Are the negative effects of antibiotics on male fertility permanent?

[swansont]

1 hour ago, Alfred001 said:

Moving the goal posts is valid when we're talking about an unknown effect. We don't know whether 100% or 10% of antibiotics have this effect. Both are possible given the data we have, so there's nothing invalid in discussing the first scenario and then moving to the second.

You seemed pretty sure in the OP, but now we’ve seen that it’s likely not even at the 10% level + 50% chance. Remember, the number I cited was annual use. That means people are likely to get several courses of antibiotics over the years. 

If you have actual information to support an argument, go ahead and post it

[Alfred001]

I'm sure some antibiotics have an effect. That's consistent with 100% and 10%.

Wait, based on what do we know it's not likely even at 10% + 50%?

I've already posted a reference backing up the claim about the effect. What I'm wondering about is whether anyone knows of data on a permanent effect (or has any relevant mechanistic reasoning or speculation, in lieu of data).

Edited March 21 by Alfred001

[swansont]

2 hours ago, Alfred001 said:

I'm sure some antibiotics have an effect. That's consistent with 100% and 10%.

Just saying so isn’t enough. Why are you sure? And let’s be clear about the numbers you use. What do 10% and 100% refer to?

You have the fraction of antibiotics that cause issues, and the probability of the side effect.

Considering how widespread antibiotic use is, most men will have taken more than one course, so the chance of being affected is somewhat higher than the simple product of the two. If the odds of being affected is random, then the chance of the effect is higher. If you take more than one course, there a chance you’re given a different antibiotic. The high number of prescriptions (there are areas of the US where it’s more than 1000 prescriptions per 1000 people) suggests that people are given multiple courses; presumably this is because one didn’t work and the doctor tried another one.

Infertility issues predate antibiotics, so the baseline rate is not zero. But if the rate is now around 8%, then the combination of factors can’t possibly exceed that. 

[swansont]

As an aside, I have to wonder if the infertility issues getting worse is partly an artifact; infertility clinics cost money, so one wouldn’t expect people to go to a doctor unless they had the means to do something about it, which would increase as household income increased. IOW, we got better at diagnosing the problem, and reduced an economic bias.

[exchemist]

8 hours ago, swansont said:

As an aside, I have to wonder if the infertility issues getting worse is partly an artifact; infertility clinics cost money, so one wouldn’t expect people to go to a doctor unless they had the means to do something about it, which would increase as household income increased. IOW, we got better at diagnosing the problem, and reduced an economic bias.

It does seem to be a contentious area: https://en.wikipedia.org/wiki/Male_infertility_crisis

Seems doctors don't believe there has been a significant fall in fertility while a number of meta-analysis studies suggest there is at least a fall in sperm count . It may be important that that does not necessarily lead to reduced fertility, provided the count remains above a certain threshold, which apparently it generally does. Curiously, I can find no mention anywhere of antibiotic use having been considered as a possible factor. 

 

Edited March 22 by exchemist

[Alfred001]

14 hours ago, swansont said:

Just saying so isn’t enough. Why are you sure? And let’s be clear about the numbers you use. What do 10% and 100% refer to?

You have the fraction of antibiotics that cause issues, and the probability of the side effect.

Considering how widespread antibiotic use is, most men will have taken more than one course, so the chance of being affected is somewhat higher than the simple product of the two. If the odds of being affected is random, then the chance of the effect is higher. If you take more than one course, there a chance you’re given a different antibiotic. The high number of prescriptions (there are areas of the US where it’s more than 1000 prescriptions per 1000 people) suggests that people are given multiple courses; presumably this is because one didn’t work and the doctor tried another one.

Infertility issues predate antibiotics, so the baseline rate is not zero. But if the rate is now around 8%, then the combination of factors can’t possibly exceed that. 

Well, I'm sure because of the review I posted on page 1 and other literature.

But how many of those 1000 prescriptions are concentrated in either the elderly, who are more prone to sickness, or are given to men who've already had children and are not trying for more (which can happen as early as your 20s, more often early-mid 30s, meaning a large share of the male population would fall into that category)? In both cases, an effect would not be discovered. Then there is the watering down effect when you consider the 10% of ABs, 50% of time effect. I don't think it's implausible that, assuming those rates, an existence of an effect would be consistent with the infertility numbers we see.

[swansont]

58 minutes ago, Alfred001 said:

But how many of those 1000 prescriptions are concentrated in either the elderly, who are more prone to sickness, or are given to men who've already had children and are not trying for more (which can happen as early as your 20s, more often early-mid 30s, meaning a large share of the male population would fall into that category)?

Seems to me this is something you could research. You might also discover how prevalent antibiotics prescriptions for children are, which would seem to be much more relevant.

[Alfred001]

Here's a pretty striking study that bears on this question: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819380/

Quote

In this survey 50 male Wistar rats 6-8 weeks (250 ± 10 g) were used: normal salin as sham and control groups and 3 treatment groups (0.03, 0.06 and 0.08 mg Levofloxacin\kg body weight) during 60 days.

So a fairly long duration, but a very small dose.

Quote

Altogether, the administration of therapeutic doses of Levofloxacin 0.08 mg/ml for 60 days can cause pathological changes such as atrophy. Seminiferous tubule and irreversible damages to the cells in the testis cause death to the spermatogonia cells and primary spermatocytes disrupt the normal cycle of spermatogenesis and caused hypo spermatogenesis and infertility in male rats.

 

[CharonY]

A couple of things to note. Animal study results are often not easily transferable especially when it comes to dose-depend results (and especially long-term effects). That being said, many drugs can affect fertility (and antibiotics also have other wide-ranging effects). But for the most part they are dose-dependent and really difficult to assess in humans. Especially as folks are at the same time impacted by many many chemicals and other potentially contributing factors. 

To give an example, inflammation and presence of certain bacteria have been implicated with reduced fertility. In these cases antibiotics treatment has been suggested to get sperm count up again. In other words, if we look at one specific measure, such as sperm count, we have to consider the thousands of factors that will affect that number. There is decent evidence that certain antibiotics can cause cellular damage in testes and, if damaged sufficiently enough it might be permanent. But if that is actually happening in a given individual, we do not know. As in the above example the primary issue is an infection, then antibiotics treatment might add to the damage, but there might be a net benefit.

Or to put it differently, biology is complex and especially for effects that are not acute (e.g. total infertility) figuring out what exactly is happening generally requires a decent understanding of the underlying mechanism as well as the quantitative contribution of the many mechanisms related to a particular outcome. In medicine, we are often lacking this information and have to rely on empirical population data. Animal models provide supporting information, but but play a secondary role (they are important to suggest mechanisms, even if they end up not being found in humans).

This is all to say that the question in OP is likely not easily answerable (or at all) with human data. Any reduction of sperm count throughout the life of a person can be caused by many, many factors. Piecing together and pinpoint exactly how much a particular treatment added to that is almost impossible to say unless the effects are dramatic (which they aren't as otherwise they would have been identified).

[Alfred001]

https://www.researchgate.net/profile/Erma-Drobnis/publication/321879207_Introduction_to_Medication_Effects_on_Male_Reproduction/links/5be077ee92851c6b27aa09b9/Introduction-to-Medication-Effects-on-Male-Reproduction.pdf

Quote

Serious adverse effects on male reproduction have been reported for rats treated
with human equivalent doses of aminoglycosides. In an uncontrolled, descriptive
study of antibiotics given to rats at approximately HED[oral] for 8 days, gentamicin
caused partial to total arrest of germ cell MI stage with swollen spermatocyte nuclei
and few sperm in the seminiferous tubule lumen (Timmermans 1974). In the same
study, neomycin at approximately HED[oral] for 8 days caused meiotic arrest at
pre-metaphase MI and nuclear degeneration in all spermatocytes. This group also
looked at the histology of human testis biopsies taken during prostate surgery from
men taking gentamicin prior to surgery; they reported spermatogenic arrest similar
to that seen in rats.

And the effect may be permanent (from a different source)

Quote

In another study,
rats were treated with approximately 0.5× or 1× HED[IM,IV] of gentamicin by IP
injection for 10 days, then followed for up to 35 days (Narayana 2008b). The day
after drug cessation, lower testis weight, daily sperm production, sperm count,
motility, and normal forms were seen at the higher dose compared with vehicle-
treated controls. After 35 days these abnormalities remained apparent in addition to
lower seminiferous epithelium height, seminal vesicle weight, and seminal vesicle
diameter at both doses. Changes in enzyme activity indicative of oxidative stress
were also seen.

 

Edited March 23 by Alfred001

[iNow]

Alfred - Would it be okay if I suggested that perhaps for you anxiety is a bigger challenge than any of the marginal side effects vaccines and antibiotics may sometimes bring ever will be?

[Alfred001]

7 hours ago, iNow said:

Alfred - Would it be okay if I suggested that perhaps for you anxiety is a bigger challenge than any of the marginal side effects vaccines and antibiotics may sometimes bring ever will be?

From Erma Z. Drobnis, Ajay K. Nangia (auth.) - Impacts of Medications on Male Fertility

Quote

Although there is little evidence in human males, aminoglycoside antibiotics are
clearly reproductive toxicants in male rats at approximately HED. Clinical trials in
humans are warranted.

So it seems the researchers studying this are concerned about it as well and it's not just my neurosis. But since you never addressed any of the arguments, rather went ad hominem immediately, and described infertility as a marginal side effect, I don't expect anything will convince you.

[Alfred001]

Same source as previous

Quote

Nitrofuran antibiotics have been known to inhibit spermatogenesis for more than
50 years (Prior and Ferguson 1950; Paul et al. 1953). In an early study (Nelson and
Bunge 1957), 36 healthy men were given therapeutic doses of nitrofurantoin for
2 weeks. Half of the men had no change in semen quality or in testicular histology.
The median total sperm counts over time from beginning of treatment were 222
million (0 weeks), 185 million (1–4 weeks), 121 million (5–8 weeks), 142 million
(9–12 weeks), and 225 million (13–32 weeks), showing a significant decrease at
5–12 weeks with return to normal at 13–32 weeks. Eight of the men (22%) showed
significantly lower sperm counts and histological evidence of spermatogenic dis-
ruption, including spermatogenic arrest.

Quote

At high doses, fluoroquinolone anti-
biotics have genotoxic effects in various cell systems. They have demonstrated anti-
fertility effects in men and experimental species.

 

Edited March 23 by Alfred001

[iNow]

That red box suggests the answer was no. Ok. 

10 hours ago, Alfred001 said:

ad hominem

I never suggested your argument was wrong bc you seem anxiety ridden or obsessive about marginal risks. I asked a question. 

[swansont]

11 hours ago, Alfred001 said:

So it seems the researchers studying this are concerned about it as well and it's not just my neurosis. But since you never addressed any of the arguments, rather went ad hominem immediately, and described infertility as a marginal side effect, I don't expect anything will convince you.

iNow has a point. You have a couple of threads where you start out in chicken little mode, and raise an issue that you could research yourself - which you’ve done here to some extent, but only after being challenged with regard to your assumptions and framing

The evidence presented thus far is that there’s an effect (which nobody really challenged) but any possible permanent effect is not common. 

[Alfred001]

11 minutes ago, swansont said:

iNow has a point. You have a number of threads where you start out in chicken little mode, and raise an issue that you could research yourself - which you’ve done here to some extent, but only after being challenged with regard to your assumptions.

The evidence presented thus far is that there’s an effect (which nobody really challenged) but any possible permanent effect is not common. 

None of my assumptions have been challenged and I didn't have any assumptions. You say I could have researched it myself, as if this is a google search. I've read probably over 100 pages of literature at this point. I came here in hope someone might make a valuable contribution and instead I've gotten this.

18 hours ago, iNow said:

Alfred - Would it be okay if I suggested that perhaps for you anxiety is a bigger challenge than any of the marginal side effects vaccines and antibiotics may sometimes bring ever will be?

As to your second paragraph - Right, and my question from the beginning has been, does anyone know of evidence of permanent effects or any plausible mechanistic reasoning that would suggest it. Can we now get onto that?

[iNow]

No

[CharonY]

4 hours ago, Alfred001 said:

As to your second paragraph - Right, and my question from the beginning has been, does anyone know of evidence of permanent effects or any plausible mechanistic reasoning that would suggest it

Not really- there are books on the subject matter and most start off with the difficulties in a) ascertaining that there is an effect or the extent of the effect. The simple answer however is that yes, depending on your health status (which includes genetic disposition, lifestyle, and prior diseases for example), the effect can be more or less pronounced and it can also last longer or shorter. For any given individual, there is not definite answer, but for many drugs beyond antibiotics, a variety of androgenic and/or cytotoxic effects have been observed. Any of those can also impact spermatogenesis. 

As does drinking alcohol, being overweight, insufficient exercise, having infections, diet ...

[paulsutton]

I am not an expert in fertility,   but I have read that there are other factors such as diet,  even sitting for long periods or wearing certain types of clothing,  heat etc.

So antibiotics may be a small factor, if use is combined with other activity.

In the US don't they use antibiotics in animals,  do those animals also suffer lower fertility, ?  Does this put those antibiotics in the food chain.?

 

[CharonY]

12 hours ago, paulsutton said:

In the US don't they use antibiotics in animals,  do those animals also suffer lower fertility, ?  Does this put those antibiotics in the food chain.?

Antibiotics is used in agriculture everywhere as it increases yield. While it is banned in the EU for purpose of fattening animals, the use has barely declined as they found loopholes to keep using that.

The ABs do not enter the food chain as in many jurisdictions (at least EU, Canada, US) the meat has to be tested. I.e. they have to be off before slaughtering.

[Alfred001]

Ok, someone please tell me I'm misinterpreting something here.

https://www.mdpi.com/2073-4409/11/24/4064

This is a young male given a normal course of H. pylori treatment, 2g of amoxicillin, 1g of clarithromycin for 15 days. Look at supplementary table 4. M1-5 are 5 samples taken at 3 day intervals throughout the treatment period, W1-5 are samples taken at 3 day intervals after treatment. Look at number of total sperm and number of normal sperm or simply ration of normal sperm. Only 10% normal sperm on first day of treatment!!!?? And then in the last day of the post-treatment period it has gotten worse, 5%!

[CharonY]

For the most part, yes. During the course of medication the sperm density increased and malformation of sperm was observed. There is some evidence of dysregulation which does not immediately went back once the treatment stopped. The results are not totally surprising. Terminal elimination of amoxicillin can take days (only the initial elimination follows first order kinetics, then slows down, IIRC). And after that, tissue regeneration will take a while. I am also fairly sure that regardless of which antibiotics you take, liver values will look fairly bad. 

You will likely find similar effects with many harsher drug treatments (including other antibiotics) but sperm reduction have also been shown e.g. for aspirin. common painkillers and so on. In animal models, in utero exposure to e.g. acetaminophen and ibuprofen occasionally have been associated with reproductive issues in the newborns.

I think there might be a misconception that drugs are precision instruments that fulfil only a highly specific target. In truth, a treatment involves flooding our bodies with a bioactive component in very high doses that will take care of the acute problem, but will also interact in undesired ways. The term side-effect is a bit of a misnomer as some think it is a minor effect. Rather, every (bio)chemical interaction is an effect, only many are undesired.

This is one of the reasons, why it baffles me why folks panic around vaccination, a short-term treatment with typical long-term benefits, but have no issues of taking drugs, even in the long-term, which is just likely to have health burden. Of course, if there are indications it is necessary to take, them especially as other health effects are more pressing (if you have an ongoing infection, sperm count is likely your least worry).

Just to make it clear- there are no safe drugs that you can eat like candy (and thinking of it, candy has also pretty bad effects on health, including sperm quality and sperm count). We can basically take any drug your are interested in, and if someone looks at it, we will see molecular aberrations that can translate into a variety of phenotypes. Everything has an effect and the baseline of looking at it (as I have said many times) is not whether it is detrimental (because to various degree, virtually everything is, including breathing), but which is less bad.

 

[Alfred001]

1 hour ago, CharonY said:

For the most part, yes. During the course of medication the sperm density increased and malformation of sperm was observed. There is some evidence of dysregulation which does not immediately went back once the treatment stopped. The results are not totally surprising.

They're quite surprising if you look at the literature on this topic. I don't think I've ever seen anything near this degree of malformation (and from day 1!) and in animal studies they often give doses way beyond human ones.

Add to that this mice study with amox in which the % of abnormal sperm continued to rise through 30 days post treatment and testicular changes were found with only a 10 day course using a smaller dose than used in that study.

1 hour ago, CharonY said:

Terminal elimination of amoxicillin can take days (only the initial elimination follows first order kinetics, then slows down, IIRC).

Can you explain this? I thought the half life of amox is quite short. I believe a 500-1000mg dose drops down to very low, near zero levels in serum somewhere past the 6th hour.

[CharonY]

3 hours ago, Alfred001 said:

They're quite surprising if you look at the literature on this topic. I don't think I've ever seen anything near this degree of malformation (and from day 1!) and in animal studies they often give doses way beyond human ones.

Exactly unsurprising if you look at the topic. The amount of stuff that affects sperm count and sperm quality is extremely broad. Mechanistically it is not terribly surprising as sperm production is pretty prolific and a lot can upset the production if you flood your body with it. In rats supplementing or replacing water with energy drinks resulted in something like 10% of deformed sperm heads. One should also add that the study you linked is a single patient, which again is difficult to extrapolate from. There are however quite a few studies linking a wide range of drugs that have shown long-term and irreversible impact on human fertility. These are mostly drugs used for cancer treatment. And they are well documented mostly because the results and impact are fairly dramatic.

For antibiotics, both results have been observed, and at least in women, amoxicillin has been associated with a reduced risk in infertility. That does not necessarily mean anything biologically, beyond that it mostly requires more investigation. In a broader sense, the whole research area is suffering from what one might call a target rich environment. So many things affect our physiology in general, so that it is very difficult to establish a successful research program on anything specific. Interest goes away so fast, but all the stuff we constantly consume beyond drugs (e.g. personal care products, plasticizers, chemicals in our homes, air quality in our homes, diets and so on), still affect our body in a very broad and poorly understood way. I understand that finding something that one didn't know about might look like a relevation, but if you ask folks working on this subject, it is just one minor bit. And especially with drugs, there is at least a reason why we risk exposure. In terms of health effects I would in general be more worried about air quality in houses, diet, and lastly chemical exposure (roughly in that order). But since it is hard to improve on those bits, outsized worry is then placed on things that are easier to control but likely have less impact on you over your lifetime. Just saying.

 

3 hours ago, Alfred001 said:

Can you explain this? I thought the half life of amox is quite short. I believe a 500-1000mg dose drops down to very low, near zero levels in serum somewhere past the 6th hour.

Elimination of compounds from the body are often not entirely linear (actually it is rare to see that). The actual values will change, depending on how it is taken and what you measure (e.g. actual serection in urine or monitor presence in serum). Data sheets suggest that in about 6-8 hours 60% of the drug is secreted via urine. A particular benefit of amoxicillin is that it penetrates tissues very well, so it moving out quickly out of serum means that it is actually distributing to organs (including testes). I.e. the first batch that finds its way into urine fast gets eliminated first, but the rest that is penetrating, bound to proteins and are otherwise present get eliminated more slowly. I do not know the precise values (or whether anyone checked, as the terminal elimination is often difficult to measure). I should add that it has a short half-life in terms of antimicrobial activity, but I am not sure whether anyone checked whether cytotoxic effects could continue beyond that (as the antimicrobial activity follows different mechanisms than its interaction with human tissue).

 

Edit: I only skimmed the result on your other link and there the effect size is really modest compared to what you have discussed in the human individual. There are likely differences in methodology and also shows that you cannot just pick and choose elements from different studies to make conclusions- you need to synthesize the whole body of available literature, which, I acknowledge is not a trivial thing to do, especially for lay persons.

[Alfred001]

9 hours ago, CharonY said:

I understand that finding something that one didn't know about might look like a relevation, but if you ask folks working on this subject, it is just one minor bit.

I have been posting for two pages now about all the literature I've read on this subject. I know the subject and that various things affect sperm parameters is not a revelation to me, as I think I've made clear in the thread. What is a revelation is that amoxicillin after a single day of administration caused abnormalities in 90% of sperm. That is a figure you don't see even in animal studies where they're fed long courses of extreme doses, if you know the subject. (Setting aside that spermatogenic arrest can be induced, I'm talking strictly about the rate of abnormalities.)

So, with that in mind, I'm curious to see a study showing reversability of amoxicillin's effect on sperm parameters and/or histology of reproductive organs, because the magnitude of the effect makes me wonder.

9 hours ago, CharonY said:

Edit: I only skimmed the result on your other link and there the effect size is really modest compared to what you have discussed in the human individual. There are likely differences in methodology and also shows that you cannot just pick and choose elements from different studies to make conclusions- you need to synthesize the whole body of available literature, which, I acknowledge is not a trivial thing to do, especially for lay persons.

How am I picking and choosing elements from different studies and what conclusions am I making, I haven't arrived at any conclusion?

The difference very well may be attributable to physiological differences. The only study of the impact of rifabutin on male fertility showed no effect in mice and baboons and a pretty significant effect in rats. It's possible amox has a more dramatic impact on the human reproductive system than that of the mouse. This is, of course, speculation, because we have (AFAIK) too little evidence.

The bottom line is, the only human evidence we have for amox, suggests a pretty dramatic impact on sperm parameters, way out of line with effects commonly observed in animal studies of antibiotics.