New Vas Deferens-based Methods of Male Contraception
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 et al., 2001). However, vasectomy is generally permanent. Therefore, researchers have long sought a reversible alternative to vasectomy. Several new approaches to vas deferens-based contraception are described below.
RISUG (previously known as SMA)
The previous edition of this report called RISUG the most promising experimental male contraceptive — and since then, many studies have confirmed its promise. However, much remains to be done to prepare RISUG for U.S. or European regulatory approval.
RISUG (which is an acronym for “Reversible Inhibition of Sperm Under Guidance”) is similar to vasectomy but with one significant advantage: it is 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 child-spacing, for young men who want to complete their schooling before having children, and 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.
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 partially 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. A small amount of leakage is actually an advantage, as it can reduce the pressure buildup that occurs with complete blockage.
RISUG can be injected either percutaneously (if the physician is very experienced and has learned this specialized technique) or by exposing the vas with the common no-scalpel method (Sethi et al., 1991). Percutaneous injection involves finding the vas under the skin and injecting into it without making a cut in the skin. Doctors who have done thousands of standard vasectomies often become skilled enough to do this. They can tell whether they have correct placement of the needle by feel and experience.
For less experienced physicians, it is easier to inject the RISUG using the “No-Scalpel Vasectomy” technique. The doctor makes a hole in the skin that is so small that it doesn’t require stitches — but that makes the vas easier to see and work on. Thus, the procedure can be semisurgical or completely nonsurgical, depending on the training of the physician. Either way, the whole procedure usually takes less than fifteen minutes.
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 et al., 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 (S. K. Guha et al., 1997). In a second study, sperm counts weren’t taken until at least day 13, but results were similar (Sujoy K. Guha et al., 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 despite some subjects not following that recommendation (personal communication, Prof. S.K. Guha , Feb. 2002).
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 et al., 2005).
Chemical markers of prostate health are in the normal range in men using RISUG, even after eight years of RISUG use (Sharma et al., 2001). A 2005 publication showed that accessory reproductive organs likewise remained normal (Manivannan et al., 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 et al., 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 et al., 2003) and that is bioacceptable in the small quantities necessary (Ali, 2001). Thus, fertility can be limited by one injection or restored by another (Misro et al., 1979). A “noninvasive” reversal is also possible (Lohiya et al., 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 et al., 1993; Guha et al., 1997), and the men from the Phase II studies have been using their RISUG for more than a decade.
RISUG has been safe and effective in 25 years of animal and human trials (Misro et al., 1979; Guha et al., 1985; Sethi, Srivastava, & Singh, 1989; Guha et al., 1990; Sethi, Srivastava, Singh, Bhatia et al., 1990; Sethi, Srivastava, Singh, & Nath, 1990; Sethi et al., 1991; Sethi et al., 1992; Lohiya, Manivannan, & Mishra, 1998; Manivannan et al., 1999; Lohiya et al., 2000; Sharma et al., 2001; Chaudhury et al., 2002; Chaki et al., 2003; Mishra et al., 2003; Manivannan et al., 2005; Lohiya et al., 2005). 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. (For a full bibliography of RISUG publications, click here.)
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 et al., 2003). However, a recently published follow-up provides reassurance and additional information: the testes and vas deferens gradually returned to normal within 150 days of reversal (Lohiya et al., 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 a decade or more. It would be reassuring and informative to reverse the procedure in some of those volunteers in order to determine their subsequent fertility.
Of all the methods discussed in MCIP’s 1994 review, RISUG is the one that has made the most significant progress. Researchers have completed preliminary trials in humans, and 140 men are enrolled so far in a larger trial. RISUG was the subject of a 2002 site visit by a World Health Organization team. However, dedication will be required to bring RISUG to market.
To gain approval in India, RISUG must have enough government support to finance the next set of studies — and enough high-level support to cut through red tape. 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, governments and the nonprofit sector must begin duplicating 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. Nonetheless, no country except India has yet begun studying RISUG. Men and women interested in RISUG should have one goal: convince policymakers to begin such research.
Additional information about RISUG is available to journalists writing extensive stories on male contraception (4000 words or more). The nine-page case study on RISUG is available by contacting the Male Contraception Information Project and includes the following sections:
- History and status of RISUG
- What is holding back RISUG in India ?
- What is holding back RISUG in the rest of the world?
- What are some questions that need to be answered about RISUG?
- What are some questions about RISUG that have already been addressed?
- What are the next steps towards RISUG’s development?
IVD (previously known as the “Shug”)
IVD stands for “Intra Vas Device.” This contraceptive consists of soft, hollow silicone plugs that are implanted in each vas deferens, two per side. (Solid silicone, unlike the controversial liquid form, has a long safety history.) Each plug is anchored to the vas wall with a tiny suture (thread) (Burton et al., 2004). The IVD can be inserted by any no-scalpel vasectomy provider and does not require extensive additional training.
The double plug design allows most sperm that get past the first plug to be stopped by the second. In primate studies, researchers found azoospermia in all nine monkeys by the second to fourth ejaculation, and upon removal of the plugs, normal sperm counts returned by the second to fourth ejaculation (Zaneveld et al., 1988). This led to quite a bit of optimism for the method. Unfortunately, funding difficulties slowed progress over the next decade.
When the researchers were finally able to test the IVD in 30 men, they did not get complete blockage of sperm in all men. They got either complete blockage or immotile sperm in 27 of the 30 men, and the other three men had extremely low motile sperm counts (Zaneveld et al., 1998). That some sperm got through may seem discouraging. However, all of the men had sperm counts below the level generally considered to be fertile. The IVD developers have since added a third (larger) size of IVD and refined their sizing techniques so they can get consistent fit.
The IVD’s prospects are looking brighter now that the rights have been acquired by Shepherd Medical Company, a consortium of researchers and entrepreneurs. Shepherd Medical successfully applied for National Institutes of Health funding to perfect the device (Office of Extramural Research, 2004). Shepherd Medical’s directors seem quite serious about moving the IVD forward.
Based on the successful monkey studies, researchers expect IVD reversal to be much simpler technically than vasectomy reversal attempts. This is important, since only men who can afford the best microsurgeons are likely to have much success with reversal of conventional vasectomies, but removing the plugs is relatively quick and easy.
However, getting the plugs out is not necessarily the same as restoring fertility. Since the plugs block the vas, questions remain about whether back-pressure will cause epididymal blowouts (ruptures) over time. This would mean that, like for vasectomy, the potential for pregnancy would drop dramatically with each year of use. Monkey reversal studies do not tell us whether or not this will happen, as the monkeys used the plugs for months, not years. Only time and testing will tell.
In the meantime, Shepherd Medical aims to start an 18-month effectiveness trial in 90 men in 2006. If the study goes well, it would be a step toward getting the IVD approved as an alternative to vasectomy — with the hope, but no guarantee, of increased reversibility. Seattle-area men considering vasectomy may want to stay informed about the study’s start date by signing up for the e-mail list of the nonprofit organization MaleContraceptives.org.
Formed-in-place Silicone and Polyurethane Injectable Plugs
Three improvements on vasectomy have been developed in China and Taiwan: no-scalpel vasectomy, which is now in use around the world; chemical vas occlusion, which is discussed in the next section; and occlusion by formed-in-place silicone or polyurethane injectable plugs. Like RISUG, these plugs can be injected in liquid form. Like the IVD, they do not have an active ingredient and are meant strictly as barriers to sperm.
Asian researchers had two primary goals in developing injectable plugs as an alternative to vasectomy:
- To eliminate the psychological barrier of surgery. A skilled provider can inject plugs into the vas deferens percutaneously (through the skin) with no skin incision needed.
- To provide one-time reversibility (for example, for men who believe they want permanent sterilization but would like the possibility of reversal in case of death of a child or some other unforeseen circumstance).
Researchers in Taiwan have reported the most success with this method. Between 1983 and 1990, at least 100,000 men received injectable plugs (Zhao, 1990). First a bit of procaine was injected into the vas deferens for its spermicidal action; then to form the plug, medical-grade polyurethane (MPU) was injected and allowed to harden. In a study of 500 of these men at one year after injection, only five (1%) had sperm concentrations in a potentially fertile range. A study of 1,000 men who had used the plugs for 10 years showed 98% effectiveness and very few complications (Zhao, 2001).
When reversal was done on 31 men who had had plugs in for two to four years, all of them fathered children within two years (Zhao, 1990). In a subsequent study of 130 reversals, 85% of the men fathered a child within a year and all the men fathered children within four years (Zhao, Lian et al., 1992).
Despite these fairly positive results, research in China has clouded the prospects for injectable polyurethane plugs. Using the methods and instruments provided by Dr. Zhao of Taiwan, the Chinese team achieved 96% azoospermia (absence of sperm) in their study of 53 men. However, this took two years: only 85% of the men were azoospermic after one year (Chen et al., 1992). The researchers identified that taking extra precautions to create properly-shaped plugs would have hastened the arrival of effective contraception in their study, since all 39 men who had regularly-shaped plugs on both sides had azoospermia at 18 months.
Curious why sperm disappearance was slower and later than in vasectomy, Dr. Chen ’s team did a follow-up study in which they looked at the vas deferens immediately after injection and in men who had been using plugs for four years. What they saw was disconcerting: all 20 of the newly-plugged vas deferens segments had ruptured, with only a small amount of the material remaining within the vas tube, most of it having leaked through to encircle the ruptured vas. In the long-term users, the situation was even messier: scar tissue had grown within and around the vas, and 4 of the 10 men had painful lumps of immune-reaction cells and sperm (Chen et al., 1996). On seeing this, the researchers formed a theory as to why sperm take so long to disappear from the semen: only when scar tissue forms in and around the burst vas deferens is the blockage complete, and this process can take months. They also expressed concerns about reversibility, which were confirmed by a World Health Organization-sponsored study in which only 9 of 29 men had fathered a child 2 years after reversal (unpublished results, personal communication, Dr. Y.Q. Gu , Nov. 2, 2005).
In the early 1990s, the World Health Organization and the Chinese government sponsored a large study of no-scalpel vasectomy versus polyurethane plugs, with more than 1200 men in each group. The results showed a sperm disappearance rate of 93.55% at one year: a disappointing rate compared to no-scalpel vasectomy’s 98.23% (personal communication, Dr. Y.Q. Gu, Nov. 2, 2005). Similarly to previous studies, it took two years to achieve an azoospermia rate close to that of no-scalpel vasectomy (Griffin, 1995). (For details on the status of this study, click here.)
