This essay is part of a series exploring what is required for scientific progress to be made in our understanding of women’s health and our ability to treat the conditions that impact the lives of women everywhere. Learn more about why this is necessary and explore the other challenges and topics.
Most Animals Don’t Menstruate
Female models are often excluded from research. When included, they lack key biological functions such as mensuration and menopause.
Scientists are well aware that male and female biology is different, however, there is deep hesitation to include female models in their studies and a lack of knowledge about how to analyze and account for their inclusion. Female humans, mice, and cells are considered to be too hormonal and to add too much uncertainty to experiments and thus they have been excluded from studies and clinical trials for decades. This results in a lack of understanding at the very earliest stages of research into how the biology of men and women is different and what the ramifications of those differences might be.
The bias towards using only male models is so strong that many researchers who do not work in women’s health are not even aware that most animals do not menstruate or experience menopause. These fundamental differences between humans and the models used in research are one of the most interesting and difficult challenges that women’s health researchers face today.
What are models and why are they important?
Researchers use models across all phases of scientific research and rely on them to provide controlled settings for their studies. There are many types of models from computational models that explore systems, to organism models that allow scientists to understand similar species. The term model is used pretty generically by biologists to refer to “experimental systems that recreate aspects of human tissue function or disease.”¹
Cellular models allow scientists to explore questions about how the basic building blocks of life work while animal models allow scientists to understand how simple (worms) and complex organisms (mice, primates) react and then apply those learnings to humans.
For some, the use of animal models brings up ethical concerns. For the purpose of my research, I did not explore these concerns.
Female Models are Excluded from Most Research
For hundreds of years, the female body has been characterized as being more complicated than the male body due to the monthly fluctuations of hormones. This belief, among others, has justified the exclusion of women in clinical trials and female models in research.²
Scientists believe that for female models to be included, the female hormone cycle needs to be taken into consideration and that this would overcomplicate their work. It becomes easier to exclude them. Research conducted in 2016 showed that male animal models have similar hormone variations³ however this finding has not changed the attitudes with regards to including female models.
A paper published in 2014 looked at research conducted between 2011 and 2012. It found that in cellular research that reported the sex of the cells being studied, 71% studied male cells and only 7% studied cells of both genders. The numbers were even worse for studies using animal models. Of those that reported on sex, “80% of publications included only males, 17% only females, and 3% both sexes.”⁴
In 2016, the NIH in conjunction with Office for Research on Women’s Health (ORWH) passed the Policy on Sex as a Biological Variable (SABV) which required NIH grants to require sex in basic and translational research funded by the NIH.
While promising, there are still several challenges. First, these requirements only apply to work that is funded by the NIH. While these requirements are beneficial to most basic science which is funded by the NIH, they have less impact on translational and clinical research which is more likely to be funded by private industry. Second, new studies are showing that 5 years after being implemented, the application of SABV is less than excellent.
One study, published in February 2022, looked at SABV reporting across 253 cardiac resynchronization therapy studies (pacemakers) that occurred in 2020. They determined that “Fourteen percent considered sex in the study design. Outcome data disaggregated by sex were only reported in 17% of the studies.”⁵
Another study, published in January 2022, looked at 251 neuropsychopharmacology studies (the study of the neural mechanisms that drugs act upon to influence behavior) and found that “only 20% (50 studies) adequately evaluated sex differences either by testing for an interaction involving sex or by stratifying analyses by sex. Of these 50 studies, 72% found statistically significant sex differences in at least one outcome.”⁶
Lastly, a study published in June 2020 compared the rates of SABV reporting in 2009 with those in 2019. They found “There was a significant increase in the proportion of studies that included both sexes across all nine disciplines, but in eight of the disciplines there was no change in the proportion studies that included data analyzed by sex. The majority of studies failed to provide a rationale for single-sex studies or the lack of sex-based analyses, and those that did relied on misconceptions surrounding the hormonal variability of females.”⁷
One current stem cell PhD candidate I spoke to was shocked halfway through her PhD to realize that the standard was to still use only male cell lines. She then procured a female cell line and determined it responded completely differently than the male cell lines being used. Unfortunately, digging into this difference was not the focus of her PhD and she had neither the funding nor the time to explore further.
Another undergraduate research assistant I spoke to commented on the lack of female mice being used in the lab where he worked that was conducting Covid-19 research. The bias against including female models is deeply entrenched in scientific thinking. Researchers understandably want to create experiments that are as controlled as possible and need to be able to explain anything that could impact the outcome of the experiment. However, the exclusion of female models limits our understanding of female biology and leads to such outcomes as women having a 50–70% greater risk of suffering from adverse drug reactions (ADRs) compared to men.”⁸
Most Animals Don’t Menstruate
Even if scientists were to use models of both genders in research conducted today, there are other challenges for those studying women’s health conditions. The reality is that most animals do not menstruate or experience menopause.
I can drop researchers’ jaws when I share this information. Many who do not study female biology are simply unaware.
There are only a handful of species that menstruate. Some primates, bats, the elephant shrew, and the spiny mouse¹⁰. There are even fewer who experience menopause. Only humans, killer whales, pilot whales¹¹, and possibly the spiny mouse¹².
Menstruation is defined as the periodic shedding of the superficial functional layer of the endometrium in the absence of embryonic implantation. This is what happens when women get their period. It occurs approximately every 28 days in humans and is preceded by the development of the endometrium. Most animals do not develop an endometrium, which is key when it comes to understanding conditions of the endometrium such as infertility, endometriosis, adenomyosis, and others.
Menopause occurs when the female body stops producing eggs monthly. It occurs due to the depletion of the ovarian reserve which begins when a female is still in utero and continues until she reaches menopause. Once a woman has reached this phase of life, she is at an increased risk of cognitive decline, insomnia, depression, heart disease, stroke, osteoporosis, weight gain, and arthritis.¹³ However, since almost no animals live beyond their reproductive years, scientists are unable to study this phenomenon in other species and look for solutions.¹⁴
The lack of model animals presents unique challenges to scientists looking to study conditions that are related to periods, menopause, the endometrium, or ovarian aging. As one researcher who doesn’t study women’s health said when we were discussing this challenge, “without models, I wouldn’t know where to begin.”
However, scientists are trying to solve this problem. They have found ways to induce menstruation in lab mice,¹⁵ are exploring how to create organoids to represent the uterus,¹⁶ and are exploring the spiny mouse as a possible animal model.¹⁷ The work is all at a very early stage and needs more work before it can be broadly leveraged.
The work to find animal models is the most basic of science. Funding is required to understand these conditions and is often deemed to be “too risky” to receive NIH funding. As a result, scientists must find other funding to support this crucial research. These challenges and hurdles may discourage early scientists from conducting research in these areas, as without funding it becomes difficult to reach the milestones required to move one’s career forward.
The lack of female model inclusion in research and the lack of representative model species are just two more hurdles scientists face when trying to better understand female biology and find treatments for women. While the NIH and the ORWH have made policy changes to effect change, those policies have had little impact on researchers’ ability and willingness to explore sex as a biological variable in their work. Additionally, the lack of funding for animal model research to find more representative models prevents researchers from being able to include more realistic models in their research.
Next in the series:
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Footnotes:
- https://www.nature.com/subjects/biological-models
- https://www.science.org/doi/10.1126/science.aaw7570
- https://bsd.biomedcentral.com/articles/10.1186/s13293-016-0087-5
- https://www.surgjournal.com/article/S0039-6060(14)00425-5/fulltext
- https://pubmed.ncbi.nlm.nih.gov/34821083/
- https://pubmed.ncbi.nlm.nih.gov/34732844/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282816/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096710/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253787/#ref9
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253787/
- https://www.sciencefocus.com/nature/do-other-mammals-go-through-the-menopause/
- https://pubmed.ncbi.nlm.nih.gov/34601586/#affiliation-1
- https://www.buckinstitute.org/wp-content/uploads/2021/01/The-Unspoken-Truth-Final-8.pdf
- https://pubmed.ncbi.nlm.nih.gov/29531669/
- https://pubmed.ncbi.nlm.nih.gov/6699534/
- https://cgr.mit.edu/research/
- https://hudson.org.au/researcher-profile/jemma-evans/
