Recalibrating the Norm

By Heather A. Bimonte-Nelson, PhD
October 3, 2025 | VOLUME 3, ISSUE 3

There is robust and incontrovertible relevance for including female and male participants at all levels of scientific research, from systems to molecular domains. Sex differences have been documented at every echelon of biological organization across a multitude of body systems, including in gross anatomical structure as well as cellular, biochemical, and molecular properties.

In some cases, sex differences are nuanced in their expression and not extreme in magnitude, while others are striking and large. This holds true for reproductive and nonreproductive domains. That the impact of sex differences is not limited to reproductive-related anatomy, physiology, and behavior underscores the importance of studying across sex for full, precise, and accurate science. Scientific evidence driving the necessity of including sex as a biological variable has been described in detail in multiple works stemming from decades ago.^1-8

The “gold standard”

Historically, research practices across a multitude of scientific inquiry levels, from molecular to clinical studies, have often underrepresented females as participants, not included information on participant sex at all, or defaulted to a male-centric approach with the male considered the “norm” and any other outcome, presentation, or response considered atypical, abnormal, or deviant.

The dogma of the female-default theory is likely related to early work suggesting that the female phenotype does not require active feminization processes.⁵ The traditional model of sexual differentiation of the brain generally parallels sexual differentiation of the genitalia, stemming from the classic work of Alfred Jost annotating sexual differentiation of accessory sex structures, where it was stated that “…the testes are the body sex differentiators; they impose masculinity on the whole genital sphere which would become feminine in their absence. The presence or absence of ovaries is of no significance.”⁹ Jost also stated that “…every structure would become feminine if not prevented from doing so by testicular hormones.”¹⁰ This traditional model maintains that if testosterone exposure occurs during a critical early developmental window, organizational effects ensue, yielding a male phenotype, and if there is no exposure to gonadal steroids during this critical early developmental window, a female phenotype results by default.

These points extend to the tenet that scientific excellence requires rigor, precision, and accuracy. Important considerations include that the expression of sex differences is due to both female and male phenotypes, varies across the lifespan, and can be quantitative or qualitative. Effects can also be latent, such that the overall measured values do not outwardly differ by sex, but the pattern or path to that same outcome differs.^21-23 Limiting evaluations to one sex, or collapsing across the sexes in data analyses, can have critical implications leading to scientific misinterpretations and inaccuracy. Since basic and preclinical research discoveries often drive clinical studies, this yields a cascade of effects across disciplines and translates to marked limitations in advancements in human health.

Innumerable scientific profiles of disease manifestation, symptom presentation, and sequelae are based on studies and profiles from males exclusively, with the male considered the norm and female data ascribed as variants from that male-centric gold standard. However, this broad-stroke perspective inhibits effective personalized health profiling, diagnoses, and treatments for women and men.

Overburdened, underfunded

To provide a few examples of research patterns, neuroscience studies devoted to female-specific factors comprise less than 3% of the literature, and, in single-sex studies, males were used as participants 5.5 times more than females.^18,24 Moreover, in diseases primarily affecting one sex, if women were primarily affected, it was underfunded regarding burden, and if men were primarily affected, it was overfunded regarding burden.²⁵

Literature has shown that 20% of 400 pharmaceutical substances had clinically relevant sex differences, and females were nearly two times more likely than males to develop an adverse drug reaction; yet, few medications have sex-specific recommendations.^26-28 Moreover, evidence suggests that females have a longer wait time than males for both pain relief and a diagnosis and have an increased likelihood of being discharged during a serious medical event.^29-32

There is evidence that the female-associated increased risk of Alzheimer’s disease is related to sex differences in hormones, brain structure, inflammatory cascades, and/or psychosocial stress responses.³³ The decreased prevalence of autism spectrum in females may be associated with X chromosome-linked genes as well as sex differences in oxytocin and vasopressin profiles.³⁴ Furthermore, females with autism show distinct phenotypic trajectories and age-related brain differences hypothesized to arise from genetic and endocrine processes involved in early development brain masculinization and feminization, puberty, and other lifespan windows of hormonal transition.³⁵

Sex differences have also been shown in incidences of some diseases, with males more susceptible to Parkinson’s disease, attention deficit hyperactivity disorder, autism spectrum disorders, and schizophrenia and females more susceptible to Alzheimer’s disease, depression, anxiety, and posttraumatic stress disorder. While these data are important, prevalence does not offer mechanistic understanding of the differences. This is especially important to consider given data showing that symptomology and the most effective treatment parameters can differ by sex. This can result in critical diagnostic misses due to knowledge deficiencies in sex-specific diagnostic criteria and biological profile-symptom relationships.

Solving for X

Due to the neglect of the biological study of females, there is still an X, that is, part of the equation missing, at every level of the biological system. This persistent knowledge gap in sex and hormone profile differences across so many biological-related disciplines associated with health and disease bears profound consequences for both females and males across the lifespan. There have been insightful and field-transformative clinical commentaries highlighting that sex as a biological variable and gender as a social construct are important for the future of precision medicine and patient care.^36-37

Deciphering the impact of sex is especially poignant when one considers that, beyond the intrigue of exploring sex differences from theoretical and evolutionary approaches, the critical need to determine sex differences directly and meaningfully extends to the advancement of human health, including factors impacting life and death. Consequences of the widespread neglect of including females in biomedical research are profound for women and men, yielding inaccurate data interpretations of factors impacting health and disease due to overlooking sex as a variable. There is great value in using a lens of sex differences to ask how associations between physiological profiles and outcomes may differ.

Indeed, if there are sex differences in the prevalence, presentation, and treatments of a life-impacting health outcome or disease, why wouldn’t we want to move toward understanding, personalizing, and optimizing treatments depending on sex? Sex is one component of individual differences that can be embraced for its opportunity to help decipher underlying complexities and mechanisms of outcomes. Sex differences need not be a barrier to scientific discovery.

Breaking bias

One power of science is that knowledge coming from it is empowering. Thus, as scientists, we are empowered to make discoveries that yield bold impacts that will make real-world change. The many scientists who I have been lucky enough to have had in my scientific orbit have taught me a lot. I have learned that being a great scientist, to which all scientists aspire, takes more than knowledge; it takes transparency, precision, rigor, innovation, plasticity, and building on the discoveries of others to form new theories. To me, most importantly, it takes courage to pointedly follow unexpected data outcomes, charter unmapped territories, and revise scientific dogma and routine practices when the data tell us to. This aligns with the wisdom imparted by my mentor, Dr. Victor Denenberg, to carry our theories lightly, as what we think we know may or may not be the truth in nature; new data can and should revise our theories.

I hope the evidence presented here serves as leverage and a continued call to action to engage deliberate strategies to progress from the bias to default to a male-centric norm and to acknowledge that the collective female phenotype is not via default biological mechanisms. The plethora of rigorous scientific evidence permits no other explanation: The expression of sex differences is not a dichotomous, one-axis continuum of feminine/masculine as the traditional model ascribes. Rather, the updated model of the brain and its functions hold a two-axis continuum, with sexually differentiated traits occurring along at least two dimensions: one representing the degree of masculinization and another the degree of feminization. The guiding parameters of feminization should be considered distinct from the guiding parameters of masculinization; and feminization and masculinization are one part of what makes any individual distinct from another.

It has been invigorating to see the best of scientific practice come together to discuss the need to fill the critical gap in knowledge in female biology and function, especially in the last few years.^38-40,24 It is also noteworthy that there are robust and repeated effects showing that women scientists and diverse medical research teams are more likely to focus upon sex and diversity within disease-related research domains.⁴¹

Thus, increased participation of women in science, behind the bench and as research participants, will enrich excellence in science across multiple levels. Given the deep knowledge gap between the sexes, there are innumerable opportunities for scientists to expand avenues and act as cartographers: building bridges, closing gaps, and mapping novel insights to enhance scientific discovery within and between sexes. Deciphering the many effects of biological sex differences—from molecular to system levels—will recalibrate the norm and transform medicine. This is central to fulfilling the mission of attaining accuracy, precision, and excellence in science to build a future inclusive of optimizing health outcomes for all.