Ignorance to sex differences may explain why nutrition interventions fail in research
The review, published by Cambridge University Press in the 'Proceedings of the Nutrition Society’ journal, explored the topic of sexual dimorphism, the systematic difference in form between individuals of different sex in the same species, in the context of nutrition implications for cardiometabolic disease.
The authors conclude that despite a considerable lack of research in women , it is apparent from emerging literature that sex differences exist in response to various dietary patterns and components such as fibre, PUFAs and plant bioactives.
“These differences are not trivial as they likely contribute to sexual dimorphism that similarly exists in patterns of health and disease,” the report concludes.
“Such discrepancies (and heterogeneity between males and females) may even explain why some promising nutritional interventions fail to show benefit at more advanced stages of experimentation.’
Equality in studies
Biological sex, distinct from gender which is related to social experience, is a fundamental biological variable.
Yet, sex differences are only recently being investigated in clinical and preclinical nutrition research.
The National Institutes of Health (NIH) Revitalisation Act first mandated the inclusion of women in clinical trials in 1993and its NIH policy for including sex as a biological variable (SABV) in research designs, analyses, and reporting went into effect in 2016.
However, a 2020 report showed that only half of the U.S. scientists surveyed reported analysing study results by sex.
Emerging evidence suggests that food components and dietary patterns may influence disease risk differently based on sex.
This discrepancy is rooted in the existence of sexual dimorphism in various body systems, such as the heart, kidney, adipose tissue, immune system, and central nervous system, as well as from a metabolic standpoint.
Sex hormones, X chromosome dosage, and the microbiome are also thought to be contributing factors.
The role of sex hormones, in particular, is likely dynamic and may evolve during the ageing process, especially for women going through menopause.
These metabolic disparities can impact the effectiveness of nutritional interventions and underscore the need for guidance that considers these variations to enhance implementation.
The authors of the current review aimed to shed light on existing knowledge gaps and potential avenues for further research in this critical area.
Sex differences in cardiometabolic disorders
Cardiometabolic diseases are a group of common but often preventable conditions that span from obesity and type 2 diabetes (T2D) right through to CVD.
Research has shown that cardiometabolic disease appears to be modulated by sex.
In the instance of T2D, it has been shown that women exhibit a stronger obesity-related diabetes risk than men who have greater susceptibility at a lower BMI.
Additionally, a UK biobank analysis (of 40–69-year-olds) suggested that higher sugar, saturated fatty acid, and dietary fibre intake may subtly modulate all-cause mortality and/or dementia risk to a greater extent in females.
The authors note that as diet and nutrition play a prominent role in the development of cardiometabolic disease, and given the emerging evidence implicating sex as a modulator of metabolism, it is probable that physiological responses to diet similarly differ across sex, perhaps contributing in part to the sex differences in cardiometabolic disorders.
Polyunsaturated Fatty Acids (PUFA)
Differences in lipid metabolism between men and women are well-documented. For example, females have higher concentrations of certain PUFAs, such as docosahexaenoic acid (DHA).
Research shows that the effects of PUFAs can differ between genders. Women may experience greater improvements in insulin resistance and triglyceride levels in response to PUFA supplementation.
Moreover, the ability of specific PUFAs to reduce platelet aggregation, a factor in cardiovascular disease, has been reported to be sex-specific.
The authors of the review comment that understanding these variations in PUFA response is essential for tailoring dietary recommendations.
It is hypothesised that this may be linked to higher Δ6-desaturase expression (a component of a lipid metabolic pathway that converts the essential fatty acids linoleate and α-linolenate into long-chain polyunsaturated fatty acids) in females relative to males, which appeared to be limited to the liver in a previous mouse study.
Additionally, females have shown a greater increase in circulating eicosapentaenoic acid (EPA) in response to alpha-linolenic acid consumption.
Similarly, EPA and DHA supplementation increases plasma triglyceride EPA to a greater extent in females.
Plant Bioactives
Sex has been suggested to modulate both the metabolism and physiological effects of plant bioactives such as (poly)phenols.
Studies suggest that women may experience more favourable outcomes in response to (poly)phenol consumption, including reduced risk of obesity, improved cognitive function, and a lower risk of certain diseases such as stroke and gastric cancer.
One cross-sectional analysis of a Korean population reported an inverse association between flavonoid intake and obesity in women, whilst for men a positive association was determined for some subclasses (namely flavonols, flavanones, and anthocyanidins).
Additionally, a combination of 548 mg/day of polyphenols and 2 g/day of L-citrulline reduced ambulatory systolic blood pressure in women, but not in men.
The authors note that these sex-specific responses may relate to changes in gut microbiota, but further research is needed to understand the underlying mechanisms.
Dietary Fibre
Dietary fibre also plays a vital role in health.
However, while some recent studies show the prebiotic effects of dietary fibres are sex-specific, the impact of soluble vs. insoluble fibre on metabolism and health outcomes across sexes remains to be explored.
It has been suggested that dietary fibre may be more favourable in females, with one study showing an inverse association between depression and dietary fibre consumption established in women only.
The authors suggest that discrepancies in the impact of dietary fibres across sex may relate to changes in the gut microbiota, noting that in one study, indeed oligofructose supplementation in rats led to broad changes in faecal community structure (increasing Bacteroidetes at the expense of Lachnospiraceae) in females but not males.
Enhancing effectiveness
The authors note that to enhance the effectiveness of dietary recommendations and treatments, future research should consistently include both men and women in their studies.
They recommend that this approach will enable the development of tailored nutritional advice to the unique needs of individuals, moving towards a more personalised and precise approach to nutrition.
Previous research has made the case for greater focus on social and economic factors to overcome implicit biases, with authors concluding: “Researchers should recruit both sexes equally, disaggregate data by sex, and be aware of gendered assumptions and expectations that can lead to hidden biases.”
Kamran Abbasi, Editor of the British Medical Journal (BMJ) recently released a editorial stating that "the under-representation of women in research is a status quo that is more accurately an enduring international scandal.”
Journal: Proceedings of the Nutrition Society
“Sexual dimorphism in the context of nutrition and health”
Authors: Matthew G. Pontifex, David Vauzour, and Michael Muller.
