A Birth-Control Pill for Men?

Jan. 5, 2000 (Boston) — Thanks to a litter of infertile mice, a new contraceptive pill for men may soon be in the works, say British and Swiss researchers in the Jan 6. issue of the journal Nature.
Unlike other male versions of “the pill” currently on the drawing board, which block the action of the male hormone testosterone on the sperm-producing cells within the testicles, the new birth-control method would maintain normal sperm production. However, it would block the release of sperm into semen, thereby significantly decreasing the likelihood of pregnancy following sexual intercourse, say Richard J. Evans, PhD, and others from the University of Leicester, England, and the Glaxo-Wellcome Geneva Biomedical Research Institute in Switzerland.
Reversing the mechanism to increase the number of sperm in semen might also help some men with infertility problems, the scientists add.
They discovered the birth-control mechanism by accident, while attempting to study the role that an important energy-carrying molecule called ATP plays in muscle contraction. ATP acts as a kind of storage battery for energy, releasing it to body tissues as it is needed. Researchers had previously found that certain smooth muscle tissues such as the vas deferens, the duct through which matured sperm are carried into the penis, have special “receptors” that accept ATP molecules in the same way that a door lock accepts a key. When the ATP key is inserted into a type of receptor called P2X1, it causes the vas deferens to contract and expel sperm into the other fluids in semen, much the way that squeezing one end of the tube causes toothpaste to be squirted out of the other end.
To see what would happen to normal body functions if the P2X1 receptor for ATP was missing, the scientists bred a strain of mice with a genetic mutation that caused the receptor to be deleted. But when they tried to breed the mutant mice with others of their kind, they found that the little critters copulated normally but couldn’t reproduce. “We came across this by accident. When we made this strain of mouse it just turned out to have this characteristic,” says researcher Catrin A. Pritchard, PhD, from the department of biochemistry at the University of Leicester.
Only male mice missing both copies of the gene for P2X1 appeared to be affected by the mutation; female mice missing one or both copies reproduced normally, as did male mice who had only a single copy of the gene. But when male mice with the full-blown mutation were mated with normal females, the matings resulted in pregnancy only 13.7% of the time, compared to a 100% fatherhood rate for males with a single copy of the gene. Other than an inability to father pups, the only abnormality the researchers could find in the affected male mice was a slight increase in blood pressure at rest.
The finding points the way to a possible birth-control pill for men, using a drug that would prevent the release of sperm into semen by effectively locking ATP out of the P2X1 receptor, Pritchard tells WebMD. “What we’re hoping is that we can stimulate some drug company interest in studying this further in terms of maybe looking at some drugs that are already available … that could maybe go into some test to see how effective they would be.” Alternatively, a drug that stimulated the activity of the receptor might help increase the amount of sperm in semen in some men with fertility problems, she says.


(c) 2000 Healtheon/WebMD. All rights reserved.

A Pill a Day Keeps the Sperm Away

Sean Swint is an Atlanta-based writer who came to WebMD after a writing and producing stint at CNN/Headline News. Before that, he earned his keep as an assistant director and set production assistant in the film and commercial industry. His credits include such films as “Driving Miss Daisy” and “Not Without My Daughter.” Upon graduating from the University of Massachusetts at Amherst with a degree in journalism and English, he was editor of a weekly Atlanta metro-area newspaper.
WebMD Medical News
Reviewed by Dr. Pamela R. Yoder
July 19, 2000 — They multiply by the millions each day, they travel in packs, and once unleashed they are single-minded in their goal: succeed or die. Sperm, it’s fair to say, are a relentless lot.
And they are no easier to stop before they’re released. Which is one of the reasons a male contraceptive has been such an elusive goal. It’s easier to stop a woman’s monthly ovulation than it is to completely stop the production of millions of sperm a day. After all, it only takes one of the little critters to do the trick.
But it seems a team of researchers in Scotland may have hit on the right formula to stop sperm production, and it could hit the market within the decade. Sixty men, half in Scotland and half in China, were given a regimen consisting of a daily pill that contained a steroidal hormone and an implant placed under the skin, such as Norplant is used in women.
The pill contains a synthetic hormone found in some female oral contraceptive pills called desogestrel, and the implant contains testosterone.
Here’s the basic logic: the pill’s steroidal hormone works to block the production of sperm, but a side effect is it minimizes the production of the body’s testosterone. That is what makes men men, so to speak. Without it, they can lose facial and pubic hair, grow breasts, or suffer a whole host of side effects. So the implant replaces the body’s testosterone.
“I think keeping the testosterone concentrations normal, neither too high or too low, is perhaps the secret,” says Richard Anderson, MD, PhD, clinical scientist at the University of Edinburgh Centre for Reproductive Biology. Anderson and his colleagues developed the regimen.
He says the men’s sperm counts dropped to zero — “not a single sperm to be seen.” Plus, “It starts working immediately, but it does take a while for the sperm count to fall to zero. It’s like after a vasectomy; it takes several months, often, to go down to zero, because you have to wash out all the sperm that are already produced. But some men have sperm counts, within six to eight weeks, of zero.”
Louis DePaolo, PhD, program director for the National Institute of Child Health and Development’s reproductive sciences branch, explains it further by saying the steroidal hormone stops the pituitary gland in the brain from releasing hormones that set sperm production into motion. The testosterone is mainly at “maintenance levels, to maintain libido and all the other actions that androgen [male hormone] has in the body.”
Anderson says the treatment is 100% reversible, with few side effects. “Most people feel absolutely normal; they don’t notice any difference at all. Some of the men put on a couple of pounds, but not enough to drop out of the study, and we didn’t have any other significant side effects.”
A European pharmaceutical company called Organon plans to market the product when it’s ready, which will be a minimum of five years, says Anderson. Organon provides the products for the trials, but otherwise, he says, the studies are funded by research grants.
This type of hormonal research, which follows in the footsteps of previous research leading to the female pill, has been going on for years, says DePaolo, and is the most heavily researched form of male contraceptive. But it’s not all.
There’s been a lot of effort invested into injected vaccines that are antibodies to specific proteins involved in fertilization. These antibodies, whether in the sperm or on the egg’s surface, attempt to prevent the sperm from binding to it, says DePaolo, adding that there have been some promising leads that seem both effective and reversible, “but it’s not something that’s easily controlled.”
Outside of condoms or vasectomies, there have also been many other contraceptive possibilities tested, some to no avail; some are still being researched. Testosterone alone was shown to reduce sperm production in most men, but depending upon the type and amount, there could be serious side effects, ranging from the lowering of “good” cholesterol, an increase in weight and decrease in the size of the testicles, to acne, mood changes, or less than complete effectiveness.
The estrogen derivatives, such as the hormonal steroid used in the Scottish trial, were added to try to get around some of these side effects. They may have gone under different names, with slightly different effects, but the goal was the same. They’ve all been used in conjunction with testosterone that’s been injected or given in a patch or implant.
Other contraceptive possibilities, some of which are promising:
* A non-hormonal pill that prevents the release of sperm into the semen. So far, experiments with genetically altered mice have had some success.
* Non-hormonal compounds that prevent the development and maturation of sperm cells. So far, only animal tests have been completed. However, there are reports that the compounds can cause up to a 40% to 50% reduction in testicular size.
* Plant extracts like gossypol and Tripterygium wilfordii. Gossypol was used in daily doses in Chinese men, but Tripterygium has primarily been studied in animals. They inhibit sperm production, but the effects may be irreversible, and gossypol was found to shrink the testicles.
* Nifedipine, a calcium channel blocker used for high blood pressure, appears to cripple sperm — making them unable to fertilize the egg.
* Mifepristone, known as RU-486, the abortion-inducing drug, has been shown to stop sperm from moving normally and fertilizing eggs. But it has hormonal side effects that make it useful as a tool for further research only.
* A silicone plug injected into the vas deferens, to stop the sperm from entering the semen. Supposedly, it’s reversible in the hands of a “skilled” surgeon. Hundreds of thousands of Chinese men have undergone the procedure.
Although it seems there are many irons in the fire, there really has been little research into male contraceptives, and very little support from the pharmaceutical companies. Why? “Well, it’s not really regarded as a terribly sexy area — is it really?” Anderson asks. “People have always treated it with a bit of suspicion and thought, ‘Well, it’s a bit of a dead end.’ It’s not something that people have thought is particularly wonderful.”
If there’s no perceived market, there’s no money for research. DePaolo also mentions that there has been some hesitation at developing hormonal contraceptives for men, because the pill for women wasn’t exactly a “smooth ride … It’s been one that’s been quite tenuous with the side effects and everything, and there’s clearly the potential to have some of these side effects.”
Susan Scrimshaw, PhD, the dean of the University of Chicago School of Public Health, tells WebMD it’s also hard to ignore the fact that “for many years, there was little or no focus on men because research was biased towards changing women’s reproductive capacity.
“An interesting question is the strength of motivation for men to use it, since men don’t get pregnant,” she says.
DePaolo says pharmaceutical companies in the U.S. still have not “bought into” the idea that men “are ready to be responsible for their fertility,” whereas a couple of pharmaceutical companies in Europe appear to believe, and invest in the belief, that European men are more willing to use contraception.
In fact, a recent survey of men in Edinburgh, South Africa, Hong Kong, and Shanghai by Anderson and his colleagues found about 90% thought a male hormonal contraceptive was a good idea, and about 66% said if it was available now, they would be willing to use it in the near decade.
But would women believe the men really used it? DePaolo calls that issue the “trust factor,” because with men, “how are you going to tell” if in fact the man has taken the contraceptive?
“If men do use it, it will have a freeing effect for many women who have biological or other reasons for not using some of the more common female contraceptives. On the other hand, many men may not want to father children outside of a conscious decision to do so. It may be most important for committed couples, where the man is willing to take this responsibility,” Scrimshaw tells WebMD.
Contraception, whether male or female, does not alone constitute safe sex, which Scrimshaw concedes would probably be hurt “to some extent” by a male contraceptive.
DePaolo says, “one of the big areas in contraception in general is the development of spermicide-microbicide combinations to combat the spread of sexually transmitted diseases. The steroid contraceptive pills aren’t going to do that unless you wear a condom.”
Many of these questions will inevitably be answered when some form of male contraception does reach the market. Will it cause a groundswell similar to the female pill? Probably not, with many researchers calling the male pill an evolution, not a revolution.
Scrimshaw agrees. “It will have an impact, but I doubt that it will have the same impact as the female pill,” she says. “For one thing, many of the cultural, social, [and] sexual changes facilitated by the control over reproduction represented by the pill have already taken place. Also, in many cultures, it will not be easy for men to accept this method.”
Still, science has come a long way. DePaolo says there’s a “semi-movement” towards male contraception, and the field of science is progressing rapidly, but “to say there are things on the horizon, it’s too early to tell.”


Male ‘Pill’ May Be Available This Decade
By Sean Swint

Birth Control Pill for Men?

I know some men get vasectomies, and I know all about condoms. But why isn’t there a contraceptive pill for men?
Aug. 7, 2000 — Eventually there probably will be. Just last month, scientists at Edinburgh University announced encouraging results from a study of a male contraceptive pill. Yet this preliminary investigation included only 60 men and ran for just six months. So at the very earliest, their pill is at least five years away (see A Pill a Day Keeps the Sperm Away.)
At the University of Washington, my colleagues and I are experimenting with several promising approaches, as are other scientists elsewhere.
Why is it so difficult to produce a hormonal contraceptive pill for men? One major reason is that while women are generally fertile during only five or six days per month, men produce sperm every day, seven days a week, all year round. Men don’t have a regular “nonfertile” period the way women do. This makes developing a male contraceptive more difficult.
Still, we’re making progress. One of the leading candidates is the male hormone testosterone. Research in our laboratory and at other centers has shown that increasing testosterone levels turns off signals from the brain that direct the production of sperm. In experiments, injections of testosterone have been shown to reduce sperm counts to zero in some men. (The new testosterone gel, designed to improve low testosterone levels in men, does not contain enough of the hormone to halt sperm production.)
Unfortunately, some problems remain with this approach. Increasing testosterone levels isn’t 100% effective. Most men’s sperm count drops substantially after the treatment — but only 50% to 75% drop to zero, the level required to ensure contraception. Creating a pill form of testosterone has also proved challenging.
Otherwise, weekly or monthly injections are necessary to reach levels high enough to block sperm production. An injection that lasts from one to three months may be possible. We may also be able to use an implant containing testosterone, which would be placed under the skin where it would slowly release the hormone, similar to Norplant for women.
As for side effects, testosterone can cause acne and, very rarely, enlargement of the breasts. But despite its reputation for fueling aggression, there hasn’t been any evidence so far of increased aggressive behavior with the doses of testosterone used in studies.
Still, a reliable male contraceptive pill is almost certainly years away from being available. That’s too bad. Recent surveys suggest that a majority of men would be willing to use one (Human Reproduction, February 23, 2000). For now, vasectomies and condoms remain the only birth control techniques available to men.


Just last month, scientists at Edinburgh University announced encouraging results from a study of a male contraceptive pill.
By John Amory, MD
John Amory, MD, is an assistant professor of medicine and a contraceptive researcher at the VA-Puget Sound Health Care System, University of Washington, Seattle.

Pill for men ‘may be available in five years’

A contraceptive pill for men could be available in five years. Scientists at Edinburgh University’s centre for reproductive biology, made the prediction after trials showed a 100 per cent success rate in making men temporarily infertile.
The trials were carried out by the Dutch drug company Organon in Edinburgh, Shanghai, Cape Town and a village outside Lagos.
Thirty men were put on the pill at each centre, with the results from China and Scotland now analyzed and due to be announced at a world conference for gynecologists and obstetricians in Washington in September.
The pill contains desogestrel, a synthetic steroid which imitates the action of the female hormone progesterone and inhibits sperm production.
Its other key ingredient is the male sex hormone testosterone, which counteracts the loss of sex drive that desogestrel alone would produce.
The Roman Catholic Church attacked the development, saying that it would lead to more unplanned pregnancies and abortions.
A spokesman for the Church in Scotland said that such a pill would have disastrous consequences for society in the same way as the women’s pill had.
“As far as we are concerned, any form of artificial contraception is wrong,” a spokesman said. “A male pill would be as wrong as a female pill.
The pill for females is widely regarded as the most effective form of contraception, with only one in 1,000 women who take it becoming pregnant. However, its use continues to be the subject of controversy over possible side-effects.


Source: The Daily Telegraph, London

Male Contraceptive Compound Developed

RESEARCH TRIANGLE PARK, N.C., March 24, 1995 — Since the introduction of a birth-control pill for women, scientists have sought an oral contraceptive drug for men. Yet, each time a potential ‘male pill’ has been found, it has proved to have serious side effects such as toxicity, impotence (which requires giving supplementary hormone), or irreversibility. Now, RTI scientists have developed new compounds that make test animals infertile without appearing to interfere with mating behavior. These compounds are described in the March 3, 1995, issue of the Journal of Medicinal Chemistry.
RTI’s research has been supported by the Contraceptive Development Branch of the National Institute of Child Health and Development at the National Institutes of Health (NIH).
‘Basic toxicity tests on the RTI compounds have yielded good results,’ reports Dr. C. Edgar Cook, the RTI chemist who led the research team. ‘Also, the compounds do not appear to be hormonal in nature, which is important because hormonal activity often is associated with side effects.’
So far, the compounds have proven effective at blocking sperm production in mice and rats. The compounds appear to react with a specific site in the testes, but the RTI team has not yet determined the precise mechanism of action.
RTI scientists caution that translating findings in animals to a human contraceptive will require much more work, as well as favorable results in further laboratory studies. Other promising male contraceptives have stumbled between lab and clinic.
To help bring this potential advance in contraceptive options to the public, the RTI team is now looking for a new member: a pharmaceutical company.
‘The compounds have been patented,’ Dr. Cook says. ‘We have prepared a technical summary that outlines the results so far and the development steps that are still needed.’
Dr. Cook points out that the compounds he and his RTI colleagues have patented could find a use in controlling fertility in overpopulated groups of wild, feral, or even domestic or zoo animals. The RTI compounds are also of interest scientifically because they can be used to probe the mechanisms by which sperm are formed.
The chemicals under study at RTI are analogs of a compound identified in the 1970s by scientists at the Sandoz Pharmaceutical Co. Dr. Vladimir Petrow, a long-time colleague of Dr. Cook’s and a pioneer in contraceptive drugs, found a 10-year-old abstract in his files that had escaped several review articles on male contraception. The article described the Sandoz compound and its side effect: it interfered with the production of sperm. Sandoz scientists described their studies in several publications and filed for a patent, but the company didn’t pursue the matter.
In 1989, with support from NIH, the RTI team began modifying the Sandoz chemical in hopes of finding a safer and more effective male contraceptive. Although the earlier Sandoz chemical causes significant sedation, the compounds RTI has developed have greatly diminished this undesirable effect.
Dr. Cook and his RTI colleagues, Y.W.(David) Lee, Mansukh C. Wani and Patricia A. Fail, focused their research on determining what parts of the original molecule’s structure were required for activity. This was accomplished by making and testing analogs and by designing new compounds that featured active structures and avoided those that might cause side effects. RTI researchers synthesized these proposed compounds and rapidly tested them for effectiveness.
Dr. Cook, who applied his interests in drug design, synthesis and metabolism in leading the work, describes the team effort that was required.
‘Dr. Fail developed a rapid screening procedure that requires only a few milligrams of material,’ he said. ‘With it, she and her RTI colleagues could test a great many compounds. Without this advantage, we might have missed the active ones, because we would have needed to make much larger quantities of fewer compounds and wait much longer for test results.
‘Early in the project, Dr. Lee separated the optical isomers (compounds that are mirror images of each other) of the original Sandoz compound. This key step allowed us to show that the activity resided in only one isomer, which suggested that a very specific interaction was occurring in the testes.
‘RTI postdoctoral chemist Joseph M. Jump followed up on this with the new active compounds. He not only separated them into optical isomers; he also developed a method for making only the desired isomer of a key intermediate compound. Dr. Jump’s synthetic work resulted in the active series of compounds.
‘Dr. Wani, who is well known for his role as codiscoverer of taxol and camptothecin, helped design and supervise the synthesis of many of the earlier analogs. Testing of these laid the ground work for developing new active compounds.
‘And finally, Andrew MacPhail of Duke University has determined the absolute stereochemistry of the compounds by x-ray crystallography. That will be important as we study their mechanism of action,’ Dr. Cook said.


March 24, 1995
Information on the status of male contraceptive research as of 1/25/2001.


New male contraceptive found 99 percent effective

LONDON (CNN) — The World Health Organization is hailing a new male contraceptive injection as 99 percent effective, and claims it could eventually revolutionize birth control.
Four hundred men in nine countries were given weekly injections of testosterone that reduced their sperm counts dramatically. Some levels dropped to zero.
The men reported few side effects, although some noted mood changes and acne.
The drug has not necessarily been perfected, but it gives men an alternative to traditional forms of birth control.
The injection ‘increases options available to males,’ who were previously limited to condoms, withdrawal or a vasectomy, says Dr. Fred Wu of Manchester University.
Scientists warn that the procedure is still in the experimental phase and will not be marketed until more tests are run. Helen Axby of the British Family Planning Center cautions that the testing could take years.
‘This research has been going on for many years and still has a long way to go before it’s a marketable contraceptive,’ she says. The drug is not expected to reach consumers for at least another five to 10 years.
Axby explains the wait by describing the imbalance in birth control research.
‘The focus has certainly been on contraceptives for women. That has been the traditional way that drug companies and scientists have developed contraceptive methods,’ Axby says.
While the tests have been successful, WHO experts are skeptical of a pill form of the male contraceptive.
Some say the wait for the contraceptive will not be as long as the wait for men to take responsibility for their own birth control.
Others pushing for the male contraceptive think men are more than ready for another option to condoms and surgery.


But it’s not on shelves yet
April 2, 1996 Web posted at: 3:30 p.m. EST

New research on a ‘male pill’ shows promise

CNN) — The day may soon arrive when both men and women can get prescriptions filled for the pill. Researchers have proven for the first time that a male birth control pill is possible, but the findings are preliminary.
‘This is the initial study just to show the feasibility or possibility to use an agent by mouth,’ says Dr. William Bremner of the VA Medical Center in Seattle.
The pill consists of two hormones: testosterone and a progestin. Presenting the results at the International Congress of Endocrinology, Italian and American researchers said that in all eight Italian men they tested, the pill lowered sperm counts to very low levels. Half the men had sperm counts of zero.
And so far, this pill appears to have few ill side effects.
‘This combination has been remarkably free of side effects so far,’ Dr. Bremner said, ‘but as I’ve stressed, it’s quite early with relatively few men, so it’s possible something additional could turn up.’
Researchers have tried for years to develop a birth control pill for men, but there have always been drawbacks, such as toxicity or causing impotence or long-term infertility.
For the pill Dr. Bremner is testing, the next step is to see if it prevents pregnancy. But even if a male pill makes it into the marketplace, will men be willing to use it?
‘It’s a popular trend of sharing family responsibilities,’ said research participant Darwin Hughes, ‘and I think it’s a wonderful alternative to condoms.’
‘I think it’s time men take responsibility of their own birth control,’ said Dave Grason, another participant.
But these men may not be a representative sample. They’re part of another study on male contraceptives that involves taking a combination of injections and pills. Since some men may not be willing to take daily pills, or have frequent injections, researchers are also experimenting with a contraceptive that lasts several months.
‘We’re trying to develop a group of options for men, as have been available for women, to try to allow an option that an individual man would find acceptable,’ Bremner said.
Bremner and other researchers predict men and women will have equal opportunity in birth control options within several years.
But because of the potential for lawsuits and society’s resistance to using male birth control, getting pharmaceutical companies interested in producing a male contraceptive presents yet another challenge.


June 13, 1996 Web posted at: 12:45 a.m. EDT
From Medical Correspondent Rhonda Rowland

Men Want Their Own Contraceptive Pill

An international survey of 2,000 men in Edinburgh, Cape Town, Hong Kong and Shanghai has shown that two thirds of all men would like to be able to take contraceptive pills themselves. Of an additional 2,000 women interviewed by the researchers, almost all would welcome this approach to contraception, and would trust their partners to be responsible about it.
The idea of a contraceptive pill for men is extremely popular among women, say the researchers. Only the men in Asian circles seem a little more skeptical: In Hong Kong, only half the men announced their willingness to take such a pill. The researchers conclude that in all, the men exhibit a great open-mindedness. Among men there is an increased willingness to accept responsibility in matters of contraception. Apparently, the main reason for this is a desire to meet the needs expressed by women.
For the pharmaceutical industry, the survey could be an impetus to finally develop the appropriate market-ready products. The researchers estimate that the pill for men could hit stores in five to ten years.


Source: BBC / Human Reproduction, Feb 23, 00
Research: Richard Anderson

Pill for men

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