Reversible inhibition of sperm under guidance
Encyclopedia
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
developed at IIT Kharagpur
in India
by 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. In the United States, there are efforts to get FDA approval under the name Vasalgel.
, the vessel through which the sperm
moves before ejaculation
. 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 monomer
s 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. (From )
Some theorize 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, stopping the sperm before they can start 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.
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. The Indian Council for Medical Research noted that dimethyl sulfoxide
used as a solvent for the injection is known to cause kidney damage. Although the ICMR has reviewed and approved the toxicology data three times, some United States
researchers say that the studies were not done according to recent international standards.
RISUG was resubmitted for a new round of tests at a US lab, and was approved as non-mutagenic in July 2005. With this new stamp of approval, the path to continued Phase III trials in India became clear.
In March 2006, the ICMR announced that Phase III trials of RISUG could resume at 4 centers around India. The announcement of this progress led to renewed interest in RISUG. Unfortunately, little progress has been made since March. The research centers do not have enough of the RISUG compound to move forward with the trial. Marksans, the pharmaceutical company which has a manufacturing agreement with the inventor and the government, is now over a year past its initial April 2005 product delivery estimate. It is not clear why the delay continues.
Once this form of contraception is released into the market, it could displace the use of condom
s. Unlike condoms, RISUG provides no protection against the spread of sexually transmitted diseases. A study, however, is underway to test the efficacy of RISUG as an anti-HIV agent, due to a hypothesis that the styrene maleic acid lowers pH to a level sufficient to destroy HIV in semen.
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
styrene maleic anhydride
Styrene maleic anhydride
Styrene maleic anhydride, also known as SMA or SMAnh, is a synthetic polymer that is built-up of styrene and maleic anhydride monomers. The monomers are almost perfectly alternating, making it an alternating copolymer. It is formed by a radical polymerization, using an organic peroxide as the...
(SMA), is the development name of a male contraceptive
Male contraceptive
Male contraceptives include condoms, withdrawal , and vasectomy. In other animals, castration is commonly used for contraception...
developed at IIT Kharagpur
Indian Institute of Technology Kharagpur
The Indian Institute of Technology Kharagpur is an autonomous engineering, technology and management oriented institute of higher education established by the government of India in 1951...
in India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
by 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. In the United States, there are efforts to get FDA approval under the name Vasalgel.
Mechanism of action
RISUG works by an injection into the vas deferensVas deferens
The vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....
, the vessel through which the sperm
Spermatozoon
A spermatozoon is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote...
moves before ejaculation
Ejaculation
Ejaculation is the ejecting of semen from the male reproductory tract, and is usually accompanied by orgasm. It is usually the final stage and natural objective of male sexual stimulation, and an essential component of natural conception. In rare cases ejaculation occurs because of prostatic disease...
. In a matter of minutes, the injection
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
coats the walls of the vas with a clear gel
Gel
A gel is a solid, jelly-like material that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady-state...
made of 60 mg of the copolymer styrene/maleic anhydride
Maleic anhydride
Maleic anhydride is an organic compound with the formula C2H22O. It is the acid anhydride of maleic acid and in its pure state it is a colourless or white solid with an acrid odour....
(SMA) with 120 µl of the solvent dimethyl sulfoxide
Dimethyl sulfoxide
Dimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...
. The copolymer is made by irradiation
Irradiation
Irradiation is the process by which an object is exposed to radiation. The exposure can originate from various sources, including natural sources. Most frequently the term refers to ionizing radiation, and to a level of radiation that will serve a specific purpose, rather than radiation exposure to...
of the two monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
s with a dose of 0.2 to 0.24 megarad
Rad (unit)
The rad is a unit of absorbed radiation dose. The rad was first proposed in 1918 as "that quantity of X rays which when absorbed will cause the destruction of the malignant mammalian cells in question..." It was defined in CGS units in 1953 as the dose causing 100 ergs of energy to be absorbed by...
for every 40 g of copolymer and a dose rate of 30 to 40 rad/s. The source of irradiation is cobalt-60
Cobalt-60
Cobalt-60, , is a synthetic radioactive isotope of cobalt. Due to its half-life of 5.27 years, is not found in nature. It is produced artificially by neutron activation of . decays by beta decay to the stable isotope nickel-60...
gamma radiation.
The effect the chemical has on sperm is not completely understood. Originally it was thought that it lowered the pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
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
Hydride
In chemistry, a hydride is the anion of hydrogen, H−, or, more commonly, a compound in which one or more hydrogen centres have nucleophilic, reducing, or basic properties. In compounds that are regarded as hydrides, hydrogen is bonded to a more electropositive element or group...
and has a positive charge. This disturbs the negative charge of the sperm membrane on contact. (From )
Some theorize that the polymer surface has a negative and positive electric charge
Electric charge
Electric charge is a physical property of matter that causes it to experience a force when near other electrically charged matter. Electric charge comes in two types, called positive and negative. Two positively charged substances, or objects, experience a mutual repulsive force, as do two...
mosaic. The differential charge from the gel ruptures the sperm's cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
as it passes through the vas, stopping the sperm before they can start their journey to the egg
Ovum
An ovum is a haploid female reproductive cell or gamete. Both animals and embryophytes have ova. The term ovule is used for the young ovum of an animal, as well as the plant structure that carries the female gametophyte and egg cell and develops into a seed after fertilization...
.
"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.
Advantages
Some of the advantages, according to Dr. Guha, are:- Effectiveness - There has been only one unplanned pregnancy among partners of the 250 men who have been injected RISUG — apparently due to an improperly administered injection. Out of the 250 men who have been injected RISUG, 15 men received the injection more than 10 years ago.
- Convenience - There is no interruption before the sexual act.
- Non-invasiveness - The process, once it is refined and approved, is expected to be operation-free. Men can leave the hospital immediately after an injection and resume their normal sex lives within a week.
- Duration of effect - According to 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 effectsAdverse effect (medicine)In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
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 (see Controversy section below for further details). - Reversibility - The contraceptive action appears to be reversible by flushing the vas deferens with another injection of dimethyl sulfoxideDimethyl sulfoxideDimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...
or sodium bicarbonateSodium bicarbonateSodium bicarbonate or sodium hydrogen carbonate is the chemical compound with the formula Na HCO3. Sodium bicarbonate is a white solid that is crystalline but often appears as a fine powder. It has a slightly salty, alkaline taste resembling that of washing soda . The natural mineral form is...
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 primates, it has been repeatedly successful. Unlike in a vasectomyVasectomyVasectomy is a surgical procedure for male sterilization and/or permanent birth control. During the procedure, the vasa deferentia of a man are severed, and then tied/sealed in a manner such to prevent sperm from entering into the seminal stream...
(see Blood-testis barrierBlood-testis barrierThe blood–testis barrier is a physical barrier between the blood vessels and the seminiferous tubules of the animal testes...
), 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 vasovasostomyVasovasostomyVasovasostomy is a surgery by which vasectomies are partially reversed. Another surgery for vasectomy reversal is vasoepididymostomy.-Limitations:...
.
Controversy
The thoroughness of carcinogenicity, teratogenicity, and toxicityToxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
testing in clinical trials has been questioned. In October 2002, India's Ministry of Health aborted the clinical trials due to reports of albumin
Human serum albumin
Human serum albumin is the most abundant protein in human blood plasma. It is produced in the liver. Albumin constitutes about half of the blood serum protein...
in urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
and scrotal swelling in Phase III trial participants. The Indian Council for Medical Research noted that dimethyl sulfoxide
Dimethyl sulfoxide
Dimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...
used as a solvent for the injection is known to cause kidney damage. Although the ICMR has reviewed and approved the toxicology data three times, some United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
researchers say that the studies were not done according to recent international standards.
RISUG was resubmitted for a new round of tests at a US lab, and was approved as non-mutagenic in July 2005. With this new stamp of approval, the path to continued Phase III trials in India became clear.
In March 2006, the ICMR announced that Phase III trials of RISUG could resume at 4 centers around India. The announcement of this progress led to renewed interest in RISUG. Unfortunately, little progress has been made since March. The research centers do not have enough of the RISUG compound to move forward with the trial. Marksans, the pharmaceutical company which has a manufacturing agreement with the inventor and the government, is now over a year past its initial April 2005 product delivery estimate. It is not clear why the delay continues.
Once this form of contraception is released into the market, it could displace the use of condom
Condom
A condom is a barrier device most commonly used during sexual intercourse to reduce the probability of pregnancy and spreading sexually transmitted diseases . It is put on a man's erect penis and physically blocks ejaculated semen from entering the body of a sexual partner...
s. Unlike condoms, RISUG provides no protection against the spread of sexually transmitted diseases. A study, however, is underway to test the efficacy of RISUG as an anti-HIV agent, due to a hypothesis that the styrene maleic acid lowers pH to a level sufficient to destroy HIV in semen.
External links
- Detailed information from Male contraceptives.org
- Studies of RISUG Experimental male contraceptive 1976-2004
- SMA
- ICMR Website
- ICMR 2004 Anuual Report
- Hindustan Times
- The Sperminator in Grist Magazine
- India Today Article
- Indian Express Article
- Canadian Doctor implements RISUG
- Country’s first male contraceptive aborted (October 2002)
- ICMR takes a shot at a male contraceptive (October 2000)
- An interpretation of "Status of Spermatogenesis and Sperm Parameters in Langur Monkeys Following Long-term Vas Occlusion With Styrene Maleic Anhydride"
- The Revolutionary New Birth Control Method for Men