Ibuprofen alters human testicular physiology including testosterone production
pnas.orgThis was discussed ~3 weeks ago. Here's the thread-- https://news.ycombinator.com/item?id=16101072
A note about one of the comments there related to Aspirin, namely, this one:
https://news.ycombinator.com/item?id=16102328
There's an alternative solution for the stomach lining issue:
https://en.wikipedia.org/wiki/Carbasalate_calcium
Which reminds me, this testicle study seems to fail to distinguish Dex(tro)ibuprofen from Levoibuprofen. That seems rather disappointing, as we've known about the difference between the two for quite a while.
This continued ignorance of medical science when it comes to (stereo)isomers never ceases to amaze me. I mean... You'd think they'd have learned their lessons by now.
(Then again, we also still fail to employ multi-compartment models of pharmacology in the vast majority of studies. And... ugh. I'll avoid ranting on how shitty medical science seems to me and just leave it at this.)
[btw., if you wonder why you can't get your hands on Dexibuprofen in the US:
"Open committee discussion. The committees will discuss new drug application (NDA) 20–373, S+ Ibuprofen (dexibuprofen, Sterling Winthrop/ Bayer) 200-milligram caplet, indicated for the temporary relief of minor aches and pains associated with the common cold, headache, toothache, muscular aches, back ache, menstrual cramps, minor pain of arthritis, and for the temporary reduction of fever for OTC status." From the Federal Register, from 1996. It never got approved, and one can't even find the application on the FDA page, thus one can't find out more about why it never made it to market!]
I read the paper, I saw the plots accompanying the paper, and I tried following the rabbit hole in search of some raw data that I can get my hands on, just to see if I can.
Perhaps the data is the result of the experiments that have been paid for by a third party, fine, but please mention that! People might be willing to pay for it, for example, me!
What's wrong with "Here's the raw data, here's how we measured it, Here's how we've shown the data, and look you can see for yourself that we are right! oh and the data costs $$$ much." ?
I understand experiment reproducibility is not incentivised in academia, but then why make it hard for an external party to reproduce it/study it?
Do we have to go through the usual "Contact the academic, maybe they answer, and maybe you'll get the same (version of) data that they used in that experiment, maybe you'll have to go through Elsevier, oh and you must have .edu/.ac.uk address to be taken seriously through all those requests."
What a chore. Just adds to the hate towards 'experts' and their opinions.
Blame the journal. Scientists are generally pretty busy. Writing a (life sciences) paper is an incredible amount of work usually done in a short period of time. Preparing raw data and explaining what everything means is quite involved. If they don't have to do something they won't.
The journal should mandate data access, then it will get done. This is crucial for human experiments, if only because the authors can lose the data and it will be gone forever.
As far as I know this is slowly changing. According to scientists I've met (life science fields) there is an ongoing trend towards demanding raw data and even the code used to analyze it. Not every journal everywhere yet of course, but the consensus seemed to be that in 5 to 10 years it would become the new norm. Which might cause quite the disruption. Having seen quite the amounts of code written by PHD students I'm 100% sure tere are many, many bugs out there. Possibly leading to faulty results.
This is exactly the motivation behind the Loom file format[0] being developed and used in the molecular neurobiology-group I work for[1]. It is an HDF5-based file format for 'omics data, to deal with the ever-growing size of the data sets.
I specifically work on the Loom Viewer[1], a SPA that we're trying to design in such a way that it will be really easy and cheap for research groups to host and share these loom files themselves. This would make easy for other groups to ask simple questions about each others data, and in the worst case the raw loom file is always available for download.
We're already hosting some of our own published datasets with this viewer, you can check it out here[3].
To lower expectations a bit: the viewer is not trying to be comparable to the big atlases like [4] or [5] (I mean, it's being developed by one dude - me - so by comparison it's a no-budget OSS project). It's much simpler and basic - the idea is that if you use the Loom file format in your pipeline in a sensible manner, the viewer will more or less know what to do with the data.
[0] https://github.com/linnarsson-lab/loompy
[2] https://github.com/linnarsson-lab/loom-viewer
[3] http://loom.linnarssonlab.org/
This is a significant amount of effort, and has some very good touches. Especially the Loom-Viewer, I really liked the ease with which one's workflow can integrate into the data analysis.
Thanks! :) It's always good to hear that we're on the right track with usability.
It's one of the things that I'm most worried about: I've been working pretty isolated for the last year and a half, and lack a background in biology or bioinformatics, and did not even have webdev experience when I took on this project (plenty of embarrassing proof of that in the code). Kudos to Sten Linnarsson, the PI of the group and my boss, for taking a gamble and hiring me anyway.
> I really liked the ease with which one's workflow can integrate into the data analysis.
Just to make this clear: the file format is a "dumb" data storage, and the viewer a "dumb" plotter of that data. To do more in-depth analysis requires loading the file in python, R, or anything else that might support the files in the future. The idea is to then store the results of this as attributes in the file. For example, the tSNE plot here[0] is just pre-calculated x/y data stored as two attributes.
Currently there is an issue with fully integrating the viewer into such a work-flow: for performance reasons, it caches accessed data from the file. This cache needs to be refreshed manually.
Sten recently added library support for keeping track of file modifications[1]. That enables me to make the viewer automatically update stale cache whenever a file is modified, making it even easier to integrate. Currently working on that.
There's still a ton of polishing and bug-fixing to do. Feedback, suggestions and help are always welcome!
[0] http://loom.linnarssonlab.org/dataset/cells/Dentate%20gyrus/...
What's the difference between this and jupyter? besides the file format itself obviously
Using loompy in Jupyter is what you would do when analysing your own data. You would connect to a loom file with the loompy library, then extract the data you're interested in, apply whatever algorithms you need to apply, and plotting the results. The difference is that this is all code of your own. Loom is just the storage format for the data in this context.
The viewer is a specialised application: it has a server and client. The server extracts (meta)data requested by the client from a loom file, and serves it as JSON. The client then uses this metadata to generate plots. The off-line viewer is actually just running that server locally and opening it on localhost:8003.
That makes it better for sharing raw data on-line: most of the time, people do not need the full dataset of 27k+ genes, they're only interested in a dozen or so. This makes it easy to access that.
Hosting your own viewer is quite simple:
(Well, you probably want to use something like a supervisor script for that, which is what we do, but you get the idea)# this also installs the loom CLI pip install loom-viewer # start the server loom --dataset-path [DATASET_PATH] --server --port [PORT_NUMBER]We don't use a database; instead the server looks for loom files in a dataset folder like this:
That means that sharing a loom file is as simple as copying it to the right folder.[DATASET_PATH]\[PROJECT_FOLDER]\[LOOM FILE]This probably not web-scale or really safe or anything, but we're talking small labs sharing data with other labs - the risks are different. These viewers will be accessed by a few biologists. Using files in a folder structure keeps it simple enough to set up for the less tech-savvy.
In theory, a third work-flow is also possible: having Jupyter open in one tab and manipulating the loom file from there, and the viewer in another.
There are three blocking issues for that, however:
- the stale cache problem I mentioned in the other comment,
- single writer/multiple reader support,
- the server needs to be an isolated sub-process due to gevent monkeypatching messing with Jupyter
Main issue here is dev-team of one person so... this might take some time.
I think this is a good trend. The opening of raw data AND the code used to analyse it will aid in others being able to find errors sooner.
I suppose you could say the same about the journals, or the academic institutions. The systems and norms are what they are, the incentives are what they are and if they don't have to do something they won't.
I'm not sure who is responsible for making a better way. Probably no one. Change is often a matter of someone taking initiative and there are a few parties that could, if they consider it important.
IMO, the "replication crisis" should be having a more far-reaching effect on the institution of science. In some fields, the crisis means that the efforts of an entire generation were largely wasted. In those same fields, it is almost business as usual, with new unreplicable experiments being published. Knowledge was not actually being built. In some fields, the institutional scientific method (journals, peer review..) was not really practicing the scientific method, not practicing science.
I don't know what the solution is, but whatever it is I cannot imagine that it does not involve working scientists making choices. What is tenure for, if not allowing senior researchers the independance to do this.
If you're interested in how this data gets exchanged you might want to read this:
https://www.crossref.org/blog/how-do-you-deposit-data-citati...
https://www.crossref.org/blog/the-research-nexus---better-re...
(I work for Crossref)
> What's wrong with "Here's the raw data, here's how we measured it, Here's how we've shown the data, and look you can see for yourself that we are right! oh and the data costs $$$ much." ?
Well, what with the current replication crisis, maybe some researchers feel it's safer not to make it too easy... /s
(Not impugning the integrity of the authors in question here, of course, just musing on this widespread phenomenon in general...)
This isn't really huge news, technically speaking. Any anti-inflammatory drug will have negative net impact on your body function. For a while we know now that NSAIDs alter ROS levels in response to injury and in fact any normal process. NSAIDs also have negative impact on training adaptation or cell death due to overexpression of ROS. So no - taking overabundant levels of oral NSAIDs isn't going to be good for you and that's why topical NSAIDs make sense in cases of joint pain, tough they're not as convenient.
Note: I remember taurine had protective effect on testicular function in men treated in 19-nor derivatives. Maybe worth checking out if it does so also for ibuprofen :)
The energy drink makers have been trying to defend the use of taurine in their ingredients for a long time. This looks like a golden opportunity for them....
Probably, not so much. The amounts of ingredients and composition of ingredients in energy drinks are just stupid. I see now a trend of "health" drinks that actually seem sensible, though a bit more pricey. Like magnesium, ginseng and vitamins.
The problem with energy drinks is that they're alike to a bottle of all things that may be fuel, combined. I've seen recently a tin of Monster that had 0.5g of caffeine. That's insane. And caffeine pills are even more insane. You can drop 1g of caffeine like it's M&Ms.
At this rate we're going to have coke and amphetamine in those next year. And, you know, you can go on a limb and say that some of the modified amphetamines or phenidatess or what not maybe should be on the market. In Canada they have effedrine in OTC supplements and people don't die from overdose.
But the thing is, we either demonise or just assume something is safe. How many people knows that acetaminophen (APAP, paracetamol) is liver toxic? And how many people knows that NAC is the antidote (N-acetylo-cysteine, popular OTC expectorant)?
I've been paying attention to the lowering fertility rate across the world. My instinct, until now, was that it was because of fire retardant chemicals found in furniture that act as an endocrine disruptor. It didn't totally fit though so I felt like there was something else that was a major contributor.
Ibuprofen being a cause of lower sperm counts could be the missing piece of the puzzle. It's also a big deal because Tylenol has been pushed aside for the last 20 years as being more unsafe for children than Ibuprofen.
At least in Italy, children are almost exclusively given paracetamol (Tylenol) to lower temperature. Ibuprofen is only used as an anti-inflammatory drug, for example if they have faryngitis
Paracetamol comes with its own set of problems. It's somewhat dangerous to people with a variety of liver conditions.
In large enough doses it is dangerous to everyone. The problem is that the large enough dose is much smaller than other OTC drugs.
Are there any good numbers on the fertility among people who actually WANT to conceive, rather than the raw total population rates (which is affected by people who don't want kids - prevented through birth control and abortions)
"One 2012 report, which presented the results of the study of over 26,000 French men, showed that the sperm count had fallen by a third between 1989 and 2005. A 2007 report in the UK presented the results of a study done on one city in the country. It showed that sperm counts had declined by over 29 percent between 1989 and 2002. And more recently, in the summer of 2017, a study by scientists at the Hebrew University of Jerusalem analyzed data from over 43,000 North American, European, Australian, and New Zealand men concluded that the average sperm count had fallen by almost 60 percent in the past 40 years. "
From an article at https://www.inquisitr.com/4757173/the-human-race-could-be-in... dated just a few days ago
Not what GP was asking. Desire might not even correlate with sperm count!
Maybe decreased desire even leads to count and motility decreases?
Funny to see this now, as I was thinking a little while ago of the break-in period for a new mattress I owned, where I dealt with a sore throat or asthma-like condition for a week before realizing the probable cause, after doing some reading about many with similar problems. (I closed off the bedroom with the windows open during that winter period and slept elsewhere for a little while after that.)
To me it's emblematic of the Safety State: a (relative) few die from mattress fires, so now everybody is gassed with possible or probable toxins in hyper-response.
PSA: Careful of those new mattresses…
I doubt there is one smoking gun. It's a basket of causes. Too much exposure to weird chemicals, ibuprofen, not enough zinc, obesity, lack of exercise, etc are all causes.
Death by 1000 papercuts.
My point here is that it's possible that there are many circumstances accumulating but that doesn't discredit efforts for finding the biggest contributors.
You can easily smuggle a couple of razors between the paper sheets.
My money would be on increasing levels of education and healthcare instead of fire retardant chemicals and ibuprofen.
How exactly would education affect the testicles?
He started by talking about global fertility rates. He then mentions lower sperm counts but it's not a given that one is solely or mostly because of the other. Fertility rates are expressed in children per woman, not sperm count.
A large drop in global fertility rates is attributable to lower infant mortality, better access to healthcare, contraception, and education about using it. Also, as levels of education in general rise, people tend to have fewer children.
My instinct, until now, was that it was because of fire retardant chemicals found in furniture that act as an endocrine disrupto
What are your thoughts on synthetic hormones, e.g. used in farming or in contraception? Those enter the water supply and are not broken down.
Is this a permanent effect, or does T production return to normal after stopping the drug?
> 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.
http://wgntv.com/2018/01/08/ibuprofen-linked-to-male-inferti...
> 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.
That could be true, but of course, there's some self-interest in that statement. Bringing long-term harm to your study participants is not exactly a good move for a medical researcher.
While the results do matter, this is probably being blown out of proportion
> One group of subjects received ibuprofen, 2 × 600 mg/d, (Ibumetin; Nycomed Denmark Aps) for a period of 6 wk
Yeah, that's a lot of Ibuprofen for a long time
Nope, that is literally the dosage mentioned in leaflet inside my box of pills: 2x200mg, up to 3 times a day, do not exceed 6 weeks.
I'm not saying it's an overdose (and their tests of renal and hepatic function corroborate that)
But it's not a dose people will commonly take in their "day to day" activities and ideally not something that is done without medical supervision
It's one of the features of Ibuprofen that you can take it at those levels without killing yourself. Most people don't, but some people do - sometimes because doctors tell them to.
This makes it different to Paracetamol, where you only have to double or triple the standard dose to cause temporary liver damage, and increasing it only slightly further puts you in danger of death.
> it's not a dose people will commonly take in their "day to day" activities
A lot of people who exercise multiple times a week take "Vitamin I" every day. So do people who have frequent headaches, back or joint pain, etc. I probably came close to these levels during a bout of plantar fasciitis, though I've since switched to naproxen in such cases. It might not be common in your immediate circle, but in the broader world it's not rare enough to raise any eyebrows.
I went through a period of heavy physical activity without good equipment, which caused quite bad shin splints. My doctor prescribed precisely this dose, along with some physiotherapy. I think it's quite common for inflammatory problems like that.
I disagree. People regularily take 800mg of ibuprophen for regular/tension/miagrane headaches. These can be quite regular and chronic occurances.
When I would visit military doctors, they would prescribe 1g pills like they were a panacea.
Wow, all the ones I have (and I don't remember seeing any different in Australia) all say do not take for more than three days at a time (except with a doctor's advice).
6 weeks is a long time to be popping 1200mg/d!
Are you sure it didn't have codine in it? In the UK, the only (AFAIK) non-prescription medication with that sort of warning is anything containing codine.
I'm in Australia and looking at a box of plain Ibuprofen. It also recommends limiting to a few days at a time unless told otherwise by a doctor.
And I believe the max dose is even higher - 3200mg per day (800mg 4 times per day).
Correct. Adults can take up to 800mg q6hrs and I routinely prescribe that dosing after ankle sprains, etc for a few days. 6 wks duration would be way out of my comfort zone.
I don't have the PDR handy but I thought it was 2400 mg/day-- 800mg * 3. (It's based on kg/body weight IIRC, but that was the indicated quantity.)
I don't have the PDR handy but I thought it was 2400 mg/day-- 800mg * 3. It's based on kg/body weight IIRC, but that was the indicated qu amount
Yep. a good friend is a doctor who does triage in an ER (amongst other things) - he said 'We start at 1500mg doses'.
I've been prescribed that sort of dosage to deal with inflammatory issues. From limited personal experience, larger does are not about pain relief, but bringing inflammation (eg bursitis) under control.
I've been through similar doses as well, though for muscular strain I was given something stronger (not opioids though)
Have you seen how some people gobble this stuff?
I've felt compelled to say to more than one person: probably shouldn't take that much ...
Sometimes pain management is a balancing act between dangerous side effects and misery that makes it hard to want to keep living. Chronic pain isn't really something a third party can make decisions about; it may be that ibuprofen isn't the right choice, but lots of other choices (opiates, for instance) may have even more negative effects (like addiction and risk of deadly overdose).
Of course, there are folks who take over-the-counter meds as though it is safe at any dose and frequency. That might warrant a nudge toward reading the label about safe dosage, or a mention of a recent study on the subject.
Exactly this. I have a chronic wrist injury from a previous job. Physiotherapy hasn't really helped, and the only thing that does help when I have a bad day is naproxen (another NSAID in the same class as ibuprofen). I feel guilty taking it in the dose I do (1000mg/day) but it's the only thing that makes life bearable and makes me functional.
I've known plenty of people who do 400mg 2-3x/day for weeks/months.
Military?
Collegiate and professional athletes easily would do this. (I've personally done it, hell.)
Construction workers, manual laborers, etc.
True.
A lot of people I know that powerlift do 4 x 800mg for 5 days or so. I think the thinking is to give the injury a "blast" of ibuprofen to bring the swelling down fast, rather than a lower dose for a longer period.
Yes (and contractors, etc.)
I remember reading in a Tom Clancy book once that it's called "Light Fighter Candy".
Six weeks isn't a long time if you've got a herniated disc.
Correct, hence if you need pain control for longer than 6w there might be other options
I know that certain herbal cookies work vastly better than ibuprofen, even a day after intake, but they're not prescribed very liberally around here.