APPLES, PEARS AND FRUIT SALADS
A few years ago, a joint Italian–New Zealand research team completed what was, at the time, one of the fastest genome sequencing projects ever undertaken. In just two years, they mapped the genetic differences between apples and pears. What they found was interesting: apples and pears have the same number of chromosomes, yet apples possess approximately 6,000 more genes and around 150 million additional DNA base pairs. So, scientifically speaking, despite belonging to the same family, apples and pears are very different1.
Of course, we did not need genome sequencing to know that. We recognise the crisp acidity of an apple and the smooth texture of a pear instinctively. The Greek poet Homer famously described pears as the ‘Fruit of the Gods’ due to their melt-in-the-mouth texture and delicate flavour, quite different from apples. Furthermore, a real American apple pie simply wouldn’t be the same with pears, and no self-respecting connoisseur of Poire Williams would ever accept apples as a substitute.
However, there’s a situation where apples and pears can be lumped together and their differences become irrelevant: when making a fruit salad.
This metaphor is relevant, because when it comes to acknowledging biological differences between male and female athletes, sports medicine often still resembles a fruit salad more than a science.
SEX DIFFERENCES: THE GENOMIC REALITY
Let us return to first principles. More than two hundred years ago, a statesman —not a scientist—asserted that “all men are created equal”2. While politically problematic today, the statement is, in a narrow genetic sense, largely accurate. Studies have revealed that human males share approximately 99.9% of their genetic material3.
However, when men and women are compared, the picture changes substantially. Both sexes have 23 chromosome pairs, but women have two X chromosomes, whereas men have one X and one Y. Of the approximately 20,000 human genes, more than 1,000 are located on the X chromosome, while fewer than 50 reside on the Y chromosome. Therefore, when considering gene numbers rather than chromosome numbers, there’s about a 0.1% difference between men and a 1% difference between men and women. Until recently, many scientists have considered this to be comparable to the difference between humans and chimpanzees4.
Consider this for a moment.
However, it’s not just about counting genes; gene expression also plays a crucial role. Research from the Weizmann Institute of Science has demonstrated that approximately 6,500 human genes—nearly one third of the genome—are expressed differently in men and women5. These differences are present in every tissue, not only in reproductive organs. In other words, every cell in the human body has a biological sex.
Crucially, many of these differences in gene expression are independent of circulating sex hormones. The intrinsic genetic sex of a cell influences metabolism, inflammation, repair, and adaptation. This has profound implications for medicine—and particularly for sports medicine.
WHY EXTRAPOLATION FAILS
Two practical conclusions follow. First, men and women are biologically different, not merely in size or strength, but at a fundamental cellular level. Second, research conducted exclusively in men cannot simply be applied to women, as it would be like comparing apples to pears - and the result resembling a fruit salad.
A clear illustration comes from pharmacology. The enzyme CYP3A is responsible for the metabolism of approximately 50% of all commonly used drugs. Female liver cells express different levels of this enzyme compared with male liver cells. The implication is obvious: for half of all medications, the metabolism and therefore, optimal dosing, may differ between sexes6.
Yet sex-specific dosing recommendations are rare. Zolpidem remains a notable exception. In 2013—two decades after its approval—the US Food and Drug Administration recommended a lower dose for women after recognising that women had almost twice the blood concentration of the drug compared with men, and a correspondingly higher risk of next-day motor vehicle accidents due to lingering drowsiness6.
This reflects a research culture in which men are over-represented, women are under-represented, and mixed-sex cohorts are analysed without sex stratification. Occasionally, this reaches the point of absurdity. In 2017, a study examining interactions between alcohol and flibanserin—the female Viagra, developed for exclusive use by women—enrolled 25 participants, 23 of whom were men7. Given established sex differences in alcohol and drug metabolism, it is difficult to imagine how such data could meaningfully inform clinical practice.
MISSED OPPORTUNITIES AND PERSISTENT BLIND SPOTS
The problem is not new. The Baltimore Longitudinal Study of Aging, initiated in 1958, has provided invaluable insights into human ageing8. Ethel Caterham, the oldest living person at 115, and Jeanne Calment, who died in 1997 at 122.5, are two notable figures. Of the 100 oldest people ever recorded, 94 were women, clearly demonstrating the importance of sex in ageing. Yet for its first two decades, only men were included in this study. Imagine what these women and others like them could have contributed to the study if they had met the inclusion criteria.
Even when women are included, failure to stratify by sex remains common. In a study examining the long-term effects of concussion on the ageing brain using data from the Baltimore cohort, 40% of participants were female. Despite known sex differences in concussion incidence and outcomes, results were not analysed by sex, nor was this omission acknowledged as a limitation9.
These blind spots persist despite clear biological signals. The same Weizmann Institute study that identified sex-specific gene expression also examined tissue-specific differences5. Unsurprisingly, breast tissue ranked highest. More notable was the finding that the musculoskeletal system ranked second. Muscles, bones, and connective tissues are among the most sexually dimorphic systems in the body at a genetic level.
EPIDEMIOLOGY CONFIRMS BIOLOGY
Sports injury epidemiology reinforces this message. Surveillance data from international athletics, Olympic Games, and FIFA tournaments consistently demonstrate that while overall injury rates between men and women may be similar, injury types differ substantially10-17. Female athletes have higher rates of stress fractures, anterior cruciate ligament injuries, and concussions—often with more severe or prolonged symptoms—whereas male athletes experience more acute shoulder dislocations and hip-groin pathologies, including cam-type femoro-acetabular impingement.
These differences have implications not only for prevention but also for surgical decision-making, rehabilitation strategies, and return-to-play criteria. Treating male and female athletes as interchangeable risks obscuring clinically meaningful patterns.
THE FOOTBALL MEDICINE DILEMMA
The consequences become particularly clear in football. When clinicians seek guidance, they turn to high-impact sports medicine journals. For male footballers, this approach is generally defensible. For female footballers, it is often not.
Evidence-based medicine depends on external validity. If the patient is a footballer, the relevant evidence should come from football. If the patient is a female footballer, the evidence should come from female football populations. Extrapolating from male cohorts is not evidence-based practice—it is convenience.
Reviews of leading sports medicine journals reveal persistent under-representation of female athletes and limited sex-specific analyses18. Although participation of women in research has improved modestly over the past decade, progress remains slow and inconsistent19. This is particularly concerning in areas such as concussion, where women are both at higher risk and under-represented in the evidence underpinning clinical consensus statements20.
HISTORICAL CONTEXT MATTERS
The roots of this problem lie beyond research design. Women have been systematically excluded from sport for centuries. Women were banned from the ancient Olympics under the penalty of death, and even the founder of the IOC believed that the Olympic Games with women would be ‘impractical, uninteresting and ‘improper21. One of the reasons cited to exclude women from long-distance or intense events, such as the marathon, was concern about their reproductive health. It was only in 1984 that women were finally allowed to compete in the marathon at the Olympic Games and Joan Benoit became the first female Olympic Gold medallist in the event. At the age of 68, she is still running, and interestingly, has two healthy children, both marathon runners.
Football offers another stark example: there is some evidence that women’s football dates back 1500 years, when both men and women in China were playing a game called Cuju, very similar to football22. By 1920 women’s football was so popular in the UK, that one match attracted 53 000 spectators, more than the men’s FA cup final that year. Then, suddenly, one year later, a group of English doctors declared that ‘the game of football is quite unsuitable for females and ought not to be encouraged’. On 5 December 1921, the English Football Association (FA) banned women from playing on their pitches, and other countries followed - from Australia to Yugoslavia. Once again, women’s bodies were considered too fragile to cope with the stress of competitive sport23.
In the meantime, the first men’s FIFA World Cup was held in Uruguay in 1930, and another eight World Cups followed in the next 50 years. Finally, in 1971 the FA lifted the ban, but by then women’s football lagged far behind that of men and it took another 20 years and a further five men’s tournaments, before FIFA held the first ever Women’s World Cup in China, in 1991. Even today there are still some countries where women’s football is either banned, or there is very little support for it.
However, things are changing. Sell-out stadiums are returning for club matches, with a record attendance of 91 648 at the Champion’s league semi-final in Barcelona in 2022, as well as FIFA World Cups, with more than 75 000 in matches at Stadium Australia in Sydney in 202324. FIFA Women’s World Cup prize money has increased from 2.4% of the men’s to 25% over the past two decades. FIFA has committed to equal prize money for the next World Cup. Transfer fees are also rising. A new women’s football strategy aims for 60 million female players by 2027. The growing popularity of women’s football has led to increased research in the field. A recent study analysed articles on women’s football’s evolution over the past 30 years (1992–2024) and found a significant rise in publications, particularly in the USA and Europe25.
FROM FRUIT SALAD TO SCIENCE
The growth of women’s football represents one of the most significant opportunities—and responsibilities—in contemporary sports medicine. Continuing to apply a fruit salad approach, where sex differences are acknowledged rhetorically but ignored methodologically, is no longer defensible.
Apples are not pears and women are not smaller men. If sports medicine is to remain scientifically credible and clinically relevant, research must be designed with external validity for the populations it intends to serve. This demands a clear-eyed recognition that sex matters—biologically, clinically, and ethically.
More than two millennia ago, the ‘father of Medicine’, Hippocrates, observed that
“It is far more important to know what person the disease has, than what disease the person has”.
Celeste Geertsema MBChB FACSEP
Sports Medicine Physician
Aspetar Orthopaedic and Sports Medicine Hospital
Doha, Qatar
Contact: celeste.geertsema@aspetar.com