Sex Hormones and Aging Skeletal Muscle and Bone

Sex Hormones and Aging: Skeletal Muscle and Bone Marybeth Brown PT, Ph. D Center for Gender Physiology, Physical Therapy, University of Missouri-Columbia APS 2006 Refresher Course

Overview of talk…. n Estrogen effects– Direct (muscle mass, bone mass) – Indirect (inactivity, increase in fat mass) n Testosterone effects– Direct (muscle mass, strength) – Indirect (bone mass, fat mass) – Unintended consequences APS 2006 Refresher Course

Why was the WHI study halted? § Higher incidence of stroke § 32 in HRT group § 24 in placebo group in 10, 000 subjects!!! § Lower incidence of hip fracture, colon cancer APS 2006 Refresher Course

Overview of E 2 effects. . Direct Estrogen effects on skeletal muscle: mass, strength, fatigue and injury n Indirect Estrogen effects on skeletal muscle: inactivity, fat n Rehabilitation implications n APS 2006 Refresher Course

E 2 and skeletal muscle mass n Skeletal muscle is loaded with estrogen receptors – – – n On the membrane In the cytoplasm On the nuclear membrane Cell membrane has both ERα and ERß but the specific function of each is not known – Greater distribution on type II fibers APS 2006 Refresher Course

APS 2006 Refresher Course

Estrogen, muscle and aging n Literature rather confusing… – Confounds: age, duration of HRT, conjugated vs. unconjugated estrogens, dose of HRT n Observation: appears to be a more rapid decline in strength with age during the menopause. APS 2006 Refresher Course

Leg Press (lb) Strength losses with age in Master Athletes Age in Years APS 2006 Refresher Course APS

Evidence for and against estrogen effects on muscle No: 64 wks of 20 -mg estradiol significantly increased bone mass, decreased fat mass by 18% and had no effect on muscle mass. Hansen et al, 2003 Yes: 12 week double-blind, cross-over design with wash-out phase in between E 2 administration and placebo. Significant increase in lean mass during E 2 phase Sorensen et al, 2001, Obes Res APS 2006 Refresher Course

Recent Meta analysis The strength of evidence (27 papers) supports an anabolic effect of estrogen in (younger*) women. n The mechanism(s) of action is unclear n *my emphasis Meeuwsen et al, Maturitas, 2000 APS 2006 Refresher Course

Does E 2 effectiveness decrease with age? n Young women with normal menstrual cycles show a 12% variation in strength. Muscle strength is highest when serum E 2 levels are at their peak. APS 2006 Refresher Course

Older women- less effect? n n Kenny et al: Incidence of sarcopenia (agerelated muscle mass loss) was the same in 189 women 59 -78 years old who had been using ERT for at least 2 years as those who were not ERT users. Brown et al: HRT did not augment gains in muscle strength or FFM in response to weight-bearing exercise. 16 vs. 17% strength increase APS 2006 Refresher Course

Our recent work with OVX n To amplify the potential anabolic effect of female sex hormones, we used hind limb unweighting (HLU) in rats – Model of weightlessness, bed rest n Ho: if ovarian hormones, notably E 2, influence muscle mass and function, OVX + HLU rats should experience > decline than intact rats. APS 2006 Refresher Course

OVX cont’d n Additionally, we hypothesized that OVX rats would recover from HLU more slowly or to a lesser extent than intact rats and in OVX rats given E 2 supplementation APS 2006 Refresher Course

Hind limb unweigting APS 2006 Refresher Course

Results APS 2006 Refresher Course

APS 2006 Refresher Course

Sham Cont Akt –p(Ser 437) Total Akt APSCourse 2006 Refresher Course APS 2006 Refresher HLU Rec Cont OVX HLU Rec

What to conclude? Data suggest that failure to recover muscle mass in OVX rats was ovarian hormone mediated, particularly E 2 n Data also suggest that conditions which result in low E 2 (hysterectomy, trauma, bed rest) may impact recovery from the loss of muscle mass and strength that occurs with inactivity n APS 2006 Refresher Course

Bouts of inactivity result in incremental losses in muscle APS 2006 Refresher Course

Indirect effects of estrogen n Estrogen has marked behavioral influence on spontaneous activity – Level of the hyothalamus n Estrogen also affects basal metabolic rate such that OVX or hysterectomy results in weight gain without a significant increase in food intake APS 2006 Refresher Course

Spontaneous daily running distance Intact ¶ HRT *+ OVX *+ ¶# # APS 2006 Refresher Course ¶# + # *

Running activity and phase of the estrus cycle Figure from Eckel et al. APS 2006 Refresher Course

Body weight changes with hormonal status gonadectomy Intact ¶ *+ APS 2006 Refresher Course OVX HRT ¶# + HRT ¶# *

Food intake varies with hormonal status gonadectomy ¶ HRT + +~ *+ APS 2006 Refresher Course # ¶# *~ #

Estrogen and fat n Estrogen regulates the amount and distribution of adipose tissues – Central adiposity with menopause or hysterectomy n n Increase in body fat mass with low hormone values – Which contributes to further inactivity! Note: inactivity predisposes to low estrogen values APS 2006 Refresher Course

Sex hormone suppression Subjects: 14 healthy, young females with mean age of 29± 5 years n Six days of Gn. RHant n Resting energy expenditure was significantly reduced from 1405± 42 to 1334± 36 kcal n – A 5% decline in 6 days! Day et al, 2005 J Clin Endocrinol Metab APS 2006 Refresher Course

n Which subsequently contributes to more inactivity less estrogen – – – Muscle atrophy Less muscle strength Higher predisposition to muscle injury – Functional decline APS 2006 Refresher Course Distance (km) More body mass= less activity=more body mass 450 g 250 g

Estrogen and Bone Metabolism Prostaglandins PTH Vitamin D TNF TGB-ß IL-1 OSTEOBLAST APS 2006 Refresher Course Il-4 Il-8 Calcitonin ESTROGEN Glucocorticoids Prostaglandins Calcium Phosphates OSTEOCLAST BONE MATRIX Stimulation ESTROGEN IL-4 IL-13 OSTEOBLAST

Estrogen, bone mineral and the menopause n Unequivocal effects – Menopause: ~10% decline in bone mass in 5 years – HRT during menopause prevents decline in bone APS 2006 Refresher Course

BMD g/cm 2 HRT effects on bone with age Age in Years APS 2006 Refresher Course

Exercise also a modifier of bone loss n Some evidence that HRT and exercise effects on bone are additive in postmenopausal women APS 2006 Refresher Course

HRT and exercise are additive Villareal et al, , 2003 N=28 women 75 yrs and older n 9 mos of exercise (home or center) n – Flexibility vs. resistance and endurance Lumbar spine increases in BMD were 1. 5% in controls and 3. 5% in exercise group n Total body BMD increases were 1. 5% in exercise group, 0. 2% in controls n APS 2006 Refresher Course

Males and Testosterone T 2 values (ng/d. L) Continuous decline in testosterone throughout the lifetime. APS 2006 Refresher Course Hypogonadal Age in Years

Other factors that affect T 2 levels Obesity n Inactivity (space travel, bed rest) n Trauma (SCI, head trauma, fracture) n Diet? ? n Disease n Drugs n APS 2006 Refresher Course

T 2 and skeletal muscle Skeletal muscle has many androgen receptors (AR) n AR receptive to IGF-1 and GH in addition to T 2 n AR also receptive to estrogen? n APS 2006 Refresher Course

Direct effects of T 2 Hypgonadal men given T 2 for 8 weeks n Muscle mass increased 7% (DEXA) n Muscle strength also increased 30% n n Results indicate marked T 2 influence on muscle mass and strength APS 2006 Refresher Course

Normal men made hypogonadal Hayes et al, 2004 8 eugonadal men given Gn. RH which caused T 2 levels to plummet to almost undetectable levels. n T 2 given back in varying doses: 25, 50, 125, 300, 600 mg n Muscle mass and strength primary outcome measures n APS 2006 Refresher Course

% increase in strength T 2 effects on strength Testosterone dose mg APS 2006 Refresher Course

Conclusions Seems to be a minimum T 2 value for an effect on skeletal muscle n Unintended consequences- 55 adverse events n – PSA above 4 µg/ml – Hematocrit >54% – edema APS 2006 Refresher Course

T 2 effects in older men Bhasin et al, 2004 Same design as for young men n Gn. RH agonist to suppress endog. T 2 n Subjects: men 60 -75 yrs, n=60 n Doses: 25, 50, 125, 300, 600 mg n Study duration: 20 weeks n Primary outcomes: muscle mass, strength n APS 2006 Refresher Course

% increase in FFM Change in fat-free mass APS 2006 Refresher Course Testosterone dose mg

Change in strength in kg Maximum voluntary strength- leg press Testosterone dose mg APS 2006 Refresher Course

Unintended consequences 147 adverse events n 12 serious adverse events in 9 men n Rx discontinued in 4 men taking 600 mg, 3 men taking 300 mg and in 1 man taking 125 mg n APS 2006 Refresher Course

Serious Adverse events Hematocrit >54% (n=6) n Leg edema with sob (n=1) n Urinary retention (n=1) n Prostate cancer (n=2) n Hematuria with elevated PSA (n=1) n APS 2006 Refresher Course

Other findings… n On the positive side. . – Fat mass decreased in a dose-dependent manner – No change in aggression n On the not so positive side. . – HDLs plummeted – PSAs increased APS 2006 Refresher Course

What to conclude? An androgen receptor modulator with anabolic properties that are free of dose-limiting adverse effects of testosterone is needed APS 2006 Refresher Course

E 2 and T 2 in men van den Beld et al, 2000 403 men 73 -94 yrs of age n Ho: decreases in bone mass, FFM and muscle strength related to fall in endogenous T 2 and E 2 n Measures: serum T 2, SHBG-T, E 2 n APS 2006 Refresher Course

Results Total and free T 2 positively related with muscle strength and bone mass n Inverse relationship between fat mass and T 2 n Non-SHBG-T and free T more strongly related to muscle strength, bone mass and fat mass that total T n APS 2006 Refresher Course

Current belief It may be the aromatization of testosterone to estrogen that is important for bone mass in men n Estrogen and testosterone use different cellular pathways to inhibit osteoclastic activity and bone resorption n APS 2006 Refresher Course

Other findings…. E 1 and E 2 also strongly related to BMD n The positive relationship between T 2 and BMD was independent of relationship of E 2 and bone mass suggesting a role for both hormones for the maintenance of bone with aging n APS 2006 Refresher Course

Summary n n n Falling T 2 with age is associated with loss in lean muscle and bone mass T 2 supplementation probably not warranted Inactivity likely a major factor contributing to lower T 2 values at all ages Exercise increases T 2 levels in young mennot clear if the same occurs in older men Appalling how little is known about functions that are so fundamental APS 2006 Refresher Course