Sex Matters: Why We Need to Optimize Medicine for the Sexes
A few weeks ago, the New York Times published a series of 7 articles addressing 7 key issues facing women today. The collection is a must read- providing eye-opening and frankly appalling statistics such as “10 percent of all Americans believe the country has gone too far in giving women equal rights with men” (are you actually kidding me?). Hitting close to home, one of the articles entitled “Better Not Get Sick” highlights the gross disparities when it comes to both understanding and managing health for women and men.
Sex (male or female) is defined by the differential organization of chromosomes, reproductive organs and sex steroid levels in the body. This differs from gender, which depends on behaviors and activities that are determined by society or culture. When it comes to medicine- sex matters. Many diseases disproportionately affect one sex over the other. For example, there is a 10:1 ratio of females to males with severe autoimmune diseases such as multiple sclerosis and Hashimoto’s thyroiditis. And now recent data suggests males are dying from COVID-19 at higher rates than females.
Why? Sadly, due to a lack of studying sex nuances in disease, for the most part we don’t know. Sex bias has been identified in nearly all basic, translational, and pre-clinical studies that utilize animal models and cell lines. An analysis of the top 5 surgery journals for animal research from 2011-2012 revealed only 3% of publications studied both sexes, while 80% included only male animals. Studies of both sexes are sparse in cell research as well: only 7% of publications specified methods that included cells of both sexes. These trends extend to an array of disciplines including otolaryngology, orthopedics, rhinology, traumatic brain injury, cardiovascular research, endocrinology and neurology.
Furthermore, women have been historically excluded from clinical trials due to unknown effects on the reproductive system and concerns that fluctuating hormones could confound results. Our understanding of any sex-based variation in potency, efficacy, or side effects is still recovering from this practice. The impact is chilling: more than 80% of drugs that have been pulled from the market over safety concerns are due to adverse effects specifically in women. Research without sex stratified analysis also affects our knowledge of drug benefits. In 1974, a randomized control trial of 1,239 patients suggested a low dose aspirin prevents death after a heart attack- the study contained only male subjects. To this day it's unclear if females have the same benefit.
Female participation in clinical trials has increased (in part due to encouragement from the FDA for sub-population analysis and increased participation of women and minorities), but clinical trials are still rarely powered to be able to detect sex-based differences. Unfortunately, these trends often only reveal themselves after drugs are being widely prescribed. And at present the trends aren’t great- women are 50-75% more likely than men to have an adverse drug reaction across all therapeutic indications.
If the influence of sex had been more rigorously included in the analysis (from research to clinical trials) could these side effects be mitigated? Likely. Known physiological differences between the sexes can explain observed differences in drug pharmacokinetics and pharmacodynamics which in turn can guide treatment.
Pharmacokinetics is the study of how drugs move through the body. Women tend to have lower body weight, slower gastrointestinal motility, differential intestinal enzyme activity and slower kidney filtration, which adds up to mean that drugs typically linger in women longer than men. This is critical information that should be factored into all drug dosing regimens as it could put females at risk. Ambien, the sleep aid, for example, after years of being dosed similarly for sexes, left many women feeling comatose. Thankfully it is now prescribed at approximately 50% lower doses in females than males.
Pharmacodynamics is the study of how drugs work in the body. Sex hormones matter here. Take antidepressants as an example, females generally respond better to selective serotonin reuptake inhibitor (SSRI) therapy like Zoloft, than males. This is thought to be due to the role of estrogen in augmenting serotonin synthesis (the molecule that makes us feel happy) and by increased production of tryptophan, a precursor to serotonin, in women when exposed to SSRI therapy. Simply put, drugs work differently in females and males, which in turn leads to different outcomes for the sexes.
“If we want to have the best treatments available for women and for men, we must acknowledge sex matters. Diagnostics and treatments will need to be optimized for the sexes.” Elizabeth O’Day, MPhil, PhD
At Olaris, every analysis includes a sex stratification. We continue to find that in every area we study ranging from cancer to Parkinson’s Disease to kidney transplantation—our biomarkers have enhanced predictive accuracy when we treat the sexes separately. And we are not the only ones. In 2016 the NIH began requiring all studies receiving funding to consider sex as a biological variable in their work. Although the percentage of human studies considering both sexes grew from 40% in 1989 to 60% in 2009, the proportion of studies including females and males has not improved accordingly. To deliver on the promise of precision medicine more is needed. Any drug on the market should have information readily available on sex differences in dosage, treatment, and risk. Unfortunately, that information is not easily found today. Table 1 highlights well-known sex-based differences of common drugs.
In no world should our healthcare system revert to a “men are from Mars and women are from Venus” strategy, but we must acknowledge that sex (chromosome organization, reproductive organs, and sex steroids) influences our health. To overlook these different outcomes in research and in healthcare would be a disservice to each and every patient.
Table 1. Just a few drugs with just a few reported sex-based differences.