Sex and gender have a great influence on our health. Nonetheless, their importance continues to be underestimated in the medical field. Why is this the case? And what can we do about it? These are the questions explored in our interview with Alyson McGregor MD.
AMBOSS: Gender medicine aims at benefiting everybody. However, it is often confused with women’s health, and women’s health often focuses on reproductive medicine. Why is there such a discrepancy between men’s and women’s health?
Alyson McGregor: When we started undergoing research and clinical trials, creating our scientific methods and research processes, we considered women to need protection because of their menstrual cycle – and what if they became pregnant? Women were also deemed complicated to study because of the fluctuation of estrogen and progesterone. So, our basic understanding of emergent conditions is based on us studying those diseases in men. The one thing we couldn't study in men was female reproductive issues. So we studied menopause, menstruation, and giving birth in women, and that became synonymous with women's health. When we thought about women's health, we just thought about their additional body parts that are different from men. That did women a great disservice because we assumed that they would respond the same way, would have heart attacks the same way, and metabolize drugs the same way. And now we're realizing that that's not true.
AMBOSS: How would you define the field of “gender medicine”?
Alyson McGregor: First, it’s helpful to define some of the vocabulary that's been evolving over the past decade. So we look at the words “sex” and “gender”. And when we think about “sex”, we think of it as a biological variable: sex chromosomes, whether you were born with XX or XY in every cell in your body. How does that affect your susceptibility to disease and infection and your hormonal milieu? We think of “gender” as a sociocultural variable, something that people can choose or feel that they were born into. There are even more options for non-binary people, for example being both genders or no gender. And that affects health and wellness as well! When you present yourself as a certain gender, certain sociocultural roles are expected from you. If you declare yourself as a woman, there are other societal expectations than if you declare yourself as a man, and that can impact health. When we take those considerations into account providing medical care, then we are using evidence-based medicine that is specific to someone's gender or someone's sex. We're tailoring our medications and the tests we order, and we’re interpreting them based on what the patient’s biological sex or gender identity is. So, gender medicine is a more personalized and tailored way of treating patients and utilizing medicine.
AMBOSS: You’re an emergency medicine specialist. How is that field linked to gender medicine?
Alyson McGregor: The emergency department is a very rich place to see all of the components at play. If it can happen in real life, it comes into the emergency department. As an emergency physician, I could see that we're making progress in certain areas, but oftentimes more likely in men than in women. I've witnessed new evidence-based treatment options and diagnostic testing in conditions that have high public health significance that show up in the emergency department: from heart attacks and strokes to infections, trauma and pain syndromes that are more common in women, and medications that have more side effects in women than in men. Every time I show up for a clinical shift, it's right there. It's in the conversations that I have with women when they feel that they've been misunderstood or misdiagnosed. Working in that clinical environment, I have collected many examples of how important it is to evolve away from this concept of males being the standard.
AMBOSS: When does this gender bias become most dangerous?
Alyson McGregor: One of the biggest problems is how we are educating health care providers to recognize disease: What does a heart attack look like? How does a patient describe it? What does a stroke look like and how does a patient describe it? What does appendicitis feel like? The base of all that knowledge and education has come from male patients. Most women think that they should be looking for signs of the way that men present with the disease. There's a huge delay in women even coming to the emergency department. And then there's a delay until frontline workers recognize that this could be something serious or until they are able to recognize certain diseases when they manifest differently, when they are expressed differently because of our gender. Women are much more emotionally driven, and a lot of that really helps us with communication and understanding. But it can seem as if the emotion was the problem instead of being the expression of a problem that still needs to be diagnosed.
AMBOSS: How can we, as health care professionals, actively work against that bias and get better at understanding the patient no matter if they’re female, male, trangender, or non-binary?
Alyson McGregor: One of the most important things that a health care professional should do when they first meet a patient is to establish what their sex assigned at birth was and what their current gender identity is. That may not be very obvious as not all of those options for gender identity are visible. One of the ways to create comfort around that is to volunteer your own. I often say: "I'm Dr. McGregor. I go by she and her. What is your gender identity and what are your preferred pronouns?" And that establishes what you need to know so that you can look for evidence in the literature as you're starting to care for them, whatever specialty you have.
AMBOSS: What resources are there?
Alyson McGregor: You can find a great PubMed search tool on sexandgenderhealth.org. There is a brand new textbook, "How Sex and Gender Impacts Clinical Practice". It provides the most up-to-date evidence on the differences between men and women. It also offers lots of tables and charts and checklists. We're trying to make it less intimidating and show that the information is already being collected for them, they just have to look up their particular subject matter. So this is very practical for medical school education. A few years ago, I wrote "The Sex And Gender In Acute Care". It goes through emergency department diagnoses and looks for differences in sex and gender in scientific literature and what that looks like in patient cases. And the website sexandgenderhealth.org has lots of resources, including entire slide sets. If you are giving a presentation on a topic, for example, urinary tract infections, you can just download them. There are colleagues out there who are trying to make this information accessible. But our main focus is longitudinal integration. We want all of your lectures, all of your small group discussions, all of your case-based studies to address: what would happen if this was a male? What would happen if this was a female? What if this was a transgender person? What if this was a person of color? Does that change your workup, your diagnosis? It should be part of your curriculum. I think people go into medicine with the understanding that it evolves. But you have to evolve it. It's just good science. It's updated evidence, and that's something that we commit to.
AMBOSS: How can we integrate that updated science into our everyday lives?
Alyson McGregor: In medical school, students are taught to present their case: "This is a forty-three year old male who presents with abdominal pain." And that piece of information, "male", never makes it back into the workup or the differential. We need to really thread that throughout our entire process of thinking, of looking up the medications and dosing we need, and having conversations about what the limitations are. We need to utilize that when we look at reference ranges: When we order blood tests like hemoglobin or cardiac troponin, they have different reference ranges on whether the biological sex is male or female. When we consciously thread this through our process, no matter the specialty, it will help mitigate some of the bias. In Emergency Medicine, we go through residency and have all this training for pattern recognition. We want to be able to recognize: “Oh, that looks like it could be Lyme disease” or “Clearly, this is appendicitis!” We look for patterns, but those patterns are based on how we were educated and trained. But we have to pause and make sure that we are taking into account these new biological and social variables and how they affect our care of the patient.
AMBOSS: You mentioned some limitations in diagnostics. What about limitations in treatment? For example, in 2014, Zolpidem became the first medication for which the FDA gave specific guidelines concerning dosage in women and men. Are there more examples?
Alyson McGregor: There are a lot of examples of differences between medications and dosing, side effects, efficacy, safety, indication. For instance: what's an indication for someone to take aspirin every morning? Those indications were not different between men and women up until recently. Zolpidem is really one of the very few that has FDA sex-specific dosing regimen recommendations. But it's not the only drug that has shown differences in pharmacokinetic dynamic parameters between men and women. Unfortunately, the FDA does not have the authority to mandate a lot of changes, so they can't force pharmaceutical companies to look at sex-based analysis. They're encouraging them, but they don't have the ability to make that into a rule. A lot of medications that women take were approved based on studies that enrolled mostly men. With some of these drugs, we see that, during the menstrual cycle, the levels of their active components change. Certain classes of anticonvulsants are very responsive to the menstrual cycle, for example. Patients take those medications to prevent having a seizure and, all of a sudden, the menstrual cycle changes metabolism and body water, the level of that protection drops, and women are susceptible to having seizures at certain times of their menstrual cycle. And we don't have a lot of guidance on how to tailor the dosing based on the menstrual cycle. We should protect women at the lowest dose effective for each phase of the cycle instead of increasing the dose risking higher incidences of side effects. So there's a lot of work that needs to be done.
AMBOSS: Eighty percent of the drugs that are taken off the market are withdrawn because of side effects in women. Shouldn’t pharmaceutical companies have an interest in studying this? It seems to be a very slow-moving industry. Do you feel the spotlight helps and is increasing?
Alyson McGregor: Absolutely. There are so many different components in a health care system: From pharmaceutical companies making this drug to getting approved, to doctors prescribing it, and then post-market surveillance – it’s very, very intricate. The more we shine a light on each component that needs to be changed or updated, the more it helps. This way, we are slowly increasing awareness of potential harm for everyone. You mentioned it, and I think it’s really important to emphasize: This is not just about improving the health of women – this is about promoting everyone’s health. It's just better research and better medicine.
AMBOSS: The whole topic is also tied to many societal aspects. As more and more women become doctors, what impact is this having on the medical field?
Alyson McGregor: I think that is the critical piece. If we're going to really make a change, that's the key to unlocking this. Because women think of women, and black women think of black women, and black men think of black men. It's been well demonstrated that when you have a female physician, the female patients receive better care. This one study looked at more than a million research papers, and discovered: When the primary researcher was female, women were more likely to be included in the study and the results were more likely analyzed based on sex. For so long, the fields of science and technology, math, and medicine have been dominated by white men. When we diversify from both biological and sociocultural factors, it's bound to include the perspective of the people who are writing the code of that app, the people who are designing the research, or the people who are caring for the patients. That is where I see the true benefit of making sure that women and diverse people have the ability to be successful in leadership positions so that they can make the change.
AMBOSS: Speaking of diverse people: What can we learn from the research on the use of hormones in gender-affirming therapy?
Alyson McGregor: To me, this was one of the most exciting pieces of the evolution of our research, because it really teases apart what effects hormones have. Someone who has a disconjugate sex versus gender might use hormones to transition into a different gender or no gender. Gender-affirming hormone therapy helps uncover how important hormones are regarding risks of developing disease or protections of certain conditions or metabolism of certain drugs. One paper demonstrated that after someone took hormones for about six months, their metabolism of drugs changed because their renal excretion of that drug changed to that of the gender that they were transitioning into. That's critical because we have really ignored how important hormones are! We just assumed that men have stable hormone levels, but not all of them do. And it was assumed that women have too complicated, fluctuating levels, which hasn't been proven. It's not that complex, these things can be studied and provide us with evidence so we can change the dose of particular medications, or change the concerns for certain conditions based on whether someone is taking hormones. Many studies don't declare who was enrolled in the study. A while ago, a paper claimed that we should make sure that, with every subject that we enroll, we collect their biological sex – their sex at birth – and their current gender identity. I think now we also need to ask: what hormones are they taking? And for how long? Because that might affect the analysis and the result.
AMBOSS: What message would you like to pass on to the colleagues reading this?
Alyson McGregor: We all have a role in this. If you become a peer reviewer for a journal, make sure you ask the authors to do analysis by sex. Start to bring this into your conversations. Even if you're not in the medical community, you still need to be aware of the limitations the health care system has for you as a woman. When my mother, who is in her mid-seventies, sees her doctor, she asks if there is anything that she should be aware of that is specific to her being a woman. That doctor now thinks: "Well, maybe I should look that up", or "maybe you should change your dose." No matter who you are, you have a sphere of influence where you can help create that “aha” moment, help create awareness – because that's really the first step.
Further information can be found on https://www.sexandgenderhealth.org/.
AMBOSS also offers more content on the principles of transgender health and sexuality and sexual medicine.
Nielsen, M.W., Andersen, J.P., Schiebinger, L. et al. One and a half million medical papers reveal a link between author gender and attention to gender and sex analysis. Nat Hum Behav 1, 791–796 (2017). https://doi.org/10.1038/s41562-017-0235-x
Andrew J Webb, PharmD, Dayna McManus, PharmD, BCPS-AQ ID, Ginger E Rouse, PharmD, BCPS, BCCCP, Robyn Vonderheyde, PharmD, BCPS, Jeffrey E Topal, MD, Implications for medication dosing for transgender patients: A review of the literature and recommendations for pharmacists, American Journal of Health-System Pharmacy, Volume 77, Issue 6, 15 March 2020, Pages 427–433, https://doi.org/10.1093/ajhp/zxz355
Clayton JA, Tannenbaum C. Reporting Sex, Gender, or Both in Clinical Research? JAMA. 2016;316(18):1863–1864. doi:10.1001/jama.2016.16405