Biological sex significantly affects the presentation, outcome of treatment and progression of disease. However, the role of sex has yet underestimated consequences for physiology and pathology. We put forward that a better understanding of the effects of sex in pathophysiology and the underlying mechanisms is necessary. This may facilitate the identification of targets that respond to specific therapies, thereby contributing towards a more appropriate and individualised medical care for both men and women

de Arellano, Maria Luisa Barcena

Dworatzek, Elke

Kararigas, Georgios

Regitz-Zagrosek, Vera

Seeland, Ute

Annali dell'Istituto Superiore di Sanità

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Commentary
Why the study of the effects of biological 
sex is important
Georgios Kararigas1,2, Ute Seeland1,2, Maria Luisa Barcena de Arellano1,2, Elke Dworatzek1,2  
and Vera Regitz-Zagrosek1,2
1Institute of Gender in Medicine (GiM), Center for Cardiovascular Research (CCR), Charité University  
Hospital, Berlin, Germany 
2German Centre for Cardiovascular Research (DZHK), partner site Berlin, Germany
Ann Ist Super Sanità 2016 | Vol. 52, No. 2: 149-150
DOI: 10.4415/ANN_16_02_03
There is no doubt that sex affects the presentation, 
outcome of treatment and progression of disease. In the 
case of cardiovascular diseases, for instance, men suf-
fer at younger ages than women from coronary artery 
disease and more often develop systolic heart failure or 
aortic aneurysms. Women are more frequently affected 
by heart failure with preserved ejection fraction, long 
QT-syndromes and Tako-tsubo cardiomyopathy. Wom-
en also exhibit a more favourable remodelling under 
pressure overload and a better survival with heart fail-
ure. These differences between men and women are me-
diated by sex-specific pathophysiological mechanisms, 
including the development of hypertrophy, fibrosis, 
inflammation and vascular remodelling. Consequently, 
sex-specific regulation of these mechanisms may lead to 
major differences between men and women following 
surgical interventions, such as coronary artery bypass 
graft and aortic valve replacement. However, the role 
of sex has yet unrecognised and underestimated con-
sequences for physiology and pathology. Therefore, we 
put forward that further research is necessary. Impact 
on the medical field and direct potential for exploitation 
of such innovative research activities are guaranteed in 
drug development and by the integration of findings 
into guidelines on optimal management for disease pre-
vention and treatment in both men and women.
Worldwide, many organisations are recognising the 
importance of studying sex differences and that the 
inclusion of sex into study designs increases scientific 
quality. In fact, considering sex may be critical to the 
interpretation, validation and extrapolation of research 
findings [1]. The Institute of Medicine (IOM) in the 
USA has stated that the understanding of biological dif-
ferences related to sex is necessary for the optimal treat-
ment of humans. Leading scientific journals have raised 
concerns about the under-representation of females in 
animal studies and clinical trials and advocate for the 
consideration of sex-specific aspects by researchers, 
agencies and journals [2]. The National Institutes of 
Health (NIH) of the USA, through its Office of Re-
search on Women’s Health (ORWH) has been spon-
soring research to detect sex differences in neurological 
and rheumatic diseases, in cancer and cardiovascu-
lar disease. Importantly, the NIH adopted in 2014 a 
policy requiring the consideration of sex as a biologi-
cal variable in preclinical research [3]. The Food and 
Drug Administration (FDA) in the USA also requires 
sex-specific data on drug metabolism, pharmacokinet-
ics and pharmacodynamics for all new drugs. Integra-
tion of sex in research and innovation is an objective of 
Horizon 2020, which is the biggest European Union 
(EU) Research and Innovation programme ever. This 
concerns all parts of Horizon 2020 and many steps of 
the Research and Innovation cycle, such as disclosing 
the sex of animals in experiments, thereby taking into 
account sex in the research process, when developing 
concepts and theories, formulating research questions, 
collecting and analysing data.
Interestingly, it is rather common practice to exclude 
female animals from experimental designs on the basis 
of putative complex physiology leading to high variabil-
ity. However, it was recently shown that variability is not 
Address for correspondence: Georgios Kararigas, Institute of Gender in Medicine (GiM), Center for Cardiovascular Research (CCR), Charité Uni-
versity Hospital, Hessische Str. 3-4, 10115 Berlin, Germany. E-mail: george.kararigas@charite.de.
Key words
•  biological sex
•  pathophysiology
•   preclinical and clinical 
research
•  treatment
Abstract
Biological sex significantly affects the presentation, outcome of treatment and progres-
sion of disease. However, the role of sex has yet underestimated consequences for physi-
ology and pathology. We put forward that a better understanding of the effects of sex 
in pathophysiology and the underlying mechanisms is necessary. This may facilitate the 
identification of targets that respond to specific therapies, thereby contributing towards 
a more appropriate and individualised medical care for both men and women.
Georgios Kararigas, Ute Seeland, Maria Luisa Barcena de Arellano et al.
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higher in females than males, even when females have 
a proper hormonal cycle [4]. In contrast, differences in 
temperature by housing may increase variability [5], a 
factor that may not be always accounted for. There is 
also currently debate whether animal models represent 
human sex differences accurately. Indeed, as with ev-
ery other animal model and experimental setup, models 
for the study of sex differences have their limitations. 
However, several animal models of myocardial infarc-
tion, vascular disease, myocardial hypertrophy, or heart 
failure, for example, exhibit major differences between 
males and females that reflect sex differences in hu-
mans. These models have so far offered valuable insight 
into sex differences arising at the molecular and cellular 
level from the control of gene transcription, intracellu-
lar signalling, organelle function, and crosstalk between 
heart, skeletal muscle, adipose tissue and the immune 
system. Accordingly, we put forward that animal mod-
els have an important role in the investigation of sex dif-
ferences that may lead to translational approaches, con-
sidering that results should be interpreted with caution 
and the model-inherent limitations are not neglected.
The study of sex is expected to have important socio-
economic implications. Therapies are designed using 
mainly male subjects. However, there are a number of 
differences in the way that men and women react to the 
same therapies. As a consequence, therapies applied in 
one of the two sexes might not have the expected ef-
fects. This leads to non-effectively-treated patients clog-
ging up health systems and their budgets. Therefore, a 
better understanding of sex-specific (patho)physiologi-
cal mechanisms represents an invaluable and strong 
foundation for the development and establishment of 
sex-specific therapeutic approaches. The impact on 
economies of such strategies, together with a detailed 
description of individual biological variation in connec-
tion with environmental factors that influence the de-
velopment of disease, might be of great dimensions and 
at the same time this could lead to a more appropriate 
treatment of the diseased alleviating pain and suffering.
Sex differences have consistently been confirmed 
throughout a large spectrum of experimental and clini-
cal studies, in different species and pathophysiological 
conditions. This strongly suggests that sex differences 
represent important biological phenomena that need 
further investigation. The examples stated above sup-
port the notion that a more careful consideration of sex 
differences will improve our understanding of frequent 
diseases and will subsequently lead to improved thera-
pies. In particular, a better understanding of sex differ-
ences in cardiovascular pathophysiology will facilitate 
the identification of targets that respond to specific 
therapies, thereby contributing towards a more indi-
vidualised medical care. At present, the development 
of new cardiovascular drugs has reached a plateau af-
ter years of continuous progress [6]. We believe that an 
improved understanding of sex-specific disease mecha-
nisms and therapeutic targets will ameliorate this situ-
ation towards more efficient treatments for both men 
and women.
Conflict of interest statement
There are no potential conflicts of interest or any fi-
nancial or personal relationships with other people or 
organizations that could inappropriately bias conduct 
and findings of this study.
Accepted on 16 March 2016.
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3. Clayton JA, Collins FS. Policy: NIH to balance sex in cell 
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4. Prendergast BJ, Onishi KG, Zucker I. Female mice 
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