aps 2006 refresher course sex hormones and aging: skeletal muscle and bone marybeth brown pt, phd...

APS 2006 Refresher APS 2006 Refresher CourseCourse

Sex Hormones and Sex Hormones and Aging: Skeletal Muscle Aging: Skeletal Muscle and Boneand Bone

Marybeth Brown PT, PhDMarybeth Brown PT, PhDCenter for Gender Physiology, Center for Gender Physiology, Physical Therapy, Physical Therapy, University of Missouri-University of Missouri-ColumbiaColumbia


Overview of talk….Overview of talk….

Estrogen effects-Estrogen effects-– Direct (muscle mass, bone mass)Direct (muscle mass, bone mass)– Indirect (inactivity, increase in fat Indirect (inactivity, increase in fat

mass)mass) Testosterone effects-Testosterone effects-

– Direct (muscle mass, strength)Direct (muscle mass, strength)– Indirect (bone mass, fat mass)Indirect (bone mass, fat mass)– Unintended consequencesUnintended consequences


Why was the WHI study Why was the WHI study halted?halted?

Higher incidence of strokeHigher incidence of stroke 32 in HRT group32 in HRT group 24 in placebo group24 in placebo group

in 10,000 subjects!!!in 10,000 subjects!!! Lower incidence of hip fracture, Lower incidence of hip fracture,

colon cancercolon cancer


Overview of EOverview of E22 effects..effects.. DirectDirect Estrogen effects on Estrogen effects on

skeletal muscle: mass, strength, skeletal muscle: mass, strength, fatigue and injuryfatigue and injury

IndirectIndirect Estrogen effects on Estrogen effects on skeletal muscle: inactivity, fatskeletal muscle: inactivity, fat

Rehabilitation implicationsRehabilitation implications


EE2 2 and skeletal muscle and skeletal muscle massmass Skeletal muscle is loaded with Skeletal muscle is loaded with

estrogen receptorsestrogen receptors– On the membraneOn the membrane– In the cytoplasmIn the cytoplasm– On the nuclear membraneOn the nuclear membrane

Cell membrane has both ERCell membrane has both ERαα and ERß and ERß but the specific function of each is not but the specific function of each is not knownknown– Greater distribution on type II fibersGreater distribution on type II fibers


APS 2006 Refresher Course


Estrogen, muscle and Estrogen, muscle and agingaging

Literature rather confusing…Literature rather confusing…– Confounds: age, duration of HRT, Confounds: age, duration of HRT,

conjugated vs. unconjugated conjugated vs. unconjugated estrogens, dose of HRTestrogens, dose of HRT

Observation: appears to be a Observation: appears to be a more rapid decline in strength more rapid decline in strength with age during the menopause.with age during the menopause.

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Age in Years

Leg P

ress

(lb

) Strength losses with age in Master Athletes



Evidence for and against Evidence for and against estrogen effects on estrogen effects on musclemuscle NoNo: 64 wks of 20-mg estradiol : 64 wks of 20-mg estradiol

significantly increased bone mass, significantly increased bone mass, decreased fat mass by 18% and had no decreased fat mass by 18% and had no effect on muscle mass. effect on muscle mass. Hansen et al, 2003Hansen et al, 2003

YesYes: 12 week double-blind, cross-over : 12 week double-blind, cross-over design with wash-out phase in between design with wash-out phase in between EE22 administration and placebo. administration and placebo. Significant increase in lean mass during Significant increase in lean mass during EE22 phase phase

Sorensen et al, 2001, Obes ResSorensen et al, 2001, Obes Res


Recent Meta analysisRecent Meta analysis

The strength of evidence (27 papers) The strength of evidence (27 papers) supports an anabolic effect of supports an anabolic effect of estrogen in (estrogen in (younger*younger*) women.) women.

The mechanism(s) of action is The mechanism(s) of action is unclearunclear

*my emphasis*my emphasis

Meeuwsen et al, Maturitas, 2000Meeuwsen et al, Maturitas, 2000


Does EDoes E22 effectiveness effectiveness decrease with age?decrease with age? Young women with normal Young women with normal

menstrual cycles show a 12% menstrual cycles show a 12% variation in variation in strength.strength. Muscle Muscle strength is highest when serum Estrength is highest when serum E22 levels are at their peak.levels are at their peak.


Older women- less Older women- less effect?effect? Kenny et alKenny et al: Incidence of sarcopenia (age-: Incidence of sarcopenia (age-

related muscle mass loss) was the same related muscle mass loss) was the same in 189 women 59-78 years old who had in 189 women 59-78 years old who had been using ERT for at least 2 years as been using ERT for at least 2 years as those who were not ERT users.those who were not ERT users.

Brown et alBrown et al: : HRT did not augment gains in HRT did not augment gains in muscle strength or FFM in response to muscle strength or FFM in response to weight-bearing exercise. 16 vs. 17% weight-bearing exercise. 16 vs. 17% strength increasestrength increase


Our recent work with Our recent work with OVXOVX To amplify the potential anabolic To amplify the potential anabolic

effect of female sex hormones, we effect of female sex hormones, we used hind limb unweighting (HLU) in used hind limb unweighting (HLU) in ratsrats– Model of weightlessness, bed restModel of weightlessness, bed rest

Ho: if ovarian hormones, notably EHo: if ovarian hormones, notably E2, 2,

influence muscle mass and influence muscle mass and function, OVX + HLU rats should function, OVX + HLU rats should experience > decline than intact experience > decline than intact rats.rats.


OVX cont’dOVX cont’d

Additionally, we hypothesized Additionally, we hypothesized that OVX rats would recover from that OVX rats would recover from HLU more slowly or to a lesser HLU more slowly or to a lesser extent than intact rats and in OVX extent than intact rats and in OVX rats given Erats given E22 supplementation supplementation


Hind limb unweigtingHind limb unweigting

ResultsResults

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Ser-473 Total

SHAM OVX

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Total Akt

Akt –p(Ser437)

Sham OVX

Cont HLU Rec Cont HLU Rec



What to conclude?What to conclude?

Data suggest that failure to recover Data suggest that failure to recover muscle mass in OVX rats was ovarian muscle mass in OVX rats was ovarian hormone mediated, particularly Ehormone mediated, particularly E22

Data also suggest that conditions Data also suggest that conditions which result in low Ewhich result in low E2 2 (hysterectomy, (hysterectomy, trauma, bed rest) may impact trauma, bed rest) may impact recovery from the loss of muscle recovery from the loss of muscle mass and strength that occurs with mass and strength that occurs with inactivityinactivity


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ActivityInactivity

Bouts of inactivity result in incremental losses in muscle


Indirect effects of Indirect effects of estrogenestrogen

Estrogen has marked behavioral Estrogen has marked behavioral influence on spontaneous activity influence on spontaneous activity – Level of the hyothalamusLevel of the hyothalamus

Estrogen also affects basal Estrogen also affects basal metabolic rate such that OVX or metabolic rate such that OVX or hysterectomy results in weight hysterectomy results in weight gain without a significant increase gain without a significant increase in food intakein food intake


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* + ¶ # +

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OVX

HRT

Spontaneous daily running distance

Intact

HRT


Running activity and Running activity and phase of the estrus phase of the estrus cyclecycle

Figure from Eckel et al.


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g)

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gonadectomy HRT

IntactOVX HRT

Body weight changes with hormonal status


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(g)

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+ ~¶ # * ~

# # * +

gonadectomy HRT

Food intake varies with hormonal status


Estrogen and fatEstrogen and fat

Estrogen regulates the amount and Estrogen regulates the amount and distribution of adipose tissuesdistribution of adipose tissues– Central adiposity with menopause or Central adiposity with menopause or

hysterectomyhysterectomy Increase in body fat mass with low Increase in body fat mass with low

hormone valueshormone values– Which contributes to further inactivity!Which contributes to further inactivity!

Note: inactivity predisposes to low estrogen Note: inactivity predisposes to low estrogen valuesvalues


Sex hormone Sex hormone suppressionsuppression Subjects: 14 healthy, young Subjects: 14 healthy, young

females with mean age of 29±5 females with mean age of 29±5 yearsyears

Six days of GnRHant Six days of GnRHant Resting energy expenditure was Resting energy expenditure was

significantly reduced from significantly reduced from 14051405±±4242 to to 13341334±±3636 kcal kcal– A 5% decline in 6 days!A 5% decline in 6 days!

Day et al, 2005 J Clin Endocrinol Metab


More body mass= less More body mass= less activity=more body activity=more body massmass Which subsequently Which subsequently

contributes to more contributes to more inactivityinactivity less less estrogenestrogen– Muscle atrophyMuscle atrophy– Less muscle strengthLess muscle strength– Higher predisposition Higher predisposition

to muscle injuryto muscle injury– Functional decline Functional decline

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OSTEOBLAST OSTEOBLASTOSTEOCLASTOSTEOCLAST

ProstaglandinsPTHVitamin DTNFTGB-ßIL-1 ESTROGEN

IL-4IL-13

Il-4Il-8CalcitoninESTROGENGlucocorticoidsProstaglandinsCalciumPhosphates

BONE MATRIX

Estrogen and Bone Metabolism

Stimulation


Estrogen, bone mineral Estrogen, bone mineral and the menopauseand the menopause

Unequivocal effectsUnequivocal effects– Menopause: ~10% decline in bone Menopause: ~10% decline in bone

mass in 5 yearsmass in 5 years– HRT during menopause prevents HRT during menopause prevents

decline in bonedecline in bone


HRT effects on bone with HRT effects on bone with ageage

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Exercise also a Exercise also a modifier of bone lossmodifier of bone loss

Some evidence that HRT and Some evidence that HRT and exercise effects on bone are exercise effects on bone are additive in post-menopausal additive in post-menopausal womenwomen


HRT and exercise are HRT and exercise are additiveadditive

Villareal et al,, 2003Villareal et al,, 2003

N=28 women 75 yrs and olderN=28 women 75 yrs and older 9 mos of exercise (home or center)9 mos of exercise (home or center)

– Flexibility vs. resistance and endurance Flexibility vs. resistance and endurance Lumbar spine increases in BMD were Lumbar spine increases in BMD were

1.5% in controls and 3.5% in exercise 1.5% in controls and 3.5% in exercise groupgroup

Total body BMD increases were 1.5% Total body BMD increases were 1.5% in exercise group, 0.2% in controlsin exercise group, 0.2% in controls


Males and Males and TestosteroneTestosterone

Continuous decline in testosterone Continuous decline in testosterone throughout the lifetime.throughout the lifetime.

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Hypogonadal


Other factors that Other factors that affect Taffect T22 levels levels ObesityObesity Inactivity (space travel, bed rest)Inactivity (space travel, bed rest) Trauma (SCI, head trauma, Trauma (SCI, head trauma,

fracture)fracture) Diet??Diet?? DiseaseDisease DrugsDrugs


TT22 and skeletal muscle and skeletal muscle

Skeletal muscle has many Skeletal muscle has many androgen receptors (AR)androgen receptors (AR)

AR receptive to IGF-1 and GH in AR receptive to IGF-1 and GH in addition to Taddition to T22

AR also receptive to estrogen?AR also receptive to estrogen?


Direct effects of TDirect effects of T22

Hypgonadal men given THypgonadal men given T22 for 8 weeks for 8 weeks Muscle mass increased 7% (DEXA)Muscle mass increased 7% (DEXA) Muscle strength also increased 30%Muscle strength also increased 30%

Results indicate marked TResults indicate marked T22 influence influence on muscle mass and strengthon muscle mass and strength


Normal men made Normal men made hypo-gonadalhypo-gonadal Hayes Hayes

et al, 2004et al, 2004

8 eugonadal men given GnRH 8 eugonadal men given GnRH which caused Twhich caused T22 levels to levels to plummet to almost undetectable plummet to almost undetectable levels.levels.

TT22 given back in varying doses: given back in varying doses: 25, 50, 125, 300, 600 mg25, 50, 125, 300, 600 mg

Muscle mass and strength Muscle mass and strength primary outcome measuresprimary outcome measures


TT22 effects on strength effects on strength

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Testosterone dose mg

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gth


ConclusionsConclusions

Seems to be a minimum TSeems to be a minimum T22 value value for an effect on skeletal musclefor an effect on skeletal muscle

Unintended consequences- Unintended consequences- 5555 adverse eventsadverse events– PSA above 4 µg/mlPSA above 4 µg/ml– Hematocrit >54%Hematocrit >54%– edemaedema


TT22 effects in older men effects in older men Bhasin et al, Bhasin et al,

20042004

Same design as for young menSame design as for young men GnRH agonist to suppress endog. TGnRH agonist to suppress endog. T2 2

Subjects: men 60-75 yrs, n=60Subjects: men 60-75 yrs, n=60 Doses: 25, 50, 125, 300, 600 mgDoses: 25, 50, 125, 300, 600 mg Study duration: 20 weeksStudy duration: 20 weeks Primary outcomes: muscle mass, Primary outcomes: muscle mass,

strengthstrength


Change in fat-free Change in fat-free massmass

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% in

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FFM


Maximum voluntary Maximum voluntary strength- leg pressstrength- leg press

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Unintended Unintended consequencesconsequences 147 adverse events147 adverse events 12 serious adverse events in 9 12 serious adverse events in 9

menmen Rx discontinued in 4 men taking Rx discontinued in 4 men taking

600 mg, 3 men taking 300 mg 600 mg, 3 men taking 300 mg and in 1 man taking 125 mgand in 1 man taking 125 mg


Serious Adverse Serious Adverse eventsevents Hematocrit >54% (n=6)Hematocrit >54% (n=6) Leg edema with sob (n=1)Leg edema with sob (n=1) Urinary retention (n=1)Urinary retention (n=1) Prostate cancer (n=2)Prostate cancer (n=2) Hematuria with elevated PSA Hematuria with elevated PSA

(n=1)(n=1)


Other findings…Other findings…

On the positive side..On the positive side..– Fat mass decreased in a dose-Fat mass decreased in a dose-

dependent mannerdependent manner– No change in aggressionNo change in aggression

On the not so positive side..On the not so positive side..– HDLs plummetedHDLs plummeted– PSAs increasedPSAs increased


What to conclude?What to conclude?

An androgen receptor An androgen receptor modulator with anabolic modulator with anabolic properties that are free of properties that are free of dose-limiting adverse effects dose-limiting adverse effects of testosterone is neededof testosterone is needed


EE22 and T and T22 in men in men van den Beld et al, van den Beld et al,

20002000

403 men 73-94 yrs of age403 men 73-94 yrs of age Ho: decreases in bone mass, FFM Ho: decreases in bone mass, FFM

and muscle strength related to and muscle strength related to fall in endogenous Tfall in endogenous T22 and E and E2 2

Measures: serum TMeasures: serum T22, SHBG-T, E, SHBG-T, E22


Results Results

Total and free TTotal and free T22 positively related positively related with muscle strength and bone with muscle strength and bone massmass

Inverse relationship between fat Inverse relationship between fat mass and Tmass and T22

Non-SHBG-T and free T more Non-SHBG-T and free T more strongly related to muscle strength, strongly related to muscle strength, bone mass and fat mass that total Tbone mass and fat mass that total T


Current beliefCurrent belief

It may be the aromatization of It may be the aromatization of testosterone to estrogen that is testosterone to estrogen that is important for bone mass in menimportant for bone mass in men

Estrogen and testosterone use Estrogen and testosterone use different cellular pathways to different cellular pathways to inhibit osteoclastic activity and inhibit osteoclastic activity and bone resorptionbone resorption


Other findings….Other findings….

EE11 and E and E2 2 also strongly related to also strongly related to BMDBMD

The positive relationship between The positive relationship between TT22 and BMD was and BMD was independentindependent of of relationship of Erelationship of E2 2 and bone mass and bone mass suggesting a role for both suggesting a role for both hormones for the maintenance of hormones for the maintenance of bone with agingbone with aging


SummarySummary

Falling TFalling T22 with age is associated with loss in with age is associated with loss in lean muscle and bone masslean muscle and bone mass

TT22 supplementation probably not warranted supplementation probably not warranted Inactivity likely a major factor contributing Inactivity likely a major factor contributing

to lower Tto lower T22 values at all ages values at all ages Exercise increases TExercise increases T22 levels in young men- levels in young men-

not clear if the same occurs in older mennot clear if the same occurs in older men Appalling how little is known about Appalling how little is known about

functions that are so fundamentalfunctions that are so fundamental

aps 2006 refresher course sex hormones and aging: skeletal muscle and bone marybeth brown pt, phd...

Documents

refresher course slide

lean mass

strength indirect bone

refresher course e

fat indirect estrogen

increased bone mass

bone mass indirect inactivity

injury direct estrogen