Embed Size (px)
Citation preview
2013
http://informahealthcare.com/gyeISSN: 0951-3590 (print), 1473-0766 (electronic)
Gynecol Endocrinol, 2013; 29(5): 418–423! 2013 Informa UK Ltd. DOI: 10.3109/09513590.2012.754879
MENOPAUSE
Menopause, estrogens and frailty
Anders Nedergaard1,2, Kim Henriksen1, Morten Asser Karsdal1, and Claus Christiansen1
1Nordic Bioscience – Biomarkers and Research (Part of CCBR Group), Herlev, Copenhagen, Denmark, and 2Institute of Sports Medicine,
Bispebjerg Hospital, Copenhagen, Denmark
Abstract
The controversy surrounding the results from the Women’s Health Initiative (WHI) trialspublished a decade ago caused a significant decline in the use of menopausal hormonereplacement therapy. However, these results have been vehemently contested and several linesof evidence suggest that in perimenopausal and non-obese women, estrogen therapy mayindeed be of benefit. There is ample proof that menopause causes a loss of musculoskeletaltissue mass and quality, thereby causing a loss of health and quality of life. There is also solidevidence that hormone replacement therapy in itself prevents most of these effects inconnective tissue in it self. Besides the independent, direct effects on the musculoskeletaltissues, estrogen deficiency also reduces the ability to adequately respond and adapt toexternal mechanical and metabolic stressors, e.g. exercise, which are otherwise the main stimulithat should maintain musculoskeletal integrity and metabolic function. Thus, normophysiolo-gical estrogen levels appear to exert a permissive effect on musculoskeletal adaptations toloading, thereby likely improving the outcome of rehabilitation following critical illness,musculoskeletal trauma or orthopedic surgical therapy. These effects add to the evidencesupporting the use of estrogen therapy, particularly accelerated gain of functional capacity andindependence following musculoskeletal disuse.
Keywords
Adaptation, bone, estrogen, menopause,muscle, tendon
History
Received 18 October 2012Accepted 11 November 2012Published online 6 February 2013
Introduction
Loss of musculotendinous and skeletal quantity and quality is anatural consequence of aging in both genders. Age-associatedhypogonadism is thought to contribute to this phenomenon,especially regarding bone loss following the onset of menopause[1–3]. Several lines of evidence support the notion that estrogenshave anabolic properties in other tissues than bone, just likeandrogens. While these properties have been thoroughly reviewedelsewhere, we want to focus on the interaction between sexsteroids, especially estrogens, and exercise in bone, tendon andmuscle tissues, as it appears that in the hypogonadal state, tissueadaptability to mechanical and metabolic stimuli is severelyimpaired.
Estrogens in women are found in the form of 17b-estradiol,estrone and estriol of which the former is the most biologicallyactive compound [4]. In healthy women, estradiol levels rangesfrom 50 to 1000 pM through the course of a menstrual cycle (withlarge inter-individual variation) and dropping to 40–150 pM inmenopause. Naturally, the menopause-associated decline of suchan important hormone has an impact on behavior, metabolism andultimately health. Scientific concern has been particularlydirected at the accelerated loss of bone mineral caused by thedecline in estrogen associated with the onset of menopause. But,low estrogen levels also affect habitual physical activity, bodycomposition and muscle directly, causing a wide range of effectson musculoskeletal quantity and quality, thereby impacting healthand quality of life in more ways than one.
Estrogen signals through the estrogen receptors a and b (ERaand ERb), which belongs to the nuclear receptor family, and theGPR30 receptor, which is a G protein coupled estrogen receptor.Although the exact tissue distributions are not fully defined, theseare more or less ubiquitously expressed, with higher receptorexpression in distinct tissues, such as gonads, sex organs, muscle,bone and certain brain regions.
Steroid hormones are known to exert their effects throughbinding to soluble nuclear receptors (ERa and ERb) which thenmigrate to the nucleus where the steroid hormone/nuclearreceptor complex, along with possible cofactors, interact directlywith genetic regulatory elements increasing or decreasingexpression of certain genes, i.e. effectively as transcriptionsfactors. This has been termed ‘‘genomic’’ steroid hormoneeffects. The last couple of decades have shown that steroidhormones exert some of their effects through non-genomic effectsalso. This means that ERa, ERb and GPR30 can also initiatesignaling like classical receptor systems, initiating signalingthrough covalent or allosteric modification of other proteins in thecytoplasm. This signaling modality has since been termed ‘‘non-genomic’’ nuclear receptor effects.
As this review will highlight, estrogens have a number ofpositive effects on most of the musculoskeletal system duringmenopause and whereas estrogen signaling is not completelyunderstood, it is known that both of the classic estrogen receptortypes have been implicated in the pro-anabolic signaling in mostof the musculoskeletal tissues [5,6], whereas it is still unknown ifthe GPR30 receptor contributes in these tissues. It is likely thatthe beneficial effects in muscle, bone and tendon are related tointeractions with the growth factor IGF and its downstreamsignaling. Interestingly, estrogens lowers the serum concentra-tions of IGF-1, most likely through an upregulation of its serum
Address for correspondence: Anders Nedergaard, MSc, PhD, NordicBioscience, Herlev hovedgade 207, 2730 Herlev, Copenhagen,Denmark. Tel: þ45 4454 7757. Fax: þ45 4452 5251. E-mail:[email protected]
Gyn
ecol
End
ocri
nol D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y U
nive
rsity
of
Zue
rich
Zen
trum
fue
r Z
ahn
Mun
d un
d on
09/
09/1
3Fo
r pe
rson
al u
se o
nly.
binding proteins, particularly IGFBP1 [7,8], but appears to utilizesome of the same downstream signaling as IGF-1 in itspro-anabolic effects [9].
With these beneficial connective tissue effects fromhormone replacement therapy, it seems like HRT should besubject to general recommendation, but the possible existence ofadverse effects reported in the Women’s Health Initiative (WHI)[10] and later confirmed in the Million Women Study (MWS),complicates the matter and the debate as to whether or notestrogen replacement therapy is recommendable is still active inthe scientific communities, although criticism of the WHI andMWS methodology has been mounting in the last decade.This criticism is particularly directed at (1) the lack ofinclusion of perimenopausal women in the WHI study as theresponse to hormone therapy depends upon metabolicphenotype and on time since onset of menopause [11,12] and(2) that women in the MWS study were included from womenundergoing mammography screening, proven to select a non-representative sub-population [13]. These selection biasesmay have impacted the findings of the studies and may meanthat the authors have stretched their material in termsof conclusion.
These large studies, the criticism against them and the pointsthat have been raised in relation to them shows that the effects ofestrogen therapy are very context dependent (Figure 1).The extent of primary effects as well as adverse depend stronglyon weight [11,14], time since onset of menopause [15,16],smoking behavior [14] and glucocorticoid treatment [17–19]. Inspite of this, a recent meta-analysis update to the U.S. PreventiveServices Task Force Recommendations concluded that long-termestrogen replacement therapy should not be recommended as ageneral preventative measure [20]. Surely, the controversyregarding whether or not, and in what doses, estrogen
replacement therapy should be recommended, will continue foryears to come.
Bone effects
Estrogen as an anabolic/catabolic mediator
The effects of estrogen on bone cells are among the bestcharacterized effects, it is well-known that estrogen (and SERM)treatment can attenuate bone loss in postmenopausal women [21].The direct effects of estrogen on bone cells are numerous, but twoeffects have gained the most attention: (1) direct inhibition ofosteoclastogenesis by antagonizing RANKL-mediated inductionof the c-jun/JNK signaling pathway [22–24] and (2) Inhibition ofosteoclastogenesis secondary to inhibition of RANKL productionby osteoblasts and lymphocytes [21,25]. There are also indica-tions that estrogen, through ERa, may attenuate osteoclasticresorption directly [26]. In summary, there is no doubt thatestrogen has anti-resorptive effects, and it appears likely that thesearise from a complex combination of inhibitory effects on bonecells. Although some degree of anabolic effect of estrogen is seendirectly on osteoblasts in culture and rat models [27], this is notobserved in vivo in humans. Here, an inhibition of bone formationis seen, although this is mediated through the inhibition of releaseof coupling signals from the osteoclasts, and not as a direct effecton osteoclasts [21]. Despite this inhibition observed in vivo inhumans, a net positive effect remains, which is the primaryrationale behind the anti-fracture efficacy of estrogen andSERMs [28].
An aspect of estrogen therapy effects on bone that is oftenforgotten, is in relation to combination with different forms ofexercise, and while mechanical stimuli are known to be beneficialfor bone volume, the interaction with estrogen in women is notcompletely understood.
Figure 1. Relationships between clinical benefit of estrogen therapy with varying patient traits (the figure is conceptual and not to be understood asquantitative). Clinical benefit of estrogen therapy is context dependant, underscoring why cohort selection bias can impact the findings and why thefindings should be presented within the constraints of the relevant phenotypes. The ‘‘timing hypothesis’’ (the upper panel) is the well-known conceptthat the accumulated health benefit of hormone therapy depends on age and the time since onset of menopause, specifically that the largest clinicalbenefit can be obtained in the years around onset of menopause. Similar hypotheses could be presented for other qualities whose symptoms estrogentherapy alleviated or whose biology interacts with estrogen effects. The musculoskeletal phenotype (the middle panel) is an example of the former,whereas the metabolic phenotype (the lower panel) is an example of the latter. Estrogens appear to be of great benefit to the musculoskeletal connectivetissues and hence the contribution of those effects to gross clinical benefit would be biggest in sarcopenic or osteopenic individuals. Poor metabolicfunction and obesity frequently changes estrogen metabolism and endogenous estrogen production. Individuals representing a poor metabolicphenotype has accelerated adverse effects associated with hormone therapy, e.g. worsened cancer prognosis.
DOI: 10.3109/09513590.2012.754879 Menopause, muscle and bone 419
Gyn
ecol
End
ocri
nol D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y U
nive
rsity
of
Zue
rich
Zen
trum
fue
r Z
ahn
Mun
d un
d on
09/
09/1
3Fo
r pe
rson
al u
se o
nly.
Estrogen effects on bone adaptability
A small series of studies have been conducted with the focus oncombination of estrogen therapy and exercise training with boneparameters as the primary output. These studies in general appearto show an additive, or even synergistic, effect on BMD whencombining exercise and estrogen [29–32] although there are someshowing no added benefit [33]. Furthermore, there are, albeitprimarily animal, studies which indicate that estrogen is neededfor the beneficial effect of exercise therapy on bone volume [34].In addition to this, the studies indicate that the exercise levelneeds to be fairly high in order to insure the beneficial effect onbone density [35]. It is appealing to speculate that the output ofthe physical exercise is linked to how well the physiologicalestrogen levels are restored, be it through classical estrogenreplacement therapy, phytoestrogens or SERMs. Another highlyinteresting aspect of exercise combined with ERT is a recentfinding that it in obese women also appears to improve insulinresistance [36].
Another important aspect of all these studies is that one cannotrule out the possibility that these osteoprotective effects are tosome extent mediated by improved muscle functionand secondary higher strength and habitual physicalactivity which will, in turn increase the mechanical stimulus tothe bones.
Tendon unit effects
Tendon is an often-overlooked organ in physiology, as it is oftenthought of as a simple force transducer or lever in biomechanics.However, in the last decade the scientific community hasuncovered a remarkable degree of tendon plasticity in responseto external stimuli, allowing for changes in tendon quantity aswell as quality.
Estrogen as an anabolic/catabolic mediator
Unlike the effects on bone, tendon is not subject to anaboliceffects from estrogen stimulation. Estrogen therapy does,however, cause changes in the architecture as well as mechanicalproperties of tendons. At the morphological level, estrogentherapy in postmenopausal women results in an altered distribu-tion of collagen fibril sizes. Normally, collagen fibril sizes(diameters) are distributed across a range of 50–200 nm.With estrogen therapy, the relative abundance of small-diameter(50–100 nm) fibrils was found to be much larger than in same-agecontrols [37] a pattern that, interestingly, also manifests withtendinopathy [38].
In the 2009 Hansen study, overall (patellar) tendon size wasfound to be equal between postmenopausal HRT and non-HRTgroups. This contrasts with two other studies. In the first, estrogentherapy in postmenopausal women was found to correlate with asmaller achilles tendon CSA, but only in the subjects displayingthe highest physical activity levels [39]. This is corroborated inanother study in which physical activity was associated withincreased tendon size and higher prevalence of abnormalities inpost-menopausal women without HRT. This phenotype wasnormalized in women receiving HRT. In the same study, inactivewomen without HRT was found to have smaller tendons andincreased prevalence of abnormalities, and again HRT wasassociated with a phenotype of normalized tendon size andlower prevalence of abnormalities [40]. The discrepancy to theHansen study could be explained by lack of stratification byphysical activity therein or by the fact that the studies look atdifferent tendons. Estrogen appears to blunt the exercise-inducedincreases in protein synthesis rates in tendon in young women[41]. Where this may help explain the lower stiffness and
over all weaker female tendons in relation to male tendons inyoung individuals [42], the previously cited studies by Cook andFinni clearly show that in the hypogonadal menopausal state,estrogen supplementation is clearly a beneficial factor to tendonsand it helps normalize the tendon which otherwise seemsto become susceptible to tendinopathy with exercise as wellas without.
Estrogens and tendon functionality
Long-term contraceptive therapy have also been associated withdecrease in tendon strain, i.e. a stiffer tendon, yielding less at thesame relative stress [43]. Whether or not, this is a consequenceof the progestagens in contraceptives or due to the depressedendogenous estrogen production remains to be answered [44].Increased tendon stiffness impairs force absorption and thusincreases forces on the tendon and the remainder of themusculoskeletal unit. This, in turn, increases risk of connectivetissue pathology in the remaining musculoskeletal unit.
Summarizing, it seems like the estrogen deficient state inmenopause increases susceptibility to tendinopathic changes,which may be related to increased tendon stiffness. In physicallyactive women, this manifests as a ‘‘classical’’ swollen tendino-pathic phenotype and in the inactive women as an atypical non-swollen or even slightly atrophic phenotype. In both cases,estrogen restore tendon function and size and the ability totolerate physical activity.
Muscle unit effects
Effects on muscle mass
It is well-known that androgens have highly anabolic qualities invertebrate muscle, but what about estrogens? Administration ofestradiol has been shown to be anabolic in growing cattle skeletalmuscle, possibly through improved feeding efficiency [45,46].Not surprisingly, no literature yet describes the consequences ofsupraphysiological estrogen administration in humans, but never-theless, in humans, an anticatabolic/pro-anabolic effect is muchweaker if present at all, only manifesting as a slight muscle loss atthe onset of estrogen ablation, e.g. through menopause orovariectomy, indicating that physiological estrogen levels arenecessary to sustain normophysiological muscle mass andfunction [47,48]. It has been shown that restoring estrogenlevels through HRT reverses this muscle loss in most [39,47–50],but not all [51–53] studies.
This discrepancy may in part be explained by the possibility ofinsufficient statistical power to detect HRT versus non-HRTmuscle mass differences, as all of the latter studies do show a non-significant tendency in favor of HRT. Overall, this supports thenotion that estrogen may indeed confer some protection againsthypogonadism-induced muscle loss in women.
Effects on muscle mass adaptability
What is more interesting is that besides these ‘‘static’’ effects,estrogen deprivation affects the adaptability of muscle to stimuli.Several studies using ovariectomized animals þ/� hormonereplacement subjected to immobilization and subsequent remobi-lization have shown that the presence of estrogens are necessaryfor regrowth of muscle, a finding of potentially grave importancein a human clinical context [9,54]. However, in previous humantrials using HRT and exercise in a crossover setup, it was foundthat HRT and high-impact circuit training were equally effectiveat reversing anthropometric changes associated with menopause,but that the combination offered little additional benefit [39,49].These results may indicate that estrogen exerts a permissive effecton exercise adaptation up to the previous levels of muscle mass,
420 A. Nedergaard et al. Gynecol Endocrinol, 2013; 29(5): 418–423
Gyn
ecol
End
ocri
nol D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y U
nive
rsity
of
Zue
rich
Zen
trum
fue
r Z
ahn
Mun
d un
d on
09/
09/1
3Fo
r pe
rson
al u
se o
nly.
but not beyond that. Obviously, this calls for more human studiesexamining the effect of HRT on recovery from muscle loss.
Effects on muscle strength
Besides these effects on muscle mass, several studies support thenotion that estrogens may impact strength irrespective of effectson muscle mass. This has been examined during estrogenfluctuation during the menstrual cycle and in comparisonsbetween HRT and non-HRT using menopausal women andsome [33,51,55], but not all [32,52] studies have shown aneffect. In one particularly well-designed study, menopausalmonozygotic twins discordant for HRT use were compared, andthey found that long term HRT (seven years on average) positivelyimpacted mobility, muscle power body and muscle composition[48]. While the literature is ambiguous concerning subjectmuscles and strength measurement methodologies, there doesappear to be an overweight of studies supporting a beneficialeffect on muscle function in the form of strength or power, as wasalso found in a recent meta-analysis of the effect of HRT onmuscle strength [56]. The mechanism of this effect has beenattributed to several possible factors between the motor cortex andactomyosin force generation:
First, loss of muscle mass is accelerated at the onset ofmenopause, as has been discussed earlier [47,48]. Second, somestudies report a decrease in strength irrespective of the loss ofmuscle mass with menopause, a so-called specific muscle tensiondeficit [51,55]. Third, estrogen status has been shown to be relatedto myosin binding capability and thus affect actomyosinmechanokinetics in skeletal muscle [54,57]. Fourth, it has beenshown that that estrogen prevents the change in muscle phenotypefrom fast to slow associated with ovariectomy. Thus, estrogen isnecessary to maintain the ‘‘youthful’’ muscle profile, fibertype-wise [58].
Effects on resistance to muscle damage
Estrogen has been known for a long time to impart a degree ofresistance to muscle damage, manifesting as reduced post-exercise levels of creatine kinase, soreness, impaired neutrophilinvasion, impaired SOD1 induction and so on. This has beenshown extensively in animal as well as human models [59–62] aswell as myocardial damage, e.g. following ischemia-reperfusioninjury [63,64]. Again, a number of explanations exist for thisphenomenon: first, estrogens may function as generic antiox-idants, like Vitamin E and thereby inhibit membrane peroxidation.Second, they may directly stabilize membrane integrity [65].Third, they increase HSP expression, that help provide resistanceto muscle damage themselves, by acting as molecular chaperones[66]. Fourth, they inhibit calpains (calcium-activated cysteineproteases), whose activity is strongly implicated in muscle proteindegradation muscle damage [67].
Thus, in menopause, the low levels of estrogen may impart asusceptibility to muscle damage, which may influence thesubjective experience of physical activity, whether related torehabilitation, habitual physical activity or exercise training.When compounded by drugs that also increase muscle damagesusceptibility, such as statins, this could even increase the risk ofdeveloping rhabdomyolysis, i.e. excessive muscle damage leadingto release of nephrotoxic proteins from muscle.
Effects on muscle metabolism
Females have better ‘‘metabolic fitness’’, i.e. they use a higherproportion of fat relative to carbohydrates during submaximalexercise [68,69]. As a well-documented consequence, femalespresent better endurance than males in low-intensity exercise, due
to glycogen sparing. This improved fat utilization disappears inmenopause [70]. Unfortunately, no studies have examined howHRT impacts substrate utilization in menopausal women atsufficiently low exercise intensity to tell if it is affected. However,it has been shown that with HRT therapy, exercise inducesstronger cortisol and Growth hormone responses, indicative ofstronger lipolytic responses [71,72]. Improved fat utilization isnormally considered an improvement in metabolic control andindeed HRT has been shown by meta-analysis to improveglycemic control, insulin tolerance, HOMA-IR, fasting glucoseand lipoproteins [73]. While these metabolic markers are notdirectly related to musculoskeletal function, they are markers ofdiabetes and/or metabolic syndrome. These metabolic conditionsaccelerate muscle loss and thus contribute to sarcopenia and lossof muscle function. Hence, also, from a metabolic perspective itappears as if HRT is beneficial to musculoskeletal function.
Summary
In summary, estrogen appears to exert a number of well-describeddirect effects on the entire musculoskeletal unit and muscle andtendon adaptability, but also indirect effects, as its presence isalmost a prerequisite for tissue adaptability to external stimuli,particularly in tendon and muscle.
During menopause, these effects combine to result in a strongdecline in musculoskeletal function: bone mineralizationdecreases, muscle contractility is impaired, the sensitivity tomuscle damage is higher, tendon abnormalities manifest and evencentral effects that may further negatively impact musculoskeletalfunction and health.
Estrogen may act permissively, as a gatekeeper, on especiallymuscle and tendon adaptations to physical activity/exercise,which should be considered in the modern clinical approach tomaintaining functional independence, especially following hospi-talization from physical trauma, critical illness or orthopedicsurgery. While the debate about use of the various types of HRTto treat generic menopause symptoms is much broader, thespecific beneficial effects on the musculoskeletal system calls forfurther research into HRT as an adjunct to existing rehabilitationstrategies. After all, what is the purpose of post-hospitalizationrehabilitation and re-mobilization if the endocrine environmentdoes not support the desired adaptations?
Declaration of interest
All authors are employees of Nordic Bioscience. Morten Karsdal andKlaus Kristiansen both have shares in Nordic Bioscience. None of theauthors have any financial interest in estrogen therapy.
For this work, the author Anders Nedergaard has received financialsupport from The Danish High Technology Foundation (Grant No. 135-2012-05).
References
1. Holinka CF, Karsdal MA, Christiansen C. Bone, cartilage andhormone therapy: established concepts and future scenarios.Climacteric J Int Menopause Soc 2007;10:270–2.
2. Palacios S, Christiansen C, Sanchez Borrego R, et al.Recommendations on the management of fragility fracture risk inwomen younger than 70 years. Gynecological Endocrinol Official JInt Soc Gynecol Endocrinol 2012;28:770–86.
3. Alexandersen P, Karsdal MA, Christiansen C. Long-term preventionwith hormone-replacement therapy after the menopause: whichwomen should be targeted? Women’s Health (London, England).2009;5:637–47.
4. Gruber DM, Huber JC. Conjugated estrogens – the natural SERMs.Gynecol Endocrinol Official J Int Soc Gynecol Endocrinol1999;13:9–12.
5. Brown M, Ning J, Ferreira JA, et al. Estrogen receptor-alpha and -beta and aromatase knockout effects on lower limb muscle mass and
DOI: 10.3109/09513590.2012.754879 Menopause, muscle and bone 421
Gyn
ecol
End
ocri
nol D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y U
nive
rsity
of
Zue
rich
Zen
trum
fue
r Z
ahn
Mun
d un
d on
09/
09/1
3Fo
r pe
rson
al u
se o
nly.
contractile function in female mice. Am J Physiol Endocrinol Metab2009;296:E854–61.
6. Velders M, Schleipen B, Fritzemeier KH, et al. Selective estrogenreceptor-b activation stimulates skeletal muscle growth andregeneration. FASEB J 2012;26:1909–20.
7. Paassilta M, Karjalainen A, Kervinen K, et al. Insulin-like growthfactor binding protein-1 (IGFBP-1) and IGF-I during oral andtransdermal estrogen replacement therapy: relation to lipoprotein(a)levels. Atherosclerosis 2000;149:157–62.
8. Hansen M, Miller BF, Holm L, et al. Effect of administration oforal contraceptives in vivo on collagen synthesis in tendon andmuscle connective tissue in young women. J Appl Physiol2009;106:1435–43.
9. Sitnick M, Foley AM, Brown M, Spangenburg EE. Ovariectomyprevents the recovery of atrophied gastrocnemius skeletal musclemass. J Appl Physiol 2006;100:286–93.
10. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits ofestrogen plus progestin in healthy postmenopausal women: principalresults From the Women’s Health Initiative randomized controlledtrial. JAMA 2002;288:321–33.
11. Tanko LB, Christiansen C. Adipose tissue, insulin resistance andlow-grade inflammation: implications for atherogenesis and thecardiovascular harm of estrogen plus progestogen therapy.Climacteric J Int Menopause Soc 2006;9:169–80.
12. Utian WH. A decade post WHI, menopausal hormone therapycomes full circle – need for independent commission. Climacteric JInt Menopause Soc 2012;15:320–5.
13. Shapiro S. The million women study: potential biases do not allowuncritical acceptance of the data. Climacteric J Int Menopause Soc2004;7:3–7.
14. Komulainen M, Kroger H, Tuppurainen MT, et al. Identification ofearly postmenopausal women with no bone response to HRT: resultsof a five-year clinical trial. Osteoporosis Int 2000;11:211–8.
15. Grodstein F, Manson JE, Stampfer MJ. Hormone therapy andcoronary heart disease: the role of time since menopause and age athormone initiation. J Women’s Health 2006;15:35–44.
16. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausalhormone therapy and risk of cardiovascular disease by age and yearssince menopause. JAMA 2007;297:1465–77.
17. Zanzi I, Roginsky MS, Ellis KJ, et al. Proceedings: skeletal mass inrheumatoid arthritis: a comparison with forearm bone mineralcontent. Am J Roentgenol 1976;126:1305–6.
18. Saville PD, Kharmosh O. Osteoporosis of rheumatoid arthritis:influence of age, sex: corticosteroids. Arthritis Rheumat1967;10:423–30.
19. Als OS, Gotfredsen A, Christiansen C. The effect of glucocorticoidson bone mass in rheumatoid arthritis patients. Influence ofmenopausal state. Arthritis Rheumat 1985;28:369–75.
20. Nelson HD, Walker M, Zakher B, Mitchell J. Menopausal hormonetherapy for the primary prevention of chronic conditions: asystematic review to update the U.S. preventive services task forcerecommendations. Ann Int Med 2012;157:104–13.
21. Henriksen K, Bollerslev J, Everts V, Karsdal MA. Osteoclast activityand subtypes as a function of physiology and pathology –implications for future treatments of osteoporosis. Endocr Rev2011;32:31–63.
22. Shevde NK, Bendixen AC, Dienger KM, Pike JW. Estrogenssuppress RANK ligand-induced osteoclast differentiation via astromal cell independent mechanism involving c-Jun repression.Proc Natl Acad Sci USA 2000;97:7829–34.
23. Srivastava S, Toraldo G, Weitzmann MN, et al. Estrogen decreasesosteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation. J Biol Chem2001;276:8836–40.
24. Sørensen MG, Henriksen K, Dziegiel MH, et al. Estrogen directlyattenuates human osteoclastogenesis, but has no effect on resorptionby mature osteoclasts. DNA Cell Biol 2006;25:475–83.
25. Wend K, Wend P, Krum SA. Tissue-specific effects of loss ofestrogen during menopause and aging. Frontiers Endocrinol2012;3:19.
26. Nakamura T, Imai Y, Matsumoto T, et al. Estrogen prevents boneloss via estrogen receptor alpha and induction of Fas ligand inosteoclasts. Cell 2007;130:811–23.
27. Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton.Trends Endocrinol Metabol 2012;23:576–81.
28. Martin TJ, Seeman E. New mechanisms and targets in thetreatment of bone fragility. Clin Sci (London, England: 1979).2007;112:77–91.
29. Kohrt WM, Snead DB, Slatopolsky E, Birge SJ. Additive effects ofweight-bearing exercise and estrogen on bone mineral density inolder women. J Bone Miner Res 1995;10:1303–11.
30. Milliken LA, Going SB, Houtkooper LB, et al. Effects of exercisetraining on bone remodeling, insulin-like growth factors, bonemineral density in postmenopausal women with and withouthormone replacement therapy. Calcif Tissue Int 2003;72:478–84.
31. Villareal DT, Binder EF, Yarasheski KE, et al. Effects of exercisetraining added to ongoing hormone replacement therapy on bonemineral density in frail elderly women. J Am Geriatr Soc2003;51:985–90.
32. Maddalozzo GF, Widrick JJ, Cardinal BJ, et al. The effects ofhormone replacement therapy and resistance training on spine bonemineral density in early postmenopausal women. Bone2007;40:1244–51.
33. Heikkinen J, Kyllonen E, Kurttila-Matero E, et al. HRT andexercise: effects on bone density, muscle strength and lipidmetabolism. A placebo controlled 2-year prospective trial on twoestrogen-progestin regimens in healthy postmenopausal women.Maturitas 1997;26:139–49.
34. Yarrow JF, McCoy SC, Ferreira JA, et al. A rehabilitation exerciseprogram induces severe bone mineral deficits in estrogen-deficientrats after extended disuse. Menopause (New York, N.Y.) 2012;19:1267–76.
35. Borer KT. Physical activity in the prevention and amelioration ofosteoporosis in women: interaction of mechanical, hormonal anddietary factors. Sports Med (Auckland, NZ) 2005;35:779–830.
36. Riesco E, Choquette S, Audet M, et al. Effect of exercise trainingcombined with phytoestrogens on adipokines and C-reactive proteinin postmenopausal women: a randomized trial. Metabol Clin Exp2012;61:273–80.
37. Hansen M, Kongsgaard M, Holm L, et al. Effect of estrogen ontendon collagen synthesis, tendon structural characteristics, andbiomechanical properties in postmenopausal women. J Appl Physiol2009;106:1385–93.
38. Pingel J, Fredberg U, Qvortrup K, et al. Local biochemical andmorphological differences in human Achilles tendinopathy: a casecontrol study. BMC Musculoskeletal Dis 2012;13:53.
39. Finni T, Kovanen V, Ronkainen PHA, et al. Combination ofhormone replacement therapy and high physical activity isassociated with differences in Achilles tendon size in monozygoticfemale twin pairs. J Appl Physiol 2009;106:1332–7.
40. Cook JL, Bass SL, Black JE. Hormone therapy is associated withsmaller Achilles tendon diameter in active post-menopausal women.Scand J Med Sci Sports 2007;17:128–32.
41. Hansen M, Koskinen SO, Petersen SG, et al. Ethinyl oestradioladministration in women suppresses synthesis of collagen in tendonin response to exercise. J Physiol 2008;586:3005–16.
42. Magnusson SP, Hansen M, Langberg H, et al. The adaptability oftendon to loading differs in men and women. Int J Exp Pathol2007;88:237–40.
43. Bryant AL, Clark RA, Bartold S, et al. Effects of estrogen on themechanical behavior of the human Achilles tendon in vivo. J ApplPhysiol 2008;105:1035–43.
44. Faria A, Gabriel R, Abrantes J, et al. Ankle stiffness inpostmenopausal women: influence of hormone therapy andmenopause nature. Climacteric J Int Menopause Soc2010;13:265–70.
45. Chung KY, Baxa TJ, Parr SL, et al. Administration of estradiol,trenbolone acetate, trenbolone acetate/estradiol implants altersadipogenic and myogenic gene expression in bovine skeletalmuscle. J Animal Sci 2012;90:1421–7.
46. Hayden JM, Bergen WG, Merkel RA. Skeletal muscle proteinmetabolism and serum growth hormone, insulin, and cortisolconcentrations in growing steers implanted with estradiol-17 beta,trenbolone acetate, or estradiol-17 beta plus trenbolone acetate.J Animal Sci 1992;70:2109–19.
47. Sørensen MB, Rosenfalck AM, Højgaard L, Ottesen B. Obesity andsarcopenia after menopause are reversed by sex hormone replace-ment therapy. Obesity Res 2001;9:622–6.
48. Ronkainen PHA, Kovanen V, Alen M, et al. Postmenopausalhormone replacement therapy modifies skeletal muscle composition
422 A. Nedergaard et al. Gynecol Endocrinol, 2013; 29(5): 418–423
Gyn
ecol
End
ocri
nol D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y U
nive
rsity
of
Zue
rich
Zen
trum
fue
r Z
ahn
Mun
d un
d on
09/
09/1
3Fo
r pe
rson
al u
se o
nly.
and function: a study with monozygotic twin pairs. J Appl Physiol2009;107:25–33.
49. Taaffe DR, Sipila S, Cheng S, et al. The effect of hormonereplacement therapy and/or exercise on skeletal muscle attenuationin postmenopausal women: a yearlong intervention. Clin PhysiolFunct Imag 2005;25:297–304.
50. Teixeira-Lemos E, Nunes S, Teixeira F, Reis F. Regular physicalexercise training assists in preventing type 2 diabetes development:focus on its antioxidant and anti-inflammatory properties.Cardiovasc Diabetol 2011;10:12.
51. Skelton DA, Phillips SK, Bruce SA, et al. Hormone replacementtherapy increases isometric muscle strength of adductor pollicis inpost-menopausal women. Clin Sci (London, England: 1979)1999;96:357–64.
52. Bemben DA, Langdon DB. Relationship between estrogen use andmusculoskeletal function in postmenopausal women. Maturitas2002;42:119–27.
53. Brown M, Birge SJ, Kohrt WM. Hormone replacement therapy doesnot augment gains in muscle strength or fat-free mass in response toweight-bearing exercise. J Gerontol Ser A Biol Sci Med Sci1997;52:B166–70.
54. Moran AL, Warren GL, Lowe DA. Removal of ovarian hormonesfrom mature mice detrimentally affects muscle contractile functionand myosin structural distribution. J Appl Physiol 2006;100:548–59.
55. Phillips SK, Rook KM, Siddle NC, et al. Muscle weakness in womenoccurs at an earlier age than in men, but strength is preserved byhormone replacement therapy. Clin Sci (London, England: 1979)1993;84:95–8.
56. Greising SM, Baltgalvis KA, Lowe DA, Warren GL. Hormonetherapy and skeletal muscle strength: a meta-analysis. J Gerontol SerA Biol Sci Med Sci 2009;64:1071–81.
57. Moran AL, Nelson SA, Landisch RM, et al. Estradiol replacementreverses ovariectomy-induced muscle contractile and myosindysfunction in mature female mice. J Appl Physiol 2007;102:1387–93.
58. Kadi F, Karlsson C, Larsson B, et al. The effects of physical activityand estrogen treatment on rat fast and slow skeletal musclesfollowing ovariectomy. J Muscle Res Cell Motility 2002;23:335–9.
59. Tiidus PM. Estrogen and gender effects on muscle damage,inflammation, oxidative stress. Can J Appl Physiol 2000;25:274–87.
60. Tiidus PM, Holden D, Bombardier E, et al. Estrogen effect on post-exercise skeletal muscle neutrophil infiltration and calpain activity.Can J Physiol Pharmacol 2001;79:400–6.
61. Enns DL, Tiidus PM. The influence of estrogen on skeletal muscle:sex matters. Sports Med (Auckland, NZ) 2010;40:41–58.
62. MacNeil LG, Baker SK, Stevic I, Tarnopolsky MA. 17b-Estradiolattenuates exercise-induced neutrophil infiltration in men. AJPRegulatory Integrative Comparat Physiol 2011;300:R1443–51.
63. Booth EA, Flint RR, Lucas KL, et al. Estrogen protects the heartfrom ischemia-reperfusion injury via COX-2-derived PGI2.J Cardiovasc Pharmacol 2008;52:228–35.
64. Tiidus PM, Zajchowski S, Enns D, et al. Differential effect ofoestrogen on post-exercise cardiac muscle myeloperoxidaseand calpain activities in female rats. Acta Physiol Scand 2002;174:131–6.
65. McNulty PH, Jagasia D, Whiting JM, Caulin-Glaser T. Effect of6-wk estrogen withdrawal or replacement on myocardial ischemictolerance in rats. Am J Physiol Heart Circulat Physiol 2000;278:H1030–4.
66. Bombardier E, Vigna C, Iqbal S, et al. Effects of ovarian sexhormones and downhill running on fiber-type-specific HSP70expression in rat soleus. J Appl Physiol 2009;106:2009–15.
67. Tiidus PM, Holden D, Bombardier E, et al. Estrogen effect on post-exercise skeletal muscle neutrophil infiltration and calpain activity.Can J Physiol Pharmacol 2001;79:400–6.
68. Hackney AC, Muoio D, Meyer WR. The effect of sex steroidhormones on substrate oxidation during prolonged submaximalexercise in women. Jpn J Physiol 2000;50:489–94.
69. Tarnopolsky MA. Sex differences in exercise metabolism andthe role of 17-beta estradiol. Med Sci Sports Exercise 2008;40:648–54.
70. Toth MJ, Gardner AW, Arciero PJ, et al. Gender differences in fatoxidation and sympathetic nervous system activity at rest and duringsubmaximal exercise in older individuals. Clin Sci (London,England: 1979) 1998;95:59–66.
71. Kraemer RR, Johnson LG, Haltom R, et al. Effects of hormonereplacement on growth hormone and prolactin exercise responses inpostmenopausal women. J Appl Physiol 1998;84:703–8.
72. Johnson LG, Kraemer RR, Haltom R, et al. Effects of estrogenreplacement therapy on dehydroepiandrosterone, dehydroepiandros-terone sulfate, cortisol responses to exercise in postmenopausalwomen. Fertil Steril 1997;68:836–43.
73. Salpeter SR, Walsh JME, Ormiston TM, et al. Meta-analysis: effectof hormone-replacement therapy on components of the metabolicsyndrome in postmenopausal women. Diabetes Obesity Metabol2006;8:538–54.
Notice of CorrectionThis paper published online on 06 February 2013 contained an error in the author list. Claus Christiansen wasmistakenly written as ‘‘Claus Cristiansen’’ on the first page. The error has been corrected for this version.
DOI: 10.3109/09513590.2012.754879 Menopause, muscle and bone 423
Gyn
ecol
End
ocri
nol D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y U
nive
rsity
of
Zue
rich
Zen
trum
fue
r Z
ahn
Mun
d un
d on
09/
09/1
3Fo
r pe
rson
al u
se o
nly.
