Miyata, H., Satouh, Y., Mashiko, D., Muto, M., Nozawa, K., Shiba, K., . . . Ikawa, M. (2015). Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive. Science (New York, N.Y.), 350(6259), 442-445.
"In the immune system, calcineurin activates T cells by dephosphorylating the transcription factor NFAT (nuclear factor of activated T cells), and the dephosphorylated NFAT up-regulates the expression of interleukin-2 (1, 2). This process is suppressed by calcineurin inhibitors, such as cyclosporine A (CsA) and FK506, that are mainstays of immunosuppressive therapy after organ transplantation (1, 2). In the male reproductive system, animal experiments have revealed that CsA and FK506 have deleterious effects on spermatogenesis and epididymal sperm maturation (3, 4).Further, in vitro treatment of spermatozoa with these drugs impairs sperm motility and the acrosome reaction (5, 6). These data suggest important roles of calcineurin in male fertility; however, the existence of several isoforms expressed in the testis hampered the clarification of their functions and pharmacological processes."
• calcineurin may have an important role in male fertility • Calcineurin ibjibitors i.e. Cyclosporine A (CsA) and FK506 can have adverse affects on spermatogenesis and epididymal sperm maturation • used in immunotherapies as well • in vitro, tx of spermatozoa w/ them impairs sperm motility and the acrosome rxn
- isoforms may hamper the effects of the inhibitors
Calcineurin exists as a heterodimer composed of a catalytic and a regulatory subunit. In mammals, three isoforms of the catalytic subunit (PPP3CA, PPP3CB, and PPP3CC) and two isoforms of the regulatory subunit (PPP3R1 and PPP3R2) have been identified. Ppp3ca, Ppp3cb, and Ppp3r1 are expressed ubiquitously, whereas Ppp3cc and Ppp3r2 are expressed strongly in the mouse testis (fig. S1A) (7). PPP3CC and PPP3R2 were not detected in the testis and epididymis of c-Kitw/wv mice, which lack differentiating germ cells (Fig. 1A). This indicates that Ppp3cc and Ppp3r2 are the only subunits expressed in spermatogenic cells.
• Ppp3cc and Ppp3r2 are isoforms of Calcineurin subunits and are expressed strongly in mouse testis only subunits expressed in spermatogenic cells
"When mouse Ppp3cc and Ppp3r2 were expressed in human embryonic kidney 293T (HEK293T) cells, heterodimerizaion of PPP3CC and PPP3R2 stabilized the calcineurin complex (Fig. 1C). "
PPP3CC -PPP3R2 complex is the sperm-specific calcineurin
"Although Ppp3cc−/− males copulated, they were infertile (Fig. 2A). When we investigated sperm migration in the female reproductive tract using transgenic spermatozoa that have DsRed2 in the mitochondria (9), fewer spermatozoa reached the ampulla compared with those of controls (fig. S4A). Although this could explain, in part, the male infertility, the presence of spermatozoa in the ampulla suggests that there are other factors that render the Ppp3cc−/− males infertile."
• knock-out PP3CC mice could engage in sexual activity but were infertile. • less spermatozoa reached the ampulla of this knockout, but they were also found in the ampulla could be other compounding factors of this knockout's infertility
Further analysis revealed that Ppp3cc-null spermatozoa could pass through the cumulus cell layers (fig. S4B) and could bind to the zona pellucida (ZP) (Fig. 2C) but failed to fertilize cumulus-free ZP intact oocytes (fig. S4C);therefore, the ZP was the site of the problem. Once the ZP was removed, Ppp3cc-null spermatozoa could fuse with oocytes (fig. S4D), which confirmed that Ppp3cc-null spermatozoa are defective in zona penetration (2)
• explored further factors that contribute to infertility of the KO identified the zona pellucida as the issue as even when it was removed, the KO sperm fused with the oocytes
To elucidate why Ppp3cc-null spermatozoa fail to exhibit hyperactivation, we further analyzed sperm motility. Although beat frequencies of Ppp3cc-null spermatozoa were normal (fig. S7E), the midpiece of null spermatozoa bent slightly in a direction opposite from the hook of the acrosome (anti-hook) (99%, 110 out of 111 spermatozoa) (14) and was inflexible (Fig. 3, C and D, and movies S1 to S4). In contrast, defects were not observed in the principal piece of null spermatozoa (Fig. 3C). When WT spermatozoa are hyperactivated, the curvature of the midpiece bend increases (14); however, Ppp3cc-null spermatozoa do not exhibit this increase. Thus, PPP3CC is required to develop the flexible midpiece for hyperactivation and to penetrate the ZP.
• further analysis of sperm motility showed that the midpiece of the null sperm bent slights in an opposite direction from the hook of the acrosome and was inflexible. • WT sperm have an increased curvature of the midpiece when hyperactivated shows PP3CC is required to develop the flexible midpiece for hyperactivation and to penetrate the ZP
To determine the effects of immunosuppressant drugs on immature spermatozoa, WT male mice were treated with CsA or FK506 for 2 weeks; these males became infertile (Fig. 4A), and spermatozoa from treated mice did not fertilize in vitro (Fig. 4B). When sperm motility was investigated, their midpiece was as inflexible as Ppp3cc- or Ppp3r2-null spermatozoa (Fig. 4C, movie S6 to S9). These results indicate that sperm calcineurin activity is important during the later stages of spermatogenesis or during sperm maturation in the epididymis. (2)
• when treated with CsA or FK506 for 2 weeks, WT male mice became infertile and spermatozoa didn't fertilize in vitro demonstrate importance of sperm calcineurin activity in later stages of spermatogenesis or sperm maturation in epididymis
As expected, fertility of male mice treated with CsA or FK506 recovered 1 week after halting drug administration (Fig. 4E). Sperm motility and midpiece flexibility also recovered after treatment (fig. S11, B to D). Considering these results in mice, we suggest that sperm calcineurin may be a target for reversible and rapidly acting human male contraceptives.
• infertility induced with CsA or FK506 treatment was reversible as well as sperm motility and midpiece flexibility • suggests that sperm calcineurin can be a target for reversible and fast acting human male contraceptices can leave testicular function in tact too
Kean, S. (2012). Contraception research. Reinventing the pill: Male birth control. Science (New York, N.Y.), 338(6105), 318-320.
IN THE LATE 1950S NEAR SALEM, OREGON, scientists started testing a birth control drug called WIN 18,446 in male prisoners. Men took responsibility for most birth control then, so a male contraceptive seemed a natural fi t for American society. WIN 18,446 worked well, too: The prisoners felt fine and seemed quite healthy, except that their sperm was suddenly stunted and feeble. Unfortunately, when clinical trials shifted to the general population, men started getting sick—vomiting, sweating, headaches, blurry vision. They seemed poisoned. After some digging, scientists pinned down the culprit: alcohol. Because prisoners couldn’t drink, no one had realized at first that WIN 18,446 did not mix well with liquor. The drug was abandoned, and 60 years later, no one has gotten any closer to the “male pill.” WIN 18,446 is a perfect example of why creating the male pill is so hard. It did exactly what it was supposed to do—stopped sperm production in everyone who took it—and it was reversible. Sperm levels returned to normal after men stopped taking it. Yet it failed anyway as a drug because of an arguably minor side effect.
• male birth control drug called WIN was tested in male prisoners in oregon in late 1950s. - first attempt at the "male pill" • subjects seemed healthy and fine with stunted and feeble sperm • when WIN reached clinical trials in general populaiton, men experienced intense side effects they realized this was b/c it did not mix well with alcohol
Male contraceptives are held to high standards partly because the calculus for male and female birth control is different. For example, taking the female pill increases a woman’s chances of developing blood clots. But because pregnancy increases the chances of blood clots by 10 times more, the pill’s side effects seem worth the risk. With men, there’s no counterbalancing risk of pregnancy, so the tolerance for side effects drops to zero. That’s especially true because “you’re dealing with healthy people, not people with an illness, and you’d have to use [the pill] for long, long periods,” says Diana Blithe, a program director at the U.S. National Institute of Child Health and Human Development (NICHD) in Bethesda, Maryland, which funds research into male contraception
• counterbalance of birth control side effects with pregnancy is a big reason for women having approved birth control over men. no counterbalance to pregnancy for men
Drug companies have all but abandoned the male contraceptive field in the past decade. After acquiring smaller companies, for instance, both Bayer and Merck shut down those programs. (Bayer refused to say why, and a Merck spokesperson said only, “It is not a priority area.”) In addition to the medical challenges like the high safety standard, Blithe points out one other obstacle for companies: The U.S. Food and Drug Administration (FDA) has no guidelines about what levels of safety and effi cacy the male pill would need to have to win approval. FDA declined to comment about whether it planned to develop guidelines or whether it has even discussed doing so.
drug companies have paid little attention to male contraceptive field as of late. • large drug companies have not commented on it or haven't prioritized it FDA has not even created guidelines for safety or efficacy of the male pill required for approval
Plugs. Hormones. Special underwear. Autoimmune attacks. The “dry orgasm.” There’s no shortage of approaches to male contraception (see diagram, p. 319). But all share the same goal: slowing down the relentless proliferation of sperm in men and holding sperm counts to about 1 million per milliliter of ejaculate. Even the reduced concentration “may sound like a lot,” says John Amory, a doctor and reproductive biologist at the University of Washington, Seattle, “but that’s a pretty good, effective contraceptive” that will reduce fertility by 99%.
• goal of male contraceptives is to slow the proliferation of sperm in men and limit counts to about 1 million per mL of ejaculate this will be an effective contraceptive, reducing feritlity by 99% if achieved
Until recently, scientists modeled most male pills on the female pill and attempted to disrupt male hormones—testosterone above all. The biochemistry is convoluted, but artifi cially raising testosterone levels suppresses other hormones necessary to make mature sperm. This works wonderfully— sperm levels plummet—but it’s a sledgehammer approach that affects tissues throughout the body, causing widespread side effects. There’s no good way to administer testosterone, either. Oral testosterone breaks down so quickly in the body that men must take several pills a day to keep levels high, and alternatives like testosterone gels or injections are a hassle. Hormonal contraception doesn’t work anyway in 10% to 20% of men, Amory says. This strategy suffered its latest blow in April 2011, when a high-profi le study led by the U.S. nonprofi t group CONRAD and co-sponsored by the World Health Organization was called off early. The study had monitored more than 200 couples taking various hormones for more than a year, but side effects such as acne, weight gain, and mood changes convinced scientists that the therapy would fail in the marketplace.
• primary approach was to dirupt testosterone (modelled after female hormonal BC) • raising TE levels suppresses other hormones necessary to make mature sperm • effective in lowering sperm levels but has bad side-effects • also no good way to administer-i.e. oral TE metabolizes so quickly that it req. several pills a day to keep levels high • also ineffective in 10%-20% of men • latest blow to male hormonal contraception was in April 2011 in high-profule study by the US. nonprodit group CONRAD where more than 200 couples taking the hormones for more tha a year had bad side effects acne, weight gain, mood changes
Most current research into a male pill has shifted away from widely circulating hormones toward molecules specific to the testes. One promising approach being explored by Amory and others involves disrupting retinoic acid, one of a group of molecules known collectively as vitamin A. Like hormones, vitamin A plays a role in many different tissues, so scientists can’t just shut down the pathway. But sperm are so sensitive to retinoic acid that reducing its levels even a little could prove effective
• most current research involves small molecule appraches in the testes i.e. disrupting retinoic acid- group of molecules collectively known as Vitamin A, sperm are very sensitive to tetinoic acid levels, so reduction can be effective
Amory’s research sprang from WIN 18,446, the failed prisoner drug. Because WIN 18,446 sickened people who drank, Amory suspected that it disrupted the breakdown of alcohols. Wine, beer, liquor, and other booze contain ethanol, which the body metabolizes into acetaldehyde. Because acetaldehyde is poisonous, an enzyme called ALDH converts it to acetic acid (vinegar, essentially). In a paper in the Journal of Andrology fi rst published online in August 2010, Amory’s team proved that WIN attaches to ALDH and gums up the process, allowing acetaldehyde to accumulate. Amory, though, saw the bright side. The testes also convert an alcohol (retinol, another form of vitamin A) into retinoic acid. During spermatogenesis, retinoic acid binds to the RAR protein, creating a complex that turns on genes necessary to convert precursor cells into mature sperm. The testes use a unique ALDH called ALDH1a2 in this conversion. So Amory’s team tried to tweak WIN 18,446’s molecular structure to make it lock onto ALDH1a2 only, and not onto the ALDH that prevents alcohol poisoning. It didn’t work. “We tweaked the hell out of WIN 18,446,” he laughs. “Our poor organic chemist made 100 versions” in 2009 and 2010, but every one proved a dead end. Still, intrigued by the specificity of ALDH1a2, his team screened 60,000 other molecules and found seven more that gummed up ALDH1a2. They’re now tweaking those seven to make them testesspecifi c. Amory expects four or fi ve of them to fall short in future tests—some might prove toxic or might not cross the blood-testis barrier, a tissue fi rewall that separates the testes from general blood circulation. But within 5 years, he hopes to approach FDA about clinical trials
• One small molecule approach was inspired by WIN after researchers discovered that the side effects were caused by the molecule's attachment to ALDH, the enzyme that converts acetaldehyde caused by the consumption of alcohol into acetic acid. This attachment allowed for the buildup of acetaldehyde and therefore the side effects similar to symptoms of poison • researchers saw that the testes also use a unique ALDH, ALDH1a2 in the conversion of percursor cells into mature sperm • retinoic acid binds to the RAR protein that creates the complex necessary for this conversion • researchers tried to tweak WIN to make it lock onto ALDH1a2 only and not the ALDH that prevents alcohol poisioning Amory's team now expectsto approach FDA about clinical trials
Anthes, E. (2017). What Do We Have To Do To Get The Male Pill? Bloomberg Businessweek, (4533), 44.
"The joke in the field is that the male contraceptive has been five years away for the last 40 years," says John Amory, a research physician at the University of Washington School of Medicine who has been working on the challenge for two decades. A new form of male birth control would be a public-health triumph and could snag a significant piece of the contraceptive market, —which is expected to surpass $33 billion by 2023, according to research firm Global Market Insights Inc.—or possibly expand it further. In a 2002 German survey of 9,000 men in nine countries, including Brazil, France, Germany, Mexico, and the U.S., more than 55 percent of the respondents said they'd be willing to use a new form of male birth control. A later study by Johns Hopkins University estimated that the demand could yield 44 million customers in those nine countries alone. And yet major pharmaceutical companies have mostly abandoned the chase.
• male birth control would be a public-health triumph and would also be a lucrative market • contraceptive market is expected to surpass #33 billion by 2023 or more • High demand for male BC also: more than 55% of respondents in 2002 German survey said they were willing to use a new form of male birth control later John Hopkins U study estimated demand that could yield 44 mil customers in those 9 countries alone
When it comes to preventing pregnancy, women have a multitude of choices. There are diaphragms and sponges; cervical caps and female condoms; spermicidal gels, foams, films, creams, and suppositories; hormone-delivery systems involving pills, implants, injections, patches, vaginal rings, and IUDs. These options are far from perfect—and they remain inaccessible and unaffordable for many women—but at least they exist.
• women have a multitude of contraceptive options relative men: diaphragms and sponges, cervical caps and female condoms, spermicidal gels, foalms, films, creas and suppositories; hormone-delivery systems with pills, implants, injections, patches, vaginal rings, and IUDs
After the U.S. Food and Drug Administration approved the first female birth control pill, which used a mixture of hormones to suppress ovulation, in 1960, researchers explored taking a hormone-based approach to men. Clinical trials in the ensuing decades showed that dosing men with testosterone or combinations of testosterone and progestin temporarily inhibited sperm production, but that the strategy had drawbacks. Testosterone is rapidly cleared from the body when taken orally, so a hormonal contraceptive for men would likely have to be delivered via injection, implant, or topical gel, rather than as a pill. What's more, the hormones don't work in all men, and because they don't only affect the gonads, they can, as with the female pill, cause nasty side effects that have nothing to do with fertility.
• USFDA approved first femal BC pill in 1960- uses hormones to suppress ovulation • tried to confer this method to men by dosing wiht testosterone or/and progestin to temporarily inhibit sperm production drawbacks: rapidly cleared from body when taken orally, hormones don't work in all men b/c they don't only affect gonads, nasty side effects
Research into hormonal solutions continues, but the challenges have prompted some investigators to seek drugs that target sperm more directly. Scientists at the University of Kansas and the University of Minnesota are studying a compound called H2-gamendazole, which prevents sperm from maturing properly, while Eppin Pharma Inc., a small North Carolina company, is developing a drug that would stop sperm from swimming by binding to a protein on the surface of the cells.
• researchers have tried to target sperm more directly- instead of hormonal solutions • i.e. at U of Kansas and U of Minnesota- studying a compound H2-gamendazole, which prevents sperm from maturing properly i.e. Eppin Pharma- developing drug to stop sperm from swimmming by binding to a protein on the surface of thecells
He tested his hypothesis in rabbits, dosing them with a WIN-laced banana-crème-flavored syrup. "Rabbits are brilliant, because their sperm counts are very similar to humans. They're mammals just like humans, and you can train them to ejaculate into an artificial vagina," he says, cuing up a video on his computer. "This is me making an artificial vagina." (The faux orifice, it turns out, can be assembled from an ultrasound-probe cover and a thermos filled with water heated to about 100F, the approximate internal temperature of a female rabbit.)
• Amory tested WIN drug in rabbits, as their sperm counts are similar to humans. They can also be trained to ejaculate into an artificial vagina
He concluded that WIN represented an elegant strategy for male contraception—it just needed to be better targeted. There are almost 20 different forms of ALDH; the liver relies primarily on ALDH2 to metabolize alcohol, while the testes use ALDH1A2 to make retinoic acid. WIN disrupted both forms of the enzyme; what they needed was a drug that blocked only ALDH1A2.
• Amory investigated the mechanism of WIN and found that it inihibits ALDH by dssrupting the synthesis of retinoic acid and also inhibits sperm production which is needed by the testes • ALDH in liver and other areas (20 dif forms) • testes use ALDH1A2 to make retinoic acid • WIN disrupted both forms of the enzyme- testes and liver identified need for drug only blocking ALDH1A2
Drug development is an inherently difficult enterprise. Only 10 percent of the drugs that enter Phase I trials—the studies in which scientists evaluate dosing and basic safety in humans—ever make it to pharmacy shelves, and it can easily cost hundreds of millions of dollars to bring a drug to market. Male contraception is a particular challenge. Contraceptives have to be extraordinarily reliable. Many drugs would be considered successes if they worked half the time, but few people would use birth control that failed so frequently.
• there are challenges in drug development to begin with, much less developing male BC • only 10% of drugs that enter phase ` trials ever make it to pharmacy shelves • can cost hundreds of millions of dollars to bring a drug to market additional challenge with male BC is that they would have to be very reliable
Then there are the basic facts of reproductive biology. Most healthy women of reproductive age release one egg per month and stop ovulating when they're pregnant; they can suppress ovulation by taking hormones that mimic pregnancy, which is essentially what the pill does. But there's no natural off switch for sperm production; men make sperm from puberty until death. "Spermatogenesis is a pretty formidable foe," Amory says. "Your body has evolved over eons to make a lot of sperm. In fact, most men make a thousand sperm every second."
• nature of reproductive biology creates another challenge: • women release one egg per month, can suppress ovulation by taking hormones that mimic pregnancy in contrast, no natural ?"off switch" for sperm production as men make sperm from puberty til death and make thousand per second
If researchers do find a promising drug, they'll also need to persuade regulators to approve it. No one's quite sure what that will take. Male contraceptive drugs represent an entirely new product category, and the FDA hasn't yet laid out clear guidelines for them. Will regulators measure a male contraceptive drug against the female pill or simply compare it to the male-directed approaches now available? Will they want a male pill to be as effective as a vasectomy or simply more reliable than a condom? "Nobody really knows, because nobody's gotten to that point," says Zahed Subhan, chief executive officer of Eppin Pharma, the North Carolina company that's testing a drug that aims to interfere with sperm movement.
There's reason to believe it will prove tougher to win approval for the first male pill than it was for the female one. Research and regulatory standards have evolved considerably in the past 60 years—the Oregon prisoner tests likely wouldn't pass muster today, nor would some early trials for the first female pill. (In one crucial study performed with low-income women in Puerto Rico, participants weren't fully informed of the potential risks, and their reports of side effects were largely dismissed.) Some scientists have also speculated that the original formulation of the female pill, which contained much higher doses of hormones than current products do, wouldn't be approved today.
• other challenge of gaining approval of drug when found as FDA lacks clear guidelines for male contraceptive drugs • will it be measured against the female pill? or comapred to male-directed approaches now available? tougher to win approval for first male pill now than it was for the femal one back in the 60s due to the evolution of regulatory standards
Moreover, while female contraceptives aren't without dangers, pregnancy entails serious health risks. This means regulators charged with making a risk-benefit calculation may conclude in some cases that unplanned pregnancies pose a greater hazard to women than the side effects of a new birth control product would. The female pill also has some non-contraceptive health benefits. The first birth control pill, Enovid, initially won FDA approval in 1957 to treat menstrual disorders; it wasn't approved as a contraceptive until three years later.
That men don't bear the medical risks of pregnancy may change the calculus for regulators assessing a male contraceptive. So might the fact that men, with their long reproductive lifespans, could find themselves using birth control for decades longer than women typically take the pill. Unless researchers manage to find a contraceptive with real health benefits for men, regulators will probably have a low tolerance for side effects. "A male contraceptive solution just has to be squeaky clean," Subhan says.
If a drug were approved and serious side effects popped up, pharmaceutical companies could face costly lawsuits. Litigation is always a risk for drugmakers, but medications designed to be taken by young, otherwise healthy patients for long periods of time, especially those affecting the reproductive system, could be particular targets. Women have filed, and sometimes won, high-profile lawsuits over female contraceptives, alleging that certain drugs and devices have caused a variety of serious injuries—including blood clots, uterine damage, birth defects, miscarriages, and infertility—or that contraceptive failures have left them with unwanted pregnancies.
• calculation of risk-benefit of male birth control pill is also complex to consider • for females, contraceptives have side effects but pregnancy can also entail serious health risks • males don't bear the risk of pregnancy and its associated risks so this may change the calculus for regulatos' assessment of a male BC pill • also to be weighed is that men would also have to use the pill for decades longer than women b/c of long reproductive lifespans • additionally, the drugs' side effects could face litigation
Some entrepreneurs say the path forward requires wholly rethinking male birth control. "What is a male contraceptive?" asks Kevin Eisenfrats, the 24-year-old co-founder and CEO of Contraline Inc., a startup based in Charlottesville, Va. "Is it a drug, or is it a medical device?" Just inside the front door of the company's two-story brick building, not far from the University of Virginia, a custom mural—a silhouette of a man and woman walking into the sunset—is splashed across a side wall. A bowl of Contraline-branded, sperm-shaped foam stress balls sits on the reception counter. Eisenfrats, who has long eyelashes and a spray of freckles on his nose, takes a seat at a cluttered conference table and delivers his elevator pitch. "What we're developing is a nonsurgical and reversible alternative to a vasectomy," he says. Contraline has created a hydrogel, called Echo-V, that can be injected into the vas deferens, the thin tube that transports sperm from the testes to the urethra. Upon injection, the gel solidifies, blocking the flow of sperm but allowing other fluid to pass through. Ideally, he says, when a man is ready to have children, a doctor would dissolve the gel.
The idea isn't novel. It's inspired by a technique known as reversible inhibition of sperm under guidance (Risug), invented in India in the 1970s. The Parsemus Foundation, a nonprofit based in Berkeley, Calif., is developing a similar product, called Vasalgel. But while Risug requires doctors to make a small opening in the skin of the scrotum to access the vas deferens, Contraline has invented a procedure, which it has dubbed " vasintomy," that allows doctors to implant the gel non-surgically, injecting it directly through the skin using an ultrasound to guide its placement. "No scalpels or sutures required," Eisenfrats says. "It's maybe a three-minute overall procedure."
Because Echo-V qualifies as a medical device, Contraline may have an advantage over rivals working on a male pill. The FDA typically requires more and larger clinical trials for drugs than it does for devices; it takes 12 years, on average, to bring a new drug to market, compared with three to seven years for a new medical device. The expense therefore tends to be much higher for drugs.
Contraline's research team is racing to be one of the first to market with a viable solution. The company is tinkering with the gel's formulation, assessing its efficacy and biocompatibility, designing an injection device, and refining the injection and reversal procedures. Eisenfrats says he plans to begin a preclinical trial in large animals next year, begin human trials in 2019, and earn FDA approval in 2021.
• other options other than a pill are emerging i.e. development of nonsurgical and revversible alternative to vasectomy • a hydrogel, Echo-V, could be injected into vas deferens (transports sperm frmom testes to urethra) • upon injection, gel solidifies to block flow of sperm but allowing other fluid to pass through • ideally the doctor could dissolve the gel when man is ready to have kids • non-surgical: injecting directly through skin using an ultrasound to guide its placement, 3-minute procedure • this alternative method is advantageous over the male pill b/c it qualifies as a medical device • FDA requires larger and more clinical trials for drugs than devices (12 yrs v. 3-7 for a device) plans to begin preclinical trial in large animals next year, begin human trials in 2019, and earn FDA approval in 2021
As for more radical scientific approaches, British researchers are working on a so-called clean-sheets pill that would stop men from ejaculating during orgasm. A German company has devised an implantable valve—advertised to be "small as a gummy bear" and "100% vegan"—that would let men turn the flow of sperm on and off with the flick of an actual switch. And a Chinese team has piloted an approach that involves injecting gold nano-particles into the testes and heating them with an infrared laser. None are likely to be commercially available soon—indeed, they haven't yet been tested in humans, though Clemens Bimek, the German who developed the spermatic duct valve, reportedly had several prototypes implanted in his scrotum.
• more radical approaches include so-called clean-sheets pill whihc would stop men from ejaculating during orgasm- uses an implantable valve that would turn the flow of sperm on and off with a click of an actual swithc • Chinese team has tried injecting gold nano particles into testes and heating them with an infrared laser these have not been tested in humans
New Male Contraceptive? (2012). Jama-Journal Of The American Medical Association, 308(1), 21.
The discovery of a key gene in sperm development may help researchers design a male contraceptive that (unlike conventional contraceptives) would not disrupt the production of hormones and would perhaps avoid such hormonerelated adverse effects as irritability, mood swings, and acne (Smith LB et al. PLoS Genet. 2012;8[5]:e1002697). The finding could also provide new information on male infertility.
• identificaiton of key gene in sperm development can allow for the design of a male contraceptive with less side effects • avoids disruption of hormones and effects associated with them i.e. irritability, mood swings, acne could also inform on causes of male infertility
To identify new genes involved in male fertility, a team led by researchers at the University of Edinburgh, in Scotland, chemically induced random mutations within the DNA of mice and then screened for animals that exhibited infertility. These experiments indicated that the Katnal1 gene is critical to enable sperm to mature in the testes.
Additional analyses revealed that the protein encoded by the geneis needed to regulatethemicrotubulesthatsupportand provide nutrients to developing sperm and enable the cells to move within the testes as they mature. Absence of the protein results in premature release of immature sperm. Male mice with mutated,nonfunctional Katnall genes were infertile.
• identified new genes by chemically inducing random mutations within DNA of mice and screening for infertility • showed Katnall gene is necessary for sperm maturation in testes<br> • protein encoded by gene regulate microtubules supporting and providing nutrients for sperm development and for motility in testes • absence of protein--> premature release of immature sperm male mice with mutated, nonfunctional Katnall genes were infertile
Amory, J. (2016). Male contraception. Fertility and Sterility, 106(6), 1303-1309.
Administration of unesterified testosterone orally or parenterally is ineffective because it is quickly degraded by the liver. Therefore, most hormonal contraceptive regimens have used longer-acting injectable testosterone esters such as testosterone enanthate (TE) administered by means of intramuscular injection on a weekly basis. Two multicenter trials of weekly TE injections as a male contraceptive were conducted by the World Health Organization (WHO). The first study enrolled 271 subjects who were dosed with 200 mg TE intramuscularly weekly (30). Sixty percent of the men became azoospermic, and an additional 30% became severely oligospermic. One hundred nineteen of the men who became azoospermic discontinued other birth control and continued on TE injections as their sole method of contraception for 1 year. During that period, only one pregnancy occurred, demonstrating that testosterone-induced azoospermia was a highly effective contraceptive.
• testosterone- induced azoospermia was a highly effective contraceptive as proven by the WHO trials of weekly TE injections • 271 subjects, dosed with 200mg TE intramuscularly weekly 119 men continued use for a year after becoming azoospermic--> only 1 pregancy occurred
The second WHO study examined contraceptive efficacy of TE injections in men who became azoospermic or oligospermic to <3 mil sperm per milliliter of ejaculate with the use of TE injections (31). Three hundred ninety-nine, mostly Asian, men were enrolled in this study. Three hundred ninety-one (98%) of the men became oligospermic or azoospermic. There were no pregnancies caused by the men who became azoospermic, and in the men who became oligospermic fertility was reduced to eight pregnancies per 100 personyears. The overall failure rate (including the eight men who failed to suppress their sperm counts) was 3.4%, for an overall contraceptive efficacy of 96.6%. In both groups, sperm counts returned to normal after the cessation of testosterone injections, and there were no major side-effects
• another WHO study with 399 men taking TE injections resulted in96.6% contraceptive efficacy with reversibility of low sperm counts • 98% of men becoming oligospermic or azoospermic. • Overall failure was rate 3.4% • no pregnancies caused by azoospermic men; 8 pregnancies per 100 personyears no major side effects
These studies demonstrated that testosterone injections are effective as a contraceptive in most men; however, a proportion of men fail to suppress to <3 milion sperm per milliliter and therefore remain potentially fertile. In addition, the necessity of weekly intramuscular injections was unpopular with subjects, 12% of whom discontinued involvement owing to dislike of the injection schedule. Side-effects were fairly minimal, but notably, high-dose TE deceases serum highdensity lipoprotein (HDL) cholesterol, which might affect the development of atherosclerosis (33, 34); however, as is the case with any male hormonal contraceptive, the longterm effects on prostate and liver health as well as mood and behavior are unknown.
• TE injections are effective as a contraceptive but there are still men who cannot suppress sperm counts and remain fertile.<br> • delivery by injection was also unpopular- 12% of subjects discontinued involvement b/c of it • side-effects were minimal • high- dose TE deceases serum HDL cholesterol that can affect the development of atherosclerosis longterm effects on prostate and liver health, mood and behavior are also unknown
Testosterone undecanoate (TU) is a long-chain ester that normalizes serum testosterone concentrations in hypogonadal men for 6–12 weeks after injection (35–37). A large trial of TU injections for male contraception was conducted in China (38). Volunteers received monthly injections of 500 or 1,000 mg TU. Ninety percent of the men had sperm concentrations of <1 million sperm/mL and used the injections as their sole method of contraception for 1 year. Only a few pregnancies were reported in treated men and side-effects were minimal; however, for unclear reasons the method was not approved for use.
• testosterone undecanoate normalizes serum testosterone concentrations in hypogonadal men for 6-12 weeks after injection. • large trial for TU injections was conducted in China: 90% of men had sperm concnetrations of <1 million sperm/mL & used their injections as their only contraception method only a few pregnancies reported and side-effects minimal but method wasn't approved for use for unclear reasons
In the hopes of achieving greater rates of azoospermia, several male contraceptive studies have combined testosterone administration with administration of progestins, which additively suppress FSH and LH from the pituitary and may have direct antisperm effects on the testes (39). Combinations of testosterone and depot injections of medroxyprogesterone acetate (DMPA) induced azoospermia in one-half of study subjects and some degree of oligozoospermia in most others. The contraceptive efficacy of these combinations, however, was poor, with several couples conceiving while receiving therapy despite simultaneous use of other contraceptives (40).
• some male contraceptive studies have combined testosterone administration with administration of progestins (additively suppress FSH and LH from the pituitary and may have direct antisperm effects on the testes) • these injections induced azoospermia in 1/2 of study subjects and some degree of oligozoopermia in most others contraceptive efficacy poor overall
Several male contraceptive studies of the potent oral progestin levonorgestrel (LNG) have been performed. For example, in one study, LNG (500 mg orally daily) was combined with TE (100 mg intramuscularly per week) for 6 months. The LNG-TE combination was superior to TE alone in terms of azoospermia (67% vs. 33%), and 94% of the men had sperm concentrations of <1million per milliliter compared with 61% of the TE-alone group (41). Drawbacks to the LNG-TE regimen included greater weight gain and decreases in HDL cholesterol compared with the TE-alone group. Other progestins, such as desogestrel, have been tested in male contraceptive regimens with similar results, but without causing weight gain or large reductions HDL cholesterol
• contraceptive studies of potent oral pregestin levonorgestrel have been performed • i.e. in one study, LNG was combined with TE for 6 months- resulted in better azoospermia than TE alone, 94% of men had sperm concentrations o f<1 mil per mL • drawbacks included greater weight gain, decreases in HDL cholesterol compared to TE alone group although other progestins have been tested with similar results and less side effects.
Nestorone is a 19-norprogesterone–derived progestin which can be applied as a transdermal gel (48). A combination of Nestorone gel and testosterone transdermal gels were studied for gonadotropin suppression (49) and in a 6-month male contraceptive trial (50). In the latter study, 89% of men achieved suppression of their sperm concentration to %1 million sperm per milliliter. Importantly, a majority of subjects on this regimen were very satisfied with the regimen, stating that they would be likely to use it if it were commercially available (51). Ongoing studies are working to simplify the regimen into a single combination gel for phase II testing at six international sites beginning in 2017.
• Nestorone can be applied as a transdermal gel and is a 19- norprogerstone-derved progestin. • combo of Nestorone gel and testosterone transdermal gels were studied in 6-month trial in which 89% of men achieved suppresion of their sperm concenration to <1mill sperm/ mL subjects were very satisfied with the regimen
Dimethandrolone undecanoate (DMAU) is a potent synthetic 19-norandrogen that acts as a ligand at both androgen and progesterone receptors, making DMAU a potential ‘‘single-agent’’ contraceptive (52). Studies in rodents and rabbits have shown both reversible suppression of gonadotropins and sperm with orally administered DMAU (53, 54). Phase I testing in humans has demonstrated short-term safety and tolerability with reversible suppression of gonadotropins (55), and phase II testing of this compound is underway. Interestingly, DMAU can be administered orally as well as by intramuscular injection, making it a very exciting compound for male hormonal contraceptive development.
• DMAU is currently in Phase I testing in humans and Phase II testing is underway • is a single agent contraceptive for which studies in rodents and rabbits have shown reversible suppression of gonadotropins and sperm with orally administered DMAU Phase I testing injumans showed short-term safety and tolerability w/ reversible suppression of gonadotropins
Several groups are examining approaches to ‘‘nonhormonal’’ male contraception, although to date none of the current generation of candidates has been tested in men. Nonhormonal male contraception does not involve the administration of hormones or compounds that block hormone secretion or hormone action. Nonhormonal contraception may be more appealing to men because it avoids any impact on testosterone concentrations or sexual function. In addition, the use of testosterone or another anabolic steroid could lead to sports disqualification. Finally, nonhormonal contraceptives may be more easily dosed orally than steroid preparations owing to rapid ‘‘first-pass’’ metabolism of testosterone in the liver
• nonhormonal options are also being explored but haven't been tested in men • doesn't involve blockage of hormone secretion or hormone action • may be more appealing to men b/c it doesn't impact testosterone conc. or sexual function ; also b/c it would avoid sports disqualitifcation • may also be more easily dosed orally • example is adjudin: antisperm comp that disrupts the adhesion of spermatidds to Sertoli cells to cause rpemature speriation and infertility 100%infertility after 5 weeks of tx in adult rats w/oth changes in serum testosterone, FSH, or LH conc.
Since the early 1990s, efforts have been underway in India and China to develop a temporary plug for the vas deferens, which could theoretically be removed or dissolved by an injection at a later date to provide reversibility. The Indian vas occlusion device is called RISUG for ‘‘reversible inhibition of sperm under guidance.’’ With the use of ultrasound guidance, sterile styrene maleic anhydrate is instilled into the vas, bilaterally occluding it and preventing the passage of sperm. Several small clinical trials in men have been performed with the use of this technique (79, 80), showing excellent contraceptive efficacy over periods of up to 1 year. The procedure has been shown to be reversible in some nonhuman models (81), but data on efficacy and reversibility from large-scale clinical trials are not available (82). Similar vas occlusion devices using medical-grade silicone and polyurethane plugs were studied in China (83, 84). Unfortunately, both compounds had problems with time to sperm suppression and recovery of sperm counts after reversal, leading the investigators to abandon that approach
• another method is a temporary plug for the vas deferns whihc could be theoretically removed or dissolved by an injection • several small clinical trials in men have been performed using ultrasound guidance to put in place an Indian vas occlusion device called RISUG resulting in excellent contraceptive efficacy up to 1 year periods procedure is reversible in nonhuman models but other evidence of reversibility in large-scale trials aren't available