Hey Guys! Put Down The Advil / Ibuprofen!!

The article implies to use sparingly and carefully, I think I’ll just stick with aspirin…

http://www.pnas.org/content/early/2018/01/03/1715035115

Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism

Hypo= little or too little
gonadism= state of The Boys

hypogonadism= ~ tiny balls or ineffective naughty bits

Significance

Concern has been raised over declining male reproductive health in humans. Our study addresses this issue by extending data showing antiandrogen effects of analgesics and suggests that such compounds may be involved in adult male reproductive problems. Using a unique combination of a randomized, controlled clinical trial and ex vivo and in vitro approaches, we report a univocal depression of important aspects of testicular function, including testosterone production, after use of over-the-counter ibuprofen. The study shows that ibuprofen use results in selective transcriptional repression of endocrine cells in the human testis. This repression results in the elevation of the stimulatory pituitary hormones, resulting in a state of compensated hypogonadism, a disorder associated with adverse reproductive and physical health disorders.

Abstract

Concern has been raised over increased male reproductive disorders in the Western world, and the disruption of male endocrinology has been suggested to play a central role. Several studies have shown that mild analgesics exposure during fetal life is associated with antiandrogenic effects and congenital malformations, but the effects on the adult man remain largely unknown. Through a clinical trial with young men exposed to ibuprofen, we show that the analgesic resulted in the clinical condition named “compensated hypogonadism,” a condition prevalent among elderly men and associated with reproductive and physical disorders. In the men, luteinizing hormone (LH) and ibuprofen plasma levels were positively correlated, and the testosterone/LH ratio decreased. Using adult testis explants exposed or not exposed to ibuprofen, we demonstrate that the endocrine capabilities from testicular Leydig and Sertoli cells, including testosterone production, were suppressed through transcriptional repression. This effect was also observed in a human steroidogenic cell line. Our data demonstrate that ibuprofen alters the endocrine system via selective transcriptional repression in the human testes, thereby inducing compensated hypogonadism.

So looks like the ladies need to avoid such NSAIDS during pregnancy or they run a higher risk of Nancy Boys…

Much concern has been raised over declining male reproductive health, and the disruption of male endocrinology has been suggested to play a central role (1, 2). Male reproduction and general health rely on androgens, as well as on other hormones, which are mainly produced by testicular Leydig and Sertoli cells. In addition to the testis, the androgens act in many somatic organs, e.g., producing anabolic effects on muscle mass and influencing cognitive functions (3). Luteinizing hormone (LH) produced by the pituitary is the primary stimulator of testosterone production, and the testosterone/LH ratio is routinely used as a clinical marker of Leydig cell function. When Leydig cell function is compromised, normal or nearly normal testosterone levels can often be sustained by augmented LH levels, as observed in the clinical entity termed “compensated hypogonadism” (4). The essential importance of the pituitary–gonadal axis is emphasized by the recent association of hypogonadism with a wide range of risk factors and all-cause mortality in men (4, 5).

The so-called “over-the-counter” mild analgesics (hereafter simply called “analgesics”), such as acetaminophen/paracetamol, acetylsalicylic acid/aspirin, and ibuprofen, are among the most commonly used pharmaceutical compounds worldwide (6, 7). Increasing evidence from recent years shows that exposure to analgesics can generate negative endocrine and reproductive effects during fetal life (6). Nonetheless, no in-depth studies have analyzed the effect of mild analgesics on the human pituitary–gonadal axis. In this context, ibuprofen is especially interesting because of its increasing use in the general population and in particular by elite athletes (8⇓⇓⇓–12).

Therefore in this study we focused on how ibuprofen, used in the general population for aches, pains, fever, and arthritis and heavily used by athletes (13), affects the pituitary–testis axis. Because of the intrinsic great challenge in identifying endocrine-disrupting effects of chemicals in the adult human, we performed a unique combination of three interconnected approaches: (i) a randomized, controlled clinical trial; (ii) an ex vivo organ model using adult human testis explants; and (iii) a standardized in vitro model system based on a steroidogenic cell line of human origin to complement the ex vivo approach. The complementary results revealed that ibuprofen induces a state of compensated hypogonadism by modifying hormonal profiles through selective repression of gene expression.

Results
Ibuprofen Affects the Hormonal Balance in Adult Men.

We conducted a randomized, controlled clinical trial of ibuprofen administration to identify its possible effects on pituitary–gonadal feedback in young men. During administration, ibuprofen levels in plasma ranged on average from 25 to 35 µg/mL (∼1.2–1.7 × 10−4 M); the highest level measured was 100 µg/mL (4.85 × 10−4 M). The mean of this ibuprofen concentration was in the range measured after administration of 600 mg of ibuprofen to healthy volunteers (14). Samples drawn before administration showed that there were no initial differences between the placebo and ibuprofen groups for hormones or sex hormone-binding globulin (SHBG), a liver protein that specifically binds a substantial part of circulating testosterone (Fig. S1).

We investigated the levels of total testosterone and its direct downstream metabolic product, 17β-estradiol. Administration of ibuprofen did not result in any significant changes in the levels of these two steroid hormones after 14 d or at the last day of administration at 44 d (Fig. 1 A and C). The levels of free testosterone were subsequently analyzed by using the SHBG levels. Neither free testosterone nor SHBG levels were affected by ibuprofen during the administration (Fig. 1 A and C).
[…]
Ibuprofen Inhibits Steroidogenesis ex Vivo and in Vitro.

To determine the direct effect of ibuprofen on the testis, we next exposed adult testis explants from donors to doses of 10−9–10−4 M, which corresponded to the oral doses producing mean plasma levels of 1.2–1.7 × 10−4 M used among the men in the trial (see above). We first investigated testosterone production after 24 and 48 h of ibuprofen exposure to assess its effects on Leydig cell steroidogenesis. Inhibition of testosterone levels was significant and dose-dependent (β = −0.405, P = 0.01 at 24 h and β = −0.664, P < 0.0001 at 48 h) (Fig. 2A) and was augmented over time (10−4 M at 24 h and 10−5–10−4 M at 48 h, −40%) (Fig. 2A). Examination of the effect of ibuprofen exposure on both the ∆4 and ∆5 steroid pathways (Fig. 2B) showed that it generally inhibited all steroids from pregnenolone down to testosterone and 17β-estradiol; the production of each steroid measured decreased at doses of 10−5–10−4 M. Under control conditions, production of androstenediol and dehydroepiandrosterone (DHEA) was below the limit of detection except in one experiment with DHEA (Fig. 2B).

And a lot more. In short, this stuff messes up how The Boys work.

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About E.M.Smith

A technical managerial sort interested in things from Stonehenge to computer science. My present "hot buttons' are the mythology of Climate Change and ancient metrology; but things change...
This entry was posted in Biology Biochem, Science Bits and tagged , , , . Bookmark the permalink.

25 Responses to Hey Guys! Put Down The Advil / Ibuprofen!!

  1. H.R. says:

    That finding doesn’t make sense when it comes to NFL players. After games and practices, I understand that the players gulp a lot of ibuprofen because even the roots of ther hair aches after a game. I believe the crop of NFL progeny is average or possibly above average.

    OTOH, because the player at the NFL level are unusual physical specimens, maybe the ibuprofen just brings their hormone levels closer to normal.

    I did like their methodology outlined in the last paragraph. There may have been confounding factors, but the effects they saw lined up with dosage levels given. That’s good evidence right there.

  2. E.M.Smith says:

    In the article proper they talk about the high use among athletes. They point to a study showing a correlation between a lot of “endurance training” and lower sexual interest…

    Do note that this is COMPENSATED hypogonadism. Meaning that while the testosterone creation ability of The Boys is dropping, the LH hormone level gets rampped up to “compensate” by over-driving whatever remaining ability there is. Only after very long use does the ability drop below what can be compensated by even the highest LH levels, then “overt hypogonadism” can show up.

    There’s also a variety of other minor symptoms that can show up, including depression. IIRC many professional sports players are found to be depressed about thngs (compared to the rest of us).

    Finally, there’s that whole doping thing to consider… Perhaps over long term use this effect nudges players to find more “compensation”…

  3. philjourdan says:

    My wife’s doctor has already told her to get off of the NSAIDs. But I doubt it was for hypogonadism (women have gonads as well – they are the ovaries) as we are a bit past that stage in our lives (and my vasectomy has not stopped me from having more grandkids!).

    The proliferation of NSAIDs may be part of the lower fertility that others are crying about in the western world (coupled with many couples just not wanting kids). They are a relative recent invention.

  4. philjourdan says:

    There’s also a variety of other minor symptoms that can show up, including depression. IIRC many professional sports players are found to be depressed about thngs (compared to the rest of us).

    That is potentially dynamite to the concussion industry. They have wrapped their whole case around the fact that it is the concussions leading to suicides, not NSAIDs. Looks like another Cyclamate issue (concussions, not necessarily NSAIDs).

  5. Larry Geiger says:

    Advil is about the only I know of that’s close to a magic potion. From the first time I ever used it it has worked magnificently. I occasionally take two right before bed time when I have sore muscles. I wake up the next morning feeling better than I have in days. Aspirin and Tylenol do not work for me. Tylenol will bring down a fever a little bit but that’s about all. Sore muscles? Headache? No use at all.

  6. E.M.Smith says:

    @Larry:

    For sore muscles, I find a 6 pack works wonders ;-)

    Just sayin’… Give the boys some beer, it’s the traditional thing to do …

  7. p.g.sharrow says:

    Well; that explains a Whole Lot! After I gave up drinking beer nearly every day I had to go on Ibuprofen often to rest at night. Now my lady complains. I really need to make beer! and solve both problems. Larry is right, those other NSAIDS are as good as nothing. I know beer really works as it was my relief of choice for 40 years. Always had a case in the veranda fridg. for after a hard day relief, but, then I accumulated too many “Friends” that knew about my fridg. and it was always empty when I needed relief from my labors. After it was empty for a few months my “Friends” evaporated ;-)…pg

  8. philjourdan says:

    “For sore muscles, I find a 6 pack works wonders ;-) “

    Seconded! Even if it does not work, you do not care after the 3rd or 4th one.

  9. beng135 says:

    Here’s one of my favorite breweries — especially “Ales of the Revolution”:
    http://www.yardsbrewing.com/ales/

  10. p.g.sharrow says:

    I found 2 beers were necessary for relief, 1was never enough. Maybe I should sample the Blackberry brandy’s medicinal value for pain relief. It certainly works well for altitude adjustment 8-) The 17 year old Manzanita Brandy worked well at 2 shots but it is far too valuable and rare for every day use. I think I have my Lady convinced that beer brewing should be pursued. She was impressed by EMs post arguments above ! even offered to buy me a case of my favorite brew. 8-) …pg

  11. E.M.Smith says:

    P.G.: Glad I could help!

    FWIW, I’ve made cider by the simple expedient of adding a little yeast to a gallon jug of apple juice and leaving the lid 1/2 turn ‘loose’ as a kind of fermentation lock.

    The Mr. Beer is an easy way to make beer too, and make it a little faster than I can drink it. The “kit” comes with some big brown plastic screw cap bottles that are essentially indistinguishable from soda bottles IMHO. The implication to me is that you could just use pint or quart or liter soda bottles, washed, for your brew and avoid all the hardware for crown capping.

    If you do go down the home brew road, I’ve got some spare gear I don’t want to move to Florida I could donate (including a few cases of nice bottles). If you just want to give it a try, but not sink money into it, I’d also be happy to loan you the whole Mr. Beer kit and bottle capper. I’m not brewing at the moment, having gotten pulled into the world of Saki ;-)

  12. Steve C says:

    Hmm, I shall bear this post in mind next time I feel I need an Ibuprofen or two. Happily, as it happens, I haven’t needed so many in recent years, so (if I’m not irrevocably destroyed at age 67) an attitude shift will have to do. I’d always previously lightheartedly thought of it as “supporting local industry”, as the drug was invented by Boots in Nottingham, though not so much since they became “just another badge” in the treasury of some holding company.

    Strange how all these modern “accidental influences”, both pharma and environmental, seem to work in the same way, suppressing male characteristics and/or promoting female ones. I can’t recall offhand ever having read of one which “masculinised” its takers, at least not outside the “FtM” transgender clinic. Bearing in mind that the biological story is the exact opposite of the Biblical one (I.e., we all start off as more female than male in the womb, until some of us are modified into males at some point), I wonder whether the “male conversion” process is more fragile than we might find comfortable.

    Re alcohol, well, “feeling no pain” is one of the scores of synonyms for “drunk” … ;-)

  13. corsair red says:

    Ibuprofen can taken several times a day to build a level in your system. One of my doctors recommended taking two every four hours until I had taken 1000 mg by bedtime so that I could sleep. It helped some. This was the result of a visit for knee pain which was nerve related. He should have noticed that when I threated him with dire results when he put his thumb on the spot where the peroneal nerve crosses the knee.

    I saw his colleague a week later for the same thing. She said, ” I think we can help, ” She prescribed Gabapentin for the nerve inflammation and meloxicam for the pain. Oh, that worked wonders! As you can understand, I vowed never to see her partner again.

    The gabapentin had the delightful side effect of giving me the focus and relaxation to finally start making solos out of scales on the guitar. Not Eric Clapton or Les Paul, but a start. I went back to her, told her about this, and said, ” You have to let me take this forever. ” She said, ” Oh, I can do that, and I’m glad to hear it has a useful side effect. “

  14. p.g.sharrow says:

    I quite Ibuprofen cold-turkey 4 days ago. Some things have improved, My Lady is happier :-)
    A cup of 40pf brandy helped the first night. We will see how this progresses. Definitely must further investigate making beer to further advance this experiment…pg

  15. E.M.Smith says:

    @P.G:

    Pick a weekend, send me an email and I’ll drive up the beer making kit…

  16. p.g.sharrow says:

    @EMSmith;Hell of a deal!, As to a weekend you tell me, I’m retarded…, errrrr retired! that is I am ways here except to go shopping. My lady insists that I buy an ingredient kit and get started, she says she likes Irish Red Beer. guess I should examine needs for fermentation temperature. I’m sure I have most everything needed as I have made wine, mead, and brandy from scratch. Big cooking pots, electric stove, Big LP Barbe, indoor and outdoor sinks, hydrometers, plastic tanks refrigerators and well insulated warehouse. Even lots of different kinds of bottles from little fliptops to 6gallon carboys.
    Just need to get her done!. 8-) …pg

  17. E.M.Smith says:

    Well, that is well equipped.

    You don’t need to start with boiling mash. You start with just canned, already malted and hopped, extract. Add hot water, cool, pitch yeast. In about a week, test and either bottle at bottling sugar or ferment to dryness and add measured sugar. Set the bottles aside to finish (pressurize) and you are good to go.

    Maybe I ought to do a “simple way to beer” posting … Pointing out what everyone says you need to do that you can actually skip…

    So bottles, capper, caps, yeast, and a can of malt. I’ve used all my canned malt, but I can pick one up… Everything is also sold on line for folks living far far away from beer making stores ;-)

    That Beer posting is sounding like a good idea…

    At to temperature: Depends on the beer you want to make.

    For Lager, you need to lager the beer, which means ferment it in a cold lagering room. Most folks use an old fridge set to 40 F to 50 F or so depending on preferences and patience.

    English Ales and similar are fermented cool, but not cold. Basically room temperature in England before heaters…

    Steam Beer (think Anchor Steam Beer) is fermented at room temperature in California ;-) i.e. relatively warm.

    And of course the old Egyptians fermented their beer at the temperature inside a stone building next to the Sahara…

    Hmmm… That beer posting looks like a real need…

    https://en.wikipedia.org/wiki/Steam_beer

    Steam beer is a highly effervescent beer made by fermenting lager yeasts at warmer ale yeast fermentation temperatures. It has two distinct but related meanings:

    Historic steam beer produced in California, and in the East at the James River Steam Brewery in Richmond, Virginia from the mid-19th century to the mid-20th century;
    Modern California common beer, a competition category name for the beer family, which includes steam beers such as Anchor Steam beer.

    Historic steam beer, popularly associated with San Francisco and the U.S. West Coast, was brewed with lager yeast without the use of true refrigeration(by ice or mechanical means). It was an improvised process, originating out of necessity, perhaps as early as the Gold Rush and at least 1860 in Nevada. It was considered a cheap and low-quality beer, as shown by references to it in literature of the 1890s and 1900s.

    Modern steam beer, also known as California common beer, was originated by Anchor Brewing Company, which trademarked the term Steam Beer in 1981. Although the modern company has corporate continuity with a small brewery which has made beer since the 1890s, Anchor Steam is a modern craft-brewed lager. The company does not claim any close similarity between its present-day product and turn-of-the-20th-century steam beer.

    I’d suggest starting with an Ale (yeast sinks, fermented warmer) and get into lagers later…

    As I can’t accept the idea of writing a “how to make simple beer” posting while drinking Sake, I think I need to make a beer run, then get started on it ;-)

    Irish Red, eh? OK, I’ll get a sample and try to spec out a how-to…

    So sometime this coming week end or the one after, depending on what my spouse says, I’ll send an email asking for directions and confirming timing.

  18. D. J. Hawkins says:

    Aww, freak’n nuts! The Meloxicam poops out around 1800 hours, and if I don’t double-tap the Advil I can’t get to sleep at night for the pain in my knees. Can’t freak’n win!

  19. E.M.Smith says:

    D.J.:

    My “problem” may be your salvation.

    I have a tendency to allergies. For that, Benadryl works nicely. ( I use the cheap Walmart knockoff). UN-fortunately it causes drowsiness and “alcohol intensifies this effect”. Which means if I take one and wash it down with a beer or two, I’m “out like a light” in about an hour…

    I’ll never need sleeping pills…

    So consider the potential of a couple of aspirin (that block the damage to the liver from booze or tylenol) coupled with a couple of beers and a Benadryl… (diphenhydramine IIRC). Let’s just say it “works for me”… when I want to go to sleep, anyway…

  20. Larry Ledwick says:

    Be very careful mixing acohol with drugs many off them have a compound effect.
    Alcohol and tylenol is highly toxic to the liver – good way to get on a list for a liver transplant.
    Mixing benedryl with alcohol can result in permanent sedation, lots of entertainment deaths are due to similar mixing, as otherwise safe doses when mixed with alcohol can stop breathing.

    Just a word to be very careful with that mixture.

  21. cdquarles says:

    That’s true, Larry, but I suspect the chemist in EM knows how to do it. Say, 25mg diphenhydramine plus ‘2 sips’ of beer. :) Also consider that there is a lot of in-built genetic variation that results in more metabolic variation. EM’s metabolism may be such that he won’t have a problem with it whereas that will not be the case with others. The only way to find out, in actuality, is to perform the experiment and see what happens. [This is one reason why I prefer synthetic/semi synthetic chemical pharmaceuticals over raw biological ones. You can’t know everything you need to know about the chemicals that are the biological. Yes, folks, biological bodies are sacks of chemicals, hundreds of them to thousands of them.]

    This issue is a prime one in medicine. Given the misuse of statistics that is rampant plus the pressure ‘government’ applies to the field, the ‘art’ is often forgotten. In other words, medicine is about customizing while the government is about commoditizing. A good doctor is more ‘expensive’ for the same reason that a good ‘plumber’ or ‘smith’ or ‘carpenter’ et. al are more expensive. They’re worth it.

  22. E.M.Smith says:

    @Larry:

    One of the “good mixes” is aspirin with alcohol, or aspirin with tylenol (acetaminophen). Aspirin blocks the metabolic pathway by which alcohol and tylenol make the stuff that damages your liver.

    Strangely, though well documented, nobody bothers to tell you that, they just spend $Millions on ads saying “don’t drink” or saying “Take tylenol not aspirin”. Tylenol is THE leading cause of liver transplants in the USA…

    Per Benadryl / Alcohol blending. it takes a LOT to be a “permanent effect”… (i.e. waking up dead). I’ve taken my normal dose of Benadryl and then had “several” brewpub beers. (i.e. not weak beer).

    Normally, Benadryl alone makes me a little drowsy, and if nothing is going on, washing one down with a single beer will have me thinking of bed in about 1/2 hour and heading off that way. But on one occasion I was invited to a brew pub by my boss and it was allergy season… Well, the major effect was just that I could not do my usual “drink them under the table” and was myself quite tipsy on just a few. (They need a package warning that says “Alcohol may cause tipsy and Benadryl can intensify this effect. It runs both ways…) A few hours later, when I got home, I went straight to bed, despite it being only 9 PM.

    So we have a sample size of one, me, so be careful to calibrate your own sensitivity. For me, I can vouch that “a few” beers + Benadryl does not cause anything permanent. I’d recommend taking the Benadryl, then waiting 20 minutes for it to get through the stomach. THEN decide if that’s enough drowsy all on its own, prior to adding any beer. When one of us can’t sleep, just the Benadryl is usually enough. Then if you do add beer, sip one over another 20 minutes so it, too, slowly titrates into the blood stream. It’s pretty easy to adjust to the amount of sleepy you want…

    FWIW also: I now take an aspirin before or with any tylenol or drinking any booze. So there was also an aspirin in that pub mix. But I doubt it had much effect beyond liver protection.

    @CDQuarles:

    Well, now you have the story of how I calibrated “me” ;-) Benadryl already on board, then slowly drinking beer and talking in the pub. Monitoring my wakefulness during the process. As I always carry aspirin and caffein pills, I was ready to pop the caffein if needed . Instead, toward the end of the evening, I ordered coffee prior to wrapping up the night. They coffee seemed to have at most modest effect.

    FWIW, I think of that combination of an “upper” (caffein) and a “downer” (alcohol, Benadryl, etc.) as a “sidewayser”… They don’t quite neutralize, it’s more like spit you out sideways ;-)

  23. Larry Ledwick says:

    Yes I stay far away from Tylenol, I have a friend that does not drink at all, who got in the habit of taking Tylenol before going to bed to ease the aches and pains of age, and he recently has discovered that his Liver is in bad shape, just from that chronic low dose usage.

    I have another friend who worked as and EMT to also is strongly averse to it, he has first hand experience with folks who took over the recommended dose for a while to deal with pain and ended up destroying their liver with just a short period of over use. It really should not be on the market the destructive dose is very close to the effective recommended dose and it is easy to cross that line due to simple mistakes like forgetting how many times you have taken it in the last 24 hours (easy to do if you are really not feeling well to begin with), or deciding to take a little extra because it is not really getting the job done.

    Some of the night time sleep inducing medications like are antihistamine alcohol mixes for just the reason you mention.

  24. E.M.Smith says:

    Perhaps worth mention for completion:

    Hops has a mild calming / sedative effect too. So the degree of hops and kind of hops might make a difference too…

    I learned this from my Mechanic. I gave him a six pack of Heineken (he being German). He said “Why that beer? It makes you sleepy.” So I tested it. Sure enough, 4 Heineken’s and I’m wanting to sleep. I can do 8 of other beers and not feel that way…

    So now I avoid Heineken unless I want to sleep… It’s a good tasting beer, and it has great aroma, but the hops that give it that also bring sleepy time… I’d be very careful about blending it with Benadryl…

  25. philjourdan says:

    I never cared for Heineken. Indeed upon returning from Europe back in the 70s, I was amused that the “colonials” thought it was a good beer. I guess it is just a matter of taste.

    I still do not care for it. The flavor is too sweet for my buds. Guess I just do not care for Dutch Bier.

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