Baggio, Giovannella

Delunardo, Federica

Malorni, Walter

Ortona, Eleonora

Annali dell'Istituto Superiore di Sanità

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A sex And gender perspective in medicine: 
A new mAndAtory chAllenge  
for humAn heAlth
Edited by Elena Ortona, Federica Delunardo and Walter Malorni
Preface
Elena Ortona1, Federica Delunardo1, Giovannella Baggio2 and Walter Malorni3
1Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, Italy 
2Dipartimento di Medicina Molecolare, Università di Padova, Padua, Italy 
3Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy
Ann Ist Super Sanità 2016 | Vol. 52, No. 2: 146-148
DOI: 10.4415/ANN_16_02_02
The analysis of the biology of sex differences as well 
as the development of gender specific medicine is 
a milestone in the advancement of our knowledge in 
different fields of life sciences [1]. Among these fields 
are included those aimed at the improvement of our 
knowledge in all the aspects of human health dealing 
with the differences between men and women: from the 
policy and public health analyses to the clinical prac-
tice, from the basic sciences to the detection of diag-
nostic gender-specific markers [2, 3]. This could lead to 
the comprehension of the pathogenetic mechanisms of 
human diseases and the appropriateness of the medi-
cal intervention in the clinical practice [4, 5]. In fact, 
the development or the improvement of the cures could 
take advantage from the knowledge of the sex and gen-
der disparity in order to ascertain and develop differen-
tial interventions between women and men. As concern 
the terms sex and gender, they are usually referred as 
to the biological or to the socio-cultural issues, respec-
tively. These definitions, at least as originally proposed, 
are quite clear if applied to humans but are quite com-
plicated by the typical approaches of the experimental 
medicine. This field of investigation takes in fact ad-
vantage from three different bodies of study: the use 
of in vitro systems, e.g., cultured cells, the classical in 
vivo preclinical studies carried out with experimental 
animals and ex vivo analysis of cells from humans. All 
these approaches, in our opinion, often comprise either 
biological or “social” dimension. In fact, even in vitro 
studies should take into account the “social” behavior 
of cells. A good example in this respect is represented 
by studies on lymphocytes in which the interactions 
among different subpopulations are of great relevance 
and the relevance of the X chromosome has been un-
derscored [6, 7]. 
The number of human pathologies displaying a signif-
icant gender disparity is rapidly growing up so that the 
need for the investigations specifically devoted to point 
out sex or gender differences appear as mandatory [8]. 
The growing number of works published in the field and 
taking into account sex/gender disparities is really im-
pressive (Figure 1). However, it should also be noted 
that the great majority of published works do not con-
sider both sexes, e.g. male and female animals in pre-
clinical studies or women and men in human studies. 
For example, the great majority of experimental works, 
either in animals or in culture cells, do not take into 
account the biology of sex differences: more than 95% 
of in vivo studies do not consider males and females but 
one sex only. Very often the sex of the studied animal 
species is unspecified (in more than 20% of studies). 
The scenario in in vitro or ex vivo studies is even worse: 
the sexual origin of the isolated cells is considered as a 
negligible issue in more than 99% of the experimental 
works. Furthermore, the experimental studies are often 
carried out irrespective to the predominance of the dis-
ease in one sex or another so that it can be observed 
that a disease with high predominance in women is 
analyzed, e.g., in pharmacological studies, in male mice 
or XY cells exclusively. This is striking but, in line with 
this, a further aspect must be taken into account: phase 
1 studies (the first step of pharmacological studies in 
humans usually based on in vitro screening and animal 
studies) in humans very often do not include women. It 
has been observed that: i) a quarter of the drug manu-
facturers in an industry survey did not deliberately re-
cruit representative numbers of women as participants 
in drug trials; ii) women, when included in clinical trials, 
are generally under represented: iii) in USA, the Food 
and Drug Administration (FDA) often does not ana-
lyze trial data to determine whether women’s responses 
to a drug differ from men’s; iv) many drug manufactur-
ers do not study whether their drugs specifically inter-
act with sex hormones. Nevertheless, women are high 
drug consumers in comparison with men (reports say: 
42.1% vs 32.2%, respectively) and adverse effects of 
drugs are essentially suffered by women. All in all, this 
scenario seems to suggest the need of a reappraisal of 
Address for correspondence: Elena Ortona, Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena 299, 
00161 Rome, Italy. E-mail: elena.ortona@iss.it.
A sex And gender perspective in medicine
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the scientific medical approach that could improve our 
knowledge and, consequently, the appropriateness of 
the intervention on our health. 
Notwithstanding, the pathological conditions that 
have been demonstrated to display a gender disparity 
are really impressive: transmissible and non-transmissi-
ble diseases have been investigated in this respect in a 
series of studies aimed at the analysis of the incidence, 
progression or outcome of very important diseases 
such as infections, cardiovascular, neurodegenerative, 
metabolic, respiratory, autoimmune diseases and sev-
eral forms of cancer. In addition, a number of works 
underscored sex/gender differences in response to 
therapy either for infections, e.g. antiviral therapy, or for 
non-transmissible diseases such as cancer response to 
therapy. Moreover, disparity has been described as con-
cern the adverse effects of pharmacological therapies 
and iatrogenic diseases. On the basis of this huge mass 
of data, some scientific Journals included sex/gender in 
their aims and ask the authors to consider this issue, 
and some Journals devoted to the analysis of differences 
between males and females have been released. Among 
these are: the American journal named Biology of Sex 
Differences: a journal dedicated not only to the study of 
gender medicine but, as one can expect from its title, 
also to the study of experimental biology and medicine, 
i.e. biological differences between XX and XY cells or 
male and female animals. More recently, the Italian 
Journal of Gender Specific Medicine (www.gendermed-
journal.it/) has also been published. This is an interdis-
ciplinary European journal aimed at the publication of 
social and biomedical aspects of gender disparities. 
Since many years a research group at the Istituto 
Superiore di Sanità (ISS, Italian National Institute of 
Health, Section of Gender Medicine) is already operat-
ing in the field of gender medicine publishing a number 
of original works and collaborating with the Italian net-
work operating on this matter. In particular, with the 
Centro Studi Nazionale su Salute e Medicina di Gene-
re (National Center for Gender Health and Medicine) 
founded in 2009 in Padua and headed by Giovannella 
Baggio created an active and intertwined series of con-
tacts including several working groups spread all over 
our Country. For example, various Italian regions con-
tributed to this networking: in Puglia the Gruppo Ital-
iano Salute e Genere (GISeG, Italian Group for Health 
and Gender) and in Veneto the Società Italiana di Me-
dicina Generale (SIMG). Many other active working 
groups operate in other regions, e.g., in Emilia-Romag-
na and Lombardia (i.e., the Lorenzini Foundation in 
Milan was the first organization operating in the field 
in Italy). Several further groups specifically working in 
the field of gender medicine have been created within 
some medical associations, such as the Federazione 
delle Associazioni dei Dirigenti Ospedalieri Internisti 
(FADOI, Internal Medicine Association), the Federa-
zione Nazionale degli Ordini dei Medici Chirurghi e 
degli Odontoiatri (FNOMCeO, Italian Federation of 
all Medical Doctors). Finally, several efforts have been 
made by the two main Italian stakeholders in the field 
of safety and risk assessment – the National Institute 
against the work-related injury, INAIL, and the ISS – in 
order to develop a gender-biased risk assessment at the 
workplaces [9].
A specific reference Center for the study of the bi-
ology of sex differences as well as gender medicine is 
now established at the ISS. In this issue of the Annali 
dell’Istituto Superiore di Sanità, some of the research 
groups working at the Institute and collaborating with 
other research groups operating in Italy and abroad 
provide a brief overview of the state of the art of their 
field of investigation. Several important areas of study 
and intervention have thus been covered: from the life 
styles and prevention to the validation of specific bio-
markers, from the pathogenesis and manifestations of 
human diseases such as autoimmune and cardiovascu-
0
2000
4000
6000
8000
10000
12000
14000
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 
Sex disparities Gender disparities 
Year
N
um
be
r o
f p
ub
lis
he
d 
ar
tic
le
s
Figure 1
Number of published articles on sex and gender disparity from year 2000 to year 2014.
Elena Ortona, Federica Delunardo, Giovannella Baggio and Walter Malorni
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lar diseases, cancer and infections, to the psychological 
stress, addiction and pain relief. The scenario is thus 
wide enough to warrant assorted and diverse compe-
tences and skills. Hence, the efforts of the Italian Na-
tional Institute of Health are still at the beginning but 
we are sure there is room enough to contribute to the 
development of an evidence-based medicine that takes 
into account sex and gender disparity. 
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A sex and gender perspective in medicine: a new mandatory challenge for human health

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A sex and gender perspective in medicine: a new mandatory challenge for human health

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