January 8, 2018

expert reaction to study looking at ibuprofen use and testicular health in men

In a new study, published in PNAS, researchers examine ibuprofen consumption and hormonal balance in male participants between 18-35 years of age.

Dr Ali Abbara, Senior Clinical Lecturer in Endocrinology at Imperial College London, and member of the Society for Endocrinology, said:

“This well conducted research paper suggests that ibuprofen use could mildly impair testicular function such that the body has to work slightly harder to maintain normal testosterone levels.

“Further studies are required to investigate whether this mild effect of ibuprofen could significantly impair testicular function in terms of testosterone levels, or fertility, after long term use – this study did not examine effects on fertility.

“The effects were very mild even after six weeks of regular consumption of ibuprofen, which is longer than is usually recommended in practice, so this data should not concern men who occasionally take ibuprofen for pain relief.  If men are known to have impaired testicular function and take ibuprofen regularly, then it would not be unreasonable to consider other painkillers until more data is available to better inform this potential risk, although we must bear in mind that many alternative painkillers may also affect the reproductive axis.”

Dr Kevin McEleny, Chair of the British Fertility Society’s Education and Training Sub-committee, and Consultant Urologist/Andrologist at Newcastle Fertility Centre, said:

“Some studies have shown that exposure to drugs such as ibuprofen can affect testicular health in the foetus.  But this is the first time that ibuprofen has been shown to have an impact on testicular health in adults.

“This was a short-term study and the effects seen on testicular health may be reversible.  No direct effect on fertility was shown, but the results of this initial study suggest that it warrants further investigation.

“Long term use of ibuprofen has other negative effects on overall health so people should only be taking it over a period of weeks, months or years if a doctor has prescribed it.”

Dr Richard Quinton, Senior Lecturer in Endocrinology at Newcastle University, and member of the Society for Endocrinology, said:

“This is a landmark study that elegantly combines clinical and basic research, at both tissue and cellular levels, to show that ibuprofen, a common over-the-counter painkiller, can reversibly hinder testosterone production by testicular cells.  This effect is probably analogous to that of long-term ibuprofen use on women, which can make then unable to ovulate.

“This hindrance leads to a compensatory effect by the pituitary gland, which produces more luteinizing hormone (LH) to maintain serum testosterone levels.  Hence the term ‘compensated hypogonadism’.

“However, the effect of ibuprofen on a different type of testicular cell (Sertoli cell), which regulates sperm production rather than testosterone production, is far more modest, raising the question of whether widespread use of ibuprofen has the capacity to contribute to the accumulating evidence for adverse environmental factors on human male fertility in Western Europe.

“Also, the hormonal pattern observed in this study is the opposite of what is normally found in the evolution of male primary hypogonadism, wherein production of sperm and other cell functions are affected long before any effect on LH and testosterone levels is observed.  The authors can only speculate whether long term ibuprofen use might contribute to the development of irreversible primary hypogonadism.  For this, primate studies would probably be required.

“In women pregnant with male foetuses, there are already data suggesting a potential long term effect on testicular function of the offspring of regular paracetamol taken during pregnancy.  Paracetamol and Ibuprofen are both no-opiate painkillers and have some similarities in their modes of action.

“The EMAS study (latest data published last month in Clinical Endocrinology) found hypogonadism (compensated or not) with raised LH to be associated with both ageing and non-gonadal illness.  We know that use of ibuprofen and other NSAID pain-killers is generally greater in older people and in those with a variety of chronic diseases, so these new data may feed into that association.

“Hitherto, most warnings regarding this family of painkillers have focused on limiting long term use in the elderly to prevent gastrointestinal, renal and cardiac adverse effects.  This study should give pause for thought to sportsmen using them routinely for exercise-induced aches and pains.”

Dr Rod Mitchell, Research Group Leader and Honorary Consultant Paediatric Endocrinologist, MRC Centre for Reproductive Health, University of Edinburgh, said:

“This comprehensive and robust study combines laboratory experiments with a study involving human subjects to investigate the effects of ibuprofen on testicular function in males.

“The small clinical study involving prolonged administration of therapeutic doses of ibuprofen to young healthy adult men demonstrates evidence for disturbed production of reproductive hormones that regulate testosterone production, although, importantly, testosterone production itself is not affected.  Therefore it is unlikely that occasional ibuprofen use would result in any adverse reproductive health effects in men.

“Whether the effects of ibuprofen on hormones that regulate testosterone persist following cessation of exposure, or whether they could subsequently lead to important clinical consequences in males, cannot be concluded from the present study.

“Interestingly, testosterone production was reduced in the experiments involving exposure of human adult testis tissue to the highest concentrations of ibuprofen in culture.  Given that these tissues were from older men than those in the clinical study it is possible that prolonged ibuprofen use could result in hypogonadism in older men; however, in-vitro culture studies cannot easily be translated into clinically relevant human effects.

“The study also provides evidence of reduced function of the cells that support the development of sperm in the testis.  This is also supported by the findings of the in-vitro culture study.  This could have the potential to affect male fertility, but given the fact that this is a small study it is not possible to determine fertility effects.  A large scale study with prolonged follow-up would therefore be required to answer this question.  However, conducting such a study would represent a significant challenge.

“Given that male fertility is dependent on the development and production of sperm, the fact that the in-vitro culture studies did not identify any effects on the germ cells (cells that will become sperm) is important; however, these studies were limited and further work would be required to conclusively determine whether ibuprofen exposure can affect germ cells and fertility in humans.

“Ibuprofen is an effective anti-inflammatory and analgesic medication.  The results of this study do not indicate a need to change the current recommendations regarding the use of ibuprofen.  Large-scale studies would be required to determine the potential for clinically relevant reproductive effects in adult men.”

Prof. Allan Pacey, Professor of Andrology, University of Sheffield, said:

“The possible effect of over the counter pain killers, such as Ibuprofen, on testicular function has been of increasing interest in recent years.  However, to date, most if not all of the research carried out has been on how it might affect the developing (male) fetus if the mother takes the pain killer when she is pregnant.  To my knowledge there has been very little research on how the use of painkillers might affect the testicle of a fully grown adult.

“The studies performed in this paper are really quite elegant because the authors approach the problem from three perspectives: they have (1) regular blood hormones from men who were given ibuprofen (or placebo) over the study period; (2) studied pieces of human testes in the laboratory; and (3) looked at the effects in a population of cultured cells which is known to mimic the way testicular hormones are produced.

“The results suggest that long-term use (several weeks) of ibuprofen can affect the production of the male hormone by the testicles.  The authors speculate that this could have health implications for such men, given the known links between the disruption of such hormones and cardiovascular disease, diabetes and infertility.  However, this is currently speculative.  So, for the time being, I would urge men who need to take ibuprofen to continue to do so.  However, it is recommended that if men (or women) need to take it for more than three days consecutively then they should first consult their family doctor.”

* ‘Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism’ by David Møbjerg Kristensen et al. published in PNAS on Monday 8 January 2018. 

Declared interests

Prof. Allan Pacey: “Chairman of the advisory committee of the UK National External Quality Assurance Schemes in Andrology, Editor in Chief of Human Fertility and Trustee of the Progress Educational Trust (all unpaid).  Also, recent work for the World Health Organisation, British Broadcasting Corporation, Purple Orchid Pharma (paid consultancy with all monies going to University of Sheffield).  Co-applicant on a research grant from the Medical Research Council (ref: MR/M010473/1).”

None others received.