How Estrogen Influences Female Muscle and Tendon

Effects of Estrogen on
Female Muscle & Tendon
LAUREN JARMUSZ, PT, DPT,
OCS
STANFORD ORTHOPEDIC &
SPORTS MEDICINE PHYSICAL
THERAPY DEPARTMENT
JANUARY 29TH, 2020

Objectives
1. Review physiology of muscle and
tendon in respect to: sex, age, and
estrogen cycle.
2. Educate audience on how estrogen
effects female muscle and tendon
tissue. THE WHY?
3. Start a conversation & Inform
audience on best PT practices to
optimally treat female muscle and
tendon dysfunction throughout
lifespan

60 second
check in.
1) Do you believe estrogen influences
tendon and muscle tissue?
2) If yes. Provide 2 ways in which estrogen
may effect tendon and muscle tissue.
3) Are you currently doing anything in
your clinical practice to address the
effects of estrogen on connective tissue?

Background 1-3
 ~50% of the US population is female
Female: Male ratio of 51:49 (2010-217)
 58.2 % of US civilian labor force is female (2014-2018)
 Female engagement in collegiate sports continues to
be on the rise; increasing from 74,239  221,042 since
1983

Problem
Women differ from men regarding muscle and tendon,
due to differences in sex hormones, and tissue
response.
Literature on the interactions of muscle & tendon tissue
and estrogen has been scarce
 ACL, Achilles Tendon, Patellar Tendon

Females vs Male Injury Rates
 Greater risk of LE musculoskeletal injuries during functional
activities 1-3
 Greater incidence of knee related injuries 3-6: knee sprains 7,8,
ACL injuries 3,4,9,10, meniscal and cartilaginous tears 4, and
patellofemoral disorders 11-14
 High school basketball players are 3.8x the risk of ACL injury.
15-16
 Collegiate soccer and basketball players demonstrate 2x the
risk of ACL and cartilage knee injury rates 3,4,13.
HYPOTHESIS: musculoskeletal
joint stability has been implicated
as contributing factor to female
injury.
Primary Male vs Female
Differences:
1. ESTROGEN (Sex Hormones)
2. Anatomical alignment & effect
on biomechanics

Systems
ENDOCRINE 1
 Endocrinology is the study of the mechanisms that
regulate essential body functions such as reproduction,
metabolism, water balance, feeding, and growth.
 Endocrine Hierarchy: hypothalamic–pituitary–thyroid,
hypothalamic–pituitary–adrenal, and hypothalamic–
pituitary–gonadal axes
The endocrine, immune, and nervous systems are
intimately linked and mutually influence each other.
MUSCULOSKELETAL 2
 The musculoskeletal system provides form,
support, stability, and movement to the body. It
is made up of the bones of the skeleton,
muscles, cartilage, tendons, ligaments, joints,
and other connective tissue that supports and
binds tissues and organs together.
 We are aware that the musculoskeletal and
nervous systems are intimately linked

Estrogen 1
Estrogen is a steroid hormone, secreted primarily from the ovaries.
 Primarily involved in physiological functions of reproductive organs
 Performs various important roles in non-reproductive organs and tissues involved in such as skeletal, immune,
cardiovascular, and central nervous systems as well as in those metabolism 2,3
 Low estrogen state experienced by women following menopause can affect the physiological functions of these
non-reproductive systems, specifically causing osteoporosis, lipid abnormalities, obesity, atherosclerosis, and
dementia 4567
 Decrease in estrogen level associated with athletic amenorrhea (RED-S) can lead to bone weakness and fatigue
fracture 8,9,10
Estrogen is considered to prevent a decrease in bone mass by acting directly on osteoblasts, osteocytes and
osteoclasts 11,12,13,14

Muscle
 Skeletal muscle accounts for 30–40% of the
total body weight in humans. 1
 Responsible for movement & glucose and lipid
metabolism. 1
 Skeletal muscle mass decreases motor
function declines obesity and metabolic
syndrome can develop 234
Muscle fibers present in women being smaller
in cross- sectional area in all the fiber types 5

Effects of Estrogen on Muscle
(General)
 Sex hormones play an important role in muscle homoeostasis 1
 inhibits disuse-induced muscle atrophy 2 3 4 5
 positive effect on muscle regeneration after injury or reloading 6
 decreases exercise-mediated muscle injury  inhibition of
inflammatory responses and increases the growth of satellite cells
after exercise 7,8
 improves muscle exercise endurance through mitochondrial
regulation 9
 Improves cross link bridging of actin & myosin 10 11

Premenopausal Muscle

 Muscle collagen synthesis was
increased 24 h post exercise
compared with resting values in
controls.
BUT
 No response to exercise was
observed in OC users.

Postmenopausal Muscle

Effects of Aging on Muscle
 Decline of sex hormone levels assumed to cause sarcopenia and
frailty 1,2
Cross-sectional area of skeletal muscle decreases & fiber types
shifts to a slower profile. 3
Decrease in mitochondrial number and enzymes  reduced
exercise endurance 3
 Sarcopenia: decrease of the total number of muscle fibers and
atrophy specific to type II fibers 4-8

Dynapenia: age-associated loss of muscle
strength that is independent of muscle
atrophy (sarcopenia) 123
Estrogen deficiency
contributes to
’dynapenia’ &
‘sarcopenia’
NS intimately
connected to
endocrine (estrogen)
& immune systems

What happens a woman’s muscular system
after menopause? 1
 Menopause = permanent cessation of menstrual cycle
 Typically occurs in women in their late 40s or early 50s
 Estrogen is reduced to a negligible level
 Reduced production of Satellite cells (muscle stem cells) 4-8
 Reduced responsiveness to anabolic stimuli (ie: exercise) and
feeding = explanation for the net loss of muscle mass in elderly
women. 23

Effects of estrogen on muscle throughout life cycle. 1
Regular Cycle:
 No significant effects noted
 Miller et al.  Protein synthesis did not differ
PRE-MENOPAUSAL WOMEN
Oral Contraceptives (OC):
 Holm et al. OCs decrease muscle protein
synthesis 3
 decreases stimulating effect of exercise on
the synthesis of intramuscular connective
tissue 3

No Hormonal Replacement Therapy
 WEAK MUSCLES
 Estrogen deficiency  dysregulation in muscle
protein turnover  contributing to the loss of
muscle mass and weakness. 1
 Cross bridge formation is impaired and muscle force
force production in reduced 1
POST-MENOPAUSAL WOMEN
Hormonal Replacement Therapy:
 STRONGER MUSCLES
 Progesterone - estradiol treatment decreased the
rate of protein degradation and increased the rate of
protein synthesis 5,6,7
 Improvement in cross bridge formation and overall
muscle force production 8 9

Tendon 12
 Connect muscle to bone- transfer muscle generated force to the
bony skeleton
 Predominant energy storing tendons are the Achilles & patellar
tendons
 Primarily composed of: 28+ types of collagen
 Collagen Type 1: 90% / Collagen Type III: 10%
 Proteoglycans (protein): 1-5%
 transferring load between discontinuous collagen fibrils via interfibrillar bridges
 Glycoproteins and Other Molecules
 Entheses: gradual connection between tendon and bone, ~100
times stiffer than tendon.
 Myotendinous Junction: abrupt transition - tendon to muscle
connection; prone to injury

Tendinopathy
• Tendon tissue
homeostasis is based on
the ability of the
tendon cells to sense and
respond to mechanical
load through
mechanotransduction. 12
• Tendinopathy = inhibition
of homeostasis
Cook et al.

Female vs Male Tendon Differences 1234
MALE
 male hormones (testosterone) has not been
shown to have protective effect on tendons
higher collagen synthesis rate
 increased stiffness
 heavy loading induces tendon hypertrophy
 reduces the stress on the tissue during
loading.
FEMALE
 lower collagen synthesis rate
 reduced stiffness (pre-menopausal only)
 heavy loading does NOT induce tendon
hypertrophy  increases stress on the tissue
during loading.
 reduced ability to adapt to training compared
with men

 Limited research c confounding variables: multiple hormonal changes during the perimenopause, interactions with different cell
types, small sample sizes.
 Most scientific research has focused on 3 anatomical structures: ACL, Achilles tendon, and patellar tendon
 Research conducted on the effect of estrogen on tendon (and ligament) tissue can be divided into 4 groups:
1. Content of collagen type I
2. Stiffness
3. Failure load
4. Healing
Effects of Estrogen on Tendon
(General)

Effects of Estrogen on Tendon:
Content of Collagen Type I
 Collagen content declines with age and significantly post
menopause 1
 Increase in or addition of estrogen had a positive effect on
the overall collagen synthesis 23

Stiffness
STIFFNESS: amount of force necessary to achieve a certain amount of deformation in each object
or structure 1
 Stiffness is considerably lower in female tendon compared to males. 23
 Lysl oxidase mediates the formation of cross links between different ECM fibrils
 Amount of lysyl oxidase present is influenced by the levels of estrogen administered 67
 Inc. estrogen = decreased cross links = inc. tendon laxity
Adaptation of tendon stiffness in reaction to physical exercise appears to differ between women
and men  especially w/ post menopausal women 45

“Cut-off point”
(~40%MVC) for post
menopausal women
to optimally improve
tendon stiffness
The magnitude and
character of resistance-
training-induced increase in
tendon stiffness at old age is
gender specific.
- Pearson et al.
- ‘Age’ 2012

Failure to Load
FAILURE TO LOAD: force necessary to break a certain object or structure under usage of a given
application.
 All research has been performed using exclusively animal models to date 1
 4 publications in total: assessing the failure load of tendon and ligament tissue  unknown if
estrogen has a direct influence
However….
 Known connection between tendon failure load and stiffness and collagen  hypothesize
significant effect

Healing
TENDON & LIGAMENT HEALING: 1
1. Inflammation
2. Proliferation
3. Matrix Remodeling
 Estrogen & other steroid hormones = positive effect on the healing process of the skin. 23
however….
 results on whether these findings translate to tendons and ligaments are conflicting.

Premenopausal Tendon

 Tendon collagen protein synthesis rates
both at rest and after exercise were lower
in women exposed to a high concentration
of synthetic female hormones (OC)
compared with women exposed to a low
concentration of endogenous female
hormones (normal cycle)
 but a higher bioavailability of IGF-I (controls) in the
the peritendinous tissue and in the interstitial fluid
of the skeletal muscle

Postmenopausal Tendon

Effects of Aging on Tendon
 Age-related changes in tenocyte behavior  altered proliferation rate, ineffective repair
processes and increase in frequency of tendon injuries 1 2
 Multiple Hypothesis for Effects of Aging on Tendon:
 Altered tendon vascularity 3 4 5
 Slower metabolic rate for tenocyte-like cells  weaker tendon to bone healing response 6
 Decrease in muscle mass + structural changes in tendon = altered biomechanical response of
tendon tissue
 Overstimulation: Inc. in mechanical load  repetitive use  increase in degradative enzymes,
apoptosis, and = tendinopathy or tendon rupture.
 Under-stimulation: reduced load tolerance  apoptosis = tendinopathy or tendon rupture.

Effects of estrogen on tendon throughout life cycle. 1
Regular Cycle:
 Increased laxity in ligaments and tendons
noted during luteal (relatively high estrogen)
phase of their menstrual cycle.
PRE-MENOPAUSAL WOMEN
Oral Contraceptives (OC):
 Reduced laxity in ligaments & tendons due to
avoidance of natural cycle progression
 BUT…. Decreased tendon collagen synthesis

No Hormonal Replacement Therapy
 overall reduction in “protective effects” of sex
hormones on tendon
 ie: post menopausal women are equally as likely to
have Achilles tendinopathy vs pre premenopausal
women who are less likely to experience Achilles
tendinopathy
POST-MENOPAUSAL WOMEN
Hormonal Replacement Therapy:
 long term HRT use = decreased cross sectional area
& stiffness of tendons

MUSCLE:
(+) Improves muscle mass and strength
(+) Increases the collagen content of connective tissues.
TENDONS (& Ligaments):
(-) Estrogen decreases stiffness/ Increases laxity of tendons &
ligaments

Pre-Menopause 1234
??? Barr et all. 2019. UC
Davis argue ….

Effects of Estrogen on Muscle & Connective
Tissue in respect to ‘The Cycle’ 1234
HRT = hormonal replaceme
therapy
PRE-Menopausal Non-
Competitive Female
PRE-Menopausal
Competitive Female
Athlete
POST-Menopausal Female
• Normal cycling is
beneficial.
• Cycling of high estrogen
levels improve anabolic
response to exercise
• Avoid OC (if possible)
• Offseason/base training:
athletes should maintain
their normal cycling.
• Preparation phase training:
consider taking an oral
contraceptive w/ LOW levels
of synthetic hormones.
• HRT improves muscle mass and bone function.
• Long term HRT decreased tendon cross-sectional area
• Result: stronger muscle pulling on brittle tendon connected to a stiffer bone  results
in differences in stiffness between connected tissues  strain  injury.
• But, not taking HRT accelerates sarcopenia and osteoporosis.
• Therefore, HRT is beneficial for musculoskeletal function, but need to maximize tendon
function. (ie PT interventions)

Direct PT Treatments To
Improve Female
Musculoskeletal
Performance

Personally, how
does this
improve my
clinical care?

Loading Preferences
PRE-MENOPAUSAL
 Traditional neuromuscular
education and strength and
conditioning practices per PT dx.
 no specific training changes
required based on normal hormonal
regulation
 If pt is on OC, consider BFR
POST-MENOPAUSAL : HRT & NO HRT
 Heavy progressive load resistance training
 eccentric training to control load through aging
tendon
Eccentric loading to improve tendon
stiffness and prevent ECM disorganization
 <40% MVC loading to improve muscular
strength and maintain/improve tendon
stiffness.

Blood Flow Restriction Training
Post- Menopausal women exhibit:
 decreased muscle strength
 decreased collagen synthesis
 poor tendon hypertrophy response to heavy
loading
 respond optimally to <40% MVC to improve
tendon health (stiffness)
 low circulating IGF-1
 lowered production of satellite cells
BFR Training: Metabolite Theory 1234
 Stimulates GH production
 Strenuous exercise  inc. GH response  prepare for the collagen
breakdown.
 low loads do not cause breakdown = positive collagen
turnover.
 Stimulates IGF-1
 hypertrophic role = fusion of satellite cells into muscle fibers
 Stimulates satellite cell production  repairs muscle,
promotes hypertrophy
 Optimal loading at ~20-40% MVC  hypertrophy
gains while protecting and optimizing tendon health
(esp. older women)
Pre- Menopausal women on OC exhibit:
• decreased tendon & muscle c collagen
protein synthesis

60 second check in.
1) Do you believe estrogen influences tendon and muscle tissue?
2) If yes. Provide 2 ways in which estrogen effects tendon and
muscle tissue.
3) How could you change your clinical practice to incorporate this
new information?

Citations
Citations placed in ‘notes section’ of PowerPoint. Please reach out for power point copy of lecture.

How Estrogen Influences Female Muscle and Tendon

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