March 8, International Women’s Day.
A day we celebrate the social, economic, cultural, and political achievements of women. A day that is far from being new – the first International Women’s Day (IWD) occurred in 1911 already!
More than 110 years old. You may think that after more than 110 years, the society has been evolving enough to reach a “gender equal world free of biases, stereotypes and discrimination”- as dreamt by the IWD [1]. Looking around me and reading the news, this feels like an utopia rather than a reality.
Compared to my grandmother, I’m glad I have the right to vote in federal elections happening in my home country and that I don’t need the approval of my husband to open a bank account. Yey. At the same time, it truly breaks my heart to witness what is happening in Iran. I’m devastated by the stories I hear and read about those incredible women (and a lot of men, too) endlessly fighting for their rights.
For women of my generation, it seems only logical that every human gets the same rights. The same chance to get a job, the same salary, the same opportunities to grow in their professional career, the same respect when walking down the street.
The same access to health and medical care.
And this is, my friends, where it also gets damn wrong.
What do you mean – women have the same access to health and medical care, haven’t they?
That is what we would expect in most developed countries, indeed.
But in real life, this is not exactly the case.
Wait – “not exactly”? It isn’t written “for males only” on a package of antibiotics or paracetamol, is it?
No, indeed, but…
Shall we have a closer look at the leaflet that comes in a paracetamol package, as an example, as paracetamol seems to be a 2023 trend on this blog?
It usually reads something like that:
“The recommended dosage is: Adults: 1-2 tablets of 500 mg at a time, up to 6 tablets of 500 mg per day”
This is typically followed by additional instructions for children, as well as some information regarding the safety of taking paracetamol while being pregnant or breastfeeding.
Ah! You see – so paracetamol is also for females if pregnancy and breastfeeding are mentioned in the leaflet!
Let’s consider two humans called Anne (assigned female at birth) and Max (assigned male at birth). Anne and Max are brother and sister, okay?
Deal. But why using this terminology “assigned female/male at birth” instead of the more convenient “woman/man” or “female/male” terms?
I use this terminology to be accurate and make a clear distinction between (biological) sex and gender.
Sex is assigned at or before birth and is usually correlated with the anatomical sex (read: whether you are born with a penis or a vulva). For 99.8% of the population, their genitals have been unambiguously assigned to male or female. The remaining 0.2% are intersex, which means they are born with sex characteristics that do not fit the typical binary notions of male or female bodies, or are born with “ambiguous genitalia”, which means that their external genitals aren’t clearly defined.
Gender is the choice that individuals do to define whether they feel closer to a woman or a man (or none, or all); it is a result of a socio-cultural process. There are multiple genders and not only two: cisgender, transgender, genderplural, genderqueer, etc. [2].
Wow, you dared to mention the words “penis” and “vulva” on your blog!
Indeed, and now that we’re here, please do me a favor and teach your kids (partners/friends/yourself) the difference between a “vulva” and a “vagina”, thanks.
So basically when people want to use the word “gender” because they are afraid of saying the word “sex” out loud, this is not correct?
No, it is not. So grab your courage and just use the correct word. You won’t be struck by lightning if you dare to say the word “sex” out loud. Yes, also in public. Even better – I’m convinced the world would be better with more people daring to say the word “sex” out loud, but this is a story for another time.
Let’s now go back to Anne and Max, and have a closer look at their body. Max is a tall and muscular guy, weighing approximately 90 kg. Anne is 173 cm tall and much lighter than her brother, around 58 kg. They are both in their twenties.
Obviously, both look quite differently.
There is another major difference that is often not directly visible between Anne and Max.
Similar to the large majority of her vulva-owner friends, Anne’s body has a “special” clock called menstrual cycle: a cycle of – in theory – 28 days which starts with the first day of her menstruation, followed by a rollercoaster of sex hormones with a bonus point roughly in the middle called “ovulation-I-am-super-fertile” until the end of the cycle. Repeat around 450 times in her life between puberty and menopause.
Note: the chances of reading in a book or anywhere else that the menstrual cycle is 28 days is significantly higher (read: close to 100%) than the actual chance of having a regular cycle of 28 days (read: close to 0%). My own data suggests (from the moment I started selling my data and my soul to an app to make my life easier): cycles lasting between 24 and 36 days. Not the type of cycle I would label as “regular”.
Anne doesn’t take any hormonal contraception; she has cycles that are sometimes regular and sometimes not.
When you say “menstruation”, that is what people also call “period”, right?
Yes; they also call that the menarche, menses, menorrhea, and other very poetic appellations including the curses, being on the rag, or – my favorite! – ragnagna, in French.
I’m looking now at both Anne and Max, and wonder what you want me to understand.
Imagine that both Anne and Max currently have a headache and want to take paracetamol to alleviate their symptoms. They would both read the leaflet and take 500 mg, as this is the dose recommended for an adult.
But… But actually, now that I think about it, this is a bit weird. They don’t have the same body mass and fat mass, they have different hormones floating around in their body, they don’t feel the same when they are suffering from a headache… It’s actually quite surprising that they both need the same dose of paracetamol.
Exactly.
Anne and Max are totally different. They don’t have the same chromosomes, they don’t have the same genes, they don’t have the same body characteristics, Anne’s body is influenced by a menstrual cycle…
So how come do they need the same dose?
Do they actually need the same dose?
Did someone investigate during the development of this drug whether the effects in men and women were different?
I am getting worried already with the answers you will give to these questions.
One of the best known example I can give in sex-specific pathology – that is still largely unknown by many readers of this blog – is the clear difference between symptoms experienced by women and men in the event of a heart attack (what we also call “myocardial infarction”) [3]. We have all heard about the following “typical” symptom of a heart attack: left-sided chest pain irradiating in the left arm. Typical, yes, but mostly in men! In women, the predominant symptoms are totally different: shortness of breath, abdominal pain and nausea. Because of this difference (and the fact that the latter symptoms aren’t very specific), women are more at risk of dying of heart attack because it is more often not diagnosed on time.
When it comes to pharmaceutical drugs, there can be significant differences in the way the drug is absorbed, transported through the body, and metabolized between men and women. The physiology of the organs involved in the action of drugs (stomach, intestines, liver, kidneys) is also different between men and women [3]. In turn, this strongly impacts the effects and toxicity of a medication.
To go back to our example of paracetamol, women are more prone to experiencing side effects when taking paracetamol compared to men. One of the reasons for this is that women have a lower volume of distribution and they metabolize paracetamol slower than men, which leads to higher concentrations in their blood, resulting in higher chances of side effects (especially the very serious ones, such as acute liver failure) [3,4].
I guess that paracetamol isn’t the only substance with such difference. But why is that? Why do we seem to know way less about women physiology?
Women have historically been excluded from clinical trials in drug development, and this for different reasons: the potential negative effects of a drug on a potentially childbearing person, the influence of sex hormones on drug response, and the variation of sex hormones concentrations throughout a female life [5-7]. All of these made a woman too complex to be included in clinical studies, so most of the studies during drug development were conducted on males only, and then the results were “simply” extrapolated to females. In 1993, the U.S. National Institute of Health (NIH, the US nation’s medical research agency) decided that this was enough and requested the inclusion of females in clinical trials. Another layer was added in 2014, when the same NIH adopted a policy to include sex as a study variable in pre-clinical studies (i.e., in cellular and animal models) [8].
That’s less than 10 years ago! It’s insane it took so long! But did this help?
Much less than what was expected, and this because of two issues.
The first issue is that even though the inclusion of women in clinical research increased in the U.S. and Europe [5], the information gathered during these studies on women remained often incomplete. For instance, studies would indeed include both women and men, but would not use the information on sex during the analysis of the data to look for potential differences between sexes [9]. This means that yes, women got more frequently included in the studies, but the outcome remains insufficient when it comes to better understanding women’s physiology.
The second issue is that most of the drugs prescribed today were developed and approved by the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA) before the NIH policies, which means they have not been adequately tested on women.
Ouch… What does it mean for women, then?
It means that today, women still have a risk that is almost two times (!!) greater than men of developing side effects when taking medicine. Women also are more at risks of being hospitalized due to an adverse drug event [10,11].
Differences in the effects and toxicity of drugs between men and women have been reported for many classes of drugs, including analgesics (paracetamol, ibuprofen), tranquilizers (benzodiazepines), and some of the medicines used for to treat high blood pressure and cardiovascular disease (statins, aspirin, beta-blockers). Yet, most prescribed drugs and over-the-counter medicine (i.e., the ones you can buy without a doctor’s prescription at your local pharmacy) do not show sex-specific recommendations on their label [3].
It is not only the simple difference between man and woman that remains understudied when it comes to the effects of drugs. Indeed, menstrual cycle, menopause, oral contraception, hormonal replacement therapy, pregnancy and breastfeeding are all factors that can strongly impact the effects of medicine. Usually, the general population is aware that pregnancy and breastfeeding lead to a “different female physiology”, but what about menopause and oral contraception?
Oral contraception? You mean that taking the pill can have an impact on the effect of other medicines I take? But no one ever told me that, not even my GP!
Indeed, oral contraceptives influence the effects of some drugs by acting on the enzymes that are responsible for the metabolism of those drugs [3]. Considering an oral contraceptive is taken at least 21 days per cycle, this is quite important to know. So yes, do tell your GP and your local Pharmacist when you take the pill and get prescribed a new treatment!
Wow. This is astonishing that women take bigger risks of developing more side effects or not being correctly treated when taking a medicine, compared with men – and this without knowing it! But is there more hope for future medicines currently developed, thanks to the NIH policy?
Hopefully yes, but there are still many hurdles to overcome. For example, many pre-clinical studies carried out using cellular models either predominantly use male sex only, or do not specify the sex they used for cells [9,12]. Yes, cells also have a sex, and it is only logical that both sexes should be tested in pre-clinical studies when available. This would help deciphering already at an early stage potential differences in the effects and toxicity of promising drugs candidates between males and females.
Another hurdle is that even though the situation seems to improve in the U.S. when it comes to a better inclusion of women in clinical studies, they will continue being underrepresented in trials in some other parts of the world. Indeed, challenging cultural settings may not favor enough autonomy for a woman to participate to such clinical trials, so it will be more difficult to remove this bias [13].
What other steps are needed, according to you, to improve the way women are medically treated?
There is a big trend now called “personalized medicine”, which aims to take individual and personalized decisions when it comes to prevention, diagnosis and treatment of diseases. There is a lot of money put into such research to help advancing the understanding of “big” diseases, such as cancer or Alzheimer’s Disease.
Better understanding woman’s physiology is for sure a crucial and huge step towards personalized medicine. Before even thinking of this personalized medicine for every individual, we should simply focus on developing a healthcare system where women are considered as a different biological entity than a man, and deserve the exact same attention than men.
Hmm… We aren’t there yet, are we?
No, but that’s why I count on the synergy IWD2023 × alittlebitofscience to shed the light on these aspects!
What are your dreams, Dr. Iza?
In an ideal world, I wish Anne and Max would have the same chances and the exact same access to healthcare and medical knowledge. In an ideal world, a box of paracetamol would indicate a sex-specific dosage. In an ideal world, medical research would focus on figuring out how a therapy needs to be adjusted through a female life, taking into account the different hormonal phases in her life – from puberty to menopause. In an ideal world, Anne would know how to adjust the dose of her medication based on her menstrual cycle and hormonal status. In an ideal world, we would not only have more attention for potential sex-specific differences in drug effects, but also investigate the differences in drug actions between ethnicities and among transgender adults. In an ideal world, people would stop being scared of saying the word “sex” out loud, which would also benefits scientific accuracy.
In an ideal world, we would not need an International Women’s Day anymore.
-Dr. Iza
References:
[1] International Woman Day home page, https://www.internationalwomensday.com/ (Accessed Feb 25, 2023).
[2] C. Richie, Sex. not gender. A plea for accuracy, Exp & Mol Med, 51 (2019)
[3] A. Farkouh, T. Riedl, R. Gottardi, M. Czeika, A. Kautzky-Willer, Sex-Related Differences in Pharmacokinetics and Pharmacodynamics of Frequently Prescribed Drugs: A Review of the Literature, Adv Ther, 37 (2020) 644-655.
[4] J.B. Rubin, B. Hameed, M. Gottfried, W.M. Lee, M. Sarkar, Acetaminophen-induced Acute Liver Failure Is More Common and More Severe in Women, Clin Gastroenterol Hepatol, 16 (2018) 936-946.
[5] I. Zucker, B.J. Prendergast, Sex differences in pharmacokinetics predict adverse drug reactions in women, Biol Sex Differ, 11 (2020) 32.
[6] I. Zucker, A.K. Beery, Males still dominate animal studies, Nature, 465 (2010) 690.
[7] A.K. Beery, I. Zucker, Sex bias in neuroscience and biomedical research, Neurosci Biobehav Rev, 35 (2011) 565-572.
[8] J.A. Clayton, F.S. Collins, Policy: NIH to balance sex in cell and animal studies, Nature, 509 (2014) 282-283.
[9] N.A. Karp, N. Reavey, Sex bias in preclinical research and an exploration of how to change the status quo, Br J Pharmacol, 176 (2019) 4107-4118.
[10] S.N. Hayes, R.F. Redberg, Dispelling the myths: calling for sex-specific reporting of trial results, Mayo Clin Proc, 83 (2008) 523-525.
[11] Y. Zopf, C. Rabe, A. Neubert, K.G. Gassmann, W. Rascher, E.G. Hahn, K. Brune, H. Dormann, Women encounter ADRs more often than do men, Eur J Clin Pharmacol, 64 (2008) 999-1004.
[12] C.M. Fuller, P.A. Insel, I don’t know the question, but sex is definitely the answer! Focus on “In pursuit of scientific excellence: sex matters” and “Do you know the sex of your cells?”, Am J Physiol Cell Physiol, 306 (2014) C1-2.
[13] B.E. Bierer, L.G. Meloney, Strategies to optimize inclusion of women in multi-national clinical trials, Contemp Clin Trials, 117 (2022) 106770.
