The Invisible Framework That Shapes Our Health
Imagine you're trying to understand why two identical cakes baked from the same recipe turn out differently. You might separate the factors into "ingredient-related" and "baking-related." But what if the oven temperature affected how the ingredients interacted? What if the humidity changed the flour's consistency? Soon, you realize the categories are hopelessly entangled—and this is precisely the challenge scientists face when studying sex and gender in human biology.
For decades, researchers have attempted to neatly separate biological attributes ("sex") from social and cultural factors ("gender") when studying health and disease. But a revolutionary perspective is emerging: these factors aren't just interacting—they're fundamentally entangled throughout our bodies and lives 1 2 .
This insight is transforming everything from how we conduct medical research to how we design treatments that work for real people in all their diversity.
Traditional biomedical research has often treated sex and gender as separate "buckets" of causal factors 1 2 .
Recognizing the limitations of the buckets approach, many researchers began describing sex and gender as entangled like threads in a knot 1 2 .
This perspective acknowledges complexity but still implies we can identify two distinct threads—one biological (sex) and one social (gender)—that become tangled together.
"The very attempt to draw sharp boundaries can 'reignite the nature/nurture debate, inadvertently bringing outdated metaphors and assumptions about innateness and causation into our research'" 2 .
Documenting hormone levels through blood samples and assessing thermal regulation
Using detailed questionnaires to document participants' gendered experiences
Recruiting participants across the spectrums of sex characteristics and gender identities
| Category | Testosterone Range (ng/dL) | Estrogen Range (pg/mL) | Progesterone Range (ng/mL) |
|---|---|---|---|
| XX Typical | 15-70 | 15-350 | 1-20 |
| XY Typical | 265-1000 | 10-40 | 0.1-0.3 |
| CAH (XX) | 80-1000 | 10-300 | 0.5-15 |
| AIS (XY) | 300-1000 | 20-50 | 0.1-0.3 |
| Hormonal Profile | Heat Tolerance | Cold Tolerance | Sweating Threshold |
|---|---|---|---|
| High Estrogen | Lower | Higher | Lower |
| High Testosterone | Higher | Lower | Higher |
| High Progesterone | Lower | Higher | Moderate |
These findings challenge the common practice of conducting "a binary female-male comparison, finding a statistically significant difference between the two groups, and then making a recommendation that men and women function 'differently'" 7 .
is often more informative than differences between categories
become biologically embedded, influencing physiological systems
across categories make binary classifications scientifically questionable
Studying sex/gender entanglement requires innovative methods and tools.
| Tool/Method | Primary Function | Application Example |
|---|---|---|
| Target Trial Emulation | Mimics RCT design using real-world data | Studying sex-specific drug effects in diverse populations |
| Digital Twins | Creates virtual patient models | Simulating female physiology and treatment responses |
| Drug Target Mendelian Randomization | Uses genetic variants to mimic drug effects | Testing sex-specific treatment effects |
| Intersectional Analysis | Examines multiple social positions simultaneously | Studying how gender, race, and class collectively shape health 6 |
| Longitudinal Life Course Designs | Tracks changes over time | Documenting how gendered experiences accumulate biological effects 2 |
Operationalizing Variables
Measuring Social Factors
Accounting for Intersectionality
Comparing Categories
Focuses on male vs. female differences
Innovative designs that account for entanglement can help close persistent evidence gaps
Recognizing how gender biases and biological factors interact can help reduce misdiagnosis
Moving beyond one-size-fits-all approaches to develop truly personalized interventions
The recognition that sex and gender are deeply entangled represents a paradigm shift in biomedical research. Rather than attempting to separate biological and social factors, scientists are developing new methods to study their dynamic interplay throughout our lives 2 5 .
This approach acknowledges that our social experiences—including gender roles, expectations, and discrimination—literally become embodied, shaping our biology from our hormones to our thermal regulation.
This perspective doesn't mean we should abandon sex and gender as categories in research. Instead, researchers recommend keeping a single, general sex/gender category—"not as a representation of biological reality, but instead as a tool used to improve analytical rigor and inferential precision" 2 . The key is to use these categories thoughtfully while paying close attention to the rich variation within them.
As this field advances, it holds the promise of more precise, effective, and equitable healthcare for everyone—not because we've discovered essential differences between men and women, but because we've finally begun to appreciate the beautiful complexity of human embodiment in all its diverse forms.