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Ibuprofen linked to male infertility, study says

Ibuprofen linked to male infertility, study says

By Susan Scutti, CNN

Updated 3:30 PM ET, Mon January 8, 2018

Photos: Photos: A guide to (legal) pain relief

Hydrocodone – Hydrocodone is available only in combination with other ingredients, with different products prescribed for different uses. Some products are used to relieve moderate to severe pain, while others combat a cough, according to the National Institutes of Health. An opiate (narcotic) analgesic, hydrocodone relieves pain by changing the way the brain and nervous system respond to it. It may be habit-forming, and abuse of drugs, including hydrocodone, has become a concern in recent years. In 2014, hydrocodone was moved from Schedule III to Schedule II. Now, in order to use these drugs, patients will have to get a written prescription from a doctor -- instead of one submitted orally by phone. And refills are prohibited; patients would have to check in with their doctors to get another prescription.

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Photos: Photos: A guide to (legal) pain relief

Fentanyl – Fentanyl is a prescription-only pain medication often given to cancer patients. They must be at least 18 years old to take it, or at least 16 for lozenges branded as Actiq, and they should also be taking regular doses of another narcotic pain medication. Patients must also be accustomed to the effects of narcotics. Fentanyl itself is a narcotic and changes the way the brain and nervous system respond to pain, according to the National Institutes of Health. This drug comes in the form of a lozenge, a tablet under the tongue, a film and a buccal (between the gum and cheek) tablet, as well as in injectable form. It is designed for sudden episodes of pain and should not be used more than four times a day. Overdose can cause drowsiness, dizziness, confusion, breathing problems or smaller pupils. The FDA has said there is growing concern about illicit fentanyl use, particularly in conjunction with heroin.

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Photos: Photos: A guide to (legal) pain relief

Morphine – Patients take morphine for moderate to severe pain. It is an opiate (narcotic) analgesic and changes the way the brain and nervous system react to pain. Forms of morphine include tablet and solution, which are taken every four hours, as needed. Controlled- or extended-release tablets and controlled- or sustained-release capsules are for patients who need around-the-clock pain relief. Morphine can also be found as a morphine sulfate injection, as added to an IV fluid that drips through a needle or catheter, or injected into a large muscle. Morphine overdose can cause serious consequences such as breathing problems, loss of consciousness, sleepiness, slow heartbeat, blurred vision, nausea and fainting, according to the National Institutes of Health. Morphine may also be habit-forming.

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Photos: Photos: A guide to (legal) pain relief

Propofol – Propofol, also known as Diprivan, became infamous when pop star Michael Jackson died after overdosing on the drug while using it as a sleep aid. The drug is typically administered intravenously by medical professionals for anesthetic purposes, such as when a patient is undergoing surgery. It's not approved to treat sleep disorders, according to the Food and Drug Administration. The drug itself does not provide pain relief but renders a patient unconscious. A patient wakes up almost immediately after an infusion is stopped, experts say. Propofol lowers blood pressure and suppresses breathing, so patients' heart function and breathing need constant monitoring, according to the Harvard Health Blog. Abuse of propofol in medical circles, however, has been a concern in recent years.

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Photos: Photos: A guide to (legal) pain relief

Ibuprofen – Ibuprofen falls into the class of drugs known as NSAIDs (nonsteroidal anti-inflammatory drugs). Sold under brand names including Motrin or Advil, it's used to treat minor aches and pains and reduce fever. It may be prescribed in stronger doses. It comes in tablet form as well as in chewable tablets, liquid suspensions and concentrated liquid drops. People who take NSAIDs may have a higher heart attack or stroke risk than those who do not, according to the National Institutes of Health. The medication can also cause ulcers, bleeding or holes in the stomach and intestine for some people. The risk may be higher if you take NSAIDs for a long time, are older or in poor health, and have three or more alcoholic drinks per day.

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Photos: Photos: A guide to (legal) pain relief

Acetaminophen – This compound can ease minor muscle, back, tooth and joint pain and reduce fever. Sold under brand names such as Tylenol, Liquiprin and Panadol, it works by regulating the part of your brain that controls your body's temperature and inhibits the synthesis of prostaglandin in the central nervous system. A study has found that it could reduce pleasure as well. Too much of the drug can cause rashes, liver failure and even death.

Hide Caption

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Photos: Photos: A guide to (legal) pain relief

Aspirin – Aspirin is one of the cheapest and oldest manufactured painkillers on the market. German-born scientist Felix Hoffman is credited with creating and popularizing what was then known as acetylsalicylic acid in 1899 to help ease his dad's arthritis pain. Today, it is used to ease minor aches and headaches. It works by reducing the substance in the body that causes inflammation and fever. Doctors also tell some adults to take an aspirin daily to help prevent a heart attack or stroke. People with bleeding conditions like ulcers or cardiovascular troubles like asthma are often advised to take another painkiller, as it may make those conditions worse. Some Americans are also allergic to aspirin. Americans consume more than 15 billion aspirin tablets a year. Here's a guide to some of the most commonly used pain relief medications:

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Photos: Photos: A guide to (legal) pain relief

Marijuana – There's been a growing acceptance of marijuana as a legitimate pain reliever. The American Medical Association supports making marijuana a Schedule I controlled substance in order to promote research into its therapeutic abilities. Doctors in some states may prescribe it to ease chronic pain that comes from arthritis, migraines, Crohn's disease or other ongoing pain issues where other medicines have failed. It works by blocking the pain sensations felt by peripheral nerves. The cannabinoids in marijuana bind to endocannabinoid receptors throughout the body and can reduce pain (but also give the feeling of being high). Some research shows that it can also slow cancer development and increase appetite. Forty states and the District of Columbia allow some legal uses of marijuana, mostly for medicinal purposes.

Hide Caption

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Photos: Photos: A guide to (legal) pain relief

Hydrocodone – Hydrocodone is available only in combination with other ingredients, with different products prescribed for different uses. Some products are used to relieve moderate to severe pain, while others combat a cough, according to the National Institutes of Health. An opiate (narcotic) analgesic, hydrocodone relieves pain by changing the way the brain and nervous system respond to it. It may be habit-forming, and abuse of drugs, including hydrocodone, has become a concern in recent years. In 2014, hydrocodone was moved from Schedule III to Schedule II. Now, in order to use these drugs, patients will have to get a written prescription from a doctor -- instead of one submitted orally by phone. And refills are prohibited; patients would have to check in with their doctors to get another prescription.

Hide Caption

5 of 8

Photos: Photos: A guide to (legal) pain relief

Fentanyl – Fentanyl is a prescription-only pain medication often given to cancer patients. They must be at least 18 years old to take it, or at least 16 for lozenges branded as Actiq, and they should also be taking regular doses of another narcotic pain medication. Patients must also be accustomed to the effects of narcotics. Fentanyl itself is a narcotic and changes the way the brain and nervous system respond to pain, according to the National Institutes of Health. This drug comes in the form of a lozenge, a tablet under the tongue, a film and a buccal (between the gum and cheek) tablet, as well as in injectable form. It is designed for sudden episodes of pain and should not be used more than four times a day. Overdose can cause drowsiness, dizziness, confusion, breathing problems or smaller pupils. The FDA has said there is growing concern about illicit fentanyl use, particularly in conjunction with heroin.

Hide Caption

6 of 8

Photos: Photos: A guide to (legal) pain relief

Morphine – Patients take morphine for moderate to severe pain. It is an opiate (narcotic) analgesic and changes the way the brain and nervous system react to pain. Forms of morphine include tablet and solution, which are taken every four hours, as needed. Controlled- or extended-release tablets and controlled- or sustained-release capsules are for patients who need around-the-clock pain relief. Morphine can also be found as a morphine sulfate injection, as added to an IV fluid that drips through a needle or catheter, or injected into a large muscle. Morphine overdose can cause serious consequences such as breathing problems, loss of consciousness, sleepiness, slow heartbeat, blurred vision, nausea and fainting, according to the National Institutes of Health. Morphine may also be habit-forming.

Hide Caption

7 of 8

Photos: Photos: A guide to (legal) pain relief

Propofol – Propofol, also known as Diprivan, became infamous when pop star Michael Jackson died after overdosing on the drug while using it as a sleep aid. The drug is typically administered intravenously by medical professionals for anesthetic purposes, such as when a patient is undergoing surgery. It's not approved to treat sleep disorders, according to the Food and Drug Administration. The drug itself does not provide pain relief but renders a patient unconscious. A patient wakes up almost immediately after an infusion is stopped, experts say. Propofol lowers blood pressure and suppresses breathing, so patients' heart function and breathing need constant monitoring, according to the Harvard Health Blog. Abuse of propofol in medical circles, however, has been a concern in recent years.

Hide Caption

8 of 8

Photos: Photos: A guide to (legal) pain relief

Ibuprofen – Ibuprofen falls into the class of drugs known as NSAIDs (nonsteroidal anti-inflammatory drugs). Sold under brand names including Motrin or Advil, it's used to treat minor aches and pains and reduce fever. It may be prescribed in stronger doses. It comes in tablet form as well as in chewable tablets, liquid suspensions and concentrated liquid drops. People who take NSAIDs may have a higher heart attack or stroke risk than those who do not, according to the National Institutes of Health. The medication can also cause ulcers, bleeding or holes in the stomach and intestine for some people. The risk may be higher if you take NSAIDs for a long time, are older or in poor health, and have three or more alcoholic drinks per day.

Hide Caption

1 of 8

Photos: Photos: A guide to (legal) pain relief

Acetaminophen – This compound can ease minor muscle, back, tooth and joint pain and reduce fever. Sold under brand names such as Tylenol, Liquiprin and Panadol, it works by regulating the part of your brain that controls your body's temperature and inhibits the synthesis of prostaglandin in the central nervous system. A study has found that it could reduce pleasure as well. Too much of the drug can cause rashes, liver failure and even death.

Hide Caption

2 of 8

Photos: Photos: A guide to (legal) pain relief

Aspirin – Aspirin is one of the cheapest and oldest manufactured painkillers on the market. German-born scientist Felix Hoffman is credited with creating and popularizing what was then known as acetylsalicylic acid in 1899 to help ease his dad's arthritis pain. Today, it is used to ease minor aches and headaches. It works by reducing the substance in the body that causes inflammation and fever. Doctors also tell some adults to take an aspirin daily to help prevent a heart attack or stroke. People with bleeding conditions like ulcers or cardiovascular troubles like asthma are often advised to take another painkiller, as it may make those conditions worse. Some Americans are also allergic to aspirin. Americans consume more than 15 billion aspirin tablets a year. Here's a guide to some of the most commonly used pain relief medications:

Hide Caption

3 of 8

Photos: Photos: A guide to (legal) pain relief

Marijuana – There's been a growing acceptance of marijuana as a legitimate pain reliever. The American Medical Association supports making marijuana a Schedule I controlled substance in order to promote research into its therapeutic abilities. Doctors in some states may prescribe it to ease chronic pain that comes from arthritis, migraines, Crohn's disease or other ongoing pain issues where other medicines have failed. It works by blocking the pain sensations felt by peripheral nerves. The cannabinoids in marijuana bind to endocannabinoid receptors throughout the body and can reduce pain (but also give the feeling of being high). Some research shows that it can also slow cancer development and increase appetite. Forty states and the District of Columbia allow some legal uses of marijuana, mostly for medicinal purposes.

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Story highlights

• Aspirin, acetaminophen (paracetamol) and ibuprofen disrupt male hormones
• Taken in high daily doses, ibuprofen induced compensated hypogonadism in young men

(CNN)Ibuprofen has a negative impact on the testicles of young men, a study published Monday in the journal Proceedings of the National Academy of Sciences found. When taking ibuprofen in doses commonly used by athletes, a small sample of young men developed a hormonal condition that typically begins, if at all, during middle age. This condition is linked to reduced fertility.

Advil and Motrin are two brand names for ibuprofen, an over-the-counter pain reliever. CNN has contacted Pfizer and Johnson & Johnson, the makers of both brands, for comment.

The Consumer Healthcare Products Association, a trade group that represents manufacturers of over-the-counter medications and supplements, "supports and encourages continued research and promotes ongoing consumer education to help ensure safe use of OTC medicines," said Mike Tringale, a spokesman for the association. "The safety and efficacy of active ingredients in these products has been well documented and supported by decades of scientific study and real-world use."

The new study is a continuation of research that began with pregnant women, explained Bernard Jégou, co-author and director of the Institute of Research in Environmental and Occupational Health in France.

Study links acetaminophen in pregnancy to ADHD, but experts question results

Jégou and a team of French and Danish researchers had been exploring the health effects when a mother-to-be took any one of three mild pain relievers found in medicine chests around the globe: aspirin, acetaminophen (also known as paracetamol and sold under the brand name Tylenol) and ibuprofen.

Their early experiments, published in several papers, showed that when taken during pregnancy, all three of these mild medicines affected the testicles of male babies.

Testicles and testosterone

Testicles not only produce sperm, they secrete testosterone, the primary male sex hormone.

All three drugs then are "anti-androgenic," meaning they disrupt male hormones, explained David M. Kristensen, study co-author and a senior scientist in the Department of Neurology at Copenhagen University Hospital.

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The three drugs even increased the likelihood that male babies would be born with congenital malformations, Kristensen noted.

Tringale noted that pregnant and nursing women should always ask a health professional before using medicines.

Knowing this, "we wondered what would happen in the adult," he said. They focused their investigation on ibuprofen, which had the strongest effects.

A non-steroidal anti-inflammatory drug, ibuprofen is often taken by athletes, including Olympians and professional soccer players for example, before an event to prevent pain, Jégou said. Are there health consequences for the athletes who routinely use this NSAID?

The research team recruited 31 male volunteers between the ages of 18 and 35. Of these, 14 were given a daily dosage of ibuprofen that many professional and amateur athletes take: 600 milligrams twice a day, explained Jégou. (This 1200-mg-per-day dose is the maximum limit as directed by the labels of generic ibuprofen products.) The remaining 17 volunteers were given a placebo.

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For the men taking ibuprofen, within 14 days, their luteinizing hormones -- which are secreted by the pituitary gland and stimulate the testicles to produce testosterone -- became coordinated with the level of ibuprofen circulating in their blood. At the same time, the ratio of testosterone to luteinizing hormones decreased, a sign of dysfunctional testicles.

This hormonal imbalance produced compensated hypogonadism, a condition associated with impaired fertility, depression and increased risk for cardiovascular events, including heart failure and stroke.

For the small group of young study participants who used ibuprofen for only a short time, "it is sure that these effects are reversible," Jégou said. However, it's unknown whether the health effects of long-term ibuprofen use are reversible, he said.

After this randomized, controlled clinical trial, the research team experimented with "little bits of human testes" provided by organ donors and then conducted test tube experiments on the endocrine cells, called Leydig and Sertoli cells, which produce testosterone, explained Jégou.

Common painkillers linked to increased risk of heart attack, study says

The point was to articulate "in vivo, ex vivo and in vitro" -- in the living body, outside the living body and in the test tube -- that ibuprofen has a direct effect on the testicles and so testosterone.

"We wanted to understand what happened after exposure (to ibuprofen) going from the global human physiology over to the specific organ (the testis) down to the endocrine cells producing testosterone," Kristensen said.

More than idle curiosity prompted such an extensive investigation.

Questions around male fertility

The World Health Organization estimates that one in every four couples of reproductive age in developing countries experiences childlessness despite five years of attempting pregnancy.

Sperm counts of Western men plummeting, analysis finds

A separate study estimated that more than 45 million couples, or about 15% of all couples worldwide, were infertile in 2010, while another unrelated study suggested that men were solely responsible for up to 30% and contribute up to 50% of cases overall.

Meanwhile, a recent analysis published in the journal Human Reproduction Update found that sperm counts of men in North America, Europe, Australia and New Zealand are plunging. Researchers recorded a 52% decline in sperm concentration and a 59% decline in total sperm count over a nearly 40-year period ending in 2011.

Erma Z. Drobnis, an associate professional practice professor of reproductive medicine and fertility at the University of Missouri, Columbia, noted that most drugs are not evaluated for their effects on human male fertility before marketing. Drobnis, who was not involved in the new study, has done extensive research into sperm biology and fertility.

Fighting the male biological clock by banking sperm

"There is evidence that some medications are particularly harmful to the male reproductive system, including testosterone, opioids, antidepressants, antipsychotics, immune modulators and even the over-the-counter antacid cimetidine (Tagamet)," she said. "However, prescribing providers rarely mention these adverse effects with patients when prescribing these medications. 

She believes the new study, though small, is "important" because ibuprofen is among the most commonly used medications.

Though the new research indicates that ibuprofen disrupts the reproductive hormones in healthy young men, she thinks it's possible there's an even greater negative effect in men with low fertility. The other OTC drugs concerning for potential fathers are cimetidine and acetaminophen. She recommends that men who are planning to father a child avoid drugs for several months.

"Larger clinical trials are warranted," she said. "This is timely work that should raise awareness of medication effects on men and potentially their offspring."

Jégou agrees that more study is needed to answer many questions, including whether ibuprofen's effects on male hormones are seen at low doses and whether long-term effects are reversible.

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"But the alarm has been raised now," he said. "if this serves to remind people that we are really dealing with medical drugs -- not with things which are not dangerous -- this would be a good thing."

"We need to remember that it is a pharmaceutical compound that helps a lot of people worldwide," Kristensen said. He noted, though, that of the three mild analgesics examined, ibuprofen had "the broadest endocrine-disturbing properties identified so far in men."