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Gender Differences in Physiology:
Cardiovascular
Virginia H. Huxley, Ph.D.
Director, National Center for Gender Physiology
University of Missouri School of Medicine
Columbia, MO USA
Research Support from the National Institutes of Health (NIH), Heart, Lung & Blood Institute, American
Heart Association, and the National Areonautics Space Agency (NASA)
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Surprize!
M≠F
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Definitions: Sex vs. Gender
Biology: “Sex” = XX or XY, genomic determination; correct
Scientific term.
“Gender” = psychological term describing the self-designation
of male or female
vs.
Societal: “Sex” is reproduction and has negative connotation
“Gender” is softer and less likely to be misinterpreted.
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Physiology: Cardiovascular
 Heart Rate: Women > Men; sleep, rest, exercise
 Women less tolerant to upright
posture or gravitational stress than
men - primarily due to reduced
ability to maintain venous return
and cardiac output.
Mechanisms behind sex difference in BP control unknown.
In response to cardiovascular stress:
 Men increase vascular resistance
HR*SV = CO = ∆P/TPR
 Women increase heart rate
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With Respect to Coronary Function:
QT interval longer in Women than Men
Atrial Fibrillation > in Men who are heavy drinkers
Contractility Women > Men
Cardiac myocyte expression of glycolytic &
mitochondrial enzymes differs
With Respect to Coagulation:
Platelet aggregation & secretion change w/ sexual
maturity differently in Males & Females
With Respect to Blood Lipids:
HDL Women > Men
After menopause lipid profile more atherogenic
Decreased HDL
Increased triglycerides
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Pathophysiology: Cardiovascular
CVD kills 2X American Women than from all cancers
combined.
~ 500,000 women die from CVD vs. ~ 41,500 by breast
cancer.
CVD declining but rate of decline for Women < Men;
African-American < Caucasian Women
Women develop CHD ~10 yr later than Men
Men have a greater risk of MI & at earlier ages
Ave 1st MI 65.8 yr Men
 70.4 yr Women
Strokes more common in Women than Men & associated with
atrial fibrillation
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Pathophysiology: Cardiovascular II
Cardiac arrest ~ 3x > in Men than Women, but lower
recovery and
survival rates in Women
Cardiac arrhythmias, drug-induced torsades de pointes, and
long QT syndrome more prevalent in Women
At younger ages, prevalence of CHF > Men; after 75
reverses
Women with CHF more likely to have co-morbid diabetes
and hypertension than Men.
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Pathophysiology:
Type II Diabetes & CVD
 Type II Diabetic Women
3-4X more likely to develop CHD
2X risk of a 2nd heart attack
have lower E2 & loose “estrogen’s protective effect”
experience reproductive problems
2-4X more likely to be African American, Hispanic,
American Indian, or Asian Pacific Islander than Caucasian
 Diabetes associated with
low total testosterone in Men
high levels of bioavailable testosterone in Women
 Lower estrogen levels may account for the same rate of
kidney and CV disease-related conditions.
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How could it be that we did not recognize
the differences until now?
Frequency
70 kg Male
Measured variable
Caucasian: 18-22 yr, military/athlete
or European Medical Student
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?
What is the physiological basis for these cardiovascular
"Sex" differences?
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More than the Sex Hormones:
XX vs. XY
Obvious:
why only males develop prostate cancer and only females get
ovarian cancer
Not Obvious:
 why Females are more likely than Males to recover language
ability after suffering a left-hemisphere stroke,
or
 why Females have a far greater risk than Males of developing
life-threatening ventricular arrhythmias in response to a variety
of K+ channel-blocking drugs
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Basic truths
Every Cell Has a Sex
Sex Begins in the Womb
Pre-natal environment
Testosterone produced first
Prepubertal sex hormone differences
E2 higher in girls than boys
Sex Affects Health
Susceptibility/prevalence
Natural history
Mobility/mortality
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Estrogen: The (?) Mediator of Sex Differences
Estrogen, E2 & Estrogen Receptors ER & ERb
Nongenomic, cytoplasmic actions
Genomic actions
Male/Female differences in receptor distribution
E2
Required by Males and Females
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Estrogen: The (?) Mediator of Sex Differences
ERactivation "protective"
Re-endothelialization post injury
Smooth muscle proliferation & matrix deposition inhibited
Lipid profile via prostacyclin production & hepatic actions
Reduced function in Males results in impaired vascular tone
& coronary arterial calcification
 Associated with eNOS activation in endothelial cells
Polymorphisms in ER identified with advanced
cardiovascular disease in both men and women
ERb
BP regulation
Vasodilitation via NO production & NOS gene induction
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Remember the others….
Thus far we have left out:
 Progesterone,
 Testosterone,
 their receptors
2 PR
1 AR,
 the aromatases, and
 d[C]/dt vs. [C]
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Figure from
Mendelsohn and Karas
(Science)
Progesterone
 Declines in Women at menopause
 May partake in variability of vascular tone with menstrual
cycle
 Lowers BP whereas synthetic progesterone elevates BP
?
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Testosterone
 Declines with age in Men & Women but more slowly than E2
 Increases in E2-deficient Males
 Androgen replacement therapy (ART)
 Controversial
 Improves cardiac ischemic indices in Men
 W/o effect on peripheral vascular ischemia
 Lower HDL-C & Lipoprotein (a)
 Activates AR & ER (via aromatase conversion to E2)
 Aromatase
 AR inhibition disrupts regulation of VSM tone in Males
 Vasodilitation
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Solution
Teach
 Physiology of what is known
 Desire to learn the basis for the differences
 Encourage use of differences to learn
mechanisms
 Hallmarks of disease as means for sussing out
pathways
 Question assumptions
 Think
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Basic Physiology: Starling's Law of Filtration in
Males & Females
Tissue
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water
Blood
Starling's Law of Filtration
Volume flow is determined by the balance of hydrostatic and
osmotic pressures across a semipermeable membrane.
Text Book for Water:
Pcap Blood
p
J
v
 L p S P  
Tissue
Gradient
Pint
∆P = Pcap - Pint
int
∆ = p - int
Men & Women are in volume
balance, except…..
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Plasma Protein
Total Protein & Albumin by Sex
7.5
“adults”
7
g/100 ml
6.5
6
Males
5.5
Females
Males
5
Females
4.5
4
3.5
3
8-19
20-39
40-59
Age ranges
Geigy Scientific Tables Vol. 3, 1984 p. 140-141
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60-95
“Oncotic Pressure, ”
Onsager’s Law: π = FnC
Oncotic Pressure
30
25
Males
Females
Males
Females
20
15
10
8-19
20-39
40-59
60-95
Age ranges
Text Book for Water:
J
v
 L p S P  
∆π male > ∆π female
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Left Heart
(Left Ventricle)
BP lower in women than men
Pcap
Right Heart
(Right Atrium)
Shore AC, Sandeman DD, Tooke JE. Capillary pressure, pulse pressure amplitude, and
pressure waveform in healthy volunteers. Am J Physiol 1995;268:H147-H154
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Males = Females?
J
v
 L p S P  
Pcap: Females<Males
∆π: Females<Males
∆P
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∆
∆P
∆
Pathophysiology: Hypertension
J
v
 L p S P  
Pcap: Females<<Males
Oncotic pressure: Females<Males
∆P
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∆
Pathophysiology: Hypertension
J
v
 L p S P  
Assume: Lp and S are the same in M & F in health and
disease
In fact: Capillary density (S)
Hypertensive Males< Females
∆P
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∆
∆P
∆
Males = Females?
Female n=55
-lactalbumin
Male n=21
*
Female n=36
Albumin
Male n=25
0
5
10
15
20
Ps x 10-7 cm s-1
From the perspective of Basal Coronary Exchange Properties,
Sure, the statistics say males = females….
Huxley, V.H., J-J Wang, and S.P. Whitt. 2005. Sexual dimorphism in the permeability response of
coronary microvessels to adenosine. Am J Physiol Heart Circ Physiol, 288: 2006 - 2 013.
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With respect to response, NO!
PADO/Pc
2.0
***
1.5
1.0
*
0.5
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*
**
***
**
*
*
*
arteriole
venule
PADO/Pc ° 1, p< 0.5
°
arteriole ° venule
Huxley, V.H.,APS
J-J Wang,
S.P. Whitt.
2005. Sexual dimorphism in the permeability response of
2006 and
Refresher
Course
coronary microvessels to adenosine. Am J Physiol Heart Circ Physiol, 288: 2006 - 2 013.
Response to Exercise Influenced by Sex
2.5
*
2.0
2.0
PSADO
PSControl
*
1.5
1.5
N=35
1.0
N=36
N=35
N=25
*
SED EX
0.5
*
2.5
N=9
*
N=7
1.0
N=6
*
SED EX
Arterioles
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*
SED EX
0.5
*
N=7
SED EX
Venules
How can “sex” influence one parameter,
permeability response to a stimulus, and
not another, basal permeability?
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2 Investigators traveling from A to B
Temp, °C
40
ND
20
0
2000
6000
10000
14000 miles
2000
6000
10000
14000 miles
-20
Rainfall, mm
2000
0
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*
Temp, °C
Rainfall, mm
2000
1000
2000
6000
10000
0
14000
London, UK
Moscow, Russia
Ottawa, Canada
Memphis, USA
Monterrey, Mexico
Bangkok
Brisbane, Australia
Tahiti, French Polynesia
Christchurch, NZ
Christchurch, NZ
Temp, °C
Rainfall, mm
2000
1000
2000
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6000
10000
0
14000
Just as the direction of travel between London and
Christchurch can matter, so too can males and
females of the same species be in balance with
respect to volume and solute exchange, but not by the
same means.
Consequences…..
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Why should Teachers of
Physiology care?
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Signs of Heart Attack:
1. Chest discomfort or uncomfortable pressure,
fullness, squeezing or pain in the center of the
chest that lasts longer than a few minutes, or
comes and goes.
2. Spreading pain to one or both arms, back, jaw, or
stomach.
3. Cold sweats and nausea.
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But,
Women often don’t experience the “hallmarks” (only
30%), instead:
 shortness of breath,
 nausea,
 vomiting
 sleeplessness
 back pain or jaw pain, and
 a feeling of generalized weakness, fatigue in
weeks prior to Acute MI!
Consequently treatment delayed, inappropriate, or
wrong leading to preventable deaths.
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Frequency
Future Challenge ~ Reality
Measured variable
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The last 10 years:
 Differences between Men and Women noted in
normal organ functions in health as well as in
disease, including diabetes and cancer.
 The Physiological basis for these differences is unknown.
Slow response as the focus has been on differences
and similarities between females and males at the
societal level by researchers evaluating how individual
behaviors, lifestyles, and surroundings affect one's
biological development and health.
 Critical gaps in our basic understanding of sex differences
create serious medical and societal shortcomings.
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