Do OTC analgesics affect testosterone and sperm?

According to the data,  male sperm counts are reducing worldwide and testicular cancer rates are increasing. But why?
 
One factor, according to male reproductive endocrinology researcher Dr Liza O’Donnell, could be the effect of common over-the-counter analgesics like paracetamol and ibuprofen.
 
She recently reviewed the up-to-date evidence for a Healthy Male article, and told newsGP that there are two broad ways in which these analgesics can affect men.
 
Firstly, the effect on male foetuses if taken by mothers during pregnancy. Secondly, from the direct effect on adult men when they take them.
 
‘The testes do a lot, producing sperm and androgens,’ Dr O’Donnell said.
 
‘They are uniquely controlled but also very susceptible to different onslaughts.’
 
She says there is a narrow window in male foetal development between eight and 14 weeks, where the Leydig cells are developing when these analgesics can have a detrimental effect.
 
‘There is evidence that by giving ibuprofen during that window, it can muck around with normal development of those Leydig cells and their function in later adulthood,’ Dr O’Donnell said.
 
‘There are many studies on mice and rats that paracetamol and ibuprofen can interfere with lots of different parts of the bodies and when it comes to the testis formation, you can have long term problems.’
 
Paracetamol and ibuprofen work by reducing prostaglandins and according to animal experiments and human testis explants, this affects hormonal production and is associated with a reduced anogenital distance (AGD) in males.
 
A reduced AGD is associated with testicular dysgenesis syndrome characterised by hypospadias, cryptorchidism, poor semen quality and testicular cancer.
 
‘This gradual idea of testicular dysgenesis syndrome, which has been going on for a long time, probably has origins in foetal life,’ Dr O’Donnell said.
 
‘There is a consensus statement by European medical teams that women need to be careful of paracetamol in pregnancy. As a researcher, I am interested in this.’
 
Many women may not know they are pregnant in the first trimester, which means they may take these analgesics unwittingly. Dr O’Donnell says pregnant women should not feel guilty for taking analgesics sporadically.
 
‘But if a woman is taking it for weeks on end, it could be a problem,’ she said.
 
Apart from analgesics, Dr O’Donnell says there are other factors to consider when it comes to testosterone and sperm quality.
 
‘The environmental risk factors are a big one,’ she said.
 
‘Testes can also be affected by endocrine disruptors in our environment, which can cross the placenta or change the mother’s hormone milieu, which then affect the foetus.
 
‘There is an increase in testis cancer rates. It’s quite terrifying really and it’s possibly all related to the effects on male babies, who are vulnerable in utero.’
 
The second way these analgesics can affect men is if they directly taken them.
 
A 2018 European study showed that men who took ibuprofen daily for six weeks exhibited compensated hypogonadism, with an increase in serum LH and a decrease in their free serum testosterone/LH radio.
 
‘The study was beautifully done, a well-controlled clinical trial, small but backed up by in vitro studies to show mechanisms,’ Dr O’Donnell said.
 
‘It really fits with my understanding of biology and how mucking around with prostaglandins can affect the testes.
 
‘Bodybuilders and athletes take paracetamol and NSAIDs a lot. I don’t think this is appreciated enough.’
 
The study did not assess sperm quality, however a 2019 study found that ibuprofen had adverse effects on sperm parameters with both in vivo and in vitro studies, but that the effect is not yet confirmed in humans.
 
Gynaecologist and Professor of reproductive medicine, Kelton Tremellen told newsGP that without human studies, this may be of limited clinical concern.
 
‘There is some evidence that ibuprofen may interfere with testicular function, but it’s probably subtle and of limited clinical concern in the majority of clinical contexts, [for example] short term analgesia,’ he said.
 
‘There are feedback loops and compensatory processes in the body that maintain homeostasis in hormone production. If ibuprofen interferes with Leydig cell production of testosterone, the anterior pituitary will respond by increasing LH drive, [thereby] maintaining testosterone levels.
 
‘If testosterone levels are still normal, then it’s hard to see that interfering with fertility.
 
‘However, if the man already has compromised testicular function due to some other pathology, say cryptorchidism with small testis producing borderline normal testosterone levels because of already raised LH drive, then a second insult of ibuprofen exposure may be detrimental.’
 
Professor Tremellen’s view is that short term exposure to NSAIDs like ibuprofen for management of pain is unlikely to cause infertility.
 
‘Long term NSAID use in a man with already compromised testicular function may impede fertility potential,’ he said.
 
A 2017 study created headlines when it showed sperm concentration has declined more than 50% in under 40 years, but it was criticised for focusing on Western countries.
 
The researchers backed the findings up with a 2022 follow up that comprised all the continents and confirmed the global reduction in sperm count from 101 mill/ml in 1973 to 49 mill/ml in 2018, accelerating at 2.64% per year.
 
Professor Tremellen notes the significant decline in sperm counts over the last four decades and says there is one factor that is likely the most important.
 
‘The number one cause of this is obesity,’ he said.
 
‘Fat tissue contains the enzyme aromatase, which breaks down testosterone to estrogen. Estrogen then negatively feeds back on pituitary LH drive, further reducing testosterone production.
 
‘This decline in testosterone combined with inflammation and associated oxidative stress damages sperm and reduces fertility. Obviously, toxins such as estrogenic plasticisers may have some role, but obesity is the number one driving cause for reduced sperm quality in my opinion.’
 
Apart from diet, heat, smoking and age, Wi-Fi and phthalates have also been implicated in reduced sperm counts. Interestingly, penis sizes have increased by 24% over the last 30 years globally.
 
Whatever is going on, researchers like Dr O’Donnell will continue to investigate this trend in men.
 
‘The testis is such a busy organ, with sperm and androgens, and those processes are really well controlled and fundamental to the species succeeding,’ she said.
 
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