Reversible inhibition of sperm under guidance
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Reversible inhibition of sperm under guidance (RISUG), formerly referred to as the synthetic polymer styrene maleic anhydride (SMA), is the development name of a male contraceptive injection developed at IIT Kharagpur in India by the team of Dr. Sujoy K Guha. Phase III clinical trials are underway in India, slowed by insufficient volunteers. It has been patented in India, China, Bangladesh, and the United States. A method based on RISUG, Vasalgel, is currently under development in the US.
Mechanism of action
RISUG works by an injection into the vas deferens, the vessel through which the sperm moves before ejaculation. RISUG is similar to vasectomy in that a local anesthetic is administered, an incision is made in the scrotum, and the vas deferens is injected with a polymer gel rather than being cut and cauterized. In a matter of minutes, the injection coats the walls of the vas with a clear gel made of 60 mg of the copolymer styrene/maleic anhydride (SMA) with 120 µl of the solvent dimethyl sulfoxide. The copolymer is made by irradiation of the two monomers with a dose of 0.2 to 0.24 megarad for every 40 g of copolymer and a dose rate of 30 to 40 rad/s. The source of irradiation is cobalt-60 gamma radiation.
The effect the chemical has on sperm is not completely understood. Originally it was thought that it lowered the pH of the environment enough to kill the sperm. More recent research claims that this is not enough to explain the effect.
One explanation is that the polymer is an anhydride, and hydrolizes in the presence of water in the spermatic fluid. Due to the breaking of a cyclic group, the polymer becomes a hydride and has a positive charge. This disturbs the negative charge of the sperm membrane on contact.
Professor SK Guha theorizes that the polymer surface has a negative and positive electric charge mosaic. The differential charge from the gel ruptures the sperm's cell membrane as it passes through the vas, deactivating sperm before they initiate their journey to the egg.
"Within an hour, the drugs produce an electrical charge that nullifies the electrical charge of the spermatozoa, preventing it from penetrating the ovum," Dr. Guha said.
Sujoy Guha developed RISUG after years of developing other inventions. He originally wanted to create an artificial heart that could pump blood using a strong electrical pulse. Using the 13-chamber model of a cockroach heart, he designed a softer pumping mechanism that would theoretically be safe to use in humans. As India's population grew throughout the 1970s, Guha modified his heart pump design to create a water pump that could work off of differences in ionic charges between salt water and fresh water in water treatment facilities. This filtration system did not require electricity and could potentially help large groups of people have access to clean water. India however decided that the population problem would be better served by developing more effective contraception. So Guha again modified his design to work safely inside the body, specifically inside the male genitalia. The non-toxic polymer of RISUG also uses differences in the charges of the semen to rupture the sperm as it flows through the vas deferens.
A similar injection known as "Vasalgel", based on the idea behind RISUG but using a different method, is currently undergoing successful animal trials in the United States. Initially it was hoped that human trials would commence by the end of 2013 and become available to within a few years. FDA regulations have delayed the approval of Vasalgel, and human trials are now expected to begin in 2016, with the earliest market release in 2018.
Some of the advantages, according to Dr. Guha, are:
- Effectiveness - There has been only one unplanned pregnancy among partners of the 250 volunteers who have been injected RISUG — apparently due to an improperly administered injection. Out of the 250 volunteers who have been injected RISUG, 15 received the injection more than 10 years ago.
- Convenience - There is no interruption before the sexual act.
- Cost - The shot itself costs less than the syringe used to administer it, and its long term effectiveness would make it theoretically only a four or five time cost, in the entire lifetime of someone who chose to continue to be on it.
- Outpatient procedure - Patients can leave the hospital immediately after an injection and resume their normal sex lives within a week.
- Duration of effect - According to Dr. Guha, a single 60 mg injection can be effective for at least 10 years.
- Reduced side effects - After testing RISUG on more than 250 volunteers, neither Guha nor other researchers in the field report side effects other than a slight scrotal swelling in some men immediately following the injection, which goes away after a few weeks, though there are also unconfirmed reports of kidney problems. Also, because sperm can still exit the body unimpeded, patients don’t experience the pressure or granulomas that can result from vasectomy.
- Reversibility - The contraceptive action appears to be reversible by flushing the vas deferens with another injection of dimethyl sulfoxide or sodium bicarbonate solution. (The sodium bicarbonate solution cannot be used as the solvent in the initial injection since it would neutralize the positive charge effect.) Although this reversal procedure has been tried only on non-human primates, it has been repeatedly successful. Unlike in a vasectomy (see blood-testis barrier), the vas deferens is not completely blocked, the body doesn't have to absorb the blocked sperm, and sperm antibodies are not produced in large numbers, making successful reversal more likely than with a vasovasostomy.
The thoroughness of carcinogenicity, teratogenicity, and toxicity testing in clinical trials has been questioned. In October 2002, India's Ministry of Health aborted the clinical trials due to reports of albumin in urine and scrotal swelling in Phase III trial participants. Although the ICMR has reviewed and approved the toxicology data three times, WHO and Indian researchers say that the studies were not done according to recent international standards. Due to the lack of any evidence for adverse effects, trials were restarted in 2011.
Smart RISUG is a newer version of the male contraception that was published in 2009. This polymer adds iron oxide and copper particles to the original compound, giving it magnetic properties and the name “Smart” RISUG. After injection the exact location of the polymer inside the vas deferens can be measured and visualized by X-ray and magnetic imaging. The polymer location can also be externally controlled using a pulsed magnetic field. With this magnetic field, the polymer can change location inside the body to maximize sterility or can be removed to restore fertility. The polymer has magnetoelastic behavior that allow it to stretch and elongate to better line the vas deferens. The iron oxide component is necessary to prevent agglomeration. With the original RISUG polymer, the SMA can possibly clump as a reaction to neighboring proteins. With the presence of iron particles, the polymer has lower protein binding and therefore prevents agglomeration. This makes Smart RISUG safer for the user as it will not accidentally block the vas deferens. The copper particles in the compound allow the polymer to conduct heat. When an external microwave applies heat to the polymer, is can liquify the polymer again to be excreted to restore fertility. Smart RISUG is therefore better choice for men who want to use RISUG as temporary birth control, since it does not require a second surgery to restore fertility. The addition of metal ions also increases the effectiveness of the spermicide. The low frequency electromagnetic field disintegrates the sperm cell membrane in the head region. This in turn causes both acrosin and hyaluronidase enzymes to leak out of the sperm, making the sperm infertile. The safety of Smart RISUG is still being investigated. With literature research, the spermicidal properties of the compound should not have negative effects on the lining of the vas deferens. The albino rats used to develop the new polymer have not had any adverse symptoms.
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-  Archived March 17, 2005, at the Wayback Machine.
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- Detailed information from Male contraceptives.org
- ICMR Website
- ICMR 2004 Annual Report