charge of RISUG clinical
RISUG team members Sumana Das, Sohini Roy, and
Doctoral student Sumana Das examines syringe prototypes. Her
Prof. Guha signs the licensing agreement that will allow
RISUG team members Sumana Das, Sohini Roy, and Pradheep
Pradheep K. Jha works on documentation, experiment
RISUG team member Rakhi Jha has a biology background and
Sohini Roy (L) and Vandana Chauhan (R) present new applications
Doctoral student Vandana Chauhan's work on prostate cancer
Sohini Roy has worked on material processing and on evaluation
Doctoral student Shubhadeep Banerjee studies drug-membrane
Doctoral students Sunil Kumar and Sohini Roy helped set up