Adv Physiol Educ 31: 2325, 2007;

doi:10.1152/advan.00118.2006.

Refresher Course

Sex-based differences in physiology: what should we teach in the

medical curriculum?
Martha L. Blair
Department of Pharmacology and Physiology, University of Rochester
School of Medicine and Dentistry, Rochester, New York
Submitted 4 December 2006; accepted in final form 7 December 2006

Blair ML. Sex-based differences in physiology: what should we

teach in the medical curriculum? Adv Physiol Educ 31: 2325, 2007;
doi:10.1152/advan.00118.2006.An abundance of recent research
indicates that there are multiple differences between males and females both in normal physiology and in the pathophysiology of
disease. The Refresher Course on Gender Differences in Physiology,
sponsored by the American Physiological Society Education Committee at the 2006 Experimental Biology Meeting in San Franciso,
CA, was designed to provide teachers of medical physiology with the
background necessary to include the most important aspects of sexbased differences in their curricula. The presentations addressed
sex-based differences in the physiology and pathophysiology of the
cardiovascular, musculoskeletal, and immune systems as well as the
cellular mechanisms of sex steroid hormone actions on nonreproductive tissues. The slides and audio files for these presentations are
available at http://www.the-aps.org/education/refresher/index.htm.
This overview highlights the key concepts relevant to the topic of
sex-based differences in physiology: why these differences are important, their potential causes, and examples of prominent differences
between males and females in normal physiological function for
selected organ systems.
sex characteristics; gonadal steroid hormones; cardiovascular physiology
THERE ARE MARKED DIFFERENCES between men and women in the
incidence and expression of many major disease entities (8, 9).
These sex-based1 differences in the pathophysiology of disease
imply, in turn, that there are important underlying differences
in physiological function. Despite the importance of this topic,
sex-based differences in physiology are typically not systematically addressed either in physiology textbooks or in the
medical physiology curriculum, with the obvious exception of
reproductive physiology. For this reason, the Americal Physiological Society (APS) Education Committee elected to address this topic for the Refresher Course presented at the 2006
Experimental Biology Meeting in San Francisco, CA.
Until recently, most basic and clinical research either was
performed exclusively in male subjects or included both sexes
but did not differentiate between males and females in the data
analysis. This reflected the broad assumption that there are

1
The Institute of Medicine Committee on Understanding the Biology of Sex
and Gender Differences has defined sex as the classification . . . as male or
female according to reproductive organs and functions assigned by the chromosomal complement and gender as a persons self-representation as male
or female, or how that person is responded to by social institutions on the basis
of the individuals gender presentation (8).
Address for reprint requests and other correspondence: M. L. Blair, Dept. of
Pharmacology and Physiology, Univ. of Rochester School of Medicine and
Dentistry, Box 711, 601 Elmwood Ave., Rochester, NY 14642 (e-mail:
martha_blair@urmc.rochester.edu).

minimal differences in the physiology and pathophysiology of

males and females other than those that specifically involve the
reproductive system. The potential complexities of controlling
for the various phases of female reproductive cycle served as
an additional deterrent for the inclusion of females in experimental design for both animal and human studies. During the
period of 19771993, furthermore, women of reproductive age
were required to be excluded from phase I clinical trials
because of concerns about potential teratogenic effects. Since
that time, there has been a progressively increasing emphasis
on the inclusion of women in clinical trials as well as statistical
analyses that specifically evaluate possible sex differences (8).
With the recent recognition of important sex-based differences in disease, there is now a burgeoning literature addressing sex-based differences in normal physiological function and
effects of sex steroid hormones on the function of multiple
organ systems (14). The goal of the Refresher Course symposium was to summarize our current state of knowledge of
sex-based differences in three systems for which there are
prominent differences between men and women: cardiovascular, musculoskeletal, and immune systems (3, 4, 7). In view of
the fact that many sex-based differences are mediated by the
actions of estrogens or androgens, the Refresher Course also
presented an update on the genomic and nongenomic mechanisms of action of sex steroid hormones (20). The slides and
audio files for these presentations are posted on the APS
Refresher Course website http://www.the-aps.org/education/
refresher/index.htm
This overview highlights the key concepts relevant to the
topic of sex-based differences in physiology: why these differences are important, their potential causes, and examples of
prominent differences between males and females in normal
physiological function for selected organ systems.
Sex-Based Differences in Human Disease
As noted above, there are important differences between
men and women in the incidence and expression of many
major disease entities. For example, 80% of patients with
osteoporosis are women. The causes of osteoporosis are multifactorial and include genetic characteristics, exercise, dietary
history, and the contributions of testosterone and estrogen to
bone metabolism; the decline in estrogen production is one of
the key factors that predisposes postmenopausal women to the
development of osteoporosis (8).
Similarly, 80% of patients with autoimmune disease also are
women, implying that sex steroid hormones and/or sex-linked
genetic characteristics can profoundly alter immune system
function (4). The discrepancy between sexes in the incidence
of autoimmune disease is particularly dramatic for Hashimo-

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SEX-BASED DIFFERENCES IN PHYSIOLOGY

tos thyroiditis, which has a 10-fold greater incidence in

women than in men; for Graves hyperthyroidism, which has a
7-fold greater incidence in women than in men; and for
systemic lupus erythematosus, which has a 6-fold greater
incidence in women than in men (2, 4, 5). There also are
prominent sex-based differences in the incidence and expression of a wide range of mental illnesses, including depression,
schizophrenia, posttraumatic stress disorder, and panic disorder. For example, depression is diagnosed two to three times
more frequently in women than in men (8).
Conversely, heart disease has traditionally been thought to
be predominantly a disease of men. In reality, this is not the
case: heart disease is the leading cause of death in both women
and men. However, the age of onset of coronary artery disease
is, on average, roughly a decade later in women than in men.
The incidence of heart disease in women increases markedly
after menopause. While this strongly implies a cardioprotective
role for estrogen, the role of estrogen in cardiovascular health
is clearly not straightforward, as shown by the outcome of the
Womens Health Initiative (13, 19). It is important to recognize, however, that as striking as the difference in the age of
onset of heart disease may be, it is only one facet of the
difference between women and men in cardiovascular pathophysiology. There are, in addition, multiple sex-based differences in the symptoms, progression, comorbidities, and outcomes of heart disease that have important implications for the
recognition and treatment of heart disease in women compared
with men and that suggest widespread sex-based differences in
the underlying physiology of the cardiovascular system. These
differences are addressed in the accompanying article by V.
Huxley (7).
Potential Causes of Sex-Based Differences in Normal
Physiology and Disease
Sex-based differences in normal physiology, or in the predisposition to a specific disease, can be due to genetic differences, to the actions of the sex steroid hormones, or to an
interaction between these factors.
The obvious genetic basis for sex-based differences lies in
the fact that females have two X chromosomes but no Y
chromosome, whereas males have a Y chromosome but only
one X chromosome. There are genes on the Y chromosome
that have no counterpart on X chromosomes, and, conversely,
genes located on the X chromosome can, in some cases, be
expressed at higher levels in females than in males. In addition,
gene expression can be altered by sex steroid hormones (8).
The sex steroid hormones include androgens, estrogens, and
progestins. Receptors for the sex steroid hormones are present
in numerous nonreproductive tissues, including the heart, bone,
skeletal muscle, vasculature, liver, immune system, and brain.
As presented in the accompanying article by M. Weirman (20),
these steroid receptors mediate their target tissue effects not
only through their well-known genomic actions but by nongenomic effects as well. It is important to note that, although
circulating androgen levels are higher in males than in females,
and circulating estrogen/progestin levels are higher in premenopausal females than in males, both males and females
produce estrogens, progestins, and androgens. Furthermore,
estrogen and androgen receptors are present in nonreproductive
tissues of both males and females and mediate physiological
effects in both sexes. Indeed, some of the important physio-

logical actions of circulating androgens, such as those on bone

metabolism, are proposed to be mediated by the conversion of
testosterone to estrogen in males by aromatase (20). The
effects of testosterone on vascular tone also may be mediated
in part by aromatase conversion to estrogen (13, 20).
One of the complexities of unraveling the contribution of
steroid hormones to either normal physiology or disease is the
changing role of these hormones across development. In utero,
the sex hormones are critical for sex determination and differentiation, and gonadal steroid hormone levels and their contributions to physiological function undergo marked changes in
the transitions from childhood to adolescence to adulthood. In
women, there are the additional variables of the menstrual
cycle, pregnancy, and menopause, and, in both women and
men, testosterone levels decline with aging.
In addition to the contribution of genetic and gonadal steroid
hormone effects to the pathophysiology of disease, it must also
be recognized that societal factors can play a marked role in the
incidence and expression of disease. Gender differences in
lifestyle, daily environment, and healthcare can all make significant contributions to physical and mental health. These
differences are present in all societies but play a particularly
substantial role in certain cultures in developing nations. While
this topic is beyond the scope of this overview, it is nonetheless
an important contributing variable to the expression of sexbased differences in pathophysiology.
Sex-Based Differences in Normal Physiology
One consequence of differences in genetic attributes and
circulating levels of sex steroid hormones is that there are
structural/morphological differences between males and females. The differences between the sexes in body composition
are well known: males typically have proportionately more
muscle mass, more bone mass, and a lower percentage of body
fat than women. These differences are, in a large part, the
consequence of the well-documented effects of gonadal steroid
hormones on skeletal muscle and bone metabolism and are
reviewed in the accompanying article by M. Brown (3). What
is less commonly recognized is that there are structural/morphological differences between adult males and females for
many (if not all) organ systems that can have significant impact
on physiological function (9). For example, sex differences in
lung size have important consequences. Men have larger lungs,
wider airways, and greater lung diffusion capacity than
women, even when these values are normalized to height. An
important consequence of this structural difference is that in
contrast to healthy young men, maximal exercise capacity may
be limited by pulmonary capacity in women, especially as they
age (6).
There are well-defined differences in brain structure that
result from fetal exposure to gonadal steroid hormones (11,
17). These morphological differences, in concert with the
effects of sex steroid hormones on neuronal function, are
proposed to support diverse nonreproductive differences between males and females such as differences in pain threshold
and cognitive style and the greater glucocorticoid response to
stressors exhibited by females compared with males (11).
Receptors for sex steroids are found in multiple brain regions
and mediate the effects both of circulating gonadal steroid
hormones and of locally produced neuroactive steroids (12).
Steroid receptors are abundantly located in brain regions in-

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SEX-BASED DIFFERENCES IN PHYSIOLOGY

volved in autonomic regulation and thus have the potential to

influence a wide range of homeostatic regulatory processes
(18).
There are multiple differences between women and men in
terms of their normal cardiovascular function. For example,
men have significantly greater left ventricular mass and chamber size than women. Because the left ventricular ejection
fraction is the same in both sexes (10), the stroke volume is
larger in men than in women (7). Furthermore, there are
sex-related differences in the expression of myosin isoforms in
animal models, suggesting that there may be sex-based cardiac
differences that are more complex than a simple difference in
size (10). In addition, blood pressure regulation differs between
sexes in several respects. Women have a lower resting blood
pressure and higher resting heart rate and exhibit reduced
tolerance to orthostatic stress and impaired venous return [see
the accompanying article by V. Huxley (7)]. The electrocardiogram Q-T interval also is longer in women than in men (13),
reflecting an underlying sex difference in the fundamental
electrophysiological properties of the heart; consequently, the
incidence of life-threatening arrhythmia (torsades de pointes)
triggered by drugs that prolong ventricular repolarization is
higher in women than in men (15). The development of sex
differences in cardiovascular function typically shows a temporal correlation with developmental changes in sex steroid
hormone levels. For example, sex differences in the heart rate
and Q-T interval do not develop until adolescence (15). Similarly, while blood pressure is lower in premenopausal women
than in men, blood pressure gradually rises in postmenopausal
women to levels equivalent to those of men. Experimental
studies (1, 7, 13, 16) have demonstrated widespread effects of
sex steroid hormones on vascular tone as well as on lipid
metabolism, hemostasis, and the regulation of fluid and electrolyte balance. However, while these documented actions of
the sex steroid hormones undoubtedly contribute to the observed differences between men and women in both normal
cardiovascular regulation and development of cardiovascular
disease, the biological basis of these differences is complex
and not yet fully understood.
Conclusions
The pronounced differences between men and women in the
prevalence and presentation of multiple major diseases dictate
that our students will be best prepared for the practice of
medicine if their physiology curriculum prepares them to
understand the basis of sex differences in pathophysiology. In
this overview and the accompanying articles summarizing the

25

2006 Refresher Course presentations, we present key concepts

that we propose should be included in a medical physiology
curriculum.
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