Exercise-Induced Muscle Damage and the Potential Protective Role of Estrogen

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REVIEW ARTICLE Sports Med 2002; 32 (2): 103-123
0112-1642/02/0002-0103/$25.00/0
© Adis International Limited. All rights reserved

Exercise-Induced Muscle Damage
and the Potential Protective Role
of Estrogen
Becky Kendall and Roger Eston
School of Sport, Health and Exercise Sciences, , University of Wales, Bangor, UK
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
1. Model of Muscle Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
1.1 Free Radicals and Muscle Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
1.2 Initial Stimulus of Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
1.3 Autogenic Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
1.3.1 Role of Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
1.3.2 Calpain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
1.4 Inflammatory and Immune Response to Muscle Damage . . . . . . . . . . . . . . . . . . . . 108
1.4.1 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
1.5 Leucocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
1.6 Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
2. Estrogen and Muscle Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
2.1 Estrogen as an Antioxidant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
2.2 Estrogen and Membrane Stabilisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
2.3 Estrogen and Gene Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
3. Estrogen and Muscle Damage Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
3.1 Effect of Estrogen on Creatine Kinase Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
3.2 Histopathological Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
3.3 The Effect of Estrogen on Indirect and Functional Measures of Muscle Damage . . . . . . . 113
3.4 Estrogen, Time Course of Muscle Damage and Immune Response . . . . . . . . . . . . . . . 114
3.5 Estrogen and the General Inflammatory Response . . . . . . . . . . . . . . . . . . . . . . . . 114
3.6 Estrogen and Specific Events Associated with Inflammation . . . . . . . . . . . . . . . . . . . 115
3.6.1 Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
3.6.2 Adhesion Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
3.6.3 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
4. Estrogen and Pain Perception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
5. Implications for Further Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Abstract Exercise-induced muscle damage is a well documented phenomenon that often
follows unaccustomed and sustainedmetabolically demanding activities. This
is a well researched, but poorly understood area, including the actualmechanisms
involved in the muscle damage and repair cycle. An integrated model of muscle
damage has been proposed by Armstrongand is generally accepted.
REVIEW ARTICLE Sports Med 2002; 32 (2): 103-123
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© Adis International Limited. All rights reserved.
A more recent aspect of exercise-induced muscle damage to be investigated
is the potential of estrogen to have a protective effect against skeletal muscle
damage. Estrogen has been demonstrated to have a potent antioxidant capacity
that plays a protective role in cardiac muscle, but whether this antioxidant capacity
has the ability to protect skeletal muscle is not fully understood.
In both human and rat studies, females have been shown to have lower creatine
kinase (CK) activity following both eccentric and sustained exercise compared
with males. As CK is often used as an indirect marker of muscle damage, it has
been suggested that female muscle may sustain less damage. However, these
findings may be more indicative of the membrane stabilising effect of estrogen
as some studies have shown no histological differences in male and femalemuscle
following a damaging protocol.
More recently, investigations into the potential effect of estrogen on muscle
damage have explored the possible role that estrogen may play in the inflammatory
response following muscle damage. In light of these studies, it may be suggested
that if estrogen inhibits the vital inflammatory response process associated
with themuscle damage and repair cycle, it has a negative role in restoring normal
muscle function after muscle damage has occurred.
This review is presented in two sections: firstly, the processes involved in the
muscle damage and repair cycle are reviewed; and secondly, the possible effects
that estrogen has upon these processes and muscle damage in general is discussed.
The muscle damage and repair cycle is presented within a model, with particular
emphasis on areas that are important to understanding the potential effect that
estrogen has upon these processes.
It is well documented that strenuous and repeated
eccentric contractions are associated with
exercise-induced muscle damage and delayed onset
muscle soreness.[1-3] This occurs in both recreational
and elite athletes. With elite athletes, these
responses are often related to relatively sudden increases
in the volume or intensity of training, or
following prolonged rest or injury.[4] For sedentary
individuals, a single episode of exercise involving
eccentric muscular contractions may produce significant
muscle soreness and damage.[4]
The ability of muscle to resist force is ~30%
greater during a maximal voluntary eccentric contraction
than its ability to exert force during a concentric
contraction.[5] Although current research is
inconclusive, several studies[5-7] have advocated
the importance of including the eccentric phase of
muscle action, in addition to the concentric phase,
to maximise gains in strength and size. It is therefore
considered to be an important inclusion in
strength training programmes.
During this type of contraction the length of the
muscle is increasing whilst the muscle itself attempts
to contract. Compared with concentric contractions,
the mechanical strain per muscle fibre is
higher, as fewer fibres are recruited.[8,9] The ‘loading
profile’ places a high stress on the tissues involved
and is most likely a primary factor of muscle
damage.[9] During shortening contractions,
work is done by the muscle, but during eccentric
contraction, work is done on the muscle by the external
lengthening forces.[3] As eccentric muscle
actions occur frequently in everyday life and during
sporting activities, exercise-induced muscle
damage is a common experience to most individuals.
Eccentric contractions can cause severe morphological
changes in the muscle fibres.[10] According
to the sliding filament theory, myosin
104 Kendall & Eston
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cross-bridges make repeated connections with actin
filaments throughout the duration of the active
state of the muscle fibre. However, during eccentric
contractions, instead of the actin filament being
propelled toward the centre of the myosin filament
they are pulled in opposite directions by the
external forces acting on the muscle.[10]
The injury can involve primary and secondary
sarcolemmal disruption, swelling or disruption of
the sarcotubular system, disruption of themyofibre
contractile components, cytoskeletal damage and
extracellular myofibre matrix abnormalities.[11]
High-tension, eccentric contractions are thought to
stretch or break the intermediate filaments between
the z disks, additionally disrupting the double/intermediate
filament z disk ring.[11]
In general, this review considers the muscle
damage that follows eccentric activity. However,
as discussed later, sustained metabolically demanding
activities can also be the initiating stimulus
resulting in very similar muscle damage. This
is discussed in more detail within the model of
muscle damage subsection.
The symptoms of exercise-induced muscle damage
include: soreness;[3,12,13] increase in volume of
limb with injured muscle;[12] increase in circumference
of limb with injured muscle;[13-15] decrease in
resting arm angle;[12-15] decrease in range of motion
of the affected limb;[3,14,16] decrease in muscular
strength;[3,12,17] leakage ofmyofibre proteins into the
blood, the most commonly measured being creatine
kinase (CK);[3,18-20] swelling and structural damage.[
3]
The most frequently reported symptom of muscle
damage is delayed-onset muscle soreness. The
soreness associated with this type of activity appears
between 8 and 24 hours following the damaging
exercise, and peaks between 24 and 48 hours
later, but can remain for up to 7 days.[13,21,22]
The sensation of pain in skeletalmuscle is transmitted
by myelinated group III and unmyelinated
group IV afferent fibres.[2,8] The myelinated group
III fibres are believed to transmit sharp pain,where
as the unmyelinated transmit dull aching pain,[2,23]
which is more commonly associated with delayedonset
muscle soreness and muscle damage. It is
believed that the pain afferents are sensitised by
chemicals released during the muscle damage and
repair cycle,[2,8] which include prostaglandin, bradykinin,
serotonin, histamine and potassium.[2,8]
1. Model of Muscle Damage
An integrated model ofmuscle damage has been
proposed by Armstrong,[24] which defines four
stages: (i) initial events; (ii) autogenic processes;
(iii) phagocytic stage; and (iv) regenerative phase.
The processes involved in muscle damage shall be
discussed further using this model as a basis. It
should be made clear that while muscle damage
can be divided up into these separate processes,
they overlap enormously, and the exact nature of
the muscle damage, the mechanisms responsible
and processes involved are not fully understood.
Before dividing the processes up according to the
above model, reactive oxygen species (ROS) will
be discussed separately, particularly as these may
play a role in the process of muscle damage. Furthermore,
there are important hypothetical mechanisms
for the role of estrogen in preventing the
potential destructive activities of these reactive
species.
1.1 Free Radicals and Muscle Damage
A common feature throughout the muscle damage
and repair cycle is the production of free radicals.
It is recognised that there are a number of
potential sites for the production of free radicals,[
25] across all stages of the theoretical model.
Free radicals are molecules or molecule fragments
containing an unpaired electron in their
outer valence shell.[26] The unpaired electron is
usually extremely exchangeable, which is the
chemical and physical reason for the reactivity of
radical species.[27] They have a potent oxidising
effect, which is the basis for their destructive effect
against lipids, proteins, nucleic acid and the extracellular
matrix.[28]
McArdle and Jackson[25] explained that free
radicals can be generated through the mitochondrial
electron transport system,[29] membrane
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bound oxidases[30] and infiltrating phagocytic
cells.[31] It is known that inflammatory events involve
the generation of free radicals via reduced
nicotinamide-adenine dinucleotide phosphate
(NADPH) and myeloperoxidase.[32,33] More recent
evidence suggests that superoxide radicals are also
of importance in neutrophil attraction and neutrophil
adherence to the endothelium.[32]
Free radicals can cause damage by lipid peroxidation
of unsaturated fatty acids in the muscle
membrane.[34] They can also cause oxidative damage
to DNA and proteins.[25,35] It is suggested that
as well as playing a role in direct tissue damage,
the generation of ROS may also amplify the general
inflammatory response of the body and promote
further cell injury, for example, through upregulation
of pro-inflammatory cytokines.[36]
Oxygen radicals generated via the neutrophil respiratory
burst are vital in clearing away muscle
tissue that has been damaged by exercise and may
also be responsible for propagation of further damage.[
33] There is abundant evidence for the involvement
of neutrophil-generated ROS in the inflammatory
response of tissues to various types of
injury,[33] and growing evidence of their involvement
in post-exercise muscle inflammatory response
and damage.[4,37] However, the results from
one recent study[38] infer that the effect of neutrophil
generated ROS activity may not be a significant
factor in the muscle damage and repair cycle,
with neutropenic rats showing the same time
course of muscle damage to non-neutropenic controls.
Since eccentric exercise requires less oxygen
consumption than equivalent concentric exercise,[
7] yet induces significantly greater damage, it
is unlikely that oxygen free radicals are always the
primary cause of exercise-induced muscle damage.
Nevertheless, exercise-induced muscle damage is
characterised by neutrophil and macrophage infiltration
intomuscle, and a subsequent inflammatory
and repair process,[33] which is promoted by free
radical activity.
It is not possible to place the generation of free
radicals within a certain phase of the muscle damage
and repair cycle as it appears to be a very important
factor throughout, and will be discussed
further in this review.
1.2 Initial Stimulus of Damage
The initial events are thought to occur either via
mechanical stress or metabolic stress.[4,24,39] In
terms of mechanical stress, high tension or a tension
imbalance[11,40,41] (associated with eccentric
contractions) can disrupt the sarcolemma (resulting
in calcium entry), the sarcoplasmic reticulum
(resulting in impaired calcium sequestration) and
myofibrillar structures.[24] Metabolic events include
high temperature, lowered pH, insufficient
mitochondrial respiration and oxygen free radical
production.[24] A number of paradigms, including
rhythmic exercise and repeated eccentric muscle
activity have related ROS production to muscle inflammation
and injury.[36]
Oxygen free radicals are produced in tissue that
is highly metabolically active. These substances
can cause irreversible damage to many cellular
constituents.[39] Oxidation of the sulfhydryl groups
of the ATPase pump by free radicals is highly correlated
with a reduction in the rate of Ca2+ uptake
by the sarcoplasmic reticulum,[39] resulting in a
loss of Ca2+ homeostasis.
A reduction in local ATP and/or a reduction in
the free energy from hydrolysis of ATP due to increased
ADP could reduce the rate of ATP splitting
and slow Ca2+ pumping by the sarcoplasmic reticulum
pump.[39]
The increase in hydrogen ions (decrease in pH)
that occurs during strenuous exercise has a profound
effect on the ability of the sarcoplasmic reticulum
to take up Ca2+. This has been attributed to
the H+ and Ca2+ ions competing for the Ca2+ binding
site on the ATPase pump.[39]
Temperature increases to above 38°C have also
been shown to uncouple the Ca2+ stimulated
ATPase activity from Ca2+ transport by the sarcoplasmic
reticulum.[39] High temperatures, similar
to those obtained during fatiguing exercise, may
alter the fluidity of the lipidmembrane surrounding
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the ATPase pump and somehow impair its ability
to sequester Ca2+.[39]
Metabolic and mechanical stress from exercise
may occur separately or simultaneously. The contribution
to muscle damage depends on the exact
nature of the physical activity undertaken,[4] that
is, whether it is eccentric in nature and involving a
relatively low metabolic demand, or a sustained
highly metabolic activity.
1.3 Autogenic Processes
The common factor that emerges in the initial
phase of exercise-induced muscle damage is the
loss of Ca2+ homeostasis. Regardless of the initiating
stimulus, it would appear that there follows a
rapid activation of autogenic destructive processes
that originate in the muscle fibres.[24]
1.3.1 Role of Calcium
The mechanisms underlying this phase of the
injury and repair process are not known, although
the loss of intracellular Ca2+ homeostasis could
play a primary role.[24] Empirical evidence supports
the theory that Ca2+ release from the sarcoplasmic
reticulum is an important factor in exercise-
induced muscle damage.
Experimental work has demonstrated that an increase
in intracellular calcium content causes damage
to the myofilaments of skeletal muscle.[25,42]
Studies that have inhibited the flux of Ca2+ across
the sarcoplasmic reticulum, following an exercise
protocol in rats, have demonstrated a decrease in
damage.[39,43] It has also been postulated that elevated
Ca2+ appears to cause a release of muscle
enzymes through activation of phospholipase A2,
which in turn may induce injury to the sarcolemma
through production of leukotrienes and prostaglandins
through free oxygen radical formation
and/or through release of detergent-like lysophospholipids.[
24] This in turn will affect the fluidity
of the membrane resulting in a ‘leaky’membrane,
loss of intracellular enzymes and an efflux of lysosomal
enzymes.[26] It is also believed that Ca2+
stimulates proteases (calpains) that are thought
to act directly on the proteins in cell membranes,
and proteases that act specifically on the z
lines.[39,44]
Low Ca2+ is necessary for cell function, whereas
high Ca2+ has long been associatedwith cell dysfunction
and cell death. The sudden increase in Ca2+ is
regarded as an important step in the cascade of events
that result in cellular damage following exercise.[39]
Calcium overload results in ultrastructural changes
in the muscle cell, including swollen and disrupted
mitochondria, dilated t-tubules and sarcoplasmic reticulum,
general cellular oedema and disruption of
the myofilaments.[39]
Processes proposed to explain how muscle
could be damaged following an elevation of intramuscular
calcium content, include: stimulation of
calcium-activated proteases, activation of lysosomal
proteases, mitochondrial overload and activation
of lipolytic enzymes. The two most important
processes appear to be the activation of lipolytic
enzymes and calcium-activated proteases, calpain.[
25] A calpain hypothesis was proposed by Belcastro
et al.,[45]who provided evidence for the importance
of this protease in the muscle damage and repair
cycle.
In addition to the cascade of autogenic processes
that follow a loss of Ca2+ homeostasis, elevated
Ca2+ has also been associated with a disruption of
the excitation-contraction coupling process.[46]
This in turn has been related to the reduction of
maximal isometric titanic force associated with eccentric
exercise.[46]
In summary, the loss of calcium homeostasis
following the mechanical/metabolic insult may activate
phospholipases and proteases. The free fatty
acids liberated will in turn have a detergent effect
on the cellmembrane andmay be vulnerable to free
radical attack.
The processes that follow the initial events can
eventually lead to complete repair of the damaged
muscle but rely upon the activities of non-muscle
cells.[47] A rise in free cytosolic calcium may also
be related, independently, to the activation of the
respiratory burst in phagocytic cells.[4] This phenomena
suggests links between the mechanisms
involved in the early stages of exercise-induced
Exercise-Induced Muscle Damage and Estrogen 107
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tissue damage and the activation of cells involved
in nonspecific immune responses.[4]
1.3.2 Calpain
While loss of Ca2+ homeostasis has been suggested
as a primary factor in producing muscle
damage, Belcastro et al.[45] proposed a calpain hypothesis
of exercise-induced muscle damage. It is
believed that Ca2+ stimulates proteases, such as
calpain, which directly act upon proteins within the
muscle. Belcastro et al.[45] reported that this nonlysosomal
protease contributes to the initiation of
immediate protein degradation, whereas lysosomal
proteases from extracellular sources (monocytes
and macrophages) play a primary role in protein
turnover several days after exercise.
The isoenzymes of calpain are typically localised
throughout the muscle cell in the I and Z band regions.[
45] It is hypothesised that when calpain is
activated, selective proteolysis of various contractile,
metabolic and structural elements occurs. It is
also believed that calpain or the resultant peptide
fragments may be associated with the neutrophil
chemotaxis reported to occur during or immediately
following exercise,[45] thus aiding the inflammatory
response and repair.
1.4 Inflammatory and Immune Response to
Muscle Damage
Tissue damage and infection both initiate a coordinated
sequence of events that are collectively
known as the acute phase response.[48] These
events initially facilitate antibacterial and anti-viral
responses before promoting the clearance of debris
and tissue fragments. This leads into the regenerative
phase with growth and repair of tissues and
restoration of normal function.[4]
Inflammation is characterised by the movement
of fluid, plasma proteins and leucocytes into the
tissue in response to injuries, infections or antigens.[
49] Signalling occurs between the injured
muscle cells and the mononucleated cells that subsequently
appear at the site of injury.[47] At least
two cell populations respond to muscle injury: inflammatory
cells involved in the removal of cellular
debris and myogenic cells involved in replacement
of the damaged muscle.[47] Infiltration of
these cells into the muscle is orchestrated by specific
cytokines.[4]
1.4.1 Cytokines
Cytokines are small polypeptides that are considered
to be an important link between the immunological
and neuroendocrinal systems involved in
inflammation, fever, chemotaxis, the acute phase
response and tumour regression.[4,49] Host defence
cytokines are produced by circulating and tissue
resident leucocytes as well as other cells.[50] It is
believed that a small group of cytokines, including
interleukin (IL)-1, interferon, IL-2, IL-6 and tumour
necrosis factor-α (TNFα), are the principle
mediators of inflammation.[51] IL-1 is expected to
have broad and important influences in muscle inflammation,
as well as possible roles in stimulating
protease synthesis.[47] TNFα and IL-1 have overlappingmechanismswithin
the body and have been
shown to increase leucocyte adhesion, priming leucocyte
function and causing macrophage activation.[
49] In addition, IL-1 is believed to induce the
expression ofmany other cytokines including IL-2,
IL-3, IL-6, TNFα and interferons.[47] Exercise and
muscle injury have been shown to increase the concentration
of IL-1 in serum and muscle, which is
expected to play a substantial role in promoting
muscle inflammation.[47] To stimulate the activity
of antigen specific host defences, these cytokines
regulate the growth, differentiation and functional
activities of T and B lymphocytes.[4]
1.5 Leucocytes
Leucocytes, primarily neutrophils and monocytes/
macrophages are thought to perform a wide
range of functions during the inflammatory response
associated with muscle damage. It is generally
believed, although still not thoroughly understood,
that these cells perform three functions
within the muscle damage and repair cycle:[44,47]
(i) attack and breakdown of debris (neutrophils and
macrophages); (ii) removal of cellular debris (macrophages);
and (iii) regeneration of cells (macrophages).
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Leucocytes are attracted to injured muscle cells,
via various chemotactic factors, possibly including
resident leucocytes,[47] calpain or peptide fragments[
45] and cytokines.[4,28] To enter the inflamed
tissue, leucocytes bind to specific adhesion molecules
of endothelial cells that line blood vessel
walls.[52]
The neutrophil is one of the first cells to arrive
at sites of injury and infection, where it releases a
number of chemoattractants to amplify the response
by recruiting additional neutrophils and
mononuclear cells. Neutrophils generate superoxide
and other ROS via a respiratory burst, which is
catalysed by the enzyme NADPH oxidase, located
in the plasma membrane.[4]
It has been suggested that the neutrophil is programmed
for overkill not caution.[53] It has little
intrinsic ability to distinguish between foreign and
host antigens, thus destroying healthy as well as
damaged cell and debris.[4]Macrophages, like neutrophils
are capable of producing oxygen free radicals.[
49] Macrophages also give rise to cytokines,
which in turn may exacerbate damage by potentiating
cytotoxic mechanisms of other inflammatory
cells to enhance free radical production and enzyme
release.[48]
Following degradation processes, some macrophages
may play a role in muscle repair.[52] Two
populations have been observed within animal
muscle,[44,47] ED1+ cells act as phagocytes and
ED2+ cells regulate the consequent repair process.[
44]
1.6 Regeneration
Muscles possess considerable powers of regeneration.
During the phagocytic phase of muscle
damage there is an associated division of surviving
satellite cells, which mature into myoblasts and
fuse to form new myotubes. A crucial, but poorly
understood, stage during this process is the stimulation
of satellite cells to divide. However, it does
appear that invasion by macrophages seems an essential
prerequisite for regeneration, possibly by
somehow stimulating satellite cell division.[23] Indeed,
it is strongly suggested that macrophage infiltration
is an important part of the regeneration
phase particularly in terms of satellite cell proliferation.[
54-56]
A brief review of the muscle damage and repair
cycle has been presented. This has, in no way, exhausted
the information available on the processes
involved, but does give a general introduction to
an area, which, although well investigated, is still
not thoroughly understood. The muscle damage
and repair cycle is summarised in figure 1.
A more recent area of interest with regard to
muscle damage is the potential protective effect of
estrogen. In the following sections is an explanation
of the possible mechanisms for the protective
role of estrogen in the muscle damage and repair
cycle.
2. Estrogen and Muscle Damage
Estrogen has an apparent protective effect on
cardiac, smooth and possibly skeletal muscle in
terms of damage and inflammation. For example,
the lower incidence of atherosclerosis and other
cardiovascular diseases in pre-menopausal females
compared with age-matched males is believed
to be partially attributable to the protective
effect of the female sex hormone estrogen.[57-63]
Estrogens are a group of 18-carbon steroids secreted
primarily by the ovary and, to a lesser extent,
the adrenals in females, and in smaller quantities
from the testes and adrenals in males.[64] The
term estrogen refers to three structurally similar
steroid hormones, estradiol-17β (E2), estrone (E1)
and estriol (E3). Of these, E2 is the primary estrogen
in humans and the one with the greatest estrogenic
properties,[63,65] and as such is studied in the
majority of investigations.[64] Estrogen is believed
to have a high antioxidant capacity, membrane
stabilising properties and a gene regulatory effect.
Through one, or all, of these interrelating properties
it has been suggested that estrogen could play
a role in reducing skeletalmuscle damage. The processes
involved in muscle damage have already
been shown to be complex with many interactions
between processes. Thus, the way in which estrogen
may have an effect in reducing skeletal muscle
Exercise-Induced Muscle Damage and Estrogen 109
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damage (if indeed it does) is very difficult to determine.
Nevertheless, the review considers the possible
effect of estrogen across the muscle damage
and repair cycle, including initial events, secondary
damage, inflammatory processes and regeneration.
The review is presented within subsections
Exercise
eccentric/unaccustomed/prolonged
Mitochondrial
calcium
accumulation
Lysosomal
proteases
Phospholipase
A2
leukotrienes +
prostaglandins
Calcium-activated
proteases
Calpain
Free radical
oxygen species
production
Loss of Ca2+ homeostasis
Neutrophils and/or cytokines
Neutrophils
Macrophages
ED1 ED2
Increase adhesion
and prime leukocytes
Cytokines
TNF/IL-1/IL-6
Mechanical
· high specific tension
Phagocytosis
(removal of debris)
Repair
Regeneration
(stimulation of satellite cells)
Reactive oxygen
species (respiratory burst,
breakdown of debris)
Metabolic
· high temperature
· insufficient mitochondrial respiration
· lowered pH
· free radical production
Autogenic
processes
Areas where estrogen may play a potential inhibitory role
Fig. 1. Illustration of a simple model of the muscle damage and repair cycle. TNF/IL-1 = tumour necrosis factor/interleukin-1.
110 Kendall & Eston
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but the interaction between processes and thus subsections
should not be forgotten.
2.1 Estrogen as an Antioxidant
An antioxidant is a molecule with a relatively
strong reductant property to quench/scavenge/neutralise
the unpaired electron from free radical species.[
27] A common denominator for these compounds
is that their molecular structure is based on
a carbon-ring structure, which originates fromphenol
species.[27] Phenol species have one or more
hydroxyl groups, which have a unique ability to
reduce electrons.[27]
Lipid peroxidation is a free radical-mediated
chain reaction, which can be initiated by the hydroxyl
radical attacking polyunsaturated fatty
acids in membranes, which results in oxidative
damage[66] and ultimately affectsmembrane stability.[
63] It has been demonstrated in vitro and in vivo
in both rat and human investigations, that estrogen
(at physiological and supraphysiological concentrations)
possesses a potent antioxidant characteristic,[
63,66-75] although themechanisms by which
estrogen acts as an antioxidant have not been fully
determined. Estrogens do possess a hydroxyl group
on their A (phenolic) ring, in the same configuration
and position as tocopherol (vitamin E) [known
to possess a strong antioxidant capacity][65,73,76]
and similar to thyroxine,[68] which also possesses
potent antioxidant activity. Estrogen may donate
hydrogen atoms fromthe phenolic hydroxyl group,
thus terminating peroxidation chain reactions, in a
way similar to tocopherol.[63,65,68,73,76]
An increase in oxygen radical production results
in a decrease in tocopherol concentrations as
a result of the above reaction.[65] However, this has
only been shown to occur in studies with male and
sexually immature female rats[77,78] in which estrogen
levels are obviously low. Sexually mature female
rats (high estrogen) are not affected in the
same manner, that is, tocopherol levels are maintained.[
79] These results suggest that estrogen may
offer an additional line of defence against oxygen
free radicals and may render skeletal muscle less
susceptible to exercise-induced oxidative damage.[
65]
2.2 Estrogen and Membrane
Stabilisation
Due to its figuration and antioxidant capacity,
estrogen is believed to have membrane stabilising
characteristics. It has been suggested that estrogen
may protectmembranes fromperoxidative damage
by decreasing membrane fluidity and increasing
membrane stability in ways similar to cholesterol.[
80,81] Estrogen is a fat-soluble hormone and
this type of stabilisation involves an interaction between
membrane phospholipids and estrogen in
ways similar to the stabilising mechanisms of tocopherol
and cholesterol.[63,76,80] As steroid hormones
are lipophilic,[82] they intercalate into the
bilayer of the cell plasma membrane, potentially
altering the fluidity and function of the membrane.
The ability to decrease membrane fluidity has
been demonstrated forE2 and related compounds.[66]
Wiseman and Quinn[81] demonstrated a positive association
between decreased membrane fluidity
and antioxidant ability. They stated that this ability,
by estrogen in particular, to decrease membrane
fluidity is a mechanism of their antioxidant action,
which results in stabilisation of the membrane
against peroxidation.
2.3 Estrogen and Gene Regulation
Pro-inflammatory cytokines, for example IL-6
and TNFα have been shown to increase during the
muscle damage and repair cycle.[32,83-88] Nuclear
factor kappa B is known to govern gene expression
involving various cytokines and cell adhesionmolecules[
89-92] and it has been shown that tocopherol
inhibits the activation of this factor.[92] Yoshikawa
and Yoshida[92] demonstrated that tocopherol can
prevent leucocyte-endothelial cell adhesion by inhibiting
signal transduction. They concluded that
tocopherol may have a protective effect against the
progression of inflammation. Research suggests
that it could be the antioxidant properties of tocopherol
which leads to this gene regulatory effect.[
92-94] Caulin-Glaser et al.[95] explained that es-
Exercise-Induced Muscle Damage and Estrogen 111
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trogen has been shown to have important gene regulatory
effects,[96-98] which again could be explained
through its strong antioxidant capacity.
Therefore, estrogen could affect the expression of
adhesion molecules and possibly allay further
damage (reduce infiltration of cells such as neutrophils)
but in doing so, inhibit inflammatory and
repair processes.
It would appear that estrogen may have a capacity
to reduce muscle damage, based on the above
three interacting processes. This possible protective
role of estrogen and the subsequent effect upon
the muscle damage and repair cycle is presented in
figure 2. There follows a review of the research in
this area and a discussion of how the interacting
processes outlined above may account for recent
observations in the literature.
3. Estrogen and Muscle
Damage Research
3.1 Effect of Estrogen on Creatine
Kinase Activity
CK is a commonly measured marker of muscle
damage, although its interindividual variability has
been criticised.[99] Despite this, a large difference
in CK activity has been demonstrated between
males and females, which has generally been attributed
to the effect of estrogen.
Women have been shown to have lower CK activity
at rest[100] and show less CK efflux after bicycle
exercise[101] or long distance running.[102,103]
In addition, Bär et al.[104] investigated the effects
of 2 hours of running in rats on CK activity. They
observed that ovariectomised females (source of
Membrane
stabilising
Gene
regulatory
Membrane
stabilisation
Adhesion molecule
expression reduced
Antioxidant
Free radicals
reduced
Reduction in
neutrophils
Reduction in
cytokines
Mechanical
damage
reduced
Further
reduction
in free
radicals
Poor
breakdown of
debris
Poor
removal of
debris
Inhibition of
repair stimulus
Further
reduction
of neutrophils
Reduction in
macrophages
Metabolic
damage
decreased
Free radicals
reduced
Reduction in
initial damage
Suppression of
inflammation
A possible
crossover point
Inhibited repair
and regeneration
Compromised repair
Fig. 2. Summary of how the interacting properties of estrogen potentially play a role in the muscle damage and repair cycle. To date,
it is not known whether estrogen-mediated inhibition of inflammatory processes would compromise repair. The potential effect of
estrogen during the early stages of the muscle damage and repair cycle may reduce injury sufficiently that an inflammatory cascade
would not be initiated. Alternatively, the inflammatory response may be required to allow the muscle to regenerate properly. To the
right of the possible crossover point indicated in the figure, inhibition by estrogen may potentially have a negative effect.
112 Kendall & Eston
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estrogen removed) showed similar levels to male
rats and that feeding of exogenous estrogen to this
group and to male rats reduced the efflux of CK.
Following a similar exercise protocol, Amelink
and Bär[105] reported that CK activity was 335% of
baseline in males, but remained unchanged in females.
As CK activity gives an indication of membrane
integrity, the research strongly suggested
that estrogen results in greater membrane stability.
It remains to be confirmed, however, if the reduction
in CK efflux is simply an indication of increasedmembrane
stability or whether themuscles
are in fact receiving less damage. Research in this
area has been minimal and inconclusive. Although
there is agreement regarding the CK response,[96-100]
the actual protection in terms of the aetiology of
muscle damage is undetermined. These findings
have led to more recent and in-depth investigations
into muscle damage and estrogen.
3.2 Histopathological Studies
Van der Meulen et al.[106] and Dumke[107] measured
histological damage and enzyme release following
a treadmill protocol in rats. Van derMeulen
et al.[106] found that gender differences in enzyme
release after exercise did not reflect differences in
the amount of histological damage (assessed by
multiple central nuclei, hyaline aspect, multiple
vacuoles and infiltration by inflammatory cells).
Dumke[107] observed that there were significant
differences between a placebo-treated and an E2-
treated group of ovariectomised females in CK activity
(reduced CK activity in E2-treated group),
but no significant differences in histological damage.
This suggests that estrogen offers no real protection
against damage, but simply helps maintain
a more stable membrane. These procedures assumed
a similar time course for males and females
and only measured histological damage once, not
following damage fully. It would therefore be difficult
to determine if muscle damage was indeed
the same in the two groups observed.
Adirect contradiction of the findings by Van der
Meulen et al.[106] and Dumke[107] are those by
Reijneveld et al..[108] A marked attenuation of the
CK response, as found in many of the studies in
this area,[101,104,105] was concurrent with a decrease
in the amount of histological damage. Clearly this
area requires further investigation.
Warren et al.[99] reported that only functional
measures could give a true indication of the extent
of muscle damage. They indicated that in both human
and animal studies, the histopathology of
muscle fibres following eccentric exercise correlated
poorly with functionalmeasurements, both in
terms of magnitude and the time course of the impairment.
Furthermore, the histological method of
assessing muscle damage has been criticised because
specimens obtained from a muscle biopsy
represent only a small fraction of the involved
muscle. They therefore strongly recommended that
measures that indicate changes in function should
be incorporated to assess and follow muscle damage.
3.3 The Effect of Estrogen on
Indirect and Functional Measures of
Muscle Damage
Buckley-Bleiler et al.[109] investigated the response
of women at different ages to exercise-induced
muscle damage. Comparisons were made
between pre-pubescent, eumenhorrheic and postmenopausal
females. They found no significant
differences between these groups in measures of
CK, muscle soreness and maximal isometric
strength. However, these results should be interpreted
with caution. The method of inducing muscle
damage was 40 maximal isometric contractions,
which may explain why the reductions in
strength and CK were small. As explained previously,
activities that contain eccentric contractions
produce more muscle damage and soreness
than other types of contraction. Therefore, this type
of exercise protocol was possibly not sufficient to
induce significant levels of damage to determine if
differences existed in the age groups.
Thompson et al.[110] investigated the effects of
regularly ingesting estrogen, in the form of oral
contraceptives (at least 30mg ethinylestradiol for
more than 6 months), on post-exercise muscle
Exercise-Induced Muscle Damage and Estrogen 113
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damage of the lower extremities especially the
quadriceps, following a bench stepping regimen.
The only criterion measure that showed a group by
time interaction was soreness, with oral contraceptive
users reporting less soreness than the nonusers.
The authors concluded that estrogen was ineffective
at attenuating muscle damage. However, as the
only measures of damage that showed significant
differences from baseline were soreness and range
of motion, it is therefore possible that the damageinducing
protocol was not sufficient to elicit significant
differences in other factors between the
two groups. In addition, the sample size in the two
groups was small (control = 6, oral contraceptive
group = 7), which again makes any strong conclusions
difficult. Nevertheless, an interesting observation
from this study was the differences between
the groups in perceived soreness. This has been
replicated in our laboratory, where following eccentric
exercise of the elbow flexors, the only
marker ofmuscle damage to show a significant difference
between oral contraceptive users and nonuserswas
perceived soreness on activation.[111] The
effect of estrogen on pain will be discussed in section
4.
Rinard et al.[112] investigated the effects of eccentric
exercise of the elbow flexors on a large
sample of adult males (n = 82) and females (n =
83). There were no differences between males and
females on relative changes in isometric strength
and soreness, althoughwomen showed the greatest
loss in range of motion, as measured by relaxed
arm angle. With such a large sample size it would
appear that estrogen has no protective effect on
muscle damage. However, it should be noted that
participants were selected based on their soreness
response, thus making generalisations from the
study very difficult.
3.4 Estrogen, Time Course of Muscle
Damage and Immune Response
In general, the studies reviewed so far have been
concerned with the initial effects ofmuscle damaging
exercise. They do not consider the damage over
its full time course. In addition, there has been no
attempt to consider possible differences in immune
response to the insult of damaging exercise between
males and females. As explained previously,
after the initial mechanical/metabolic damage to
the muscle, there follows a multitude of events resulting
in secondary damage and eventual repair.
Infiltration of the muscles by neutrophils and macrophages
may not occur until 24 to 96 hours after
the exercise and may persist for over a week.[113]
This is an area that has recently received greater
attention, and has enhanced our understanding of
the gender differences in muscle damage and repair.
3.5 Estrogen and the General
Inflammatory Response
Komulainen et al.[114] investigated the time
course of structural changes within the muscle following
downhill running. The results demonstrated
that the general histopathological changes in both
genders were essentially similar, but that these occurred
more slowly (myofibre swelling) and to a
lesser extent (necrosis and macrophagy invasion)
in females than in males.
Tiidus and Bombardier[113] hypothesised that
as estrogen may be responsible for differences in
gender-related susceptibility ofmuscle to exerciseinduced
muscle damage, and may act as an antioxidant,
it would be of interest to determine the effects
of estrogen administration on phagocytic
cell infiltration of the muscle following exercise.
They hypothesised that diminished neutrophil and
macrophage infiltration may ultimately reduce the
time-course and severity of the inflammatory response
of the muscle after exercise and possibly enhance
the healing process. Conversely, it could have
a negative effect by hindering repair. These investigators
measured post-exercise tissue myeloperoxidase
activity inmale and female ratswhich were
treated (40 μg/kg bodyweight) and untreated with
estrogen. Their results suggested that estrogen
might significantly affect post-exercise leucocyte
infiltration into skeletalmuscle. Themechanism by
which this may have occurred is difficult to determine,
as the control of infiltration by neutrophils
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and macrophages is complex. Factors affecting
these processes include calcium homeostasis and
calpain production, cytokines, oxygen free radical
activity and prostaglandin E2,[45,113,115] to name
but a few, with interactions amongst these given
factors. This and the possible effect that estrogen
has on some of these factors will be discussed in
section 3.6.
Stupka et al.[116] reported that the possible difference
in the extent of muscle damage between
males and females is caused by differences in the
inflammatory response and not by differences in
sarcomere damage. They demonstrated that following
an eccentric protocol, women showed less
muscle inflammation compared with men despite
the same amount of z-line streaming. This has implications
when considering regeneration and in
fact the female muscle may be compromised in
terms of regeneration, despite experiencing a similar
amount of initial damage.
St Pierre Schneider et al.[52] investigated the
time course and concentration of leucocyte invasion
in injured soleus muscles of male and female
mice, to determine if any gender differences existed.
Leucocyte invasion began 1 day after injury
in both genders and diminished on day 5 in males,
but remained evident after day 7 in females.During
the period of maximal leucocyte invasion at 1 day
after injury, muscle sections from males contained
more fibres invaded by acid phosphatase-positive
cells than muscle sections from females. They suggested
that estrogen prevented elevated macrophage
concentrations in blood vessels by limiting
the availability of endothelial cell adhesion molecules.
This suggests that estrogen could reduce
macrophage or other leucocyte emigration into inflamed
tissue, because fewer endothelial cell adhesion
molecules result in an inability of leucocytes
to move out of blood vessels and into the area of
inflammation. They therefore postulated that removal
of damaged myofibres is slower in the female
mice.
A direct contradiction to these studies are the
findings from MacIntyre et al.,[117] who observed
a greater presence of neutrophils in muscles of
women 4 hours after exercise compared with men.
They concluded that this was probably caused by
increased adherence and migration of neutrophils
into themuscle. As exercise workload was normalised
to body mass and was not significantly different
between the two groups, the results suggest that
estrogenmay be themost likely factor affecting the
infiltration of the inflammatory cells into the muscle.
The observation of differences in leucocyte
concentration or time course of infiltration between
males and females does not provide substantive
evidence that the damage-repair process is mediated
by estrogen concentration. As previously
explained, many complex events occur that result
in migration and infiltration of these cells and will
be discussed further.
3.6 Estrogen and Specific Events
Associated with Inflammation
3.6.1 Calcium
The loss of Ca2+ homeostasis is believed to be a
major factor resulting in the cascade of autogenic
and inflammatory processes in muscle degradation.
Prakash et al.[118] investigated the effect that
estrogen had on smooth muscle cells. They observed
that estrogen had an inhibitory effect on
Ca2+ influx, and also enhanced Ca2+ efflux via a
receptor mediated mechanism. It is expected that
this would reduce the Ca2+ overload, and therefore
suppress the cascade of events that can result in
more severe muscle damage. If the same is true for
skeletal muscle, this could be an important process
by which estrogen may affect the inflammatory response
to exercise-induced muscle damage.
Jovanovic et al.[119] demonstrated that physiological
levels of E2 provided resistance to female,
but not male cardiomyocytes against intracellular
Ca2+ loading. As in skeletal muscle cells, Ca2+
loading in cardiac muscle leads to cell injury. It is
possible therefore that the protection conferred by
estrogen in cardiac muscle may also be found
within skeletal muscle, preventing, or certainly
dampening, the secondary muscle damage pro-
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cesses. However, this requires empirical verification
with skeletal muscle cells.
Arecent investigation by Tiidus et al.[120] seems
to suggest that estrogen has the potential to reduce
Ca2+ overload within skeletal muscle following an
exercise protocol. In the calpain hypothesis proposed
by Belcastro et al.,[45] a very important role
is suggested for this Ca2+ sensitive protease, including
chemotaxis of leucocytes (see section
1.3.2). The investigation by Tiidus et al.[120] demonstrated
that following an exercise protocol,
ovariectomised rats treated with estrogen, not only
showed significant attenuation of 1-hour postexercise
neutrophil number and myeloperoxidase
activity, but also reduced calpain-like activity, compared
with placebo-treated ovariectomised rats.
They suggested that estrogen supplementation increased
post-exercisemuscle sarcolemma stability,
possibly preventing Ca2+ influx into skeletal muscle
and therefore preventing the activation of
calpain. This would consequently lead to diminished
calpain-induced proteolysis and neutrophil
chemotaxis.
Although the above study was limited to 1-hour
post-exercise observations only, the findings certainly
suggest an important role for estrogen within
this specific (Ca2+ and calpain) process of the muscle
damage and repair cycle.
3.6.2 Adhesion Molecules
To enter the inflamed tissue, leucocytes bind to
specific adhesion molecules of endothelial cells
that line blood vessel walls.[52] St Pierre Schneider
et al.[52] attributed the reduced leucocyte infiltration
in injured soleusmuscle to the inhibitory effect
of estrogen on adhesion molecules.
Previous research has shown that E2 can inhibit
cytokine-mediated endothelial cell adhesion molecule
activation, thereby reducing leucocyte chemotaxis
and adhesion.[95] However, Cid et al.[121] reported
that estradiol treatment of cultured human
umbilical vein endothelial cells stimulated up to a
2-fold increase in TNFα-induced adhesion of leucocytes.
This is a very complex area. In general, it has
been found that women of childbearing age are
more susceptible to autoimmune diseases (involving
an up-regulation of immune response)[122-125]
and this has been suggested to be caused by estrogen.
This could in some way explain the findings
of Cid et al.,[121] who explained that their results
demonstrate that estradiol has important regulatory
functions in promoting leucocyte-endothelial cell
interactions. It is unclear why Caulin-Glaser et
al.[95] and St Pierre Schneider et al.[52] observed a
different relationship. To elucidate further on the
potential effects of estrogen on the specific aspect
of muscle damage and the inflammatory response
to muscle damage, further research on skeletal
muscle is warranted.
Cytokines are important factors in inducing the
expression of endothelial cell molecules.[126] The
possible effect that estrogen has upon cytokines is
discussed in section 3.6.3. Another important consideration
in relation to the influence of estrogen,
is the role that oxidative stress may play in regulating
adhesion molecule gene expression. Marui et
al.[126] tested the hypothesis that cytokines selectively
induced adhesion molecule gene regulation
through an antioxidant sensitive pathway. The
findings of their study suggested that regulation of
some adhesion molecules are reduced in the presence
of a potent antioxidant. As estrogen has been
demonstrated to have a strong antioxidant capacity,
it is feasible that it could also reduce expression of
these molecules through a similar pathway.
3.6.3 Cytokines
Cytokines are very important in orchestrating
inflammatory processes. Thus, any factor that can
regulate cytokines will also play an important role
in the inflammatory response. As previously explained,
there is an increased incidence of autoimmune
diseases in pre-menopausal females. Zuckerman
et al.[127] explained that the effect of estrogen
on autoimmunity and inflammation may involve
changes in secretion of inflammatory mediators,
for example, cytokines. They showed that treatment
of mice with pharmacological doses (0.2 to 2
μg/kg) of estriol resulted in a significant increase
in serum TNFα levels and a rapid elevation in serum
IL-6 levels following challenge.
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Both Schwarz et al.[128] and Angstwurm et
al.[129] investigated the influence of menstrual cycle
status upon cytokine levels. Angstwurm et
al.[129] found that during the follicular phase, the
increase of E2 was accompanied by an increase in
IL-6 (p = 0.07, r = 0.35). Following ovulation,
when progesterone rose therewas a 1.5- to 4.4-fold
drop in plasma IL-6. Schwarz et al.[128] demonstrated
that in male participants no differences existed
in cytokine response between initial samples
and those taken 1 to 3 weeks later. In pre-menopausal
females, release of TNFα and IL-6 was significantly
decreased in the luteal phase compared
with the male group and this difference was more
pronounced in females taking oral contraceptive
pills. In addition, they found a diminished response
during the luteal phase compared with the follicular
phase. Thus, it would appear that estrogen has
an inhibitory effect on cytokine activation. However,
Schwarz et al.[128] also demonstrated a positive
correlation between the concentration of estradiol
in plasma and the release of TNFα and IL-6
following a challenge during the luteal phase.
These two studies demonstrate the complicated
relationship between estrogen and cytokines. During
the follicular phase (when estrogen is at its lowest)
cytokine release was enhanced compared with
the luteal phase. However, during the luteal phase,
cytokine release has a positive relationship with
estrogen concentration.
Pottratz et al.[130] reported an inhibitory effect
of E2, in in vitro and in vivo studies. These investigators
observed that ovariectomised mice demonstrated
an up-regulation of granulocytes and
macrophages and that such changes could be prevented
by a neutralising antibody against IL-6, as
well as estrogen replacement. They suggested that
the inhibition of IL-6 production by E2 was via a
receptor-mediated action.
Chao et al.[122] observed that estrogen can, in
some cases, inhibit and in others stimulate cell-mediated
immune function. They concluded that
within the physiological range of E2, TNFα release
is finely regulated and dramatically affected by relatively
small changes in hormone concentrations.
The complexities of this area are clearly demonstrated
in this review. Estrogen is known to have
a potent antioxidant capacity and a membrane
stabilising ability. As free radicals are implicated
in the development of damage (metabolic stress),
propagation of damage (respiratory burst) and
even to some extent repair, it would seem a fair
assumption that an antioxidant would play a role
within this damage, inflammation and repair cycle.
In addition to this direct effect upon the skeletal
muscle cells, oxygen free radicals may also play a
role in mediating other factors associated with the
inflammatory response, for example pro-inflammatory
cytokines.[33] This, in turn, can prime leucocytes
enhancing superoxide production. Thus, a
reduction in initial free radical production, possibly
through estrogen, could feasibly reduce inflammation.
In addition to this, estrogen may also
have a direct effect upon specific events within the
inflammatory process, for example Ca2+ overload,
cytokines, and adhesion molecules. These factors
of course are themselves not mutually exclusive; a
reduction in cytokines will have a direct effect
upon adhesion molecule expression. It seems that
there are several possible levels at which estrogen
could play a role within the muscle damage and
repair cycle, as presented in figure 2.
Thus, the literature on the time course and immune
response of males and females to exerciseinduced
muscle damage is sparse, ambiguous and
equivocal, and clearly requires further investigation.
In addition, further research would help to
determine whether the possible inhibition of the
immune response either: (i) aids repair by reducing
further secondary damage; or (ii) is negative in
terms of the repair and the return of normal function
to themuscle. Tidball[47] stated that inflammatory
cells in injured muscle have been implicated
in several aspects of successful repair. As explained
previously, ED2+ cells have been shown
to stimulate repair processes. Thus, it could be suggested
that inhibition of inflammatory processes
has the potential to compromise regeneration. Research
into nonsteroidal anti-inflammatory drugs
and muscle regeneration have been inconclusive,
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with reports of both compromised[131] and uninhibited
repair.[132] Understanding the role of estrogen
in terms of repair would be useful to both recreational
and elite sports participants.
4. Estrogen and Pain Perception
In addition to the potential mediating effect of
estrogen on the muscle damage and repair cycle, it
may also affect the perception of pain associated
with muscle damage. Individuals with higher levels
of estrogen (oral contraceptive users) have
shown similar responses in markers of muscle
damage to those with lower levels (non-oral contraceptive
users) following a bout of damageinducing
exercise, but have reported significantly
less soreness.[110,111] The potential ability for sex
steroids to modulate pain has been investigated but
findings have been inconclusive. In addition, the
suggested mechanisms by which sex hormones are
able to play a role are equivocal.
A review article by Bethea et al.[133] indicated
that the ovarian steroid hormones, estrogens and
progestogens, affect the function of the serotonin
neural system. While this has the capability to impact
upon mood, cognition and other autonomic
functions, serotonin is also associated with pain
perception.
Riley et al.[134] reviewed 16 studies that investigated
pain perception across the menstrual cycle in
healthy females. They observed that for pressor
stimulation, cold pressor pain, thermal heat stimulation
and ischaemic muscle pain, a clear pattern
emerged. It was shown that during the follicular
phase higher pain thresholds were demonstrated.
The authors acknowledged the enormous problems
within the literature regarding determination of the
menstrual cycle phase, length of phase and even the
terminology associated with the phase, making
generalisations across studies difficult. Nevertheless,
the results of this review suggest that when
estrogen and progesterone are at their lowest, pain
thresholds are at their highest. Potentially, this suggests
that estrogen and/or progesterone increase
sensitivity to pain.
In contrast, Martinez-Gomez et al.[135] investigated
tail flick latency across the cycle in rats.
Shorter latencies were recorded in phases with
lower estrogen. Ovariectomy (removal of estrogen
source) abolished these fluctuations. Administration
with estrogen, but not progesterone increased
response time, which suggests that estrogen increases
pain thresholds. Similarly, Rao et al.[136]
carried out a very simple investigation on pain perception
across a broad range of participant groups.
They showed that the pain threshold was low in
oophorectomised women (who were not on hormone
replacement therapy), boys and girls, intermediate
in males, but high in oral contraceptive
users and normally menstruating women. Fluctuations
in pain thresholds occurred in menstruating
women, with higher thresholds midcycle, when estrogen
concentrations are highest. While findings
are inconclusive, there is certainly the possibility
that estrogen and progesterone can potentially play
a role in the perception of pain.
The human body contains its own mechanism
for dealing with pain. Endogenous opioids are neuropeptides
that have an analgesic property. These
include enkephalins, endorphins and dynorphins,
which have the capability to modify pain transmission
and inhibit prostaglandin synthesis.[137] These
opioids are released in response to stimuli such as
pain or stress, and produce their effect by binding
to opioid receptors located in the brain and spinal
cord.[138] These receptors include mu (μ), kappa (κ),
and delta (δ) receptors. It has been suggested that
both estrogen and progesterone could potentially
play a role within this natural pain relief system.
Antinociception of pregnancy and parturition has
been observed in rats[139-141] and in women.[142,143]
It has been suggested that the elevated levels of the
hormones estrogen and progesterone can account
for these effects. Pseudopregnancy has been investigated,
by manipulation of these hormones, to separate
the effects of these hormones from other
events associated with pregnancy. The findings of
these investigations show a higher pain threshold
in pseudopregnant rats.[144-147]
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Some authors take the standpoint that the high
levels of these hormones during pregnancy and
pseudopregnancy result in the activation of opiate
receptors, mediating the analgesia. Research using
receptor antagonists has reinforced this suggestion.[
144,146] Conversely, other research has rejected
such a conclusion.[148]
Estrogen receptors have also been suggested to
play a role in this natural analgesia. Estrogen receptors
are present on small-diameter dorsal root
ganglion neurons.[149] Estrogen has been shown to
regulate the expression of messenger RNA encoding
receptors, which modulate nociception.[149]
Additionally, it has been shown that enkephalin
synthesising neurons display intracellular estrogen
receptors,[150] which have been demonstrated to increase
the gene expression of an enkephalin precursor.[
150,151]
Thus, although equivocal, the research demonstrates
the potential for estrogen to mediate pain
perception. Studies investigating exercise-induced
muscle damage and estrogen levels therefore need
to consider the possibility that estrogen levels may
also mediate the perception of pain.
5. Implications for Further Research
The implications for further research are clearly
dependent on verification of the role of estrogen in
muscle damage. This therefore requires further investigation.
At what levels does estrogen have an
effect during the damage and repair cycle? Are
these effects in fact negative because of inhibition
of inflammation, a necessary process for clearance
of debris, or is the initial damage reduced sufficiently
so that an inhibited inflammatory response
is non-consequential?
If estrogen is found to play a role within the
muscle damage cycle, then implications and applications
are considerable and require further investigation.
For example, it may not be appropriate to
ignore gender when conducting muscle damage research.
Fluctuations in estrogen found across the
menstrual cycle may need to be considered within
a training environment and schedule, as should the
perception of pain as a gauge of damage.
Another area of research is the possible negative
effect of estrogen on, for example, tissue regeneration.
Are females less protected from the repeated
bout effect, because of inhibition of repair following
the initial bout of damage?
There are also health considerations for
postmenopausal females. Older males have the advantage
of testosterone, known for its anabolic
properties, to help maintain, in some way, their
muscle mass. Postmenopausal females could
therefore benefit from estrogen replacement in
terms of protecting their skeletal muscle from degeneration.
Phillips et al.[152] have shown that there
is no significant difference in the specific force of
muscles between young males and premenopausal
women. However, around the time of the menopause
therewas a dramatic decline in specific force
in women, which was prevented by the use of hormone
replacement therapy. In men, weakness
started later and the declinewasmore gradual. This
decrease in strength associated with reduced levels
of estrogen is believed to account for the increases
in falling incidents in postmenopausal women.[152]
Naessen et al.[153] also found that estrogen replacement
therapy has a positive effect in terms of postural
balance in postmenopausal females. However,
direct contradictions to these findings have
also been reported.[154-157]
6. Conclusion
Research in terms of the protective effect of estrogen
against skeletal muscle damage is sparse,
especially in terms of secondary damage and inflammatory
processes. Assumptions and theories
on the possible protective role of estrogen on skeletal
muscle can be made based upon the known
properties of estrogen and research carried out on
cardiac and smooth muscle. However, specific
skeletal muscle research is required for any true
assumptions and conclusions to be made.
Acknowledgements
The authors have no conflicts of interest.
Exercise-Induced Muscle Damage and Estrogen 119
 Adis International Limited. All rights reserved. Sports Med 2002; 32 (2)
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Correspondence and offprints: Becky Kendall, School of
Sport, Health and Exercise Sciences, University of Wales,
Bangor, LL57 2PX, UK.
E-mail: [email protected]
Exercise-Induced Muscle Damage and Estrogen 123
 Adis International Limited. All rights reserved. Sports Med 2002; 32 (2)

 

[Cypefececlacy]

Nice forum, hi from a new member

Hello, New here just wanted to say hi

hey everybody

Just signed up, thought i'd say a quick hello

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