Technology

Why sex matters in science

Female participation in scientific research needs to increase dramatically, if discoveries are to benefit all of humanity. It's a familiar theme. But this time, there's a twist.

At issue is the under-representation of female rats and mice in biomedical research.

Neuroscientist Dr Rachel Hill says it is unscientific to overlook female rodents in animal trials.
Neuroscientist Dr Rachel Hill says it is unscientific to overlook female rodents in animal trials. Photo: Wayne Taylor

"I was really quite flabbergasted at how few studies actually look at females," said Florey Institute of Neuroscience and Mental Health neuroscientist Rachel Hill.

Dr Hill has just completed a review of 710 scientific papers, with the results published this month in the journal Neuroscience and Biobehavioral Reviews.

The under-representation of female mice in animal trials could have dramatic implications.
The under-representation of female mice in animal trials could have dramatic implications. Photo: Jesse Marlow

She found just 15 per cent of studies analysed used rodents of both sexes. Of those that did, 80 per cent established there were sex-specific results. In other words, males and females responded differently.

"I think it is unscientific not to include both males and females and it's extraordinary that people don't," she said.

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Variation between the sexes in medical trials could have significant implications, especially if the differences translate to humans because this raises questions about whether the drug design and dose recommendations that originate from single-sex animal studies serve the entire population or just half of it.

"Females differ slightly in their behaviour, in their mental health and how they respond to certain stressors," Dr Hill said.

Mice are naturally social creatures.
Mice are naturally social creatures.  Photo: Jesse Marlow

The gender bias favouring male test animals originates because historically females were considered less stable or reliable due to their estrous cycle - the rodent equivalent of the human menstrual cycle. Unlike every 28 days in humans, rodents cycle every two or three days.

However, Dr Hill said rather than being a reason not to study female rodents, this was a perfect illustration as to why it was so important.

"Big changes in hormone levels have been shown to do all sorts of things not only to peripheral tissue but to the brain and their behaviour," Dr Hill said. "A female at a certain stage of the cycle compared to another stage of the cycle will respond differently - in rodents and humans."

Once single-sex study models become standard, subsequent studies tend to follow suit - partly because it maintains consistency to the data set.

However there are numerous examples where sex differences have been documented in studies, largely due to the differences in hormones and metabolism rates between males and females.

Dermatologic researcher Tatiana Oberyszyn from Ohio State University Medical Centre, found male mice had about 50 per cent more tumours than females - and that their malignancies were more aggressive.

Another 2015 study looking at hypersensitivity to pain found different results in male and female mice. This is because in males, inhibiting the function of immune cells called microglia relieves pain. But in female mice, targeting these immune cells had no effect. And the same may be the case for humans, meaning a pain-relief drug that targets microglia cells could be useless.

Dr Hill said she had always used mice of both sexes in her research into schizophrenia.

"Probably 90 per cent of the time we will see a difference in behaviour," she said, adding that at a molecular level there are also differences between the sexes.

Dr Hill said the average onset of schizophrenia in males was early 20s compared to late 20s or early 30s for females, possibly because the high oestrogen levels females have in puberty delay the onset.

A similar analysis of studies published in 2009 found male animals outnumbered females 5.5 to 1 in neuroscience, 5 to 1 in pharmacology and 3.7 to 1 in physiology.

Only 45 per cent of animal studies involving depression or anxiety and only 38 per cent involving strokes used females - even though these conditions are more common in women.

BATTLE OF THE SEXES 

Female mice are: 

  • Less aggressive 
  • Easier to handle 
  • Smaller, requiring less weight-administered drugs 
  • Generally less expensive Male mice are: 
  • Larger (easier targets for attaching electrodes) 
  • Don't have estrous cycles that can complicate pharmacology trials 
  • Part of a significantly larger body of literature and data sets on which to build

Male mice are:

  • Larger (easier targets for attaching electrodes)
  • Don't have estrous cycles that can complicate pharmacology trials
  • Part of a significantly larger body of literature and data sets on which to build